bioadhesive

Abstract

Disclosed is a bioadhesive material. The material includes a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer. The material also includes a membrane embedded in the hydrogel. Embodiments also relate to formation of the bioadhesive material, and uses thereof in soft tissue repair.

Description

[0001] Bioadhesive

[0002] Field of the Invention

[0003] The disclosure relates to a bioadhesive material, such as those that can be used to replace sutures for tissue repair.

[0004] Background

[0005] Peripheral nerve injuries and cerebrospinal fluid (CSF) leaks are the common orthopaedic and neurosurgical conditions and surgical complications leading to debilitating functional consequences. Meticulous intraoperative repair, with rapid and timely manners is a major challenge for surgeons. Traditionally, the mechanical closure methods, such as suturing, are commonly used as treatment. However, despite of the disadvantages for those techniques, such as granulomatous reactions, prolonged surgical time with increased risk of infection caused by suturing, their use is also limited in the complicated scenarios, for example, the blocked operative field due to generalized oozing and invisible bleeding, and the uncontrollable CSF leakage due to irregular-shaped dural tear.

[0006] One potential solution to solve the above-mentioned problem is the use of tissue adhesive agents. By utilizing the self-adhesive and cohesive properties from the polymerization process of biopolymers, tissue adhesives could seal the bleeding or leakage sites within a short time. So far, there are several surgical adhesives have been approved by FDA and clinically available for the applications. However, current products pose many unignorable shortcomings, such as weak adhesion in wet condition, suboptimal biocompatibility, and complications occurrence. The fibrin hemostatic agents, such as Tisseel®, EVICEL® and Beriplast®, have been reported to have poor adhesion in wet conditions. This constrained the clinical application to low pressure bleeding. Moreover, those agents also pose thrombus risk if applied intravascularly. Some of the adhesives have been reported displaying unsatisfied biocompatibility. For example, ETHICONTM could break down to cytotoxic degradation products; a case study reported BioGlue® can evoke a chronic granulomatous inflammatory reaction. For dural sealing application, due to the expansion when gluing, current dural sealants (DuraSeal® and Adherus®) carries risks of compressing surrounding tissue. This brings unwanted complications such as spinal impingement or cauda equina syndrome. Thus, there is a call for an update of the adhesives for a safer use in more complicated surgical scenarios.

[0007] Summary

[0008] An embodiment provides a bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

[0009] An embodiment provides a bioadhesive material comprising: a hydrogel that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

[0010] An embodiment provides a bioadhesive material comprising: a hydrogel formed from a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

[0011] An embodiment provides a bioadhesive material comprising: a hydrogel formed from gelatin methacrylate and hyaluronic acid methacrylate, the hydrogel having up to 20wt.% of hyaluronic acid methacrylate; and a membrane embedded in the hydrogel.

[0012] An embodiment provides a method of forming a bioadhesive material, comprising: providing a membrane immersed in a pre-polymer solution, the pre-polymer solution comprising a gelatin species modified with polymerisable groups and a secondary biopolymer modified with polymerisable groups; and polymerising the pre-polymer solution to form a hydrogel to embed the biodegradable membrane.

[0013] An embodiment provides a system for forming a bioadhesive material to repair a soft-tissue injury, the system comprising: a pre-polymer solution comprising gelatin species modified with polymerisable groups, a secondary biopolymer modified with polymerisable groups, and an initiator to initiate polymerisation of the gelatin species modified with polymerisable groups and the secondary biopolymer modified with polymerisable groups; and a membrane that is capable of being immersed in the pre-polymer solution to absorb at least some of the pre-polymer solution; wherein the system is configured such that polymerising the pre-polymer solution form a hydrogel that embeds the biodegradable membrane. An embodiment provides a method of repairing a peripheral nerve injury or dural tear using the system as set forth above, the method comprising: providing the membrane immersed in the pre-polymer solution; contacting the membrane immersed in the pre-polymer solution with the peripheral nerve injury or dural tear such that the membrane covers at least a portion of peripheral nerve injury or dural tear; and activating the initiator to polymerise the pre-polymer solution to form a hydrogel thereby embedding the membrane in the hydrogel such that the hydrogel is adhered to the peripheral nerve injury or dural tear.

[0014] An embodiment provides a method of repairing a peripheral nerve injury, the method comprising: providing a membrane immersed in a pre-polymer solution comprising gelatin species modified with polymerisable groups, a secondary biopolymer modified with polymerisable groups, and an initiator to initiate polymerisation of the gelatin species modified with polymerisable groups and the secondary biopolymer modified with polymerisable groups; contacting the membrane immersed in the pre-polymer solution with the peripheral nerve injury such that the membrane covers at least a portion of peripheral nerve injury; and activating the initiator to polymerise the pre-polymer solution to form a hydrogel thereby embedding the membrane in the hydrogel such that the hydrogel is adhered to the peripheral nerve injury.

[0015] An embodiment provides a method of repairing a dural tear, the method comprising: providing a membrane immersed in a pre-polymer solution comprising gelatin species modified with polymerisable groups, a secondary biopolymer modified with polymerisable groups, and an initiator to initiate polymerisation of the gelatin species modified with polymerisable groups and the secondary biopolymer modified with polymerisable groups; contacting the membrane immersed in the pre-polymer solution with the dural tear such that the membrane covers at least a portion of the dural tear; and activating the initiator to polymerise the pre-polymer solution to form a hydrogel thereby embedding the membrane in the hydrogel such that the hydrogel is adhered to the dural tear.

[0016] An embodiment provides use of a bioadhesive material in the manufacture of a medicament for repairing a peripheral nerve injury, the bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel. An embodiment provides use of a bioadhesive material in the manufacture of a medicament for repairing a dural tear, the bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

[0017] An embodiment provides use of a bioadhesive material in the manufacture of a medicament for repairing soft tissue injuries selected from peripheral nerve injuries and dural tears, the bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

[0018] Brief Description of the Drawings

[0019] The present disclosure will now be described, by way of example only, with reference to the accompanying non-limiting drawings, in which:

[0020] Figure 1 is an illustration of a wet dynamic test.

[0021] Figure 2 show adhesion properties of bioadhesive patch: A) Shear strength from patch-to- patch adhesion test; B) Adhesion strength from patch-to-tissue adhesion test; C) Maximum force from patch-to-tissue adhesion test; D) Burst pressure from burst pressure test.

[0022] Figure 3 shows Young’s modulus (A) and ultimate strength (B) of bioadhesive patch obtained from tensile tests.

[0023] Figure 4 shows scanning electron micrograph (SEM) images of surfaces and cross-sections of bioadhesive patches. The brown, green and blue dotted boxes show rough side, smooth side, and cross-section images of the patches, respectively. The images of each patch are separated by red dashed lines. The scale bars of rough and smooth sides show 20 pm; however, the scale bars of cross-sections indicate 100 pm.

[0024] Figure 5 shows swelling and degradation results of the bioadhesive patch: (A) The gained mass ratio after adding each hydrogel to CelGro; (B) the swelling ratio within 120 minutes; and the mass loss ratios under hydrolytic degradation (C) and enzymatic (D) conditions.

[0025] Figure 6 shows wet dynamics results: (A) the total score of C-G10 after 7 days as an example of scoring method; and (B) the total scores of bioadhesive patches over 35 days.

[0026] Figure 7 shows visual images of gross examination of specimens comparing the effects of dural defect repair using Heal-Dura® with sutures versus the sutureless bioadhesive patch. Figure 8 shows histological analysis of specimens retrieved at 4 weeks, comparing dural defect repair using Heal-Dura® with sutures versus a sutureless bioadhesive patch. Representative histological sections illustrate tissue responses and integration at the repair site. Figure legend abbreviations: B - brain parenchyma; A - arachnoid mater; CS - central sulcus; C - cartilage tissue; HD - Heal-Dura®; BP - bioadhesive patch.

[0027] Figure 9 shows Sciatic Function Index (SFI) assessment results: (A) Illustration of the measurement method for SFI parameters; (B) Representative footprints from different groups at 2, 4, 8, and 12 weeks. Red footprints represent the affected side, and blue footprints represent the healthy side; (C) Equation used for SFI calculation; (D) Comparison of SFI among the Suture, Remplir, and Bioadhesive Patch groups at different time points. * P < 0.05, ** P < 0.01 Suture group vs. Remplir group; # P < 0.05 Suture group vs. Bioadhesive Patch group.

[0028] Figure 10 shows gross examination of specimens comparing the effects of peripheral nerve repair using Suture, Remplir™, and bioadhesive patch.

[0029] Figure 11 shows histological analysis comparing peripheral nerve repair using neurorrhaphy, Remplir™, and a sutureless bioadhesive patch. (A) Low-magnification representative histological sections (1.5x). (B) High-magnification representative histological sections (8.5x). (C) Quantitative comparison of the ratio between the diameter at the proximal and distal ends of the transection site across different treatment groups. Figure legend abbreviations: S - suture; V - vascularization; B - bioadhesive patch; R - Remplir™ collagen fibers; E - epineurium; B-gel - unresorbed hydrogel from the bioadhesive patch.

