Artificial periosteum suitable for complex bone surface and preparation method of artificial periosteum

Abstract

The invention relates to an artificial periosteum suitable for a complex bone surface. The artificial periosteum is an integrated single-layer membrane. The artificial periosteum is provided with an anti-adhesion area, a directional pore channel structure area and a bone contact area which are sequentially distributed in the thickness direction. The directional pore channels are sequentially filled with composite hydrogel for filling bone surface pores and promoting bone repair and bonding gel for bonding bone surfaces in the extending direction of the directional pore channels; an expanding agent and prestretching memory polymer fibers are dispersed in a matrix of the artificial periosteum; the expanding agent is enriched in the matrix of the directional pore channel structure area and the bone contact area and is used for driving the composite hydrogel to leave the directional pore channel so as to seal bone surface gaps or cracks; and the pre-stretched memory polymer fibers are enriched in the matrix of the anti-adhesion area and are used for limiting the expansion direction of the expanding agent. The artificial periosteum can solve the technical problems that in the prior art, the attaching effect of the artificial periosteum on the complex bone surface is poor, and the long-term reliability is poor.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of bone repair technology, and particularly relates to an artificial bone membrane suitable for complex bone surfaces and a preparation method thereof. BACKGROUND

[0002] Bone defects, especially irregular and complex-shaped bone defects caused by severe trauma, tumor resection or infection, are major challenges in clinical orthopedic and maxillofacial surgical reconstruction. An ideal repair strategy not only needs to fill the volume of the defect, but also needs to restore the original contour, mechanical support and biological function of the bone in a complex anatomical site.

[0003] Autologous bone grafting is considered as the "gold standard", but its source is limited, and it will cause secondary damage to the donor site and complications. Therefore, the development of biomaterials that can guide bone tissue regeneration has become a research focus. Among them, the artificial bone membrane, as a functional barrier covering the surface of the bone defect, aims to simulate the key role of the natural bone membrane, to provide guidance and protection for bone regeneration, and has received extensive attention. However, the existing artificial bone membrane has certain defects in achieving reliable initial fit and long-term functional stability when dealing with complex three-dimensional bone surfaces such as the spine and the pelvic bone:

[0004] Firstly, in the prior art, in order to make the artificial bone membrane have the functions of anti-adhesion, bone fixation and the like, a multi-layer composite membrane is a common design strategy, however, the superposition of functional layers of different materials often leads to a relatively thick overall thickness and low flexibility of the membrane body. When applied to curved or complex-shaped bone defects, such a relatively thick and insufficiently flexible membrane body is difficult to deform sufficiently to fit the subtle undulations of the bone surface, and it is easy to produce gaps or "cavities" that are not closely fitted at the membrane-bone interface, which not only weakens the initial mechanical fixation effect of the artificial bone membrane, may cause the artificial bone membrane to shift or partially fall off, and more importantly, forms a "repair dead space" that cannot be quickly filled with new tissue after surgery, which seriously hinders cell migration, nutrient exchange and bone repair process, and may cause slow bone repair, and in severe cases, may even cause complications. Moreover, when a multi-layer structure is used, the continuity between different material layers cannot be achieved at a high level, and there is often a relatively obvious bonding interface, which is easy to cause delamination and other problems after the artificial bone membrane is used for a certain period of time or degrades, resulting in premature failure of the membrane and poor reliability.

[0005] Although there are also single-layer film structure artificial bone membranes in the prior art (such as homogeneous cast bone membranes or electrospinning non-woven bone membranes), they can achieve good standards in thickness and flexibility, but their structures cannot be differentiated in space, and their functional integration is insufficient, which is difficult to meet the needs of complex bone surfaces for artificial bone membranes with multiple functions, such as difficult to achieve directional drug release and selective barrier while ensuring strong adhesion and high strength. This insufficient functional integration also makes it difficult to provide long-term, stable and efficient repair guidance for complex bone defects in a dynamic physiological environment.

[0006] Therefore, there is an urgent need for an artificial bone membrane with high flexibility, which can adapt to complex bone surface morphology, achieve initial close fitting, and have long-term and stable effects during bone repair. It is of great significance for the clinical repair of irregular bone defects. SUMMARY

[0007] (1) Technical problems to be solved

[0008] In view of the above shortcomings and deficiencies of the prior art, the present application provides an artificial bone membrane suitable for complex bone surfaces, which solves the technical problems of poor fitting effect and poor long-term reliability of artificial bone membranes for complex bone surfaces in the prior art.

[0009] (2) Technical solutions

[0010] In order to achieve the above-mentioned purpose, the main technical solutions adopted by the present application include:

[0011] In a first aspect, the present application provides an artificial bone membrane suitable for complex bone surfaces, which is a single-layer film; the artificial bone membrane has an anti-adhesion region, a directional pore structure region and a bone contact region distributed in turn in the thickness direction;

[0012] The bone contact region is located on the side that fits the bone surface;

[0013] The directional pore structure region has directional pores extending from the anti-adhesion region to the bone contact region, and the pore size of the directional pores shows an increasing trend along the extension direction;

[0014] In the directional pores, a composite hydrogel for filling bone surface pores and promoting bone repair and an adhesive gel for bonding the bone surface are filled in turn along the extension direction of the directional pores;

[0015] The matrix of the artificial bone membrane is dispersed with an expanding agent and a pre-stretched memory polymer fiber; the expanding agent is enriched in the matrix of the directional pore structure region and the bone contact region, and is used to swell and drive the composite hydrogel out of the directional pores to close the bone surface gap or crack after contacting body fluid; the pre-stretched memory polymer fiber is enriched in the matrix of the anti-adhesion region, and is used to contract to limit the expansion direction of the expanding agent and continuously apply a fitting pressure to the bone contact region under the trigger of body temperature.

[0016] According to a preferred embodiment of the present invention, the thickness of the artificial bone membrane is not more than 1 mm; the porosity of the anti-adhesion region is less than 10%, and the porosity of the bone contact region is not less than 50%; the surface of the bone contact region is also coated with an adhesive gel.

[0017] According to a preferred embodiment of the present invention, the expanding agent is a high molecular weight polymer with a volume swelling rate of not less than 400% and a swelling equilibrium time of 3-12h; the expanding agent is blended or dispersed in the matrix of the directional pore structure region and the bone contact region in the form of microspheres; when the expanding agent is dispersed in the form of microspheres, the particle size of the microspheres does not exceed 25 micrometers.

[0018] According to a preferred embodiment of the present invention, the pre-stretched memory polymer fiber is a short-cut fiber with a length of 50μm–1000μm and a diameter of 1μm–20μm; the pre-stretching ratio of the pre-stretched memory polymer fiber is 100%–200%, the triggering temperature is 36–42℃; the shape recovery rate after triggering is not less than 85%, the recovery stress is 0.1–1.0MPa, and the half-recovery time is 2–10h.

[0019] According to a preferred embodiment of the present invention, the outer surface of the bone contact area is also covered with an adhesive gel; both the adhesive gel and the matrix of the artificial periosteum contain a first hydrogel matrix polymer;

[0020] By weight, the matrix material of the artificial bone membrane includes 80-120 parts of film-forming substrate, 4-16 parts of pre-stretched memory polymer fiber, 15-35 parts of expansion agent, and 10-20 parts of first hydrogel matrix polymer.

[0021] The filling amount of the adhesive gel is 8%-20% of the total weight of the matrix, and the filling amount of the composite hydrogel is 10% to 35% of the total weight of the matrix.

[0022] The first hydrogel matrix polymer is a composition of at least one of polydopamine, gelatin-modified dopamine, and sodium alginate-modified dopamine with graphene oxide.

[0023] All of the above raw materials can be degraded in human body fluids, and in human body fluids, the degradation half-life of the pre-stretched memory polymer fiber is less than or equal to the degradation half-life of the film-forming substrate.

[0024] According to a preferred embodiment of the present invention, the film-forming substrate is at least one selected from polylactic acid (PLA), polylactic acid, polycaprolactone, polyglycolic acid, polytrimethylene carbonate, polybutylene succinate, sodium carboxymethyl cellulose, and silk fibroin.

[0025] The polymer material in the pre-stretched memory polymer fiber is at least one of polylactic acid-polyglycolic acid copolymer, polycaprolactone-polyethylene glycol copolymer, polyglycerol sebacic acid-polyethylene glycol copolymer, polyurethane-polylactic acid copolymer, and polyglycolic acid.

