Composite collagen dressing and preparation method thereof

Abstract

The invention discloses a composite collagen dressing and a preparation method thereof, and relates to the technical field of composite collagen, the dressing comprises a body formed by a double-layer composite structure, and the double-layer composite structure comprises a chitosan fiber non-woven fabric layer and a functional layer. According to the invention, through compounding of collagen and regenerated cellulose, active crosslinking of heparan sulfate, and multiple technological innovations of a PCL drug-loaded microsphere and adhesive-free double-layer structure, the composite dressing which has excellent mechanical properties, an active repair function, long-acting drug sustained release and good biocompatibility is cooperatively constructed.

Description

Technical Field

[0001] This invention relates to the field of composite collagen technology, and in particular to a composite collagen dressing and its preparation method. Background Technology

[0002] Collagen, a major structural protein in animal connective tissue, is also a key component of human skin, bones, and blood vessels. Due to its excellent biocompatibility, biodegradability, and low immunogenicity, collagen has been widely used in medical dressings. Traditional collagen dressings can create a moist environment for wounds and promote healing, but they also have certain limitations.

[0003] Current collagen dressings face multiple technical bottlenecks in clinical applications: They suffer from fundamental defects such as limited functionality and poor mechanical properties, as well as deeper issues like easy loss of active ingredients, unreasonable structural design, and potential biosafety risks introduced by the manufacturing process. These interconnected defects collectively limit the clinical efficacy of collagen dressings, necessitating systematic improvements through material innovation, structural design, and process optimization to develop a new generation of collagen-based dressings that combine excellent biological functions with suitable physicochemical properties.

[0004] To address these issues, researchers have made several attempts. For example:

[0005] Referring to a Chinese patent publication, publication number CN106139232A, publication date 2016-11-23, a method for preparing a collagen-regenerated cellulose composite dressing is disclosed, the purpose of which is to enhance the mechanical properties of collagen through cellulose.

[0006] Referring to Chinese patent publication CN107441549A, published on 2017-12-08, a method for preparing a collagen-heparan sulfate composite dressing is disclosed, the purpose of which is to enhance the retention of active ingredients.

[0007] Referring to a Chinese patent publication, publication number CN109793920A, publication date 2019-05-24, a collagen dressing containing PCL microspheres and its preparation method and 3D printing application are disclosed, the purpose of which is to improve the mechanical properties and drug sustained-release ability of the dressing.

[0008] However, these solutions still have shortcomings, as they all fail to comprehensively consider the balance of multiple performance requirements, and the manufacturing process remains relatively complex. Summary of the Invention

[0009] To address the aforementioned technical problems, the present invention provides a composite collagen dressing, comprising a body composed of a double-layer composite structure, wherein the double-layer composite structure includes a chitosan fiber nonwoven fabric layer and a functional layer.

[0010] Preferably, the functional layer comprises the following components (in percentage): collagen 12%-15%, regenerated cellulose 28%-32%, heparan sulfate 6%-8%, sodium alginate 3.2%-3.8%, hydroxyapatite 2%-2.5%, and plasticizer 38.7%-49.8%;

[0011] The collagen includes macromolecular collagen and small molecule collagen, and the mass ratio of macromolecular collagen to small molecule collagen is (0.7-1.3):(0.7-1.3).

[0012] Preferably, the regenerated cellulose is obtained by treating the plant fiber with a mixed aqueous solution of lithium hydroxide and urea, followed by oxidative modification with sodium periodate.

[0013] Preferably, the heparan sulfate and the collagen are cross-linked by a cross-linking agent, wherein the cross-linking agent is an EDC / NHS cross-linking solution.

[0014] Preferably, the functional layer comprises macromolecular chitosan, macromolecular collagen, small molecule collagen, and small molecule chitosan, with a mass ratio of (0.7-1.3):(0.1-0.3):(0.7-1.3):(0.1-0.3).

[0015] Preferably, the skin-friendly surface of the functional layer is coated with a layer of polycaprolactone drug-loaded microspheres, wherein the polycaprolactone drug-loaded microspheres are loaded with antibacterial agents or growth factor drugs.

