Hydrogel composite material for nose repair and preparation method thereof

Abstract

The invention relates to the technical field of special materials for biomedical additive manufacturing, and discloses a hydrogel composite material for nose repair and a preparation method thereof.The hydrogel composite material comprises surface modified polymer microspheres and a dual-network hydrogel matrix formed by cross-linking methacrylated gelatin and methacrylated hyaluronic acid, a swelling layer is arranged on the surface of the microsphere, a molecular chain entanglement recrystallization interface area is formed between the microsphere and a matrix through molecular chain permeation and in-situ co-crystallization, and the composite material has a mechanical gradient changing along with microsphere content distribution. And meanwhile, the additive manufacturing resolution ratio is improved in cooperation with a photopolymerization inhibition mechanism, and the mechanical property distribution matched with the nose anatomical partition is achieved.

Description

Technical Field

[0001] This invention belongs to the field of special materials technology for biomedical additive manufacturing, and in particular relates to a hydrogel composite material for nasal repair and its preparation method. Background Technology

[0002] Current nasal tissue repair utilizes biomimetic prostheses constructed from specialized materials for biomedical additive manufacturing. The material system consists of a hydrogel matrix and polymer microspheres, designed to simulate the morphology and mechanical environment of natural tissues. The implants must maintain structural integrity under cyclic physiological stress. Modulus distribution is optimized by adjusting the content distribution of polymer microspheres. However, due to the hydrophobicity of polymer microspheres and the high water content of the hydrogel matrix, there is an interfacial stress shielding effect between the rigid reinforcing phase and the flexible continuous phase. Load transfer abruptly occurs at the phase interface, leading to the propagation of interfacial microcracks during the prosthesis's service life.

[0003] Schemes that attempt to optimize macroscopic geometry to improve support performance focus on external physical reinforcement of the structure, but fail to address the contradiction between the stability of the internal interface and mechanical compatibility of the material. For example, Chinese invention patent CN106137455B discloses a craniofacial and nasal repair patch. The longitudinal and transverse reinforcing sheets set on the surface of the substrate form a grid framework, which is guided by a pre-set arc-shaped ridge for manual bending and shaping. The reinforcement method based on the macroscopic rib structure is a physical stacking of heterogeneous materials. When subjected to respiratory and facial movement cyclic loads, the rigid reinforcing sheets and the flexible substrate will experience interfacial shear failure due to the mismatch of elastic modulus. Such solutions rely on macroscopic structure to maintain shape, and cannot achieve a precise gradient distribution of mechanical properties in the anatomical regions of the bridge and tip of the nose. It is difficult to balance the requirements of support strength and flexible deformation. The long-term service of the prosthesis faces the risk of structural delamination or step-like modulus collapse.

[0004] Therefore, the technical problem to be solved by this invention is how to use the osmotic pressure gradient induced by surface modification to induce molecular chain interpenetration and entanglement under mild conditions, construct an interpenetrating network with physical and chemical dual locking, achieve smooth load transfer and ensure the physiological homeostasis of the implant. Summary of the Invention

[0005] This invention provides a hydrogel composite material for nasal repair, comprising: Surface-modified polymer microspheres, comprising 10% of a hydrogel composite material for nasal repair. Up to 40 ; The dual-network hydrogel matrix consists of a mass percentage concentration of 5 Up to 15 Methacrylamide gelatin and a mass percentage concentration of 1 Up to 3 It is formed by cross-linking methacryloyl hyaluronic acid; The surface-modified polymer microspheres have a surface thickness of 50 mm. Up to 100 The swollen layer has a thickness of 150 mm between it and the double-network hydrogel matrix. Up to 300 The molecular chain entanglement recrystallization interface region; The molecular chain entanglement recrystallization interface region contains a molecular chain cooperative entanglement structure extending from the swelling layer to the double network hydrogel matrix side. Furthermore, the molecular chain segments on the surface of the surface-modified polymer microspheres are distributed with in-situ recrystallized crystals using the molecular chain segments of methacryloyl hyaluronic acid as nucleation sites. This forms a modulus transition structure between the surface-modified polymer microspheres and the double network hydrogel matrix, where the elastic modulus decreases in a gradient from the surface of the surface-modified polymer microspheres to the double network hydrogel matrix. The storage modulus of the hydrogel composite material used for nasal repair exhibits a gradient distribution with varying content of surface-modified polymer microspheres, with a storage modulus of 50 in the corresponding nasal bridge repair area. Up to 100 The energy storage modulus in the corresponding nasal tip repair area is 20. Up to 50 ; Furthermore, the hydrogel composite material used for nasal repair also includes a content of 0.1%. Up to 1.0 The photoinitiator and its content is 0.01 Up to 0.05 Thioflavin T.

[0006] Preferably, the surface-modified polymer microspheres are selected from at least one of polycaprolactone microspheres, polylactic acid microspheres, and polylactic acid-glycolic acid copolymer microspheres; the particle size of the surface-modified polymer microspheres is 10. Up to 50 Furthermore, the spatial distribution accuracy deviation of the surface-modified polymer microspheres in the dual-network hydrogel matrix is ​​less than 5%. The surface of the surface-modified polymer microspheres has amino groups introduced through amination treatment, carboxyl groups introduced through alkali treatment, catechol groups introduced through dopamine coating, or methacryloyl groups introduced through silane coupling agent modification; the surface of the surface-modified polymer microspheres also has an average pore size of 300 μm. Up to 500 Anchoring micropores.

