Naturally derived hydrogels for wound healing

ABSTRACT

Natural hydrogels have garnered increasing attention due to their natural origins and beneficial roles in wound healing. Hydrogel water-retaining capacity and excellent biocompatibility create an ideal moist environment for wound healing, thereby enhancing cell proliferation and tissue regeneration. For this reason, naturally derived hydrogels formulated from biomaterials such as chitosan, alginate, gelatin, and fibroin are highly promising due to their biodegradability and low immunogenic responses. Recent integrated approaches to utilizing new technologies with bioactive agents have significantly improved the mechanical properties of hydrogels and the controlled release and delivery of active compounds, thereby increasing the efficiency of the treatment processes. Herein, this review highlights the advantages and the challenges of natural hydrogels in wound healing, focusing on their mechanical strength, controlled degradation rates, safety and efficiency validation, and the potential for incorporating advanced technologies such as tissue engineering and gene therapy for utilization in personalized medicine.

GRAPHICAL ABSTRACT

1. Introductions

Wound treatments have always been one of the most significant challenges in biomedical sciences and require an effective, high-technology, usable, and safe solution [1]. A general wound healing process consists of four main stages, including (1) hemostasis – platelets promote blood coagulation, (2) inflammation – white blood cells act to fight against bacteria and viruses and clean up impurities, (3) proliferation – an amorphous gel forms to synthesize collagen and foster the development of new tissue, and (4) remodeling – collagen type-III is replaced by collagen type-I, further strengthening the tissue of the injured area [2–4]. Wound healing requires subtle management to reduce the risk of complications, involving the prevention, early detection, and timely intervention of complications. A humid environment favors wound healing by reducing discomfort, preventing bacterial infection, and keeping the area optimal for developing new tissues [5]. To this end, hydrogel, a three-dimensional network of cross-linked polymers with high water content, demonstrates a promising approach [6–9]. It is made of chains connected at several cross-linked points and can hold large amounts of water. Due to excellent biocompatibility, biodegradability, and ability to load and release drugs, natural hydrogels have been the first choice for many biomedical applications [10–13]. They show good compatibility with biological tissues, a minimum immune response, and help in faster healing. Most importantly, these hydrogels can be degraded sustainably, reducing the danger of accumulating unwanted material in the human body and minimizing environmental impacts during non-medical usage [14]. This makes them potential candidates for wound healing and treatments of skin-related issues and viral and bacterial infections.

Besides the wound healing process, wounds often comprise of other infections. Traditional treatments for wound infections caused by bacteria and viruses often lack significant improvements, for example, bandages, topical creams, and oral medications [1]. Besides demonstrating low efficiency, these methods exert undesirable side effects, resistance to the drugs, off-target effects, or adverse reactions arising due to the uncontrolled release of drugs [15]. For this reason, hydrogels of natural origin offer an interesting alternative. Hydrogels could be fabricated by extracting natural polymers from raw materials, followed by chemical and/or physical methods. This process involves extraction, the addition of medicinal agents, structural improvement, and the incorporation of additives to favorably alter hydrogel physicochemical properties [10,12,16]. Although synthetic hydrogels are commercially available, they are often associated with problems regarding limited biocompatibility, poor biodegradability, and the presence of residual synthetic by-products, giving rise to safety and ecological concerns when their application persists for months [17].

Ultimately, developing natural, nontoxic, and highly efficient hydrogels has become urgent. Advanced hydrogels, such as intelligent, stimuli-responsive hydrogels, and disease-specific or self-healing hydrogels integrated with new wound healing technologies, have gained particular interest [8,18]. Although numerous reviews have examined the applications of hydrogels in wound healing [6–9], few articles have focused on the utilizations of naturally derived hydrogels (hydrogels made from natural materials) for this purpose. Hence, this review aims to elucidate the origins, nature, properties, and mechanisms of wound healing for a range of natural hydrogels and to outline new trends in hydrogel materials – new frontiers in wound healing. The review first focuses on the wound healing mechanisms, providing basic information, followed by the challenges in wound treatments of the current conventional approaches/therapies. Then, the advantages of the advanced methods are discussed, with an emphasis on hydrogels. Next, the discussion covers hydrogel-related information, including definitions, key properties, formulation methods, and especially, the applications of hydrogels in tissue engineering and gene therapy for personalized treatments. Finally, the common natural materials (polysaccharides, proteins) used for hydrogels fabrications are summarized.

2. Wound healing mechanisms

2.1. Phases of wound healing

The wound healing process is a complex procedure yet could be simplified into four steps (Figure 1). The first step is the hemostasis stage, during which platelets become activated and build a clot of blood to stop further bleeding within a matter of minutes or hours after an injury, depending on the wound size [1,19]. More importantly, platelets also release platelet-derived growth factor, which acts as a mediator by initiating the body to the inflammation stage [20]. The inflammation stage occurs, typically around three days after the injury [19,21]. This phase involves the action of neutrophils and macrophages, which fight bacteria and viruses, remove debris and dead cells, ensuring that infection does not escalate in the body. The proliferation phase follows after inflammation, lasting about 17 days [19]. Fibroblasts and collagen type-III contribute to the formation of granulation tissues. Epithelial cells migrate to cover the wound, and new vessels are formed, allowing the wound sites to receive nourishment and oxygen. The final stage, occurring after approximately 11 months, is remodeling [19]. During this stage, collagen type-III is replaced by collagen type-I, further strengthening the tissue of the injured area [22].

Figure 1.

Phases of wound healing.

During every phase of wound healing, the extracellular matrix (ECM) provides a structural and functional foundation for repairing the damaged tissue [23]. In the initial stages, the provisional matrix, formed by fibrin and fibronectin, serves as a conduit for the migration of new cells into the injury site [24]. The role of the ECM is to provide a temporary scaffold to ensure structural stability at or around the site of injury throughout the various phases of wound healing. Its components, such as fibronectin, glycosaminoglycans (including hyaluronic acid), proteoglycans, and collagen, promote the adhesion and migration of critical cells involved in wound healing, including fibroblasts, epithelial cells, and endothelial cells [25]. Subsequently, it regulates cell-cell and cell-matrix interactions [26], provides a physical framework, and acts as a reservoir for growth factors and cytokines, which are controlled released to stimulate inflammation, proliferation, and the generation of new tissue. Heparin sulfate regulates angiogenesis by facilitating the growth and migration of endothelial cells. Activated fibroblasts in the proliferation phase synthesize collagen, forming new granulation tissue. The synthesis of collagen type-III is initially supported by the ECM and later replaced during tissue remodeling by collagen type-I, thus increasing the strength of the newly formed tissue [23]. During remodeling, the ECM also aids in reorganizing collagen fibers to provide optimal resistance and stability to the tissue. This reorganization minimizes the formation of thick scar tissue. The interactions between the ECM components and cells are critical during the repair of damaged tissue.

