Biopolymeric Materials in the Management of Diabetic Wound Healing: A Comprehensive Review

Harish Bhardwaj^1,*, Sulekha Khute², Rajendra Kumar Jangde³

¹ University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur (C.G) 492010 India.

*Corresponding author: Email: rjangdepy@gmail.com

The compromised wound healing observed in diabetic patients poses significant hurdles, escalating the risk of infections. The growing interest in natural polymeric materials is fueled by their abundant availability, cost-effectiveness, and eco-friendly attributes. Advances in polymer science have expanded the applications, especially in tissue engineering and regenerative medicine. These interdisciplinary fields integrate knowledge and technology from diverse domains to restore damaged tissues and organs in medical interventions. Polymers function as versatile tools, serving as carriers for drugs and cells and facilitating host-cell integration to meet the requisites of regeneration and repair. This intricate process involves multiple stages, necessitating the development of various components to construct the desired neo-tissue or organ. Diverse biopolymers, encompassing biological, synthetic, and hybrid varieties, find extensive utility across various medical applications. Their tunable physical, chemical, and biological properties render them ideal for tailoring to specific application requirements. This review provides a comprehensive overview of the wound-healing process, with a specific focus on the challenges presented by diabetic wounds. Additionally, it explores various biopolymers, including alginate, gelatin, cellulose, silk sericin, chondroitin sulfate, chitosan, xanthan gum, cyclodextrin, and hyaluronic acid, elucidating their roles in the management of diabetic wounds.

Keywords: Diabetic wound, Challenges, Biopolymers.

Introduction

Diabetes mellitus is a complex metabolic disorder that disturbs millions of people worldwide. Around the world, millions of people are affected. The diabetes epidemic among adults (20-79 years old) Currently, there are 285 million adults, but by 2030, that number will increase to 439 million adults (Bai et al., 2020). Hemostasis, inflammation, proliferation, and remodeling are the four sequential biological stages of wound healing that work together to restore damaged tissue. When any of the above wound-healing phases are perturbed by both external and internal factors, the outcome may be prolonged and unsatisfactory, further resulting in chronic wounds. Concerning complete wounds, the most common problem is during healing, pathogens colonize the wound site at the site of the injury during a wound's healing process. Wounds are protected from pathogen colonization by bacteria that compose the skin microbiota. Healing is retarded when pathogenic bacteria produce a significant amount of biofilm and reach a critical level. Most frequently, Staphylococcus aureus colonizes wounds in the early stages of healing, while Pseudomonas aeruginosa and Escherichia coli reside in chronic wounds (Naskar & Kim, 2020). The complexity of these issues limits success in wound management, resulting in negative effects on patients and high costs for global healthcare systems. So far, imperfect clinical success has been accomplished in treating chronic wounds contempt extensive efforts to develop therapeutic approaches (F. Wu et al., 2021).

A huge molecule (macromolecule) made up of repeated structural units is a polymer. These subunits are often joined together by covalent chemical bonds. In pharmaceutical applications, both synthetic and natural polymers are available, but natural polymers are more cost-effective, readily available, and non-toxic. With a few exceptions, they are also biocompatible, potentially biodegradable, and chemically modifiable (Gajre & Kulkarni, 2012; Rao et al., 2018). All biological systems employ the multiple assembling of the basic structural components to produce a three-dimensional product is the core concept behind polymers. The cytoskeleton, intracellular fibers, structural proteins of the soft extracellular matrix, matrices with a mechanical function in cartilage, keratin of skin and hair at the human surface interface with the environment—even insects can produce silk polymers for external structures—all fall under this category (Maitz, 2015). In contrast to material-based drug carriers that only entrap a drug for controlled release, the term "polymer therapeutics" was originally used in the 20th century to refer to those sophisticated therapies in which a polymer performs an essential part of the delivery system (Ashford et al., 2021). To target a drug to a specific organ or tissue and control the rate of distribution, a correctly designed prolonged-release dosage form is chosen as one of the main solutions (Diksha et al., 2019). Natural polymers are frequently analogs, if not identical, as in the case of collagen, to materials now offered in the human body, reducing the risks of cell damage and immunogenic reaction upon implanting in the physique are also highly biocompatible, have natural biodegradation movement, and can be chemically tuned. Natural substances used in neural tissue engineering come in a variety of forms, including extracellular matrix components (ECM), like collagen, polymers derived from seafood, like chitosan, and silk, and polymers derived from aquatic organisms, such as alginate (Boni et al., 2018). Naturally occurring polymers, synthetic biodegradable polymers, and nonbiodegradable polymers are all employed as biomaterials. Polymeric scaffolds are of tremendous interest because of their unique qualities, which include an extensive variety of biodegradation rates, high porosity with different pore sizes, high surface-to-volume ratios, and durability. They have unique functional, adaptable, and biological advantages that are crucial in diabetic wound healing and biomedical fields (Reddy et al., 2021). Understanding the essential elements that affect the healing process has been the focus of recent investigations. This research may result in therapies that support appropriate tissue repair and enhance sluggish wound healing, even though there is still much to learn in this area. The goal of this study is to highlight the molecular mechanisms underlying incomplete wound healing, the biopolymers for full healing, and new developments in the treatment of such lesions.

2. The phase of wound healing

One of the biggest issues is DWs, which primarily involves leg ulcers and diabetic ulcers. Diabetes slows down the healing process by affecting each stage of wound healing, including hemostasis, inflammation, proliferation, and remodeling shown in Fig.1. This has a long-term detrimental impact on morbidity and mortality as well as the quality of lifestyle(Burgess et al., 2021). Chronic wounds that reveal poor repair as a result of a delayed, insufficient, or disorganized process of healing are characteristics of DWs. the DWs display an extended phase of inflammation that is followed by a delay in the formation of fully developed granulation tissue and a reduction in the tensile strength of the wound. This might be because of the ischemia-induced vascular damage (Glover et al., 2022).