[0026] The expanding agent is at least one of carboxymethyl starch, oxidized starch, hydroxypropyl starch, oxidized hyaluronic acid, carboxymethyl chitosan, oxidized sodium alginate, hyperbranched polyglycerol, and polyethylene glycol copolymer.

[0027] According to a preferred embodiment of the present invention, the solidification time of the composite hydrogel in body fluid is not less than 1 hour;

[0028] The raw materials of the composite hydrogel include: 80-120 parts by weight of a second hydrogel matrix polymer and 0.1-5 parts by weight of growth activity factor and / or 5-20 parts by weight of functional additives dispersed therein;

[0029] The growth-active factor is at least one of bone morphogenetic protein, vascular endothelial growth factor, transforming growth factor, and platelet-derived growth factor; the functional additive is at least one of black phosphorus, hydroxyapatite, tricalcium β-phosphate, and bioactive glass.

[0030] The second hydrogel matrix polymer is at least one of dopamine or gallic acid modified gelatin, sodium alginate, and chitosan.

[0031] According to a preferred embodiment of the present invention, the growth-active factor is encapsulated in a sustained-release carrier; the sustained-release carrier is made of at least one of polylactic acid-glycolic acid copolymer, chitosan, sodium alginate, polycaprolactone, gelatin, and liposomes; the diameter of the sustained-release carrier does not exceed 50 micrometers.

[0032] Secondly, the present invention also provides a method for preparing an artificial periosteum as described in any one of the first aspects, comprising the following steps:

[0033] S1: Mix pre-stretched memory polymer fibers, 10%-30% of film-forming substrate and a first solvent to obtain a first coating slurry;

[0034] The remaining film-forming substrate, expanding agent, first hydrogel matrix polymer, and second solvent are mixed to obtain second coating slurry;

[0035] S2: The first coating slurry is coated onto the substrate. After the surface gels, the second coating slurry is immediately coated. After standing for a certain period of time, an integrated wet film is obtained.

[0036] S3: The integrated wet membrane is pore-forming and cured using an induced phase separation method to obtain a base membrane with directional gradient pores;

[0037] S4: Using a vacuum-assisted injection method, the composite hydrogel is filled into the directional channels of the base membrane to obtain a semi-filled base membrane. Using a vacuum-assisted injection method, the precursor of the adhesive gel is filled into the directional channels of the semi-filled base membrane, and cross-linked on one side of the bone contact area to form an adhesive gel, thus obtaining an artificial bone membrane.

[0038] According to a preferred embodiment of the present invention, in S1, the first solvent and the second solvent are at least one of water, dimethyl sulfoxide, acetone, ethyl acetate, ethyl lactate, ethyl levulinate, valerate, and tetrahydrofuran; in S3, the integrated wet film is placed in an environment with a humidity of not less than 80% to perform humidity-induced phase separation and / or mixed solvent-induced phase separation; the curing temperature during curing does not exceed 45°C and the time does not exceed 90 min; in S4, after obtaining the semi-filled base film, it is immersed in the crosslinking agent solution of the composite hydrogel to crosslink and densify the surface of the composite hydrogel, forming a densified barrier layer.

[0039] (III) Beneficial Effects

[0040] The beneficial effects of this invention are as follows: The artificial periosteum of this invention, suitable for complex bone surfaces, utilizes an integrated single-layer membrane with continuous anti-adhesion regions, directional pore structure regions, and bone contact regions along its thickness direction. This effectively avoids the risk of delamination in body fluid environments caused by interlayer bonding defects and degradation rate differences in traditional composite laminated membranes. Compared to existing technologies, it ensures that the artificial periosteum of this invention maintains long-term structural consistency and integrity during long-term stress and tissue ingrowth, exhibiting long-term reliability. Furthermore, since there are no obvious physical delamination interfaces in the structure, the matrix flexibility of this invention is not reduced. The artificial periosteum of this invention as a whole, especially the directional pore structure region and the bone contact region, possesses strong flexibility, enabling better adhesion to complex bone surfaces and improving the adhesion effect.

[0041] Secondly, because this invention also employs a structure with directional channels extending from the anti-adhesion area to the bone contact area and with gradually increasing pore size, and sequentially fills the channels with composite hydrogel and adhesive gel along the extension direction, it can improve the infiltration capacity of tissue fluid through the directional, gradient channel structure and effects such as capillary action, and ensure that the two different types of gel can be filled and released in an orderly manner. Compared with the prior art, it can effectively prevent the loss of active ingredients used to repair bone during the initial fixation stage, and ensure that the bone regeneration process takes place at a stable interface, thereby improving the efficiency of bone repair.

[0042] Furthermore, this invention also utilizes the expansion stress generated by the expansion agent after absorbing body fluids (mainly water) as an active driving force to push the functional gel in the channels towards the bone surface and press it into the bone contact area and the bone surface gap that may exist between the bone contact area and the bone surface, as well as the micro-cracks that may exist on the bone surface, thereby avoiding problems such as dead space. This invention also constrains the overall deformation effect of the artificial periosteum by restricting the expansion direction and range of the membrane through the contraction of the pre-stretched memory polymer fibers triggered by body temperature. This contraction improves the extrusion effect of the composite hydrogel and deforms the bone contact area to better adapt to and contact the bone surface. At the same time, it can also work synergistically with the expansion agent to guide the expansion stress generated by the expansion agent. By continuously applying continuous stress to the bone through the bone contact area, compared with the prior art, the artificial bone surface of this invention can actively adapt to complex bone surface morphology, achieve long-term tight mechanical fitting, and maintain dynamic interfacial compressive stress during the bone healing period. While promoting bone healing, it significantly improves the mechanical strength, initial fixation strength and long-term stability of the artificial periosteum.

[0043] Finally, this invention also employs a method of stepwise coating to form a component gradient, followed by induced phase separation to create pores and then curing. This enables the simultaneous formation of the spatial gradient distribution of functional components within a single-layer membrane and the interconnected pore structure, allowing for the formation of interfaces without physical separation between functional regions and achieving a continuous gradient transition between components and pore structure. Furthermore, this invention utilizes a vacuum-assisted potting process for sequential filling, ensuring precise spatial positioning and complete filling of the two functional gels within complex pores, thereby reliably achieving the designed sequential functional release. Attached Figure Description

[0044] Figure 1 This is a schematic diagram of the structure of the artificial periosteum in Embodiment 1 of the present invention.

[0045] [Explanation of Labels in the Attached Image]

[0046] 1: Anti-adhesion area; 2: Directional channel structure area; 3: Bone contact area; 4: Directional channel; 5: Composite hydrogel; 6: Adhesive gel; 7: Expanding agent; 8: Sustained-release carrier. Detailed Implementation

[0047] To better explain and facilitate understanding of the present invention, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0048] This invention provides an artificial periosteum suitable for complex bone surfaces, such as... Figure 1As shown, it is an integrated, continuous single-layer membrane. The artificial periosteum of the present invention has an anti-adhesion region 1, a directional pore structure region 2, and a bone contact region 3 distributed sequentially in the thickness direction. The directional pore structure region 2 has directional pores 4 extending from the anti-adhesion region 1 to the bone contact region 3, and the diameter of the directional pores 4 increases along its extension direction, or gradually increases. The anti-adhesion region 1 is located on the side of the artificial periosteum away from the bone surface, and is used to resist adhesion to external soft tissues. The bone contact region 3 is located on the side that adheres to the bone surface, and during use, the artificial periosteum of the present invention contacts the bone, connecting the bone surface to the artificial periosteum. The directional pore structure region 2 is located between the two, and it is the main body of the artificial periosteum of the present invention, providing basic structural strength and providing space for the filling of materials such as composite hydrogel 5. Simultaneously, its directional pore structure can ensure the orderly and effective filling and release of the filling components and guide the infiltration of tissue fluid through capillary action and other effects over a certain length. In addition, the porous structure of the bone contact area 3 and the directional pore structure area 2 can further guide the growth of cells such as osteoblasts, which is beneficial to bone healing.

[0049] Within the directional channel 4, a composite hydrogel 5 for filling bone pores and promoting bone repair, and an adhesive gel 6 for bonding to the bone surface are sequentially filled along its extension direction. Specifically, the composite hydrogel 5 is filled in the deeper internal region of the directional channel 4, and its main function is to release active factors over a long period to promote bone repair. The adhesive gel 6 is filled near the opening of the directional channel 4 (i.e., the bone contact area 3), and its core function is to achieve immediate and strong adhesion between the artificial periosteum of this invention and the bone surface. At the same time, the adhesive gel 6 can also seal the opening of the directional channel 4 to prevent leakage of the composite hydrogel 5. When using the artificial periosteum of this invention, it is first bonded to the bone with the adhesive gel 6 for anchoring. After ensuring that the artificial periosteum is stably attached to the bone surface, the wound is sutured, and the internal composite hydrogel 5 then begins its long-term repair and filling process, effectively avoiding the ineffective loss of repair factors in the initial unstable stage.

