Formulations and designs for degradable soft tissue implants

Abstract

A photocurable formulation usable in additive manufacturing a three-dimensional object is disclosed. The formulation features, in at least a portion thereof, a biological or a biocompatible material, the photocurable formulation comprising a photoinitiator, a photocurable biological or biocompatible material, and a carrier, the formulation further comprising at least two photocurable polymeric materials. Implants comprising same are also disclosed.

Description

[0001] FORMULATIONS AND DESIGNS FOR DEGRADABLE SOFT TISSUE IMPLANTS

[0002] RELATED APPLICATION

[0003] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 696,908 filed on 20 September 2024 and U.S. Provisional Patent Application No. 63 / 696,902 filed on 20 September 2024. This application also incorporates by reference a PCT application having title “Light-absorbing substances suitable for use in additive manufacturing and methods of identification thereof’, filed on even date with the present application and having a same applicant and having docket number 104968. The contents of all of these applications are incorporated herein by reference in their entirety. In particular, the PCT application describes light- absorbing substances that can be added to formulations which may be used for additive manufacturing of 3D objects, when carrying out some embodiments of the invention.

[0004] SEQUENCE LISTING STATEMENT

[0005] The XML file, entitled 104970.xml, created on 03 September, 2025, comprising 57,034 bytes, submitted concurrently with the filing of this application is incorporated herein by reference

[0006] FIELD AND BACKGROUND OF THE INVENTION

[0007] The present invention, in some embodiments thereof, relates to additive manufacturing, and, more particularly, but not exclusively, to collagen-based formulations usable in additive manufacturing of degradable scaffolds and / or soft tissue implants that feature mechanical properties suitable for breast implants, and to design thereof.

[0008] Mammoplasty (breast cosmetic surgery) includes augmentation, for increasing the size, form, and feel of breasts, or reconstruction following damage to breast tissues by trauma, disease (breast cancer), and anatomic deformations. In the United States breast augmentation is the top cosmetic surgical procedure performed and has been since 2006 (American Society of Plastic Surgeons, 2018 Plastic Surgery Statistics Report). The main types of breast implants in use are saline-filled and silicone gel-filled implants. The shell for both types of implants is manufactured from polysiloxane silicone rubber. Complications following breast augmentation include breast pain, altered sensation, impeded breast-feeding function, visible wrinkling, asymmetry, and thinning of the breast tissue.

[0009] One of the main safety concerns associated with breast implants is implant rupture. A rupture is a tear or hole in the outer shell of the breast implant and is not always noticeable. In saline-filled breast implants, the breast deflates as the saline is absorbed by the body. In silicone- gel filled breast implants, the rupture is “silent”, the gel can remain in the shell or within the scar tissue that forms around the implant, or the gel can move outside the scar tissue, and in some cases, may migrate outside the vicinity of the augmented or reconstructed breast.

[0010] Clinical complications from the leaked silicone filler-gel are usually manifested as granulomas (inflammatory nodules) and axillary lymphadenopathy (enlarged lymph glands in the armpit area) (Hdlmich et al., (2004). Untreated Silicone Breast Implant Rupture Plastic and Reconstructive Surgery. 114 (1): 204-214, Katzin et al., (2005). Pathology of Lymph Nodes from Patients with Breast Implants: A Histologic and Spectroscopic Evaluation American Journal of Surgical Pathology. 29 (4): 506-11, FDA Breast Implant Consumer Handbook - Study of Rupture of Silicone Gel-filled Breast Implants (MRI Component) - 2004). Rupture rates increase the longer implants are in place. Overall, rupture rates are generally less than 5% before Year 4 and then increase around 4-6 years post-implanting. After Year 6, the rupture rates continue to increase at variable rates. Rupture is resolved by explantation (surgical removal) of the implant.

[0011] In 2016, the World Health Organization (WHO) designated breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) as a T-cell lymphoma that can develop from breast implants (Swerdlow et al., (2016) The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood, 127(20), 2375-2390). Clinically, BIA-ALCL typically originates in the capsule around breast implants and presents as a fluid collection or tumor adjacent to the implant surface (FDA Executive Summary Breast Implant Special Topics Prepared for the Meeting of the General and Plastic Surgery Devices Advisory Panel, March 25-26, 2019). As of July 6, 2019, the Food and Drug Administration (FDA) has received a total of 573 US and global medical device reports (MDRs) of BIA-ALCL, including 33 deaths (“Medical Device Reports of Breast Implant-Associated Anaplastic Large Cell Lymphoma”, www(dot)fda(dot)gov(dot) as of 24 July 2019).

[0012] Fat transfer breast augmentation, or autologous fat grafting, is an increasingly popular technique that utilizes a patient's own adipose tissue to enhance breast volume and contour, offering a natural alternative to traditional implants with reduced risks of capsular contracture and implant rupture. This two-step procedure begins with the harvesting of fat via low-pressure syringe liposuction from donor areas such as the abdomen, thighs, hips, or flanks using a 2.4-3 mm cannula to preserve cell viability. The harvested fat may be processed using methods such as centrifugation (Coleman technique), shearing into nano-fat, or using absorbent pads to concentrate viable adipocytes. Injection is performed using 1.2-1.5 mm blunt or bulb-tip cannulas in a radial, retrograde manner with multiplane placement, typically delivering 80-158 mL per breast per session, with an average of 113 mL. However, volume retention remains variable, ranging from 27.1 % to 86.9% depending on factors such as fat processing, injection technique, and recipient site vascularity. To enhance graft survival and long-term outcomes, stromal vascular fraction (SVF) — isolated via enzymatic digestion and centrifugation — is often added to the fat graft, improving retention by 20-30%. SVF yield typically ranges from 5-20 mL per 80 mL of lipoaspirate. Fat grafting is also used in reconstructive settings to correct contour irregularities following lumpectomy, radiotherapy, or implant removal, and in hybrid procedures combining fat with smaller implants to improve aesthetic outcomes. Typically, 2-3 sessions spaced 3-6 months apart are required to achieve the desired breast volume and shape.

[0013] Several factors have been investigated for their ability to enhance adipogenesis, either directly by promoting adipocyte differentiation and survival, or indirectly by optimizing the microenvironment for adipose tissue regeneration. Among these, nano-fat offers a higher concentration of stem cells and is particularly useful at the initial grafting stage; however, its use is time-consuming, requires a larger volume of fat, and has high viscosity, complicating handling. Platelet-rich plasma (PRP), known for stimulating angiogenesis, may improve graft survival, although it demands significant preparation time (over two hours per sample in some models) and does not consistently demonstrate a significant improvement in fat retention outcomes. The stromal vascular fraction (SVF) shows promise by significantly improving long-term volume retention when compared to fat grafting alone, but it also necessitates complex, sterile processing and a greater fat harvest volume. Platelet-derived growth factor (PDGF), a key component of PRP, has theoretical regenerative benefits, yet clinical evidence remains inconclusive; its use is further limited by cost, regulatory hurdles, and the potential to promote fibrosis. Immunosuppressive drugs have been explored for enhancing graft engraftment, though their use is generally limited to non- autologous settings due to the added complexity and need for monitoring. Finally, insulin has shown potential in improving adipocyte metabolism and viability and benefits from its well- established clinical profile; nonetheless, its application in this context is still constrained by limited clinical data and regulatory considerations.

[0014] WO 2021 / 191897, by the present Assignee, describes photocurable (photoinitiated) formulations comprising methacrylated-rhCollagen for use as soft tissue implants, including breast implants.

[0015] Additional background art includes WO 2006 / 035442, WO 2009 / 053985, WO 2011 / 064773, WO 2013 / 093921, WO 2014 / 147622, WO 2018 / 225076, WO 2019 / 211854, WO 2023 / 073711 and WO 2024 / 089699. SUMMARY OF THE INVENTION

[0016] According to an aspect of the present invention, there is provided a photocurable formulation usable in additive manufacturing a three-dimensional object featuring, in at least a portion thereof, a biological or a biocompatible material, the photocurable formulation comprising a photoinitiator, a photocurable biological or biocompatible material, and a carrier, the formulation further comprising at least two photocurable polymeric materials, wherein: at least one of the at least two photocurable polymeric materials has an average molecular weight lower than 10,000 grams / mol (low MW photocurable polymeric material), and at least another one of the at least two photocurable polymeric materials has an average molecular weight higher than 10,000, or higher than 15,000 (high MW photocurable polymeric material), grams / mol; a total amount of the at least two photocurable polymeric materials is in a range of from 1 to 20, or from 5 to 20, or from 5 to 15, or from 7.5 to 15, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:9, or from 1: 1 to 1:5.

[0017] According to one embodiment, each of the photocurable polymeric material independently is a multifunctional photocurable polymeric material featuring two or more photocurable groups.

[0018] According to one embodiment, the photocurable groups are (meth) acrylic groups.

[0019] According to one embodiment, the (meth)acrylic groups are selected from acrylate and methacrylate groups, provided that at least one of the photocurable polymeric materials features acrylate groups.

[0020] According to one embodiment, one of the at least two photocurable polymeric materials features a plurality of acrylate groups and another one of the photocurable polymeric materials features a plurality of methacrylate groups.

[0021] According to one embodiment, at least one of the photocurable polymeric materials comprises a poly(alkylene glycol) polymeric backbone.

[0022] According to one embodiment, the low MW photocurable polymeric material is a poly(alkylene glycol) that terminates by two (or more) acrylate or methacrylate groups.

[0023] According to one embodiment, an average molecular weight of the low MW photocurable polymeric material ranges from 500 to 10,000, or from 500 to 5,000, or from 500 to 4,000, or from 500 to 3,500, or from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 3,500, or from 500 to 3,500, or from 1,000 to 3,000, or from 1,000 to 2,000, grams / mol.

[0024] According to one embodiment, the high MW photocurable polymeric material comprises a poly(alkylene glycol) polymeric backbone and terminates by two (or more) acrylate or methacrylate groups.

[0025] According to one embodiment, an average molecular weight of the poly(alkylene glycol) polymeric backbone is higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol.

[0026] According to one embodiment, an average molecular weight of the poly(alkylene glycol) polymeric backbone ranges from 10,000 to 40,000, or from 10,000 to 30,000, or from 15,000 to 40,000, or from 15,000 to 30,000, or from 20,000 to 40,000, or from 20,000 to 30,000, or from 20,000 to 25,000, grams / mol.

[0027] According to one embodiment, the high MW photocurable polymeric material is a multiblock (e.g., diblock or triblock) co-polymer that comprises the poly(alkylene glycol) polymeric backbone as one block and at least one additional block that comprises a polymeric backbone of a biodegradable polymer other than poly(alkylene glycol).

[0028] According to one embodiment, the high MW photocurable polymeric material is a tri-block co-polymer that comprises the poly(alkylene glycol) polymeric backbone as a middle block having attached to its termini two additional blocks, each comprising a polymeric backbone of a biodegradable polymer other than poly(alkylene glycol) that terminates by a photocurable group.

[0029] According to one embodiment, the biodegradable polymer is a polyester.

[0030] According to one embodiment, the biodegradable polymer is poly(caprolactones) (PCL).

[0031] According to one embodiment, a molecular weight of the at least one additional block is lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol.

[0032] According to one embodiment, a molecular weight of the at least one additional block ranges from 500 to 5,000, or from, 500 to 4,000, or from 500 to 3,000, or from 500 to 2,000, or from 1,000 to 5,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, grams / mol.

[0033] According to one embodiment, the high MW photocurable polymeric material is a triblock polymeric material that comprises a poly(alkylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by at least one (meth)acrylate group.

[0034] According to one embodiment, the low MW photocurable polymeric material is a poly(alkylene glycol) that terminates by two of the acrylate or methacrylate groups and has an average molecular weight that ranges from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, grams / mol; and the high MW photocurable material is a triblock polymeric material that comprises a poly(alkylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by the (meth)acrylate group.

[0035] According to one embodiment, the low MW photocurable polymeric material terminate by two acrylate groups.

[0036] According to one embodiment, the high MW photocurable polymeric material terminates by two methacrylate groups.

[0037] According to one embodiment, the weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material is about 1:3.

[0038] According to one embodiment, the amount of the photoinitiator in the curable formulation ranges from 0.1 to 1, or from 0.1 to 0.5, % by weight of the total weight of the formulation.

[0039] According to one embodiment, the photoinitiator is an acyl phosphine oxide type photoinitiator such as a 2,4,6-trimethylbenzolydiphenyl phosphine oxide (TMPO) or a salt thereof (e.g., Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), or Sodium phenyl-2,4,6- trimethy Ibenzoy Ipho sphinate (N AP) .

[0040] According to one embodiment, the photocurable biological or biocompatible material comprises a collagen that features a plurality of photocurable groups.

[0041] According to one embodiment, the photocurable groups comprise (meth)acrylic groups.

[0042] According to one embodiment, the collagen is a human Type I collagen.

[0043] According to one embodiment, the collagen is a recombinant collagen.

[0044] According to one embodiment, the collagen is a plant-derived recombinant collagen.

[0045] According to one embodiment, the collagen is a plant-derived recombinant human Type I collagen.

[0046] According to one embodiment, the amount of the photocurable biological or biocompatible material ranges from 0.1 to 1 % by weight of the total weight of the formulation.

[0047] According to one embodiment, the carrier is an aqueous carrier.

[0048] According to one embodiment, the curable formulation further comprises a photoblocker.

[0049] According to one embodiment, the photoblocker is characterized by at least one of: biocompatibility; solubility of at least 0.05 mg / mL in the aqueous carrier or the curable formulation; absorbance at wavelength from 300 nm to 800 nm; absorbance stability at the wavelength in the presence of the photoinitiator.

[0050] According to one embodiment, the amount of the photoblocker ranges from 0.1 to 1 % by weight of the total weight of the formulation.

[0051] According to one embodiment, the photoblocker is represented by Formula III: wherein:

[0052] Re, R7, Rs, R9 and Rio are each independently hydrogen; and

[0053] Ri, R2, R3, R4 and R5 are each independently selected from hydrogen, hydroxyalkyl and a saccharide moiety.

[0054] According to one embodiment, the saccharide moiety is selected from a monosaccharide and disaccharide moiety.

[0055] According to one embodiment, the saccharide moiety comprises a glucose moiety.

[0056] According to one embodiment, the R3 is the saccharide moiety.

[0057] According to one embodiment, the Ri is hydrogen.

[0058] According to one embodiment, the R2, R4 and Rs are each hydrogen.

[0059] According to one embodiment, the R2, R4 and Rs are each a hydroxyalkyl.

[0060] According to one embodiment, the hydroxyalkyl is hydroxyethyl.

[0061] According to one embodiment, the saccharide moiety; and Ri, R2, R4 and Rs are each hydrogen. According to one embodiment, the saccharide moiety is rutinose, the photoblocker being 3-glucoside quercetin.

[0062] According to one embodiment, the saccharide moiety; Ri hydrogen; and R2, R4 and R5 are each independently a hydroxyalkyl.

[0063] According to one embodiment, each of R2, R4 and R5 is hydroxyethyl.

[0064] According to one embodiment, the saccharide moiety is rutinose, the photoblocker being troxerutin.

[0065] According to one embodiment, the photoblocker is represented by Formula I*

[0066] Formula I* wherein:

[0067] Rx and Ry are each independently selected from hydrogen (H), alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), cycloalkyl and aryl; and Rz is an alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), aryl or cycloalkyl.

[0068] According to one embodiment, the photoblocker is HC yellow 9 (HC9).

[0069] According to one embodiment, the curable formulation comprises the components as set forth in any one of Tables B-O.

[0070] According to an aspect of the present invention, there is provided a biocompatible soft tissue implant comprising, by volume of solid portions thereof, at least 40% of a curable formulation as described herein, with a 3D structure including a surface lattice defining segments and apertures therebetween.

[0071] According to an aspect of the present invention, there is provided a biocompatible 3D soft tissue implant having a surface defined by a lattice over at least 30%, 50% 70% or smaller or intermediate percentages of an outer surface of a containing geometry of the implant. In some embodiments of the invention, the lattice is defined by interconnected segments, the segments defining apertures therebetween and at least 50% of angles at intersection between segments having fillets with a minimal radius of curvature of at least 0.05 or 0.5 mm. According to one embodiment, the implant is formed as a breast implant having a generally flattened ovoid or spherical section geometry and a volume of between 70 cc and 800 cc.

[0072] According to one embodiment, the lattice is a 3D lattice including a plurality of segments that extend from the surface, inwards of the surface.

[0073] According to one embodiment, the implant has an overall porosity selected from at least 30%, at least 40%, at least 50% and at least 60%.

[0074] According to one embodiment, the implant has a resistance to failure under compression forces of at least 156 Newton.

[0075] According to one embodiment, the implant comprises a skirt having less than 30% aperture area, for example, less than 50% or 30% of an aperture area of a top surface of the implant. According to some embodiments, the circumference of the skirt is free of apertures whereas the bottom of the implant comprises apertures. According to one embodiment, the skirt is solid wherein both the circumference of the skirt and the bottom of the implant is free of apertures.

[0076] According to one embodiment, the lattice is a regular lattice formed of repeating elements and occupies, by volume at least 60 % of the implant. Optionally and / or alternatively, at least 60% of a material, by volume, of the implant is defined by such lattice.

[0077] According to one embodiment, the implant comprises a plurality of structural elements having a geometry different from the segments.

[0078] According to one embodiment, the fillets increase a compressive strain bearable by the implant by at least 5% relative to a same design absent the fillets.

[0079] According to one embodiment, the fillets increase a compressive load bearable by the implant by at least 50% relative to a same design absent the fillets.

[0080] According to one embodiment, the implant is biodegradable in the body over a period of between 1 week and 2 years.

[0081] According to one embodiment, the implant is formed of the curable formulation described herein.

[0082] According to one embodiment, the segments are non-uniform in cross-section at different parts of the implant.

[0083] According to one embodiment, the segments are thicker at a base central area of the implant.

[0084] According to one embodiment, the lattice comprises a 3D lattice made of layers and comprising at least one internal segment interconnecting two layers at an angle.

[0085] According to one embodiment, the curable formulation provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by:

[0086] (i) Strain of 20 % at a range between 10-100 N and

[0087] (ii) Strain of 50 % at a range between 100-200 N; b. Compressive strain-at-break higher than 50%; or c. Compressive force limit of at least 156N.

[0088] According to one embodiment, the curable formulation described herein, provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at 10N force, as determined in a compression force versus strain measurements as described herein; b. compressive strain-at-break higher than 50%; or c. compressive force limit of at least 156N.

[0089] According to one embodiment, the implant obtained while using a curable formulation which provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by

[0090] (i) Strain of 20 % at a range between 10-100 N and

[0091] (ii) Strain of 50 % at a range between 100-200 N; b. Compressive strain-at-break higher than 50%; or c. Compressive force limit of at least 156N.

[0092] According to one embodiment, the implant obtained while using a curable formulation which provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at 10N force, as determined in a compression force versus strain measurements as described herein; b. compressive strain-at-break higher than 50%; or c. compressive force limit of at least 156N.

[0093] According to another aspect of the invention, there is provided a biocompatible 3D soft tissue implant comprising a surface defined by a lattice, the surface extending over at least 30% of an outer surface of a containing geometry of the implant, the lattice defined by interconnected segments, the segments defining apertures therebetween and at least 50% of angles at intersections between segments having fillets with a minimal radius of curvature of at least 0.05 mm.

[0094] According to embodiments of the invention, the surface defined by a lattice extends at least

[0095] 50% of the outer surface. According to embodiments of the invention, the surface defined by a lattice extends at least 70% of the outer surface.

[0096] According to embodiments of the invention, the implant is formed as a breast implant having a generally flattened ovoid or spherical section geometry and a volume of between 70 cc and 800 cc.

[0097] According to embodiments of the invention, the lattice is a 3D lattice including a plurality of segments that extend from the surface, inwards of the surface.

[0098] According to embodiments of the invention, at least 30% of the segments are hollow.

[0099] According to embodiments of the invention, the hollow segments define a fluid pathway between a surface of the implant and pores defined in the implant between segments of the lattice.

[0100] According to embodiments of the invention, the plurality of segments include a plurality of vertically extending segments, from a surface of the breast implant to a base of the implant configured for placement against a pectoral muscle covering the chest wall.

[0101] According to embodiments of the invention, at least 50% of the vertically extending segments are hollow and wherein at least some conduits are defined between the hollow vertical segments to pores defined in the implant between segments of the lattice.

[0102] According to embodiments of the invention, the conduits are staggered.

[0103] According to embodiments of the invention, the implant has an overall porosity selected from at least 30%, at least 40%, at least 50%, between 35% and 47% and at least 60%.

[0104] According to embodiments of the invention, the implant has a resistance to failure under compression forces (Compressive force limit) of at least 156 Newton.

[0105] According to embodiments of the invention, the implant comprises a skirt having less than 30% apertured area.

[0106] According to embodiments of the invention, the lattice is a regular lattice formed of repeating elements for at least 60% of a volume of material of the implant.

[0107] According to embodiments of the invention, the implant comprises a plurality of structural elements having a geometry different from the segments.

[0108] According to embodiments of the invention, the fillets increase a compressive strain bearable by the implant by at least 5% relative to a same design absent the fillets.

[0109] According to embodiments of the invention, the fillets increase a compressive load bearable by the implant by at least 50% relative to a same design absent the fillets.

[0110] According to embodiments of the invention, the implant is biodegradable in the body over a period of between 1 week and 2 years. According to embodiments of the invention, the implant is formed of the curable formulation of any of claims 1-51.

[0111] According to embodiments of the invention, the segments are non-uniform in cross-section at different parts of the implant.

[0112] According to embodiments of the invention, the segments are thicker at a base central area of the implant.

[0113] According to embodiments of the invention, the lattice comprises a 3D lattice made of layers and comprising at least one internal segment interconnecting two layers at an angle.

[0114] According to embodiments of the invention, the photocurable formulation of provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by:

[0115] (i) Strain of 20 % at a range between 10-100 N and

[0116] (ii) Strain of 50 % at a range between 100-200 N; b. Compressive strain-at-break higher than 50%; or c. Compressive force limit of at least 156N.

[0117] According to embodiments of the invention, the curable provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at 10N force, as determined in a compression force versus strain measurements; b. compressive strain-at-break higher than 50%; or c. compressive force limit of at least 156N.

[0118] According to embodiments of the invention, the implant, obtained while using a curable formulation provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by:

[0119] (i) Strain of 20 % at a range between 10-100 N and

[0120] (ii) Strain of 50 % at a range between 100-200 N; b. Compressive strain-at-break higher than 50%; or c. Compressive force limit of at least 156N.

[0121] According to embodiments of the invention, the implant, obtained while using a curable formulation provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at ION force, as determined in a compression force versus strain measurements as described herein; b. compressive strain-at-break higher than 50%; or c. compressive force limit of at least 156N.

[0122] According to another aspect there is provided a breast implant manufactured by the process of:

[0123] (a) selecting a desired clinical outcome;

[0124] (b) selecting a set of parameters including one or more of design parameter(s), formulation parameter(s) and printing parameter(s) putatively suitable to achieve the outcome;

[0125] (c) generating a digital design based on the outcome;

[0126] (d) digitally evaluating the design; and

[0127] (e) manufacturing the evaluated design by 3D printing thereof.

[0128] According to embodiments of the invention, the digitally evaluating comprises evaluating the design functioning in a time window including during printing and / or during a degradation process thereof in a body.

[0129] According to embodiments of the invention, the digital design uses a unit cell design for a lattice filling at least 40% of a volume of the implant.

[0130] According to embodiments of the invention, the selecting a set of parameters and / or the digitally evaluating takes tissue penetration into the implant into account.

[0131] According to embodiments of the invention, the selecting a set of parameters and / or the digitally evaluating takes implantation process into account.

[0132] According to embodiments of the invention, the selecting a set of parameters and / or the digitally evaluating takes into account forces applied to the implant while in the body.

[0133] According to embodiments of the invention, the selecting a set of parameters comprises performing an iterative search over a range of values of at least one parameter, using the digital evaluation as an evaluation mechanism for the search.

[0134] According to embodiments of the invention, the selecting a set of parameters comprises selecting by a machine intelligence model trained on a plurality of examples of parameter sets and outcomes generated thereby.

[0135] According to embodiments of the invention, the selecting an outcome comprises a selecting an outcome based on at least one patient measurement other than size and shape. Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of embodiments of the invention, exemplary methods and / or materials are described below. In case of conflict, the patent specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be necessarily limiting.

[0136] Implementation of the method and / or system of embodiments of the invention can involve performing or completing selected tasks manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of embodiments of the method and / or system of the invention, several selected tasks could be implemented by hardware, by software or by firmware or by a combination thereof using an operating system.

[0137] BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0138] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0139] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0140] In the mechanical drawings each figure is divided into four subfigures. The main subfigure appearing at the top panel, presents the stress-strain (or load-strain) curves. A legend indicating the line type and (grayscale) color is available on the top-left side of each subfigure. The bottom panel of the figure presents bar-plots of three main mechanical properties derived from the main subfigure. The strength (or load-limit), strain-at-break, and accumulated energy subfigures appear on the left-, middle-, and right-hand side of the bottom panel respectively. Within each of these subfigures, bars are ordered from left to right correlating to the main subfigure order from top to bottom (e.g., the top group in the legend of the main subfigure will appear as the left bar in each subfigure), and are filled with a pattern colored in the same color as the lines in the main subfigure.

[0141] Tensile mechanical drawings of dogbone specimens present only the top half of the specimens ranked by their performance. The number of dogbone specimens tested varied between 10-15, and out of the valid tests, only half were selected for generation of the stress-strain curves and bar plots. The reason for such selection was to better distinguish between different groups (e.g., different formulations). The bottom half of the specimens were consistent in stiffness compared to the rest, yet at times, they were weaker due to local stress concentrations. Therefore, as the comparison between formulations was based on the top half of the tensile specimens, it was effectively compared to the tensile mechanical potential of the formulation. In the compression tests, all cylinders and scaffolds were selected for plot generation as their mechanical properties were more consistent inter alia due to simpler testing fixtures) thus fewer specimens were printed for testing (about 5 cylinders and up to 3 scaffolds).

[0142] In the drawings:

[0143] FIGs. 1A-C illustrate 3D designs of an exemplary (e.g., 40 cc) implant according to embodiments of the invention. A) Simple cubic (SC) design with square pore (model A). B) hexagonal polyhedron shape (HPS) design. C) Spider design. The measurements indicated in the images are as printed, before hydration. Dimensions are in mm. Side, top, and perspective views for each design are depicted in each column respectively.

[0144] FIGs. 1D-E present a SC 20 cc implant with round pores (FIG. ID) (model A’) and dog bones (FIG. IE) used when evaluating the mechanical properties obtained while using exemplary formulations according to some of the present embodiments.

[0145] FIG. IF shows a comparison between two designs of a SC 20 cc implant model which differ in volume fraction 50%VF (left) versus 40% VF (right).

[0146] FIG. 1G presents the dimensions of dog bones, cylinder and 40% VF SC 20 cc fillets model specimens used to evaluate the mechanical properties, for example as described herein, in accordance with some embodiments.

[0147] FIG. 1H presents the dimensions in mm of 50%VF SC 20cc (top panel) and lOOcc after air drying, sterilization with ETO and full rehydration which were implanted in preclinical studies in sheep (bottom left panel) or after lyophilization, sterilization with ETO and short rehydration implanted in fat injection preclinical studies in sheep (bottom right panel).

[0148] FIGs. 2Aa-2Ad are graphs illustrating compression test results for the three designs shown in FIGs. 1A-C, when printed using formulations Fl (CPZ) and F2 (DMA); (Table 3). Bars of graphs FIG. 2Ab-2Ad (from left to right) correspond with the labels which appear in FIG. 2Aa (from top to bottom).

[0149] FIGs. 2Ba-2Be illustrate the effect of altering the shape of the pores in model A of FIG. 1 A from square (design A) to round (design A’), on the mechanical properties, when 40cc implants were printed using formulation Fl (Table 3). Bars of graphs FIG. 2Bb-2Bd (from left to right) correspond with the labels which appear in Figure 2Ba (from top to bottom). A close-up pictorial view of the round pores is also shown (FIG. 2Be).

[0150] FIGs. 2Ca-2Cd are graphs illustrating that the mechanical properties of the implant (100 cc) are influenced not only by the shape or the pore size as described above, but also by both the type of lattice composed of a different unit cell (cubic versus ex shaped lattice shown in FIG. 25A) and the type of formulation (F13 versus Fl 1 - Table 3). Bars of graphs FIGs. 2Cb-2Cd (from left to right) correspond with the labels which appear in FIG. 2Ca (from top to bottom).

[0151] FIGs. 3A-D are graphs presenting compression test results of a 20cc SC breast implant model printed using formulations Fl and F2 (Table 3). Bars of graphs FIGs. 3B-3D (from left to right) correspond with the labels which appear in FIG. 3A (from top to bottom).

[0152] FIGs. 4A-D are graph presenting tensile test results of dogbone model printed using formulations Fl and F2 (Table 3). Bars of graphs FIGs. 4B-4D (from left to right) correspond with the labels which appear in FIG. 4 A (from top to bottom).

[0153] FIGs. 5A-D are graphs presenting compression test results of a 40cc SC breast implant model printed using formulations Fl and F3 (Table 3). Bars of graphs FIGs. 5B-5D (from left to right) correspond with the labels which appear in FIG. 5A (from top to bottom).

[0154] FIGs. 6A-D are graphs presenting tensile test results of a dogbone model printed using formulations Fl and F3 (Table 3). Bars of graphs FIGs. 6B-6D (from left to right) correspond with the labels which appear in FIG. 6 A (from top to bottom).

[0155] FIGs. 7A-D are graphs presenting compression test results of a 20cc SC breast implant model printed using formulations Fl and F4 (Table 3). Bars of graphs FIG. 7B-7D (from left to right) correspond with the labels which appear in FIG. 7 A (from top to bottom).

[0156] FIGs. 8A-D are graphs presenting tensile test results of a dogbone model printed using formulations Fl and F4 (Table 3). Bars of graphs FIGs. 8B-8D (from left to right) correspond with the labels which appear in FIG. 8 A (from top to bottom).

[0157] FIGs. 9A-D are graphs presenting compression test results of a 20cc SC breast implant model printed using formulations Fl, F5 and F6 as presented in Table 3. Bars of graphs FIGs. 9B- 9D (from left to right) correspond with the labels which appear in FIG. 9 A (from top to bottom).

[0158] FIGs. 10A-D are graphs presenting tensile test results of a dogbone model printed using formulations Fl, F5 and F6 (Table 3). Bars of graphs FIGs. 10B-10D (from left to right) correspond with the labels which appear in FIG. 10A (from top to bottom).

[0159] FIGs. 11A-D are graphs presenting compression test results of a 40cc SC breast implant model printed using formulations Fl, F2, F9 and F10 (Table 3). Bars of graphs FIGs. 11B-11D (from left to right) correspond with the labels which appear in FIG. 11 A (from top to bottom). FIGs. 12A-D are graphs presenting tensile test results of dogbone model printed using formulations Fl, F2, F9 and F10 (Table 3). Bars of graphs FIGs. 12B-12D (from left to right) correspond with the labels which appear in FIG. 12A (from top to bottom).

[0160] FIGs. 13A-D are graphs illustrating stress-strain response (13A), average tensile strength (13B), average tensile strain-at-break (13C), and accumulated energy (13D) of dogbone models printed using formulations F11-F15 (Table 3). Bars of graphs FIGs. 13B-13D (from left to right) correspond with the labels which appear in FIG. 13A (from top to bottom).

[0161] FIGs. 14A-D are graphs illustrating stress-strain response (FIG. 14A); average compression strength (FIG. 14B), average compressive strain-at-break (FIG. 14C), and accumulated energy (FIG. 14D) of cylinder models printed using formulations F11-F15, as these formulations are presented in Table 3. Bars of graphs FIGs. 14B-14D (from left to right) correspond with the labels which appear in FIG. 14 A (from top to bottom).

