Composite recombinant collagen protein repair-promoting hydrogel
By combining recombinant collagen hydrogels with thermosensitive polymers and cross-linking components, the problems of mismatched composition, easy oxidation, weak adhesion, and degradation of existing collagen hydrogels are solved, achieving a highly efficient wound repair effect.
Patent Information
- Application Number
- CN202611467821.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-09-21
- Publication Date
- 2026-11-03
AI Technical Summary
Existing collagen hydrogels cannot simulate the real extracellular matrix environment in which type I and type III collagen coexist in human skin. They have insufficient mechanical strength, poor adhesion, are easily oxidized and inactivated, lack synergistic anti-inflammatory and antibacterial effects, and their degradation cycle does not match the wound healing process.
The product utilizes a composite recombinant collagen hydrogel containing recombinant human type I and type III collagen. Thermosensitive polymers and cross-linked components form a dual network structure. Combined with antioxidant and bioactive auxiliaries, it provides antioxidant, antibacterial, and repair-promoting effects. It is designed as an injectable, thermosensitive phase-change hydrogel.
It achieves a repair effect consistent with the skin matrix, enhances adhesion and mechanical properties, protects collagen activity, regulates the wound microenvironment, matches the degradation cycle, and promotes wound healing.
Smart Images
Figure CN123024203A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biomedical materials technology, specifically to a composite recombinant collagen repair-promoting hydrogel. Background Technology
[0002] As we all know, the skin, as the largest barrier organ in the human body, is extremely susceptible to wound damage caused by factors such as abrasions, minimally invasive surgery, cosmetic laser treatments, and burns. The wound repair process involves multiple physiological processes, including protein deposition, cell migration and proliferation, and inflammation regulation. An ideal wound dressing needs to have good biocompatibility, suitable mechanical properties, and wound adhesion ability, while maintaining a moist wound environment, reducing the risk of infection, and accelerating tissue repair.
[0003] Currently, collagen-based hydrogel dressings on the market still have many shortcomings: First, the single-type recombinant collagen component makes it difficult to simulate the real extracellular matrix environment where type I and type III collagen coexist in human skin, resulting in limited cell-induced repair effects. Second, ordinary temperature-sensitive hydrogels have low mechanical strength, making them prone to flow and displacement after being applied to the wound, resulting in poor adhesion to the wound. Third, collagen is highly susceptible to oxidative denaturation during sterilization and storage, leading to a significant decrease in protein activity. Fourth, most hydrogels only achieve physical coverage, lacking synergistic effects of antioxidation, antibacterial, and anti-inflammatory properties, and cannot simultaneously regulate the inflammatory microenvironment of the wound. Fifth, the gel degradation cycle and the skin healing cycle are poorly matched; either the degradation is too rapid, resulting in premature loss of active substances, or degradation residues cause local foreign body reactions. Summary of the Invention
[0004] (a) Technical problems to be solved
[0005] To address the shortcomings of existing technologies, this invention provides a composite recombinant collagen repair hydrogel that solves the problems of existing collagen hydrogels, such as collagen ratios not matching the skin matrix composition, easy protein oxidation and inactivation, weak adhesion to wounds, insufficient mechanical properties, lack of anti-inflammatory and antibacterial synergistic effects, and mismatch between degradation cycle and wound healing. This invention provides an injectable, temperature-sensitive phase-change, dual-network cross-linked medical repair hydrogel that integrates moisturizing, anti-oxidation, antibacterial, and repair-promoting effects.
[0006] (II) Technical Solution
[0007] The above-mentioned technical objective of the present invention is achieved through the following technical solution: a composite recombinant collagen repair hydrogel, comprising a gel raw material, the gel raw material comprising composite recombinant collagen, temperature-sensitive polymer, cross-linking component, antioxidant auxiliaries, bioactive auxiliaries, moisturizing and soothing component and water, wherein the composite recombinant collagen is composed of recombinant human type I collagen and recombinant human type III collagen in a mass ratio of 2:1. The gel raw material is flowable at room temperature and hardens rapidly upon contact with human body temperature, and can be adsorbed and locked onto the wound surface to promote wound repair.