[0050] The artificial periosteum contains a swelling agent 7 and pre-stretched memory polymer fibers dispersed in its matrix. The swelling agent 7 is enriched in the matrix of the directional pore structure region 2 and the bone contact region 3, and is used to expand upon contact with body fluids and drive the composite hydrogel 5 away from the directional pores 4 to seal gaps or fissures in the bone surface. The pre-stretched memory polymer fibers are enriched in the matrix of the anti-adhesion region 1, and are used to contract upon temperature triggering to limit the expansion direction of the swelling agent 7 and to continuously apply adhesion pressure to the bone contact region 3.

[0051] Among them, the swelling agent 7 is a high molecular weight polymer with a high volume swelling rate. When it comes into contact with body fluid, or water, the swelling agent 7 will slowly absorb water and swell, generating significant swelling stress in the local matrix. This actively causes the directional pore structure region 2 to expand, reducing the space within the directional pores 4. This gradually pushes the composite hydrogel 5 filled within it outward (towards the bone surface) along the directional pores 4. At the same time, due to the change in the pore size of the directional pores, the expansion will further seal the existing pores in the anti-adhesion region 1, or seal any possible openings of the directional pores 4 on one side of the anti-adhesion region 1, preventing the composite hydrogel 5 from being squeezed out of the anti-adhesion region 1. The extrusion of the expanding agent 7 can further adapt to the shape of the bone surface by changing the stress and volume of the expanding agent 7 in the contact area, thus achieving a better fit. At the same time, the composite hydrogel 5, which is extruded as it expands, can be pressed into the gap between the artificial bone surface and the bone contact area 3, as well as the micro-cracks and irregular pores on the bone defect surface, through the pores formed after the adhesive gel 6 is cured, under the extrusion. This achieves deep mechanical integration and tight sealing, and its filling effect is far superior to traditional methods such as passive diffusion or adhesive application of hydrogel adhesives. It is especially suitable for bone surfaces with complex shapes.

[0052] The pre-stretched memory polymer fiber (hereinafter referred to as memory fiber) is a memory polymer fiber that has been pre-stretched at high temperature and cooled and shaped before implantation. After implantation, triggered by the body temperature, it tends to return to its original length, thereby shrinking. This further generates an overall contractile stress in the entire anti-adhesion area 1, oriented towards the membrane plane. The force generated by the contraction of the memory fiber and the force generated by the expansion of the expansion agent 7 work synergistically. The contractile force of the memory fiber can anchor the basic shape of the artificial bone surface of the present invention and guide the direction of expansion. It counteracts and restrains the tendency of the membrane to deform randomly or warp from the bone surface due to the expansion of the expansion agent 7, forcing the expansion stress to be released more concentratedly along the preset axial direction, i.e., towards the bone surface, ensuring the directionality of the adhesion force, ensuring tight adhesion, and avoiding problems such as slippage. Meanwhile, the contractile force of the memory fiber itself can also serve as a continuous prestress source. After the expansion force is transmitted to the bone contact area 3 through the membrane, it can apply a lasting and uniform compressive stress to the bone surface. This not only enhances the stability of the periosteum of the present invention during further adhesion and ensures the fixation effect, but more importantly, it can dynamically maintain a tight interface contact when the bone tissue undergoes microscopic deformation or absorption during the healing period. This solves the problem of long-term reliability decline caused by loosening of the bonding pressure and promotes bone healing through stress stimulation.

[0053] Furthermore, it should be noted that the description of the "directional channels 4" above aims to clarify the geometric characteristics and functions of its channel structure, which transitions gradually from the dense anti-adhesion region 1 to the porous bone contact region 3. In actual material structures, it may include various forms such as a continuous porous network composed of a large number of micropores oriented in the thickness direction with gradient changes in pore size, vertical or inclined continuous channels, finger-like or clustered channels, etc. Moreover, the directional channels 4 are not completely isolated independent channels; they may have a large number of connecting points. This channel structure is a common and reliable result in phase separation molding processes, and its overall arrangement still conforms to a gradient distribution, without affecting the performance of the directional channels 4. In practical applications, the morphology, number, and connectivity of specific channels may also change depending on the selected film-forming substrate, phase separation process parameters, and methods, as long as the overall structure meets the requirements of pore size gradient change and continuity, porosity, etc., and can achieve the directional filling and driving functions described in this invention.

[0054] Preferably, the thickness of the artificial periosteum does not exceed 1.2 mm, more preferably 1 mm, and even more preferably 0.6-0.9 mm. It is necessary to control the thickness to ensure that the artificial periosteum has sufficient flexibility to conform to irregular / curved bone surfaces under natural conditions or with slight external force, and to ensure that the artificial periosteum can be used to construct directional gradient channels with sufficient depth and structural stability through subsequent phase separation processes, providing sufficient space for functional components (such as expanding agent 7, memory fibers) dispersed or filled in the matrix, thus ensuring the effective realization of their functions. An excessively thick artificial periosteum will reduce flexibility, increase rigidity, and may also lead to poor adhesion or pressure on surrounding tissues; an excessively thin membrane may break during processing or implantation due to insufficient mechanical strength, or may be unable to maintain the integrity of the channel structure or effectively fill the cavity.

[0055] Preferably, the porosity of the anti-adhesion region 1 is greater than that of the bone contact region 3. More preferably, the porosity of the anti-adhesion region 1 is no more than 10%, and the porosity of the bone contact region 3 is no less than 40%, and more preferably 50%. The surface of the bone contact region 3 is also coated with adhesive gel 6. The anti-adhesion region 1 has a low-porosity, dense structure, which physically blocks soft tissues such as fibroblasts and connective tissue, preventing them from growing in rapidly. At the same time, its relatively dense structure can also effectively prevent the composite hydrogel 5 in the directional channels 4 from leaking out of the anti-adhesion region 1. The directional channel structure region 2, with its higher porosity on the side closer to the bone, together with the bone contact region 3, forms an open, high-porosity three-dimensional network. This high-porosity structure provides a large specific surface area and space for bone tissue, facilitating the adhesion and migration of osteoprogenitor cells and the deposition of extracellular matrix, and promoting the ingrowth of new bone tissue into it, forming a mechanical interlock and realizing the biointegration of the artificial periosteum with the host bone. At the same time, maintaining a high porosity on the side in contact with the bone can ensure the efficient exchange of nutrients, oxygen and metabolic waste, and maintain an active bone regeneration microenvironment.

[0056] Preferably, the swelling agent 7 is a high molecular weight polymer with a volume swelling rate of not less than 400% and a swelling equilibrium time of 3-12 hours. The high volume swelling rate of the swelling agent 7 ensures that it generates a sufficiently large volume change and expansion stress after absorbing water, enabling it to drive matrix deformation and allow the functional gel to move and fill the gaps between the bone surfaces. Simultaneously, controlling the swelling equilibrium time of the swelling agent 7 within 3 to 12 hours ensures that its expansion process matches the early stage of bone healing. This ensures that in the early post-implantation period, typically when the inflammatory response begins to weaken and repair cells begin to be recruited, the expansion-driven process is essentially complete, allowing the composite hydrogel 5 to be extruded in a timely manner, delivering and fixing its active ingredients, or drugs, to the bone surface, promoting bone repair, and avoiding problems such as stress impact due to excessively rapid expansion or treatment delays due to excessively slow expansion.

[0057] More preferably, the volume swelling rate of the expanding agent 7 is 400%-800%, more preferably 500%-600%. This ensures that the expanding agent 7 can provide sufficient driving effect while avoiding excessive volume expansion caused by excessive swelling rate (such as exceeding 800%), which could generate excessive instantaneous stress on the polymer matrix, increase matrix microcracks, cause excessive expansion displacement leading to excessively fast movement speed of the filling gel, and insufficient integration with the bone surface structure. This ensures the effectiveness and reliability of the entire extrusion-filling process.

[0058] Preferably, the expanding agent 7 is dispersed in the matrix of the oriented pore structure region 2 and the bone contact region 3 in the form of molecular chain blends and / or in the form of pre-crosslinked polymer microspheres. When the expanding agent 7 is dispersed in the form of microspheres, the particle size of the microspheres does not exceed 25 micrometers.

