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Back to Journal »Drug Design, Development and Treatment» Volume 12

Authors: Song R, Murphy M, Li C, Ting K, Soo C, Zheng Z 

Published on September 24, 2018, the 2018 volume: 12 pages 3117-3145

DOI https://doi.org/10.2147/DDDT.S165440

Single anonymous peer review

Editor approved for publication: Dr. Anastasios Lymperopoulos

Richard Song,1 Maxwell Murphy,1 Chenshuang Li,1 Kang Ting,1–3 Chia Soo,2 Zhongzheng1 1 Department of Growth and Development, School of Dentistry, University of California, Los Angeles, Department of Orthodontics, United States; 2 University of California, Los Angeles, UCLA Orthopaedic Surgery and Orthopedics Hospital Research Center University of California, Los Angeles, Los Angeles, California; 3 Department of Bioengineering, School of Engineering, University of California, Los Angeles University of California, Los Angeles, Los Angeles, California Abstract: Used for biomedical applications in the past half century Significant progress has been made in the development of biodegradable polymer materials. Biodegradable polymer materials are favored in the development of therapeutic devices, including temporary implants and three-dimensional scaffolds for tissue engineering. Further progress has been made in the use of biodegradable polymer materials for pharmacological applications, such as delivery vehicles for controlled/sustained drug release. These applications require materials with specific physicochemical, biological, and degradation properties to provide effective treatments. Therefore, various natural or synthetic polymers capable of hydrolysis or enzymatic degradation are being studied for biomedical applications. This review outlines the current development of biodegradable natural and synthetic polymer materials for various biomedical applications, including tissue engineering, temporary implants, wound healing, and drug delivery. Keywords: tissue engineering, drug delivery, wound healing, natural biomaterials, synthetic biomaterials

A biological material can be defined as a material designed to interact with a biological system to evaluate, treat, enhance, or replace any tissue, organ, or function of the body. 1 In 2013, the global implantable biomaterials market was valued at nearly 75.1 billion U.S. dollars. The market is expected to grow at a compound annual growth rate (CAGR) of 6.7% between 2014 and 2019, resulting in a global market size of 79.1 billion U.S. dollars in 2014. The global market size in 2019 was 109.5 billion U.S. dollars. 2 Although the biomedical applications of natural enzymatically degradable polymers dated thousands of years ago, the application of synthetic biodegradable polymers only began in the second half of the 1960s. 3 Considering their advantages over biostable materials in terms of long-term biocompatibility and the technical and ethical issues that accompany revision surgery, the investigation of the application is for biodegradable biomaterials that assist tissue repair and regeneration rather than permanent prostheses Device h 4-6 Therefore, polymer biomaterials are rapidly replacing other material categories, such as metals, alloys, and ceramics, as biomaterials due to their versatility. 3-5 In the global implantable biomaterials market, the polymer biomaterials industry is expected to achieve the highest growth at a compound annual growth rate of 22.1% because it has broad potential in a wide range of biomedical applications. 2 With this in mind, the purpose of this review is to highlight the most frequently studied polymer biomaterials and highlight their great potential in the fields of drug design, development, and treatment.

A key requirement of biomaterials is biocompatibility-the ability of the material to function with an appropriate host response in a specific application. 1 Many biological and physicochemical properties of the implant material control the host tissue's response to the material. For example, molecular weight, solubility, hydrophilicity/hydrophobicity, surface energy, material chemistry, degradation and/or erosion mechanisms, lubricity, and implant shape and structure all affect the biocompatibility of the material. 7 It is important that biodegradable biomaterials require excellent performance and biocompatibility over time, because the physicochemical, mechanical, and biological properties of biodegradable biomaterials will vary over time, so Compared with the original parent material, the resulting degradation products may have different degrees of tissue compatibility. The ideal biodegradable biomaterial should have degradation products that are non-toxic and easy to metabolize and clear from the body.

In addition to biocompatibility, several other important characteristics must be considered when selecting biodegradable biomaterials. First, the degradation time of the biomaterial should be consistent with the regeneration and/or healing process to ensure proper tissue remodeling. Second, the biomaterial must maintain the proper permeability and processability for its intended application. Finally, the mechanical properties of biomaterials should be sufficient to promote regeneration in patients’ daily activities, and any changes in mechanical properties due to degradation should maintain compatibility with the healing or regeneration process.

In view of the complexity of the human body and the current application range of polymer biomaterials, no polymer system can be considered an ideal biomaterial for all medical applications. Therefore, recent advances in the synthesis of biodegradable biomaterials have been directed towards the development and synthesis of polymers with properties tailored for specific biomedical applications. In addition, the current development of combining multifunctional and combinatorial methods in the design of biomaterials has accelerated the innovation of new biodegradable biomaterials. Another hot spot in biomaterial research is the development of therapeutic devices, including temporary prostheses, three-dimensional (3D) porous scaffolds for tissue engineering, and vehicles for pharmacological applications. Recently, 3D bioprinting has also been recognized, and preliminary data collection has begun for potential bio-inks for biomaterials used as 3D scaffold printing. Since biodegradable biomaterials have a variety of biological and physicochemical properties, they can replicate the properties of different tissues. Therefore, these materials are evaluated as 1) large implants, including bone screws, bone plates, and contraceptive depots; 2 ) Small implants, in the form of sutures and staples; 3) Flat membranes to guide tissue regeneration; and 4) Porous structures or multi-wire meshes for tissue engineering. 8 In addition, by appropriately designing structures and degradation parameters, these biodegradable materials can be used to generate micro- or nano-scale drug delivery carriers, used to control drug delivery by erosion or diffusion, or as a combination of the two. 9

Due to the interest of people in the field of biodegradable biomaterials, including regenerative medicine, tissue engineering, controlled drug delivery, gene therapy and nanotechnology, synthetic biodegradable polymers and biomedical applications similar to natural polymers have been obtained With strong expansion, our review will focus on exploring the latest developments in biomedical applications of these polymers in these fields. Although many other reviews focus on the topic of medical biodegradable biomaterials, as far as we know, in the past 5 years, there has not been a review covering the most commonly studied biodegradable materials like our review. developing. Biodegradable polymer biomaterials are used in drug delivery, tissue engineering and wound applications.

Biodegradable biological materials can be roughly divided into two categories based on their source and whether they are composed of naturally occurring extracellular matrix (ECM)-natural and synthetic. Natural biodegradable polymer biomaterials usually include protein (collagen, fibrin, silk, etc.) and polysaccharides (starch, alginate, chitin/chitosan, hyaluronic acid derivatives, etc.). 10-12 In addition, the family of natural polyesters-polyhydroxyalkanoates (PHAs)-have been recognized as natural biodegradable biomaterials. Recently, drosera binders (hydrogels based on natural polysaccharides) and Ivy nanoparticles (a macromolecular composition of nanospherical arabinogalactan proteins) are due to their ability to produce effective nanocomposite adhesives and their respective potential uses as nanocarriers in drug delivery. 13,14

As the most common protein in the human body, collagen provides physical support for the tissue by residing in the intercellular space, not only as the natural structural support of the cells in the connective tissue of the tissue, but also as a mobile, dynamic and flexible substance necessary for the cells. Behavior and organizational function. 15 Generally, collagen is a rod-shaped polymer with a length of about 300 nm and a molecular weight of about 300 kDa. Free amino acids in the body are synthesized into subunit chains of collagen, which are then transcribed, translated, and post-translationally modified in appropriate cells (such as osteoblasts and fibroblasts). 13 More than 22 different types of collagen have been identified in the human body. Type I-IV is the most common, and type I collagen is the single protein with the highest content in mammals. 15 Collagen is enzymatically degraded by a variety of enzymes (such as matrix metalloproteinases and collagenases) in the body to produce its corresponding amino acids. Due to its enzymatic degradability; unique mechanical, biological and physicochemical properties; non-toxic; and high tensile strength, collagen has been widely studied for biomedical applications. 16,17

Collagen plays a key role in maintaining the biological and structural integrity of ECM, and is highly dynamic, constantly remodeling to achieve proper physiological functions. For most soft and hard connective tissues (for example, blood vessels, cornea, skin, tendons, cartilage, and bone), collagen fibers and their networks function through their highly organized 3D structure. Tissue regeneration attempts to repair the structural integrity of the natural ECM and the complex remodeling process, especially to restore the fragile collagen network that occurs in normal physiological regeneration; therefore, recent efforts have focused on developing and mimicking its complex fibrous structure and serving as a cell scaffold. New functional biomaterials to replace ECM based on natural collagen. Animal-derived and recombinant collagen, especially type I collagen, is considered one of the most valuable biological materials, and is now widely used in tissue engineering, drug delivery, and cosmetic surgery. For example, a composite of fibrous collagen, hydroxyapatite, and tricalcium phosphate (Collagraft®, Angiotech Pharmaceuticals) has been approved by the U.S. Food and Drug Administration (FDA) as a biodegradable synthetic bone graft substitute. 18

The main sources of collagen currently used in biomedical applications are cow or pig skin and cow or horse Achilles tendon. They are used in their natural fibril form or after denaturation in various manufacturing forms, such as sponges, sheets, plugs and pellets. Collagen-based materials have been successfully used for skin repair. 19 For example, Promogran® (Systagenix)-a spongy collagen matrix containing oxidized cellulose-is used in the United States and Europe to treat diabetic and ulcer wounds. 20 Similarly, the FDA-approved two-layer skin substitute (Integra® Dermal Regeneration Template, Integra LifeSciences) consists of a cross-linked dermal layer of bovine collagen and glycosaminoglycan (GAG) and a polysiloxane sheet that deposits ECM components. Cortical composition, used in the market for full-thickness or deep partial-thickness heat damage. In addition, these skin substitutes constructed from cell-inoculated collagen have been widely commercialized (for example, Apligraf®, Organogenesis, Inc.) and (OrCel™, Ortec International Inc.). Interestingly, type I collagen sponge has also been used to design rabbit patellar tendons under different culture conditions. 21-23 Using collagen sponge combined with bone marrow mesenchymal stem cells, Juncosa-Melvin et al. proved that engineered tendon tissue obtains almost 75% of the mechanical properties of natural tendon. 22 In other studies, collagen has also been successfully used as a scaffold in nerve and bladder engineering. 24-26 In addition, a suture-free 3D collagen matrix graft-DuraGen® (Integra LifeSciences)-has been developed for spinal cord dural repair and regeneration, and has now been approved by the FDA. 27

In addition, collagen is a key initiator of the coagulation cascade, and therefore, it has been successfully developed as a hemostatic agent due to its high thrombosis. A variety of collagen-based hemostatic agents are currently available or are undergoing clinical trials for various surgical indications; including Sulzer-Spine® Tech's sealant, which is composed of bovine collagen and bovine thrombin, and is used in cardiovascular and spinal surgery ; Floseal® (Baxter Healthcare), a high-viscosity gel hemostatic agent, composed of collagen particles and local bovine thrombin; and CoStasis® Surgical Hemostat (Cohesion Technologies), which is composed of bovine thrombin and bovine microfibril collagen and Autologous plasma composition.

