In vivo 3D bioprinting device and method

Abstract

The present invention provides a device for 3D bioprinting in vivo, the device comprising an elongated hollow tube configured to be insertable into a living body. A feed tube within the hollow tube delivers the liquid polymerizable biological material to an extrusion nozzle positioned at a target site. A light guide within the hollow tube conducts polymerized light from a light source to polymerize the biological material that has been extruded at the target site. Arthroscopic procedures employing the device enable attachment of tissue to bone or other tissue in vivo, or replacement of missing tissue or bone volume.

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 346,807, filed on May 27, 2022, which is incorporated herein by reference in its entirety. Technical Field

[0003] The present invention relates to apparatus and methods for in vivo printing of biomaterials, and more particularly to apparatus and methods for 3-dimensional arthroscopic bioprinting. Background Art

[0004] Three-dimensional (3D) printing technology, an advanced additive manufacturing technology, has been demonstrated to be useful for fabricating custom-designed or complex structures with a wide range of medical applications. Bioprinting, the use of cell-containing bio-inks to 3D print living obstacles such as tissues or organs, has great potential in advancing medicine, especially in regenerative medicine. Currently, commonly used 3D bioprinting systems include inkjet printing, extrusion printing, light-assisted printing, and laser direct writing. Currently, the in vivo application strategy of 3D-printed macroscale products is limited to surgical implantation or in situ 3D printing at exposed wounds, both of which require exposure of the application site. However, the main goal of clinical treatment involves the use of minimally invasive or non-invasive methods. For internal injuries under the skin, surgery that exposes the wound can damage surrounding tissues, leading to secondary injuries. Meanwhile, for plastic surgery, non-invasive methods are highly desirable to reduce scars. Such goals are unattainable using existing 3D printing technologies, which has prompted efforts to develop non-invasive 3D printing technologies that can non-invasively fabricate tissue-covered bio-inks into customized products, including in situ living tissue constructs.

[0005] 3D bioprinting technology (a light-assisted bioprinting method) based on digital light processing (DLP) has attracted much attention in recent decades due to its high cell viability after printing and excellent printing speed and resolution. Systems for bioprinting based on DLP are known and have been described in many publications. For example, see P. Wang et al., "Controlled Growth Factor Release in 3D-Printed Hydrogels", Adv. Healthcare Mater. 2019, 1900977 and J. Koffler et al., "Biomimetic 3D-printed scaffolds for spinalcord injury repair", Nature Medicine, 25 (2), February 2019, each of which is incorporated herein by reference. At present, 3D printing based on DLP has been demonstrated to be used in multi-tissue reconstruction or repair (including spinal cord, peripheral nerve and vascular injuries). Traditionally, ultraviolet light (UV) or blue light (wavelength of about 380nm to about 410nm) is used to assist bioprinting via photopolymerization. However, UV or blue light is difficult to be used as a tool for non-invasive manufacturing due to its poor tissue penetration ability. Near infrared (NIR) light can penetrate into deep tissues and has been used for controlled drug release, photodynamic therapy, photothermal therapy, in vivo imaging, 3D image visualization and in vivo optogenetics. In addition, similar to UV or blue light, NIR light has the potential to initiate photopolymerization. The use of NIR-induced photopolymerization for transdermal 3D printing has been reported as follows: Y. Chen et al., "Noninvasive in vivo 3D bioprinting", Science Advances, Vol. 6, No. 23, June 5, 2020, and A. Urciulo et al., "Intravital three-dimensional bioprinting", Nature Biomed. Eng., 4, 901-915 (2020), these documents are incorporated herein by reference. Although transdermal provides certain advantages, biomaterials still have to be introduced into the target location, so that the procedure cannot be completely non-invasive.

