Biopolymers in Biotechnology and Tissue Engineering: A Comprehensive Review

Abstract

Since the mid-19th century, researchers have explored the potential of bio-based polymeric materials for diverse applications, with particular promise in medicine. This review provides a focused and detailed examination of natural and synthetic biopolymers relevant to tissue engineering and biomedical applications. It emphasizes the structural diversity, functional characteristics, and processing strategies of major classes of biopolymers, including polysaccharides (e.g., hyaluronic acid, alginate, chitosan, bacterial cellulose) and proteins (e.g., collagen, silk fibroin, albumin), as well as synthetic biodegradable polymers such as polycaprolactone, polylactic acid, and polyhydroxybutyrate. The central aim of this manuscript is to elucidate how intrinsic properties—such as molecular weight, crystallinity, water retention, and bioactivity—affect the performance of biopolymers in biomedical contexts, particularly in drug delivery, wound healing, and scaffold-based tissue regeneration. This review also highlights recent advancements in polymer functionalization, composite formation, and fabrication techniques (e.g., electrospinning, bioprinting), which have expanded the application potential of these materials. By offering a comparative analysis of structure–property–function relationships across a diverse range of biopolymers, this review provides a comprehensive reference for selecting and engineering materials tailored to specific biomedical challenges. It also identifies key limitations, such as production scalability and mechanical performance, and suggests future directions for developing clinically viable and environmentally sustainable biomaterial platforms.

1. Introduction

Biopolymers are a diverse group of macromolecules that share the trait of biodegradability—being able to decay in a natural environment. This quality has earned them favour over other, non-degradable polymers popularized in the last century, as they do not negatively impact the environment. Biopolymers can be split into two main groups—natural and synthetic biopolymers [1,2]. As the name suggests, natural biopolymers are naturally produced by living organisms. For example, collagen, cellulose, and hyaluronic acid are natural biopolymers [1]. Synthetic biopolymers are obtained by either modifying natural polymers or by synthesis from artificial monomers, and they have been garnering increasingly more attention in recent years thanks to their flexibility. Examples of synthetic biopolymers are polycaprolactone, polyvinyl alcohol, and polyhydroxyalkanoates [2]. Biopolymers’ diverse properties allow them to find many uses, most notably in medicine and bioengineering, where biopolymers fulfil many purposes, including sutures, tissue engineering, and cancer therapy. Biopolymers and ecological construction materials are also used as additives in the food industry [3].

2. Polysaccharides

Polysaccharides (PSD) are complex biopolymers that play a significant role in the biology of living organisms. They are substantial biomolecules with complex structures and functions that serve various purposes in the life processes of all living organisms [4]. A polysaccharide is a large polymer composed of at least ten monosaccharides linked by glycosidic bonds [5]. These bonds are formed when the hemiacetal or hemiketal group in one sugar unit reacts with the hydroxyl group in another, creating the glycosidic linkage [5]. Due to their inherent properties, such as non-immunogenicity, anti-inflammatory and antioxidant properties, PSD is used in a wide range of applications, i.e., diagnostics, therapeutics, drug delivery, engineering, biosensing, and more. The most commonly used PSDs in the biomedical field are hyaluronic acid (HA), alginate (ALG), chitosan (CH), agarose (AGR), carrageenan (CG), bacterial cellulose (BC), and dextran (DX), along with their combinations [6,7]. In addition, these polysaccharides possess numerous functional groups that can be modified to tailor their properties. They can also be attachment points for creating polymer–drug combinations [6,7].

2.1. Hyaluronic Acid

Hyaluronic acid (HA) is a linear macromolecular, negatively charged, mucopolysaccharide consisting of alternately linked D-glucuronic acid and N-acetylglucosamine monomers (Figure 1). The moieties of these acids are linked by β(1→3) and β(1→4) glycosidic linkages. When both monosaccharides are in the β configuration, a very energetically stable structure is formed because each large functional group (hydroxyl, carboxyl, acetyl, anomeric carbon) is in a sterically favourable equatorial position. In contrast, each hydrogen atom is in a less energetically favourable axial position [8]. HA belongs to the family of glycosaminoglycans (GAGs), which includes chondroitin sulfate, keratan sulfate, or heparan sulfate, each with a characteristic repeating disaccharide structure that can be carboxylated or sulfonated. HA is distinct among GAGs in that it is neither sulfated nor covalently attached to a proteoglycan core protein.

In addition, it is not synthesised by enzymes of the Golgi apparatus, but on the inner surface of the cell membrane. HA can also reach a very high molecular weight. In a recent systematic study performed by Di Meo et al., pharmaceutical-grade HA samples with molecular weights ranging from 60 kDa to 2.5 MDa [9]. This structural feature enables hyaluronan to retain extremely large amounts of water. According to experimental studies, HA’s actual water-binding capacity is between 0.36 and 0.86 g of water per gram of HA [10]. This gives it the pseudoplastic properties of a liquid, and consequently, it exhibits viscoelastic properties, high elasticity at high shear rates, and high viscosity at low shear rates [11,12]. The global market for HA was valued at approximately USD 9.2 billion in 2023 and is expected to expand to around USD 18.2 billion by 2030, reflecting a compound annual growth rate (CAGR) of 10.4% over the forecast period [13].

Applications

Due to its properties and numerous biological functions, HA has found many applications in both biotechnology and tissue engineering.

HA hydrogels offer a unique formulation for tissue engineering that incorporates space-filling agents and mucoadhesive materials. These hydrogels possess the ability to modify the three-dimensional architecture of the natural extracellular matrix (ECM), which facilitates the release of cytokines, thereby supporting the versatile design of tissue engineering strategies. A primary application of HA hydrogels is as space-filling agents that function as biological adhesives, enhancing the therapeutic efficacy of matrices or scaffolds by preventing unwanted cell adhesion [14]. This property also contributes to their anti-aging potential. Additionally, HA hydrogels are used in cell transplantation for tissue repair and regeneration, with bone, cartilage, and smooth muscle regeneration applications [15]. Regenerative medicine employs integrated strategies from tissue engineering to replace tissues damaged by injury or disease, and HA hydrogels, serving as cell carriers, play a crucial role in tissue regeneration. The biocompatibility of HA hydrogels, encompassing cell, blood, and histocompatibility, is a critical factor for their successful application [15].

HA is also widely utilized in cosmetic formulations due to its exceptional water-retention properties. It plays a crucial role in maintaining the skin’s turgidity, moisture, and elasticity. By incorporating HA-based modifications, the permeation across biological membranes can be enhanced, thereby improving the efficacy of targeted delivery [16]. HA demonstrates significant nutricosmetic and cosmetic benefits in addressing various skin concerns, including aging, nasolabial folds, and wrinkles. To evaluate its nutricosmetic and cosmetic effects, HA is employed in diverse formulations such as creams, serums, gels, lotions, intradermal filler injections, and facial fillers. The beneficial effects of HA in these applications are primarily attributed to its ability to promote facial rejuvenation, stimulate collagen production, and facilitate tissue augmentation [17].

HA is a natural component of the eye’s vitreous humour and has numerous practical applications in ophthalmic surgical procedures. HA is particularly beneficial as a space-filling matrix within the eye, with intraocular HA injections commonly used during surgeries to maintain the shape of the anterior chamber [18]. HA solutions also serve as tackifiers for eye drops and adjuncts in ocular tissue repair. Due to its protective properties, HA is employed in various ophthalmic procedures, including visual inspection, cataract extraction, ocular surgeries, anterior and posterior segment operations, lens implantation, and vitreoretinal surgeries. It protects delicate tissues such as the corneal endothelium, making HA an essential facilitator in the restorative operations of ocular structures [19].