[0162] FIGs. 15A-D are graphs illustrating load-strain response (FIG. 15A); average compression force limit (FIG. 15B), average compressive strain-at-break (FIG. 15C), and accumulated (loadstrain) energy (FIG. 15D) of 20cc SC breast implant models printed using formulations F11-F15, as these formulations are presented in Table 3. Bars of graphs FIGs. 15B-15D (from left to right) correspond with the labels which appear in FIG. 15A (from top to bottom).

[0163] FIGs. 16A-D present images taken during exemplary resolution tests for F13 formulation in XY&Z direction for two types of resolution models. The small resolution model was used to assess the bioink printability at a resolution of 50 microns layers (higher resolution not shown) and the Large Resolution model was used to assess printing resolution of 150 microns layers (lower resolution as shown in FIG. 28A). The first value (e.g., 120 mJ / cm2or 150 mJ / cm2) is energy required for printing the model layers, whereas the second value (e.g., 400 mJ / cm2), is the energy required for printing the foundation layers, i.e., the first layers of the model that stick to the printing platform: Large-XY Resolution model at 120 mJ / cm2400 mJ / cm2(FIG. 16A), Small-XY Resolution model at 150 mJ / cm2400 mJ / cm2(FIG. 16B), Large-Z Resolution at 120 mJ / cm2400 mJ / cm2(FIG. 16C), and Small-Z Resolution model at 150 mJ / cm2400 mJ / cm2(FIG. 16D).

[0164] FIGs. 17A-D are graphs presenting compression test results of a 20cc SC breast implant model printed using formulations F13 and F18 as presented in Table 3. Bars of graphs FIGs. 17B- 17D (from left to right) correspond with the labels which appear in FIG. 17 A (from top to bottom).

[0165] FIGs. 18A-D are graphs presenting compression test results of a 20cc SC breast implant model printed using formulations F16 and F21 as presented in Table 3. Bars of graphs FIGs. 18B- 18D (from left to right) correspond with the labels which appear in FIG. 18A (from top to bottom). FIGs. 19A-E are graphs presenting compression test results of a 20cc SC breast implant model printed using formulations F13, F16, F17 and F22 as presented in Table 3, including closeup to low compression forces (FIG. 19E). Bars of graphs FIGs. 19B-19D (from left to right) correspond with the labels which appear in FIG. 19A (from top to bottom).

[0166] FIGs. 20A-E are graphs presenting compression test results of a lOOcc SC breast implant model printed using formulations F13 and F20 as presented in Table 3, including close-up to low compression forces (FIG. 20E). Bars of graphs FIGs. 20B-20D (from left to right) correspond with the labels which appear in FIG. 20A (from top to bottom).

[0167] FIGs. 21A-F present images taken during exemplary resolution tests for Fl 8 formulation in XY&Z direction: XY-Resolution at 120 mJ / cm2(FIG. 21 A), and Z-Resolution at 120 mJ / cm2(FIG. 2 IB), and for F19 formulation in XY&Z direction: XY-Resolution at 120 mJ / cm2(FIG. 21C), Z-Resolution at 120 mJ / cm2(FIG. 21D), XY-Resolution at 180 mJ / cm2(FIG. 21E), and for Z- Resolution at 180 mJ / cm2(FIG. 2 IF).

[0168] FIGs. 22A-D are graphs of a 20cc SC breast implant model illustrating load-strain response (FIG. 22A); average compression force limit (FIG. 22B), average compressive strain-at-break (FIG. 22C), and accumulated (load- strain) energy (FIG. 22D) of breast implant models printed using formulations F1,F13,F18,F23,F24,F25, and F26. Bars of graphs FIGs. 22B-22D (from left to right) correspond with the labels which appear in FIG. 22A (from top to bottom).

[0169] FIG. 23A-D are graphs illustrating compressive load-strain response (FIG. 23A); average compression force limit (FIG. 23B), average compressive strain-at-break (FIG. 23C), and accumulated (load-strain) energy (FIG. 23D) of a design A’ varying in size and formulation type as follows: lOOcc breast implant models printed using formulation F23 or F25 , or a 200cc breast model implant printed using formulation F23, as these formulations are presented in Table 5. Bars of graphs FIGs. 23B-23D (from left to right) correspond with the labels which appear in FIG. 23A (from top to bottom).

[0170] FIG. 24Aa is a bar graph illustrating the mass loss after 2 and 7 days for Formulations F24 and F23 in comparison to control sample Fl 3 with minocycline.

[0171] FIG. 24Ab presents bar graphs comparing the degradation (represented by precent mass loss) of samples printed from two formulations (F13 and F18) in bicarbonate / carbonate buffer (pH 10) at 37°C after 2 or 7 days compared to control samples in PBS after 7 days as presented in Table 3.

[0172] FIG. 24B presents graphs comparing degradation rate of samples printed from F23 and F25 in bicarbonate / carbonate buffer (pH 10) at 37°C until fully degraded compared to control samples in PBS at 37°C after 80 days. FIG. 24C presents graphs comparing degradation rate of samples printed from F23 and F25 in 6% H2O2 at 37°C (pH 6) until fully degraded compared to control samples in PBS at 37°C after 50 days.

[0173] FIG.24D presents graphs comparing the degradation rate of samples printed from F23& F25 subjected to identical real-time degradation conditions under physiological temperature and humidity over at 3, 6 and 9 months.

[0174] FIG. 24E is a representative image of samples printed from F23& F25 subjected to identical real-time degradation conditions under physiological temperature and humidity over a 9-month period.

[0175] FIGs. 25A-D illustrate exemplary 3D designs of a breast implant of reduced material (VF 40%) according to some embodiments of the invention. Simplex D2.5 design as depicted in FIG. 25A, Simple Cubic Gradual Point (SC-GP) as depicted in FIG. 25B, Simple Cubic D3.0 UC7.3 as depicted in FIG. 25C, Simple Cubic D2.5 UC6.0 as depicted in FIG 25D.

[0176] FIG. 26A are graphs illustrating load-strain response (top); average compression force limit (bottom left), average compressive strain-at-break (bottom middle), and accumulated (load-strain) energy (bottom right) lOOcc of breast implant models printed using formulation F23, according to the 40%VF designs presented in FIGs. 25A-D as a compared to 50%VF SC model A’ (AKA Simple Cubic A’(D3.0 UC6.0).

[0177] FIGs. 26B-C are graphs illustrating compressive test results of 20cc SC breast implant models with 40%VF (FIG. 26B; the design is presented in FIG. 25D) or 50%VF (FIG. 26C; the design is presented in FIG. ID) printed with formulations F23 and F25. FIG. 26B also includes a close-up of the low compression forces region.

[0178] FIGs. 26D-E are the same graphs respectively for lOOcc breast implant models 40%VF and 50% VF respectively. Buckling region of 20cc 40%VF scaffolds which underscores the moderate buckling effect on the instantaneous stiffness as opposed to 20cc 50% VF wherein buckling is more pronounced. Such close-up view is not provided for either of the lOOcc scaffolds as both VFs buckled in a relatively controlled manner with no major impact on the strength properties of the scaffolds.

[0179] FIG. 26F shows a Vertical Hollow Beam with horizontal Holes (VHBH) designed implant. Such a design of an implant is characterized by hollow beams and optional horizontal connecting channels, optionally in a helical pattern, potentially allowing for pore interconnection in accordance with some embodiments of the invention. The left panel shows vertical hollow beams. The columns comprising vertical channels are connected to helically arranged horizontal channels, the center panel shows a single beam including helically arranged hollow channels and the right panel shows a cross-sectional view of an implant showing channels formed between pores.

[0180] FIG. 26G shows graphs showing comparative results of a compression test for a post process lOOcc implant such as shown in FIG. 26F and those of FIG. 1H, both printed with formulation F25.

[0181] FIG. 27 presents plots showing the kinetics rate (time to reach storage modulus (G’)) of H5 formulation.

[0182] FIG. 28Aa-c presents an isometric view (28Aa), the XY plane (28Ab) and the Z axis (28Ac) of a calibration model used in printing resolution studies.

[0183] FIG. 28Ad presents a drawing of both views of a unit cell model used to ensure sufficient resolution is kept in XY (left) and Z (right) while printing a representative part of the SC breast scaffold.

[0184] FIG. 28Ba and 28Bb presents pictorial representations of the XY plane (28Ba) and Z axis (28Bb) of a calibration model printed with H4 curable formulations.

[0185] FIG. 28C and 28D presents pictorial representations of the XY plane (left) and Z axis (right) of a calibration model printed with curable formulations H8 and H9 printed at 80 mJ / cm2respectively.

[0186] FIGs. 29A-D present comparative data obtained using Instron machine, showing the mechanical properties of dogbone models printed with H6, a curable formulation that comprises HC9, compared to the same formulation (F0) comprising minocycline as a photoblocker. Bars of graphs FIGs. 29B-D (from left to right) correspond with the labels which appear in FIG. 29 A (from top to bottom).

[0187] FIG. 30 is a bar graph showing cell viability upon incubating cell seeded on a model made of a curable formulation that comprises MC or HC9 for 15 days.

[0188] FIG. 31 presents the absorbance spectra of a solution containing 3-0-D-Glucosylquercetin (GQ) (10 mM solution in 10 mM HC1), NAP in DDW (25mg / ml and 0.5 w / w%), 3- -D- Glucosylquercetin (10 mM solution in 10 mM HC1) and NAP (0.5 w / w%), before and post irradiation at 385nm lOsec.

[0189] FIGs. 32A-B presents plots showing the kinetics rate (time to reach storage modulus (G’)) of curable formulations F24 and F26.

[0190] FIG. 33A (a) and (b) present pictorial representations of the XY plane and Z axis respectively of a calibration model printed with curable formulation A printed with an energy of 110 mJ / cm2. FIG. 33B (a) and (b) pictorial representations of the XY plane and Z axis respectively of a calibration model printed with curable formulation F24 at printing energy of 120 mJ / cm2.

[0191] FIG. 33C(a) and (b) pictorial representations of the XY plane and Z axis respectively of a calibration model printed with curable formulation F26 at printing energy of 120 mJ / cm2.

[0192] FIGs. 34Aa-34Ad present comparative data of compression test, which demonstrate the mechanical properties of 20 cc scaffolds printed with a curable formulation that comprises GQ, formulation A, compared to the same formulations comprising 0.2 w / w% minocycline, Fl. Bars of graphs FIGs. 34Ab-34Ad (from left to right) correspond with the labels which appear in FIG. 34Aa (from top to bottom).

[0193] FIGs. 34Ba-34Bd present comparative data of compression test, which demonstrate the mechanical properties of 20cc scaffolds printed with a curable formulation that comprises 3- -D- Glucosylquercetin F24, compared to the same formulations comprising 0.2 w / w% minocycline, F13. Bars of graphs FIGs. 34Bb-34Bd (from left to right) correspond with the labels which appear in FIG. 34Ba (from top to bottom).

[0194] FIGs. 34Ca-34Cd present comparative data of compression test, which demonstrate the mechanical properties of 20cc scaffolds printed with a curable formulation that comprises 3-0-D- Glucosylquercetin F26, compared to the same formulations comprising 0.2 w / w% minocycline, F18. Bars of graphs FIGs. 34Cb-34Cd (from left to right) correspond with the labels which appear in FIG. 34Ca (from top to bottom).

[0195] FIG. 35 presents the UV-VIS absorbance spectra at 385 nm of a solution containing 10 mM solution Troxerutin, Troxerutin (10 mM solution in 10 mM HC1) and NAP (0.5 w / w%), before and after irradiation at 385nm lOsec.

[0196] FIGs. 36A-B presents plots showing the kinetic rate of formulations F23 or F25 respectively.

[0197] FIG. 37 A (a)&(b) present pictorial representations of the XY plane and Z axis respectively of a calibration model printed with curable formulation AA printed with energy of 150 mJ / cm2.

[0198] FIG. 37B (a)&(b) presents pictorial representations of the XY plane and Z axis respectively of a calibration model printed with curable formulation F23 printed with energy of 150 mJ / cm2.

[0199] FIG. 37C (a)&(b) presents pictorial representations of the XY plane and Z axis respectively of a calibration model printed with curable formulation F25 printed with energy of 140 mJ / cm2.

[0200] FIGs. 38A-D present comparative data of the mechanical properties of dogbone models with curable formulation F23 that comprises Troxerutin compared to the same formulations comprising minocycline F13. Bars of graphs FIGs. 38B-38D (from left to right) correspond with the labels which appear in FIG. 38A (from top to bottom). FIGs. 38E-H present comparative data of the mechanical properties of cylinder models with curable formulation F23 that comprises Troxerutin compared to the same formulations comprising minocycline F13. Bars of graphs FIGs. 38F-38H (from left to right) correspond with the labels which appear in FIG. 38E (from top to bottom).

[0201] FIGs. 38I-L present comparative data of the mechanical properties of 20cc lattice models with curable formulation F23 that comprises Troxerutin compared to the same formulations comprising minocycline Fl 3. Bars of graphs FIGs. 38J-38L (from left to right) correspond with the labels which appear in FIG. 381 (from top to bottom).

[0202] FIGs. 38M-P present comparative data of the mechanical properties of dogbone models with curable formulation F25 that comprises Troxerutin compared to the same formulations comprising minocycline F18. Bars of graphs FIGs. 38N-38P (from left to right) correspond with the labels which appear in FIG. 38M (from top to bottom).

[0203] FIGs. 38Q-T present comparative data of the mechanical properties of cylinder models with curable formulation F25 that comprises Troxerutin compared to the same formulations comprising minocycline F18. Bars of graphs FIGs. 38R-38T (from left to right) correspond with the labels which appear in FIG. 38Q (from top to bottom).

[0204] FIGs. 38U-X present comparative data of the mechanical properties of 20cc lattice models with curable formulation F25 that comprises Troxerutin compared to the same formulations comprising minocycline F18. Bars of graphs FIGs. 38V-38X (from left to right) correspond with the labels which appear in FIG. 38U (from top to bottom).

[0205] FIGs. 38Y-38AE material tensile tests, material compression tests and lattice compression test respectively comparing mechanical properties “as print” of dogbones, cylinders and 20cc lattice printed from three different batches of F25. FIGs. 38 AB and 38 AC material tensile and compression tests of F25 dogbones and cylinders respectively comparing mechanical properties of as print and post-process. FIG. 38AD lattice compression test comparing mechanical properties of 40% and 50% vf lOOcc implants post process printed from the same F25 batch. FIG. 38AE lattice compression test comparing mechanical properties of F25 50% vf VBHB lOOcc implants prior and post process.

[0206] FIGs. 39A-D presents comparative data of mechanical properties of scaffolds printed with curable formulations F24, F26 (both GQ-based) F23, F25 (both TR-based) compared to the comparable formulations F13 and Fl 8 comprising 0.2% minocycline. Bars of graphs FIGs. 39B- 39D (from left to right) correspond with the labels which appear in FIG. 39A (from top to bottom).

[0207] FIGs. 40A-O are graphs illustrating Stress-strain response of dogbone (FIGs. 40A-E, cylinder (FIGs. 40F-J), 40%vf 20cc SC breast implant models (FIGs. 40K-O) printed using formulations F27-F30 compared to F23, presented in Table 15 and Table 13 respectively. FIGs. 40B, 40G and 40L also include a close-up view of low compression forces region. For each of these figures, bars of graphs (from left to right) correspond with the labels which appear in the line graphs (from top to bottom).

[0208] FIG. 41A-H Compression test results of lOOmL 50% breast implants, at 5 weeks at 2-8°C or RT (A-D) Load-strain response for F23 implants; (E-H) Load-strain response for F25 implants.

[0209] FIG. 42A presents printed model (lattice scaffold) for human adipose derived stem (hACS) cell seeding

[0210] FIG. 42B presents bar graphs of hASCs proliferation on printed models A total of 80,000 cells were seeded onto models and incubated for 4 days. Cell proliferation was measured using the Presto Blue assay, and cell numbers were calculated based on a calibration curve. The average cell count from three models is presented.

[0211] FIG. 42C presents representative microscopic images of hASCs grown on lattice scaffolds. After 4 days of growth, cells were fixed and stained by Actin Red (Red) and NucBlue (Blue).

[0212] FIG. 43 presents representative microscopic images of hASCs adipogenic differentiationn on printed models. After 7 days of incubation in adipogenic induction medium cells were fixed and stained by Actin Green (Green), NucBlue (Blue) and Nile Red (red).

[0213] FIGs. 44A-D present representative pictorial images of TO fat injection.

[0214] FIG. 44E presents representative microscopic image showing a qualitive evaluation of the effect of shear stress on fat injection.

[0215] FIGs. 45A-B present representative pictorial images of ultrasound-guided delayed fat injection (4-6 weeks post implantation).

[0216] FIGs. 45C-D present representative pictorial images of blind delayed fat injection into the center of the scaffold (4-6 weeks post implantation).

[0217] FIG. 46A presents representative pictorial images MRI scans of F23 and F25 lOOcc 50% breast implants in sheep at 3 months post implantation.

[0218] FIGs. 46Ba-46Bb present representative pictorial images of cross sections of F25 lOOcc 50% breast implants in sheep at 1 and 3-months post implantation respectively and FIGs. 46Bc- 46Bd representative pictorial images of cross sections of F23 at 1 &3 months post implantation respectively.

[0219] FIGs. 46Ca-46Cc Representative histological images of F25 implant at 3-months. FIG. 46Ca Tissue ingrowth into the implant space filled with residual fibrocellular debris. Asterix - implant matrix , dotted line - leading edge of tissue ingrowth (arrows), arrow - fibrous connective tissue ingrowth, a=artificial separation between tissue ingrowth and implant material box - area detailed in FIG. 46Cb; FIG. 46Cb Asterix- implant matrix, arrow - fibrous connective tissue ingrowth with collagen deposition, arrowhead- residual fibrin along the implant, a=artificial separation between tissue ingrowth and implant material; and FIG. 46Cc Asterix- implant matrix, double clear arrow=artificial separation between tissue ingrowth and implant material, solid arrow - fibrous connective tissue ingrowth, clear arrow- scant inflammatory cells along the implant.

[0220] FIGs. 46Cd-46Cf Representative histological images of F23 implant at 3 -months. FIG. 46Cd Asterix- implant matrix; fibrous tissue ingrowth throughout the implant, arrow - fibrous connective tissue ingrowth, a=artificial separation between tissue ingrowth and implant material, box - area detailed in FIG. 46Ce; FIG. 46Ce Asterix- implant matrix, arrow - fibrous connective tissue ingrowth with collagen deposition, arrowhead- residual fibrin along the implant, a=artificial separation between tissue ingrowth and implant material; and FIG. 46Cf Asterix- implant matrix, solid arrow - fibrous connective tissue ingrowth, clear arrow- scant inflammatory cells along the implant, arrowhead-residual fibrin.

[0221] FIGs. 46Da-c present compression test results of lOOmL 50% breast implants in sheep - at 0M, 4weeks, 13weeks post implantation for F23 and F25 respectively.

[0222] FIGs. 47 Aa implantation sites trimmed between parallel lines for histological analysis. Representative histological images of F25 implant at 3-months post implantation. FIG. 47 Ab dotted line - delineation of central area lacking solid fibrocellular ingrowth. Arrows- peripheral fibrocellular tissue ingrowth within implant spaces; arrowheads thin strands of fibrocellular tissue along serum and fibrin-filled sinus spaces; double arrows=artificial separation of the pre-implant fibrous tissue and the implant; box - area detailed in FIG. 47 Ac. FIG. 47 Ac Asterix- implant polymer; arrows - limited fibrocellular granulation tissue peripherally within the implant spaces; arrowheads- edge of fibrocellular ingrowth and site hemorrhage.

[0223] DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

[0224] The present invention, in some embodiments thereof, relates to additive manufacturing, and, more particularly, but not exclusively, to collagen-based formulations usable in additive manufacturing of degradable scaffolds and / or soft tissue implants that feature mechanical properties suitable for breast implants, and to design thereof.

[0225] Before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details set forth in the following description or exemplified by the Examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Currently practiced additive manufacturing (AM) methodologies (including digital light processing bioprinting) require the use of curable formulations which are selected according to the requirements of the biological implant. Unlike silicone implants, Applicant’s novel hydrogel breast implants are regenerative and bioresorbable scaffolds, aiming for natural tissue regrowth with high safety profile. Their mechanical properties (e.g., elasticity, and load-bearing properties), and behavior in-vivo should match its degradation profile kinetics, tissue remodeling and interaction with the host tissue. For example, breast implants should ideally be of a stiffness that resembles that of a natural woman breast, such that it exhibits substantial deformation when an external force is applied, yet it can withstand external forces without breaking or cracking, and can withstand deformation (strain). Thus, formulations used to fabricate biological implants are selected according to implant requirements.

[0226] Stiffness is represented by a force-strain curve measured in a compression force test as described herein, such that strain of 50 % at 100-200 N, means the force required to compress the implant by 50% should be in the range of 100-200 N; and strain of 20 % at 10-100 N, means the force required to compress the implant by 20% should be in the range of 10-100 N.

[0227] The stiffness of a specimen (or lattice) is represented by the slope of the measured stressstrain (or load-strain) response curve. For a nonlinear curve, the stiffness is calculated using a linear regression within a given range, for example, 0-10% of strain, or 5-15% of strain, or 10- 20% of strain, or 10-30% of strain, or 10-40% of strain, or 20-50% of strain, or 40-60% of strain, or 60-70% of strain. Stiffness could also be referred to as instantaneous stiffness, especially if measured in a very narrow range such as 0-5% of strain, 5-10% of strain, and 10-15% of strain, which is common for nonlinear materials (or structures).

[0228] Compressive strain-at-break represents the strain level in which the specimen (or lattice) is partially or completely broken during a compressive test. One way to determine the breaking point of the implant is by analyzing the measured stress-strain (or force-strain) curve and determining the point where the stress (or force) starts to sharply decrease while the strain is still rising, thus being indicative of unstable mechanical response which implies on implant failure (break). Failure as such indicates an irreversible defect in the shape or integrity of the specimen (or lattice). Other smoothly, controlled fluctuations in the stress-strain (or force-strain) curves that appear during test are typically for the cylinder specimens (and breast scaffold) indicating meaningful elastic deformation named buckling. Tensile strain-at-break has the same meaning and measured in a tensile dogbone test.

[0229] Compressive-strength (or force limit) is the corresponding stress (or force) value to its strain-at-break one. This value is typically the maximal stress (or force) measured in a compression material test on cylinders (or scaffold test on breast implants), but can also be lower than the maximal value as it is determined according to the moment of breakage / other failure mechanism. Tensile strength has the same meaning and measured in a tensile dogbone test.

[0230] Volume retention of a specimen (or scaffold) is its ability to withstand loads within its elastic deformation range. Meaning that once loads are removed from the specimen (or scaffold), it returns to its undeformed shape. This ability is measured in-vitro during non-destructive tests, and in-vivo while the implants are under physiological loads.

[0231] In-vitro and ex-vivo, load and displacement are continuously accurately measured using mechanical and electronical components of a universal tester machine, Instron 68SC-1, capable of conducting tests with loads up to 1000N. Test methods were defined in Instron’ s dedicated software, Bluehill, controlling test parameters such as cross-head displacement speed, preload cycling properties, and end-of-test conditions. Standards such as ASTM F2150-19, ASTM D695, and ASTM D638 can be used to guide the test protocol and methods.

[0232] The present inventors have now uncovered combinations of particular photocurable polymeric materials which bring about a desired property.

[0233] Whilst reducing the present invention to practice, the present inventors uncovered that for additive manufacturing of breast implants the formulation should ideally produce (following photocuring and post-printing processes) an implant which exhibits one or more, or all, of the following properties (e.g., when measured as described herein for breast implant models obtained by additive manufacturing as described herein):

[0234] 1. a stiffness represented by a slope (e.g. compressive force / %strain ) which meets both of the following requirements: a. Strain of 20 % is in the range of 10-100 N, meaning the force required to compress the implant by 20% should be in the range of 10-100 N; and b. Strain of 50 % in a range between 100-200 N, meaning the force required to compress the implant by 50% should be in the range of 100-200 N;

[0235] In some embodiments, for example when considering the behavior of an implant after implantation, the stiffness of the implant is alternatively or additionally required such that under physiological loads, which typically ranges from 5 to 10 N in human breasts, the deformation is no more than 30% of strain relative to the implant’s undeformed shape.

[0236] 2. Compressive strain- at-break higher than 50 %, such that the implant can exhibit strain (deformation) of at least 50 %, or at least 60 %, or higher, before breaking or before an irreversible defect in its shape or integrity occurs; and 3. Compressive force limit of at least 156 N, such that the implant can withstand a compressive load of at least 156N, without breaking or before a defect in its shape or integrity occurs.

[0237] Whilst reducing the present invention to practice, the present inventors uncovered that for additive manufacturing of breast implants the formulation should ideally produce (following photocuring and washing (“as print”) and optionally post process) a hardened material which exhibits tensile strain-at-break of at least 70 % or even at least 100% and tensile strength of at least 0.7 MPa or even at least IMPa (e.g., when measured as described herein for standard models such as dogbone models as described, obtained by additive manufacturing as described herein).

[0238] The stiffness of such dogbones could vary according to the manufacturing and postprinting processes, allowing for the design of different applications. For example, at 70 % strain, the material exhibits tensile stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or higher. For example, at 80% strain, the material exhibits stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or higher. For example, at 100 % strain, the material exhibits tensile stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or of 0.85 MPa, or of 0.9 MPa, or of 0.95 MPa, or of 1.00 MPa, or higher. For example, at 110 % strain, the material exhibits tensile stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or of 0.85 MPa, or of 0.9 MPa, or of 0.95 MPa, or of 1.00 MPa, or of 1.10 MPa, or of 1.15 MPa, or of 1.20 MPa, or higher. All when measured as described herein.

[0239] Whilst reducing the present invention to practice, the present inventors uncovered that scaffolds fabricated from a combination of short chain curable polymer and long chain curable polymer PEG-PCL 23k degrade significantly faster than those printed with the same formulation other than long chain curable polymer PEG 20k under the same real time conditions (i.e., pH 7 temperature of 37°C and humidity). The degradation observed in PEG-PCL 23k is attributed to the hydrolytically labile PCL block, in contrast to the higher stability of PEG 20k. The study results after a 9-month period in vitro emphasize the critical role of polymer composition in designing biodegradable scaffolds and the importance of tailoring degradation rates to synchronize specific regenerative requirements. The fast degradation mechanism of the PEG PCL may be prone to limit this synchronization while PEG provides longer stability periods.

[0240] This study is aligned with the conclusions of accelerate degradations study wherein PEG 20K DMA exhibited relatively higher resistance to degradation in pH 10, compared to PEG PCL 23 K. The PEG PCL 23 K combines two degradation mechanisms. The main mechanism is via hydrolysis of methacrylate ester while the ether PEG chain undergoes oxidation slowly over time.

[0241] The present inventors found that the structural design of the implant affects both mechanical and biological properties. Thus, according to an aspect of the invention there is provided a photocurable formulation usable in additive manufacturing a three-dimensional object featuring, in at least a portion thereof, a biological or a biocompatible material, the photocurable formulation comprising a photoinitiator, a photocurable biological or biocompatible material, and an aqueous carrier, the formulation further comprising at least two photocurable polymeric materials, wherein: at least one of the at least two photocurable polymeric materials has an average molecular weight lower than 10,000 grams / mol (low MW photocurable polymeric material), and at least another one of the at least two photocurable polymeric materials has an average molecular weight higher than 10,000, or higher than 15,000 (high MW photocurable polymeric material), grams / mol; a total amount of the at least two photocurable polymeric materials is in a range of from 1 to 20, or from 5 to 20, or from 5 to 15, or from 7.5 to 15, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:9, or from 1: 1 to 1:5.

[0242] As used herein, the term “curable” describes a formulation or a material that is capable of undergoing curing, or hardening (e.g., a change in viscosity or in storage modulus (G’ )), as defined herein, when exposed to a suitable curing condition.

[0243] In some of any of the embodiments described herein, when a curable formulation / material is exposed to a curing condition (e.g., radiation), it polymerizes by any one, or combination, of chain elongation, entanglement and cross -linking. The cross-linking can be chemical and / or physical and can be between molecules of the same material and / or with other curable components in the formulation.

[0244] In some of any of the embodiments described herein, a curable material can be a monofunctional curable material or a multi-functional curable material.

[0245] Herein, a mono-functional curable material comprises one curable group - a functional group that can undergo polymerization, entanglement and / or cross-linking when exposed to a curing condition (e.g., radiation, presence of calcium ions).

[0246] A multi-functional curable material comprises two or more, e.g., 2, 3, 4 or more, curable groups. Multi-functional curable materials can be, for example, di-functional, tri-functional or tetra-functional curable materials, which comprise 2, 3 or 4 curable groups, respectively.

[0247] A formulation that comprises photocurable materials is also referred to herein as a bioink formulation or bioink composition or simply as bioink. According to some embodiments, the curable formulation is usable in additive manufacturing of a 3D object as described herein (e.g., in bioprinting). According to some embodiments, the composition is usable, or is for use, in the preparation of, or as, one or more modeling material formulation(s) for an additive manufacturing process (e.g., bioprinting). In one embodiment, the formulation is for bioprinting a breast implant.

[0248] According to some embodiments, the additive manufacturing is of a three-dimensional object that comprises, in at least a portion thereof, a biological material, for example, a collagen material as described herein.

[0249] According to some of any of the embodiments described herein, the curable formulation features, when cured or hardened, storage modulus (G’) that ranges from about 100 Pa to about 50,000 Pa, or from about 1,000 Pa to about 50,000 Pa, or from about 100 Pa to about 40,000 Pa, or from about 1,000 Pa to about 40,000 Pa, or from about 100 Pa to about 30,000 Pa, or from about 1,000 Pa to about 30,000 Pa, or from about 100 Pa to about 25,000 Pa, or from about 1,000 Pa to about 25,000 Pa, or from about 1,000 Pa to about 20,000 Pa, or from about 100 Pa to about 20,000 Pa, or from about 1,000 Pa to about 20,000 Pa, or from about 5,000 Pa to about 30,000 Pa, or from about 5,000 Pa to about 25,000 Pa, or from about 10,000 Pa to about 30,000 Pa or from about 10,000 Pa to about 25,000 Pa, including any intermediate values and subranges therebetween.

[0250] According to a preferred embodiments described herein, the curable formulation features, when cured or hardened, storage modulus (G’) that ranges from about from about 7170Pa to about 24,770Pa, from 8,000 Pa to about 20,000 Pa, or from about 4,240 Pa to about 5,020 Pa.

[0251] According to some of any of the embodiments described herein, the curable formulation features, when hardened, storage modulus (G’) that ranges from about 10,000 Pa to about 24,000 Pa or from 12,000 Pa to about 23,000Pa including any intermediate values and subranges therebetween.

[0252] According to some of any of the embodiments described herein, the curable formulation features a pH that ranges from about 2 to about 9, or from about 3 to about 9, or from about 3 to about 8.5, or from about 3 to about 8, or from about 3.5 to about 9, or from about 3.5 to about 8.5, or from about 3.5 to about 8, or from about 4 to about 8.5, or from about 4 to about 8, or from about 4.5 to about 8.5, or from about 4.5 to about 8, or from about 5 to about 8.5, or from about 5 to about 8, or from about 5.5 to about 8.5, or from about 5.5 to about 8, or from about 6 to about 8, including any intermediate values and subranges therebetween.

[0253] According to some of any of the embodiments described herein, the curable formulation features a pH that ranges from about 2 to about 7, or from about 2 to about 6, or from about 2 to about 5, or from about 2 to about 4, or from about 2 to about 3, or from about 2.4 to about 3, including any intermediate values and subranges therebetween.

