Trends in protein derived materials for wound care applications

Abstract

Natural resource based polymers, especially those derived from proteins, have attracted significant attention for their potential utilization in advanced wound care applications. Protein based wound care materials provide superior biocompatibility, biodegradability, and other functionalities compared to conventional dressings. The effectiveness of various fabrication techniques, such as electrospinning, phase separation, self-assembly, and ball milling, is examined in the context of developing protein-based materials for wound healing. These methods produce a wide range of forms, including hydrogels, scaffolds, sponges, films, and bioinspired nanomaterials, each designed for specific types of wounds and different stages of healing. This review presents a comprehensive analysis of recent research that investigates the transformation of proteins into materials for wound healing applications. Our focus is on essential proteins, such as keratin, collagen, gelatin, silk, zein, and albumin, and we emphasize their distinct traits and roles in wound care management. Protein-based wound care materials show promising potential in biomedical engineering, offering improved healing capabilities and reduced risks of infection. It is crucial to explore the potential use of these materials in clinical settings while also addressing the challenges that may arise from their commercialization in the future.

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1. Introduction

Effective wound care is of great importance in healthcare due to the growing prevalence of acute and chronic injuries.¹ Managing chronic wounds can be especially challenging, as they are often caused by conditions such as diabetes, disorders affecting the cardiovascular system, and reduced mobility.² The National Institute of Health (NIH) projects that the number of people with chronic wounds will increase from 6 million to 77 million by 2060 if the current management or treatment methods do not improve.^3,4 According to the World Health Organization (WHO), burn injuries result in approximately 180 000 fatalities and over 11 million cutaneous wounds per year.⁵ Due to the diverse nature of wounds, they may be classified based on their dimensions, types, locations, depths, and thickness.⁶ Open wounds and closed wounds are two distinct categories; open wounds are characterized by damage to the mucous membrane, which allows foreign substances to infiltrate the tissue, such as abrasion, laceration, or avulsion.⁷ In contrast, closed wounds do not involve any damage to the skin surface, they instead cause tissue damage and bleeding beneath the skin, which results in blisters, seromas, or contusions.⁸

In recent times, the focus of biomedical engineering has been on developing biodegradable wound dressings composed of natural and synthetic polymers. These dressings are designed to provide efficient and rapid treatment for wound injuries while simultaneously minimizing the potential for bacterial infections.⁹ This method, which utilizes biopolymers, is considered to have significant promise for enhancing skin restoration and recovery. It is reported to overcome the constraints associated with autografting, debridement, and allografting techniques.¹⁰ The rise of persistent high-risk wounds, particularly in the elderly, immunocompromised individuals, and diabetics, has enhanced the relevance of wound management. Four successive physiological phases, namely coagulation, inflammation, cell proliferation, and tissue regeneration, make up the intricate process of wound healing. Bacteria can readily infect the wound during these processes, increasing inflammation and inhibiting wound healing.¹¹ Currently, most commercial dressings available are made from cotton-based sterile gauze, which often has large pores, making it challenging to prevent the entry and growth of germs. Infection is a crucial issue that can slow down the healing process of wounds.¹² To promote better wound healing, advanced wound dressings can be designed to protect the wound from bacteria and maintain moisture.¹³ These dressings offer comfort, allow oxygen to penetrate, and shield the wound bed from mechanical shock. The materials used in wound dressings must also satisfy specific criteria, including nontoxicity, biocompatibility, and biodegradability.¹⁴

Natural polymers that are biodegradable, biocompatible, and have chemical properties similar to the extracellular matrix (ECM) are promising materials that can be used as efficient wound dressing applications. Living organisms produce these polymers which consist of proteins and carbohydrates that combine chemically. Natural polymers, unlike synthetic ones, are predominantly hydrophilic and biocompatible, as illustrated in Table 1. These characteristics make them particularly suitable for biomedical applications.¹⁵ Recently, a study reported by Wei and coworkers synthesized gelatin-based anti-inflammatory hydrogels with carboxymethyl chitosan, aloe vera, and glutaraldehyde, showing elasticity, self-repair, shear properties, and anti-S. aureus and E. coli activities, and 12-hour lomefloxacin release, suitable for wound dressings.¹⁶ Reisi-Vanani et al. developed wound dressings from thymus oil, PVA, gelatin, and licorice extract, producing smooth nanofibers with enhanced diameter, strong resistance to S. aureus and K. pneumoniae, and efficient fibroblast migration in vitro.¹⁷ Gong et al. (2023) developed a biphasic aerogel-hydrogel (AHB-gel) dressing using β-lactoglobulin fibrils (BLGFs) and polyvinyl alcohol (PVA), enhancing liquid interaction, softness, and in vitro biocompatibility. In vivo, studies confirmed the effectiveness of AHB-gel dressings with BLGFs for hemostasis and wound healing.¹⁸ Wang et al. (2023) developed a genipin-cross-linked carboxymethyl chitosan-gelatin hydrogel delivering dimethyloxallyl glycine (DMOG) for improved wound healing. The study indicated enhanced cell migration and proliferation in vitro, and the co-loaded drug hydrogels significantly accelerated in vivo wound recovery.¹⁹ Jia et al. (2024) created a sodium alginate (SA) hydrogel with recombinant human collagen III (rhCol III) for site-specific, sustained release of extracellular vehicles (EVs). The rhCol III/SA-EVs hydrogel's antioxidant and anti-inflammatory properties aid in healing diabetic wounds, characterized by hyper-inflammation and high oxidative stress. This multifunctional hydrogel offers sustained EV release for multimodal wound healing therapy in diabetic mice.²⁰ Sellappan & Manoharan (2024) developed an antibacterial wound dressing using C. roseus leaf extract and M. recutita chamomile flower, incorporating green synthesized ZnO into keratin and alginate based dressings. The biopolymeric mats exhibited better mechanical, thermal, and hydrophilic properties, and allowed oxygen and water vapor permeability, promoting cell–material interactions. The mat also showed potent antibacterial activity against E. coli and B. subtilis.²¹ Similarly, phloretin and γ-cyclodextrin complex-incorporated polycaprolactone and silk protein nanofiber wound dressings displayed antibacterial activity against S. aureus, antioxidant capacity, blood compatibility, improved cell viability,²² and suitable physical and chemical properties for promoting diabetic wound healing and reducing bacterial infections.

Table 1 Comparison of protein based wound healing materials with synthetic polymers

Sr. no.	Feature	Protein-based wound care materials	Synthetic polymer-based materials	Ref.
1	Biocompatibility	Highly biocompatible, composed of natural materials like keratin, silk, and collagen, which lowers the possibility of allergic responses	Exhibit reduced biocompatibility, requiring alterations to minimize immune responses or inflammatory reactions	25
2	Healing promotion	Collagen and silk proteins, for example, actively stimulate tissue regeneration to improve wound healing	Provide defensive barriers and inactive support, they lack the ability to promote active healing processes	26
3	Biodegradability	Biodegradable and readily absorbed by the body	Non-biodegradable or degrading slowly	27
4	Moisture Regulation	Maintain optimal moisture levels	Certain materials can hold water, they often need extra processing to replicate the conditions found in natural wounds	28
5	Mechanical Properties	Exhibiting exceptional elasticity and durability	Potentially possesses increased stiffness or necessitates substantial alterations to align with the mechanical characteristics of biological tissues	29
6	Antimicrobial properties	Some proteins possess inherent antimicrobial properties (e.g., keratin), reducing infection risk	Do not possess innate antimicrobial properties; they require special coatings or substances to achieve such properties	30 31
7	Cost and availability	Cost may be higher due to the use of natural ingredients, and the supply could be constrained by the availability of biological resources	Abundantly available, cost-effective and easy to scale up	30
8	Environmental impact	Eco-friendly, with minimal harmful environmental	Commonly synthesized from petroleum-based resources, leading to environmental issues	31
9	Customizability	Ability of modification is constrained by its biological nature, though enhancements can be achieved through techniques such as crosslinking or genetic manipulation	Offers extensive customization options; can be tailored and developed with characteristics	32
10	Risk of disease transmission	If not properly obtained and handled, there exists a slight, albeit possible, chance of transmitting diseases	While there is no danger of transmitting biological diseases, it may trigger reactions to foreign substances in the body	29
11	Adhesion to tissue	Superior adherence to tissues occurs through natural interactions with components of cells	Enhancing adhesion to biological tissues might necessitate the use of adhesives or modifications to the surface	26 33

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Despite abundant research on natural polymers and their potential for wound treatment, there is a lack of commercial natural polymer-based wound dressings in the market. The disconnect between academic research and commercial products creates a gap in the market where not all the capabilities of natural polymers are utilized to treat different types of wounds. Given the various forms of wounds, it is crucial to have access to a broad range of wound dressings with diverse compositions and structures. Natural polymer-based wound dressings often exhibit the ideal qualities for treating wounds, but the primary differences between them are cost and patient comfort.²³

Proteins are a necessary component of almost all tissues and have been widely used in tissue repair. Proteins have good biocompatibility, low immunogenicity, and regulated disintegration.²⁴ The advantages of protein-based biomaterials compensate for the limitations of traditional non-biogenic materials. The present review article aims to provide a comprehensive analysis of studies conducted within the past five years, which focus on protein transformation into wound care materials using various chemical methods, their different 7forms and various proteins that are used so far in the wound care applications aimed at accelerating the wound healing process. Additionally, this review delves into the attributes of keratin, collagen, gelatin, silk, zein and albumin derived material for wound care applications in great detail. Lastly, the review concludes by highlighting the limitations and challenges associated with using protein wound care materials.

2. Modification methods to design protein based wound healing materials

Various approaches can be employed to design wound healing materials using proteins (summarized in Table 2), which promote tissue regeneration, minimize the risk of infection, and facilitate a conducive environment for healing.

Table 2 Summary of methods to design protein based wound healing materials

Methods	Description	Advantages	Disadvantages	Examples
Electrospinning	Produces nano-scale fibers from protein solutions using electric field	High surface area, biocompatibility and fine nano-fibers	Limited control over fiber diameter and protein complexity	Zein, soy, pea proteins, casein and lactoferrin based materials
Phase separation	Separates homogeneous solution into phases forming scaffolds or wound dressings	Simple, scalable, porous structures and favorable for cell growth	Limited control over pore size	Protein-based polymers and Coacervates
Self-assembly	Spontaneous arrangement of molecules into ordered structures	Biodegradable, non-toxic, controllable size and biocompatibility	Complex design requirements	Gelatin-recombinant type III hydrogels, aneroin-based hydrogels and Fibronectin-based hydrogels
Ball milling	Grinds materials into nanoparticles using stainless steel balls	High surface area, customizable size and suitable for drug delivery	Energy-intensive, potential contamination	Metal-based Nps and protein-based Nps (PBNps)

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2.1. Electrospinning

Electrospinning is used to synthesize extremely thin fibers, ranging from micro to nano scales, by applying an electric field to a protein solution or molten form.^34,35 There are three main ways of electrospinning, which are blend spinning, co-axial spinning and emulsion spinning.³⁶ In blend spinning, the drug or active therapeutic agent is mixed into the protein liquid, which is then subjected to a high voltage.³⁷ This method is used to produce fine nano fibers derived from proteins that can be used as a wound healing material.³⁸ The use of natural proteins instead of harsh chemicals is a key aspect of the process. However, the complexity of proteins presents challenges due to variations in size, charge, and bonding types.³⁹ So, it could be overcome by the choice of suitable material. Furthermore, cross-linking and blending with synthetic polymers like polyvinyl alcohol (PVA), polycaprolactone (PCL) and polyethylene oxide (PEO) improved their compatibility with the process.^40,41 Plant and animal proteins can be used in electrospinning processes to create various drug delivery systems. For example, zein, soy and pea proteins are commonly utilized.⁴² A study reported zein in combination with polymers to create antimicrobial wound dressings through methods like UV cross-linking or co-axial electrospinning.¹⁷ Soy protein isolates exhibit beneficial and potentially harmful properties, when combined with suitable polymers through electrospinning, i.e., as antioxidants and allergens.⁴³ Pea proteins are also isolated via electrospinning and contain globulins and albumin as major proteins.⁴⁴ However, pea protein nanofibers face challenges such as non-uniform structure and size.⁴² Cinnamaldehyde, when combined with pea protein through electrospinning, has proven to be an effective antibacterial agent for wound healing.⁴⁵ A significant portion of animal-based proteins originates from milk. For instance, casein, whey, lactoferrin, and lysozyme possess innate antimicrobial characteristics.⁴⁶ This is due to their ability to bind to iron and break down bacteria. Consequently, these proteins are valuable components in wound healing materials.⁴⁰

Lactoferrin is a protein with a wide range of beneficial properties, including its ability to fight bacteria, reduce inflammation, and protect against oxidative damage.⁴⁷ Researchers have found that it can be combined with materials like polycaprolactone (PCL), polyacetic acid (PLA), and gelatin using electrospinning.⁴⁸ Moreover, lactoferrin can be applied to the affected area of the skin to prevent the growth of harmful bacteria.^49,50

2.2. Phase separation

Phase separation is a process in which a homogeneous solution is separated into multiple phases, typically a rich polymer phase and a phase with a higher solvent concentration.⁵¹ This technique can be utilized in wound healing materials to develop porous structures.⁵² A polymer solution containing protein-based polymers and a solvent is placed in a mold or spread over a surface.⁵³ The polymer-rich phase solidifies upon evaporation of the solvent, leaving behind a porous structure that can be utilized as a scaffold or wound dressing.^53,54

Certain aspects of proteins are considered in the process of phase separation; for example how they rearrange themselves during evaporation as its rate determines the pore size of the scaffold.⁵⁵ During this process, depending on the length and amount of the proteins, two different structures can be formed i.e., clumps and small jelly-like globs known as coacervates. The coacervates possess special properties that change with the size of the protein. They act as good adsorbers and can support the wound healing process.⁵⁶

2.3. Self-assembly

Self-assembly refers to the process by which molecules or materials spontaneously arrange themselves into ordered structures without the need for external influences.⁵⁷ Self-assembly involves the use of molecules, such as peptides, that have been designed to interact with one another in a specific way. It results in structures that resemble natural extracellular matrix components. These structures can create a favourable environment for cell growth and tissue regeneration. By manipulating the materials dimensions and pore structure through self-assembly processes, we can create wound dressings with specific desired characteristics.⁵⁸ Self-assembled hydrogels are designed for wound dressing because they are biodegradable, non-toxic and safe for the skin. Hydrogels like gelatin-recombinant type III have an amazing ability to respond to the body's requirements by forming microscopic structures that enhance wound healing. Work has been reported where rat skin cell regeneration is quicker as compared to the control group.⁵⁹ Hydrogels are particularly beneficial for managing the various stages of the healing process.⁴³ For instance, chronic wounds like diabetic ulcers can complicate the healing process. So, hydrogels facilitate the healing process due to a moist environment.⁶⁰ Self-assembling peptides automatically arrange themselves into a structure that conforms to the wound without any external assistance. This concept is analogous to the self-assembly of settling material, such as aneroin-based hydrogels,⁶¹ organophosphorous hydrolyse combined with lucine, fibronectin (large glycoprotein found in blood plasma) for sensitive body parts like eyes,⁶² Bovine Serum Albumin based self-assembly hydrogels⁶³etc.