[0007] Preferably, the dual-network hydrogel matrix is ​​at 37°C. The equilibrium swelling rate under the environmental conditions is 800. Up to 1200 The network density of methacrylamide gelatin and methacrylamide hyaluronic acid in the cross-linked state is positively correlated with the thickness of the interface region of molecular chain entanglement and recrystallization, which can be used to achieve synergistic deformation between surface-modified polymer microspheres and dual-network hydrogel matrix under dynamic breathing load.

[0008] Preferably, the hydrogel composite material used for nasal repair is a porous solid with three-dimensional interconnected pores and an average pore size of 100. Up to 300 Porosity is 60 Up to 85 The three-dimensional interconnected pores are jointly constructed by the interlayer overlap gaps in the additive manufacturing process and the occupancy effect of the surface-modified polymer microspheres.

[0009] Preferably, the hydrogel composite material for nasal repair generates a molecular chain entanglement recrystallization interface region through the following steps: Step S101, utilizing the osmotic pressure gradient between the swollen layer and the dual-network hydrogel matrix solution, drives the methacryloyl hyaluronic acid molecular chains to penetrate into the amorphous region of the surface-modified polymer microspheres; Step S102, at 60 Under heat treatment conditions, the molecular chain segments on the surface of the surface-modified polymer microspheres are transformed into a semi-molten state and undergo synergistic entanglement with the infiltrated methacrylamide hyaluronic acid molecular chains; step S103, with 1 Up to 5 The cooling rate induces in-situ recrystallization of the entangled molecular chain segments.

[0010] Preferably, the hydrogel composite material for nasal repair further comprises a content of 1 Up to 5 The bioactive ceramic filler is selected from at least one of nano-hydroxyapatite, bioactive glass, and decellularized bone matrix micropowder, and the particle size of the bioactive ceramic filler is not greater than 500 μm. .

[0011] Preferably, the apparent elastic modulus of the hydrogel composite material used for nasal repair is... Follow the following quantitative relationship: ,in, The apparent elastic modulus of the hydrogel composite material used for nasal repair. The elastic modulus of the dual-network hydrogel matrix. The value represents the volume fraction of surface-modified polymer microspheres in the dual-network hydrogel matrix.

[0012] Preferably, the surface of the surface-modified polymer microspheres has a polydopamine layer, which reacts with residual amino groups in the dual-network hydrogel matrix via a Schiff base reaction to provide chemical crosslinking sites outside the molecular chain entanglement recrystallization interface region.

[0013] Preferably, the hydrogel composite material for nasal repair is at 25 The shear thinning index under the given conditions was 0.2 to 0.5, and at 100... The apparent viscosity at the shear rate is 10 Up to 50 The hydrogel composite material used for nasal repair is suitable for digital light processing additive manufacturing processes with micron-level resolution. Thioflavin T is used as a photocuring inhibitor, and its performance at 405... The free radical trapping effect generated under wavelength light excitation matches the decomposition rate of the photoinitiator, enabling the control of the monolayer curing depth of hydrogel composites used for nasal repair within 50 nm during additive manufacturing. Up to 150 .

[0014] A method for preparing a hydrogel composite material for nasal repair includes the following steps: Step S1101: Mix surface-modified polymer microspheres, methacrylamide gelatin, methacrylamide hyaluronic acid, photoinitiator and thioflavone T in an aqueous medium to obtain composite printing ink; Step S1102, using digital light processing additive manufacturing equipment, at 405 The composite printing ink is cured layer by layer under wavelength light initiation, and the volume fraction of surface-modified polymer microspheres in the composite printing ink is adjusted during the curing process. This results in the shaped solid having a storage modulus of 50 in the corresponding nasal bridge repair area. Up to 100 The energy storage modulus in the corresponding nasal tip repair area is 20. Up to 50 ; Step S1103: Place the cured entity at 60°C. Thermal strengthening treatment in the environment induces methacrylamide hyaluronic acid molecular chains to penetrate and entangle into the surface of surface-modified polymer microspheres, according to 1 Up to 5 The cooling rate causes the molecular chain segments on the surface of the surface-modified polymer microspheres to recrystallize in situ, thereby forming a molecular chain entanglement recrystallization interface region between the surface-modified polymer microspheres and the dual-network hydrogel matrix.

[0015] Compared with existing technologies, the hydrogel composite material of the present invention for nasal repair has the following advantages: 1. In the hydrogel for nasal repair, the charge induction and osmotic pressure gradient between the amorphous swelling region on the surface of the modified polymer microspheres and the double-network hydrogel matrix allow hydrogel molecular chain segments to actively infiltrate into the surface of the microspheres. Through low-temperature thermal strengthening, the molecular chain segments are entangled in situ and an interpenetrating interlocking network is constructed, eliminating the physical boundary between the hard reinforcing phase and the flexible continuous phase. This enables smooth load transfer at the phase interface and avoids stress concentration and interfacial debonding caused by abrupt changes in modulus when the composite material is under stress.

[0016] 2. By utilizing the interfacial locking mechanism between modified polymer microspheres and a dual-network hydrogel matrix, combined with the controlled distribution of microsphere content during the three-dimensional molding process, the implant exhibits mechanical gradients in different regions that match the biomechanics of the nose. This ensures the support strength of the nasal bridge area while also taking into account the flexibility and deformation capacity of the nasal tip area. Furthermore, the stable volume locking structure at the interface ensures that the implant does not experience step-like modulus collapse or delamination under long-term cyclic physiological loads, thus guaranteeing the structural integrity of the implant.

