Recent updates in nanotechnological advances for wound healing: A narrative review

3.1 Electrospun nanofibers

Electrospinning technology, as a process for manufacturing ultrafine fibers, has experienced decades of development [88]. The electrostatic spinning equipment consists largely of four components: a high-voltage generator, a fluid driver, a spinneret, and a collection mechanism [89]. After the voltage is applied during the electrospinning technique, the original electrospinning fluid undergoes a gradual change in morphology until it reaches the critical voltage form of a Taylor cone. There are two stages of whiplash when the liquid jet reaches its maximum length. For example, the jet may be prolonged to micrometers or even a few hundred nanometers in length by using solvent volatilization [90,91]. For nanofibers to change their shape and size, it is necessary to regulate many factors, such as the molecular weight and viscosity of the polymer as well as the flow rate, the receiving distance, and the ambient conditions (humidity or temperature) [92,93]. Electrospinning is a simple, top-down, one-step preparation approach that provides nanofibers with microscopic pore size, high porosity, and a structure akin to ECM (as shown in Figure 3). As a consequence, it has gained considerable attention from researchers and is used to generate functionalized nanofibers for biomedical and other purposes (as shown in Figure 3) [94,95,96]. Moreover, electrospinning technology is consistently refined and increased. Figure 3 depicts the process of formation of nanofibers using the electrospinning technique, and their use as wound dressings for wound-healing activity, while the last part of Figure 3 defines the healing action of nanofibers including various inflammatory mediators.

Figure 3

Various processes involved in the preparation of nanofibers and their applications in the wound-healing process.

Nanofibers filled with berberine have been developed as a therapy for DFUs and were fabricated using electrospun cellulose acetate/gels (CA/gel) and filled with berberine (Beri) [97]. The hemocompatibility test showed that the produced dressings induced less hemolysis than the positive control (RBC lysed in distilled water). Moreover, the berberine-infused dressing displayed less hemolysis than the pure CA/gel dressing. Positive control and CA/gel dressings were shown to have lower antibacterial activity than the Beri dressing. Berberine inclusion in the CA/gel nanofiber matrix is responsible for the improved bactericidal action of CA/gel/Beri dressing described in research, and this value is advantageous for wound-dressing applications [97].

To improve wound healing by absorbing exudate at the wound site, speeding hemostasis, and preventing bacteria development and inflammation, Chen et al. created a three-dimensional (3D) layered nanofiber sponge (3D-AgMOF-CUR) with an in situ formed silver-metal organic framework (Ag-MOF) and curcumin (CUR) [98]. Reduced inflammation, higher collagen deposition, increased granulation and angiogenesis, and quicker skin regeneration are all examples of 3D-AgMOF-improved CUR’s wound dressing effectiveness. In part, this is due to its unique 3D layered structure, which allows for increased water absorption and air permeability during wound healing, as well as superior hemostatic capabilities. A possible antibacterial property of Ag-MOF formed on the sponge is enhanced if wound infection is assumed. This property might help to avoid infection and unhealing by rapidly destroying bacteria in the wound. Aside from reducing inflammation, increasing collagen deposition, and stimulating skin tissue regrowth, CUR loading may also speed wound healing.

Another study describes the development of a polycaprolactone-polyethylene glycol-egg yolk oil (PCL-PEG-EYO) scaffold for burn healing, using egg yolk oil, polycaprolactone, and polyethylene glycol (PEG) [99]. Results showed that the scaffold had a uniform morphology, hydrophilicity, and improved cell viability and attachment compared to the PCL-PEG scaffold. It also demonstrated antibacterial activity and enhanced wound closure, re-epithelialization, angiogenesis, and collagen synthesis in vivo. Overall, the PCL-PEG-EYO nanofibrous scaffold shows potential for the management of full-thickness burn wounds.

The study reported by Bouhajeb et al. described the fabrication of an implantable dressing material for reducing anti-pressure ulcer disease using electrospun poly(lactic acid) (PLA) nanofibers containing the hydroethanolic extract of T. ramosissimum [100]. The optimized synthesis conditions resulted in a homogeneous and nonwoven mat structure with identified chemical compounds including flavonoids, monoterpenoids, hydroxycinnamic derivatives, and phenolic acids. In vivo wound-healing investigations on induced pressure ulcers in mice showed that the implantable 17-PLA/HE NF material improved wound-healing capabilities, reduced the injury area, and provided a high wound closure percentage from the first days of application. Histological assays showed complete re-epithelialization with 17-PLA/HE NFs. This study offers the possibility to fabricate implantable materials containing only the determined released compounds for further research.

Anaya Mancipe et al. reported on a coaxial electrospinning process to fabricate a polycaprolactone-collagen/poly(vinyl alcohol) (PCL-Col_1/PVA) core–shell nanofiber mat for potential use as a skin wound dressing [101]. The PCL core improves mechanical properties, while PVA improves collagen processability. The triple helix structure of collagen is preserved, and common post-processing can be avoided. The resulting nanofiber mat exhibits high liquid absorption, structural stability, hydrophilicity, and collagen release capacity. The optimized nanofiber mat showed no cytotoxicity, making it a potential novel dressing for skin damage regeneration, especially for chronic wound treatment.

The research reported by Koohzad and Asoodeh discussed the development of a bioresponsive nanodrug delivery system for tissue engineering applications [102]. The system comprises HA–chitosan (CS)–polyvinyl alcohol complex nanofibers that are pH-sensitive, exhibit excellent properties for wound dressing, and are cross-linked using citric acid. The nanofiber scaffold is designed to release peptide molecules that accelerate wound healing, which was confirmed by in vitro and in vivo studies. The peptide-loaded nanofiber samples showed better adhesion, proliferation, migration, and fibroblast cell growth than other groups. In vivo studies in a mouse model demonstrated that the designed nanofiber was gradually absorbed without causing dryness or infection, and it showed excellent tissue repair ability. Gene expression studies indicate that the antimicrobial peptide promotes the inflammatory phase of wound healing in a shorter time frame by accelerating the tumor necrosis factor-α cytokine response. Various other studies reported on the development of electrospinned nanofibers for wound-healing purpose are given in Table 1.

3.2 NPs for wound healing

The difficulties involved with the care of refractory wounds are often linked to microbial contamination and infection. Elimination of these is essential for prompt wound healing [150]. The growth of multidrug-resistant infections has led to an increase in the usage of antimicrobial treatments based on NPs. As potent antimicrobials, metallic NPs are currently thoroughly explored and investigated. It is known that the NPs’ antibacterial activity is proportional to the surface area in contact with microbes. While the healing properties of silver have been known for millennia, its therapeutic potential has recently been greatly enhanced by the use of silver NPs in wound dressings and topical treatments. Silver ion release from wound dressings, hydrogels, lotions, and sprays may be prolonged with the help of these NPs. Silver nanoparticles’ (AgNPs’) sustained antibacterial action and less cytotoxicity toward healthy cells result from their regulated release of silver ions. AgNPs aid in wound healing in ways other than their antibacterial capabilities. They have been found to stimulate the growth of new blood vessels, a process essential for delivering oxygen and nutrients to injured tissue throughout the healing process. In addition, the healing process may be aided by AgNPs because of their ability to control inflammatory reactions. They have been shown to have antioxidant capabilities, making for an optimal wound-healing environment by shielding cells from oxidative stress.

