Research On The Control Of The Performance Of Multifunctional Injectable Alginate-based Hydrogels And Their Applications In Tissue Repair

Injectable hydrogel is a commonly used interventional material in minimally invasive surgery,and it also has great prospect for biology and medicine.Sodium alginate(SA)is one of the injectable hydrogels with the most extensive application,it’s a natural polysaccharide composed of glucuronic acid(G)and mannuronic acid(M).When G unit meets divalent metal ions in aqueous solution,it is easy to form sodium alginate hydrogel through electrostatic interaction.The gel process triggered by the ion is rapid and the required conditions are simple and mild,which makes sodium alginate hydrogel have good injectability.At present,sodium alginate hydrogel is one of the most widely used injectable hydrogels in minimally invasive surgery.However,the development of sodium alginate hydrogel is restricted by the factors such as difficult control of gel process,insufficient mechanical properties and weak biological function.How to achieve physical and chemical performance regulation and endow it with good biological functionality through functional modification is currently a research hotspot and difficulty.In view of the above problems of sodium alginate hydrogels,four injectable alginate-based hydrogels were designed and constructed by introducing a variety of physical and chemical mechanisms such as fiber reinforcement,nano particle reinforcement,internal gel,dynamic covalent bond,and double crosslinking.This not only improves and regulates the injectability of the hydrogel,but also optimizes its stability,mechanical properties,degradation properties and other physical and chemical properties.At the same time,it also gives alginate-based hydrogels a variety of biological functions.In this paper,the structure,physical and chemical properties and biological activities of these four alginate-based hydrogels were systematically characterized,and they were applied to the research of different tissue repair,including the treatment of bone defects,osteochondral defects,rheumatoid arthritis and endometrial damage.The specific research contents are as follows:(1)Based on the ionic crosslinking characteristics of sodium alginate hydrogel,by introducing carboxymethyl bacterial cellulose(CMBC),nanoparticles composed of calcium carbonate(CaCO3)and hydroxyapatite(HA),this paper constructed injectable nanocomposite hydrogel(SA-CMBC),systematically characterized and regulated the gel process of SA-CMBC hydrogel,in order to optimize the injectability of hydrogel.Under the dual mechanism of fiber reinforcement and nano particle reinforcement,the compressive strength of SACMBC hydrogel can be increased to five times that of the traditional ion crosslinked sodium alginate hydrogel,and it has good stability in simulated body fluid,releasing Ca2+ and nano particles while degrading.In the rat model of medial femoral condyle injury,it proved that SA-CMBC hydrogel can promote the repair of bone tissue,and is conducive to the integration of new bone tissue and surrounding tissue.(2)Based on oxidized sodium alginate(OSA),an injectable double interpenetrating network dynamic hydrogel(OSAGC)was constructed by introducing gelatin and chondroitin sulfate(CS).OSAGC hydrogel has strong injectability and self-healing ability.Increasing the oxidation degree of OSA and the content of CS is beneficial for increasing the compressive strength of OSAGC and can be increased to 3 MPa.CS not only participated in the construction of gel network,but also maintained its own activity.It will be gradually released during degradation,which is conducive to anchoring articular cartilage tissue and enhancing the affinity of OSAGC hydrogel.Animal experiments have shown that OSAGC can reconstruct rat bone tissue within 1～2 months and continuously stimulate the repair of cartilage tissue,achieving bone cartilage regeneration 12 weeks after surgery.(3)Through the interaction of borate ester bond and static electricity,an injectable double crosslinked antioxidant drug carrying hydrogel containing triptolide(TPL)was constructed(SPT@TPL).SPT@TPL The hydrogel also has good injectability and the ability to remove ROS.The clearance rate of hydrogen peroxide and DPPH radical exceeded 80%,and its compression strength can reach more than 150 KPa.The dual cross-linked network structure is beneficial for the sustained release of TPL and reduces its acute toxicity,while allowing for sustained therapeutic effects.Evaluation was conducted on a rat model of rheumatoid arthritis cartilage damage,and the results showed that SPT@TPL Hydrogel can inhibit the development of joint inflammation and promote the repair of bone and cartilage tissue in the lesion.(4)In this paper,recombinant collagen Ⅲ was innovatively introduced to construct injectable dynamic double crosslinked hydrogel(OSA/RC)based on dynamic covalent bond and electrostatic interaction.RC will also form selfassembled structure under the action of dynamic covalent bond and hydrogen bond.OSA/RC hydrogel has good viscosity,injectability,degradability and absorbability.OSA/RC hydrogel has high biological activity.It is injected into the mouse endometrial injury model as a non-invasive treatment method that does not rely on hormones and cells which plays a synergistic role in promoting cell proliferation and regulating hormone levels,and significantly repairs the endometrium within 7 days.In this study,multifunctional injectable alginate-based hydrogels were used in a variety of tissue repair topics,and the structure and properties of hydrogels and their effects on various tissue repair were studied,which provided new ideas and research basis for expanding the application of sodium alginate hydrogels in biomedical fields.