[0030] Figure 12 shows the ratio of the diameters of the proximal and distal ends at the transection area, measurement from histological analysis.

[0031] Detailed Description

[0032] The disclosure provides a bioadhesive material that may address limitations of current surgical adhesives and suturing techniques for soft-tissue repair. The bioadhesive material comprises a hydrogel formed from a gelatin species modified with polymerisable groups and a secondary biopolymer, with a membrane embedded within the hydrogel. The hydrogel may be formed in situ through photopolymerisation, allowing rapid adhesion to tissue in wet conditions. The membrane may provide structural support and help retain the pre-polymer solution prior to polymerisation, whilst the hydrogel component may provide adhesive properties and promote tissue integration. The bioadhesive material may be biodegradable, eliminating the need for subsequent removal procedures.

[0033] The bioadhesive material may be used for repairing various soft-tissue injuries, including both central and peripheral nerve system tissue such as peripheral nerve injuries and dural tears. For peripheral nerve repair, the bioadhesive material may be wrapped around the nerve transection site and polymerised in situ, providing sutureless coaptation that may reduce surgical time and minimise iatrogenic injury to neural tissue. For dural repair, the bioadhesive material may be placed over a dural defect and polymerised to seal the defect, potentially reducing complications associated with suturing and material expansion. The bioadhesive material may demonstrate favourable properties including sufficient adhesive strength in wet conditions, biocompatibility, controlled degradation, and the ability to support tissue regeneration and vascularisation at the repair site. The bioadhesive material may also avoid the need to sutures. Accordingly, in an embodiment, the bioadhesive material may be considered as forming a sutureless neuroprotective and / or neuroregenerative scaffold.

[0034] Bioadhesive material

[0035] An embodiment provides a bioadhesive material. The material comprises a hydrogel that is formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer. The hydrogel has up to 20wt.% of the secondary biopolymer.

[0036] In an embodiment, a wt.% content of the gelatin species modified with polymerisable groups is greater than a wt.% of the secondary biopolymer. In an embodiment, a wt.% of the secondary biopolymer can be adjusted to fine tune properties of the hydrogel such as water content, mechanical properties, adhesiveness, and so on.

[0037] The hydrogel may have up to 19wt.% of the secondary biopolymer. The hydrogel may have up to 18wt.% of the secondary biopolymer. The hydrogel may have up to 17wt.% of the secondary biopolymer. The hydrogel may have up to 16wt.% of the secondary biopolymer. The hydrogel may have up to 15wt.% of the secondary biopolymer. The hydrogel may have up to 14wt.% of the secondary biopolymer. The hydrogel may have up to 13wt.% of the secondary biopolymer. The hydrogel may have up to 12wt.% of the secondary biopolymer. The hydrogel may have up to 11wt.% of the secondary biopolymer. The hydrogel may have up to 10wt.% of the secondary biopolymer. The hydrogel may have up to 9wt.% of the secondary biopolymer. The hydrogel may have up to 8wt.% of the secondary biopolymer. The hydrogel may have up to 7wt.% of the secondary biopolymer. The hydrogel may have up to 6wt.% of the secondary biopolymer. The hydrogel may have up to 5wt.% of the secondary biopolymer. The hydrogel may have up to 4wt.% of the secondary biopolymer. The hydrogel may have up to 3wt.% of the secondary biopolymer. The hydrogel may have up to 2wt.% of the secondary biopolymer. The hydrogel may have up to 1wt.% of the secondary biopolymer. The hydrogel may have at least 1wt.% of the secondary biopolymer. The hydrogel may have at least 2wt.% of the secondary biopolymer. The hydrogel may have at least 3wt.% of the secondary biopolymer. The hydrogel may have at least 4wt.% of the secondary biopolymer. The hydrogel may have at least 5wt.% of the secondary biopolymer. The hydrogel may have at least 6wt.% of the secondary biopolymer. The hydrogel may have at least 7wt.% of the secondary biopolymer. The hydrogel may have at least 8wt.% of the secondary biopolymer. The hydrogel may have at least 9wt.% of the secondary biopolymer. The hydrogel may have at least 10wt.% of the secondary biopolymer.

[0038] The hydrogel may have from 1wt.% up to 20wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 15wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 10wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 9wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 8wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 7wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 6wt.% of the secondary biopolymer. The hydrogel may have from 1wt.% up to 5wt.% of the secondary biopolymer.

[0039] The hydrogel may have up to 20wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 19wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 18wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 17wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 16wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 15wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 14wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 13wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 12wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 11wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 10wt. of the gelatin species modified with polymerisable groups. The hydrogel may have up to 9wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 8wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 7wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 6wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have up to 5wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have from 5wt.% up to 20wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have from 5 wt.% up to 15wt.% of the gelatin species modified with polymerisable groups. The hydrogel may have from 5wt.% up to 10wt.% of the gelatin species modified with polymerisable groups. In an embodiment, a molecular weight (Mw) of the secondary biopolymer may be greater than a molecular weight (Mw) of the species modified with polymerisable groups. In an embodiment, a molecular weight (Mw) of the secondary biopolymer modified with polymerisable groups may be greater than a molecular weight (Mw) of the species modified with polymerisable groups.

[0040] In an embodiment, the gelatin is modified with photo-crosslinkable moieties or groups including vinylic, acrylate, acrylates, methacrylate and / or acrylamide.

[0041] The terms “groups” and “moieties” are used interchangeably throughout this disclosure to refer to chemical substituents that may be provided on e.g. the gelatin and secondary biopolymer.

[0042] The gelatin may be modified with two or more different moieties. For example, the gelatin may be modified with acrylates and acrylamides. In an embodiment, the gelatin is modified with methacrylate groups. It should be appreciated that mention of the term “gelatin modified with photo-crosslinkable moieties” is in relation to its pre-polymerised form and that after polymerisation to form the hydrogel the crosslinkable moieties are converted from their non-olefin form and that some of the crosslinkable moieties may be unpolymerised. In an embodiment, the gelatin is modified with ‘click chemistry’ moieties such as alkynes and strained alkynes, azides, thiols, acrylates, and so on. When ‘click chemistry’ moieties are used, the gelatin may be modified with one part of the click system, such as strained alkynes, and the secondary biopolymer may be modified with the other part of the click system, such as azides. Other chemistries may be used to modify the gelatin such as using activated carboxy groups for example NHS-activated (meth)acrylates.

[0043] A degree of gelatin modification (also termed functionalisation) may be about 10%. A degree of gelatin modification may be about 20%. A degree of gelatin modification may be about 30%. A degree of gelatin modification may be about 40%. A degree of gelatin modification may be about 50%. A degree of gelatin modification may be about 60%. A degree of gelatin modification may be about 70%. A degree of gelatin modification be about 80%. A degree of gelatin modification may be about 90%. A degree of gelatin modification may be about 100%. A degree of gelatin modification may range from about 50% to about 90%. A degree of gelatin modification may range from about 60% to about 90%. A degree of gelatin modification may range from about 70% to about 90%.

[0044] The secondary biopolymer may include two or more different biopolymers. The secondary biopolymer may be a polysaccharide. The polysaccharide may include heparin, chondroitin, keratin, cellulose and / or hyaluronic species. The secondary biopolymer may include two or more types of polysaccharides. The secondary biopolymer may be modified with one or more different types of polymerisable groups. For example, the secondary biopolymer may be modified with vinylic, acrylate, acrylates, methacrylate and / or acrylamide groups. In an embodiment, the secondary biopolymer may be a hyaluronic acid species modified with polymerisable groups. In an embodiment, the hyaluronic acid species modified with polymerisable groups is hyaluronic acid methacrylate.

[0045] A degree of hyaluronic acid modification, such as methacrylation (also termed functionalisation), may be about 10%. For example, hyaluronic acid may have a degree of methacrylation of about 10%. A degree of hyaluronic acid modification may be about 20%. A degree of hyaluronic acid modification may be about 30%. A degree of hyaluronic acid modification may be about 40%. A degree of hyaluronic acid modification may be about 50%. A degree of hyaluronic acid modification may be about 60%. A degree of hyaluronic acid modification may be about 70%. A degree of hyaluronic acid modification be about 80%. A degree of hyaluronic acid modification may be about 90%. A degree of hyaluronic acid modification may be about 100%. A degree of hyaluronic acid modification may range from about 5% to about 70%. A degree of hyaluronic acid modification may range from about 5% to about 60%. A degree of hyaluronic acid modification may range from about 5% to about 50%. A degree of hyaluronic acid modification may range from about 10% to about 50%. A degree of hyaluronic acid modification may range from about 2% to about 50%.

[0046] In an embodiment, the hydrogel is formed from a pre-polymer solution that consists of gelatin methacrylate and hyaluronic acid methacrylate. Accordingly, in an embodiment, the hydrogel may be formed from gelatin methacrylate and hyaluronic acid methacrylate.

[0047] The bioadhesive material also has a membrane embedded in the hydrogel. In an embodiment, the membrane is a bilayer membrane. A first side of the membrane may be smooth and a second side of the membrane may have an increased surface roughness compared to the first side. In an embodiment, the membrane is a bilayer collagen membrane. In an embodiment, the bioadhesive material may have greater adhesion to tissue on a rough side compared to the smooth side of the membrane. Examples of a membrane that may be used in one or more embodiments include CelGro™ and Remplir™ sold by Orthocell®.