[0006] Currently there are no known arthroscopic 3D printing methods. The closest procedure previously described involves transdermal 3D printing, where targeted biomaterials are injected subcutaneously and polymerized light energy is delivered through the skin. The effectiveness of this approach may be limited, at least in terms of the depth of the target site, due to diffusion and possible uneven transmission through the skin and vascular structure. In addition, the lack of direct visualization poses challenges to the precise targeting of radiation and is inherently disadvantageous for the fabrication of complex structures.

[0007] In view of the foregoing, there remains a need for methods and apparatus for in vivo printing of biological structures and supports. Summary of the invention

[0008] According to embodiments disclosed herein, a device is provided to facilitate direct printing or deposition of biomaterials at target sites of living subjects during minimally invasive arthroscopic surgery. The device is preferably used in combination with an arthroscope to enable visualization of the printing process and target. Biomaterials that can be used for local printing / deposition include, but are not limited to, methacrylated gelatin, thiolated heparin (Hep-SH), glycidyl methacrylate hyaluronic acid (HA-GM), poly(glycerol sebacate) acrylate (PGSA), polyethylene glycol diacrylate (PEGDA), and polyacrylamide. These materials can be used to manufacture mechanical support structures at target sites and / or as implants that provide controlled release of biochemical substances (e.g., growth factors (GF)) to regulate the biochemical environment at the target site. The device provides a combined tool for simultaneously depositing biomaterials at target sites in vivo during arthroscopic surgery, and delivering polymerized radiation (light) directly to the deposited biomaterials to solidify the structure. After exposure to a specified wavelength, the biomaterial will be cross-linked to transform it from its initial liquid state to a solid state.

[0009] The device of the present invention provides 3D printing of biomaterials in vivo, wherein the light source and biomaterial deposition source are directly inserted into the surgical field under clinical operating conditions. This 3D printing method is compatible with any biomaterial that can be cross-linked under light exposure, providing a wide range of applications and adjustability based on the desired goals.

[0010] In one aspect of the present invention, an apparatus for in vivo 3D bioprinting includes: an elongated hollow tube having a distal end and a proximal end, the hollow tube being configured for insertion into a living body at a target site; a feed tube contained in the hollow tube, the feed tube being configured to deliver liquid polymerizable biomaterial from a biomaterial source disposed near the proximal end to the distal end; an extrusion nozzle disposed at the distal end of the feed tube, the nozzle being configured to extrude the biomaterial at the target site; a light guide disposed in the hollow tube, the light guide being configured to conduct polymerized light from a light source to the distal end; and a light-transmitting lens disposed at the distal end for guiding the polymerized light toward the biomaterial already extruded at the target site. In one embodiment, the light-transmitting lens has an annular configuration concentric with the extrusion nozzle. In some embodiments, the hollow tube can be associated with an observation arthroscope so that the hollow tube and the observation arthroscope are inserted together in conjunction with arthroscopic surgery. The biomaterial source can be a container in fluid communication with a feed tube, wherein a plunger can be used to apply pressure to the biomaterial in the container to force the biomaterial into the feed tube at a controlled rate. A plunger motor can be provided to drive the plunger when activated by a user of the device. In some embodiments, the biomaterial is one or more materials selected from the group consisting of poly(glyceryl sebacate) acrylate (PGSA), glycidyl methacrylate HA (HA-GM) and polyethylene glycol diacrylate (PEGDA). The biomaterial may further include one or more of thiolated heparin (Hep-SH) and growth factor (GF).

