Nanofiber-based wound dressings have a mean diameter size of less than 1 micrometer [50]. They are easily removed from the injury after their application. Among the preparation methods that are employed to fabricate nanofibers, electrospinning is the most employed one because of its several advantages such as adjustment of mechanical properties of nanofibers, control nanofiber porosity, cost-efficiency, simplicity, and versatility [51,52,53]. The formulation of nanofibers using the electrospinning technique is shown in Figure 3. Nanofibers present many advantages, including a small diameter, high porosity, narrow diameter distribution, gas permeation, and high-specific surface to area ratio [54]. These wound dressings have been used for drug delivery, especially for the management of chronic injuries [55]. They employ the accessories or excipients to transport the drugs to the wound with low toxicity and high efficiency. Nanofibrous wound dressings display related diameters with the extracellular matrix (ECM), making them suitable for improving wound healing and supporting cell proliferation and adhesion [56]. Many research reports have discussed the therapeutic outcomes of nanofibers in diabetic wound management. Most of the nanofibers were formulated from poly (α-esters) (PLA, PGA, and PLGA), chitosan, gelatin, chitosan, HA, and alginate.

Cam et al., fabricated bacterial cellulose-gelatin nanofibers co-loaded with glibenclamide and metformin for diabetic wound treatment [57]. The scanning electron microscope (SEM) results of drug-encapsulated nanofibers exhibited bead-less and uniform structure (with a fiber diameter of 0.22 μm), mimicking that one of ECM. The cytotoxicity studies in vitro displayed high cell viability of mouse fibroblasts (L929) when they were incubated with plain nanofibers and glibenclamide/metformin-loaded nanofibers for 48 h, indicating non-toxicity and good biocompatibility of nanofibers [57]. The encapsulation efficiencies of glibenclamide and metformin in hybrid nanofibers were ~78% and ~80%, respectively. The in vivo wound healing studies performed on drug-loaded fibers using type -1 diabetic Wistar rats displayed superior wound healing on full-thickness wounds than the pristine nanofibers, revealing that glibenclamide and metformin significantly accelerated diabetic wound healing [57]. The co-loading of bioactive agents promoted an effective wound healing process. Choi et al., formulated PEG-PCL hybrid nanofibers encapsulated with human epidermal growth factor (EGF) using the electrospinning technique for the treatment of diabetic ulcers. The in vivo wound closure studies utilizing full-thickness injuries on streptozotocin (STZ)-induced diabetic mice demonstrated that the injury treated with EGF-encapsulated nanofibers was superior healed on day 7 than those dressed with plain nanofibers or EGF alone [58]. The EGF-loaded significantly increased the rate of wound healing process resulting in complete wound closure in 7 days than the usual (14 or 15 days).

Films are wound dressing materials that are usually formulated adherent and transparent PU, which permits the permeation of gases such as oxygen, water vapor, and carbon dioxide between the injury and the surrounding [73]. These dressing materials also useful for autolytic removal of dead tissues from the injury. The polymer-based films display excellent mechanical properties, including high elasticity and flexibility, leading to their ability to be altered to any shape of interest, and do not require extra tapping [74]. The transparency of film dressings provides the inspection of the recovery process of the wound without removing the dressing (Figure 4), making them appropriate for wound management of superficial wounds, epithelizing injury with low exudates, and shallow wounds [75]. Tan et al., prepared sodium alginate-based hydrocolloid films incorporated with vicenin-2 for diabetic wound management [76]. The in vivo wound closure studies employing diabetic STZ-induced SD rats showed that the lesions wrapped with vicenin-2-encapsulated films induced faster healing than those dressed with plain films. Also, the histological experiments indicated that pristine film-dressed diabetic wounds exhibited incomplete reepithelialization and poorly developed granulation tissue, while the vicenin-2 film-dressed diabetic rats showed moderate reepithelialization with well-developed granulation tissue after 2 weeks of treatment [76]. The incorporation of vicenin into films significantly promoted the important processes (re-epithelization and granulation) of wound healing.

