Multi-response type programmable self-disintegrating structural body

Abstract

The invention relates to a multi-response type programmable self-disintegration structural body which is composed of an inner temperature-sensitive response layer and an outer liquid absorption layer wrapping the outer side of the inner temperature-sensitive response layer, and the outer liquid absorption layer is prepared from the following raw materials in parts by weight: 20-25 parts of sodium alginate, 10-12 parts of sodium carboxymethyl cellulose, 8-10 parts of chitosan and 3-5 parts of a plasticizer. 2-3 parts of a cross-linking agent; the inner temperature-sensitive response layer is prepared from the following raw materials in parts by weight: 30 to 35 parts of a PLA-co-PEGDA copolymer, 10 to 12 parts of drug-containing nanoparticles, 0.2 to 0.5 part of a low-toxicity photoinitiator, 2 to 3 parts of a mixed cross-linking agent and 2 to 3 parts of a flexibility regulator; the composition can effectively replace existing materials, can realize disintegration triggering under preset conditions, and is wide in clinical application range and suitable for large-scale production and application.

Description

Technical Field

[0001] This invention relates to the field of medical materials science, specifically to a multi-response programmable self-disintegrating structure. Background Technology

[0002] In medicine, the physical dissolution process of drugs, pharmaceuticals, or mixtures before absorption or action is called disintegration. Currently, common products with disintegration mechanisms on the market include disintegrating tablets, effervescent tablets, multi-layered tablet-coated products, and microenvironment-responsive disintegration products. Disintegration is essentially the process of dissolving pills, blocks, tablets, or capsules under certain time, pressure, temperature, or other conditions. Disintegration does not imply absorption but is a precisely controlled mechanism. With the development of technology, the demand for disintegration technology is increasing in areas such as chronic wound dressings (diabetic foot ulcers, pressure ulcers), postoperative sustained-release films, tissue engineering scaffold materials, and tumor local controlled-release membrane carriers. Therefore, this invention provides a multi-response programmable self-disintegrating structure that meets the needs of the above-mentioned scenarios, fully integrates disintegration technology, effectively replaces existing materials, can achieve disintegration triggering under preset conditions, has a wide range of clinical applications, is suitable for large-scale production and application, and has broad market prospects. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a multi-response programmable self-disintegrating structure that meets the usage requirements of the aforementioned scenarios, fully integrates disintegration technology, can effectively replace existing materials, can achieve disintegration triggering under preset conditions, has a wide range of clinical applications, and is suitable for large-scale production and application, thereby overcoming the deficiencies in existing technologies.

[0004] The technical solution of this invention is implemented as follows: a multi-responsive programmable self-disintegrating structure, which is composed of an inner thermosensitive response layer and an outer liquid-absorbing layer wrapped around the outer side of the inner thermosensitive response layer. The outer liquid-absorbing layer is prepared from the following raw materials in parts by weight: sodium alginate 20-25 parts, sodium carboxymethyl cellulose 10-12 parts, chitosan 8-10 parts, plasticizer 3-5 parts, and crosslinking agent 2-3 parts. The inner thermosensitive response layer is prepared from the following raw materials in parts by weight: PLA-co-PEGDA copolymer 30-35 parts, drug-containing nanoparticles 10-12 parts, low-toxicity photoinitiator 0.2-0.5 parts, mixed crosslinking agent 2-3 parts, and flexibility modifier 2-3 parts.

[0005] Furthermore, the plasticizer is glycerin.

[0006] Furthermore, the crosslinking agent is a CaCl2 solution.

[0007] Furthermore, the drug-containing nanoparticles are PLGA drug-containing nanoparticles.

[0008] Furthermore, the low-toxicity photoinitiator is Irgacure2959.

[0009] Furthermore, the hybrid crosslinking agent is a mixture of acrylamide and MBAA crosslinking agent.

[0010] Furthermore, the flexibility modifier is glycerin or PEG400.

[0011] Furthermore, the outer liquid-absorbing layer is a porous membrane structure with high water absorption.