In terms of drug delivery, collagen has been specifically studied for the delivery of low molecular weight drugs, proteins, genes and plasmids. Currently, there are some collagen-based gentamicin carriers on the global market (such as Sulmycin®-Implant and Collat​​amp®-G, Innocoll Pharmaceuticals Ltd). These delivery systems allow continuous local delivery of antibiotics with limited systemic exposure. In addition, another product, Septocoll® (Biomet), achieves prolonged collagen delivery by adding two gentamicin salts with different solubility, and has been approved for the prevention of infection. 28 Recently, a new biodegradable, collagen-based chlorhexidine chip has been shown to provide chlorhexidine release time longer in the periodontal pocket compared with simple chlorhexidine subgingival irrigation. Longer and more sustainable. The continuous flow of gingival crevicular fluid from the periodontal pocket (up to 40 times per hour) makes chlorhexidine subgingival irrigation useless in providing significant antibacterial benefits, reducing the depth of exploration and the level of clinical adhesion, to control chronic periodontitis; However, the use of collagen-based release carriers can control the release of chlorhexidine to achieve the desired drug effect. 29 In addition, current clinical trials are studying cross-linked and absorbable collagen sponges as protein carriers. According to reports, due to the ideal interaction between the collagen matrix and protein, the release of biologically active proteins (such as recombinant human bone morphogenetic protein 2 (rhBMP-2)) will be prolonged when used in combination with the collagen matrix. 30 This combination product has been approved by the FDA for simultaneous use of titanium interbody fusion cages for anterior lumbar fusion (InFUSE® Bone Graft/LT-CAGE® Lumbar Tapered Fusion Device, Medtronic Spinal and Biologics) and similar products InductOs® (Medtronic Spinal and Biologics) ) It is approved in Europe for the treatment of acute tibial fractures in adult patients. In addition, a recent study reported that the delivery of rhBMP-2 through an absorbable collagen sponge stimulated bone remodeling in advanced alveolar ridge defects. 31 In addition to being used as a protein delivery vector, collagen has been shown to retain gene vector/plasmid DNA while protecting it from the body’s enzymatic or immune response, which highlights its potential for gene and plasmid DNA delivery. 32

One disadvantage of these collagen-based biomaterials is that they have mild immunogenicity due to the composition of the antigenic sites and terminal regions in the central helix, which greatly limits their clinical applications. 33 The immune response varies with processing technology and implantation site. 34 Other disadvantages of animal-derived collagen include different physicochemical and degradation characteristics, the high cost of pure collagen, and allogeneic or heterogeneous sources, which increase the risk of infectious disease transmission. In response to these limitations, current research has focused on recombinant systems that can produce human collagen. 35,36 There are already several potentially useful systems for large-scale production and purification of recombinant collagen, such as yeast, transgenic animals and, more recently, Escherichia coli. 37,38 Since the amino acid sequence of recombinant collagen can be directly modified, it is possible to manufacture controlled and targeted collagen products for specific applications, thereby diversifying collagen-based products and increasing their potential. 39 However, recombinant collagen cannot undergo natural post-translational modifications and therefore may lack the key biological activities of natural tissues. 33 The lack of post-translational modification means that although recombinant collagen can flexibly create countless different amino acid sequences for different targeted applications, it may not be suitable for many biomedical applications, especially those that require stability and strength, such as the heart valve. In addition, the production cost of commercially available recombinant collagen is still high, and so far, only a limited amount is available. 39

As a biological material, collagen has been widely used in several specific applications such as skin repair, hemostatic agent and drug delivery, but its slight immunogenicity, high cost, and different physical, chemical and degradation characteristics prevent The further expansion of collagen biomaterials. Although recombinant collagen has the potential to push collagen-based biomaterials to a wide range of applications, it needs to be continuously studied for its lack of post-translational modification and other major limitations in order to have any significant impact on its use as biomaterials.

Gelatin is a natural biopolymer extracted from collagen by controlled alkali, acid or enzymatic hydrolysis. 40 Because of its biological origin, it has excellent biodegradability and biocompatibility, and because of its wide availability, gelatin is a relatively low-cost polymer. 40 Gelatin has been used as a matrix for implants in the medical and pharmaceutical fields, and as a stabilizer in vaccines such as measles, mumps and rubella. 41 In addition, gelatin is water-permeable and water-soluble, and has multifunctional properties as a drug delivery carrier. 42 The mechanical properties, swelling behavior, thermal properties, and many other physical and chemical properties of gelatin may depend on the source of collagen, the extraction method, and the method used. The heat denaturation amount and the degree of crosslinking make gelatin a versatile polymer. 43 In addition, its ability to produce thermoreversible gels makes it a very good candidate for targeted drug delivery carriers, and as a result, gelatin can be used to develop specific drug release profiles, which has a wide range of drug delivery. Applications. 43

Gelatin is a general-purpose biopolymer. Traditionally, many different drug carrier systems can be designed, such as microparticles, nanoparticles, fibers, and hydrogels. 44 Each of these different systems has certain characteristics that make it particularly suitable for drug delivery. 44 For example, gelatin particles are commonly used as carriers for cell expansion and delivery of large biologically active molecules, while gelatin nanoparticles are more suitable for delivering drugs to the brain or intravenously. 44 Recently, a novel and relatively simple method for producing gelatin particles has been discovered. Allows very high protein and drug loading efficiency. 45 In the experiment, bovine serum albumin (BSA) was added at a gelatin concentration of 0.1%–0.4% to form a gelatin solution. 45 The solution is freeze-dried, and then the resulting sponge-like film is hardened with liquid nitrogen, and then ground into a powder to produce BSA-loaded particles. 45 These particles are then mixed with polylactide (PLLA) and polycaprolactone (PCL) The structure of the porous scaffold. 45 The in vitro release curves of protein from individual particles and particle-incorporated scaffolds demonstrated protein loading efficiency of up to 90%, indicating that BSA-loaded particles combined with particles for the release of growth factors may be suitable for bone tissue engineering. 45 Another study investigated the in vitro efficacy and toxicity of incorporating polyene into electrospun gelatin fibers. 46 The research team found that polyene-loaded antifungal gelatin mats showed better antifungal activity than traditional electrospun gelatin fiber mats. 46 In addition, they found that polyene stabilizes the triple-helical conformation of gelatin, while gelatin reduces the activity of hemolytic polyene, making polyene antifungal loaded gelatin fiber mats possible to manage superficial skin infections in the future. 46 Cohen et al. studied a new type of tissue adhesive based on gelatin, with alginate as a polymer additive, loaded with bupivacaine or ibuprofen for pain management. 47 They found that the drug release from the adhesive matrix is ​​mainly controlled by the characteristics of the gelatin/alginate bioadhesive, such as swelling and hydrophilic group concentration, which can be adjusted by changing the ratio of gelatin to alginate. 47 In addition, they found that the hydrophilicity and electrical interaction between bupivacaine and ibuprofen and the adhesive components have some influence on the release profile of the drug. The addition of bupivacaine improves the adhesive’s performance due to its inertness. Adhesive strength, while ibuprofen reduces the adhesive strength due to its reactivity with alginate/gelatin. 47 Overall, studies have shown that this gelatin/a alginate bioadhesive can be used in wounds Close the application. 47

The main advantages of gelatin are its biodegradability, availability and low cost. 44 Pigskin-derived gelatin is the most popular source, followed by cow hides and bones. 48 However, religious issues may arise because pig-derived products and cattle-derived products are banned in Judaism and Hinduism, respectively. 48 In addition, there are health problems with the transmission of pathogenic vectors such as prions. 48 However, recombinant gelatin can be used to overcome the shortcomings of animal tissue-derived materials. 49 At present, the main uses of gelatin are in the food, pharmaceutical and photographic industries. 49 In the field of biomedicine, gelatin is used for drug delivery and some wound dressing and tissue regeneration applications, but due to its poor mechanical properties. 49 These mechanical properties can be enhanced by physical cross-linking and chemical cross-linking, because there are a large number of functional side-group gelatins; however, the reagents used to stabilize cross-linked gelatin are usually toxic to the human body. 49 In the future, research on improving the mechanical properties of gelatin is needed so that gelatin has broad prospects as the main biological material; however, before then, the most likely blend of gelatin will be composite materials with other natural or synthetic biological materials, or as a The carrier of drug delivery.

Fibrin is a 360-kD fibrinogen derivative biopolymer that participates in the natural coagulation process and enhances cell adhesion and proliferation. 50 In addition to excellent biodegradability and biocompatibility, fibrin also has high elasticity and viscosity; it becomes hard in response to shear, stretching or compression; 51 one of the first fibrin-based products developed is fibrin Glue (fibrin sealant). Tissucol/Tisseel™ (Baxter Healthcare) and Beriplast HS/Beriplast P™ (CSL Behring) are the first generation fibrin sealants sold in Europe. Today, there are a wide variety of products with different compositions and bonding properties on the market. These products are widely used in hemostasis and tissue sealing applications in various surgical procedures, including neurosurgery, plastic and reconstructive surgery. 52-54

In addition, fibrin has been used as a scaffold for regeneration of many tissues, such as adipose tissue, bones, heart tissue, cartilage, muscle tissue, nerve tissue, eye tissue, respiratory tissue, skin, tendons and ligaments, and vascular tissue, such as and due to its Injectability and biodegradability make it a carrier of biologically active molecules (drugs, antibiotics or chemotherapeutics). 55-60 For example, some studies have shown that the clinical application of fibrin significantly improves the healing of intraosseous defects in chronic periodontitis. 61,62 There is further evidence that proteins interact differently with fibrin clots. Therefore, several cross-linking techniques are currently being studied to control the release profile of biologically active molecules from the fibrin matrix. 63 In addition, the fibrin matrix has been used as an excellent cell carrier vehicle. Bioseed® (DCM Shriram Limited) is a successful example obtained by mixing keratinocytes with fibrin, a fibrin-based product used to treat chronic skin wounds.

Fibrin is natural, highly available, implantable, inexpensive, easy to use, and has a low concentration of fibrinogen. Due to its porous form, the fibrin scaffold system is sufficient for cell attachment, proliferation, differentiation, 58,64 and as a release system for growth factors such as vascular endothelial growth factor and basic fibroblast growth factor (bFGF). 60,65 Fibrin-fixed growth factor has been shown to be released continuously for several days in a controlled manner, making it the best choice for many tissue engineering purposes. 50 Therefore, autologous fibrin can prevent technical complications arising from the use of currently commercially available fibrin products and should be further investigated. Fibrin-based scaffolds do have some limitations, such as weak mechanical strength and fast degradation; however, these characteristics have been improved by adding stronger natural and synthetic polymers, using various cross-linking methods, and using micro/nanospheres. Prove that it can be improved. 50 Next-generation scaffolds may involve specific cell lines that combine biomolecules and growth factors to accelerate and increase cell proliferation and differentiation on various tissue fixation scaffolds, as well as fibrin-based drug delivery vehicles and tissue engineering scaffolds, including relatively new ones The development of scaffolds of fibrin microspheres, nanospheres, microfibers, microtubes and porous sheets, all of which will play an important role in regenerative medicine. 50

HA is an important part of ECM. Its structure and biological characteristics mediate cell signal transduction, morphogenesis, matrix tissue and wound repair. 66,67 In 1943, Meyer and Palmer isolated HA from vitreous humor for the first time. 68 HA is a member of the GAG ​​family, including linear polysaccharides, composed of alternating units of N-acetyl-d-glucosamine and glucuronic acid. The body size ranges from 5,000 to 20,000,000 Daltons, and it exists in almost every vertebrate. Organizations. Natural sources of HA include cockscomb, bovine vitreous fluid and synovial fluid. 69 HA is degraded in the body through free radicals, such as nitric oxide and matrix metalloproteinases in ECM, and then undergoes endocytosis. Lysosomal enzymes further digest HA to produce monosaccharides and disaccharides, which are then converted into ammonia, carbon dioxide and water. 69

Figure 1 The structure of hyaluronic acid (HA).