Self-assembled hydrogels have diverse applications in wound healing such as hemostasis, infection prevention, and inflammation control.⁶⁴ These materials are designed to deliver drugs, cytokines, or cells to the wound site, they degrade into bio-active peptides or natural amino acids for tissue repair.⁶⁵ Advanced self-assembled materials enable spatio-temporal analysis throughout various healing stages, offering long-term, multi-modal treatments and regulating the wound microenvironment.⁶⁶

2.4. Ball milling

The process of acquiring extremely fine particles known as nanoparticles (Nps) involves obtaining them via pore uniformity.⁶⁷ Nps possess a high surface area and can absorb moisture. They provide a suitable environment that is beneficial for wound healing.⁶⁸ Nps can be derived from either metal-based or protein-based sources (PBNps).⁶⁹ These particles can be combined with drugs to serve as a matrix that delivers the drug to the wound site and addresses wound-related issues during the process of regeneration and healing.⁷⁰ This process generates a fine powder with specific electrical and chemical properties. This powdered form is further grinded for several hours to attain the more porous Nps.⁷¹ The heat generated from the continuous movement of the balls helps to control the size of the Nps produced. These particles can be customized based on the weight and number of balls used.⁷² They are then shaped as needed for a specific wound and mixed with drugs or antibiotics to serve as a wound dressing to prevent exposure to dirt and microorganisms.⁷³

2.5. Physical cross linking

Physical crosslinking technique involves connecting proteins such as those found in soybeans through non-covalent interactions. Wound care materials like hydrogels are formed by various physical interactions, including hydrogen bonding, electrostatic and ionic interactions, hydrophobic interactions, and chain entanglement. Altering physical factors can induce changes in proteins, as seen in soy protein, where a folded conformation develops from an initially random coiled structure. Further aggregation of soy protein results in the creation of a hydrogel, which is a 3D networked structure. For topical application or wound care, hydrogels are produced using methods such as freeze-thawing, self-assembly, and heat treatment, without the addition of chemicals.⁷⁴

Another method is freeze–thawing, which involves subjecting the protein to repeated cycles of freezing and thawing without chemical linkers. This process crystallizes the protein to a higher degree, forming a 3D hydrogel with enhanced elasticity and interconnections. Increasing the number of cycles leads to more crystalline regions in the hydrogels, resulting in a stiffer structure. Varshney and colleagues conducted a study where they employed the freeze–thaw method to design gels from soya protein isolates (SPI) and polyvinyl alcohol (PVA). They found that increasing the freezing time and number of cycles improved the mechanical properties of the gel. The interaction between the –COOH group of SPI and the –OH group of PVA resulted in a gel with improved biocompatibility, proliferation, and cell attachment.⁷⁵

The layer-by-layer assembly offers another approach to creating protein-based nanoparticles for wound care. This process involves depositing oppositely charged polyelectrolytes onto a charged layer, which can be either a protein or a nanoparticle with the opposite charge. This technique allows for the design of protein-based nanomaterials with specific surface charges and controlled sizes, enabling features such as the regulated release of therapeutic agents or drugs.^76,77

Zhou and coworkers developed a self-assembled bio-gel using SPI, polydopamine-reduced graphene oxide (PGO), and gallic acid (GA) in a dopamine-glycerol/water solvent through self-assembly.⁷⁸ Similarly, researchers employed self-assembly to produce beta-conglycinin/bacterial cellulose (BC) and glycinin/BC membranes. These combinations stabilized soybean release, enhancing wound healing by reducing inflammation and promoting angiogenesis and collagen deposition. The glycinin /BC membrane demonstrated superior wound healing compared to beta-conglycinin /BC.⁷⁹ Heating proteins unfolds molecules, revealing active sites and promoting aggregation through covalent and noncovalent bonds, forming a gel network at high concentrations. Chien et al. developed an injectable, biocompatible, and biodegradable SPI hydrogel dressing with sustained drug release, as confirmed by in vivo and in vitro analyses.⁸⁰

2.6. Chemical cross linking

This technique involves creating covalent bonds between soy protein chains, resulting in a more robust interconnected structure with enhanced spatial networks. Hydrogels modified through chemical means demonstrate superior physical stability and mechanical strength. Cross-linking agents can form bonds with soy protein molecules by interacting with various reactive groups, including hydroxyl (–OH), amino (–NH₂), and carboxyl (–COOH). This process generates a network-like structure, reinforcing the protein material. Due to their ability to produce a wide range of desired properties, cross-linking agents are the most commonly used method for modifying soy protein hydrogels.⁸¹ Epichlorohydrin (ECH) is a frequently used chemical linking agent. The most prevalent chemical modification methods involve the use of chemical cross-linking agents and photopolymerization.⁸²

Photopolymerization employs visible or ultraviolet light to initiate the polymerization reaction in the creation of photopolymerized hydrogels. The molecules become excited upon absorbing energy from UV or visible light, generating free radicals. These radicals then trigger the formation of unsaturated bonds in monomeric units, which subsequently undergo polymerization to form hydrogels. A study reported the hybrid hydrogels of SPI and silk fibroin (SF) by subjecting them to 50 W (LED) visible light for 2 minutes. The SPI hydrogel produced through photo cross-linking exhibited superior water resistance and mechanical strength compared to hydrogels obtained through conventional methods.⁸³

This method improves protein solubility and distribution by altering the pH of the solution to a value considerably different from the protein's isoelectric point, causing the protein to unfold. The solution is then cast into a mold and dehydrated to form a film. The drying process can be expedited using ambient temperature, infrared radiation, or microwave energy.⁸⁴. In a study by Zhao et al., a composite film was developed by blending hydroxypropyl chitosan (HPCS) and soy protein isolate (SPI). Utilizing the solution casting technique, they discovered that a 50% SPI content yielded a film with ideal cytocompatibility and hemocompatibility. This film demonstrated enhanced wound healing, accelerated skin regeneration, and notably improved granulation tissue formation and collagen deposition.⁸⁵

2.7. Genetically engineered protein nanomaterials

The field of genetically engineered protein-based nanomaterials has seen growing interest in creating protein-based nanomaterials with particular attributes such as size, controlled release, and stability.⁸⁶ This method involves modifying proteins genetically or chemically to change their amino acid sequence. Furthermore, specific functional groups are incorporated at regular intervals to control the size and shape of the resulting nanomaterial, which is formed through the interaction of these introduced functional groups.

3. Forms of proteins derived wound healing materials

3.1. Hydrogels

Protein-based hydrogels are a promising option for wound healing due to their flexibility, smooth surfaces, and high water content.⁴³ These hydrogels can adapt to different temperatures, pH levels, and the presence of specific ions or enzymes, making them suitable for treating wounds at various stages of healing.⁶⁰ Functional hydrogels can be categorized as those that can adjust their surface in response to the changing requirements of a wound. This ability allows the hydrogel to adapt to the specific needs of the wound at any given moment, whether it requires acceleration or deceleration.⁸⁷ Hydrogels have been successfully synthesized that can respond to the wound's requirements in a timely and effective manner.^62,63,61,66 Different types of hydrogels can be categorized based on their capacity to sustain their structural and functional properties under diverse circumstances.⁸⁸ One such type of hydrogel is the peptide-based hydrogel, which can rapidly stop bleeding by forming a barrier at the site of the wound. This process occurs more rapidly than other hemostatic materials, such as gauze or chitosan.⁸⁹ Hydrogels infused with antimicrobial peptides (AMPs) demonstrate a broad spectrum of antimicrobial activity and makes them ideal to prevent wound infections.⁹⁰ Moreover, they can be combined with fungicides to boost their antimicrobial properties, making them effective as antiseptics during the healing process.⁹¹ Peptide-based hydrogels which contain anti-inflammatory drugs are used for the controlled and targeted drug release to reduce and minimize inflammation during wound healing.⁶⁶ Protein-based hydrogels can serve as a scaffold that encourages cell growth, migration, and tissue repair. Their ability to adhere to cells can be enhanced via the incorporation of bioactive epitopes.⁹² The use of keratin protein hydrogels and silk protein fibers in regenerative medicine is aimed at resolving the widespread issue of cartilage defects in conditions such as osteoarthritis (OA), as well as healing irregular wound surfaces.⁹³ These hydrogels and fibers are particularly beneficial due to their cell adhesion and mechanical properties, making them well-suited for drug injection and cartilage regeneration.^24,90 Researchers have successfully developed a hydrogel system using polypeptide proteins derived from bovine serum albumin (BSA) sourced from cows and silver ions (Ag⁺).^94,95 It results in a sterile environment with strong antibacterial properties and improved blood vessel formation.⁹⁶

An innovative injectable polypeptide-protein hydrogel was created for treating infected wounds by forming a porous structure through the coordination of thiolated BSA protein and thiolated polypeptide with Ag⁺ ions.⁹⁵ The hydrogel demonstrated efficient gelation and self-healing properties, along with biological functions such as vascularization and antibacterial activity, due to the S–Ag coordination in the presence of Ag⁺ ions.⁹⁷In vitro studies confirmed its role in the healing process, while in vivo experiments on infected mouse wounds revealed its antibacterial effect, wound healing, hair follicle formation, and angiogenesis. These findings highlight the hydrogel's potential in treating infected wounds.⁹⁸

3.2. Scaffold

Healing can be impeded in the inflammatory stage by excess fluid impacting nearby cells, infections, or other health issues.⁹⁹ Appropriate wound dressings are crucial to promote healing and preventing infections. Although widely used, common dressings like cotton, bandages, and gauzes have limitations.¹⁰⁰ These typical materials show rapid drying, which is unfavourable healing environment, and get adhered to the wound and skin, causing discomfort during removal.¹⁰¹ To tackle these problems, biomaterial-based scaffolds offer structural support and an ideal environment for cell regeneration, acting similarly to natural tissues.⁴³ These three-dimensional (3D) scaffolds have been utilized in a variety of sectors, such as bone, muscle, and skin regeneration.^102,103 Effective wound healing requires a scaffold that exhibits high porosity, substantial surface area-to-volume ratio, interconnectivity, flexibility, biocompatibility, and biodegradability.⁵⁵ Moreover, its degradation rate is synchronized with tissue regeneration that promotes cell attachment, growth, and specialization.^104,105

Scaffold construction employs diverse techniques which modify properties significantly. Despite the availability of various methods, developing scalable and cost-effective approaches for producing customized scaffolds in large quantities remains a continuous struggle.^106,107 An ideal wound healing scaffold should possess appropriate physical and mechanical properties to prevent infections, promote cell adhesion and proliferation while absorbing fluids and maintaining a moist environment.¹⁰⁸ Conventional materials, such as cotton pads, have limited fluid retention capacity.¹⁰⁰ Therefore, the optimal scaffold should exhibit high absorbency, porosity, and the ability to retain fluids and swell effectively.^109,110

3.3. Sponges

Various types of sponges, having mineral skeletons and scleroproteins, play a crucial role in wound care applications.¹¹¹ The use of special patterns on wound dressings is essential for accelerating healing by appropriately directing cells.¹¹² Although substantial knowledge exists regarding two-dimensional(2D) dressings, research is scarce on three-dimensional dressings that facilitate healing from the exterior to the interior.^113–115 Sponge shape influences blood vessel formation, with Radial-196 showing the highest increase in CD31(cluster of differentiation 31) marker as compared to Radial-40, Radial-15, and random sponges.¹¹⁶ Human umbilical vein endothelial cells (HUVECs) produce vascular endothelial growth factor (VEGF), which promotes angiogenesis.¹¹⁷ Western blotting revealed the highest levels of VEGF, phosphorylated akt (p-AKT), endothelial nitric oxide synthase (eNOS), and VE-Cadherin in HUVECs on Radial-196. In vivo studies confirmed superior blood vessel development in the Radial-196 group, indicating that specific sponge shapes enhance angiogenesis.¹¹⁸ Researchers utilized ice templating to form layered, ridged sponge structures for promoting fluid flow and organized cell alignment, thus expediting cell movement.¹¹⁹ Extended sponge shapes boosted protein production for angiogenesis. The Radial-196 sponge was most effective in swiftly healing deep skin wounds in rats, resulting in increased blood vessel formation.¹²⁰ The application of natural components like proteins can be harnessed to fabricate radial sponges. These sponges possess a design that promotes healing, initiating from the periphery and progressing toward the center. The development of these sponges at decreased temperatures, with thicker layers and ridges, is advantageous for accelerating wound healing.^116,121

3.4. Films

Films are developed from various materials, including natural proteins derived from silk, soy, or egg.^122,123 They have thin layers or sheets and have been applied in a variety of uses, such as wound healing and tissue regeneration. Similarly, they serve as carriers for drug delivery.⁴⁶ The dressing materials resemble films and are designed to enhance the attributes of wound dressings, such as tensile strength and flexibility.¹²⁴ Some recently reported films include the following, bovine serum albumin (BSA) films are created through a process that entails protein fibrillation and reverse dialysis.¹²⁵ These films are biodegradable, non-toxic, and have a variable thickness. They exhibit high transparency and exceptional durability across various solutions.³⁸ Films composed of renewable resources such as soybean polysaccharide and catechol-functionalized soy protein isolate are utilized in a combined form to improve mechanical properties.⁶¹ Studies demonstrated a 44% improvement in tensile strength for soy protein isolate (SPI) films, and polydopamine-modified microcrystalline celluloses (MCC) enhanced the duration of usage by 82.3% in comparison to SPI films.¹²⁶ Egg white is transformed into insoluble hydrogels with the help of 5,6-dihydroxyindole (DHI), which leads to the formation of a black, water-soluble artificial biomelanin (ABM) film.¹²⁷

Silk fibroin and chitin are combined to synthesize films with remarkable dimensional structure, which have applications in electronic and smart contact lenses.¹²⁸ Plasticizers such as glycerol are added to replace water to increase the flexibility of silk fibroin films. It stabilizes the helical structures in the films.⁷³ These films can be easily molded and adapted to fit any wound location on the upper skin of the body. Films that incorporate bitter vetch protein sourced from Vicia Ervilia display remarkable tensile strength when combined with a small amount of glycerol and the positively charged compound spermidine.¹²⁹ Spermidine functions as a plasticizer, enhancing the flexibility and extensibility of the films. Additionally, these films exhibit improved barrier properties against gases and water vapor.⁷³

3.5. Protein bioinspired nanomaterials

Bioinspired protein-based nanomaterials (PBNs) are the smallest particles used to control physical and chemical properties. Their high surface area aids in the adsorption of vapors and air molecules, making them an effective alternative for wound healing environments.^124,130 Nanoparticles are frequently paired with antibiotics and medications to support wound healing throughout its stages. This material combination has diverse uses, such as tissue engineering, drug delivery, disease diagnosis, and fluid or exudate management.¹³¹ Serum albumin-based nanomaterials, such as nanoparticles coated with serum albumin or peptides, improve stem cell adhesion and proliferation, significantly enhancing bone cell growth and function in vivo.¹²⁵ This accelerates the usually slow bone regeneration process, aiding faster bone repair in athletes with fractures.⁷³

Silk nanomaterials are ideal for repairing damaged corneal tissue due to their transparency, flexibility, and slow degradation.¹³² These nanoparticles can be functionalized with specific molecules to enhance cell attachment, growth, and corneal regeneration. Consequently, they are advantageous in optical surgeries and can expedite healing for individuals recovering from eye injuries or surgeries.¹²⁴ These nanomaterials are similar to the extracellular matrix (ECM) in our bodies and help in repairing damaged blood vessels. They mainly deal with an inner layer of skin injuries which are sometimes not detectable by the naked eye. An interesting fact is that we can use them for a long time unless the wound heals and it does not affect the skin cells during the process.¹³³ It safeguards the wound from external bacterial or viral infections. A 3D environment constructed with fibrin nanomaterials can encourage the growth of blood vessels by releasing various growth factors in pre-established settings. This facilitates the transformation of stem cells into muscle cells and accelerates the regeneration process.⁶² Another example of a material used in dental gums regeneration is silk fibroin nanoparticles (Nps). By combining these Nps with a sensor molecule called basic fibroblast growth factor (bFGF), the dental pulp stem cells can grow more effectively. This process can result in the formation of tissue that is similar to natural tissue and the development of blood vessels within the new tissue.¹³⁴ A comparison of different forms of proteins derived materials for wound care applications is summarized in the Table 3.

Table 3 Comparison of protein based wound healing materials

Material	Properties	Advantages	Limitations
Hydrogels	Biodegradable, porous and moist support	Enhances wound healing and tissue regeneration	Limited mechanical strength
Scaffolds	3D structure, biocompatible and porous	Enhances tissue regeneration	Commercial scalability challenges
Sponges	Porous, radial shape and promotes angiogenesis	Accelerates wound healing and blood vessel growth	Variable efficacy
Films	Thin, flexible and biodegradable	Wound protection and drug delivery	Limited durability
Protein-based nanoparticles (NPs)	High surface area and biocompatible	Enhances stem cell adhesion and bone regeneration	Potential toxicity

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4. Protein based wound care materials

Polymers that are derived from natural resources, and extensively utilized in medical and pharmaceutical sectors are favoured due to their hydrophilic properties, biocompatibility, non-toxicity, biodegradability, affordability, and cost-effectiveness.^135,136 Additionally, some natural polymers possess inherent antibacterial activity, making them suitable for wound dressing applications. Among the antibacterial natural polymers that have been studied in recent years are aloe vera, chitosan, curcumin, honey, keratin, pectin, and propolis. Carbohydrates and proteins are the two main classes of natural polymers that can be obtained from either animal or plant sources. For instance, chitosan, silk, and honey are derived from animal sources, while pectin, aloe vera, and cellulose are extracted from plants. Conversely, collagen, gelatin, and keratin are widely used animal-derived proteins.⁶

The sequence of amino acids that form peptide bonds and bind together to form the basic structure of proteins interact to form a three-dimensional structure. Hydrophobic, electrostatic, and hydrogen bonds, as well as covalent bonds like disulfide bonds, are all present in protein interactions. Because proteins include a variety of functional groups that may change chemically, enzymatically, and physically, they can be designed for different uses. Protein-based biopolymers 3D structure and functional characteristics are closely linked. Foaming/emulsibility and fat binding ability are primarily influenced by hydrophilic–hydrophobic and hydrophobic interactions, respectively, whereas hydro-solubility, swelling capacity, and gelation capability are pertinent to hydrophilic interactions within the protein network.¹³⁷

Since biopolymers have been used for years to heal wounds and illnesses, the use of protein based biomaterials in the biomedical field is not new. The advancement of methods to assess and classify protein materials as well as better extraction procedures from their sources have influenced trends in protein based biopolymers for medicinal applications. Biomedical applications often utilize non-immunogenic proteins to create nano/microfibers due to their exceptional fiber-forming properties, high nutritional value, relatively biocompatible polymers, and other advantages.¹³⁸

The exceptional qualities and distinctive tunability of protein-based biomaterials remain intriguing as the biomedical industry turns its attention to smart materials. They may be made to react to a variety of stimuli, such as temperature changes, oxidative agents, pH changes, and even the presence of specific biomolecules. Additionally, protein based biomaterials provide a multitude of potential for the development of precisely engineered biomaterials since they can be made to self-assemble into a wide variety of forms, from porous architectures to nano-sized materials.¹³⁹

4.1. Keratin derived materials

Keratin, often found in natural materials like feathers, hair, hooves, horns, and wool, is a widespread choice for its high sulfur content and other functional groups in creating these materials.¹⁴⁰ Researchers are particularly interested in incorporating keratin-based formulations (KFs) due to their compatibility with living tissues and biocompatibility. KFs have proven useful in various fields, such as drug delivery, wound healing, and the development of artificial tissues.^141,142 Additionally, studies are being carried out to explore the combination of keratin with other natural or synthetic materials to create new products. However, it is important to note that the specific peptide composition and molecular weight of keratin extracted from different sources can significantly affect its properties and performance.^141,143 Unlike other natural polymers like starch, gelatin, and chitosan, the complex three-dimensional structure of keratin requires the use of powerful chemicals for extraction due to its unique characteristics.¹⁴⁴ As a wound dressing material, keratin shows great potential due to its numerous beneficial properties. These include its capacity to biodegrade, exhibit biocompatibility, allow water vapor transmission, and form gel-like structures. Keratin-based dressings, such as films, hydrogels, sponges, and patches, help promote the healing process by aligning with the body's natural healing mechanisms.^144–146 The use of keratin and eco-friendly solvents makes it a practical and cost-effective choice.