[0017] 3. The coordination effect between the photocuring stabilizer and the charged modified microspheres in the composite ink system effectively suppresses light scattering interference during the projection molding process, improves the spatial resolution of the three-dimensional structure molding, ensures the accurate reproduction of the through-anchored micropores and fine anatomical structures on the surface of the prosthesis, provides a precise physical scaffold for postoperative tissue ingrowth and vascularization, and maintains the high bioactivity inside the hydrogel matrix; the polarization distribution of surface active functional groups and the biorecognition sites of the dual-network hydrogel form spatial synergy, improve the interfacial biocompatibility of the hydrophobic polymer microspheres, and combined with the physical barrier effect of the surface interpenetrating interlocking layer on the permeability of body fluids, maintain the chemical stability of the gradient structure. Attached Figure Description

[0018] Figure 1 This is a schematic diagram of the microscopic interface structure and component composition principle of the hydrogel composite material of the present invention; Figure 2 This is a comparison chart of the measured and theoretically predicted storage modulus values ​​of the hydrogel composite material of the present invention under different microsphere volume fractions; Figure 3 This is a flowchart of the preparation process and the overall system architecture of the present invention. Detailed Implementation

[0019] The technical solutions of the embodiments of this application will be clearly described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of this application are within the scope of protection of this application.

[0020] It should be noted that all directional and positional terms used in this invention, such as: up, down, left, right, front, back, vertical, horizontal, inner, outer, top, bottom, transverse, longitudinal, center, etc., are only used to explain the relative positional relationship and connection between components in a specific state (as shown in the accompanying drawings). They are only for the convenience of describing this invention and do not require that this invention be constructed and operated in a specific orientation. Therefore, they should not be construed as limiting this invention. In addition, the descriptions of "first," "second," etc., in this invention are for descriptive purposes only and should not be construed as indicating or implying their relative importance or implicitly specifying the number of technical features indicated.

[0021] In the description of this invention, unless otherwise explicitly specified and limited, the terms installation, connection, and linking should be interpreted broadly. For example, they can refer to fixed connections, detachable connections, or integral connections; they can refer to mechanical connections; they can refer to direct connections or indirect connections through an intermediate medium; they can refer to the internal communication between two components. For those skilled in the art, the specific meaning of the above terms in this invention can be understood according to the specific circumstances.

[0022] In the description of this specification, references to the terms "an embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example, and the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples.

[0023] A hydrogel composite material for nasal repair and its preparation method thereof, comprising surface-modified polymer microspheres and a dual-network hydrogel matrix, wherein the content of the surface-modified polymer microspheres in the hydrogel composite material for nasal repair is [missing information]. (w / v) to (w / v); The dual-network hydrogel matrix consists of a mass percentage concentration of to Methacrylamide gelatin and a mass percentage concentration of to It is made by cross-linking methacryloyl hyaluronic acid; the surface-modified polymer microspheres have a surface thickness of nm to A swollen layer of nm thickness; the swollen layer and the double-network hydrogel matrix have a thickness of [missing information]. nm to The molecular chain entanglement recrystallization interface region at nm; the thickness of the molecular chain entanglement recrystallization interface region. Cryo-transmission electron microscopy combined with energy dispersive X-ray spectroscopy X-ray spectral line scanning confirmed the sample was at -160°C. Ultrathin sections were obtained from the environment to pinpoint the swelling phase, and the carbon-nitrogen mass ratio distribution was linearly acquired from the edge of the surface-modified polymer microspheres towards the dual-network hydrogel matrix. The glass transition temperature range of the surface-modified polymer microsphere swelling layer was 55°C. Up to 58 The heat strengthening treatment temperature was set at 60°C. This temperature is lower than that of the dual-network hydrogel matrix (72°C). The thermal denaturation threshold drives the methacrylamide hyaluronic acid molecular chains to penetrate into the amorphous region of the microsphere surface through the osmotic pressure gradient, causing the molecular chain entanglement and recrystallization interface region thickness. It remains stable in the 150nm to 300nm range.

[0024] To address the stress concentration and bonding failure issues arising from the difference in interfacial properties between the polymer-reinforced phase and the continuous hydrogel phase, this scheme employs the following procedure to construct the interfacial structure: the molecular chain entanglement and recrystallization interface region includes a cooperatively entangled molecular chain structure extending from the swollen layer towards the dual-network hydrogel matrix; in-situ recrystallized crystals are distributed on the surface of the surface-modified polymer microspheres, with methacryloyl hyaluronic acid molecular chain segments as nucleation sites; the surface-modified polymer microspheres and the dual-network hydrogel matrix form a modulus transition structure with a gradient decrease in elastic modulus from the surface of the surface-modified polymer microspheres to the dual-network hydrogel matrix; considering the mechanical property distribution requirements of the nasal anatomical regions, the storage modulus of the hydrogel composite material used for nasal repair exhibits a gradient distribution with varying content of surface-modified polymer microspheres; its storage modulus in the corresponding nasal bridge repair area is... kPa to kPa, the energy storage modulus in the corresponding nasal tip repair area is kPa to kPa; Apparent elastic modulus of hydrogel composites used for nasal repair Follow the following quantitative relationship: ,in, The apparent elastic modulus of the hydrogel composite material used for nasal repair. The elastic modulus of the dual-network hydrogel matrix. The value represents the volume fraction of surface-modified polymer microspheres in the dual-network hydrogel matrix.