Recently, HA has been recognized as an important part of creating new biomaterials for cell therapy, 3D cell culture, and tissue engineering. 70-72 Since HA is secreted in the early stage of wound healing, it has been widely used in research for wound dressing applications. 73,74 HA can be recognized by receptors on various cells related to tissue repair, so it has the ability to stimulate angiogenesis and regulate inflammation caused by injury as a free radical scavenger. 75 In addition, HA promotes the migration and differentiation of epithelial and mesenchymal cells, making them essential for tissue repair. 75 These properties, combined with its immunoneutral efficacy, make HA an ideal biomaterial for tissue engineering. 75 In addition, its water solubility allows HA to be modified into various porous and 3D structures for drug delivery. For example, the HA-based product HYAFF®11 (Anika Therapeutics, Inc.) is currently used as a carrier for various growth factors, morphogens, and stem cells. 76 In a comparative study, Hunt et al. reported that the healing response of rhBMP-2 provided by HYAFF®11 was improved compared to absorbable collagen sponge. 76 A recent study showed that HA-based materials may still replace collagen-based materials as injectable soft tissue fillers. 77 In terms of tissue engineering, HA has been successfully integrated into multiple complex systems. For example, HA modified poly(D,L-lactic-co-glycolic acid) (PLGA) scaffold successfully induced the expression of type II collagen and the formation of cartilage tissue with histological characteristics. 78 In addition, high-molecular-weight viscous HA solutions (eg, AMVISC® and AMVISC® PLUS, Bausch & Lomb) are currently used as vitreous humor substitutes and protect sensitive ocular tissues during glaucoma surgery, cataract extraction, and corneal transplantation. Viscous HA solutions (for example, SYNVISC®, Sanofi Biosurgery; and ORTHOVISC®, Anika Therapeutics, Inc.) are also clinically used as synovial fluid substitutes to relieve pain in patients with osteoarthritis and enhance joint mobility. 79

In addition, HA derivatives, such as HA esters and cross-linked HA gels, have been thoroughly studied for wound dressing applications. The report shows that these chemical modifications significantly reduce the degradation of HA. 69,80 For example, in the absence of enzymatic activity, benzyl HA ester undergoes hydrolytic degradation through ester bonds, and the degradation time ranges from 1 to 2 weeks to 2 to 3 weeks. Month depends on the degree of esterification. 69,80 Together, these studies emphasize the potential of HA in combinatorial systems for a range of biomedical applications, including tissue engineering, drug delivery, wound healing, and temporary implants.

Chitosan is another naturally derived biodegradable polysaccharide commonly used in tissue engineering. 81 Chitosan is a derivative of chitin, the second most abundant natural polymer in the cell walls of crustaceans and insects and fungal cell walls. 81 Chitin is partially deacetylated to form chitosan, which is linked by glucosamine and N-acetylglucosamine in a β(1-4) manner. 82 Molecular weight and degree of deacetylation are critical to assessing the characteristics of chitosan, depending on the source and production process.

Chitin and chitosan can be biodegraded by human enzymes (such as lysozyme), which break the connection between acetylation units and degrade chitin/chitosan into oligosaccharides. 83 The degradability of chitin/chitosan-based materials is essential for scaffold construction because it affects cell behavior and 84 However, the low mechanical resistance of chitosan makes it unfavorable for use as a support in tissue engineering Material. 85 In order to create better mechanical properties, crosslinking agents are used together with functional reactive groups to allow them to be used to build bridges between polymer chains and optimize the resistance and elasticity of chitosan membranes. 85 In addition, chitin/chitosan has the ability to chelate with the Ca2+ or Mg2+ present in the bacterial cell wall, thereby destroying the entity of the bacterial cell wall, and using them to react with the anionic phosphate group of the phospholipid found on the bacterial cell membrane NH3+ amino group, This leads to changes in cell membrane permeability and ultimately release of bacterial cell contents. 84,86 These functions enable chitin/chitosan-based materials to exhibit bactericidal effects on both gram-negative bacteria and gram-positive bacteria, making them have a wide range of medical applications in tissue engineering and biomedical applications. 84,86

Figure 2 The structure of chitin and chitosan.

Specifically, chitin/chitosan-based materials have shown potential in connective tissue, nerve, fat, and vascular tissue engineering applications. 87-89 For example, silk fibroin (SF)/chitin-based scaffolds are used to repair myofascial abdominal wall defects, showing continuous integration with adjacent natural tissues and similar mechanical strength to natural tissues. 88 Similarly, chitosan/hydroxyapatite-based scaffolds loaded with bFGF for periodontal tissue regeneration promoted the vigorous proliferation and migration of periodontal ligament cells and cementoblasts. 87 A recent study produced nanoscale chitosan/hydroxyapatite-based scaffolds through thermally induced phase separation and freeze-drying technology, and found that compared with pure chitosan scaffolds, this combination showed greater Compression mechanical properties-this is the key performance tissue engineering scaffold for the successful use of the scaffold. 90 Further testing is needed, but it is expected that this scaffold will also allow cell attachment and tissue growth in vivo. Taken together, these results highlight the potential of chitin/chitosan-based scaffolds to provide a cell-friendly microenvironment for connective tissue healing.

Although chitosan is widely used in bone tissue engineering applications due to its various advantageous properties, as mentioned earlier, its tensile strength and modulus range are lower than that of natural bone. 91,92 In an effort to enhance the mechanical properties of chitosan, Tamburaci et al. combined natural silica material diatomaceous earth (diatomite) with chitosan to make bone tissue regeneration scaffolds; they found that diatomite-enhanced shells The glycan composite film improves the surface area, roughness, swelling characteristics and protein adsorption capacity of the traditional chitosan film, and at the same time has no cytotoxic effect on the Saos-2 osteosarcoma cell line with excellent biocompatibility. 93 Interestingly, Tamburaci et al. also found that the incorporation of diatomaceous earth into the chitosan scaffold significantly increased the proliferation and alkaline phosphatase activity of Saos-2 cells. 93 Overall, diatomite-enhanced chitosan scaffolds showed improved performance while maintaining the high biological activity typical of traditional chitosan scaffolds, indicating the potential of chitosan for bone tissue engineering applications.

In addition, glutaraldehyde cross-linked collagen-chitosan hydrogel has been successfully applied to adipose tissue engineering. A study confirmed the in vitro viability of preadipocytes (PA) on glutaraldehyde cross-linked collagen-chitosan hydrogel scaffolds. Subsequently, the rat subcutaneous bag test was used to evaluate the PA implanted stent in vivo, which showed excellent biocompatibility, formed adipose tissue, and induced vascularization. 89 In addition, due to the success of chitin/chitosan-based materials as biomaterials for cartilage repair, they have biocompatibility and structural similarity with GAG found in cartilage. 12,94,95 Recently, Lee's team synthesized an injectable hydrogel composed of ethylene glycol methacrylate chitosan and HA by photocrosslinking with riboflavin photoinitiator under visible light. 12 Results During the formation of the cross-linked chitosan network, high molecular weight HA was encapsulated in it, forming a semi-interpenetrating network, providing a more favorable microenvironment for cartilage formation. 12 Similarly, these photopolymerizable hydrogels have shown strong capabilities as cell carriers and further emphasize the advantages of chitin/chitosan-based materials in tissue engineering.

In addition, chitin/chitosan-based materials have been successfully incorporated into skin wound management. Many studies have reported the use of chitin/chitosan stents and membranes to treat patients with deep burns. 96,97 Recently, new α-chitin/silver nanoparticles (AgNPs) and β-chitin/AgNP composite scaffolds have been tested for use in wounds-96,97 These chitin/AgNPs composite scaffolds have been found to be golden yellow Staphylococcus and Escherichia coli have excellent antibacterial activity and good blood clotting ability. 96,97 In addition, the function of β-chitin/AgNP composite scaffolds is promising. In addition to antibacterial activity, the matrix can also provide good cell attachment, indicating that these composite scaffolds are ideal for wound healing applications. 97

Finally, chitin/chitosan-based materials show excellent potential in drug delivery systems. For example, in a study, when carboxymethyl chitin nanoparticles were cross-linked with FeCl3 and CaCl2, they were shown to be non-toxic to mouse L929 cells and showed significant antibacterial activity against Staphylococcus strains. 98 Studies have shown that materials based on chitin/chitosan may be more exciting for the management of controlled drug delivery for HIV. In a study of chitosan nanoparticles coupled with anti-transferrin and anti-bradykinin B2 antibodies, researchers found that chitosan nanoparticles have the potential to effectively penetrate the blood-brain barrier, thereby enhancing the brain Drug delivery to inhibit HIV 99 Another study showed that the use of chitosan nanoparticles to encapsulate conventional antiretroviral drugs that target HIV can more effectively control virus proliferation in target T cells. 100 achieves higher cell targeting efficiency, mainly because chitosan nanoparticles have a slight immunogenicity, making them more visible to the immune system, so that they can be absorbed by phagocytes more effectively. 100 A separate study investigated the loading of lamivudine (a selective inhibitor of HIV types 1 and 2) in mouse L929 fibroblasts. 101 In vitro drug release study When the pH of the medium changes from alkaline to acidic and further from acidic to neutral, the drug release rate of PLA/chitosan nanoparticles decreases, which may be due to the presence of polymer nanoparticles The repulsion between H+ ions and cationic groups. 101 Because the drug encapsulated in the delivery system is best protected in the gastric environment at acidic pH, and then released continuously in the intestine (neutral pH), these findings indicate Chitosan-based nanoparticles show excellent potential, such as a carrier system for HIV-controlled drug delivery.

In addition to HIV management, chitin/chitosan-based materials can also be used as drug delivery vehicles for cancer treatment. For example, a pH-responsive magnetic nanocomposite material was wrapped in chitosan for targeted and controlled drug delivery, and it was found that the yield product was non-toxic and exhibited high anti-tumor activity, and at pH <6.0.102 Maintain its excellent pH sensitivity

In addition to improving the targeting and efficiency of cancer and HIV drug delivery vehicles, chitin/chitosan-based materials have been used in various other delivery systems. In a recent study, Di et al. developed an ultrasound-triggered insulin delivery system that allows pulsed insulin release to provide a long-term, continuous, and fast on-demand response. 103 This system contains encapsulated insulin loaded in PLGA nanocapsules in chitosan microgel. After ultrasonic treatment, the stored insulin can be quickly released to regulate blood sugar levels. 103 The research team found that in a mouse model of type 1 diabetes, 30-second ultrasound administration can effectively control blood sugar for 1 week and concluded that the delivery system may be used to release other therapeutic agents in a non-invasive and convenient manner. 103 In addition, Liang et al. 104 and Jing et al. 105 showed that chitosan derivatives as a delivery system can also enhance the absorption of biologically active compounds from oral tablets and may allow oral administration of protein and certain peptide drugs. In addition, hydroxyethyl chitosan (a derivative of chitosan) has shown great potential as a drug delivery material for the treatment of glaucoma and other ocular diseases due to its good water solubility and excellent biocompatibility. . 106 Further research must be conducted to evaluate any side effects or instability of chitosan-based materials; however, chitosan-derived drug controlled release systems seem to have great potential.