Antibacterial, antifungal, and cytocompatible polysulfobetaine/keratin-based hydrogels incorporating chlorhexidine were reported through free radical polymerization of sulfobetaine and oxidative self-crosslinking of reduced keratin. These hydrogels exhibited release behaviors of acidity, glutathione, and trypsin, leading to the rapid release of chlorhexidine within the wound matrix. The hydrogels were transformed into powders (xerogels) and applied to wounds, where they reformed in situ by absorbing wound fluid. In vivo testing on infected wounds showed that the xerogel powder dressing reduced inflammation and promoted collagen deposition, resulting in accelerated wound closure. The study demonstrated that the prepared xerogel powder has great potential for promoting wound healing.¹⁴⁷ A nanofibrous hydrogel composed of keratin and poly(L-lactate-caprolactone) (PLCL) copolymer, incorporating fibroblast growth factor (FGF-2), was developed using the low-pressure filtration-assisted method in one study. The hydrogel was designed to mimic the dermis, with keratin representing the dermis and PLCL replicating it. The hydrogel was highly porous, biodegradable, and biocompatible, and in vivo experiments demonstrated enhanced re-epithelialization, collagen deposition, hair follicle regeneration, and new blood vessel formation. Moreover, the incorporation of FGF-2 resulted in a superior wound-healing effect as exhibited in. Fig. 1. The study provided an in-depth explanation of the role and mechanism of the bilayer hydrogel dressing in wound healing and resolved the issue of poor interface adhesion of electrospinning nanofibers.¹⁴⁸

Fig. 1 In vivo studies of wound healing process. (A) Representative photographs of wound tissues in different groups on days 0, 3, 7, 11, and 14. (B) Traces of wound-bed closure in three groups during 14-day observation. (C) Wound healing rate of samples in different groups. Reproduced from ref. 148 with permission from Elsevier, copyright 2023.

According to Demir et al., both xanthan/gelatin and keratin/xanthan/gelatin hydrogel dressings with exceptional fluid absorption capacity have been developed for the local delivery of vitamin C. The xanthan/gelatin hydrogels were prepared through crosslinking with varying concentrations of glycerol. The addition of keratin with the xanthan/gelatin/glycerol (1 : 1 : 2) hydrogel, improved its mechanical properties, collagen synthesis, and viability of L929 fibroblasts, as well as the release of protein. Both xanthan/gelatin and keratin/xanthan/gelatin hydrogels containing vitamin C exhibited excellent water absorption capabilities, making them suitable for exudate wounds. All the synthesized hydrogels tested inhibited bacterial growth, indicating that both xanthan/gelatin and keratin/xanthan/gelatin hydrogels incorporating vitamin C can be utilized as wound dressing materials.¹⁴⁹

Kaviyashri and colleagues examined the potential of keratin, activated carbon, and aqueous garlic extract as components of wound dressings. The study revealed that activated carbon exhibited effective adsorption of keratin due to its numerous pores, making it a suitable carrier. The presence of 5% to 10% garlic extract was found to inhibit bacterial growth effectively. Based on these findings, the study concluded that these components could be optimized and combined to design an ideal dressing material for wound repair.¹⁵⁰ On the other hand, carboxymethyl cellulose (CMC) was used by Sadeghi and coworkers to develop novel antibacterial sponge-type dressings using keratin, derived from human hair, for the topical delivery system for clindamycin. In addition, the researchers incorporated halloysite nanotubes to facilitate the sustained release of the antibiotic. The addition of larger amounts of keratin to CMC hydrogels resulted in improved water stability, slower clindamycin release, enhanced antibacterial activity, and increased cell attachment and proliferation, although it did not significantly affect water vapor transmission rate.¹⁵¹ In another study, Yao et al. reported a bilayer wound dressing that consisted of a gelatin/keratin nanofibrous mat as the inner layer and a commercial polyurethane dressing as the outer layer. Scanning electron microscope (SEM) analysis revealed a uniform morphology without beads and with an average fiber diameter of 160.4 nm. In vitro analysis using L929 fibroblast cells showed that the gelatin/keratin nanofibrous mat promoted cell attachment and proliferation. Furthermore, the gelatin/keratin/polyurethane bilayer wound dressing demonstrated a better healing response by producing more blood vessels and reducing the wound area at 4 and 14 days compared to the bilayer membrane without keratin, gauze, and the commercial wound dressing (Comfeel),¹⁵² as depicted in Fig. 2.

Fig. 2 In vivo study of healed wounds. (a) Macroscopic appearance of the wounds after treatment with the gelatin/keratin/commercial polyurethane (GKU) membrane, gelatin/keratin (GU) membrane, gauze and Comfeel® on the fourth, seventh and fourteenth postoperative days. (b) Wound closure with the healing time (4, 7 and 14 days). Reproduced from ref. 152 with permission from Elsevier, copyright 2017.

Keratin from chicken feathers was also utilized to synthesize three types of nonwoven dressings, including pure keratin, keratin-sodium alginate, and keratin-chitosan compositions. These dressings were analyzed using FTIR and SEM, and their physical properties, such as thickness, air permeability, and areal density, indicated their potential use as wound dressings. The keratin-sodium alginate and keratin-chitosan dressings exhibited antibacterial activity against both Gram-negative and Gram-positive bacterial strains, with inhibition zones greater than 2.0 cm. Further investigation of these dressings’ potential was assessed through cytotoxicity, cell viability, and in vivo studies on Albino Wistar rats. The results revealed that the prepared materials were non-toxic and provided good support for cell viability. Wound dressings composed of keratin-chitosan and keratin-sodium alginate exhibited complete wound healing in rat models within 15, 17, 21, and 23 days, respectively. In contrast, dressings made solely of keratin proved to be less efficient in promoting wound closure.¹⁵³

4.2. Gelatin derived materials

Gelatin is commonly utilized in wound dressings because it has a molecular resemblance to the extracellular matrix of human tissues and organs. Its properties, such as biocompatibility, biodegradability, cell-interactivity, non-immunogenicity, and processability, make it an excellent biopolymer for wound care applications (Table 4).^154,155 Additionally, gelatin's low antigenicity makes it suitable for various biomedical applications. However, gelatin's hydrophilic nature requires crosslinking to improve its mechanical strength and stability, ensuring insolubility in biological environments.¹⁵⁵ The studies reported the use of enzymatic techniques with transglutaminase or chemical techniques with carbodiimides, fructose, diepoxy, genipin, diisocyanates, glutaraldehyde, formaldehyde or dextran dialdehyde.^156,157

Table 4 Gelatin derived materials for wound care applications

Material shape	Composition	Active ingredients	Method of fabrication	Animal Tested	Wound size	Healing time	Notable findings	Ref.
N.A: not available.
Fibrous scaffolds	PCL, gelatin, ε-polylysine	—	Fused deposition modeling and electrospinning	S. aureus, P. aeruginosa, E. coli	N. A	N. A	Antibacterial, skin cell toxicity	162
Hydrogels	Xanthan, gelatin, keratin	Vitamin C	Crosslinking with glycerol	N.A	N. A	N. A	Biocompatible, sustained release up to 100 hours, good mechanical properties	149
Bilayer sponge/nanofibers	Gelatin, carrageenan	Fibrin	Cross-linking of gelatin with sodium tripolyphosphate, solution casting, electrospinning	Male Wister rats	10 mm	14 days	Tensile strength increased by addition of carrageenan/fibrin layer, adhesion and proliferation of L929 cells, angiogenic potential	163
Hydrogels	Gelatin, dimethyl aminoethyl methacrylate	—	Chemical and physical cross-linking	Wister rats	—	21 days	Mechanical strength improved by cross-linking, biodegradable, non-toxic	164
Hydrogels	Gelatin, oxidized chondroitin sulfate	Curcumin loaded chitosan nanoparticles	Freeze drying	—	—	—	Non-toxic, In vitro Curcumin stable release	165
Electrospun membranes	Poly(L-lactide-co-glycolide)/gelatin	Zinc oxide nanoparticles	Electrospinning	Rat	10 mm	14 days	Cytocompatible, hemostatic, antibacterial	166
Nanocomposite hydrogels	Modified gelatin/iron	Camellia sinensis extract	Metal organic framework (MOF)	B. serous, S. aureus, S. mutans, P. aeruginosa, E. coli, K. pneumoniae	—	—	Antibacterial, sustained release, adding MOF increased water absorption	167
Hydrogels	Modified hyaluronate, gelatin	Doxycycline	Crosslinking by boronate ester and encapsulation of doxycycline	Rats	20 mm burn wound	14 days	Antibacterial, bioadhesive, injectable, biocompatible	168
Film	Carboxymethyl chitosan-gelatin-	mesoporous silica nanoparticles containing Myrtus communis L. extract	—	Mice	7 mm	6 to 12 days	Antioxidant, increased tensile strength by adding nanoparticles, reduced cytotoxicity, reduced drug release	169
Film	Gelatin/Persian gum/bacterial nanocellulose	Frankincense essential oil and Teucrium polium extract	Solution casting	S. aureus, P. aeruginosa, E. coli, A. baumannii	—	—	Better anti-inflammatory and antibacterial activity, biocompatible	170

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To tackle the challenge of rapid degradation and poor adhesion in gelatin-based traditional dressings in fluid environments, Lin and colleagues developed more adhesive dressings using gelatin, silica, and 3-glycidoxypropyltrimethoxysilane as a coupling agent. By employing the sol–gel method to create hydrogels, the stability of the structure was enhanced through the formation of covalent bonds between gelatin and silica, as a result of the coupling reaction. Moreover, dopamine was added to further increase adhesiveness. The study showed that these hybrid dressings were 2.5 times more adhesive to soft tissues than pure gelatin in humid conditions. In vitro and in vivo tests also revealed their superior healing capabilities as exhibited in Fig. 3.¹⁵⁸

Fig. 3 (a) In vivo skin wound healing assessment. Untreated (control), gelatin, gelatin-silica hybrid (G-H) and gelatin-silica-dopamine (G-H-D) samples were applied to a 2 cm diameter round wound created using a surgical scalpel for wound recovery observation over different time periods (b) the wound recovery trend was calculated based on the changes in wound area observed in (a) Reproduced from ref. 158 with permission from Elsevier, copyright 2024.

Developing wound dressings that can effectively control rapid bleeding during accidents and surgeries is a significant challenge. Li and his team developed effective sponges for wounds based on methacrylated gelatin-dopamine, quaternized chitosan, and glycerol to control rapid bleeding. The results demonstrated that these composite sponges were biocompatible, could absorb water, displayed good self-adhesion properties, and exhibited better antibacterial activity compared to commercial gelatin and chitosan dressings. Animal studies conducted on rat tail and liver bleeding models showed that the hemostasis time and blood loss in these prepared dressings were better than those of commercial gelatin and chitosan dressings. Therefore, these dressings/sponges have significant potential to be employed as hemostatic agents for surgeries and emergency accident treatments.¹⁵⁹ Khan et al., have developed a multilayer nanofibrous wound dressing using electrospinning, chemical functionalization, and electrospray techniques with a layer-by-layer method. The dressing comprises a coating of diethylenetriamine-functionalized polyacrylonitrile TiO₂ nanoparticles and a bioderived gelatin layer. It includes an outer layer that acts as a barrier against pathogens, an interlayer that kills microbes, and a contact layer for improved biocompatibility and cell viability. The nanofibrous membranes demonstrated antibacterial properties, and showed better cell morphology, proliferation, and viability in comparison to 3T3 (3-day transfer) fibroblasts (Fig. 4), making them suitable for wound healing applications.¹⁶⁰

Fig. 4 Fibroblast (3T3) cell morphology on the various NFs membrane scaffolds at 24, 48 and 72 h. Reproduced from ref. 160 with permission from Elsevier, copyright 2023.

In response to the growing need for plant derived antibiotic alternatives, Vanani et al. have developed antibacterial core–shell nanofibers as wound healing scaffolds to evaluate their synergistic effect. The scaffolds were composed of PVA/gelatin/thymus essential oil as the core and PVA/gelatin/licorice extract as the shell. The nanofibers were found to be free of beads, smooth, and had an average diameter of 119 nm. The addition of essential oil and licorice extract increased the diameter of the nanofibers. The nanofibrous scaffolds exhibited antibacterial properties, were non-hemolytic, and promoted the viability and proliferation of L929 fibroblasts, (Fig. 5) showing them as potential candidates for use as wound dressings.¹⁷

Fig. 5 Wound healing micrographs and fibroblast migration into the scratch area after one- and two-days cell culture on the nanofibrous scaffolds. Reproduced from ref. 17 with permission from Elsevier, copyright 2017.

Chronic wound healing is often hindered by infections, creating a need for wound dressings that can release antibacterial and antioxidant substances. These advanced dressings are highly sought after due to their potential to combat infection-related complications in the healing process. Lv and his team have developed nanofibrous membranes composed of polycaprolactone (PCL) and gelatin, incorporating varying ratios of curcumin and borneol using the electrospinning technique. The resulting membranes demonstrated excellent water absorption capabilities, improved mechanical properties, and enhanced dissolution of curcumin. Additionally, the membranes were shown to exhibit antibacterial and antioxidant properties, while also demonstrating biocompatibility. These features, combined with the use of biodegradable polymers, an eco-friendly production method, and promising results in living organisms, indicate the potential for large-scale production.¹⁶¹

4.3. Collagen derived materials

Collagen's diverse applications are well-recognized, encompassing its utilization as a material for sutures, in viscous formulations, as lenses for bandages, for grafts to replace vitreous humor, and as a protective agent during surgical procedures.¹⁷¹ Collagen is a crucial protein in humans that is abundant and plays a vital role in maintaining the structural integrity of the skin. It functions as a scaffold within the extracellular matrix (ECM) and serves as an essential signalling molecule.^172,173 Numerous approaches have been tested to evaluate the use of collagen in wound healing (Table 5). They have been employed as scaffolds or matrices in soft tissue repair, hemostasis, tissue engineering, and more recently nano-medication.^174–180

Table 5 Collagen derived materials for wound care applications

Material shape	Composition	Active ingredients	Method of fabrication	Animal tested	Wound size	Healing time	Notable findings	Ref.
N.A: not available.
Hydrogel	Collagen, xanthum gum	Ketorolac, methylene blue, dexamethasone and quinic acid	Interaction of functional groups	Fibroblast cells	N. A	N. A	Controlled release of ketorolac and methylene blue	200
Hydrogels	Collagen-polyurethane-alginate	Ketorolac	Electrostatic interaction	E. coli, In vitro wound healing on fibroblast cells, anti-cancer activity on colon and breast cancerous cells	N. A	N. A	Proliferation of fibroblast and monocytes, anti-cancer activity against breast and colon cancer, anti-bacterial activity against E. coli	201
Vesicles	Peptides [CLP (G8): (GPO)8GG or (GPO)8GC and ELP (F6): (VPGFG)6G′]	Vancomycin	Vancomysin encapsulation in prepared vesicles and in liposome	Methicillin-resistant Staphylococcus aureus	—	—	Sustained release and higher % encapsulation compared to liposomal version Novel antibiotic delivery system	202
Infuse	Recombinant human bone morphogenetic protein-2 (rhBMP-2) on an absorbable collagen sponge (ACS)	rhBMP-2	rhBMP-2 absorbed on ACS	Non-human primates	—	—	Osteoinductive autograft replacement	203
Hydrogels	Collagen	Gallic acid and naproxen Metal nanoparticles	Through polymerization and cross linking	—	—	—	Potential drug delivery agents, anti-microbial hydrogel films Higher encapsulation and release of drugs	204
Scaffold	Collagen-chondroitin sulfate scaffold	Stromal derived factor-1 alpha (SDF-1α]	Dehydrothermal treatment	Human umbilical vein endothelial cells	—	—	Enhanced pro angionic response for wound healing	205
Scaffold	Collagen/heparin bi-affinity multilayer delivery system (CHBMDS)	CBD-bFGF (a collagen-binding domain (CBD))	Specific or electrostatic interaction	SD rat	—	5 weeks	Sustained and localized release of CBD-bFGF Enhanced angiogenesis	206
Nanofiber	Collagen and chitosan	Curcumin	Electrospinning	Escherichia coli Pseudomonas aeruginosa, and Staphylococcus aureus	—	—	Sustained release of curcumin up to 72 hours, tend to be potential patches for wound healing	207
Hydrogel	Collagen and chitosan	Cross linked by dialdehyde starch	Mixing different ratios	—	—	—	Characterized as potential biocompatible wound dressing	208
Hydrogel	Human like collagen and chitosan	Crosslinked via dialdehyde starch	Mixing in different ratios	In vitro and In vivo Model (post injection)	—	1, 9, 12 and 28 weeks	Reduces inflammation, can be potential skin patch scaffolds, wrinkle treatments, and tissue cavity fillers	209

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Collagen is mixed with natural and synthetic polymers, including alginate, chitosan, hyaluronic acid, elastin, polyethylene oxide and silk fibroin, etc., to develop collagen based wound dressings.^181–183 These modified fabrics have also additives such as antibiotics,¹⁸⁴ insulin,¹⁸⁵ or gold nanoparticles^186,187 and have primarily been studied in small animal wound healing models or in vitro investigations. Although initial findings are promising, a comprehensive evaluation of the effectiveness of antibacterial wound dressings for clinical diabetic foot ulcers remains inconclusive. To establish the true efficacy of this treatment, more extensive and rigorous clinical studies are necessary.