[0012] Furthermore, the inner temperature-sensitive response layer is a gel-like structure that has been frozen.

[0013] A multi-response programmable self-disintegrating structure is disclosed. When local liquid seepage or temperature rise occurs, the structure activates a responsive structural layer, inducing structural disintegration and sequential release of functional components. The disintegration time of the structure ranges from 48 to 72 hours, and the response process can be adjusted according to the actual application scenario.

[0014] The present invention has the following positive effects: 1. This invention provides a multi-response programmable self-disintegrating structure that can meet the needs of various scenarios, fully integrates disintegration technology, can effectively replace existing materials, can achieve disintegration triggering under preset conditions, has a wide range of clinical applications, and is suitable for large-scale production and application.

[0015] 2. The invention has high overall biosafety, precise and controllable drug release in the inner layer, and protection of the wound surface and provision of a micro-humid environment in the outer layer. It has temperature-sensitive intelligent responsiveness, adapts to changes in wound temperature, and is suitable for the following biomedical scenarios: chronic wound dressings (diabetic foot, pressure ulcers), postoperative sustained-release dressings, tissue engineering scaffold materials, tumor local controlled-release membrane carriers, etc. Detailed Implementation

[0016] A multi-responsive programmable self-disintegrating structure is composed of an inner thermosensitive responsive layer and an outer liquid-absorbing layer surrounding the inner thermosensitive responsive layer. The outer liquid-absorbing layer is prepared from the following raw materials in parts by weight: sodium alginate 20-25 parts, sodium carboxymethyl cellulose 10-12 parts, chitosan 8-10 parts, plasticizer 3-5 parts, and crosslinking agent 2-3 parts. The inner thermosensitive responsive layer is prepared from the following raw materials in parts by weight: PLA-co-PEGDA copolymer 30-35 parts, drug-containing nanoparticles 10-12 parts, low-toxicity photoinitiator 0.2-0.5 parts, mixed crosslinking agent 2-3 parts, and flexibility modifier 2-3 parts.

[0017] The plasticizer is glycerol. The crosslinking agent is CaCl2 solution. The drug-containing nanoparticles are PLGA drug-containing nanoparticles. The low-toxicity photoinitiator is Irgacure2959. The mixed crosslinking agent is a mixture of acrylamide and MBAA crosslinking agent. The flexibility modifier is glycerol or PEG400. The outer liquid-absorbing layer is a highly absorbent porous membrane structure. The inner temperature-sensitive response layer is a gel-like structure after freezing.

[0018] The structure activates the responsive structural layer when local liquid seeps out or the temperature rises, inducing structural disintegration and sequential release of functional components. The disintegration time of the structure ranges from 48 to 72 hours, and the response process can be adjusted according to the actual application scenario.

[0019] Example 1: The following is a formulation of a multi-responsive programmable self-disintegrating structure based on temperature and liquid exudation, totaling 100 parts by weight. All materials have good biocompatibility and in vivo biodegradability. The outer absorbent layer is prepared from the following raw materials in parts by weight: 25 parts sodium alginate, 10 parts sodium carboxymethyl cellulose, 10 parts chitosan, 3.5 parts glycerol, and 3 parts CaCl2 solution. The inner temperature-sensitive responsive layer is prepared from the following raw materials in parts by weight: 30 parts PLA-co-PEGDA copolymer, 12 parts PLGA drug-containing nanoparticles, 0.5 parts low-toxicity photoinitiator, 3 parts a mixture of acrylamide and MBAA crosslinking agent, and 3 parts PEG400 or glycerol.