[0059] In practical applications, appropriate dispersion forms can be selected based on different performance requirements such as swelling range control and stress transfer efficiency. For example, dispersion using pre-crosslinked polymer microspheres facilitates more precise and independent swelling control. When dispersed using molecular chain blending, the polymer chains of the expanding agent 7 and the molecular chains of the film-forming substrate can be blended in solution and form an interpenetrating or tightly bonded interface structure during subsequent curing, achieving efficient and direct transfer of expansion stress from the expanding agent 7 phase to the matrix material. Considering the actual situation of complex bone surfaces and avoiding problems such as stress weak points, more preferably, the expanding agent 7 is dispersed through molecular chain blending to ensure the mechanical reliability of the artificial bone membrane of the present invention during expansion.

[0060] Preferably, the pre-stretched memory polymer fiber is a chopped fiber. By using chopped fibers, it is ensured that the memory fiber can be uniformly dispersed in the corresponding raw material slurry and the final cured matrix, and function as a distributed prestressed network.

[0061] Preferably, the length of the pre-stretched memory polymer fiber is 50μm–1000μm, more preferably 100μm–500μm, and the diameter is 1μm–20μm, more preferably 5μm–10μm, to ensure that the memory fiber has a sufficient aspect ratio to effectively bear and transmit stress, while avoiding entanglement due to excessive fiber length, which would affect the uniformity of film formation.

[0062] Preferably, the pre-stretch ratio of the pre-stretched memory polymer fiber is 100%-200%, the shape recovery rate after triggering is not less than 85%, and the recovery stress is 0.1-1.0 MPa. This provides sufficient deformation and ensures that the memory fiber can generate significant shrinkage strain in the matrix of the artificial periosteum, while avoiding breakage or plastic damage due to excessive stretching or excessive shrinkage stress. It also ensures that the memory fiber can provide sufficient continuous compressive stress to maintain close adhesion without causing compressive damage to newly formed tissue.

[0063] Preferably, the triggering temperature of the pre-stretched memory polymer fiber is 36-42℃, and the half-recovery time is 2-10 hours. The memory fiber needs to recover slowly after triggering and adapt to the expansion time of the expanding agent 7 to ensure its synergistic effect with the expanding agent 7. Furthermore, it should be noted that the memory fiber can be made to shrink slowly after triggering by adjusting the modification ratio of the pre-stretched memory polymer fiber, the triggering temperature, etc. For example, setting the triggering temperature to 38-40℃ can achieve slow triggering and shrinkage in a human body environment of 36-37℃. Specific adjustments are not detailed in this invention.

[0064] Preferably, the outer surface of the bone contact area 3 is also covered with adhesive gel 6, which, in conjunction with the adhesive gel 6 in the pores, forms a continuous and uninterrupted adhesion interface, ensuring effective initial adhesion. At the same time, it should be noted that the thickness of the adhesive gel 6 on the outer surface of the bone contact area 3 should not be too thick, preferably not exceeding 0.1 mm, to avoid slippage of the artificial periosteum.

[0065] Preferably, both the adhesive gel 6 and the matrix of the artificial periosteum contain a first hydrogel matrix polymer. Specifically, the first hydrogel matrix polymer in the matrix is ​​enriched in the directional pore structure region 2 and the bone contact region 3. The first hydrogel matrix polymer is an adhesive component used to impart an adhesive effect between the adhesive gel 6 and the matrix. The combination of the two allows the first hydrogel matrix polymer in the matrix to undergo molecular chain interdiffusion, entanglement, or cross-linking with the first hydrogel matrix polymer in the adhesive gel 6, thereby forming a strong and tough bonding interface between the adhesive gel 6 and the matrix. This ensures that when the expanding agent 7 expands and generates driving pressure, the matrix can effectively transfer stress to the entire membrane, pushing the bone contact region 3 towards the bone surface, rather than squeezing or peeling the adhesive gel 6 itself from the pore interface. This ensures a continuous adhesive effect and further avoids slippage problems.

[0066] Preferably, by weight, the matrix material of the artificial bone membrane includes 80-120 parts of film-forming substrate, 4-16 parts of pre-stretched memory polymer fiber, 715-35 parts of expansion agent, and 10-20 parts of first hydrogel matrix polymer.

[0067] In this process, the film-forming substrate serves as the continuous phase, forming the main structure of the artificial bone membrane matrix and ensuring its basic strength and processability. By controlling the addition ratio of pre-stretched shape memory polymer fibers, an effective shrinkage network is formed without excessively increasing the membrane stiffness or affecting phase separation and pore formation due to excessive content. The amount of expanding agent 7 is controlled to ensure sufficient and controllable driving force. The stability of the bonding effect is ensured by controlling the amount of the first hydrogel matrix polymer.

[0068] Preferably, in human body fluids, the degradation half-life of the pre-stretched memory polymer fiber is less than or equal to the degradation half-life of the film-forming substrate. The degradation half-life of the expander 7 in body fluids is greater than or equal to the degradation half-life of the film-forming substrate. This ensures that both have a relatively fast degradation rate, enabling rapid degradation and providing space for the growth of structures such as bones and blood vessels.

[0069] More preferably, in human body fluids, the degradation half-life of the pre-stretched memory polymer fibers does not exceed half the degradation half-life of the film-forming substrate. This ensures that after the memory fibers provide contractile force and guide expansion in the early stages of healing, they can preferentially begin to degrade before the main structure of the artificial periosteum. The micropores or channels left after the memory fibers degrade can further promote the overall biodegradability of the membrane, especially the anti-adhesion region 1, and improve the wetting effect of body fluids on the artificial periosteum of the present invention. While providing more space for the ingrowth of new tissue, it can also ensure that the bone in the interstitial areas receives sufficient nutrients, avoiding problems such as slower bone healing in the central area.

[0070] In addition, the faster degradation rate can also avoid problems such as stress shielding caused by shrinking memory fibers and artificial periosteum under their influence, and avoid unnecessary mechanical effects or interference to tissues by residual memory fibers that have completed their task in the mid-to-late stages of bone healing when the new bone has begun to bear the load.

[0071] The amount of adhesive gel 6 is 8%-20% of the total weight of the matrix (this weight includes adhesive gel 6 on the outer surface of the bone contact area 3 and adhesive gel 6 in the directional channels 4), to ensure that it can form a complete and appropriately thick strong adhesion interface in the bone contact area 3, and to avoid problems such as excessive gel overflow or excessively thick interface layer caused by excessive filling amount, which would hinder the function of the porous structure of the bone contact area and affect its internal curing quality.

[0072] The filling amount of the composite hydrogel 5 is 10% to 35% of the total weight of the matrix. It is necessary to ensure that the bioactive ingredients loaded with the composite hydrogel 5 are sufficient to exert their effects during the repair period through appropriate loading, and to avoid the problem that a large amount of composite hydrogel 5 will occupy the pore space excessively, thereby avoiding the generation of excessive internal stress during extrusion and weakening the interfacial bonding effect.

[0073] More preferably, by weight, the adhesive gel 6 comprises 80-120 parts of the first hydrogel matrix polymer and 0.1-10 parts of an anti-inflammatory drug. The anti-inflammatory drug is at least one of a non-steroidal anti-inflammatory drug, a natural anti-inflammatory active molecule (antimicrobial peptide), and an antibiotic. The anti-inflammatory drug addresses potential postoperative inflammation and other problems. Of course, the addition of an anti-inflammatory drug is only a preferred option. In practice, other methods can be used to apply the anti-inflammatory drug to the fracture site without affecting the adhesion of the artificial periosteum. Alternatively, the anti-inflammatory drug may not be applied, and inflammation can be eliminated through oral medication or other means.

[0074] The aforementioned matrix materials, adhesive gel 6, and composite hydrogel 5 can all be degraded in human body fluids.

[0075] Preferably, the first hydrogel matrix polymer is a composition of at least one of polydopamine, gelatin-modified dopamine, and sodium alginate-modified dopamine with graphene oxide. Dopamine or its modified derivatives provide a strong wet adhesion effect, while graphene oxide further enhances the structural strength, toughness, and stability of the matrix. The hydrophilicity of graphene oxide ensures the wetting effect of body fluids and the swelling effect of the swelling agent 7. Furthermore, graphene oxide itself can promote osteogenic differentiation and angiogenesis. The ratio of dopamine or its modified derivatives to graphene oxide is adjusted according to actual needs to ensure the adhesion and hydrophilicity-related effects.

