Multilayer substrate and use thereof

Abstract

An article comprising a multilayer matrix is provided, the matrix comprising a viscoelastic polymer film sandwiched between two or more layers of an elastic polymeric material; wherein each of the two or more layers of the elastic polymeric material is in the form of a fibrous mat; the fibrous mat (i) comprising a plurality of electrospun fibers characterized by an average cross-sectional dimension of between about 1 and about 5 microns, and (ii) characterized by an average pore size of between about 5 and about 50 microns; the viscoelastic polymer film characterized by a thickness of between about 10 and about 60 um; the viscoelastic polymer film characterized by a melting peak temperature of between 30 and about 45 °C; and the two or more layers of the elastic polymeric material comprising PLCL characterized by a Mw of between 78 and about 100 kDa. Methods of making the article are also provided.

Description

[0001] Cross Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 540,963, filed September 28, 2023, entitled “MULTI-LAYERED MATRICES AND USES THEREOF.” The entire contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present invention, in some embodiments thereof, relates to multi-layered fibrous matrices composed of biocompatible / degradable polymers and their preparation and uses. BACKGROUND

[0003] Leakage of liquid or air from or into damaged tissue is a potentially life-threatening condition that can be caused by a variety of situations, including surgery and traumatic injury.

[0004] Soft tissues are particularly susceptible to damage. Furthermore, these tissues sometimes form various chambers that contain liquid or air (e.g., lungs, blood vessels, dural matter, urinary bladder, etc.), and when damaged, their damage also extends to other areas. Furthermore, due to the mechanical properties of these tissues, connecting the matrix with sutures or staples can cause damage therein and by itself, for example, preventing proper sealing, increasing the likelihood of bacterial infection or reducing the speed of recovery or healing. Examples of such soft tissues include dural matter, brain tissue, retina, skin tissue, liver tissue, pancreatic tissue, connective tissue, muscle tissue, heart tissue, blood vessel tissue, kidney or urogenital system tissue, lung tissue, gonadal tissue, hematopoietic tissue, digestive tract tissue (such as colon or stomach), and adipose tissue.

[0005] Despite the various synthetic matrices based on synthetic and / or natural polymers known in the art for repairing or replacing dural matter, the need for a non-tissue-adhesive polymer-based product featuring sufficient strength and sealing ability remains unmet. SUMMARY

[0006] In one aspect of the invention, there is provided a sterile article comprising a multi-layered matrix, the matrix comprising a viscoelastic polymer film sandwiched between two or more layers of an elastic polymer material; wherein each of the two or more layers of the elastic polymer material is in the form of a fibrous mat; the fibrous mat (i) comprises a plurality of electrospun fibers characterized by an average cross-section of between about 1 and about 5 microns, and (ii) is characterized by an average pore size of between about 5 and about 50 microns; the viscoelastic polymer film is characterized by a thickness of between about 10 and about 60 um; the viscoelastic polymer film is characterized by (i) a melting onset temperature of between about 32 to about 37 °C, (ii) a melting peak temperature of between about 36 to about 45 °C, or both (i) and (ii); the two or more layers of the elastic polymer material comprise PLCL characterized by a MW of between 78 to about 100 kDa.

[0007] In one embodiment, the substrate is a stitchable substrate, a stapleable substrate, or both; and wherein the viscoelastic polymer film is a continuous film characterized by a uniform thickness.

[0008] In one embodiment, the sterile article is characterized by at least one of the following as determined according to ASTM D882-12: (i) an average elongation at break of at least 200%; and (ii) an ultimate tensile strength between 3.5 and 6 MPa.

[0009] In one embodiment, the two or more layers of elastic polymer material comprise PLLA / CL, characterized in that MW is between 80 and 90 kDa and Mz is between about 150 and about 200 kDa.

[0010] In one embodiment, the matrix or sterile article is characterized by an elastic modulus in the range of 0.5 to 2 MPa, as determined according to ASTM International Standard D882-12.

[0011] In one embodiment, multiple electrospun fibers are randomly distributed within the fiber pad.

[0012] In one embodiment, the article is an article irradiated with beta radiation.

[0013] In one embodiment, the article is characterized by a burst pressure of at least 1.5 psi when measured according to ASTM F2392-04.

[0014] In one embodiment, the fiber mat is characterized by a porosity in the range of 40% to 70%.

[0015] In one embodiment, the article is characterized by at least one property selected from the following: ultimate tensile strength between 3.2 and 8 MPa when measured according to ASTM D882-12; elongation at break between 200% and 700% when measured according to ASTM D882-12; and suture retention force of at least 1.3 N when measured according to ANSI / AAMI / ISO 7198:1998 / 2001 / (R)2004.

[0016] In one embodiment, each layer of the matrix or two or more layers of elastic polymer material is characterized by a self-healing rate of at least 90%.

[0017] In one embodiment, the viscoelastic polymer film comprises PDLLA / CL, characterized in that the molar percentage of caprolactone is between about 70% and about 80%.

[0018] In one embodiment, the molecular weight of PDLLA / CL is between about 20 and about 60 kDa; and the Mn of PDLLA / CL is between about 10 and about 45 kDa.

[0019] In one embodiment, the article is identified for use in the treatment of diseases selected from: dura mater repair, hernia repair, internal and / or local wound closure, skin closure and / or repair, sealing of tissues and / or organs to contain body fluids or air, sealing of anastomoses, inhibition of postoperative adhesions between tissues, promotion of hemostasis, treatment of burns, and administration of therapeutically effective agents.

[0020] In another aspect, a method of manufacturing a sterile article of the present invention is provided, comprising providing a multilayer matrix; and exposing the multilayer matrix to beta radiation under conditions suitable for matrix sterilization to obtain a sterile article; wherein the multilayer matrix comprises a viscoelastic polymer membrane sandwiched between two or more layers of elastic polymer material in the form of fibrous pads; the viscoelastic polymer membrane comprises PDLLA / CL, characterized in that the molar percentage of caprolactone is between about 70% and about 80%, and the Mw is about 64 kDa; the fibrous pads (i) comprise a plurality of electrospun fibers, characterized in that the average cross-section is between about 1 and about 5 micrometers, and (ii) characterized in that the average pore size is between about 5 and about 50 micrometers; the viscoelastic polymer membrane is characterized in that the thickness is between about 10 and about 60 μm; the two or more layers of elastic polymer material comprise PLCL, characterized in that the Mw is between about 115 and about 120 kDa.

[0021] In one implementation, the Mn of PDLLA / CL is between approximately 40 and 45 kDa.

[0022] In one embodiment, the method further includes a preliminary step of manufacturing a multilayer matrix, the preliminary step comprising providing a first layer of elastic polymer material, a second layer of elastic polymer material, and a viscoelastic polymer film including a first surface and a second surface, wherein at least the first surface faces the environment, wherein the thickness of the viscoelastic polymer film is between 70 and 300 μm, and comprises PDLA / CL; contacting the first surface of the viscoelastic polymer film with the first layer of elastic polymer material to obtain a viscoelastic polymer film bonded to the first layer of elastic polymer material; removing the viscoelastic polymer film bonded to the first layer of elastic polymer material from a support; and contacting the first surface of the viscoelastic polymer film with the second layer of elastic polymer material to obtain a multilayer matrix.

[0023] In one embodiment, contact includes applying pressure sufficient to bond at least one layer of elastic polymer material to at least one surface of the viscoelastic polymer film.

[0024] In one embodiment, the method further includes exposing the multilayer matrix to conditions suitable for drying.

[0025] In one implementation, the dose of beta radiation is between about 20 and 25 kGy.

[0026] The following implementation methods and aspects thereof are described and illustrated in conjunction with systems, tools and methods that are intended as examples and illustrations and not as limiting the scope.

[0027] In addition to the exemplary aspects and implementations described above, other aspects and implementations will become apparent from the following detailed description. Attached Figure Description

[0028] Figure 1 This is a differential scanning calorimetry (DSC) plot of an exemplary matrix of the present invention, showing the melting temperature of PDCL.

[0029] Figures 2A-2D These are optical microscope images showing cross-sections of the exemplary matrix of the present invention before (2C) and after (2D) the expansion test, as well as a similar control matrix having a PDLCL-like film, characterized in that Tm is below 29°C before (2A) and after (2B) the expansion test. Detailed Implementation

[0030] In some embodiments of the invention, the invention relates to tissue substitutes, and more specifically, but not exclusively, to elastic layered matrices and their use as tissue substitutes.

[0031] Before explaining at least one embodiment of the present invention in detail, it should be understood that the application of the present invention is not necessarily limited to the details of the construction, component arrangement, and / or methods set forth in the following description and / or embodiments. The present invention can have other embodiments, or can be practiced or implemented in various ways.

[0032] The inventors have discovered a matrix capable of exhibiting the desired degree of biocompatibility, mechanical strength, flexibility, and / or impermeability, and further capable of responding to punctures (such as punctures formed by suturing or staples) in a manner that limits their harmful effects.

[0033] Embodiments of the present invention relate to impermeable layered matrices exhibiting a unique combination of mechanical and rheological properties and their use in various medical applications, particularly but not limited to implants, and especially as tissue substitutes, such as but not limited to dura mater substitutes. Embodiments of the present invention also relate to regenerative matrices that are capable of self-recovering during suturing or stapling to seal pores formed by these processes.

[0034] As described herein, the layered matrix (also referred to herein as the “patch”) can be formed from biodegradable and biocompatible materials that exhibit considerable mechanical strength, high elasticity and flexibility, ease of handling, folding ability (potentially suitable for laparoscopic surgery) without permanent deformation (e.g., without wrinkling), low density (which reduces inflammation and infection), and high water resistance, making it suitable for forming a tight seal, preventing fluid leakage, and protecting against bacterial and viral infections.

[0035] According to one aspect of some embodiments of the present invention, an article comprising a multilayer matrix is ​​provided, the matrix comprising a viscoelastic polymer film sandwiched between two or more layers of elastic polymer material; wherein: each of the two or more layers of elastic polymer material is in the form of a fiber pad; the fiber pad comprises a plurality of electrospun fibers, characterized in that the average cross-section is between about 1 and about 5 micrometers; the viscoelastic polymer film is characterized in that the thickness is between about 10 and about 60 μm; the two or more layers of elastic polymer material comprises PLCL, characterized in that the molecular weight is between 78 and about 100 kDa.

[0036] According to another aspect, an article comprising a multilayer matrix is ​​provided, the matrix comprising a viscoelastic polymer film sandwiched between two or more layers of elastic polymer materials; wherein: each of the two or more layers of elastic polymer materials is in the form of a fiber pad; the fiber pad (i) comprises a plurality of electrospun fibers, characterized in that the average cross-section is between about 1 and about 5 micrometers, and (ii) is characterized in that the average pore size is between about 5 and about 50 micrometers; the viscoelastic polymer film is characterized in that the thickness is between about 10 and about 60 μm; the two or more layers of elastic polymer materials comprise PLCL, characterized in that the MW is between 78 and about 100 kDa; the viscoelastic polymer film is characterized in that the melting peak temperature is between 30 and 40°C.

[0037] According to another aspect, an article comprising a multilayer matrix is ​​provided, the matrix comprising a viscoelastic polymer film sandwiched between two or more layers of elastic polymer materials; wherein: each of the two or more layers of elastic polymer materials is in the form of a fiber pad; the fiber pad comprises a plurality of electrospun fibers, characterized in that the average cross-section is between about 1 and about 5 micrometers; the viscoelastic polymer film comprises or is substantially composed of PDLCL, characterized in that the thickness is between about 10 and about 60 μm; the two or more layers of elastic polymer materials comprise or are substantially composed of PLCL, characterized in that the MW is between 78 and about 100 kDa; the viscoelastic polymer film is characterized in that the melting peak temperature is between 30 and 40°C.

[0038] In some embodiments, the articles of the present invention are composed of or substantially of the multilayer matrix disclosed herein.