[0016] A method for preparing a dressing, used to prepare the composite collagen dressing described in the above scheme, the method comprising the following steps:

[0017] S01. The plant fiber is crushed and mixed with sodium hydroxide solution. The resulting wet powder is filtered and added to a mixed aqueous solution of lithium hydroxide and urea. After dispersion, it is placed at -20°C. After thawing, carbomer, sodium citrate and glutaraldehyde are added and stirred to obtain a regenerated cellulose solution.

[0018] S02. Add sodium periodate to the regenerated cellulose solution, adjust the pH to 2-3, stir the reaction in the dark to obtain a modified cellulose solution;

[0019] S03. Add collagen to the modified cellulose solution, adjust the pH to 6-7, and after the reaction, add N,N-dimethylacrylamide, plasticizer and calcium alginate to obtain a uniformly dispersed mixed dispersion.

[0020] S04. The mixed dispersion is injected into a mold, frozen at -20°C for 5 hours, and then freeze-dried at -50°C and 10Pa for 24 hours to obtain a composite collagen dressing.

[0021] Preferably, after step S04 is completed, the freeze-dried composite collagen dressing is vacuum thermally cross-linked at 110-125°C for 48-72 hours, and then heparan sulfate is added to the EDC / NHS cross-linking solution for secondary cross-linking for 12-36 hours. After washing, it is freeze-dried a second time.

[0022] Preferably, in step S03, after adding N,N-dimethylacrylamide, plasticizer and calcium alginate, hydroxyapatite and gluconolactone are also added.

[0023] The amount of hydroxyapatite added is 1-15g per 100mL of water, and the amount of gluconolactone added is 2-5g per 100mL of water.

[0024] Preferably, the method further includes preparing a bilayer composite structure: after pre-freezing the chitosan fiber nonwoven fabric, a sponge layer material solution containing macromolecular chitosan, macromolecular collagen, small molecule collagen and small molecule chitosan is sprayed onto the pre-frozen nonwoven fabric, and then freeze-dried.

[0025] The present invention has at least the following beneficial effects:

[0026] 1. By combining collagen with regenerated cellulose, the bioactivity of collagen is preserved while the mechanical strength of the dressing is significantly improved, enabling it to withstand certain stretching and compression without breaking.

[0027] 2. Through the cross-linking of heparan sulfate with collagen, the effective concentration and stable fixation of bioactive factors are ensured, which can actively induce cell growth and proliferation and accelerate the wound healing process.

[0028] 3. By introducing PCL drug-loaded microspheres, the slow release of antibacterial agents or growth factors is achieved, which can maintain the effective drug concentration in the wound area for a long time and reduce the frequency of replacement.

[0029] 4. The double-layer composite structure requires no adhesive and is bonded through physical interlocking, avoiding the irritation that may be caused by chemical adhesives, while also having good breathability, liquid absorption and antibacterial properties. Detailed Implementation

[0030] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0031] Example 1

[0032] This embodiment aims to provide a composite collagen dressing, which includes a body composed of a two-layer composite structure, comprising a chitosan fiber nonwoven fabric layer and a functional layer.

[0033] The chitosan fibers in the chitosan fiber nonwoven fabric layer include the following components (in percentage):

[0034] Collagen, comprising 12%-15%, serves as the primary matrix material, providing biocompatibility and promoting wound healing. This invention specifically employs a combination of macromolecular and small-molecule collagen in a mass ratio of (0.7-1.3):(0.7-1.3). Macromolecular collagen provides structural support, while small-molecule collagen is more easily absorbed by the skin, accelerating wound repair.

[0035] Regenerated cellulose (28%-32%) serves as a reinforcing phase, improving the mechanical properties of the dressing. Regenerated cellulose is derived from plant fibers, treated with a mixed aqueous solution of lithium hydroxide and urea, and then oxidized with sodium periodate to enhance its hydrophilicity and compatibility with collagen.

[0036] Heparan sulfate (6%-8%) can be cross-linked with collagen through EDC / NHS cross-linking agents, which can actively induce cell growth and proliferation and promote wound healing.