[0008] By weight percentage, the contents of each component of the gel raw material are as follows: 1.5-4 wt% recombinant collagen, 16-22 wt% thermosensitive polymer, 0.3-1.2 wt% crosslinking component, 0.2-0.8 wt% antioxidant, 0.1-0.6 wt% bioactive agent, 1-3 wt% moisturizing and soothing component, and the balance being water.
[0009] Furthermore, the thermosensitive polymer is a compound of poloxamer 407 and poloxamer 188 in a mass ratio of 7-9:1, and the phase transition temperature of the hydrogel is set at 33-36℃, which is close to the temperature of the human body surface.
[0010] Using the above technical solution, poloxamer 407 provides the main temperature-sensitive gelling ability, while poloxamer 188 regulates the phase transition temperature to avoid premature gelation at room temperature. After being applied / injected onto the skin surface, it can quickly change from a liquid state to a solid gel upon contact with the body surface temperature, making it suitable for use on various wounds on the body surface.
[0011] Furthermore, the crosslinking component is composed of genipin and β-cyclodextrin in a mass ratio of 1:2, forming a dual-network structure that combines physical crosslinking and dynamic chemical crosslinking.
[0012] Using the above technical solution, β-cyclodextrin can form host-guest physical cross-links with temperature-sensitive polymers, while genipin, as a natural low-toxicity cross-linking agent, undergoes chemical cross-linking with collagen amino groups. The dual network synergistically enhances the mechanical strength of the gel after molding. At the same time, the cross-linking is dynamically reversible, ensuring that the gel has a certain degree of flexibility, follows the deformation of the skin, and will not crack.
[0013] Furthermore, the antioxidant is a compound of vitamin C derivative and tea polyphenols in a mass ratio of 2:1, used to protect the bioactivity of recombinant collagen and resist protein oxidative denaturation during preparation, sterilization and storage.
[0014] Using the above technical solution, vitamin C derivatives scavenge reactive oxygen species in the system, tea polyphenols synergistically resist oxidation, inhibit the oxidative breakage of collagen peptide chains, reduce the probability of collagen inactivation during γ-ray sterilization and long-term storage, and retain the cell proliferation-promoting activity of collagen.
[0015] Furthermore, the bioactive adjuvant is a compound of mussel adhesive protein and hyaluronic acid oligosaccharides in a 1:1 mass ratio, used to enhance the adhesion of the gel to the wound surface, promote cell adhesion and proliferation, and provide a mild antibacterial effect.
[0016] The moisturizing and soothing component is a compound of panthenol and trehalose in a mass ratio of 1:2, which is used to maintain a moist microenvironment on the wound and relieve redness and inflammation.
[0017] Using the above technical solution, mussel adhesive protein provides a wet surface adhesion effect similar to that of mussels, allowing the gel to adhere closely to the exudative wound surface. Hyaluronic acid oligosaccharides regulate inflammation and promote fibroblast migration, panthenol promotes epithelial regeneration, and trehalose stabilizes the protein structure, reducing redness, swelling, and stinging pain in the wound.
[0018] Furthermore, the gel material hardens rapidly within 10-60 seconds after contact with body temperature, with a molding compression modulus of 5-22 kPa. After molding, it adheres to the wound surface and is not easily flowed or detached. The gel material has a gradient porous structure with a surface pore size of 20-50 μm and an internal pore size of 80-150 μm.
[0019] Using the above technical solution, the surface microporous structure can reduce the rapid evaporation of wound moisture and block the invasion of foreign objects and bacteria, while the internal macroporous structure facilitates the absorption of wound exudate and provides space for cell ingrowth. The 5-22kPa modulus is matched with the mechanics of skin and soft tissue, resulting in high comfort during use.
[0020] Furthermore, the degradation cycle of the gel raw material is 7-14 days, which matches the skin wound healing cycle. The degradation process can continuously release the compound recombinant collagen and active additives.
[0021] Using the above technical solution, the gel gradually degrades as the wound heals, eliminating the need for frequent dressing changes. The active substances are released slowly, continuously promoting the repair effect, and no gel residue that is difficult to remove is produced.
[0022] Furthermore, the gel material is an injectable sterile preparation sterilized by gamma rays, suitable for repairing skin wounds such as superficial abrasions, post-minimally invasive surgery, post-laser surgery barrier damage, and superficial second-degree burns.