[0039] The terms “layered matrix” and “multi-layered matrix”, including any of their grammatical forms, are used interchangeably in this document.

[0040] In some embodiments, the article of the present invention is a sterile article. In some embodiments, the article of the present invention is a sterilized article. In some embodiments, the article of the present invention is a beta-radiation sterilized article.

[0041] As used herein, the term "multilayer" refers to the presence of at least two distinct layers. These distinct layers may differ, for example, in chemical composition, molecular configuration (such as crystallinity and type), physical structure, and / or mechanical properties.

[0042] In this document, the term "multilayer matrix" refers to two or more elastic and viscoelastic layers (as described herein, according to any of the corresponding embodiments), and also includes any material incorporated into and / or inserted between the elastic and / or viscoelastic layers. That is, the multilayer matrix does not include any constituent components outside the elastic and viscoelastic layers (i.e., neither within nor between the elastic and viscoelastic layers).

[0043] As used herein, the term "matrix" refers to an elastic polymer material primarily composed of polymer fibers (i.e., electrospun fibers) randomly distributed therein. A matrix includes any bulk 3D material, as opposed to a single polymer fiber or nanoscale material (such as 1D or 2D materials). In some embodiments, the terms "fiber mat" and "matrix" are used interchangeably herein. A matrix may also include any materials incorporated therein. Optionally, the matrix may be free of any material incorporated into or inserted into the polymer fibers within or between the polymer fibers. In some embodiments, the matrix comprises randomly oriented polymer fibers. In some embodiments, each polymer fiber within the matrix is ​​in contact with at least one additional polymer fiber. In some embodiments, the polymer fibers are randomly distributed in the matrix to obtain a three-dimensional network structure including void spaces between the fibers. In some embodiments, the polymer fibers are randomly distributed in the matrix to form a plurality of pores (or void spaces).

[0044] In some embodiments, the terms "layer" and "film" are used interchangeably herein, referring to a material having a substantially uniform thickness. In some embodiments, the term "layer" refers to a substantially homogeneous material characterized by substantially the same chemical composition and / or substantially the same three-dimensional structure. In some embodiments, a layer is characterized by homogeneous or uniform features throughout the layer, wherein such features are selected from the spatial distribution of polymer fibers, fiber thickness, pore size, porosity, thickness, and any range thereof. In some embodiments, the term "entire layer" refers to at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 97% of the surface area and / or volume of the layer, and any range thereof.

[0045] In this document, the terms “elasticity” and “elastic” refer to the tendency of a material (optionally in the form of a layer) to return to its original shape after being deformed by stress (e.g., tensile stress and / or shear stress) at a specified temperature or at a temperature of 37°C (in the absence of a specified temperature).

[0046] As used in this article, the phrase “viscoelastic layer” refers to a layer of material in which the layer exhibits viscoelasticity.

[0047] In this paper, the terms "viscoelasticity" and "viscoelastic" refer to the tendency of a material (optionally in the form of layers). Viscoelastic materials are those that exhibit both viscous and elastic properties when deformed. The viscous behavior enables the material to resist flow and dissipate energy, while the elastic behavior allows it to return to its original shape after stress is relieved.

[0048] The degree of viscoelasticity can optionally be characterized by the loss tangent (G'' / G'), which is the ratio of the loss shear modulus (G'', also interchangeably referred to as the "shear loss modulus" in this paper) to the storage shear modulus (G', also interchangeably referred to as the "shear storage modulus" in this paper). The shear loss modulus reflects viscous behavior, while the storage shear modulus reflects elastic behavior. The loss tangent provides insight into the viscoelastic equilibrium of a material; a higher ratio indicates more viscous behavior, and a lower ratio indicates more elastic behavior.

[0049] In viscoelastic materials, behavior under stress can be characterized by two key moduli: the shear storage modulus (G') and the shear loss modulus (G''). The shear storage modulus (G') reflects the elastic behavior of the material, indicating its ability to store energy and return to its original shape after deformation. A higher G' value implies a more elastic response, where the material can effectively recover its shape. Conversely, the shear loss modulus (G'') represents viscous behavior, indicating that the material tends to dissipate energy as heat. A higher G'' value indicates greater energy loss during deformation, which is characteristic of a more viscous response.

[0050] In some embodiments, in any of the embodiments described herein, the viscoelastic material (e.g., a viscoelastic layer) is characterized by a loss tangent of at least 0.01.

[0051] In some embodiments, in any of the embodiments described herein, the viscoelastic polymer film is characterized in that its loss tangent is greater than that of the elastic layer. In some embodiments, the viscoelastic polymer film is characterized in that its loss tangent is at least 200% (twice) of the loss tangent of the elastic layer.

[0052] The energy storage shear modulus and loss shear modulus can optionally be determined using a shear rheometer, such as a strain-controlled rotational rheometer, at specified temperatures and frequencies (e.g., using the procedures described in the Examples section of this document).

[0053] In this document, the term "polymer material" (including the phrases "elastic polymer material" and "viscoelastic polymer film") means a material comprising one or more polymers (as defined herein), wherein at least 20, at least 50, or at least 80% by weight (on a dry weight basis) of the material is composed of one or more polymers disclosed herein.

[0054] Elastic layer: In some embodiments, the elastic layer is a porous layer. In some embodiments, the elastic layer is a fiber layer or fiber mat. The terms "fiber layer" and "fiber mat" are used interchangeably herein. The fibers forming the elastic layer can be woven or nonwoven. In some embodiments, the fibers are nonwoven.

[0055] In this document, the term "porous layer" refers to a layer containing voids (e.g., containing voids in addition to the polymeric materials described herein), where the spaces between the polymeric materials are not filled with additional material. However, a porous layer may optionally contain additional material in the spaces between the polymeric materials, provided that at least a portion of the void volume is not filled with additional material.

[0056] In some implementations, each of the two or more elastic layers is a single-layer fiber pad.

[0057] In some embodiments, each of the two or more elastic layers is substantially composed of electrospun fibers. In some embodiments, at least 90% by weight or 95 to 100% by weight of the elastic layer is composed of electrospun fibers. In some embodiments, the electrospun fibers are PLCL fibers. In some embodiments, the chemical composition of the two or more elastic layers is identical. In some embodiments, the two or more elastic layers have substantially the same structure (i.e., fiber thickness, porosity, layer thickness, etc.), wherein substantially therein includes at most + / - 20% variation between the elastic layers.

[0058] In some embodiments, at least 90% by weight or 95 to 100% by weight of the elastic layer is composed of electrospun PLCL fibers. In some embodiments, the weight content of PLCL in the elastic layer, on a dry weight basis, is between 90% and 100%, 95% and 99%, or 97% and 100% of the elastic layer. In some embodiments, the weight content of PLCL fibers in the elastic layer, on a dry weight basis, is between 90% and 100%, 95% and 99%, or 97% and 100% of the elastic layer.

[0059] In some embodiments, the fibers of the elastic layer (i.e., PLCL fibers) are characterized by an average cross-section (or average diameter) in the range of 1 to 5 µm (e.g., 1, 2, 3, 4 or 5, or between 1 and 3 µm, between 2 and 5 µm, or any range therein).

[0060] In some embodiments, the PLCL within the article of the present invention is characterized by a mean value (MW) between 77 and about 110 kDa, 78 and about 105 kDa, 78 and 100 kDa, 80 and about 90 kDa, 80 and 95 kDa, 77 and 95 kDa, 79 and 95 kDa, 78 and 85 kDa, 78 and 88 kDa, 78 and 97 kDa, and 78 and 93 kDa, including any range therebetween, where Mw refers to the average value determined by GPC. In some embodiments, the MW of the PLCL of the article of the present invention is reduced by at least 10%, or between 10% and 30%, or between 20% and 30%, compared to an unsterilized identical PLCL layer (or an article comprising it) (e.g., an unirradiated article).

[0061] In some embodiments, the PLCL within the article of the present invention is characterized by Mn being between 45 and 70 kDa, between 47 and 70 kDa, between 47 and 60 kDa, between 47 and 55 kDa, between 47 and 52 kDa, and any range therein, wherein Mn refers to an average value determined by GPC or based on viscosity. In some embodiments, the Mn of the PLCL in the article of the present invention is reduced by at least 10%, or between 10% and 35%, between 20% and 33%, or between 25% and 33%, compared to an unsterilized identical PLCL layer (or an article containing it) (e.g., an unirradiated article).

[0062] In some embodiments, the PLCL within the article of the present invention is characterized by Mz being between 142 and 250 kDa, 142 and 200 kDa, 150 and 250 kDa, 150 and 200 kDa, and 160 and 180 kDa, or any range therein, wherein Mz refers to an average value determined by GPC, or an average value based on viscosity (calculated based on specific logarithmic viscosity). In some embodiments, compared to an unsterilized PLCL layer (or an article containing it) (e.g., an unirradiated article), the Mz of the PLCL in the article of the present invention is reduced by at least 20%, at least 30%, or 10% to 40%, 20% to 40%, 25% to 37%, or 30% to 40%.

[0063] In some embodiments, the molar percentage of caprolactone (i.e., polycaprolactone) in the PLCL is between about 20% and about 40%, between about 20% and about 35%, between 25% and 35%, between 27% and 35%, between 25% and 33%, between 25% and 32%, between 25% and 31%, between 27% and 33%, between 28% and 33%, between 28% and 32%, 30% or about 30%, and any range therein.

[0064] In some embodiments, the molar percentage of lactide (i.e., poly-L-lactide) in the PLCL is between about 50% and about 90%, between about 60% and about 80%, between about 60% and about 75%, between 65% and 75%, between 67% and 75%, between 65% and 73%, between 65% and 72%, between 65% and 71%, between 67% and 73%, between 68% and 73%, between 68% and 72%, 70% or about 70%, and any range therein.

[0065] In some embodiments, the molar percentage of lactide (i.e., poly-L-lactide) in the PLCL is between about 60% and about 80%, and the molar percentage of caprolactone (i.e., polycaprolactone) in the PLCL is between about 20% and about 40%.

[0066] In some embodiments, the PLCL in the article of the present invention is characterized by a melting peak temperature above 90°C, above 100°C, above 105°C, between 100°C and about 120°C, between 100°C and 115°C, between 110°C and 120°C, and between 110°C and 115°C, including any range therebetween, wherein the melting peak temperature is determined by DSC. In some embodiments, the DSC chart of the article of the present invention is characterized by at least one Tm peak corresponding to the PLCL, wherein the at least one Tm peak is in the range of 100 to about 120°C.

[0067] In some embodiments, the PLCL / elastic layer is characterized by a crystallinity between 5% and 20%, 8% and 20%, 10% and 20%, 8% and 15%, 10% and 20%, 10% and 15%, and any range therein.

[0068] In some embodiments, each of the two or more elastic layers is characterized by an average thickness in the range of 20 to 500 µm, 25 to 350 µm, 80 to 200 µm, 100 to 200 µm, or 50 to 250 µm, inclusive. In some embodiments, each of the two or more elastic layers is characterized by an average thickness in the range of about 100 to about 200 µm.

[0069] In some embodiments, each of the two or more layers of elastic polymer material is characterized by an average pore size between about 5 and about 50 micrometers, about 10 and about 40 micrometers, about 10 and about 30 micrometers, about 20 and about 50 micrometers, and any range therein.

[0070] In some embodiments, each layer of two or more layers of elastic polymer material is characterized by a porosity of at least 40%, or any range between 40% and 70%, between 50% and 70%, between 50% and 60%, between 40% and 60%, and in between. Hereinafter, the term "porosity" refers to the percentage of the volume of a substance consisting of voids (e.g., the elastic polymer material described herein).