Chitin/chitosan-based materials have been extensively studied for several different tissue engineering applications, regenerative medicine, wound healing, and drug delivery, for good reasons. They have excellent biodegradability and biocompatibility, and are known to have anti-ulcer, anti-acid, cholesterol-lowering effects, wound healing, anti-tumor and hemostatic properties. 107-110 Although chitin/chitosan-based materials often lack mechanical properties, they have functional reactive side groups that can be cross-linked to bridge between polymer chains, optimizing the electrical resistance and elasticity of these materials. 85 Due to their unique combination of physical and chemical properties, chitin/chitosan can be molded into porous scaffolds relatively easily, and their cationic properties allow them to form polyelectrolyte complexes with many types of anionic GAGs, making them It can regulate the activity of various growth factors and cytokines for tissue engineering purposes. 85 An important feature of chitin/chitosan is its mucoadhesive properties and its ability to open tight epithelial junctions, making them very suitable for drug delivery through the nasal cavity and internal organs to the ear, eye, cheek, and lung systems. 85 However, some challenges do exist. Chitosan is insoluble in most organic solvents, making the delivery of hydrophobic drugs difficult; in addition, various methods that adapt to the dissolution of chitosan, such as alkylation, acetylation and carboxymethylation, have certain disadvantages And limitations. 111

In general, chitin/chitosan is a polymer, which has very important applications in the future industrial and biomedical fields. Its unique chemical properties have recently allowed it to be studied as part of the biofunctionalization of microelectromechanical systems, which will enable it to perform functions such as biometric recognition, enzyme catalysis, and drug release control, all of which are critical to the advancement of drugs. -Delivery and scaffolding technology. 85

Starch is the main energy storage polysaccharide in plants, and it exists in the form of granules composed of amylose and amylopectin. 112 Amylose is a linear polymer composed of glucose monomers connected by α-D-(1-4) glycosidic bonds, while amylopectin molecule is a huge amylopectin polymer, known to have the highest molecular weight One of the natural polymers. 113 The particle size, amylose/amylose ratio, mineral content, and phosphorus and phospholipid content of different plants are slightly different, resulting in different starch properties. 112 Due to different swelling, solubility, gelatinization, mechanical behavior, enzyme digestibility, rheological properties, and surface properties, the specific characterization of starch is particularly important, which affects the way it needs to be processed to transform it into more useful, for example, Hydrogels, pastes and nanoparticles. 114 Generally, natural starch nds isolated from different plants have limited shear resistance, heat resistance, thermal decomposition and high retrogradation tendency. 112 These limitations have been overcome by combining starch with more stable synthetic thermoplastic polymers, or using physical treatment of starch (such as heating or humidity), or using chemical modification to introduce certain functional groups to significantly change its physical and chemical properties. Make starch more useful in tissue engineering, drug delivery, and delivery of biologically active compounds. 112

In its tissue engineering applications, starch is due to its osseointegration behavior enhanced with hydroxyapatite, good mechanical properties, non-cytotoxicity and biocompatibility, excellent cell adhesion matrix and when combined with thermoplastic polymers. The thermoplastic behavior. 115 Recently, these starch-based scaffolds have been further improved. In a recent study, Mahdieh et al. synthesized a nanocomposite biomaterial that consists of a mixture of thermoplastic starch and ethylene vinyl alcohol as a polymer matrix, and added nanostructured forsterite and vitamin E as ceramic reinforcing phases. And heat stabilizer. 116 They found that compared with the traditional starch-ethylene-vinyl alcohol matrix, nanoapatite is a newly developed bioceramic that can improve the biological and mechanical properties, thereby reducing the degradation rate of the scaffold, and at the same time stimulating the proliferation of bone cells. 116

In particular, the application of starch and PCL mixture (SPCL) as a tissue engineering structure has received extensive attention from many research groups. 117 PCL improves the processing performance of starch, reduces its high rigidity, and can overcome the high moisture sensitivity of starch, which is one of the biggest weaknesses of starch as a biological material. 118 On the other hand, starch improves the biodegradability of PCL, and as the cheapest biomaterial on earth, starch can greatly reduce the high cost of the final product. 119 Through the proper mixing of starch and PCL, SPCL can overcome the limitations of PCL and starch, while also allowing the control of mechanical and degradation characteristics by adjusting the ratio of components-this is a significant advantage that allows it to adapt to many different Tissue regeneration rate. 120 SPCL is particularly effective in bone engineering, because one of the biggest biological specifications of SPCL composites is their abi 117. In fact, several different research groups have recently tested SPCL for this purpose. 117 Carvalho et al. studied the bone regeneration potential of undifferentiated human adipose-derived matrix/stem cells loaded in SPCL scaffolds to enhance and stimulate the proliferation of osteoblasts. 121 They found that SPCL is a suitable scaffold for bone tissue engineering, allowing new tissue in a skull defect to be approximately 20% of the defect size after 4 weeks and 43% at 8 weeks. week. 121 Link et al. conducted a similar study on critical-size skull defects in male Fisher rats and found that SPCL fiber mesh proved to be an effective bone regeneration material. 122 Requicha et al. studied a new type of in vivo behavior in a mandibular rodent model with a double-layer SPCL scaffold functionalized with silanol groups (SPCL-Si) and compared the results with commercial collagen membranes. 12 3 They found that compared with commercial collagen membranes, SPCL-Si scaffolds induced a significant increase in new bone formation. 123

Starch has been proposed as a possible drug delivery system. 124 In its hydrogel form, it can effectively encapsulate drugs in interstitial spaces, thereby protecting them from adverse human conditions. 125 In addition, starch hydrogels are resistant to gastric juice, allow potential oral drug delivery systems, and they can be modified to degrade in very specific parts of the gastrointestinal tract, thereby allowing site-specific delivery. 126 In addition, the physical modification of starch through retrogradation has led to a high level of development of type III resistant starch, a very thermally stable, low-solubility starch form, making it suitable for colon-specific delivery systems. 124 However, in practice, research on starch as a possible drug delivery system is very limited. Most of the research on starch as part of the drug delivery system is theoretical, and scientists are still exploring the possible effects of physical modification of starch on the mechanical and structural properties of hydrogels. So far, there is no conclusive data on this issue.

As the cheapest and most bioavailable natural polymer, starch is an interesting renewable resource that may have many different biomedical applications. 119 Starch is completely biodegradable, non-cytotoxic, biocompatible, and exhibits high Young's modulus and low elongation at break. 117 is relatively easy to be chemically modified, and it has the ability to replace some of the more expensive synthetic polymers in the manufacture of composite biopolymers. 127 When starch is combined with PCL, SPCL exhibits additional properties, such as better processability, increased mechanical properties, and controllability. 117 As the recent study by Requicha et al. has shown, it is mixed with traditional (30:70) SPCL. In comparison, the bone formation rate induced by functionalized SPCL-Si polymer is much higher. , Further showing the potential of starch-based biopolymers as scaffolds. 123 However, bone tissue engineering outside of research is largely limited. Compared with many other natural polymers, although the potential of drug delivery is theoretically studied, it is relatively unexplored. Further research is needed to utilize the abundant starch not only for bone tissue engineering.

Alginate is a polysaccharide derived from the cell wall of brown seaweed and the extracellular of some bacteria. It is an anionic polymer that is biocompatible, non-toxic, and non-inflammatory—as long as it goes through multiple purification steps—but it is mainly due to its mild gel conditions, low cost, and relatively simple modification. It is well-known that new alginate derivatives can be used to make alginate derivatives. 128 In particular, alginate hydrogels have been prepared by various chemical or physical cross-linking methods, which can be used for wound healing, bioactive agent delivery and tissues. Engineering and many other applications. 129 The main disadvantage of alginate is that it generally lacks strong mechanical properties. 128 However, by combining alginate with other biological materials such as agarose and chitosan, and partially oxidizing alginate through molecules such as sodium periodate, Scientists have managed to improve its mechanical properties and degradability, bringing great hope to alginate-based biomaterials. 129

Recently, there has been a surge in research on the regeneration and engineering of alginate in various tissues and organs in the body. A study attempted to create a tissue engineered skin substitute by developing fish collagen/alginate (FCA) sponge scaffolds, and then functionalized by combining chitooligosaccharides (COS) of different molecular weights with the help of cross-linking agents. 130 found that the excellent biological and functional properties of collagen and the controllable porosity of sodium alginate help to create a matrix for cell growth in skin tissue regeneration. 130 Adding COS to FCA produces FCA/COS1, resulting in a scaffold with improved cell adhesion and proliferation, ECM compatibility, improved porosity and water absorption, and overall excellent physical, mechanical and biological properties, which may become skin tissue Candidates for engineering applications. 130 Another study mixed alginate with polyethylene oxide (PEO), and then modified the resulting product with trifluoroacetic acid (TFA) acidified carboxylate groups to produce e-poly(alginic acid) . 131 Although the use of electrospun scaffolds of sodium alginate in tissue engineering is usually limited due to high solubility and uncontrollable degradation kinetics, poly(alginic acid) exhibits enhanced stability and controllability in an aqueous environment By changing the duration of the TFA-alginate reaction, the degradability of TFA makes it attractive in the production of tissue engineering biomedical equipment. 131