[0076] Preferably, the film-forming substrate is at least one selected from polylactic acid (PLA), polylactic acid, polycaprolactone, polyglycolic acid, polytrimethylene carbonate, polybutylene succinate, sodium carboxymethyl cellulose, and silk fibroin. More preferably, it is one selected from polylactic acid (PLA), polylactic acid, polycaprolactone, polyglycolic acid, and polytrimethylene carbonate.

[0077] The polymer material in the pre-stretched memory polymer fiber is at least one of polylactic acid-polyglycolic acid copolymer, polycaprolactone-polyethylene glycol copolymer, polyglycerol sebacate-polyethylene glycol copolymer, polyurethane-polylactic acid copolymer, and polyglycolic acid.

[0078] The expanding agent 7 is at least one of carboxymethyl starch, oxidized starch, hydroxypropyl starch, oxidized hyaluronic acid, carboxymethyl chitosan, oxidized sodium alginate, hyperbranched polyglycerol, and polyethylene glycol copolymer.

[0079] The film-forming substrate, the polymer material in the pre-stretched memory polymer fiber, and the swelling agent 7 are selected from one or more of the various biodegradable biomaterials listed above. Of course, the above materials are only some preferred choices in this invention. In actual implementation, the selection, combination, and ratio of specific materials can be optimized and adjusted according to the healing cycle of the target bone defect, the specific requirements for membrane flexibility or strength, and the process adaptability. As long as the selected materials can synergistically achieve the matrix structure integrity, body temperature triggered contraction function, and efficient swelling driving function required by this invention, and meet the basic requirements of biocompatibility and biodegradability.

[0080] Preferably, the solidification time of the composite hydrogel 5 in body fluid is not less than 1 hour, more preferably not less than 3 hours. Specifically, it is necessary to ensure that the composite hydrogel 5 has a relatively slow solidification rate in body fluid, to ensure that the composite hydrogel 5 maintains good fluidity when extruded, to ensure that it can effectively fill the gaps between bone surfaces, and to ensure that during vacuum perfusion, the precursor of the hydrogel has sufficient time to fully wet and fill the depth of the directional channels 4, achieving uniform loading.

[0081] Preferably, the composite hydrogel 5 comprises: 80-120 parts by weight of a second hydrogel matrix polymer and 0.1-5 parts by weight of growth-active factors and / or 5-20 parts by weight of functional additives dispersed therein. The second hydrogel matrix polymer is the main component of the composite hydrogel 5, used to fill the bone surface gaps and provide a carrier for the growth-active factors and / or functional additives, enabling them to diffuse along with the second hydrogel matrix polymer.

[0082] The growth-active factor is at least one of bone morphogenetic protein, vascular endothelial growth factor, transforming growth factor, and platelet-derived growth factor, used to regulate related cell behaviors and promote bone growth and healing. The functional additive is at least one of black phosphorus, hydroxyapatite, β-tricalcium phosphate, and bioactive glass, used to provide a scaffold for bone healing and related ion stimulation.

[0083] The proportions of growth-active factors and functional additives should be adjusted according to actual needs to ensure the bone healing-related effects.

[0084] The second hydrogel matrix polymer is at least one of dopamine, gallic acid or modified gelatin, sodium alginate modified with dopamine or gallic acid, and chitosan modified with dopamine or gallic acid. By modifying with dopamine or gallic acid, the solidification time of natural polysaccharide polymers can be controlled on the basis of biodegradability, so as to ensure that the composite hydrogel 5 can slowly solidify in body fluid and be filled and bonded.

[0085] More preferably, the second hydrogel matrix polymer also includes graphene oxide.

[0086] Preferably, the growth-active factors are encapsulated in the sustained-release carrier 8. The sustained-release carrier 8 is made of at least one of polylactic-co-glycolic acid copolymer, chitosan, sodium alginate, polycaprolactone, gelatin, and liposomes. The diameter of the sustained-release carrier 8 does not exceed 50 micrometers. Encapsulating the growth factors in the micrometer- or nanometer-scale sustained-release carrier 8, and then cooperating with the sustained-release carrier 8 through a hydrogel network formed after the composite hydrogel 5 is cured, allows the growth-active factors to be released uniformly, for a longer period, and in a controlled manner along the hydrogel network after leaving the sustained-release carrier 8. This further adapts to the long-term bone repair process and prevents the bioactive factors from being decomposed, dissolved, or inactivated in the early stages of processing and implantation.

[0087] The specific ratio of these two bioactive factors in the sustained-release microspheres should be determined based on the actual situation, as long as it can ensure the bone repair effect.

[0088] When the artificial bone membrane of the present invention is used, it can be fixed by itself through the adhesive gel 6 on it and achieve a good fixation effect. Of course, in actual operation, in order to ensure the stability of the connection and fixation, if the bone condition allows, it can also be further fixed by methods such as membrane nails, sutures or biological adhesives.

[0089] This invention also provides a method for preparing an artificial periosteum suitable for complex bone surfaces, comprising the following steps:

[0090] S1: Mix pre-stretched memory polymer fibers, 10%-30% of film-forming substrate and a first solvent to obtain a first coating slurry.

[0091] The remaining film-forming substrate, expanding agent 7, first hydrogel matrix polymer, and second solvent are mixed to obtain second coating slurry.

[0092] S2: Apply the first coating slurry to the substrate, wait for the surface to gel, and then immediately apply the second coating slurry. Let it stand for a certain period of time to obtain an integrated wet film.

[0093] S3: The integrated wet membrane is pore-forming and cured using an induced phase separation method to obtain a base membrane with directional gradient pores.

[0094] S4: Using a vacuum-assisted injection method, the composite hydrogel 5 is filled into the directional channels 4 of the base membrane to obtain a semi-filled base membrane. Using a vacuum-assisted injection method, the precursor of the adhesive gel 6 is filled into the directional channels 4 of the semi-filled base membrane, and crosslinked on one side of the bone contact area 3 to form the adhesive gel 6, thus obtaining an artificial bone membrane.

[0095] Preferably, in S1, the first solvent and the second solvent are water and / or organic solvents; the organic solvent is preferably at least one selected from dimethyl sulfoxide, acetone, ethyl acetate, ethyl lactate, ethyl levulinate, valproic acid, and tetrahydrofuran (2-methyltetrahydrofuran). It should be noted that when using organic solvents, they must be thoroughly removed in subsequent processes to ensure their suitability for human use.

[0096] Preferably, in S1, the composition of the first solvent can be the same as or different from that of the second solvent, and the different components in the solvent can be adjusted according to the selected phase separation method.

[0097] More preferably, in S1, the first solvent contains at least one of the same components as the second solvent, further ensuring that in S2, the first and second coating slurries can fully diffuse after coating to form an integrated film structure.

[0098] More preferably, the solid content of the first coating slurry is greater than that of the second coating slurry, further ensuring phase separation and effective formation of the gradient structure of the directional channels 4. The specific solid content is determined according to actual needs, as long as it ensures the coating effect.

[0099] Preferably, in step S1, to ensure uniform dispersion of components such as memory fibers and avoid agglomeration, a combination of mechanical stirring and ultrasonic treatment is used for mixing to ensure the formation of a uniform, stable slurry without obvious particles or fiber clumps. More preferably, in step S1, the stirring speed is 500-1000 rpm, the ultrasonic power is 200W, the frequency is 30-50KHz, and the treatment time is 5-15 minutes to ensure uniform dispersion.

[0100] Preferably, in S1, the pre-stretched memory polymer fiber is a short fiber obtained by pre-stretching the corresponding fiber material to form a long fiber and then cutting the long fiber.

[0101] Preferably, in S1, a conventional glass substrate or plastic substrate can be selected as the substrate.

[0102] In addition, the area covered by the first coating can be slightly larger than that covered by the second coating to provide redundant space and ensure the stability of the subsequently formed membrane structure. The excess portion can be removed later or used as a redundant fixing surface during implantation, reducing the potential impact of structures such as membrane staples.

[0103] Specifically, in S2, after the first coating slurry is applied, it is left to stand for a certain period of time until the surface of the first coating slurry gels or solidifies, but the interior is not yet solidified or still retains fluidity. Then, the second coating slurry is immediately applied. The resulting wet film is then left to stand at room temperature with a relative humidity of 40%-60% for 30-120 seconds or longer. During this standing process, the gelled surface in contact with the second coating slurry will swell or partially dissolve to a certain extent, causing the solvent molecules and polymer molecules at the interface of the two slurries to diffuse and flow with each other. This achieves molecular interpenetration and integration between the two materials, resulting in a continuous interface without visible gaps, effectively preventing problems such as interlayer delamination of the artificial bone membrane.