[0048] As used herein, the term "embedded" in relation to the membrane within the hydrogel may refer to the membrane being in contact with, at least partially surrounded by, encased within, or integrated into the hydrogel. The membrane may be wholly embedded such that the hydrogel completely surrounds all surfaces of the membrane, or the membrane may be partially embedded such that one or more surfaces of the membrane remain exposed whilst other portions are in contact with or surrounded by the hydrogel. In some cases, the hydrogel may be present on only one surface of the membrane, forming a layer in contact with that surface. In some cases, the hydrogel may penetrate into the porous structure of the membrane, creating an interpenetrating network between the membrane and the hydrogel. In some cases, the membrane may be positioned such that the hydrogel is present on one or both major surfaces of the membrane. The term "embedded" encompasses configurations where the membrane is impregnated with the pre-polymer solution prior to polymerisation, such that upon polymerisation the hydrogel forms within and around the membrane structure, as well as configurations where the hydrogel is formed on, adjacent to, or merely in contact with one or more membrane surfaces.

[0049] The membrane may be biodegradable. A biodegradable membrane may help to improve tissue regeneration compared to a non-degradable membrane. A degradable membrane can also remove the need for any post-operative procedure to remove the membrane when it is no longer required. The biodegradable membrane can include those based on or formed from proteins and / or polysaccharides. For example, the membrane can include collagen and keratin. In an embodiment, the membrane is formed from collagen.

[0050] The membrane may have a thickness ranging from about 50 pm to about 1000 pm. The membrane may have a thickness ranging from about 100 pm to about 1000 pm. The membrane may have a thickness ranging from about 100 pm to about 900 pm. The membrane may have a thickness ranging from about 100 pm to about 800 pm. The membrane may have a thickness ranging from about 100 pm to about 700 pm. The membrane may have a thickness ranging from about 100 pm to about 600 pm. The membrane may have a thickness ranging from about 100 pm to about 500 pm. The membrane may have a thickness ranging from about 200 pm to about 700 pm. The membrane may have a thickness ranging from about 200 pm to about 600 pm. The membrane may have a thickness ranging from about 200 pm to about 500 pm. The membrane may have a thickness ranging from about 200 pm to about 400 pm. The membrane may have a thickness up to about 500 pm.

[0051] The bioadhesive material may be biodegradable. A biodegradable material may help to improve tissue repair and eliminate the need for removal after tissue repair. A degradation time of the bioadhesive material may depend upon its application, such as the type of tissue the bioadhesive material is adhered to.

[0052] The bioadhesive material may have a Young’s modulus ranging from about 20 Mpa to 30 Mpa. The bioadhesive material may have a tensile strength ranging from about 5.5 Mpa to 7 Mpa. The bioadhesive material may be used to repair a soft-tissue injuries. For example, the bioadhesive material may be used to repair damage to dura, nerves, tendons, blood vessels, and so on. In an embodiment, the bioadhesive material may be configured to repair a peripheral nerve injury or a dural defect.

[0053] Formation of the bioadhesive material

[0054] An embodiment provides a method of forming a bioadhesive material. The method includes providing a membrane immersed in a pre-polymer solution. The pre-polymer solution comprises a gelatin species modified with polymerisable groups and a secondary biopolymer modified with polymerisable groups.

[0055] The pre-polymer solution may have up to 20wt.% of the secondary biopolymer. The wt.% is relative a weight of the solution used to form the pre-polymer solution. The pre-polymer solution may have up to 19wt.% of the secondary biopolymer. The pre-polymer solution may have up to 18wt.% of the secondary biopolymer. The pre-polymer solution may have up to 17wt.% of the secondary biopolymer. The pre-polymer solution may have up to 16wt.% of the secondary biopolymer. The pre-polymer solution may have up to 15wt.% of the secondary biopolymer. The pre-polymer solution may have up to 14wt.% of the secondary biopolymer. The pre-polymer solution may have up to 13wt.% of the secondary biopolymer. The pre-polymer solution may have up to 12wt.% of the secondary biopolymer. The pre-polymer solution may have up to 11wt.% of the secondary biopolymer. The pre-polymer solution may have up to 10wt.% of the secondary biopolymer. The pre-polymer solution may have up to 9wt.% of the secondary biopolymer. The pre-polymer solution may have up to 8wt.% of the secondary biopolymer. The pre-polymer solution may have up to 7wt.% of the secondary biopolymer. The pre-polymer solution may have up to 6wt.% of the secondary biopolymer. The pre-polymer solution may have up to 5wt.% of the secondary biopolymer. The pre-polymer solution may have up to 4wt.% of the secondary biopolymer. The prepolymer solution may have up to 3wt.% of the secondary biopolymer. The pre-polymer solution may have up to 2wt.% of the secondary biopolymer. The pre-polymer solution may have up to 1wt.% of the secondary biopolymer.

[0056] The pre-polymer solution may have at least 1wt.% of the secondary biopolymer. The pre-polymer solution may have at least 2wt.% of the secondary biopolymer. The pre-polymer solution may have at least 3wt.% of the secondary biopolymer. The pre-polymer solution may have at least 4wt.% of the secondary biopolymer. The pre-polymer solution may have at least 5wt.% of the secondary biopolymer. The pre-polymer solution may have at least 6wt.% of the secondary biopolymer. The pre-polymer solution may have at least 7wt.% of the secondary biopolymer. The pre-polymer solution may have at least 8wt.% of the secondary biopolymer. The pre-polymer solution may have at least 9wt.% of the secondary biopolymer. The pre-polymer solution may have at least 10wt.% of the secondary biopolymer.

[0057] The pre-polymer solution may have from 1wt.% up to 20wt.% of the secondary biopolymer. The pre-polymer solution may have from 1wt.% up to 15wt.% of the secondary biopolymer. The prepolymer solution may have from 1wt.% up to 10wt.% of the secondary biopolymer. The prepolymer solution may have from 1wt.% up to 9wt.% of the secondary biopolymer. The pre-polymer solution may have from 1wt.% up to 8wt.% of the secondary biopolymer. The pre-polymer solution may have from 1wt.% up to 7wt.% of the secondary biopolymer. The pre-polymer solution may have from 1wt.% up to 6wt.% of the secondary biopolymer. The pre-polymer solution may have from 1wt.% up to 5wt.% of the secondary biopolymer.

[0058] The pre-polymer solution may have up to 20wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 15wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 10wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 9wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 8wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 7wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 6wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have up to 5wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have from 5wt.% up to 20wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have from 5 wt.% up to 15wt.% gelatin species modified with polymerisable groups. The pre-polymer solution may have from 5wt.% up to 10wt.% gelatin species modified with polymerisable groups.

[0059] The gelatin species modified with polymerisable groups and a secondary biopolymer modified with polymerisable groups may be that as described above. In an embodiment, the pre-polymer solution consists of gelatin methacrylate, hyaluronic acid methacrylate, and an initiator. The solution used to form the pre-polymer solution may be buffered. For example, the solution used to form the prepolymer solution may be phosphate-buffered saline (PBS). However, the disclosure is not limited to PBS and other buffered solutions used in biological settings may be used to form the pre-polymer solution.

[0060] The method also includes polymerising the pre-polymer solution to form a hydrogel that embeds the biodegradable membrane. Throughout this disclosure, the term “polymerise” includes one or more of the formation of a polymer backbone chain, any associated crosslinking that may occur, and only crosslinking of adjacent polymer chain(s). The term “polymerisation” in its broadest sense is not limited to any specific form of polymerisation and may include free radical, anionic and controlled polymerisation techniques unless context makes it clear otherwise. For example, photoinitiated polymerisation will generally relate to free-radical polymerisation but may also relate to control polymerisation if polymerisation control agents are used. In an embodiment, the hydrogel of the bioadhesive material is formed using free radical polymerisation techniques.

[0061] The method of polymerisation depends on how polymerisation is initiated. For example, if redox initiation is used, a solution of redox initiator may be added to the pre-polymer solution to initiate polymerisation. Likewise, if a thermal or photoinitiator is used, polymerisation is initiated by heating or exposing the pre-polymer solution to light having wavelength(s) that initiate polymerisation. In an embodiment, the pre-polymer solution includes a photoinitiator that is activated upon exposure to light such that polymerisation of the pre-polymer solution is photo-initiated. The light may be UV or visible light. An advantage of initiation using wavelengths in the visible spectrum (i.e. 400nm- 700nm) is that it may reduce the change of tissue damage due to light exposure as would be the case for UV-activated initiators.

[0062] If the gelatin and secondary biopolymer are functionalised with groups that can participate in “click chemistry”, polymerisation may be initiated by mixing the different ‘click’ components together.

[0063] In an embodiment, a LED light source is used to initiate polymerisation of the pre-polymer solution. An advantage of utilising photopolymerisation is the high gelation kinetics, leading to the formation of the hydrogel in short periods of time e.g. up to 2 minutes. For in vivo applications, it may be desirable to form the hydrogel quickly to ensure there is no leakage or loss of the pre-polymer solution into surrounding tissue prior to gelation of the pre-polymer solution.