[0023] The present invention also provides a method for preparing the composite recombinant collagen repair-promoting hydrogel, comprising the following steps:
[0024] S1. Low-temperature pre-dissolution: Poloxamer 407 and Poloxamer 188 are dissolved in purified water at 4℃ with stirring, and fully swollen for 12-16 hours to obtain a temperature-sensitive polymer matrix solution.
[0025] S2. Preparation of active ingredients: Add the compound recombinant collagen, antioxidant, bioactive additives, and moisturizing and soothing components sequentially to the above matrix solution, and stir at low temperature and low speed to avoid protein denaturation caused by high-speed shearing.
[0026] S3. Add cross-linking components: Add genipin and β-cyclodextrin premixed to the system, stir evenly at 4°C, and allow to stand at 4°C to remove bubbles.
[0027] S4. Dispensing and Sterilization: Dispense the degassed liquid gel into smaller portions, sterilize it by gamma irradiation with an irradiation dose of 20-25 kGy, and store it at 4°C in the dark to obtain the finished injectable hydrogel.
[0028] (III) Beneficial Effects
[0029] Compared with the prior art, the present invention provides a composite recombinant collagen repair-promoting hydrogel with the following beneficial effects:
[0030] This composite recombinant collagen repair hydrogel uses a 2:1 blend of recombinant human type I and type III collagen to mimic the composition of the natural skin extracellular matrix. Compared with single collagen, it is more conducive to the adhesion and migration of fibroblasts, thus promoting skin tissue regeneration and repair at the matrix level.
[0031] This composite recombinant collagen repair hydrogel adopts a dual-network cross-linking system, with physical cross-linking of thermosensitive polymer host and guest + chemical cross-linking of genipin. After molding, it has a compression modulus of 5-22 kPa and excellent mechanical properties. It can be rapidly molded at body temperature in 10-60 seconds and can also adhere firmly to wet wounds without easily flowing or falling off.
[0032] This composite recombinant collagen repair hydrogel, combined with an antioxidant auxiliaries, significantly reduces collagen oxidative denaturation during sterilization and storage, effectively extending the active preservation time of collagen in the hydrogel;
[0033] This is a composite recombinant collagen repair hydrogel that incorporates bioactive additives and moisturizing and soothing components. It combines wound adhesion, mild antibacterial properties, anti-inflammatory and soothing effects, maintains a moist healing microenvironment for the wound, and relieves redness and stinging. It is suitable for various wounds such as post-medical aesthetic procedures, abrasions, and superficial second-degree burns.
[0034] This is a composite recombinant collagen repair hydrogel. The gel has a gradient porous structure. The surface pores block external pollution, while the internal macropores absorb wound exudate. It can be controlled to degrade in 7-14 days, matching the skin wound healing cycle. The degradation process continuously releases active ingredients. It is fluid at room temperature and can be injected or applied topically, making it convenient to use. Attached Figure Description
[0035] Figure 1 This is an overall structural diagram of a composite recombinant collagen repair-promoting hydrogel according to the present invention;
[0036] Figure 2 This is a schematic diagram of the structure of the novel partial component of the present invention;
[0037] Figure 3 This is a schematic diagram of the structure of the composite recombinant collagen of the present invention.
[0038] In the diagram: 1. Gel raw material; 101. Composite recombinant collagen; 1011. Recombinant human type I collagen; 1012. Recombinant human type III collagen; 102. Temperature-sensitive polymer; 103. Crosslinking component; 104. Water; 2. Antioxidant. Detailed Implementation
[0039] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. 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 skilled in the art without creative effort are within the scope of protection of the present invention.
[0040] Example 1
[0041] A composite recombinant collagen repair-promoting hydrogel, with the following components by mass percentage:
[0042] Recombinant collagen (recombinant human type I: recombinant human type III = 2:1) 2.5 wt%
[0043] Thermosensitive polymer (poloxamer 407:poloxamer 188=8:1) 19wt%;
[0044] Crosslinking component (genipin:β-cyclodextrin = 1:2) 0.7wt%;
[0045] Antioxidant auxiliaries (vitamin C derivatives: tea polyphenols = 2:1) 0.5 wt%
[0046] Bioactive adjuvant (mussel adhesive protein: hyaluronic acid oligosaccharide = 1:1) 0.3wt%;
[0047] Moisturizing and soothing ingredients (panthenol: trehalose = 1:2) 2wt%
[0048] Add purified water to bring the total to 100 wt%.
