Following an injury, blood arteries undergo a fast constriction process to minimize bleeding from damaged microvasculature. The method of achieving this phenomenon involves the reflexive contraction of vascular smooth muscle, which is initiated by vasoconstrictors such as endothelin (44). The regulation of vasoconstriction is also influenced by circulating catecholamines, such as epinephrine, norepinephrine, and prostaglandins. Platelets are responsible for the production of platelet-derived growth factor (PDGF). This signaling molecule stimulates the activation of mesenchymal cells, namely smooth muscle cells located inside the walls of blood vessels (45).

Nevertheless, the first reflexive contraction of muscles only temporarily reduces bleeding. This is due to the fact that the wound experiences a rise in hypoxia and acidity, leading to passive muscle relaxation and subsequent resumption of bleeding. The subsequent activation of the coagulation cascade is necessary to control the process of vasoconstriction further and facilitate the resolution of long-term bleeding. Vasoconstriction, accompanied by clot formation, is crucial in preserving life by preventing excessive blood loss. However, this physiological response may also result in impaired local perfusion, heightened glycolytic activity, and alterations in pH levels (43, 46).

After an injury and the subsequent rupture of blood vessels, the thrombogenic subendothelial matrix becomes exposed, which facilitates the binding of platelets and initiates the inside-out signaling route for platelet activation. Consequently, this phenomenon results in the activation of integrins, promoting enhanced platelet adhesion to both neighboring platelets and the adjacent ECM. The external-to-internal signaling route enhances platelet activation and regulates the actin cytoskeleton, resulting in the transformation of the platelet into a cell with a fried-egg-like morphology that exhibits robust adhesion to the ECM, undergoes contraction, and effectively occludes the blood a blood vessel (39, 47, 48). The surface area of the activated platelet is increased as a result of the fusion between intracellular granules and the plasma membrane or surface-connected membranes of the open canalicular system (OCS). The granules mentioned above are responsible for the secretion of more than 300 bioactive compounds, including ADP, serotonin, calcium, histamine, as well as vWF and integrins, which play crucial roles in both primary and secondary hemostasis (42, 49). The surface area of the activated platelet is increased as a result of the fusion between intracellular granules and the plasma membrane or surface-connected membranes of the OCS. The granules, as mentioned above, are responsible for the secretion of more than 300 bioactive compounds, including ADP, serotonin, calcium, histamine, as well as vWF and integrins, which play crucial roles in both primary and secondary hemostasis (50). Activated platelets also secrete molecules such as thromboxane A2, which enhance platelet aggregation, resulting in the formation of the “platelet plug.” The release of cytokines and growth factors by platelets inside the plug plays a crucial role in cellular mediation for the process of healing. The intensity of platelet factor release is highest during the first hour after activation. However, the release of these factors by activated platelets persists for seven days, hence imposing paracrine impacts on many cell types present in the wound (47).

Platelets are crucial in assembling and activating coagulation complexes, triggered by contact with the subendothelial matrix, with traditional coagulation routes recognized in the field. These pathways are triggered upon contact with the subendothelial matrix. The activation of Factor X initiates the process of fibrin synthesis, ultimately resulting in the development of a blood clot. The blood clot consists of cross-linked fibrin, along with cellular components such as erythrocytes and platelets. Additionally, various ECM proteins, including fibronectin, vitronectin, and thrombospondin, are present in the clot (6, 51). Factor XIII is responsible for the covalent crosslinking of fibrin, which results in the binding of the aggregated platelet plug. This process leads to the formation of a final secondary hemostasis plug, also known as the thrombus. The thrombus functions as the temporary ECM for the invasion of various cells throughout the following phases of the healing process. The adhesion of platelets is facilitated by activated integrin receptors located on their surface (52, 53). The adhesion of platelets is facilitated by activated integrin receptors located on their surface. Platelets in the clot degranulated, producing powerful inflammatory cell chemoattractants, local fibroblast and EC activation factors, and vasoconstrictors. CCL5, thrombin, TGF β, PDGF, and VEGF are important chemokines that regulate coagulation and restrict blood vessel formation (54). The process of fibrin breakdown and the subsequent activation of the complement system are essential components in initiating the inflammatory response, promoting the formation of new blood vessels in wounds, and enabling the proliferation of stromal cells. Fibrin interacts with integrin CD11b/CD18 on invading monocytes and neutrophils, as well as fibroblast growth factor 2 (FGF 2) and VEGF, hence facilitating the process of wound tissue vascularization. In cases of thrombocytopenia, macrophages and T lymphocytes present at the site of injury serve to compensate for the deficiency of platelet-derived growth factors (PDGFs) and commence the inflammatory phase (35, 38, 55–57).