Fig. 1.  Phases of wound healing

Every wound needs immediate attention since it is a health alarm. On the assumption of their origin, wounds can be divided into two categories: internal and exterior. Cuts, abrasions, burns, and bruises are examples of external origin wounds. Due to peripheral neuropathy, these exterior lesions may commonly go undiagnosed by diabetes patients. Ulcers in the skin and calluses that have an internal origin wreak havoc on the surrounding tissues and increase the risk of bacterial infection. The currently accepted standard of care uses several medical procedures to disinfect and remove contaminated tissue while maintaining moisture and sufficient blood flow (Patel et al., 2019).

3. Impaired wound healing in diabetes

The major challenges for the diabetic wound healing microvascular complication this illustrated in Fig. 2. a, b, and c. The four phases of normal healing are hemostasis, inflammation, proliferation, and remodeling. Phases of a chronic injury may become caught in a single stage for a prolonged period, and they may also lose the synchronization of the chain of mechanisms that promotes rapid recovery (S. C. Wu et al., n.d.). The initial phases of recovery after damage include hemostasis and inflammation, during which inflammatory cells are drawn in by the formation of fibrin clots. The recruitment of neutrophils as well as macrophages at the site of injury is supported by a ring of growth factors, including platelet-derived growth factor (PDGF), TGF-1, epidermal growth factor (EGF), and proinflammatory cytokines including interleukin - 1 (IL-1). Neutrophils decontaminate the wound by phagocytosing microorganisms that have gathered at the location of the injury(Alven et al., 2022). By producing growth factors such as EGF, TGF-, PDGF, fibroblast growth factor (FGF), and cytokines such as IL-1 and, IL-6, IL-8, and tissue necrosis factor - 1 (TNF-1), macrophages and neutrophils boost the immune system's response to infection. After being activated by chemical signals, neutrophils enter the wound area, where they promote cell adhesion and ECM leaking. Hyperglycemia microcirculatory abnormalities lead to a longer inflammatory phase and a delayed healing cascade because neutrophil adhesion is impaired. Growth factor secretion is induced by fibroblasts and keratinocytes, which also promote tissue regeneration(Alamoudi et al., 2022; Pyun et al., 2015). The metalloproteases (MMP) that break down damaged extracellular matrix and structural proteins are produced by fibroblasts as part of their activity.

(a)

(b)

(c) Diabetic Wound Healing Phase

Fig.2.   (a)  Activation of wound healing (b) Normal Wound Healing Phase (c) Diabetic Wound Healing Phase

The matrix of cells and wound site still exist in diabetic wounds despite the fibroblasts' resistance to endogenous growth hormones and cytokines. The vascular system, which is responsible for producing prostaglandin E2, works to encourage revascularization and permeability by activating vascular endothelial growth factors (VEGF). Myofibroblasts, a particular type of fibroblast, promote wound healing by expressing soft tissue actin and focal attachment protein(Choi et al., 2017; Jee et al., 2019; Sanju et al., 2021). These enzymes create and break down extracellular proteins, and MMPs finish the remodeling phase of the process of recovery. The four stages of wound healing are said to be hindered in those with diabetes. The primary causes of vascular problems in diabetic individuals are endothelial damage, malfunction of smooth muscle cells, and damage to the neuron axon (Shah et al., 2019).

4. Challenges of Diabetic wound

The complex nature of diabetes and its considerable effect on the body's ability to repair damaged tissues make diabetic wound healing rife with difficulties. The tendency for delayed healing is among the biggest barriers to diabetic wound healing. The body's natural healing processes are hampered by diabetes, which causes wounds to take a long time to heal. Several things, including poor blood flow, insufficient oxygen getting to the wound site, and a weakened immune system, can be blamed for this delayed progress (Frykberg & Banks, 2015). The development of chronic sores in diabetics is a serious problem as well. These wounds frequently do not heal according to the typical stages and are left open for long periods, making them extremely susceptible to infections and other problems. Diabetes-related wound healing raises serious concerns about the increased risk of infection. The chance of wound infections rises when the immune system is impaired and blood glucose levels are raised, as these two factors together foster bacterial growth (El-Salamouni et al., 2021). Diabetes-related wounds can develop consequences like cellulitis, abscess growth, or even osteomyelitis, an infection of the bone. It can be difficult to manage these issues, and surgery may be required. A multidisciplinary strategy is frequently required for effective diabetic wound management, comprising medical specialists such as endocrinologists, wound care specialists, podiatrists, and infectious disease specialists. Although intricate, care coordination between these professionals is crucial for a good outcome (Chereddy et al., 2015; Edmonds & Foster, 2004; Gao et al., 2021a, 2021b).

5. Types of biopolymers in wound management

5.1. Gelatine

Gelatin has garnered interest as one of the biopolymers that form films because of its affordability, reusability, excellent transparency, ability to degrade, biocompatibility, and superior film-forming capabilities. A naturally occurring polymer known as gelatin is produced when the collagen protein is hydrolyzed (Kanungo et al., 2021; Moradpoor et al., 2022). Gelatin provides several health benefits because of the distinctive amino acid composition of the substance. Usually available as pills, pellets, or particles gelatin can also occasionally be before use, dissolved in water. Scientists are carefully examining gelatin as a matrix for three-dimensional cell culture and as a component of scaffolds for manipulating tissue. In some healthy dishes, gelatin can take the place of fat and carbs due to its high protein concentration. Collagen is the most naturally occurring protein in both humans and animals, and it is a source of the protein matrix known as gelatin (Alipal et al., 2019).