Alginate-due to its favorable gelling conditions, biocompatibility and relatively simple modification-has also been studied for bone regeneration and myocardial tissue regeneration. 132 A study showed that using alginate as a dispersant in hydroxyapatite/chitosan composites helps to create a more uniform pore structure than using only hydroxyapatite/chitosan composites. 133 The increased pore shape helps increase the elastic modulus and compressive strength of the scaffold, thereby significantly improving the differentiation of osteoblasts to promote bone regeneration. 133 In another study, a new type of nano-biocomposite scaffold combining chitosan, gelatin, alginate and hydroxyapatite showed mechanical and biological properties that mimic natural bones. 134 They found that they can take advantage of the anionic properties of alginate and their excellent crosslinking ability—especially multivalent cations in the presence of them—to produce a company's red stable nanocomposite scaffold, which is needed to form new tissues and ECM The prolonged degradation time. 134 In terms of tissue engineering, the treatment of heart tissue has attracted much attention, especially in the case of myocardial infarction (MI), where most of the functional tissue is often lost. In a study on a rat model of acute MI, Kim et al. tried to locally inject alginate-chitosan hydrogel into the peri-infarct area immediately after MI, and evaluated the results 8 weeks later. 135 They found that this treatment promoted greater angiogenesis by recruiting cardiac stem cells to increase the recruitment of endogenous repair in the infarct area, preventing apoptosis, inducing re-entry of cardiomyocytes, and most importantly, preventing deterioration of heart function. 135 Animals injected with hydrogels showed significant improvement after extensive myocardial infarction. Given the simple manufacturing and completely natural composition of this hydrogel, alginate-based biomaterials for myocardial regeneration may be in the heart of the future. Play a huge role in vascular repair. 135 In addition, sodium alginate is one of the largest applications in wound healing, partly because of its excellent bioabsorbability and biocompatibility, but also because of its easy gelation and physical cross-linking ability. Execution, so it is generally more favored than chemical cross-linking. 132,136 A study formulated a freeze-dried wafer-gelatin ratio of 75/25 sodium alginate and loaded it with silver sulfadiazine (a metal antibacterial agent) for use in infected wounds. 137 Sodium alginate gel is used as the main biological material, mainly because it allows wound exudate to exchange ions in the dressing, thereby creating a humid environment. 137 Mixed with gelatin to prevent hydration of alginate over time The loss of the cationic crosslinker enables the wound dressing to release silver sulfadiazine within 7 hours, which greatly reduces the bacterial bioburden compared with traditional wound dressings. 137 Another study found that the combined use of alginate and deoxyribonucleic acid (DNA) gel can lead to the sustained release of biologically active factors, such as the growth of endothelial cells, neuropeptides and growth factors used to treat diabetic foot ulcers. This results in significantly better healing results than the delivery of these biologically active factors alone. 138 In addition, in a different study, scientists found that the integration of hyaluronic acid, compared with any biomaterial alone, promoted a significant gap in skin wound damage in the ionically cross-linked alginate-based hydrogel closure. 139 The addition of hyaluronic acid significantly improves the mechanical properties required for wound dressings, but has little effect on the gelation time of alginate, providing an effective and simple method for improving excisional wound damage in a clinical environment. This is not to say that alginate-derived wound dressings have been completely successful. 139 In one study, a 500-area randomized prospective study was conducted to test the effect of silver-eluting alginate dressings on reducing complications of lower extremity vascular surgery compared with standard dry surgical dressings. They found that using this silver alginate dressing had no significant difference in reducing postoperative wound complications. 140 However, it is clear from these new and other studies that alginate-based wound dressings will continue to play an important role in the future, because the relatively easy modification of alginate properties will allow researchers to explore infinitely Number of possibilities and solutions to promote better healing.

Alginate is a widely used biological material, especially in regenerative medicine and tissue engineering. Due to its biocompatibility, mild physical gelation process, chemical and physical crosslinking ability, non-thrombotic properties and its The similarity of hydrogel matrix textures132 In addition, alginate happens to be easily modified into any form, such as microspheres, sponges, foams, elastomers, fibers and hydrogels, thus broadening the alginate-based biomaterials. The scope of application, it can be combined with other natural biological materials to create and enhance new and existing properties. 141 Due to the abundance of algae in water bodies, alginate is one of the most common natural biological materials in the world, making it a relatively low-cost and feasible biological material. 142 However, to achieve breakthroughs in many tissue engineering applications, it is necessary to better control the properties of polymers and develop their tissue interaction patterns. 132 The introduction of cell interaction characteristics into alginate biomaterials will become crucial in the future for the correct production of replacement tissues and even organs. 132 The types of adhesion ligands and spatial tissues in alginate hydrogels are the key to the normal function of regenerating tissues, although arginylglycyl aspartate has so far been used mainly for cell adhesion Ligands, combinations of multiple ligands and solubility factors are necessary for further application of alginate-based biomaterials for regeneration purposes. 129 For wound healing applications, compared to the rather passive process they play in current clinical applications, alginate-based gels will need to play a more active role, combining one or more bioactive agents to promote wounds heal. 129 The future of alginate-based wound dressings depends on establishing more control over the delivery of one or more drugs, as well as their duration and sequence. 129 A better understanding of the basic principles of alginate properties will help researchers use seaweeds The remarkable characteristics and bioavailability of salt, and the use of genetic engineering technology to control the synthesis of alginate with new and improved characteristics by bacteria, thereby completely changing the use of this material. 129

Silk fiber is a natural biopolymer mainly derived from the silkworm Bombyx mori. 143 Silk fiber consists of two parallel SF proteins, glued together by a layer of sericin on the surface. 144 Until recently, sericin was considered immunologically incompatible with the human body, so it was largely ignored as a biopolymer. 145 However, SF has been used as a biomedical suture material for centuries. 143 It is a semi-crystalline structure with an incredible combination of mechanical properties, very high tensile strength, coupled with excellent elasticity and flexibility. 143 In fact, its strength density is ten times higher than steel. 146 SF's unique mechanical properties, adjustable biodegradability, diversified side chain chemistry, and in fact, genetic engineering technology can be used to customize proteins to have various new characteristics, functions and applications in biomedicine 143 In addition SF from other species of Lepidoptera usually has other unique characteristics, increasing their potential for biomedical applications. 145 In addition, it has been found that some spiders, such as Antheraea mylitta, produce silk with better cell adhesion and a more highly ordered crystal structure, which improves mechanical strength and reduces solubility in acidic solvents. 145 In addition, since SF can be easily processed into gels, films, nanoparticles, membranes, nanofibers, scaffolds and foam-like forms, they can be adapted to simulate extremely diverse tissues in the human body. 143 Therefore, SF has recently been studied for several different applications, including almost all areas of tissue engineering, wound repair, drug delivery, and possibly even bio-inks for 3D bioprinting.147

SF combines the unique combination of elasticity, strength and potential self-healing modification (through cross-linking), together with its biocompatibility, adjustable biodegradability, antibacterial and other mechanical properties, making it an attractive material , Can be used as a part of composite scaffold for tissue engineering. 148 In the past few years, several different studies have explored SF-based biomaterials for tissue engineering. In a study, Shao et al. designed a nanostructured composite scaffold whose core is composed of hydroxyapatite and SF149. Then compare it with the pure SF nanofibers. 149 They found that the initial modulus and fracture stress of the composite stent increased by 90 times and 2 times, respectively. 149 Osteoblast-like cells were cultured on the composite material. Shao et al. found that the composite scaffold showed higher biocompatibility, better cell adhesion and proliferation, and functionally promoted alkaline phosphatase and biomineralization. change. 149 The team concluded that the nanostructured composite scaffold composed of hydroxyapatite and SF core has excellent biomimetic and mechanical properties, and has the potential as a biocompatible scaffold for bone tissue engineering. g.149 In another study In, Tian et al. used the same coaxial electrospinning technology to fabricate a nanofiber scaffold (p-PS/N) composed of nerve growth factor, SF and PLA. 150 After 11 days, PC12 cells (a model for neuron differentiation) cultured on these scaffolds showed elongated neurites up to 95 μm, leading the research team to conclude that p-PS/N scaffolds can support PC12 cell attachment And differentiation for neural tissue engineering. 150 Another research team independently developed a 3D porous SF scaffold derived from non-mulberry silkworm Antheraea assamensis to examine its ability to support cartilage tissue engineering. 151 They found that SF scaffolds can produce enhanced sulfated glycosaminoglycans and type II collagen, and demonstrated in vivo biocompatibility after 8 weeks of implantation in a rat subcutaneous model, indicating that these non-mulberry SF scaffolds may be suitable for Chondrocyte-b 151 In another study, the same research team developed a 3D hybrid scaffold composed of SF and human hair-derived keratin to study their ability to promote enhanced fibroblast adhesion and proliferation . 152 They found that the scaffold showed high porosity and interconnected pores, with excellent thermal, degradation, and mechanical properties. 152 In addition, they found that the expression of type I collagen increased in cultured cells, indicating the proliferation of functional fibroblasts. The research team concluded that hybrid biomaterials, especially SF and human hair keratin hybrid scaffolds, are used as the dermis for skin tissue engineering. Alternatives may have broad prospects. 152 In order to create attachment points (functional repair of tendons and ligaments), another research team Tellado et al. designed a complex scaffold, including a biphasic SF scaffold with a comprehensive anisotropic and isotropic hole arrangement, similar to wha t Respectively exist in natural tendons/ligaments and bone/cartilage. 153 The scaffold was functionalized with heparin. Human primary adipose-derived mesenchymal stem cells were cultured on the scaffold and their ability to deliver transforming growth factor β2 (TGF)-β2) and growth/differentiation factor 5 (GDF5) was evaluated. 153 The research team found that functionalization of heparin increased the amount of TGF-β2 and GDF5 attached to the scaffold, resulting in increased cartilage and collagen II protein content and the expression of attachment points, proving that growth factor-loaded biphasic SF scaffolds may be used Tendon/ligament repair. 153

In addition to its numerous tissue engineering applications, SF has recently been explored as a biomaterial for skin repair due to its excellent hemostatic properties, low inflammatory potential, and permeability to oxygen and water vapor. 154 Preliminary studies even show that compared with traditional hydrocolloids, SF film and sponge-based dressings can promote wound healing and enhance skin regeneration. 154,155 Currently, there are only three SF-based medical products approved for clinical use in the world: SeriScaffold (Allergan Medical, Inc.), the US Food and Drug Administration, TymPaSil (CG Bio Inc.) of the Korean Ministry of Food and Drug Safety, and China Food and Drug Administration Sidaiyi (Suzhou Suhe Biomaterials Technology Co., Ltd.) of the Administration. 156 Among the three, only Sidaiyi is suitable for skin wound healing, but none of these three products have been widely used in clinical practice. 156 A recent clinical study conducted by Zhang et al. in 2017 focused on the development of translational SF films for clinical applications. 156 They conducted a single-blind, parallel, controlled clinical trial on 71 patients to treat wounds at the donor site. 156 Compared with the positive control fourth-generation doctors, the SF film showed significantly faster wound healing. The average time to complete wound healing was about 9.86 days, while the fourth-generation doctors took 11.35 days. 156 In addition, 100% of patients treated with SF film healed on the 14th day, and 88.6% of the patients treated by the fourth-generation medicine healed on the 19.156 day. 3 cases of inflammatory reaction and 4 cases of adverse reaction were observed in the SF film group, and 3 cases of inflammatory reaction and 4 cases of adverse reaction were observed in the SF film group. The wounds of the 156 SF film group are cleaner than the wounds of the Sidaiyi group that are prone to exudation, due to its better fluid handling capacity and gas permeability. 156 This translational study, together with previous successful studies on rabbit and pork wound models, shows that this newly developed SF film may indeed be safer and more secure than the fourth-generation clothing materials currently used in China for the treatment of skin repair and regeneration. efficient. 156 To date, many other studies have recently shown the in vitro results of using electrospun nanofiber SF dressings or composite SF dressings as a way to enhance the volume properties of SF. 157-161 Based on all these studies, it is clear that SF has very good prospects for the future. 156

In addition to the properties already mentioned, SF has many other unique and outstanding properties that make it very suitable for use as a drug carrier. 148 Because of its mildness, it can even load the most sensitive drugs, such as proteins and nucleic acids. 148 In addition, SF has a variety of amino acids and multiple functional groups, which can simplify the connection of different types of biomolecules or antibodies, so that it has a wide range of functionalization. 162 Finally, SF naturally has an inherent response to pH changes, which makes it easy to control the drug release kinetics, and the mechanism of clearance from the body is easily completed by the degradation of proteolytic enzymes in the body without leaving any possible side effects. 163 Recently, most research groups have been studying the mechanism components of using SF nanoparticles for protein delivery, small molecule delivery and even anti-cancer delivery. 164-166 These studies have focused on the characteristics of SF, such as electrostatic interactions with loading efficiency, different drug delivery media and packaging efficiency that control drug release kinetics, as well as compatibility, degradability, and drug retention. 163 However, the potential role of SF in drug delivery has not yet been determined. Since SF nanoparticles are still in their infancy, it remains to be seen how SF properties can be best utilized and improved for drug delivery. 163