[0037] Sodium alginate 3.2%-3.8% and hydroxyapatite 2%-2.5%. Sodium alginate provides gelling properties and moisturizing ability, while hydroxyapatite enhances the dressing's bioactivity and bone repair potential, making it particularly suitable for deep wounds.

[0038] Plasticizer content: 38.7%-49.8%.

[0039] The aforementioned functional layer has a skin-friendly surface coated with a layer of polycaprolactone drug-loaded microspheres, which are loaded with antibacterial agents or growth factor drugs.

[0040] Example 2

[0041] This embodiment aims to provide a method for preparing the dressing of Embodiment 1, the steps of which include:

[0042] S01. The plant fiber is crushed and mixed with sodium hydroxide solution. The resulting wet powder is filtered and added to a mixed aqueous solution of lithium hydroxide and urea. After dispersion, it is placed at -20°C. After thawing, carbomer, sodium citrate and glutaraldehyde are added and stirred to obtain a regenerated cellulose solution.

[0043] S02. Add sodium periodate to the regenerated cellulose solution, adjust the pH to 2-3, stir the reaction in the dark to obtain a modified cellulose solution;

[0044] S03. Add 3g of collagen (1.5g of macromolecular collagen and 1.5g of small molecule collagen) to the modified cellulose solution, adjust the pH to 6.5, react for 1 hour, add 0.5g of N,N-dimethylacrylamide, 0.3g of plasticizer and 2g of calcium alginate, stir for 2 hours to obtain a uniformly dispersed mixed dispersion.

[0045] S04. The mixed dispersion is injected into a mold, frozen at -20°C for 5 hours, and then freeze-dried at -50°C and 10Pa for 24 hours to obtain a composite collagen dressing.

[0046] Example 3

[0047] This embodiment aims to provide a composite collagen dressing with a cross-linked structure based on Embodiment 2. In addition to steps S01-S04, it also includes step S05, in which the freeze-dried composite collagen dressing is vacuum thermally cross-linked at 110-125°C for 48-72 hours, and then heparan sulfate is added to the EDC / NHS cross-linking solution for secondary cross-linking for 12-36 hours. After washing, it is freeze-dried a second time.

[0048] Example 4

[0049] This embodiment aims to provide a double-layer composite structure comprising a chitosan fiber nonwoven fabric layer and a functional layer. The functional layer contains macromolecular chitosan, macromolecular collagen, small molecule collagen, and small molecule chitosan, with a mass ratio of (0.7-1.3):(0.1-0.3):(0.7-1.3):(0.1-0.3).

[0050] Example 5

[0051] This embodiment aims to provide a method for preparing Example 4, the steps of which include:

[0052] Chitosan fiber nonwoven fabric (20×20cm) 2 Pre-freeze at -20℃ for 2 hours.

[0053] Add 1g of macromolecular chitosan, 0.2g of macromolecular collagen, 1g of small molecule collagen and 0.2g of small molecule chitosan to 100mL of weakly acidic aqueous solution and stir until completely dissolved.

[0054] Take out the pre-frozen chitosan nonwoven fabric and quickly and evenly spray the sponge layer material solution onto the nonwoven fabric, with a spray volume of 40ml / 20*20cm. 2 .

[0055] Chitosan nonwoven fabric coated with a sponge layer material solution was frozen at -30°C for 8 hours, and then freeze-dried at -50°C and 10Pa for 24 hours to obtain a double-layer composite dressing.

[0056] Comparative Example 1

[0057] Dissolve 5g of collagen in 100mL of weakly acidic aqueous solution, pour into a mold, freeze-dry, and obtain pure collagen dressing.

[0058] The performance of the dressings prepared in Comparative Examples 1 to 5 and Comparative Example 1 was tested, and the results are shown in the table below:

[0059] Test Project Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Tensile strength (kPa) 85 92 96 88 88 45 Elongation at break (%) 25 28 30 35 35 22 Water absorption ratio (g / g) 22 25 28 30 30 20 <![CDATA[Gas content (g / m 2 ·24 h)]]> 4500 4800 5200 5500 5500 3500 Antibacterial rate (%) 95 98 Cell compatibility excellent excellent excellent excellent excellent good

[0060] Test results show that the composite collagen dressings prepared in each embodiment of the present invention are significantly superior to the pure collagen dressing in Comparative Example 1 in terms of mechanical properties, liquid absorption, and air permeability. In particular, Examples 3 and 4 also exhibit excellent antibacterial properties.