5.2. Cellulose

The most prevalent organic polymer and a crucial structural element in plant life is cellulose. Cellulose is a linear, unbranched polysaccharide made up of several parallel cellulose molecules that come together to form crystalline microfibrils and -1, 4-linked D-glucose units. The crystalline microfibrils are aligned with one another to provide shape to the cell wall and are mechanically robust and extremely resistant to enzyme degradation. Cellulose cannot be digested by humans and is not soluble in water. fortunately, termites and animals both metabolize it. granulated cellulose, which has been utilized in the pharmaceutical sector as a filler in tablets, can be created by mechanically disintegrating cellulose produced from fibrous substances such as wood and cotton (Ogaji et al., 2012).

5.3. Albumin

Albumin, which makes up the majority of plasma proteins and has the highest concentration, accounts for about 50% of all plasma proteins. It is essential to the body's functioning. Maintaining a constant plasma permeability in the body of an individual, albumin is a crucial food ingredient that serves as a natural source of amino acids (Ghosh & Karmakar, 2021). In addition, albumin has a free sulfhydryl group, eight disulfide connections, and a high water solubility (up to 40% w/v at pH 7.4). To be able to bind with numerous insoluble organic compounds and inorganic ions in vivo and create soluble complexes, albumin might be employed as a generalized transport protein. Albumin is a naturally occurring biomaterial that is biodegradable, non-immunogenic, and biocompatible. Relevant research indicates that the hepatobiliary system may effectively remove made-from protein nanoparticles (NPs), making albumin-based NPs simple to clear in vivo (Lei et al., 2021).

5.4. Alginates

Alginates come from a variety of brown seaweed organisms, such as the enormous kelp belonging to the genera Ascophyllum, Macrocystis, and Laminaria. Macrocystis, which only occurs in the southern hemisphere's subtropical, temperate, and sub-Antarctic waters, and Ascophyllum, which is only found in the North Atlantic Ocean, are mostly employed in the production of alginate(Riseh et al., 2022). Laminaria, also referred to as tangle kelp, has a variety of uses, including as a food ingredient, and a potential source of biofuel, which is as a medication. Additionally, two bacterial genera-Pseudomonas, which is frequently found in water and plant seeds, and Azotobacter, which is frequently found in soils and aquatic environments alginates. Alginates sometimes referred to as alginates, algin, and alginic acid, are hydrophilic anionic polysaccharides produced from brown algae/seaweed or bacteria that display a variety of structural variations and therefore differing physical and chemical characteristics. Alginate is a natural polymer that is frequently employed in drug- and protein-delivery systems and has various benefits, including being simple to prepare, biocompatible, biodegradable, and non-toxic. It can be used for several medication delivery methods, such as targeted or localized medication delivery platforms (Kabir et al., 2021).

5.5. Chitosan

Deacetylated chitin is known as chitosan. It is the second biopolymer on the globe that is widely accessible. Glucosamine and N-acetyl glucosamine residues make up the chemical makeup of chitosan. Chitin and chitosan are useful polymers because they can be separated from marine debris such as crustaceans, as the outer coverings of dead crabs, prawns, arthropods, and fungi, as well as other kinds of microorganisms. The key factors affecting chitosan solubility include the main chain, MW, DA, ionic concentration, pH, the kind of acid, and the distribution of acetyl groups. Usually, mild acids, primarily acetic acid (1%, 0.1 M), are used to disperse the chitosan. Additionally, chitosan in its very advantageous water-soluble form has been created for use in applications in plants (El-Aassar et al., 2021; Ilyas et al., 2022; J. Yu et al., 2021). In the presence of glycerol 2-phosphate, this type of chitosan can dissolve in water at a neutral pH. Obtaining a stable solution is possible at room temperature, but once the temperature rises over 40 C, reversible gel formation begins. Chitosan has a superior capacity for complex formation than chitin, which is primarily attributable to the presence of free -NH2 groups scattered along the main chain of the chitosan (J. Yu et al., 2021).

5.6. Chondroitin sulfate

A naturally occurring anionic glycosaminoglycan called chondroitin sulfate (CS) is made up of repeated disaccharide units of sulfated N-acetyl galactosamine (GalNAc) and 1,4-linked D-glucuronic acid (GlcA) (Maarof et al., 2021). Because of its advantageous physiochemical characteristics, such as biodegradability, cytocompatibility, lack of immunogenicity, and high water-binding capacity, CS has been widely used in the biomedical and pharmaceutical industries. Because of its derivable groups, including carboxyl groups and hydroxyl groups, CS can be easily changed hydrophobically aside from its biocompatible and biodegradable qualities. The capacity of CS to target tumors through interacting with the CD44 receptor, which is overexpressed on the surfaces of many tumor cells, is even more significant (Li et al., 2021).

5.7. Collagen

An insoluble fibrous protein called collagen makes up the extracellular matrix of animals. Although collagen has been utilized as a biomaterial since 1881, its characteristics and intricate structure continue to be active research areas on a global scale. The majority of the extracellular matrix (ECM) in all mammals is made up of collagen, a protein that is extremely plentiful and fibrous. Numerous kinds of collagen can be isolated from tissues of mammals, fish, alligators, and other sources, but due to their hydrophilicity, these native collagens are insoluble in organic solvents. Molecules and fibers of collagen can be found (Lee et al., 2015; L. Yu & Wei, 2021). Collagens, which form a highly organized 3D structure that may catch things, are often complicated molecules with three chains arranged adjacent to one another and twisted together to form a rigid helix-shaped region. Collagen can give fibroblasts a comfortable place to rest so they can proliferate around the wound and mend more quickly. Collagen aids in hemostasis, inflammation, and remodeling throughout the wound healing process in addition to proliferation (Rezvani Ghomi et al., 2021) This is not surprising given its prevalence in peripheral nerve ECM and its function in supporting injured axons' mechanical regeneration. Collagen is the main part of four out of nine artificial tubes for the rebuilding of peripheral nerves that have received FDA approval, making it an effective substrate to support the biological processes that enable regeneration (Gregory & Phillips, 2021).