The use of AgNPs has become evident in several clinical trials in wound therapy, particularly chronic wounds and burns [151]. It has been shown that Ag-alginates and collagen preparations are being used in clinical settings and that the efficacy of these products has been well studied. In most cases, the kind of silver used in the preparation of these condiments is a mystery. Nanocrystalline Ag is utilized in Acticoat instead of ionic Ag, which is used in other materials. Acticoat has been shown to reduce wound healing time for severe partial-thickness burns when compared to standard paraffin gauze dressings in a retrospective study of burn wounds in humans [152]. Overall, AgNP-based dressings are more effective than Ag sulfadiazine cream in terms of effectiveness [153]. AgNPs accelerate the process of healing by promoting contractility of wounds by induction of differentiation of myofibroblasts from normal fibroblasts. Further re-epithelialization of the epidermis is stimulated by AgNPs through keratinocyte proliferation as well as relocation [154]. Antibacterial wound dressings made of silver nanocomposites, which combine AgNPs with hydrogels for improved antibacterial activity and cytocompatibility, have been widely studied. Again, in animal trials, it has been observed that inorganic particles like silica adhere tightly to open wounds. This leads to the integration of AgNPs into silica NPs (mesoporous) with the help of disulfide bonds. The resultant compound has demonstrated excellent antimicrobial activities with minor toxicity at the cellular level [155].

Preclinical investigations have considered electrospinned scaffolds as well as those made using different techniques and AgNPs. Silver and CS nanocomposite dressings were synthesized and evaluated in rats with severe partial-thickness wounds using nanoscale and self-assembly technologies. Compared to Ag sulfadiazine, the nanocomposite dressings considerably accelerated wound healing and reduced Ag levels in the blood and tissues [156]. When exposed to a wound dressing made of cellobiose, CS, and AgNPs, laboratory rats with experimental wounds recovered more quickly than their untreated counterparts [157]. The wound contraction in rats treated with silver-based dressings was larger than that in rats treated with distilled water or ionic or nanocrystalline silver dressings [157]. In comparison to a commercially available silver alginate cream, guar gum alkylamine impregnated with AgNPs showed faster wound healing in rats [158]. The proliferation and migration of keratinocytes at the site of wound healing were aided by the nano-biomaterial. AgNPs derived from Naringi crenulata leaf extracts increased wound healing in rats when applied topically [159]. For wound healing and collagen and granulation tissue deposition, activated carbon fibers containing AgNPs showed great biocompatibility in vitro [160]. An alginate fiber-integrated AgNP increased fibroblast movement, decreased inflammation, and improved wound healing in preclinical and in vitro experiments, respectively [161]. In vivo studies of AgNPs for wound healing showed that in addition to decreasing inflammation and regulating fibrogenic cytokines, these NPs have antimicrobial properties [162]. Biosynthesis of AgNPs using Phytophthora infestans microbes revealed stability and better wound contraction ability when compared to Ag sulfadiazine in an in vivo excision wound model [153]. Synthesis employing the two glycosaminoglycans (chondroitin and acharan) as reducing agents improved the endurance of these composites without any observed aggregates.

To promote wound closure, these nanocomposites were applied to the wound surface and accelerated the formation of new tissue, including granulation tissue and collagen, in a mouse wound healing model [163]. Sulfobetaine was treated with a silver–clay nanohybrid to produce an antibacterial polymer with a long-lasting and protein-resistance antibacterial activity that was regulated by diffusion [164].

These biopolymers and NPs have considerable potential to improve wound healing, especially in the treatment of DFUs [154], which are still a huge issue and are connected to high amputation rates and clinical expenses. Testing of antimicrobial peptide-AgNPs composite on diabetic rats by Dai et al. has shown that the compound has wide-spectrum activity without causing resistance, as well as improved wound healing without affecting the dermal tissues [165]. Silver, which has a lot of antibacterial properties on several levels [166], makes it less likely that multidrug-resistant bacteria would acquire resistance. The wound-healing effects of AgNP were studied in albino rats by Kumar et al. AgNP-containing cream formulations reduced wound area, increased collagen deposition, fewer macrophages, necrosis, and increased levels of fibrous fibroblasts in mice [167]. When applied to bandages after thermal damage in BALB/C mice, AgNPs (14 nm) decreased inflammation and scarring while also preventing bacterial development [168]. Albino rats have also been proven to benefit from biosynthesized AgNP ointments, which demonstrate the usefulness of AgNPs [169]. Adibhesami et al. reported that the common pathogen Staphylococcus aureus, which causes wound infections, was suppressed by AgNPs in the wounds of mice implanted with the NP. Wounds infected with bacteria recovered more rapidly and efficiently in this study, with no side effects [170]. It was shown that nano-biocomposites containing AgNPs expedited wound healing in diabetic mice by dramatically increasing the expression of collagen and growth factors, improving re-epithelialization, vasculogenesis, and collagen deposition in comparison to control groups [171].

According to recent research [166], AgNPs may speed up myofibroblast differentiation, which in turn increases wound contraction and healing time. Silver has also been proved to promote keratinocyte proliferation and relocation throughout the healing process. An excisional wound model in mice was used to study the impact of AgNPs on skin cells. According to histology and wound model experiments, AgNPs increase keratinocyte proliferation and migration as well as keratinocyte growth and maturation, which results in wound contraction. AgNP-treated wounds healed faster than those in the control group [172,173]. While wound healing, Frankova et al. studied the effects of AgNPs on primary human keratinocyte and fibroblast cells to observe how they compared to the effects of AgNPs on the most exposed cells. Proinflammatory cytokines and bacterial growth inhibition are benefits of AgNPs in wound healing. A study by Tian et al. found that AgNPs may cause an inflammatory response in a mouse model when applied topically. To better understand the function of cytokines in wound healing, scientists employed quantitative real-time RT-PCR (reverse transcription polymerase chain reaction) to examine the levels of TGF-β1 (transforming growth factor-beta-1), IL-10 (interleukin 10), VEGF (vascular endothelial growth factor), and IFN-α (interferon alpha). Changes in the mRNA levels of many cytokines were shown by AgNPs in the cytokine profile. According to Tian et al.’s findings [162], scars would be less obvious if they were coated with AgNPs. In another study, researchers formulated AgNP-based biocompatible film. In vitro experiments on HDFa cell lines confirmed the biocomposite films’ biocompatibility and revealed their antibacterial effectiveness against S. aureus. In vivo testing on rabbits revealed that the C2P4.10.Ag1-IBF film sample showed reduced fibrosis through the expression of TNFAIP8 (TNF alpha-induced protein 8) factors, MHCII (major histocompatibility complex class II) as an anti-apoptotic marker that promotes immune cooperation among local cells, SMA as a marker of the presence of myofibroblasts moving toward the interepithelial spaces in preparation for epithelialization, and Cox2 as an indicator of inflammation [174].

There is a promotion of healing and inhibition of colonization of microbes by gold nanoparticles (AuNPs). Growth as well as differentiation of keratinocytes is enhanced by AuNPs at low concentrations [175]. When AuNPs are combined with polymers or stem cells, wound-healing activity increases. The CS-AuNP enhances the free radical scavenging activity of AuNPs several-fold. As a result, polycationic CS is an important intermediary molecule in the production of AuNPs. Combining the Tegaderm dressing with chitin-AuNPs boosted hemostasis and accelerated wound healing in a rat surgical wound model, according to Volkova et al. [176]. In a second rat in vitro study, AuNPs were delivered to burn sites together with cryopreserved human fibroblasts (CrHFC-AuNP). Enhanced collagen deposition was seen in CrHFC-AuNP-treated wounds compared to non-treated wounds [177]. Gold nanoshells have shown considerable absorption cross-links without photobleaching, allowing laser-tissue repair. Using molecular chemistry and self-assembly techniques, peptide NPs may be created. Peptide-based NPs with medicinal uses, such as drug delivery, are a hot topic in synthetic biology at present. Peptide nanostructures may also be employed in the study of cell signaling and the development of biological therapies. As a result, these self-assembled peptide scaffolds may be functionally changed so that they can better interact with a variety of cell and tissue types. Peptide hydrogels, which are often used as examples of biocompatibility and cytocompatibility, are compatible with a wide range of mammalian cells and biological systems. Because of their ability to transport therapeutic substances to the site of damage and stimulate tissue regeneration, lipid NPs play a crucial role in the healing process. These lipid-based NPs, including phospholipids and solid lipids, offer desirable qualities for use in wound healing. The capacity of lipid NPs to encapsulate and distribute therapeutic substances such as drugs, growth hormones, and nucleic acids directly to the wound site is one of their key roles in wound healing. Lipidomic NPs preserve and improve the stability of these therapeutic substances, allowing for their continuous release at the wound site. By delivering the medicine directly to the site of the injury, this technique speeds up the healing process and lowers the negative effects of systemic dosing. Wound healing is aided by the innate capabilities of lipid NPs. Because of their compact size and high surface area to volume ratio, for instance, they may efficiently absorb cells and penetrate the wound bed. As a result, more therapeutic chemicals are able to reach the surrounding cells and tissues, boosting their potential to heal. The lipid-based structure of these NPs makes them biocompatible and less likely to induce unfavorable immune responses since they match the makeup of cell membranes. Further improving their targeting effectiveness and therapeutic efficacy is the addition of ligands to the surface of lipid NPs that preferentially bind to receptors expressed on wound-associated cells [178,179,180,181,182,183,184].