[0064] When polymerisation is photoinititated, the irradiation time may be up to 5 minutes. The irradiation time may be up to 4 minutes. The irradiation time may be up to 3 minutes. The irradiation time may be up to 2 minutes. The irradiation time may be up to 90 seconds. The irradiation time may be up to 60 seconds. The irradiation time may be up to 30 seconds. The irradiation time may be at least 30 seconds. The irradiation time may be at least 60 seconds. The irradiation time may be at least 90 seconds. The irradiation time may range from about 30 seconds to about 5 minutes. The irradiation time may range from about 60 seconds to about 3 minutes. The irradiation time may range from about 90 seconds to about 2 minutes. In an embodiment, the irradiation time is about 90 seconds. In an embodiment, the irradiation time is about 2 minutes.

[0065] A photoinitiator used to polymerise the pre-polymer solution may include water-soluble photoinitators such as 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2-methyl-1 -propanone (Irgacure 2595), water-soluble derivatives of acylphosphine oxides such as monoacylphosphine oxide (MAPO) and bisacylphosphine oxide (BAPO), diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide (TPO), lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Eosin-Y, Riboflavin-based initators, and initiators based on aliphatic a-ketones.

[0066] A concentration of the initiator may be up to 2 w / v%. A concentration of the initiator may be up to 1 .5 w / v%. A concentration of the initiator may be up to 1 w / v%. A concentration of the initiator may be up to 0.9 w / v%. A concentration of the initiator may be up to 0.8 w / v%. A concentration of the initiator may be up to 0.7 w / v%. A concentration of the initiator may be up to 0.6 w / v%. A concentration of the initiator may be up to 0.5 w / v%. A concentration of the initiator may be up to 0.4 w / v%. A concentration of the initiator may be up to 0.3 w / v%. A concentration of the initiator may be up to 0.2 w / v%. A concentration of the initiator may be up to 0.1 w / v%. A concentration of the initiator may range from 0.1 w / v% to 0.2 w / v%. In an embodiment, a concentration of the initiator is 0.15 w / v%. The initiator may be provided as a stock solution. The initiator stock solution may be formed from the same solution as the pre-polymer solution. In an embodiment, the initiator is provided in the pre-polymer solution. In an embodiment, the pre-polymer solution consists of a solvent such as PBS, gelatin methacrylate, hyaluronic acid methacrylate, and an initiator.

[0067] Polymerisation may be performed at a temperature close to in vivo conditions. This may help to minimise any temperature-induced damage to tissue when the bioadhesive is formed in vivo. Polymerisation may be performed at a temperature up to 40 °C. In an embodiment, polymerisation is performed at a temperature greater than 10 °C. Reducing a temperature of polymerisation too far may result in a viscosity of the pre-polymer solution increasing such that it impedes formation of the bioadhesive material. In an embodiment, polymerisation is performed at a temperature ranging from about 20 °C to 40 °C. In an embodiment, polymerisation is performed around 37 °C.

[0068] The method may include hydrating the membrane prior to immersing the hydrated member in the pre-polymer solution. For example, the membrane may be provided in its dried form and then hydrated immediately prior to polymerisation. The membrane may be hydrated in a hydrating solution, or alternatively may be hydrated in the pre-polymer solution. Hydrating the membrane in the pre-polymer solution may help to ensure that the membrane is impregnated with the gelatin species modified with polymerisable groups and / or the secondary biopolymer modified with polymerisable groups prior to polymerisation to ensure that the membrane is fully embedded within the hydrogel. During polymerisation, the membrane may become crosslinked and / or covalently bonded to the gelatin species modified with polymerisable groups and / or the secondary biopolymer modified with polymerisable groups.

[0069] The membrane may be that as described above.

[0070] The method may include placing the biodegradable membrane immersed in the pre-polymer solution onto tissue prior to polymerisation such that following polymerisation the bioadhesive material is formed on the tissue in vivo. In an embodiment, the bioadhesive is first formed, then a surface of the outside of the bioadhesive is coated with further GelMA and / or HAMA. This surface coated GelMA and / or HAMA can then be polymerisation in vivo. Formation of the bioadhesive material in vivo can help to achieve sufficient adhesion to tissue to prevent e.g. bursting due to increased pressure. The membrane can act as a sponge to help retain the pre-polymer solution prior to gelation during polymerisation. This may help to allow a user to manipulate the membrane to be positioned optionally on the tissue prior to polymerisation without worry of leakage or loss of the pre-polymer solution.

[0071] In an embodiment, the membrane is pre-impregnated with the pre-polymer solution and then dried (e.g., via freeze-drying) such that the membrane is loaded with the dried gelatin species modified with polymerisable groups and the dried secondary biopolymer modified with polymerisable groups. The membrane, the dried gelatin species modified with polymerisable groups, and the dried secondary biopolymer modified with polymerisable groups can then all be hydrated simultaneously prior to polymerisation.

[0072] In an embodiment, the hydrogel is fully hydrated following polymerisation. An advantage of having the hydrogel be fully hydrated following polymerisation is that there is no expansion of the hydrogel during hydration which helps to reduce impingement onto neighbouring tissue if the bioadhesive material is formed in vivo. The membrane may help to reduce swelling of the hydrogel.

[0073] The pre-polymer solution may be provided in a light-proof package, such as a sterile light-proof package, to prevent photoinitiation of the pre-polymer solution. This may help to increase shelf-life of the pre-polymer solution. The membrane may be provided in the light-proof package with the pre-polymer solution or alternatively may be provided in its own sterile packaging.

[0074] In an embodiment, the pre-polymer solution and membrane may form part of a system. The system may be in the form of a kit. For example, the pre-polymer solution and membrane may be provided in sterilised separate packets that can be opened when needed. Typically, the packet(s) would be opened during surgery and the bioadhesive material formed in vivo when the bioadhesive material is required to joint segments of tissue together.

[0075] An embodiment provides a method of repairing a peripheral nerve injury using the system as described above. The method includes providing the membrane immersed in the pre-polymer solution, and contacting the membrane immersed in the pre-polymer solution with the peripheral nerve injury such that the membrane covers at least a portion of peripheral nerve injury. The method also includes activating the initiator to polymerise the pre-polymer solution to form a hydrogel thereby embedding the membrane in the hydrogel such that the hydrogel is adhered to the peripheral nerve injury. Polymerisation of the pre-polymer solution is described above.

[0076] Use of the bioadhesive material

[0077] The bioadhesive material may be used for repairing various soft-tissue injuries. The bioadhesive material may be used to repair damage to neural tissue, dura mater, tendons, blood vessels, and other soft tissues. In an embodiment, the bioadhesive material may be configured to repair peripheral nerve injuries. In an embodiment, the bioadhesive material may be configured to repair dural tears.

[0078] For peripheral nerve repair, the bioadhesive material may be wrapped around a nerve transection site. The membrane immersed in the pre-polymer solution may be positioned to cover at least a portion of the peripheral nerve injury, and the pre-polymer solution may then be polymerised in situ to form the hydrogel. This approach may provide sutureless coaptation of nerve tissue, which may reduce surgical time compared to traditional suturing techniques. The bioadhesive material may help to minimise iatrogenic injury to neural tissue that can occur during suturing procedures.

[0079] For dural repair, the bioadhesive material may be placed over a dural defect. The membrane immersed in the pre-polymer solution may be positioned to cover the dural tear or defect, and the pre-polymer solution may then be polymerised to seal the defect. The bioadhesive material may provide a watertight seal to prevent cerebrospinal fluid leakage. The bioadhesive material may help to reduce complications associated with suturing, such as prolonged surgical time and increased risk of infection.

[0080] The bioadhesive material may demonstrate sufficient adhesive strength in wet conditions to maintain tissue coaptation during healing. The bioadhesive material may provide a burst pressure sufficient to withstand physiological pressures at the repair site. In some cases, the bioadhesive material may provide a burst pressure of at least 30 mmHg. In some cases, the bioadhesive material may provide a burst pressure of at least 40 mmHg. In some cases, the bioadhesive material may provide a burst pressure of at least 45 mmHg.

[0081] The bioadhesive material may support tissue regeneration at the repair site. The bioadhesive material may promote vascularisation within the repair site. Early vascularisation may be observed within the bioadhesive material, which may help to preserve blood supply to the repaired tissue. The bioadhesive material may help to reduce tissue atrophy at the repair site.

[0082] The bioadhesive material may be biodegradable, which may eliminate the need for subsequent removal procedures. The degradation rate of the bioadhesive material may be tailored to match the healing timeline of the repaired tissue. The bioadhesive material may degrade over a period of weeks to months, depending on the composition of the hydrogel and the physiological environment.

[0083] The bioadhesive material may reduce the need for specialised surgical equipment. In some cases, the bioadhesive material may reduce or eliminate the need for an operating microscope during nerve repair procedures. This may reduce training requirements for surgeons and may reduce the number of specialised instruments required for the procedure.