5.8. Fibrin

Blood's interaction with the surface of the biomaterial which causes plasma proteins to adhere and the development of a temporary matrix, is one of the very first processes that occurs after tissue injury brought on by implantation. Upon being drawn from the vasculature to the implant site, neutrophils and monocytes use this matrix as an adhesive substrate before differentiating into macrophages. When the acute inflammatory response changes into chronic inflammation, macrophages near the biomaterial interface then unite to produce FBGCs (de Melo et al., 2020; Losi et al., 2013). Both the presence of substantial foreign surfaces and the creation of a milieu close to the implanted biomaterial are necessary for macrophage fusion. In particular, the cytokines IL-4 and IL-13 were found near the implant site and have been proven to program macrophages into a fusion-competent condition in vitro. Additionally, macrophages attached to biomaterials release MCP-1, a chemokine involved in macrophage fusion both in vitro and in vivo. Silk fibroin protein has garnered a lot of interest as a drug delivery carrier due to its ease of purification, sterilization, processability without the use of chemical crosslinkers, strong biocompatibility, tailorable biodegradability, low immunogenicity, and high capacity to stabilize loaded pharmaceuticals. (Farokhi et al., 2020).

5.9. Guar gum

In nature, guar gum, a non-ionic polysaccharide, is widely distributed. It is derived from the seeds of Cyamopsis tetragonolobus, a plant belonging to the Leguminosae family. Guar gum, a naturally occurring polymer with several intriguing qualities including biodegradability, biosafety, biocompatibility, and sustainability, may be useful in drugs and drug release investigations(Sanchez Ramirez et al., 2021). While guar gum's high swelling properties in aqueous medium prevent it from being widely used as a delivery vehicle in its natural form, this characteristic can be significantly changed through functional group derivatization, cross-linking, and grafting to be used in a variety of biomedical areas. Because it tends to be microbially degraded in the large intestine, guar gum has drawn a lot of interest in controlled oral medication administration. More specifically, research has looked into the potential use of guar gum as a transdermal, colon-specific, and antihypertensive drug delivery method(George et al., 2019).

5.10. Cyclodextrin

A cyclodextrin is a glucose macrocycle that can be modulated by macrostructures to include nonpolar solutes. Five types of new materials may be produced by the incorporation of cyclodextrin moieties: amphiphilic cyclodextrins, crosslinked networks, functionalized chains, polyrotaxanes, and nanocomposites  (Silva Pereira et al., 2021). The first landmark in cyclodextrin polymer research was Solms and Egli's 1965 paper (Solms and Egli 1965). In those early years, Wiedenhof et al. produced bead microparticles that, for example, could be used in chromatography columns by improving the characteristics of particles made of crosslinked cyclodextrin. Diisocyanates were used by Buckler et al. to prepare polyurethane cyclodextrin networks. Various possible applications of those "anchored" cyclodextrins were also explored in the same patent, including acid dihalides and other potentially useful space arms (Petitjean et al., 2021).

5.11. Keratin

Keratin proteins are defined by amino acid chains that form their primary structure. Various factors affect the size and shape of these chains, including amino acid sequence, polarity, charge, and polarity. Despite their differences in species or function, their structures are similar. Changing the amino acid sequence of keratin alters its properties significantly since amino acid is the entirety of the molecular structure and the bond type (e.g., covalent or ionic). There are many opportunities for producing profitable and sustainable advanced ingredients using keratin, one of the greatest abundant biopolymers from animal sources. "Keratin" (from the Greek "kera" meaning horn) refers to all proteins derived from horns, nails, claws, and hooves. However, further research revealed that those were protein and keratin associations. This definition of keratin derives from the cornified layer of the epidermis, which is composed of proteins that form filaments and have particular physicochemical characteristics. Recent definitions of the term include all intermediate filament-forming proteins found in vertebrate epithelia, with their unique physicochemical properties (Donato & Mija, 2020)

5.12. Pectin

Pectin is a heteropolysaccharide that is prevalent in plant cell walls and mostly found in fruit (apples and citrus), hence it is especially susceptible to alterations that take place during the stages of ripening. The string-like shape (conformation, stiffness), which governs how the molecules relate to one another as well as their surroundings, is what gives pectin its distinctive characteristics (Chen et al., 2021). A heteropolysaccharide that is prevalent in plants' middle lamella and the main cell wall is called pectin. Pectin may make up as much as 30% of a cell wall. Numerous studies have been conducted on the structure of pectin in different environments and the adaptable nature of its chains, mostly using hydrodynamic, viscometrical, and modeling simulator approaches, which offer a thorough biophysical understanding of these molecules. Pectin helices are relatively flexible coils with a high degree of structural diversity and sensitivity to solution conditions due to the persistence length equating to multiple monomers. It is well-known that a biomolecule's spiral shape has a significant impact on how it functions (Zdunek et al., 2021).