[0011] In another aspect of the present invention, a method for in vivo 3D bioprinting includes: inserting the distal end of an elongated hollow tube into a living body at a target site; delivering a liquid polymerizable biomaterial from a biomaterial source through a feed tube disposed in the hollow tube to an extrusion nozzle disposed at the distal end of the feed tube, the nozzle being configured to extrude the biomaterial at the target site; delivering polymerized light to the distal end through a light guide disposed in the hollow tube, reaching a light-transmitting lens, and directing the polymerized light toward the biomaterial already extruded at the target site to solidify the biomaterial. In some embodiments, the method may further include repeating the steps of feeding and delivering polymerized light to build multiple layers of biomaterial. In some embodiments, at least one of the multiple layers may have a different composition than one or more other layers. The step of inserting may include associating the hollow tube with an observation arthroscope so that the hollow tube and the observation arthroscope are inserted together. The biomaterial source may be a container in fluid communication with the feed tube, wherein a plunger may be used to apply pressure to the biomaterial in the container to force the biomaterial into the feed tube at a controlled rate. A plunger motor may be provided to drive the plunger when activated by a user of the device. In some embodiments, the biomaterial is one or more materials selected from the group consisting of poly(glyceryl sebacate) acrylate (PGSA), glycidyl methacrylate HA (HA-GM) and polyethylene glycol diacrylate (PEGDA). The biomaterial may further include one or more of thiolated heparin (Hep-SH) and growth factor (GF). BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1A is an exploded perspective view of an embodiment of a device for delivering a liquid polymerizable biomaterial; Figure 1B An exemplary use of an embodiment of the delivery device of the present invention is shown for local in vivo printing to fix a shoulder tendon to a humerus during arthroscopic surgery.

[0013] Figure 2 is based on Figure 1A A cross-sectional view of the optical path of an embodiment.

[0014] Figure 3 yes Figure 1A Detailed perspective view of an exemplary delivery tip of an embodiment of .

[0015] Figure 4 is a graph showing the variation of effective Young's modulus under different light intensities.

[0016] FIG. 5A to FIG. 5B The tensile modulus and ultimate tensile strength are plotted, respectively, along with the changes in exposure and composition of the biomaterials in the dual network structure. DETAILED DESCRIPTION

[0017] refer to Figures 1A to 3 As shown, the combined delivery and exposure device includes an extrusion tip for introducing a biomaterial (also referred to as "bio-ink") into a target site in a subject, and a polymerized light source for inducing cross-linking of the selected biomaterial at the target site. In one embodiment, a UV light source having a wavelength in the range of about 380 nm to about 410 nm may be used, wherein the appropriate wavelength and other energy parameters are selected based on the specific biomaterial and application being used.

[0018] The scheme of the present invention employs the general principles of 3D bioprinters known in the art. See, for example, the 3D bioprinters disclosed in U.S. Patent Nos. 10,464,307, 9,361,171, and 11,440,225, each of which is incorporated herein by reference. In short, in such printers, printing is achieved by exposing a prepolymer solution to polymerized light modulated by a series of patterned masks to gradually form structures. According to the method of the present invention, instead of projecting modulated light onto a printing platform or surface of a container supporting a prepolymer solution, the biomaterial is extruded through a delivery assembly 10, a sample embodiment of which is shown in FIG. Figure 1A The assembly 10 includes a long thin tube 18 having a distal end 30 configured to be inserted through a surgical incision or through a body opening of a patient, such as Figure 1B As shown. Tube 18 is formed of medical grade stainless steel or a rigid polymer suitable for standard medical sterilization procedures, with a coaxial feed tube 32 formed therein to define an optical channel 21 between the inner wall of tube 18 and the outer surface of tube 32. The dimensions of assembly 10 fall within the general dimensions of a typical arthroscope: the outer diameter of tube 18 can be approximately 2.5 mm to 6 mm, with a total length of approximately 100 mm to 190 mm. The selection of an appropriate inner diameter for feed tube 32 will be guided by a combination of the size of tube 18 and the characteristics of the biomaterial to be dispensed. As will be apparent to those skilled in the art, the use of the device to dispense biomaterials with relatively high viscosities can support the selection of a large inner diameter. Polymerized light from light source 36 is directed into optical channel 21 through port 28 into the interior of tube 18. Optical channel 21 acts as a light guide, directing light 42 into and toward distal end 30 to expose and polymerize biomaterial that has been extruded from the end of the tube.

