Table 1.

Comprehensive analysis of naturally occurring and synthetic biopolymers along with their advantages and disadvantages.

Polymer			Structure	Desirable Properties and Advantages	Disadvantages	Ref
Natural polymer-,	Polypeptide-, and Protein-based scaffolds	Collagen	Triple helical structure held together by hydrogen bonds. Major amino acid groups include: Glycine Proline Hydroxyproline	Favorable for cell adhesion, proliferation, differentiation, and ECM secretion. Excellent biocompatibility. Biodegradability. Low toxicity. Rough surface morphology. Low immunogenicity. Weak antigenicity.	Low mechanical strength. Difficult disinfection. The deformation and contraction of collagen-based scaffolds have restricted their use in load-bearing tissues. Poor stability in an aqueous environment. Potential for antigenicity through telopeptides.	[52,124,125]
		Silk fibroin	Consists of short amino acid side chains that assemble into β-sheet structures.	SFs are sturdy, lightweight, and have exceptional strength and elasticity. Osteoconductivity. Biocompatible. Deliver good support for cell adhesion and proliferation without initiating cell toxicity. Promote cell migration and vascularization. Moderately degradable. Thermostable (up to ∼250 °C). Commonly employed as a cell carrier for cell seeding on scaffolds.	Prolonged presence of silk may induce degradation, which releases certain residues or degraded products that may prompt the immune response.	[64,126,127]
		Fibrinogen and fibrin	Fibrinogen: Dimer consisting of three pairs of polypeptide chains (Aα, Bβ, and γ)	Biocompatibility. High affinity for biological surfaces and molecules. Promotes cellular interactions. Variety of cell-adhesive/binding properties. Nonimmunogenicity.	Low mechanical strength. Quick rate of degradation.	[67,128,129,130]
		Gelatin	Contains glycine residues, proline, and 4-hydroxyproline residues	Better infiltration, adhesion, spreading, and proliferation of cells on resulting scaffolds. Good stability at high temperature in a broad range of pH. Biodegradability. Osteoconductivity. Non-immunogenic. Low antigenicity.	Bioactivity is questionable in higher-order gelatin structures in scaffolds. Low stability in physiological conditions.	[60,131,132]
		Keratin	It is a cysteine-rich fibrous protein that associates with intermediate filaments (IFs) forming the bulk of the cytoskeleton and epidermal appendageal structures	Facilitates cell adhesion and proliferation. Unique chemistry afforded by high sulfur content. Propensity for self-assembly. Intrinsic cellular recognition. Intrinsic biological activity. Cytocompatibility. Gradual degradation.	Poor mechanical properties. Quick loss of mechanical integrity.	[133,134]
	Polysaccharide-based scaffolds	Starch	Comprised of carbohydrates. The structure consists of two types of alpha glucan which are amylose and amylopectin.	Biocompatible. Thermoplastic behavior. Non-cytotoxic. Guides various developmental stages of cells. Hydrophilicity. Good substrate for cell adhesion. Good biodegradation period.	Very high water uptake. Low mechanical strength. Unstable for long-term application. Chemical modifications may lead to toxic byproducts and reduce the rate of degradation.	[135,136]
		Chitin/chitosan	Chitin: N-acetyl glucosamine and N-glucosamine monomers Chitosan: N-deacetylated derivative of chitin	Accelerates tissue repair. Prevents formation of scar tissue. Promotes cell adhesion. Non-toxic and non-allergenic. Bioactivity. Anti-inflammatory. Osteoconductivity. Hemostatic potential. Scaffolds could be used for a longer period. Chitosan-based scaffolds can immobilize growth factors.	Poor mechanical strength and stability. High viscosity and low solubility at neutral pH. Rapid in vivo degradation rate.	[75,137,138,139,140,141,142,143,144,145,146,147,148,149]
		Agarose	Contains repeating units of agarobiose (a disaccharide of D-galactose and 3,6-anhydro-l-galactopyranose).	Excellent biocompatibility. Thermo-reversible gelation behavior. Exceptional electroresponsiveness. Suitable medium for cell encapsulation. Non-immunogenic.	Low cell adhesion. Nondegradability due to the absence of an appropriate enzyme in the body.	[140,141,142]
		Alginate	Made up of mannuronate and gluronate monomers. Different block configurations give rise to different materials properties. Mainly made up of carboxyl groups.	Mimicking function of the extracellular matrix of body tissue. Thickening/gel-forming agent. Biocompatibility. Cytocompatibility. Biodegradability. Bioabsorbable. Hydrophilicity.	Difficult to sterilize. Low cell adhesion. Poor mechanical characteristics.	[143,144,145]
		Cellulose	Polysaccharides are formed by many D-glucose units connected by glycosidic bonds.	Stable matrix for tissue engineering applications. Better mechanical strength. Hydrophilicity. Biocompatibility. Cytocompatibility. Bioactivity.	Cellulose in the human organism behaves as a nondegradable or very slowly degradable material.	[146,147,148]