Although the current tissue engineering technology has been greatly improved over a few years ago, it still cannot capture the complexity of the 3D anatomical structure and function of human tissue. Therefore, few engineering structures have entered human clinical trials. 147 3D bioprinting offers an untapped potential for capturing the complexity of human tissues, and it is touted as the future of tissue regeneration strategies. 167 One of the most critical aspects of 3D printing is bio-ink design, which not only provides 3D architecture, but also functions as the first contact point for cells to synthesize regulatory proteins and cytokines suitable for their simulated tissues. 168 Silk has become one of the most popular choices for bio-ink preparations. The ability to physically cross-link its protein polymer chains through the intermolecular and intramolecular β-sheet semi-crystalline structure makes it stable after printing without any chemical or photochemical reactions or additives. 169 In addition, silk is a very strong and durable material as mentioned above. Its inherent spinnability, cell compatibility and controlled degradation make silk a strong candidate for future bio-ink preparations. . 147 Of course, the research is still in its infancy. So far, there have been reports in the literature that silk 3D bioprinting has proved that the cell viability after printing is between 45% and 98%. 170 However, among the limited available hydrogel bio-inks currently tested, the optimized blend of B. Mori silk-gelatin bio-ink shows the potential for the most 3D bioprinting functional tissue equivalents. 147 Before the commercialization of 3D bioprinting technology, there are still significant levels of scientific and regulatory challenges, and more experimental studies are needed to optimize silk as a potential bio-ink. 147

SF-based biomaterials have great potential as one of the outstanding natural biopolymers researched today. It is easy to structure modification, controllable degradation, high tensile strength, elasticity and flexibility, the potential to introduce physical cross-linking, hemostatic and self-healing properties, and the ability to be processed into many different forms, such as sponges, films and Hydrogel makes SF a polymer with various biomedical applications. 143 However, unlike starch or more bioavailable polymers, silk is produced by only a few species, and only in the silkworms, their numbers are considerable. 143 Although spider silk has proven to show impressive toughness, stiffness, strength, and ductility, it is impractical to obtain any large amount of silk from any spider. 145 A study pointed out the transgene expression of spider silk in plants (such as tobacco and potato) or the use of mammalian epithelial cells as a way to obtain more substantial silk production, but so far, there is no solution. 171,172 In addition to sustainability, the key lies in the development of new silk-incorporated biomaterials and advancement of our current technology in tissue engineering is to study surface modification or composite with other synthetic polymers, and figure out how to use heat treatment or mechanical Control the crystallization in SF during stretching. 145 With the new cross-connection method, SF-based materials can be designed to self-heal, which will bring new applications to tissue engineering and wound healing. 145 Sericin-the neglected protein in silk fibers-also needs more in-depth research. Although it has long been believed that sericin is biologically incompatible with the human body, new research shows that sericin is immunogenic only when used in combination with SF. 145 When used alone or in combination with other biopolymers, sericin has been shown to have attractive biologically active properties, with antioxidant properties, moisture retention and mitogenic effects on mammalian cells. 173 Its promotion of keratinocytes and fibroblasts has led to the development of sericin-based biomaterials for skin tissue repair. Its ability to cross-link with genipin allows it because it can be used in bone, skin and nerve tissue engineering. . 174 In addition, sericin can be used for drug delivery because it can help promote the production-responsiveness of nanoparticles and microparticles, hydrogels, and conjugated molecules through its chemical reactivity and pH, thereby improving the biological activity of drugs. 173 At present, most of the methods for purifying sericin have encountered the edible results of unpr in terms of size, composition and biological activity. However, future technological advances and recycling methods may make sericin an important organism in the fields of tissue engineering and drug delivery. Material. 144

PHA is a type of natural, biodegradable polyester, synthesized by microorganisms, as an intracellular carbon and energy storage compound, under uneven growth conditions. 175 They have excellent biodegradability and biocompatibility, and produce non-toxic degradation products, making them very suitable for biomedical applications, such as drug delivery, tissue engineering and implantable device replacement, 176 including sutures , Repair patch straps, orthopedic needles, stents, stents and adhesion barriers. 177 However, unmodified PHA-despite their special abilities mentioned above-have some important limitations, such as poor mechanical properties due to the presence of large crystals, 178 poor thermal stability, high hydrophobicity, and slow degradation, which make It is not conducive to many biomedical applications. 179 The inherent hydrophobicity of PHA hinders their application in biomedical applications.177 Many biomedical devices require better hydraulic power.179 In addition, PHA lacks chemical functions, and polyesters are often incompatible when combined with drugs. 177 Although biodegradable, PHA is very stable when unmodified, which impairs their therapeutic function in other areas. 177 At the same time, uncommon PHA is functional. Some organisms have produced side groups including hydroxyl and/or carboxyl groups, methylated branches and other hydrophilic derivatives to expand the applicability of PHA. 180 Therefore, it is essential that PHAs need to be modified to fix these properties while maintaining their special properties so that they can be used in biomedical applications.

Figure 3 The structure of poly-(R)-hydroxybutyrate (polyhydroxyalkanoate, PHA).

A very important feature of PHA is that by simply selecting suitable production strains, culture conditions, and carbon sources, they can be developed in a variety of physical and chemical behaviors, such as amphiphilicity, crystallinity, and mechanical properties. 181,182 Because PHA is PHA produced by more than 300 different types of gram-positive and gram-negative bacteria, there are many ways to produce PHA with different properties, making PHA the largest group of biopolymers, so it is a biological One of the most promising applications in medical applications. 176 In addition, for the biosynthesis of PHA using different bacteria, several alternative methods have been developed to make PHA a very readily available biopolymer. Mixing one kind of PHA with another kind of PHA, mixing PHA with other biodegradable polymers and polyesters, and chemical modification of PHA, such as grafting and copolymerization, and recent electrospinning, 183 can all be easily And more importantly, the structure of PHA is precisely adjusted, resulting in 179. Although mixing has been shown to produce extreme properties in PHA, grafting and copolymerization have led to the development of various PHAs with different properties. These PHAs can be used in a variety of ways. Biomedical applications. 179 With the development of metabolic engineering, various combinations of PHA with different ratios of monomers can also be produced from inexpensive substrates such as glucose and fatty acids. 175

PHA has been widely studied and used in a wide range of biomaterial applications. For example, a study compared the various characteristics of different PHA scaffolds and their manufacturing techniques for bone tissue engineering, and hypothesized that composite scaffolds made by mixing different PHA materials may produce better scaffolds. 184 Another study specifically identified poly-3-hydroxycaprylate—a PHA produced by Pseudomonas mendocina—as a PHA biomaterial that successfully demonstrated outstanding and unique properties in cardiac tissue engineering. 185 A different study investigated the use of poly(3-hydroxybutyrate-co-4-hydroxybutyric acid) solutions as experimental wound dressings and found that they accelerated the wound blood vessel formation and healing process. 186 Another study evaluated different variants of PHA—a composite scaffold composed of PHA/ceramic composites—that showed greater biological activity and bone regeneration potential in vitro and in vivo. 187

Some studies have found that, compared with poly(3-hydroxybutyrate) (PHB) or poly(ethylene glycol) (PEG), a new type of alternating block copolymer based on PHB and PEG (PHB-alt-PEG) With enhanced adjustable mechanical properties. Performance and improved processability, while maintaining no cytotoxicity, thereby overcoming the aforementioned major limitations of single unmodified PHA. 188 In addition, Loh et al. found that by adjusting the ratio of 3-hydroxybutyrate (3HB) to ethylene glycol in the synthetic thermal gel PHA-alt-the PEG copolymer or the copolymer itself in the hydrogel Concentration, the drug release rate of multi-block PHB-alt-PEG can be easily controlled. 189 Further studies have shown that the PHB-alt-PEG system can also be used as a long-term drug delivery system for mouse models of hepatocellular carcinoma by changing the concentration of the gel, showing great potential for further development in anti-cancer applications. 190

In addition, in the past few years, there have been discoveries about more therapeutic applications of PHA monomers, including the treatment of epilepsy and neurodegenerative diseases. A study showed that increasing the blood concentration of 3HB (a monomer of PHB) helps control seizures: In mice treated with 3HB, the average incubation period of seizures was significantly prolonged, indicating that the ketone body 3HB remains as an anticonvulsant Drug potential 191 Another study on mouse L929 fibroblasts, human umbilical vein endothelial cells and rabbit articular cartilage showed that 3HB has a stimulating effect on cell cycle progression, which is mediated by a signal pathway that depends on the increase of [Ca2+] . 192 Similarly, Maalouf et al. found that 3HB significantly reduced the ROS produced by mitochondria and the accompanying excitotoxic changes by increasing the oxidation of nicotinamide adenine dinucleotide (NADH) in the mitochondrial respiratory chain, but did not affect endogenous resistance. The level of the oxidant glutathione. Therefore, 3HB reduces glutamate-induced free radical formation by increasing the ratio of NAD+/NADH and increasing the mitochondrial respiration of neocortical neurons. 193 In the same study, the combined use of 3HB and acetoacetate reduced neuronal cell death and inhibited changes in neuronal membrane properties. Together, these studies show that the ability to modify and design PHA with widely accessible properties shows great promise for PHA as a potential therapeutic biomaterial.

Obviously, extensive research has been conducted on PHA and its potential for success, but only one PHA approved by the FDA for biomedicine-poly(4-hydroxybutyrate)-has very high elasticity and is available For absorbable sutures. 194 Since each individually modified PHA needs to undergo extensive testing to prove that its biocompatibility and biodegradability are still as good as its unmodified form, more testing is needed to expand the use of PHA. This is especially true for composite PHA, which seems to have almost unlimited potential in the creation of various biomaterials with better properties to meet their specific purposes. In addition, although PHA has great potential, its commercial application is limited due to the inconsistent polymer properties and the high production cost of the raw polymer. 195 In addition, sustainability is another important issue. A recent article argued that since the substrate for PHA production can be found in carbon-rich wastes mainly located in economically poor countries, integrating biopolymer production into these regions will provide these countries with sustainable PHA production and a wider range Labor market. 196 However, in order to achieve this sustainable practice, policy makers, scientists, and relevant industry sector leaders need to work together.

