WO2024228619A1

WO2024228619A1 - Collagen-based materials

Info

Publication number: WO2024228619A1
Application number: PCT/NL2024/050226
Authority: WO
Inventors: Jan Bastiaan VAN BOCHOVE; Dirk Wybe Grijpma; Andreas Anthonius POOT; Lieke Henrica Anna VAN DOMMELEN; Antonius Henricus Minardus Severus Marie VAN KUPPEVELT; Wilhelmina Francisca Daamen
Original assignee: Twente Universiteit; Stichting Radboud Universitair Medisch Centrum
Current assignee: Twente Universiteit; Stichting Radboud Universitair Medisch Centrum
Priority date: 2023-05-04
Filing date: 2024-05-03
Publication date: 2024-11-07
Anticipated expiration: 2025-11-04

Abstract

Disclosed is a functionalized collagen material comprising insoluble collagen fibrils having attached acrylic side groups, preferably methacrylate groups, and a crosslinked network of said functionalized collagen. Also disclosed is a hybrid polymer co-network made of acryl-functionalized collagen, particularly insoluble collagen fibrils, and an acryl-functionalized hydrophobic biodegradable polymer, preferably poly(trimethylene carbonate). The polymers are dissolved or dispersed in a common solvent, and subjected to reaction so as to enable the acryl groups to form crosslinks within either polymer, and between both of the polymers.

Description

Title: COLLAGEN-BASED MATERIALS

Field of the invention

The invention relates to collagen-based materials suitable for preparing medical implants such as tissue engineering scaffolds. Also, the invention pertains to a method to produce such materials, and an intermediate material.

Background

For many tissue engineering purposes materials are required that are biocompatible and tough, and preferably porous. An interesting material, from a biocompatibility point of view, is collagen. Porous collagen- based structures for use as tissue engineering scaffolds or medical devices have been made before. Although these structures are biodegradable and show very good interactions with cells and tissues, their mechanical properties are poor. In the dry state, these materials tear easily and may give unsatisfactory properties when stretched in tension or sutured. Upon hydration, porous collagen scaffolds take up much water and show limited form stability.

The foregoing issues limit the applicability of collagen fibrils in the field of tissue engineering. Enhancing the toughness of collagen-based materials, more particularly of porous collagen-based materials, would significantly increase their applicability in medical applications, e.g., where an implant is subjected to mechanical loads. Background art includes Brouwer KM, et al., J. Tissue Eng. Regen. Med. 2011, 5, 501-504 and Liang J et al., European Polymer Journal 2020, 123, art. no. 109420.

In the art, several attempts are made to apply collagen in tissue engineering. A background reference is US20120220691A1, in which soluble collagen is subjected to methacrylation, in order to thereupon have the methacrylated collagen form fibrils. Further background literature relates to first modifying soluble collagen with either acrylate or methacrylate groups prior to photoinitiator-activated cross-linking (Poshusta et al., “Photopolymerized Biomaterials for Application in the Temporo-mandibular Joint,” Cells Tiss. Orgs., 169(3), 272-278 (2001); Brinkman et al., “Photo- cross-linking of Type I Collagen Gels in the Presence of Smooth Muscle Cells: Mechanical Properties, Cell Viability and Function,” Biomacromols., 4(4), 890-895 (2003)). However, these methods are not secure in avoiding effects such as unwanted gelation during reaction, or partial denaturation of the collagen. These effects present a risk factor in losing the collagen’s ability to self-assemble into fibrils, as native collagen does. A further background reference is WO2015/138970. Herein, inter alia, methacrylated collagen is dissolved and the resulting solution is subjected to electrospinning, resulting in methacrylated collagen fibers. This process thereby produces fibers, random or aligned. As concluded by Sizeland et al., Materialia, Volume 3, November 2018, pages 90-96, no native collagen architecture exists in electrospun collagen fibers.

Summary of the invention

In order to better address one or more of the aforementioned issues, the invention presents, in one aspect, a functionalized collagen material comprising insoluble collagen fibrils having attached acrylic side groups, preferably methacrylate groups.

In another aspect, the invention provides a polymer network comprising a functionalized collagen material comprising insoluble collagen fibrils having attached acrylic side groups, said collagen material being crosslinked via covalent bonds, wherein the covalent bonds are formed between acrylic side groups of the functionalized collagen.