The potential of HA in drug delivery has been investigated, particularly as a carrier for antitumor and anti-inflammatory agents. As a key component of the ECM, HA also serves as a primary ligand for CD44 and RHAMM, both of which are overexpressed on the surface of various tumor cells, including those in colon cancer, human breast epithelial cells, lung cancer, and acute leukaemia [20]. HA and its derivatives selectively interact with specific cell surface receptors, which are predominantly localized in the kidneys, vasculature, body fluids, liver, and, most notably, tumor tissues [21]. This targeted binding capability is crucial for HA-based drug delivery systems, facilitating the transport of proteins, nucleic acids, peptides, and various anticancer agents. Additionally, HA can be conjugated with folic acid (FA) to enhance tumor-targeted drug delivery and improve anticancer efficacy [21]. Since its discovery, HA has been highly valued for its role in precisely recognizing overexpressed CD44 receptors. In this context, HA-based hydrophilic nanoparticles have been employed to enhance CD44 receptor targeting, thereby increasing cancer cell cytotoxicity [21]. This strategy leverages two biological targeting mechanisms: CD44 Receptor Targeting via HA and Folate Receptor Targeting via FA.

First, HA binds selectively to CD44 receptors, which are highly overexpressed on the surface of many tumor cells. This interaction triggers CD44-mediated endocytosis, allowing HA-functionalized nanocarriers to be preferentially internalized by cancer cells, thereby enhancing targeted delivery of therapeutic agents.

Second, folic acid is conjugated to the carrier system to exploit its high binding affinity for folate receptors. These receptors are similarly overexpressed in various cancers—including ovarian, breast, lung, and colorectal tumors—while largely absent in normal tissues. FA on the delivery vehicle enables folate receptor-mediated endocytosis, further increasing the selectivity and accumulation of the therapeutic payload within malignant cells.

This dual-targeting approach enhances cellular uptake, improves intracellular drug delivery efficiency, and minimizes off-target effects, contributing to increased anticancer efficacy [22].

HA plays a significant role in various biological processes and contributes notably to wound healing. This complex process involves a series of coordinated events, including granulation tissue formation, inflammation, epithelial reconstruction, and tissue remodelling. HA functions as a key mediator throughout these stages, making it a valuable therapeutic agent for wound healing in external skin injuries, scars, and pressure ulcers. HA contributes to tissue remodelling and formation, exerting a multifaceted influence on cellular and extracellular matrix interactions [23]. Consequently, it is widely used in the treatment of both acute and chronic wounds, such as postoperative incisions, abrasions, and burns. HA has unique properties that distinguish it from other wound-healing agents; it lacks allergenic effects while promoting bio-stimulation and modulating inflammation to enhance tissue regeneration [24].

2.2. Alginate

Alginate (ALG), a hydrophilic anionic polysaccharide, is among the most abundantly biosynthesized biomaterials globally. This naturally occurring polymer is predominantly sourced from brown seaweed and specific bacterial genera, including Pseudomonas and Azotobacter. Commercial production of ALG is primarily derived from various marine macroalgae species, such as Laminaria hyperborea, Laminaria digitata, Macrocystis pyrifera, Ascophyllum nodosum, Ecklonia maxima, Laminaria japonica, Lessonia nigrescens, Durvillaea antarctica, and Sargassum spp. Structurally, ALG consists of polymeric chains composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G) monomers linked via 1→4 glycosidic bonds. These monomeric units are organized into three distinct block structures: G-blocks, M-blocks, and alternating GM-blocks (Figure 2) [25].

The molecular weight of commercially available sodium alginates typically ranges from 32 kDa to 400 kDa [26]. Increasing alginate molecular weight generally enhances the mechanical properties of the resulting gels. However, solutions prepared from high-molecular-weight alginates exhibit elevated viscosity, which can be problematic during processing [27]. For instance, when proteins or cells are incorporated into highly viscous alginate solutions, they may be exposed to damaging shear forces during mixing or injection. By adjusting the molecular weight and distribution, it is possible to independently modulate the viscosity of the pre-gel solution and the stiffness of the final gel. Notably, combining high and low molecular-weight alginate polymers allows for a substantial increase in gel elasticity with only a minimal rise in solution viscosity [28,29].

Alginate-based biomaterials have been extensively developed into diverse forms, including hydrogels, foams, sponges, fibres, microspheres, and microcapsules, utilizing various fabrication techniques [30]. Among these, ALG hydrogels have garnered significant interest in biomedical applications, mainly as structural matrices or controlled delivery systems in tissue engineering and regenerative medicine. The fabrication of ALG hydrogels relies on different physicochemical crosslinking strategies, including covalent and non-covalent approaches, which are largely dictated by the polymer’s structural configuration [31]. In this regard, ionic crosslinking via chelation with divalent cations (e.g., Mg²⁺, Ca²⁺) represents the most efficient and cost-effective method for hydrogel formation, enabling gelation under mild aqueous conditions [32].

The global Alginate Market was valued at USD 1.12 billion in 2024 and is projected to expand at a CAGR of 5.0% during the forecast period, reaching a value of USD 1.47 billion by 2032 [33].

Applications

ALG gels have numerous applications in tissue engineering. As a non-toxic, inert, and non-immunogenic biomaterial, ALG possesses the essential properties required for an effective scaffold in tissue regeneration [34]. However, the utility of ALG fibres in tissue engineering remains limited due to insufficient cell adhesion and viability. To enhance cellular attachment and proliferation, the incorporation of bioactive compounds onto ALG fibres has been explored, rendering these fibres promising candidates for scaffold development [34]. ALGs are also recognized as natural polymers employed in hydrogel-based nanocomposites. A widely adopted strategy for the development of alginate-based nanocomposites involves the chemical modification of the polymer, thereby facilitating the formation of hydrogels with improved mechanical stability. However, such chemical modifications may compromise the biocompatibility of natural polymers, highlighting the advantage of utilizing unmodified biopolymers in specific applications.

ALG is among the most widely utilized biopolymers in wound dressing applications due to its favourable properties, including biodegradability, biocompatibility, high absorbency, low toxicity, and cost-effectiveness [35]. When ALG fibres interact with wound exudates, they exhibit ion-exchange behaviour, wherein calcium ions are replaced by sodium ions from bodily fluids, forming a moist gel on the wound surface. Incorporating additional compounds into ALG fibres enables the development of advanced materials with enhanced functionalities, such as improved gel-forming ability and hemostatic properties [36].

2.3. Chitosan

Chitosan (CH) is a linear, semi-crystalline polysaccharide consisting of (1→4)-2-acetam ido-2-deoxy-β-D-glucan (N-acetyl-D-glucosamine) and (1→4)-2-amino-2-deoxy-β-D-glucan (D-glucosamine) units. Figure 3 illustrates its molecular structure. CH is not naturally abundant in the environment, but it is primarily produced from chitin, a naturally abundant biopolymer found in the exoskeletons of crustaceans such as shrimp, crabs, and lobsters. The transformation of chitin to CH typically involves three main steps: demineralization, deproteinization, and deacetylation. These can be carried out through either chemical or biological methods [37].

Demineralization is typically conducted using hydrochloric acid, effectively removing calcium carbonate from crustacean shell matrices. Subsequent deproteinization and deacetylation steps are commonly performed using potent alkaline agents such as sodium hydroxide or potassium hydroxide. These chemical treatments facilitate the production of CH with a high degree of deacetylation and reduced molecular weight. These physicochemical characteristics are strongly associated with enhanced solubility and pronounced biological activity [38,39].

Alternatively, biological approaches—including enzymatic hydrolysis and fermentation-based methodologies—offer environmentally benign processing conditions and operate at comparatively lower temperatures and milder pH ranges [37,40]. Despite these advantages, such methods are generally constrained by lower efficiency, prolonged processing times, and elevated production costs, primarily due to the expense of enzymatic reagents and the technical complexity involved in sustaining microbial cultures under optimal conditions [38].

Figure 3. Structure of CH [41].

Figure 3. Structure of CH [41].