Drosera binder is a hydrogel based on natural polysaccharides, and people discovered it when scientists began to study a carnivorous plant known for its special lifestyle. 197 This plant Drosera uniquely uses two different glands: sessile glands, which secrete digestive enzymes, and stalked glands, which produce sticky secretions to attract prey, and then restrict their escape. 197 This viscous secretion produced by the latter gland has particularly attracted the interest of many researchers because it not only has biocompatibility, biodegradability and eco-friendly properties, but also because of its antibiotic properties and enhance cell adhesion. Echoes the unique characteristics of differentiation, and extremely high flexibility. 198 In fact, studies have shown that its elasticity is so remarkable that it can be drawn into a cord with a length of about 1 m. 198 After further investigation, the scientists discovered the chemical structure of the secretions. The biological adhesive made from drosera is composed of xylose, mannose, galactose, glucuronic acid and sulfate according to 1:6:6:6: 1.199 ratio composition

Most of the research conducted on Mao Lushui returned with positive results. For example, Zhang et al. found that the adhesive produced by dried felt moss plants can allow neuron-like cells to attach and grow on nanofibers made from the dried adhesive, which shows the potential of felt moss adhesives for tissue engineering. . 199 In recent studies, it has been found that fibrous scaffolds obtained from Sundew adhesive can increase the adhesion of many types of cells, including fibroblasts and smooth muscle cells. The study found that the nano-network within the drosera adhesive exhibited viscoelastic behavior, among other things, allowing for stronger adhesion of a variety of mammalian cells. 197

However, although Sundew adhesives have shown promise, some concerns have also been raised that may limit the potential of Sundew adhesives. A study found that Drosera adhesives are extremely susceptible to temperature changes, and the bonding strength is significantly reduced at temperatures between -20°C and -80°C. 197 However, a more important issue that may obscure the therapeutic potential of the Drosera adhesive is the ability to collect a sufficient amount of hydrogel. 200 However, Sun et al. were able to develop an adhesive hydrogel that mimics the natural hair grass adhesive and is inspired by hair grass. Compared with other in vitro hydrogels, it has excellent adhesion strength, nanostructure and Shear resistance, and also shows excellent wound healing ability when paired with mouse fat-derived stem cells in vivo. 200 Despite these findings, more research is needed to see if there is a more effective way to collect natural drizzle glue binders and to evaluate the safety and effectiveness of the viscous hydrogel inspired by drosera.

Ivy belongs to the genus Ivy and is known for its unique ability to attach to and grow upwards on surfaces such as rocks, trees, and fences. 201 To this end, ivy was found to use an adhesive disc produced by the stem of the ivy plant. 201 These adherent discs consist of four to seven tendrils or "fingers", which produce substances called ivy nanoparticles (INP). 201 These INPs are completely organic, formed by a group of macromolecules and composed of arabinogalactan proteins. It is the INP that bears the main responsibility for the tremendous power that ivy can produce. 202 In fact, it has been shown that an ivy disk weighing only 0.5 milligrams can generate a pulling force of about 0.9 kg, which is 1.8 million times greater than the weight of the bonded disk itself. 203 This incredible bond strength-combined with its excellent water solubility, low intrinsic viscosity, biocompatibility and biodegradability-demonstrates the importance of huge pot INPs in the field of tissue engineering. 14

In a recent study investigating the potential of INPs in drug delivery, INP-conjugated doxorubicin showed stronger cytotoxicity against a variety of cancer cell lines in vitro and in vivo. 14 In the same study, it was also found that INPs allowed stronger smooth muscle adhesion. Once cells in the collagen scaffold were embedded in INPs, it indicated that INPs can be used not only as drug carriers for cancer treatment, but also as nanofillers to enrich the scaffold. 14 In addition, INPs exhibit unique optical properties, exhibiting strong ultraviolet (UV) absorption and scattering, which may make them play an important role as sun protection agents. 204 Currently, most sunscreens today use metal oxide nanoparticles as fillers; however, environmental issues and the safety issues of using these nanoparticles on the skin make the use of traditional sunscreens less than ideal. Compared with metal oxide nanoparticles TiO2 nanoparticles that are often used in traditional sunscreens today, ivy nanoparticles can block more ultraviolet rays, are less toxic to mammalian cells, and are more easily biodegradable, which indicates that ivy Nanoparticles may be used as sunscreens. A better and safer sunscreen. 205

Considering their excellent physical properties, these INPs may have more applications. Unfortunately, the application of INPs has been severely restricted because they have been unknown. 202 In fact, the structure of INPs has not been determined until recently. More research needs to be done to verify their safety and effectiveness, and to find a sustainable way to produce these nanoparticles-whether they are naturally derived or synthetically simulated. 202

Although natural polymers have proven to support the potential advantages of cell function and adhesion, there are some limitations and problems in their use. For example, it is difficult to control the mechanical properties and degradation rate of natural polymers, and natural polymers may trigger an immune response or carry microorganisms or viruses. 16,206 Conversely, synthetic polymers can be modified to have a wider range of mechanical and chemical properties than natural polymers. Although synthetic polymers can avoid immunogenicity problems, biocompatibility presents new challenges. 207 Therefore, degradable synthetic polymers are currently being extensively studied to avoid the potential long-term effects associated with non-degradable polymers, such as scars and inflammation. 207,208 At the same time, synthetic polymers can be produced under controlled conditions and therefore exhibit predictable and repeatable mechanical and physical properties, such as tensile strength, elastic modulus, and degradation rate. 207 Another advantage of synthetic polymers is the control of material impurities. Finally, a pure synthetic polymer with a well-defined and simple structure has lower toxicity, immunogenicity and infection risk.

Saturated aliphatic polyesters, such as polyglycolic acid (PGA), PLA and PLGA copolymers, are the most commonly used biodegradable synthetic polymers for 3D scaffolds in tissue engineering. 207-211 The chemical nature of these polymers allows for hydrolytic degradation by deionization. -Esterification. For example, PLA and PGA can be easily processed, and their degradation rate and physical and mechanical properties can be adjusted in a wide range by using various molecular weights, structures, compositions and copolymers. 207,208,211 In addition, the body contains a highly regulated mechanism to completely remove the monomer components of glycolic acid and lactic acid when these polyesters are degraded: glycolic acid is converted to metabolites or eliminated by other mechanisms, while lactic acid can be eliminated through the tricarboxylic acid cycle. 212 Due to their biodegradability and biocompatibility, PGA and PLA have been approved by the FDA for use in medical devices, such as degradable sutures and other implantable devices. 213

PGA is a hydrophilic and highly crystalline polymer with a relatively fast degradation rate. It degrades rapidly in aqueous solutions or in the body, and loses its mechanical integrity within 2 to 4 weeks-depending on the molecular weight and degradation conditions. 212,214 In addition, PGA has great flexibility in adjusting its material properties and physical parameters, such as pore size and curvature, which is important for the development of scaffold-based tissue engineering structures. 212,214 Therefore, PGA can be used not only for tissue engineering, but also for wastewater treatment, food and other biomedical applications, such as drug delivery or biology. 215–219 In addition, previous research has successfully developed a PGA sheet combined with fibrin glue treatment Open soft tissue wounds during oral surgery. 220,221 Similarly, PGA sheets containing fibrin glue can effectively prevent postoperative bleeding, reduce postoperative pain and enhance epithelialization in the process of bone surface reconstruction after oral tumor resection. 222 How has always been, the relatively fast degradation rate—along with acidic degradation products and low solubility—brings inherent disadvantages, thus limiting the biomedical applications of PGA. 223 Therefore, ongoing research on several PGA-based copolymers continues to circumvent these obstacles.

Figure 4 The structure of poly(glycolic acid) (PGA).

PLA is another biodegradable scaffold material widely used in biomedical applications. 224 Although similar in structure to PGA, PLA exhibits different chemical, physical and mechanical properties due to the presence of additional methyl groups in its repeating unit. For example, it can take months to years to lose the mechanical integrity of PLA stents.224 This makes PLA a more suitable biomaterial for load-bearing applications (such as orthopedic fixation devices). So far, there are many PLA-based orthopedic products on the market, including Phantom Soft Thread Soft Tissue Fixation Screw® (DePuy), Phantom Suture Anchor® (DePuy), Full Thread Bio Interference Screw® (Arthrex), BioScrew® (Conmed) , Bio-Anchor® (Conmed), Meniscal Stinger® (Linvatec) and Clearfix Meniscal Dart® (innovative equipment). A new promising biomedical engineering application of PLA involves photoluminescent graphene quantum dots (GQD) with large surface area and excellent mechanical flexibility, which have interesting optical and electronic properties. 225 A recent study reported that the multifunctional nanocomposites (f-GQDs) of PLA and PEG grafted with GQDs are biocompatible and low cytotoxic, which makes them suitable for simultaneous intracellular microRNAs (miRNAs) imaging analysis And gene delivery. 225 These results emphasize the potential of the extremely versatile multifunctional nanocomposite f-GQDs for biomedical applications in intracellular molecular analysis and clinical gene therapy.

There are three forms of PLA: L-PLA, D-PLA and a racemic mixture of D,L-PLA. Recently, the stereoisomer D, L-PLA has been widely used as a biomedical coating for orthopedic materials due to its high mechanical stability and excellent biocompatibility. 207,226,227 In addition, low molecular weight D,L-PLA can be combined with drugs such as growth factors, antibiotics or thrombin inhibitors to establish a local drug delivery system. 9 Therefore, due to these highly desirable characteristics, recent efforts have shifted the focus to using D,L-PLA as a scaffold material for tissue engineering.

It is possible to synthesize PLGA with different lactide/glycolide ratios to achieve a moderate degradation rate between PLA and PGA. In general, copolymer PLGA is more suitable for the development of bone replacement structures than its constituent homopolymers, because PLGA provides better control over degradation characteristics by changing the ratio between its monomers. 228 For example, PLGA has a broad degradation rate chain composition, hydrophobic/hydrophilic balance, and crystallinity. 228 However, despite its biocompatibility, the clinical application of pure PLGA for bone regeneration is hampered by the suboptimal mechanical properties of low osteoinductivity and load-bearing applications. Therefore, PLGA is usually used in combination with other materials (such as ceramics or bioactive glass) and is often modified to make it more biomimetic, thereby improving its ability to enhance bone regeneration. 229 By implanting the AgNP/PLGA composite graft into a bone segment defect with a critical size for infection, our group demonstrated that the AgNP/PLGA composite graft has significant antibacterial properties and osteoconductivity in vivo. 209 In follow-up experiments, we unexpectedly found that AgNP/PLGA coated stainless steel alloy materials not only exhibit strong antibacterial activity, but also exhibit significant osteoinductive properties, which is not observed in a single component. Arrived. Identified as a precursor of osteoclasts, and as p may lead to osteoporosis, while improving the proliferation of osteoblasts and up-regulating the expression of the key osteoblast enzyme-alkaline phosphatase. 230 In conclusion, these findings require more research on the osteoconduction and osteoinductive properties of PLGA-based systems, but, despite this, it provides promising treatment materials for the following diseases in orthopedic surgery.

Figure 5 The structure of polylactic acid isomers (L-PLA, D-PLA, D, L-PLA).

Figure 6 The structure of poly(lactic-co-glycolic acid) (PLGA). X=number of lactic acid units, Y=number of glycolic acid units.