In a further aspect, the invention pertains to a hybrid polymer conetwork comprising a first and at least one second polymer network-forming material, wherein said co-network comprises a plurality of covalent bonds between said first and second polymer network-forming materials, wherein the first polymer network -forming material is insoluble fibrillar collagen provided with acrylic side groups, and the second polymer network-forming material is a hydrophobic biodegradable polymer provided with acrylic groups, wherein said covalent bonds are formed between acrylic groups of either polymer network-forming material.

In yet another aspect, the invention presents a process for the preparation of a functionalized collagen material comprising insoluble collagen fibrils having attached acrylic side groups, preferably methacrylate groups, the process comprising

- providing insoluble collagen fibrils;

- subjecting said fibrils to swelling in an aqueous, preferably acidic environment, so as to provide swollen collagen fibrils;

- subjecting said swollen collagen fibrils to reaction with an acrylic compound, thereby obtaining insoluble collagen fibrils having attached acrylic side groups.

In a still further aspect, the invention provides a process for the preparation of a hybrid polymer co-network comprising a first and at least one second polymer network, wherein said co-network comprises a plurality of covalent bonds between said first and second polymer networks, the process comprising providing (a) a first polymer network-forming material comprising functionalized insoluble collagen fibrils having acrylic side groups and (b) at least one second polymer network -forming material comprising a hydrophobic biodegradable oligomer or polymer having attached acrylic groups; dissolving and/or dispersing both polymer networkforming materials in a common solvent so as provide a co-network forming mixture; subjecting the co-network forming mixture to reaction so as to form covalent bonds between acrylic groups within and between either polymer network -forming material, thereby forming a crosslinked hybrid polymer conetwork.

In yet a further aspect, the invention resides in process for the preparation of a medical implant, comprising providing a co-network forming mixture in accordance with the previous paragraph; subjecting the co-network forming mixture to shaping so as to provide a shaped co-network forming mixture; activating the reaction of the acrylic groups in the shaped co-network forming mixture so as to form a crosslinked hybrid polymer conetwork.

Brief description of the drawings

Fig. 1 shows pictures of crosslinked network structures.

Fig. 2 is a graph displaying tensile properties of crosslinked network structures.

Fig. 3 is a graph displaying suture retention strengths of crosslinked network structures. Detailed description

In a broad sense, the invention is based on the judicious insight to enhance the properties of collagen-based polymer networks by providing insoluble, fibrillar collagen with acrylic side groups. This allows forming a network directly from fibrillar, insoluble collagen. I.e., the invention makes use of insoluble fibrillar collagen having its native collagen architecture. Without wishing to be bound by theory, the inventors believe that forming a collagen network specifically on the basis of insoluble, fibrillar collagen results in a collagen network structure providing enhanced properties, such as a desirably higher modulus of elasticity.

The term “insoluble” with regard to “insoluble collagen”, “insoluble fibrillar collagen”, and “insoluble collagen fibrils” refers to insolubility in at least water.

The terms “collagen fibrils” and “fibrillar collagen” are known to the skilled person. These refer to staggered arrays of tropocollagen molecules. Reference is made to Buehler; PNAS August 15, 2006, vol.103, no.23, 12285-12290.

More particularly, the acrylic -functionalized insoluble fibrillar collagen judiciously allows such collagen fibrils to be applied in forming a conetwork with at least one second polymer network-forming material having attached acrylic groups, preferably a hydrophobic biodegradable polymer network -forming material.

A co-network of two or more different network-forming polymers or oligomers is characterized by covalent bonds between the different networkforming oligomers or polymers. This is different from, e.g., an interpenetrating network in which two different polymers each form a network, and the networks are made to interpenetrate each other, without binding to each other. In the co-network of the invention, both the collagen and the hydrophobic biodegradable oligomers or polymers as such are capable of forming a network, by allowing the acrylic groups to react with each other. Since both polymer network -forming materials have groups of the same nature, this also enables the generation of covalent bonds between the different polymer networks.