[0104] More preferably, in S2, surface gelation refers to the state in which a gel skin forms on the surface of the slurry due to solvent evaporation. The specific time for gelation can be determined by methods such as contact angle change and surface viscosity testing. The specific settling time may also vary depending on the coating thickness, material composition, and ratio, requiring confirmation based on actual process conditions, but it is generally within the range of 30-180 seconds. In actual operation, an empirical method can also be used: after the film surface has essentially lost its fluidity, it is determined by lightly touching it with a finger or other object; if the surface does not separate and its internal cross-section still maintains fluidity.

[0105] The proportion of film-forming substrate used in the first coating slurry in S1 and the overall thickness of the wet film coated in S2 also need to be selected according to actual needs, which will not be elaborated in this invention.

[0106] It should be noted that in S3, the composite hydrogel 5 is a hydrogel with a low degree of cross-linking, or rather, a precursor of the uncross-linked composite hydrogel 5, to ensure its strong fluidity and ensure full filling.

[0107] Preferably, in step S3, the integrated wet membrane is placed in a constant temperature and humidity environment with a humidity of not less than 80% to perform humidity-induced phase separation and / or mixed solvent-induced phase separation. More preferably, humidity-induced phase separation and mixed solvent-induced phase separation are used (when using mixed solvent-induced phase separation, both the first and second solvents need to include water and an organic solvent miscible with water). In a high-humidity environment, the solvent in the wet membrane, especially hydrophilic solvents such as acetone, exchanges with and evaporates water molecules in the environment, thereby inducing phase separation of the wet membrane. The polymer-rich phase, or the region where the solvent evaporates quickly, solidifies densely, forming the anti-adhesion region 1. The solvent-rich phase, or the region where the solvent evaporates slowly, forms a large number of gradient pores, forming the directional pore structure region 2 and the bone contact region 3. Simultaneously, the use of mixed solvents can generate further gradients within the material, and by differentiating the evaporation rates, the accurate and uniform formation of the directional gradient pores is ensured.

[0108] During the phase separation process, the orientation, pore size gradient, and connectivity of the pores can be further controlled by adjusting parameters such as humidity gradient, temperature (usually room temperature), and time (usually 2-6 hours), which will not be elaborated in this invention.

[0109] In step S3, curing is performed after phase separation. Curing can be carried out using methods such as hot air drying or vacuum drying. It should be noted that curing can also be achieved by adding photocurable components or modifying the relevant raw materials, and then curing via photocuring. This will not be elaborated upon in this invention.

[0110] Preferably, in S3, when hot air drying and curing is used, the curing temperature does not exceed 45°C, more preferably does not exceed 35°C, and the time does not exceed 90 minutes, to prevent the memory fiber from undergoing a large amount of shape recovery during the manufacturing stage.

[0111] Preferably, in step S3, after drying and curing, the organic solvent in the base film is removed by further vacuum drying or other methods.

[0112] In step S4, specifically, the obtained base film is placed in a container and mixed with the precursor solution of the composite hydrogel 5 or the low-crosslinked composite hydrogel 5. A vacuum-assisted casting method is used. First, a vacuum is drawn and maintained at a negative pressure of -0.095MPa to -0.1MPa for 10-30 minutes to remove the air in the pores. Then, the vacuum is slowly released, and atmospheric pressure is used to press the precursor solution of the composite hydrogel 5 or the low-crosslinked composite hydrogel 5 into and completely fill the oriented pores 4. The base film is then removed, and excess material on the surface is removed (cleaned) to obtain a semi-filled base film.

[0113] In step S4, after obtaining the semi-filled base film, it is immersed in the crosslinking agent solution of the composite hydrogel 5 (such as a solution containing genipin, calcium ions or photoinitiator, the specific concentration and composition are determined according to the actual composition of the composite hydrogel 5) for 1-5 minutes, so that the surface of the composite hydrogel 5 is rapidly crosslinked and densified to form a dense barrier layer, which protects the incompletely crosslinked composite hydrogel 5 inside, ensuring that the composite hydrogel 5 can be effectively extruded in the future, and preventing the subsequent injection of the adhesive gel 6 precursor from mixing with the internal composite hydrogel 5 in large quantities, and preventing it from being pressed out of the pores in the future, ensuring that the two maintain a relatively independent layered structure in the pores.

[0114] In S4, after forming a dense barrier layer, the membrane is cleaned, and then the semi-filled base membrane is placed into the container. Using the same vacuum-assisted injection method, the precursor of the adhesive gel 6 or the low-crosslinked adhesive gel 6 is filled into the directional channel 4, and the composite hydrogel 5 is completely squeezed into the depth of the directional channel 4. The adhesive gel 6 on one side of the bone contact area 3 is cured according to the selected curing method. If ionic crosslinking is used, the bone contact area 3 can be placed downwards and immersed in the corresponding crosslinking agent solvent (such as a crosslinking agent solution of genipin, calcium ions, etc.). After cleaning, the filling and attachment of the adhesive gel 6 are completed, and the artificial bone membrane of the present invention is obtained.

[0115] The precursor solution of the composite hydrogel 5 or the low-crosslinking composite hydrogel 5 is obtained by mixing 5-15 parts of the second hydrogel matrix polymer, 80-120 parts of water, 0.1-5 parts of growth activity factor (if there is a sustained-release carrier 8, the weight part includes the sustained-release carrier 8) and / or 5-20 parts of functional additives.

[0116] More preferably, the precursor solution of the composite hydrogel 5 or the low-crosslinking composite hydrogel 5 is subjected to a shear rate of 10 / s (or 10 s) at 25°C. -1 The viscosity at the specified temperature should not exceed 1000 mPa·s to ensure good subsequent flowability.

[0117] The precursor of adhesive gel 6 or the low-crosslinked adhesive gel 6 is obtained by mixing 15-30 parts of the first hydrogel matrix polymer, 100-220 parts of water and 1-5 parts of anti-inflammatory drug (if any).

[0118] More preferably, the precursor of the adhesive gel 6 or the low-crosslinking adhesive gel 6 has a viscosity of not less than 4000 mPa·s at 25°C and a shear rate of 0.1 / s, ensuring that it can effectively fill and continuously adhere to the bone contact area 3.

[0119] In actual operation, after obtaining the artificial bone membrane of the present invention, release films can be set on both sides to encapsulate the artificial bone membrane of the present invention for easy storage and use.

[0120] Furthermore, it is understood that the above operations should be performed in a sterile environment, and all raw materials used should be sterile and medical-grade.

[0121] To better understand the above technical solutions, exemplary embodiments of the present invention will be described in more detail below with reference to the accompanying drawings. Although exemplary embodiments of the present invention are shown in the drawings, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided so that the present invention can be understood more clearly and thoroughly, and that the scope of the present invention can be fully conveyed to those skilled in the art.

[0122] Example 1

[0123] This embodiment provides an artificial periosteum suitable for complex bone surfaces and its preparation method, such as... Figure 1As shown, the thickness of the artificial periosteum is 0.85±0.05 mm, the porosity of the anti-adhesion region 1 is 8±2%, and the porosity of the bone contact region 3 is 55±2%. The pore size of the directional channel structure region 2 increases from 5-15 μm in the anti-adhesion region 1 to 70-90 μm in the bone contact region 3. The matrix material of the artificial periosteum includes 100 parts of polycaprolactone, 8 parts of polylactic acid-polyglycolic acid copolymer memory fiber, 25 parts of carboxymethyl starch microspheres (particle size 10-25 μm), and 15 parts of a composition of gelatin-dopamine graft polymer and graphene oxide nanosheets (mass ratio 95:5). Among them, the polylactic acid-glycolic acid copolymer memory fiber has a length of 200±20 μm, a diameter of 10±2 μm, a pre-stretch ratio of 140%-160%, and a trigger temperature range of 38-39℃. The equilibrium swelling rate of the carboxymethyl starch microspheres is 400%.

[0124] The directional pore structure region 2 is filled with composite hydrogel 5 and adhesive gel 6, and the surface of the bone contact region 3 is also covered with adhesive gel 6. The composite hydrogel 5 fills 20% of the total matrix weight, and its raw materials include 12 parts of dopamine-modified gelatin, 100 parts of sterile water, and 0.5 parts of chitosan / sodium alginate composite microspheres loaded with bioactive factors (microsphere average diameter 30 μm). The adhesive gel 6 fills 12% of the total matrix weight, and its raw materials include 25 parts of gelatin-dopamine graft polymer, 180 parts of sterile water, and 1 part of ketoprofen.