[0019] Figure 2Details of the optical path of the assembly and the internal construction of the delivery assembly 10 are shown. Light from the light source 36 is directed (via a conventional fiber optic cable (not shown)) to the port 28 connected to the tube 18, where the light 42 is redirected by the reflector 38 through the optical channel 21 toward the distal end 30. The configuration of the port 28 shown perpendicular to the tube 18 is exemplary only. Shallow angle intersections may not require a reflector - the goal is to direct the light 42 toward the distal end 30. Where a reflector is used, it will typically have an annular configuration to allow the coaxial feed tube 32 to pass through its center. In the example shown, the reflector 38 is arranged at a 45° angle to redirect the incident light 42 from the port 28 at a right angle. As will be apparent to those skilled in the art, the angle of entry of the port and the angle of the reflector 38 (if used) can be varied to ensure that the optical path coincides with the axis of the tube 18. One or both of the inner surface of the tube 18 and the outer surface of the feed tube 32 can optionally be polished or coated to obtain maximum reflection, thereby effectively transmitting light through the optical channel 21.

[0020] like Figure 3 As shown in , at the distal end 30, the tube 18 terminates in an extrusion nozzle 38, wherein an annular lens 40 surrounds the nozzle. The lens 40 can be configured to focus, expand, or diffuse the light 42 based on the desired exposure parameters, which can depend on a number of variables, including the biomaterial, the wavelength of the exposing light, the size and characteristics of the structure to be manufactured, etc. The extrusion nozzle 38 has an opening 34 at its distal end through which the biomaterial is dispensed. The shape and length of the nozzle tip 38 and the shape and size of the opening 34 can vary depending on the biomaterial properties, the target site characteristics, and the structure to be manufactured. For example, in some embodiments, the opening 34 can be an elongated rectangular or oval to dispense a strip of biomaterial, while in other embodiments, a circular opening (as shown) or an oval dispenses a bead of material.

[0021] Reference again Figure 1A , the proximal end of the tube 18 is attached to be fluidly connected to the handle 22. For simplicity, the handle 22 is shown as a cylinder, however, the outer shape can be tapered and wavy to facilitate operation. The biomaterial container 20 is inserted into the cavity in the handle 22, and the plate 14 of the plunger 16 is placed against the bottom of the container 20 to compress the bottom of the container, thereby forcing the biomaterial to flow out of the container and into the feed tube within the tube 18. The container 20 can be refillable and reusable, or it can be a disposable container pre-filled with the appropriate biomaterial for a particular procedure. In some embodiments, the motor 12 can be used to activate the plunger 16 by pressing a button 26 (on the handle 22), which is electrically connected to the motor 12 to turn the motor on and off. In an alternative embodiment, an example of which is shown in FIG. Figure 1BAs shown in the figure, the biomaterial can be applied by manually pressing the flange 114 using a syringe-like plunger 116. The button 24 on the handle 22 can be electrically connected (via a cable or conductor (not shown)) to the light source 36 to activate the light for polymerization of the biomaterial when the biomaterial is dispensed from the nozzle 38 to the target location. As will be apparent to those skilled in the art, the user control can take a variety of different forms. The button shown in the exemplary embodiment is provided as one possible implementation and is not intended to be limiting.

[0022] Still see Figure 1B During the procedure, the distal end 30 of the device is inserted through an incision 52 at the surgical site. In the example shown, the procedure involves surgical repair of the shoulder of a patient 50. In a typical procedure, the delivery assembly of the present invention will be used in conjunction with a viewing scope 60 to allow the surgeon to observe the procedure. The viewing scope 670 can be separated from the delivery assembly (as shown), or can be physically coupled to the tube 18 to facilitate manipulation. During the printing process, the biomaterial is extruded from the nozzle 38 at a user-defined rate, which can be selected by pressing the button 26 to activate the motor 12 or pressing the plunger 116 to introduce the biomaterial 19 from the container 20 into the feed tube 32 and discharge it from the nozzle opening 34 to a selected location of the patient's humerus 54. When the biomaterial is extruded from the nozzle 38, the user presses the button 24 to activate the polymerizing light source 36. When the biomaterial 56 leaves the tip, the biomaterial will solidify after being exposed to the light of the lens 40 that has been guided to the end of the tube 18 through the light guide, thereby allowing the surgeon to effectively "spot weld" the tissue. In the example shown, the goal of the procedure is to stabilize the supraspinatus tendon 58 at the greater tuberosity of the humerus 54 .