In scaffolds and matrices, collagen is applied as a surface coating to maintain a moist environment and enhance cell adhesion.¹⁸⁸ Water retention is essential for preserving moisture in the wound bed. In vitro studies on collagen have demonstrated that the arginine-glycine-aspartic acid (RGD) sequences interact with cell integrins, promoting the attachment and movement of fibroblasts and keratinocytes. In recent years, there has been growing interest in collagen nanostructures. A relatively new material has emerged, consisting of collagen reduced to nanoparticulate dimensions. This nanoscale form provides an enhanced surface area to volume ratio. A key advantage of these nano-collagens is their ability to be delivered to specific targets using a material that is biocompatible with the microenvironment of wounds.^189,190 One constraint is the lack of understanding and investigation into these nanoparticles, necessitating more in-depth study. A recent pilot study using Porcine derived hydrolyzed collagen (PDHC) to treat chronic ulcers of various causes revealed that the product was safe to use and sped up the healing process.¹⁹¹ The large-scale production of recombinant human collagens from non-animal sources may face challenges due to the potential requirement for post-translational proline hydroxylation. Following the identification of collagen-like proteins (Scl1 and Scl2) in Streptococcus pyogenes, researchers developed constructs in a recombinant E. coli system to explore large-scale production methods. Utilizing bacterial collagens provides a synthetic approach to creating non-animal collagen without specific bioactivity, allowing for customized interactions. An experiment using human mesenchymal stem cells demonstrated this system's potential for chondrogenesis.¹⁹² Research findings indicate that recombinant human collagen shows promise as a future wound healing agent.

Shields of collagen were synthesized as corneal bandages to aid in the healing of wounds following radial keratomy, corneal transplantation, keratorefractive surgery, and epithelial debridement procedures. When applied to the eye, the thin collagen films take on the shape of the cornea, allow for adequate oxygen transmission to support corneal metabolism, and function as temporary bandages. When the shields dissolve, a layer of collagen solution is left behind that appears to lubricate the eye's surface, reduce rubbing of the lids against the cornea, and promote epithelial healing.^193–196 Li Zhiye and colleagues recently reported a study on phycocyanin-loaded hydrogels made from collagen, chitosan, and genipin. The study evaluated the biocompatibility and cell migration potential of these hydrogels in vitro. A gel containing collagen/chitosan (25 : 75) demonstrated the best performance in promoting cell migration. Subsequent in vivo studies confirmed these results, establishing nanocomposite hydrogel as the most effective formulation for promoting diabetic wound healing through increased cell migration and reduced MMP-9 expression.¹⁹⁷ Malathi and coworkers studied about the use of collagen-based zinc oxide nanoparticles (ZnO NPs) for wound healing. Their study proved that the developed nanocomposite enhanced the rate of wound healing to a high level. These innovative bio-nanocomposites possess several advantageous properties including strong antibacterial properties, non-toxicity, short, adjustable, economical, and large-scale fabrication process.¹⁹⁸ Recently, researchers developed a novel wound dressing made from a blend of fish collagen, oxidized sodium alginate derived from seaweed, borax (a boron compound), and polyvinyl alcohol (a plastic-like material). This dressing is designed to effectively heal deep wounds. The fish-skin collagen-based dressing is self-healing, injectable, adheres to various surfaces, and degrades naturally in the body. In experiments involving mice, the dressing demonstrated superior performance compared to traditional gauze, rapidly stopping bleeding and accelerating wound healing by stimulating skin cell growth, collagen production, and new blood vessel formation.¹⁹⁹

4.4. Silk fibroin based materials

Silk fibroin and its derivatives are being assessed for their potential application in wound dressings due to their biocompatibility, exceptional mechanical strength, biodegradability and high water absorption capacity. Additionally, silk fibroin has been shown to promote cell migration and proliferation, which is essential for accelerating wound healing.^{114,128,210–213} The Food and Drug Administration (FDA) has approved the use of silk as a surgical mesh due to its utility as a stitching material and the fact that it has minimal negative effects. Silk fibroin, the primary constituent of silk produced by silkworms, functions in a coordinated manner to promote wound healing. It exerts control over cellular processes on both a macroscopic and molecular scale. By activating a pathway known as NF-κB (Nuclear Factor kappa-light-chain-enhancer of activated B cells) signaling, silk fibroin accelerates the healing process. This signalling mechanism is crucial for various cellular activities, such as cell adhesion, proliferation, and anti-inflammatory responses.²¹⁴

Tatlisulu et al. (2024) explored the use of honeybee silk (HS) as an alternative to silkworm silk in tissue engineering (TE) applications. Their research revealed the potential of HS, a previously unexplored material, for TE purposes, paving the way for new research directions. The study findings, based on the materials employed and the favorable results obtained, indicate that the developed CH-HS scaffold displays antibacterial qualities and exhibits cellular characteristics. These discoveries hold promise for additional biomedical applications, particularly in the realm of wound healing.²¹⁵ In another study, a natural hydrogel composed of silk fibroin (SF) and soybean protein isolate (SPI) was prepared using the main components. To enhance the bioactivity of the hydrogel, quercetin was incorporated to create an SF/SPI-Q hydrogel. The resulting hydrogel was effective in accelerating wound healing in an infected burn wound model as shown in Fig. 6. The SF/SPI-Q hydrogels promoted the re-epithelialization process, collagen synthesis, and neovascularization in burn wounds. Additionally, they exhibited anti-inflammatory effects that further helped reduce inflammation. Therefore, the SF/SPI-Q hydrogels have the potential to be one of the most effective treatments for wound healing.⁸²

Fig. 6 (A) Effect of different treatments on chorioallantoic membrane (CAM)-trypan blue stained assay CAM. A−: negative control (0.9% NaCl solution); A+: positive control (0.1 M NaOH). (B) The amount of trypan blue adsorbed on CAM after different treatments. (C) Hemolysis ratio of quercetin, silk fibroin (SF)/soybean protein isolate (SPI), SF/SPI-quercetin (Q) 10%, SF/SPI-Q 20% and SF/SPI-Q 30% hydrogels; A−: negative control (0.9% NaCl solution); A+: positive control (H₂O). Reproduced from ref. 82 with permission from Elsevier, copyright 2024.

A study was conducted by Shuiqing and their colleagues to construct a scaffold using silk fibroin nanofibers films (SNF) to promote wound healing and prevent scar formation. The scaffold was engineered to resemble the extracellular matrix of the skin, and the resulting silk film exhibited greater mechanical strength and hydrophobicity, protecting the wound and dermis from external stimuli. Additionally, the scaffold displayed improved water uptake, which facilitated moisture retention at the wound site. This feature, along with the scaffold's resemblance to the components of normal epidermis and dermis, inhibited scar formation. In vitro and in vivo studies confirmed the scaffold's effectiveness in promoting tissue regeneration and preventing scar formation²¹⁶ as exhibited in Fig. 7.

Fig. 7 Observations of wound healing and scarring in the rabbit ear, after treatment with different artificial grafts. (A) Scheme of scaffold application in a rabbit ear wound model, (B) wound changes, including control (untreated), SNF films, and SNF-silk fibroin (SF)-hyaluronic acid (HA) scaffold, (C) wound closure time, (D) scar elevation index. Reproduced from ref. 216 with permission from Elsevier, copyright 2024.

Silk sericin based hydrogels with plant extracts were synthesized by Zahoor and coworkers. They studied their efficacy in promoting wound healing in mice with alloxan-induced diabetes. Researchers produced 6 mm excision wounds and then applied topical hydrogel treatments. Results indicated that all hydrogel-treated groups showed significantly higher wound contraction from day 3 to day 11 compared to the negative control, with the 4% sericin + 4% banyan + 4% onion hydrogel performing best as shown in Fig. 8. Serum levels of anti-inflammatory cytokine Interleukin-10 and tissue inhibitor metalloproteinase (TIMP) were significantly higher in the hydrogel groups, while pro-inflammatory cytokines tumour necrosis factor-α and Interleukin-6, and matrix metalloproteinases MMP (matrix metalloproteinases)-2 and MMP-9, were significantly lower.²¹⁷ Silk fibroin hydrogels show potential as burn wound dressings due to their regenerative properties, but difficult gelation conditions limit their clinical application. Sushma Indrakumar and his colleagues employed a white light-responsive photopolymerization technique for gelation through tyrosine photooxidation. A silk fibroin gel-incorporated dressing (SFD) was developed to fit irregular burn surfaces. The mild gelation conditions enabled drug incorporation for localized delivery. The dressing demonstrated favourable swelling capacity and moisture retention. In vitro, cytocompatibility was assessed using HaCaT cells, and in vivo performance was evaluated on a rodent model with a second-degree burn, showing scarless healing in SFD-treated groups via gross and histological analyses. The SFD developed in this study shows promise as an advanced burn wound care solution.²¹⁸

Fig. 8 Wound healing area at different post-wounding days in mice of (A) negative control; (B) positive control; (C) sericin based treatment group; (D) sericin + banyan based treatment group; (E) sericin + onion based treatment group and (F) sericin + banyan + onion based treatment group. Reproduced from ref. 217 with permission from Elsevier, copyright 2023.

A study revealed that sericin, a bio-waste product derived from the degumming of silk cocoons, effectively exfoliates the MoS₂ layers, resulting in improved dispersity and stability of MoS₂ nanosheets (MoS₂-NSs). MoS₂-NS/Sericin maintains its photothermal properties when illuminated by an 808 nm light source, exhibits strong antibacterial activity, and accelerates wound healing by promoting fibroblast migration. In vitro experiments have shown that MoS2-NS/Sericin scavenges reactive oxygen species (ROS) during the inflammatory stage of wound healing and transforms M1-type macrophages into M2-type, which supports recovery. Full-thickness skin wound tests conducted on rats demonstrated that MoS₂/Sericin, under 808 nm irradiation, optimally promotes wound healing. Consequently, MoS₂-NS/Sericin holds significant potential for treating bacteria-infected wounds.²¹⁹

Regenerated silk, derived from protein extracted from Bombyx mori silkworm cocoons, exhibits numerous desirable properties. These include high transparency, compatibility with biological systems, ability to degrade naturally, and suitability for modification with optically active nanoparticles and biochemical markers. Its porous structure facilitates the transfer of nutrients and oxygen while also providing protection against bacterial infections in wounds, making it an ideal material for wound dressing applications. Various chemical and physical cues can enhance the bioactivity of silk fibroin (SF) wound matrices, simultaneously optimizing these cues is challenging due to their complex interactions during the fabrication process.^220–222 A recent study explored a biodegradable silk-curcumin composite for extended drug release in wound treatment. The study found that curcumin integrated into the silk surface exhibited sustained release for 10 days, significantly outperforming traditional wound care drug delivery systems. The silk's superhydrophobic nature prevented wound wetting, while its pH sensitivity allowed for visual monitoring of wound healing progress.²²³ Another study utilized β-Sheet β-rich silk nanofiber (BSNFs) and amorphous silk nanofibers to create bioactive matrices with various cues optimized through aqueous media self-assembly.^224,225 Additionally, BSNFs were employed to develop an anisotropic gel under electric field influence. Nerve growth factors (NGF) were immobilized within this hydrogel to fabricate bioactive systems, providing multiple physical and biological cues for addressing spinal cord injuries.²²⁶ Similarly, researchers designed a silk fibroin-based matrix with adjusted hierarchical microstructures and introduced various physical cues. An anisotropic porous scaffold was created using silk fibroin nanofibers under an electric field. This engineered nanomaterial demonstrated improved cell migration, leading to more effective wound healing.²²⁷ The incorporation of Desferrioxamine (DFO) into a silk nanofiber hydrogel, demonstrated prolonged drug release over a 40-day period. Both in vitro and in vivo analyses revealed improved endothelial cell migration and gene expression, along with a decrease in inflammatory macrophages.²²⁸ In a similar study, Sang and colleagues developed scaffolds with a microstructure resembling the extracellular matrix, using amorphous silk fibroin. These scaffolds showed potential for tissue repair and regenerative medicine applications.²²⁸ Gang and coworkers engineered scaffolds using β-sheet rich silk nanofiber infused with deferoxamine. They combined deferoxamine-loaded BSNF with amorphous silk nanofibers (ASNFs) under an electric field to create a uniform mixture. This novel scaffold exhibited enhanced wound healing efficacy in both in vitro and in vivo.²²⁹

Bari et al. investigated silk sericin (SS) microparticles for non-surgical intervertebral disk degeneration treatment, enhancing SS with growth factors, platelet lysate (PL), and platelet-poor plasma (PPP). Spray-drying produced smooth microparticles, and the PL and PPP combination promoted nucleus pulposus cell growth. SS microparticles, with or without PPP, exhibited antioxidant properties by reducing reactive oxygen species (ROS). Co-incubating SS microparticles with PL protected nucleus pulposus cells from hydrogen peroxide-induced oxidative stress. This indicates that SS microparticles with PL + PPP are promising for non-invasive drug delivery in regenerative medicine and wound treatment.²³⁰ Karaly et al. developed an aerosolized nano-powder using Avicenna marina extract and neomycin-loaded SF nanoparticles for wound healing. The extract exhibited antioxidant, antibacterial, and cell proliferation properties, effectively combating various bacterial strains. In vitro and in vivo studies demonstrated superior wound healing, achieving complete closure within 24 hours in fibroblast scratch assays and enhancing fibroblast proliferation while reducing inflammation in rodent models, suggesting its potential for wound healing applications.²³¹

4.5. Zein based materials

Zein, a cost-effective amphiphilic prolamine,²³² is an excellent candidate for wound healing applications due to its inherent characteristics such as non-toxicity, non-inflammatory stimulation, biodegradability, flexibility, and biocompatibility.^233,234 Moreover, zein based wound care materials have unique features, including resistance to water, heat, abrasion, and humidity, make them an attractive option for a range of biomedical applications^232,235,236 for wound care applications (Table 6).