Apoptosis, a regulated form of cell death, serves a critical function in the stages of tissue healing, as shown by its complex involvement in the resolution of these phases (112). The occurrence of apoptosis in inflammatory cells may be noticed as early as 12 hours after the occurrence of a lesion, as shown by the findings of Brown et al. in their research conducted in 1997. Additional investigations conducted on rats have demonstrated the occurrence of apoptosis in scab-inflammatory cells and myofibroblasts, which play a critical role in wound healing and tissue regeneration. This process was seen to begin around the twelfth day, reach its highest point on the twentieth day, and then resolve by the sixtieth day (113).

The research findings demonstrate a temporal association between the process of myofibroblast apoptosis and the healing of wounds, explicitly highlighting the role of stromal keratocytes (114). The initiation of cellular processes crucial for corneal wound healing is facilitated by apoptosis, whereas a delay in healing might occur due to delayed phagocytosis of apoptotic neutrophils by macrophages. The investigation also examines the involvement of apoptotic cells in the release of growth signals that induce cell proliferation. The fundamental determinant of wound healing is the process of apoptosis in immune cells, which prompts inquiries about the principal component (115).

The cellular process of autophagy, which involves the degradation and recycling of cellular components, is known to have a significant impact on wound healing. It actively participates in several phases of the healing process, contributing to its overall efficiency and effectiveness (121). The early phase of inflammation after an injury serves to commence the process of wound healing by recruiting monocytes and neutrophils to the site of damage. Neutrophils are essential in the defense against microorganisms and the facilitation of inflammation by using antibacterial and proinflammatory processes such as phagocytosis, formation of ROS, degranulation, and the release of neutrophil extracellular traps (122). Autophagy is of great importance in the context of neutrophil-specific activities since it has been seen to enhance the phagocytic activity of human neutrophils when subjected to Streptococcus pneumoniae. The reduction of autophagy leads to a decrease in rates of phagocytosis. The investigation using mice that lack specific autophagy-related genes (Atg5/7) demonstrates a reduction in neutrophil degranulation and levels of ROS, therefore emphasizing the complex relationship between autophagy and neutrophil functionality ( Figure 3 ) (123).

Moreover, the stimulation of autophagy enhances the creation of NETs. It increases the survival rate in mice afflicted with sepsis, therefore emphasizing its significance in the immune response. Furthermore, the impact of autophagy on macrophages is evident in the observation that the administration of 3-methyladenine amplifies their capacity to engulf pathogens, therefore emphasizing the intricate interplay between autophagy and macrophage functionality (121, 124). Moreover, the impairment of autophagy in macrophages results in their polarization towards the M1 phenotype, while the stimulation of autophagy favors the M2 phenotype, hence diminishing inflammation and facilitating tissue regeneration. However, the precise underlying mechanism remains ambiguous and needs additional research (125).

Recent research has demonstrated that MSCs have crucial functions in the process of tissue regeneration and wound healing. These functions include encouraging the growth of new blood vessels (angiogenesis), controlling inflammatory responses, and improving the formation of new epithelial tissue (126). Prior research has shown that controlling autophagy could be a successful approach to enhance the survival of MSCs and enhance the results of wound healing (127). A prior investigation discovered that palmitate stimulates the programmed cell death of MSCs by causing an increase in the levels of ROS inside the cells. However, the activation of autophagy, which occurs via the ROS–JNK–p38 MAPK signaling pathway, safeguards MSCs from undergoing apoptosis (128). Overexpression of hypoxia-inducible factor-1α enhances the survival of MSCs in low oxygen circumstances by stimulating autophagy via the suppression of PI3K/AKT/mTOR signaling (129).

Furthermore, the serine/threonine kinase aurora kinase A triggers autophagy by specifically targeting FOXO3a in order to safeguard adipose-derived stem cells from death caused by hyperglycemia. Other research has shown that blocking microRNA (miR)-34a enhances the effectiveness of MSCs in treating diabetic wounds by activating the sirtuin-1/FOXO3a pathway-mediated autophagy (130). Furthermore, An et al. demonstrated that autophagy inducer-pretreated MSCs injected subcutaneously stimulate VEGF production by triggering MSC-specific paracrine signaling via the ERK1/2 pathway, which in turn improves wound healing (121, 126).