Acrylic groups refer to the residue of an acrylic carboxylic compound, typically acrylic acid, an acrylic ester, acrylic anhydride, or acrylic acid chloride. The term “acrylic” as used herein encompasses methacrylic groups, which refers to the residue of a methacrylic carboxylic compound, typically methacrylic acid, a methacrylic ester, methacrylic anhydride, or methacrylic acid chloride. Typical acrylic groups are the residues of methyl(meth)acrylate, ethyl(meth)acrylate, butyl(meth)acrylate, 2 -ethylhexyl (meth)acrylate, (meth)acrylic anhydride, glycidyl(meth)acrylate. It will be understood that, within either network -forming polymer, all of the acrylic groups can be the same, or different. Also, between both polymer network -forming materials, the acrylic groups can be the same or different.

The reaction between the acrylic groups, within one polymer network -forming material as well as between the two different polymer network -forming materials, can be accomplished in various ways known to the skilled person.

The first polymer network-forming material is collagen provided with acrylic side groups. Collagen exists in various types, currently estimated as 28 (Type I to Type XXVIII). The most common types are Types I, II, III, IV, and V. The five most common types, with their most common source, are:

Type I: skin, tendon, vasculature, organs, bone (main component of the organic part of bone);

Type II: cartilage (main collagenous component of cartilage); Type III: reticulate (main component of reticular fibres), commonly found alongside type I;

Type IV: forms basal lamina, the epithelium-secreted layer of the basement membrane;

Type V: cell surfaces, hair, and placenta.

Collagen comes in fibril-forming and non-fibril-forming types. In the present invention collagen of types I, III, V, and XI can be applied, all comprising insoluble, fibrillar collagen. Collagen types I and III are preferred.

Accordingly, the present invention provides fibrillar collagen with acrylic (including methacrylic) side groups. This is markedly different from attempts made in the art, e.g. US20120220691A1, in which soluble collagen is subjected to methacrylation, seeking to thereupon have the methacrylated collagen form fibrils. Further background literature relates to first modifying collagen with either acrylate or methacrylate groups prior to photoinitiator-activated cross-linking (Poshusta et al., “Photopolymerized Biomaterials for Application in the Temporo-mandibular Joint,” Cells Tiss. Orgs., 169(3), 272-278 (2001); Brinkman et al., “Photo-cross-linking of Type I Collagen Gels in the Presence of Smooth Muscle Cells: Mechanical Properties, Cell Viability and Function,” Biomacromols., 4(4), 890-895 (2003)). However, these methods are not secure in avoiding effects such as unwanted gelation during reaction, or partial denaturation of the collagen. These effects present a risk factor in losing the collagen’s ability to selfassemble into fibrils, as native collagen does.

The collagen fibrils can be modified by subjecting the fibrillar collagen to swelling in an aqueous, preferably weakly acidic medium, mixing the appropriate acrylic compound into the swollen fibrils, and allowing reaction to start. The swelling is generally conducted for a period of from 1 hour to 1 week, preferably 1-5 days, such as 3-4 days. A suitable weakly acidic medium is, e.g., 0.25 M acetic acid. Other suitable acids are, e.g., diluted HC1, formic acid, propionic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, maleic acid, fumaric acid. Suitable pH ranges generally are pH 1-6, preferably pH 2-4.

Suitable acrylic compounds include those mentioned above. A preferred acrylic compound for the functionalization of collagen fibrils is glycidyl methacrylate. The reaction is suitably conducted in the presence of weak acid, which may be the same as the swelling medium, or different from it. The reaction temperature will generally range of from 1°C to the denaturation temperature of the collagen involved, which generally will be below 50°C, more typically below 40°C. Preferably the temperature is in a range of from 4°C to 40°C, more preferably 15°C to 25°C, such as room temperature. The reaction is generally allowed to take place for a period of at least 0.5 hour, such as from 1 hour to 1 week, such as 4 hours to 4 days, such as 0.5 day to 3 days, such as 1-2 days. Unreacted acrylic compound is removed, e.g., by dialysis against aqueous acetic acid, preferably applying an instant or gradual decrease of the acid concentration, and preferably ending with water as the dialysis fluid.