5.13. Xanthan Gum

A naturally occurring exopolysaccharide produced by microbes with significant commercial value is xanthan gum (XG). Due to its exceptional physicochemical characteristics, biodegradability, and non-toxicity, it has shown substantial potential in specific uses such as improved drug administration, protein delivery, and tissue fabrication. despite this, some restrictions, such as a small surface area, temperature stability, poor mechanical performance, and the development of bacteria, can make it less useful in some applications. Additionally, XG contains a secondary structure that takes the form of a five-fold helical molecule with a diameter of 1.9 nm and an angle of 4.7 nm that is primarily stabilized by a non-covalent link. The ionic strength and temperatures can be changed to the secondary framework of XG and can undergo a reversible order-disorder conformational shift. In general, height temperatures and low salt concentrations favor the abnormal type (Berninger et al., 2021).

5.14. Hyaluronic acid

Natural polymers such as HA are common in connective, epithelial, and neural tissue. It is a non-sulfated, linear polysaccharide that is a member of the glycosaminoglycans (GAGs) family and is composed of alternate N-acetyl-D-glucosamine and D-glucuronic acid linked by (13) and (14) glycoside linkages. In the treatment of diabetic wounds, antioxidant hydrogels based on hyaluronic acid (HA) have produced outstanding results. Their glucose-responsive antioxidant properties still need to be realized, which is a big challenge. The most common natural polysaccharides used to make biomimetic hydrogels are cellulose, chitosan, alginate, hyaluronic acid (HA), starch, chondroitin sulfate, etc. Substrates for wound dressing should have an intrinsic antibacterial potential to make them even more appealing, acting as a barrier to safeguard tissues from bacterial infections on the skin in addition to acting as a barrier to stop wound infections and aid in an efficient healing progression. The demonstrated ability of HA to diminish bacterial adhesion and biofilm formation in many circumstances is related to its capacity to limit microbial attack during wound healing; HA is bacteriostatic rather than bactericidal, delaying or preventing bacterial growth without actually killing it (Della Sala et al., 2022; Yang et al., 2022).

Conclusion

Biopolymers show promise in addressing the challenges of impaired diabetic wound healing. These materials, both natural and synthetic, offer biocompatibility, biodegradability, and tunability, making them attractive for medical applications. They can help restore the disrupted phases of wound healing and create a conducive environment for tissue regeneration. Natural biopolymers like chitosan and alginate can be modified for controlled drug release, and collagen plays a crucial role in supporting cellular activity and tissue repair. Continued research in this field holds the potential to improve diabetic wound healing, enhance patient quality of life, and reduce the risk of infections. Further exploration and refinement of biopolymer applications in clinical settings are essential for global healthcare advancements.

Acknowledgment

I am deeply grateful to Dr. Rajendra Kumar Jangde for his invaluable guidance, and I extend my heartfelt thanks to the University Institute of Pharmacy at Pt. Ravishankar Shukla University, Raipur, for their constant support and resources.

Conflict of interest

The author declares that they have no conflict of interest.

References

Alamoudi, A. A., Alharbi, A. S., Abdel-Naim, A. B., Badr-Eldin, S. M., Awan, Z. A., Okbazghi, S. Z., Ahmed, O. A. A., Alhakamy, N. A., Fahmy, U. A., & Esmat, A. (2022). Novel Nanoconjugate of Apamin and Ceftriaxone for Management of Diabetic Wounds. Life, 12(7), 1096. https://doi.org/10.3390/life12071096

Alipal, J., Mohd Pu’ad, N. A. S., Lee, T. C., Nayan, N. H. M., Sahari, N., Basri, H., Idris, M. I., & Abdullah, H. Z. (2019). A review of gelatin: Properties, sources, process, applications, and commercialisation. Materials Today: Proceedings, 42, 240–250. https://doi.org/10.1016/j.matpr.2020.12.922

Alven, S., Peter, S., Mbese, Z., & Aderibigbe, B. A. (2022). Polymer-Based Wound Dressing Materials Loaded with Bioactive Agents: Potential Materials for the Treatment of Diabetic Wounds. In Polymers (Vol. 14, Issue 4). MDPI. https://doi.org/10.3390/polym14040724

Ashford, M. B., England, R. M., & Akhtar, N. (2021). Highway to Success—Developing Advanced Polymer Therapeutics. In Advanced Therapeutics (Vol. 4, Issue 5). John Wiley and Sons Inc. https://doi.org/10.1002/adtp.202000285

Bai, Q., Han, K., Dong, K., Zheng, C., Zhang, Y., Long, Q., & Lu, T. (2020). Potential applications of nanomaterials and technology for diabetic wound healing. In International Journal of Nanomedicine (Vol. 15, pp. 9717–9743). Dove Medical Press Ltd. https://doi.org/10.2147/IJN.S276001

Berninger, T., Dietz, N., & González López, Ó. (2021). Water-soluble polymers in agriculture: xanthan gum as eco-friendly alternative to synthetics. In Microbial Biotechnology. John Wiley and Sons Ltd. https://doi.org/10.1111/1751-7915.13867

Boni, R., Ali, A., Shavandi, A., & Clarkson, A. N. (2018). Current and novel polymeric biomaterials for neural tissue engineering. In Journal of Biomedical Science (Vol. 25, Issue 1). BioMed Central Ltd. https://doi.org/10.1186/s12929-018-0491-8

Burgess, J. L., Wyant, W. A., Abujamra, B. A., Kirsner, R. S., & Jozic, I. (2021). Diabetic wound-healing science. In Medicina (Lithuania) (Vol. 57, Issue 10). MDPI. https://doi.org/10.3390/medicina57101072

Chen, J., Cheng, H., Zhi, Z., Zhang, H., Linhardt, R. J., Zhang, F., Chen, S., & Ye, X. (2021). Extraction temperature is a decisive factor for the properties of pectin. Food Hydrocolloids, 112. https://doi.org/10.1016/j.foodhyd.2020.106160