[0023] For example, following the example procedure described above, a tendon can be "welded" to a bone. Depending on the purpose, one or more biomaterials (in the form of a combination or discrete layers) can be used to manufacture a variety of different structures and perform procedures using the delivery component 10. The desired structure can be manufactured in a single activation, or the desired structure can be gradually built through a series of activations, i.e., a first extrusion and exposure, followed by a second extrusion and exposure, and so on. In such a sequence, different biomaterials and / or different exposure conditions can be used during each step to modify the characteristics and mechanical properties of the resulting structure. The resulting polymeric biomaterial can be designed to have different physical properties to provide mechanical support for the repaired tissue, and can be designed to slowly elute growth factors, drugs or other biologically effective materials over an extended period of time (e.g., 30 days or more). The mechanical properties of the printed material can be controlled by changing the light intensity and exposure duration to form softer or harder areas.

[0024] The device may be incorporated into or otherwise combined with an arthroscope to allow in situ, real-time visualization of the printing procedure, thereby providing precise placement and sizing of the biomaterial at the target site.

[0025] The devices of the present invention can be used in a variety of different arthroscopic procedures, including but not limited to rotator cuff repair, microdiscectomy, cartilage microfracture repair, labrum repair, intervertebral disc repair, bone repair, ligament reconstruction, etc. Many different surgical procedures can be improved by using the devices of the present invention to create custom designed mechanical reinforcements in the patient's body to help stabilize the surgical site to promote healing. In addition, the ability to provide controlled release of biologically effective materials (such as growth factors) further enhances the healing process.

[0026] Examples

[0027] The following examples describe different materials and procedures that can be used in conjunction with the described delivery device during arthroscopic surgery. These examples are not intended to be limiting, but merely illustrative of possible applications.

[0028] Example 1: Muscle Regeneration

[0029] Volumetric muscle loss (VML) damage due to trauma, tumor ablation or other degenerative muscle diseases can be debilitating and currently has limited options for self-repair. 3D printing according to the apparatus and procedures described above provides rapid manufacture of biocompatible scaffolds with customized patterns or simply replaces the missing tissue volume. The commonly used materials selected are usually hard or brittle, which is not optimal for muscle tissue engineering. In addition, more successful manufacturing methods have adopted cell-based regeneration technologies, which aim to induce organized muscle regeneration. However, regulatory barriers and immunogenicity issues associated with cell tissue engineering scaffolds make acellular scaffolds more attractive in biomedical applications for treating VML. Poly(glycerol sebacate) (PGS) has been shown to be a highly tunable, biodegradable elastic polymer. PGS is highly elastic and has robust mechanical properties and can maintain its structural integrity in an aqueous environment. Its disadvantage is that it has high viscosity and high glass transition temperature, making it difficult to manufacture with geometric arrangements. To circumvent these problems, PGS was modified to make poly(glycerol sebacate) acrylate (PGSA), allowing precise fabrication of structures with tunable material properties similar to those of skeletal muscle. PGSA has also been shown to be biocompatible with fibroblasts, cardiomyocytes, and vascular endothelial cells (e.g., HUVEC).

[0030] As disclosed in W. Kiratitanaporn et al. (Biomaterials Advances 142 (2022) 213171) (which is incorporated herein by reference), a PGSA printing solution was prepared and exposed to light at 385 nm. The stiffness of the resulting structure can be varied as a function of exposure intensity to achieve a stiffness similar to that of normal skeletal muscle (107 kPa to 225 kPa). Figure 4 A graph of the effective Young's modulus of PGSA as a function of light exposure intensity is provided. 5.6 mW / cm at 385 nm 2 Light exposure can be used in conjunction with PGSA introduced to the target site via the delivery device of the present invention, also allowing for printing of fine structures without over-polymerization.