2.2. Challenges in chronic wounds and infection management

Chronic wounds are frequently colonized with biofilms, a community of microorganisms encased in a protective matrix [5]. Such biofilms resist elimination by antibiotics and the host immune system, and treatments against infection are often ineffective in the face of biofilm-forming bacteria and antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus and Neisseria gonorrhoeae, which are commonly associated with infections of chronic wounds [27]. These bacteria reduce drug permeability, alter drug targets or receptors, and modify metabolic pathways to make the drugs ineffective [28]. Some bacteria produce enzymes that modify the molecular structure of antibiotics, degrading them or inactivating their effects. As a result, conventional treatments become ineffective or even life-threatening, thus demanding alternative treatments when patients are infected with antibiotic-resistant bacteria. Other chronic conditions, such as a weakened immune system and liver and kidney dysfunctions, also impede the process of wound healing [29]. The current antibiotic treatments in the pharmaceutical market have largely failed to meet the demand for effective infection control. Thus, treatment protocols often involve combination therapies to manage the infections and underlying conditions [29,30]. Hence, the treatment course requires the patients to follow the prescribed course strictly, as noncompliance can exacerbate the condition and lead to further complications.

An effective treatment plan must be in place because the process of treatment process for chronic wounds is lengthy and costly. Whereas the demand is continuously emerging for therapies that target biofilms, combat bacterial resistance, and enhance the body’s natural healing processes, some methodologies are currently in practice or being researched, such as natural hydrogels [31]. In fact, wound healing therapies can be broadly categorized into conventional and modern (advanced) approaches [32,33]. Conventional therapies focus on basic wound care methods aimed at infection prevention, healing promotion, and symptoms management. These include (1) primary closure techniques (sutures, staples, or adhesives used to close wounds directly), which are suitable for clean, acute wounds; (2) dressings (gauze, bandages, or cotton dressings), which provide a physical barrier and maintain moisture balance; (3) antimicrobial/antibiotic use; and (4) debridement (surgical or mechanical removal of necrotic tissue to promote granulation). Nevertheless, these therapies often come with numerous unwanted effects and limited efficacy such as (1) reduced effectiveness for chronic wounds (diabetic ulcers, venous leg ulcers, or pressure sores) due to inadequate cares to the underlying issues like poor vascularization or persistent inflammation; (2) risk of infection; (3) inadequate moisture balance; (4) pain and discomfort; (5) slow healing times due to a lack of advanced materials or bioactive agents; (6) no real-time monitoring; and (7) scarring and poor aesthetic outcomes [34,35].

Addressing these limitations often requires integrating modern wound healing techniques, such as biomaterials, growth factors, or advanced therapies, for faster, more effective, and patient-specific care. Advanced dressings such as hydrogels, hydrocolloids, electrospun fibers, and nanoparticle-infused dressings could maintain optimal moisture, mimic the ECM, and simultaneously deliver antimicrobial or bioactive agents locally [7,8,36]. Additionally, bioengineered skin substitutes, grafts, and stem cell therapy could accelerate wound healing and tissue regeneration, particularly for chronic wounds and burns [37]. Moreover, the technology of 3D bioprinting, in combination with smart and responsive materials, could fabricate customized and personalized scaffolds that mimic skin layers, using bioinks loaded with cells [38]. Amongst these advanced healing methods, hydrogels stand out as a cost-effective, simple, and efficient approach.

2.3. Hydrogels support wound healing

Hydrogel, in general, supports wound healing through several key mechanisms. As previously discussed, the wound healing process consists of four main phases of hemostasis, inflammation, proliferation, and remodeling. Hydrogels play a significant role in all of these stages. Firstly, in the hemostasis phase, hydrogels provide a moist environment that aids platelet aggregation and activation, which are critical for clot formation. Some hydrogels are also designed to release hemostatic agents (thrombin or fibrinogen) or contain components like chitosan that enhance clotting [39,40]. Secondly, during the inflammation phase, hydrogels loaded with anti-inflammatory agents such as dexamethasone or antimicrobial compounds such as silver nanoparticles could mitigate excessive inflammation, reduce oxidative stress and pro-inflammatory cytokines, enhance macrophage activity for debris clearance, and control infection [41,42]. Thirdly, in the proliferation phase, hydrogels can deliver and sustain the release of growth factors that promote fibroblast proliferation and angiogenesis, while also providing a scaffold for cellular migration and ECM deposition [43–45]. Lastly, during the remodeling phase, hydrogels promote tissue maturation and scar reduction by releasing remodeling agents, specifically matrix metalloproteinase inhibitors, to balance collagen synthesis and degradation [46,47].

Hydrogel also possesses moisture-retentive properties, creating an environment of proper moisture for the wound [9]. An open wound generally discharges fluids that may cause the skin in that area to dry up and itch. Therefore, moisture monitoring along with disinfection is essential to protect and hasten the healing of open wounds, enhancing the oxygen and nutrient supply. The moist environment also allows cell migration [15] and prevents drying out of the wound, thereby reducing pain. Moreover, hydrogel provides a protective barrier against the invasion of infections since bacteria and other pathogens cannot penetrate through it into the wound, thus effectively minimizing the chances of infections [48]. This defensive barrier can also coat some bacteria with a water-like layer, rendering them resistant to phagocytosis and antibiotics. Whether a barrier forms depends on the material’s roughness, chemical composition, and hydrophobicity [49]. Additionally, hydrogel can also control the release of drugs, such as antimicrobial drugs or growth factors, while it supports the healing process by gradually providing necessary substances. One of the significant disadvantages of conventional drugs is that they require constant administration, which causes fluctuating levels of the drug in the blood. Therefore, there is a need to formulate drugs into controlled or sustained-release forms to reduce the administrative frequency and ensure consistent levels of the active ingredients in the bloodstream, thereby enhancing treatment efficiency [50]. Alternatively, drugs can be delivered locally, which often reduces side effects and improves therapeutic efficacy. Hydrogel could change either the site, the timing, or the rate of release of active ingredients in an attempt to improve treatment or to provide greater convenience compared to the traditional form of drugs [51]. Finally, hydrogel provides the medium for the proliferation of new cells and the rebuilding of tissues. It reduces inflammatory processes, improves immunity, and provides energy input to cells, which results in rapid regenerative processes without loss of functions.

3. Hydrogels

3.1. Key properties of hydrogels

Hydrogel is a type of scaffold with high water retention capability, finding wide applications in medicine, biology, and biotechnology. Based on the formulation materials, hydrogels can be divided into two categories of natural and synthetic. Natural hydrogels are fabricated from collagen, chitosan, hyaluronic acid, among others, which suitable biocompatibility and biodegradation, reducing immune reactions upon their introduction to the body [52]. Synthetic hydrogels, prepared from synthetic polymers such as polyacrylamide and PEG, on the other hand, allow much better control over mechanical properties, whereas this is usually at the cost of treatments needed to ensure the material’s biocompatibility [17]. Both kinds are used in specific medical applications of dressing wounds, drug delivery systems, and tissue engineering.