PCL is another saturated aliphatic biodegradable polyester used in the development of tissue engineering scaffolds and other biomedical applications. 231–233 PCL is a semi-crystalline polymer with a melting temperature of 55°C–60°C and a very low glass transition rate around -54°C. Therefore, it tends to maintain a rubbery state under physiological conditions. High material permeability. 231-233 Under physiological conditions, it can be degraded by microorganisms, hydrolysis, enzymes, or intracellular mechanisms; however, compared with PLA, PGA and PLGA, the slow degradation rate of PCL for 2-4 years and its hydrophobicity make it more resistant to general The application of tissue regeneration is less attractive, but more attractive for long-term implants and drug delivery systems. 234,235 A recent study showed that gravity-spun collagen-coated PCL fibers increased the proliferation rate of human osteoblasts. 234 Therefore, these findings emphasize the potential of gravity-spun PCL fibers as an ECM protein delivery platform to enhance cell adhesion and tissue proliferation repair. Similarly, PCL has been used to effectively capture antibiotic drugs and then incorporated into drug delivery systems to promote bone ingrowth and regeneration when treating bone defects. 236 In addition, ongoing research on micro- and nano-scale drug delivery is still continuing with PCL-centric vehicle systems. 237 In addition, a solid, free-form, manufacturing-based injection molding process for the manufacture of PCL has been developed. The resulting PCL-calcium phosphate scaffold shows in vitro cell compatibility and mechanical properties suitable for hard tissue repair . 238 In addition, Chiari et al. reported the feasibility of using a composite matrix composed of PCL and HA as a possible meniscus replacement. 239 Overall, PCL is a useful biodegradable biomaterial, which deserves further research as a porous scaffold and drug-delivery vehicle for bone tissue engineering.

PLA, PGA, and PLGA have great drug delivery effects, but they do have limitations, including the tendency of some drugs to have uneven release profiles. Therefore, in response to these problems, polyanhydrides have been produced. Polyanhydrides were originally designed for drug delivery applications because of their hydrophobicity and ability to degrade through surface erosion rather than overall degradation, which allows certain drugs to have a constant release profile and is especially important in the case of extremely strong drugs. 240 Polyanhydride is biocompatible and can be degraded in the body into non-toxic diacid by-products, which are excreted from the body as metabolites. 240 For these reasons, since there is almost no water penetration before the polymer corrodes, the drug can be well protected when this type of polymer is implanted. 241 Therefore, in 1996, after a comprehensive drug release and biocompatibility evaluation, polyanhydride was approved by the FDA as a drug delivery vehicle. 242

Generally, polyanhydrides can be easily synthesized from widely available low-cost sources and modified to have desired properties. 243 Poly[(carboxyphenoxypropane)-(sebacic acid)] is the most widely studied polyanhydride approved by the FDA. It is commonly used as a local delivery vehicle, especially for the controlled delivery of the chemotherapeutic agent dichloroethylnitrosourea (Gliadel®, Arbor Pharmaceuticals, LLC) during brain cancer treatment. 244 In addition, the results of previous animal studies in recent human trials have verified the potential of this polymer drug delivery system. 244 Obviously, it is necessary to explore polyanhydrides in drug delivery systems in the future.

Figure 7 The structure of poly(ε-caprolactone) (PCL).

Due to their toughness, durability, biocompatibility and biostability, PUR is an ideal choice for medical devices. Since the 1960s, they have been commonly used as biostabilization and biostability in heart valves, vascular grafts, catheters, and prostheses. Inert materials. 245,246 However, in the late 1990s, due to its relative sensitivity to biodegradation and the desire to further understand the biological mechanisms of biodegradation in the body, interest in the design of biodegradable PUR for tissue engineering and drug delivery surged. 246 Biodegradable PUR has compelling potential because it is used as a scaffold for tissue regeneration. 245,246 Because of their segmented block structure, they exhibit a wide range of versatility in terms of modifiable mechanical properties, biological properties, physical properties, biodegradability, and blood and tissue compatibility.

PUR is usually synthesized by the polycondensation reaction of diisocyanate and alcohol/amine, while the synthesis of biodegradable PUR allows the incorporation of hydrolyzable segments into its backbone. 247 However, common diisocyanates such as toluene diisocyanate and 4,4'-methylene diphenyl diisocyanate have led to consideration of the use of other biocompatible aliphatic diisocyanates to develop a new generation of biodegradable PUR. Recently, the development of biocompatible aliphatic diisocyanates and amino acid-derived diisocyanates with reduced toxicity, such as lysine diisocyanate and 1,4-diisocyanatobutane, is the synthesis of biocompatibility and availability. Biodegradable PURs provide new opportunities. These PURs can enhance cell proliferation and adhesion without adverse effects. 247 In addition, a biodegradable elastic PUR-Degrapol® (Abmedica)-is currently being used For the development of highly porous scaffolds for tissue engineering applications. 248 It is also worth noting that a unique, injectable, two-component lysine diisocyanate-based on the PUR system-PolyNova® (PolyNovo Biomaterials Pvt. Ltd)-has been developed for orthopedic applications. 249 PolyNova® polymerizes in situ at physiological temperature, therefore, arthroscopic administration in liquid form can produce suitable mechanical support and equivalent or superior bond strength compared to standard bone cement. In addition, it supports favorable cell adhesion and proliferation. 249 In conclusion, this study shows that PUR has great potential in various biomedical applications, such as porous scaffolds for tissue engineering and drug delivery. 250

Polyphosphazenes are a relatively new class of inorganic-organic hybrid polymers, consisting of an inorganic backbone with alternating single and double bonds of repeating phosphorus and nitrogen atoms. So far, polyphosphazene has been studied as a potential biodegradable biological material due to its synthetic flexibility, unparalleled function and adaptability to many applications.

The phosphorous nitrogen backbone of polyphosphazene gives extraordinary flexibility, and their side groups determine the different properties of these polymers. Taking these characteristics into account, the side groups can be modified to design and develop polymers with highly controllable properties, including solubility, hydrophobicity/hydrophilicity, crystallinity, and appropriate thermal transition. 251 In addition, modification can be used to control the degradation profile of the polymer. 251 Laurencin et al. studied different poly[(amino acid ester) phosphazenes] and found that polyphosphazenes degraded fastest after being modified with ethyl glycinate. 252 and polyester, poly[(amino acid ester) phosphazene] is degraded into neutral and non-toxic products, such as ammonia, phosphate and corresponding ester side groups. 252 Using this unique property, a recent study combined polyphosphazene and PLGA to form a self-neutralizing hybrid system. 253 In addition, polyphosphazene is also suitable for drug delivery, has a unique ability to withstand surface and overall erosion, while maintaining a controllable degradation rate and pattern. 254

Regarding biocompatibility and toxicity, most subcutaneously implanted poly[(amino acid ester) phosphazenes] cause minimal to mild tissue reactions. 251,255-257 In addition, several poly[(amino acid ester)phosphazenes] have shown remarkable osteoconductivity. Polyphosphazene self-setting calcium phosphate composite cement system. 258 However, due to its flexibility in the main chain, many poly[(amino acid ester) phosphazenes] are soft and elastic polymers and therefore have limitations as biomaterials for load-bearing applications. In addition, a recent study found that the use of glycine-based photopolymerizable polyphosphazene as a scaffold for adipose tissue regeneration is successful. 259 The preliminary results demonstrated the non-cytotoxicity of polymers and their degradation products, as well as the cell adhesion and proliferation of fat. 259 At the same time, another report indicated that a mixture with PLGA may be beneficial for the application of polyphosphazene in bone formation. The initial hydrolytic degradation of PLGA produces a porous structure with a certain residual strength, which then degrades over a longer period of time. Therefore, fine-tuning the system may produce biomaterials with tissue engineering properties superior to PLGA. 260 However, their utility as tissue engineering scaffolds is still under investigation and deserves further study.

In fact, in terms of market applications and clinical research, polyphosphazenes are severely lacking compared to more mature polymers for drug delivery applications. However, many promising in vitro and in vivo studies cover a wide range of treatments, highlighting the potential of polyphosphazenes in this field. 251-260 In addition, the inherent high functionality of the phosphorus-nitrogen framework and the inherent, adjustable, and biodegradable polyphosphazenes 251 emphasize their greatness as a group of biomaterials for drug delivery and other biomedical applications. potential.

Due to the existence of various natural and synthetic biological materials, the quality of material formulations are different, and there is a general lack of comparative studies of different biological materials for specific biomedical applications, it is impossible to determine which polymer is the most ideal. Generally speaking, compared with synthetic biological materials, natural biological materials have greater inherent biocompatibility, but they are also inferior in terms of machinery, because their mechanical, structure, and chemical properties cannot be changed like synthetic biological materials.

However, instead of trying to classify specific polymers for specific biomedical applications, the future of biopolymer applications seems to be to use different combinations of polymers to develop hybrid polymers with better specificity for specific biomedical applications—no matter what It is used for tissue engineering, drug delivery or wound healing. In fact, many recent studies on polymers for biomedical applications have solved the problem of combining different biological materials through techniques such as mixing, grafting, and chemical cross-linking reactions, and the results are mostly positive. With the help of technologies such as electrospinning, which allow the creation of various forms of nano-scale polymers such as nanotubes, nanofibers, and nanospheres, the combination produces an almost unlimited number of different combinations of natural and synthetic biological materials Potential, there is a very good opportunity to make more effective biomaterial-based materials with appropriate biocompatibility, degradability and physicochemical properties for specific biomedical applications. Today, most or all biological materials still have many challenges, such as the feasibility of large-scale production at a relatively low cost and overcoming certain physical and chemical limitations of specific biological materials; however, as they are expressed in various host systems The cloning of natural and synthetic biological materials and the emergence of genetic engineering technologies, the application of biopolymers in medicine still has a bright future.

Currently, in the field of tissue engineering, temporary and artificial composite scaffolds are being researched and developed for cell adhesion, differentiation and formation of new tissues. However, people are more and more interested in developing 3D scaffolds, which can not only support tissue regeneration, but also act as a biological matrix, supporting cues and signals to promote functional tissue connections. 145 An increasingly popular method of generating such scaffolds is to use 3D bioprinting technology to use polymer biomaterials as bio-inks. This technology will allow us to better control scaffold properties that are traditionally difficult or impossible to control, such as cell distribution, fluid flow, and porosity. These resulting 3D engineering structures will enable us to simulate the characteristics of human tissue better than any other traditional engineering methods, making it more suitable for tissue regeneration. The ultimate goal of 3D bioprinting is to eventually be able to develop patient-specific tissues and organs. Although there are still some technical, scientific, regulatory and even ethical challenges, research and interest have grown exponentially to make such technology a reality.

Drug delivery systems are traditionally administered orally or injected, but there are problems when using such methods for protein and nucleic acid delivery. In addition, traditional drug delivery systems still face problems such as drug side effects, efficacy, and patient compliance. Recently, the use of nanotechnology ushered in a new drug delivery strategy. Many new types of carriers have been developed using nanotechnology. These carriers can not only release a wider range of molecules, proteins, peptides and nucleic acids, but also can achieve more specific targeted delivery through controlled release. In particular, nanoparticles based on biodegradable and biocompatible polymers have recently shown potential in cancer treatment and as a continuous drug delivery vehicle, extending drug half-life, improving solubility, and reducing immunogenicity. In addition, they have shown the ability to co-deliver multiple drugs at the same time, making patients more likely to comply, while also enhancing the potential synergy of certain drugs and inhibiting drug resistance. These biodegradable and biocompatible polymer-based nanoparticles can also be applied to wound healing through the delivery of bioactive agents. Current clinical wound healing applications play a more passive role, and the development of this technology will help better and more effective wound healing. Nanoparticles for drug delivery clearly show significant advantages over traditional drug delivery systems, and the key to the future development of drug delivery systems is more understanding and applications of nanotechnology.

The authors report no conflicts of interest in this work.

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