[0084] The bioadhesive material may be applied quickly during surgical procedures. The time required to achieve tissue coaptation using the bioadhesive material may be significantly less than the time required for traditional suturing techniques. In some cases, the bioadhesive material may achieve tissue coaptation in less than 2 minutes. In some cases, the bioadhesive material may achieve tissue coaptation in about 90 seconds or less.

[0085] The bioadhesive material may demonstrate favourable tissue integration properties. The bioadhesive material may form direct contact with underlying tissue, such as the arachnoid mater, without gap formation between the material and the tissue surface. The bioadhesive material may provide a smooth interface between the material and surrounding tissue. The bioadhesive material may help to reduce or prevent hypertrophic fibrosis at the repair site. In some cases, the bioadhesive material may promote early vascularisation at the repair site, which may help to preserve distal blood supply to the repaired tissue. The preservation of blood supply may result in reduced tissue atrophy compared to traditional repair methods. The bioadhesive material may help to maintain nerve bundle diameter at the repair site. In some cases, a ratio of proximal bundle diameter to distal bundle diameter at a nerve transection site repaired with the bioadhesive material may be maintained at approximately 1.05 to 1.10, which may indicate reduced atrophy compared to traditional suturing techniques where the ratio may be approximately 1.55 or higher.

[0086] The bioadhesive material may provide substantial time savings during surgical procedures, requiring approximately 20% of the time needed for traditional suturing techniques, with peripheral nerve repair achievable in approximately 1 to 1.5 minutes compared to 7 to 9 minutes for traditional epineural suturing, thereby reducing overall surgical duration, patient exposure to anaesthesia, and risk of complications associated with prolonged procedures. The bioadhesive material may reduce or eliminate the need for an operating microscope during nerve repair procedures, as traditional suturing techniques typically require microscopic visualisation for accurate suture placement, whilst the bioadhesive material may allow surgeons to perform nerve repair without microscopic visualisation, reducing technical complexity, training requirements, and the need for specialised equipment, making the procedure more accessible in settings where operating microscopes are not readily available. Additionally, the bioadhesive material may avoid needle-related iatrogenic injury to neural tissue that occurs with traditional suturing techniques, where needle passage through or adjacent to neural tissue may cause mechanical trauma to nerve fibres and damage axons, thereby contributing to impaired nerve regeneration, whilst the bioadhesive material eliminates this source of iatrogenic injury, helping to preserve nerve fibre integrity at the repair site and potentially contributing to improved functional outcomes following nerve repair.

[0087] In the claims that follow and in the preceding description, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments.

[0088] It is to be understood that, if any prior art publication is referred to herein, such reference does not constitute an admission that the publication forms a part of the common general knowledge in the art, in Australia or any other country.

[0089] Modifications and variations as would be apparent to a skilled addressee are deemed to be within the scope of the present disclosure.

[0090] Examples

[0091] Embodiments will now be described with reference to the following non-limiting Examples.

[0092] Example 1 - hydrogel preparation and properties 1. 1 Materials and Methods

[0093] 1.1.1 Materials

[0094] Hyaluronic acid methacrylate (HAMA; DoM: 20% - 50%, Mw: 120,000-150,000), Lithium phenyl- 2,4,6-trimethylbenzoylphosphinate (LAP; >95%), Protease from Streptomyces griseus (Type XIV, >3.5 units / mg solid, powder), phosphate buffered saline (PBS; 1X, pH 7.4) were purchased from Sigma-Aldrich (Sydney, Australia) and used without modification. Collagen membranes were kindly provided by Orthocell Ltd (Perth, Australia). Gelatin Methacrylate (GelMA; porcine type A, bloom 300, DoM: 80%, supplied as sterile stock solution, 20% w / v in PBS) was obtained from Gelomics Pty Ltd (Brisbane, Australia)).

[0095] 1. 1.2 Adhesive patch preparation

[0096] First, the hybrid cross-linkable hydrogel is prepared by dissolving GelMa (20 w / v%), HAMA and LAP solution under magnetic stirring at 37 °C for 5 h. The LAP solution with concentration of 0.15 w / v% is preliminary prepared by dissolving LAP powder in PBS 1x through ultrasonic dispersion for 5 minutes. Then, collagen membranes are soaked in the prepared hybrid cross-linkable hydrogel for 10 minutes before irradiation. The concentration of the hydrogels used for fabricating the adhesive patches are shown in Table 1.

[0097] Table 1. Compositions for adhesive patch.

[0098] Collagen

[0099] GelMA Portion HAMA Portion Group name

[0100] Membrane

[0101] Celgro 10% GelMa - G10

[0102] Celgro 15% GelMa - G15

[0103] Celgro 10% GelMa 2.5% HAMA G10H2.5

[0104] Celgro 10% GelMa 5% HAMA G10H5

[0105] Celgro 15% GelMa 2.5% HAMA G15H2.5

[0106] Celgro 15% GelMa 5% HAMA G15H5

[0107] 1. 1.3 LED light irradiation The adhesive patches (soaked collagen membrane) are removed from each hybrid cross-linkable hydrogel and photo crosslinked under LED light irradiation (405 nm) for up to 2 minutes, such as 90 seconds. The patches are layered on top the tissue before irradiation for tissue adhesion tests.

[0108] 1. 1.4 Ex-vivo Adhesion tests

[0109] The adhesive strength of patches was evaluated through three different tests, including patch-to- patch adhesion test, patch-to-tissue adhesion test and burst pressure test. The patch-to- patch adhesion test is designed to measure the strength of bonding between two layers of collagen after rolling the patch in surgical procedure of peripheral nerve repair. The patch-to-tissue adhesion test can remodel the adhesive strength of patch on the peripheral nerve tissue when the patch the wraps and connects two sides of the ruptured peripheral nerve tissue. However, burst pressure test is designed to study the bonding strength between patch and tissue in Dural repair applications.

[0110] 1. 1.5 Patch-to-patch adhesion

[0111] The strips of patches, with dimensions of 2.0 cm x 0.5 cm, were cut for patch-to-patch adhesion test. The specimen was prepared by layering two strips, with a contact of 1.0 x 0.5 cm2, followed by photo-crosslinking as outlined in Section 2.3. The specimen was then clamped into a uniaxial tensile tester machine (Univert, Cellscale, Canada) and subjected to a loading rate of 0.5 mm s-1until sample failure was reached. The bonding strength was calculated by dividing the measured maximum force versus distance profile by the area of the patch. The adhesion energy was calculated by measuring the area under the force versus distance profile.

[0112] 1.1.6 Patch-to-tissue adhesion

[0113] The adhesive strength of the patches on intestine mucosa tissue was measured on similar in vitro models reported in previous studies. First, the tissues were cut into smaller strips, bisected and reconnected. Then, the patches, with dimensions of 1.0 cm x 0.6 cm, were located above the tissue followed by LED light crosslinking. The tissues were kept moist with PBS during the sample preparation and before tensile testing to remodel in vivo conditions. The tensile tests were conducted, and the bonding strength and tissue adhesion energy of patch were calculated as described above. The force values at failure points were also reported as maximum force.

[0114] 1. 1.7 Burst Pressure Test

[0115] The burst pressure (air-sealing strength) test was carried out similar to a previous method described by Azuma et al (Biomaterials 2015, 42, 20-29). First, a section of the intestine mucosa tissue (2.0 cm x 2.0 cm) was cut and then, a 2-mm circular incision was made with a surgical blade. After that, a circular patch with a diameter of 3 mm was placed slightly on the tissue to cover the incision. The tissue with covering patch was irradiated by LED light for 2 min and then, fixed to the measurement device. Finally, the burst pressure was measured by digital manometer. The pressure was continually increased by injecting air through a control valve connected to a compressed air bottle. The pressure at which it began to decrease was considered the rupture pressure, measurements were repeated three times.

[0116] 1. 1.8 Mechanical properties

[0117] The tensile properties of the bioadhesive patches were studied by using the uniaxial tensile tester machine (Univert, Cellscale, Canada). The samples with dimensions of 2.0 cm x 0.5 cm were subjected to a loading rate of 0.5 mm s-1until the tensile failure occurred. Prior to the tensile test, the samples were hydrated in before conducting the tests to remodel the wet conditions in vivo. The force-distance curve was converted to stress-strain curves and the Young’s modulus was calculated by using the initial linear slope of the curve. The ultimate tensile strength was also recorded at the maximum stress value.

[0118] 1.1.9 Morphological properties

[0119] The bioadhesive patched were imaged under scanning electron microscope (SEM) to measure the effect of hydrogel formulation on morphology. First, the patches were photo crosslinked followed by freeze drying (pre-frozen at -25 °C for 6 h and freeze dried at -50 °C, 0.1 mbar for 24 h). Then, the samples were attached onto aluminum stubs using double-sided conductive carbon tape and coated with a layer of platinum. Images were acquired from surface and cross-section of the samples using a Zeiss Gemini SEM (Carl Zeiss Microscopy, Germany) with a 30 pm aperture, 5 kV accelerating voltage. For cross-section observation, the samples were fractured under liquid nitrogen.