		Hyaluronic acid	It is a linear, anionic, non-sulfated glycosaminoglycan with a structure composed of repeating disaccharides units: β-1,4-D-glucuronic acid and β-1,3-N-acetyl-D-glucosamide.	Encapsulation capability. Cell activity. HA scaffolds are frequently used in the case of both hard and soft tissue regeneration. Nonimmunogenic. Nonantigenic. Biocompatibility. Osteocompatibility.	Brittle; mechanical properties need fine-tuning via chemical modification. Low biodegradability in the crystalline phase.	[81,149,150,151]
		Glycosaminoglycans	Consist of repeating disaccharides linked by glycosidic bonds creating individual complex structures.	Biocompatibility. Anticoagulant activity. Antithrombotic activity. Anti-inflammatory. Have multiple regulatory functions, e.g., in the anticoagulation of blood, inhibition of tumor growth, and metastasis. Control the inflammatory processes.	Very fast degradation. Potential risk of contamination with infectious agents.	[152,153]
Synthetic polymers		Poly(ƹ-caprolactone) (PCL)	Aliphatic semicrystalline polyester.	Controls cell proliferation and angiogenesis. Slow degradation rate (lower than that of PLA and PLGA). Non-toxic. Cytocompatibility. Good mechanical properties. Degraded by hydrolysis or bulk erosion.	Low bioactivity. Hydrophobicity of PCL is another major issue that hinders wound healing application. Some problems related to withstanding mechanical loads.	[154,155,156]
		Polylactic acid (PLA)	Highly crystalline.	Biocompatible. Cytocompatibility. Thermal stability. Excellent mechanical strength. Good degradation rate. Nontoxic degradation products.	PLA-based materials suffer from the lack of ideal surface chemistry that could aid cell adhesion and proliferation. Brittleness. Poor thermal stability. Hydrophobicity.	[92,157,158]
		Polylactic-co-glycolic acid (PLGA)	The copolymer of hydrophobic PLA and hydrophilic PGA.	Excellent cell adhesion and proliferation. Good mechanical properties. Features faster degradation than either PGA or PLA. Wide range of degradation rates.	Poor osteoconductivity. May develop biocompatibility problems.	[159]
		Polyglycolic acid (PGA)	Linear highly crystalline aliphatic polyester.	Biocompatible. High tensile modulus. High melting point. Undergoes bulk degradation. Hydrophilicity.	High sensitivity to hydrolysis. Difficult to obtain porous PGA scaffolds without toxic solvents.	[160,161]
		Polyhydroxybutyrate (PHB)	It is a homopolymer having a stereoregular structure with high crystallinity. Naturally occurring b-hydroxy acid.	Non-toxic. Biostable. Biocompatible. Advantages over PLA and PGA. Slow rate of degradation. Can be obtained naturally.	Inherent brittleness and rigidity. Thermal instability during melt processing impedes its commercial application.	[159,162,163]
		Polypropylene fumarate (PPF)	Linear and unsaturated copolyester based on fumaric acid.	Biocompatibility. Crosslinked PPF matrices have high mechanical strength. PPF degrades in the presence of water into propylene glycol and fumaric acid, the degradation products that are easily cleared from the human body by normal metabolic processes. Non-toxic.	It is a viscous liquid at room temperature (21 °C), making the handling of the polymer somewhat cumbersome	[159,164,165]
		Poly(ethylene glycol) (PEG)	Synthesized using ring-opening polymerization of ethylene oxide.	Non-ionic. Biocompatible. Elasticity. Bioadhesive. Mucoadhesive. Hinders protein adsorption. Hydrophilic. PEG as a blank template can be modified to different moieties to pass different requirements of a skin substitute like cell adhesion, short-term degradation, and minimum inflammation. Non-immunogenic.	Lacks cell-interactive character due to its bio-inert nature. Nonreactive, creates insoluble networks.	[123,166,167]
		Polyurethane (PU)	Urethane groups are the major repeating units. Synthesized by reactions of di- or polyisocyanates (hard segments) with di- or polyols (soft segments) via the catalyzed polymerization process.	Bio- and hemocompatibility. Nontoxic. Biodegradable. Non-allergenic. Non-sensitizing. Excellent mechanical properties. High flexural endurance and fatigue resistance.	PUs are less compatible with blood and found unsuitable for in vivo drug delivery application. Limited stability in vivo.	[113,168]
		Polyvinyl alcohol (PVA)	Semicrystalline polyhydroxy polymer. Prepared via hydrolysis of poly(vinyl acetate).	Biocompatible. Nontoxic. Noncarcinogenic. Displays a reduced protein-binding tendency, relatively higher elasticity and water content; a highly hydrated water-soluble synthetic polymer. Has relatively similar tensile strength to human articular cartilages. Good lubrication.	Lack of cell-adhesive property. Less ingrowth of bone cells.	[169,170,171]
		Polypropylene carbonate (PPC)	Product of alternating copolymerization of propylene oxide and CO2. Amorphous.	Biodegradable amorphous polymer because of the aliphatic polycarbonate ester structure on its backbone. No inflammatory response. Thermoplastic behavior. Biocompatibility. Impact resistance.	PPC has shortcomings such as viscous flow at room temperature and a relatively large brittleness at low temperature. Poor thermal and processing properties. Cell attachment to PPC is very limited due to its highly hydrophobic nature.	[172,173,174]