[0049] Preparation method:
[0050] S1. At a low temperature of 4℃, poloxamer 407 and poloxamer 188 were added to purified water, stirred and dispersed, and then allowed to stand at 4℃ for 14 hours to swell, thus obtaining a clear temperature-sensitive polymer matrix.
[0051] S2. Keep the system at 4°C, and add the compound recombinant collagen, antioxidant aid, bioactive aid, and moisturizing and soothing components in sequence. Mix evenly at low speed, and control the stirring speed at 150 rpm to avoid shearing and high temperature damage to the protein.
[0052] S3. Add the premixed genipin-β-cyclodextrin crosslinking component to the system, stir at 4°C for 30 min to mix, and let stand for 40 min to remove bubbles.
[0053] S4. Aseptic packaging, sterilization by 22kGy γ-ray irradiation, and storage at 4°C in the dark to obtain the injectable liquid hydrogel product.
[0054] Please see Figures 1-3 In this embodiment, the gel is a flowable liquid at room temperature (25°C); it undergoes phase transition hardening at 34.5°C for 32 seconds, with a molding compressive modulus of 13 kPa, a microscopic surface pore size of 25-40 μm, and an internal pore size of 90-130 μm; the in vitro degradation period is 10 days; after sterilization, the collagen activity retention rate is 86%, and it has a mild inhibitory effect on Staphylococcus aureus. In an animal model of full-thickness skin defect, the wound healing rate is 92% on day 10.
[0055] The working principle of this embodiment is as follows: At room temperature, the gel raw material 1 is a flowable liquid that can be applied to the wound by smearing or injection. When it comes into contact with the human body surface at a temperature of 33-36°C, the temperature-sensitive polymer 102 undergoes micelle aggregation. With the help of the dual network effect of the cross-linking component 103, it solidifies and forms a shape in a short time. The gradient porous structure absorbs the exudate from the wound. The bioactive adjuvant 105 achieves adhesion to the wound surface. The antioxidant component 104 protects the protein activity of the composite recombinant collagen 101. As the wound heals, the gel gradually degrades, continuously releasing active substances such as recombinant human type I collagen 1011, recombinant human type III collagen 1012, and hyaluronic acid oligosaccharides, which regulate inflammation, promote cell migration and proliferation, and accelerate skin repair.
[0056] Example 2
[0057] A composite recombinant collagen repair-promoting hydrogel, with the following components by mass percentage:
[0058] Recombinant collagen (recombinant human type I: recombinant human type III = 2:1) 1.5 wt%
[0059] Thermosensitive polymer (poloxamer 407:poloxamer 188=7:1) 16wt%;
[0060] Crosslinking component (genipin:β-cyclodextrin = 1:2) 0.3 wt%;
[0061] Antioxidant adjuvant (vitamin C derivative: tea polyphenols = 2:1) 0.2wt%;
[0062] Bioactive adjuvant (mussel adhesive protein: hyaluronic acid oligosaccharide = 1:1) 0.1 wt%
[0063] Moisturizing and soothing ingredients (panthenol: trehalose = 1:2) 1wt%
[0064] Add purified water to bring the total to 100 wt%.
[0065] The preparation method is the same as in Example 1.
[0066] Performance testing: Phase transition temperature 35.2℃, molding time 48s, compressive modulus 6kPa, degradation period 7 days, suitable for mild barrier damage after laser surgery.
[0067] The working principle of this embodiment is as follows: the system remains liquid under low temperature conditions. When applied to the damaged skin after laser treatment, the surface temperature triggers a phase change and solidification. The gel flexibly adheres to the thin damaged wound, providing rapid moisturizing and soothing. It degrades synchronously with the barrier repair in about 7 days.
