CN107320786A - Anti-infectious composite soft-tissue repair materials of one kind sustained release and preparation method thereof - Google Patents

Abstract

The invention relates to a sustained-release anti-infection compound soft tissue repair material and a preparation method thereof, which comprises biological material and a medium containing anti-infection components. The medium containing anti-infection components is placed between the layers or on the surface of the biological material according to the radius interval of the antibacterial zone of the drug susceptibility test, and is formed as a whole by means of adhesives, sutures or pressure. The invention can effectively and continuously release the anti-infection components without changing the biocompatibility of biological materials, is non-toxic and harmless, and has good application prospects.

Description

A slow-release anti-infection composite soft tissue repair material and preparation method thereof

technical field

The invention belongs to the field of soft tissue repair materials and preparation thereof, in particular to a slow-release anti-infection composite soft tissue repair material and a preparation method thereof.

Background technique

Biomaterials are an important advance in the study of soft tissue repair materials. Representative materials that are resistant to infection and remodelable include synthetic biomaterials (such as P4HB, silk fibroin fibers, collagen, chitosan, etc.) and acellular matrix biomaterials. Compared with traditional non-absorbable polymer materials, biomaterials act as temporary tissue scaffolds after implantation in the body, and as the patch material degrades, host cells infiltrate it and produce autologous collagen fibers. Such an endogenous tissue remodeling process can achieve early local rapid revascularization, early entry of phagocytes, and difficulty in the formation of bacterial biofilms, so it has a certain resistance to infection. However, it is undeniable that biomaterials are only partially resistant to infection rather than anti-infection, and have no antimicrobial activity themselves. Non-cross-linked acellular matrix biological patches can be digested by collagenase secreted by bacteria in an infected environment. disintegrate. Therefore, there is an urgent need for biomaterials to improve their resistance to infection.

In this regard, the existing progress includes: Chinese invention patents CN102014790A and CN101623518A respectively disclose the use of antibacterial metal particles such as nano-silver and silver ions to infiltrate acellular matrix biomaterials to improve the anti-infection properties of biological patches. The results of in vitro antibacterial experiments and animal experiments show that it can reduce the infection rate of acellular matrix biomaterials and improve the success rate of contaminated wound repair. The anti-infection effect of this improved biological patch is satisfactory, but because the antibacterial components are only adsorbed to the material network structure, the combination is relatively loose, and a large amount of antibacterial components are released in a short time after implantation, resulting in poor antibacterial effect in the later stage of the repaired area . Chinese invention patent CN103751844A discloses a method for preparing an antibacterial and antidegradable porcine small intestinal mucosa acellular matrix and its application. The invention uses genipin, dopamine and nano silver-treated porcine small intestinal mucosal decellularized matrix to prepare antibacterial and antidegradable biomaterials. Dopamine is viscous and can bind antibacterial components to collagen fiber scaffolds through chemical bonds. Experiments have confirmed its Compared with the natural porcine small intestinal mucosa acellular matrix, the anti-degradation performance and antibacterial performance are significantly enhanced, and can be applied in tissue repair of high-stress parts. However, when the acellular matrix biomaterial is applied to the contaminated surface, the infection rate of the repair area is significantly increased compared with the non-crosslinked material. This may be due to the fact that crosslinking will reduce the pores of the material, and too small pores are not conducive to cell invasion to achieve early vascularization. , and easy for bacterial colonization to form bacterial biofilms. Chinese invention patent CN101810883A discloses a bio-derived material with high histocompatibility and long-acting anti-infection. Its components include acellular matrix and absorbable anti-infection nanoparticles. The drug is released suddenly, and the effective concentration is reached rapidly, and the effective blood concentration lasts for 2 weeks to 3 months. Chinese invention patent CN102172418A discloses a cell-free matrix material for slow-release growth factors. Its components include degradable hydrophobic polymers, growth factors for angiogenesis and cell-free matrix. The nano-slow release system is compounded into the cell-free matrix. The slow-released growth factors still effectively maintain the biological characteristics, and the slow-release process is long and stable. However, the preparation process of the nanoparticles involved in these two patents is complicated, and the biological safety is unknown. Nanoparticles with small particle size (<50nm) may have certain cytotoxicity and lack clinical application prospects. Therefore, methods to improve the anti-infection properties of biomaterials still need to be improved.