[0071] In some embodiments, each layer of the two or more layers of elastic polymer material is characterized by a recovery rate, wherein "recovery rate" is as described below. In some embodiments, each layer of the two or more layers of elastic polymer material is characterized by a recovery rate and self-recovery rate of at least 80%, at least 85%, or 80% to 99.9%, 80% to 90%, 80% to 99.9%, 80% to 95%, 90% to 97%, and any range therein.

[0072] Viscoelastic layer The viscoelastic polymer film according to any embodiment described in this section can be combined with any of the elastic polymer materials according to the corresponding embodiments described herein. In some embodiments, the viscoelastic polymer film is in the form of a continuous layer or continuous film. In some embodiments, the viscoelastic polymer film is a monolayer film. In some embodiments, the viscoelastic polymer film is a multilayer film. In some embodiments, the viscoelastic polymer film is free of fibers and / or particulate matter. In some embodiments, the viscoelastic polymer film is in the form of a continuous layer having a substantially uniform thickness (e.g., a thickness variation of up to 20%). In some embodiments, the viscoelastic polymer film is a homogeneous material (e.g., characterized by a substantially uniform polymer morphology, density, distribution, or concentration, and / or the absence of aggregates or particles with a particle size greater than 10 nm or greater than 100 nm throughout the material). In some embodiments, the viscoelastic polymer film comprises (and optionally is substantially composed of) one or more hydrophobic polymers.

[0073] In some embodiments, the viscoelastic polymer film comprises a polymer characterized by a crystallinity of 1% to 40%, 1% to 10%, 1% to 5%, 1% to 15%, 5% to 20%, 5% to 15%, 5% to 10%, or 1% to about 25%, including any range therein.

[0074] In some embodiments, the viscoelastic polymer film comprises a polymer (also referred to herein as a “viscoelastic polymer”) characterized by a melt peak temperature (Tm) above 29°C, above 30°C, between 30°C and about 40°C, between 30°C and 39°C, between 30°C and 38°C, between 31°C and 38°C, and any range thereof.

[0075] In some embodiments, the DSC chart of the article of the present invention is characterized by corresponding to at least one Tm for the viscoelastic polymer, wherein the at least one Tm is in the range of 30 to 40°C, 30 to 38°C, 30 to 35°C, 30 to 33°C, 31 to 35°C, 31 to 37°C, 31 to 38°C, 31 to 39°C, 31 to 40°C, or any range therein. The melting peak temperature is determined by DSC according to the conditions described in the Materials and Methods section. The Tm value of the viscoelastic polymer disclosed herein refers to: (i) at least one peak temperature, (ii) the maximum peak temperature, or (iii) the average temperature, for example, when multiple peak temperatures are present in the corresponding DSC chart. Figure 1An exemplary DSC plot of an exemplary multilayer matrix of the present invention, obtained using the DSC method disclosed in the Materials and Methods section, is shown, displaying the Tm value of the PDLCL with a melting point of 29°C, a first Tm peak (maximum peak) at 32.7°C, and another Tm peak at approximately 38°C. Therefore, those skilled in the art will understand that, based on the DSC plot, the tested PDLCL has at least one peak (and maximum peak) temperature of 32.7°C and an average peak temperature of approximately 35.3°C.

[0076] In some embodiments, the viscoelastic polymer is PDLCL, characterized by (i) a molar percentage of caprolactone of about 75%, and (ii) a melting peak temperature between 30 and about 40°C or 31 and 35°C (as determined by DSC). In some embodiments, the melting peak temperature of PDLCL is the maximum peak temperature.

[0077] In some embodiments, the viscoelastic polymer is PDLCL, characterized by (i) a molar percentage of caprolactone between about 70% and about 80% or about 75%, (ii) a melting peak temperature (Tm) between 30 and about 40°C or between 31 and 35°C (as determined by DSC), and (iii) Mw between about 20 and about 60 kDa; and / or Mn between about 10 and about 45 kDa (as determined by GPC or based on viscosity).

[0078] In some embodiments, the viscoelastic polymer film is characterized by a swelling ratio between about 0.9 and 1.8, about 1 and 1.8, about 1 and 1.7, about 1.1 and 1.8, about 1.2 and 1.7, about 1.3 and 1.8, about 1.2 and 1.6, or less than 2, less than 1.9, less than 1.8, or any range thereof, wherein the swelling ratio refers to the average thickness ratio of the viscoelastic polymer film after incubation in an aqueous solution relative to the average thickness ratio of the viscoelastic polymer film in a dried article. Specific test conditions are as described in the Materials and Methods section.

[0079] In some embodiments, the viscoelastic polymer film comprises or is substantially composed of a hydrophobic polymer. Without being bound by any particular theory, it is believed that hydrophobic polymers can significantly reduce the permeability of the matrix. For example, the pores in a porous hydrophobic viscoelastic polymer layer may be too small to allow water to pass through because the contact between water and the hydrophobic polymer is energy-adverse.

[0080] In this document, "hydrophobic polymer" is a polymer characterized by having a solubility of less than 1 g / L in water at pH 7.0 and not absorbing more than 20% by weight of water (the weight of water absorbed relative to the weight of the polymer).

[0081] In some embodiments, the viscoelastic polymer membrane comprises or is substantially composed of a biodegradable and / or biocompatible polymer. In some embodiments, the viscoelastic polymer comprises or is substantially composed of a biodegradable and / or biocompatible polymer. In some embodiments, the biodegradable and / or biocompatible polymer is a hydrophobic polymer. In some embodiments, the viscoelastic polymer membrane comprises or is substantially composed of a single polymeric substance.

[0082] According to this embodiment, the preferred biodegradable polymer is a non-toxic and benign biocompatible polymer. In some such embodiments, the biodegradable polymer is a bioabsorbable polymer that decomposes into non-toxic and benign decomposition products that are absorbed by the subject's biochemical system.

[0083] Non-limiting examples of biodegradable polymers suitable for use as viscoelastic polymers include homopolymers and copolymers, such as aliphatic polyesters made from glycolide (glycolic acid), lactide (lactic acid, including L-lactic acid and / or D-lactic acid), ε-caprolactone, dioxanone (such as p-dioxanone), trimethylene carbonate, hydroxybutyrate, and / or hydroxyvalerate; polypeptides made from natural and / or modified amino acids (e.g., collagen, alginate, elastin, elastin-like polypeptides, albumin, fibrous protein, chitosan, filament, poly(γ-glutamic acid), and polylysine); and polypeptides made from natural and / or modified sugars (e.g., hygroscopic sugars). Polysaccharides made from hyaluronic acid; polydepsipeptides; biodegradable nylon copolyamides; polydihydropyran; polyphosphazene; poly(orthoester); poly(cyanoacrylate); polyanhydride; polyurethane, polycarbonate, silicone, polyamides (such as nylon), polysulfone, polyetheretherketone (PEEK), polytetrafluoroethylene, polyethylene, poly(methyl methacrylate), poly(ethyl methacrylate), poly(methyl acrylate), poly(ethyl acrylate), and non-biodegradable polyesters, such as poly(ethylene terephthalate), including any copolymers thereof and any combination thereof.

[0084] While any polymer, copolymer, or mixture of polymers and / or copolymers may be used to produce the elastic and / or viscoelastic polymer films described herein, in some embodiments of any of the embodiments relating to elastic and / or viscoelastic polymer films described herein, the elastic and / or viscoelastic polymer films are formed from biocompatible and / or biodegradable polymers.

[0085] In some embodiments, the viscoelastic polymer film comprises or is primarily composed of DL-lactic acid / ε-caprolactone copolymer (abbreviated as PDLLA / CL or PDLCL). In some embodiments, the viscoelastic polymer comprises or is substantially composed of PDLCL. In some embodiments, PDLLA / CL constitutes 80% to 100%, 90% to 100%, 95% to 100%, 80% to 95%, 80% to 99%, and 95% to 99% of the polymer content of the viscoelastic polymer film on a dry weight basis. In some embodiments, PDLLA / CL constitutes 80% to 100%, 90% to 100%, 95% to 100%, 80% to 95%, 80% to 99%, and 95% to 99% of the viscoelastic polymer film on a dry weight basis. In some embodiments, the viscoelastic polymer film is substantially composed of PDLLA / CL (and optionally includes residual amounts of additional polymer, small molecules, or solvents, wherein the residual amounts are at most 0.1% by weight).

[0086] In some embodiments, PDLLA / CL is characterized in that the molar percentage of caprolactone is between about 70% and about 80%, between about 72% and about 80%, between about 74% and about 80%, between about 70% and 78%, between about 72% and 78%, between about 70% and 77%, between about 70% and about 75%, between about 80% and 75%, between about 73% and 77%, between about 73% and 76%, between 74% and 77%, between 74% and 76%, or about 75%, or any range therein. In some embodiments, PDLLA / CL is characterized in that the molar percentage of PDLLA is between about 20% and about 30%, between about 20% and about 40%, between about 20% and about 26%, between 22% and 28%, between 23% and 26%, between 20% and 27%, between 23% and 27%, between 24% and 26%, 25% or about 25%, and any range therein.

[0087] In some implementations, a further feature of PDLLA / CL is that Mw is between about 20 and about 60 kDa, between 20 and 64 kDa, between 20 and 60 kDa, between 20 and 55 kDa, between 20 and 50 kDa, between 20 and 40 kDa, between 40 and 64 kDa, between 40 and 60 kDa, between 40 and 55 kDa, between 40 and 50 kDa, or below 64 kDa, below 62 kDa, below 60 kDa, below 58 kDa, below 55 kDa, below 50 kDa, and any range therein.

[0088] In some implementations, a further feature of PDLLA / CL is that Mn is between about 10 and about 40 kDa, between 10 and 41 kDa, between 10 and 40 kDa, between 20 and 35 kDa, between 20 and 30 kDa, between 10 and 40 kDa, between 10 and 35 kDa, between 10 and 30 kDa, or below 42 kDa, below 40 kDa, below 38 kDa, or any range therein.

[0089] In some implementations, a further feature of PDLLA / CL is that Mz is between about 30 and about 90 kDa, between 30 and 94 kDa, between 30 and 90 kDa, between 30 and 85 kDa, between 30 and 80 kDa, or below 95 kDa, below 90 kDa, below 92 kDa, or any range therein.

[0090] In some embodiments, the viscoelastic polymer film is primarily composed of PDLLA / CL, wherein the PDLLA / CL is characterized by a caprolactone molar percentage between about 70% and about 80%, Mw between 20 and 60 kDa, at least one Tm value in the range of 30 to 40°C, and optionally Mn and / or Mz as described above. The terms Mw, Mn, and / or Mz as used herein refer to average values ​​and are determined based on GPC or viscosity.

[0091] In some embodiments, the viscoelastic polymer membrane is a non-porous continuous membrane, or is characterized by a finite porosity. In some embodiments, the viscoelastic polymer membrane is characterized by a porosity lower than that of each of the two or more adjacent layers of elastic polymer material.

[0092] In some such embodiments, the viscoelastic polymer film is characterized by a porosity less than 20%, less than 10%, or less than 5% of the porosity of each of two or more adjacent layers of elastic polymer material.

[0093] In some embodiments, the viscoelastic polymer membrane is characterized by a porosity in the range of 0 to 50%, 0 to 30%, or 0 to 10%, or any range therein.

[0094] Unbound by any particular theory, it is believed that viscoelastic polymer membranes, characterized by being non-porous or having finite porosity, reduce the permeability of the core matrix to water and other liquids, thereby enhancing the ability of the material composition, for example, to act as a sealant to prevent fluid leakage. Furthermore, it is thought that such a layer, for example, without any fibrous structure, can readily deform in response to the stress of viscous flow, and that this deformation can lead to the closure of pores formed in the viscoelastic layer.

[0095] In some embodiments, the viscoelastic polymer film is characterized by an average thickness in the range of 10 to 60 µm, 10 to 50 µm, 10 to 40 µm, 20 to 0 µm, 30 to 60 µm, 10 to 30 µm, 20 to 40 µm, or any range therebetween.