CH is frequently classified into high molecular weight (HMW CH), medium molecular weight (MMW CH), and low molecular weight (LMW CH) categories. However, precise molecular weight thresholds for these classifications remain poorly defined. According to Matica et al., chitosan molecular weight ranges can be broadly delineated as follows: Oligochitosan: ~4.7 kDa; HMW CH: 310–375 kDa; MMW CH: 190–310 kDa; LMW CH: approximately 3.7–190 kDa. These classifications are based on compiled experimental data from various studies, though discrepancies remain due to methodological differences in molecular weight determination and source material variability [42]. CH has garnered significant attention in medical and pharmaceutical applications due to its outstanding biocompatibility, biodegradability, and non-toxicity. Biocompatibility is particularly crucial among these properties, as CH does not elicit immune system responses in tissues [43]. This immunological inertness can be attributed to its natural origin, structural similarity to components found in the extracellular matrix, and enzymatic degradability into non-toxic products such as glucosamine. Chitosan’s positive charge and mucoadhesive properties facilitate gentle interaction with cell membranes without triggering pro-inflammatory pathways [44].

Its ability to avoid triggering the body’s defence mechanisms ensures compatibility with living cells, facilitating the acceptance of CH-based materials in biomedical applications. In addition to these properties, CH possesses unique functional characteristics, including hemostatic activity through the aggregation of red blood cells, platelet adhesion, and subsequent aggregation. It also exhibits anti-thrombogenic properties, the ability to form polyoxysalts, film-forming capabilities, and molecular adsorption potential. Further studies indicate that CH, a biocompatible and biodegradable biopolymer, possesses antimicrobial properties that enhance blood coagulation [43,45].

In 2024, the global CH market was valued at approximately USD 14.47 billion. It is projected to experience substantial growth over the forecast period from 2025 to 2034, reaching an estimated value of USD 96.55 billion by 2034. This represents a CAGR of 20.90%. The market expansion is primarily attributed to the increasing utilization of chitosan in wastewater treatment [46].

Applications

CH-based hydrogels and scaffolds are among the most extensively developed skin and bone tissue engineering materials. Their numerous advantages, including accelerated recovery, reduced reliance on transplants, lower demand for donors, non-toxicity, and a decreased number of animals used in biological experiments, make CH-based polymeric materials a subject of intensive research [47]. Due to their geometric structure and high porosity, these materials facilitate tissue regeneration by promoting healing and supporting the recovery of damaged organs through enhanced cell adhesion and proliferation [47]. Compared to other polymers, a key distinguishing feature of CH is its ability to form a gel network without the addition of crosslinking agents. While crosslinkers can be introduced to enhance mechanical strength for specific applications, minimizing chemical reagents is preferable in medical applications to prevent potential adverse interactions with the skin [48]. Chitosan forms hydrogels primarily by neutralising its protonated amino groups, which reduces electrostatic repulsion between polymer chains. This process facilitates chain association via hydrogen bonding and hydrophobic interactions, forming a three-dimensional network. These physical cross-links enable chitosan to self-assemble into hydrogels without chemical cross-linkers, making it highly suitable for biomedical applications [48].

Beyond soft tissue engineering, CH is widely applied in bone and cartilage regeneration. Hydroxyapatite, a material structurally similar to bone minerals, has reinforced CH’s mechanical properties. Recent studies have demonstrated that lyophilized CH/hydroxyapatite scaffolds can regulate osteoblast maturation depending on hydroxyapatite particle size, with smaller particles promoting osteoblast differentiation while reducing inflammatory responses. In addition to hydroxyapatite, other materials, such as zirconia, nano calcium zirconate, and metal alloys, have been combined with CH to enhance its mechanical properties for bone reconstruction [49,50].

CH is also widely utilized in wound healing as a dressing material. To be effective in this application, the material must exhibit biocompatibility, non-toxicity, and the ability to maintain a moist environment, all essential for optimal wound recovery. CH-based wound dressings are typically designed in various forms, including films, gels, fibres, spheres, and membranes. In addition to these fundamental properties, the antibacterial activity of the dressing is a crucial factor, as wound infections are a common complication that can hinder the healing process. An ideal CH-based dressing should provide a suitable temperature to support re-epithelialization and collagen deposition while ensuring comfort upon application. Furthermore, it should allow for easy and non-traumatic removal after tissue regeneration, minimizing discomfort and the risk of disrupting newly formed tissue [51].

CH is also used in drug delivery systems due to its biodegradability, bioactivity, and ability to enhance drug retention time without inducing adverse effects. Its structural properties can also be modified to achieve specific porosity or form, allowing for controlled drug release [36]. The drug delivery mechanism varies depending on the targeted site and the required release profile. Several factors influence therapeutic agents’ encapsulation efficiency and release kinetics within CH-based systems. The stability of CH’s interactions with drug molecules is primarily determined by molecular weight, temperature, pH, and the surface charge of the drug, all of which affect its binding affinity and release behaviour [52].

CH exhibits broad-spectrum antibacterial activity, which is further enhanced when combined with materials such as graphene oxide or zinc oxide. These combinations have been extensively explored for biomedical and water treatment applications [53]. CH antimicrobial activity is very valuable in antibacterial membranes, particularly in wastewater treatment, where bacterial fouling can significantly reduce membrane efficiency. Several studies have demonstrated the antibacterial properties of zinc oxide nanoparticles in combination with CH [54]. One such study investigated using bentonite-supported silver and zinc oxide nanoparticles embedded in a CH matrix for water disinfection, revealing vigorous antibacterial activity against Escherichia coli [53,54].

2.4. Agarose

Agarose (AGR) is a natural polysaccharide extracted from red algae, consisting of a linear chain of alternating D-galactose and 3,6-anhydro-L-galactose units, which contain numerous hydroxyl groups capable of forming hydrogen bonds within its structure and with water molecules [55] (Figure 4).

AGR is extracted from red algae species such as Gelidium and Gracilaria through a multi-step process. It begins with cleaning and alkali treatment of the algae, followed by hot water extraction (95–100 °C) to solubilize polysaccharides. The extract is then filtered, gelled, and purified using bleaching and dialysis to remove impurities. Finally, the AGR is dried and milled into a powder. The resulting high-purity AGR is widely used in electrophoresis, chromatography, and biomedical applications [56].

The molecular weight of AGR typically ranges between 80 and 140 kDa. One of its key properties is forming a stable hydrogel with controlled hysteresis [55]. At elevated temperatures (90–100 °C), the hydrogen bonds between structural units of AGR break, causing the polymer to disperse into water as random coils, resulting in a clear solution. Upon cooling to 30–40 °C, the molecular chains of AGR undergo reorganization, forming a tightly packed double-helix structure stabilized by hydrogen bonding, ultimately leading to gel formation [57].

Figure 4. Structure of AGR. The repeating disaccharide units are called agarobiose and neoagarobiose [58].

Figure 4. Structure of AGR. The repeating disaccharide units are called agarobiose and neoagarobiose [58].

Recent market analyses indicate a promising future for the global AGR industry, with an estimated market size of USD 83.35 million in 2022. Projections suggest that this value will reach USD 99.35 million by 2028, reflecting a compound annual growth rate of 2.97% over the forecast period [59].

Applications

AGR has the capability to form a gel that can closely mimic the physical properties of the ECM and biological tissues [60]. Its biocompatibility can be further enhanced by blending or coupling with other polymers and proteins, such as collagen, CH, and BC, which improve cell affinity toward AGR-based materials. Additionally, AGR provides a supportive microenvironment for dentine remineralization, facilitating the repair of enamel loss. In one application, a human-derived dentine slice was coated with both ionic (CaCl₂) and non-ionic AGR hydrogel to promote the regeneration of noncarious tooth loss. This approach highlights the potential of AGR-based hydrogels in dental tissue engineering and regenerative medicine [60]. However, pure AGR’s inherent structure, composition, and mechanical properties restrict its adaptability, limiting its mechanical strength, biofunctionality, and versatility in biomedical applications. AGR is commonly combined with other polysaccharides to overcome these limitations and expand its applicability.

AGR hydrogel has been utilized as a cartilage scaffold to maintain the chondrocyte phenotype and enhance the deposition of proteoglycans and glycosaminoglycans [61]. Injectable hydrogels offer a non-invasive approach to implantation, allowing for the encapsulation of cells within the hydrogel matrix due to their favorable biological and rheological properties. AGR, in particular, exhibits low immunogenicity, reducing the risk of rejection within the body. As a result, concerns regarding AGR cytotoxicity are minimized in clinical trials, further supporting its biomedical applications [62,63]. One promising advancement in drug delivery systems is electro-responsive drug delivery, which leverages external electrical stimuli to control drug release. This method holds significant potential for enhancing targeted and controlled therapeutic administration, further expanding the utility of AGR-based hydrogels in biomedical engineering [62,63].