Ferroptosis is characterized by the absence of nucleosomal DNA condensate, chromatin condensate, and apoptotic body development, distinguishing it from conventional necrosis features such as organelle enlargement and cytoplasmic rupture (131). Ferroptosis is a metabolic anomaly characterized by a diminution in the size of mitochondria, a reduction in cristae density, and an increase in membrane density. Notably, the nucleus remains unaffected in terms of its size. The condition is based on a metabolic imbalance that relies on iron, resulting in the excessive buildup of lipid ROS and subsequent cell death. Cysteine metabolism is the fundamental process (132). The cellular uptake of cystine occurs through a cysteine-glutamate antiporter known as system xc-, while the efflux of glutamate takes place. Thioredoxin reductase 1 (TrxR1) facilitates the reduction of cystine, leading to its conversion into glutathione (GSH) via the enzymatic actions of GCL and GSS (133). The lipid-repairing enzyme GPX4 is responsible for the conversion of phospholipid hydroperoxides into non-peroxide forms, therefore effectively suppressing their pro-oxidative properties. The interference of Erastin with the uptake of cystine by the system xc- transporter results in the depletion of glutathione, thus inhibiting the activity of GPX4. Consequently, this disruption leads to the buildup of ROS in lipids, an excess of iron, and an enhanced vulnerability to ferroptosis (134). The condition of iron overload leads to the occurrence of cellular ferroptosis, a process in which external Fe³⁺ molecules bind to ferritin, subsequently entering the cell via the transferrin receptor 1 (TFR1) and undergoing reduction to Fe²⁺ facilitated by STEAP3. The introduction of an excessive amount of Fe²⁺ ions into the Fenton reaction leads to the occurrence of ferroptosis (133, 135).

There is a strong correlation between ferroptosis and skin wounds (136). Multiple investigations have shown that the use of ferroptosis inhibitors may enhance the healing of diabetic wounds by suppressing the process of ferroptosis. For instance, when ferrostatin-1 (a substance that inhibits ferroptosis) is applied directly to a wound in rats with diabetes, it may speed up the healing process by blocking ferroptosis via the activation of the PI3K/Akt signaling pathway (137). Furthermore, several studies have shown that the use of DFO, an alternative form of ferroptosis inhibitors, might enhance the healing process of diabetic wounds. Gao and colleagues discovered that the simultaneous use of DFO and hydroxysafflor yellow A in a hydrogel may expedite the recovery of diabetic wounds in rats by promoting angiogenesis (138).

Excessive exposure to radiation may injure the nearby blood vessels and lead to the development of angiosclerosis. This occurs due to the detrimental effects on the structure and functions of proteins and DNA, resulting in a delay in the healing process of wounds (139). Gan et al. have shown that injecting plasma-derived exosomes (RP-Exos) locally may enhance the healing of rat irradiation wounds by increasing the growth, movement, cell division, and survival of fibroblasts. Additionally, it has been shown that RP-Exos can interfere with the ferroptosis pathway, hence preventing ferroptosis in irradiated fibroblasts (140). In addition to irradiation treatment options for tumors, excess exposure to UV radiation, particularly UVA and UVB, may also result in UV-induced cutaneous wounds. Kavita Vats and her colleagues have shown that an overabundance of UVB radiation may trigger inflammation and the death of human keratinocytes by generating ferroptosis. This process can be suppressed by ferrostatin-1. In addition, an overabundance of UV radiation may lead to a deficiency in GSH, which in turn disrupts the balance of redox reactions in the body ( Figure 4 ) (136, 141).

Ferroptosis, which involves lipid metabolism, requires lipid peroxidation. Free polyunsaturated fatty acids (PUFAs) are converted into PUFAs-phosphatidylethanolamine (PUFAs-PE), especially arachidonic acid (AA) and adrenaline, which are substrates for lipid peroxidation. ACSL4 and LPCAT3 are critical enzymes in this pathway (136, 142, 143). ACSL4 and LPCAT3 regulate Ferroptosis. LPCAT3 creates PUFAs-PE from PUFAs-CoA, while ACSL4 creates PUFAs-CoA. Ferroptosis results from PUFAs-PE oxidation and lipid peroxidation. ACSL4 is expressed more in ferroptosis-sensitive cells like HepG2 and HL60. MLE cells without LPCAT3 are more resistant to ferroptosis, lowering cell death ( Figure 5 ) (136, 144).