[0025] The surface-modified polymer microspheres are selected from at least one of polycaprolactone microspheres, polylactic acid microspheres, and polylactic acid-glycolic acid copolymer microspheres; the particle size of the surface-modified polymer microspheres is [missing information]. μm to μm, and the spatial distribution accuracy deviation in the dual-network hydrogel matrix is ​​lower than μm; to obtain a specific pore size distribution on the surface of the surface-modified polymer microspheres, a concentration of μm was used. mol / L to An etching process was performed on surface-modified polymer microspheres using a sodium hydroxide solution at a concentration of mol / L. The controlled hydrolysis of polymer ester bonds in the alkaline medium was utilized, and the etching time was adjusted to create an average pore size on the surface of the surface-modified polymer microspheres. μm to Anchoring micropores of μm are used to provide physical engagement sites for postoperative tissue ingrowth; the hydrogel composite material used for nasal repair is a porous entity with three-dimensional interconnected pores, with an average pore size of [missing information]. μm to μm, porosity to The hydrogel composite material used for nasal repair also includes a content of [missing information]. (w / v) to (w / v) of photoinitiator and a content of (w / v) to (w / v) Thioflavin T; the composite material is suitable for digital light processing additive manufacturing processes with micron-level resolution; thioflavin T acts as a photocurable polymerization inhibitor in... The free radical trapping effect generated under nm wavelength light excitation matches the decomposition rate of the photoinitiator, which is used to control the monolayer curing depth within a certain range. μm to μm, improving the spatial resolution of the molding process; the digital light processing additive manufacturing equipment integrates a dual-channel microfluidic pump module, which respectively carries the first ink with a mass-to-volume ratio of 10% surface-modified polymer microspheres and the second ink with a mass-to-volume ratio of 40% surface-modified polymer microspheres; the control logic adjusts the flow rate ratio of the two feed channels in real time according to the anatomical partition coordinates of the slice layer of the 3D model, so that the mixed fluid enters the molding tank, and the ultrasonic homogenization array at the bottom of the tank eliminates the horizontal concentration distribution deviation of the microspheres, so that the volume fraction of the microspheres is... To meet the preset modulus mapping requirements, a continuously changing mechanical gradient is constructed between the corresponding nasal bridge repair area and the nasal tip repair area.

[0026] The method for preparing hydrogel composite materials for nasal repair includes the following steps: Step 1, mixing surface-modified polymer microspheres, methacrylamide gelatin, methacrylamide hyaluronic acid, a photoinitiator, and thioflavone T in an aqueous medium to obtain a composite printing ink; Step 2, using digital light processing additive manufacturing equipment, in... The composite printing ink is cured layer by layer under nm wavelength light initiation; during the curing process, the volume fraction of surface-modified polymer microspheres in the composite printing ink is adjusted. Step 3: Control the modulus of the solidified object in different regions after molding; Step 4: Place the cured object in... Thermal strengthening treatment was performed in the environment; the osmotic pressure gradient between the swollen layer and the double-network hydrogel matrix solution was utilized to drive the methacryloyl hyaluronic acid molecular chains to penetrate into the amorphous region of the surface-modified polymer microspheres; Under certain conditions, the molecular chain segments on the surface of the surface-modified polymer microspheres transform into a semi-molten state and undergo synergistic entanglement with the infiltrated methacrylamide hyaluronic acid molecular chains; according to / min to Cooling at a rate of / min induces in-situ recrystallization of the entangled molecular chain segments, forming a molecular chain entanglement-recrystallization interface region.

[0027] Example 1: In a specific scenario of nasal defect repair engineering prototype preparation, the prosthesis needs to provide rigid support in the nasal bridge area to maintain the nasal shape and adapt to high-frequency physiological deformation in the nasal tip area. Simultaneously, it faces cyclic fatigue loads generated by long-term respiratory airflow pressure and facial soft tissue movement. Due to the significant difference in apparent elastic modulus between the rigid reinforcing phase (i.e., surface-modified polymer microspheres) and the flexible matrix (i.e., double-network hydrogel matrix), abrupt load transfer at the interface between the two phases easily induces stress concentration, leading to interfacial debonding of the prosthesis under cyclic loading. To verify the technical performance of the aforementioned preparation procedure in handling this type of interfacial failure problem, polycaprolactone microspheres were used as surface-modified polymer microspheres and placed in a substrate with a mass fraction of... In a mixed solution of hexamethylenediamine and isopropanol, Environmental processing Hours, a thickness of [thickness value missing] is generated on the surface of the surface-modified polymer microspheres. A swollen layer of nm was formed, and the treated surface-modified polymer microspheres were placed at a mass-to-volume ratio of [missing value]. The content is dispersed in a mass percentage concentration of Methacrylamide gelatin with a mass percentage concentration of In a dual-network hydrogel matrix composed of methacrylamide hyaluronic acid, by adding (w / v) photoinitiator and (w / v) thioflavone T was used to obtain a composite printing ink, which was then processed using digital light processing additive manufacturing equipment. The composite printing ink is cured layer by layer under the induction of nm wavelength light, and the formed object is placed at a temperature of Thermal intensification was performed in an environment where the osmotic pressure gradient between the swollen layer and the dual-network hydrogel matrix solution was utilized to drive the methacrylamide hyaluronic acid molecular chains to penetrate into the amorphous region of the surface-modified polymer microspheres. After cooling, a layer with a depth of [missing information] was formed at the interface. The molecular chain entanglement recrystallization interface region of nm.