Contents of the invention

The technical problem to be solved by the present invention is to provide a slow-release anti-infection composite soft tissue repair material and its preparation method, including biological materials and a medium containing anti-infection components. The medium containing anti-infection components is placed between the layers or on the surface of the biological material according to the radius interval of the antibacterial zone of the drug susceptibility test, and is formed as a whole by means of adhesives, sutures or pressure. The invention can effectively and continuously release the anti-infection components without changing the biocompatibility of biological materials, is non-toxic and harmless, and has good clinical application prospects.

The invention relates to a sustained-release anti-infection compound soft tissue repair material, which includes biological material and a medium containing anti-infection components.

The biological material is a single-layer, multi-layer or multi-component composite structure, and the medium containing anti-infection components is placed between the layers or on the surface of the biological material according to the radius interval of the antibacterial zone.

The radius of the inhibition zone should be the minimum radius of the inhibition zone within the effective time of the anti-infective ingredients, depending on factors such as the selected anti-infection ingredients, application site, indications, etc., but the inhibition zone should completely cover the anti-infective ingredients The layer of the medium.

The biological material is one or more of extracellular matrix/acellular matrix, collagen, fibrin, chitosan, chondroitin sulfate, hyaluronic acid, gelatin, P4HB, and silk protein. Good capacity.

The extracellular matrix/acellular matrix is derived from the submucosa, basement membrane, dermis, pericardium, peritoneum, pleura or amnion of human or mammalian hollow viscera, and the crosslinking degree of the material is 0% to 100%.

The medium containing the anti-infection component is composed of an anti-infection component and a medium, and the anti-infection component is uniformly and stably distributed inside the medium.

The anti-infective component is an inorganic antibacterial agent and/or an organic antibacterial agent.

The anti-infection component is one or more of nano-silver, silver ions, bismuth, triclosan, chlorhexidine, bismuth compounds, antibiotics, and antibacterial polypeptides.

The added amount of the anti-infective component should be determined according to the use of the repair material, the conventional dosage of the anti-infective component and the required release curve of the anti-infective component during application.

The medium is a three-dimensional interpenetrating network cross-linked structure, and its components include one or more of components such as extracellular matrix, collagen, fibrin, chitosan, hyaluronic acid, chondroitin sulfate, gelatin, and polymer hydrogel. Several kinds, the medium has characteristics such as degradability, shape plasticity, biocompatibility, biosafety, etc., preferably extracellular matrix gel.

The effective release time of the anti-infection components in the composite soft tissue repair material is 1-48 days.

The preparation method of a sustained-release anti-infection composite soft tissue repair material of the present invention includes: biomaterials and media containing anti-infection components are bound together with degradable sutures, bonded with adhesives, and fixed by vacuum lamination.

The fixation method of biomaterials and media containing anti-infection components can be selected from one of medical degradable suture binding, medical adhesive bonding, vacuum lamination or other physical, chemical or biological methods that can fix multi-layer materials. one or more species.

Beneficial effect

(1) Sustained release and controlled release of anti-infective ingredients: the medium involved in the present invention is used as a delivery carrier for anti-infective ingredients, and plays the role of slow-release and controlled release. As a drug delivery carrier, the medium is a kind of solid or semi-solid three-dimensional scaffold material with chemical or physical cross-linked structure, absorbable and water-insoluble. The medicine involved in the present invention can be free in the gap of the network structure in a liquid state, or form a covalent or non-covalent connection with molecules, and the medicine in the two states can reach a certain dynamic balance. After being implanted into the organism, a large amount of drugs dissociated in the gap of the network structure in a liquid state will be released in the early stage, and in the middle and later stages, with the growth of host cells and tissues, the medium will slowly degrade, and at the same time, the remaining drugs will be released continuously. In addition, the biomaterial itself is a three-dimensional network structure with a certain thickness, moisture permeability and porosity, which is conducive to the exchange of nutrients and oxygen and water of the growing cells in it, and can be used as a semi-permeable membrane to further play a slow-release role.

(2) Good biological safety: the inclusion of the medium ensures that no large doses of antibacterial agents are directly exposed to body tissues, and the arrangement of intervals not only ensures that the drug can be effectively released in the material as a whole, but also maintains the effective drug concentration while reducing the drug concentration. The dose used reduces the area where the drug-carrying medium is in direct contact with the body, does not change the histocompatibility of the material and the type of host-material immune response, does not cause allergic reactions, can further reduce toxicity and side effects, and alleviate adverse reactions.