2.5. Carrageenan

Carrageenan (CG) is a seaweed-derived polysaccharide that has recently garnered increasing attention due to its diverse biological properties. It is a collective term for a group of naturally occurring anionic sulfated polysaccharides extracted from the Rhodophyceae family of red seaweeds.

The production process involves several extraction methods, most notably alkaline treatment, which is the industry standard. This method treats seaweed with hot alkali (e.g., NaOH or KOH) at temperatures between 95 and 110 °C to extract CG, followed by purification steps such as filtration and alcohol or potassium chloride precipitation. Two primary commercial grades are produced: refined CG, which undergoes thorough purification and is suitable for food and pharmaceutical use, and semi-refined CG, which retains more impurities and is used in applications where high purity is not essential [64]. Commercially available CGs typically exhibit an average molecular weight ranging from 100 to 1000 kDa [65].

The fundamental disaccharide repeating unit of CG consists of alternating G-, D-, or DA-units. CGs are classified into various types based on the number and specific positions of sulfate groups attached to each disaccharide unit along the galactose backbone. This structural variability gives rise to several distinct forms, including kappa (κ), iota (ι), mu (μ), nu (ν), theta (θ), and lambda (λ) CGs. Among these, κ-CG (Figure 5) is the most abundant, accounting for approximately 60% of total CGs [66]. Each type exhibits unique physical and functional properties, such as gel strength, solubility, and interaction with other molecules.

The distinct physicochemical properties of κ-, ι-, and λ-CGs make them highly suitable for various industrial applications, particularly in the food and pharmaceutical sectors. Additionally, due to their unique biological characteristics—such as biocompatibility, biodegradability, high molecular weight, viscosity, and gelation ability—CGs have gained significant interest in biotechnological and biomedical fields. Their multifunctionality further enhances their potential as valuable materials for drug delivery, tissue engineering, and other biomedical applications [68].

The global CG market is estimated to account for USD 1 billion in 2025. It is anticipated to grow at a CAGR of 4.8% during the assessment period and reach a value of USD 1.5 billion by 2035 [69].

Applications

CGs exhibit a wide range of bioactive properties as a biomaterial, including antibacterial, antiviral, anticoagulant, antihyperlipidemic, antitumor, antioxidant, and immunomodulatory activities. CGs have demonstrated significant potential in inhibiting viral infections across a broad spectrum of enveloped and non-enveloped viruses. Studies have highlighted their efficacy against various pathogens, including human papillomavirus (HPV), herpes simplex virus (HSV), human rhinoviruses, and varicella-zoster virus (VZV) [70,71]. The antiviral mechanism of CGs is primarily attributed to their ability to create a protective barrier around host cells. This effect arises from electrostatic interactions between the negatively charged sulfate groups of CGs and the positively charged viral surface sites, effectively preventing viral attachment and entry into host cells. This unique antiviral property makes CGs promising candidates for antiviral therapies and biomedical applications [72,73].

CGs have shown significant potential as antihyperlipidemic agents in pharmaceutical applications. Research indicates that the ingestion of CG-based formulations increases the viscosity of gastric contents, thereby slowing the rate of digestion and absorption. This reduction in absorption leads to decreased uptake of substrates and nutrients in the intestine, contributing to lipid-lowering effects. Among the different types of CGs, κ-CG has demonstrated particular efficacy in reducing total lipoprotein levels. This property makes CGs promising candidates for developing functional foods and pharmaceutical products to manage hyperlipidemia and related metabolic disorders [74,75].

Carrageenan (CG)-based hydrogels have demonstrated significant potential in supporting bone tissue regeneration by promoting both angiogenesis and osteogenesis. Angiogenesis, the formation of new blood vessels, is essential for supplying nutrients and oxygen to regenerating tissues, while osteogenesis refers to the development of new bone tissue. The ability of CG-based hydrogels to enhance these biological processes makes them attractive candidates for bone repair and regenerative medicine, offering a supportive environment that mimics the extracellular matrix and facilitates cellular activities crucial for tissue healing and integration [76].

Additionally, injectable κ-CG hydrogels have exhibited chondrogenic potential, addressing cartilage’s limited self-repair capacity. These hydrogels are efficient delivery systems, transporting many functional stem cells to the target site. This property is particularly valuable for regenerative therapies, as it enhances cellular activity and supports tissue regeneration [77].

2.6. Bacterial Cellulose

Cellulose is the most abundant natural polymer and represents an inexhaustible raw material on Earth. In addition to its natural formation through photosynthesis and chemical synthesis, cellulose can also be obtained through enzymatic synthesis in vitro or via biosynthesis by various microorganisms, including algae, fungi, and bacteria.

Bacterial cellulose (BC) (Figure 6) is synthesized extracellularly by various Gram-negative bacterial genera, including Gluconacetobacter, Acetobacter, Agrobacterium, Achromobacter, Aerobacter, Sarcina, Azobacter, Rhizobium, Pseudomonas, Salmonella, and Alcaligenes. Among these, the Gluconacetobacter genus is recognized as one of the most efficient producers of BC. BC’s nanostructure significantly influences its physical and mechanical properties, with its morphology being adjustable through cultivation methods and bioreactor conditions [78].

The molecular weight of BC can vary significantly based on production conditions and measurement techniques. For instance, a study published in Cellulose (2024) reported that the MW of BC, determined through gel permeation chromatography of its cellulose acetate derivative, ranged from approximately 92.8 kDa to 199.4 kDa, depending on the degradation time during sample preparation [80]. Following production, BC can be processed into a hydrogel or a dry form via freeze-drying. The optimization of growth media plays a crucial role in microbial development, as bacteria respond to environmental changes through alterations in protein synthesis and cell morphology. Compared to plant-derived cellulose, BC possesses a finer nanofiber-based three-dimensional network, which increases the surface-area-to-volume ratio and enhances interactions with adjacent components [81].

BC is distinguished by its exceptional physicochemical properties, making it highly suitable for various biomedical and industrial applications. One of its most notable features is its superior mechanical strength, which arises from the dense nanofibril network that confers tensile durability and flexibility. Additionally, BC possesses a high degree of polymerization and remarkable crystallinity, typically around 90%, contributing to its structural stability and resistance to enzymatic degradation [82,83].

This high crystallinity, coupled with its ultrafine fibre structure, results in a material that is mechanically robust and exhibits excellent water retention capacity. BC can absorb and retain significant amounts of water relative to its dry weight, forming hydrogels that maintain a moist environment—an essential feature for applications such as wound dressings, tissue scaffolds, and drug delivery systems [82,83].

These combined properties—mechanical integrity, high crystallinity, and water-holding ability—underscore the versatility of bacterial cellulose and support its growing use in biomedical engineering, particularly in tissue regeneration and wound healing [82,83].

Furthermore, BC is highly valued for its purity—being free from lignin, hemicellulose, and pectin—along with its non-toxicity and biodegradability. These properties make BC a promising material for biomedical applications, particularly as a tissue engineering and wound healing scaffold. Additionally, the hydroxyl functional groups present along its molecular chains enable BC to be chemically modified, hybridized, or grafted with various biopolymers, facilitating its integration into nanocomposite fabrication [82].

The global microbial and bacterial cellulose market was valued at approximately USD 0.48 billion in 2024 and is projected to grow significantly, reaching an estimated USD 2.24 billion by 2033. This growth corresponds to a CAGR of roughly 18.8% over the forecast period from 2025 to 2033 [84].

Applications

BC has triggered considerable interest in the biomedical area, including tissue repairing and controlled release of drugs, due to its unique properties and biocompatibility.