Chereddy, K. K., Lopes, A., Koussoroplis, S., Payen, V., Moia, C., Zhu, H., Sonveaux, P., Carmeliet, P., des Rieux, A., Vandermeulen, G., & Préat, V. (2015). Combined effects of PLGA and vascular endothelial growth factor promote the healing of non-diabetic and diabetic wounds. Nanomedicine: Nanotechnology, Biology, and Medicine, 11(8), 1975–1984. https://doi.org/10.1016/j.nano.2015.07.006

Choi, J. U., Lee, S. W., Pangeni, R., Byun, Y., Yoon, I. S., & Park, J. W. (2017). Preparation and in vivo evaluation of cationic elastic liposomes comprising highly skin-permeable growth factors combined with hyaluronic acid for enhanced diabetic wound-healing therapy. Acta Biomaterialia, 57, 197–215. https://doi.org/10.1016/j.actbio.2017.04.034

de Melo, B. A. G., Jodat, Y. A., Cruz, E. M., Benincasa, J. C., Shin, S. R., & Porcionatto, M. A. (2020). Strategies to use fibrinogen as bioink for 3D bioprinting fibrin-based soft and hard tissues. In Acta Biomaterialia (Vol. 117, pp. 60–76). Acta Materialia Inc. https://doi.org/10.1016/j.actbio.2020.09.024

Della Sala, F., Longobardo, G., Fabozzi, A., Di Gennaro, M., & Borzacchiello, A. (2022). Hyaluronic Acid‐Based Wound Dressing with Antimicrobial Properties for Wound Healing Application. In Applied Sciences (Switzerland) (Vol. 12, Issue 6). MDPI. https://doi.org/10.3390/app12063091

Diksha, S., Dhruv, D., & Mansi, H. (2019). Sustained Release Drug Delivery System with the Role of Natural Polymers: A review. https://doi.org/10.22270/jddt.v9i3

Donato, R. K., & Mija, A. (2020). Keratin associations with synthetic, biosynthetic and natural polymers: An extensive review. In Polymers (Vol. 12, Issue 1). MDPI AG. https://doi.org/10.3390/polym12010032

Edmonds, M., & Foster, A. (2004). The use of antibiotics in the diabetic foot. American Journal of Surgery, 187(5 SUPPL. 1), S25–S28. https://doi.org/10.1016/S0002-9610(03)00300-3

El-Aassar, M. R., Ibrahim, O. M., Fouda, M. M. G., Fakhry, H., Ajarem, J., Maodaa, S. N., Allam, A. A., & Hafez, E. E. (2021). Wound dressing of chitosan-based-crosslinked gelatin/ polyvinyl pyrrolidone embedded silver nanoparticles, for targeting multidrug resistance microbes. Carbohydrate Polymers, 255. https://doi.org/10.1016/j.carbpol.2020.117484

El-Salamouni, N. S., Gowayed, M. A., Seiffein, N. L., Abdel- Moneim, R. A., Kamel, M. A., & Labib, G. S. (2021). Valsartan solid lipid nanoparticles integrated hydrogel: A challenging repurposed use in the treatment of diabetic foot ulcer, in-vitro/in-vivo experimental study. International Journal of Pharmaceutics, 592. https://doi.org/10.1016/j.ijpharm.2020.120091

Farokhi, M., Mottaghitalab, F., Reis, R. L., Ramakrishna, S., & Kundu, S. C. (2020). Functionalized silk fibroin nanofibers as drug carriers: Advantages and challenges. In Journal of Controlled Release (Vol. 321, pp. 324–347). Elsevier B.V. https://doi.org/10.1016/j.jconrel.2020.02.022

Frykberg, R. G., & Banks, J. (2015). Challenges in the Treatment of Chronic Wounds. Advances in Wound Care, 4(9), 560–582. https://doi.org/10.1089/wound.2015.0635

Gajre, V. (, & Kulkarni, ). (2012). Natural Polymers-A comprehensive Review. In Article in International Journal of Research in Pharmaceutical and Biomedical Sciences. https://www.researchgate.net/publication/236217541

Gao, D., Zhang, Y., Bowers, D. T., Liu, W., & Ma, M. (2021a). Functional hydrogels for diabetic wound management. In APL Bioengineering (Vol. 5, Issue 3). American Institute of Physics Inc. https://doi.org/10.1063/5.0046682

Gao, D., Zhang, Y., Bowers, D. T., Liu, W., & Ma, M. (2021b). Functional hydrogels for diabetic wound management. In APL Bioengineering (Vol. 5, Issue 3). American Institute of Physics Inc. https://doi.org/10.1063/5.0046682

George, A., Shah, P. A., & Shrivastav, P. S. (2019). Guar gum: Versatile natural polymer for drug delivery applications. In European Polymer Journal (Vol. 112, pp. 722–735). Elsevier Ltd. https://doi.org/10.1016/j.eurpolymj.2018.10.042

Ghosh, D., & Karmakar, P. (2021). Insight into anti-oxidative carbohydrate polymers from medicinal plants: Structure-activity relationships, mechanism of actions and interactions with bovine serum albumin. In International Journal of Biological Macromolecules (Vol. 166, pp. 1022–1034). Elsevier B.V. https://doi.org/10.1016/j.ijbiomac.2020.10.258

Glover, K., Mathew, E., Pitzanti, G., Magee, E., & Lamprou, D. A. (2022). 3D bioprinted scaffolds for diabetic wound-healing applications. Drug Delivery and Translational Research. https://doi.org/10.1007/s13346-022-01115-8