[0096] Based on extensive experimentation, the inventors surprisingly discovered that the thickness range of the viscoelastic polymer film, between 10 and 60 µm, is crucial for the optimal burst strength (and sealing ability) of the matrix disclosed herein. Furthermore, Example 3 provides additional experimental results highlighting the importance of the aforementioned viscoelastic polymer film thickness range.

[0097] In this document, the terms "viscoelastic" and "viscoelastic" refer to the tendency of a material (optionally in the form of layers) to resist stress at a specified temperature or a temperature of 37°C (in the absence of a specified temperature), the degree of which is related to the rate of deformation (e.g., strain, shear). That is, when deformation is relatively slow, the material has low resistance (e.g., due to viscous flow during deformation), and when the rate of deformation (e.g., shear) approaches zero, the resistance can optionally approach zero. The resistance is generally insufficient to allow the material to return to its original shape, except in certain cases where the rate of deformation is very high.

[0098] The degree of viscoelasticity can be optionally characterized by the loss tangent (G'' / G'), which is the ratio of the loss shear modulus (G'', also referred to as "shear loss modulus" in this paper) to the storage shear modulus (G', which can also be interchanged as "shear storage modulus" in this paper). The loss shear modulus reflects viscous behavior, while the storage shear modulus reflects elastic behavior.

[0099] In some embodiments of any of the embodiments described herein, the viscoelastic polymer film is characterized by a loss tangent of at least 0.01.

[0100] In some embodiments of any of the embodiments described herein, the viscoelastic polymer film is characterized in that its loss tangent is greater than that of the elastic layer. In some embodiments, the viscoelastic layer is characterized in that its loss tangent is at least 200% (twice) of the loss tangent of the elastic layer.

[0101] The energy storage shear modulus and loss shear modulus can optionally be determined using a shear rheometer, such as a strain-controlled rotational rheometer, at specified temperatures and frequencies (e.g., using the procedures described in the Examples section of this document).

[0102] matrix In some embodiments, the matrix of the present invention is a multilayer matrix comprising a viscoelastic polymer membrane (e.g., a monolayer membrane) inserted or sandwiched between two adjacent layers of elastic polymer material. The terms “multilayer matrix” and “matrix” are used interchangeably herein.

[0103] In some embodiments, each of the two adjacent elastic polymer materials is independently a single-layer fiber mat, or a multilayer fiber mat as described herein. In some embodiments, the two adjacent layers are in contact with each outer surface of the viscoelastic polymer film, respectively. In some embodiments, both adjacent layers are stably bonded to the viscoelastic polymer film.

[0104] In some embodiments, the term "stable bond" includes a matrix that is stable (maintaining its physical multilayer structure, its mechanical or functional integrity, and does not disintegrate), as determined by microscopic visual inspection. In some embodiments, the term "stable bond" includes a matrix that remains stable when stored under environmental conditions (e.g., in an airtight or sealed container at a temperature between 5 and 30°C) for at least 0.5 years, at least 1 year, or at least 1.5 years.

[0105] In some embodiments, the matrix includes a boundary region adjacent to the contact points between adjacent layers of the matrix (i.e., between the viscoelastic polymer membrane and the fiber pad), optionally wherein the thickness of the boundary region is between 1 and 20 µm. In some embodiments, the boundary region is characterized in that the elastic polymer material fibers are partially permeated or incorporated into the viscoelastic polymer membrane, and / or vice versa.

[0106] Unbound by any particular theory, it is believed that placing a viscoelastic polymer membrane between elastic layers allows the elastic layers to contain the viscoelastic polymer membrane within the matrix and prevent significant leaching of the membrane. Furthermore, it is believed that viscoelastic polymer membranes in the form of an interlayer are well-suited for use as barriers and for sealing pores, as described herein, while being effectively contained by the elastic layers.

[0107] In some embodiments, the matrix has a sheet-like geometry. In some embodiments, the matrix is ​​in the form of a continuous layer. In some embodiments, the matrix is ​​in the form of a continuous, uniform layer, characterized by a substantially uniform thickness.

[0108] In some implementations, the sheet geometry is characterized in that the average thickness in one dimension (e.g., the average width in the narrowest dimension of the matrix) is less than 20%, less than 10%, less than 5%, or between 0.1% and 20% of the average width in each of the two vertical dimensions.

[0109] In some embodiments, the matrix is ​​characterized by an average thickness between 100 µm and 3 mm.

[0110] In some embodiments, the average total thickness of two or more layers of elastic polymer material is at least 50% or between 50% and 90% of the average thickness of the matrix.

[0111] In some embodiments, the article is in the form of a patch. In some embodiments, the article is in the form of a tissue patch (e.g., a topical patch). In some embodiments, the article is for local application to the tissue of a subject. In some embodiments, the article is in the form of a ready-to-use topical patch.

[0112] In some embodiments, the article is in the form of a patch, characterized by at least one of the following: a length between 1 and 10 mm; a width between 1 and 10 mm; and a thickness between 0.1 and 3 mm, including any range therebetween.

[0113] In some embodiments, the DSC chromatogram of the article of the present invention is characterized in that (i) at least one Tm peak corresponding to PLCL is in the range between about 100 and 120°C, and (ii) at least one Tm peak corresponding to viscoelastic polymer (PDLCL) is in the range between 30 and 38°C.

[0114] In some embodiments, the article is identified for treating a disorder in a subject. In some embodiments, the disorder is selected from dural repair, hernia repair, closure of internal and / or local wounds, closure and / or repair of skin, sealing of tissues and / or organs to contain body fluids or air, sealing of anastomoses, inhibition of postoperative adhesions between tissues, promotion of hemostasis, treatment of burns, and administration of therapeutically effective agents.

[0115] In some embodiments, the article is packaged in a sealed package. In some embodiments, the sealed package is an airtight (e.g., airtight) package. In some embodiments, the sealed package is a breathable package and is impermeable to pathogens (e.g., airborne pathogens such as viruses, bacteria, fungi, and their spores). Sealed packages for sterile articles involve materials and designs that ensure the integrity and sterility of the contents. These packages may include features that prevent contamination and facilitate sterilization. Non-limiting examples of sealed packages include, but are not limited to: 1. Tyvek® bags: Made of high-density polyethylene fibers, Tyvek® is breathable and antimicrobial, making it ideal for sterilization methods such as ethylene oxide and gamma radiation. 2. Foil-laminated bags: These bags combine layers of aluminum foil with a plastic film, providing excellent moisture, light, and gas barrier properties. Commonly used for products requiring a high level of protection. 3. Polypropylene blister packs: These packages are made of rigid polypropylene, allowing clear visibility of the product while providing a strong barrier against contaminants. Commonly used for medical devices and pharmaceuticals. 4. Nylon / Polyethylene Bags: These bags combine strength and flexibility, with nylon providing puncture resistance and polyethylene providing a moisture barrier. Suitable for vacuum sealing. 5. PET / Aluminum / LDPE Laminates: This multi-layered structure provides excellent barrier performance for products requiring oxygen and moisture protection. Select these packaging options based on the specific requirements of the aseptic product, including the type of sterilization method, visibility requirements, and the desired level of barrier protection.

[0116] In some embodiments, the article is a sterile or sterilized article. In some embodiments, the matrix is ​​a sterile or sterilized matrix. In some embodiments, the sterile matrix is ​​in the form of a sterile or sterilized article having a defined shape and / or size. In some embodiments, the sterile or sterilized article is substantially composed of the matrix of the present invention (i.e., the sterile matrix). In some embodiments, the matrix is ​​a β-sterilizing matrix. In some embodiments, the β-sterilizing matrix is ​​obtained by sterilizing the matrix (i.e., the non-sterile matrix) with β radiation at a dose sufficient to sterilize it.

[0117] The terms “sterile” and “sterilized” used in this article are interchangeable.

[0118] As used herein, the term "sterile" refers to the sterility requirements for medical products / devices as recorded in the United States Pharmacopeia or the European Pharmacopeia (i.e., 0 CFU), the maximum microbial load threshold of the matrix of this invention, etc. Exemplary sterility testing may involve culturing the product in a nutrient-rich culture medium to detect microbial contamination. This test is typically performed under sterile conditions to prevent external contamination.

[0119] Place the product in a sterile container containing a nutrient medium (such as tryptone soybean broth (TSB) or fluid thioglycolate medium (FTM)). Incubate the container at a specific temperature, typically 20–25°C for fungi and 30–35°C for bacteria, for 14 days. Test the medium to determine microbial growth (by counting the CFU of the tested microorganisms), which indicates contamination.

[0120] The pathogens tested are typically: (i) bacterial pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, Bacillus subtilis, etc.; and (ii) fungal pathogens, including Candida albicans, Aspergillus brasiliensis, etc. This test ensures that the product is free of live microorganisms (0 CFU for each test microorganism) and confirms that it meets the sterility standards according to the pharmacopoeia.

[0121] In some embodiments, the sterilized article comprises a matrix / article of the present invention that has been exposed to a dose of beta radiation sufficient to sterilize it. In some embodiments, the dose is sufficient to obtain a sterile matrix / article of the present invention, wherein "sterile" is as described herein. In some embodiments, the dose is sufficient to reduce the microbial load of an unsterilized matrix / article, thereby obtaining a sterile matrix / article. Beta radiation sterilization can be performed by applying a high-energy electron beam to an unsterilized matrix (e.g., a manufactured matrix).

[0122] The inventors unexpectedly discovered that the matrix of the present invention sterilized by β radiation exhibits superior mechanical properties compared to similar γ-radiation matrices.

[0123] In some embodiments, a sufficient dose of beta radiation for sterilization is between 10 and 50 kGy, 20 and 25 kGy, 15 and 25 kGy, and 15 and 30 kGy, or any range therein. “Dose” refers to the radiation exposure of the article.

[0124] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by a reduction in MW and / or Mn of PLLA / CL and / or PDLLA / CL compared to a similar unsterilized matrix, wherein the reduction is as described above.

[0125] In some embodiments, the substrate (i.e., the sterilized substrate) is characterized by self-recovery. In some embodiments, the self-recovery rate of the substrate is at least 90%, or between 90% and 99%.

[0126] As used herein, the term "self-recovery" refers to the ability of a material (e.g., material in a matrix) to at least partially close a cavity (optionally formed by a 21-gauge needle) formed in the material, such that the area of ​​the remaining needle cavity (if present) in the material is less than 50% of the cross-sectional area of ​​the object that formed the cavity (e.g., optionally through a 21-gauge needle). Self-recovery is measured under ambient conditions (pressure approximately 1 atm, temperature between 19 and 37°C).

[0127] In some embodiments, the substrate (i.e., the sterilized substrate) is a sutureable and / or stapleable substrate that is self-healing.

[0128] The term “stitchable” as used in this article refers to the ability of a needle tip to pass through a matrix without causing a break (e.g., crack or tear) in the matrix, except for localized holes in the region similar to the cross-sectional area of ​​the needle tip.

[0129] As used in this article, the term "stitchable" refers to the ability of a staple to penetrate the matrix without causing rupture (e.g., cracks or tears) in the matrix, except for localized holes in the region similar to the cross-sectional area of ​​the staple.

[0130] The needles and staples in the above definitions of "suitable for suturing" and "suitable for stitching" have a diameter of no more than 1 mm. 2 The cross-section (optionally, circular cross-section). Optionally, the needle is a size 21 needle (approximately 0.51 mm in diameter).

[0131] Unbound by any particular theory, it is believed that the fibrous structure of the elastic layer made of polymer fibers advantageously allows the needle to pass through the layer by pushing the fibers aside without causing any significant permanent deformation or mechanical damage to the layer, and the elasticity of the fibers causes the layer to spring back, thereby closing the suture hole and securing the suture tightly.