Hydrogels possess ideal properties for biomedical and pharmaceutical applications. Biocompatibility is the main priority; hydrogels do not produce any immune or inflammatory reactions after contact with an organism, therefore, they can be safely used in wound dressings. The high capability for water retention allows hydrogels to absorb and hold high volumes of water [12]. This keeps the surrounding environment moist to promote wound healing and helps maintaining tissue-fluid equilibrium. The flexibility of the hydrogel also plays a critical role in allowing the material to quickly adapt to different shapes and surfaces, improving its practical effectiveness. Their biodegradability permits hydrogels to degrade naturally inside the body without harmful by-products. Properties such as gas permeability and mechanical strength must be maintained during treatment for hydrogels to continue their functionality, which differs from the stability and effectiveness sought in specific applications [53,54].

The usability of the material used in hydrogel formulation is considered based on key mechanical and physicochemical parameters, such as (1) tensile strength – the ability of the hydrogel to bear stress when applied to a wound [55], and (2) elongation at break – the flexibility of hydrogel, showing how much hydrogel may stretch before breaking, which is necessary for wounds in areas with frequent movements [56]. Hydrogel has to be biocompatible because it will be in contact with tissue and should not elicit any immune response or irritation. The water retention capacity is another crucial factor in providing a moist environment, which is also essential for healing [57]. Tests conducted in simulated models in cells, animals, and humans could be used to determine the hydrogel healing efficiency by determining its anti-inflammatory and antibacterial properties, and the cell growth or regeneration of tissues [12,53,54].

3.2. Hydrogel formulation methods and structures

The hydrogel raw material extraction and the physicochemical hydrogel formulations are multi-step processes. Natural hydrogel materials are often extracted from plants and/or animal sources, namely chitosan from crustacean shells, alginate from seaweed, gelatin from collagen, which in turns, extracted from animal skin/bone/connective tissues, and silk fibroin from silkworm silk. Additives such as synthetic polymers could be employed to enhance the hydrogel’s physical, chemical, and biological activity. The common hydrogel formulation methods are presented in Table 1. In short, hydrogel formulation methods vary based on the desired properties and applications of the hydrogel, which include (1) chemical cross-linking – covalent bonds are formed between polymer chains using a cross-linking agent or initiator, resulting in a 3D network; (2) physical cross-linking – hydrogels are formed by physical interactions like hydrogen bonding, ionic interactions, or crystallization without the use of chemical agents; (3) ionic cross-linking – electrostatic interactions formed between polyelectrolytes multivalent ions such as alginate and chitosan; (4) self-assembly – some hydrogel-forming materials, such as peptides or block copolymers, can self-assemble into hydrogels through non-covalent interactions like hydrophobic effects, π-π stacking, or β-sheet formation; (5) radiation-induced cross-linking – high-energy radiation (UV or gamma rays) is used to induce cross-linking between polymer chains, forming hydrogels; (6) enzyme-mediated cross-linking – enzyme-catalyzed cross-linking is popular for proteins like silk fibroin, collagen, and fibrin due to their biological compatibility and ability to form hydrogels via enzymatic reactions; (7) thermo-sensitive gelation – thermal polymers such as gelatin and agarose can form hydrogels due to temperature-dependent gelation; (8) pH-sensitive gelation – polymers with varied pKa such as chitosan can form hydrogels in response to pH changes due to its amine groups; and (9) freeze-thaw method – this method involves cycling the temperature to freeze and thaw the hydrogel, inducing physical cross-linking through crystallization of natural polymers such as gelatin or starch.

Table 1.

Common hydrogel formulation methods for wound healing purposes.

Method	Definition	Procedure	Materials	Advantages	Disadvantages
Chemical cross-linking	Covalent bonding between polymer chains.	Introduce cross-linking agents or UV light to form bonds between polymer chains.	PEG, hyaluronic acid, gelatin	High mechanical stability; tunable properties; long-term stability.	Potential toxicity of cross-linkers; complex synthesis process.
Physical cross-linking	Forming hydrogels through physical interactions (hydrogen bonding, ionic interactions).	Combine polymers and induce physical interactions through methods like freeze-thaw cycles, ionic gelation, or hydrophobic interactions.	Alginate, chitosan, gelatin, PVA	Avoids toxic cross-linking agents; reversible gelation; mild processing conditions.	Lower mechanical strength; may not be stable under physiological conditions.
Ionic cross-linking	Cross-linking induced by interactions between oppositely charged ions or polymers.	Mix polyelectrolytes (alginate) with multivalent ions (Ca2+), which form ionic bonds.	Alginate, chitosan	Mild and simple process; avoids harsh chemicals; biocompatible.	Weak mechanical properties; stability may be affected by ion diffusion over time.
Self-assembly	Spontaneous organization of molecules into structured hydrogels.	Combine self-assembling peptides or amphiphilic molecules in an aqueous solution, allowing them to self-assemble through non-covalent interactions.	Peptides, amphiphilic copolymers	No need for external stimuli; biocompatible; mimics natural extracellular matrix.	Limited mechanical strength; sensitive to environmental conditions.
Radiation-induced cross-linking	Using light to induce cross-linking reactions in photosensitive materials.	Mix photosensitive polymers with photoinitiators and expose them to light (UV) to form a hydrogel.	Methacrylated gelatin, hyaluronic acid	Precise spatial and temporal control; suitable for complex structures.	Requires photoinitiators, which may be cytotoxic; limited penetration depth of light.
Enzyme-mediated cross-linking	Using enzymes to catalyze polymer cross-linking reactions.	Add specific enzymes (transglutaminase, horseradish peroxidase) to polymer solutions to trigger cross-linking.	Silk fibroin, gelatin, fibrin	Mild and biocompatible conditions; suitable for bioactive materials.	High cost of enzymes; slow reaction rates in some cases.
Thermo-sensitive gelation	Hydrogels form in response to temperature changes.	Use temperature-sensitive polymers that gel when the solution temperature reaches a specific threshold.	PNIPAM, Pluronic F127	Controlled gelation based on temperature; injectable properties.	Limited mechanical strength; potential cytotoxicity of some thermo-responsive polymers.
Freeze-thaw method	Hydrogel formation via repeated freezing and thawing of a polymer solution.	Subject polymer solutions (PVA) to alternating freezing and thawing, leading to physical cross-linking via hydrogen bonding and crystalline domain formation.	PVA, gelatin	Simple and chemical-free method; improves mechanical strength.	Limited applicability to certain polymers; long processing time.