The native BC membrane is a lightweight, transparent material that exhibits an exceptional combination of mechanical properties with a stress–strain behaviour comparable to soft tissues such as skin. Its transparency allows for easy wound inspection, while additional benefits include pain relief, infection reduction due to exudate retention, shorter healing times, firm wound adherence, and easy removal following epithelialization [79,85,86]. These attributes make BC dressings superior to conventional wound dressings. BC dressings form a dense physical barrier that protects against microbial contamination and external injury while permitting gas exchange. Furthermore, BC is highly flexible, conforming to wound contours and reducing the risk of microbial infiltration. These membranes can be tailored to various sizes and shapes, enabling the coverage of even large wounds with a single sheet. A distinctive feature of BC membranes is their differential interaction with wounded and intact skin. The section of the membrane in contact with healthy skin dries out, forming a thin, cellophane-like layer that adheres to the outermost layer of the epidermis (stratum corneum). In contrast, the central membrane segment that remains in contact with the wound retains moisture, preventing the maceration of surrounding skin that can result from prolonged exposure to moist dressings [79,85,86].

BC exhibits remarkable physicochemical and biocompatible properties, with a nanofiber structure closely resembling collagen fibres in bone tissue. Its density, Young’s modulus, and tensile strength are approximately 1600 kg/m³, 138 GPa, and 2 GPa, respectively, making it mechanically comparable to high-performance materials such as aramid fibres. These characteristics highlight BC’s potential for applications in bone tissue engineering and regenerative medicine [78].

BC can be employed in various forms, such as hydrogels, films, and nanoparticles, to enable controlled and targeted drug delivery. Its remarkable water retention capacity and biocompatibility make it an ideal material for the localized administration of pharmaceuticals, growth factors, and other therapeutic agents to specific tissues or organs, enhancing treatment efficacy and minimizing side effects [87].

2.7. Dextran

Dextran (DX) is a naturally occurring polysaccharide produced by bacterial secretion, primarily consisting of linear α-1,6-linked D-glucopyranose residues (Figure 7). Its molecular weight varies from several thousand to several million Da, and it undergoes enzymatic degradation in the spleen, liver, and colon. Due to the presence of active hydroxyl groups, DX has been widely studied for its potential in developing chemically crosslinked hydrogel scaffolds [88]. DX is produced primarily by lactic acid bacteria such as Leuconostoc, Lactobacillus, Weissella, and Streptococcus species in the presence of sucrose [89]. The biosynthesis is catalyzed by extracellular enzymes called dextransucrases, which cleave sucrose into glucose and fructose, using the glucose to build α-(1→6)-linked glucan chains with various branch linkages. Industrially, Leuconostoc mesenteroides NRRL B512 is the principal strain used for large-scale dextran production under controlled fermentation conditions. Additionally, enzymatic synthesis methods have been developed using isolated or engineered dextransucrases to produce DXs with specific molecular weights and branching structures. DX molecular weights can vary widely, from low molecular weight oligodextrans (<40 kDa) to very high molecular weight polymers exceeding 400 MDa, depending on the strain and synthesis conditions [90].

DX with molecular weights of 40, 60, and 70 kDa is commonly used due to its classification as a clinical-grade material. DX-based hydrogels offer several advantages as biomaterials, including excellent swelling capacity, biocompatibility, mechanical strength, biodegradability, and non-toxicity. One of the distinguishing features of DX is its solubility in various solvents such as water, dimethyl sulfoxide, glycerol, and ethylene glycol, which provides a significant advantage over other polysaccharides [92,93].

Due to its non-toxicity, biocompatibility, and availability across a broad molecular weight range, DX is a versatile base material for hydrogel synthesis [92,93].

Unlike other polysaccharides, DX is resistant to digestion by common amylases, enhancing the bioavailability of its hydrogels and the therapeutic agents they encapsulate [94].

DX can be easily degraded under physiological conditions by dextranase, an enzyme in the human colon, preventing accumulation within the body and minimizing the risk of adverse effects. As a neutral polysaccharide, DX-based hydrogels used as drug delivery vehicles effectively penetrate the mucus barrier, overcoming a significant challenge in targeted drug administration [94].

The global DX market was valued at approximately USD 229.29 million in 2024 and is projected to increase to USD 240.06 million by 2025, reaching an estimated USD 346.68 million by 2033. This growth corresponds to a CAGR of 4.7% over the forecast period from 2025 to 2033 [95].

Applications

The studies have demonstrated using DX-based hydrogels as functional scaffolds to promote neovascularization and facilitate skin regeneration in third-degree burn wounds [96]. These hydrogels were developed through the copolymerization of DX allyl isocyanate–ethylamine with polyethene glycol diacrylate. When applied to burn wounds, the hydrogel enhanced blood flow to the affected area more effectively than the control hydrogel or standard dressing. The DX-based hydrogel also appeared to accelerate the recruitment of endothelial cells to the wound site, leading to rapid neovascularization within a week of treatment. Furthermore, the hydrogel-treated wounds demonstrated successful skin regeneration, including the formation of appendages. In addition to burn treatment, DX-based hydrogels have proven beneficial in reducing intra-abdominal adhesions. Hydrogels composed of succinyl CH and DX aldehyde significantly mitigated the formation of these adhesions without negatively impacting the wound healing process [96,97].

DX-based hydrogels can be engineered to include functional groups that interact with biomolecules. For instance, numerous protein growth factors, such as heparin, contain domains that specifically engage with extracellular matrix components. Heparin, a sulfated polysaccharide with a negative charge, has a well-documented ability to bind to various growth factors containing heparin-binding domains, including vascular endothelial growth factor and fibroblast growth factor family members. Consequently, the functionalization of DX with carboxylate, benzylamine, and sulfate groups creates a hydrogel-forming macromonomer with an enhanced negative charge, which promotes more excellent retention of transforming growth factor beta (TGFß1). Furthermore, the aldehyde groups generated through DX oxidation can be employed to immobilize various drugs onto a single polymer chain, i.e., immobilizing amphotericin B [98,99].

DX was considered a non-bioactive polymer from a biomaterial perspective for many years, as it was believed that cells could not recognize it as a biological substance. However, this assumption may not be entirely accurate, and further research is required to better understand how cells respond to this polysaccharide. While the receptors and signalling pathways associated with polysaccharides like HA have been identified, similar levels of understanding have not yet been achieved for DX [100]. A comparison of polysaccharide biopolymers is presented in

Table 1. Polysaccharides.

Biopolymer	Type/Structure	Origin	Key Properties	Applications	Sources
Hyaluronic Acid (HA)	Linear macromolecular mucopolysaccharide consisting of alternately linked D-glucuronic acid and N-acetylglucosamine monomers	Rooster combs, Pig umbilical cord, Bovine vitreous body, Bovine synovial fluid, Streptococci, Streptococcus thermophilus, Bacillus subtilis, Lactococcus lactis	Non-immunogenicity, anti-inflammatory, antioxidant, high water retention, pseudoplasticity, and viscoelasticity	Diagnostics, therapeutics, drug delivery, tissue engineering, cosmetics, ophthalmology, cancer treatment, wound healing	[14,15,16,17,18,19,20,21,23,24]
Alginate (ALG)	Anionic polysaccharide composed of β-D-mannuronic acid (M) and α-L-guluronic acid (G) monomers	Brown seaweed, specific bacterial genera (Pseudomonas, Azotobacter), and marine macroalgae species	Hydrophilic, non-toxic, inert, non-immunogenic, high absorbency, biodegradability, and biocompatibility	Tissue engineering (hydrogels, scaffolds), wound dressings	[25,34,35,36]
Chitosan (CH)	Linear, semi-crystalline polysaccharide consisting of (N-acetyl-D-glucosamine and D-glucosamine units	Partial deacetylation of chitin	Biocompatibility, biodegradability, non-toxicity, non-immunogenic hemostatic activity, antimicrobial	Tissue engineering (hydrogels, scaffolds), wound healing, drug delivery	[43,45,47,48,49,50,51,53,54]
Agarose (AGR)	Linear polymer composed of D-galactose and 3,6-anhydro-L-galactose units	Red algae	numerous hydroxyl groups,	Tissue engineering, drug delivery, and dental applications	[60,61,62,63]
Carrageenan (CG)	Anionic sulfated polysaccharide, various types: kappa (κ), iota (ι), mu (μ), nu (ν), theta (θ), lambda (λ)	Red seaweeds (Rhodophyceae)	Bioactive properties (antibacterial, antiviral, anticoagulant)	Drug delivery, tissue engineering	[70,71,72,73,76,77]
Bacterial Cellulose (BC)	Nanostructure	Gram-negative bacteria (Gluconacetobacter, Acetobacter, Agrobacterium, Achromobacter, Aerobacter, Sarcina, Azobacter, Rhizobium, Pseudomonas, Salmonella, and Alcaligenes)	High mechanical strength, high purity, and biocompatibility	Tissue repairing, drug-controlled release, and wound healing	[78,79,85,86,87]
Dextran (DX)	Linear a-1,6-linked D-glucopyranose residues	Bacterial secretion	Solubility in various solvents, non-toxicity, and biocompatibility	Skin regeneration, prevention of intra-abdominal adhesions, and drug delivery	[88,92,93,96,97]

.