[0132] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by at least one of the following as determined according to ASTM D882-12: (i) a mean elongation at break of at least 200%; and (ii) an ultimate tensile strength (UTS) between 3.2 and 6 MPa, or a combination of (i) and (ii).

[0133] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by an average elongation at break of at least 200%, at least 250%, at least 300%, at least 350%, at least 450%, or any range between 300 and 700%, 350 and 700%, 400 and 700%, 450 and 700%, and 450 and 600%, wherein the elongation at break is determined according to ASTM D882-12. In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by an elongation at break of at least 200%, at least 250%, at least 300%, at least 350%, at least 450%, or any range between 300 and 700%, 350 and 700%, 400 and 700%, 450 and 700%, and 450 and 600%, wherein the elongation at break is determined according to ASTM D882-12.

[0134] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by an average UTS between 3.2 and 8 MPa, 3.2 and 7 MPa, 4 and 8 MPa, 5 and 8 MPa, 5 and 7 MPa, 3.5 and 7 MPa, 3.5 and 6 MPa, 4 and 6 MPa, or 5 and 6 MPa, including any range therebetween, wherein the UTS is determined according to ASTM D882-12.

[0135] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by the average elongation at break and the average UTS as disclosed above. The terms "average elongation" and "average UTS" include the average values ​​obtained from at least 10 measurements.

[0136] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by any of the properties disclosed in Table 1 below.

[0137] Table 1: Non-limiting exemplary mechanical properties of the matrix of the present invention "Wet product" refers to a product that has been immersed in salt water for 15 minutes before the relevant tests and measurements are performed.

[0138] In some embodiments, the matrix (i.e., the sterilized matrix) is characterized by an elastic modulus, as determined according to ASTM International Standard D882-12, in the range of 0.5 to 2 MPa, 0.5 to 1 MPa, 0.5 to 1.5 MPa, 0.8 to 2 MPa, 0.8 to 1.5 MPa, or any range therein.

[0139] In some embodiments, the matrix described herein (i.e., the sterilized matrix) is characterized by a burst pressure of at least 1.1 psi, at least 1.5 psi, at least 2 psi, or between 1.1 and 6 psi, 1.5 and 6 psi, and 2 and 6 psi, or any range therebetween, as measured according to ASTM F2392-04.

[0140] In some embodiments, the substrate (i.e., the sterilized substrate) is characterized by the burst pressure disclosed in Table 2 below.

[0141] Table 2: Non-limiting exemplary burst pressure values ​​of the matrix of the present invention "Wet products" refers to products that have been immersed in physiological saline for 15 minutes before the relevant tests and measurements are performed.

[0142] In some embodiments, the matrix described herein (i.e., the sterilized matrix) is characterized by a suture retention force of at least 1.3 N, at least 1.5 N, or between 1.2 and about 3 N, or between about 1.2 and about 2.8 N, as measured according to ANSI / AAMI / ISO 7198:1998 / 2001 / (R) 2004. In some embodiments, the matrix described herein (i.e., the sterilized matrix) is characterized by an average suture retention force of at least 1.3 N, at least 1.5 N, or between 1.3 and about 2 N, as measured according to ANSI / AAMI / ISO 7198:1998 / 2001 / (R) 2004. In some embodiments, the matrix described herein (i.e., the sterilized matrix) is characterized by an average suture retention force of at least 1.3 N, or between 1.4 and about 2.5 N, as measured according to ANSI / AAMI / ISO 7198:1998 / 2001 / (R) 2004 when used in dried products.

[0143] In some embodiments, the matrix described herein (i.e., the sterilized matrix) is characterized by at least one or more of the following properties: ultimate tensile strength of 3.2 to 8 MPa as determined by ASTM D882-12; elongation at break of 200% to 700% as determined by ASTM D882-12; and suture retention force of 1.3 N to about 3 N as determined by ANSI / AAMI / ISO 7198:1998 / 2001 / (R) 2004.

[0144] In some embodiments, the article and / or matrix further comprise at least one additional ingredient (also referred to herein as an “additive”) that imparts additional functionality.

[0145] In some such embodiments, the additional component is in the form of at least one additional layer. The additional layer is optionally located on at least a portion of at least one surface of the core matrix, and / or within the core matrix (e.g., between two other layers of the core matrix, as described herein).

[0146] Optionally or additionally, in some embodiments, the additional components are dispersed within the core matrix and / or present on at least one surface of the matrix or a portion thereof.

[0147] Unless otherwise stated, when an additional component is present within the core matrix, it is considered part of the matrix, but when it is present outside the matrix (e.g., on the surface of the matrix or a portion thereof), it is not considered part of the matrix.

[0148] Examples of additional functions that additional components may impart include, but are not limited to: impermeability, which may optionally be provided by additives in the form of impermeable layers and / or by hydrophobic additives; inhibition of tissue adhesion formation, which may optionally be provided by additives that reduce tissue adhesion and / or by agents that inhibit cell growth; reduction of infection risk, which may optionally be provided by antimicrobial agents (such as antibiotics) and / or by membranes that inhibit pathogen penetration; reduction of the risk of tissue rejection and / or immune response, which may optionally be provided by agents that modulate the immune system; and sutureless tissue adhesion, which may optionally be provided by adhesives (e.g., applied to a surface) and / or by agents and / or surfaces that promote cell growth and / or attachment (e.g., growth factors, extracellular matrix proteins, and / or other proteins). Examples of layers that may be formed from additional components that impart such functions include, but are not limited to: impermeable layers, tissue adhesion layers (i.e., layers with enhanced cell adhesion compared to a core matrix without a tissue adhesion layer), cell growth promoting layers, and antifouling layers (i.e., layers with reduced cell adhesion compared to a core matrix without an antifouling layer).

[0149] Examples of additional components that may be included in the composition of a substance include, but are not limited to: adhesive materials, non-adhesive materials (e.g., materials with particularly low adhesion to tissues and / or other substrates), hydrophobic polymer particles, biological and / or bioactive materials, cellular components (e.g., cell signaling proteins, extracellular matrix proteins, cell adhesion proteins, growth factors, protein A, proteases and protease substrates), growth factors, and therapeutically active agents.

[0150] Additional components that can be beneficially incorporated into the composition of a substance (e.g., therapeutically active agents) include natural or synthetic polymers (large biomolecules, such as proteins and enzymes) and non-polymers (small molecule therapeutic agents) natural or synthetic agents.

[0151] Examples of suitable therapeutic agents include, but are not limited to: antiproliferators, cytotoxic factors or cell cycle inhibitors, including CD inhibitors such as p53, thymidine kinase (“TK”) and other agents used to interfere with cell proliferation.

[0152] Examples of therapeutically active agents (antiproliferative drugs) particularly suitable for drug elution systems used in anticancer therapy that inhibit cell proliferation and / or angiogenesis include: paclitaxel, sirolimus (rapamycin), farnesylthiosalicylic acid (FTS, salirasib), fluoro-FTS, everolimus, zotamolimus, daunorubicin, doxorubicin, N-(5,5-diacetoxypentyl)doxorubicin, anthracycline antibiotics, mitomycin C, mitomycin A, and 9-aminocamptothecin. Bases, aminopterin, actinomycin, N8-acetylspermidine, 1-(2-chloroethyl)-1,2-dimethylsulfonylhydrazine, bleomycin, tamethasone, etoposide, camptothecin, irinotecan, topotecan, 9-aminocamptothecin, paclitaxel, docetaxel, esperamycin, 1,8-dihydroxy-bicyclo[7.3.1]tridecane-4-ene-2,6-diyn-13-one, anguidine, morpholino-doxorubicin, vincristine, vinblastine and their biomolecules.

[0153] Additional therapeutically active agents that can be beneficially incorporated into the composition of a substance include antibiotic agents. Non-limiting examples of suitable antibiotic agents include: gentamicin, ceftazidime, sulfamidone benzoyl peroxide, octopirox, erythromycin, zinc, silver, tetracycline, triclosan, azelaic acid and its derivatives, phenoxyethanol and phenoxypropanol, ethyl acetate, clindamycin and meclocycline; sebostats such as flavonoids; α-hydroxy acids and β-hydroxy acids; polydiallyl dimethyl ammonium chloride; and bile salts such as squalene sulfate and its derivatives, deoxycholates, and bile salts.

[0154] Additional therapeutically active agents that can be beneficially incorporated into the composition of a substance include analgesics, anesthetics, pain relievers, and pain reducers (including NTHes, COX-2 inhibitors, K+, etc.). + Channel openers, opioids and morphine analogues; as well as hemostatic agents and antihemorrhagic agents.

[0155] Manufacturing method In another aspect of the invention, a method for manufacturing the matrix of the invention is provided, comprising contacting a viscoelastic polymer film with a first layer of elastic polymer material to obtain a coated elastic polymer material comprising a viscoelastic polymer layer bonded to the elastic polymer material; and contacting the viscoelastic polymer layer with a second layer of elastic polymer material to obtain a multilayer matrix; wherein the viscoelastic polymer film comprises or is substantially composed of viscoelastic polymers disclosed herein; and wherein either the first or second layer of elastic polymer material comprises or is substantially composed of electrospun fibers as described above, wherein the polymer contents of the elastic polymer material comprise or are substantially composed of PLLA / CL. In some embodiments, one surface of the viscoelastic polymer film is in contact with a support layer or a mold. In some embodiments, the support layer / mold comprises a glass material.

[0156] In another aspect of the present invention, a method for manufacturing the matrix of the present invention is provided, comprising: (i) Applying a viscoelastic polymer solution to a first layer of elastic polymer material to obtain a coated elastic polymer material comprising a viscoelastic polymer layer bonded to the elastic polymer material; (ii) Contacting a viscoelastic polymer layer with a second layer of elastic polymer material to obtain a multilayer matrix; wherein the viscoelastic polymer comprises or is substantially composed of one or more polymers disclosed herein; and wherein either of the first / second layer of elastic polymer material comprises or is substantially composed of electrospun fibers as described above, wherein the polymer contents of the elastic polymer material comprises or is substantially composed of PLLA / CL.

[0157] In some embodiments, the multilayer matrix is ​​an unsterilized matrix. In some embodiments, the method further includes sterilizing the unsterilized (also referred to herein as "non-sterile") matrix. In some embodiments, sterilization includes exposing the unsterilized matrix to a beta radiation source to obtain the matrix of the present invention (i.e., the sterilized matrix).

[0158] In some embodiments, the beta radiation source is an electron beam. In some embodiments, the method includes sterilizing a multilayer matrix by irradiating it with a beta radiation dose suitable for sterilizing the multilayer matrix. In some embodiments, the beta radiation dose is between 10 and 50 kGy, 20 and 25 kGy, 15 and 25 kGy, and 15 and 30 kGy, and any range therein.

[0159] In some embodiments, the first / second layer of elastic polymer material is characterized by an average thickness ranging from 20 to 500 µm, 25 to 350 µm, 50 to 250 µm, or 80 to 200 µm, or any range therein.

[0160] In some embodiments, PLLA / CL is characterized by a Mw between about 115 and about 120 kDa, and a caprolactone molar content between about 20% and about 40% or about 30%.

[0161] In some embodiments, the thickness (e.g., average thickness) of the viscoelastic polymer film is between 70 and 300 μm, 80 and 200 μm, 80 and 150 μm, 100 and 300 μm, 100 and 200 μm, 70 and 100 μm, 70 and 150 μm, or any range therein.

[0162] In some embodiments, the polymer contents of the viscoelastic polymer membrane comprise or are substantially composed of PDLCL, characterized in that Mw is between about 60 and 65 kDa and Mn is between about 40 and 45 kDa. In some embodiments, the layer is a PDLCL membrane or layer as disclosed herein, characterized in that the average thickness is between 70 and 300 µm, and is substantially composed of PDLCL characterized in that Mw is between about 60 and 65 kDa and Mn is between about 40 and 45 kDa; and wherein the PDLCL is characterized in that the molar percentage of caprolactone is between about 70% and about 80%, or about 75%.