Table 6 Zein derived materials for wound care applications

Material	Composition	Active ingredient	Method	Animal tested	Wound size	Healing time	Notable findings	Ref.
N.A: not available.
Hydrogel	Pectin	Doxorubicin	Liquid–liquid dispersion method	N/A	N. A	N. A	Controlled release of Doxorubicin	248
Zein solution	Propylene glycol alginate	Curcumin	Hydrogen bonding	—	N. A	N. A	Sustained release of curcumin	249
Zein solution	Polyacrylate, glycerin	β-Carotene	Hydrogen bonding, hydrophobic interactions	Female Sprague-Dawley rats	—	21 days	Promotion of wound healing and collagen synthesis	250
Zein nanoparticles	Glycerin	Quercetin	Electrostatic interactions	N/A	—	N/A	Delivery and controlled release Higher % encapsulation efficiency	251
Emulsion gel	Sodium alginate	Curcumin and resveratrol	Electrospinning	—	—	—	Encapsulation of nutrients	252
Membrane nanoparticles	Oleic acid, pectin	^253—	Solvent evaporation	—	—	—	The viscous behavior of pectin was changed	253
Nanoparticles	Chitosan-polyvinyl alcohol, Fe^3+	Gentamicin	Liquid–liquid dispersion method, imine bond	E. coli (K12) and S. aureus (ATCC 96)	—	—	Synergistic antibacterial effect, against drug-resistant bacteria.	254
Nanofilm	Zein prolamine, tea carbon spot, CaO2	Ir-Zein protien	Electrospinning	Male Sprague-Dawley (SD) rats	15 mm	10 days	A versatile antibacterial wound dressing, promoted diabetic wound healing	243
Zein nanofiber	Zein/CeNP1%, 3%, and 5% NFs	Cerium oxide nanoparticles	Electrospinning	E. coli, Pseudomonas aeruginosa, and Staphylococcus aureus	—	—	Significant mechanical, antioxidant, and cytotoxicity properties	255
Nanofiber	Zein protein and tungsten oxide	Tungsten oxide	Electrospinning	Melanoma cell lines	—	—	Promising and safe candidate for anticancer applications	256

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Using phase separation methodology, Lu et al. developed ivermectin (IVM)-loaded zein microspheres with an average diameter of 1 μm. The researchers proposed these zein microspheres as potential nanocarriers, noting that their dimensions were suitable for macrophage uptake. The study concluded that the sustained-release properties of zein microspheres could be beneficial in creating scaffolds that promote cell growth and tissue engineering. Zein-based composites have diverse applications, including drug delivery systems, tissue engineering, bone reconstruction, and wound repair.²³⁷ In a related investigation on biomimetic mineralization, Yao et al. conducted a study where hydroxyapatite (HA) nanocrystals were formed on zein fibers produced through electrospinning. The researchers reported that the HA crystals were irregularly dispersed on the nanofibers, and these biomineralized structures had a beneficial effect on osteoblast proliferation. Additionally, Zhang et al. explored the formation of calcium phosphate using zein as a template and examined the process of biomineralization at the interface between air and concentrated simulated body fluid (SBF).²³⁸ Studies have shown that applying a continuous calcium phosphate layer to pure zein film enhances its mechanical properties, including hardness and modulus. Additionally, research indicates that zein films with biomineralization are excellent for supporting fibroblast cell attachment, multiplication (Fig. 9), and development, owing to their water-attracting nature and mechanical characteristics. These films also have potential applications as a biometric scaffold in bone tissue regeneration.

Fig. 9 Fluorescence micrographs of the fibroblast cells that were cultured for 7 days on (a) the pure zein film and zein/minerals films biomimetic mineralized for (b) 0.5 h, (c) 1 h, and (d) 2 h. Reproduced from ref. 238 with permission from the American Chemical Society, copyright 2013.

Studies on zein composites have explored combining zein with other substances to enhance matrix properties. Zhang et al. used zein as an additive to impart antibacterial qualities, creating a zein protein composite by mixing it with silver nanoparticles. They found no significant difference in the effects on Escherichia coli and Staphylococcus aureus between silver nanoparticle composites and silver alone. However, silver samples with acidified zein showed superior bacterial inhibition. The study suggested that zein improves hemocompatibility and broadens wound care applications. To avoid potential toxicity, the silver content in the composite must be optimized.²³⁹

Agnes Gagliardi and colleagues developed a biocompatible, eco-friendly gel composed of zein loaded with rutin. They assessed its efficacy in vitro and in vivo for treating burns and sores compared to DuoDERM®. The gel showed improved migration and rapid gap closure within 24 hours in vitro, and a 90% reduction in wound area within 10 days in vivo in Wistar rats, outperforming both the free form and standard gel. Additionally, the gel significantly reduced inflammatory markers like TNF-α, IL-1β, IL-6, and IL-10.²⁴⁰ Similarly, Momgain et al. developed zein nanoparticles incorporating Moringa oleifera leaf extracts via nanoprecipitation for wound treatment. They optimized the formulation, prepared a gel, and characterized it for pH, spreadability, extrudability, and homogeneity. Testing in an animal model demonstrated significant wound healing activity. The study suggested Moringa oleifera leaves as a superior intervention for wound healing over other oral or topical extracts, indicating zein-loaded Moringa oleifera extract's potential as a diabetic wound healing agent.²⁴¹

A study conducted by Gabriela et al. utilized electrospinning to prepare zein nanofibers reinforced with graphene oxide, enhancing their mechanical properties. The team incorporated various concentrations of curcumin into these GO-strengthened nanofibers to boost bioavailability, adhesion, and oxygenation. In vitro testing of this curcumin-loaded GO-Zein nanofiber composite showed improved safety, with evidence of cell growth throughout the fiber structure. The engineered nanofibers displayed a biphasic release pattern in vitro, suggesting cell proliferation. However, the effectiveness of these nanofibers in living organisms remains to be investigated.²⁴² Lenian Zhou and colleagues developed zein proteins with hydrophilic and hydrophobic properties, loaded with CaO₂/carbon dots (CD), for improved healing of diabetic wounds. The modified zein film with irradiated (Ir-Zein) calcium oxide nanoparticles and carbon dots used as a wound dressing demonstrated remarkable effectiveness in accelerating the healing of diabetic wounds. The study demonstrated the effectiveness of the CaO₂/CD@Ir-Zein film in enhancing the progression of chronic wounds from the inflammatory stage to skin repair²⁴³ as shown in Fig. 10.

Fig. 10 In vivo assessment of CaO₂/CD@Ir-Zein for diabetic wound healing in rat. (A) The representative images of full-thickness skin wounds after treatment with control, Ir-Zein, CD@Ir-Zein, and CaO₂/CD@Ir-Zein. (B) Change of wound closure percentages with time. (C) H&E staining of the wound on day 10. (D) Quantitative analysis of scar widths in re-epithelialization. (E) Masson's trichrome staining of tissue regeneration within the wound on day 10. (F) Quantitative analysis of mean intensity. Reproduced from ref. 243 with permission from Elsevier, copyright 2024.

Nasrin Salehi and colleagues developed curcumin-loaded zein nanofibers as a wound dressing with poly(sodium 4-styrene sulfonate) serving as a polyanion and poly(diallyldimethylammonium chloride) (PDADMAC) acting as a polycation, using electrospun nanofibers. The designed nanofiber facilitated the controlled release of curcumin, which exhibited antioxidant activity, and the PDADMAC demonstrated antibacterial properties. The nanofiber also exhibited better cell migration and adhesion, and cell attachment.²⁴⁴

Moiz Uddin Khan and his fellow researchers developed an innovative invasive thermo-responsive hydrogel that combines glycerophosphate and biologically active zein for tissue engineering applications. Chitosan (CS) and hydroxyapatite (HA) were used to fabricate the gel. The gel exhibited a solution phase between 4 to 10 °C and transitioned to a gel at body temperature within 4 to 6 minutes. The gel's mechanical strength (52.2 MPa at 40% strain) was significantly enhanced by the addition of zein, and it demonstrated good injectability and ease of shaping into complex structures for treatment.²⁴⁵

Zein scaffolds were transformed into fibrous structures resembling the extracellular matrix using electrospinning. The zein scaffold was crosslinked with trimethylpropane triglycidyl ether and then evaluated for human mesenchymal stem cell (MSC) adhesion, growth, and infiltration into the scaffold in vitro. The study revealed that the plant-derived zein scaffold was a potential carrier for MSCs for tissue engineering applications, offering an alternative to animal-derived gelatin protein-based carriers.²⁴⁶ Biopolymer-based films, such as chitosan and zein, may be more effective than conventional bandages in promoting wound healing. These films can store and release beneficial molecules like ellagic acid to combat infection and promote healing over time. The films demonstrated bactericidal and fungicidal properties against samples of bacteria and fungi while retaining their elasticity and comfort. Additionally, one of the formulations showed an accelerated wound healing rate in animal models, reducing inflammation, and could be a promising candidate for future wound dressings.²⁴⁷

4.6. Albumin based materials

Albumin is a protein found in large quantities in the bloodstream, making it a promising option for various therapeutic uses, such as wound healing. This is due to its inherent properties, including non-immunogenicity, biocompatibility, and antibacterial characteristics, as well as its ability to promote angiogenesis.^257–259 The studies have shown that albumin-based nano-materials have either gone through clinical trials or have already obtained FDA approval.²⁶⁰ The use of albumin, which is both hydrophilic and hydrophobic, makes it a safer and non-toxic option for encapsulating drugs as a biocompatible nanocarrier.^261–263 The albumin nanoclusters were reported by the incorporation of diethylenetriamine diazeniumdiolate (DT/NO) through electrostatic interaction and cross-linking. These nanoclusters were capable of releasing nitric oxide and exhibited a prominent anti-bacterial effect against methicillin-resistant Staphylococcus aureus (MRSA)-infected wounds. Additionally, the nanoclusters showed a remarkable in vivo anti-bacterial effect, which enhanced wound healing in an MRSA-challenged wound mouse model. The amount of NO released was sufficient to ensure the effectiveness of the nanoclusters against MRSA-infected wounds²⁶⁴ as exhibited in Fig. 11.

Fig. 11 Histological assessments. (a) Representative microscopic images of the tissue sections treated with or without NO/ANCs, ANCs, and DT/NO after H&E staining. (b) Representative microscopic images of the tissue sections after Masson's trichrome staining. The scale bar represents 200 μm. Reproduced from ref. 264 with permission from Springer Nature, copyright 2024.

Fatemeh Saadat prepared nanofibers containing albumin and caffeine to enhance wound healing. The application of these nanofibers to wounds resulted in improved blood flow to the affected area, thus speeding up the recovery process. The study found that caffeine played a crucial role in stimulating the growth of new blood vessels in the skin, which led to more effective wound closure.²⁶⁵ In another study, Mohammed A. Naseer and fellows designed albumin based composite material with greater biodegradability and biocompatibility for enhanced wound healing applications. Novel sutures were designed using extrusion method from human albumin serum. Promising results were obtained from physicochemical and mechanical tests of the designed suture. The designed suture is proposed to be used as a 3D filament to design custom scaffolds.²⁶⁶ Furthermore, Elias Madadian and colleagues have developed a hybrid foam for use as a wound dressing. Sodium alginate and albumin were used as the main components, with calcium chloride mist serving as a cross-linking agent. The researchers employed rhodamine B as their model drug in the study. The designed scaffold underwent porosity, degradation, mechanical, and drug release tests. The results showed exceptional mechanical properties and sustained drug release. Additionally, they found that altering the concentrations of sodium alginate, albumin, and the crosslinking agent could regulate the drug release.²⁶⁷ A study conducted by Neives Vanaclocha et al. discovered that individuals with higher serum prealbumin levels experienced improved re-epithelialization and wound healing compared to those with lower prealbumin levels. Patients with higher prealbumin levels demonstrated a shorter time to full wound recovery and were found to be an independent predictor of successful graft outcomes.²⁶⁸ Adnan and his colleagues developed a hydrogel comprised of bovine serum albumin-riboflavin retinoic acid. This bovine serum albumin (BSA)-riboflavin retinoic acid (BHG) hydrogel increased the expression of the transglutaminase-2 enzyme, leading to improved epithelial cell regeneration and Wnt-B-caretin signaling, which promotes stromal cell growth. The study showed promise for healing wounded corneas and could be further explored for wound healing and progenitor cell remodeling in an in vivo model.²⁶⁹ Recently Jia and fellows²⁷⁰ developed human serum albumin-Zn-vascular endothelial growth factor (HMS-Zn@VEGF) microspheres, integrating antibacterial and angiogenic human serum albumin to address infected wounds. In vitro experiments showed total bacterial elimination with one application, while rat studies demonstrated fast wound healing via decreased inflammation, improved collagen production, and enhanced angiogenesis (eee Fig. 12). VEGF was successfully loaded onto the microspheres through HSA adsorption on zinc ions and His-tagged VEGF crosslinking. The microspheres displayed potent, broad-spectrum antibacterial activity and promoted neovascularization, confirming their biocompatibility, antimicrobial efficacy, and angiogenic properties, indicating their potential as an infected wound treatment.

Fig. 12 HMS-Zn@VEGF promoted healing of infected wounds in rats (a) representative pictures of different treatment groups on days 0, 3, 6, 9, 12, and 15. The scale bar is 50 mm. (b) H&E staining of the wound. The scale bar is 1000 μm. (c) Mockup of wound healing. (d) Healing curves of infected wounds in each group of rats. (e) Quantitative statistics on wound width. Reproduced from ref. 270 with permission from Elsevier, copyright 2024.

Moreover, researchers have synthesized a wound dressing that accelerates the healing of diabetic wounds by using a composite hydrogel containing bovine serum albumin and aloe vera. This hydrogel is unique due to its porous structure, self-fluorescence, and biocompatibility, which were achieved without adding any toxic chemicals or dyes. In preclinical studies, this hydrogel showed promising results in promoting collagen synthesis and angiogenesis, leading to faster healing. Additionally, this hydrogel can be 3D printed for customized wound care treatments.²⁷¹

5. Challenges and future perspectives

Protein-derived wound care materials face several challenges. The lack of preclinical research and limitations in biomimetic wound dressings pose significant problems. Regulating the breakdown rate of biomimetic substances is also challenging. While these dressings aim to create a moist healing environment, their ability to retain moisture can fluctuate greatly, potentially causing the wound bed to become excessively dry or waterlogged.^77,272 Additionally, the elastic and strength properties of these dressings may not always meet the specific needs of the wound site. The intricate production processes raise concerns about consistency between batches, which is crucial for ensuring reproducible clinical outcomes. Inconsistencies in manufacturing can undermine the reliability and effectiveness of these dressings in wound healing.^273,274

A further crucial issue is the long-term safety and biocompatibility of protein derived materials used in wound healing and dressings. Despite their promising potential for wound care applications, it is vital to confirm their compatibility with biological systems and establish a comprehensive safety profile for successful clinical use.^275,276 Finally, there is an urgent need for more comprehensive clinical trials to fully determine the efficacy and safety of wound dressings. Although preclinical studies and early-stage clinical trials often show promising results, the transition to routine clinical application can reveal unexpected complications, such as allergic responses, increased infection risks, or long-term biocompatibility issues.²⁷⁷

The field of wound healing has seen remarkable progress due to innovations in protein based materials. Various techniques for creating protein derived wound care products yield specific forms and notable advantages for different wound types. These materials are excellent in facilitating the biochemical processes necessary for wound repair. Research indicates that variations in cellular shape, movement, specialization, and survival significantly impact the healing process.^278,279 It is anticipated that next-generation wound care technologies incorporating advanced proteins will precisely track crucial healing indicators, such as oxygen concentration and heat, and make appropriate modifications. These innovative devices are expected to relay collected data to medical professionals for further evaluation.

Despite progress, challenges persist in the field of protein-based wound care technologies. To achieve efficient and cell-specific transformation, these technologies require refinement without causing any adverse effects. Optimal wound healing treatments should enable precise, autonomous delivery of multiple molecules at the wound site to speed up the healing process. Advancements necessitate identifying specific wounds, protein mechanism of action and developing materials with adjustable properties. Continued research in this field is crucial for the development of translational wound care materials and their applications. Prospect studies should emphasize developing methods and mechanistic insights to produce different forms of wound care materials from abundant protein resources. Only a small number of protein based wound dressings have made it to the commercialization stage, despite substantial research on the use of proteins in wound healing applications. The majority of research on proteins in wound healing has primarily focused on their ability to promote cell migration and their antimicrobial properties. Nevertheless, there is a lack of research on multifunctional smart systems derived from proteins, especially regarding smart dressings that demonstrate specific stimulus-responsive behaviors. In the future, the focus should be on developing intelligent systems substantiated by understanding healing and infection mechanisms, particularly in the context of chronic wounds. These systems can potentially showcase the effectiveness of proteins in promoting the healing process.

6. Summary

Protein derived wound care materials are frequently utilized and have the potential to replace traditional materials due to their hydrophilic properties, biodegradability, abundance in nature, and ease of access. Considering the numerous forms of skin injury, such as burns, abrasions, tears, and diseases, the appropriate type of wound and the protein derived materials employed for treatment should be determined based on the specific type of damage. There are many proteins available to transform into wound care materials. However, keratin, collagen, gelatin, zein, albumin and silk are the most studied proteins for wound care management. The development of advanced wound dressings necessitates the utilization of sophisticated techniques, such as electrospinning, phase separation, self-assembly, and ball milling, which are intended to promote tissue regeneration and minimize the risk of infection. Studies have shown that incorporating proteins with other polymeric materials improves their characteristics, making them appropriate for application in advanced wound care products. These attributes include antibacterial and antifungal hydrogels, nanofibrous hydrogels, and bilayer wound dressings, all of which exhibit improved healing, cell viability, and antimicrobial activity. In the future, it is anticipated that proteins will become more widely available in medical markets, with doctors recommending their use for a range of wound care applications. However, we will require collaborative action from a diverse group of professionals, including researchers, medical practitioners, pharmacists, biochemists, and government officials to achieve this goal.