[0254] According to some of any of the embodiments described herein, the curable formulation features a pH that ranges from about 1 to about 5, from about 1 to about 4, from about 1 to about 3, from about 1 to about 2, from about 2 to about 5, from about 2 to about 4, from about 2 to about 3, from about 2 to about 3.5 or from about 2.5 to about 3.5 including any intermediate values and subranges therebetween. In a preferred embodiment the curable formulation features a pH that ranges between 2.4-3.0.

[0255] According to some of any of the embodiments described herein, the curable formulation features a shear-thinning behavior (e.g., at room temperature, for example, of from 20 to 25 °C) and is a shear-thinning composition.

[0256] The term “shear-thinning” describes a property of a fluidic material that is reflected by a decrease in its viscosity (increase in its fluidity) upon application of shear forces (under shear strain), at an indicated temperature, when determined using a rheometer as described in the Examples section that follows.

[0257] In some of the present embodiments, a shear-thinning material is such that exhibits a significant, e.g., at least 100 %, reduction in its shear modulus upon increasing the shear strain from about 1% to above 50 %. Shear-thinning materials therefore exhibit a shear-dependent viscosity profile.

[0258] According to some of any of the embodiments described herein, the curable formulation features a fast recovery rate upon a change in the applied shear force (a fast shear recovery).

[0259] According to some of any of the embodiments described herein, the curable formulation features a change of no more than 6 %, or of no more than 10 % upon shear rest (zero shear force) of 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes and even 10 minutes.

[0260] According to some of any of the embodiments described herein, the curable formulation features at least 80 % recovery, or at least 85 % recovery, or at least 90 % recovery, or at least 92 % recovery, of its viscosity upon increasing the shear rate from about 0 1 / sec or 1 1 / sec to above 50 1 / sec, for a time period of at least 1 minute (e.g., from about 60 seconds to about 120 seconds, e.g., about 100 seconds).

[0261] According to some of any of the embodiments described herein, the curable formulation features a viscosity at room temperature that ranges from 70 to 2500 centipoises (Cps), when determined using a rheometer as described in the Examples section that follows.

[0262] Herein, “room temperature” encompasses temperature is a range of 15 to 25 °C, or from 20 to 25 °C, or about 22 °C. According to some of any of the embodiments described herein, the curable formulation features a viscosity of no more than 100 centipoises (cP), no more than 200 cP, or no more than 250 cP, no more than 300 cP, no more than 1000 cP at a shear rate of 10 1 / sec, at room temperature, as described herein, when determined using a rheometer as described in the Examples section that follows.

[0263] According to some embodiments of the invention, the curable formulation features a viscosity at room temperature, at a shear rate of 10 1 / sec, that ranges from 80 to 3,000 cP. According to some embodiments of the invention, the curable formulation features a viscosity at room temperature, at a shear rate of 10 1 / sec, that ranges from 80 to 250 cP. According to some embodiments of the invention, the curable formulation features a viscosity at room temperature, at a shear rate of 10 1 / sec, that ranges from 720 to 3000 cP. According to some embodiments of the invention, the curable formulation features a viscosity at a room temperature, at a shear rate of 10 1 / sec, that ranges from 250 to 3000 cP. According to some embodiments of the invention, the curable formulation features a viscosity at room temperature, at a shear rate of 10 1 / sec, that ranges from 250 to 720 cP. According to some embodiments of the invention, the curable formulation features a viscosity at room temperature, at a shear rate of 10 1 / sec, that ranges from 80 to 720 cP. According to a preferred embodiments described herein, the curable formulation features a viscosity at room temperature, at a shear rate of 10 1 / sec, that ranges from 80 to 250cP or from 266 to 294cP or from 952 to 963cP

[0264] Overly viscous formulations at room temperature or higher in inkjet technology are undesirable as this can lead to clogging of the printing head, unless cooled. In DLP technology, when the formulation is overly viscous, it may not adequately flow within the vat, hence creating regions without ink to be cured. This poor flow can cause a “missed layer,” as the projected light will not be applied on an uncured ink, meaning that some parts (features) of the model will be missing. Additionally, excessive viscosity can also trap air within the uncured ink. Air bubbles that form in the layers lead to defects, or weak points in the final structure, and inhomogeneous implants.

[0265] Exemplary viscosity values are presented in Table 4 in the Examples section that follows.

[0266] According to some embodiments described herein, the curable formulation comprises a solvent and features a viscosity ranging between about 720 to 3000cP or between about 80 to 250 cP at RT. According to some embodiments, the curable formulation features a viscosity ranging between about 720 to 3000cP or between about 80 to 250 cP at RT is essentially free or free of a solvent. Monomers are typically small, low-viscosity molecules. When mixed with the higher- viscosity polymerizable formulation, they act as diluents. This reduces the overall viscosity of the formulation, ensuring better flow and more uniform distribution across the curing surface.

[0267] While adding a monomer to reduce viscosity has several benefits, it may change the polymer network structure, potentially leading to a less tightly crosslinked material depending on the monomer used. This can affect mechanical properties such as elasticity, strength. Some monomers may not fully integrate with the rest of the formulation, potentially causing phase separation or inconsistent polymer structure. This might lead to incomplete curing, which affects the structural and chemical stability of the final implant. Even though monomers are meant to be incorporated into the final product, residual unreacted monomer can remain, especially if curing is not 100% efficient.

[0268] In one embodiment, the polymerizable formulation comprises N-(2- Hydroxyethyl)acrylamide (HEAA), which is a hydrophilic, water-soluble monomer having an acrylamide group (responsible for polymerization) and hydroxyethyl side chain (hydrophilic and reactive).

[0269] According to some embodiments described herein, the curable formulation comprises one or more monomers and features a viscosity ranging between about 720 to 3000cP or between about 80 to 250 cP at RT. According to some embodiments, the curable formulation features a viscosity ranging between about 720 to 3000cP or between about 80 to 250 cP at RT is essentially free or free of one or more monomers. According to some embodiments, the curable formulation is free of HEAA.

[0270] Short polymers in their uncured form more readily diffuse into cells are cytotoxic in their uncured form. According to some embodiments, essentially free or free short polymer having low Mw (e.g., PEG polymers of a Mw less than 1000 such as PEGDA 700 or PEGD700mA).

[0271] According to some of any of the embodiments described herein, the curable formulation features kinetic curing parameters suitable for additive manufacturing.

[0272] Exemplary such parameters are presented in Table 4 in the Examples section that follows.

[0273] Herein throughout, “centipoise” or “Cp” and Pa- second value (1 Pa- second = 1,000 centipoise) are used interchangeably.

[0274] Herein throughout, whenever the phrase “weight percent”, or “% by weight” or “% wt.”, is indicated in the context of embodiments of a formulation (e.g., a modeling formulation, a curable formulation, a bioink composition), it is meant weight percent of the total weight of the respective uncured formulation. As mentioned, the formulation of this aspect of the present invention comprises a photocurable biological or biocompatible material, which can be materials derived from a biological material and / or are biocompatible synthetic materials.

[0275] In medical applications such as implants or tissue engineering scaffolds — where materials are intended for implantation into a patient's body — it is essential that all components of the curable formulation, including the photocurable synthetic polymer, photocurable biological polymer (light- polymerizable materials), photoinitiators, dyes (photoblockers), solvents, and other additives, are biocompatible. This means they must not pose a significant risk of toxicity, injury to living cells tissues, or immune system rejection. In certain cases, non-biocompatible substances may be used during manufacturing, but their concentrations must be as low as possible or tested for biocompatibility. Otherwise, they may be safely removed prior to implantation in the body.

[0276] Resorbability — the ability of the scaffold to degrade within the body — is a key factor in scaffolds engineering. Effective tissue regeneration, (retention, ingrowth and / or integration), relies on scaffolds that gradually resorb in response to tissue development and specifically, for breast scaffolds, relies on integration of native fat tissue. Controlled resorption timing is also vital to allow enough time for proper vascularization, supporting the incorporation of new tissue. Therefore, predictable scaffold resorption is important, including ensuring the retention of mechanical properties of the implanted site; i.e., degradable scaffold, original and regenerated tissue , predictable degradation profiles (e.g., selecting polymers that erode or fracture at controlled rates rather than bulk degrading), and predictable pH shifts during breakdown.

[0277] A fine balance must be struck between scaffold strength / stiffness and its resorption rate. Typically, increasing the total concentration of polymers (e.g., from 10% to 15%) results in stronger but less resorbable scaffolds.

[0278] A possible solution to increase resorption rate is to decrease the total material volume of the implant. Hence, different designs of reduced volume fraction models were contemplated by inventors. Such models could be used with formulations characterized by a higher total concentration of polymers (e.g., 15%) while maintaining the same ratio between high and low molecular weight polymers (e.g., 3: 1) or a low total polymer concentration (e.g., 10%) with a different high and low molecular weight polymers ratio (e.g., 1: 1). In addition, slower degrading polymers (e.g., PEGDMA20k compared to PEG-PCL23k) could be used with such reduced volume fraction models.

[0279] In addition to resorbability, implants should ideally possess adequate ‘green strength’ — the mechanical strength immediately after printing step, but before any unpolymerized material is removed and prior to post process treatment. This green strength enables effective cleaning of residual material from within the structure, including pores. In some embodiments the mechanical properties of the implant or material bulk samples are assessed prior to washing to assess green strength. In some embodiments the mechanical, chemical or biological properties are assessed “as print” post washing step to remove residual material. In some embodiments the mechanical, chemical or biological properties of the implant or material bulk samples are assessed post printing processes such as post-cure, drying, rehydration or terminal sterilization.

[0280] According to some of any of the embodiments described herein, the one or more biocompatible photocurable materials comprise a curable collagen.

[0281] The term "collagen" as used herein, refers to a polypeptide having a triple helix structure and containing a repeating Gly-X- Y triplet, where X and Y can be any amino acid but are frequently the amino acids proline and hydroxyproline. According to one embodiment, the collagen is a type I, II, III, V, XI, or biologically active fragments therefrom.

[0282] A collagen according to some of the present embodiments also refers to homologs (e.g., polypeptides which are at least 50 %, at least 55 %, at least 60 %, at least 65 %, at least 70 %, at least 75 %, at least 80 %, at least 85 %, at least 87 %, at least 89 %, at least 91 %, at least 93 %, at least 95 % or more say 100 % homologous to collagen sequences such as listed in Table A as determined using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters). The homolog may also refer to a deletion, insertion, or substitution variant, including an amino acid substitution, thereof and biologically active polypeptide fragments thereof.

[0283] According to some embodiment, the collagen is a human or animal-derived collagen, such as from human cadaver or animal sources (bovine, porcine, equine etc.). According to a particular embodiment, the collagen is a human collagen.

[0284] In another embodiment, the collagen comprises a naturally occurring amino acid sequence of human collagen.

[0285] Table A below lists examples of collagen NCBI sequence numbers.

[0286] Table A The annotation of SEQ ID NO: 1 is as follows:

[0287] Amino acids 1-22 - signal peptide;

[0288] Amino acids 23-161 - N-terminal peptide;

[0289] Amino acids 162-1218 - collagen alpha- 1(1) chain;

[0290] Amino acids 1219-1464 - C -terminal peptide;

[0291] The annotation of SEQ ID NO: 2 is as follows:

[0292] Amino acids 1-22 - signal peptide;

[0293] Amino acids 23-79 - N-terminal peptide;

[0294] Amino acids 80-1119 - collagen alpha-2(I) chain;

[0295] Amino acids 1120-1366 - C-terminal peptide.

[0296] According to one embodiment, the collagen comprises a sufficient portion of its telopeptides such that under suitable conditions it is capable of forming fibrils.

[0297] Thus, for example, the collagen may be atelocollagen, a telocollagen or procollagen.

[0298] As used herein, the term "atelocollagen" refers to collagen molecules lacking both the N- and C-terminal propeptides typically comprised in procollagen and at least a portion of its telopeptides, but including a sufficient portion of its telopeptides such that under suitable conditions it is capable of forming fibrils.

[0299] The term "procollagen" as used herein, refers to a collagen molecule (e.g., human) that comprises either an N-terminal propeptide, a C-terminal propeptide or both. Exemplary human procollagen amino acid sequences are set forth by SEQ ID NOs: 3, 4, 5 and 6.

[0300] The term "telocollagen" as used herein, refers to collagen molecules that lack both the N- and C-terminal propeptides typically comprised in procollagen but still contain the telopeptides. The telopeptides of fibrillar collagen are the remnants of the N-and C-terminal propeptides following digestion with native N / C proteinases.

[0301] According to another embodiment, the collagen is devoid of its telopeptides and is not capable of undergoing fibrillogenesis.

[0302] According to another embodiment, the collagen is a mixture of the types of collagen above.

[0303] According to a particular embodiment, the collagen is genetically engineered using recombinant DNA technology (e.g., human collagen).

[0304] Methods of isolating collagen from animals are known in the art. Dispersal and solubilization of native animal collagen can be achieved using various proteolytic enzymes (such as porcine mucosal pepsin, bromelain, chymopapain, chymotrypsin, collagenase, ficin, papain, peptidase, proteinase A, proteinase K, trypsin, microbial proteases, and, similar enzymes or combinations of such enzymes) which disrupt the intermolecular bonds and remove the immunogenic non-helical telopeptides without affecting the basic, rigid triple -helical structure which imparts the desired characteristics of collagen (see U.S. Pat. Nos. 3,934,852; 3,121,049; 3,131,130; 3,314,861; 3,530,037; 3,949,073; 4,233,360 and 4,488,911 for general methods for preparing purified soluble collagen). The resulting soluble collagen can be subsequently purified by repeated precipitation at low pH and high ionic strength, followed by washing and resolubilization at low pH.

[0305] Plants expressing collagen chains and procollagen are known in the art, see for example, International Patent WO 2006 / 035442; Merle et al., FEBS Lett. 2002 Mar 27;515(l-3): 114-8. PMID: 11943205; and Ruggiero et al., 2000, FEBS Lett. 2000 Mar 3;469(1): 132-6. PMID: 10708770; and U.S. Patent Applications Publication Nos. 2002 / 098578 and 2002 / 0142391, as well as U.S. Patent No. 6,617,431.

[0306] It will be appreciated that embodiments of the present invention also contemplate genetically modified forms of collagen / atelocollagen - for example collagenase-resistant collagens and the like [see, for example, Wu et al., Proc Natl. Acad Sci, Vol. 87, p. 5888-5892, 1990],

[0307] Recombinant procollagen or telocollagen (e.g., human) may be expressed in any nonanimal cell, including but not limited to plant cells and other eukaryotic cells such as yeast and fungus.

[0308] Plants in which procollagen or telocollagen may be produced (i.e., expressed) may be of lower (e.g., moss and algae) or higher (vascular) plant species, including tissues or isolated cells and extracts thereof (e.g., cell suspensions). Preferred plants are those which are capable of accumulating large amounts of collagen chains, collagen and / or the processing enzymes described herein below. Such plants may also be selected according to their resistance to stress conditions and the ease at which expressed components or assembled collagen can be extracted. Examples of plants in which human procollagen may be expressed include, but are not limited to tobacco, maize, alfalfa, rice, potato, soybean, tomato, wheat, barley, canola, carrot, lettuce and cotton.

[0309] Production of recombinant procollagen is typically effected by stable or transient transformation with an exogenous polynucleotide sequence encoding human procollagen.

[0310] In some of any of the embodiments described herein, the recombinant human collagen is a recombinant human type I collagen.

[0311] In some of any of the embodiments described herein, the recombinant human collagen is a plant-derived recombinant human collagen and in some embodiments the plant is tobacco. An exemplary collagen is described in Stein H. (2009) Biomacromolecules; 10:2640-5, WO 2006 / 035442, WO 2009 / 053985, WO 2011 / 064773, WO 2013 / 093921 and WO 2014 / 147622. In some of any of the embodiments described herein, the recombinant human collagen is a recombinant human type I collagen comprising two al units having the amino acid sequence which is at least 90 % homologous, at least 91 % homologous, 92 % homologous, at least 93 % homologous, at least 94 % homologous, at least 95 % homologous, at least 96 % homologous, at least 97 % homologous, at least 98 % homologous, at least 99 % homologous or 100 % homologous to the sequence as set forth in SEQ ID NO: 15 as determined using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters), and one a2 unit having the amino acid sequence which is at least 90 % homologous, at least 91 % homologous, 92 % homologous, at least 93 % homologous, at least 94 % homologous, at least 95 % homologous, at least 96 % homologous, at least 97 % homologous, at least 98 % homologous, at least 99 % homologous or 100 % homologous to the sequence as set forth in SEQ ID NO:6. According to a particular embodiment, the type I collagen consists of two al units which consists of the sequence as set forth in SEQ ID NO: 15 and one a2 unit consisting of the sequence as set forth in SEQ ID NO: 6, as determined using BlastP software of the National Center of Biotechnology Information (NCBI) using default parameters).

[0312] In some of any of the embodiments described herein, the al unit is encoded by a polynucleotide sequence being at least which is at least about 80 %, at least about 81 %, at least about 82 %, at least about 83 %, at least about 84 %, at least about 85 %, at least about 86 %, at least about 87 %, at least about 88 %, at least about 89 %, at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, e.g., 100 % identical to the nucleic acid sequence as set forth in SEQ ID NO: 16. The a2 unit is encoded by a polynucleotide sequence being at least which is at least about 80 %, at least about 81 %, at least about 82 %, at least about 83 %, at least about 84 %, at least about 85 %, at least about 86 %, at least about 87 %, at least about 88 %, at least about 89 %, at least about 90 %, at least about 91 %, at least about 92 %, at least about 93 %, at least about 93 %, at least about 94 %, at least about 95 %, at least about 96 %, at least about 97 %, at least about 98 %, at least about 99 %, e.g., 100 % identical to the nucleic acid sequence as set forth in SEQ ID NO: 10.

[0313] Identity (e.g., percent homology) can be determined using any homology comparison software, including for example, the BlastN software of the National Center of Biotechnology Information (NCBI) such as by using default parameters.

[0314] In some of any of the embodiments described herein, the human recombinant collagen (rhCollagen) as described herein in any of the respective embodiments is a monomeric rhCollagen. By “monomeric” it is meant a rhCollagen as described herein which is soluble in an aqueous solution and does not form fibrillar aggregates.

[0315] In some of any of the embodiments described herein, the human recombinant collagen (rhCollagen) as described herein in any of the respective embodiments is a fibrillar rhCollagen.

[0316] By “fibrillar” it is meant a rhCollagen as described herein which is in a form of fibrillar aggregates in an aqueous solution containing same. Typically, but not obligatory, fibrillar rhCollagen is formed by subjecting monomeric rhCollagen to a fibrillogenesis buffer, typically featuring a basic pH. An exemplary procedure for forming fibrillar rhCollagen, is described in WO 2018 / 225076.

[0317] As described therein plant-derived rhCollagen, is a bioidentical to human collagen and offers high purity, homogeneity, biofunctionality biocompatibility and reproducibility thereby facilitating mass production. As rhCollagen is not sourced from animals it eliminates the risks of animal-derived materials and supports a more ethical, animal-free approach to regenerative medicine.

[0318] According to some of any of the embodiments described herein, the collagen is a tissue- derived collagen, for example, a tissue-derived human Type I collagen.

[0319] By “curable collagen” it is meant a collagen as described herein in any of the respective embodiments (e.g., human recombinant collagen), which features one or more curable groups as defined herein. According to some of any of the embodiments described herein, the curable collagen is a multi-functional curable material that comprises a plurality of curable groups, as defined herein.

[0320] The terms “curable collagen” and “collagen featuring one or more (or at least one) curable groups” are used herein interchangeably.

[0321] According to some of any of the embodiments described herein, the curable collagen comprises an amino acid sequence as described herein in any of the respective embodiments, and features one or more, preferably a plurality of, curable groups generated at least a portion of the amino acid residues forming the collagen, preferably by covalent attachment of a compound that comprises a curable group to functional groups of the side chains of the amino acid residues. Alternatively, or in addition, curable groups can be generated at the N-terminus and / or C-terminus of one or more the units forming the collagen, for example, by covalent attachment of a compound that comprises a curable group to a respective amine or carboxylate.

[0322] According to some of any of the embodiments described herein, the curable collagen is as described in WO 2018 / 225076. According to some of any of the embodiments described herein, a curable collagen describes a collagen as described herein (e.g., rhCollagen as described herein in any of the respective embodiments) to which one or more curable groups are attached directly (e.g., by means of a covalent bond to a respective lysine residue of the collagen), or are not attached by means of an elastic moiety that terminates by a curable group as described herein.

[0323] According to some of any of the embodiments described herein, at least a portion of the curable groups in a curable collagen as described herein are cross -linkable photocurable groups, which undergo cross-linking when exposed to irradiation as the curing condition.

[0324] In some embodiments, curable groups can undergo polymerization and / or cross-linking via free -radical mechanism.

[0325] Exemplary curable groups include acrylic groups, including acrylate, methacrylate, acrylamide and methacrylamide groups, which are collectively referred to herein as (meth)acrylic groups. Other free-radical curable groups may include thiols, vinyl ethers and other groups that feature a reactive double bond.

[0326] In some embodiments, curable groups can undergo polymerization and / or cross-linking via other mechanisms, such as cationic polymerization, or (cationic or anionic) ring opening polymerization. Exemplary such curable groups include, but are not limited to, epoxy-containing groups, caprolactam, caprolactone, oxetane, and vinyl ether.

[0327] Other curable groups can include, for example, formation of amide bonds between functional carboxylate and amine group (each being a curable group that reacts with the other and can effect cross-linking); formation of an imine bond between and amine and an aldehyde group; formation of urethane between isocyanate groups and hydroxyl groups via polycondensation in the presence of a catalyst and / or upon exposure to UV radiation; and formation of disulfide bonds between two thiols.

[0328] Any other photocurable groups are contemplated.

[0329] The photocurable groups in the curable collagen can be generated by means of chemical reactions between a material that comprises or can generate the photocurable group(s) when reacted with chemically-compatible functional groups present in the collagen, as described herein, either directly, or be means of a spacer or a linker, using chemistries well known in the art. For example, a material that comprises a curable group and a functional group can be reacted with a compatible functional group in the collagen, for example, a functional group in an amino acid side chain, such that the curable group is a substituent of the amino acid side chain. In some embodiments, a compatible functional group is first generated within the collagen by chemical modification of chemical groups of the collagen, and is then reacted with a material that comprises or generates a curable group upon the reaction.

[0330] Whenever a curable collagen comprises more than one photocurable groups, the photocurable groups can be the same or different.

[0331] According to some of any of the embodiments described herein, at least a portion, or all, of the curable groups in a curable collagen of the present embodiments are photopolymerizable groups (e.g., UV-curable groups) that are capable of undergoing polymerization and / or crosslinking upon exposure to irradiation as described herein.

[0332] According to some of any of the embodiments described herein the curable group is a photocurable or photopolymerizable group (e.g., a (meth)acrylic group such as an acrylate or methacrylate).

[0333] Alternatively, one or more of the curable groups is a thiol-containing group, which provides disulfide bridge upon curing.

[0334] Alternatively, one or more of the curable groups is cured upon undergoing a chemical reaction, such as glycation or conjugation (using coupling agents such as EDC).

[0335] According to some embodiments, one or more of the curable groups comprise an amine and a carboxyl group which form peptide bonds upon curing.

[0336] According to some of any of the embodiments described herein, at least a portion, or all, of the curable groups in a curable collagen of the present embodiments are (meth)acrylic groups, as defined herein.

[0337] According to some of any of the embodiments described herein, an acrylic group such as methacrylamide can be generated by reacting an acrylate or methacrylate (e.g., acrylic acid, methacrylic acid, acrylic or methacrylic ester, acrylic or methacrylic anhydride) with an amine functional group (of, for example, lysine residues).

[0338] According to some of any of the embodiments of the present invention, the number of the curable groups in a curable collagen as described herein can determine the degree of curing (e.g., the degree of cross-linking) and can be manipulated in order to achieve a desired curing (e.g., crosslinking) degree.

[0339] According to some of any of the embodiments described herein, the curable collagen features a plurality of acrylamide or methacrylamide curable groups generated by reacting with lysine residues as described herein. According to some of any of the embodiments described herein, the curable collagen features a plurality of acrylamide or methacrylamide curable groups substituting the amine groups of lysine residues in the collagen.

[0340] In some embodiments, at least 20 %, or at least 30 %, or at least 40 %, or at least 50 %, or at least 60 %, or at least 70 %, or at least 80 %, or at least 90 % of the lysine residues in the collagen are substituted by a methacrylamide or acrylamide group. In some embodiments, the curable collagen features from 10 % to 90 %, or from 10 % to 80 %, or from 10 % to 60 %, or from 10 to 50 %, or from 20 to 90 %, or from 20 to 80 %, or from 20 to 60 %, or from 20 to 50 %, of its lysine residues substituted by a methacrylamide or acrylamide group, including any intermediate values and subranges therebetween.

[0341] In a particular embodiment, the curable collagen is 50 % methacrylated.

[0342] In another embodiment, the curable collagen is 90 % methacrylated.

[0343] A curable collagen (e.g., rhCollagen) as described herein can be prepared by reacting a material that comprises a curable group or which generates a curable group with the collagen (e.g., rhCollagen), as described, for example, in WO 2018 / 225076.

[0344] The number of curable groups in the collagen (e.g., rhCollagen) can be controlled by manipulating the amount of the material reacted with the collagen (e.g., rhCollagen) for generating the curable groups.

[0345] According to some of any of the embodiments described herein, the curable collagen is a recombinant human type I collagen as described herein in any of the respective embodiments and any combination thereof.

[0346] According to some of any of the embodiments described herein, the one or more of the curable materials comprise(s) collagen, as described herein in any of the respective embodiments and any combination thereof, including a curable collagen as described herein, which features a plurality of curable elastic moieties covalently attached to the collagen.

[0347] According to some of any of the embodiments described herein, the curable collagen is an elastomeric recombinant human type I collagen, as described, for example, in WO2023 / 073711.

[0348] The terms “elastic” and “elastomeric” as indicated herein with regard to a group (e.g., curable group) or material (e.g., curable material) are used herein interchangeably.

[0349] The plurality of elastomeric moieties can be the same or different. When different, the difference can be in the chemical composition or stereochemistry of the elastic moiety and / or in the type of the curable group and / or in the position of the curable group.

[0350] An elastic moiety that features a curable group is also referred to herein interchangeably as a “curable elastic moiety” or as a “curable elastomeric moiety” or as “an elastomeric moiety that features a curable group”, or as “an elastic moiety that features a curable group”, and all means that an elastic or elastomeric moiety features one or more curable groups.

[0351] According to some of any of the embodiments described herein, the elastomeric moiety is a moiety that confers elasticity to the hardened material formed upon polymerization and / or crosslinking of the respective curable material. Such moieties typically comprise alkyl, alkylene chains, hydrocarbon chains, alkylene glycol groups or chains (e.g., oligo or poly(alkylene glycol) as defined herein, urethane, oligourethane or polyurethane moieties, as defined herein, and the like, including any combination (e.g., co-polymers) of the foregoing.

[0352] By “elasticity” it is meant an ability of a deformed material body to return to its original shape and size when the forces causing the deformation are removed. Elasticity can be determined, for example, by the determining storage modulus, elastic modulus, and / or shear recovery rate of the hardened material. Exemplary methods of determining these parameters are described in the Examples section that follows. Other methods are well-known in the art and arc also contemplated.

[0353] According to some of any of the embodiments described herein, the collagen is a human Type I collagen, as described herein.

[0354] According to some of any of the embodiments described herein, the collagen is a recombinant collagen, as described herein.

[0355] According to some of any of the embodiments described herein, the collagen is a plant- derived recombinant collagen, as described herein.

[0356] According to some of any of the embodiments described herein, the collagen is a plant- derived recombinant human Type I collagen, as described herein, for example, tobacco-derived collagen.

[0357] Contemplated amounts of curable collagen in the formulations are between 0.1-2 % by weight of the total weight of the formulation. It will be appreciated, when the formulation lacks a polymer, the amount of curable collagen (e.g. CMR50 or CMR90) in the formulation is between 1-2 %. When the formulation comprises a polymer, the amount of curable collagen (e.g. CMR50) may be between 0.1-1 % by weight of the total weight of the formulation.

[0358] As mentioned, the curable compositions described herein also comprise a photoinitiator.

[0359] The photoinitiator is selected in accordance with the curing mechanism (e.g., free-radical, cationic, etc.) and as suitable for the irradiation wavelength or wavelength range.

[0360] A free-radical photoinitiator may be any compound that produces a free radical on exposure to radiation such as ultraviolet or visible radiation and thereby initiates a polymerization reaction. Non-limiting examples of suitable photoinitiators include benzophenones (aromatic ketones) such as benzophenone, methyl benzophenone, Michler's ketone and xanthones; acylphosphine oxide type photo-initiators such as 2,4,6-trimethylbenzolydiphenyl phosphine oxide (TMPO) and salts thereof (e.g., Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Sodium phenyl-2,4,6- trimethylbenzoylphosphinate (NAP)) 2,4,6-trimethylbenzoylethoxyphenyl phosphine oxide (TEPO) and salts thereof, and bisacylphosphine oxides (B APO's) and salts thereof); benzoins and bezoin alkyl ethers such as benzoin, benzoin methyl ether and benzoin isopropyl ether and the like. Examples of photoinitiators are alpha-amino ketone, and bisacylphosphine oxide (B APO's).

[0361] Exemplary photoinitiators include, but are not limited to, those of the Irgacure® family, riboflavin, rose Bengal, and more.

[0362] A free-radical photo-initiator may be used alone or in combination with a co-initiator. Coinitiators are used with initiators that need a second molecule to produce a radical that is active in the photocurable free-radical systems. Benzophenone is an example of a photoinitiator that requires a second molecule, such as an amine, to produce a free radical. After absorbing radiation, benzophenone reacts with a ternary amine by hydrogen abstraction, to generate an alpha-amino radical which initiates polymerization of acrylates. Non-limiting examples of a class of coinitiators are alkanolamines such as triethylamine, methyldiethanolamine and triethanolamine.

[0363] Suitable cationic photoinitiators include, for example, compounds which form aprotic acids or Bronsted acids upon exposure to ultraviolet and / or visible light sufficient to initiate polymerization. The photoinitiator used may be a single compound, a mixture of two or more active compounds, or a combination of two or more different compounds, i.e., co-initiators. Non-limiting examples of suitable cationic photoinitiators include aryldiazonium salts, diaryliodonium salts, triarylsulphonium salts, triarylselenonium salts and the like. An exemplary cationic photoinitiator is a mixture of triarylsolfonium hexafluoroantimonate salts.

[0364] Non-limiting examples of suitable cationic photoinitiators include P-(octyloxyphenyl) phenyliodonium hexafluoroantimonate UVACURE 1600 from Cytec Company (USA), iodonium (4-methylphenyl)(4-(2-methylpropyl)phenyl)-hexafluorophosphate known as Irgacure 250 or Irgacure 270 available from Ciba Speciality Chemicals (Switzerland), mixed arylsulfonium hexafluoroantimonate salts known as UVI 6976 and 6992 available from Lambson Fine Chemicals (England), diaryliodonium hexafluoroantimonate known as PC 2506 available from Polyset Company (USA), (tolylcumyl) iodonium tetrakis (pentafluorophenyl) borate known as Rhodorsil® Photoinitiator 2074 available from Bluestar Silicones (USA), iodonium bis(4-dodecylphenyl)- (OC-6-1 l)-hexafluoro antimonate known as Tego PC 1466 from Evonik Industries AG (Germany).

[0365] According to some of any of the embodiments described herein, the photoinitiator is a free- radical photoinitiator, as described herein, for example, a photoinitiator of the acylphosphine oxide type, such as, for example, Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) and / or Sodium phenyl-2,4,6-trimethylbenzoylphosphinate (NAP).

[0366] According to some of any of the embodiments described herein, the photoinitiator is an acyl phosphine oxide type photoinitiator such as a 2,4,6-trimethylbenzolydiphenyl phosphine oxide (TMPO) or a salt thereof (e.g., Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Sodium pheny 1-2 ,4 , 6-trimethy Ibenzoy Ipho sphinate (N AP) , 2,4 , 6-trimethy Ibenzoy lethoxypheny 1 phosphine oxide (TEPO), and bisacylphosphine oxides (B APO's).