Among the lipid NPs, the capability to augment the accumulation of drugs in the skin is exhibited by liposomes thereby contributing to the healing of wounds. For the development of liposomes and lipid NPs, phospholipids are commonly used. Lipids exhibit biocompatibility and biodegradability as well as controlled release and greater loading of drugs. They also facilitate the transport of drugs because of their capability to convert lipids of skin into fluid [185].

When manufactured peptides are employed, peptides may be folded into fibrils and activated with the right cell culture media. When evenly given in cultured cells, these peptide hydrogels had no negative impact on cell survival. Peptide hydrogels, recently produced, seem to promote cell adhesion and hepatocyte development in vitro, according to preliminary investigations [186]. As a result, liver tissue regeneration is significantly affected. Native endothelial cells (ECs) may benefit from an improved microenvironment when given using peptide hydrogels [187].

Peptide amphiphile (PA) systems with bioactive epitopes have been used to improve scaffolds for certain cell types of interest. Cell adhesion antigens, for example, have been proven to be effective when combined with a specific ligand. RGDS and PA collaborated to prove an alternative support system for bone marrow mononuclear cells and enamel epithelial cells. The experimental group missing the RGDS epitope had fewer bone marrow mononuclear cells than the control group [188]. The hydrogels made by including PA into an adhesion epitope had a progressive cell-responsive matrix, and this offered a favorable environment for the proliferation of dental stem cells, according to a separate study. The combination of several HAs has also recently been identified to generate a self-sealing pouch [189]. For tissue regeneration, this bag, which is filled with the proper liquids, may surely include human mesenchymal stem cells (MSCs). Conjugated polypeptides have been found to promote bone regeneration and functional recovery of chondrocytes in bone injury [190]. In tissue regeneration, peptide hydrogel biomaterial outperformed more traditional natural biomaterial in terms of efficacy and safety. Cell proliferation and differentiation during tissue repair were first aided by self-assembled nanostructures. You et al. formulated AgNPs (Nag) loaded with CS and collagen scaffolds [191]. The use of dermal scaffolds made of collagen and covered with AgNPs might serve as a novel non-toxic antibacterial dressing. The membrane is readily destroyed by NAg, which then enters the microbial body and converts into silver ions (Ag⁺) in the cytoplasm, harming the intracellular structure as a secondary effect. To interact with the Gram-negative bacteria E. coli, as a result, the possibility exists that NAg with the same surface area, but different shapes, might have distinct biological effects (as shown in Figure 4).

Figure 4

Antibacterial effect of NAg on wound-healing mediators. Various inflammatory mediators involved in the wound-healing action of Nag are defined.

Various other types of NP-based systems for wound healing are defined in Table 2.

Insufficient delivery of the desired concentration of antibiotics to the target bacterial cells is a major limitation of conventional antibiotic or antimicrobial treatment against biofilm infections in non-healing chronic wounds [201]. This is associated with the presence of a complex matrix network of biofilms and the avascular nature of chronic wounds [202]. If this occurs, not only may the therapeutic efficacy of orally or topically delivered medications be significantly reduced, but drug resistance could also be induced. Since extracellular polymeric substance (EPS)-forming biofilms may bind soluble antimicrobials to matrix components, preventing them from reaching target cells, they can reduce the diffusion of antimicrobial drugs to individual bacterial cells [203].

NP-encapsulated medicines have a greater chance of penetrating EPS and reaching their intended targets than do free drug molecules allowing for more effective therapeutic antibiotic administration to bacteria. NPs that are both biocompatible and biodegradable have been used as carriers for antibiotics, increasing their efficacy and allowing them to remain in the body for longer. The use of liposomes and polymeric NPs as carriers for antibiotic delivery against biofilms [204] is one example. Because their lipid bilayer structure is similar to that of cell membranes, liposome NPs have found widespread usage as drug delivery carriers in numerous biological applications [205]. The encapsulated medicine may be delivered to the cell membranes or the inside of the bacterium once the liposome NP fuses with the bacterial cell wall [206]. Liposomal antibiotic delivery to biofilms has been shown to be more therapeutically effective than free antibiotic administration, according to recent investigations. For instance, the β-lactam antibiotic piperacillin can be protected from hydrolysis by staphylococcal β-lactamase if it is encapsulated within liposomes [207]. This increased activity for piperacillin-encapsulated liposomes against S. aureus was correlated with the drug’s resistance to hydrolysis by β-lactamase. Liposomal encapsulation of gentamycin has been shown to dramatically increase its antibacterial effectiveness against P. aeruginosa biofilms, as shown in a separate investigation by Mugabe et al. [208].

NPs constructed from PLGA are well-studied polymeric NPs. The benefits of PLGA NPs include their biocompatibility and biodegradability, as well as the ability to tune the degradation profile of PLGA to regulate the release kinetics of loaded medicines [209]. Antibiotics delivered by PLGA NPs have been proven to be effective against numerous bacterial species, including P. aeruginosa [210], S. aureus [210], and Escherichia coli [211]. Lately, a novel kind of drug delivery platform called lipid–polymer hybrid NPs has evolved [212], which combines the benefits of liposomes and polymeric NPs. The core of the hybrid NP is formed of polymeric NPs, and the lipid layers around it provide structural stability and regulated biodegradability [213]. Lipids are very biocompatible; therefore, the hybrid NP has the benefits of lipids as well. Few studies have been conducted on the use of lipid–polymeric hybrid NPs for the controlled release of antibiotics [213], but it has been shown that hybrid NPs exhibit a higher cellular delivery efficacy than either liposomes or polymeric NPs when targeting cancer cells [214]. Because of this, the hybrid NPs may serve as an alternate antibiotic delivery platform to liposomes or polymeric NPs for the treatment of wound biofilm infections.

NPs’ potential to boost healing is impressive, and there are many opportunities for further development and use. Nevertheless, it should be noted that the wound site is not protected by unbroken skin. Since NPs utilized for wound healing are in touch with living tissue, ensuring their biological safety is essential before application [215]. Skin irritation and allergy are examples of the transdermal noxiousness of NPs that are often cited. Carbon nanotubes (CNTs) and nickel NPs, for example, have been linked to skin hypersensitivity due to their ions and surface coatings [216]. Transdermal skin exposure to NPs has been shown to aggravate preexisting skin inflammation, irritation, and psoriasis [217,218]. Exposure to NPs has been shown in certain investigations to cause oxidative stress, autophagy, and programmed cell death in fibroblasts and keratinocytes [219]. An NP’s toxicity is decided by its size, shape, surface charge, consistency, and concentration. Thus, it is essential to modify the physicochemical features of new NPs when developing them for wound therapy, in order to lessen their toxicity to skin cells [220].