Author contributions

Muhammad Zubair: conceptualization, writing – original draft, – review & editing. Saadat Hussain: writing. Mujeeb-ur-Rehman: writing and reviewing, Ajaz Hussain: writing and reviewing. Muhammad Ehtisham Akram: writing. Sohail Shahzad: writing and reviewing, Zahid Rauf: writing and editing, Maria Mujahid: writing, Aman Ullah: supervision, review & editing.

Data availability

This review article is based on previous studies that have been already reported. Therefore, there are no new data to reveal. All referenced studies have been properly cited, showing respect for the intellectual property of their original authors.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the use of Paperpal for paraphrasing assistance in the preparation of this review article, which helped improve the clarity and coherence of the text.

References

1. A. Sharma, D. Sharma and F. Zhao, Adv. Healthcare Mater., 2023, 12, 2300556.
2. L. Su, Y. Jia, L. Fu, K. Guo and S. Xie, Heliyon, 2023, e22520.
3. G. C. Gurtner, S. Werner, Y. Barrandon and M. T. Longaker, Nature, 2008, 453, 314–321.
4. C. K. Sen, Adv. Wound Care, 2021, 10, 281–292.
5. A. Markiewicz-Gospodarek, M. Kozioł, M. Tobiasz, J. Baj, E. Radzikowska-Büchner and A. Przekora, Int. J. Environ. Res. Public Health, 2022, 19, 1338.
6. W. Huang, Y. Wang, Z. Huang, X. Wang, L. Chen, Y. Zhang and L. Zhang, ACS Appl. Mater. Interfaces, 2018, 10, 41076–41088.
7. S.-K. Han, in Innovations and Advances in Wound Healing, Springer, 2023, pp. 1–42.
8. T. Velnar, T. Bailey and V. Smrkolj, J. Int. Med. Res., 2009, 37, 1528–1542.
9. E. M. Tottoli, R. Dorati, I. Genta, E. Chiesa, S. Pisani and B. Conti, Pharmaceutics, 2020, 12, 735.
10. M. Mirhaj, S. Labbaf, M. Tavakoli and A. M. Seifalian, Int. Wound J., 2022, 19, 1934–1954.
11. B. Balakrishnan, M. Mohanty, P. Umashankar and A. Jayakrishnan, Biomaterials, 2005, 26, 6335–6342.
12. E. Rezvani Ghomi, S. Khalili, S. Nouri Khorasani, R. Esmaeely Neisiany and S. Ramakrishna, J. Appl. Polym. Sci., 2019, 136, 47738.
13. M. Farahani and A. Shafiee, Adv. Healthcare Mater., 2021, 10, 2100477.
14. B. Gupta, R. Agarwal and M. Alam, Indian J. Fibre Text. Res., 2010, 174–187.
15. J.-S. Jeon, H.-T. Kim, M.-G. Kim, M.-S. Oh, S.-R. Hong, M.-H. Yoon, H.-C. Shin, J.-H. Shim, N. A. Afifi and A. Hacımüftüoğlu, Chromatographia, 2016, 79, 851–860.
16. C. Wei, S. Xing, Y. Li, M. Koosha, S. Wang, H. Chen, Y. Zhai, L. Wang, X. Yang and R. Fakhrullin, Int. J. Biol. Macromol., 2024, 261, 129720.
17. V. Reisi-Vanani, S. Hosseini, E. Soleiman-Dehkordi, S. N. Boroujeni, M. Farzan, V. V. Ebani, M. Gholipourmalekabadi, K. Lozano and Z. Lorigooini, J. Drug Delivery Sci. Technol., 2023, 81, 104282.
18. M. Gong, H. Shi, Z. Hu, F. Wang, M. Dong, R. Lei, Z. Zeng, Y. Wang and J. Chen, Chem. Eng. J., 2023, 473, 145394.
19. X. Wang, J. Wu, M. Wang, C. Lu, W. Li, Q. Lu, Y. Li, B. Lian and B. Zhang, J. Biomed. Mater. Res., 2023, 111, 404–414.
20. Y. Jia, Y. Han, Y. Zhang, L. Li, B. Zhang and X. Yan, Regener. Ther., 2024, 27, 329–341.
21. L. K. Sellappan and S. Manoharan, Int. J. Biol. Macromol., 2024, 259, 129162.
22. T. Zhao, N. Wang, Y. Wang, J. Yang, Y. Tang, Y. Wang, H. Wei, J. Yang, T. Yu and X. Sun, Int. J. Biol. Macromol., 2024, 135724.
23. Y. Long, M. Bai, X. Liu, W. Lu, C. Zhong, S. Tian, S. Xu, Y. Ma, Y. Tian and H. Zhang, Carbohydr. Polym., 2022, 297, 119974.
24. W. Wei, Y. Ma, X. Yao, W. Zhou, X. Wang, C. Li, J. Lin, Q. He, S. Leptihn and H. Ouyang, Bioact. Mater., 2021, 6, 998–1011.
25. R. A. M. Osmani, E. Singh, K. Jadhav, S. Jadhav and R. Banerjee, in Applications of Advanced Green Materials, Elsevier, 2021, pp. 573–630.
26. A. Basit, H. Yu, L. Wang, M. A. Uddin, Y. Wang, K. M. Awan, B. E. Keshta and M. O. Malik, Eur. Polym. J., 2024, 113260.
27. M. R. Alam, M. A. Shahid, S. Alimuzzaman and A. N. Khan, Biomed. Eng. Adv., 2022, 4, 100064.
28. V. Gounden and M. Singh, Gels, 2024, 10, 43.
29. A. Sadeghianmaryan, N. Ahmadian, S. Wheatley, H. A. Sardroud, S. A. S. Nasrollah, E. Naseri and A. Ahmadi, Int. J. Biol. Macromol., 2024, 131207.
30. G. Satchanska, S. Davidova and P. D. Petrov, Polymers, 2024, 16, 1159.
31. H. Zhang, X. Lin, X. Cao, Y. Wang, J. Wang and Y. Zhao, Bioact. Mater., 2024, 33, 355–376.
32. P. C. Pires, F. Damiri, E. N. Zare, A. Hasan, R. E. Neisiany, F. Veiga, P. Makvandi and A. C. Paiva-Santos, Int. J. Biol. Macromol., 2024, 130296.
33. S. Cai, C. Wu, W. Yang, W. Liang, H. Yu and L. Liu, Nanotechnol. Rev., 2020, 9, 971–989.
34. M. N. Uddin, M. Jobaer, S. I. Mahedi and A. Ali, J. Text. Inst., 2023, 114, 1592–1617.
35. D. Ji, Y. Lin, X. Guo, B. Ramasubramanian, R. Wang, N. Radacsi, R. Jose, X. Qin and S. Ramakrishna, Nat. Rev. Methods Primers, 2024, 4, 1.
36. M. Ahmadi Bonakdar and D. Rodrigue, Macromol, 2024, 4, 58–103.
37. A. Moreira, D. Lawson, L. Onyekuru, K. Dziemidowicz, U. Angkawinitwong, P. F. Costa, N. Radacsi and G. R. Williams, J. Controlled Release, 2021, 329, 1172–1197.
38. M. Hayat, S. A. R. Bukhari and M. Irfan, Biotechnol. J., 2023, 2300279.
39. A. Miserez, J. Yu and P. Mohammadi, Chem. Rev., 2023, 123, 2049–2111.
40. A. Akhmetova and A. Heinz, Pharmaceutics, 2020, 13, 4.
41. Z. Terzopoulou, A. Zamboulis, I. Koumentakou, G. Michailidou, M. J. Noordam and D. N. Bikiaris, Biomacromolecules, 2022, 23, 1841–1863.
42. E. Zdraveva, V. Gaurina Srček, K. Kraljić, D. Škevin, I. Slivac and M. Obranović, Polymers, 2023, 15, 2684.
43. M. Pandian, G. Reshma, C. Arthi, M. Másson and J. Rangasamy, Eur. Polym. J., 2023, 198, 112390.
44. P. Farshi, S. N. Mirmohammadali, B. Rajpurohit, J. S. Smith and Y. Li, J. Agric. Food Res., 2023, 100927.
45. M. Raeisi, M. A. Mohammadi, V. Bagheri, S. Ramezani, M. Ghorbani, M. Tabibiazar, O. Coban, R. Khoshbakht, S. Marashi and S. Noori, Biointerface Res. Appl. Chem., 2023, 13, 486.
46. A. Fatima, S. Adeel, M. A. Qayyum and H. A. Tanveer, in Biopolymers in the Textile Industry: Opportunities and Limitations, Springer, 2024, pp. 273–313.
47. M. A. M. Fathil and H. Katas, Pharmaceutics, 2023, 15, 991.
48. Z. Zhang, Y. Zhang, Y. Guo, C. Qian, K. Chen, S. Fang, A. Qiu, L. Zhong, J. Zhang and R. He, J. Biomater. Appl., 2024, 39, 48–57.
49. X. Cao, Y. Ren, Q. Lu, K. Wang, Y. Wu, Y. Wang, Y. Zhang, X.-s. Cui, Z. Yang and Z. Chen, Front. Nutr., 2023, 9, 1018336.
50. C. Coccolini, E. Berselli, C. Blanco-Llamero, F. Fathi, M. B. P. Oliveira, K. Krambeck and E. B. Souto, Int. J. Pept. Res. Ther., 2023, 29, 71.
51. Z. Jiang, Z. Zheng, S. Yu, Y. Gao, J. Ma, L. Huang and L. Yang, Pharmaceutics, 2023, 15, 1829.
52. C. Yang, Z. Zhang, L. Gan, L. Zhang, L. Yang and P. Wu, Int. J. Mol. Sci., 2023, 24, 7319.
53. F. Chen, X. Li, Y. Yu, Q. Li, H. Lin, L. Xu and H. C. Shum, Nat. Commun., 2023, 14, 2793.
54. Y. Yang, Y. Ru, T. Zhao and M. Liu, Chem, 2023, 3113–3137.
55. A. R. Calore, V. Srinivas, L. Groenendijk, A. Serafim, I. C. Stancu, A. Wilbers, N. Leoné, A. A. Sanchez, D. Auhl and C. Mota, Acta Biomater., 2023, 156, 158–176.
56. X. Peng, Y. Li, T. Li, Y. Li, Y. Deng, X. Xie, Y. Wang, G. Li and L. Bian, Adv. Sci., 2022, 9, 2203890.
57. L. Hu, S. Zhou, X. Zhang, C. Shi, Y. Zhang and X. Chen, Polymers, 2024, 16, 2097.
58. Y. Nie, X. Han, Z. Ao, S. Ning, X. Li and D. Han, Mater. Chem. Front., 2021, 5, 7022–7031.
59. J. Huang, X. Lei, Z. Huang, Z. Rong, H. Li, Y. Xie, L. Duan, J. Xiong, D. Wang and S. Zhu, Int. J. Bioprint., 2022, 8, 517.
60. Y. Xu, Q. Hu, Z. Wei, Y. Ou, Y. Cao, H. Zhou, M. Wang, K. Yu and B. Liang, Biomater. Res., 2023, 27, 36.
61. F. Wang, C. Yang and X. Hu, in Lightweight Materials from Biopolymers and Biofibers, ACS Publications, 2014, pp. 177–208.
62. Y. Hu, H. Shi, X. Ma, T. Xia, Y. Wu, L. Chen, Z. Ren, L. Lei, J. Jiang and J. Wang, Acta Biomater., 2023, 159, 128–139.
63. P. T. Smith, B. Narupai, J. H. Tsui, S. C. Millik, R. T. Shafranek, D.-H. Kim and A. Nelson, Biomacromolecules, 2019, 21, 484–492.
64. A. Sola, A. Trinchi and A. J. Hill, Smart Mater. Manuf., 2023, 1, 100013.
65. N. Falcone, M. Ermis, D. G. Tamay, M. Mecwan, M. Monirizad, T. G. Mathes, V. Jucaud, A. Choroomi, N. R. de Barros and Y. Zhu, Adv. Healthcare Mater., 2023, 12, 2301096.
66. T. Guan, J. Li, C. Chen and Y. Liu, Adv. Sci., 2022, 9, 2104165.
67. K. Bischoff, C. Esen and R. Hellmann, Nanomaterials, 2023, 13, 2693.
68. L. Doveri, G. Dacarro, Y. A. D. Fernandez, M. Razzetti, A. Taglietti, G. Chirico, M. Collini, I. Sorzabal-Bellido, M. Esparza and C. Ortiz-de-Solorzano, Colloids Surf., B, 2023, 227, 113373.
69. A. A. E.-S. A. E.-K. Nafeh, I. M. A. E.-A. Mohamed and M. F. Foda, Nanomaterials, 2024, 14, 1254.
70. A. A. Aljabali, M. Rezigue, R. H. Alsharedeh, M. A. Obeid, V. Mishra, A. Serrano-Aroca, M. El-Tanani and M. M. Tambuwala, Ther. Delivery, 2022, 13, 321–338.
71. B. A. Hemdan, G. K. Hassan, A. B. Abou Hammad and A. M. El Nahrawy, Microbial Nanotechnology: Green Synthesis and Applications, 2021, pp. 155–190.
72. S. Kumar, B. Kumar, R. Sehgal, M. Wani, D. Kumar, M. D. Sharma, V. Singh, R. Sehgal and V. Kumar, in Nanoparticles reinforced metal nanocomposites: mechanical performance and durability, Springer, 2023, pp. 209–235.
73. D. Zhang and Y. Wang, Int. J. Mol. Sci., 2019, 20, 3054.
74. C. Cai, W. Li, X. Zhang, B. Cheng, S. Chen and Y. Zhang, Adv. Wound Care, 2024 DOI:10.1089/wound.2024.0024.
75. N. Varshney, A. K. Sahi, S. Poddar, N. K. Vishwakarma, G. Kavimandan, A. Prakash and S. K. Mahto, ACS Appl. Mater. Interfaces, 2022, 14, 14033–14048.
76. W. Li, X. Lei, H. Feng, B. Li, J. Kong and M. Xing, Pharmaceutics, 2022, 14, 297.
77. M. U. A. Khan, M. A. Aslam, R. A. Rahman, M. F. B. Abdullah, A. Mehmood and G. M. Stojanović, J. Biomater. Sci., Polym. Ed., 2024, 1–44.
78. D. Zhou, H. Liu, L. Han, D. Liu, X. Liu, Q. Yan, D. He, Z. Li, X. Lu and C. Jiang, Chem. Eng. J., 2023, 469, 143914.
79. W. He, J. Xu, Y. Zheng, J. Chen, Y. Yin, D. A. Mosselhy, F. Zou, M. Ma and X. Liu, Int. J. Biol. Macromol., 2022, 211, 754–766.
80. K. B. Chien, E. J. Chung and R. N. Shah, J. Biomater. Appl., 2014, 28, 1085–1096.
81. J. Amirian, Y. Zeng, M. I. Shekh, G. Sharma, F. J. Stadler, J. Song, B. Du and Y. Zhu, Carbohydr. Polym., 2021, 251, 117005.
82. J. Li, Y. Li, C. Guo and X. Wu, Chem. Eng. J., 2024, 481, 148458.
83. P. Dorishetty, R. Balu, A. Sreekumar, L. de Campo, J. P. Mata, N. R. Choudhury and N. K. Dutta, ACS Sustainable Chem. Eng., 2019, 7, 9257–9271.
84. S. Kaya and A. Kaya, J. Food Eng., 2000, 43, 91–96.
85. Y. Zhao, Z. Wang, Q. Zhang, F. Chen, Z. Yue, T. Zhang, H. Deng, C. Huselstein, D. P. Anderson and P. R. Chang, Int. J. Biol. Macromol., 2018, 118, 1293–1302.
86. D. Diaz, A. Care and A. Sunna, Genes, 2018, 9, 370.
87. W. Zhang, X. Li, W. Chen, X. Huang, T. Hua, J. Hu, J. Zhu, S. Ye and X. Li, RSC Adv., 2024, 14, 18317–18329.
88. M. H. Norahan, S. C. Pedroza-González, M. G. Sánchez-Salazar, M. M. Álvarez and G. T. de Santiago, Bioact. Mater., 2023, 24, 197–235.
89. H. Shao, X. Wu, Y. Xiao, Y. Yang, J. Ma, Y. Zhou, W. Chen, S. Qin, J. Yang and R. Wang, Int. J. Biol. Macromol., 2024, 129752.
90. Z. Arabpour, F. Abedi, M. Salehi, S. M. Baharnoori, M. Soleimani and A. R. Djalilian, Int. J. Mol. Sci., 2024, 25, 1982.