[0367] According to some of any of the embodiments described herein, an amount of the photoinitiator in the formulation ranges from about 0.1 to about 10, or from about 0.1 to about 5, or from about 0.1 to about 3, or from about 0.1 to about 2, or from about 0.1 to about 1, % by weight, including any intermediate values and subranges therebetween.

[0368] According to the present embodiments, the formulation further comprises a mixture of photocurable polymeric materials that, when combined with the photocurable biological or biocompatible material, and exposed to irradiation as a curing condition, provides a hardened material that features mechanical properties suitable for or meeting the requirements of a breast implant.

[0369] According to the embodiments described herein, a curable polymeric material is a photopolymerizable or photocurable material, which polymerizes and / or undergoes cross-linking upon exposure to radiation, as described herein, and in some embodiments the curable material is a UV-curable material, which polymerizes or undergoes cross-linking upon exposure to UV-vis radiation, as described herein.

[0370] According to some of any of the embodiments described herein, the curable polymeric materials are photocurable polymeric materials, preferably UV-curable polymeric materials, which comprise one or more UV-curable groups.

[0371] It is to be understood that the photocurable polymeric materials according to these embodiments do not encompass the curable biological material as described herein in any of the respective embodiments.

[0372] According to the present embodiments, the photocurable polymeric materials are non- proteinaceous materials.

[0373] Herein, the phrase “polymeric material” encompasses homopolymers, copolymers, and a mixture of two or more of homopolymers, two or more co-polymers or of one or more homopolymer and one or more copolymer. When all the repeating units that form the polymeric material are the same, a polymeric material is considered a homopolymeric material. When the polymeric material comprises two or more types of repeating units, which can differ from one another by the type of the backbone units that form the polymeric backbone and / or by the type of the pendant groups, the polymeric material is a co-polymeric material. Co-polymeric materials comprise two or more different types of monomeric unit which may be distributed randomly or non-randomly throughout the polymeric backbone. When different types of monomeric units are distributed non-randomly, the copolymer may be characterized by any non-random distribution, and can be, for example, an alternating copolymer, a periodic copolymer, and / or a block copolymer.

[0374] As used herein, the phrase “alternating copolymer” describes a copolymer in which two adjacent backbone units alternate in a regular sequence along the polymer chain, such that the polymer has a repeating pattern of the two distinct backbone units. Typically, in an alternating copolymer, each two adjacent backbone units are different from one another (e.g., Y1-Y2-Y1-Y2 or Y1-Y2-Y3-Y1-Y2-Y3). As used herein, the phrase “periodic copolymer” describes a copolymer in which the arrangement of monomeric units follows a repeating sequence with a defined periodicity, which may involve more than two types of monomers, creating a regular and predictable sequence along the polymer chain (e.g., Y 1-Y2-Y2-Y 1-Y2-Y2-Y 1-Y2-Y2-). As used herein, the phrase “block copolymer” describes a copolymer in which distinct blocks of repeating backbone units are linked together in segments, such that the polymer consists of large sequences ("blocks") composed of a plurality (e.g., 3 or more) of one type of backbone unit followed by a block of a plurality of another type of backbone unit (e.g., Y1-Y1-Y1-Y2-Y2-Y2).

[0375] As demonstrated in the Examples section that follows, the present inventors have studied ample combinations of photocurable polymeric materials, combined with the photocurable biological or biocompatible material and the photoinitiator as described herein, in a search for photocurable polymeric material or a mixture of materials that would result in a hardened material that exhibits the abovementioned properties of a breast implant.

[0376] The present inventors have uncovered, upon laborious experimentation, that a mixture of a photocurable polymeric material that has an average molecular weight (Mw) lower than 10,000 grams / mol (also referred to herein as a low MW photocurable polymeric material; as low MW polymer or simply as short polymer), and another photocurable polymeric material has an average molecular weight (Mw) higher than 10,000, or higher than 15,000, grams / mol (also referred to herein as a high MW photocurable polymeric material, or high MW polymer or simply as long polymer), imparts to the hardened material the desired properties.

[0377] While studying various combinations, total amount (concentration) and weight ratios of the photocurable polymeric materials, the present inventors have further uncovered that a desirable performance is achieved when a total amount of these photocurable polymeric materials is in a range of from 1 to 20, or from 5 to 20, or from 5 to 15, or from 7.5 to 15, or from 5 to 10, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and / or when a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:9, or from 1: 1 to 1:5.

[0378] According to some of any of the embodiments described herein, a total amount (concentration) of the photocurable polymeric materials in the formulation is lower than 20, or lower than 18, or lower than 16, % by weight of the total weight of the formulation.

[0379] According to some of any of the embodiments described herein, a total amount (concentration) of the photocurable polymeric materials in the formulation is at least 5, preferably at least 7, or at least 10, % by weight of the total weight of the formulation.

[0380] According to some of any of the embodiments described herein, a total amount (concentration) of the photocurable polymeric materials in the formulation ranges from 5 to 15, or from 5 to 10, or from 7.5 to 15, or from 7.5 to 10, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween.

[0381] According to some of any of the embodiments described herein, a total amount (concentration) of the low MW polymeric material(s) in the formulation ranges from 1 to 10, preferably from 1 to 8, or from 1 to 5, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween.

[0382] According to some of any of the embodiments described herein, a total amount (concentration) of the high MW polymeric material(s) in the formulation ranges from 5 to 12, preferably from 5 to 10, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween.

[0383] According to some of any of the embodiments described herein, an amount (concentration) of the high MW polymeric material is at least the same and preferably higher than an amount (concentration) of the low MW polymeric material in the formulation.

[0384] According to some of any of the embodiments described herein, a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:9, or from 1: 1 to 1:5, or from 1: 1 to 1:2, including any intermediate values and subranges therebetween, and can be, for example, 1:2, 1:3, 1:4 or 1:5.

[0385] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 5 to 15, or from 7.5 to 15, or from 5 to 10, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:5, including any intermediate values and subranges therebetween.

[0386] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 7.5 to 15, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:5, including any intermediate values and subranges therebetween.

[0387] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 7.5 to 15, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1:2 to 1:5, or from 1: 1 to 1:4, including any intermediate values and subranges therebetween.

[0388] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 5 to 10, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1: 1 to 1:5, including any intermediate values and subranges therebetween.

[0389] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 5 to 10, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material ranges from 1:2 to 1:5, or from 1: 1 to 1:4, including any intermediate values and subranges therebetween.

[0390] According to some of any of the embodiments described herein, a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material is about 1:3.

[0391] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 1 to 20, or from 5 to 20, or from 5 to 15, or from 7.5 to 15, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material is about 1:3. According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 5 to 15, or from 5 to 10, or from 7.5 to 10, or from 7.5 to 15, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material is about 1:3.

[0392] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 5 to 10, or from 7.5 to 10, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material is about 1:3.

[0393] According to some of any of the embodiments described herein, a total amount of the high MW and low MW photocurable polymeric materials is in a range of from 7.5 to 10, or from 7.5 to 15, % by weight, of the total weight of the curable formulation, including any intermediate values and subranges therebetween; and a weight ratio between the low MW photocurable polymeric material and the high MW photocurable polymeric material is about 1:3.

[0394] According to some of any of the embodiments described herein, each of the photocurable polymeric materials (low and high MW polymers) is a multifunctional photocurable polymeric material that features two or more photocurable groups as described herein, e.g., (meth)acrylic groups such as (meth) acrylate groups, as described herein.

[0395] According to some of any of the embodiments described herein, each of the photocurable polymeric materials (low and high MW polymers) is independently a di-functional or a trifunctional photocurable polymeric material that features two or three photocurable groups as described herein, e.g., (meth)acrylic groups such as (meth)acrylate groups, as described herein.

[0396] According to some of any of the embodiments described herein, each of the photocurable polymeric materials (low and high MW polymers) is a di-functional photocurable polymeric material that features two photocurable groups as described herein, e.g., (meth)acrylic groups such as (meth)acrylate groups, as described herein.

[0397] The two or more photocurable groups can be terminal groups, which substitute the termini of the polymeric chain of the polymeric material, and / or can be pendant groups, substituting one or more of the backbone units of the polymeric material.

[0398] According to some of any of the embodiments described herein, the two or more photocurable groups are each a terminal group. According to some of any of the embodiments described herein, each of the photocurable polymeric materials (low and high MW polymers) is a di-functional photocurable polymeric material that features two photocurable groups as described herein, e.g., (meth)acrylic groups such as (meth)acrylate groups, as described herein, at each terminus of the polymeric chain (in case the polymeric material is made of a linear polymer).

[0399] According to some of any of the embodiments described herein, each of the photocurable polymeric materials (low and high MW polymers) is a di-functional photocurable polymeric material that features a linear polymeric chain and two photocurable groups as described herein, e.g., (meth)acrylic groups such as (meth)acrylate groups, as described herein, at each terminus of the linear (non-branched) polymeric chain.

[0400] According to some of any of the embodiments described herein, in each of the polymeric materials, each of the photocurable groups is independently an acrylate or methacrylate group.

[0401] For example, a di-functional high MW polymeric material can comprise two acrylate groups, or two methacrylate groups, or one acrylate group and one methacrylate group.

[0402] For example, a di-functional low MW polymeric material can comprise two acrylate groups, or two methacrylate groups, or one acrylate group and one methacrylate group.

[0403] For example, a di-functional high MW polymeric material can comprise two acrylate groups, or two methacrylate groups, and a di-functional low MW polymeric material can comprise two acrylate groups, or two methacrylate groups.

[0404] For example, a multi-functional high MW polymeric material can comprise a plurality of acrylate groups, or a plurality of methacrylate groups, and a multi-functional low MW polymeric material can comprise a plurality of acrylate groups, or a plurality of methacrylate groups.

[0405] According to some of any of the embodiments described herein, at least one of the photocurable polymeric materials features a plurality of acrylate groups.

[0406] According to some of any of the embodiments described herein, at least one of the photocurable polymeric materials is a di-functional polymeric material that features a plurality of acrylate groups.

[0407] For example, a multi-functional high MW polymeric material can comprise a plurality of acrylate groups, or a plurality of methacrylate groups, and a multi-functional low MW polymeric material can comprise a plurality of acrylate groups.

[0408] For example, a multi-functional high MW polymeric material can comprise a plurality of acrylate groups, and a multi-functional low MW polymeric material can comprise a plurality of acrylate groups, or a plurality of methacrylate groups. For example, a multi-functional high MW polymeric material can comprise a plurality of acrylate groups, and a multi-functional low MW polymeric material can comprise a plurality of acrylate groups.

[0409] For example, a di-functional high MW polymeric material can comprise two acrylate (e.g., terminal) groups, or two (e.g., terminal) methacrylate groups, and a di-functional low MW polymeric material can comprise two (e.g., terminal) acrylate groups.

[0410] For example, a di-functional high MW polymeric material can comprise two (e.g., terminal) acrylate groups, and a di-functional low MW polymeric material can comprise two (e.g., terminal) acrylate groups, or two (e.g., terminal) methacrylate groups.

[0411] For example, a di-functional high MW polymeric material can comprise two (e.g., terminal) acrylate groups, and a di-functional low MW polymeric material can comprise two (e.g., terminal) acrylate groups.

[0412] According to some of any of the embodiments described herein, the low MW polymeric material features a plurality of acrylate groups.

[0413] According to some of any of the embodiments described herein, the low MW polymeric material is a di-functional polymeric material that features two (e.g., terminal) acrylate groups.

[0414] According to some of any of the embodiments described herein, the high MW polymeric material is a di-functional polymeric material that features two terminal acrylate or methacrylate groups and the low MW polymeric material is a di-functional polymeric material that features two terminal acrylate groups.

[0415] According to some of any of the embodiments described herein, the high MW polymeric material is a di-functional polymeric material that features two terminal methacrylate groups and the low MW polymeric material is a di-functional polymeric material that features two terminal acrylate groups.

[0416] According to some of any of the embodiments described herein, the high MW polymeric material is a di-functional polymeric material that features two terminal acrylate groups and the low MW polymeric material is a di-functional polymeric material that features two terminal acrylate groups.

[0417] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) lower than 10,000 grams / mol, or lower than 8,000, or lower than 7,000, or lower then 6,000, or lower than 5,000, or lower than 4,000 grams / mol. According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) lower than 3,000 grams / mol, or lower than 2,000, grams / mol. According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) in a range of from 500 to 10,000, or from 500 to 8,000, or from 500 to 6,000, or from 500 to 5,000, or from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween.

[0418] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) in a range of from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween.

[0419] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) in a range of from 500 to 4,000, or from 500 to 3,000, or from 500 to 2,000, or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween.

[0420] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) in range of from 500 to 1,500, or from 800 to 1,200, or from 900 to 1,100, grams / mol, including any intermediate values and subranges therebetween or of about 1,000, grams / mol.

[0421] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has an average molecular weight (Mw) in range of from 1,000 to 4,000, or from 2,000 to 4,000, or from 3,000 to 4,000, or from 3,000 to 3,500, grams / mol, including any intermediate values and subranges therebetween or of about 3,400, grams / mol.

[0422] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has an average molecular weight (Mw) higher than 10,000, or higher than 15,000, or higher than 20,000, grams / mol.

[0423] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has an average molecular weight (Mw) higher than 20,000, grams / mol.

[0424] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has an average molecular weight (Mw) in a range of from 10,000 to 50,000, or from 10,000 to 40,000, or from 10,000 to 30,000, or from 10,000 to 25,000, or from 25,000 to 50,000, or from 15,000 to 40,000, or from 15,000 to 30,000, or from 15,000 to 25,000, or from 20,000 to 50,000, or from 20,000 to 40,000, or from 20,000 to 30,000 or from 20,000 to 25,000, grams / mol, including any intermediate values and subranges therebetween.

[0425] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has an average molecular weight (Mw) in a range of from 20,000 to 50,000, or from 20,000 to 40,000, or from 20,000 to 30,000 or from 20,000 to 25,000, grams / mol, including any intermediate values and subranges therebetween.

[0426] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has an average molecular weight (Mw) in a range of from 15,000 to 30,000, or from 20,000 to 30,000 or from 15,000 to 25,000, or from 20,000 to 25,000, grams / mol, including any intermediate values and subranges therebetween.

[0427] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has an average molecular weight (Mw) of about 20,000, or of about 21,000, or of about 22,000, or of about 23,000, or of about 24,000, grams / mol.

[0428] According to some of any of the embodiments described herein, each of the high and low MW polymeric materials is a biocompatible polymeric material.

[0429] According to some of any of the embodiments described herein, each of the high and low MW polymeric materials is a biodegradable polymeric material.

[0430] According to some of any of the embodiments described herein, each of the high and low MW polymeric materials is a biocompatible and biodegradable polymeric material.

[0431] According to some of any of the embodiments described herein, each of the high and low MW polymeric materials is a water-soluble or water-miscible polymeric material, and / or is included in an amount that when mixed with water in equal volumes or weights, a homogeneous solution is formed.

[0432] Herein throughout, the term “water-miscible” describes a material which is at least partially dissolvable or dispersible in water, that is, at least 50 % of the molecules move into the water upon mixture. This term encompasses the terms “water-soluble” and “water dispersible”.

[0433] Herein throughout, the term “water-soluble” describes a material that when mixed with water in equal volumes or weights, a homogeneous solution is formed.

[0434] According to some of any of the embodiments described herein, one or both of the low and high curable polymeric materials is or comprises a poly(alkylene glycol) backbone such as a poly(ethylene glycol), that features one or more photocurable group(s), for example, one or more acrylic group(s) as described herein. In some of these embodiments, the curable material can be, for example, a poly(alkylene glycol) (meth) acrylate such as a polyethylene glycol) (meth)acrylate, and / or a poly(alkylene glycol) di(meth)acrylate such as a poly(ethylene glycol) di(meth)acrylate, and / or a copolymer that comprises any of the foregoing, for example, a copolymer of poly caprolactone and poly(ethylene glycol) (meth) acrylate and / or di(meth)acrylate; a copolymer of poly(lactic acid) and poly(ethylene glycol) (meth) acrylate and / or di(meth)acrylate; a copolymer of poly(lactic acid co-glycolic acid) and poly(ethylene glycol) (meth)acrylate and / or di(meth)acrylate, including any combination of the foregoing.

[0435] As used herein, the term “alkylene glycol” describes a -O-[(CR’R”)Z-O]y- group, with R’ and R” being each independently hydrogen or alkyl, and with z being an integer of from 1 to 10, preferably, from 2 to 6, more preferably 2 or 3, and y being an integer of 1 or more. Preferably R’ and R” are both hydrogen. When z is 2 and y is 1, this group is ethylene glycol. When z is 3 and y is 1, this group is propylene glycol. When y is 2-4, the alkylene glycol is referred to herein as oligo(alkylene glycol). When y is higher than 4, it is a poly(alkylene glycol) backbone. When z is 2, R and R” are each hydrogen, and y is higher than 4, and R and it is a poly(ethylene glycol) backbone.

[0436] When a poly(alkylene) glycol such as a poly(ethylene glycol) terminates by photocurable groups such as (meth) acrylate groups, the (meth)acrylate groups are attached to each terminus of the polymeric backbone.

[0437] According to some of any of the embodiments described herein, one or both of the low and high curable polymeric materials is or comprises a poly(alkylene glycol) that features at least one (meth)acrylic group at its terminus, that is, it is a polymer or copolymer of poly(alkylene glycol) that features at least one (meth)acrylic group at its terminus.

[0438] According to some of any of the embodiments described herein, one or both of the low and high curable polymeric materials is or comprises a poly(alkylene glycol) that features two (or more) (meth)acrylic group at its terminus, that is, it is a polymer or copolymer of poly(alkylene glycol) that features two (meth)acrylic group at both of its termini.

[0439] According to some of any of the embodiments described herein, each of the low and high MW polymeric materials comprise a poly(alkylene glycol) polymeric backbone.

[0440] According to some of any of the embodiments described herein, each of the low and high MW polymeric materials comprise a poly(alkylene glycol) polymeric backbone and terminates by two (meth) acrylate groups, as described herein in any of the respective embodiments and any combination thereof.

[0441] According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a poly(alkylene glycol) that terminates by two (or more) acrylate or methacrylate groups. According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a poly(alkylene glycol) that terminates by two (or more) acrylate groups.

[0442] According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a poly(ethylene glycol) that terminates by two (or more) acrylate or methacrylate groups.

[0443] According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a polyethylene glycol) that terminates by two (or more) acrylate groups, that is, it has a poly(ethylene glycol) backbone as described herein, that terminates by two (or more) acrylate groups, preferably two acrylate groups.

[0444] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a polyethylene glycol) backbone featuring an average molecular weight (Mw) lower than 10,000 grams / mol, or lower than 8,000, or lower than 7,000, or lower then 6,000, or lower than 5,000, or lower than 4,000 grams / mol. According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a poly(ethylene glycol) backbone featuring an average molecular weight (Mw) lower than 3,000 grams / mol, or lower than 2,000, grams / mol.

[0445] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a poly(ethylene glycol) backbone featuring an average molecular weight (Mw) in a range of from 500 to 10,000, or from 500 to 8,000, or from 500 to 6,000, or from 500 to 5,000, or from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween.

[0446] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a poly(ethylene glycol) backbone featuring an average molecular weight (Mw) in a range of from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween.

[0447] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a poly(ethylene glycol) backbone featuring an average molecular weight (Mw) in a range of from 500 to 4,000, or from 500 to 3,000, or from 500 to 2,000, or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween. According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a poly(ethylene glycol) backbone featuring an average molecular weight (Mw) in range of from 500 to 1,500, or from 800 to 1,200, or from 900 to 1,100, grams / mol, including any intermediate values and subranges therebetween or of about 1,000, grams / mol.

[0448] According to some of any of the embodiments described herein, the low MW photocurable polymeric material has a poly(ethylene glycol) backbone featuring an average molecular weight (Mw) in range of from 1,000 to 4,000, or from 2,000 to 4,000, or from 3,000 to 4,000, or from 3,000 to 3,500, grams / mol, including any intermediate values and subranges therebetween or of about 3,400, grams / mol.

[0449] According to some of any of the embodiments described herein, the high MW photocurable polymeric material comprises a poly(alkylene glycol) polymeric backbone as described herein and terminates by two (or more) acrylate or methacrylate groups, as described herein.

[0450] According to some of these embodiments, an average molecular weight of the poly (alkylene glycol) polymeric backbone is higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol.

[0451] According to some of these embodiments, an average molecular weight of the poly (alkylene glycol) polymeric backbone ranges from 10,000 to 40,000, or from 10,000 to 30,000, or from 15,000 to 40,000, or from 15,000 to 30,000, or from 20,000 to 40,000, or from 20,000 to 30,000, or from 15,000 to 25,000, or from 20,000 to 25,000, grams / mol, including any intermediate values and subranges therebetween.

[0452] According to some of these embodiments, an average molecular weight of the poly(alkylene glycol) polymeric backbone ranges from 15,000 to 30,000, or from 20,000 to 30,000, or from 15,000 to 25,000, or from 20,000 to 25,000, grams / mol, including any intermediate values and subranges therebetween.

[0453] According to some of these embodiments, an average molecular weight of the poly(alkylene glycol) polymeric backbone is about 20,000, or about 21,000, or about 22,000, or about 23,000, grams / mol.

[0454] According to some of any of the embodiments described herein, the high MW photocurable polymeric material has a polymeric backbone which is a co-polymer of a high MW poly(alkylene glycol), e.g., a high MW poly(ethylene glycol) as described herein in any of the respective embodiments, and an additional polymeric material, that is, the polymeric backbone comprises backbone units of a poly(alkylene glycol) such as poly(ethylene glycol) and backbone units of an additional polymeric material, and the MW of the polymeric backbone is as described herein for the high MW polymeric material. In some of these embodiments, the co-polymeric material comprises one or more, preferably two or more photocurable groups as described herein, and in some embodiments, it is a linear co-polymer terminates at each terminus by a photocurable group as described herein (e.g., acrylate or methacrylate).

[0455] According to some of any of these embodiments, the additional polymeric material is a biodegradable polymer other than poly(alkylene glycol).

[0456] According to some of any of these embodiments, the additional polymeric material is a biodegradable polymer other than poly (alkylene glycol), which features degradation rate higher than that of poly(ethylene glycol).

[0457] According to some of any of these embodiments, the additional polymeric material is a polyester or a copolymer thereof.

[0458] Exemplary polyesters include, without limitation, poly(lactic acid), poly(caprolactones), and poly(lactic acid-glycolic acid).

[0459] According to some of any of these embodiments, the additional polymeric material is or comprises poly(caprolactones), which is abbreviated herein as PCL.

[0460] According to some of any of these embodiments, the high MW photocurable polymeric material is a copolymer which is a block copolymer, as described herein.

[0461] According to some of any of these embodiments, the high MW photocurable polymeric material is a copolymer which is a block copolymer, as described herein, which comprises one or more blocks of a poly(alkylene glycol) such as poly(ethylene glycol) and one or more blocks of an additional polymeric material as described herein in any of the respective embodiments.

[0462] According to some of any of these embodiments, the high MW photocurable polymeric material is a copolymer which is a block copolymer, as described herein, which comprises one or more blocks of a poly(alkylene glycol) such as poly(ethylene glycol) and one or more blocks of a polyester as described herein in any of the respective embodiments.

[0463] According to some of any of these embodiments, the high MW photocurable polymeric material is a copolymer which is a block copolymer, as described herein, which comprises one or more blocks of a poly(alkylene glycol) such as poly(ethylene glycol) and one or more blocks of PCL.

[0464] According to some of any of these embodiments, the high MW photocurable polymeric material is a copolymer which is a block copolymer, as described herein, and comprises at least one of a poly(alkylene glycol) that features a high MW as described herein in any of the respective embodiments, that is, higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol, as described herein in any of the respective embodiments. According to some of any of these embodiments, the high MW photocurable polymeric material is a copolymer which is a block copolymer, as described herein, and comprises a poly(alkylene glycol) that features a high MW as described herein in any of the respective embodiments, that is, higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol, as described herein in any of the respective embodiments, and one or more blocks of the additional polymeric material, for example, one or more blocks of PCL.

[0465] According to some of these embodiments, an average molecular weight of each of the one or more blocks of the additional polymeric material (e.g., PCL) is lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol.

[0466] According to some of these embodiments, an average molecular weight of each of the one or more blocks of the additional polymeric material (e.g., PCL) ranges from 500 to 5,000, or fro, 500 to 4,000, or from 500 to 3,000, or from 500 to 2,000, or from 1,000 to 5,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, grams / mol, including any intermediate values and subranges therebetween.

[0467] According to some of any of these embodiments, the high MW photocurable polymeric material is a tri-block co-polymer that comprises the poly(alkylene glycol) polymeric backbone as a middle block having attached to its termini two additional blocks, each comprising a polymeric backbone of a biodegradable polymer other than poly(alkylene glycol) that terminates by a photocurable group.

[0468] According to some of the embodiments that relate to a tri-block co-polymer, an average MW of the poly (alkylene glycol) middle block higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol, as described herein in any of the respective embodiments, for example, is in a range of from 10,000 to 40,000, or from 10,000 to 30,000, or from 15,000 to 40,000, or from 15,000 to 30,000, or from 20,000 to 40,000, or from 20,000 to 30,000, or from 15,000 to 25,000, or from 20,000 to 25,000, or from 15,000 to 20,000, or from 18,000 to 22,000, grams / mol, including any intermediate values and subranges therebetween. According to some of these embodiments, an average MW of the poly(alkylene glycol) middle block is 15,000, or 16,000, or 17,000, or 18,000, or 20,000, or 21,000 or 22,000 or 23,000, grams / mol.

[0469] According to some of the embodiments that relate to a tri-block co-polymer, an average molecular weight of the one or more blocks of the additional polymeric material (e.g., PCL) is independently lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol.

[0470] According to some of the embodiments that relate to a tri-block co-polymer, an average molecular weight of the one or more blocks of the additional polymeric material (e.g., PCL) is independently is a range of from 500 to 5,000, or fro, 500 to 4,000, or from 500 to 3,000, or from 500 to 2,000, or from 1,000 to 5,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, grams / mol, including any intermediate values and subranges therebetween.

[0471] According to some of the embodiments that relate to a block co-polymer, whenever it comprises two or blocks other than poly(alkylene glycol), these blocks can be the same or different. When different, the blocks can differ in the average MW (Mw) and / or in the type of the polymeric material. In some embodiments, whenever a block co-polymer comprises two or blocks other than poly(alkylene glycol), these blocks are the substantially the same.

[0472] According to some of any of the embodiments described herein, the high MA photocurable polymeric material is a triblock polymeric material that comprises a poly(alkylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol, as described herein in any of the respective embodiments, and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by at least one (meth) acrylate group.

[0473] According to some of any of the embodiments described herein, the high MA photocurable polymeric material is a triblock polymeric material that comprises a poly(alkylene glycol) polymeric backbone having a MW in a range of from 10,000 to 30,000, or from 15,000 to 30,000, or from 20,000 to 30,000, or from 15,000 to 25,000, or from 20,000 to 25,000, or from 15,000 to 20,000, or from 18,000 to 22,000, grams / mol, including any intermediate values and subranges therebetween, and having attached to each of its termini a block of a polyester (e.g., PCL) having a MW independently is a range of from 500 to 3,000, or from 500 to 2,000, or from 1,000 to 2,000, grams / mol, including any intermediate values and subranges therebetween, and terminating by at least one (meth) acrylate group.

[0474] A tri-block copolymer of poly(ethylene glycol) and PCL can be readily synthesized by reacting 2 mol equivalents e-caprolactone with 1 mol equivalent of poly(ethylene glycol) that features a high MW as described herein, in the presence of a catalysts usable for polymerizing caprolactones (e.g., tin octanoate), to thereby obtain the tri-block copolymer that terminates by hydroxy groups, and reacting this tri-block copolymer with chloroacrylate or metharylate under suitable conditions.

[0475] As exemplary structure of a high MW tri-block copolymer is as follows: wherein n and m are such that provide respective values of an average MW of the poly(ethylene glycol) (PEG) and of the PCL. According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a poly(alkylene glycol), such as poly(ethylene glycol) that terminates by two of the acrylate or methacrylate groups, preferably acrylate groups, and has an average molecular weight that ranges from 500 to 10,000, or from 500 to 8,000, or from 500 to 6,000, or from 500 to 5,000, or from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween; and the high MW photocurable material is a triblock polymeric material that comprises a poly(alkylene glycol) such as poly(ethylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by the (meth)acrylate group.

[0476] According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a poly(alkylene glycol), such as poly(ethylene glycol) that terminates by two of the acrylate or methacrylate groups, preferably acrylate groups, and has an average molecular weight that ranges from 1,000 to 5,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween; and the high MW photocurable material is a triblock polymeric material that comprises a poly(alkylene glycol) such as poly(ethylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by the (meth)acrylate group.

[0477] According to some of any of the embodiments described herein, the low MW photocurable polymeric material is a poly(alkylene glycol), such as poly(ethylene glycol) that terminates by two of the acrylate or methacrylate groups, preferably acrylate groups, and has an average molecular weight that ranges from 500 to 10,000, or from 500 to 8,000, or from 500 to 6,000, or from 500 to 5,000, or from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, or from 500 to 2,000 or from 500 to 1,500, grams / mol, including any intermediate values and subranges therebetween; and the high MW photocurable material is a triblock polymeric material that comprises a poly(alkylene glycol) such as poly(ethylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol, as described herein in any of the respective embodiments, and having attached to each of its termini a block of a polyester such as PCL having a MW in a range of from 500 to 3,000, or from 500 to 2,000, or from 1,000 to 2,000, grams / mol, including any intermediate values and subranges therebetween, and terminating by the (meth)acrylate group.

[0478] The formulations described herein may further comprise a photoblocker.

[0479] According to some of any of the embodiments described herein, the photoblocker is such that is capable of absorbing light at a wavelength of from 300 nm to 800 nm, or from 300 nm to 600 nm, or from 300 nm to 500 nm, or from 300 nm to 450 nm, or from 350 nm to 450 nm, or preferably from 365 nm to 405 nm. In exemplary embodiments, the photoabsorber is such that is capable of absorbing light at a wavelength of 385nm. In exemplary embodiments, the photoblocker is such that is capable of absorbing light at a wavelength of at 365 nm.

[0480] According to some embodiments of the present invention, the photoblocker is naturally occurring. According to some embodiments of the present invention, the photoblocker is water soluble. According to some embodiments of the present invention, the photoblocker is chemically stable prior to and post curing in the absence or presence of a photoinitator. According to some embodiments of the present invention, the photoblocker is compatible with and chemically stable in the composition. According to some embodiments of the present invention, the photoblocker is chemically stable meaning it is not oxidized and / or degraded within less than a day, and in some cases, in less than an hour upon exposure to air, light, acidic solution, or water under ambient conditions. According to some embodiments of the present invention, the photoblocker is free of a plurality of negatively-charged groups (functional groups that are ionizable at physiological pH or at the pH of the bioink composition comprising same). Exemplary negatively charged groups include, but are not limited to, hydroxy, sulfate, sulfonate, thiol, phosphate, phosphonate, and the like. Exemplary photoblockers that feature a plurality of negatively charged groups are poly sulfate dyes.