[0120] 1. 1. 10 Degradation and swelling

[0121] For the degradation and swelling tests, the bioadhesive patched with dimensions of 0.5 cm x 0.5 cm were cut and photo crosslinked by LED light for 2 min. Then, the samples were initially weighed (Mi) and then incubated in 5 mL of phosphate-buffered saline (PBS) (pH 7.4) at 37 °C and their changes in mass were measured at certain time points.

[0122] The degradations tests were performed in enzymatic and hydrolytic conditions. While hydrolytic degradation only involved PBS media, the enzymatic degradation was conducted in PBS solutions containing 0.3 U / mL Protease XIV. At day 1, 3, 5, 7, and 14 the films were removed, lyophilised (pre-frozen at -25 °C for 6 h and freeze dried at -50 °C, 0.1 mbar for 24 h) and reweighed (Md). The enzyme solution and PBS were replaced with a fresh media every 3 days for both enzymatic and hydrolytic degradations. The degradation rate was stated as the percentage of mass loss relative to the initial dry mass as shown in Eq. (1): Mt - Md

[0123] Mass loss (%) = - x 100 (1)

[0124] Mt

[0125] The patch’s swelling properties were measured by suspending pre-weighed films (Mi) in PBS at 37 °C. The patches were taken out after 15, 30, 45, 60, and 120 minutes, gently dry-blotted with a Kim Wipe and reweighed (Ms). The swelling ratio at each time point was then calculated as defined in Eq. (2): 100 (2)

[0126] 1.1.11 Wet dynamic test

[0127] The adhesion strength of the bioadhesive patches were also evaluated in a wet dynamic condition according to a procedure reported by Chandrasekharan et al (J. Polym. Sci. part A Polym. Chem. 2019, 57 (4), 522-530). First, the circular patches were cut with a diameter of 3 mm. Then, the patches were placed on the rectangular tissue (intestine mucosa from porcine) in five specific spots, as shown in Figure 1 , followed by irradiating LED light for 2 min. The upper and lower edge of the tissue were fixed on glass slide by water-proof tape. After that, each glass slide holding the tissue with adhered patched was vertically placed in a falcon tube containing 50 mL of distilled water (Figure 1). The falcon tubes were placed in shaker incubator at 37 °C with the shaking speed of 80 rpm. The media was changed every 3 days, and stability of the attached patches were scored after 1, 7, 10, 25, 35 days. The scoring method of the patches is based on three stability situations of the patch on tissue, including prefect attachment (2 points), partial attachment (1 point), and detachment (0 point). Hence, a tissue with five completely attached patches is scored 10 points, which is the maximum score of a tissue.

[0128] 1.2 Results and discussions

[0129] 1.2.1 Adhesion properties

[0130] The patch-to-patch adhesion test was performed to study shear strength between to the two layers of adhered patches after rolling the patch in surgical procedure of peripheral nerve repair. From Figure 2A, the patches without HAMA, C-G10 and C-G15, show the lowest strengths among the groups. In general, the shear strength grows by increasing the hydrogel’s concentration, from 39.6 kPa for C-G10 to 132.3 kPa for C-G15H5. Although the addition of HAMA to C-G10 and C-G15 increased the shear strength values, there is a big growth in the strength when the concentration of gelMA increased for the fixed content of HAMA. For instance, the shear strength jumped from 72.5 kPa for C-G10H2.5 to 131.3 KPa for C-G15H2.5. The maximum shear strength of 132.3 kPa was obtained for C-G15H2.5 among all groups. The patch-to-tissue adhesion tests were conducted to remodel the adhesive strength of patch on the peripheral nerve tissue when the patch the wraps and connects two sides of the ruptured peripheral nerve tissue. From tensile test, the adhesive strength of patches on the intestine mucosa tissue and the maximum forces (forces at failure) were obtained and represented in Figure 2B and 2C, respectively. C-G10 and C-G15 shows the similar and lowest adhesive strengths (less 2 kPa) among all groups; however, addition of 2.5 w / v% of HAMA (C-G10H2.5) increased the strength to 3.7 kPa. The addition of HAMA increased the strength value more than 4 times (9.1 kPa) in C-G10H5 in comparison with G15 (1.9 kPa) containing the same concertation of hydrogels (i.e. 15 w / v%). C-G15H2.5, C-G15H5 and C-G10H5 showed the highest values of 14.75 kPa, 13.2 kPa, and 9.1 kPa. The lower strength for C-G15H5 than C-G15H2.5 might be due to the degree of crosslinking; HAMA is opaque unlike gelMA so the high content of HAMA in combination with 15 w / v% of gelMa could hinder the LED light irradiation through the sample and result in imperfect photo-crosslinking. The same trend can be seen for maximum force values of the patches in Figure 20 in comparison with the values sutured tissues. Although sutured tissue showed a highest maximum force (1.5 N) than all patches, it includes high standard deviation because of the tear progression during the tensile test. Overall, C-G15H2.5 revealed the highest values for adhesive strength (14.75 kPa) and maximum force (0.9 N) among the bioadhesive patches.

[0131] The burst pressure test is conducted to study the bonding strength between patch and tissue for Dural repair applications since the test can remodel the capacity of the patches to withstand blood pressure, while at the same time rapidly adhering to tissue walls to seal the rupture. Figure 2D shows the critical pressure needed to burst the adhered patches on tissues. The lowest burst pressures were measured for C-G10 and C-G15, indicating the poor sealing effect of gelMa. The addition of HAMA to gelMA resulted in higher sealing capacity of the patches. The measured burst pressures of C-G15H2.5 and C-G10H5 were 48.3 mm Hg and 47.3 mm Hg, the highest values among all bioadhesive patches. However, the burst pressure of C-G15H5 (37.5 mm Hg) was lower than the pressure of C-G15H2.5 (48.3 mm Hg), which could be related to the lower degree of crosslinking in C-G15H5 due to the high content of HAMA as described before.

[0132] 1.2.2 Mechanical properties

[0133] Young’s modulus and ultimate tensile strength of bioadhesive patches as well as wet CelGro are represented in Figure 3. The wet CelGro showed the highest Young’s modulus (27 MPa) than all patches, suggesting that the addition of hydrogels does not increase the stiffness of CelGro. The C-G15H2.5 and C-G10 showed the Young’s modulus of 25.2 MPa and 24.1 MPa, respectively, which were the highest values among the patches. From Figure 3B, however, all patches showed higher tensile strengths than wet CelGro, which indicates that the effect of hydrogels on stress distribution inside the patches. While the stretched collagen fibres of wet CelGro concentrated the tensile stresses, the hydrogels disturbed and damped the stress to the certain extend; this results in a lower stress on collagen fibres and reaching a higher stress for failure. It is difficult to find out the effect of HAMA on tensile properties as there is no trend in changing the values for the HAMAbased patches.

[0134] 1.2.3 Morphological properties

[0135] Figure 4 shows SEM images of bioadhesive patches at different compositions. CelGro is a bilayer collagen membrane with a smooth side consisting of well-orientated collagen fibres and a rough side comprising randomly aligned collagen fibres. Hence, the bilayer structural characteristics may result in different gel uptakes for each side. In Figure 4, the images are represented in three columns, separated by brown, green and blue dotted boxes, to show rough sides, smooth sides, and cross-sections of the patches. In general, the porosity was found more on the rough side than smooth side of the freeze-dried patches, because of higher gel uptake on the rough side of CelGro.

[0136] The rough sides of C-G10 and C-G15 showed large pores with an average size of 12.2 pm and 12.9 pm, respectively. The randomly organized collagen fibres are obvious in the rough side of C- G10. These fibres are not compacted so the pore structure of gels could be easily disordered. As a result, the shape of the pores is not perfectly organized and circular in the rough side of C-G10 and C-G15. Adding HAMA to the gel formulation resulted in higher number of pores and smaller sizes with a honeycomb pattern. This behaviour may result from the fact that HAMA is denser than GelMA, forming smaller ice crystals during freezing, thus giving rise to smaller pore sizes after lyophilization. The morphology of C-G10H5 showed a combination of small and large pores on the rough side, revealing the effect of HAMA in formulation. Although the average size of pores was decreased in C-G15H2.5 (6.05 ± 2.1 pm) and C-G15H5 (5.2 ± 2.2 pm), C-G15H5 includes more homogenous pore structure.

[0137] As can be seen, the smooth sides of all patches include lower gel porosity than the rough sides, since the smooth side of CelGro cannot carry the gels as much as the rough side. The SEM images of smooth side of C-G10 and C-G15 show the fibre orientation similar to structure of CelGro on its smooth side. The SEM images of cross-section are in agreement with the images of rough side; adding HAMA to the gel formulation resulted in higher number of pores and smaller sizes, which are obvious in the images of C-G10H5, C-G15H2.5 and C-G15H5 samples.

[0138] 1.2.4 Degradation and swelling

[0139] The mass gain (%) after adding the hydrogels to CelGro was measured for each bioadhesive patch as shown in Figure 5A. As can be seen, the mass gain is corresponded with the hydrogel concentrations; hence, C-G10 and C-G15H5 showed the lowest and highest (400% and 709%) mass gain, respectively, among the patches. Similarly, from Figure 5B, the swelling ratio depends on the hydrogel’s concentration of each bioadhesive patch. The swelling ratio grows by increasing the hydrogel’s concentration. C-G10 and C-G10H2.5 showed similar swelling ratios, around 14%; however, C-G15, C-G10H5 and C-G15H2.5 swelled 22.2%, 24.0%, and 24.1% after 120 minutes, respectively. C-G10H5 showed the highest swelling ratio (34.2%) among the samples after 120 minutes incubation in PBS.