[0031] Example 2: Controlled release of growth factors

[0032] Growth factors (GF) regulate cell proliferation and differentiation to promote tissue regeneration. GF turnover is rapid in vivo, resulting in a short serum half-life. In order to better stimulate tissue regeneration, tissue engineering strategies generally seek to control the release of GF. In view of its controllable degradability and the ability to protect the envelope molecules from degradation, hydrogels can be used to regulate GF release. However, due to the high water content, GF tends to diffuse out of the hydrogel quickly because there is no part available for them to attach.

[0033] Due to its high negative charge density, heparin can capture common positively charged proteins (such as GF) by electrostatic forces, which can be used to prolong the release of GF from hydrogels that are traditionally released quickly from hydrogels. Previous studies have found that the kinetics of GF release can be adjusted by changing the molecular weight and concentration of heparin in hydrogels. Increased heparin molecular weight and increased heparin concentration can lead to extended GF release.

[0034] Hyaluronic acid (HA) is a hydrogel that has been widely designed for applications such as wound healing and atopic dermatitis due to its role in granulation and cell migration. Previous studies have shown that the synthesis of glycidyl methacrylate HA (HA-GM) allows HA to be compatible with light-based 3D printing and provides a mechanism to adjust the physical properties and geometry of hydrogels. The combination of HA and heparin further allows the ability to change the release kinetics of GF from hydrogels over an extended period of time. Thiolated heparin (Hep-SH) can be incorporated into hydrogel structures printed using the technology described herein to adjust GF retention without affecting the mechanical properties of the resulting structure.

[0035] In order to provide controlled release of GF at the target site to promote healing and tissue growth, a multi-material approach can be used, in which a double-layer structure of HA-GM and Hep-SH can be formed using continuously distributed and exposed distributed biomaterials for delayed and / or sequential release of multiple GFs. Additional details of the processing and performance of the multilayered structure for controlled release of GF are provided by P. Wang et al. (Adv. Healthcare Mater. 2019, 1900977, which is incorporated herein by reference).

[0036] Example 3: Dual network structure

[0037] Many biomaterials used to form structures with complex geometries, such as polyethylene glycol diacrylate (PEGDA), do not exhibit mechanical properties that appropriately mimic their intended tissue environment. Synthetic biomaterials used clinically are often too brittle or too soft, limiting their use in more compliant tissues such as skin, vasculature, muscle, and nerves. Tough and elastic biomaterials allow for the development of scaffolds and devices with mechanical properties similar to those of tissues such as skeletal muscle, which typically undergo cycles of lengthening and shortening, have a specific tension between 125 kPa and 250 kPa, and withstand strains up to 40%. Poly(glycerol sebacate) (PGS) has emerged as a tough biomaterial and biodegradable elastomer, however, due to its high viscosity and glass transition temperature, it is challenging to manufacture complex structures with PGS. Therefore, most applications using PGS are limited to molding and electrospinning manufacturing techniques, which limit their structural complexity for applications such as tissue engineering, where patient-specific designs are particularly important.

[0038] As described in Example 1 above, when PGS is acrylated to PGSA, it becomes more easily tunable for manufacturing. The multilayer structure of PGSA and PEGDA combines the benefits of both materials into a structure in which PGSA enhances the elasticity of the final structure in a double network (DN) structure and PEGDA enhances the mechanical strength of the final structure. In addition to varying the composition of the polymers, the mechanical properties of the resulting structure can be tailored by varying the exposure time used for printing, which is directly related to the degree of crosslinking. Using light at 405 nm, increasing the light exposure time increases the tensile modulus and ultimate tensile strength of the resulting polymer, as Figure 5A and Figure 5B Additional details on the processing and properties of DN structures are provided by Wang et al., Adv. Funct. Mater. 2020, 30, 1910391, which is incorporated herein by reference.