The study by Vijayakumar et al. focused on using probiotic bacteria to produce NP-conjugated probiotics for improved antibacterial and wound-healing activity [221]. The isolated Lactiplanti bacillus plantarum strain was found to synthesize AgNPs, which were confirmed using ultraviolet-Vis spectroscopy, Fourier transform infrared spectroscopy, and high-resolution transmission electron microscopy. The biosynthesized AgNPs showed increased antioxidant and antibacterial activities and demonstrated significant wound-healing capabilities with 96% wound closure observed through an in vitro scratch-wound assay. The study provides a new green synthesis platform for probiotic bacteria to produce AgNPs, showing potential for wound healing against infectious pathogens.

Another study developed a method for synthesizing stable Nzo NP gels using zinc acetate as a precursor and optimized the synthesis parameters to achieve the most stable gels at room temperature, with a molar concentration of zinc C(Zn²⁺) ranging from 0.05 to 0.2 M at pH 8. Hydroxyethyl cellulose was found to be the optimal polysaccharide for stabilizing the ZnO NP gels, which showed irregularly shaped particles assembled into aggregates, with sizes ranging from 150 to 1,400 nm [222]. Dressings have been prepared by incorporating ZnO NPs in a matrix (bioresorbable), which is constituted of collagen and essential oil (1%). Such wound dressing has facilitated the closure of wounds and has helped in the prevention of the growth of bacteria both in vivo and in vitro [223]. The gel of ZnO NPs modified with hydroxyethyl cellulose was found to have a regenerative effect on burn wounds, significantly higher than that of the control group and the group treated with a gel of ZnO microparticles and hydroxyethyl cellulose. The healing rate of burn wounds in animals treated with gel of ZnO NPs with hydroxyethyl cellulose was 16.23% higher than in animals treated with gel of ZnO microparticles with hydroxyethylcellulose and 24.33% higher than in the control group treated with hydroxyethylcellulose. Successful impregnation of ZnO NPs in the cellulose membranes of bacteria was carried out. It has been shown to exhibit antibacterial activity against E. coli, S. aureus, and P. aeruginosa. In a burn model of mice ZnO containing bacterial cellulose, nanocomposites have shown the activity of healing significantly with fine regeneration of tissue proven by analysis histologically [224]. AuZnO core–shell composite NPs have been found to exhibit anti-biofilm as well as antibacterial activities against Staphylococcus haemolyticus (methicillin resistant) and S. aureus by releasing ROS. Thus, the proficiency of wound healing is accelerated [225].

Delayed wound healing is a common problem in many cases due to disruptions in the physiological healing process using the current wound-healing procedures. Hydrogel wound dressings have shown promise in enhancing granulation tissue and epithelium formation in the wound area by providing a moist environment. However, challenges such as exudate accumulation, bacterial proliferation, and reduced levels of growth factors have limited their effectiveness. To address these challenges, researchers developed a hydrogel wound dressing by loading platelet-rich fibrin–CS NPs into gelatin–CS hydrogel (Gel-CH/CH-PRF) using a solvent mixing method [226]. The goal was to evaluate the characteristics of the hydrogel dressings, sustained release of proteins, and reduction in the risk of infection in the wound area. The Gel-CH/CH-PRF hydrogel demonstrated excellent swelling behavior, porosity, absorption of wound exudates, and proper vapor permeability rate, providing the requisite moisture without dehydration around the wound area. The hydrogel dressing also showed a sustained release of proteins with excellent control over the release. Additionally, the hydrogel dressing showed high antimicrobial activity against both Gram-positive and Gram-negative bacteria. The presence of CS in the hydrogels resulted in the lowest scavenging capacity-50 value and the highest 2,2-diphenylpicrylhydrazyl (DPPH) radical scavenging activity at a concentration of 25 μg mL⁻¹ for the Gel-CH/CH-PRF hydrogel. The hydrogels also demonstrated excellent cell viability and proliferation. In vivo studies on a full-thickness wound model showed that the Gel-CH/CH-PRF hydrogel dressing significantly increased wound closure and epidermis thickness. The findings demonstrate the potential of the Gel-CH/CH-PRF hydrogel as an ideal wound dressing for accelerated wound healing.

Researchers developed a multifunctional wound material by modifying camelina oil bodies with AgNPs and covalently bonding them with human fibroblast growth factor 2 (hFGF₂) for the treatment of bacterial infection wounds [227]. The AgNPs-hFGF₂-OB demonstrated broad-spectrum antibacterial activity against S. aureus and E. coli, and effectively promoted the migration of NIH/3T3 cells, showing good biocompatibility. In a mouse bacterial infection wound model, the AgNPs-hFGF₂-OB group showed a significantly higher wound healing rate compared to other treatment groups, especially on the seventh day after treatment. Therefore, AgNPs-hFGF₂-OB has the potential to inhibit bacterial growth, promote collagen deposition, granulation tissue regeneration, and angiogenesis, without any significant toxicity, making it a promising wound dressing for the repair of bacterial infection wounds.

A new approach using a mussel-inspired strategy was developed to create a multifunctional hydrogel named CAC/PDA/Cu(H₂O₂), which is composed of carboxymethyl CS/sodium alginate (Alg)-based hydrogel with a PDA coating induced by H₂O₂/CuSO₄ [228]. The CAC/PDA/Cu(H₂O₂) hydrogel has excellent biocompatibility, mechanical properties, and degradability, and it is capable of antibacterial, anti-inflammatory, and angiogenesis-promoting effects in vitro. In a rat model of methicillin-resistant S. aureus (MRSA)-induced infection, CAC/PDA/Cu(H₂O₂) hydrogel efficiently eliminates MRSA, reduces inflammatory expression, promotes angiogenesis, and shortens wound-healing time. On days 7, 11, and 14, the CAC/PDA/Cu(H₂O₂) hydrogel exhibited the best wound-healing rates at 80.63 ± 2.44, 92.45 ± 2.26, and 97.86 ± 0.66%, respectively. The multifunctional hydrogel provides a promising potential for wound management and therapy for wound healing.

3.3 Hydrogels

Hydrogels have been studied as a viable wound dressing material in recent years [229]. Hydrogel wound dressings are used for both incisional and excisional wounds [230,231]. Hydrogels fit the definition of a 3D cross-linked polymeric network structure because they can hold a large amount of water while preserving their structural integrity after expanding [1,2,232,233,234]. The hydrogels consist of several hydrophilic groups that crossinteract thereby causing the formation of a matrix (3D), which can trap liquids, viz. exudates from the wound [235]. Materials for tissue regeneration that mimic natural 3D structures have elasticity like native tissue, can supply a moist environment, and absorb wound exudates including biomimetic hydrogels. These hydrogels allow for gas exchange to prevent the growth of anaerobic bacteria, act as a barrier to bacteria growth, and improve epithelization and cell migration into wound hydrogels (Figure 5) [236,237]. Another possibility is injectable hydrogels. Using injectable hydrogels for skin regeneration has several advantages, including the ability to fill wounds with uneven space, adherence to wounds, and the ability to contain bioactive substances and cells in situ [238] Traditional hydrogels may not be effective for wound healing because of their poor mechanical properties and inability to mimic the native tissue architecture [239]. In contrast, conventional hydrogels can only supply a moist environment and are restricted in their capabilities. Hydrogels having diverse functionalities that enhance wound healing have been the subject of several investigations. Added wound healing capabilities may be provided by multifunctional hydrogels in addition to creating a milieu replicating the natural tissue ECM. To reduce microbial invasion and hydrogel dehydration, these hydrogels may also be constructed in a bilayer form.

Figure 5

Representation of advantages of hydrogel cell therapies for wound healing. The hydrogels can prevent the entry of pathogens on the wound site, as they act as a protective barrier.

Due to the advancement in the field of synthetic chemistry and materials science, in situ formation of hydrogel is now possible upon delivery through standard needles. This ensures minimum invasion while delivering therapeutic payloads, and can help in induction of the regeneration process of the part of the body that is damaged [240].