[0125] This embodiment also provides a method for preparing an artificial periosteum suitable for complex bone surfaces, comprising the following steps:

[0126] S1: Slurry Preparation: 8 parts of pre-stretched polylactic acid-glycolic acid copolymer chopped fibers and 20 parts of polycaprolactone were added to a first solvent composed of 65 parts of ethyl lactate, 25 parts of acetone, and 10 parts of sterile water, and mixed evenly to obtain the first coating slurry. 80 parts of polycaprolactone, 25 parts of carboxymethyl starch microspheres, and 15 parts of gelatin-dopamine / graphene oxide composite were added to a second solvent composed of 55 parts of ethyl levulinate, 25 parts of acetone, and 20 parts of sterile water, and mixed evenly to obtain the second coating slurry.

[0127] S2: Continuous coating: The first coating slurry is coated onto a clean polytetrafluoroethylene (PTFE) vinyl sheet, with a wet film thickness of 0.3 mm. After standing for 90 seconds at 25°C and 50% relative humidity to allow the surface to gel, the second coating slurry is immediately coated onto it. Then, it is left to stand for 90 seconds under the same conditions to obtain an integrated wet film.

[0128] S3: Gradient pore formation and curing:

[0129] The substrate carrying the integrated wet film was transferred into a constant temperature and humidity chamber at 25°C and 95% relative humidity, and allowed to stand for humidity-induced phase separation and mixed solvent-induced phase separation. After 4 hours, it was transferred to a 35°C circulating hot air oven for curing and drying for 60 minutes. After curing, it was vacuum dried and continuously dried at 30°C for 72 hours to remove the solvent, thus obtaining a base film with oriented gradient channels.

[0130] S4: Vacuum Sequential Injection and Crosslinking: The base membrane with oriented gradient channels is placed in a container with a composite hydrogel 5 precursor at the bottom. A first vacuum injection is performed, with the vacuum level evacuated to -0.095 MPa and maintained for 20 minutes. The vacuum is then slowly released, allowing the gel precursor to permeate into the channels. The base membrane is removed, cleaned, and excess liquid is absorbed with filter paper, resulting in a semi-filled base membrane. The semi-filled base membrane is immersed in a 0.5% (w / w) genipin aqueous solution for 2 minutes, then removed and cleaned. A second vacuum injection is performed, injecting the adhesive gel 6 precursor into the remaining space of the channels and the surface of the bone contact area 3. The membrane is then placed with the bone contact area 3 facing down and immersed in a 1% (w / w) genipin aqueous solution for 60 seconds for crosslinking and curing. After cleaning, the artificial bone membrane of this embodiment is obtained.

[0131] After obtaining the artificial periosteum of this embodiment, its performance is tested. The testing method includes the following steps:

[0132] 1. Sample Preparation and Processing: Take fresh pig femoral condyles and prepare several bone pieces with irregular curved surfaces and natural trabecular bone structures. Cut the artificial periosteum of this embodiment to the same size, attach it tightly to the surface of the moist pig bone pieces, and press lightly for 30 seconds to complete the initial adhesion.

[0133] 2. Simulated immersion: The bone fragment sample with the membrane attached was completely immersed in a simulated body fluid at a constant temperature of 37°C for 3 days.

[0134] 3. Adhesion Strength Test: After soaking, the samples were removed and subjected to a 90-degree peel test. The peeling rate was 10 mm / min, and the peeling strength was recorded and averaged as the peeling strength of the artificial periosteum in this embodiment. Several other samples after soaking were cut perpendicular to the bone surface, and the gap ratio (or porosity) between the artificial periosteum and the bone was scanned and calculated by computer, and the average value was calculated as the gap ratio of the artificial periosteum in this embodiment. The gap ratio is calculated as: Gap ratio = Total gap area / Total contact surface area, where the contact surface is the area between the bone surface and the bone contact area; the gap is the gap in the contact surface. Specific parameters for peel strength and gap ratio are shown in Table 1.

[0135] Example 2

[0136] This embodiment provides an artificial periosteum suitable for complex bone surfaces and its preparation method. The difference from Embodiment 1 is that the thickness of the artificial periosteum is 1.0 ± 0.05 mm. Testing was performed using the same method as in Embodiment 1, and specific parameters are shown in Table 1.

[0137] Example 3

[0138] This embodiment provides an artificial periosteum suitable for complex bone surfaces and its preparation method. The difference from Example 1 is that the pre-stretching ratio of polylactic acid-polyglycolic acid copolymer memory fiber is 170%-190%, and the equilibrium swelling rate of carboxymethyl starch microspheres is 500%. The test was conducted according to the same method as in Example 1, and the specific parameters are shown in Table 1.

[0139] Example 4

[0140] This embodiment provides an artificial periosteum suitable for complex bone surfaces and its preparation method. The difference from Embodiment 1 is that the porosity of the anti-adhesion region 1 is 5±2%, and the porosity of the bone contact region 3 is 65±2%. The composite hydrogel 5 fills 22% of the total matrix weight, and the adhesive gel 6 fills 14% of the total matrix weight. In the preparation method, in S1, the first solvent includes 70 parts ethyl lactate, 20 parts acetone, and 10 parts sterile water. The second solvent includes 50 parts ethyl levulinate, 20 parts acetone, and 30 parts sterile water. In S3, the relative humidity is 99%. Testing was conducted using the same method as in Embodiment 1; specific parameters are shown in Table 1.

[0141] Example 5

[0142] This embodiment provides an artificial periosteum suitable for complex bone surfaces and its preparation method. The difference from Embodiment 1 is that the pre-stretching ratio of the memory fiber is 170%-190%, and the equilibrium swelling rate of the expanding agent 7 is 500%. The composite hydrogel 5 fills 22% of the total matrix weight, and the adhesive gel 6 fills 14% of the total matrix weight. The porosity of the anti-adhesion region 1 is 5±2%, and the porosity of the bone contact region 3 is 65±2%. In the preparation method, in S1: S1: Slurry preparation: The first solvent includes 70 parts ethyl lactate, 20 parts acetone, and 10 parts sterile water. The second solvent includes 50 parts ethyl levulinate, 20 parts acetone, and 30 parts sterile water. In S3, the relative humidity is 99%. Testing was conducted using the same method as in Embodiment 1; specific parameters are shown in Table 1.

[0143] Comparative Example 1

[0144] This comparative example provides an artificial periosteum and its preparation method, which differs from Example 1 in that its matrix does not contain carboxymethyl starch microspheres. Tests were performed using the same method as in Example 1, and specific parameters are shown in Table 1.

[0145] Comparative Example 2

[0146] This comparative example provides an artificial periosteum and its preparation method, which differs from Example 1 in that its matrix does not contain polylactic acid-polyglycolic acid copolymer memory fibers. Tests were conducted using the same method as in Example 1, and specific parameters are shown in Table 1.

[0147] Comparative Example 3

[0148] This comparative example provides an artificial periosteum and its preparation method. The difference from Example 1 is that in S2, after standing for 300 seconds to allow the surface of the first coating slurry to cure, a second coating slurry is applied. Testing was conducted using the same method as in Example 1, and specific parameters are shown in Table 1.

[0149] Table 1: Peel strength and gap ratio of the artificial bone membrane of the present invention after bonding

[0150]

[0151] According to the experimental results in Table 1, the memory fiber and the expansion agent 7 in the integrated gradient structure of Example 1 work together to achieve a good benchmark level in terms of peel strength and gap sealing, and can fill the gaps in the bone surface very well.

[0152] Compared to Example 1, Example 2 has a higher gap ratio because the increased film thickness reduces the material's flexibility and adaptability to irregular bone surfaces, resulting in a lower bonding pressure transmission efficiency, a slight decrease in peel strength and gap sealing effect.

[0153] Compared to Example 1, Example 3 enhances shrinkage stress and expansion driving force by increasing the pre-stretch ratio of memory fiber and the swelling rate of expansion agent 7, thereby synergistically improving active bonding and filling capabilities, significantly increasing peel strength, and further reducing gap ratio.

[0154] Compared to Example 1, Example 4, by optimizing the solvent ratio and increasing the phase separation humidity, obtained a base film structure with a more significant pore gradient and stronger connectivity, which is more conducive to the complete filling of the composite hydrogel 5 and the adhesive gel 6, significantly improving the interfacial gap ratio and correspondingly increasing the peel strength.

[0155] Compared to Example 1, Example 5 combines the stronger stress and driving force of Example 3, the optimized structure of Example 4, and more composite hydrogels 5 and adhesive gels 6, resulting in better synergistic effects, stronger adhesion and sealing performance, and lower gap ratio.