Gregory, H., & Phillips, J. B. (2021). Materials for peripheral nerve repair constructs: Natural proteins or synthetic polymers? Neurochemistry International, 143. https://doi.org/10.1016/j.neuint.2020.104953

Ilyas, R. A., Aisyah, H. A., Nordin, A. H., Ngadi, N., Zuhri, M. Y. M., Asyraf, M. R. M., Sapuan, S. M., Zainudin, E. S., Sharma, S., Abral, H., Asrofi, M., Syafri, E., Sari, N. H., Rafidah, M., Zakaria, S. Z. S., Razman, M. R., Majid, N. A., Ramli, Z., Azmi, A., … Ibrahim, R. (2022). Natural-Fiber-Reinforced Chitosan, Chitosan Blends and Their Nanocomposites for Various Advanced Applications. In Polymers (Vol. 14, Issue 5). MDPI. https://doi.org/10.3390/polym14050874

Jee, J. P., Pangeni, R., Jha, S. K., Byun, Y., & Park, J. W. (2019). Preparation and in vivo evaluation of a topical hydrogel system incorporating highly skin-permeable growth factors, quercetin, and oxygen carriers for enhanced diabetic wound-healing therapy. International Journal of Nanomedicine, 14, 5449–5475. https://doi.org/10.2147/IJN.S213883

Kabir, I. I., Sorrell, C. C., Mofarah, S. S., Yang, W., Yuen, A. C. Y., Nazir, M. T., & Yeoh, G. H. (2021). Alginate/Polymer-Based Materials for Fire Retardancy: Synthesis, Structure, Properties, and Applications. In Polymer Reviews (Vol. 61, Issue 2, pp. 357–414). Bellwether Publishing, Ltd. https://doi.org/10.1080/15583724.2020.1801726

Kanungo, M., Wang, Y., Hutchinson, N., Kroll, E., Debruine, A., Kumpaty, S., Ren, L., Wu, Y., Hua, X., & Zhang, W. (2021). Development of gelatin‐coated microspheres for novel bioink design. Polymers, 13(19). https://doi.org/10.3390/polym13193339

Lee, C. H., Chang, S. H., Chen, W. J., Hung, K. C., Lin, Y. H., Liu, S. J., Hsieh, M. J., Pang, J. H. S., & Juang, J. H. (2015). Augmentation of diabetic wound healing and enhancement of collagen content using nanofibrous glucophage-loaded collagen/PLGA scaffold membranes. Journal of Colloid and Interface Science, 439, 88–97. https://doi.org/10.1016/j.jcis.2014.10.028

Lei, C., Liu, X. R., Chen, Q. B., Li, Y., Zhou, J. L., Zhou, L. Y., & Zou, T. (2021). Hyaluronic acid and albumin based nanoparticles for drug delivery. In Journal of Controlled Release (Vol. 331, pp. 416–433). Elsevier B.V. https://doi.org/10.1016/j.jconrel.2021.01.033

Li, Y., Chen, X., Ji, J., Li, L., & Zhai, G. (2021). Redox-responsive nanoparticles based on Chondroitin Sulfate and Docetaxel prodrug for tumor targeted delivery of Docetaxel. Carbohydrate Polymers, 255. https://doi.org/10.1016/j.carbpol.2020.117393

Losi, P., Briganti, E., Errico, C., Lisella, A., Sanguinetti, E., Chiellini, F., & Soldani, G. (2013). Fibrin-based scaffold incorporating VEGF- and bFGF-loaded nanoparticles stimulates wound healing in diabetic mice. Acta Biomaterialia, 9(8), 7814–7821. https://doi.org/10.1016/j.actbio.2013.04.019

Maarof, M., Nadzir, M. M., Mun, L. S., Fauzi, M. B., Chowdhury, S. R., Idrus, R. B. H., & Lokanathan, Y. (2021). Hybrid collagen hydrogel/chondroitin-4-sulphate fortified with dermal fibroblast conditioned medium for skin therapeutic application. Polymers, 13(4), 1–14. https://doi.org/10.3390/polym13040508

Maitz, M. F. (2015). Applications of synthetic polymers in clinical medicine. Biosurface and Biotribology, 1(3), 161–176. https://doi.org/10.1016/j.bsbt.2015.08.002

Moradpoor, H., Mohammadi, H., Safaei, M., Mozaffari, H. R., Sharifi, R., Gorji, P., Sulong, A. B., Muhamad, N., & Ebadi, M. (2022). Recent Advances on Bacterial Cellulose-Based Wound Management: Promises and Challenges. In International Journal of Polymer Science (Vol. 2022). Hindawi Limited. https://doi.org/10.1155/2022/1214734

Naskar, A., & Kim, K. S. (2020). Recent advances in nanomaterial-based wound-healing therapeutics. In Pharmaceutics (Vol. 12, Issue 6). MDPI AG. https://doi.org/10.3390/pharmaceutics12060499

Ogaji, I. J., Nep, E. I., & Audu-Peter, J. D. (2012). Advances in Natural Polymers as Pharmaceutical Excipients. Pharmaceutica Analytica Acta, 03(01). https://doi.org/10.4172/2153-2435.1000146

Patel, S., Srivastava, S., Singh, M. R., & Singh, D. (2019). Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. In Biomedicine and Pharmacotherapy (Vol. 112). Elsevier Masson SAS. https://doi.org/10.1016/j.biopha.2019.108615

Petitjean, M., García-Zubiri, I. X., & Isasi, J. R. (2021). History of cyclodextrin-based polymers in food and pharmacy: a review. In Environmental Chemistry Letters (Vol. 19, Issue 4, pp. 3465–3476). Springer Science and Business Media Deutschland GmbH. https://doi.org/10.1007/s10311-021-01244-5