Colobatiu et al., reported chitosan-based films encapsulated with alcoholic extracts of various plants such as Symphytum officinale, Plantago lanceolata, Tagetes patula, Arnica montana, Geum urbanum, and Calendula officinalis for diabetic wound dressing application [77]. These biopolymeric films displayed acceptable appearance, colour, structure, and flexibility as well as a good swelling ability, thus demonstrating a significant capability to prevent wound dehydration. The in vitro cytotoxicity experiments utilizing MTT assay displayed more than 80% cell viability of the Hs27 human fibroblast cells when incubated with bioactive extracts-loaded films, revealing good biocompatibility and non-toxicity. The in vivo experiments on diabetic STZ-induced Wister rats demonstrated that the injuries dressed with the bioactive-loaded films were observed to be almost fully closed (97.47%) on day 14, compared to the plain films that displayed only a 61.07% wound closure. Furthermore, histopathological analysis of chitosan-based films showed an important wound repairing ability, which could stimulate reepithelialization and hasten the wound healing mechanism in diabetic as well as normal wounds [77]. The non-cytotoxic effects of films loaded with alcoholic extracts and other factors resulted in an improved diabetic wound healing process. The chitosan-based films were also formulated by Mizuno et al., that were loaded with fibroblast growth factors. The in vivo wound healing study showed high wound closure of full-thickness wounds on diabetic rats when treated with chitosan films when compared to control [78]. The growth factors play a vital role in wound healing and accelerated the wound healing process.

Hydrogels have attracted much attention in various biomedical applications in the past decades. They are 3-dimensional networks of cross-linked polymers (Figure 5) which consist of more than 90% moisture content and are fabricated naturally, or through synthesis, via chemical or physical crosslinking methods [96]. They have similarities with living tissues, adhesive nature, and they are malleable, and these characteristics make them considered as the best choice for wound dressing. Hydrogel dressings can accelerate the wound healing process since they can cool the wound through a gaseous exchange, reduce the pain by absorbing wound exudate, and preventing infections, and they can maintain a moist environment for cell migration. Furthermore, hydrogels can act as a delivery system that minimizes side effects and drug toxicity [97,98,99]. There are several reports on the formulation of polymer-based bioactive hydrogels to improve the therapeutic effects of the currently used wound dressing materials to accelerate the wound healing process.

Wang et al., fabricated promising self-healing polypeptide-based hydrogel (denoted as FHE@exo hydrogel) with pH-responsive long-term exosomes release using Poly-ε-L-lysine (EPL), oxidative HA (OHA), and Pluronic (denoted as FHE hydrogel) by loading adipose mesenchymal stem cells (AMSCs)-derived exosomes through electrostatic interaction between EPL and exosomes [100]. The in vivo studies of FHE@exo hydrogel, FHE hydrogel, and free exosomes were used with saline as a blank control demonstrated that all of them showed decreased diabetic wound size in all treated wounds within 14–21 days after surgery and FHE@exo hydrogel showed faster contraction rates with 88.67 ± 6.9% closure rate on day 14, compared to 36.3 ± 10.4% (saline), 64.3 ± 9.8% (FHE hydrogel) and 76.3 ± 3.2% (exosomes), respectively and at day 21 diabetic injuries treated with FHE@exo hydrogel were completely closed with remarkable hair growth [100]. The loading of exosome into hydrogels significantly improve the wound healing process in vivo.

Foams are solid porous wound dressings (Figure 6) that are made of hydrophobic and hydrophilic foam with bioadhesive boundaries [42]. The external hydrophobic layer protects the injury from the liquid but allows gaseous exchange and water vapor permeation. These wound dressings can be sterilized and applied on injuries without resulting in pains to the patient if their parameters (such as mechanical properties, density, and thickness) are appropriately tailored. Foam wound dressings possess several advantages such as improved gaseous exchange, protect the wound from maceration, offer suitable moisture for the fast wound healing process, and absorb large amounts of exudate, making them appropriate for the management of burns, diabetic ulcers, traumatic wounds, etc. [120]. The shortcoming of foam wound dressing materials is that they are inappropriate for dry wounds or injury with low exudates and dry scars [121]. Pyun et al., formulated PU-based foams incorporated with recombinant human epidermal growth factor (rhEGF) for diabetic wound treatment. The FTIR spectrums confirmed the successful fabrication of the PU foam dressings. The water vapor transmission experiments of foams demonstrated a WVTR of about 3000 g/m²/day, which is close to ideal wound dressings (2000–2500 g/m²/day) [122].