3. Proteins

Proteins are polymers constructed from amino acids linked together by covalent peptide bonds. They form macromolecules with a molecular weight > 10 kDa [101]. Proteins are synthesized by living organisms and play a crucial role in all biological processes. This makes them naturally occurring molecules and classifies them into compounds known as biopolymers [102]. Biopolymers offer significant advantages compared to synthetic polymers due to their biocompatibility and biodegradability. The breakdown of some synthetic polymers can trigger an immunological response in the body. This issue does not arise with the use of biopolymers; therefore, their application in medicine, including drug delivery, tissue engineering, and wound healing, has significantly increased in recent years [103,104]. Below are examples of protein biopolymers and their applications in medicine.

3.1. Collagen

Collagen (CL) is a fibrous protein found in the extracellular matrix. A structural protein occurs most in animal tissues, mainly in connective tissues. It owes its exceptional tensile strength to its unique triple right-handed helical structure [105]. Collagen, in its native triple-helical form, has a molecular weight of approximately 300 kDa, with a structure composed of around 3000 amino acids. This form is typically 300 nanometers in length and 1.5 nanometers in diameter. In processed forms, such as hydrolyzed collagen or collagen peptides, the molecular weight is significantly reduced, often ranging from 2 to 10 kDa, to enhance solubility and bioavailability [106].

Key features of CL include compatibility with living organisms, the ability to degrade naturally, and the possibility of modifying functional groups [103,104]. The chemical structure of CL is presented in Figure 8.

Industrial collagen production typically involves extraction from animal sources such as bovine, porcine, or marine tissues. The extracted collagen is processed into various forms, including hydrolysates and gels, for medical, cosmetic, and food applications. The final product may be cross-linked or modified depending on the intended use [108].

The global collagen market was valued at approximately USD 7.74 billion in 2024 and is anticipated to grow at a CAGR of 7.10% during the forecast period from 2025 to 2034, reaching an estimated USD 15.37 billion by 2034 [109].

Applications

Due to its properties, CL is most often used in tissue engineering [103,104,105,110]. Various strategies for modifying the composition and structure of CL-based biomaterials introduce new possibilities for broader applications of CL in tissue engineering by creating materials that demonstrate greater effectiveness in the regeneration of specific tissues and organs. The enzymatic cross-linking process involving SrtA and FXIII proves effective in optimizing the biostability and mechanical characteristics of the material, which is widely used in the reconstruction of vascular tissues [110].

CL hydrogels are frequently used in 3D printing. However, a problem is often encountered during fabrication, which involves the loss of shape of hydrogel structures caused by interaction with the cells within them. To prevent this, a composite gel combining CL and modified HA has been developed. This material is characterized by high shape fidelity, biocompatibility, and rheological properties suitable for 3D printing [111].

CL is also used as a drug carrier. In dentistry, CL sponges saturated with anti-inflammatory and analgesic drugs are used and placed in the tooth socket after tooth extraction [112].

3.2. Gelatin

Gelatin (Figure 9) is a collagen derivative obtained through acid or alkaline hydrolysis. The reaction results in a fibrous protein with amphoteric properties [113]. Chemically, gelatin is composed of 18 amino acids. The main components are glycine, proline, and hydroxyproline, which together constitute 57% of the total. Other amino acids present include alanine, aspartic acid, and glutamic acid [114]. The most common industrial sources include porcine skin, bovine hides, and bones, accounting for most global gelatin production. Alternative sources, such as poultry and fish by-products, have recently gained attention due to religious, health, and environmental considerations [115]. Gelatin extraction is typically carried out using chemical or enzymatic methods. Acidic or alkaline pretreatments break down the collagenous matrix, followed by thermal hydrolysis to yield gelatin. The extraction process significantly influences the final product’s molecular weight distribution, gel strength, and functional properties. Gelatin exhibits a broader molecular weight distribution, generally between 10 and 400 kDa, depending on the method of extraction and processing [116].

Its ability to form complex polyionic complexes with proteins, growth factors, nucleotides, and polysaccharides means it is frequently used as a modifier [117]. The application of modifiers in tissue engineering enables the creation of composite biomaterials, leading to the production of materials similar to natural tissues [113,117]. Further advantages include biocompatibility, biodegradability, and non-cytotoxicity. Additionally, it promotes cell adhesion, is water-soluble, has low immunogenicity, and is cost-effective. These characteristics contribute to its frequent use in tissue engineering [84,86].

Figure 9. Chemical structure of GL [118].

Figure 9. Chemical structure of GL [118].

In 2023, the global gelatin market was valued at USD 3.07 billion and is expected to grow from USD 3.20 billion in 2024 to USD 5.51 billion by 2032, reflecting a compound annual growth rate (CAGR) of 7.03% over the forecast period. Europe led the market, accounting for 41.04% of the total share in 2023 [119].

Applications

GL’s ability to form complex polyionic complexes with proteins, growth factors, nucleotides, and polysaccharides means it is frequently used as a modifier. Applying modifiers in tissue engineering enables the creation of composite biomaterials, producing materials similar to natural tissues. Further advantages include biocompatibility, biodegradability, and non-cytotoxicity [117,120]. Additionally, it promotes cell adhesion, is water-soluble, has low immunogenicity, and is cost-effective. These characteristics contribute to its frequent use in tissue engineering. Due to its adhesive capabilities, GL is used as a scaffold for 3D cell growth. Such scaffolds are used for the repair and regeneration of bone defects and heart tissue, as well as the regeneration of the cornea, cartilage, blood vessels, and periodontal tissues. Despite its numerous applications, GL has weak mechanical properties, necessitating the creation of hybrid biopolymers to improve them [120,121]. Gelatin scaffolds are produced using various methods, each with distinct advantages. Scaffold production via lyophilization allows for the creation of highly porous materials, ideal for use in soft tissue regeneration and wound healing [122,123]. Scaffolds tailored to specific patient needs, configurable and with desired geometries, are achievable through the use of 3D printing. Electrospinning utilizes a high-voltage electric field to obtain nanofibers. This process yields materials with a large surface area, mimicking the extracellular matrix, suitable for vascular, skin, and nerve tissues [121,122,123].

3.3. Silk Fibroin

Silk fibroin (SF) is a water-insoluble glycoprotein produced by silkworms of the species Bombyx mori. It is composed of alanine, serine, and glycine, giving it an anti-parallel beta-sheet structure. Silk must be dissolved in solvents for biomedical applications to obtain a regenerated silk solution (RSF), which is then transformed into powder, fibre, and film forms through various processes [124].

The production of SF typically involves four main stages: degumming, dissolution, dialysis, and centrifugation. Degumming removes sericin using agents such as sodium carbonate or urea, preserving the integrity of the fibroin. The degummed fibroin is then dissolved using various solvents—acidic, alkaline, saline, or ionic liquids—each of which affects the molecular weight, secondary structure, and properties of the RSF. Following dissolution, dialysis is employed to eliminate residual solvents, and centrifugation helps purify the RSF solution. The RSF can be further processed into films, sponges, fibres, gels, and nanoparticles, enabling its application in biomedicine, tissue engineering, cosmetics, and food technology [125].