The insoluble collagen fibrils are generally functionalized with a degree of functionalization of 5 to 50, preferably 10 to 40, more preferably 20 to 30. The degree of functionalization (DoF) is calculated by determining the ratio of the number of acrylic groups and the number of functional groups present on the insoluble, fibrillar collagen as follows: moles acrylic groups

DoF = - * 100%. moles functional groups collagen

Herein the functional groups are those groups that are capable of reacting with an acrylic agent at the selected pH. These functional groups are normally selected from the group consisting of -NH2, -OH, COOH, and combinations thereof. The invention, in one aspect, pertains to the modified collagen fibrils as such. This refers to insoluble collagen fibrils comprising a collagen backbone having attached acrylic side groups. As described hereinbefore these modified collagen fibrils are useful as an intermediate in making a network on the basis of insoluble, fibrillar collagen, as well as of a hybrid polymer co-network.

In the hybrid polymer co-network of the invention, the at least one second polymer network-forming material is a hydrophobic biodegradable oligomer or polymer provided with attached acrylic groups. The terms “oligomer” and “polymer” are known to the skilled person. Both indicate the result of a polymerization reaction, resulting in chains of repeating units. It will be understood that a polymer generally has a higher degree of polymerization than an oligomer. With a view to formation of a polymer conetwork, the skilled person will be able to determine the desired oligomeric or polymeric chain lengths of the polymer network -forming material. The second polymer network-forming materials can be linear oligomers or polymers, but preferably are constructed so as to have three arms of oligomeric or polymeric chains. The oligomers, either in a linear form or as an arm of a three-armed network-forming material, will generally have 2 to 200 repeating units, preferably 10 to 100, such as 20 to 80, such as 30 to 70, such as 40 to 60. Polymers, herein defined as having a degree of polymerization of more than 200 can also be used as a network -forming material, preferably having a degree of polymerization below 1000, more preferably below 500, such as below 400, such as below 300. In the event of co-polymers or co-oligomers, the degrees of polymerization mentioned herein refer to the overall degree of polymerization of both of all co-monomers taken together.

The at least one second polymer network-forming material in the polymer co-network of the invention is hydrophobic. In the art, generally consensus exists as to whether a material is to be regarded as hydrophobic. A hydrophobic polymer is generally characterized by a water contact angle larger than 90°. It will be understood that the measurement of contact angles is conducted on a flat, non-porous surface of the material concerned, and concerns a test which the person skilled in the art is well familiar with.

Biodegradable polymers frequently have repeating units linked by ester, amide, or ether bonds. Preferred are ring-opening polymerization polymers or oligomers, e.g. of a cyclic lactone such as caprolactone, yielding poly(c -caprolactone) or cyclic dimeric glycolic or lactic acid, wherein the resulting dimers polymerize into poly(a-esters). A particularly preferred class of biodegradable hydrophobic polymers or oligomers are polycarbonates, preferably obtained from the ring-opening polymerization of cyclic carbonate. Preferably the biodegradable hydrophobic polymer to be applied in the present invention is selected from the group consisting of poly (trimethylene carbonate), poly(c-caprolactone), and combinations thereof. Most preferably the biodegradable hydrophobic polymer is poly (trimethylene carbonate), also known as PTMC. The skilled person is familiar with the aforementioned polymers, and methods of making them. Reference is made, e.g., to Handbook of Ring Opening Polymerisation, Dubois P, Coulembier O, Raquez J-M, Eds., Wiley-VCH Verlag, Weinheim, Germany, 2009. Preferably, the acrylic-functionalized polymers or oligomers are prepared by conducting a ring opening polymerization so as to yield an oligomeric or polymeric material having hydroxyl end groups, followed by functionalizing at least part of the hydroxyl groups with the desired acrylic groups, so as to yield an acrylic-functionalized oligomer or polymer.

Advantageously, a combination of two, or even more, different hydrophobic biodegradable polymers can be applied, with the combination of PTMC and poly(c-caprolactone) being preferred. Also, one or more biodegradable co-polymers of two, or even more, different hydrophobic monomers can be applied, with the combination of TMC and c-caprolactone being preferred. Making such combinations allows a further tuning of the properties, e.g. flexibility, elasticity, tear-resistance, biodegradability, of the resulting hybrid polymer co-network. The hydrophobic biodegradable polymer network -forming material preferably comprises PTMC. More preferably, it comprises three-armed PTMC. The synthesis of three-armed PTMC does not present any difficulty to the skilled person, and can be accomplished by starting the ring-opening polymerization of TMC in the presence of a compound having three hydroxyl groups that are available for reaction with TMC, preferably an aliphatic trihydroxy compound, more preferably 1, 1, 1-trimethylolpropane.