[0068] A composite recombinant collagen repair-promoting hydrogel, with the following components by mass percentage:
[0069] Compound recombinant collagen (recombinant human type I: recombinant human type III = 2:1) 4wt%;
[0070] Thermosensitive polymer (poloxamer 407:poloxamer 188=9:1) 22wt%;
[0071] Crosslinking component (genipin:β-cyclodextrin = 1:2) 1.2 wt%;
[0072] Antioxidant adjuvant (vitamin C derivative: tea polyphenols = 2:1) 0.8wt%
[0073] Bioactive adjuvant (mussel adhesive protein: hyaluronic acid oligosaccharide = 1:1) 0.6 wt%;
[0074] Moisturizing and soothing ingredients (panthenol: trehalose = 1:2) 3wt%
[0075] Add purified water to bring the total to 100 wt%.
[0076] The preparation method is the same as in Example 1.
[0077] Performance testing: Phase change temperature 33.1℃, rapid molding in 14s, compression modulus 21kPa, degradation cycle 14 days, suitable for abrasions and superficial second-degree burns with a lot of exudate.
[0078] The working principle of this embodiment is as follows: The higher content of temperature-sensitive polymer and cross-linking components gives the gel higher mechanical strength, making it less likely to disintegrate in the face of burns and abrasions with large exudates. It slowly degrades over 14 days to continuously supply collagen active ingredients.
[0079] This specific embodiment is merely an explanation of the present invention and is not intended to limit the invention. Those skilled in the art can make modifications to this embodiment without contributing any inventive step after reading this specification. Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A composite recombinant collagen repair-promoting hydrogel, comprising gel raw material (1), characterized in that: The gel material (1) contains composite recombinant collagen (101), thermosensitive polymer (102), cross-linking component (103), antioxidant (2), bioactive agent, moisturizing and soothing component and water (104). The composite recombinant collagen (101) is composed of recombinant human type I collagen (1011) and recombinant human type III collagen (1012) in a mass ratio of 2:
1. The gel material (1) is fluid at room temperature and hardens rapidly after contact with human body temperature. It can adsorb and adhere to the wound surface and promote wound repair. By mass percentage, the contents of each component of the gel raw material (1) are as follows: 1.5-4wt% of recombinant collagen (101), 16-22wt% of thermosensitive polymer (102), 0.3-1.2wt% of cross-linking component (103), 0.2-0.8wt% of antioxidant auxiliary agent (2), 0.1-0.6wt% of bioactive auxiliary agent, 1-3wt% of moisturizing and soothing component, and the balance is water (104).
2. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The thermosensitive polymer (102) is a compound of poloxamer 407 and poloxamer 188 with a mass ratio of 7-9:
1. The phase transition temperature of the water (104) gel is set at 33-36℃, which is close to the temperature of the human body surface.
3. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The crosslinking component (103) is composed of genipin and β-cyclodextrin in a mass ratio of 1:
2. The crosslinking component (103) forms a dual network structure combining physical crosslinking and dynamic chemical crosslinking.
4. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The antioxidant auxiliary (2) is a compound of vitamin C derivative and tea polyphenols in a mass ratio of 2:
1. It is used to protect the bioactivity of recombinant collagen and resist protein oxidative denaturation during preparation, sterilization and storage.
5. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The bioactive adjuvant is a compound of mussel adhesive protein and hyaluronic acid oligosaccharides in a 1:1 mass ratio. It is used to enhance the adhesion of the gel to wound surfaces, promote cell adhesion and proliferation, and provide a mild antibacterial effect. The moisturizing and soothing component is a compound of panthenol and trehalose in a mass ratio of 1:2, which is used to maintain a moist microenvironment on the wound and relieve redness and inflammation.
6. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The gel material (1) hardens rapidly in 10-60 seconds after contact with body temperature, and the molding compression modulus is 5-22 kPa. After molding, it adheres to the wound surface and is not easy to flow or fall off. The gel material (1) has a gradient porous structure with a surface pore size of 20-50 μm and an internal pore size of 80-150 μm.
7. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The degradation cycle of the gel raw material (1) is 7-14 days, which matches the skin wound healing cycle. The degradation process can continuously release the compound recombinant collagen (101) and active additives.
8. The composite recombinant collagen repair-promoting hydrogel according to claim 1, characterized in that: The gel material (1) is an injectable sterile preparation sterilized by gamma rays, suitable for repairing skin wounds such as superficial abrasions, post-minimally invasive surgery, post-laser surgery barrier damage, and superficial second-degree burns.