Application of biomimetic hydrogels in cartilage tissue engineering

Tissue engineering is an interdisciplinary field that combines materials science and cell biology to repair biological tissues that are difficult to regenerate. Once a cartilage defect occurs, due to its complex structure, and lack of blood vessels, nerves, and lymphatic vessels, tissue self-limitation is poor, especially full-thickness cartilage defects that are difficult to repair and regenerate. Therefore, tissue engineering has become an effective method to repair cartilage defects (especially full-thickness cartilage defects): artificial materials are developed to simulate the mechanical properties and biological properties of natural osteocartilage and used to implant into the defect to replace its biological function. Scaffolds used in cartilage regeneration can be divided into sponges, membranes, nonwovens, non-injectable, and injectable hydrogels. Each of these scaffold materials has its own uses and characteristics. Sponge scaffolds are conducive to cell seeding, but their structure is single; membrane-like Scaffolds are suitable for fine repairs, but they have high process requirements and high costs and are inconvenient to transport and store. Non-woven scaffolds have high toughness and are suitable for cartilage surface defects. Hydrogels are hydrophilic polymers with excellent mechanical and biological properties that are critical for modeling cartilage with high water content. In addition, hydrogels are easy to store and carry, which has high application prospects.

1. Raw materials used to synthesize biomimetic hydrogels

Hydrogels can be divided simply into natural hydrogels and synthetic hydrogels based on the nature of the material components. Natural polymers used to prepare hydrogels include protein-based materials (such as gelatin, collagen, silk fibroin, etc.) and polysaccharide materials (such as hyaluronic acid, chitosan, alginate, etc.). In addition, natural hydrogel glue does not cause immune or toxic reactions, and the degradation products are non-toxic and non-immune. However, its poor stability, fast degradation rate, and low mechanical properties greatly limit its application. Synthetic hydrogels include polyvinyl alcohol, polyethylene glycol, polylactic acid, polylactide-co-glycolide, polyglycolide, polycaprolactone, and polyacrylamide, and the incorporation of these polymers can be used to enhance mechanical properties or serve as carriers for drug delivery. However, there are immune responses and toxicity when combined with certain polymers.

1.1 Synthetic polymers

Polyvinyl alcohol: It is a reliable high-performance carrier with excellent film-forming, emulsifying, and film-forming properties. It is reported that polyvinyl alcohol hydrogel obtained by the casting drying method has mechanical properties similar to natural cartilage, indicating that this hydrogel can be used as a substitute material for repairing cartilage defects. In addition, polyvinyl alcohol-chitosan hydrogels containing mesenchymal cells showed promoting effects on chondrogenic differentiation and glycosaminoglycan deposition in vitro studies.

Polyethylene glycol: It is a polymer approved by the U.S. Food and Drug Administration for use in pharmaceuticals and personal care products and is even considered safe for oral administration. This polymer is easily modified and has good mechanical properties after forming a hydrogel.

Poly-N-vinylcaprolactam: It is a cell-compatible thermosensitive polymer that can be used to synthesize injectable hydrogels for cartilage tissue engineering. Chondrocytes and mesenchymal stem cells showed high viability in this hydrogel. It was demonstrated in both in vivo and in vitro experiments that a cartilage-specific extracellular matrix was generated in poly-N-vinylcaprolactam hydrogels. Over time, the content of specific components in cartilage, including glycosaminoglycans and type II collagen, increases.

1.2 Natural polymers

(1) Polysaccharides

Hyaluronic acid: It is a linear biological macromolecule that plays an important role in many cellular functions. It is the main component of cartilage extracellular matrix, is bioactive and is often used to create hydrogel scaffolds that interact with cells. In terms of the biosafety of implanted materials, the degradability of materials has received increasing attention in tissue engineering. Some studies have combined synthetic polysaccharide polymers and natural polysaccharide polymers to prepare a completely biodegradable hydrogel. The prepared hyaluronic acid hydrogel can support the adhesion and adhesion of human bone marrow mesenchymal stem cells. growth, promote interactions between cells, and are enzymatically biodegradable, expanding the scope of biodegradable materials for tissue engineering. However, using hyaluronic acid in vivo remains a challenge because hyaluronidase, nitrogen, and reactive oxygen species can degrade hyaluronic acid, affecting its cell adhesion ability.

Chondroitin sulfate: It is a polysaccharide molecule that is the most abundant glycosaminoglycan in the human body, accounting for 80% of the glycosaminoglycans in adult joint cartilage. Chondroitin sulfate is a linear sulfated glycosaminoglycan formed from 1-3 bonds of D-glucuronic acid and N-acetylgalactosamine. It has the ability to integrate tissue and has anti-inflammatory effects. As we age, chondroitin sulfate in cartilage degenerates and decreases. Due to its high charge density and high water content, its mechanical strength is weak. Therefore, chondroitin sulfate is often combined and cross-linked with other materials to improve mechanical properties.