[0039] The foregoing examples illustrate various materials and processing conditions that may be employed in the in vivo printing scheme of the present invention. Based on this disclosure, those skilled in the art will recognize that variations in delivery component configurations, biomaterials, and exposure conditions, as well as different material allocations and exposure sequences (e.g., multiple layers) may be used without departing from the general principles disclosed herein.

Claims

1. A device for in vivo 3D bioprinting, the device comprising: an elongated hollow tube having a distal end and a proximal end, the hollow tube being configured for insertion into a living body at a target site; a feed tube received within the hollow tube, the feed tube being configured to deliver liquid polymerizable biomaterial from a biomaterial source disposed proximate the proximal end to the distal end; an extrusion nozzle disposed at the distal end of the feeding tube, the nozzle being configured to extrude biomaterial at the target site; a light guide disposed within the hollow tube, the light guide configured to conduct aggregated light from a light source to the distal end; and A light-transmitting lens is disposed at the distal end for directing polymerized light toward the biological material that has been extruded at the target site. 2 . The device according to claim 1 , wherein the light-transmitting lens has an annular configuration concentric with the extrusion nozzle.

3. The device of claim 1, wherein the hollow tube is physically associated with a sight glass.

4. The apparatus of claim 1 , wherein the source of biomaterial comprises a container in fluid communication with the feed tube, and further comprising a plunger for applying pressure to the biomaterial within the container to force the biomaterial into the feed tube at a controlled rate.

5. The device of claim 4, further comprising a plunger motor configured to drive the plunger when activated by a device user.

6. The device of claim 1, wherein the biomaterial is one or more materials selected from the group consisting of poly(glyceryl sebacate) acrylate (PGSA), glycidyl methacrylate HA (HA-GM), and polyethylene glycol diacrylate (PEGDA).

7. The device of claim 1, wherein the biomaterial further comprises one or more of thiolated heparin (Hep-SH) and growth factor (GF).

8. A method for in vivo 3D bioprinting, the method comprising: inserting the distal end of the elongated hollow tube into a living body at a target site; feeding a liquid polymerizable biomaterial from a biomaterial source through a feeding tube disposed within a hollow tube to an extrusion nozzle disposed at a distal end of the feeding tube, the nozzle being configured to extrude the biomaterial at the target site; The polymerized light is delivered to the distal end through a light guide disposed within the hollow tube, reaches a light-transmitting lens, and is directed toward the biomaterial that has been extruded at the target site to solidify the biomaterial.

9. The method of claim 8, further comprising repeating the steps of feeding and delivering polymerized light to build up multiple layers of the biomaterial.

10. The method of claim 9, wherein at least one layer of the plurality of layers has a different composition than one or more other layers.

11. The method of claim 1 , wherein the source of biological material comprises a container in fluid communication with the feed tube, and wherein feeding comprises applying pressure to the biological material within the container to force the biological material into the feed tube at a controlled rate.

12. The method of claim 11, wherein applying pressure to the biomaterial comprises activating a plunger motor configured to drive a plunger against the biomaterial.

13. The method of claim 8, wherein the biomaterial is one or more materials selected from the group consisting of poly(glyceryl sebacate) acrylate (PGSA), glycidyl methacrylate HA (HA-GM), and polyethylene glycol diacrylate (PEGDA).

14. The method of claim 8, wherein the biomaterial further comprises one or more of thiolated heparin (Hep-SH) and growth factor (GF).

15. The method of claim 8, wherein inserting further comprises associating the hollow tube with a scope such that the hollow tube and scope are inserted together in conjunction with an arthroscopic procedure.

16. The method of any one of claims 8 to 15, wherein the solidified biomaterial is configured to attach or stabilize tissue to bone at the target site.

17. The method of any one of claims 8 to 15, wherein the solidified biomaterial is configured to replace missing tissue volume at the target site.

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