[0028] In the cyclic load test simulating the physiological environment of the nose, the prosthesis was subjected to a frequency of [frequency missing]. Hz and the number of cycles is The test results of the compressive stress test showed that the molecular chain entanglement recrystallization interface region transformed the load transfer at the interface from a step-like to a smooth transition, thus increasing the apparent elastic modulus of the material. In the case of formula Within the determined predicted value range, where, The apparent elastic modulus of the hydrogel composite material used for nasal repair. The elastic modulus of the dual-network hydrogel matrix. The volume fraction of surface-modified polymer microspheres in the dual-network hydrogel matrix is ​​given by the elastic modulus of the dual-network hydrogel matrix. for kPa and volume fraction for At that time, the measured apparent elastic modulus for kPa, and no microcracks or microsphere peeling were observed at the interface. The implant maintained its position in the nasal bridge repair area. The energy storage modulus of kPa is maintained in the nasal tip repair area. The energy storage modulus of kPa was achieved by constructing a transition layer with molecular chain-level locking characteristics between surface-modified polymer microspheres and a dual-network hydrogel matrix.

[0029] Example 2: To verify the mechanical stability and interfacial bonding strength of the hydrogel composite material used for nasal repair under simulated physiological conditions, a dynamic mechanical analysis platform was used to analyze hydrogel composites with different volume fractions. The sample group underwent fatigue cycle testing. The data used in this experiment were acquired from a machine with a displacement resolution better than [missing information]. μm, and the force value accuracy is not lower than The dynamic fatigue testing machine with a capacity of mN was used, and the test environment was set at a temperature of mN. Furthermore, within a sealed, temperature-controlled bath filled with simulated bodily fluids, to simulate the pressure conditions experienced by the soft tissues of the nose during respiration, the test signal frequency was set to [frequency value missing]. Hz, and the range of compressive loads during the test is based on the sample volume fraction. The corresponding theoretical storage modulus is dynamically adjusted to ensure that the sample group... to It operates within the physiological strain range, while introducing an amplitude of [value] during the test. The static pre-compression displacement is used as an environmental disturbance factor to characterize the dynamic response stability of the material under constant compressive stress in facial soft tissue.

[0030] The experimental groups included experimental groups and a control group as a comparison. The volume fraction of surface-modified polymer microspheres in experimental groups 1, 2, and 3 was [not specified]. Set as , as well as and all of them are executed Thermal strengthening treatment was used to construct the molecular chain entanglement recrystallization interface region. Control group 1 used volume fraction for Surface-modified polymer microspheres were used, but no thermal strengthening treatment was performed. Control group 2 used volume fraction... for Surface-modified polymer microspheres, control group 3 used volume fraction for Surface-modified polymer microspheres are shown in Table 1.

[0031] Table 1: Comparison of Performance Parameters of Sample Groups

[0032] Analyzing the data shown in Table 1, experimental groups 1 to 3 at different volume fractions The average should remain no lower than The retention rate of the storage modulus, its measured storage modulus and apparent elastic modulus. The predicted values ​​are consistent; the predicted values ​​are based on the formula. The calculation shows that, The apparent elastic modulus of the hydrogel composite material used for nasal repair. The elastic modulus of the dual-network hydrogel matrix. The volume fraction of surface-modified polymer microspheres in the dual-network hydrogel matrix was measured. The results showed that the molecular chain entanglement and recrystallization interface region... nm to Within a depth range of nm, the stress concentration at the phase interface was resolved through co-crystallization of molecular chain segments; control group 1, lacking this interface structure, developed microcracks and caused interface delamination under cyclic loading; control group 2, although exhibiting high stability, suffered from insufficient storage modulus to meet nasal cavity support requirements due to its low reinforcing phase content; control group 3, due to its low volume fraction... Exceed This leads to an increase in the viscosity of the composite printing ink, causing the rheological resistance during the digital light processing to exceed the single-layer peel strength, resulting in initial defects inside the molded entity.

[0033] Example 3: This example combines Figures 1 to 3 This document describes a hydrogel composite material for nasal repair and its preparation method, as follows: Figure 1As shown, the product comprises surface-modified polymer microspheres with a content of 10% to 40% (w / v) and a 50 nm to 100 nm swelling layer on the surface, and a dual-network hydrogel matrix composed of 5% to 15% by mass of methacryloyl gelatin and 1% to 3% by mass of methacryloyl hyaluronic acid crosslinked together. The two components penetrate the matrix through the swelling layer to form a molecular chain entanglement recrystallization interface region with a thickness of 150 nm to 300 nm, thereby forming an elastic modulus with a gradient decrease and eliminating abrupt changes in interfacial load transfer. The modulus transition structure consists of a molecular chain entanglement structure extending from the swollen layer to the matrix side and an in-situ recrystallized crystal with hyaluronic acid segments as nucleation sites. It exhibits a gradient energy storage modulus distribution that varies with the microsphere content, specifically 50 kPa to 100 kPa for the bridge of the nose and 20 kPa to 50 kPa for the tip of the nose. It also contains 0.1% to 1.0% photoinitiator and 0.01% to 0.05% thioflavone T as a functional additive system to assist in molding and improve resolution.