[0163] In some embodiments, the viscoelastic polymer is a PDLCL characterized by a molecular weight (MW) between about 60 and 65 kDa and a molecular weight (Mn) between about 40 and 45 kDa. In some embodiments, the Mw / Mn ratio of the PDLCL and PLCL mentioned herein is based on the specific logarithmic viscosity determination of the polymer.

[0164] In some embodiments, the viscoelastic polymer is further characterized in that the molar percentage of caprolactone is between about 70% and about 80%. In some embodiments, the viscoelastic polymer has any of the following characteristics: (i) a melt peak temperature between 32.5°C and 45°C, between 32.5°C and 38°C (determined by DSC), and (ii) a specific logarithmic viscosity between 0.83 and 0.9 dl / g, 0.84 and 0.9 dl / g, 0.84 and 0.89 dl / g, or 0.85 and 0.9 dl / g, including any range therebetween; or the viscoelastic polymer has both characteristics (i) and (ii). The melt peak temperature and specific logarithmic viscosity are determined according to the methods described in the "Materials and Methods" section. It is noteworthy that the Tm values ​​of the raw material polymer and the same polymer contained in the multilayer matrix of the present invention are different.

[0165] In some embodiments, the viscoelastic polymer film is obtained by molding or shaping a viscoelastic polymer solution. In some embodiments, molding or shaping is performed by casting (e.g., solution casting). In some embodiments, casting includes film casting.

[0166] In some embodiments, casting includes contacting a sufficient amount of solution with a support material or mold to obtain a film; and further includes partially drying the film to obtain a settled viscoelastic film. In some embodiments, the settled viscoelastic film is a non-flowing film (i.e., without free flow). In some embodiments, the settled viscoelastic film has a reduced organic solvent content compared to the viscoelastic polymer solution. In some embodiments, the reduced organic solvent content includes a reduction of at least 10%, at least 20%, at least 30%, at least 50%, at least 60%, or a reduction of 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, and any range therein.

[0167] In some embodiments, the viscoelastic polymer solution is an organic solution comprising a viscoelastic polymer and an organic solvent, wherein the organic solvent is capable of dissolving the viscoelastic polymer at a temperature of 20 to 40°C. In some embodiments, the organic solvent comprises one or more solvents. In some embodiments, the organic solvent comprises a water-immiscible solvent. In some embodiments, the organic solvent comprises a water-immiscible aprotic solvent. In some embodiments, the organic solvent comprises an ether solvent. In some embodiments, the ether solvent is characterized by a boiling point between 40 and 120°C. Examples of ether solvents include tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, dimethoxyethane (glycol dimethyl ether), diisopropyl ether, methyl tert-butyl ether (MTBE), ethyl tert-butyl ether (ETBE), dibutyl ether, anisole, and tetraethylene glycol dimethyl ether (tetraethylene glycol dimethyl ether).

[0168] In some embodiments, the organic solvent further comprises an amide solvent. In some embodiments, the amide solvent is characterized by a boiling point between 120 and 300°C. Examples of amide solvents include dimethylformamide (DMF), dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), N,N-diethylacetamide (DEAc), N,N-dimethylpropionamide (DMPA), N,N-dimethylbutyramide (DMBA), N,N-dimethylisobutyramide (DMIBA), N,N-dimethylpentanamide (DMVA), N,N-dimethylhexamamide (DMCA), and N,N-dimethylbenzamide (DMBA).

[0169] In some embodiments, the w / w concentration of the viscoelastic polymer in the solution is between about 20% and about 60%, about 25% and about 35%, about 20% and about 40%, about 20% and about 50%, and any range therein.

[0170] In some embodiments, contacting the viscoelastic polymer layer (i.e., the cured viscoelastic film) with the second layer further includes applying pressure to the multilayer matrix to induce bonding between the first and second layers and the viscoelastic polymer film. In some embodiments, pressure is applied using any suitable pressure source such as a mechanical press, hydraulic press, pneumatic press, or roller press to ensure sufficient bonding and integration of the layers within the multilayer matrix.

[0171] In some embodiments, the pressure applied to the multilayer matrix is ​​at least 50 Pa, at least 70 Pa, at least 100 Pa, or between 50 and 1000 Pa, including any range therebetween.

[0172] In some embodiments, the method further includes drying a multilayer matrix to obtain a dried matrix. In some embodiments, drying is performed prior to sterilization.

[0173] In some embodiments, the method further includes drying the multilayer matrix to obtain a dried matrix. In some embodiments, drying is performed prior to sterilization (by beta radiation). In some embodiments, drying includes vacuum drying, thermal drying, or both. Other drying methods that may be used include: 1. Vacuum drying: This method involves removing moisture under reduced pressure, which lowers the boiling point of water and allows drying at lower temperatures while maintaining the integrity of the material.

[0174] 2. Freeze-drying (lyophilization): This method involves freezing the material and then reducing the ambient pressure to allow the frozen water to sublimate directly from the solid to the gaseous state. It is suitable for heat-sensitive materials.

[0175] 3. Desiccant drying: Using desiccants such as silica gel or molecular sieves to absorb moisture from materials in a controlled environment.

[0176] 4. Infrared drying: Utilizes infrared radiation to heat and evaporate moisture from the material surface, providing rapid and uniform drying.

[0177] 5. Microwave drying: Uses microwave energy to heat and evaporate moisture, providing fast drying time and high energy efficiency.

[0178] These methods can be selected based on the material properties and the required drying efficiency.

[0179] In some embodiments, the dried matrix is ​​characterized by a total residual solvent content of at most 0.5%, at most 0.2%, or at most about 0.1%. In some embodiments, the total residual solvent contents include one or more of THF (e.g., less than 1000 ppm), dioxane, and DMF.

[0180] In some embodiments, the dried matrix is ​​characterized by (i) a residual solvent content of up to 0.2%; and (ii) a water content of up to 5%, up to 2%, or up to 1% relative to the total weight of the dried matrix.

[0181] General content The term “about” as used in this article refers to ±10%.

[0182] The terms “comprises,” “comprising,” “includes,” “including,” “having,” and their related terms mean “including but not limited to.”

[0183] The term "consisting of" means "including and limited to".

[0184] The term "consisting essentially of" means that a composition, method, or structure may contain additional ingredients, steps, and / or portions, provided that such additional ingredients, steps, and / or portions do not materially alter the essential and novel characteristics of the claimed composition, method, or structure. For example, the term "consisting essentially of" may cover a composition (e.g., a matrix or any matrix layer) comprising at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, at least 99% by weight, or 80% to 100%, 80% to 99%, 90% to 95%, 90% to 96%, 90% to 97%, 90% to 98%, 93% to 97%, 93% to 98%, 93% to 99%, 95% to 99%, 96% to 99%, or 97% to 99% of the listed ingredients, including any of the foregoing ranges or any values ​​between them.

[0185] As used herein, the term "exemplary" means "used as an example, illustration, or description." Any implementation described as "exemplary" is not necessarily to be construed as preferred or superior to other implementations and / or as excluding features from other implementations.

[0186] As used herein, the term "optionally" means "provided in some embodiments but not in others." Any particular embodiment of the invention may include multiple "optional" features unless such features conflict with each other. The terms "furthermore" and "optionally" are used interchangeably.

[0187] The singular forms “a,” “an,” and “the” used herein include plural references unless the context clearly specifies otherwise. For example, the terms “a compound” or “at least one compound” may include multiple compounds, including mixtures thereof.

[0188] The term “substantially” as used herein means at least 80%, at least 90%, at least 92%, at least 95%, at least 97%, at least 98%, or at least 99% of the composition by weight, including any range or value therein.

[0189] As used in this article, the term "method" refers to the manner, means, techniques and procedures for accomplishing a given task, including but not limited to manner, means, techniques and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine, or manner, means, techniques and procedures that can be easily developed from known manner, means, techniques and procedures.

[0190] The term “treatment” or “treating” as used in this article includes abolishing, substantially inhibiting, slowing or reversing the progression of a disease, substantially improving the clinical or aesthetic symptoms of a disease, or substantially preventing the occurrence of the clinical or aesthetic symptoms of a disease.

[0191] It should be understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided individually or in any suitable sub-combination, or as suitable features in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiment cannot be implemented without these elements.

[0192] The various embodiments and aspects of the invention described above and claimed in the claims section are experimentally supported in the following examples.

[0193] The phrase “elastic modulus” as used throughout this document refers to Young’s modulus, which is determined by the material’s response to tensile stress (e.g., according to the procedure described in the Examples section of this document).

[0194] The tensile properties described herein (e.g., modulus of elasticity, elongation at break, recovery rate, and ultimate tensile strength) are determined according to ASTM International Standard D882-12 for testing the tensile properties of thin plastic sheets. Unless otherwise specified, tensile properties are determined before or after immersing each layer in an aqueous liquid (e.g., water, phosphate-buffered saline) at a temperature of 37°C (e.g., according to the procedure described in the Examples section of this document). Tensile testing characterizes the magnitude of the tensile stress applied to the test material as a function of the tensile strain of the material (the percentage increase in length relative to the original length due to the tensile stress).

[0195] Ultimate tensile strength is defined as the maximum stress that can be applied to the material being tested, such that any further strain is obtained under reduced stress (a phenomenon known as "necking") or cannot be obtained due to tensile stress causing the material to break (e.g., tearing, cracking).

[0196] Elongation at break is defined as the maximum strain (elongation) that can occur before the material under test fails (e.g., cracks or necking) (when a tensile stress equal to the ultimate tensile strength is applied).

[0197] The elastic modulus is defined as the stress gradient as a function of strain over a range of stresses and strains where stress is a linear function of strain (e.g., from stress and strain to the elastic proportional limit, and optionally from zero strain to strain not exceeding 50% of the elongation at break).

[0198] Recovery rate is determined by subjecting the test material to post-release tensile stress and is the ratio of the reduction in length to the previous strain after subjecting the material (e.g., an elastic layer) to a strain approximately equal to the elongation at break (optionally about 80% or 90% of the elongation at break, optionally about 95%, optionally about 98%, optionally about 99%, where the elongation at break can be determined using an equivalent sample). Recovery rate is determined under ambient conditions (approximately 1 atmosphere of pressure and a temperature between 19°C and 30°C).

[0199] Therefore, for example, a material stretched to 200% elongation at break, which recovers to a strain of 20% relative to its original length after the tensile stress is released, will be characterized as having a recovery rate of 90% (i.e., 200% minus 20% divided by 200%).

[0200] As used herein, the term "biocompatible" refers to materials that are generally expected by those skilled in the art to be acceptable to the body without producing significant toxicity, immune response and / or rejection, or excessive fibrosis. In some embodiments, a moderate immune response and / or fibrosis is optionally acceptable or desirable.

[0201] As used in the context of this invention, the term "biodegradable" describes materials that can decompose into decomposition products (e.g., polymer fragments, monomers, CO2, methane, or other gases) under physiological and / or environmental conditions. Such physiological and / or environmental conditions include, for example, hydrolysis (decomposition via hydrolytic cleavage), enzymatic catalysis (enzymatic degradation), and mechanical interactions, or decomposition under composting conditions, such as exposure to ambient temperatures (e.g., between 0°C and 40°C), ambient air atmosphere, and ambient pressure (e.g., about 1 atmosphere) in moist soil. The term generally refers to substances that decompose under these conditions such that between 90% and 100% of the substance decomposes within a period of less than one year, or within a period of between one week and one year, or between one week and 0.5 years (inclusive).

[0202] In the context of this invention, the term "biodegradable" also includes the term "bioabsorbable," which describes substances that, under physiological conditions, decompose into products that are bioabsorbed within the host organism, i.e., become metabolites of the host organism's biochemical system.