91. N. Rezaei, H. G. Hamidabadi, S. Khosravimelal, M. Zahiri, Z. A. Ahovan, M. N. Bojnordi, B. S. Eftekhari, A. Hashemi, F. Ganji and S. Darabi, Int. J. Biol. Macromol., 2020, 164, 855–862.
92. C. D. Spicer, Polym. Chem., 2020, 11, 184–219.
93. Y. Lyu, Y. Liu, H. He and H. Wang, Gels, 2023, 9, 431.
94. X. Liu, Z. Guo, J. Wang, W. Shen, Z. Jia, S. Jia, L. Li, J. Wang, L. Wang and J. Li, Adv. Healthcare Mater., 2024, 2303824.
95. Z. Yu, Z. Wang, Y. Chen, Y. Wang, L. Tang, Y. Xi, K. Lai, Q. Zhang, S. Li and D. Xu, Biomaterials, 2024, 122772.
96. F. Kong, N. Mehwish and B. H. Lee, Acta Biomater., 2023, 157, 67–90.
97. S. Wei, Z. Wang, X. Liang, T. Xiong, Z. Kang, S. Lei, B. Wu and B. Cheng, Am. J. Transl. Res., 2023, 15, 4467.
98. C. Chen, L. Chen, C. Mao, L. Jin, S. Wu, Y. Zheng, Z. Cui, Z. Li, Y. Zhang and S. Zhu, Small, 2023, 2306553.
99. V. Kumar, A. Kumar, N. S. Chauhan, G. Yadav, M. Goswami and G. Packirisamy, ACS Appl. Bio Mater., 2022, 5, 2726–2740.
100. R. Yadav, R. Kumar, M. Kathpalia, B. Ahmed, K. Dua, M. Gulati, S. Singh, P. J. Singh, S. Kumar and R. M. Shah, J. Mater. Chem. B, 2024, 12, 7977–8006.
101. C. Shi, C. Wang, H. Liu, Q. Li, R. Li, Y. Zhang, Y. Liu, Y. Shao and J. Wang, Front. Bioeng. Biotechnol., 2020, 8, 182.
102. N. Bhardwaj, D. Chouhan and B. B. Mandal, in Functional 3D tissue engineering scaffolds, Elsevier, 2018, pp. 345–365.
103. P. Chocholata, V. Kulda and V. Babuska, Materials, 2019, 12, 568.
104. I. Negut, G. Dorcioman and V. Grumezescu, Polymers, 2020, 12, 2010.
105. A. Rahmani Del Bakhshayesh, N. Annabi, R. Khalilov, A. Akbarzadeh, M. Samiei, E. Alizadeh, M. Alizadeh-Ghodsi, S. Davaran and A. Montaseri, Artif. Cells, Nanomed., Biotechnol., 2018, 46, 691–705.
106. Y. P. Afsharian and M. Rahimnejad, Polym. Test., 2021, 93, 106952.
107. R. B. Attasgah, B. Velasco-Rodríguez, A. Pardo, J. Fernández-Vega, L. Arellano-Galindo, L. C. Rosales-Rivera, G. Prieto, S. Barbosa, J. F. A. Soltero and M. Mahmoudi, Iscience, 2022, 25, 104019.
108. M. Rasouli, M. Soleimani, S. Hosseinzadeh and J. Ranjbari, J. Polym. Environ., 2023, 31, 4621–4640.
109. T. Su, M. Zhang, Q. Zeng, W. Pan, Y. Huang, Y. Qian, W. Dong, X. Qi and J. Shen, Bioact. Mater., 2021, 6, 579–588.
110. G.-M. Lanno, C. Ramos, L. Preem, M. Putrins, I. Laidmae, T. Tenson and K. Kogermann, ACS Omega, 2020, 5, 30011–30022.
111. T. Nawaz, L. Gu, J. Gibbons, Z. Hu and R. Zhou, Biomimetics, 2024, 9, 373.
112. Kirti and S. S. Khora, Encyclopedia of Marine Biotechnology, 2020, vol. 2, pp. 1175–1193.
113. Y. Feng, X. Li, Q. Zhang, S. Yan, Y. Guo, M. Li and R. You, Carbohydr. Polym., 2019, 216, 17–24.
114. M. Pollini and F. Paladini, Materials, 2020, 13, 3361.
115. S. Singaravelu, G. Ramanathan, M. Raja, N. Nagiah, P. Padmapriya, K. Kaveri and U. T. Sivagnanam, Int. J. Biol. Macromol., 2016, 86, 810–819.
116. J. Li, L. Xiao, S. Gao, H. Huang, Q. Lei, Y. Chen, Z. Chen, L. Xue, F. Yan and L. Cai, Adv. Healthcare Mater., 2023, 12, 2202737.
117. S. Chandel, R. Kumaragurubaran, H. Giri and M. Dixit, in Vascular Hyperpermeability: Methods and Protocols, Springer, 2023, pp. 147–162.
118. E. Tassara, C. Oliveri, L. Vezzulli, C. Cerrano, L. Xiao, M. Giovine and M. Pozzolini, Mar. Drugs, 2023, 21, 428.
119. H. Zhou, L. Chen, C. Huang, Z. Jiang, H. Zhang, X. Liu, F. Zhu, Q. Wen, P. Shi and K. Liu, J. Nanobiotechnol., 2024, 22, 530.
120. D. W. Green, J.-M. Lee and H.-S. Jung, Tissue Eng., Part B, 2015, 21, 438–450.
121. J. E. Brown, J. E. Moreau, A. M. Berman, H. J. McSherry, J. M. Coburn, D. F. Schmidt and D. L. Kaplan, Adv. Healthcare Mater., 2017, 6, 1600762.
122. G. Egan, An investigation into silk fibroin for diverse wound healing applications, 2023,  DOI:10.48730/54mr-wj35.
123. A. Krishna, V. Arya, D. Geethanjali, J. Joji and N. John, in Advances in Bionanocomposites, Elsevier, 2024, pp. 211–224.
124. K. DeFrates, T. Markiewicz, P. Gallo, A. Rack, A. Weyhmiller, B. Jarmusik and X. Hu, Int. J. Mol. Sci., 2018, 19, 1717.
125. Z. A. Raza, S. Khalil, M. I. Majeed and T. Sarwar, Polym. Bull., 2023, 80, 2019–2043.
126. L. R. Amado, K. de Souza Silva and M. A. Mauro, Food Biophys., 2024, 19, 256–268.
127. F. Guarderas, Y. Leavell, T. Sengupta, M. Zhukova and T. L. Megraw, Adv. in Skin & Wound Care, 2016, 29, 131–134.
128. P. P. Patil, M. R. Reagan and R. A. Bohara, Int. J. Biol. Macromol., 2020, 164, 4613–4627.
129. S. Saray Tarkasheh, M. Alizadeh, S. Amiri and I. Karimi Sani, J. Polym. Environ., 2024, 1–22.
130. S. Chen, X. Tong, Y. Huo, S. Liu, Y. Yin, M. L. Tan, K. Cai and W. Ji, Adv. Mater., 2024, 2406192.
131. A. Ghareeb and M. Shalaby, bioRxiv, 2023,  DOI:10.1101/2023.02.21.529363.
132. B. Pourjabbar, E. Biazar, S. Heidari Keshel and A. Baradaran-Rafii, Int. Wound J., 2023, 20, 484–498.
133. T. Selvaras, S. A. Alshamrani, R. Gopal, S. K. Jaganathan, S. Sivalingam, S. Kadiman and S. Saidin, J. Biomed. Mater. Res., Part B, 2023, 111, 1171–1181.
134. M. Fathi-Achachelouei, D. Keskin, E. Bat, N. E. Vrana and A. Tezcaner, J. Biomed. Mater. Res., Part B, 2020, 108, 2041–2062.
135. I. Benalaya, G. Alves, J. Lopes and L. R. Silva, Int. J. Mol. Sci., 2024, 25, 1322.
136. D. Verma, M. Okhawilai, S. Nangan, V. K. Thakur, S. Gopi, K. Kuppusamy, M. Sharma and H. Uyama, Nano-Struct. Nano-Objects, 2024, 37, 101086.
137. M. Rostami, M. Yousefi, A. Khezerlou, M. A. Mohammadi and S. M. Jafari, Food Hydrocolloids, 2019, 97, 105170.
138. S. R. Falsafi, H. Rostamabadi, K. Nishinari, R. Amani and S. M. Jafari, Food Chem., 2022, 374, 131826.
139. H. Rostamabadi, E. Assadpour, H. S. Tabarestani, S. R. Falsafi and S. M. Jafari, Trends Food Sci. Technol., 2020, 100, 190–209.
140. S. Feroz, N. Muhammad, J. Ratnayake and G. Dias, Bioact. Mater., 2020, 5, 496–509.
141. K. M. Salleh and N. F. Abd Rashid, in Polymer Composites Derived from Animal Sources, Elsevier, 2024, pp. 219–242.
142. S. Soleymani Eil Bakhtiari and S. Karbasi, J. Biomater. Sci., Polym. Ed., 2024, 35, 916–965.
143. S. Banasaz and V. Ferraro, Polymers, 2024, 16, 1999.
144. S. Sharma, H. Rostamabadi, S. Gupta, A. K. Nadda, M. S. Kharazmi and S. M. Jafari, Eur. Polym. J., 2022, 111614.
145. L. Wang, Y. Shang, J. Zhang, J. Yuan and J. Shen, Adv. Colloid Interface Sci., 2023, 103012.
146. M. El-Azazy, in Protein-Based Biopolymers, Elsevier, 2023, pp. 59–91.
147. Y. Shang, P. Wang, X. Wan, L. Wang, X. Liu, J. Yuan, B. Chi and J. Shen, Int. J. Biol. Macromol., 2023, 242, 124754.
148. M. Zhang, S. Xu, C. Du, R. Wang, C. Han, Y. Che, W. Feng, C. Wang, S. Gao and W. Zhao, Colloids Surf., B, 2023, 222, 113119.
149. G. C. Demir, Ö. Erdemli, D. Keskin and A. Tezcaner, Int. J. Pharm., 2022, 614, 121436.
150. Y. Kaviyashri, T. Arunachalam and B. Paramasivan, Mater. Today: Proc., 2021, 47, 321–325.
151. S. Sadeghi, J. Nourmohammadi, A. Ghaee and N. Soleimani, Int. J. Biol. Macromol., 2020, 147, 1239–1247.
152. C.-H. Yao, C.-Y. Lee, C.-H. Huang, Y.-S. Chen and K.-Y. Chen, Mater. Sci. Eng., C, 2017, 79, 533–540.
153. O. Shanmugasundaram, K. S. Z. Ahmed, K. Sujatha, P. Ponnmurugan, A. Srivastava, R. Ramesh, R. Sukumar and K. Elanithi, Mater. Sci. Eng., C, 2018, 92, 26–33.
154. S. P. Ndlovu, K. Ngece, S. Alven and B. A. Aderibigbe, Polymers, 2021, 13, 2959.
155. P. Pankongadisak, U. R. Ruktanonchai, P. Supaphol and O. Suwantong, Polym. Adv. Technol., 2017, 28, 849–858.
156. J. Dias, S. Baptista-Silva, C. De Oliveira, A. Sousa, A. L. Oliveira, P. Bártolo and P. Granja, Eur. Polym. J., 2017, 95, 161–173.
157. M.-k. Yeh, Y.-m. Liang, K.-m. Cheng, N.-T. Dai, C.-c. Liu and J.-j. Young, Polymer, 2011, 52, 996–1003.
158. Y.-C. Lin, H.-Y. Wang, Y.-C. Tang, W.-R. Lin, C.-L. Tseng, C.-C. Hu and R.-J. Chung, Int. J. Biol. Macromol., 2024, 258, 128845.
159. W. Li, Z. Su, Y. Hu, L. Meng, F. Zhu, B. Xie, J. Wan and Q. Wu, Int. J. Biol. Macromol., 2023, 241, 124102.
160. R. Khan, S. Haider, M. U. A. Khan, A. Haider, S. I. Abd Razak, A. Hasan, R. Khan and M. U. Wahit, Int. J. Biol. Macromol., 2023, 253, 127169.
161. Y. Lv, Z. Yu, C. Li, J. Zhou, X. Lv, J. Chen, M. Wei, J. Liu, X. Yu and C. Wang, Int. J. Biol. Macromol., 2022, 219, 1227–1236.
162. E. R. Ghomi, V. Chellappan, R. E. Neisiany, N. Dubey, K. Amuthavalli, N. K. Verma, R. Lakshminarayanan and S. Ramakrishna, Compos. Sci. Technol., 2023, 110402.
163. M. Alizadeh, S. Salehi, M. Tavakoli, M. Mirhaj, J. Varshosaz, N. Kazemi, S. Salehi, M. Mehrjoo and S. A. M. Abadi, Int. J. Biol. Macromol., 2023, 233, 123491.
164. B. Pourbadiei, M. A. A. Monghari, H. M. Khorasani and A. Pourjavadi, J. Photochem. Photobiol., B, 2023, 112750.
165. M. Soltani, M. H. Nazarpak, A. Zamani and A. Solouk, Mater. Today Commun., 2023, 35, 106167.
166. Z. Yuan, L. Zhang, H. Zheng, M. Shafiq, J. Song, B. Sun, E.-N. Mohamed, E.-H. Hany, Y. Morsi and C. Huang, J. Drug Delivery Sci. Technol., 2023, 89, 105072.
167. S. Hezari, A. Olad and A. Dilmaghani, Int. J. Biol. Macromol., 2022, 218, 488–505.
168. Y. Hu, B. Yu, Y. Jia, M. Lei, Z. Li, H. Liu, H. Huang, F. Xu, J. Li and Z. Wei, Acta Biomater., 2023, 164, 151–158.
169. Y. Haririan, A. Asefnejad, H. Hamishehkar and M. R. Farahpour, Int. J. Biol. Macromol., 2023, 253, 127081.
170. S. Abdollahi and Z. Raoufi, J. Drug Delivery Sci. Technol., 2022, 72, 103423.
171. D. DeVore, D. Wise, D. Trantolo, D. Altobelli, M. Yaszemski and J. Gresser, Encyclopedic Handbook of Biomaterials and Bioengineering, Marcel Dekker, New York, 1995, pp. 1233–1260.
172. G. Tronci, in Advanced Textiles for Wound Care, Elsevier, 2019, pp. 363–389.
173. S. S. Mathew-Steiner, S. Roy and C. K. Sen, Bioengineering, 2021, 8, 63.
174. H. Elgharably, S. Roy, S. Khanna, M. Abas, P. DasGhatak, A. Das, K. Mohammed and C. K. Sen, Wound Repair Regen., 2013, 21, 473–481.
175. M. Marchand, C. Monnot, L. Muller and S. Germain, Semin. Cell Dev. Biol., 2019, 89, 147–156.
176. M. S. El Masry, S. Chaffee, P. D. Ghatak, S. S. Mathew-Steiner, A. Das, N. Higuita-Castro, S. Roy, R. A. Anani and C. K. Sen, FASEB J., 2019, 33, 2144.
177. X. Liu, C. Zheng, X. Luo, X. Wang and H. Jiang, Mater. Sci. Eng., C, 2019, 99, 1509–1522.
178. H. Elgharably, K. Ganesh, J. Dickerson, S. Khanna, M. Abas, P. D. Ghatak, S. Dixit, V. Bergdall, S. Roy and C. K. Sen, Wound Repair Regen., 2014, 22, 720–729.
179. P. J. Kallis and A. J. Friedman, J. Drugs Dermatol., 2018, 17, 403–408.
180. E. O. Osidak, V. I. Kozhukhov, M. S. Osidak and S. P. Domogatsky, Int. J. Bioprint., 2020, 6, 270.
181. A. Hernández-Rangel and E. S. Martin-Martinez, J. Biomed. Mater. Res., Part A, 2021, 109, 1751–1764.
182. S. K. Ramadass, L. S. Nazir, R. Thangam, R. K. Perumal, I. Manjubala, B. Madhan and S. Seetharaman, Colloids Surf., B, 2019, 175, 636–643.
183. R.-E. Geanaliu-Nicolae and E. Andronescu, Materials, 2020, 13, 5641.
184. L. Shi, F. Lin, M. Zhou, Y. Li, W. Li, G. Shan, Y. Xu, J. Xu and J. Yang, J. Biomater. Appl., 2021, 36, 219–236.
185. A. Ehterami, M. Salehi, S. Farzamfar, A. Vaez, H. Samadian, H. Sahrapeyma, M. Mirzaii, S. Ghorbani and A. Goodarzi, Int. J. Biol. Macromol., 2018, 117, 601–609.
186. M.-Y. Bai, F.-Y. Ku, J.-F. Shyu, T. Hayashi and C.-C. Wu, Polymers, 2021, 13, 516.
187. P. Boomi, R. Ganesan, G. Prabu Poorani, S. Jegatheeswaran, C. Balakumar, H. Gurumallesh Prabu, K. Anand, N. Marimuthu Prabhu, J. Jeyakanthan and M. Saravanan, Int. J. Nanomed., 2020, 7553–7568.