[0034] like Figure 2 As shown in the figure, the horizontal axis represents the volume fraction of microspheres. The values ​​are 0.10, 0.15, 0.25, 0.35, and 0.40, respectively. The vertical axis represents the energy storage modulus in kPa. The legend distinguishes between the measured energy storage modulus and the theoretical predicted value. The measured energy storage modulus is represented by a horizontal striped bar chart, while the theoretical predicted value is represented by a diagonal striped bar chart. The data shows the energy storage modulus as a function of the microsphere volume fraction. The trend of increasing with the increase of volume fraction, and the high consistency between the measured values ​​and the theoretical model predictions at each volume fraction point, confirms the controllability of the material's mechanical properties.

[0035] like Figure 3 As shown, the fabrication process system consists of a material preparation terminal, a manufacturing execution center (DLP) platform, a thermally enhanced post-processing workstation, and a process monitoring and feedback layer. The material preparation terminal includes a surface-modified microsphere preparation module responsible for swelling layer pretreatment, a dual-network matrix formulation module (GelMA+HAMA), and a composite ink mixing device for adding photoinitiators / polymerization inhibitors. It supplies composite printing ink to the manufacturing execution center. The manufacturing execution center is equipped with a digital light processing additive manufacturing device with a 405nm light source, and integrates a gradient distribution control system for microsphere content / modulus mapping, a single-layer curing depth calibration module for light intensity / exposure time adjustment, and a light scattering compensation unit for pixel scaling correction. The cured solid is transferred to the thermally enhanced post-processing workstation, which includes a temperature-controlled heat treatment environment of 60°C. The entire process, including isothermal and programmed cooling control unit to induce recrystallization and interface locking verification for microcrack / peeling detection, is controlled by a process monitoring and feedback layer. This layer covers ink rheological property monitoring (viscosity / sedimentation), incident light energy density monitoring (photometer calibration), and micropore diameter measurement feedback (scanning electron microscope / size calibration). The modules work collaboratively through data or material flow.

[0036] Example 4: In the preparation of engineering prototypes for printing fine structures of nasal alar cartilage, in order to ensure that the molded entity... Maintaining the structural integrity of the through-anchored micropores at a single-layer thickness, a calibration procedure for the polymerization inhibition efficiency of thioflavin T was performed, utilizing light power density of A single-layer curing experiment was conducted using digital light processing additive manufacturing equipment to record the critical curing depth at different thioflavone T concentrations. When the thioflavone T concentration increased from... Increase to At that time, the absorption coefficient of the material was measured. The curing depth exhibits a linear growth trend, and is fitted based on measured data. With exposure time The relationship follows the formula ,in, This refers to the curing depth of a single layer, in units of... ; The apparent absorbance of the composite printing ink is expressed in units of light absorption. ; The incident light energy density is expressed in units of... It is obtained by multiplying the optical power density by the exposure time; The critical curing energy of the material is given by a mass percentage concentration of [value missing]. In the methacrylamide gelatin system, this value is calibrated as .

[0037] To determine the apparent elastic modulus The feature parameters in the prediction model are obtained by preparing three sets of parameters with defined volume fractions. Model regression validation was performed using standard stretched splines, volume fraction Selected as , as well as After execution Heat strengthening treatment and After cooling at a rate of / min, the storage modulus of the specimen was measured using a universal testing machine, and the formula was adjusted using the least squares method. Regression verification was performed on the coefficients in the data. Experimental data showed that when polycaprolactone microspheres were used as surface-modified polymer microspheres, the deviation rate between the measured storage modulus value and the theoretical prediction value was lower than that of the theoretical prediction value. This confirms the coefficient and Corresponding to the geometric morphology factor and interphase interaction constant of the reinforcing phase in the dual-network hydrogel matrix, respectively, and based on the boundary setting of the thermal strengthening treatment temperature, differential scanning calorimetry analysis confirmed that the glass transition temperature range of the selected surface-modified polymer microsphere swelling layer is [missing information]. to The thermal denaturation initiation temperature of the dual-network hydrogel matrix in the cross-linked state is not lower than Based on this physical property, the heat strengthening temperature is set to This temperature, above the trigger point for the movement of molecular chain segments in the swelling layer and below the thermal damage threshold of the dual-network hydrogel matrix, is used to drive the methacryloyl hyaluronic acid molecular chains to enter the amorphous region of the microsphere surface through the osmotic pressure gradient, achieving physical locking of molecular chain segments at the interface without damaging the bioactivity of the matrix. Through the above parameter calibration and temperature boundary verification, this embodiment enables the molded nasal repair support to achieve the desired effect in the corresponding nasal bridge repair area. The measured elastic modulus at kPa, and internal No physical blockage caused by over-curing occurred in the μm through anchoring micropores.

[0038] Example 5: In an engineering deployment scenario of nasal implant fabrication using digital light processing additive manufacturing, to ensure that different batches of hydrogel composite materials used for nasal repair maintain a constant monolayer curing depth under a specific light power density, a pre-calibration procedure based on critical energy density is performed, and the incident light energy density at the bottom of the molding window is measured using a photometer. Prepare a thickness of Standard single-layer cured samples were used to record the actual cured thickness at different exposure times. This thickness was then calculated by substituting the values ​​into the formula. Calculate the apparent absorbance of this batch of composite printing inks. ;in, This refers to the curing depth of a single layer, in units of... ; The apparent absorbance of the composite printing ink is expressed in units of light absorption. ; The incident light energy density is expressed in units of... ; The critical curing energy of the material, in units of When detected When the curing depth of the single layer fluctuates due to sedimentation or spatial distribution deviations of the surface-modified polymer microspheres, the exposure time of the digital light processing additive manufacturing equipment can be adjusted to achieve the desired curing depth. In to Within the range.