[0140] To evaluate how hydrogels formulation alters degradation behaviour, we studied the degradation of bioadhesive patches in enzymatic and hydrolytic conditions as shown in Figure 5C and Figure 5D, respectively. While hydrolytic degradation only involved PBS media, the enzymatic degradation was conducted in PBS solutions containing 0.3 U / rnL Protease XIV. Form Figure 5C, CelGro showed a minimum mass loss of 1.4% over 14 days in hydrolytic degradation; however, the patches showed at least 12.5% of mass loss for same period. Generally, the increase in the concentration of hydrogels resulted in slower degradation. C-G10 were degraded 24.9%, whereas G10H5 and C-G15H5 showed 13.5% and 12.5% of mass loss after 14 days incubation in PBS. The last-mentioned groups were degraded lower than other samples, indicating that HAMA can effectively reduce degradation rate, especially in high concentration (5 w / v%).

[0141] Contrary to hydrolytic degradation, CelGro were almost completely degraded after 3 days exposure to enzymatic media at 37 °C (Figure 5D). On the other hand, all bioadhesive patches showed a higher mass loss in enzymatic condition compared to hydrolytic. However, the increase in the concentration of hydrogels resulted in slower degradation similar to hydrolytic degradation. C-G10 and C-G15H5 showed highest (96%) and lowest (59.2%) mass loss ratios after 7 days, respectively.

[0142] 1.2.5 Wet dynamic test

[0143] The bioadhesive patches must be able to remain adhered to the target tissue under wet and dynamic conditions for neurological applications. Hence, the wet dynamic tests were conducted ex vivo to determine the adhesion capability of the patches under wet and dynamic conditions like the physiological conditions in human body. The adhered patches on intestine mucosa tissues were incubated in PBS at 37 °C with the shaking speed of 80 rpm over 35 days. The media was changed every 3 days and the stability of the patches were scored based on three situations of the patch on tissue, including prefect attachment (2 points), partial attachment (1 point), and detachment (0 point). Figure 6A show an example of scoring method for C-G10 after 7 days, which involves three patches with prefect attachment (6 points) and two patches with partial attachment (2 points), resulting in a total score of 8. Figure 6B represents the total score of patches after 1, 7, 10, 25, 35 days. While all patches remained intact (score =10) within one day incubation, C- G10H2.5 was the only patch perfectly attached over 15 days with the maximum score. C-G10 showed the lowest adhesive properties over 35 days. Although C-G10H2.5 and C-G15H5 revealed the highest score of 7.6 after day 35 among all groups, C-G15 and C-G15H2.5 also showed the score higher than 7, which are expected to last long in physiological environments.

[0144] Example 2 - Dural repair

[0145] 2. 1 Background

[0146] Use of an embodiment of the bioadhesive patch was used to assess dural repair using an animal model.

[0147] 2.2 Materials and methods

[0148] A collagen membrane and prepolymer solution were prepared as outlined in Example 1.

[0149] The animal model was a rabbit dural defect model (0.8*0.6cm longitudinal orbital defect above the midline of the brain). A control material was Heal-Dura ® acellular dermal matrix, ZH-Bio CN, National Medical Device Registration Certificate No. 20223131789 (China, CFDA).

[0150] The collagen membrane was soaked in the prepolymer solution, placed on the dural defect and irradiated to polymerise the prepolymer solution to form the bioadhesive patch.

[0151] 2.3. Results

[0152] 2.3. 1 Gross examination of specimens

[0153] As shown in Figure 7, the dural defect was successfully sealed by both materials. However, the bioadhesive patch of the present disclosure demonstrated superior tissue-dura integration, evidenced by early neovascularization (4 weeks) within the scaffold and a smooth interface between the material and surrounding tissue. In contrast, the Heal-Dura® group exhibited prominent Hypertrophic fibrosis, resulting in an elevated graft site compared to the adjacent tissue. At 8 weeks, Heal-Dura® implant area is still elevated, sutures are still visible, while for the bioadhesive patch implant it has nearly recovered as surrounding tissue.

[0154] 2.3.2 Histology assessment (4 weeks data)

[0155] As shown in Figure 8, the bioadhesive patch is observed to be in direct contact with the arachnoid mater, whereas a gap is present between the Heal-Dura® and the arachnoid mater. Despite the firm adherence of the bioadhesive patch to the arachnoid mater, no signs of excessive inflammatory reaction were noted. In contrast, sporadic giant cells were observed in the Heal- Dura® group. Due to the lack of adhesion between Heal-Dura® and the arachnoid mater — and its proximity to the skull defect — cartilage tissue formation was detected along the upper edge of the material.

[0156] 3.3.3 Evaluation

[0157] An evaluation of the feasibility and user experience, along with the potential correlation to enhanced clinical outcomes is provided in Table 2.

[0158] Table 2.

[0159] Bioadhesive patch Heal-Dura®

[0160] Timely seal Yes. Defect sealed within No. Graft stabilized with at least 4 stitches; approximately 30 seconds.

[0161] Risks of iatrogenic Low High due to risk of sharp injury to brain / spinal injury cord during suturing, and potential nerve tissue compression or impingement due to postoperative scarring

[0162] Example 3 - Peripheral nerve repair

[0163] 3. 1 Background

[0164] Use of an embodiment of the bioadhesive patch was used to assess peripheral nerve repair using an animal model.

[0165] 3.2 Materials and methods

[0166] A collagen membrane and prepolymer solution were prepared as outlined in Example 1.

[0167] The animal model was a Sprague-Dawley (SD) rat transected sciatic nerve model. Two controls were used:

[0168] A) Direct end-end neurorrhaphy with 3* epineurial coaptation sutures (control A is referred to a Suture Group);

[0169] B) Sutureless repair in transection part with Remplir™ Nerve Wrap (Orthocell, Australia) with anchor sutures to the epineurium in distal and proximal ends of the wrap.

[0170] The collagen membrane was soaked in the prepolymer solution, wrapped around the peripheral nerve defect and irradiated to polymerise the prepolymer solution to form the bioadhesive patch.

[0171] 3.3 Results

[0172] 3.2. 1 Footprint analysis-Sciatic function index As shown in Figure 9, early recovery from foot drop was observed in both the Remplir™ and Bioadhesive Patch groups, as evidenced by earlier reappearance of heel prints compared to the Suture group. At 8 and 12 weeks, both Remplir™ and Bioadhesive Patch groups achieved satisfactory toe spread, indicating progressive recovery from muscle atrophy and neural denervation. Throughout all time points, there was no statistically significant difference in the Sciatic Function Index (SFI) between the Remplir™ and Bioadhesive Patch groups.

[0173] 3.3.2 Evaluation

[0174] Nerve coaptation was successfully achieved with all materials. A vascularization network was observed in both the Remplir™ and Bioadhesive Patch scaffolds. The Bioadhesive Patch appeared more inflamed compared to Remplir™ at 4 weeks; however, by 12 weeks, their appearances were largely similar. In contrast, hyperplastic tissue was observed adjacent to the suture knot in the neurorrhaphy sample. Gross examination of these results is shown in Figure 10 with an overview of the results outlined in Table 3.

[0175] Table 3.

[0176] 3x epineural sutures Remplir™ Bioadhesive Patch

[0177] Time for coaptation 7-9 mins 4-5mins 1-1.5mins

[0178] Risk of axonal injury High Low (related to anchor Very low during operation suture)

[0179] Microscopy Essential Likely essential May not be required requirement

[0180] 3.3.3 Histology analysis

[0181] Figure 11 and Figure 12 show the results from histological analysis. For nerve regeneration, at the transection site, both Remplir™ and the bioadhesive patch promote early vascularization (4 weeks) in the peripheral and central regions of the nerve. This helps preserve the distal blood supply, resulting in reduced atrophy and better maintenance of nerve bundle diameter (Figure 5). For inflammation, in the Suture Group, a distinct foreign body reaction is observed around the suture material, accompanied by reactive hyperplasia in the epineural region. For Remplir™, lymphocytic infiltration is evident at 4 weeks, indicating an acute inflammatory response, which largely subsides by 12 weeks. In contrast, the Bioadhesive Patch induces a stronger inflammatory response compared to Remplir™, though no foreign body reaction is observed. By 12 weeks, the hydrogel component of the bioadhesive patch is largely resorbed; however, residual gel persists and continues to elicit localized inflammation.

Claims

Claims1. A bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

2. A bioadhesive material as claimed in claim 1, wherein the hydrogel comprises up to 20wt.% gelatin species modified with polymerisable groups.

3. A bioadhesive material as claimed in claim 2, wherein the hydrogel comprises up to 15wt.% gelatin species modified with polymerisable groups.

4. A bioadhesive material as claimed in any one of claims 1 to 3, wherein the hydrogel comprises up to 10 wt.% secondary biopolymer.