[0061] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0062] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A composite collagen dressing, characterized in that, It includes a body composed of a dual-layer composite structure, which comprises a chitosan fiber nonwoven fabric layer and a functional layer.

2. The composite collagen dressing according to claim 1, characterized in that, The functional layer comprises the following components (in percentage): collagen 12%-15%, regenerated cellulose 28%-32%, heparan sulfate 6%-8%, sodium alginate 3.2%-3.8%, hydroxyapatite 2%-2.5%, and plasticizer 38.7%-49.8%; The collagen includes macromolecular collagen and small molecule collagen, and the mass ratio of macromolecular collagen to small molecule collagen is (0.7-1.3):(0.7-1.3).

3. The composite collagen dressing according to claim 2, characterized in that, The regenerated cellulose is obtained by treating the plant fiber with a mixed aqueous solution of lithium hydroxide and urea, followed by oxidative modification with sodium periodate.

4. The composite collagen dressing according to claim 2, characterized in that, The heparan sulfate and the collagen are cross-linked by a cross-linking agent, which is an EDC / NHS cross-linking solution.

5. The composite collagen dressing according to claim 1, characterized in that, The functional layer comprises macromolecular chitosan, macromolecular collagen, small molecule collagen, and small molecule chitosan, with a mass ratio of (0.7-1.3):(0.1-0.3):(0.7-1.3):(0.1-0.3).

6. The composite collagen dressing according to claim 1, characterized in that, The skin-friendly surface of the functional layer is coated with a layer of polycaprolactone drug-loaded microspheres, which are loaded with antibacterial agents or growth factor drugs.

7. A method for preparing a dressing, used to prepare the composite collagen dressing according to any one of claims 1-6, characterized in that, The method includes the following steps: S01. The plant fiber is crushed and mixed with sodium hydroxide solution. The resulting wet powder is filtered and added to a mixed aqueous solution of lithium hydroxide and urea. After dispersion, it is placed at -20°C. After thawing, carbomer, sodium citrate and glutaraldehyde are added and stirred to obtain a regenerated cellulose solution. S02. Add sodium periodate to the regenerated cellulose solution, adjust the pH to 2-3, stir the reaction in the dark to obtain a modified cellulose solution; S03. Add collagen to the modified cellulose solution, adjust the pH to 6-7, and after the reaction, add N,N-dimethylacrylamide, plasticizer and calcium alginate to obtain a uniformly dispersed mixed dispersion. S04. The mixed dispersion is injected into a mold, frozen at -20°C for 5 hours, and then freeze-dried at -50°C and 10Pa for 24 hours to obtain a composite collagen dressing.

8. The composite collagen dressing according to claim 7, characterized in that, After step S04 is completed, the freeze-dried composite collagen dressing is vacuum thermally cross-linked at 110-125°C for 48-72 hours, and then heparan sulfate is added to the EDC / NHS cross-linking solution for secondary cross-linking for 12-36 hours. After washing, it is freeze-dried a second time.

9. A composite collagen dressing according to claim 7, characterized in that, In step S03, after adding N,N-dimethylacrylamide, plasticizer and calcium alginate, hydroxyapatite and gluconolactone also need to be added. The amount of hydroxyapatite added is 1-15g per 100mL of water, and the amount of gluconolactone added is 2-5g per 100mL of water.

10. A composite collagen dressing according to claim 7, characterized in that, The method further includes preparing a bilayer composite structure: after pre-freezing the chitosan fiber nonwoven fabric, a sponge layer material solution containing macromolecular chitosan, macromolecular collagen, small molecule collagen and small molecule chitosan is sprayed onto the pre-frozen nonwoven fabric, and then freeze-dried.