[0203] In this application, various embodiments of the invention may be presented in a scope format. It should be understood that the scope format is merely for convenience and brevity and should not be construed as an inflexible limitation of the scope of the invention. Therefore, the description of a scope should be considered as specifically disclosing all possible sub-scopes and the individual values ​​within those scopes. For example, a description of a scope such as 1 to 6 should be considered as specifically disclosing sub-scopes such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., and the individual numbers within those scopes, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the scope.

[0204] Wherever a range of numbers is specified in this document, it means that any number (fraction or integer) mentioned within the specified range is included. The phrases “range between the first and second indicator numbers” and “range from the first to the second indicator number” are used interchangeably in this document and are intended to include the first and second indicator numbers and all fractions and integers in between.

[0205] Example Materials and Methods Logarithmic viscosity Single point method (chloroform) Weigh 0.25g of the polymer into a 50ml volumetric flask. Add approximately 25ml of chloroform to the flask and shake the mixture until the polymer dissolves. The minimum dissolution time is set to overnight. This solution is stable for up to 72 hours.

[0206] Fill the viscometer to 50 ml and shake several times. Turn on the water bath and set it to 25°C. The water bath temperature must be checked before taking measurements. Rinse the viscometer twice with chloroform, then fill it with chloroform. The solution or solvent should always be added to the viscometer through a glass filter to prevent solid particles from entering the viscometer.

[0207] Use WinVisco software to measure the blank. Then, rinse the viscometer twice with the polymer solution and fill it. Measure the sample using WinVisco software. When measuring a very viscous solution (t>160 seconds), rinse the viscometer twice with chloroform before measuring the next sample.

[0208] Single point method (HFIP) When the polymer is insoluble in chloroform, use HFIP as the solvent. Weigh the same amount of polymer, but now weigh it into a 25 ml volumetric flask. Using a small fraction of the sample, i.e., <1 mm, will dissolve the polymer more quickly. If this is still insufficient or not feasible, the solution can be heated to a maximum of 35°C to obtain a completely dissolved polymer solution.

[0209] The method is the same as with chloroform, except that the viscometer is cleaned with HFIP and, instead of being rinsed and filled with chloroform at the end of the measurement, it is filled with acetone. Blanks and samples are measured using WinVisco software.

[0210] WinVisco The flow time measurements for both blank and sample samples are controlled by WinVisco software. Variables can be set within the software, and these variables can be used to calculate the specific logarithmic viscosity. The software uses Hagenbach correction to calibrate the flow time of the Ubbelohde Din 0c viscometer.

[0211] The average flow time is calculated from three flow time measurements. The software uses a maximum deviation setting to determine which flow times are available for averaging (when more than three flow times are acquired). If the maximum deviation setting is not reached after five measurements, the blank or sample must be discarded and the test tube refilled. The average flow time cannot be derived from more than five measurements.

[0212] Calculation The software calculates the specific logarithmic viscosity using the corrected average value, the input volume of solution, and the sample weight. If the sample is poly(L-lactide), poly(D-lactide), or poly(DL-lactide), the viscosity-average molecular weight can be calculated using the Mark-Houwink parameters and Equation 6.

[0213] The Mark-Houwink parameters for poly(L-lactide) and poly(D-lactide) are: K = 5.45•10. -4 And a=0.73.

[0214] Equation 1: Corrected flow time t c = t u - t hc Equation 2: Relative viscosity Equation 3: Specific viscosity Equation 4: Intrinsic viscosity Equation 5: Logarithmic viscosity of specific concentration Equation 6: Molecular weight Equation 7: Kinematic viscosity in: t c =Corrected flow time [s] t u =Uncorrected flow time [s] t hc =Hagenbach correction[s] t s =Corrected sample flow time [s] t b =Corrected blank flow time [s] c = concentration [g / dl] M v =Viscosity-average molecular weight [g / mol] K, a = Mark-Houwink parameters η rel =Relative viscosity[-] η sp =Specific viscosity[-] η intr =Intrinsic viscosity [dl / g] η inh =Specific viscosity logarithmic viscosity [dl / g] K' = Ubbelohde tube constant [mm] 2 / s 2 ] The software calculates the maximum deviation based on Equation 8.

[0215] Equation 8: Maximum Deviation in: t x =Measure the flow time of 1 or 2 t 平均 =Measure the average flow time of 1 and 2.

[0216] DSC Using TA Instruments Trios V5.0.0.44616, 5-10 mg of sample was tested at 10°C min in a temperature range of -60°C to +60°C (or +180°C). -1 The heating rate was measured by DSC.

[0217] Crystallinity As used herein, the term “crystallinity” refers to a value calculated from (i) the raw material polymer, namely PDLCL or PLLCL (in determining the crystallinity of the raw material, for example, the raw material used in the manufacturing method disclosed herein) or (ii) the DSC plot of the article / multilayer matrix.

[0218] Crystallinity (Xc) is calculated according to the following equation: Where Δ H 0 f It is the enthalpy of fusion of a PLLA crystal with infinite thickness (see Sarasua, JR, Prud'homme, RE, Wisniewski, M., Le Borgne, A., Spassky, N., 1998. Macromolecules 31, 3895–3905), Δ Hf It is the total normalized enthalpy obtained from the phase transition (such as Tc and Tm) of the polymer (PDLCL or PLLCL), (LA) ) represents the mass fraction of lactide in the copolymer. In this paper, Δ H 0 f It is 106 (J g) -1 ).

[0219] Swelling test The tests were conducted in sealed containers containing phosphate-buffered saline (PBS, pH 7.4). Test samples were immersed in PBS and incubated at 37°C ± 1°C for 7 days. The average thickness of the samples was measured before incubation (t0) and after incubation (t1) using an optical microscope equipped with image analysis software. The swelling ratio was determined by dividing t1 by t0.

[0220] Example 1 The exemplary article of the present invention has been manufactured as follows.

[0221] The viscoelastic polymer membrane was prepared by casting a polymer solution onto a glass surface using a membrane coater. PDLLA / CL (PDLC 2509, available from Corbion, or Evonik, Nomisma Healthcare) was dissolved in a mixture of THF:DMF:dioxane, characterized by a caprolactone molar percentage of approximately 75% and a molecular weight (MW) of approximately 64 kDa (based on viscosity). The resulting 30% w / w solution was then coated onto the glass surface using a membrane coater to form a pre-adjusted film of the desired thickness (approximately 150 micrometers).

[0222] After the viscoelastic polymer film is partially dried (i.e., cured by air drying in a hood for about 1-10 minutes), a first electrospun PLCL tape (obtained by electrospinning a PLCL solution, characterized by a MW between about 115 and about 120 kDa) is placed on the first surface of the film, and pressure is applied to achieve complete adhesion between the two layers. Subsequently, a second electrospun PLCL tape is applied to the second surface of the viscoelastic polymer film. Pressure is applied again (a plastic weight on top of the interlayer matrix) to ensure complete integration of the third layer. The resulting three-layer patch is then dried to completely remove solvent residues (e.g., below the following maximum thresholds: THF 720 ppm, dioxane 380 ppm, DMF 88 ppm).

[0223] A more detailed description of the manufacturing conditions is provided in PCT / IL2014 / 051109, the entire contents of which are incorporated herein by reference.

[0224] In addition, the manufactured three-layer patch is sterilized by beta radiation (electron beam, radiation dose between 17 and 25 kGy) to obtain a sterile product (sterile patch).

[0225] Example 2 The chemical composition and physicomechanical properties of the sterile product of Example 1 have been tested and compared with unsterilized and gamma-sterilized products. The results of these tests are summarized below. Furthermore, due to technical challenges in determining the molecular weight parameters of PLCL in the three-layer patch, the inventors used an electrospun PLCL sheet from Example 1 (instead of the three-layer patch) and compared the unradiated sheet with the β / γ-radiated sheet.

[0226] Surprisingly, the inventors observed that, compared to the counterpart of gamma radiation, PLCL sterilization by beta radiation was characterized by a significant reduction in Mw / Mn (as determined by GPC) (see Table 3 below).

[0227] Table 3 The non-limiting test results and test methods for example γ / β radiation patches are summarized below.

[0228] Test No.: 1 (Tensile Assessment) The purpose of this test procedure is to evaluate: (a) the ultimate tensile strength (UTS) [MPa] of the test patch, and (b) the elongation at break [%] when direct tension is applied.

[0229] Test methods A "dog bone" shaped test specimen was cut from each patch and mounted on a designated stretching machine. Tensile testing was performed at a constant speed of 50 mm / min. The maximum force and displacement of each test specimen were recorded accordingly.

[0230] Sample size considerations To assess the mean and calculate the 95% confidence interval for continuous parameters, while maintaining a 5% Type I error (α) and at least 80% statistical power (1-β), a minimum sample size of 10 was required; this figure excludes samples dropped out due to irrelevant technical malfunctions (typically estimated at 10% to 20%). At least 30 products from different batches were tested.

[0231] result For the test specimen subjected to gamma radiation, the minimum UTS value is 3.07 MPa, and the minimum elongation before fracture is 154%.

[0232] For the test article subjected to β radiation, the minimum UTS value is 5.04 to about 7 MPa, and the minimum elongation before fracture is 369%.

[0233] For non-radiated items, the beta-radiated patch almost maintained the elongation (reduced by no more than 5% relative to the non-radiated patch); and showed only a reduction in UTS of about 30%.

[0234] Test No.: 2 (Suture Retention Assessment) The purpose of this test procedure is to evaluate the suture retention strength of the test patch and compare it with Integra's control product, Suturable Duragen®.

[0235] Test methods The suture retention test is adapted from the methods described in ANSI / AAMI / ISO 7198:1998 / 2001 / (R) 2004 and ASTM D882-12: Standard Test Method for Tensile Properties of Thin Plastic Sheets. Prior to testing, at least three test patches and three DuraGen® patches are cut and immersed in PBS for 15 minutes. One end of the dog bone-shaped sample is removed with a scalpel, and the sample is sutured at least 2 mm from its free end (suture type: Premilene™, 4 / 0). The sample is then placed on a tensile testing machine, with the patch attached to the first clamp and the suture attached to the other clamp. Tensile testing is performed using an LLOYD LS1 uniaxial tensile testing machine (equipped with a 10 N load cell for gamma-radiated products and a 100 N load cell for beta-radiated products) to measure the force required to fail the sample.

[0236] Note: For comparative purposes, Duragen conducted similar tests in both test setups.

[0237] Sample size considerations This test was used for research purposes and no statistical analysis was performed.

[0238] result For the gamma-radiated patch, the average breaking force was 1.1 ± 0.03 N, which is greater than the average breaking force of DuraGen (0.86 ± 0.2 N).

[0239] For the beta-radiated patch, the average breaking force was 4.19 N ± 0.233 N, greater than the average breaking force of DuraGen (1.15 ± 0.36 N). The non-radiated patch showed essentially the same values ​​as the beta-radiated patch (or even slightly lower).

[0240] Test No.: 3 (Bursting Pressure Test) The purpose of this test procedure is to evaluate the burst pressure that the test patch can withstand before failure and / or leakage after a constant flow of saline solution is applied.

[0241] Test methods Burst pressure tests were conducted according to ASTM F2392-04, "Standard Test Method for Burst Strength of Surgical Sealant" (with some modifications). A custom testing apparatus was built according to ASTM standards. Each test specimen being evaluated was mounted on the test fixture base and secured with an O-ring. Brine was injected into the test fixture at a flow rate of 2 ml / min, and the burst strength of each specimen was calculated as the peak pressure at which fluid is allowed to leak from the specimen.

[0242] Sample size considerations To assess the mean and calculate the 95% confidence interval for continuous parameters, while maintaining a 5% Type I error (α) and at least 80% statistical power (1-β), a minimum sample size of 10 was required; this figure excludes samples dropped out due to irrelevant technical malfunctions (typically estimated at 10% to 20%). At least 30 products from different batches were tested.

[0243] For the results of the gamma radiation patch, the minimum pressure measured was 1 psi.