These methods produce hydrogels with different structures, depicted in Figure 2. In brief, the conventional hydrogel features a basic polymer network with uniform cross-links distributed throughout the matrix. This kind of hydrogel is typically soft, with limited mechanical strength and poor resistance to deformation. The tetra-amine terminated hydrogel contains polymer chains terminated with functional tetra-amine groups, which interact with other reactive species, creating a denser or chemically modified network. The (semi) inter-penetrating network has two or more independent polymer networks physically interwoven without covalent bonding between them. This formula improves mechanical strength, elasticity, and resilience by combining the properties of the two networks. The double-network hydrogels compose of two interpenetrating networks where one is rigid and densely cross-linked, while the other is more flexible and loosely cross-linked. The nanocomposite/microgel-filled/microgel-reinforced hydrogels embed nanoparticles/microgel within the hydrogel matrix, contributing to mechanical reinforcement and added functionality (conductivity, responsiveness to stimuli like pH, temperature, or light). Finally, the doubly cross-linked microgels and composites consist of microgel particles that are cross-linked both internally and externally with each other, creating a highly interconnected network. This advanced kind of hydrogel provides exceptional toughness and elasticity due to the hierarchical network structure that balances strength and flexibility.

Figure 2.

Schematic images of different hydrogel structures, dependent on the formulation processes.

3.3. Requirements of an ideal wound dressing material

An effective dressing material has to meet the following basic key characteristics to create an appropriate environment for wound healing. First, it should possess a high degree of biocompatibility, without any immune or allergic reactions [58]. It is also essential for moisture retention, thus creating conditions close to optimum tissue restoration and pain reduction [59]. It should also allow for breathability, enabling oxygen exchange that would serve the dual purpose of optimum conditions for the growth of new cell tissues and inhibiting infection by not allowing bacterial invasion. The hydrogel must have fluid absorbing capacity for managing wound exudates, besides possessing mechanical strength and flexibility to easily conform to different body areas [58]. In some instances, hydrogel has to be biodegradable without its removal. Last but not least, the ideal dressing material should be able to deliver therapeutic agents, such as antibiotics or growth factors, which provide accelerated and efficient wound healing in a controlled, sustained manner.

3.4. Hydrogels applications in tissue engineering and gene therapy for personalized treatments in wound healing

Recently, the personalized medicinal treatments, also preferred as precision therapy, have gained increasingly attentions due to their unique belief that each individual had different characteristics at the physiological, molecular, environmental, and behavioral levels, and thus, they may need different therapeutic approaches for their diseases [60]. For that reason, hydrogels, with their versatile properties, are rapidly emerging as a cornerstone in the development of personalized treatments for wound healing, particularly through their applications in tissue engineering and gene therapy.

Hydrogels provide a hydrated, porous environment for cell adhesion, proliferation, and differentiation. Tissue engineering leverages hydrogels to create scaffolds that mimic the ECM, enabling cellular growth and tissue regeneration. These scaffolds can be customized for individual wound characteristics with different patient inherent traits [61–64]. For instance, Wang et al., introduces a multifunctional hydrogel composed of polyacrylamide and chitosan quaternary ammonium salt designed as a wound dressing for advanced wound monitoring [64]. This hydrogel not only exhibits antibacterial, hemostatic, and adhesive properties that effectively enhance wound healing but also enables real-time monitoring of wound conditions, such as pH levels. Notably, the hydrogel is customizable to fit the wound’s contour, ensuring precise treatment. Additionally, a personalized wound management system, achieving a high accuracy of 94.47% through a convolutional neural network machine learning algorithm, evaluates and analyzes wound healing and infection states using colorimetric signals from the hydrogel. By combining targeted treatment, real-time monitoring, and tailored management, this hydrogel represents an innovative approach to accelerate wound healing, reduce bacterial infections, and establish a foundation for future intelligent wound care solutions [64].

Moreover, hydrogels can deliver genes (nucleic acids including DNA and RNA) or vectors (viral or non-viral) for controlled release and transfection of wound cells, enhancing gene expression at the site, thus promoting angiogenesis and tissue repair, offering sustained and localized release [65–68]. Additionally, hydrogels can deliver gene-editing tools to modulate genes involved in inflammation, fibroblast activity, or ECM synthesis, tailored to the patient’s genetic makeup [69]. For example, Duran-Mota et al., formulated a biodegradable injectable hydrogel-based wound dressing that delivers and releases poly(β-amino ester)s nanoparticles in a controlled mechanism [70]. In in-vivo studies, these formulas successfully protect the mRNA payload and achieve efficient transfection of human dermal fibroblasts through controlled release from the hydrogel wound dressing. This innovative wound dressing technology holds potential for advancing new gene therapies aimed at treating chronic wounds [70].

Although demonstrating much potentials, this area of research is still new, with limited reported data and information. Therefore, future works could consider this idea, as well as novel approaches such as hybrid systems that combining natural hydrogels with synthetic components or nanomaterials to enhance their strength, functionality, and drug-loading capabilities; hydrogel-based platforms that integrate real-time monitoring devices or sensors for dynamic, patient-specific therapeutic adjustments; and incorporating natural hydrogels into tissue engineering and gene therapy to leverage their inherent properties and biotechnological advancements, positioning them as pivotal tools in revolutionizing personalized medical approaches and wound care solutions.

4. Naturally derived hydrogels

4.1. Types of naturally sourced hydrogels used in wound healing

Natural hydrogels have numerous advantages over synthetic hydrogels in wound healing and regenerative medicine. Firstly, they possess high biocompatibility because they are formulated from naturally-extracted substances, which help minimizing immune and allergic reactions compared to synthetic hydrogels. Additionally, natural hydrogels are biodegradable, ensuring safety and environmental friendliness without leaving harmful by-products. Another significant advantage is their ability to support the natural healing process, such as promoting cell migration, enhancing collagen synthesis, and creating an ideal moist environment for tissue regeneration. Furthermore, many natural hydrogels, such as collagen and fibrin, have structures and compositions similar to the ECM, which aids in supporting cell growth and effective tissue regeneration. A summary of these hydrogels is presented in Table 2 and the common natural materials for fabricating hydrogels are illustrated in Figure 3.

Table 2.

Preparation and physicochemical characteristics of natural hydrogels, formulated from polysaccharides and proteins.