Alginate: It is an anionic polysaccharide that is abundant in the cell walls of brown algae. Because alginate simply gels with divalent cations such as Ca2+, it is often used in non-invasive methods of cartilage repair as an injectable hydrogel. Additionally, alginate is commonly used in 3D printing technology due to its rapid cross-linking capabilities. However, there are still some shortcomings in the application of alginate in cartilage tissue engineering: First, the stability of physically cross-linked alginate hydrogels is poor. Even under physiological tissue conditions, it will lose its mechanical strength in a short time, but Its mechanical properties can be increased through subsequent cross-linking; secondly, due to the low cell adhesion of alginate in mammals, cell adhesion peptides are often introduced to support cell function. To overcome these deficiencies, other bioactive substances are often added to alginate hydrogels.

Chitosan: A polysaccharide extracted from the shells of shrimp and other crustaceans, it has antibacterial properties and is highly bioadhesive. Hydrogels prepared with chitosan can induce chondrogenic differentiation of mouse chondrocytes in vitro, showing good potential for cartilage tissue engineering applications.

(2) Proteins

Collagen: It is an extracellular matrix protein that exists in natural cartilage and can support the growth of chondrocytes. Therefore, it is widely used in cartilage tissue engineering. Collagen hydrogels reduce the risk of immune rejection by stimulating the formation of extracellular matrix, reduce the immunogenicity of exogenous cells seeded in engineered hydrogel constructs, and promote cartilage regeneration. In addition, collagen can also be combined with other materials to form hybrid hydrogel scaffolds with enhanced properties compared to the individual components.

Gelatin: It is a denatured collagen with the advantages of biocompatibility, degradability, and good cell adhesion. However, the main disadvantages of gelatin for cartilage repair are poor mechanical properties and low thermal stability. To overcome its shortcomings, researchers have developed a hybrid hydrogel composed of gelatin and hydroxybenzoic acid that can increase the strength of the material.

Silk fibroin: It is the main component of silk and has excellent biocompatibility and degradability. Silk fibroin can mimic the collagen structure of natural cartilage and has great potential in cartilage tissue engineering. The hydrogel formed by silk fibroin has high biocompatibility with mouse articular chondrocytes and is conducive to cell adhesion.

Mechanical properties and biological properties of biomimetic hydrogels

Biomimetic hydrogels can simulate the composition and structure of cartilage extracellular matrix and have similar mechanical properties and biological properties to natural tissues. Natural materials such as gelatin and chondroitin sulfate are nontoxic and have tunable biodegradability; however, their mechanical properties are poor, which limits their application in tissue engineering. Based on this, researchers combine natural and synthetic materials to improve the mechanical properties and biological properties of hydrogels. In terms of mechanical properties, hydrogels should provide a suitable microenvironment for cell growth and promote extracellular matrix production and new tissue formation. Hydrogels that are too hard will affect the biological behavior of the body, such as changing cell phenotypes or stimulating the differentiation of bone marrow mesenchymal stem cells into bone cells. In addition, after increasing the matrix to increase the hardness of the hydrogel, the production of extracellular matrix by chondrocytes is reduced, inhibiting the adhesion between cells and hydrogel, and reducing the production of stress fibers. However, if the hydrogel stiffness is insufficient in the early stages, chondrocytes will produce large amounts of extracellular matrix, which can enhance the hydrogel stiffness and withstand high stress over time. In terms of biological properties, hydrogels exhibit good cell viability when used in cartilage tissue engineering. In terms of the extracellular matrix, gelatin-based hydrogels stimulate the secretion of glycosaminoglycans. In the past few years of research, hydrogels based on natural polymers such as chondroitin sulfate, hyaluronic acid and gelatin have been extensively developed. Improvements in mechanical properties and biological properties have been achieved after improvements in physical or chemical cross-linking, such as photo-cross-linking, enzymatic cross-linking, and interpenetrating networks. Biomimetic hydrogels based on extracellular matrix derivatives already possess mechanical properties similar to those of natural cartilage. In general, naturally derived biomaterials (such as chondroitin sulfate, hyaluronic acid, and gelatin) are ideal biomimetic sources for cartilage tissue engineering. However, some related factors such as mechanical properties and degradation rate limit its clinical application. In this review, it has been clarified that in recent years, chemical or physical modification of hydrogel materials of natural origin can improve their mechanical properties and biological properties, and perform better than single or biosynthetic preparations. Produce better biocompatibility and mechanical properties.

An ideal biomimetic hydrogel for cartilage tissue engineering should have the following characteristics at the same time: ① bioactivity and biomimetic properties; ② superior mechanical properties; ③ the ability to integrate cartilage and bone tissue; ④ the transport function of drugs and growth factors. Based on the huge potential of hydrogel materials in cartilage tissue engineering, related research on this material has become a hot topic in recent years. Matexcel provides related raw materials for hydrogel preparation, if you have any interest, feel free to contact us.

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