The hydrophobic biodegradable polymer network -forming material can be modified by subjecting it to reaction with an acrylic compound as listed above. Said polymer network-forming material is preferably modified with acrylic or methacrylic anhydride. The reaction generally takes place in a suitable organic medium, e.g. in dichloromethane. Possibly an amine is added as a catalyst, e.g. triethylamine, and a radical polymerization inhibitor such as hydroquinone is suitably added.

The hydrophobic biodegradable polymer network -forming material, i.e., the biodegradable oligomer or polymer is generally functionalized with a degree of functionalization of 60 to 100, preferably 80 to 100.

The modified collagen fibrils and the modified hydrophobic biodegradable (co-)polymer(s) are suitable for forming a hybrid polymer conetwork in accordance with the invention. To this end, the two modified polymers need to be brought together before reaction of acrylic groups is initiated. This can be accomplished in an organic solvent that is capable of dissolving or suspending the modified hydrophobic polymer, as well as the modified fibrillar collagen. It will be understood that the latter preferably is dispersed (suspended) rather than dissolved. In fact, insoluble collagen fibrils are not only insoluble in water, but tend to be insoluble in most media. A particularly preferred solvent as surprisingly found in accordance with the invention is DMSO with HC1. Preferably, HC1 of more than 30% concentration is applied, more preferably HC1 of at least 35%, and most preferably fuming HC1 (36.5-38% HC1). In lieu of HC1, also other acids can be used, such as formic acid or acetic acid. The combinations with DMSO to be made are preferably, if calculated on the basis of fuming HC1, diluted with DMSO in a range of 150 to 250 times dilution, preferably 160 to 200 times dilution, most preferably 175 to 190 times dilution, such as 180 times diluted with DMSO.

In the hybrid co-network of the invention, the insoluble, fibrillar collagen and the hydrophobic biodegradable polymer are combined in a weight ratio generally in a range of collagen to hydrophobic polymer of from 1:1 to 1:10, preferably 1:1.5 to 1: 6, such as 3:5 to 1:5.

The functionalized collagen fibrils, modified with acrylic side groups, can also be used to form a crosslinked collagen network as such. Herein said functionalized collagen is crosslinked via covalent bonds, wherein the covalent bonds are formed between acrylic side groups of the functionalized collagen. It will be understood that in this case, suitable solvents do not necessarily need to dissolve a second polymer. In addition to the above solvents. Suitable solvents in which the modified insoluble collagen fibrils can be dispersed, include trifluoroethanol and hexafluoroisopropanol, glacial acetic acid and glacial formic acid.

After mixing the solutions and/or suspensions of the acrylic modified polymers, initiating the polymerization reaction between the acryl groups will result in the formation of network bonds. This involves a polymerization reaction of two or more acryl groups attached to different chains of the same polymer, as well as of acryl groups present on different sites on the same polymer chain. These reactions result in either polymer becoming crosslinked. Additionally, a polymerization reaction also takes place between two or more acryl groups attached to chains of two different polymers. These reactions serve to link the two different polymer networks to each other. Overall, these reactions result in the formation of a co- network involving covalent bonds not only within each polymer separately, but also between the two types of polymers making up the hybrid polymer co-network. Due to the fast, radical polymerization nature of the acrylic reactions, it will be understood that the reaction rates for all of the mentioned bonding reactions are of the same order of magnitude.

For many applications of the hybrid polymer co-networks of the invention, it will be important to first determine shape, and then conduct the network -forming reaction. To this end, the mixture of both polymer solutions/suspensions is preferably subjected to freezing in a desired shape. Freezing can be accomplished such as to result in a random pore orientation. In an interesting embodiment of the invention in general, directional freezing is applied, in order to obtain a desirable direction in pore orientation. Directional freezing can be defined by steering the growth of ice crystals in a certain direction, using a temperature gradient. The directional freezing is preferably done in such a way as to achieve a radial pore orientation, since this will facilitate a proper alignment of cells infiltrating in the scaffold or patch.