[0244] For the beta-radiation patch, the minimum pressure measured was 3 psi.

[0245] Another test was conducted, comparing the beta-radiated patch with the unradiated patch. The unradiated patch showed an average burst pressure of approximately 2.5 psi, while the beta-radiated patch showed an average burst pressure of approximately 1.55 psi.

[0246] To this end, the inventors were surprised to observe that, despite being exposed to the same radiation dose, the β-radiated patch exhibited (i) improved physical and mechanical properties and (ii) a higher Mw / Mn value for PLCL compared to the γ-radiated patch.

[0247] Therefore, the inventors observed that the three-layer patch sterilized by beta radiation essentially retained the physical and mechanical properties of the un-radiated product. In contrast, the physical and mechanical properties of the three-layer patch sterilized by gamma radiation were significantly impaired compared to the un-radiated product (see below). Therefore, the inventors concluded that sterilization of the three-layer patch by beta radiation was unexpectedly more preferred than sterilization based on gamma radiation.

[0248] Example 3 The inventors observed a correlation between the Tm of PDLCL and the swelling properties of the patch (matrix) of the present invention. Briefly, as described in Example 1, different production batches of PDLCL obtained from the manufacturer were used to manufacture the patch. Subsequently, the Tm of the PDLCL in each batch of the prepared patch was determined by DSC (example Tm is shown in Figure 1). Figure 1 (As shown).

[0249] In addition, a swelling test (as described above) was performed on each patch to determine its swelling ratio (i.e., the swelling ratio of the viscoelastic PDLCL film), and the obtained swelling ratio was compared with the measured Tm of the PDLCL in the prepared patch. Exemplary patches before and after the swelling test are shown below. Figure 2A - As shown in Figure D.

[0250] The inventors were surprised to observe that, compared with the exemplary patch of the present invention comprising PDLCL with a Tm of 34.7°C and a specific logarithmic viscosity of 0.85 dl / g, ( Figure 2DThe average swelling ratio of the control patch (not of this invention), which includes PDLCL with a Tm of 28.6 °C and a specific logarithmic viscosity of 0.81 dl / g, was only 1.4. In contrast, the control patch (not of this invention), including PDLCL with a Tm of 28.6 °C and a specific logarithmic viscosity of 0.81 dl / g, exhibited a significantly higher average swelling ratio of 2.5 (see [link to invention] Figure 2B ).

[0251] Furthermore, the inventors conducted multiple tests on patches with viscoelastic polymer films of varying thicknesses. They observed that patches with viscoelastic polymer film thicknesses below 10 μm underwent fatty acid decomposition. It is speculated that a viscoelastic polymer film thickness below 10 μm is insufficient to hold the elastic polymer material layers together.

[0252] In another experiment, in vivo testing (by implanting them into mice) was conducted on a control patch comprising a viscoelastic polymer film with a thickness exceeding 60 μm (e.g., 80-100 μm) and an exemplary patch of the present invention comprising a viscoelastic polymer film with a thickness between 20 and 60 μm. Surprisingly, the control patch underwent tissue degradation / separation in vivo, while the patch of the present invention remained stable during the testing period.

[0253] Although the invention has been described in conjunction with specific embodiments thereof, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be apparent. Therefore, the invention is intended to cover all such alternatives, modifications, and variations falling within the spirit and broad scope of the appended claims.

[0254] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety, to the same extent that each individual publication, patent, or patent application is specifically and individually indicated to be incorporated herein by reference. Furthermore, any reference or identification of any reference in this application should not be construed as an admission that such reference is prior art to the invention. The use of section headings should not be construed as an inherent limitation.

Claims

1. An article comprising a multilayer matrix, said multilayer matrix comprising a viscoelastic polymer film sandwiched between two or more layers of elastic polymer material; wherein: Each of the two or more layers of elastic polymer material is in the form of a fiber pad; The fiber pad comprises a plurality of electrospun fibers, characterized in that the average cross-section is between about 1 and about 5 micrometers; The viscoelastic polymer film is characterized by a thickness between about 10 and about 60 μm; The viscoelastic polymer film is characterized by a melting peak temperature between about 30 and about 40°C, as determined by DSC. The two- or more-layered elastic polymer materials include PLCLs characterized by Mw between 78 and about 100 kDa.

2. The article of claim 1, wherein the multilayer matrix is ​​a stitchable matrix, a stapleable matrix, or both; and wherein the viscoelastic polymer film is a continuous film characterized by uniform thickness.

3. The article of claim 1 or 2, wherein the fiber pad is further characterized in that the average pore size is between about 5 and about 50 micrometers.

4. The article according to any one of claims 1 to 3, wherein the article is characterized by at least one of the following as determined according to ASTM D882-12: (i) an average elongation at break of at least 200%; and (ii) an ultimate tensile strength of 3.5 to 6 MPa.

5. The article of claim 1 to 4, wherein the two or more layers of elastic polymer material comprises PLLA / CL, characterized in that... Mw is between 80 and 90 kDa, and Mz is between approximately 150 and approximately 200 kDa.

6. The article of claim 1 to 5, characterized in that, The elastic modulus, as determined by ASTM International Standard D882-12, is in the range of 0.5 to 2 MPa.

7. The article of any one of claims 1 to 6, wherein the plurality of electrospun fibers are randomly distributed within the fiber pad.

8. The article of any one of claims 1 to 7, wherein the article is a sterile article.

9. The article of claim 8, wherein the sterile article is an article subjected to beta radiation.

10. The article of claim 8 or 9, wherein the sterile article is packaged in a sealed container.

11. The article of any one of claims 1 to 10, wherein the article is characterized in that the burst pressure is at least 1.5 psi when measured according to ASTM F2392-04.

12. The article of any one of claims 1 to 11, wherein the fiber pad is characterized by a porosity in the range of 40% to 70%.

13. The article of manufacture according to any one of claims 1 to 12, characterized in that... At least one of the following properties: When measured according to ASTM D882-12, the ultimate tensile strength is between 3.2 and 8 MPa; When measured according to ASTM D882-12, the elongation at break is 200% to 700%; When measured according to ANSI / AAMI / ISO 7198:1998 / 2001 / (R)2004, the suture retention force is at least 1.3 N.

14. The article of any one of claims 1 to 13, wherein each of the multilayer matrix or each of the two or more layers of elastic polymer material is characterized by a self-healing rate of at least 90%.

15. The article of claim 1 to 14, wherein the viscoelastic polymer film comprises PDLLA / CL, characterized in that... The molar percentage of caprolactone is between approximately 70% and approximately 80%.

16. The article of claim 15, wherein the Mw of said PDLLA / CL is between about 20 and about 60 kDa; the molar percentage of caprolactone is about 75; and wherein the Mn of said PDLLA / CL is between about 10 and about 45 kDa.

17. The article of claim 15 or 16, wherein 95% to 100% by weight of the viscoelastic polymer film is composed of the PDLLA / CL; and wherein the DSC chart of the article includes at least one melting peak corresponding to the PDLLA / CL at a temperature of 30 to 40°C.

18. The article of any one of claims 15 to 17, wherein the PDLLA / CL is characterized by a crystallinity between 1% and 20% as determined by DSC.

19. The article of any one of claims 1 to 18, wherein the viscoelastic polymer film is characterized by a swelling ratio of less than 1.

8.

20. The article of claim 19, wherein the swelling ratio is between 0.9 and 1.

7.

21. The article of any one of claims 1 to 20, wherein the plurality of electrospun fibers constitute between 95% and 100% by weight in each of the two or more layers of elastic polymer material; and wherein the plurality of electrospun fibers are substantially composed of the PLCL.

22. The article of any one of claims 1 to 20, wherein the molar percentage of PLCL caprolactone is between about 20% and about 40%.

23. The article of claim 22, wherein the molar percentage of caprolactone is about 30%.

24. The article of any one of claims 1 to 23, wherein the PLCL is characterized by a melting peak temperature between about 100 and about 120°C; and optionally a crystallinity between 8% and 20%.

25. The article of any one of claims 1 to 24, wherein the average thickness of each layer of the two or more layers of elastic polymer material is between about 100 and about 200 µm.

26. The article of any one of claims 1 to 25, wherein it is identified for the treatment of disorders or conditions selected from: dura mater repair, hernia repair, closure of internal and / or local wounds, closure and / or repair of skin, sealing of tissues and / or organs to contain body fluids or air, sealing of anastomoses, inhibition of postoperative adhesions between tissues, promotion of hemostasis, treatment of burns, and administration of therapeutically effective agents.

27. A method for manufacturing the article of any one of claims 1 to 25, comprising: A first layer of elastic polymer material, a second layer of elastic polymer material, and a viscoelastic polymer film including a first surface and a second surface are provided, wherein at least the first surface faces the environment, the second surface is in contact with a support material, and wherein the thickness of the viscoelastic polymer film is between 70 and 300 μm and includes PDLLA / CL. The first surface of the viscoelastic polymer film is brought into contact with the first layer of the elastic polymer material to obtain the viscoelastic polymer film bonded to the first layer of the elastic polymer material; Remove the viscoelastic polymer film bonded to the first layer of the elastic polymer material from the support material; The first surface of the viscoelastic polymer film is brought into contact with the second layer of the elastic polymer material to obtain the multilayer matrix.

28. The method of claim 27, wherein the contact comprises applying pressure sufficient to bond at least one layer of the elastic polymer material to at least one surface of the viscoelastic polymer film; and wherein the pressure is at least 50 Pa.

29. The method of claim 27 or 28, wherein the method further comprises exposing the multilayer substrate to conditions suitable for drying to obtain a dried substrate.

30. The method of claim 29, wherein the dried matrix is ​​characterized in that the total residual solvent content is less than 0.5% by weight.

31. The method according to any one of claims 27 to 30, wherein the PDLLA / CL is characterized in that the molar percentage of caprolactone (CL) is between about 70% and about 80%, and the Mw is between about 60 and 65 kDa.

32. The method according to any one of claims 27 to 31, wherein the viscoelastic polymer film is substantially composed of the PDLLA / CL and optionally one or more organic solvents, and wherein the PDLLA / CL is characterized by Mw being about 64 kDa, Mn being about 40 to 45 kDa, and CL content being about 75% mol.

33. The method according to any one of claims 27 to 32, wherein the PDLLA / CL is further characterized by any one of the following: (i) a melting peak temperature between 32.5 and 45 °C, and (ii) a specific viscosity logarithmic viscosity between 0.83 and 0.9 dl / g.

34. The method according to any one of claims 27 to 33, wherein the Mw of the PLCL is between about 115 and about 120 kDa.

35. The method according to any one of claims 27 to 34, wherein the molar content of caprolactone in the PLCL is between about 20% and about 40%.

36. The method according to any one of claims 27 to 35, further comprising a preliminary step of forming the viscoelastic polymer film, the step comprising casting a polymer solution containing the PDLLA / CL onto the support material.

37. The method of claim 36, wherein the casting comprises applying the polymer solution onto the support material to obtain a film; and further comprises partially drying the film to obtain a cured viscoelastic film.

38. The method according to claim 37, wherein the cured viscoelastic film does not have free flowability, and is characterized in that, The organic solvent content is reduced by at least 20% by weight compared to the organic solvent content of the polymer solution.

39. The method according to claim 37 or 38, wherein the membrane is characterized in that its thickness is between 70 and 300 μm; and wherein the concentration of PDLLA / CL in the polymer solution is between 20% w / w and 60% w / w.

40. The method according to any one of claims 27 to 39, further comprising sterilizing the multilayer matrix by exposing the multilayer matrix to a dose of β radiation suitable for sterilizing the matrix, thereby obtaining the sterile article of any one of claims 8 to 25.

41. The method of claim 40, wherein the dose is between about 15 and 30 kGy.

42. The method of claim 40 or 41, wherein the β radiation is performed by electron beam radiation.

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