[0156] Compared to Example 1, Comparative Example 1 lost the function of driving the gel to actively fill because no expanding agent 7 was added, resulting in a large number of unfilled voids at the interface, a sharp increase in the gap ratio, and adhesion that could only rely on the surface adhesive layer, leading to a significant decrease in peel strength.

[0157] Compared to Example 1, Comparative Example 2, lacking the addition of memory fibers, lost the sustained shrinkage prestress triggered by body temperature, making it unable to balance expansion and maintain long-term tight adhesion. This resulted in easy warping and separation at the interface, significantly weakened peel strength, and a higher gap ratio.

[0158] Compared to Example 1, in Comparative Example 3, the first coating slurry was left to stand for too long after application, resulting in excessive curing of the interlayer interface. The molecules could not diffuse and fuse into an integrated structure, forming a weak interface and affecting the stress transfer effect between different functional areas. When the memory fiber shrinks and the expansion agent 7 expands, it may damage the interface, causing a sharp decrease in its overall peel strength and a worse gap sealing effect.

[0159] In summary, the artificial periosteum of the present invention can solve the technical problems of poor adhesion to complex bone surfaces and poor long-term reliability of artificial periosteum in the prior art.

[0160] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. An artificial periosteum suitable for complex bone surfaces, characterized in that, It is an integrated single-layer membrane; the artificial bone membrane has an anti-adhesion region (1), a directional pore structure region (2) and a bone contact region (3) distributed sequentially in the thickness direction; the bone contact region (3) is located on the side that is in contact with the bone surface; the directional pore structure region (2) has directional pores (4) extending from the anti-adhesion region (1) to the bone contact region (3), and the diameter of the directional pores (4) tends to increase along its extension direction; The directional channel (4) is sequentially filled with a composite hydrogel (5) for filling the gaps in the bone surface and promoting bone repair, and an adhesive gel (6) for bonding the bone surface. The artificial periosteum contains a swelling agent (7) and pre-stretched memory polymer fibers dispersed in its matrix. The swelling agent (7) is enriched in the matrix of the directional channel structure region (2) and the bone contact region (3) to expand upon contact with body fluid and drive the composite hydrogel (5) away from the directional channel (4) to seal the gaps or cracks in the bone surface. The pre-stretched memory polymer fibers are enriched in the matrix of the anti-adhesion region (1) to contract under body temperature triggering to limit the expansion direction of the swelling agent (7) and to continuously apply adhesion pressure to the bone contact region (3).

2. The artificial periosteum suitable for complex bone surfaces as described in claim 1, characterized in that, The thickness of the artificial bone membrane is no more than 1 mm; the porosity of the anti-adhesion region (1) is less than 10%, and the porosity of the bone contact region (3) is not less than 50%; the surface of the bone contact region (3) is also coated with the adhesive gel (6).

3. The artificial periosteum suitable for complex bone surfaces as described in claim 1, characterized in that, The expanding agent (7) is a high molecular polymer with a volume swelling rate of not less than 400% and a swelling equilibrium time of 3-12h; the expanding agent (7) is blended or dispersed in the matrix of the directional pore structure region (2) and the bone contact region (3) in the form of microspheres; when the expanding agent (7) is dispersed in the form of microspheres, the particle size of the microspheres does not exceed 25 micrometers.

4. The artificial periosteum suitable for complex bone surfaces as described in claim 1, characterized in that, The pre-stretched memory polymer fiber is a short-cut fiber with a length of 50μm–1000μm and a diameter of 1μm–20μm; the pre-stretching ratio of the pre-stretched memory polymer fiber is 100%–200%, the triggering temperature is 36–42℃; the shape recovery rate after triggering is not less than 85%, the recovery stress is 0.1–1.0MPa, and the half-recovery time is 2–10h.

5. The artificial periosteum suitable for complex bone surfaces as described in claim 1, 3, or 4, characterized in that, The outer surface of the bone contact area (3) is also covered with the adhesive gel (6); both the adhesive gel (6) and the matrix of the artificial bone membrane contain the first hydrogel matrix polymer. By weight, the matrix material of the artificial bone membrane includes 80-120 parts of film-forming substrate, 4-16 parts of pre-stretched memory polymer fiber, 15-35 parts of expansion agent (7) and 10-20 parts of first hydrogel matrix polymer. The amount of adhesive gel (6) is 8%-20% of the total weight of the matrix, and the amount of composite hydrogel (5) is 10% to 35% of the total weight of the matrix. The first hydrogel matrix polymer is a composition of at least one of polydopamine, gelatin-modified dopamine, and sodium alginate-modified dopamine with graphene oxide. All of the above raw materials can be degraded in human body fluids, and in human body fluids, the degradation half-life of the pre-stretched memory polymer fiber is less than or equal to the degradation half-life of the film-forming substrate.

6. The artificial periosteum suitable for complex bone surfaces as described in claim 5, characterized in that, The film-forming substrate is at least one of the following: polylactic acid (PLA), polylactic acid, polycaprolactone, polyglycolic acid, polytrimethylene carbonate, polybutylene succinate, sodium carboxymethyl cellulose, and silk fibroin. The polymer material in the pre-stretched memory polymer fiber is at least one of polylactic acid-polyglycolic acid copolymer, polycaprolactone-polyethylene glycol copolymer, polyglycerol sebacic acid-polyethylene glycol copolymer, polyurethane-polylactic acid copolymer, and polyglycolic acid. The expanding agent (7) is at least one of carboxymethyl starch, oxidized starch, hydroxypropyl starch, oxidized hyaluronic acid, carboxymethyl chitosan, oxidized sodium alginate, hyperbranched polyglycerol, and polyethylene glycol copolymer.

7. The artificial periosteum suitable for complex bone surfaces as described in claim 1, characterized in that, The coagulation time of the composite hydrogel (5) in body fluid is not less than 1 hour; The raw materials of the composite hydrogel (5) include: 80-120 parts by weight of the second hydrogel matrix polymer and 0.1-5 parts by weight of growth activity factor and / or 5-20 parts by weight of functional additives dispersed therein; The growth-active factor is at least one of bone morphogenetic protein, vascular endothelial growth factor, transforming growth factor, and platelet-derived growth factor; the functional additive is at least one of black phosphorus, hydroxyapatite, tricalcium β-phosphate, and bioactive glass. The second hydrogel matrix polymer is at least one of dopamine or gallic acid modified gelatin, sodium alginate, and chitosan.

8. The artificial periosteum suitable for complex bone surfaces as described in claim 7, characterized in that, The growth-active factor is encapsulated in a sustained-release carrier (8); the sustained-release carrier (8) is made of at least one of polylactic acid-glycolic acid copolymer, chitosan, sodium alginate, polycaprolactone, gelatin and liposomes; the diameter of the sustained-release carrier (8) does not exceed 50 micrometers.

9. A method for preparing an artificial periosteum as described in any one of claims 1-8, characterized in that, Includes the following steps: S1: Mix pre-stretched memory polymer fibers, 10%-30% of film-forming substrate and a first solvent to obtain a first coating slurry; The remaining film-forming substrate, the expanding agent (7), the first hydrogel matrix polymer, and the second solvent are mixed to obtain the second coating slurry; S2: The first coating slurry is coated onto the substrate. After the surface gels, the second coating slurry is immediately coated onto the substrate. After standing for a certain period of time, an integrated wet film is obtained. S3: The integrated wet membrane is pore-forming and cured using an induced phase separation method to obtain a base membrane with directional gradient channels; S4: The composite hydrogel (5) is filled into the directional channels (4) of the base membrane by vacuum-assisted injection to obtain a semi-filled base membrane. The precursor of the adhesive gel (6) is filled into the directional channels (4) of the semi-filled base membrane by vacuum-assisted injection to crosslink and form the adhesive gel (6) on one side of the bone contact area (3) to obtain the artificial bone membrane.

10. The preparation method according to claim 9, characterized in that, In S1, the first solvent and the second solvent are at least one of water, dimethyl sulfoxide, acetone, ethyl acetate, ethyl lactate, ethyl levulinate, valerol lactone, and tetrahydrofuran; the solid content of the first coating slurry is greater than the solid content of the second coating slurry. In step S3, the integrated wet film is placed in an environment with a humidity of not less than 80% to perform humidity-induced phase separation and / or mixed solvent-induced phase separation; the curing temperature during curing does not exceed 45°C and the time does not exceed 90 minutes. In S4, after obtaining a semi-filled base film, it is immersed in the crosslinking agent solution of the composite hydrogel (5) to crosslink and densify the surface of the composite hydrogel (5) to form a densified barrier layer.

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