[0481] Exemplary photoblockers that are known in the art suitable for use in the context of these embodiments include, but are not limited to, food dyes, tartrazine, Sunset Yellow FCF (Yellow No. 6), Brilliant Blue FCF (FD&C Blue No. 1), indigo carmine (FD&C Blue No. 2), Fast Green FCF (FD&C Green No. 3) anthocyanins, anthocyanidin, erythrosine (FD&C Red No. 3), Allura Red AC (FD&C Red No. 40), riboflavin (Vitamin B2, E101, ElOla, E106), ascorbic acid (vitamin C), Quinoline Yellow WS, carmoisine (azorubine), Ponceau 4R (E124), Patent Blue V (E131), Green S (E142), Yellow 2G (E107), Orange GGN (El 11), Red 2G (E128), caramel color, phenol red, methyl orange, 4-nitrophenol, and NADH disodium salt, curcumin (E100), turmeric, alpha carotene, beta carotene, canthaxanthin (keto-carotenoid), cochineal extract, paprika, saffron, ergocalciferol (vitamin D2), cholecalciferol (vitamin D3), Citrus Red 2, annatto extract, avobenzone, 2,5-bis(5-tert-butyl-benzoxazol-2-yl)thiophene (Benetex OB+), disodium 4,4'-bis(2- sulfonatostyryl)biphenyl (Benetex 0B-M1), benzenepropanoic acid (BLS 99-2), 2, 3,6,7- tetrahydro-9-methyl-lH,5H-quinolizino(9,l-gh)coumarin (Coumarin 102), Martins Yellow, morin hydrate, nitrofurazone, 2-nitrophenyl phenyl sulfide (NPS), 5,12-naphthacenequinone (NTAQ), octocrylene, phenazine, l,4-bis-(2-(5-phenyloxazolyl))-benzene (POPOP), Quinoline Yellow, 3,3',4',5,6-pentahydroxyflavone (Quercetin), salicylaldehyde, Sudan I, triamterene, UV386A, 1- phenylazo-2-naphthol (sudan I), l-(2,4-dimethylphenylazo)-2-naphthol (sudan II), l-(4- (phenyldiazenyl)phenyl) azonaphthalen-2-ol (sudan III), l-[{2-methyl-4-[(2- methylphenyl)diazenyl]phenyl}diazenyl]naphthalen-2-ol (sudan IV), 2,5-bis(5-tert-butyl- benzoxazol-2-yl)thiophene, fluorescein, poly(3-hexylthiophene-2,5-diyl), oligothiophenes, triphenylamines, diketopyrrolopyrroles derivatives, 2,5-dihydro-3,6-di-2-thienyl-pyrrolo[3,4- c]pyrrole- 1,4-dione, borondipyrromethenes derivatives, l,3,5,7-tetramethyl-8-phenyl-4,4- difluoroboradiazaindacene, 2,2'-(2,5-thiophenediyl)bis(5-tert-butylbenzoxazole), (±)-a- tocopherol, 2-phenyl-2H-benzotriazole derivatives, 2,2-dimethyl-l,3-dihydroperimidin-6-yl)-(4- phenylazo-l-naphthyl)diazene (sudan black B), l-(2-methoxyphenylazo)-2-naphthol (sudan red G), 2,5-bis(5-tert-butyl-benzoxazol-2-yl)thiophene, 4-methoxyphenol, butylated hydroxytoluene, 2-hydroxyphenyl-s-triazine, 2-(2H-benzotriazol-2-yl)phenol, and any combination thereof.

[0482] According to some embodiments, exemplary photoblockers that are usable in the context of the present embodiments can be collectively represented by Formula III:

[0483] Formula III wherein:

[0484] Re, R7, Rs, R9 and Rio are each independently hydrogen; and

[0485] Ri, R2, R3, R4 and R5 are each independently selected from hydrogen, hydroxyalkyl and a saccharide moiety.

[0486] The term “saccharide” as used herein encompasses monosaccharides, disaccharides and oligosaccharides. The term "monosaccharide", as used herein and is well known in the art, describes a simple form of a sugar that consists of a single saccharide molecule, which can be open-chain or cyclic (e.g., pyranose- or furanose-based), and which cannot be further decomposed by hydrolysis. Most common examples of monosaccharides include glucose (dextrose), fructose, galactose, and ribose. Monosaccharides can be classified according to the number of carbon atoms of the carbohydrate, i.e., triose, having 3 carbon atoms such as glyceraldehyde and dihydroxyacetone; tetrose, having 4 carbon atoms such as erythrose, threose and erythrulose; pentose, having 5 carbon atoms such as arabinose, lyxose, ribose, xylose, ribulose and xylulose; hexose, having 6 carbon atoms such as allose, altrose, galactose, glucose, gulose, idose, mannose, talose, fructose, psicose, sorbose, rhamnose and tagatose; heptose, having 7 carbon atoms such as mannoheptulose, sedoheptulose; octose, having 8 carbon atoms such as 2-keto-3-deoxy-manno- octonate; nonose, having 9 carbon atoms such as sialose; and decose, having 10 carbon atoms. Monosaccharides are the building blocks of oligosaccharides and disaccharides like sucrose (common sugar).

[0487] The term “disaccharide” describes a compound two monosaccharide units, which can be the same or different, covalently bound to one another, typically via a glucosyl bond. Examples include sucrose and maltose.

[0488] The term “oligosaccharide” as used herein describes a compound that comprises three or more monosaccharide units, as these are defined herein, which can be the same or different. Preferably, the oligosaccharide comprises 3-6 monosaccharides units.

[0489] According to some of any of the embodiments described herein for Formula III, the saccharide moiety is a monosaccharide moiety or a disaccharide moiety.

[0490] According to some of any of the embodiments described herein for Formula III, the saccharide moiety, whether a monosaccharide or a disaccharide, comprises a glucose moiety.

[0491] According to some of any of the embodiments described herein for Formula III, the saccharide moiety is a disaccharide moiety.

[0492] According to some of any of the embodiments described herein for Formula III, the saccharide moiety is a disaccharide moiety and one of the saccharides is glucose. According to some of any of the embodiments described herein for Formula III, the saccharide moiety is a disaccharide moiety that comprises glucose and rhamnose.

[0493] According to some of any of the embodiments described herein for Formula III, the saccharide moiety is rutinose: wherein the dashed line represents the attachment point to the respective oxygen in Formula I.

[0494] According to some of any of the embodiments described herein for Formula III, R3 is the saccharide moiety, as described herein in any of the respective embodiments.

[0495] According to some of any of the embodiments described herein for Formula III, R3 is a disaccharide moiety that comprises glucose.

[0496] According to some of any of the embodiments described herein for Formula III, R3 is rutinose.

[0497] According to some of any of the embodiments described herein for Formula III, Ri is hydrogen.

[0498] According to some of any of the embodiments described herein for Formula III, R2, R4 and Rs are each hydrogen.

[0499] According to some of any of the embodiments described herein for Formula III, Ri, R2, R4 and R5 are each hydrogen and R3 is a saccharide moiety as described herein. According to some of these embodiments, R3 is a disaccharide moiety that comprises glucose.

[0500] According to some of these embodiments, R3 is rutinose, and the photoblocker is 3- glucoside quercetin:

[0501] 3-glucoside quercetin.

[0502] According to some of any of the embodiments described herein for Formula III, at least one of Ri, R2, R4 and R5 is hydroxy alkyl.

[0503] Herein and in the art, the term “alkyl” describes any saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever a numerical range; e.g., “1 to 20”, is stated herein, it implies that the group, in this case the hydrocarbon, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. Preferably, the alkyl is a medium size alkyl having 1 to 10 carbon atoms. Most preferably, unless otherwise indicated, the alkyl is a lower alkyl having 1 to 4 carbon atoms. The alkyl group may be substituted or non-substituted.

[0504] Herein, a “hydroxyalkyl” describes an alkyl, as defined herein, preferably a lower alkyl of 1 to 4 carbon atoms, which is substituted by one or more hydroxy (-OH) substituents. Preferably, the term “hydroxyalkyl” refers to an alkyl that is terminated by a hydroxy substituent, that is, the hydroxy substituent is a substituent of a terminal carbon atom of the alkyl substituent.

[0505] In some embodiments, the hydroxyalkyl comprises one hydroxy substituent on the terminal carbon atom of the alkyl, and the alkyl is otherwise not substituted.

[0506] In some embodiments, the hydroxyalkyl is hydroxyethyl, -CH2-CH2-OH. Alternatively, the hydroxyalkyl can be hydroxymethyl, hydroxybutyl or hydroxypropyl.

[0507] According to some of any of the embodiments described herein for Formula III, at least two or at least three of Ri, R2, R4 and R5 are each independently a hydroxy alkyl.

[0508] According to some of any of the embodiments described herein for Formula III, at least two or at least three of Ri, R2, R4 and R5 are each hydroxy ethyl.

[0509] According to some of any of the embodiments described herein for Formula III, Ri is hydrogen and one, two or all of R2, R4 and R5 are each a hydroxyalkyl such as hydroxyethyl.

[0510] According to some of any of the embodiments described herein for Formula III, Ri is hydrogen and each of R2, R4 and R5 is independently a hydroxyalkyl such as hydroxyethyl. According to some of any of the embodiments described herein for Formula III, Ri is hydrogen and each of R2, R4 and R5 is hydroxyethyl. According to some of these embodiments, R3 is a saccharide moiety as described herein. According to some of these embodiments, R3 is a disaccharide moiety that comprises glucose. According to some of these embodiments, R3 is rutinose, and the photoblocker is troxerutin.

[0511] Troxerutin.

[0512] According to some embodiments, the photoblocker is an analog of HC yellow 9, featuring the following structure or a salt thereof (e.g., HC1 salt):

[0513] Wherein Rx and Ry are each independently selected from hydrogen (H), alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), cycloalkyl and aryl; and Rz is an alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), aryl or cycloalkyl.

[0514] According to some embodiments, the photoblocker is HC yellow 9, featuring the following structure or a salt thereof (e.g., HC1 salt).

[0515] The photoblockers described herein, are capable of absorbing light at a wavelength suitable for curing (hardening) a curable formulation of interest.

[0516] According to some of any of the embodiments described herein, the photoblockers described herein are capable of absorbing light at a wavelength at the UV-visual range (e.g. in a range of from 300 nm to 800 nm, or from 300 nm to 600 nm, or from 300 nm to 500 nm, or from 350 nm to 450 nm, or, for example, at 385 or at 405 nm).

[0517] In one embodiment, the photoblocker features an absorbance at the wavelength at which the curable formulation is irradiated and subsequently crosslinks or hardens.

[0518] Preferably, the absorbance does not significantly change in the presence of a selected photoinitiator (as further described herein below) following irradiation at the selected wavelength.

[0519] According to some embodiments, a significant change is a change of no more than 50 %, no more than 40 %, no more than 30 %, no more than 25 %, no more than 20 %, no more than 15 %, no more than 10 %, no more than 5 %, in absorbance following the irradiation.

[0520] In still another embodiment, the photoblockers described herein are soluble in an aqueous carrier. According to some of any of the embodiments, the photoblockers are water-soluble, as defined herein. According to some of any of the embodiments, the photblockers are water- miscible, as defined herein.

[0521] Herein throughout, the term “water-miscible” describes a material which is at least partially dissolvable or dispersible in water, that is, at least 50 % of the molecules move into the water upon mixture. This term encompasses the terms “water-soluble” and “water dispersible”.

[0522] Herein throughout, the term “water-soluble” describes a material that when mixed with water in equal volumes or weights, a homogeneous solution is formed.

[0523] For example, the photoblockers described herein feature solubility of at least 0.05, or at least 1, or at least 10, mg / mL in water and / or in the selected carrier.

[0524] The photoblockers described herein are biocompatible (e.g., non-toxic, preferably recognized as safe for use by animated subjects). According to a particular embodiment, the photoblocker is Troxerutin (TR).

[0525] TR is commercially available from a variety of sources including, but not limited to ChemSene, Angene (e.g. Lot No. AG00397y), Merk and AA Blocks (e.g., Cat. No.:AA00IC16).

[0526] According to a particular embodiment, the photoblocker is 3-P-D-Glucosylquercetin (GQ).

[0527] GQ is commercially available from a variety of sources including, but not limited to Angene (e.g. Lot No. AGN23-14582181), Merk and AA Blocks.

[0528] According to some embodiments, the photoblocker is an analog of HC yellow 9, featuring the following structure or a salt thereof (e.g., HC1 salt):

[0529] Wherein Rx and Ry are each independently selected from hydrogen (H), alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), cycloalkyl and aryl; and Rz is an alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), aryl or cycloalkyl.

[0530] According to a particular embodiment, the photoblocker is HC yellow no. 9 (HC9).

[0531] HC9 is commercially available from a variety of sources including, but not limited to Merk, ChemSene and Angene.

[0532] Exemplary formulations contemplated by the present invention for HC9 as the photoblocker are provided in Tables B-I herein below.

[0533] Each of the formulations provided in the tables further comprises a carrier. In one or more embodiments the carrier is an aqueous or hydrophilic carrier. In one or more embodiments, the carrier is a basic aqueous solution, a neutral aqueous solution e.g., PBS, or an acidic aqueous solution e.g., HC1. In some embodiments the carrier is an emulsion. In some embodiments the carrier is a microemulsion. In some embodiments the carrier is a nanoemulsion. In one or more embodiments the collagen is methacrylated to any degree (e.g., 50 % or 90 %). In one or more embodiments the collagen is lyophilized. According to a particular embodiment, the collagen is plant-derived recombinant collagen. In one or more embodiments, the photoinitiator is a salt of an acylphosphonate e.g., LAP or NAP.

[0534] Table B

[0535] Table C

[0536] Table D Table E Table F

[0537] Table G Table H

[0538] Table I

[0539] Exemplary formulations contemplated by the present invention for HC9 as the photoblocker and which do not include synthetic polymeric materials are provided in Tables J-U hereinbelow. In one or more embodiments the carrier is an aqueous or hydrophilic carrier. In one or more embodiments, the carrier is a basic aqueous solution, a neutral aqueous solution e.g., PBS, or an acidic aqueous solution e.g. HC1. In some embodiments the carrier is an emulsion. In some embodiments the carrier is a microemulsion. In some embodiments the carrier is a nanoemulsion. In one or more embodiments the collagen is methacrylated to any degree (e.g., 50 % or 90 %). In one or more embodiments the collagen is lyophilized. According to a particular embodiment, the collagen is plant-derived recombinant collagen. In one or more embodiments, the photoinitiator is a salt of an acylphosphonate e.g., LAP or NAP.

[0540] Table J Table K

[0541] Table L

[0542] Table M Table N

[0543] Table O

[0544] Table P

[0545] Table Q

[0546] Table R Table S

[0547] Table T

[0548] Table U

[0549] Exemplary formulations contemplated by the present invention for GQ as the photoblocker are provided in Tables V-Y herein below. In one or more embodiments, GQ is dissolved in a polar solvent (e.g., ethanol). Each of formulations provided in the tables further comprises a carrier. In one or more embodiments, the carrier is a basic aqueous solution, a neutral aqueous solution e.g., PBS, or an acidic aqueous solution e.g., HCL. In some embodiments the carrier is an emulsion. In some embodiments the carrier is a microemulsion. In some embodiments the carrier is a nanoemulsion. In one or more embodiments the collagen is methacrylated to any degree (e.g. 50 % or 90 %). In one or more embodiments the collagen is lyophilized. According to a particular embodiment, the collagen is plant-derived recombinant collagen. In one or more embodiments, the photoinitiator is a salt of an acylphosphonate e.g., LAP or NAP. Table V (corresponds to A in Examples)

[0550] Table W(corresponds to B in Examples) Table X (corresponds to F24 in Examples)

[0551] Table Y (corresponds to F26 in Examples)

[0552] Exemplary formulations contemplated by the present invention for TR as the photoblocker are provided in Tables Z-AB hereinbelow. Each of formulations provided in the tables further comprises a carrier. In one or more embodiments, the carrier is a basic aqueous solution, a neutral aqueous solution e.g., PBS or an acidic aqueous solution, e.g., HCL. In some embodiments the carrier is an emulsion. In some embodiments the carrier is a microemulsion. In some embodiments the carrier is a nanoemulsion. In one or more embodiments the collagen is methacrylated to any degree (e.g. 50 % or 90 %). In one or more embodiments the collagen is lyophilized. According to a particular embodiment, the collagen is plant-derived recombinant collagen. In one or more embodiments, the photoinitiator is a salt of an acylphosphonate e.g., LAP or NAP.

[0553] Table Z (corresponds to A A in Examples)

[0554] Table AA (corresponds to F23 in Examples)

[0555] Table AB (corresponds to F25 in Examples)

[0556] As mentioned, according to some of any of the embodiments described herein, the curable formulation further comprises a carrier and in some embodiments, the carrier is an aqueous carrier. In some embodiments the carrier is a hydrophilic carrier. In some embodiments the carrier is an emulsion. In some embodiments the carrier is an microemulsion. In some embodiments the carrier is a nanoemulsion.

[0557] The aqueous carrier can be water, a buffer featuring pH in a range of from about 2 to about 10, or from about 2 to about 9, or from about 3 to about 9, or from about 3 to about 8, a basic aqueous solution, a neutral aqueous solution or an acidic aqueous solution.

[0558] The aqueous carrier can comprise salts and other water-soluble materials at varying concentrations. In some embodiments, a concentration of a salt in the carrier ranges from about 0.1 mM to about 0.2 M, or from about 0.1 mM to about 0.1 M, or from about 0.1 mM to about 100 mM, or from about 0.1 mM to about 50 mM, or from about 0.1 mM to about 20 mM, including an intermediate values and subranges therebetween. In some embodiments, the aqueous carrier comprises salts at physiologically acceptable concentrations, such that the formulation features osmolarity around a physiological osmolarity.

[0559] In some embodiments the aqueous carrier comprises a phosphate salt, for example, a sodium phosphate monobasic (NaFEPCk) and / or a sodium phosphate dibasic (sodium hydrogen phosphate; NaiHPC ). In some embodiments, the total concentration of the phosphate salt(s) in the formulation is about 0.1 M.

[0560] In some embodiments, the aqueous carrier comprises NaCl or any other physiologically acceptable salt.

[0561] In some embodiments, the aqueous carrier comprises a phosphate buffer and in some embodiments, the aqueous carrier comprises a phosphate buffer saline, which comprises sodium phosphate monobasic and / or sodium phosphate dibasic and NaCl or any other physiologically acceptable salt.

[0562] The phosphate buffer saline (PBS) can be a commercially available PBS (e.g., DPBS) or a custom-made buffer featuring a desirable pH and / or osmolarity.

[0563] In exemplary embodiments, the aqueous carrier comprises a phosphate buffer that comprises a phosphate sodium salt as described herein at a concentration of about 0.1M and NaCl at a concentration of from about 0.01 mM to about 200 mM, including any intermediate value and subranges therebetween.

[0564] Any other buffers are also usable in the context of the present embodiments.

[0565] In some of any of the embodiments described herein, the aqueous carrier comprises an acid.

[0566] In some embodiments, a concentration of the acid is lower than 100 mM, and can be, for example, of from 0.1 mM to 50 mM, or from 0.1 mM to 30 mM, or from 0.1 mM to 40 mM, or from 0.1 mM to 30 mM, or from 1 to 30 mM, or from 10 to 30 mM, including any intermediate values and subranges therebetween.

[0567] The acid can be an inorganic acid (e.g., HC1) or an organic acid, preferably which is water soluble at the above-indicated concentrations (e.g., acetic acid).

[0568] In some of any of the embodiments described herein, the aqueous carrier comprises a culturing medium. The culturing medium can be a commercially available culturing medium or a custom-made culturing medium. The culture medium can be any liquid medium which allows at least cell survival. Such a culture medium can include, for example, salts, sugars, amino acids and minerals in the appropriate concentrations and with various additives and those of skills in the art are capable of determining a suitable culture medium to specific cell types. Non-limiting examples of such culture medium include, phosphate buffered saline, DMEM, MEM, RPMI 1640, McCoy’s 5A medium, medium 199 and IMDM (available e.g., from Biological Industries, Beth Ha’emek, Israel; Gibco-Invitrogen Corporation products, Grand Island, NY, USA).

[0569] The culture medium may be supplemented with various antibiotics (e.g., Penicillin and Streptomycin), growth factors or hormones, specific amino acids (e.g., L-glutamin) cytokines and the like.

[0570] According to some of any of the embodiments described herein, the printing media (building material) in general or the curable formulation as described herein in particular further comprises a biological component or material other than the biocompatible curable material(s) (collectively referred to herein also as a biological material). According to some of any of the embodiments described herein, the biological component or material is included in an injectable filler and optionally further included in the printing media (building material).

[0571] Biological components or materials that can be included in one or more curable (e.g., modeling material) formulations as described herein or injectable fillers include cellular components, including, for example, culturing cells, and other cellular components such as cytokines, chemokines, growth factors; as well as other biological components such as proteins, agents that act to increase cell attachment, cell spreading, cell proliferation, cell differentiation and / or cell migration; an amino acid, peptides, polypeptides, proteins, DNA, RNA, lipids and / or proteoglycans.

[0572] Cells may comprise a heterogeneous population of cells or alternatively the cells may comprise a homogeneous population of cells. Such cells can be for example stem cells (such as embryonic stem cells, bone marrow stem cells, cord blood cells, mesenchymal stem cells, adult tissue stem cells), progenitor cells, or differentiated cells such as chondrocytes, osteoblasts, connective tissue cells (e.g., fibrocytes, fibroblasts and adipose cells), endothelial and epithelial cells. The cells may be naive or genetically modified.

[0573] According to one embodiment of this aspect of the present invention, the cells are mammalian in origin.

[0574] Furthermore, the cells may be of autologous origin or non- autologous origin, such as postpartum-derived cells (as described in U.S. Application Nos. 10 / 887,012 and 10 / 887,446). Typically, the cells are selected according to the desired application.

[0575] Suitable proteins which can be used include, but are not limited to, extracellular matrix proteins [e.g., fibrinogen, collagen, fibronectin, vimentin, microtubule-associated protein ID, Neurite outgrowth factor (NOF), bacterial cellulose (BC), laminin and gelatin], cell adhesion proteins [e.g., integrin, proteoglycan, glycosaminoglycan, laminin, intercellular adhesion molecule (ICAM) 1, N-CAM, cadherin, tenascin, gicerin, RGD peptide and nerve injury induced protein 2 (ninjurin2)], growth factors [epidermal growth factor, transforming growth factor-a, fibroblast growth factor-acidic, bone morphogenic protein, fibroblast growth factor-basic, erythropoietin, thrombopoietin, hepatocyte growth factor, insulin-like growth factor-I, insulin-like growth factor-II, Interferon-P, platelet-derived growth factor, Vascular Endothelial Growth Factor and angiopeptin], cytokines [e.g., M-CSF, IF-lbeta, IE-8, beta-thromboglobulin, EMAP-II, G- CSF and IL- 10], proteases [pepsin, low specificity chymotrypsin, high specificity chymotrypsin, trypsin, carboxypeptidases, aminopeptidases, proline-endopeptidase, Staphylococcus aureus V8 protease, Proteinase K (PK), aspartic protease, serine proteases, cysteine proteases, metalloproteases, AD AMTS 17, tryptase-gamma, and matriptase-2] and protease substrates.

[0576] In addition, calcium phosphate materials, such as hydroxyapatite, for example, in a form of particles, can be used, including, but not limited to, nanoHA and nanoTCP. When the AM process involves dispensing the curable formulation through dispensing heads, the particles size should be compatible with the dispensing heads so as to avoid clogging.

[0577] Non-curable materials, other than the biological materials as described herein, that can be included in one or more curable (e.g., modeling material) formulations as described herein can be materials that impart a certain property to the formulation or to the hardened formulation or material and to the part of the object formed thereby. Such a property can be a physical property (e.g., an optical property such as transparency or opacity, color, a spectral property, heat resistance, electrical property and the like), or a mechanical or rheological property such as viscosity, elasticity, storage modulus, loss modulus, stiffness, hardness, and the like. Alternatively, or in addition, non-curable materials can be such that provide a biological function, for example, therapeutically active agents.

[0578] Exemplary non-curable materials include thixotropic agents, reinforcing agents, toughening agents, fillers, colorants, pigments, dye substances (e.g., as described herein), etc.

[0579] An exemplary non-curable material includes titanium dioxide.

[0580] An exemplary non-curable material includes oxidized cellulose.

[0581] According to some of any of the embodiments described herein, one or more of the curable (e.g., modeling material) formulations comprises hyaluronic acid.

[0582] According to some of any of the embodiments described herein, one or more of the curable (e.g., modeling material) formulations comprises hyaluronic acid featuring a curable group as defined herein.

[0583] According to some of any of the embodiments described herein, the curable formulation provides, when hardened or cured, a hydrogel material, formed upon cross-linking the photocurable materials within an aqueous carrier such as described herein. Herein and in the art, the term “hydrogel” describes a three-dimensional fibrous network containing at least 20 %, typically at least 50 %, or at least 80 %, and up to about 99.99 % (by mass) water. A hydrogel can be regarded as a material which is mostly water, yet behaves like a solid or semi-solid due to a three-dimensional crosslinked solid-like network, made of polymeric chains (e.g., collagen chains), within the liquid dispersing medium. The polymeric chains are inter-connected (crosslinked) by chemical bonds (covalent, hydrogen and ionic / complex / metallic bonds, typically covalent bonds).

[0584] Herein throughout, whenever polymeric chains or a polymeric material is described, it encompasses a polymeric biological materials (e.g., macromolecules) such as peptides, proteins, oligonucleotides and nucleic acids.

[0585] Hydrogels may take a physical form that ranges from soft, brittle and weak to hard, elastic and tough material. Soft hydrogels may be characterized by rheological parameters including elastic and viscoelastic parameters, while hard hydrogels are suitably characterized by tensile strength parameters, elastic, storage and loss moduli, as these terms are known in the art.

[0586] The softness / hardness of a hydrogel is governed inter alia by the chemical composition of the polymer chains, the “degree of cross-linking” (number of interconnected links between the chains), the aqueous media content and composition, and temperature.

[0587] A hydrogel, according to some embodiments of the present invention, may contain macromolecular polymeric and / or fibrous elements which are not chemically connected to the main crosslinked network but are rather mechanically intertwined therewith and / or immersed therein. Such macromolecular fibrous elements can be woven (as in, for example, a mesh structure), or non-woven, and can, in some embodiments, serve as reinforcing materials of the hydrogel’s fibrous network. Non-limiting examples of such macromolecules include polycaprolactone, gelatin, cross-linked gelatin formed of, for example, gelatin methacrylate, alginate, cross-linked alginate formed of, for example, alginate methacrylate, chitosan, crosslinked chitosan formed of, for example, chitosan methacrylate, glycol chitosan, cross-linked glycol chitosan from of, for example, glycol chitosan methacrylate, hyaluronic acid (HA), cross-linked hyaluronic acid form of, for example, HA methacrylate, and other cross-linked or non-crosslinked natural or synthetic polymeric chains and the likes. Alternatively, or in addition, such macromolecules are chemically connected to the main crosslinked network of the hydrogel, for example, by acting as a cross-linking agent, or by otherwise forming a part of the three- dimensional network of the hydrogel.

[0588] In some embodiments, the hydrogel is porous and in some embodiments, at least a portion of the pores in the hydrogel are nanopores, having an average volume at the nanoscale range. According to some of any of the embodiments described herein, the curable formulation further comprises one or more additional materials, including, for example, one or more non- curable materials and / or one or more biological components or materials.

[0589] The hydrogel, according to embodiments of the present invention, can be of biological origin or synthetically prepared.

[0590] According to some embodiments of the present invention, the hydrogel is biocompatible, and is such that when a biological moiety is impregnated or accumulated therein, an activity of the biological moiety is maintained, that is, a change in an activity of the biological moiety is no more than 30 %, or no more than 20 %, or no more than 10 %, compared to an activity of the biological moiety in a physiological medium.

[0591] Exemplary polymers or co-polymers usable for forming a hydrogel according to the present embodiments include, but are not limited topoly acrylates, polymethacrylates, polyacrylamides, polymethacrylamides, polyvinylpyrrolidone and copolymers of any of the foregoing. Other examples include polyethers, polyurethanes, and poly(ethylene glycol), functionalized by cross-linking (e.g., curable) groups or usable in combination with compatible cross linking agents.

[0592] Some specific, non-limiting examples, include: poly(2-vinylpiridine), poly(acrylic acid), poly(methacrylic acid), poly(N-isopropylacrylamide), poly(N,N’-methylenbisacrylamide), poly(N-(N-propyl)acrylamide), poly(methacyclic acid), poly (2-hydroxy acrylamide), poly(ethylene glycol) acrylate, poly(ethylene glycol) methacrylate, and polysaccharides such as hyaluronic acid, dextran, alginate, agarose, and the like, and any co-polymer of the foregoing.

[0593] Hydrogel precursors (hydrogel-forming materials) forming such polymeric chains are contemplated, including any combination thereof.

[0594] Hydrogels are typically formed of, or are formed in the presence of, di- or tri- or multifunctional monomers, oligomer or polymers, which are collectively referred to as hydrogel precursors or hydrogel-forming agents or hydrogen-forming materials, having two, three or more polymerizable groups. The presence of more than one polymerizable group renders such precursors cross-linkable, and allow the formation of the three-dimensional network.

[0595] Exemplary cross -linkable monomers include, without limitation, the family of di- and triacrylates monomers, which have two or three polymerizable functionalities, one of which can be regarded as a cross-linkable functional group. Exemplary diacrylates monomers include, without limitation, methylene diacrylate, and the family of poly(ethylene glycol)ndimethacrylate (nEGDMA). Exemplary triacrylates monomers include, without limitation, trimethylolpropane triacrylate, pentaerythritol triacrylate, tris (2-hydroxy ethyl) isocyanurate triacrylate, isocyanuric acid tris(2-acryloyloxyethyl) ester, ethoxylated trimethylolpropane triacrylate, pentaerythrityl triacrylate and glycerol triacrylate, phosphinylidynetris(oxyethylene) triacrylate.

[0596] In some of any of the embodiments described herein, a curable material, whether monomeric or oligomeric, can be a mono-functional curable material or a multi-functional curable material.

[0597] According to some of any of the embodiments described herein, the curable material is or comprises a poly(alkylene glycol) such as a poly(ethylene glycol) that features one or more photocurable group(s), for example, one or more acrylic group(s) as described herein. In some of these embodiments, the curable material can be, for example, a poly(alkylene glycol) (meth)acrylate such as a poly(ethylene glycol) (meth)acrylate, and / or a poly(alkylene glycol) di(meth)acrylate such as a poly(ethylene glycol) di(meth)acrylate, and / or a copolymer that comprises the foregoing, for example, poly caprolactone (meth)acrylate and / or di(meth)acrylate / poly (ethylene glycol); poly (lactic acid) (meth)acrylate and / or di(meth)acrylate / poly(ethylene glycol); poly(lactic acid co-glycolic acid) (meth) acrylate and / or di(meth)acrylate / poly(ethylene glycol), including any combination of the foregoing.

[0598] According to some of any of the embodiments described herein, the curable material is or comprises a poly(alkylene glycol) that features at least one (meth)acrylic group at its terminus, that is, it is a polymer or copolymer of poly(alkylene glycol) that features at least one (meth)acrylic group at its terminus.

[0599] According to some of any of the embodiments described herein, one or more of the curable (e.g., modeling material) formulations comprises one or more biological components or materials such as, but not limited to, cells, growth factors, peptides, heparan sulfate and fibronectin.

[0600] According to some of any of the embodiments described herein, one or more of the curable (e.g., modeling material) formulations comprises one or more agents that modify a mechanical property of the formulation and / or the object, as described herein, such as, but not limited to, alginate, hyaluronic acid, fibrinogen, elastin, peptides and a thixotropic agent (e.g., Crystalline nano cellulose (CNC)), oxidized cellulose, titanium dioxide, Clay mineral and carbon nanotubes.

[0601] In some of any of the embodiments described herein the curable formulation further comprises a thixotropic agent, as defined herein.

[0602] Herein throughout, the term “thixotropic” describes a property of a fluidic compound or material that is reflected by a time-dependent shear- thinning, that is its viscosity is decreased in correlation with the time at which shear forces are applied, and returns back to its original value when application of shear forces is ceased. In some of the present embodiments, a thixotropic material or agent is such that exhibits or imparts a significant, e.g., at least 100 %, reduction in shear modulus under 50 % strain.