Hydrogels with antimicrobial NPs have been widely investigated. In the study of wound healing, zinc oxide nanoparticles (ZnO NPs) [241], AgNPs [242], and AuNPs [243] have been used as nanocomposites in hydrogels. Antibacterial effects of most metallic NPs are decided by adherence to the membrane, destruction of the cell wall, and leakage through the outer layer of bacterial components, such as nucleic acids. Suppression of protein synthesis is the last step. In the case of metallic oxide NPs, photocatalysis serves as the principal antibacterial mechanism. There are two types of free radicals that are formed when UV irradiation strikes metallic oxide NPs: oxygen and hydroxyl radicals [244,245]. The antibacterial properties of metal NPs may be altered by a wide range of factors. AuNP’s form and surface modification were examined in one study, for example, to see how they affect wound healing. Based on the results of this study, a thermosensitive hydrogel incorporating AuNPs was developed for wound healing (rods of AuNR or spheres of AuNS). As a result, of this research, the charge of material was altered using PEG, PAH (polycyclic aromatic hydrocarbon), and PAA (peroxyacetic acid). After 21 days of therapy with poloxamer hydrogels having PEG-modified and PAH-modified AuNRs, significant wound healing without scarring was seen. In addition, compared to the other groups, the hydrogel having PAH-AuNRs exhibited considerable collagen deposition, suggesting that the lesion had healed. Despite the nanocomposite hydrogels’ antibacterial characteristics, the PEG-AuNR group had a low number of bacterial colonies. There was no bacterial growth when PAH-AuNR wounds were swapped in vivo for wounds from other groups. PAA-AuNRs, PEG-AuNS, and poloxamer hydrogels all showed mixed bacterial growth [246]. There may be a correlation between wound healing and the formation of gold aggregates in the form of gold–protein aggregation and a better organization of collagen in wounds treated with the PAH-AuNRs hydrogel. Using PEG-AuNRs hydrogel may help heal wounds because of its hydrophilicity, high absorption, and adhesiveness. The higher antibacterial activity of AuNRs in comparison to AuNS may be explained by the fact that wound healing is influenced by NP shape [247].

Anthocyanins, which are flavonoids present in a variety of fruits and vegetables, have been shown to have a wide range of beneficial effects on human health, including anti-inflammation, antibacterial, antioxidant, and angiogenesis. Hydrogels were created by adding hesperidin to the alginate/CS solution of Bagher et al. [248]. Researchers found that combining hesperidin with hydrogel improved wound healing positively. Polyphenols in grapefruit seed extract (GFSE) are classified as tannins because of the presence of these compounds. Hydroxypropyl cellulose and sodium carboxymethyl cellulose hydrogel films have improved their ability to suppress bacteria growth after being treated with GFSE [249]. A toxicologically diverse, marine natural product is found in a variety of Chinese herbal treatments such as Sophora flavescens, Radix sophorae, and many more. Although it helped maintain a good wound-healing environment, the marine-loaded konjac/fish gelatin hydrogel also inhibited the spread of germs from developing on the wound surface [250]. These hydrogels may be used in wrist-healing applications.

Huang et al. produced CS and polyethylene glycol diacrylate (PEGDA) hydrogels [251] by directly combining PEGDA/CS-PSI hydrogels with trp-rich PSI and CS. Although PSI has a broad variety of antibacterial characteristics, its cytotoxicity is low, and it does not build bacterial resistance when overused. PSI-loaded hydrogels outperform PSI-free hydrogels in terms of antibacterial efficacy against E. coli and S. aureus.

Chronic wounds were treated with GelMA and recombinant tropoelastinmethacryloyl-substituted (MeTro) hydrogels [252]. Later, AMP Tet213 was put right into the hydrogel solution, which was then used to photo-cross-link the hydrogel precursor solution. The bactericidal activities of AMP Tet213 and ZnO NPs were also studied using MeTro/GelMAZnO hydrogels. In terms of both qualitative and quantitative antibacterial activity, AMP Tet213 and ZnO NPs were compared. To address the limitations of ZnO NPs, AMP-based antibacterial techniques may be able to supply an alternative. Because of their long-term activity, noble metal ions have long-term suppressive effects on bacterial growth and photothermal properties. When combined with heat treatment, inherent antibacterial activity may have a quick, highly effective, and long-lasting antibacterial impact. Gallic acid-modified Ag (GA-Ag) NPs were implanted into the carrageenan network structure to form an antibacterial hydrogel [253]. GA-AgNPs may be employed as a photothermal agent to kill bacteria when exposed to NIR irradiation.

CNTs supply a long-term antibacterial activity that is persistent in the presence of light. NIR radiation may be converted to heat energy with their help. CNTs may be added to hydrogels to improve cell adhesion, proliferation, and differentiation. CNT-based hydrogels for PTA treatment of bacterial wounds have been attracting increasing attention during the last several years. Antibacterial sticky and conductive gelatin-grafted-dopamine (GT-DA)/CS/CNT composite hydrogels were generated by the oxidative coupling of catechol groups between GT-DA and PDA-coated CNTs [254]. Guo et al. have developed a CEC-PF CNT hydrogel that has excellent NIR stimuli responsiveness and remarkable photothermal antibacterial activity. Antibacterial properties and therapeutic efficacy were equivalents between the PTA group and the antibiotic-loaded group [255]. These photothermal hydrogels are a promising way for the treatment of infected skin defect wounds.

Researchers have developed an all-natural hydrogel wound dressing with intrinsic immunomodulatory ability that can regulate macrophage heterogeneity by increasing the conversion of pro-inflammatory macrophages to anti-inflammatory phenotypes [256]. The hydrogel is bioadhesive, scavenges ROS, and has antibacterial properties, providing effective protection to the trauma surface from secondary damage. The prepared FGMA/FG/PA hydrogel has been shown to have good anti-infective and immunomodulatory abilities in vitro and in vivo experiments. The hydrogel can regulate the immune microenvironment at the trauma site, shorten the inflammation period, promote vascular regeneration, and have good therapeutic effects on diabetic trauma. The hydrogel has been found to be able to activate the immune regulation of macrophages, and it shows promising applications for diabetic wound repair and other immune-related disease treatments. The hydrogel can potentially improve wound healing by regulating macrophage heterogeneity, and it is expected to have significant implications for the development of advanced wound dressings. Interestingly, it has been found that compared to hydrogels without bFGF and wound-healing products commercially available, bioinspired hydrogels with bFGF can cause significant enhancement of proliferation of cells. Moreover, they are also more efficient in inducing re-epithelialization of the wound, deposition of collagen, and contraction of the wound without any significant inflammation and toxicity [257].

Titanium-oxo-clusters (TOCs) are widely used in various fields but their application in biomedical areas is limited due to their unstable structure and lack of antibacterial and anti-inflammatory properties. Luo et al. developed a stable, antibacterial, and anti-inflammatory Ag-titanium-oxo-cluster (Ag-TOC) by introducing silver and salicylic acid using a solvothermal method [258]. The Ag9Ti4 cluster was then incorporated into a dopamine-containing hydrogel system, which demonstrated good antibacterial and photothermal properties in vitro. The Ag9Ti4 hydrogel system also showed better anti-inflammatory and wound-healing ability in vivo under NIR conditions. The study suggests that the Ag-TOC hydrogel system could provide a new strategy for the expanding biomedical applications of TOCs.