[0020] The fabrication process of the structure includes the following steps: S1. Preparation of the outer absorbent layer 1) Raw material preparation: Weigh chitosan, sodium alginate and sodium carboxymethyl cellulose according to the proportion, and dissolve them separately in an appropriate amount of purified water; stir the chitosan and sodium alginate solutions slowly at room temperature of 20-25°C until completely dissolved; heat the sodium methyl cellulose solution to 50-60°C to ensure complete dissolution; 2) Crosslinking reaction: Add CaCl2 solution to sodium alginate solution for crosslinking to form a stable colloidal structure. Control the pH value to 6-7 to improve the reaction efficiency. After mixing, let stand for 4 hours to degas and remove bubbles to ensure material uniformity. 3) Add plasticizer: Add glycerin and continue stirring until homogeneous to enhance flexibility and biocompatibility; 4) Molding: Pour the mixture into a mold and dehydrate it using freeze-drying technology to form an outer liquid-absorbing layer with a porous membrane structure that has high water absorption.

[0021] S2. Preparation of the inner temperature-sensitive response layer 1) Preparation of PLA-co-PEGDA copolymer: Add PNIPAM and PEGDA to an appropriate amount of water, stir until completely dissolved, and adjust the temperature sensitivity and degradation rate according to the ratio of PNIPAM:PEGDA = 3:1; 2) Preparation of drug-containing nanoparticles: Add PLGA drug-containing nanoparticles to PLA-co-PEGDA copolymer solution, stir evenly to form a controlled release system, maintain the temperature at 20-25°C to avoid premature phase change; 3) Copolymerization reaction initiation: Add acrylamide and MBAA crosslinking agent, add Irgacure2959 photoinitiator and PEG400, and start free radical polymerization under 365nm ultraviolet light irradiation. The reaction is controlled at 10-20 minutes. 4) Photocrosslinking curing: using 365nm wavelength ultraviolet light, 10–20 mJ / cm². 2 Cross-linking and curing are carried out; 5) Washing and purification: Wash repeatedly with deionized water to remove residual monomers and initiators, and further purify by dialysis; 6) Freeze-drying: Freeze-dry the gel to obtain the inner temperature-sensitive response layer.

[0022] S3. Assembly and molding of composite layer structures 1) Composite layering: The outer liquid-absorbing layer and the inner temperature-sensitive response layer are combined in proportion to form a structural layer. 3D printing technology is applied, and the nozzle temperature is 28-35°C for layer printing to control the structural shape. 2) Structural optimization: Control the thickness of each layer to 100-300μm, and adjust the pore size and morphology according to the response model to improve the temperature-sensitive and liquid permeation response efficiency; 3) Freeze-drying treatment: The composite structure is freeze-dried again to enhance its porosity and biodegradability; 4) Final inspection: Check the structural integrity and biological performance, conduct biocompatibility tests, and ensure that there are no toxic residues.

[0023] At 37°C, the inner thermosensitive layer can be induced to undergo phase transition collapse, triggering overall disintegration and achieving controlled release. Its response window and degradation rate are regulated by the ratio of PNIPAM to AAM. The outer absorbent layer has high absorbency and bioadhesion. When postoperative exudation occurs, it expands and deforms, promoting the disintegration of the outer absorbent layer or drug exudation, thus enhancing the ability to deliver drugs to specific sites.

[0024] During actual operation, at a physiological temperature of approximately 37°C in vivo, the inner thermosensitive response layer undergoes a thermosensitive phase transition via PNIPAM, initiating its self-disintegration behavior. Simultaneously, liquid infiltration activates the expansion and structural disintegration of the outer absorbent layer. This coupling effect allows the material to complete its self-degradation within 48–72 hours. The outer absorbent layer exhibits good biocompatibility and biodegradability, and the synergistic response of the two layers significantly enhances postoperative wound control and drug delivery efficiency.

[0025] In actual operation, the inner temperature-sensitive response layer regulates the phase transition threshold and degradation rate through copolymerization of PNIPAM and AAM, and encapsulates PLGA drug-containing nanoparticles to achieve multi-stage drug release behavior, which is suitable for postoperative inflammation regulation and wound repair.

[0026] During actual operation, the outer absorbent layer can expand in the postoperative exudate environment to form a gel barrier, absorbing the liquid while promoting structural degradation and drug release. Its exudate response capability is related to the ratio of sodium carboxymethyl cellulose and sodium alginate.