No	Hydrogels	Preparation and physicochemical characteristics of hydrogels	Ref.
1	Silk fibroin hydrogel loaded with Sesbania sesban L. leaf extract	Preparations The extract was obtained using ultrasound-assisted extraction at 50°C for 60 minutes, yielding a total polyphenol content of 92.8 ± 8.30 mg GAE/g. The silk from Bombyx mori was treated to remove sericin using a solution of calcium chloride, calcium nitrate, ethanol, and water in a weight ratio of 5:30:5:20:45. The hydrogel was formulated by physical mixing of fibroin solution and the extract. Characteristics: The hydrogel had fibroin concentration of 2%, loading 1 mg of polyphenols. The gelation time was 2 hours. The gel viscosity was 2530 ± 50 cPs, gel strength was 1880.14 ± 35.10 g, the gel was stable at 4°C and 25°C for over 6 months, with porous structure.	[12]
2	Silk fibroin hydrogel loaded with metronidazole	Preparations The fibroin solution was prepared by dissolving freeze-dried fibroin powder in sterile water, while methylcellulose and Pluronic F127 (PF127) solutions were dispersed in water. Metronidazole at a concentration of 0.05% was mixed with all the gel ingredients for 30 minutes at 37°C. The gel was formed spontaneously. Characteristics: The gel was stable at 4°C for up to 6 months, with an adequate viscosity. The hydrogel provided a sustained release of metronidazole over 10 days and dissolved slowly in phosphate-buffered saline at 37°C for more than 9 days.	[10]
3	Chitosan hydrogel loaded with glutaraldehyde	Preparations Chitosan was extracted from shrimp shells with NaOH solution to remove proteins, followed by HCl solution to remove calcium. Add 0.5 mL of 25% (w/v) glutaraldehyde to 100 mL of chitosan solution in acetic acid, stir for 30 minutes, then allow the gel to stabilize and form over 24 hours. Characteristics: High elasticity and softness, high water absorption capacity, nano-fibrillar structure, high biocompatibility, and good biodegradability.	[53,54]
4	Chitosan hydrogel loaded with lactic acid	Preparations A 4% (w/w) chitosan solution was dispersed in 2% (v/v) lactic acid, followed by pouring into molds (14 × 7 cm2). The molds were placed in a sealed chamber exposing to 4 L of 2.5% (v/v) ammonium hydroxide solution. After formulation, the hydrogel was washed with distilled water, removed from the molds, and placed in Petri dishes to eliminate any remaining ammonia. The prepared hydrogel was individually packaged and sterilized using UV light for 30 minutes. The hydrogel samples were then stored at room temperature in a dry and clean environment. Characteristics: High biocompatibility, making the hydrogel suitable for biomedical applications.	[87]
5	Multifunctional chitosan hydrogel QCSMA/DAMA/Zn-nWH	Preparations Chitosan was modified with quaternary ammonium salts to form quaternized chitosan (QCS), which was then reacted with methacrylate anhydride to produce QCSMA. Dopamine hydrochloride was modified into methacrylate anhydride dopamine (DAMA) through an amidation reaction. Zinc-doped whitlockite nanoparticles (Zn-nWH) were synthesized by substituting Ca2+ and Mg2+ ions with Zn2+ ions. QCSMA, DAMA, and Zn-nWH were dissolved in deionized water at specific concentrations, and the mixture was exposed to UV irradiation at a wavelength of 405 nm to form the multifunctional hydrogel QCSMA/DAMA/Zn-nWH. Characteristics: Adhesive properties, high compressive strength, excellent swelling capacity, injectable, and low hemolysis rate (<2%).	[88]
6	Alginate hydrogel loaded with Aloe vera extract	Preparations Dissolve sodium alginate in distilled water (1.5% w/v) and add glycerol at a ratio of 15% (w/w) to improve the flexibility of the alginate hydrogel. Dissolve Aloe vera extract in distilled water (1.0% w/v) and slowly mix the extract with the alginate solution to achieve the desired ratio (95:5, 85:15, 75:25 v/v). Pour 25 mL of the mixture into a 9.5-cm-diameter Petri dish, allow the solution to dry at 25°C and controlled humidity (50%) for two days. Cut the dried film samples into appropriate sizes and immerse them in a 5% (w/v) CaCl2 solution for 5 minutes to initiate the cross-linking reaction. Then, rinse the hydrogel with distilled water and allow it to dry at room temperature until a constant weight is achieved before use. Characteristics: Tensile strength of 42.36 to 50.91 MPa, elongation at break of 5.94% to 13.27%, thickness of 66.14 to 69.00 µm. The hydrogel films exhibited high light transmission in the visible range and are nearly insoluble in water after 24 hours of immersion.	[75,78,95]
7	Alginate/gelatin hydrogel loaded with niosomal Aloe vera extract	Preparations Aloe vera extract was encapsulated into niosome by reverse-phase evaporation method. Span 60 and cholesterol were dissolved in diethyl ether, then emulsified with Aloe vera solution (5 mg/mL) by vortexing for 1 minute and sonicating in a water bath at 10°C for 10 minutes. The solvent was removed using a rotary evaporator at 40°C and 60 rpm. The alginate/gelatin hydrogel was formed by the cross-linking reactions of 4% alginate and gelatin solution with CaCl2 solution (40 mg/mL), at 70°C for 1 hour. The niosome was loaded into the hydrogel by similar cross-linking process at 4°C for 15 minutes. Characteristics: The niosome had an average size of 270.1 nm and an encapsulation efficiency of Aloe vera of 42.039 ± 4.090%. The hydrogel exhibited an average Young’s modulus of 12.64 ± 1.3 kPa, a prolonged extract release with about 20% Aloe vera released after 7 days, and a low swelling ratio. The degradation rate of the hydrogel samples gradually increased over time.	[75]
8	Oxidized alginate/chitosan hydrogels	Preparations Dissolve 2 g of sodium alginate in 200 mL of purified water, add 20 mL of NaIO₄ solution (0.5 M), react for 12 hours in the dark, then transfer the solution into a dialysis bag to remove unreacted substances, and freeze-dry to obtain oxidized alginate (OAlg). Mix OAlg/H₂O solution and carboxymethyl chitosan/H₂O in a 1:1 ratio. Evenly mix the loaded nanoparticles in the hydrogel. Characteristics: Good tensile strength, toughness, and load-bearing capacity.	[80]
9	Gelatin/keratin hydrogel loaded with protocatechuic aldehyde/Fe/phellopterin	Preparations Keratin was extracted from duck feathers with 8 mol/L urea, 0.2 mol/L SDS, and 0.5 mol/L Na₂S₂O₅, for 1 hour at 70°C. Protocatechuic aldehyde was dissolved in deionized water at 80°C, with FeCl₃ at a molar ratio of 3:1. Keratin solution (15 w/v%) was added to the protocatechuic aldehyde/Fe complex at room temperature to form the hydrogel. Phellopterin micelles were prepared by physical mixing of 50 μg of phellopterin, 26.7 mg of Pluronic F127, and 13.3 mg of Pluronic F68 in 1 mL of absolute ethanol, followed by solvent evaporation under reduced pressure to obtain a thin film. The film was hydrated with 2 mL of water and ultrasonicated to form a micelle suspension. The final product was obtained by mixing 200 μL of phellopterin micelle with 800 μL of the hydrogel. Characteristics: A cross-linked network was formed via the thiol-aldehyde addition reaction between keratin thiol groups and protocatechuic aldehyde groups, and between catechol-metal ions bondings. The hydrogel had good injectability, high self-healing ability, strong tissue adhesion, and adequate antibacterial and anti-inflammation properties in streptozotocin-induced diabetic mice. The product achieved complete wound closure after 10 days for a 6-mm diabetic wound.	[108]

Figure 3.