Pyun, D. G., Choi, H. J., Yoon, H. S., Thambi, T., & Lee, D. S. (2015). Polyurethane foam containing rhEGF as a dressing material for healing diabetic wounds: Synthesis, characterization, in vitro and in vivo studies. Colloids and Surfaces B: Biointerfaces, 135, 699–706. https://doi.org/10.1016/j.colsurfb.2015.08.029

Rao, S. H., Harini, B., Shadamarshan, R. P. K., Balagangadharan, K., & Selvamurugan, N. (2018). Natural and synthetic polymers/bioceramics/bioactive compounds-mediated cell signalling in bone tissue engineering. In International Journal of Biological Macromolecules (Vol. 110, pp. 88–96). Elsevier B.V. https://doi.org/10.1016/j.ijbiomac.2017.09.029

Reddy, M. S. B., Ponnamma, D., Choudhary, R., & Sadasivuni, K. K. (2021). A comparative review of natural and synthetic biopolymer composite scaffolds. In Polymers (Vol. 13, Issue 7). MDPI AG. https://doi.org/10.3390/polym13071105

Rezvani Ghomi, E., Nourbakhsh, N., Akbari Kenari, M., Zare, M., & Ramakrishna, S. (2021). Collagen-based biomaterials for biomedical applications. In Journal of Biomedical Materials Research - Part B Applied Biomaterials (Vol. 109, Issue 12, pp. 1986–1999). John Wiley and Sons Inc. https://doi.org/10.1002/jbm.b.34881

Riseh, R. S., Vazvani, M. G., Zarandi, M., & Skorik, Y. A. (2022). Alginate-Induced Disease Resistance in Plants. In Polymers (Vol. 14, Issue 4). MDPI. https://doi.org/10.3390/polym14040661

Sanchez Ramirez, D. O., Cruz-Maya, I., Vineis, C., Tonetti, C., Varesano, A., & Guarino, V. (2021). Design of asymmetric nanofibers-membranes based on polyvinyl alcohol and wool-keratin for wound healing applications. Journal of Functional Biomaterials, 12(4). https://doi.org/10.3390/jfb12040076

Sanju, S., Tallapaneni, V., Narukulla, S., Pamu, D., Mude, L., & Karri, V. V. S. R. (2021). Micro and nanoparticles for the delivery of growth factors in diabetic wounds. In Journal of Medical Pharmaceutical and Allied Sciences (Vol. 10, Issue 5, pp. 3552–3559). MEDIC SCIENTIFIC. https://doi.org/10.22270/jmpas.V10I5.1470

Shah, S. A., Sohail, M., Khan, S., Minhas, M. U., de Matas, M., Sikstone, V., Hussain, Z., Abbasi, M., & Kousar, M. (2019). Biopolymer-based biomaterials for accelerated diabetic wound healing: A critical review. In International Journal of Biological Macromolecules (Vol. 139, pp. 975–993). Elsevier B.V. https://doi.org/10.1016/j.ijbiomac.2019.08.007

Silva Pereira, R. L., Campina, F. F., Costa, M. do S., Pereira da Cruz, R., Sampaio de Freitas, T., Lucas dos Santos, A. T., Cruz, B. G., Maciel de Sena Júnior, D., Campos Lima, I. K., Xavier, M. R., Rodrigues Teixeira, A. M., Alencar de Menezes, I. R., Quintans-Júnior, L. J., Araújo, A. A. de S., & Melo Coutinho, H. D. (2021). Antibacterial and modulatory activities of β-cyclodextrin complexed with (+)-β-citronellol against multidrug-resistant strains. Microbial Pathogenesis, 156. https://doi.org/10.1016/j.micpath.2021.104928

Wu, F., Misra, M., & Mohanty, A. K. (2021). Challenges and new opportunities on barrier performance of biodegradable polymers for sustainable packaging. In Progress in Polymer Science (Vol. 117). Elsevier Ltd. https://doi.org/10.1016/j.progpolymsci.2021.101395

Wu, S. C., Marston, W., & Armstrong, D. G. (n.d.). Strategies to Prevent and Heal Diabetic Foot Ulcers: A Joint Publication of APMA and SVS SPECIAL COMMUNICATION Wound Care The Role of Advanced Wound-healing Technologies.

Yang, X., Wang, B., Peng, D., Nie, X., Wang, J., Yu, C.-Y., & Wei, H. (2022). Hyaluronic Acid‐Based Injectable Hydrogels for Wound Dressing and Localized Tumor Therapy: A Review. Advanced NanoBiomed Research, 2(12), 2200124. https://doi.org/10.1002/anbr.202200124

Yu, J., Wang, D., Geetha, N., Khawar, K. M., Jogaiah, S., & Mujtaba, M. (2021). Current trends and challenges in the synthesis and applications of chitosan-based nanocomposites for plants: A review. In Carbohydrate Polymers (Vol. 261). Elsevier Ltd. https://doi.org/10.1016/j.carbpol.2021.117904

Yu, L., & Wei, M. (2021). Biomineralization of collagen-based materials for hard tissue repair. In International Journal of Molecular Sciences (Vol. 22, Issue 2, pp. 1–17). MDPI AG. https://doi.org/10.3390/ijms22020944

Zdunek, A., Pieczywek, P. M., & Cybulska, J. (2021). The primary, secondary, and structures of higher levels of pectin polysaccharides. Comprehensive Reviews in Food Science and Food Safety, 20(1), 1101–1117. https://doi.org/10.1111/1541-4337.12689