(3) The basic type of immune response at the host-material interface has not been significantly changed: the anti-infective component is placed between the layers of the biological material without directly contacting the host tissue, and the anti-infective component is attached to the surface of the biological material like a stamp, which is realized by the principle of the inhibition zone With a smaller antimicrobial/biomaterial surface area ratio, the impact on the basic type of immune response at the host-material interface is minimized.

Description of drawings

Figure 1 is a schematic structural view of a slow-release anti-infection composite tissue repair material described in Example 1; wherein 1 is a biological material and 2 is a medium containing anti-infection components;

Fig. 2 in vitro antibacterial test result (escherichia coli);

Figure 3 In vitro antibacterial test results (Staphylococcus aureus).

detailed description

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Example 1

A drug-loaded and sustained-release tissue repair material comprises decellularized small intestinal submucosa (SIS) and drug-loaded chitosan flakes. Chitosan powder is mixed with an antibacterial agent and dissolved, and shaped into a sheet-like material. The SIS was prepared into sheets with an area of 10×10 cm ² in a staggered splicing manner. Referring to Figure 1, the drug-loaded sheets (2) were intermittently laid on the surface of the SIS (1) according to the diameter of the inhibition zone, and a total of 6 sheets were laid. The interlayers are fixed with medical chitosan adhesive, and pressed together under the pressure of -200mmHg.

The antibacterial effect of the material in vitro was observed by the inhibition zone method: it has effective antibacterial activity for 7-21 days against methicillin-resistant Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Escherichia coli.

Evaluate the cytotoxicity of the material according to the method specified in GB/T 16886.5. NIH3T3 and L929 were used as model cells. The cells were cultured with the cell culture medium as the leaching medium, and the leaching liquid of gradient concentration was used to replace the culture medium, and the cell viability was determined by the MTT method. The cytotoxicity of the material is grade 0-Ⅰ.

A canine model of abdominal wall defect with severe bacterial infection was constructed to repair it with repair materials. After 1, 3, 7, 14, and 30 days of observation, no severe abdominal infection occurred in the animals, and the number of bacteria in the secretion was inhibited.

Claims (8)

1. A slow-release anti-infection composite soft tissue repair material, characterized in that: the repair material includes biological materials and a medium containing anti-infection components. 2. A slow-release anti-infective composite soft tissue repair material according to claim 1, characterized in that: the biological material is a single-layer, multi-layer or multi-component composite structure, and the medium containing the anti-infection components according to the pH The radius of the bacterial circle is placed between the layers or on the surface of the biological material, and the periphery of the antibacterial circle overlaps to ensure that the surface of the composite material is not missed. 3. A slow-release anti-infective composite soft tissue repair material according to claim 1, characterized in that: said biological material is extracellular matrix/acellular matrix, collagen, fibrin, chitosan, cartilage sulfate One or more of protein, hyaluronic acid, gelatin, P4HB, silk protein. 4. A slow-release anti-infection composite soft tissue repair material according to claim 1, characterized in that: the medium containing the anti-infection component is composed of an anti-infection component and a medium, and the anti-infection component is distributed inside the medium. 5. A slow-release anti-infection composite soft tissue repair material according to claim 4, characterized in that: the anti-infection components are nano-silver, silver ions, bismuth, triclosan, chlorhexidine, bismuth compounds, One or more of antibiotics and antibacterial polypeptides. 6. A slow-release anti-infection composite soft tissue repair material according to claim 4, characterized in that: the medium is a three-dimensional interpenetrating network cross-linked structure, and its components include extracellular matrix, collagen, fibrin, shell One or more of ingredients such as polysaccharides, hyaluronic acid, chondroitin sulfate, gelatin, and polymer hydrogel. 7. A slow-release anti-infection composite soft tissue repair material according to claim 1, characterized in that: the effective release time of the anti-infection components in the composite soft tissue repair material is 1-48 days. 8. A preparation method of the slow-release anti-infection composite soft tissue repair material as claimed in any one of claims 1-7, comprising: biomaterials and media containing anti-infection components are bound by degradable sutures, adhesive Combination, vacuum lamination fixed as one.