Accordingly, the common solvent preferably allows for directional freezing. The suitability of a solvent for directional freezing can be tested in advance by just subjecting it as such to the intended directional freezing temperature gradient, and observing whether a macroscopic orientation of ice crystals takes place. The acidified DMSO described hereinbefore is highly suitable for directional freezing, particularly also for obtaining a radial pore orientation.

The network-forming reaction requires initiating a coupling reaction of available acrylic groups. This refers to a radical reaction comparable with the radical polymerization of acrylic compounds. These reactions can be photo-initiated, thermally initiated, or initiated by a redox couple. These reactions are well-known in the art. Reference is made to Handbook of Radical Polymerization, Matyjaszewski K, Davis TP, Eds., Wiley-Interscience, New York, USA, 2002.

As noted above, the network-forming reaction is optionally conducted with the polymers in a frozen state. This is particularly done with the aim to generate a porous network, which is a preference in view of a variety of practical uses, e.g., a scaffold for tissue engineering, or a patch. In such case, after the reaction has been completed, thawing follows, generally also with washing. Suitably, thereafter the resulting porous material can be subjected to drying by freezing and lyophilization. Alternatively, the material is stored in a wet state until use.

The hybrid polymer co-networks of the invention can be broadly applied in applications related to tissue engineering, implants for humans or animals, surgical suture, or other medical applications, such as in vitro or ex vivo systems for dynamic cell culturing, microfluidics, controlled delivery devices, organ engineering and assessment of pharmaceuticals.

In an interesting embodiment, the hybrid polymer co-network of the invention is used in preparing a patch for diaphragmatic hernia closure. This is an important development for treating infants suffering from a congenital diaphragmatic hernia (CDH). This refers to a defect in the diaphragm, the incidence of which is rare (1:2000-3000 live births), and which comes with a substantial mortality rate, viz. 20-40%. The hybrid polymer co-network of the invention serves to better address the need for a biodegradable material with improved performance in respect of retaining toughness for 6-12 months and orienting muscle cell influx in the correct direction.

The invention will be illustrated with reference to the following non-limiting examples. Example 1

Three-arm PTMC of 17.5 kg/mol was functionalized using methacrylic anhydride (PTMC-tMA), glycidyl methacrylate was used to functionalize insoluble fibrillar collagen (I-ColMA). DMSO/HC1 was used to dissolve PTMC-tMA and to swell and disperse I-ColMA. The (mixed) polymer solutions and dispersions were frozen at -25 °C and photocrosslinked by UV irradiation. The sol fraction was extracted with DMSO/HC1, after which the solvent was replaced with demi-water and the structures were freeze-dried. Fig. 1 shows pictures of the resulting crosslinked network structures prepared from PTMC-tMA, I-ColMA, and a 5:1 (w/w) PTMC-tMA and I-ColMA hybrid network (scale bars: 1 mm).

Gel contents, swelling ratios, porosity and water uptake of the obtained structures were determined gravimetrically.

The polymer mixtures could be UV-crosslinked in the solid state. Macroscopically and microscopically, the structures appear porous, as follows from their white color. High gel contents were obtained, as outlined in Table 1, indicating that the polymers were covalently crosslinked.

Table 1 compares porous structures of methacrylated PTMC (PTMC-tMA), methacrylated collagen fibrils (I-ColMA) and the resulting hybrid polymeric co-network of the invention. Indicated are the weight ratios of the two macromolecular monomers (macromers), the macromer content in weight per volume (g/100 mL solution or dispersion) before freezing and photo-crosslinking, and the results in terms of gel content, degree of swelling, porosity, and water uptake. Table 1.

The water uptake increased with higher collagen content of the networks. The degree of swelling in DMS0/HC1 was lowest for networks prepared at the highest macromer contents.

Example 2

Crosslinked network structures were prepared from PTMC-tMA, I-ColMA and mixtures of I-ColMA and PTMC-tMA (3%/5% and 3%/15% (w/v)) as described in Example 1. Network samples were swollen in water, after which the tensile properties and suture retention strengths were determined using a TA Instruments DMA 850.