Adipose-derived stem cells (ADSC)-originating exosomes (ADSC-Exos) have been identified as a potential strategy for diabetic wound repair. However, the fast decrease in biological activity and unknown biological mechanisms limit their clinical application. To address these issues, hypoxia-pretreated ADSC-Exos (ADSC-HExos)-embedded GelMA hydrogels (GelMA-HExos) were developed via non-covalent force and physical embedding, creating a new approach for clinical treatment of diabetic wound repair [259]. In vitro, GelMA-HExos hydrogels had a loose porous structure, stable degradation, and expansion rate. In vivo, GelMA-HExos hydrogels promoted wound healing in diabetic mice. Furthermore, ADSC-HExos had an enhanced therapeutic effect, in which circ-Snhg11 expression was increased. circ-Snhg11-modified ADSC-Exos increased the migratory, proliferative, and blood vessel regeneration potential of vascular ECs. Overexpression (OE) of NFE2L2-HIF1α or inhibition of miR-144-3p – both of which are members of the miR-144-3p/NFE2L2/HIF1α pathway downstream of circ-Snhg11 – reversed the therapeutic effects of circ-Snhg11 [259]. This study explored the effects and downstream targets of hypoxic engineered exosome hydrogels in managing diabetic wound repair and these hydrogels are expected to have application possibilities in other disease areas. The regulation mechanism study found that circ-Snhg11 delivery from GelMA-HExo incremented survival and maintained EC function, possibly via the activation of miR-144-3p/NFE2L2/HIF1α signaling. These findings suggest a new therapeutic strategy for patients with diabetic ulcer. However, further investigation is needed to reverse the problems associated with poor mechanical properties, low biological activity, short duration of effect, and high risk of sudden release of exosomes [259].

A new physical dual-network multifunctional hydrogel adhesive has been designed based on polysaccharide material for the treatment of full-thickness skin defects infected with multidrug-resistant bacteria [260]. The hydrogel uses ureido-pyrimidinone (UPy)-modified Bletilla striata polysaccharide and dopamine-conjugated di-aldehyde-HA as matrix materials for strong biocompatibility and wound-healing ability. The catechol-Fe³⁺ and quadrupole hydrogen-bonding cross-linking of UPy-dimer provide a highly dynamic physical dual-network structure that imparts good rapid self-healing, injectability, shape adaptation, NIR/pH responsiveness, high tissue adhesion, and mechanical properties of this hydrogel. Bioactivity experiments showed that the hydrogel also possesses antioxidant, hemostatic, photothermal-antibacterial, and wound-healing effects. This functionalized hydrogel shows promise as a candidate for clinical treatment of full-thickness bacteria-stained wound dressing materials.

The development of a thermosensitive hydrogel that undergoes a sol–gel transition at body temperature has been presented as an effective wound dressing for promoting healing and preventing infections. A study introduces a ROS-scavenging hydrogel based on polydopamine-modified poly(ε-caprolactone-co-glycolide)-b-poly(ethyleneglycol)-b-poly(ε-caprolactone-co-glycolide) (PDA/P2) triblock copolymer [261]. The PDA/P2 solution at 30 wt% concentration forms a gel at 34–38°C and was found to have ROS-scavenging properties through DPPH and ABTS assays and intracellular ROS downregulation in RAW264.7 cells. Additionally, AgNPs were encapsulated in the hydrogel to provide antibacterial activity against E. coli and S. aureus. An in vivo study on an S. aureus-infected rat model demonstrated that the PDA/P2–4@Ag hydrogel dressing could promote wound healing by inhibiting bacterial growth, alleviating the inflammatory response, and inducing angiogenesis and collagen deposition. This study highlights a new approach to preparing temperature-sensitive hydrogel-based multifunctional wound dressings.

The development of novel hemostatic materials with wound-healing properties has gained significant attention in recent years [262]. A series of ultrafast cross-linked adhesive hydrogels have been developed using biomass-derived materials such as Schiff base and ionic coordinate bonds among catechol-conjugated gelatin, dialdehyde cellulose nanocrystals, calcium ions, and ferric iron. The hydrogels exhibit adjustable gelation time and mechanical properties by altering the contents of dialdehyde cellulose nanocrystals and ferric iron. The hydrogels are also endowed with self-healing and injectable performance, enhanced adhesiveness, near-infrared responsiveness, and antibacterial activity due to the introduction of catechol groups and the formation of catechol–Fe complexes. The hydrogels demonstrate rapid hemostasis and biodegradability in vitro and in vivo experiments. Furthermore, the hydrogels accelerate the regeneration of wound tissues in a rat full-thickness skin defect model, suggesting their potential as hemostatic materials for wound-healing applications in the biomedical field.

3.4 Smart dressings

In most instances, dressings based on nanotechnology are used for delivering actives to the wound bead. When the size of the materials is reduced to nanoscales, there is a change in the physicochemical features. This can also help in influencing and accelerating the process of healing [263,264]. The pH of healthy skin is between 4.0 and 6.0. Further evidence that the pH of the wound environment changes from alkaline to neutral and then acidic as a wound heals was reported by Gethin, who also discussed the significance of pH in acute and chronic wound healing [265]. But this is a widely accepted concept [266]. The wound site has a lower pH than the surrounding skin, regardless of the pH. pH-responsive dressings have been utilized to treat infected and chronic wounds [267,268,269] based on this pH difference. Externally controlled change and pH change may be categorized as stimulus-sensitive materials using the following: the work of Kiaee et al. [268] demonstrates an example of an externally controlled wound dressing that reacts to pH variations. The pH of the wound dressing was adjusted using electrical voltage throughout the study. Wounds were treated with CS NPs enclosed in a PEG-diacrylate/laponite dressing.

A whole new hydrogel material constituted of genipin and polysaccharide of Bletilla striata crosslinked with CS has been used for wound dressing. This combination presented comparatively better features than CS crosslinked solely with genipin. However, this material exhibited poor activity against bacteria. Thus, to overcome this issue, the proposal of a nanohybrid has been given. The nanohybrid in its final formulation is incorporated with AgNPs. The dressing with nanohybrid provides permeation of gas and has the ability to retain water. Moreover, it suppresses the proliferation of bacteria and augments the proliferation of fibroblasts thereby showing its great potential for using in order to facilitate the healing of wounds further [270].

Zinc and copper wires were used as anodes and cathodes, respectively, to apply a direct current voltage to the hydrogel. As the positive charge moved away from the anode in this experiment, a redox reaction at the electrode increased the pH (the cathode was not immersed in the hydrogel). The deprotonation and shrinking of CS NPs in a basic environment, and the weakening of the electrostatic link between laponite and these NPs as pH rises, might promote drug release from these particles. With this externally managed pH change, wound dressing drug release may be consistently and swiftly increased. The external control is cumbersome in practice for this pH-sensitive wound dressing, which requires a very high pH value for best medicine release.

The acidic environment of the stomach, on the other hand, is a given. They developed an acidic pH-responsive hydrogel to prevent stomach bleeding, and this enhanced gastric wound healing considerably [271]. When acryloyl-6-aminocaproic acid and acryloyl-NHS (AA) were polymerized, hydrogels were created. This hydrogel shows exceptional adhesion properties due to its reactivity with amino groups found in biological tissues. The hydrogels expanded less in acidic solution because of an intramolecular hydrogen link between carboxyl groups at low pH (pH 2.0). Because of its low swell ratio, this hydrogel could endure an acidic environment. In a pig gastrointestinal hemorrhage model, these hydrogels have been found to successfully minimize delayed bleeding. The hydrogel’s initiator and catalyst, if used, might be cytotoxic. Gel-preparation research in the future will use safer techniques.

NIR-responsive wound dressings may be used in a variety of ways, including releasing gaseous molecules and creating photothermal effects. NIR activation of a hydrogel-NP composite wound dressing from Liu et al. effectively inhibits bacterial infection and releases NO to stimulate angiogenesis [272]. ZIF-8 (zeolitic imidazolate framework-8) changed with PDA (BNN6) and was used as a loading agent. Hydrogels composed of gelatin methacrylate and oxide dextran were used to enclose them (GelMA). This increased the photothermal activity of NPs, which resulted in the death of bacteria when exposed to NIR light. BNN6, on the other hand, may continually create NO when subjected to an 808 nm NIR laser. With the help of our NIR-responsive multifunctional wound dressing, wound healing and angiogenesis were significantly improved. The photothermal effect combined with other NIR-triggered releases may be a solution for adaptive wound dressings that can employ NIR light to its maximum potential.