[0039] When the system encounters conditions such as fluctuations in the molecular weight distribution or differences in the degree of substitution of methacrylamide hyaluronic acid, in order to maintain the thickness consistency of the molecular chain entanglement recrystallization interface region, a process parameter fine-tuning procedure based on permeation kinetics is executed, placing the composite printing ink containing surface-modified polymer microspheres in... Determining initial viscosity under environmental conditions And establish the infiltration time based on the diffusion law. With interface thickness The functional relationship between them; utilizing the osmotic pressure gradient between the swollen layer and the double-network hydrogel matrix solution, the static settling time before thermal strengthening treatment was set to... min to min is used to adjust the diffusion rate change caused by the difference in molecular chain segment length, so that the methacrylamide hyaluronic acid molecular chains form at a depth of [value missing] within the amorphous region of the surface-modified polymer microspheres. nm to The nm-based collaborative entanglement structure, after molding, acquires a storage modulus in the nasal bridge repair area, and is in a state of... kPa to Response within the kPa range.

[0040] Example 6: In the high-precision fabrication of nasal implants with customized anatomical structures, a light scattering compensation calibration procedure targeting the dimensional accuracy of anchoring micropores is performed. Digital light processing additive manufacturing equipment is used to solidify the implant containing a diameter of... The calibration sample with a preset pore size of μm was used to measure the actual pore size of the molded solid. And calculate for a specific volume fraction Light scattering compensation coefficient ;in, This is the light scattering compensation coefficient; This is the preset pore size value, in μm; The measured pore size of the sample is expressed in μm; it follows the formula... When the surface-modified polymer microspheres in the composite printing ink experience enhanced light scattering due to variations in particle size distribution, the pixel scaling ratio in the digital molding command is adjusted to compensate for dimensional deviations, ensuring that the average pore size of the anchoring micropores in the nose tip and bridge regions of the molded entity remains stable. μm to Within the μm range.

[0041] When faced with fluctuating thicknesses of the swelling layer on the surface of different batches of surface-modified polymer microspheres, the optimal duration of the thermal strengthening treatment is determined. The calibration procedure was followed to prepare three sets of test samples containing the microspheres from this batch and... Performed in different environments min、 min and The thermal strengthening treatment was performed at the minimum level, and the depth of the molecular chain entanglement-recrystallization interface region at the interface was measured using scanning electron microscopy. Based on the linear regression model fitted from the measured data Calculation makes achieve nm to The time required to reach the target depth of nm allows the formed entity to withstand [the pressure / temperature]. Under cyclic loading at a Hz breathing rate, maintain the energy storage modulus retention rate at a level not lower than The level; in a surface microporousization treatment task for a specific batch of polylactic acid microspheres, a calibration procedure for determining the optimal alkali treatment concentration was performed, and three groups were prepared by immersing in a concentration of [missing information]. mol / L mol / L and The sample group in mol / L sodium hydroxide solution, Continuous etching in the environment The morphological evolution of the microsphere surface in the sample group was observed using scanning electron microscopy over a period of time; the experimental results showed that when the sodium hydroxide concentration was set to [value missing], [the morphology evolution was observed]. At mol / L, the measured average pore size of the anchored micropores on the surface of the microspheres in the sample group was [value missing]. μm, and the sphericity deviation of the microspheres is within Within the tolerance range, the prepared hydrogel composite material for nasal repair meets the requirements for tissue integration while maintaining rheological stability during the printing process.

[0042] The embodiments of this application have been described above with reference to the accompanying drawings. Unless otherwise specified, the embodiments and features in the embodiments of this application can be combined with each other. This application is not limited to the specific embodiments described above. The specific embodiments described above are merely illustrative and not restrictive. Those skilled in the art can make many other forms under the guidance of this application without departing from the spirit and scope of the claims, and all of these forms are within the protection scope of this application.

Claims

1. A hydrogel composite material for nasal repair, characterized in that, include: The content of surface-modified polymer microspheres in the hydrogel composite material for nasal repair is 10%. Up to 40 ; The dual-network hydrogel matrix consists of a mass percentage concentration of 5 Up to 15 Methacrylamide gelatin and a mass percentage concentration of 1 Up to 3 It is formed by cross-linking methacryloyl hyaluronic acid; The surface-modified polymer microspheres have a surface thickness of 50 mm. Up to 100 The swollen layer has a thickness of 150 mm between it and the double-network hydrogel matrix. Up to 300 The molecular chain entanglement recrystallization interface region; The molecular chain entanglement recrystallization interface region contains a molecular chain cooperative entanglement structure extending from the swelling layer to the double network hydrogel matrix side. Furthermore, the molecular chain segments on the surface of the surface-modified polymer microspheres are distributed with in-situ recrystallized crystals using the molecular chain segments of methacryloyl hyaluronic acid as nucleation sites. This forms a modulus transition structure between the surface-modified polymer microspheres and the double network hydrogel matrix, where the elastic modulus decreases in a gradient from the surface of the surface-modified polymer microspheres to the double network hydrogel matrix. The storage modulus of the hydrogel composite material used for nasal repair exhibits a gradient distribution with varying content of surface-modified polymer microspheres, with a storage modulus of 50 in the corresponding nasal bridge repair area. Up to 100 The energy storage modulus in the corresponding nasal tip repair area is 20. Up to 50 ; Furthermore, the hydrogel composite material used for nasal repair also includes a content of 0.1%. Up to 1.0 The photoinitiator and its content is 0.01 Up to 0.05 Thioflavin T.