During tensile measurements, the PTMC network did not break (Fig. 2). At a strain of 110%, the tensile stress amounted to 0.25 MPa. The collagen network was weaker and could only be elongated up to 55% until break. Compared to the collagen network, the two co-networks of the invention showed higher tensile stresses and strains at break, especially the I- ColMA/PTMC-tMA 3%/15% (w/v) network. Similar results were obtained for the suture retention strengths (Fig. 3). The two co-networks of the invention were significantly tougher, more tear resistant and more resilient than the collagen-only networks.

Claims

1. A functionalized collagen material comprising insoluble collagen fibrils having attached acrylic side groups.

2. A functionalized collagen material according to claim 1, wherein the acrylic groups are methacrylate groups.

3. A polymer network comprising the functionalized collagen of claim 1 or 2, said functionalized collagen being crosslinked via covalent bonds, wherein the covalent bonds are formed between acrylic side groups of the functionalized collagen.

4. A hybrid polymer co-network comprising a first and at least one second polymer network-forming material, wherein said co-network comprises a plurality of covalent bonds between said first and second polymer network -forming materials, wherein the first polymer networkforming material is insoluble fibrillar collagen provided with acrylic side groups, and the second polymer network -forming material is a hydrophobic biodegradable polymer provided with acrylic groups, wherein said covalent bonds are formed between acrylic groups of either polymer network-forming material.

5. A hybrid polymer co-network according to claim 4, wherein the hydrophobic biodegradable polymer is a ring-opening polymerization polymer, preferably poly (trimethylene carbonate).

6. A hybrid polymer co-network according to claim 4 or 5, wherein the acrylic groups are methacrylate groups.

7. A hybrid polymer co-network according to any one of the claims 4 to 6, wherein the hydrophobic biodegradable polymer is a copolymer of two or more different hydrophobic monomers, preferably trimethylene carbonate and c-caprolactone.

8. A hybrid polymer co-network according to any one of the claims 4 to 7, wherein the second polymer network -forming material comprises a combination of two or more different hydrophobic biodegradable polymers.

9. A medical implant comprising a polymer network according to any one of the claims 3 to 8.

10. A medical implant according to claim 9, being a scaffold for tissue engineering or a patch.

11. A process for the preparation of a functionalized collagen material according to claim 1 or 2, the process comprising

- providing insoluble collagen fibrils;

12. A process for the preparation of a hybrid polymer co-network according to any one of the claim 4 to 8, the process comprising providing (a) a first polymer network-forming material comprising functionalized insoluble collagen fibrils having acrylic side groups and (b) at least one second polymer network-forming material comprising a hydrophobic biodegradable oligomer or polymer having attached acrylic groups; dissolving and/or dispersing both polymer network -forming materials in a common solvent so as provide a co-network forming mixture; subjecting the co-network forming mixture to reaction so as to form covalent bonds between acrylic groups within and between either polymer network-forming material, thereby forming a crosslinked hybrid polymer co-network.

13. A process according to claim 12, wherein the common solvent is dimethyl sulfoxide (DMSO), preferably acidified DMSO.

14. A process according to claim 12 or 13, wherein the step of subjecting the co-network forming mixture to reaction comprises photoinitiation.

15. A process for the preparation of a medical implant according to claim 9 or 10, wherein the implant comprises a hybrid polymer co-network according to any one of the claim 4 to 8, the process comprising providing (a) a first polymer network-forming material comprising functionalized insoluble collagen fibrils having acrylic side groups and (b) at least one second polymer network-forming material comprising a hydrophobic biodegradable oligomer or polymer having attached acrylic groups; dissolving and/or dispersing both polymer network -forming materials in a common solvent so as provide a co-network forming mixture; subjecting the co-network forming mixture to shaping so as to provide a shaped co-network forming mixture; activating the reaction of the acrylic groups in the shaped co-network forming mixture so as to form a crosslinked hybrid polymer conetwork, preferably comprising subjecting the shaped co-network forming mixture to freezing so as to form a frozen co-network forming mixture, and subjecting the frozen polymer mixture to the activation, so as to form a porous crosslinked hybrid polymer co-network.