Chronic wounds, such as diabetic ulcers, supply a significant challenge to wound healing. Diabetics often have abnormalities in wound-healing angiogenesis, which may cause healing to be delayed or cause other issues. Wounds become more prone to infection in hyperglycemia. In the treatment of diabetic wounds, a wound dressing that reacts to changes in blood glucose may be beneficial. An easy-to-implement method for making wound dressings that respond to changes in blood glucose is the glucose-responsive drug release method. When Zhao et al. developed a glucose-triggered drug release mechanism using the Schiff-base and phenylboronate ester reaction, it was the method they employed [273]. For the crosslinking of CS with PVA, we used phenylboronate (CSPBA) and PEG with a benzaldehyde cap, while for the amino group modification we used CSPBA. This two-network configuration proved the hydrogel’s pH and glucose reactivity. If glucose competes with PVA for the synthesis of phenylboronate esters with CSPBA, the crosslinking of this hydrogel may weaken, allowing insulin release from CSPBA hydrogels. This glucose-responsive wound dressing may help control blood glucose levels in addition to speeding up wound healing. A whole new approach to the treatment of wounds and sickness is offered by this study.

Wang et al. developed an injectable polysaccharide-based bandage including exosomes (FEP@exosome) for the treatment of diabetic wounds [274]. FEP@exosome dressing’s pH-responsive release of exosomes, as well as its antibacterial, rapid hemostasis, tissue-adhesive, and UV shielding characteristics, may help angiogenesis. These results imply that the long-term release of bioactive chemicals from an exosome-based dressing and the pace with which the wound heals might work together to speed up healing and minimize scar formation. “Exosome-based wound dressing” treatments based on the release of therapeutic chemicals have also been reported in the literature [275,276,277]. Patients no longer have to travel far to a local clinic for traditional hospital-centered wound management, which is shifting its focus toward the development of multifunctional and self-sustaining wound dressings, which emphasize long-term, continuous monitoring, early diagnosis, and prompt treatment for the benefit of both patients and clinicians.

3.5 Microneedles (MNs)

The use of MNs in medicine is on the rise. They can help with medication delivery [278,279] and are minimally invasive devices that can go through the skin [280]. Due to their capability to deliver transdermally and greater surface area specifically, there is recognition of MNs as encouraging biomaterials for the healing of wounds [281]. There is evidence that their use aids in the repair of scar tissue in dermatology as well [282]. They will not cause any discomfort since they are designed to go just 50–100 µm deep into the skin without touching any nerves. MNs manufactured from carbohydrates offer a number of benefits [283], in contrast to those from more traditional materials like silicon, metal, ceramic, or silica glass. Before shaping the MNs, the medications may be mixed into the mixture, and then the MNs can dissolve into the skin. Yao et al. developed a moldable, biodegradable, and wound-friendly Zn-MOF encapsulated methacrylate hyaluronic acid (MeHA) MN array (MNA) to speed up the healing process [284]. Such an MNA displays good antibacterial activity and great biocompatibility due to the damaging ability against the bacterium capsule and oxidative stress of the zinc ion emitted by the Zn-MOF. Furthermore, the photo crosslinked MeHA in the degradable MNA has better capabilities for releasing the loaded active ingredients slowly and gradually to prevent further wound injury. Also helpful for tissue regeneration is the low molecular weight HA that is produced when MeHA is hydrolyzed. The Zn-MOF-encased degradable MNA has been shown to significantly speed up epithelial regeneration and neovascularization due to these properties [284].

Zeng et al. introduced an MN dressing with synergistic flexibility to promote wound healing in diabetic patients [285]. The anti-diabetic medicine metformin may be placed onto MNs, which can then puncture the skin of diabetic rats to elicit a reaction for managing blood glucose levels. CaO₂@polydopamine (CaO₂@PDA) is a unique multifunctional nanosystem incorporated into polycaprolactone and gelatin (PCL/Gel) Electrospinned nanofiber films, as MN back patches to reduce inflammation, increase oxygen delivery, and soak up any exudate that could otherwise be left behind. As a bonus, the CaO₂@PDA applied to the back patches showed promising antibacterial activity against S. aureus and E. coli. In addition, a high CD31 and low TNF- level was shown by the as-fabricated flexible MN dressings loaded with metformin and CaO₂@PDA NPs, resulting in rapid diabetic skin-wound closure.

Mechanical strength and toughness are important for MNs to avoid deformation and breakage during penetration of the stratum corneum [286]. MNs should have their size perfected to maximize medication load with minimal needle size. Furthermore, various MN sizes and uses need distinct production methods. Based on their research, Du et al. concluded that the mechanical characteristics of MNs were similarly affected by the molecular weight of the polymer and the kinds of drug loadings [287]. The MNs were made using HA of two distinct molecular weights (10 and 300 kDa) and two HA MNs (10 and 300 kDa) were loaded with bupivacaine and lidocaine, respectively. Therefore, HA (10 kDa) MN and HA (300 kDa) MN have comparable mechanical strength, exceeding those of their drug-loaded MNs.

A double-layer MN patch for diabetic wound healing was developed, comprising an HA-loaded antibiotic drug and an angiogenic drug-containing CS and SF substrate [288]. The system showed excellent mechanical properties, biocompatibility, antibacterial, and angiogenesis-promoting capabilities. The tip of the MN was loaded with tetracycline hydrochloride for early antibacterial activity, while the substrate containing deferoxamine promoted wound contraction and angiogenesis. In vivo experiments in diabetic rats demonstrated reduced inflammation and accelerated wound healing. DMN@TCH/DFO has the potential for clinical applications in diabetic wound healing.

A core–shell HA MN patch has been developed which contains artificial nanovesicles derived from ferrum-MSCs and the needle tips are encapsulated with PDA NPs. MSC-derived artificial nanovesicles augment the mRNA and protein expression in a more heightened manner in comparison to the exosomes secreted naturally and the yield production is also increased [289,290]. The development of a methacrylate gelatin (GelMA) MNs patch has been reported. It is used for achieving the release of exosomes and tazarotene transdermally and in a controlled manner. In this context, it is to be noted that tazarotene is a drug that has got similarity to retinoic acid and it causes effective promotion of angiogenesis: regeneration of hair follicle as well as collagen in repair of wound. Clinically, the MN patch mentioned above can be used to repair diabetic wounds [291,292].

Researchers have developed a multifunctional MN patch for rapid wound healing through chemo-photodynamic antibacterial effects and sustained release of growth factors [293]. The MN tips contain antibiotics and bioactive small molecule-encapsulated metal–organic frameworks (MOFs) that dissolve and deliver the payloads to the wound upon piercing the skin. Upon light irradiation, the MOF-based NPs convert O₂ into ¹O₂, which synergistically removes pathogenic bacteria from the wound, reducing the required antibiotic amount. The NPs also achieve continuous growth factor release in the wound tissue, promoting epithelial tissue and neovascularization, and accelerating chronic wound healing. The MOF-based MN patches offer a simple, safe, and effective alternative for chronic wound management. Regeneration of epithelium and neovascularization can be accelerated dramatically by a degradable MNA encapsulated with Zn-MOF. Such results are indicative of the fact that when a degradable MNA is used combinedly with MOFs, it is highly effective in the promotion of healing of wounds [281].

Researchers have developed triple-helical recombinant collagen (THRC) dressings that accelerate the healing of acute skin wounds caused by MNs and photodamage [294]. The dressings were found to be biocompatible and non-irritating in cell and animal studies. Histological analysis of animal models showed that the THRC dressings effectively healed damaged dermis by accelerating re-epithelialization and enhancing collagen deposition. The dressings were also found to exhibit rapid epithelialization rates similar to commercial bovine collagen dressings in MN-injured rat defects. The triple-helical structure of collagen was confirmed by circular dichroism measurements. In vitro tests using L929 fibroblasts revealed that THRC dressings were highly biocompatible and promoted the proliferation and adhesion of fibroblasts. The research suggests that THRC dressings could provide an advanced treatment for acute skin wounds and have attractive applications in postoperative care for facial rejuvenation.