2. The hydrogel composite material for nasal repair according to claim 1, characterized in that, The surface-modified polymer microspheres are selected from at least one of polycaprolactone microspheres, polylactic acid microspheres, and polylactic acid-glycolic acid copolymer microspheres; the particle size of the surface-modified polymer microspheres is 10. Up to 50 Furthermore, the spatial distribution accuracy deviation of the surface-modified polymer microspheres in the dual-network hydrogel matrix is ​​less than 5%. The surface of the surface-modified polymer microspheres has amino groups introduced through amination treatment, carboxyl groups introduced through alkali treatment, catechol groups introduced through dopamine coating, or methacryloyl groups introduced through silane coupling agent modification; the surface of the surface-modified polymer microspheres also has an average pore size of 300 μm. Up to 500 Anchoring micropores.

3. The hydrogel composite material for nasal repair according to claim 1, characterized in that, Dual-network hydrogel matrix at 37 The equilibrium swelling rate under the environmental conditions is 800. Up to 1200 The network density of methacrylamide gelatin and methacrylamide hyaluronic acid in the cross-linked state is positively correlated with the thickness of the interface region of molecular chain entanglement and recrystallization, which can be used to achieve synergistic deformation between surface-modified polymer microspheres and dual-network hydrogel matrix under dynamic breathing load.

4. The hydrogel composite material for nasal repair according to claim 1, characterized in that, The hydrogel composite material used for nasal repair is a porous entity with three-dimensional interconnected pores and an average pore size of 100. Up to 300 Porosity is 60 Up to 85 The three-dimensional interconnected pores are jointly constructed by the interlayer overlap gaps in the additive manufacturing process and the occupancy effect of the surface-modified polymer microspheres.

5. The hydrogel composite material for nasal repair according to claim 1, characterized in that, The hydrogel composite material for nasal repair generates a molecular chain entanglement recrystallization interface region through the following steps: Step S101, utilizing the osmotic pressure gradient between the swollen layer and the dual-network hydrogel matrix solution, drives the methacryloyl hyaluronic acid molecular chains to penetrate into the amorphous region of the surface-modified polymer microspheres; Step S102, at 60... Under heat treatment conditions, the molecular chain segments on the surface of the surface-modified polymer microspheres are transformed into a semi-molten state and undergo synergistic entanglement with the infiltrated methacrylamide hyaluronic acid molecular chains; step S103, with 1 Up to 5 The cooling rate induces in-situ recrystallization of the entangled molecular chain segments.

6. The hydrogel composite material for nasal repair according to claim 1, characterized in that, The hydrogel composite material used for nasal repair also contains a content of 1 Up to 5 The bioactive ceramic filler is selected from at least one of nano-hydroxyapatite, bioactive glass, and decellularized bone matrix micropowder, and the particle size of the bioactive ceramic filler is not greater than 500 μm. .

7. The hydrogel composite material for nasal repair according to claim 1, characterized in that, Apparent elastic modulus of hydrogel composites used for nasal repair Follow the following quantitative relationship: ,in, The apparent elastic modulus of the hydrogel composite material used for nasal repair. The elastic modulus of the dual-network hydrogel matrix. The value represents the volume fraction of surface-modified polymer microspheres in the dual-network hydrogel matrix.

8. The hydrogel composite material for nasal repair according to claim 1, characterized in that, The surface of the surface-modified polymer microspheres has a polydopamine layer. The polydopamine layer reacts with the residual amino groups in the dual-network hydrogel matrix through a Schiff base reaction to provide chemical crosslinking sites outside the molecular chain entanglement recrystallization interface region.

9. A hydrogel composite material for nasal repair according to claim 1, characterized in that, Hydrogel composite material for nasal repair at 25 The shear thinning index under the given conditions was 0.2 to 0.5, and at 100... The apparent viscosity at the shear rate is 10 Up to 50 ; Hydrogel composite materials for nasal repair are suitable for digital light-processing additive manufacturing processes with micron-level resolution. Thioflavin T acts as a photocuring inhibitor, and its performance at 405... The free radical trapping effect generated under wavelength light excitation matches the decomposition rate of the photoinitiator, enabling the control of the monolayer curing depth of hydrogel composites used for nasal repair within 50 nm during additive manufacturing. Up to 150 .

10. A method for preparing a hydrogel composite material for nasal repair, used to prepare the hydrogel composite material for nasal repair as described in claim 1, characterized in that, Includes the following steps: Step S1101: Mix surface-modified polymer microspheres, methacrylamide gelatin, methacrylamide hyaluronic acid, photoinitiator and thioflavone T in an aqueous medium to obtain composite printing ink; Step S1102, using digital light processing additive manufacturing equipment, at 405 The composite printing ink is cured layer by layer under wavelength light initiation, and the volume fraction of surface-modified polymer microspheres in the composite printing ink is adjusted during the curing process. This results in the shaped solid having a storage modulus of 50 in the corresponding nasal bridge repair area. Up to 100 The energy storage modulus in the corresponding nasal tip repair area is 20. Up to 50 ; Step S1103: Place the cured entity at 60°C. Thermal strengthening treatment in the environment induces methacrylamide hyaluronic acid molecular chains to penetrate and entangle into the surface of surface-modified polymer microspheres, according to 1 Up to 5 The cooling rate causes the molecular chain segments on the surface of the surface-modified polymer microspheres to recrystallize in situ, thereby forming a molecular chain entanglement recrystallization interface region between the surface-modified polymer microspheres and the dual-network hydrogel matrix.

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