[0603] In some of any of the embodiments described herein, the curable formulation further comprises a gel-forming agent, for example, a hydrogel-forming agent as described herein.

[0604] In some of any of the embodiments described herein, the curable formulation further comprises a biological component or material as described herein.

[0605] In some of any of the embodiments described herein, the curable formulation further comprises one or more curable or non-curable materials as described herein in any of the respective embodiments.

[0606] According to some of any of the embodiments described herein, the curable formulation further comprises one or more biological components such as, but not limited to, hyaluronic acid (including curable HA), cells, growth factors, peptides, heparan sulfate and / or fibronectin.

[0607] According to some of any of the embodiments described herein the curable formulation further comprises one or more agents that modify a mechanical property of the formulation and / or the object, such as, but not limited to, alginate, hyaluronic acid, fibrinogen, elastin, peptides and a thixotropic agent (e.g., Crystalline nano cellulose (CNC)).

[0608] In some of any of the embodiments described herein, all the curable materials in the building material are cured under the same curing condition, and are photocurable.

[0609] According to some of any of the embodiments described herein, the curable formulation provides, when hardened or cured (e.g., when used in an additive manufacturing process as described herein and following photocuring), a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by (i) Strain of 20 % at a range between 10-100 N and (ii) Strain of 50 % at a range between 100-200 N (as determined in a compression force versus strain measurements as described herein); b. Compressive strain-at-break higher than 50% (as determined in a compression force versus strain measurements as described herein); c. Compressive force limit of at least 156 N (as determined in a compression force versus strain measurements as described herein).

[0610] According to some of any of the embodiments described herein, the curable formulation provides, when hardened (e.g., when used in an additive manufacturing process as described herein and following photocuring), a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at 10 N force, as determined in a compression force versus strain measurements as described herein; b. compressive strain-at-break higher than 50% (as determined in a compression force versus strain measurements as described herein); and c. compressive force limit of at least 156 N (as determined in a compression force versus strain measurements as described herein).

[0611] According to some of any of the embodiments described herein, the curable formulation provides, when hardened (e.g., when used in an additive manufacturing process as described herein and following photocuring), a hardened material which exhibits Tensile strain of at least 70 %; and / or Tensile stress of at least 0.7 MPa (as determined in stress versus strain measurements as described herein (e.g., for dog bone or cylinder model).

[0612] According to some of any of the embodiments described herein, the curable formulation provides, when hardened or cured (e.g., when used in an additive manufacturing process as described herein and following photocuring and washing), a hardened or cured material which exhibits Tensile strain of at least 70 %; and / or Tensile stress of at least 0.7 MPa (as determined in stress versus strain measurements as described herein (e.g., for dog bone or cylinder model). For example, at 70 % strain, the material exhibits stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or higher. For example, at 80 % strain, the material exhibits stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or higher. According to some of any of the embodiments described herein, the curable formulation provides, when hardened or cured (e.g., when used in an additive manufacturing process as described herein and following post process steps as described herein ), a hardened or cured material which exhibits at 100 % strain, the material exhibits stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or of 0.85 MPa, or of 0.9 MPa, or of 0.95 MPa, or of 1.00 MPa, or higher. For example, at 110 % strain, the material exhibits stress of 0.7 MPa, or of 0.75 MPa, or of 0.8 MPa, or of 0.85 MPa, or of 0.9 MPa, or of 0.95 MPa, or of 1.00 MPa, or of 1.10 MPa, or of 1.15 MPa, or of 1.20 MPa, or higher). All when measured as described herein.

[0613] In some embodiments, the formulation of the implant is selected to avoid fibrosis.

[0614] The following describes embodiments of additive manufacturing processes and methodologies for which the method as described herein can be employed.

[0615] According to an aspect of some embodiments of the present invention, there is provided a process (a method) of additive manufacturing (AM) of a three-dimensional object using the formulations described herein. According to embodiments of this aspect, the method is effected by sequentially forming a plurality of layers in a configured pattern corresponding to the shape of the object, thereby forming the object. According to some embodiments of this aspect, formation of each layer is effected by dispensing at least one uncured building material, and exposing the dispensed building material to a curing condition to thereby form a hardened (cured) material. According to some embodiments of this aspect, formation of each layer is effected by exposing a layer of uncured building material to a curing condition, and the method is effected by sequentially exposing, in a layer- wise manner, an uncured building material to a curing condition, whereby the exposure to the curing condition is effected in a configured pattern corresponding to the shape of the object.

[0616] Herein throughout, the phrase “building material” encompasses the phrases “uncured building material” or “uncured building material formulation” or “curable formulation” or “modeling material” or “ink“ or bioink” or “hydrogel” and collectively describes the materials that are used for sequentially forming the layers, as described herein. This phrase encompasses uncured materials which form the final object, namely, one or more uncured modeling material formulation(s), and optionally also uncured materials used to form a support, namely uncured support material formulations. The building material can also include non-curable materials that preferably do not undergo (or are not intended to undergo) any change during the process, for example, biological materials or components (other than a curable collagen as described herein) and / or other agents or additives as described herein.

[0617] The building material that is used to sequentially form the layers as described herein is also referred to herein interchangeably as “printing medium” or “bioprinting medium” or “bioink”.

[0618] According to a particular embodiment, the formulations described herein are free or essentially free of monomers (e.g., HEAA) or short chain synthetic polymers having a molecular weight of less than 1000MW (e.g., PEGDMA700 or PEGDA700). According to some embodiments of the invention, the curable formulation is free of poly(caprolactones) (PCL) polymers.

[0619] An uncured building material can comprise one or more modeling material formulations, and can be utilized such that different parts of the object are made upon hardening (e.g., curing) of different modeling formulations, and hence are made of different hardened (e.g., cured) modeling materials or different mixtures of hardened (e.g., cured) modeling materials.

[0620] The method of the present embodiments manufactures three-dimensional objects in a layerwise manner by forming a plurality of layers in a configured pattern corresponding to the shape of the object.

[0621] Each layer is formed by an additive manufacturing apparatus which scans a two- dimensional surface and patterns it. While scanning, the apparatus visits a plurality of target locations on the two-dimensional layer or surface, and decides, according to a pre-set algorithm, for each target location or a group of target locations, whether or not the target location or group of target locations is to be occupied by a building material, and which type of a building material is to be delivered thereto. The decision is made according to a computer image of the surface. When the AM is by three-dimensional inkjet printing, an uncured building material, as defined herein, is dispensed from a dispensing head having a set of nozzles to deposit building material in layers on a supporting structure. The AM apparatus thus dispenses building material in target locations which are to be occupied and leaves other target locations void. The apparatus typically includes a plurality of dispensing heads, each of which can be configured to dispense a different building material (for example, different modeling material formulations, each containing a different biological component; or each containing a different curable material; or each containing a different concentration of a curable material, and / or different support material formulations). Thus, different target locations can be occupied by different building materials (e.g., a modeling formulation and / or a support formulation, as defined herein).

[0622] The final three-dimensional object is made of the hardened modeling material or a combination of hardened modeling materials or a combination of hardened modeling material / s and support material / s or modification thereof (e.g., following curing). All these operations are well-known to those skilled in the art of additive manufacturing (also known as solid freeform fabrication).

[0623] In some exemplary embodiments of the invention an object is manufactured by dispensing a building material that comprises two or more different modeling material formulations, each modeling material formulation from a different dispensing head of the AM apparatus. The modeling material formulations are optionally and preferably deposited in layers during the same pass of the dispensing heads. The modeling material formulations and / or combination of formulations within the layer are selected according to the desired properties of the object.

[0624] An exemplary process according to some embodiments of the present invention starts by receiving 3D printing data corresponding to the shape of the object. The data can be received, for example, from a host computer which transmits digital data pertaining to fabrication instructions based on computer object data, e.g., in a form of a Standard Tessellation Language (STL) or a StereoLithography Contour (SLC) format, Virtual Reality Modeling Language (VRML), Additive Manufacturing File (AMF) format, Drawing Exchange Format (DXF), Polygon File Format (PLY), Digital Imaging and Communications in Medicine (DICOM) or any other format suitable for Computer-Aided Design (CAD).

[0625] The process continues by dispensing the building material as described herein in layers, on a receiving medium, using one or more dispensing (e.g., printing) heads, according to the printing data.

[0626] The dispensing can be in the form of droplets, or a continuous stream, depending on the additive manufacturing methodology employed and the configuration of choice. The receiving medium can be a tray of a printing system, or a supporting article or medium made of, or coated by, a biocompatible material, such as support media or articles commonly used in bioprinting, or a previously deposited layer.

[0627] In some embodiments, the receiving medium comprises a sacrificial hydrogel or other biocompatible material as a mold to embed the printed object, and is thereafter removed by chemical, mechanical or physical (e.g., heating or cooling) means. Such sacrificial hydrogels can be made of, for example, a Pluronic material or of Gelatin.

[0628] Once the uncured building material is dispensed on the receiving medium according to the 3D data, the method optionally and preferably continues by hardening the dispensed formulation(s). In some embodiments, the process continues by exposing the deposited layers to a curing condition. Preferably, the curing condition is applied to each individual layer following the deposition of the layer and prior to the deposition of the previous layer.

[0629] As used herein throughout, the term “curing” describes a process in which a formulation is hardened. The hardening of a formulation typically involves an increase in viscosity of the formulation and / or an increase in a storage modulus of the formulation (G’). In some embodiments, a formulation which is dispensed as a liquid becomes solid or semi-solid (e.g., gel) when hardened. A formulation which is dispensed as a semi-solid (e.g., soft gel) becomes solid or a harder or stronger semi-solid (e.g., strong gel) when hardened.

[0630] The term “curing” as used herein encompasses, for example, polymerization of monomeric and / or oligomeric materials and / or cross-linking of polymeric chains (either of a polymer present before curing or of a polymeric material formed in a polymerization of the monomers or oligomers). The product of a curing reaction is therefore typically a polymeric material and / or a cross-linked material. This term, as used herein, encompasses also partial curing, for example, curing of at least 20 % or at least 30 % or at least 40 % or at least 50 % or at least 60 % or at least 70 % of the formulation, in addition to curing of 100 % of the formulation.

[0631] Herein, the phrase “a condition that affects curing” or “a condition for inducing curing”, which is also referred to herein interchangeably as “curing condition” or “curing inducing condition” describes a condition which, when applied to a formulation that contains a curable material, induces a curing as defined herein. Such a condition can include, for example, application of a curing energy, as described hereinafter to the curable material(s), and / or contacting the curable material(s) with chemically reactive components such as catalysts, co-catalysts, and activators.

[0632] When a condition that induces curing comprises application of a curing energy, the phrase “exposing to a curing condition” and grammatical diversions thereof means that the layers are exposed to the curing energy and the exposure is typically performed by applying a curing energy to the layers.

[0633] A “curing energy” typically includes application of radiation (irradiation) or application of heat.

[0634] The radiation can be electromagnetic radiation (e.g., ultraviolet or visible light), or electron beam radiation, or ultrasound radiation or microwave radiation, depending on the materials to be cured. The application of radiation (or irradiation) is effected by a suitable radiation source. For example, an ultraviolet or visible or infrared or Xenon or mercury or lamp, or LED source, can be employed, as described herein.

[0635] A curable material or system that undergoes curing upon exposure to radiation is referred to herein interchangeably as “photopolymerizable” or “photoactivatable” or “photocurable”.

[0636] When the curing energy comprises heat, the curing is also referred to herein and in the art as “thermal curing” and comprises application of thermal energy. Applying thermal energy can be effected, for example, by heating a receiving medium onto which the layers are dispensed or a chamber hosting the receiving medium, as described herein. In some embodiments, the heating is effected using a resistive heater.

[0637] In some embodiments, the heating is effected by irradiating the dispensed layers by heatinducing radiation. Such irradiation can be effected, for example, by means of an IR lamp or Xenon lamp, operated to emit radiation onto the deposited layer.

[0638] In some embodiments, heating is effected by infrared radiation applied by a ceramic lamp, for example, a ceramic lamp that produces infrared radiation of from about 3 pm to about 4 pm, e.g., about 3.5 pm.

[0639] A curable material or system that undergoes curing upon exposure to heat is referred to herein as “thermally-curable” or “thermally-activatable” or “thermally-polymerizable”.

[0640] In some of any of the embodiments described herein, hardening the formulation(s) comprises exposing the formulation to a curing condition which is irradiation (illumination), as described herein.

[0641] In some embodiments, the exposure to a curing condition (irradiation) is for a short time period, for example, a time period of less than 3 minutes, less than 300 seconds, for example, of from 10 seconds to 240 seconds, or from 10 seconds to 120 seconds, to from 10 seconds to 60 seconds, including an intermediate values and subranges therebetween.

[0642] In some embodiments, exposing to the curing condition (irradiation) is for a time period that ranges from 1 second to 120 second.

[0643] In some embodiments, the irradiation is at wavelength within the UV-vis range. In some embodiments, the irradiation is at wavelength in a range of from about 300 to about 800, or from about 300 to about 600, or from about 300 to about 500, or from about 350 to about 450, nm, including any intermediate values and subranges therebetween. In exemplary embodiments, the irradiation is at 385 nm. In exemplary embodiments, the irradiation is at 365 nm.

[0644] In some embodiments, the irradiation is at level that ranges from about 1 to about 150, or from about 1 to about 130, or from about 1 to about 100, or from about 10 to about 150, or from about 10 to about 130, or from about 10 to about 100, or from about 50 to about 150, or from about 50 to about 130, or from about 50 to about 100, or from about 1 to about 50 or from about 1 to about 30, from about 1 to about 20, or from about 1 to about 15, from about 1 to about 10, from about 1 to about 9, from about 1 to about 10 mW / cm2, including any intermediate values and subranges therebetween.

[0645] In some embodiments, the irradiation of the base layer is no less than 100 and no more than 400 mJ / cm2.

[0646] In some of any of the embodiments described herein, the exposure, controls the amount of energy delivered by the light source to the printed layer. In some embodiments, the exposure is at a level that ranges from about 1 to about 150, or from about 1 to about 130, or from about 1 to about 100, or from about 10 to about 150, or from about 10 to about 130, or from about 10 to about 100, or from about 50 to about 150, or from about 50 to about 130, or from about 50 to about 100, or from about 1 to about 50, or from about 1 to about 40, or from about 1 to about 30 or from about 1 to about 20, from about 1 to about 15, from about 1 to about 10, from about 1 to about 9, from about 1 to about 10 mJ / cm2, including any intermediate values and subranges therebetween.

[0647] According to one preferred embodiment, the irradiation is at a power intensity level that ranges from about 1 to about 30 mW / cm2, or from about 10 to about 30 mW / cm2. According to one preferred embodiment, the irradiation is at a power intensity level that ranges from about 5 to about 15 mW / cm2, or from about 20 to about 30. According to one preferred embodiment, the irradiation is at a power intensity level that ranges from about 10 to about 30 mW / cm2. According to one preferred embodiment, the irradiation is at a power intensity level of about 10 or about 27 mW / cm2

[0648] In some of any of the embodiments described herein, the exposure time, controls the amount of energy delivered by the light source to the printed layer. In some embodiments, the exposure energy is at a level that ranges from about 1 to about 250, 1 to about 200, 1 to about 150, or from about 1 to about 130, or from about 1 to about 100, or from about 10 to about 150, or from about 10 to about 130, or from about 10 to about 100, or from about 50 to about 150, or from about 50 to about 130, or from about 50 to about 100, or from about 1 to about 50, or from about 1 to about 40, or from about 1 to about 30 or from about 1 to about 20, from about 1 to about 15, from about

[0649] 1 to about 9, from about 1 to about 10 mJ / cm2, including any intermediate values and subranges therebetween.

[0650] In some of any of the embodiments described herein, the exposure time, controls the amount of energy delivered by the light source to the printed layer. In some embodiments, the exposure energy is at a level that ranges from about 100 to about 600, 200 to about 600, or from about 300 to about 600, or from about 400 to about 600, or from about 500 to about 600, or from about 100 to about 200, or from about 100 to about 300, 100 to about 400 or from about 100 to about 500, or from about 450 to about 530, or from about 450 to about 600, or from about 450 to about 550, or from about 500 to about 640, or from about 500 to about 630 or from about 500 to about 620, from about 500 to about 550, from about 550 to about 600, from about 300 to about 400 mJ / cm2, including any intermediate values and subranges therebetween.

[0651] In some embodiments, the irradiation of the base layer is ranges from about 100 to about 400 mJ / cm2

[0652] In some embodiments, printing is controlled by one or more parameters comprising exposure energy, exposure time, layer thickness, concentration of the photo initiator or the concentration photo blocker.

[0653] In some of any of the embodiments described herein, the method further comprises exposing the cured modeling material formulation(s) either before or after removal of a support material formulation, if such has been included in the building material, to a post-treatment condition. The post-treatment condition is typically aimed at further hardening the cured modeling material(s). In some embodiments, the post-treatment hardens a partially-cured formulation to thereby obtain a completely cured formulation.

[0654] In some embodiments, the post-treatment (post cure) is effected by exposure to heat or radiation, as described in any of the respective embodiments herein.

[0655] Some embodiments contemplate the fabrication of an object by dispensing different formulations from different dispensing heads. These embodiments provide, inter alia, the ability to select formulations from a given number of formulations and define desired combinations of the selected formulations and their properties.

[0656] According to the present embodiments, the spatial locations of the deposition of each formulation with the layer are defined, either to effect occupation of different three-dimensional spatial locations by different formulations, or to effect occupation of substantially the same three- dimensional location or adjacent three-dimensional locations by two or more different formulations so as to allow post deposition spatial combination of the formulations within the layer.

[0657] The present embodiments thus enable the deposition of a broad range of material combinations, and the fabrication of an object which may consist of multiple different combinations of modeling material formulations, in different parts of the object, according to the properties desired to characterize each part of the object.

[0658] A system utilized in additive manufacturing may include a receiving medium and one or more dispensing heads. The receiving medium can be, for example, a fabrication tray that may include a horizontal surface to carry the material dispensed from the printing head. In some embodiments, the receiving medium is made of, or coated by, a biocompatible material, as described herein.

[0659] The dispensing head may be, for example, a printing head having a plurality of dispensing nozzles arranged in an array of one or more rows along the longitudinal axis of the dispensing head. The dispensing head may be located such that its longitudinal axis is substantially parallel to the indexing direction.

[0660] The additive manufacturing system may further include a controller, such as a microprocessor to control the AM process, for example, the movement of the dispensing head according to a pre-defined scanning plan (e.g., a CAD configuration converted to a Standard Tessellation Language (STL) format and programmed into the controller). The dispensing head may include a plurality of jetting nozzles. The jetting nozzles dispense material onto the receiving medium to create the layers representing cross sections of a 3D object.

[0661] In addition to the dispensing head, there may be a source of curing energy, for curing the dispensed building material. The curing energy is typically radiation, for example, UV radiation or heat radiation. Alternatively, there may be means for providing a curing condition other than electromagnetic or heat radiation, for example, means for cooling the dispensed building material or for contacting it with a reagent that promotes curing.

[0662] Additionally, the AM system may include a leveling device for leveling and / or establishing the height of each layer after deposition and at least partial solidification, prior to the deposition of a subsequent layer.

[0663] According to the present embodiments, the additive manufacturing method described herein is for bioprinting a biological object.

[0664] As used herein, "bioprinting" means practicing an additive manufacturing process while utilizing one or more curable formulation(s) that comprise(s) biological components, as described herein, via methodology that is compatible with an automated or semi-automated, computer-aided, additive manufacturing system as described herein (e.g., a bioprinter or a bioprinting system).

[0665] In some embodiments, the bioprinting comprises sequential formation of a plurality of layers of the uncured building material in a configured pattern, preferably according to a three- dimensional printing data, as described herein. At least one, and preferably most or all, of the formed layers (before hardening or curing) comprise(s) one or more biological component(s) as described herein (e.g., a curable Collagen as described herein). Optionally, at least one of the formed layers (before hardening or curing) comprises one or more non-biological curable materials, and / or non-curable biological or non-biological components, preferably biocompatible materials which do not interfere (e.g., adversely affect) with the biological and / or structural features of the biological components (e.g., collagen) in the printing medium and / or bio-ink.

[0666] According to some embodiments described herein, the bioprinting process further comprises exposing at least a portion of the formed layers to a curing condition which comprises curing energy, for example, light energy (irradiation, illumination).

[0667] In some of any of the embodiments described herein, the bioprinting method is configured to effect formation of the layers under conditions that do not significantly affect structural and / or functional properties of the biological components in the bioink composition.

[0668] In some embodiments, a bioprinting system for effecting a bioprinting process / method as described herein is configured so as to allow formation of the layers under conditions that do not significantly affect structural and / or functional properties of the biological components in the bioink.

[0669] In some of any of the embodiments described herein, the additive manufacturing (e.g., bioprinting) process and system are configured such that the process parameters (e.g., temperature, shear forces, shear strain rate) do not interfere with (do not substantially affect) the functional and / or structural features of the biological components.

[0670] According to some of the present embodiments, the additive manufacturing is of a three- dimensional object featuring, in at least a portion thereof, a collagen-based material, and comprises dispensing at least one modeling material formulation to sequentially form a plurality of layers in a configured pattern corresponding to a shape of the object, wherein for at least a portion of the layers, the dispensing is of one or more modeling material formulation(s) that comprise the curable formulation as described herein in any of the respective embodiments and any combination thereof.

[0671] According to some of any of the embodiments described herein, the process further comprises exposing at least a portion of the dispensed layers to a curing condition which comprises curing energy, for example, light energy (irradiation, illumination). According to some of any of the embodiments described herein, for at least a portion of the layers, the dispensing is further of a modeling material formulation that comprises an agent that modifies a mechanical and / or rheological and / or physical property of the formulation and / or of a respective portion of the object.

[0672] According to some of any of the embodiments described herein, or at least a portion of the layers, the dispensing is further of a modeling material formulation that comprises a biological material other than the biocompatible photocurable material (e.g., curable collagen) as described herein.

[0673] According to some of any of the embodiments described herein, the dispensing or forming of layer is at a temperature that ranges from -10 to 50 °C, or from -4 to 50 °C, or from -4 to 37 °C or from 4 to 20 °C or from 4 to 25 °C or from 10 to 20 °C or from 10 to 25 °C, or from 20 to 30 °C or from 10 to 30 °C or from 20 to 37 °C or from 25 to 37 °C or from 4 to 37 °C . In some embodiments, the temperature is at least 10 °C, or at least 15 °C or of at least 20 °C, or at least 22, °C or at least 25 °C, or at least 30 °C or of 37 °C.

[0674] In some of any of the embodiments described herein, the additive manufacturing process (the bioprinting) is performed at a temperature of at least 10 °C, or of at least 20 °C, for example, at a temperature that ranges from about 10 to about 40 °C, preferably from about 10 °C to 37 °C, or from about 20 °C to 37 °C, or from about 20 °C to about 30 °C, or from about 20 °C to about 28 °C, or from about 20 °C to about 25 °C, including any intermediate values and subranges therebetween, or at room temperature, or at 37 °C.

[0675] In some of any of the embodiments described herein, the above-indicated temperatures / temperature ranges are the temperatures at which the building material (e.g., at least a modeling material formulation that comprises a biological component as described herein) are dispensed, that is, a temperature of a dispensing head in the AM system and / or a temperature at which the modeling material formulation is maintained prior to passing in the dispensing head and / or a temperature at which the modeling material formulation is maintained in the vat prior to curing.

[0676] In some of any of the embodiments described herein, the AM process is performed without cooling the AM system (e.g., without cooling the dispensing heads and / or a modeling material formulation and / or vat), to a temperature below room temperature, e.g., a temperature lower than 25 °C or lower than 20 °C or lower than 10 °C, or lower than 5 °C (e.g., 4 °C).

[0677] In some of any of the embodiments described herein, the AM system is devoid of means for cooling the system or a part thereof (e.g., means for cooling the dispensing heads and / or the modeling material formulation and / or the vat), to a temperature below room temperature, e.g., 25 °C or lower than a temperature lower than 20 °C or lower than 10 °C, or lower than 5 °C (e.g., 4 °C).

[0678] In some of any of the embodiments described herein, the additive manufacturing process (bioprinting) is performed while applying a shear force that does not adversely affect structural and / or functional properties of biological components (e.g., cells). Applying the shear force can be effected by passing the building material (e.g., at least a modeling material formulation that comprises a biological component as described herein) through the dispensing head, and is to be regarded also as subjecting the building material to shear force.

[0679] Some embodiments of the present invention allow to perform AM bioprinting processes under conditions that do not affect the functional and / or structural features of biological components included in the bio-ink (e.g., at low shear force and room temperature or a physiological temperature), while maintaining the required fluidity (a viscosity that imparts fluidity, e.g., lower than 10,000 centipoises or lower than 5,000 centipoises, or lower than 2,000 centipoises), and while further maintaining the curability of the building material.

[0680] The following describes exemplary AM bioprinting methodologies that are usable in the context of embodiments of the present invention.

[0681] A bioprinting method and a corresponding system can be any of the methods and systems known in the art for performing additive manufacturing, and exemplary such systems and methods are described hereinabove. A suitable method and system can be selected upon considering its printing capabilities, which include resolution, deposition speed, scalability, bio-ink compatibility and ease-of-use.

[0682] Exemplary suitable bioprinting systems usually contain a dispensing system (either equipped with temperature control module or at ambient temperature), and stage (a receiving medium), and a movement along the x, y and z axes directed by a CAD-CAM software. A curing source (e.g., a light or heat source) which applies a curing energy (e.g., by applying light or heat radiation) or a curing condition to the deposition area (the receiving medium) so as to promote curing of the formed layers and / or a humidifier, can also be included in the system. There are printers that use multiple dispensing heads to facilitate a serial dispensing of several materials.

[0683] Generally, bioprinting can be effected using any of the known techniques for additive manufacturing. The following lists some exemplary additive manufacturing techniques, although any other technique is contemplated.

[0684] 3D Inkjet printing:

[0685] 3D Inkjet printing is a common type of 3D printer for both non-biological and biological (bioprinting) applications. Inkjet printers use thermal or acoustic forces to eject drops of liquid onto a substrate, which can support or form part of the final construct. In this technique, controlled volumes of liquid are delivered to predefined locations, and a high-resolution printing with precise control of (1) ink drops position, and (2) ink volume, which is beneficial in cases of microstructureprinting or when small amounts of bioreactive agents or drugs are added, is received. Inkjet printers can be used with several types of ink, for example, comprising multiple types of biological components and / or bioactive agents. Furthermore, the printing is fast and can be applied onto culture plates.

[0686] A bioprinting method that utilizes a 3D inkjet printing system can be operated using one or more bio-ink modeling material formulations as described herein, and dispensing droplets of the formulation(s) in layers, on the receiving medium, using one or more inkjet printing head(s), according to the 3D printing data.

[0687] PolyJet or MJP printing:

[0688] Other technologies suitable for bioprinting applications involving UV-cured materials, thanks to their precision, multi-material capabilities, and effective UV curing process are MultiJet Printing (MJP) or PolyJet technology which jets photopolymer droplets and cures them using UV light after each layer is deposited. While MJP / PolyJet shares some commonalities with 3D inkjet printing due to their use of inkjet technology for material deposition, they differ significantly in the types of materials used, curing processes, and typical applications.

[0689] Two-Photon Polymerization (2PP) and some forms of Selective Laser Sintering (SLS) or / Selective Laser Melting (SLM):

[0690] Additional printing technologies which can utilize the formulations described herein are Two-Photon Polymerization (2PP) and Selective Laser Sintering (SLS) or / Selective Laser Melting (SLM). These technologies may use different wavelengths of light, often in the nearinfrared or visible spectrum, and do not always rely on UV for curing. In 2PP a femtosecond laser induces polymerization within a photoresist.

[0691] Stereolithography (SLA) and Digital Light Processing (DLP):

[0692] SLA and DLP are additive manufacturing technologies in which an uncured building material in a bath or vat is converted into hardened material(s), layer by layer, by selective curing using a light source while the uncured material is later separated / washed from the hardened material. SLA is widely used to create models, prototypes, patterns, and production parts for a range of industries including for Bioprinting. DLP differs from laser-based SLA in that DLP uses a projection of ultraviolet (UV) light (or visible light) from a digital projector to flash a single image of the layer across the entire uncured material at once. One of the key components of DLP is a digital micromirror device (DMD) chip, which is typically composed of an array of reflective aluminum micromirrors that redirect incoming light from the UV source to project an image of a designed pattern. For achieving a high-resolution structure, parameters such as the curing time of each layer, layer thickness, and intensity of the UV light should be tuned, for example, by controlling the concentration and types of the curable materials, the photoabsorber and / or the photoinitiator.

[0693] Laser-assisted printing:

[0694] Laser-assisted printing technique, in the version adopted for 3D bioprinting, is based on the principle of laser- induced forward transfer (LIFT), which was developed to transfer metals and is now successfully applied to biological material. The device consists of a laser beam, a focusing system, an energy absorbing / converting layer and a biological material layer (e.g., cells and / or hydrogel) and a receiving substrate. A laser assisted printer operates by shooting a laser beam onto the absorbing layer which convert the energy into a mechanical force which drives tiny drops from the biological layer onto the substrate. A light source is then utilized to cure the material on the substrate.

[0695] Laser assisted printing is compatible with a series of viscosities and can print mammalian cells without affecting cell viability or cell function. Cells can be deposited at a density of up to 108cells / ml with microscale resolution of a single cell per drop.

[0696] Electrospinning:

[0697] Electrospinning is a fiber production technique, which uses electric force to draw charged threads of polymer solutions, or polymer melts. In one embodiment, the electrospinning includes a light-induced reaction. According to some of any of the embodiments described herein, the additive manufacturing (bioprinting) is (or comprises) digital light processing (DLP), as described herein.

[0698] Direct Ink Writing (DIW):

[0699] DIW uses high-viscosity photocurable inks (e.g., resins with ceramic, polymer, or nanoparticle fillers). Ink is extruded as filaments, then cured either continuously (with a UV lamp near the nozzle) or after deposition (layer by layer). It allows much higher filler content (ceramics, composites, hydrogels) than inkjet. Resolution is lower than inkjet because extrusion filaments are thicker than droplets.

[0700] According to an aspect of some embodiments of the present invention, there is provided a process (or method) of additive manufacturing using DLP technology, wherein a three-dimensional object featuring, in at least a portion thereof, a biological or a biocompatible material is prepared. In some embodiments, a 3D digital model is created or obtained through the use of computer-aided design (CAD) software, as described herein. In an embodiment, specialized slicing software is employed, slicing the 3D model into distinct cross-sectional layers, or "slices" as described herein, with varying layer thickness and slicing parameters. In accordance with some embodiments, a curable formulation is chosen with specific regard to the desired properties and characteristics of the final object (as described herein), and the vat is prepared. In some embodiments, the DLP 3D printing process is implemented by following the method steps as described herein in any of the respective embodiments. In an embodiment, the digital light projector, through the projection of highly detailed images onto the curable formulation surface, ensures precision and accuracy in layer-by-layer additive printing. According to some embodiments, post-processing procedures are carried out after the completion of printing, including rinsing to remove excess, uncured formulation and optional post-curing (e.g., by application of electromagnetic irradiation and / or heat). According to some embodiments, post-processing procedures are carried out after the completion of printing including drying and / sterilization. In some embodiments, post-processing procedures do not significantly affect mechanical, biological, structural and / or functional properties of the biological components in the bio-ink or the bioprinted object.

[0701] The exposure (energy) mJ / cm2, is the power intensity (mW / cm2) multiplied by the time of exposure (seconds), wherein the energy of irradiation is equal to the light source power intensity multiplied by the time of exposure. The exposure (energy) mJ / cm2, is the power intensity (mW / cm2) multiplied by the time of exposure (seconds), wherein the energy of irradiation is equal to the light source power intensity multiplied by the time of exposure.