Wang et al. developed patch for diabetic wounds to treat them non-invasively [295]. A PLGA-based MN patch was loaded with magnesium hydride (MgH₂) macroparticles (MN-MgH₂) for transdermal administration and extended release of H₂ and Mg ions (Mg²⁺). MgH₂ is a commonplace kind of H₂ storage for portable uses. MgH₂ has more storage and generation capacity for H₂ than Mg powder and is substantially more stable at room temperature. However, MgH₂ treatment is a relatively unexplored area. The resulting Mg²⁺ has the potential to convert macrophages into repairing M2 macrophages and boost angiogenesis to reduce hyperglycemic-induced microvascular damage. Hence, MgH₂ may be a useful therapeutic agent for diabetic wound healing. However, using a PLGA-based MN patch allows for transdermal delivery of MgH₂ with minimal invasiveness, protects MgH₂ from contact with water to prolong its lifetime, and permits sustainable release of MgH₂ into the physiological microenvironment, all of which have previously been demonstrated for subcutaneous drug delivery. Moreover, the local acidity was increased by the dissolved PLGA and its breakdown products (lactic acid and glycolic acid), which promoted the release of Mg²⁺ from Mg(OH)₂. As a consequence, MN-MgH₂ has been shown to improve wound healing in vitro and in vivo by decreasing ROS production, promoting M2 polarization, increasing cell proliferation and migration, and enhancing angiogenesis and tissue regeneration [295].

One of the leading causes of mortality is excessive bleeding, especially after trauma. Controlling fatalities requires immediate action to stop bleeding after a trauma, such as a gunshot. Hydrogels, which change phase from liquid to a crosslinked solid, stick to tissue and provide hemostatic effects; they have largely replaced sutures and staples in surgical applications. These materials are not ready for immediate use since they need extensive preparation and sophisticated processing, such as photo-/thermoactivation. By nanoengineering of GelMA, a popular cell-friendly biopolymer, researchers have generated hemostatic MNAs with silicate nanoplatelets (SNs) that can greatly enhance the contact area with blood and stick to the wound through an interlocking mechanism [295]. They demonstrated that the clotting time may be reduced by 89% in vitro by doping GelMA MNAs with only 2% w/v of SNs, which is not achievable with hydrogels of the same composition. After applying designed GelMA-SN MNAs to the perforated liver wound, they noticed a 92% decrease in bleeding compared to the untreated damage group. Moreover, the hemostatic MNAs might degrade in vivo in a timeframe (4 weeks) that is suitable for the wound-healing process without eliciting substantial inflammatory reactions. Because of their good bio/hemocompatibility and biodegradability, hemostatic MNAs may be placed on the site post-surgery to prevent internal bleeding without causing difficulties or requiring removal. It is also possible to enhance the hemostatic and wound healing effects of the MNAs by loading them with medicines, growth factors, or other biologics.

Thermal and mineral ingredients present in underwater hot springs offer enough energy for life to arise in these conditions [296,297]. Certain disorders may be treated by soaking in a spa bath heated to between 30 and 42°C and infused with a variety of trace elements and minerals (including iron, metasilicates, and Ag⁺). Mice suffering from hind limb ischemia may benefit from EC tube formation and angiogenesis when subjected to thermal stimulation [298,299]. Spa baths have been found to speed up wound healing in a nude rat model by increasing the vascular density of granulation tissue [298]. Using photothermal effects and the release of bioactive ions (Fe²⁺ and SiO 4 4 − ), Sheng et al. showed the fabrication of hydrogels mimicking “hot springs” that stimulate angiogenesis and wound healing in vivo [296]. Additionally, Kang et al. [300] proposed that vascular tube development and angiogenesis might be induced by polyvinylpyrrolidone-coated AgNPs. The “hot spring” effect may be achieved by combining the bioactive molecule Ag⁺ and BP with NIR irradiation, which creates a confined and moderate thermal environment. According to this hypothesis, a highly antimicrobial wound dressing with a “hot spring” effect was developed [301]. Electrospinning using PCL as a carrier yielded PCL/AgNPs/BP (polycaprolactone [PCL], nanosilver [AgNP], and black phosphorus [BP]) nanofibers, as illustrated in Figure 6. Using a full-thickness skin injury model (Figure 6), it was found that applying this wound dressing resulted in the release of AgNPs or silver ions from the nanofibers with bactericidal activity, which then destroyed bacterial biofilms, boosted cell proliferation, and stimulated angiogenesis. Stimulating blood pressure increases temperatures, which in turn boosts the release of silver ions, susceptibility to microorganisms, and vascular regeneration. The combined effects of AgNPs and BP expedite wound healing by decreasing inflammation and promoting the growth of granulation tissue, collagen deposition, and vascularization. Infected skin wounds may be treated clinically using PCL/AgNPs/BP nanofibers due to their favorable features.

Figure 6

Illustration representing preparation and application of PCL/AgNPs/BP nanofibers. (a) Fabrication of nanofibers using electrospinning technique. (b) NIR-assisted action of nanofibers to promote wound healing. Reproduced with permission from Zhao et al. [301].

3.6 Role of AI in wound healing

The printing settings in 3D (bio)printing must be optimized for the production of scaffolds with desired architectures and acceptable homogeneities [234]. Conventional methods for improving the settings often need the operators’ earlier knowledge and time-consuming optimization tests. Furthermore, such a conventional approach may be less successful due to the fast expansion in the variety of biomaterial inks and the geometrical complexity of the scaffolds to be constructed. To overcome this difficulty, researchers suggested the use of an AI-assisted image-analysis algorithm in conjunction with a programmable pneumatic extrusion (bio)printer to create a high-throughput printing-condition-screening system (AI-HTPCSS) [287]. In a high-throughput way, the AI-HTPCSS decides the best printing parameters for producing hydrogel designs with consistent morphology and arrangement. Results reveal that scaffolds printed under the greatest circumstances have desirable mechanical qualities, in vitro biological performances, and effectiveness in speeding the healing of diabetic wounds in vivo.

Interest in applying AI to simulate the healing process of wounds has been increasing. One example of such an AI model is described in an article published in “Advances In Wound Care” and used to predict the healing of chronic wounds within 12 weeks [302]. The research concluded that the AI model could accurately predict wound healing. Wound features, rather than patient demographics, were shown to be better indicators of success in the model. AI has shown promise for predicting pressure ulcers in other research as well, and has shown promise as a tool for predicting when wounds will heal, and it has the potential to do the same for evaluating wounds. A report from 2022 claims that AI software that analyzes digital images has great potential to provide reliable data on wound evaluation [303] in contrast to the subjectivity of human observers while evaluating wound size and tissue changes manually. By eliminating observer bias, computer-based image analysis may greatly enhance wound evaluation. The results of wound treatment will improve, and so will the satisfaction of patients.

The utilization of AI-based software and telemedicine has the potential to be a crucial factor in the provision of uninterrupted healthcare services to the populace by means of prognostication and evaluation. The implementation of this technology would facilitate enhanced accessibility for a broader range of patients to avail the services of proficient wound care specialists. The utilization of camera applications, AI, and telemedicine in conjunction with smartphones enables patients and their careers to capture images of their persistent wounds, which are subsequently employed in the evaluation and treatment of the wounds. The images can be expeditiously shared via an application, enabling healthcare professionals to promptly assess the visuals in real-time. The proposed solution would facilitate remote monitoring of chronic wounds by wound care specialists, thereby enabling them to assess the wound status even in the absence of in-person clinic visits. The relevance of telemedicine’s accessibility is evident as certain patients with chronic wounds may be confined to their beds and unable to physically attend appointments with their healthcare provider. In the absence of an application, these individuals would encounter difficulties in obtaining essential healthcare services. Considering these factors, it is evident that the implementation of AI and telemedicine holds immense potential to transform the delivery of wound care to patients. The implementation of this approach has the potential to reduce expenses, enhance efficacy, and promote equitable access to healthcare.