188. V. D. Constantin, A. Carâp, S. Bobic, V. Budu, M. A. Kaya, S. Marin, M. M. Marin and B. Socea, Tissue engineering-collagen sponge dressing for chronic wounds, International Conference on Advanced Materials and Systems (ICAMS). The National Research & Development Institute for Textiles and Leather-INCDTP, 2018, 63–68.
189. S. Lo and M. B. Fauzi, Pharmaceutics, 2021, 13, 316.
190. S. Mondal, G. Hoang, P. Manivasagan, M. S. Moorthy, T. T. V. Phan, H. H. Kim, T. P. Nguyen and J. Oh, Ceram. Int., 2019, 45, 2977–2988.
191. I. Wiser, E. Tamir, H. Kaufman, E. Keren, S. Avshalom, D. Klein, L. Heller and E. Shapira, Wounds, 2019, 31, 103–107.
192. P. A. Parmar, J. P. St-Pierre, L. W. Chow, J. L. Puetzer, V. Stoichevska, Y. Y. Peng, J. A. Werkmeister, J. A. Ramshaw and M. M. Stevens, Adv. Healthcare Mater., 2016, 5, 1656–1666.
193. D. E. Poland and H. E. Kaufman, J. Cataract Refractive Surg., 1988, 14, 489–491.
194. J. Robin, C. Keys, L. Kaminski and M. Viana, Invest. Ophthalmol. Visual Sci., 1990, 31, 1294–1300.
195. G. J. Shaker, S. Ueda, J. A. LoCascio and J. V. Aquavella, Invest. Ophthalmol. Visual Sci., 1989, 30, 1565–1568.
196. R. H. Marmer, J. Cataract Refractive Surg., 1988, 14, 496–499.
197. Z. Li, C. Qian, X. Zheng, X. Qi, J. Bi, H. Wang and J. Cao, Int. J. Biol. Macromol., 2024, 266, 131220.
198. S. Malathi, P. Balashanmugam, T. Devasena and S. N. Kalkura, J. Drug Delivery Sci. Technol., 2021, 63, 102498.
199. P.-F. Cai, B.-D. Zheng, Y.-L. Xu, B.-X. Li, Z.-Y. Liu, Y.-Y. Huang, J. Ye and M.-T. Xiao, Int. J. Biol. Macromol., 2024, 266, 131179.
200. J. E. Gutierrez-Reyes, M. Caldera-Villalobos, J. A. Claudio-Rizo, D. A. Cabrera-Munguía, J. J. Becerra-Rodriguez, F. Soriano-Corral and A. Herrera-Guerrero, Biomed. Mater., 2023, 18, 035011.
201. R. Lara-Rico, C. M. López-Badillo, J. A. Claudio-Rizo, D. A. Cabrera-Munguía, J. J. Becerra-Rodríguez, R. Espinosa-Neira and B. R. Cruz-Ortiz, Biopolymers, 2023, e23538.
202. J. Hwang, H. Huang, M. O. Sullivan and K. L. Kiick, Mol. Pharm., 2023, 20, 1696–1708.
203. W. F. McKay, S. M. Peckham and J. M. Badura, Int. Orthop., 2007, 31, 729–734.
204. M. Sahiner, D. Alpaslan and B. O. Bitlisli, Polym. Bull., 2014, 71, 3017–3033.
205. A. L. Laiva, R. M. Raftery, M. B. Keogh and F. J. O'Brien, Int. J. Pharm., 2018, 544, 372–379.
206. W. Hao, J. Han, Y. Chu, L. Huang, Y. Zhuang, J. Sun, X. Li, Y. Zhao, Y. Chen and J. Dai, Macromol. Biosci., 2018, 18, 1800086.
207. M. Castellano, A. Dodero, S. Scarfi, S. Mirata, M. Pozzolini, E. Tassara, A. Sionkowska, K. Adamiak, M. Alloisio and S. Vicini, Polymers, 2023, 15, 2931.
208. F. Valipour, E. Z. Rahimabadi and H. Rostamzad, Int. J. Biol. Macromol., 2023, 253, 126704.
209. X. Ma, J. Deng, Y. Du, X. Li, D. Fan, C. Zhu, J. Hui, P. Ma and W. Xue, J. Mater. Chem. B, 2014, 2, 2749–2763.
210. F. P. Seib, G. T. Jones, J. Rnjak-Kovacina, Y. Lin and D. L. Kaplan, Adv. Healthcare Mater., 2013, 2, 1606–1611.
211. V. Werner and L. Meinel, Eur. J. Pharm. Biopharm., 2015, 97, 392–399.
212. H. Tao, D. L. Kaplan and F. G. Omenetto, Adv. Mater., 2012, 24, 2824–2837.
213. J. Zhang, E. Pritchard, X. Hu, T. Valentin, B. Panilaitis, F. G. Omenetto and D. L. Kaplan, Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 11981–11986.
214. D. W. Infanger, W. Abdel-Naby, J. J. Kalal, N. B. Paulson, Y. Bai and B. D. Lawrence, Invest. Ophthalmol. Vis. Sci., 2019, 60, 2820–2820.
215. S. Tatlisulu, E. Ozgor, D. Kavaz and M. B. Djamgoz, J. Med. Biol. Eng., 2024, 44, 266–279.
216. S. Zhou, Q. Wang, W. Yang, L. Wang, J. Wang, R. You, Z. Luo, Q. Zhang and S. Yan, Int. J. Biol.Macromol, 2024, 255, 128350.
217. S. Zahoor, H. M. Tahir, S. Ali, A. Ali, A. Muzamil, Z. Murtaza and N. Zahoor, Int. J. Biol. Macromol., 2023, 242, 125184.
218. S. Indrakumar, A. Joshi, T. K. Dash, V. Mishra, B. Tandon and K. Chatterjee, Int. J. Biol. Macromol., 2023, 233, 123569.
219. L. Qiu, L. Duan, H. Lin, M. Wang, H. Liang, G. Peng, X. Yang, Y. Si and S. Yi, Adv. Fiber Mater., 2024, 1–18.
220. M. H. Khosropanah, M. A. Vaghasloo, M. Shakibaei, A. L. Mueller, A. M. Kajbafzadeh, L. Amani, I. Haririan, A. Azimzadeh, Z. Hassannejad and M. M. Zolbin, J. Tissue Eng. Regener. Med., 2022, 16, 91–109.
221. Q. Wang, S. Zhou, L. Wang, R. You, S. Yan, Q. Zhang and M. Li, Composites, Part B, 2021, 224, 109165.
222. A. Kumar Sahi, S. Gundu, P. Kumari, T. Klepka and A. Sionkowska, Biomimetics, 2023, 8, 55.
223. N. J. Prakash, D. Shanmugarajan, B. Kandasubramanian, P. Khot and K. Kodam, Mater. Today Chem., 2023, 27, 101289.
224. D. Lin, M. Li, L. Wang, J. Cheng, Y. Yang, H. Wang, J. Ye and Y. Liu, Adv. Funct. Mater., 2024, 34, 2405255.
225. Q. Lu, F. Zhang, W. Cheng, X. Gao, Z. Ding, X. Zhang, Q. Lu and D. L. Kaplan, Adv. Healthcare Mater., 2021, 10, 2100427.
226. X. Gao, W. Cheng, X. Zhang, Z. Zhou, Z. Ding, X. Zhou, Q. Lu and D. L. Kaplan, ACS Appl. Mater. Interfaces, 2022, 14, 3701–3715.
227. G. Lu, Z. Ding, Y. Wei, X. Lu, Q. Lu and D. L. Kaplan, ACS Appl. Mater. Interfaces, 2018, 10, 44314–44323.
228. Z. Ding, Y. Zhang, P. Guo, T. Duan, W. Cheng, Y. Guo, X. Zheng, G. Lu, Q. Lu and D. L. Kaplan, ACS Biomater. Sci. Eng., 2021, 7, 1147–1158.
229. G. Xu, L. Xiao, P. Guo, Y. Wang, S. Ke, G. Lyu, X. Ding, Q. Lu and D. L. Kaplan, ACS Biomater. Sci. Eng., 2023, 9, 5813–5823.
230. B. G. Bernardes, A. Veiga, J. Barros, C. A. García-González and A. L. Oliveira, Int. J. Mol. Sci., 2024, 25, 3133.
231. A. H. Karaly, W. A. Sarhan and I. M. El-Sherbiny, Int. J. Biol. Macromol., 2021, 182, 413–424.
232. L. Han, J. Zhu, K. L. Jones, J. Yang, R. Zhai, J. Cao and B. Hu, Int. J. Biol. Macromol., 2024, 132796.
233. H. Hodaei, Z. Esmaeili, Y. Erfani, S. S. Esnaashari, M. Geravand and M. Adabi, Sci. Rep., 2024, 14, 23796.
234. N. Ibrahem Khaled and D. Santhiya, Adv. Compos. Mater., 2024, 33, 324–346.
235. S. Tortorella, M. Maturi, V. V. Buratti, G. Vozzolo, E. Locatelli, L. Sambri and M. C. Franchini, RSC Adv., 2021, 11, 39004–39026.
236. E. Oleandro, M. Stanzione, G. G. Buonocore and M. Lavorgna, Nanomaterials, 2024, 14, 414.
237. H. M. Lai and G. W. Padua, Cereal Chem., 1997, 74, 771–775.
238. C.-Y. Zhang, W. Zhang, H.-B. Yao, H.-Z. Zhu, L.-B. Mao and S.-H. Yu, Cryst. Growth Des., 2013, 13, 3505–3513.
239. B. Zhang, Y. Luo and Q. Wang, Biomacromolecules, 2010, 11, 2366–2375.
240. A. Gagliardi, E. Giuliano, S. Voci, N. Costa, S. Bulotta, M. C. Salvatici, N. Ambrosio, D. Paolino, F. Siddique and M. Majid, Int. J. Biol. Macromol., 2024, 269, 132071.
241. A. Mamgain, R. Kenwat and R. Paliwal, Int. J. Biol. Macromol, 2024, 263, 130314.
242. G. L. Breitenbach, B. S. Caldas, M. C. G. Pellá, E. C. Muniz and D. C. Dragunski, Colloids and Surfaces A: Physicochemical and E. Aspects, 2024, 134872.
243. L. Zhou, S. Guo, Z. Dong, P. Liu, W. Shi, L. Shen and J. Yin, Mater. Today Adv., 2024, 21, 100458.
244. N. Salehi, A. Ghaee, H. Moris, S. Derhambakhsh, M. M. Sharifloo and F. Safshekan, Biomed. Mater., 2024, 19, 025044.
245. M. U. din Khan, A. Afzaal, M. A. Gilani, S. Perveen, F. Sharif, A. Asif, A. Faisal, M. S. Nazir, O. Huck and S. Tabassum, Smart Mater. Struct, 2024, 33, 085007.
246. A. Limaye, V. Perumal, C. M. Karner and T.L. Livingston Arinzeh, Adv. Nanobiomed. Res., 2024, 4, 2300104.
247. W. de Souza Tavares, G. A. V. Barreto, E. P. Pinto, P. G. de Barros Silva and F. F. O. de Sousa, J. Drug Delivery Sci. Technol., 2023, 88, 104942.
248. P. Kaushik, E. Priyadarshini, K. Rawat, P. Rajamani and H. Bohidar, Int. J. Biol. Macromol., 2020, 152, 1027–1037.
249. F. Liu, R. Li, L. Mao and Y. Gao, Food Chem., 2018, 255, 390–398.
250. X.-W. Chen, S.-Y. Fu, J.-J. Hou, J. Guo, J.-M. Wang and X.-Q. Yang, Food Chem., 2016, 211, 836–844.
251. S. Chen, Y. Han, Y. Wang, X. Yang, C. Sun, L. Mao and Y. Gao, Food Chem., 2019, 276, 322–332.
252. J. Yan, X. Liang, C. Ma, D. J. McClements, X. Liu and F. Liu, Food Hydrocolloids, 2021, 113, 106473.
253. S. Soltani and A. Madadlou, Food Hydrocolloids, 2015, 43, 664–669.
254. M. Bavya, K. V. Rohan, G. Gaurav and R. Srivasatava, Mater. Sci. Eng., C, 2019, 95, 226–235.
255. N. Fereydouni and M. E. Astaneh, J. Mol. Struct., 2023, 136006.
256. G. El Fawal, A. M. Omar and M. M. Abu-Serie, Sci. Rep., 2023, 13, 22216.
257. M. Karimi, S. Bahrami, S. B. Ravari, P. S. Zangabad, H. Mirshekari, M. Bozorgomid, S. Shahreza, M. Sori and M. Hamblin, Expert Opin. Drug Delivery, 2016, 13, 1609–1623.
258. T. P. H. Hutapea, K. A. Madurani, M. Y. Syahputra, M. N. Hudha, A. N. Asriana and F. Kurniawan, J. Sci.: Adv. Mater. Devices, 2023, 8, 100549.
259. F. Kong, N. Mehwish and B. H. Lee, Acta Biomater., 2023, 157, 67–90.
260. E. S. Lee and Y. S. Youn, J. Pharm. Invest., 2016, 46, 305–315.
261. A. Spada, J. Emami, J. A. Tuszynski and A. Lavasanifar, Mol. Pharmaceutics, 2021, 18, 1862–1894.
262. K. Naik, P. Singh, M. Yadav, S. K. Srivastava, S. Tripathi, R. Ranjan, P. Dhar, A. K. Verma, S. Chaudhary and A. S. Parmar, J. Mater. Chem. B, 2023, 11, 8142–8158.
263. S. Homaeigohar, T.-Y. Tsai, E. S. Zarie, M. Elbahri, T.-H. Young and A. R. Boccaccini, Mater. Sci. Eng., C, 2020, 116, 111248.
264. D. Kwak, J. Lee, J. Kim, H. Kim, J.-Y. Lee, D.-D. Kim and J. W. Yoo, J. Pharm. Invest., 2024, 54, 51–60.
265. F. Saadat and A. F. AzarbayjaniAlbumin-loaded nanofiber for topical wound healing, 2024, https://doi.org/10.21203/rs.3.rs-2523511/v2.
266. M. A. Naser, A. M. Sayed, W. Abdelmoez, M. T. El-Wakad and M. S. Abdo, Sci. Rep., 2024, 14, 7912.
267. E. Madadian, E. Naseri, R. Legault and A. Ahmadi, 3D Print. Addit. Manuf., 2024, 11, e1175–e1185.
268. N. Vanaclocha, L. M. Gómez, M. D. P. Del Caz, V. V. Vanaclocha and F. J. M. Alonso, Burns, 2024, 50, 903–912.
269. A. AliKhan, A. Masmali, S. Alanazi, T. Almubrad and S. Akhtar, Therapeutic efficacy of bovine serum albumin-riboflavin-retinoic acid formulated hydrogel on corneal wound healing and progenitor cell remodeling: An ex vivo study 2024,  DOI:10.21203/rs.3.rs-4407359/v1.
270. Z. Jia, D. Lin, C. Tang, X. Sun, L. Cao and L. Liu, Mater. Des., 2024, 239, 112810.
271. K. Naik, P. Singh, M. Yadav, S. K. Srivastava, S. Tripathi, R. Ranjan, P. Dhar, A. K. Verma, S. Chaudhary and A. S. Parmar, J. Mater. Chem. B, 2023, 11, 8142–8158.
272. W. Zhao, X. Yang and L. Li, ACS Appl. Mater. Interfaces, 2024, 16, 40356–40370.
273. P. Sanjarnia, M. L. Picchio, A. N. P. Solis, K. Schuhladen, P. M. Fliss, N. Politakos, L. Metterhausen, M. Calderón and E. R. Osorio-Blanco, Adv. Drug Delivery Rev., 2024, 115217.
274. F. Xu, C. Dawson, M. Lamb, E. Mueller, E. Stefanek, M. Akbari and T. Hoare, Front. Bioeng. Biotechnol., 2022, 10, 849831.
275. L. Yan, Y. Wang, J. Feng, Y. Ni, T. Zhang, Y. Cao, M. Zhou and C. Zhao, Front. Endocrinol., 2024, 15, 1430543.
276. J. Nandhini, E. Karthikeyan and S. Rajeshkumar, Biomed. Technol., 2024, 6, 26–45.
277. N. I. M. Fadilah, M. Maarof, A. Motta, Y. Tabata and M. B. Fauzi, Biomedicines, 2022, 10, 2226.
278. Y. Wang, K. Vizely, C. Y. Li, K. Shen, A. Shakeri, R. Khosravi, J. R. Smith, E. A. I. Alteza, Y. Zhao and M. Radisic, Regener. Biomater., 2024, 11, rbae032.
279. N. J. Murugan, S. Cariba, S. Abeygunawardena, N. Rouleau and S. L. Payne, Cell. Mol. Life Sci., 2024, 81, 9.

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