[0702] In some embodiments, when the intensity is 27 mW / cm2, the exposure time ranges from 1 to 60 sec to obtain an energy of irradiation which ranges from 27 to 1620 mJ / cm2.In some embodiments, the intensity is 27 mW / cm2, and the exposure time for printing the foundation layers ranges from 15 to 60 or from 15 to 30 seconds. In some embodiments, the intensity is 27 mW / cm2, and the exposure time for printing the scaffold layers ranges from 1 to 12 seconds,! to 16 seconds or 1 to 20 seconds. In some embodiments, the intensity is 27 mW / cm2, and the exposure time for printing the scaffold layers ranges from 10 to 15 seconds.

[0703] In some embodiments, when the exposure duration is 44 seconds, the intensity is fixed at 27 mW / cm2to obtain an energy of irradiation of approximately 1200 mJ / cm2. In some embodiments, the exposure duration is 10 sec, and the intensity for printing the foundation layers ranges from 1 to 120 mW / cm2. In some embodiments, the exposure duration is 10 sec, and the intensity for printing the scaffold layers ranges from 1 to 90 mW / cm2.

[0704] In other embodiments, the exposure duration may be 20 sec with intensity ranging from 1 to 60 mW / cm2or 100 sec with intensity ranging from 1 to 12 mW / cm2. In some embodiments, the exposure duration is 5 sec with intensity ranging from 1 to 240 mW / cm2. In some embodiments, the exposure duration is 10 sec with intensity ranging from 1 to 120 mW / cm2. In some embodiments, the exposure duration is 50 sec with intensity ranging from 1 to 24 mW / cm2.

[0705] In some embodiments, the intensity is 40 mW / cm2and the exposure duration ranges from 1 to 30 sec or from 1 to lOsec or from from 1 to 5sec. In some embodiments, the intensity is 27 mW / cm2and the exposure duration is 44 seconds. In some embodiments, the intensity is 10 mW / cm2and the exposure duration ranges from 1 to 120 sec or 1 to 40sec or 1 to 20 sec. In some embodiments, the intensity is 20mW / cm2, and the exposure duration ranges 1 to 20 sec or 1 to 10 sec. In some embodiments, the intensity is 5 mW / cm2and the exposure duration ranges from 1 to 240 sec or 1 to 80 sec or 1 to 40sec.

[0706] In some embodiments, the energy of irradiation ranges from 27 to 1620 mJ / cm2In some embodiments, the energy of irradiation ranges from 100 to 1600 mJ / cm2, 120 to 1200 mJ / cm2, 150 to 1350 mJ / cm2, 200 to 1400 mJ / cm2, 300 to 1500 mJ / cm2In some embodiments, the energy of irradiation ranges from 1100 to 1300 mJ / cm2, or from 1150 to 1250 mJ / cm2, or specifically at approximately 1200 mJ / cm2.

[0707] In some embodiments, the energy of irradiation for printing the foundation layers ranges from 1000 to 1600 mJ / cm2. In some embodiments, the energy of irradiation for printing the scaffold layers ranges from 1000 to 1200 mJ / cm.

[0708] In some embodiments, the intensity of the printer’s light source ranges from 1 to 150 mW / cm2, 1 to 100 mW / cm2, 1 to 50 mW / cm2, 1 to 27 mW / cm2, or 1 to 20 mW / cm2.

[0709] In some embodiments, when the intensity is 10mW / cm2, the exposure time ranges from 1 to 60 sec to obtain an energy of irradiation which ranges is from 10 to 600 mJ / cm2. In some embodiments, the intensity is 10mW / cm2, the exposure time for printing the foundation layers ranges from 50 to 60 seconds. In some embodiments, the intensity is 10mW / cm2, and the exposure time for printing the foundation layers ranges or from 15 to 30 seconds. In some embodiments, the intensity is 10mW / cm2, and the exposure time for printing the for printing the scaffold layers ranges from 1 to 12 seconds, or 1 to 16, or 1 to 20 seconds. In some embodiments, the intensity is 10mW / cm2, and the exposure time for printing the scaffold layers ranges or from 10 to 15 seconds.

[0710] In some embodiments, when the exposure duration is lOsec, the intensity ranges from 1 to 60mW / cm2to obtain the energy of irradiation which ranges from 10 to 600 mJ / cm2. In some embodiments, the exposure duration is lOsec, and the intensity for printing the foundation layers ranges from 1 to 23mW / cm2. In some embodiments, the exposure duration is lOsec, and the intensity for printing the scaffold layers ranges from 1 to 15mW / cm2.

[0711] In some embodiments, the exposure duration is lOsec, the intensity ranges from 1 to 40mW / cm2. In some embodiments, the exposure duration is 20sec, the intensity ranges from 1 to 20mW / cm2. In some embodiments, the exposure duration is lOOsec, the intensity ranges from 1 to 4mW / cm2.

[0712] In some embodiments, the exposure duration is 5sec, the intensity ranges from 1 to 40mW / cm2. In some embodiments, the exposure duration is 50sec, the intensity ranges from 1 to 4mW / cm2.

[0713] In some embodiments, the energy of irradiation ranges from 10 to 600 mJ / cm2. In some embodiments, the energy of irradiation ranges from 10 to 500 mJ / cm2, 10 to 400mJ / cm2, 10 to 300 mJ / cm2, 10 to 200 mJ / cm2, 10 to 160 mJ / cm2, 10 to 150 mJ / cm2, 10 to 140 mJ / cm2, 10 to 130 mJ / cm2, 10 to 120 mJ / cm2, 10 to 110mJ / cm2, 10 to 100mJ / cm2, 10 to 90mJ / cm2, 10 to 80 mJ / cm2, 10 to 70 mJ / cm2, 10 to 60mJ / cm2, 10 to 50mJ / cm2, 10 to 40mJ / cm2, 10 to 30mJ / cm2, 10 to 20mJ / cm2. In some embodiments, the energy of irradiation ranges from 110 to 300 mJ / cm2, 110 to 200mJ / cm2, 120 to 300 mJ / cm2, 120 to 200 mJ / cm2, 120 to 160 mJ / cm2, 110 to 250 mJ / cm2, 110 to 240 mJ / cm2, 110 to 230 mJ / cm2, 110 to 220 mJ / cm2, 110 to 210mJ / cm2, 115 to 200mJ / cm2, 110 to 190mJ / cm2, 110 to 180 mJ / cm2, 110 to 170 mJ / cm2, 160 to 260mJ / cm2, 160 to 250mJ / cm2, 160 to 240mJ / cm2, 160 to 230mJ / cm2, 160 to 220mJ / cm2, 160 to 210mJ / cm2, 180 to 220 mJ / cm2, 190 to 220 mJ / cm2, 200 to 220mJ / cm2, 180 to 210mJ / cm2, 180 to 210mJ / cm2, 190 to 210mJ / cm2, 190 to 200mJ / cm2. In some embodiments, the energy of irradiation for printing the foundation layers ranges from 150 to 600 mJ / cm2. In some embodiments, the energy of irradiation for printing the scaffold ranges from 100 to 150 mJ / cm2. In some embodiments, the energy of irradiation for printing the foundation layers ranges from 150 to 300 mJ / cm2. In some embodiments, the energy of irradiation for printing the scaffold ranges from 110 to 150 mJ / cm2.

[0714] In some embodiments, the power intensity of the printer’s light source ranges from 1 to 150 mW / cm2. In some embodiments, the intensity of the printer’s light source ranges from 1 to 100 mW / cm2, 1 to 90 mW / cm2, 1 to 80 mW / cm2, 1 to 70 mW / cm2, 1 to 60 mW / cm2, 1 to 50 mW / cm2, 1 to 40 mW / cm2, 1 to 30 mW / cm2, 1 to 20 mW / cm2, 1 to 10 mW / cm2, 1 to 9 mW / cm2, 1 to 8 mW / cm2, 1 to 7 mW / cm2, 1 to 6 mW / cm2.

[0715] In some embodiments, a thickness of exposed layers, a level of the irradiation, a time of the exposing, and / or an amount of the photoblocker are determined while executing a method as described herein in any of the respective embodiments, for example, while determining a curing kinetics and / or printing resolution in the presence of a selected formulation.

[0716] In some embodiments, the additive manufacturing is DLP.

[0717] Figs. 1A-1C show structures suitable for use as breast implants, in accordance with some embodiments of the invention. It is noted that breast implants are only one type of implant contemplated by this disclosure and other implants may be formed as well, for example, with sizes and shapes and / or volume different from those used for breast implants. A particular feature of breast implants is the tissue being modeled and supported by the implant.

[0718] Referring specifically to Fig. 1A showing a side, top and perspective views of a breast implant 100, in accordance with some embodiments of the invention.

[0719] Implant 100, which may have a volume of, for example, lOOcc, is shown as having a top surface 102 defined by a lattice of segments 108, defining apertures 106 therebetween. In some embodiments of the invention, apertured surface 102 covers at least 30%, 50%, 70%, 80%, 90% or more or intermediate values of the surface of the volume enclosed by implant 100. Surface 102 is optionally curved, for example, a uniform or a varying curvature. In some embodiments of the invention, the curvature of a top surface of implant 100 is within a bending radius range of 2 to 12 cm. In some embodiments of the invention, surface 102 may include one or more protrusions and / or depressions (e.g., with a dimension along the surface of at between 10% and 30% of the implant maximum dimension). Such a depression may extend, for example, to a point between 5% and 30% away or into surface 102, as a percentage of the implant maximum dimension.

[0720] The overall shape of the implant is shown as part of a sphere or semi- sphere or cut-off flattened ovoid. This may be suitable for breast implants. The implant is optionally rotationally symmetric around a central axis, optionally defining a height direction and a lateral plane extending away from and perpendicular to the axis. The dimensions of the implant can be, for example, a diameter between 40 and 200 mm, for example, between 50 and 140, for example between 90 and 130 mm. The height of the implant can be, for example, between 10 and 80 mm, for example, between 15 and 60 mm, for example between 30 and 50 mm. In some embodiments of the invention, the implant does not sag under its own weight when laid flat so as to reduce in height by more than, for example, 20%, 10%, 5%, 2%, 1%, 0.5% or less or intermediate amounts. In some embodiments of the invention, the implant does not sag under its own weight when laid flat and does not reduce in height. Optionally alternatively or additionally, the implant sags less than 20%, 10% 5%, 2%, 1%, 0.5% or intermediate percentages when positioned vertically, so the peak of the implant is horizontal. In some embodiments of the invention, the implant does not sag when positioned vertically and peak retains its horizontal position. Sag in this sense means that the peak does not move down by more the stated percentage of its now vertical dimension.

[0721] The volume of a breast implant can be, for example, between 70cc and lOOOcc, for example, between 200 and 700cc, for example, between 300 and 600 cc and / or other intermediate or larger sizes.

[0722] According to one embodiment, the biocompatible soft tissue implant having a volume of solid portions selected from at least 10%, at least 15%, at least 20%, at least 25%, at least 30% and at least 35% of a curable formulation as described herein, with a 3D structure including a surface lattice defining segments and apertures therebetween. According to one embodiment, there is provided a biocompatible soft tissue implant comprising, by volume of solid portions thereof, the volume of solid portions implant is selected from no more than 70%, no more than 65%, no more than 60%, no more than 55%, no more than 50%, no more than 45% , no more than 40%, no more than 35% no more than 30% and no more than 25% of a curable formulation as described herein, with a 3D structure including a surface lattice defining segments and apertures therebetween.

[0723] An optional skirt 112 surrounding part or all of the implant is printed for example for improving adhesion to the printing platform and may be provided with other implant designs as well. An underside of the implant may be made solid and / or with fewer and / or smaller apertures than other parts and this may improve adhesion to the printing platform. In one embodiment the entire skirt 112 or part thereof is removed post printing. In one embodiment of a breast implant, the entire skirt 112 or part thereof is not removed post printing. In one embodiment of a breast implant, it may be useful to have skirt 112 surrounding part or all of the implant and designated to lie against underlying tissue layers, for example for attachment thereto. Optionally, the skirt is used for suturing and / or adhesive application. Optionally, additional holes can be located in the circumference of the skirt to allow easy access for suturing and / or adhesion. Optionally, the thickness of the skirt and location of the holes are selected to accommodate the stuttering tools and avoid tearing. In some embodiments the skirt and / or other parts of the implant includes or has thereon a fibrosis encouraging material.

[0724] According to one embodiment, the implant comprises a skirt having less than 30% aperture area. According to some embodiments, the circumference of the skirt is free of apertures whereas the underside of the implant comprises apertures. According to some embodiment, the skirt is solid wherein both the circumference of the skirt and the base of the implant is free of apertures. The skirt may extend, for example, between 1 and 30 mm, for example, between 4 and 20 mm, for example between 5 and 15 mm laterally away from the implant. The skirt may surround, for example, between 50% and 100% of the implant circumference, for example, between 70 and 90%, for example, about 80% or smaller percentages. Apertures on an underside of the implant and / or in skirt, where provided, other than suturing apertures, may be, for example, similar in size, larger or smaller than in an upper part of the implant and may have distances between them smaller or larger than on an upper part of the implant.

[0725] According to one embodiment, the lattice is a regular lattice formed of repeating elements and occupies, by volume at least 60 % of a volume of the implant. Optionally and / or alternatively, at least 60% of a material, by volume, of the implant is defined by such lattice. In some embodiments, the structure of the implant is selected to avoid fibrosis.

[0726] It is noted that other types of implant location may result in other shapes and / or dimensions.

[0727] Reference 110 indicates an inside of implant 100. In some embodiments of the invention, implant 100 is hollow, for example, including pores (e.g., open cell) and / or channels, and may include a flattened base. In other embodiments, an inside structure is provided, optionally integral, alternatively added after the fact. Optionally, the inside structure defines an extension of the lattice shown on surface 102.

[0728] In some embodiments of the invention, the structure is expandable, for example, using saline or implant material, such as filler comprising fat cells or fat tissue, the structure swells or expands. Such structure may have an adhesion encouraging surface. When not expanded the structure optionally defines pores which allow and / or encourage tissue migration, for example, between 500 microns to 5mm, 800 microns to 1mm, 100 microns to 2.5mm, 1mm to 8mm 1.3 and 5 mm in minimal dimension, for example, 2.9 mm to 4.1 mm or intermediate values.

[0729] According to some embodiments described herein, the implant comprises pores dimensioned to allow insertion of a canula or a needle therethrough for injection of an injectable filler into the inner cavity.

[0730] According to some embodiments described herein, the injectable filler once injected into the scaffold provides lifting and volume retention to mechanically support the degradable scaffold until proper replacement by host tissue.

[0731] According to some embodiments described herein, the injectable filler is characterized by a viscosity that is a semi-liquid which on the one hand facilitates ease of injection and distribution throughout the voids of the porous scaffold, but on the other hand remains intact at least until tissue ingrowth into the scaffold and tissue regeneration within the scaffold.

[0732] According to some embodiments described herein, the injectable filler comprises at least one or more cells or adipose tissue. According to some embodiments, the cells comprise pericytes, adipose derived stem cells, pre-adipocytes, endothelial cells, progenitor cells, hematopoietic cells, adipocytes, or any combination thereof.

[0733] According to some embodiments, the cells comprise a stromal vascular fraction (SVF) isolated from fat tissue. According to some embodiments described herein, the cells comprise a minimally processed extract from a fat tissue.

[0734] According to some embodiments described herein, the volume of the filler is from about 5 ml to about 400 ml.

[0735] According to some embodiments, the injectable filler further comprises at least one extracellular matrix (ECM) component. According to some embodiments, the at least one ECM component comprises rhCollagen, hyaluronic acid (HA), fibronectin, heparin, elastin, or laminin, or any combination thereof. According to some embodiments described herein, the rhCollagen comprises at least one of a cross-linked fibrillar rhCollagen and rhCollagen-derived nanoparticles. According to some embodiments described herein, the matrix further comprises an integrin- binding material. According to some embodiments, a weight ratio between the ECM component and the cells or adipose tissue in the filler ranges from 1: 1 to 1:5.

[0736] In some embodiments of the invention, the inside structure (and / or surface 102) includes one or more membranes which may guide tissue ingrowth preferences. Optionally or additionally, the structure includes one or more fibers which provide tensile strength. Optionally, such fibers are inserts made of a non-degrading material or of a material that degrade slower and / or materials that encourage fibrosis creation. In some embodiments, the fibers are made of a material that is selected to avoid fibrosis.

[0737] Referring back to the lattice of surface 102, a segment also referred to herein as beam 108 can be, for example, generally cylindrical in shape, with, for example, a circular, oval, twisted and / or triangular cross-section. In some embodiments, the segments may have a flat face, for example facing away or towards the inside of implant 100. In some embodiments of the invention, the lateral cross-sectional dimension of a segment is between 0.2 and 2 mm, for example, between 0.5 and 1.2 mm or smaller or intermediate sizes. In some embodiments of the invention, the lateral cross-sectional dimension of a segment is between 2 and 5mm, for example, between 2 and 4 mm or smaller or intermediate sizes, for example, 2.5 mm or 3 mm. The dimensions of the segments may be matched to the material used and / or intended use, so as to control how much structural strength of implant 100 degrades over time and, optionally desirably, in coordination with tissue growth. Apertures 106 have, for example, a size between 0.5 and 8 mm in maximal dimension, for example, between 1 and 3 mm or smaller or larger sizes. In some embodiments of the invention, the ratio between aperture sizes and segment sizes is greater than 1, for example, being between 0.8 and 3, for example, between 1.2 and 2. Greater apertures may assist in tissue ingrowth (e.g., for a same or similar number of apertures) and / or reduce overall fill volume of the implant and amount of material used and / or which needs to degrade.

[0738] In some embodiments of the invention, segments 108 are solid. Alternatively, they may be hollow and / or grooved. A hollow segment may include one or more openings in its walls, for example, to allow tissue ingrowth.

[0739] As shown in Fig. 1A, implant 100 may be based on a lattice structure with substantially repeating units, in this case an aperture and half of its neighboring segments. In some embodiments of the invention, the lattice inside of implant 100 is a Cartesian lattice, including multiple layers, for example, between 2 and 10 layers or between 4 and 8 layers intermediate the base and the cover surface, for example, 3, 4, 5 or 6 layers. The layers may be interconnected by Cartesian segments (e.g., which align with the height axis and / or lateral plane). In some embodiments of the invention, one or more angled segments are provided to interconnect layers.

[0740] The implant may include between 2 and 20 internal columns along the diameter formed of segments that interconnect layers, for example, between 8 and 12. The implant may include in total between 20 and 300 internal columns formed of segments that interconnect layers, for example, between 100 and 200, for example 150.

[0741] In some embodiments of the invention, the number of layers and / or columns can depend, for example, on the implant volume and / or desired mechanical properties. In some particular examples, the implant has a volume between 35 and 150 cc, for example 40 cc; and / or between 3 and 5 layers, for example 3; and / or between 27 and 42 columns overall, for example 35; and / or between 35 and 53 beams, for example 42 (a beam defined as a continuous sequence of segments from one side of the implant to another)

[0742] Fig. IB shows an alternative design also using modules, this time with a triangular, rather than a rectangular or hexagonal or square shape for a module.

[0743] Fig. 1C shows yet another design, a polar design, in which there is no lateral uniformity between modules, but the design may be rotationally symmetric and may include arc- sectors of similar or same structure.

[0744] As can be seen, all three designs share an optional base ring 104 which circumscribes the implant and may provide resistance against collapse.

[0745] One potential advantage of modular designs, for example as shown in Figs. 1A-1C is potential ease of non-3D printing manufacturing methods. Another potential advantage is more uniform tissue ingrowth and device degradation properties. Another potential advantage is ease of modeling behavior and / or of designing various implants and / or sizes. Another potential advantage is relative symmetry allowing insertion in any orientation.

[0746] In some embodiments of the invention, the segments and / or added tensile elements or structures are oriented according to expected deformation forces to be resisted and / or to avoid damage under deformation. In some embodiments of the invention, these forces and / or deformation directions are not expected to be uniform and implant 100 is designed in a non- uniform manner. This may suggest a preferred orientation direction which may be marked on the implant. In some embodiments of the invention, this non-uniformity is in shape. Optionally or additionally, the non-uniformity is in materials used. It is noted that even in a symmetric implant different parts may be amenable to faster or to slower degradation due to forces they are to resist, expected tissue ingrowth and / or the existing or desired breast tissue volume, mechanical behavior and / or aesthetic effect. In some embodiments of the invention, this results in a greater density and / or segment size in some parts of the implant compared to others.

[0747] In use, implant 100 is optionally compressed, optionally twisted and inserted (typically manually) through a small incision, for example, between 4 and 10 cm, for example between 4 and 5 cm and / or between 7 and 9 cm and then spread out. In some embodiments the incision is between 5 and 6cm and / or between 6 and 7 cm and then spread out. The mechanical structure and resilience are optionally selected to avoid damage to the structure while allowing implantation through a smallest possible incision. The manipulation of the implant is typically by hand and the structure and formulation used is optionally selected to allow such manipulation without significant damage to the implant. One example family of structures which may be more suitable for aggressive manipulation is shown in Fig. 25B. For example, the diagonal segments can contribute to implant flexibility (see Fig. 26A and Fig. 2Ca) and fillets can contribute to its toughness and strength (see Fig. 2Ba).

[0748] Optionally, adjustment to the formulation may be made to impart higher strength under compression. The use of a lattice structure may also contribute to such resilience and flexibility, for example, as compared to a solid implant (e.g., mostly non-porous). Different lattice designs (e.g., as in Figs. 1A-1D) may have different flexibilities and may be suitable for different size incisions (e.g., for a same overall implant volume). The material (e.g., as described herein or if a different material is used) is optionally stretchable and compressible and thereby contributes to the overall flexible behavior of the implant. Larger pores (e.g., larger apertures and / or smaller diameter segments) can also contribute to the softness of the implant and / or provide an overall increase of strain which may help reduce the incision size. In some embodiments of the invention, the material used is elastic, so that the structure can return to its original shape after inserted through the incision.

[0749] In some embodiments of the invention, the material used is transparent or translucent. This may assist in visualization, for example, using an endoscope or other intrabody imager. Optionally alternatively or additionally, transparent structures are potentially less visible through the skin, potentially resulting in patient compliance. Another potential advantage is when the product is presented to a physician or a patient, transparent scaffolds may have a psychological advantage, especially as compared to colored and / or opaque structures, which may appear more massive and / or invasive. In some embodiments of the invention, implant 100 is designed for imaging and / or monitoring from outside the body. In one example, implant 100 includes one or more radio-opaque markers, optionally in the form of a liquid, which show the location of certain implant features. A potential advantage of liquids is that once the device degrades, the markers dissipate and this may also indicate a state of degradation. Other dissipating markers may be used, for example, as described in US6174330B1.

[0750] Optionally alternatively or additionally to a radio-opaque marker, an MRI marker may be used, for example, to help assess degradation. In some embodiments of the invention, the implant is visible in MRI without any special markers. Optionally alternatively or additionally, an ultrasound marker may be used, for example an air bubble or microbubbles. In one example, microbubble or other ultrasonic contrast materials are injected into implant 100 and remain as markers while implant 100 maintains its structural integrity. Different locations may degrade sooner and lose ultrasound properties (or radio opacity properties) at different times and this is optionally used to track degradation. Degradation tracking is optionally by assessing changes in the geometry and / or dimensions of segments 108, e.g., as observed using ultrasound or MRI or other imaging technology. In some embodiments, indicator segments are included which have a known and different size and degradation monitoring observes the tracking of degradation of such preselected indicator segments. In some embodiments of the invention, micro-CT, is used to track degradation.

[0751] Implant 100 may be made, for example, by 3D printing methods. In some embodiments of the invention, other manufacturing methods are used, for example, a molding method may be used, optionally with an investment casting method (e.g., lost wax, possibly with a material other than wax, optionally 3D printed) method or using a flexible internal mold to fill in spaces between segments 108.

[0752] In some embodiments of the invention, implant 100 is formed by taking a plurality of modules and connecting them together (optionally within a confining structure such as a mold). One method of connecting implant parts is using a formulation such as described herein and using UV (e.g., with a transparent mold) and / or adhesive (potentially the photocurable formulations described herein) to the modules to attach to each other. In one example, large implants such as 800cc implants are formed from two or more pieces printed separately and then attached. Optionally and / or alternatively molds are printed lying on their side. Due to different behavior of intra-layer and inter-layer material mechanical properties (e.g., due to typically weaker adhesion between layers), printing in a lateral direction (e.g., so the base of the implant is perpendicular to the printer base - layer 0) may require changing the design, for example, by providing more robust inter-layer interfaces. The resolutions between and within layers may also differ. In some, but not all, embodiments of the invention, the lattice is aligned with the 3D printer coordinates. For example, the X-Y plane (and lattice plane) are parallel to the printer base plane. Optionally and / or alternatively the z-axis is perpendicular to the printing plane and lattice elements may all, or mainly, be aligned with such axis. The examples tested in this application are printed with the base of the implant lying on the base of the printer volume. In some embodiments of the invention, interlayer adhesion is modified by tuning of layer thickness formulations and / or energy, optionally guided by testing of adhesion within or between layers.

[0753] In some embodiments of the invention, a standard size implant is cut to size, as needed.

[0754] A potential advantage of some of these methods of manufacture is the option of shaping implant geometry and / or mechanical properties and / or degradation rate and / or control of tissue ingrowth to match the needs of a particular patient. In some embodiments of the invention, such making to order includes an analysis of implant properties. In some embodiments of the invention, a finite element analysis is used to determine a desired implant shape and / or properties thereof.

[0755] In some embodiments the shape and / or internal structure are found by a search process which may include optimization, optionally starting with one of the designs herein with constraints on segment and / or aperture size. For example, a user may indicate a general shape and may indicate forces to be resisted optionally in certain directions. Circuitry (e.g., a computer with software) can then search the space of possible implants, by varying one or more design parameters until one or more satisfactory designs are found. In such designs, some or all symmetry and / or uniformity in the original design may be lost.

[0756] In some embodiments of the invention, the searching also takes into account a time dimension - for example, what forces and what tissue ingrowths are expected at different times and / or how the implant might be stressed, for example, what type of support (e.g., brassiere) might be used and / or what type of activity, such as mammography, jumping, bouncing on a ball, exercise (e.g., running or swimming) the recipient of the implant might practice, and / or when.

[0757] Fig. ID shows a variant implant 230, where segment intersections have fillets, such as a fillet 232. A potential result of using fillets is that the apertures can have the shape of a rounded pore. This may increase the resistance to load of implant 230 as compared to implant 100, for example as shown in Fig. 2B. Optionally alternatively or additionally, the fillets may serve to control the uniformity of tissue adhesion and / or ingrowth, which might otherwise be different between flat surfaces and sharp angles. In some cases, it is desirable to avoid sharp edges. Cells that grow into sharp corners might suffer from lack of nutrients and / oxygen supply. Optionally alternatively or additionally, such comers may subject cells to mechanical / tactile signals. Fillets may also have an advantage of avoiding or reducing blockage of an aperture to cell migration. In some embodiments of the invention, at least 50% of the apertures are limited to have minimum and maximum dimensions within the range of 2-8 mm, for example, 3-5 mm, for example up to 4mm.

[0758] Not all intersections need to have fillets. Such fillets may be provided, for example, on at least 50%, 70% or more of the intersection in surface 102 and / or in inner intersections below surface 102. In some embodiments of the invention, the fillets have a 3D shape, for example, conforming to the 3D shape of the segments.

[0759] In some embodiments of the invention, the fillets serve to thicken segments 108 and provide resistance to buckling or breakage. Optionally alternatively or additionally, fillets serve to avoid or reduce concentration of stress which may cause implant structure failure.

[0760] It is noted that fillets may be provided in any of the implant designs shown herein and in other designs as well.

[0761] In some embodiments of the invention, a fillet defines a radius of curvature that is at least 10%, 30%, 50%, 70% or more of the maximal dimension of an aperture 106. Different fillets may be used for different size apertures.

[0762] It is noted that, in general, it may be desirable to trade off two or more or all of high porosity, initial mechanical strength, added material due to fillets and internal structure, to provide an implant that is both function and resistant and with a typical preference to reducing the overall amount of material. For example, in some embodiments of the invention, the porosity of implant 100 (e.g., how much of the volume defined by the implant is formed of the implant material(s)) is increase, for example, by 10%, 20% or more, due to the use of fillets and / or structural elements to improve mechanical behavior so that thinner segments may be used. For example, implants shown in Fig. 1A-1C may have a porosity about between 40% and 60 % and Implant 230 may have a porosity of between 50% and 70%, for example, 60%.

[0763] One way of reducing porosity while maintaining or increasing strength, in addition to or instead of using fillets is by non-uniformities and non-Cartesian structures in the implant.

[0764] Fig. 25A shows an implant design which is generally Cartesian, but which includes diagonally oriented segments (e.g., 302) interconnecting different horizontal layers. Segments 302, which may also be termed diagonal struts in a plane at an angle to the base of the implant and generally at an angle to lattice directions (e.g., in a design where a 3D Cartesian lattice is provided). In some cases, such angled strut segments replace in-plane segments, for example on a one to one or one to two basis. Such strut segments can be diagonal in one dimension or two, e.g., connecting between lattice nodes that lie in a same perpendicular plane or not. Triangular shapes generated by such struts may be more effective in resisting collapse than pure Cartesian lattice arrangements and / or may define zig-zag paths for compression forces.

[0765] Such design is potentially used to ameliorate a weakness of the material to stretching, preventing failure due to buckling. Optionally or additionally, such design may help in reducing buckling which does not damage the structure, but interferes with implant geometry and / or tissue growth, via a mechanism of collapsed apertures. In some embodiments, the structure may be required to act elastic under static loads, for example, as expected in typical use.

[0766] In some embodiments, the cross-sectional diameter of a segment is greater near a center of the implant than towards a periphery thereof. This may reflect the greater amount of connected tissue and / or expected forces near such center. For example, a thickness of a segment may go down by, for example, 10%, 30%, 50% or intermediate or larger percentages at the center region of the implant (e.g., within 15% of the central axis) as compared to the periphery. In one example, the segments decline from a diameter of 3 mm to a diameter of 2.5 mm. Such decrease is optionally, but not necessarily, associated with an increase in aperture dimension or may result in layers being misaligned and of different sizes. Fig. 25B shows an example where the segments are made thicker towards a center axis, and optionally (or possibly alternatively) a lower part of the central axis, of the implant, potentially resulting in a smaller aperture size in such locations, as compared to a periphery (e.g., with a distance, center to center, of segments remaining the same). Also shown in Fig 25B is an optional feature which may be provided in other designs as well, that the segments of the surface may have a different cross-section than internal segments, for example, flattened and conforming to a surface curvature.

[0767] A potential advantage of greater segment thickness in parts of the implant that are thicker / have a greater height, is more resistance to collapse (or buckling) under vertical forces.

[0768] A potential advantage of having thicker segments towards a base of the implant is delaying contact between segments when the implant is vertically collapsed. In some example embodiments, thicker segments towards the base increases the implant stiffness (e.g., lower compression strain under higher forces) which results in delayed contact between the segments resulting in pores remaining open allowing for tissue infiltration.

[0769] Fig. 25C and 25D show implants with different sizes of apertures and segments. Fig. 25D has smaller apertures and smaller segments and more layers and columns than that the design of Fig. 25C. It is noted in comparison to Fig. 25A, for example, that segments diameter is significantly smaller than aperture diameter, and segments include non-filleted sections over between 30% and 80% of their length, for example, between 40% and 60%, while in other designs, the fillet-free length of a segment may be between 0% and 30%, for example, between 10% and 20% of a segment length. Segment length is defined being between node center and node center. It is noted that smaller segment diameters result in a larger surface to volume ratio and / or, per segment, a smaller overall maximal distance between an innermost part of a segment and an outer surface of a segment, which may result in faster degradation for some degradation methods. These may result in faster degradation. Optionally alternatively or additionally, segment size is selected to match or affect a desired degradation rate. Aperture size may affect the rate of tissue growth. As shown herein, various combinations of segment diameters and (at least to some extent, independently) aperture sizes (and the hollows defined between them). In some embodiments of the invention, the two parameters (optionally together with a formulation property) are selected to achieve a desired ratio between tissue ingrowth and implant degradation.