SF exhibits a variable MW depending on its source and processing conditions. Native SF consists of a heavy chain (~391 kDa) and a light chain (~26 kDa), connected by a disulfide bond, yielding a theoretical MW around 420 kDa. However, the actual MW of regenerated SF can vary widely based on dissolution methods. According to Cho et al., SF dissolved in lithium bromide solution under mild conditions retained a high MW. In contrast, SF samples dissolved in calcium chloride/ethanol/water mixtures exhibited reduced MWs, with values decreasing to 110–150 kDa depending on dissolution time [126].

It has many advantages, such as non-toxic degradation products, exceptional mechanical strength, and low immunogenicity, which make it an ideal material for designing drug carriers [127,128,129]. The structure of SF is presented in Figure 10.

The global SF market was valued at USD 96.7 million in 2022 and is projected to reach approximately USD 148.5 million by 2029, growing at a CAGR of 6.3% over the forecast period [131].

Application

SF, a biopolymer with significant modification potential, allows for the production of biomaterials with diverse shapes and structures [132]. This makes it a valuable material in tissue engineering. 3D-printing inks based on SF have demonstrated a range of beneficial features, including rapid gel formation, shape integrity, long-term stability, and good adhesion to surrounding healthy tissues. Furthermore, the obtained hydrogels were characterized by satisfactory mechanical properties and resistance to enzymatic degradation [132].

SF’s biocompatibility makes it useful in wound healing processes [133]. Hydrogel dressings with SF enable integration with host tissues, minimizing the risk of rejection. SF dressings can effectively deliver drugs, growth factors, and bioactive substances directly to the wound, promoting an optimal healing process [133].

SF’s slow biodegradation properties make it ideal as a drug delivery material. Combining SF with polymers enables the creation of a composite that allows for better control over the release of active substances [134].

3.4. Albumin

Albumin (ALB) is a globular protein and the most abundant component of blood plasma, accounting for over 50% of total serum protein content in healthy individuals. It plays a vital role in maintaining various physiological functions [135]. It is synthesized predominantly in the liver and circulates in the bloodstream at a normal physiological concentration of approximately 0.6 mM. The term “albumin” originates from albumen, derived from the Latin word albus, meaning “white.” Several structurally and functionally distinct forms of A/B are recognized, including human serum albumin (HSA), bovine serum albumin (BSA), and ovalbumin. Among its physiological functions, ALB plays a central role in maintaining plasma colloid osmotic pressure, accounting for approximately 80% of this osmotic activity in the circulatory system [136]. A separation process is employed to isolate pure ALB, and various techniques have been developed depending on the source, including human, animal, and plant-derived ALB. Reported methods include chromatography, solvent extraction, electrophoresis, and adsorption, each offering distinct advantages in efficiency, selectivity, and purity [137]. The molecular weight of HSA is approximately 66.5 kDa, BSA is approximately 66.3 kDa, and ovalbumin is 45 kDa [138,139]. Key features of ALB include biocompatibility, biodegradability, and non-immunogenicity [135].

The global ALB market was valued at approximately USD 5.95 billion in 2024 and is projected to grow at a compound annual growth rate (CAGR) of 5.21% from 2025 to 2032, reaching an estimated value of USD 8.93 billion by the end of the forecast period [140].

Application

ALB is a versatile protein biopolymer with significant potential in drug delivery systems. A key advantage of ALB-based drug delivery systems is their versatility in binding to various compounds, such as metal nanoparticles and antibodies. According to recent studies, ALB nanoparticles demonstrate effectiveness in diagnosing and treating many diseases, including cancer, diabetes, and Alzheimer’s disease. Furthermore, ALB-based carriers exhibit exceptional stability under physiological conditions and enable controlled and prolonged drug release, which increases therapeutic efficacy [135,141].

Table 2. Proteins.

Biopolymer	Type/Structure	Origin	Key Properties	Applications	Sources
Collagen (CL)	Fibrous protein, triple right-handed helical structure	Animal tissues	Tensile strength, biocompatibility, and biodegradability	Tissue engineering, drug carrier	[103,104,105,110,111,112]
Gelatin (GL)	Fibrous protein, amphoteric properties	Acid or alkaline hydrolysis of collagen	Biocompatibility, biodegradability, non-cytotoxicity, and cell adhesion	Tissue engineering, 3D cell growth scaffolds	[113,114,117,120,121,122,123]
Silk Fibroin (SF)	glycoprotein, anti-parallel beta-sheet structure	Silkworms (Bombyx mori)	Non-toxic degradation products, mechanical strength, low immunogenicity, water-insoluble	Tissue engineering, drug carriers, wound healing	[127,128,129,132,133,134]
Albumin (ALB)	Globular protein	Blood plasma	Biocompatibility, biodegradability, non-immunogenicity, and versatile binding	Drug delivery systems	[121,135,141]

provides a comparison of selected protein biopolymers.

4. Others

4.1. Polycaprolactone

Polycaprolactone (PCL) belongs to synthetic biopolymers [142]. It is a biodegradable polyester built from a chain of ε-caprolactone units (C₆H₁₀O₂)_n (Figure 11), usually obtained by ring-opening polymerization [143,144]. PCL is a hydrophobic, linear polymer with a melting temperature of around 60 °C [145]. The synthesis of PCL was first reported by Van Natta et al. through the thermal polymerization of ε-caprolactone [146]. Since this initial development, the primary method for PCL production has continued to be ring-opening polymerization of ε-caprolactone, typically catalyzed by ionic or metal-based systems due to their efficiency and control over molecular weight and polymer architecture [147]. Alternative synthetic approaches have been investigated, including radical ring-opening polymerization of 2-methylene-1,3-dioxepane under various experimental conditions. Additionally, polycondensation of 6-hydroxycaproic acid has been explored, albeit infrequently, and is documented in a limited number of studies [148]. Among these, enzymatic polycondensation using lipases represents a promising green chemistry route, offering synthesis under milder conditions, though it remains less established in the literature [149]. PCL exhibits molecular weights ranging from approximately 14 to 80 kDa [150].

PCL is biocompatible, biodegradable, and bioresorbable [143]. Its degradation time depends on its molecular mass and degree of crystallization and usually equals 2 to 4 years [145]. The degradation rate also depends on permeability, pH, and temperature. Degradation of PCL implants usually happens due to non-enzymatic hydrolysis of ester bonds within the polymer chain. It can also be catalyzed by free radicals, present during an inflammatory state, or by esterase enzymes [143,151]. Regardless of the degradation mechanism, once the PCL fragments are small enough, they are absorbed by cells. The intracellular fragmentation products can then be incorporated into the citric acid cycle [151,152].

Figure 11. PCL structure [153].

Figure 11. PCL structure [153].

The global PCL market was valued at approximately USD 499.78 billion in 2023 and is expected to grow at a CAGR of 10.5%, reaching an estimated USD 1110.91 billion by 2031 over the forecast period from 2024 to 2031 [154].

Application

The properties of PCL and its copolymers allowed it to find diverse applications in medicine and bioengineering.

Copolymers of PCL with polyglycolide are used in sutures under the trade name Monocryl because of their high tensile strength and safety, as they cause minimal response from the patient’s tissue [7].

Slow degradation, excellent biocompatibility, and good permeability to many drugs make PCL useful in long-term drug-release systems. Microcapsules made from PCL can be loaded with a variety of drugs, including anticancer drugs, anti-inflammatory drugs, and others [144,155].

The slow degradation rate under physiological conditions and the ability to fabricate porous scaffolds make PLC a popular polymer for producing long-lasting implants for various tissues and 3D scaffolds to promote the regeneration of tissues such as bone and skin [144]. Scaffolds made from PCL do, however, require surface modification, such as by coating with a layer of CL, to improve cell adhesion [156]. PCL is suitable for making tissue scaffolds by 3D printing due to its low melting point and good formability [156,157].

4.2. Polyhydroxybutyrate

Polyhydroxybutyrate (PHB) belongs to polyhydroxyalkanoates (PHAs), a group of biodegradable polyesters [158]. It is a linear polymer built from 3-hydroxybutyrate units (Figure 12). It is produced by various bacteria as a carbon reserve, as a homopolymer, or part of copolymers. Industrial-scale PHB production predominantly relies on microbial fermentation using strains such as Cupriavidus necator, Azotobacter, and Bacillus spp.