Common natural materials for hydrogel formulations.

The most common naturally-derived hydrogels used in wound healing are based on collagen, elastin, fibrin, gelatin, silk fibroin, polysaccharides, and de-cellularized tissues [14]. Collagen hydrogels, as the primary protein of the ECM, can support tissue regeneration in wound healing due to their biocompatibility and biodegradability [71]. Elastin hydrogels impart elasticity in a wound [72], while fibrin hydrogels form a scaffold in tissue regeneration due to being a significant component in blood clotting [73,74]. Gelatin hydrogels possess significant biodegradability and low immunogenicity [75,76]. Among all the protein hydrogels, silk fibroin hydrogels exhibit excellent mechanical properties and deficient immune responses, which help in efficient wound healing [77]. Polysaccharides, including alginate from brown algae [78,79] and chitosan from chitin [53,80], have been extensively used as wound dressings due to their antimicrobial properties and fluid-absorbing capacity. Tissues obtained through de-cellularization methods provide a replica of the natural environment that favors efficient tissue regeneration and wound healing in their applications as hydrogels.

4.2. Polysaccharide-based hydrogels

Polysaccharide, specifically chitosan and alginate, is a good matrix material for hydrogel production. It can be used in many applications, such as wound dressing, controlled drug release systems, and cosmetics [54,59]. In food technology, chitosan is applied as a natural preservative due to its antimicrobial and antifungal properties, which produces a protective effect that prolongs product shelf-life [81]. Other applications include water purification and filtration, where chitosan is used for coagulation agent that removes impurities and heavy metals. In agriculture, it is used as an inducer for crop growth to increase productivity and quality of agricultural products. Additionally, chitosan is applied in managing pathogenic insects and fungi as a bio-pesticide with antibacterial and antifungal natural properties [81,82]. Thus, with various properties and applications, chitosan has become increasingly researched in diverse fields, opening broad potential for its biomedical uses. The unique point of chitosan is that it possesses a positively charged (cationic), which allows interactions with negatively charged molecules like cell membranes, thus enhancing adhesion and promoting tissue regeneration [83,84]. Moreover, chitosan has intrinsic biological activity of antibacterial or hemostatic properties, which could be beneficial for wound healing process [85]. On the other hand, chitosan shows disadvantages of (1) mechanical weakness, which could be overcome by combinations with other rigid polymers, (2) limited solubility in normal pH (chitosan is pH-sensitive and highly dissolves in acidic environments), which could be solved by utilizing low molecular weight chitosan, and (3) potential allergenicity, which could be overcome by using different sources of chitosan.

In that regard, chitosan hydrogel provides superior advantages in wound healing. This hydrogel produces moisture that promotes the healing process and prevents secondary infections [16,53,86–88]. Secondly, its biological compatibility and biodegradability reduce unexpected side effects in long-term use. Besides, chitosan hydrogels act as natural antibacterial agents, which help to control bacterial activity and minimize inflammation and infection. Finally, since chitosan enhances the process of regeneration and granulation of tissues, chitosan hydrogel helps wounds heal quicker, with reduced scarring [86]. For instance, the multifunctional hydrogel compounded from methacrylate anhydride dopamine, Zn-doped whitlockite nanoparticles, and methacrylate anhydride quaternized chitosan exhibits hemostatic, antibacterial, and wound-healing promotion capabilities [88]. This hydrogel possesses superior adhesive properties, high compressive strength, and excellent swelling ability, making it highly effective in absorbing blood and exudates from wounds. Notably, the hydrogel demonstrated outstanding hemostatic performance with the shortest bleeding time (129 ± 22 seconds) and the most minor blood loss (27 ± 5 mg) while also promoting cell growth and migration to facilitate rapid wound healing [88]. However, further clinical trial research is necessary to assess the hydrogel’s effectiveness and safety under practical conditions and its stability during long-term storage and use. One of the main disadvantages of the current hydrogel is that its mechanical ability is inadequate, which can limit the usage of hydrogels for wounds in various places where body parts need to move at the maximum level. New cross-linking methods need to be developed to improve chitosan hydrogels’ self-healing and injury-recovery properties. Moreover, producing chitosan hydrogels involves complex procedures and requires strict control over preparation conditions, which can increase production costs. Finally, hydrogels’ drug retention and release properties still need improvement to ensure optimal therapeutic efficacy.

Alginate is another natural polysaccharide commonly used in wound healing. Alginate is generally extracted from brown seaweeds, primarily species belonging to the genera Laminaria, Ascophyllum, and Macrocystis [89]. It has a linear polymer structure composed of mannuronic acid (M) and guluronic acid (G) units linked together by 1,4-glycosidic bonds. The ratio and distribution of M and G units in the polymer chain affect alginate’s physical and chemical properties. One of the standout properties of alginate is its ability to form gels in the presence of multivalent ions like Ca²⁺, which are abundant in wounds, enabling easy on-site applications [90]. When exposed to these ions, alginate polymer chains cross-link with each other to form a three-dimensional gel structure. This makes alginate ideal for medical applications, food technology, and tissue engineering. In medicine, alginate is widely used in creating wound dressings and implant materials. Alginate hydrogels can maintain moisture, absorb wound exudate, and create an ideal environment for wound healing [91,92]. Additionally, alginate is used in drug delivery systems due to its ability to control the release of active substances over time. In food technology, alginate is used as a thickening, stabilizer, and gelling agent. It is added to products like ice cream, yogurt, pudding, and beverages to improve texture and stability. Alginate is also used in modern culinary techniques, particularly spherification, to create tiny spheres with a gel-like outer shell and liquid interior. Alginate is also a scaffold material for cell culture and tissue regeneration in tissue engineering [91,93]. Alginate can support the growth of new cells and tissues due to its biocompatibility and biodegradability [94]. Nevertheless, similar to chitosan, alginate is mechanically weak, which should be formulated to hydrogel in combinations with other polymers. Additionally, it tends to have poor adhesion to tissues, requiring additional adhesives or cross-linking strategies. Alginate rapid degradation in physiological conditions could lead to a loss of structure and functionality. Lastly, unlike chitosan, alginate lacks intrinsic biological activity.

For example in hydrogel applications, alginate/Aloe vera hydrogels have high transparency, helping to protect wounds from UV rays and allowing observation of the healing process without removing the dressing [95]. Additionally, this hydrogel membrane can absorb water and maintain a moist environment for the wound, which is crucial for healing. The thermal stability of hydrogel membranes is also improved due to the chemical interactions between alginate and Aloe vera. Notably, this hydrogel can release Aloe vera extracts directly into the wound, enhancing therapeutic efficacy compared to other methods. These properties make alginate hydrogel a potential choice for medical applications like wound dressings. Although alginate/Aloe vera hydrogel membranes have many advantages, research has identified some drawbacks that must be addressed. First, these hydrogel membranes are relatively thin and can tear easily on body areas requiring high flexibility. Second, increasing the proportion of Aloe vera reduces the mechanical strength of the hydrogel, making it prone to deformation when exposed to water or biological fluids. Additionally, water absorption and swelling of the hydrogel membranes can cause uneven changes in size and shape, posing challenges for practical use. Lastly, the calcium content decreases as the proportion of Aloe vera increases, reducing alginate’s cross-linking ability and affecting the hydrogel membrane’s durability and water-retention capacity [95].