[0770] As used herein the term “about” refers to ± 10 % or ± 5 %.

[0771] The terms “comprises”, “comprising”, “includes”, “including”, “having” and their conjugates mean “including but not limited to”.

[0772] The term “consisting of’ means “including and limited to”.

[0773] The term “consisting essentially of’ means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure.

[0774] As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a compound” or “at least one compound” may include a plurality of compounds, including mixtures thereof.

[0775] Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0776] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging / ranges between” a first indicate number and a second indicate number and “ranging / ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0777] As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

[0778] Herein throughout, whenever “centipoise” or “Cp” is indicated, the corresponding Pa- second value (1 Pa- second = 1,000 centipoise) is encompassed.

[0779] Herein throughout, whenever the phrase “weight percent”, or “% by weight” or “% wt.”, is indicated in the context of embodiments of a formulation (e.g., a modeling formulation, a curable formulation, a bioink composition), it is meant weight percent of the total weight of the respective uncured formulation.

[0780] Herein throughout, the phrase “linking moiety” or “linking group” describes a group that connects two or more moieties or groups in a compound. A linking moiety is typically derived from a bi- or tri-functional compound, and can be regarded as a bi- or tri-radical moiety, which is connected to two or three other moieties, via two or three atoms thereof, respectively.

[0781] Exemplary linking moieties include a hydrocarbon moiety or chain, optionally interrupted by one or more heteroatoms, as defined herein, and / or any of the chemical groups listed below, when defined as linking groups.

[0782] When a chemical group is referred to herein as “end group” it is to be interpreted as a substituent, which is connected to another group via one atom thereof.

[0783] Herein throughout, the term “hydrocarbon” collectively describes a chemical group composed mainly of carbon and hydrogen atoms. A hydrocarbon can be comprised of alkyl, alkene, alkyne, aryl, and / or cycloalkyl, each can be substituted or unsubstituted, and can be interrupted by one or more heteroatoms. The number of carbon atoms can range from 2 to 30, and is preferably lower, e.g., from 1 to 10, or from 1 to 6, or from 1 to 4. A hydrocarbon can be a linking group or an end group.

[0784] As used herein, the term “amine” describes both a -NR’R” group and a -NR'- group, wherein R’ and R" are each independently hydrogen, alkyl, cycloalkyl, aryl, as these terms are defined hereinbelow.

[0785] The amine group can therefore be a primary amine, where both R’ and R” are hydrogen, a secondary amine, where R’ is hydrogen and R” is alkyl, cycloalkyl or aryl, or a tertiary amine, where each of R’ and R” is independently alkyl, cycloalkyl or aryl. Alternatively, R' and R" can each independently be hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, carbonyl, C -carboxylate, O-carboxylate, Nthiocarbamate, Othiocarbamate, urea, thiourea, Ncarbamate, Ocarbamate, C-amide, Namide, guanyl, guanidine and hydrazine.

[0786] The term “amine” is used herein to describe a -NR'R" group in cases where the amine is an end group, as defined hereinunder, and is used herein to describe a -NR'- group in cases where the amine is a linking group or is or part of a linking moiety.

[0787] The term "alkyl" describes a saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 30, or 1 to 20 carbon atoms. Whenever a numerical range; e.g., " 1-20", is stated herein, it implies that the group, in this case the alkyl group, may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. The alkyl group may be substituted or unsubstituted. Substituted alkyl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, Nthiocarbamate, Othiocarbamate, urea, thiourea, Ncarbamate, Ocarbamate, C-amide, N-amide, guanyl, guanidine and hydrazine.

[0788] The alkyl group can be an end group, as this phrase is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, which connects two or more moieties via at least two carbons in its chain. When the alkyl is a linking group, it is also referred to herein as “alkylene” or “alkylene chain”.

[0789] Alkene and Alkyne, as used herein, are an alkyl, as defined herein, which contains one or more double bond or triple bond, respectively.

[0790] The term "cycloalkyl" describes an all-carbon monocyclic ring or fused rings (z.e., rings which share an adjacent pair of carbon atoms) group where one or more of the rings does not have a completely conjugated pi-electron system. Examples include, without limitation, cyclohexane, adamantine, norbomyl, isobomyl, and the like. The cycloalkyl group may be substituted or unsubstituted. Substituted cycloalkyl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C- carboxylate, O-carboxylate, Nthiocarbamate, Othiocarbamate, urea, thiourea, Ncarbamate, Ill Ocarbamate, Camide, Namide, guanyl, guanidine and hydrazine. The cycloalkyl group can be an end group, as this phrase is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties at two or more positions thereof.

[0791] The term "heteroalicyclic" describes a monocyclic or fused ring group having in the ring(s) one or more atoms such as nitrogen, oxygen and sulfur. The rings may also have one or more double bonds. However, the rings do not have a completely conjugated pi-electron system. Representative examples are piperidine, piperazine, tetrahydrofurane, tetrahydropyrane, morpholino, oxalidine, and the like.

[0792] The heteroalicyclic may be substituted or unsubstituted. Substituted heteroalicyclic may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, Nthiocarbamate, Othiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine. The heteroalicyclic group can be an end group, as this phrase is defined hereinabove, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties at two or more positions thereof.

[0793] The term "aryl" describes an all-carbon monocyclic or fused-ring polycyclic (z.e., rings which share adjacent pairs of carbon atoms) groups having a completely conjugated pi-electron system. The aryl group may be substituted or unsubstituted. Substituted aryl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, Nthiocarbamate, Othiocarbamate, urea, thiourea, Ncarbamate, Ocarbamate, C-amide, N-amide, guanyl, guanidine and hydrazine. The aryl group can be an end group, as this term is defined hereinabove, wherein it is attached to a single adjacent atom, or a linking group, as this term is defined hereinabove, connecting two or more moieties at two or more positions thereof.

[0794] The term "heteroaryl" describes a monocyclic or fused ring (z.e., rings which share an adjacent pair of atoms) group having in the ring(s) one or more atoms, such as, for example, nitrogen, oxygen and sulfur and, in addition, having a completely conjugated pi-electron system. Examples, without limitation, of heteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline and purine. The heteroaryl group may be substituted or unsubstituted. Substituted heteroaryl may have one or more substituents, whereby each substituent group can independently be, for example, hydroxyalkyl, trihaloalkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, hetero alicyclic, amine, halide, sulfonate, sulfoxide, phosphonate, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, cyano, nitro, azo, sulfonamide, C-carboxylate, O-carboxylate, Nthiocarbamate, Othiocarbamate, urea, thiourea, O-carbamate, N-carbamate, C-amide, N-amide, guanyl, guanidine and hydrazine. The heteroaryl group can be an end group, as this phrase is defined hereinabove, where it is attached to a single adjacent atom, or a linking group, as this phrase is defined hereinabove, connecting two or more moieties at two or more positions thereof. Representative examples are pyridine, pyrrole, oxazole, indole, purine and the like.

[0795] The term "halide" and “halo” describes fluorine, chlorine, bromine or iodine.

[0796] The term “haloalkyl” describes an alkyl group as defined above, further substituted by one or more halide.

[0797] The term "carbonyl" or "carbonate" as used herein, describes a -C(=O)-R’ end group or a -C(=O)- linking group, as these phrases are defined hereinabove, with R’ as defined herein.

[0798] The term "thiocarbonyl" as used herein, describes a -C(=S)-R’ end group or a -C(=S)- linking group, as these phrases are defined hereinabove, with R’ as defined herein.

[0799] The term “oxo” as used herein, describes a (=0) group, wherein an oxygen atom is linked by a double bond to the atom (e.g., carbon atom) at the indicated position.

[0800] The term “thiooxo” as used herein, describes a (=S) group, wherein a sulfur atom is linked by a double bond to the atom (e.g., carbon atom) at the indicated position.

[0801] The term “oxime” describes a =N-0H end group or a =N-0- linking group, as these phrases are defined hereinabove.

[0802] The term “hydroxyl” describes a -OH group.

[0803] The term "alkoxy" describes both an -O-alkyl and an -O-cycloalkyl group, as defined herein. The term alkoxide describes -R’0“ group, with R’ as defined herein.

[0804] The term "aryloxy" describes both an -O-aryl and an -O-heteroaryl group, as defined herein.

[0805] The term "thiohydroxy" or “thiol” describes a -SH group. The term “thiolate” describes a -S’ group.

[0806] The term "thioalkoxy" describes both a -S-alkyl group, and a -S-cycloalkyl group, as defined herein.

[0807] The term "thioaryloxy" describes both a -S-aryl and a -S-heteroaryl group, as defined herein. The “hydroxyalkyl” is also referred to herein as “alcohol”, and describes an alkyl, as defined herein, substituted by a hydroxy group.

[0808] The term “acyl halide” describes a -(C=O)R"" group wherein R"" is halide, as defined hereinabove.

[0809] The term “carboxylate” as used herein encompasses C-carboxylate and O-carboxylate.

[0810] The term “Ccarboxylate” describes a -C(=O)-OR’ end group or a -C(=0)-0 linking group, as these phrases are defined hereinabove, where R’ is as defined herein.

[0811] The term “Ocarboxylate” describes a -OC(=O)R’ end group or a -OC(=O) linking group, as these phrases are defined hereinabove, where R’ is as defined herein.

[0812] A carboxylate can be linear or cyclic. When cyclic, R’ and the carbon atom are linked together to form a ring, in C-carboxylate, and this group is also referred to as lactone. Alternatively, R’ and O are linked together to form a ring in O-carboxylate. Cyclic carboxylates can function as a linking group, for example, when an atom in the formed ring is linked to another group.

[0813] The term “thiocarboxylate” as used herein encompasses C-thiocarboxylate and O- thiocarboxylate.

[0814] The term “Cthiocarboxylate” describes a -C(=S)-OR’ end group or a -C(=S)-0 linking group, as these phrases are defined hereinabove, where R’ is as defined herein.

[0815] The term “Othiocarboxylate” describes a -OC(=S)R’ end group or a -OC(=S) linking group, as these phrases are defined hereinabove, where R’ is as defined herein.

[0816] A thiocarboxylate can be linear or cyclic. When cyclic, R’ and the carbon atom are linked together to form a ring, in C-thiocarboxylate, and this group is also referred to as thiolactone. Alternatively, R’ and O are linked together to form a ring in O-thiocarboxylate. Cyclic thiocarboxylates can function as a linking group, for example, when an atom in the formed ring is linked to another group.

[0817] The term “carbamate” as used herein encompasses N-carbamate and O-carbamate.

[0818] The term “N-carbamate” describes an R”OC(=O)-NR’- end group or a OC(=O)-NR’- linking group, as these phrases are defined hereinabove, with R’ and R” as defined herein.

[0819] The term “O-carbamate” describes an -OC(=O)-NR’R” end group or an -OC(=O)-NR’ linking group, as these phrases are defined hereinabove, with R’ and R” as defined herein.

[0820] A carbamate can be linear or cyclic. When cyclic, R’ and the carbon atom are linked together to form a ring, in O-carbamate. Alternatively, R’ and O are linked together to form a ring in N-carbamate. Cyclic carbamates can function as a linking group, for example, when an atom in the formed ring is linked to another group.

[0821] The term “carbamate” as used herein encompasses N-carbamate and O-carbamate.. The term “thiocarbamate” as used herein encompasses N-thiocarbamate and O- thiocarbamate.

[0822] The term “O-thiocarbamate” describes a OC(=S)NR’R” end group or a OC(=S)NR’ linking group, as these phrases are defined hereinabove, with R’ and R” as defined herein.

[0823] The term “N-thiocarbamate” describes an R”OC(=S)NR’- end group or a OC(=S)NR’- linking group, as these phrases are defined hereinabove, with R’ and R” as defined herein.

[0824] Thiocarbamates can be linear or cyclic, as described herein for carbamates.

[0825] The term “dithiocarbamate” as used herein encompasses S -dithiocarbamate and N- dithiocarbamate.

[0826] The term “S -dithiocarbamate” describes a SC(=S)NR’R” end group or a SC(=S)NR’ linking group, as these phrases are defined hereinabove, with R’ and R” as defined herein.

[0827] The term “N-dithiocarbamate” describes an R”SC(=S)NR’- end group or a SC(=S)NR’- linking group, as these phrases are defined hereinabove, with R’ and R” as defined herein.

[0828] The term "urea", which is also referred to herein as “ureido”, describes a -NR’C(=O)- NR”R’ ’ ’ end group or a -NR’C(=O)-NR”- linking group, as these phrases are defined hereinabove, where R’ and R” are as defined herein and R'" is as defined herein for R' and R".

[0829] The term “thiourea”, which is also referred to herein as “thioureido”, describes a -NR’- C(=S)-NR”R”’ end group or a -NR’-C(=S)-NR” linking group, with R’, R” and R’” as defined herein.

[0830] The term “amide” as used herein encompasses C-amide and N-amide.

[0831] The term “C-amide” describes a -C(=O)-NR’R” end group or a -C(=O)-NR’- linking group, as these phrases are defined hereinabove, where R’ and R” are as defined herein.

[0832] The term “N-amide” describes a R’C(=O)-NR”- end group or a R’C(=O)-N- linking group, as these phrases are defined hereinabove, where R’ and R” are as defined herein.

[0833] An amide can be linear or cyclic. When cyclic, R’ and the carbon atom are linked together to form a ring, in C-amide, and this group is also referred to as lactam. Cyclic amides can function as a linking group, for example, when an atom in the formed ring is linked to another group.

[0834] As used herein, the term “alkylene glycol” describes a -O-[(CR’R”)Z-O]y-R”’ end group or a -O-[(CR’R”)Z-O]y- linking group, with R’, R” and R’” being as defined herein, and with z being an integer of from 1 to 10, preferably, from 2 to 6, more preferably 2 or 3, and y being an integer of 1 or more. Preferably R’ and R” are both hydrogen. When z is 2 and y is 1, this group is ethylene glycol. When z is 3 and y is 1, this group is propylene glycol. When y is 2-4, the alkylene glycol is referred to herein as oligo(alkylene glycol). When y is higher than 4, it is a poly(alkylene glycol). Capped poly(alkylene glycol) has R’” which is other than hydrogen and which can be, for example, an alkyl (e.g., lower alkyl), a carbonyl, and like moieties.

[0835] Exemplary methods and protocols, as described herein, are described in the Examples section that follows, although any other methods and protocols known in the art are contemplated. A person skilled in the art would readily recognized how to perform these steps, typically using conventional and / or widely applied protocols known in the art.

[0836] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0837] Various embodiments and aspects of the present invention as delineated hereinabove and as claimed in the claims section below find experimental support in the following examples.

[0838] EXAMPLES

[0839] Reference is now made to the following examples, which together with the above descriptions illustrate some embodiments of the invention in a non-limiting fashion.

[0840] MATERIALS, DESIGN AND EXPERIMENTAL METHODS

[0841] Table 1 below identifies the materials used in the studies.

[0842] Table 1

[0843] All the formulations were prepared in accordance with the following general procedure.

[0844] A 10 mM HC1 stock solution was prepared in water for injection (WFI). The stock solution was then filtered using a 0.22-micron PES filter.

[0845] A NAP stock solution (25 mg / mL) was prepared in WFI in a light-protected bottle, by vortexing or stirring the solution at room temperature, followed by filtration through a 0.22- micron filter. Dissolution was verified visually.

[0846] The NAP stock solution and the HC1 stock solution were added to a formulation bottle, a low MW photocurable polymeric material (short polymer) was weighed and transferred to the formulation bottle, and the mixture was stirred using an overhead stirrer for at least 30 minutes. Dissolution was verified visually. High MW photocurable polymeric material (long polymer) was weighed and transferred to the formulation bottle, and the mixture was again stirred with an overhead stirrer for at least 30 minutes, until dissolution was visually confirmed. Low MW photocurable polymeric material (short polymer) was weighed and transferred to the formulation bottle, and the mixture was again stirred with an overhead stirrer for at least 30 minutes. The PB was then weighed and transferred to the formulation bottle, with the mixture stirred using an overhead stirrer until dissolution was visually verified.

[0847] A CMR stock solution (13-17mg / mL) was added slowly to the formulation bottle, and solubility was confirmed. The actual weight percentage in the experimenta...

Claims

WHAT IS CLAIMED IS:

1. A photocurable formulation usable in additive manufacturing a three-dimensional object featuring, in at least a portion thereof, a biological or a biocompatible material, the photocurable formulation comprising a photoinitiator, a photocurable biological or biocompatible material, and a carrier, the formulation further comprising at least two photocurable polymeric materials, wherein: at least one of said at least two photocurable polymeric materials has an average molecular weight lower than 10,000 grams / mol (low MW photocurable polymeric material), and at least another one of said at least two photocurable polymeric materials has an average molecular weight higher than 10,000, or higher than 15,000 (high MW photocurable polymeric material), grams / mol; a total amount of said at least two photocurable polymeric materials is in a range of from 1 to 20, or from 5 to 20, or from 5 to 15, or from 7.5 to 15, or from 7.5 to 10, % by weight, of the total weight of the curable formulation; and a weight ratio between said low MW photocurable polymeric material and said high MW photocurable polymeric material ranges from 1: 1 to 1:9, or from 1: 1 to 1:5.

2. The photocurable curable formulation of claim 1, wherein each of said photocurable polymeric material independently is a multifunctional photocurable polymeric material featuring two or more photocurable groups.

3. The photocurable formulation of claim 2, wherein said photocurable groups are (meth)acrylic groups.

4. The photocurable formulation of claim 3, wherein said (meth)acrylic groups are selected from acrylate and methacrylate groups, provided that at least one of said photocurable polymeric materials features acrylate groups.

5. The photocurable formulation of claim 4, wherein one of said at least two photocurable polymeric materials features a plurality of acrylate groups and another one of said photocurable polymeric materials features a plurality of methacrylate groups.

6. The photocurable formulation of any one of claims 1 to 5, wherein at least one of said photocurable polymeric materials comprises a poly(alkylene glycol) polymeric backbone.

7. The photocurable formulation of any one of claims 1 to 6, wherein said low MW photocurable polymeric material is a poly(alkylene glycol) that terminates by two (or more) acrylate or methacrylate groups.

8. The photocurable formulation of any one of claims 1 to 7, wherein an average molecular weight of said low MW photocurable polymeric material ranges from 500 to 10,000, or from 500 to 5,000, or from 500 to 4,000, or from 500 to 3,500, or from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, or from 1,000 to 3,500, or from 500 to 3,500, or from 1,000 to 3,000, or from 1,000 to 2,000, grams / mol.

9. The photocurable formulation of any one of claims 1 to 7, wherein said high MW photocurable polymeric material comprises a poly(alkylene glycol) polymeric backbone and terminates by two (or more) acrylate or methacrylate groups.

10. The photocurable formulation of claim 9, wherein an average molecular weight of said poly(alkylene glycol) polymeric backbone is higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol.

11. The photocurable formulation of claims 9 or 10, wherein an average molecular weight of said poly (alkylene glycol) polymeric backbone ranges from 10,000 to 40,000, or from 10,000 to 30,000, or from 15,000 to 40,000, or from 15,000 to 30,000, or from 20,000 to 40,000, or from 20,000 to 30,000, or from 20,000 to 25,000, grams / mol.

12. The photocurable formulation of any one of claims 9 to 11, wherein said high MW photocurable polymeric material is a multi-block (e.g., diblock or triblock) co-polymer that comprises said poly(alkylene glycol) polymeric backbone as one block and at least one additional block that comprises a polymeric backbone of a biodegradable polymer other than poly(alkylene glycol).

13. The photocurable formulation of claim 12, wherein said high MW photocurable polymeric material is a tri-block co-polymer that comprises said poly(alkylene glycol) polymeric backbone as a middle block having attached to its termini two additional blocks, each comprising a polymeric backbone of a biodegradable polymer other than poly(alkylene glycol) that terminates by a photocurable group.

14. The photocurable formulation of claim 12 or 13, wherein said biodegradable polymer is a polyester.

15. The photocurable formulation of any one of claims 12 to 14, wherein said biodegradable polymer is poly(caprolactones) (PCL).

16. The photocurable formulation of any one of claims 12 to 15, wherein a molecular weight of said at least one additional block is lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol.

17. The photocurable formulation of any one of claims 12 to 16, wherein a molecular weight of said at least one additional block ranges from 500 to 5,000, or from, 500 to 4,000, or from 500 to 3,000, or from 500 to 2,000, or from 1,000 to 5,000, or from 1,000 to 4,000, or from 1,000 to 3,000, or from 1,000 to 2,000, grams / mol.

18. The photocurable formulation of any one of claims 1 to 17, wherein said high MW photocurable polymeric material is a triblock polymeric material that comprises a poly(alkylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by at least one (meth) acrylate group.

19. The photocurable formulation of claim 4, wherein: said low MW photocurable polymeric material is a poly(alkylene glycol) that terminates by two of said acrylate or methacrylate groups and has an average molecular weight that ranges from 1,000 to 10,000, or from 2,000 to 10,000, or from 1,000 to 8,000, or from 2,000 to 8,000, or from 1,000 to 6,000, or from 2,000 to 6,000, or from 1,000 to 5,000 or from 2,000 to 5,000, or from 3,000 to 6,000 or from 3,000 to 5,000 or from 3,000 to 4,000, grams / mol; andsaid high MW photocurable material is a triblock polymeric material that comprises a poly(alkylene glycol) polymeric backbone having a MW higher than 10,000, or higher than 15,000 or higher than 20,000 grams / mol and having attached to each of its termini a block of a polyester having a MW lower than 5,000, or lower than 3,000, or lower than 2,000, grams / mol and terminating by said (meth)acrylate group.

20. The photocurable formulation of claim 19, wherein said low MW photocurable polymeric material terminate by two acrylate groups.

21. The photocurable formulation of claim 19 or 20, wherein said high MW photocurable polymeric material terminates by two methacrylate groups.

22. The photocurable formulation of any one of claims 1 to 21, wherein a weight ratio between said low MW photocurable polymeric material and said high MW photocurable polymeric material is about 1:3.

23. The photocurable formulation of any one of claims 1 to 22, wherein an amount of said photoinitiator in said curable formulation ranges from 0.1 to 1 , or from 0.1 to 0.5, % by weight of the total weight of the formulation.

24. The photocurable formulation of any one of claims 1 to 23, wherein said photoinitiator is an acyl phosphine oxide type photoinitiator such as a 2,4,6- trimethylbenzolydiphenyl phosphine oxide (TMPO) or a salt thereof (e.g., Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP), or Sodium phenyl-2,4,6-trimethylbenzoylphosphinate (NAP).

25. The photocurable formulation of any one of claims 1 to 24, wherein said photocurable biological or biocompatible material comprises a collagen that features a plurality of photocurable groups.

26. The photocurable formulation of claim 25, wherein said photocurable groups comprise (meth)acrylic groups.

27. The photocurable formulation of claim 25 or 26, wherein the collagen is a human Type I collagen.

28. The photocurable formulation of any one of claims 25 to 27, wherein the collagen is a recombinant collagen.

29. The photocurable formulation of claim 28, wherein the collagen is a plant-derived recombinant collagen.

30. The photocurable formulation of any one of claims 25 to 29, wherein the collagen is a plant-derived recombinant human Type I collagen.

31. The photocurable formulation of any one of claims 25 to 30, wherein an amount of said photocurable biological or biocompatible material ranges from 0.1 to 1 % by weight of the total weight of the formulation.

32. The photocurable formulation of any one of claims 1 to 31, wherein said carrier is an aqueous carrier.

33. The photocurable formulation of any one of claims 1 to 32, further comprising a photoblocker.

34. The photocurable formulation of claim 33, wherein said photoblocker is characterized by at least one of: biocompatibility; solubility of at least 0.05 mg / mL in said aqueous carrier or the curable formulation; absorbance at wavelength from 300 nm to 800 nm; absorbance stability at said wavelength in the presence of said photoinitiator.

35. The photocurable formulation of claim 33 or 34, wherein an amount of said photoblocker ranges from 0.1 to 1 % by weight of the total weight of the formulation.

36. The photocurable formulation of claims 33-35 wherein said photoblocker is represented by Formula III:wherein,Re, R7, Rs, R9 and Rio are each independently hydrogen; andRi, R2, R3, R4 and R5 are each independently selected from hydrogen, hydroxyalkyl and a saccharide moiety.

37. The photocurable formulation of claim 36, wherein said saccharide moiety is selected from a monosaccharide and disaccharide moiety.

38. The photocurable formulation of claims 36 or 37, wherein said saccharide moiety comprises a glucose moiety.

39. The photocurable formulation of any one of claims 36 to 38, wherein R3 is said saccharide moiety.

40. The photocurable formulation of any one of claims 36 to 39, wherein Ri is hydrogen.

41. The photocurable formulation of any one of claims 36 to 40, wherein R2, R4 and Rs are each hydrogen.

42. The photocurable formulation of any one of claims 36 to 41, wherein R2, R4 and Rs are each a hydroxyalkyl.

43. The photocurable formulation of any one of claims 36 to 42, wherein said hydroxyalkyl is hydroxyethyl.

44. The photocurable formulation of claim 36, wherein R3 is said saccharide moiety; and Ri, R2, R4 and R5 are each hydrogen.

45. The photocurable formulation of claim 44, wherein said saccharide moiety is rutinose, the photoblocker being 3-glucoside quercetin.

46. The photocurable formulation of claim 36, wherein R3 is said saccharide moiety; Ri hydrogen; and R2, R4 and Rs are each independently a hydroxyalkyl.

47. The photocurable formulation of claim 46, wherein each of R2, R4 and Rs is hydroxyethyl.

48. The photocurable formulation of claim 47, wherein said saccharide moiety is rutinose, the photoblocker being troxerutin.

49. The photocurable formulation of any one of claims 33-35, wherein said photoblocker is represented by Formula I*Formula I* whereinRx and Ry are each independently selected from hydrogen (H), alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), cycloalkyl and aryl; and Rz is an alkyl (e.g., lower alkyl as described herein, for example, of 1 to 4 carbon atoms), aryl or cycloalkyl.

50. The photocurable formulation of claim 49, wherein said photoblocker is HC yellow 9 (HC9).

51. The photocurable formulation of claim 1, comprising the components as set forth in any one of Tables B-O.

52. A biocompatible soft tissue implant comprising, by volume of solid portions thereof, at least 40% of a curable formulation according to any of claims 1-51, with a 3D structure including a surface lattice defining segments and apertures therebetween.

53. A biocompatible 3D soft tissue implant comprising a surface defined by a lattice, said surface extending over at least 30% of an outer surface of a containing geometry of the implant, said lattice defined by interconnected segments, said segments defining apertures therebetween and at least 50% of angles at intersections between segments having fillets with a minimal radius of curvature of at least 0.05 mm.

54. The implant according to claim 53, wherein said surface defined by a lattice extends at least 50% of said outer surface.

55. The implant according to claim 53, wherein said surface defined by a lattice extends at least 70% of said outer surface.

56. The implant according to any of claims 53-55, formed as a breast implant having a generally flattened ovoid or spherical section geometry and a volume of between 70 cc and 800 cc.

57. The implant according to claim 56, wherein said lattice is a 3D lattice including a plurality of segments that extend from said surface, inwards of said surface.

58. The implant according to claim 57, wherein at least 30% of said segments are hollow.

59. The implant according to claim 58, wherein said hollow segments define a fluid pathway between a surface of said implant and pores defined in said implant between segments of said lattice.

60. The implant of any of claims 57-59, wherein said plurality of segments include a plurality of vertically extending segments, from a surface of said breast implant to a base of said implant configured for placement against a pectoral muscle covering the chest wall.

61. The implant according to claim 60, wherein at least 50% of said vertically extending segments are hollow and wherein at least some conduits are defined between said hollow vertical segments to pores defined in said implant between segments of said lattice.

62. The implant according to claim 61, wherein said conduits are staggered.

63. The implant of any of claims 56-62, having an overall porosity selected from at least 30%, at least 40%, at least 50%, between 35% and 47% and at least 60%.

64. The implant of any of claims 56-63, having a resistance to failure under compression forces (Compressive force limit) of at least 156 Newton.

65. The implant of any of claims 56-64, comprising a skirt having less than 30% apertured area.

66. The implant of any of claims 56-65, wherein said lattice is a regular lattice formed of repeating elements for at least 60% of a volume of material of said implant.

67. The implant of any of claim 56-66, wherein said implant comprises a plurality of structural elements having a geometry different from said segments.

68. The implant of claim 53, wherein said fillets increase a compressive strain bearable by said implant by at least 5% relative to a same design absent the fillets.

69. The implant of claim 53, wherein said fillets increase a compressive load bearable by said implant by at least 50% relative to a same design absent the fillets.

70. The implant of any of claims 53-69, wherein the implant is biodegradable in the body over a period of between 1 week and 2 years.

71. The implant of claim 53, wherein the implant is formed of the curable formulation of any of claims 1-51.

72. The implant of any of claims 53-71, wherein said segments are non-uniform in cross-section at different parts of said implant.

73. The implant of any of claims 53-71, wherein said segments are thicker at a base central area of said implant.

74. The implant of any of claims 53-71, wherein said lattice comprises a 3D lattice made of layers and comprising at least one internal segment interconnecting two layers at an angle.

75. The photocurable formulation of any one of claims 1-51, providing, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by:(i) Strain of 20 % at a range between 10-100 N and(ii) Strain of 50 % at a range between 100-200 N; b. Compressive strain-at-break higher than 50%; or c. Compressive force limit of at least 156N.

76. The curable formulation of any one of claims 1-51, providing, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at 10N force, as determined in a compression force versus strain measurements; b. compressive strain-at-break higher than 50%; or c. compressive force limit of at least 156N.

77. The implant of any one of claims 52-76, obtained while using a curable formulation that provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by:(i) Strain of 20 % at a range between 10-100 N and(ii) Strain of 50 % at a range between 100-200 N; b. Compressive strain-at-break higher than 50%; or c. Compressive force limit of at least 156N.

78. The implant of any one of claims 52-76, obtained while using a curable formulation that provides, when hardened, a biological or a biocompatible implant featuring one or more of: a. stiffness characterized by volume retention under physiological stress of no more than 30 % strain, at ION force, as determined in a compression force versus strain measurements as described herein; b. compressive strain-at-break higher than 50%; or c. compressive force limit of at least 156N.

79. A breast implant manufactured by the process of:(a) selecting a desired clinical outcome;(b) selecting a set of parameters including one or more of design parameter(s), formulation parameter(s) and printing parameter(s) putatively suitable to achieve said outcome;(c) generating a digital design based on said outcome;(d) digitally evaluating the design; and(e) manufacturing the evaluated design by 3D printing thereof.

80. The breast implant of claim 79, wherein said digitally evaluating comprises evaluating said design functioning in a time window including during printing and / or during a degradation process thereof in a body.

81. The breast implant of claim 79 or claim 80, wherein said digital design uses a unit cell design for a lattice filling at least 40% of a volume of said implant.

82. The breast implant of any of claims 79-81, wherein said selecting a set of parameters and / or said digitally evaluating takes tissue penetration into the implant into account.

83. The breast implant of any of claims 79-82, wherein said selecting a set of parameters and / or said digitally evaluating takes implantation process into account.

84. The breast implant of any of claims 79-83, wherein said selecting a set of parameters and / or said digitally evaluating takes into account forces applied to the implant while in the body.

85. The breast implant of any of claims 79-84, wherein said selecting a set of parameters comprises performing an iterative search over a range of values of at least one parameter, using said digital evaluation as an evaluation mechanism for the search.

86. The breast implant of any of claims 79-85, wherein said selecting a set of parameters comprises selecting by a machine intelligence model trained on a plurality of examples of parameter sets and outcomes generated thereby.

87. The breast implant of any of claims 79-86, wherein said selecting an outcome comprises a selecting an outcome based on at least one patient measurement other than size and shape.

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