[0027] In actual operation, the structure of the present invention is formed into a cylindrical, mesh or honeycomb structure by 3D printing technology, with a structural layer thickness of 100-300μm, to adapt to different clinical application scenarios such as anti-adhesion, hemostasis or temporary support. The structural parameters can be optimized and designed according to the temperature response and exudation response coupling model.

[0028] As another embodiment of the present invention, natural or synthetic polymers containing a large number of hydroxyl, carboxyl, or amino groups are selected, such as gelatin, polyvinyl alcohol (PVA), sodium hyaluronate (HA), etc. These groups can form hydrogen bonds with water molecules, enhancing the material's affinity for water.

[0029] As another embodiment of the invention, a three-dimensional polymer network is constructed by introducing a natural cross-linking system (such as gelatin and aldehyde-modified chitosan). This structure has a high free volume, can absorb and retain a large amount of water, thereby forming an expansive hydrogel. The degree of cross-linking can be precisely controlled to regulate the water absorption rate and material stability.

[0030] In another embodiment of the present invention, a porous structure is formed using techniques such as freeze-drying and emulsion polymerization to increase the specific surface area of ​​the material and promote water penetration and rapid absorption. Controlling the pore size (generally in the range of 10–100 μm) can further enhance the water absorption rate.

[0031] In another embodiment of the present invention, the absorbent material can be synergistically integrated with temperature-sensitive (e.g., PNIPAM), enzyme-sensitive (e.g., containing MMP-sensitive peptides), or pH-responsive modules. After absorbing water and swelling, the material disintegrates or releases drugs under specific physiological conditions (e.g., 37°C, inflammatory pH, or high enzyme concentration), achieving a self-regulating programmable function.

[0032] As another embodiment of the present invention: 2% sodium carboxymethyl cellulose and 1% gelatin are dissolved in warm water, a cross-linking agent is added to form a gel, and after freeze-drying, a porous water-absorbing membrane is formed. Its water absorption ratio can reach 15-20 times the dry weight, and it can remain in the body fluid environment for 48-72 hours, providing a barrier for postoperative adhesion prevention and synergistic drug release.

[0033] The embodiments of the present invention have been shown and described. It will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A multi-response programmable self-disintegrating structure, characterized in that: It consists of an inner thermosensitive response layer and an outer liquid-absorbing layer wrapped around the outer side of the inner thermosensitive response layer. The outer liquid-absorbing layer is made of the following raw materials in parts by weight: sodium alginate 20-25 parts, sodium carboxymethyl cellulose 10-12 parts, chitosan 8-10 parts, plasticizer 3-5 parts, and crosslinking agent 2-3 parts. The inner thermosensitive response layer is made of the following raw materials in parts by weight: PLA-co-PEGDA copolymer 30-35 parts, drug-containing nanoparticles 10-12 parts, low-toxicity photoinitiator 0.2-0.5 parts, mixed crosslinking agent 2-3 parts, and flexibility modifier 2-3 parts.

2. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The plasticizer mentioned is glycerin.

3. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The crosslinking agent is a CaCl2 solution.

4. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The drug-containing nanoparticles mentioned are PLGA drug-containing nanoparticles.

5. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The low-toxicity photoinitiator mentioned is Irgacure2959.

6. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The aforementioned crosslinking agent is a mixture of acrylamide and MBAA crosslinking agent.

7. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The flexibility modifier is glycerin or PEG400.

8. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The outer absorbent layer is a porous membrane structure with high water absorption.

9. The multi-response programmable self-disintegrating structure according to claim 1, characterized in that: The inner temperature-sensitive response layer is a gel-like structure after freezing.

10. A multi-response programmable self-disintegrating structure as described in any one of claims 1-9, characterized in that: The structure activates the responsive structural layer when local liquid seeps out or the temperature rises, inducing structural disintegration and sequential release of functional components. The disintegration time of the structure ranges from 48 to 72 hours, and the response process can be adjusted according to the actual application scenario.