Another example is hydrogels combining alginate and gelatin containing Aloe vera niosomes that have prolonged release capabilities and stimulate fibroblast cell growth, making them potential candidates for wound dressing applications [75]. The niosomes containing Aloe vera help improving and extending the efficacy of Aloe vera extract in hydrogels without adversely affecting other properties. One of the significant challenges is maintaining a stable release rate of Aloe vera from the hydrogel, as it tends to release rapidly in the initial days. Additionally, incorporating niosomes into the hydrogel must be optimized to avoid reducing its mechanical properties. Further experiments are required to ensure these results can be widely applied under clinical conditions [75].

Furthermore, injectable alginate/chitosan hydrogels containing silver-coated epigallocatechin gallate (EGCG) nanoparticles and keratin nanoparticles can improve wound healing [80]. The hydrogels can accelerate wound healing, especially in the early stages, and increase the thickness of the newly regenerated epidermis by up to 21% [80]. This hydrogel also exhibits self-healing capabilities that support efficient tissue regeneration, high biocompatibility, and good moisture retention, helping to maintain a moist environment for the wound [80]. However, evaluating the biosafety of metal-containing hydrogels requires further consideration. New methods are also needed to design and control the formulation process of these intelligent hydrogels. Lastly, the present hydrogel membranes can be developed to be multifunctional by incorporating antibacterial agents, cell growth stimulants, or other compounds to enhance therapeutic efficacy.

4.3. Protein-based hydrogels

Proteins are another natural sources for hydrogel formulations. Amongst various kinds, silk fibroin, collagen, and gelatin are the most utilized ones. Silk fibroin is a biomaterial sourced from the silk filaments of Bombyx mori silkworm cocoon and has a primary structure that contains light and heavy chains connected by disulfide bonds [96–101]. Its chemical compositions are mainly glycine, valine, and serine, making up a unique structure that allows the fibroin to gel in water [12]. The mechanical properties of this hydrogel are unique, possessing both strength and elasticity, making it suitable for utilizations in biomedical applications. Silk fibroin hydrogel is biodegradable, has high biocompatibility, and does not elicit inflammatory reactions in the body, making it safe for use in people [77,102]. The drugs can be loaded into the porous structure of the hydrogel and released externally at a slow rate, commonly follows the Higuchi equation, which is effective for controlled drug delivery. Silk fibroin hydrogel can be used as wound covers and interfaces in transdermal drug delivery systems and cosmetics as anti-aging and skin-care agents. The unique points of fibroin are (1) excellent mechanical properties compared to many other biopolymers, making it suitable for structural integrity in hydrogels, (2) controlled degradation by altering its crystallinity, enabling customized healing durations based on wound type, (3) high thermal stability, and (4) low immunogenicity. The disadvantages of this material is processing challenges with lengthy and costly extraction and purification processes, and batch variability due to the different sources of silkworms.

The silk fibroin hydrogel loaded with Sesbania sesban L. extract exhibits effective anti-inflammatory activity through the prolonged release of phenolic compounds from the Sesbania sesban extract [12]. When tested on RAW 264.7 macrophage cell lines stimulated by lipopolysaccharide, the hydrogel proved nontoxic and significantly reduced nitric oxide levels. This demonstrates that the fibroin hydrogel is safe and possesses anti-inflammatory capabilities, making it suitable for wound healing. The disadvantages of the preparation method and the fibroin hydrogel product loaded with Sesbania sesban L. extract include a long gelation time, which reduces effectiveness in applications requiring rapid gel formation. There is difficulty in homogenizing and controlling the extract concentration, leading to an uneven distribution of the active substance. Uneven drug release causes variations in the dosage provided over time, and high production costs result from the expensive processes of fibroin extraction and hydrogel formation. Additionally, the stability of the extract may be affected during storage and formulation, reducing its therapeutic effectiveness.

The thermosensitive silk fibroin hydrogel loaded with metronidazole can release the drug over up to 10 days, helping to reduce dosing frequency and enhance the effectiveness of periodontitis treatment [10]. Notably, silk fibroin has significantly improved the gel’s strength, while methylcellulose increases the gel’s viscosity, making applying the gel into periodontal pockets easier. This system ensures stable drug release and minimizes the risk of the drug being washed into the gastrointestinal tract, thereby reducing systemic side effects. The hydrogels tend to dissolve quickly in solution environments, and the hydrogels are not strong enough to maintain their shape throughout the testing period. Moreover, further in-vitro and in-vivo studies are needed to confirm the clinical effectiveness of this hydrogel in the treatment of periodontitis.

Collagen is a natural protein essential in wound healing, constituting a significant part of the ECM of animal tissues such as skin, bones, tendons, ligaments, and cartilage [71,103]. The raw material is demineralized using hydrochloric acid, deproteinized with sodium hydroxide, and then purified with acetic acid to obtain collagen. With high biocompatibility, biodegradability, and minimal immune response, collagen is ideal for wound treatment. It provides a moist environment to support healing and a scaffold for new cells to adhere to, promoting cell proliferation and tissue regeneration. Thanks to these abilities, collagen effectively supports blood clotting, helping wounds quickly transition to the healing phase. However, collagen also has certain mechanical limitations, making it unsuitable for applications requiring high load-bearing capacity. Nevertheless, collagen remains an essential choice in many modern wound treatment methods due to its outstanding healing properties and biocompatibility. Research is ongoing to improve the combination of collagen with other materials to enhance therapeutic effectiveness and expand its applications in regenerative medicine.

The structure of collagen hydrogel is formed when collagen is modified or interacts with water and other substances to create a hydrogel mass capable of absorbing water [104]. It has a soft 3D network structure, elasticity, and the ability to create a moist environment. It has a high water retention capacity, forming a loosely connected network that makes it softer and more flexible than collagen in its natural state. This hydrogel is widely used in moisturizing and tissue regeneration applications, while natural collagen is primarily used in cosmetics, dietary supplements, and medical products that require higher rigidity [105].