PHB synthesis occurs via a three-step enzymatic pathway beginning with acetyl-CoA: (1) condensation to acetoacetyl-CoA by β-ketothiolase (PhaA), (2) reduction to (R)-3-hydroxybutyryl-CoA by acetoacetyl-CoA reductase (PhaB), and (3) polymerization by PHB synthase (PhaC). Various fermentation strategies, including batch, fed-batch, and continuous processes, have been developed to optimize yield and polymer quality [159]. Molecular weight of PHB can exceed 1000 kDa, with some reports indicating values up to 3000 kDa. Molecular weight variations affect the mechanical properties, processability, and biodegradation rate of PHB. Higher molecular weight PHB tends to exhibit improved mechanical strength and elasticity, while lower molecular weight forms may be more brittle and degrade faster [160].

PHB is biocompatible, completely biodegradable, thermoplastic, brittle, and hydrophobic. It exhibits good flexibility and tensile strength [161,162]. Pure PHB contains both crystalline and amorphous phases and is highly crystalline [163]. An issue in PHB processing arises due to its melting temperature being close to its degradation temperature. This can be remedied by introducing hydroxyvalerate (HV) units, which reduce crystallinity and lower the melting temperature of the resulting copolymer-polyhydroxybutyrate-co-polyhydroxyvalerate (PHBV) [162].

Figure 12. Structure of PHB [164].

Figure 12. Structure of PHB [164].

The global polyhydroxybutyrate (PHB) market was valued at USD 178 million in 2024 and is expected to grow at a compound annual growth rate (CAGR) of 15.9%, reaching approximately USD 643 million by 2032 during the forecast period from 2026 to 2032 [165].

Application

PHB and its copolymers, like PHBV, have found many applications in the medical field, including orthopaedic engineering, nerve regeneration, and drug delivery.

PHB and its copolymers can be used as scaffolds for tissue regeneration. PHBV composites are used in implants for bone and cartilage regeneration [166]. Scaffolds made from PHB can be used to repair peripheral nerves [161,166]. PHBV composites also work as materials for vascular grafts, and PHB can be a coating for the manufacturing of synthetic heart valves.

PHB-based nano- and microparticles are excellent drug delivery materials thanks to their biodegradability and lack of toxicity. They can carry various drugs, with the focus in recent years being on their use in cancer therapy. PHB and PHBV also find uses as materials for sutures and wound dressings [166].

4.3. Polylactic Acid

Polylactic acid (polylactide, PLA) is a biodegradable polymer built from lactic acid units (Figure 13). It is an aliphatic polyester whose mechanical properties can vary depending on its molecular weight and degree of crystallinity [167,168]. PLA is a thermoplastic polymer with a melting temperature between 140 and 210 °C [169,170]. It is transparent, hydrophobic, and brittle [169,171]. Its degradation time is much shorter than that of polymers obtained from petrochemical materials, like polyethene, and usually equals less than 2 years, with degradation occurring by non-enzymatic hydrolysis [167]. In a living organism, the degradation products can then be incorporated into the citric acid cycle [167]. PLA can be produced by chemical synthesis or, more often employed, bacterial fermentation [167,171]. PLA is typically produced through the chemical synthesis of acetaldehyde and the polymerization of lactic acid, which is derived via carbohydrate fermentation. The initial synthesis of lactic acid, a key monomer in PLA production, was first reported by Swedish chemist Carl Wilhelm Scheele in 1780 [172]. PLA is primarily synthesized via two main routes: the direct polycondensation of lactic acid and the ring-opening polymerization of its cyclic dimers, known as lactides. In addition to these conventional methods, recent studies have also explored enzymatic synthesis pathways. PLA can be categorized based on its stereochemistry into poly(L-lactic acid), poly(D-lactic acid), and poly(DL-lactic acid), which are polymers of L-lactic acid, D-lactic acid, and racemic DL-lactic acid, respectively [173].

PLA exhibits a broad range of molecular weights depending on the synthesis route and intended application. According to scientific data, high molecular weight PLA can reach up to 1000 kDa, while lower molecular weight PLA typically measures around 60 kDa, which is often preferred for biomedical applications due to its faster degradation rate [174].

Figure 13. PLA structure [174].

Figure 13. PLA structure [174].

The global PLA market was valued at USD 2594.57 million in 2024 and is expected to grow to USD 3060.6 million by 2025, reaching approximately USD 11,473.1 million by 2033. This growth reflects a projected CAGR of 17.96% over the forecast period from 2025 to 2033 [175].

Applications

PLA’s good biocompatibility allowed it to be widely used in medicine. PLA has found use in tissue engineering, drug delivery systems, and the manufacturing of implants and sutures [176,177].

PLA nanoparticles make promising drug carriers for anticancer drugs and polynucleotides used in gene therapy, increasing their efficiency and safety [176]. PLA works as a scaffold material in bone regeneration procedures, usually as a part of a composite with hydroxyapatite or bioglass. It can also be used in stents, vascular scaffolds, and fibrous mats for skin healing. PLA-based materials have found use in the manufacturing of biodegradable screws, pins, plates and sutures for treating fractures and ligament injuries [168,176].

PLA is also a promising material for surgical tools, such as surgical retractors, needle drivers, hemostats, and others, which can be easily and cheaply produced using 3D printing [168].

Table 3. Synthetic Polymers.

Biopolymer	Type/Structure	Origin	Key Properties	Applications	Sources
Polycaprolactone (PCL)	ε-caprolactone units	Chemical synthesis	Biocompatible, biodegradable, bioresorbable	Sutures, drug-release systems, tissue scaffolds	[7,143,144,155,156,157]
Polyhydroxybutyrate (PHB)	linear polymer built from 3-hydroxybutyrate units	Bacteria	Biocompatible, biodegradable, thermoplastic	Orthopaedic engineering, nerve regeneration, drug delivery, tissue regeneration	[159,160,161,162,166]
Polylactic Acid (PLA)	aliphatic polyester built from lactic acid units	Chemical synthesis or bacterial fermentation	Biocompatible, biodegradable, hydrophobic, short degradation time	Tissue engineering, drug delivery systems, implants, sutures	[167,168,169,171,176,177]

provides a comparison of selected synthetic biopolymers.

5. Conclusions and Future Challenges

This comprehensive review demonstrates that natural and synthetic biopolymers offer immense promise for applications in biotechnology and tissue engineering. Thanks to their inherent biocompatibility, biodegradability, and unique structural properties, they are becoming ideal candidates to replace synthetic polymers in therapeutic systems. Natural biopolymers such as hyaluronic acid, alginate, chitosan, bacterial cellulose, and collagen have proven valuable in wound healing, tissue scaffolding, and targeted drug delivery due to their inherent biological activity and structural similarity to the extracellular matrix. Furthermore, advances in processing technologies, including chemical modification, nanocomposite formation, and bioprinting, have significantly expanded these materials’ application range and performance. For example, protein- and polysaccharide-based hydrogels have shown outstanding utility in regenerative medicine. At the same time, synthetic biopolymers like PLA, PHB, and PCL offer tunable degradation rates and mechanical properties suitable for implants and controlled drug release.

Nevertheless, significant challenges remain. Among them are the scalability, cost-effectiveness, and mechanical performance of soft biomaterials such as hydrogels. Growing emphasis on sustainability and the reduction in environmental impact positions biopolymers as essential materials for the next generation of medical and bioengineering innovations. Moreover, increased consumer awareness about sustainable development can contribute to the growth of the biopolymer market [129]. Significant attention is being paid to reducing greenhouse gas emissions and waste and decreasing dependence on fossil fuels due to the increasing signs of climate change and limited oil resources. Increasing the scale of production remains a significant challenge for many biopolymer-based systems. Current efforts aim to develop industrial-scale production methods to eliminate the disparities between laboratory and industrial production. Future research directions will also focus on improving the mechanical properties of low-viscosity hydrogels to enhance their printability [113].