The cytotoxicity analysis in vitro exhibited very high cell proliferation and viability of CCD986-skin human fibroblast cell lines and HaCaT human keratinocyte when incubated with rhEGF-loaded foams, suggesting excellent biocompatibility of PU foams. The in vitro release profile displayed rapid release of rhEGF from the surface of foams in the first 24 h, followed by plateau release for 7 days. The in vivo studies using STZ induced diabetic SD rats showed that the full-thickness wounds were almost completely closed by more than 97% when treated with rhEGF-loaded foams. The histological analysis demonstrated that the diabetic wounds were completely resolved by regenerating the epithelial cell in the rats on day 21 after wounding [122]. The moderate WVTR and release profile promoted enhanced healing of the diabetic wounds by inducing epithelial cell regeneration. Coutts et al., conducted clinical studies of PVA foam wound dressings co-loaded with gentian violet and methylene blue for bacterial-infected diabetic wounds [123]. The outcomes of these studies presented enhancements in surface critical colonization and pain score at the end of the assessment period in some patients, especially in patients with DFUs. Furthermore, decreasing wound size was observed in 8 of the 14 patients at week 4 [123]. The other clinical studies reported by Moon et al., demonstrated that the wounds in diabetic patients dressed with Ag-incorporated PU foams were restored in 15.6 ± 3.8 days while those treated with plain foams healed in 14.4 ± 2.2 days, revealing that the presence of silver in the foams delayed the epithelialization of the diabetic injuries in patients. However, the difference was statistically significant in this study [124].

Choi et al., fabricated PU foams loaded with Ag nanoparticles and rhEGF for bacteria-infected diabetic wound management [125]. These foam wound dressings significantly demonstrated fluid retention, excellent absorbency, and fluid handling features. SEM micrographs exhibited that the PU foams demonstrated a relatively uniform pore size that ranges between 200–400 µm and it was not affected by the incorporation of bioactive agents, suggesting that these foams can provide high cell granulation rate and proliferation with an excellent gaseous exchange during wound healing. The in vitro cytotoxicity analysis utilizing MTT assay exhibited the high cell viability of L929 mouse fibroblasts when cultured with dual bioactive agent-loaded foams. The antimicrobial analysis using the inhibition zone method displayed that the PU foams loaded with Ag nanoparticles and rhEGF exhibited outstanding antibacterial efficacy (high inhibition zone) against E. coli and S. aureus, while unloaded foams did not display any inhibition effects. The in vivo experiments utilizing diabetic Balb/b mice demonstrated that injuries wrapped with the foams loaded with both Ag nanoparticles and rhEGF demonstrated excellent healing after 5 days of treatment than the gauze, suggesting a synergistic effect of incorporating bioactive agents together with growth factors [125].

Sponges are wound dressings that possess interconnected porous structures (Figure 7), soft and flexible [135]. Their porous structure influences their high swelling capacity, making them appropriate for the management of exuding wounds. They also support cell migration and high water absorption capability appropriate for providing moisture to the wound bed while protecting the injury from bacterial infections [136]. The sponge wound dressings formulated from PVA, alginate, chitosan, and graphene oxide demonstrated excellent antimicrobial efficacy [137]. Several sponges have been prepared for the delivery of therapeutic agents for the treatment of diabetic wounds. Wang et al., formulated chitosan-cross-linked collagen sponges encapsulated with recombinant human acidic fibroblast growth factors to stimulate the diabetic wound healing process [138]. These hybrid sponges exhibit several advantages required in an ideal wound dressing, such as uniform and porous ultrastructure, in vitro slow release of fibroblast GFs from the sponges, and high resistance to collagenase digestion [138]. The remedial impact of the novel wound dressing comprising fibroblast growth factors on diabetic wound healing was studied in a type 1 diabetic rat model in which hyperglycemia was prompted by a single dosage of STZ and continued for a very long time. The diabetic wound healing was discovered to be significantly enhanced by chitosan-cross-linked collagen sponges loaded with fibroblast growth factor compared to the pristine sponges, revealing the capability of growth factor-loaded chitosan-cross linked collagen sponges wound dressings for diabetic wound healing [138]. The presence of fibroblast growth factors and their sustained drug release mechanism from sponges significantly resulted in accelerated wound healing process.

The polymer-based sponges and bandages loaded with therapeutic agents displayed high porosity that can promote high cell growth and attachment, which are suitable for the diabetic wound healing process. Also, the initial rapid drug release of bioactive agents from these scaffolds followed by sustained release is appropriate for improving the treatment of diabetic wounds (Table 1 and Table 2). Most of the reported sponges and bandages for the treatment of diabetic injuries were loaded with antibacterial agents (metallic nanoparticles and antibiotics) and they demonstrated excellent antibacterial activity against various antibiotic-resistant bacterial strains, suggesting that these are potential materials for the management of infected diabetic wounds. The encapsulation of bioactive agents into the sponges and bandages significantly accelerated the wound healing process of the diabetic injuries in vivo when compared with diabetic wounds dressed with plain scaffolds. Nevertheless, the very high porosity of polymeric sponges or bandages can result in high uptake of wound exudate and high WVTR that may cause dehydration of diabetic wounds. A dehydrated injury can lead to a delayed wound healing process.