5. A bioadhesive material as claimed in any one of claims 1 to 4, wherein a molecular weight (Mw) of the secondary biopolymer is greater than a molecular weight (Mw) of the species modified with polymerisable groups.

6. A bioadhesive material as claimed in any one of claims 1 to 5, wherein the gelatin is modified with photo-crosslinkable moieties including vinylic, acrylate, methacrylate, acrylamide.

7. A bioadhesive material as claimed in claim 6, wherein the gelatin modified with polymerisable groups is gelatin methacrylate.

8. A bioadhesive material as claimed in any one of claims 1 to 7, wherein the secondary biopolymer is a hyaluronic acid species modified with polymerisable groups.

9. A bioadhesive material as claimed in claim 8, wherein the hyaluronic acid species modified with polymerisable groups is hyaluronic acid methacrylate.

10. A bioadhesive material as claimed in any one of claims 1 to 9, wherein the hydrogel is formed from a pre-polymer solution that consists of gelatin methacrylate and hyaluronic acid methacrylate.

11. A bioadhesive material as claimed in any one of claims 1 to 10, wherein the membrane is biodegradable.

12. A bioadhesive material as claimed in any one of claims 1 to 11, wherein the membrane is a bilayer membrane, wherein a first side of the membrane is smooth and a second side of the membrane has an increased surface roughness compared to the first side.

13. A bioadhesive material as claimed in any one of claims 1 to 12, wherein the membrane comprises collagen.

14. A bioadhesive material as claimed in claim 13, wherein the member is formed from collagen.

15. A bioadhesive material as claimed in any one of claims 1 to 14, wherein the membrane has a thickness up to 500 pm.

16. A method of forming a bioadhesive material, comprising: providing a membrane immersed in a pre-polymer solution, the pre-polymer solution comprising a gelatin species modified with polymerisable groups and a secondary biopolymer modified with polymerisable groups; and polymerising the pre-polymer solution to form a hydrogel to embed the biodegradable membrane.

17. A method as claimed in claim 16, further comprising hydrating the membrane prior to immersing the hydrated biodegaradable member in the pre-polymer solution.

18. A method as claimed in claim 17, wherein the membrane is hydrated in the pre-polymer solution prior to polymerisation.

19. A method as claimed in any one of claims 16 to 18, wherein the pre-polymer solution includes a photoinitiator that is activated upon exposure to light such that polymerisation of the pre-polymer solution is photo-initiated.

20. A method as claimed in any one of claims 16 to 19, further comprising placing the biodegradable membrane immersed in the pre-polymer solution onto tissue prior to polymerisation such that following polymerisation the bioadhesive material is formed on the tissue in vivo.

21. A method as claimed in any one of claims 16 to 20, wherein the pre-polymer solution comprises up to 20wt.% gelatin species modified with polymerisable groups.

22. A method as claimed in claim 21, wherein the pre-polymer solution comprises up to 15wt.% gelatin species modified with polymerisable groups.

23. A method as claimed in any one of claims 16 to 22, wherein a molecular weight (Mw) of the secondary biopolymer is greater than a molecular weight (Mw) of the species modified with polymerisable groups.

24. A method as claimed in any one of claims 16 to 23, wherein the gelatin is modified with photo-crosslinkable moieties including vinylic, acrylate, methacrylate, acrylamide.

25. A method as claimed in claim 24, wherein the gelatin modified with polymerisable groups is gelatin methacrylate.

26. A method as claimed in any one of claims 16 to 25, wherein the secondary biopolymer is a hyaluronic acid species modified with polymerisable groups.

27. A method as claimed in claim 26, wherein the hyaluronic acid species modified with polymerisable groups is hyaluronic acid methacrylate.

28. A method as claimed in any one of claims 16 to 27, wherein the pre-polymer solution consists of a solvent, gelatin methacrylate, hyaluronic acid methacrylate, and an initiator.

29. A method as claimed in any one of claims 16 to 28, wherein the pre-polymer solution comprises up to 10 wt.% secondary biopolymer.

30. A method as claimed in any one of claims 16 to 29, wherein the membrane is a bilayer memberane, wherein a first side of the membrane is smooth and a second side of the membrane has an increased surface roughness compared to the first side.

31. A method as claimed in any one of claims 16 to 30, wherein the membrane is biodegradable.

32. A method as claimed in any one of claims 16 to 31 , wherein the membrane comprises collagen.

33. A method as claimed in any one of claims 16 to 32, wherein the membrane is formed from collagen.

34. A method as claimed in any one of claims 16 to 33, wherein the biodegradable membrane has a thickness up to 500 pm.

35. A method as claimed in any one of claims 16 to 34, wherein the hydrogel is fully hydrated following polymerisation.

36. A method as claimed in any one of claims 16 to 35, wherein polymerisation is performed at a temperature up to 40°C.

37. A method as claimed in any one of claims 16 to 36, wherein polymerisation is performed at a temperature greater than 10 °C.

38. A system for forming a bioadhesive material to repair a soft-tissue injury, the system comprising: a pre-polymer solution comprising gelatin species modified with polymerisable groups, a secondary biopolymer modified with polymerisable groups, and an initiator to initiate polymerisation of the gelatin species modified with polymerisable groups and the secondary biopolymer modified with polymerisable groups; and a membrane that is capable of being immersed in the pre-polymer solution to absorb at least some of the pre-polymer solution; wherein the system is configured such that polymerising the pre-polymer solution forms a hydrogel that embeds the biodegradable membrane.

39. A system as claim in claim 38, wherein the membrane is immersed the pre-polymer solution.

40. A system as claimed in claim 38 or 39, wherein the membrane is dried such that the dried biodegradable membrane can be hydrated in the pre-polymer solution prior to polymerisation.

41. A system as claimed in any one of claims 38 to 40, wherein the pre-polymer solution is provided in a light-proof package to prevent photoinitiation of the pre-polymer solution.

42. A system as claimed in any one of claims 38 to 41 , wherein the pre-polymer solution comprises up to 20wt.% gelatin species modified with polymerisable groups.

43. A system as claimed in claim 42, wherein the pre-polymer solution comprises up to 15wt.% gelatin species modified with polymerisable groups.

44. A system as claimed in any one of claims 38 to 43, wherein a molecular weight (Mw) of the secondary biopolymer is greater than a molecular weight (Mw) of the species modified with polymerisable groups.

45. A system as claimed in any one of claims 38 to 44, wherein the gelatin is modified with photo-crosslinkable moieties including vinylic, acrylate, methacrylate, acrylamide.

46. A system as claimed in claim 45, wherein the gelatin modified with polymerisable groups is gelatin methacrylate.

47. A system as claimed in any one of claims 38 to 46, wherein the secondary biopolymer is a hyaluronic acid species modified with polymerisable groups.

48. A system as claimed in claim 47, wherein the hyaluronic acid species modified with polymerisable groups is hyaluronic acid methacrylate.

49. A system as claimed in any one of claims 38 to 48, wherein the pre-polymer solution consists of gelatin methacrylate, hyaluronic acid methacrylate, and an initiator.

50. A system as claimed in any one of claims 38 to 49, wherein the pre-polymer solution comprises up to 10 wt.% secondary biopolymer.

51. A system as claimed in any one of claims 38 to 50, configured to repair a peripheral nerve injury.

52. A method of repairing a peripheral nerve injury, the method comprising: providing a membrane immersed in a pre-polymer solution comprising gelatin species modified with polymerisable groups, a secondary biopolymer modified with polymerisable groups, and an initiator to initiate polymerisation of the gelatin species modified with polymerisable groups and the secondary biopolymer modified with polymerisable groups; contacting the membrane immersed in the pre-polymer solution with the peripheral nerve injury such that the membrane covers at least a portion of peripheral nerve injury; andactivating the initiator to polymerise the pre-polymer solution to form a hydrogel thereby embedding the membrane in the hydrogel such that the hydrogel is adhered to the peripheral nerve injury.

53. A method of repairing a dural tear, the method comprising: providing a membrane immersed in a pre-polymer solution comprising gelatin species modified with polymerisable groups, a secondary biopolymer modified with polymerisable groups, and an initiator to initiate polymerisation of the gelatin species modified with polymerisable groups and the secondary biopolymer modified with polymerisable groups; contacting the membrane immersed in the pre-polymer solution with the dural tear such that the membrane covers at least a portion of the dural tear; and activating the initiator to polymerise the pre-polymer solution to form a hydrogel thereby embedding the membrane in the hydrogel such that the hydrogel is adhered to the dural tear.

54. Use of a bioadhesive material in the manufacture of a medicament for repairing a peripheral nerve injury, the bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

55. Use of a bioadhesive material in the manufacture of a medicament for repairing a dural tear, the bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

56. Use of a bioadhesive material in the manufacture of a medicament for repairing soft tissue injuries selected from peripheral nerve injuries and dural tears, the bioadhesive material comprising: a hydrogel formed from a pre-polymer solution that includes a gelatin species modified with polymerisable groups and a secondary biopolymer, the hydrogel having up to 20wt.% of the secondary biopolymer; and a membrane embedded in the hydrogel.

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