Gelatin is a natural protein derived from collagen (found in the skin, bones, and connective tissues of animals such as pigs, cows, and fish) by hydrolysis reactions at a temperature of 50–60°C for 48 hours [76,106]. With its long peptide structure and solubility in hot water, gelatin forms a clear, viscous solution that can transform into hydrogel upon cooling. A prominent feature of gelatin is its high mechanical strength, biocompatibility, and biodegradability [107]. Gelatin is widely used in the food industry as a thickening and gelling agent for products like gummy candies, pudding, and ice cream, enhancing texture and stability. In the medical and pharmaceutical fields, gelatin makes soft and hard capsules, wound dressings, and scaffolding materials for tissue engineering. Additionally, gelatin is an adhesive in the paper and textile industries and is used in the photography industry to create film and photographic paper coatings. With these diverse properties and applications, gelatin is an essential and versatile ingredient in many sectors. The unique points of gelatin are that (1) it is derived from collagen, thus retaining many of its bioactive properties, such as promoting cell attachment, migration, and proliferation, (2) it exhibits reversible gelation behavior, transitioning between sol and gel states with temperature changes, which is ideal for in-situ gelation applications, (3) it can be easily chemically modified to improve mechanical properties, stability, or responsiveness to stimuli, and (4) it is inexpensive and widely available due to its derivation from animal by-products, making it a practical choice for large-scale hydrogel production. However, gelatin possesses disadvantages of poor mechanical strength, high susceptibility to enzymatic degradation, namely proteases, and potential allergenicity due to animal sources.

The multifunctional hydrogel derived from chicken feathers, featuring a double dynamic cross-linking network, has demonstrated feasibility and effectiveness in treating diabetic wounds. The double dynamic cross-linking network structure is formed through thiol-aldehyde click reactions between thiol groups in keratin and aldehyde groups in protocatechuic aldehyde, along with coordination bonds between catechol groups in protocatechuic aldehyde and Fe³⁺ ions [108]. As a result, this hydrogel possesses injectability, self-healing capabilities, good tissue adhesion, and excellent antibacterial properties. The phellopterin-loaded hydrogel reduced inflammation time and promoted wound healing in diabetic mice, showing nearly complete wound closure after 10 days. Although this hydrogel has demonstrated great potential in treating diabetic wounds, future research still needs to address several challenges. Further optimization of the fabrication process is necessary to improve its stability. Additionally, more studies are required on the long-term interactions between the hydrogel and various types of tissues and its impact on different stages of the wound healing process [108].

4.4. Other natural polymers

Hyaluronic acid, a glycosaminoglycan found in the skin, joints, and connective tissues, is notable for its antibacterial properties, non-allergenic nature, and high biocompatibility [109,110]. It can be extracted from rooster combs by using acids, oxidation, or extraction through fermentation with Streptococcus bacteria [14]. Hyaluronic acid helps reduce inflammation, promotes epithelial cell migration, and stimulates new tissue development [111]. Additionally, hyaluronic acid retains moisture in the wound area, lubricates joints, facilitates tissue regeneration, prevents infections, plumps the skin, and combats aging. Furthermore, hyaluronic acid is used in supplement products to improve skin, joints, and eye health.

Fibrin, an essential biodegradable protein involved in the blood coagulation process, plays an important role in the hemostasis stage of wound healing [74]. Fibrin is extracted from fresh blood samples (human or animal) by using anticoagulants and hemolysing agents to obtain the fibrinogen precursor. It is then supplemented with the enzyme thrombin and calcium ions to convert into fibrin. Fibrin helps stopping bleeding, provides a temporary scaffold for leukocytes, platelets, and growth factors, connects tissues, and accelerates tissue regeneration and healing [73,74]. Currently, fibrin is being researched in various aspects, such as blood coagulation, hemostasis, and cell interactions in the wound healing process.

5. Challenges and limitations

Although natural hydrogels have numerous advantages, they still face several challenges and limitations in their applications. One potential limitation of natural hydrogels is their low mechanical strength, making them insufficient for load-bearing or enduring applications that require high stability. The degradation rate of natural hydrogels also needs to be controlled, as they can degrade either too quickly or too slowly, affecting treatment efficacy. Additionally, challenges related to management and production play an important role. The hydrogel production process must adhere to strict safety and efficacy standards, while production costs must also be considered to ensure feasibility in bringing the product to market. Furthermore, addressing specific patient needs, such as allergic reactions or biocompatibility, is a significant challenge. Each patient may have different responses to hydrogels, therefore, developing customized hydrogels tailored to each individual is essential to ensure the safety and effectiveness of the treatment.

6. Future directions

Advancements in hydrogel development are leading to significant breakthroughs in the medical field, especially in wound healing, particularly with intelligent hydrogels and stimuli-responsive hydrogels. Smart hydrogels can self-adjust their physical or chemical properties in response to environmental changes such as temperature, pH, or the presence of biological substances, thereby enhancing treatment efficacy. The potential of bioengineered hydrogels in personalized medicine is also substantial, as they can be designed according to the unique physiological characteristics of each patient, optimizing healing effectiveness and minimizing side effects. Furthermore, integrating of natural hydrogels with advanced wound healing technologies such as tissue engineering and gene therapy accelerates tissue regeneration. It enhances comprehensive healing capabilities, especially in complex and difficult-to-treat cases. This combination opens up significant potential for applying hydrogels in modern medical therapies.

7. Conclusion

Naturally derived hydrogels, formulated from natural polysaccharides or proteins, have demonstrated superior benefits in wound healing due to their unique characteristics of high biocompatibility, excellent moisture retention, biodegradability, controllable drug release, cell proliferation promotion, and tissue regeneration enhancement. These benefits help improving treatment efficacies while minimizing the unwanted side effects often encountered with traditional/conventional methods. In the future, the potential of bioengineered hydrogels in personalized medicine should be further explored. Integrating natural hydrogels with advanced technologies such as tissue engineering, gene therapy, and nanoparticles promises to open up new clinical applications and enhancing healing capabilities. Upcoming research and clinical trials will be an essential stepping stone in determining the safety and efficacy of these hydrogels in practical applications.

Funding Statement

This paper was not funded.

Article highlights

• The review article focuses on the utilizations of naturally derived hydrogels for wound healing.

• First, the basic wound healing mechanisms are presented, followed by the challenges in wound treatments of the current conventional approaches.

• Second, the advantages of novel methods are discussed, with an emphasis on hydrogel.

• Third, the hydrogel information is presented, including the characteristics, formulation methods, and especially, the applications of hydrogels for personalized wound healing.

• Finally, the common natural materials (polysaccharides, proteins) used for hydrogels fabrications are summarized.

Author contributions

Conceptualization: D.T.P., B.T.P.T.; methodology: D.T.P., N.T.N.T., N.T.P.T., L.T.N., B.T.P.T.; investigation: D.T.P., N.T.N.T., N.T.P.T., L.T.N.; data curation: D.T.P., B.T.P.T.; validation: D.T.P., B.T.P.T.; project administration: D.T.P., B.T.P.T.; resource: B.T.P.T.; writing-original draft: D.T.P., B.T.P.T.; writing-review and editing: D.T.P., N.T.N.T., N.T.P.T., L.T.N., B.T.P.T. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.