Chronic wounds are characterized by an overactive inflammatory response, which hinders the normal progression of the wound-healing process. This disruption ultimately results in the development of scars since it interferes with the sequential progression of the four phases of wound healing (145). The NLRP3 inflammasome, which is primarily located in cutaneous epithelial tissues, plays a pivotal role in orchestrating the immunological response of the organism. Recent studies have demonstrated that the administration of mulberry leaf and fruit extract (MLFE) has the potential to augment the process of wound healing, with a specific focus on its impact on the NLRP3 inflammasome. The combination of MLFE with mulberry leaf extract has been shown to exhibit enhanced anti-inflammatory and anti-obesity properties (146). The research proposes that MLFE can restore NLRP3 inflammasome levels in individuals with obesity, which might facilitate prompt wound healing. This finding underscores the possible associations between MLFE and obesity (147, 148).

TFNAs, DNA nanomaterials, promote corneal and skin healing with their angiogenic, antioxidant, anti-inflammatory, anti-fibrotic, and low-toxicity functions (146, 149). TFNAs heal diabetic wounds faster, decrease skin fibrosis, and block pyroptotic pathways (150). Bioactive glass (BG) may work for wound healing and soft tissue restoration. It controls the Cx43/ROS signaling pathway to suppress EC pyroptosis and improve wound healing (151). BG inhibits caspase-1 activation and perforation, slows ROS generation, and regulates connexin 43 expression, promoting blood vessel development and wound healing (148, 152).

The interaction between inflammasome, pyroptosis, and wound healing is complicated and needs additional study (153). Novel carriers and Chinese herbal extracts are being tested for therapeutic use. Recent studies have shown that the TFNAs, NLRP3 inflammasome, and BG improve healing and reduce problems. Understanding these relationships may help design chronic wound treatments and individualized wound healing techniques (148, 154).

Pyroptosis can be induced with caspase-1, NLPR3, ILβ and IL18. The natural healing process of wounds depends upon NALP3 signaling. Elevated pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, facilitate wound healing. Multiple research studies show that the signaling pathway of the NALP3 inflammasome is of significant importance in the process of skin wound healing (155). Research conducted both in vitro and in vivo has shown that TFNAs improve corneal transparency, hasten the process of wound reepithelialization, and have a beneficial effect on the healing of corneal epithelial wounds (150). TFNAs have advantages not only in promoting the healing of corneal wounds but also in facilitating the healing of skin wounds. The research findings demonstrated that the use of TFNAs expedited the skin wound healing process and mitigated scarring. The first study indicates that nanophase materials with nucleic acid biological characteristics have the potential to expedite wound healing and minimize scarring. These findings suggest that TFNA might be used to facilitate the regeneration of skin tissue (156). Studies have shown that TFNA suppresses the pyroptotic pathway, which in turn lowers levels of inflammatory cytokines and increases the amount of collagen in the skin. Following treatment with TFNA, levels of NLRP3 inflammasome and pro-caspase-1 were found to be decreased. This suggests that the inflammasome was reduced together with the active form of caspase-1, which led to a subsequent decrease in N-terminal GSDMD levels. According to the findings, TFNA has both anti-inflammatory and anti-fibrotic properties, although it does not cause cytotoxicity (152). Pro-caspase-1, caspase-1, NLRP3, GSDMD, and a number of other proteins associated with the pyroptosis and inflammasome signaling pathways were shown to be present in this research. In summary, TFNAs have essential scientific relevance for skin wound healing, and it has been established that they are strongly associated with pyroptosis and inflammasome pathways. This suggests that TFNAs may play a role in the activation of these pathways ( Figure 6 ) (148, 152).

Tsvetkov et al. discovered “cuproptosis,” a cellular death process characterized by the transportation of Cu to mitochondria (157). The finding mentioned above has inspired investigations into the control of mitochondrial copper and its possible implications in cancer treatment. Previous studies have shown a connection between the toxicity of elesclomol in cancer cells and many parameters, such as the levels of ferredoxin-1 and the rates of mitochondrial respiration, which are influenced by the availability of Cu (157).

Cuproptosis, a particular type of cell death that is reliant on Cu and occurs inside mitochondria, exhibits distinct characteristics when compared to well-established processes such as ferroptosis, apoptosis, or necroptosis. FDX1, an essential participant in this mechanism, functions as a ligand for elesclomol, facilitating the conversion of Cu³⁺ ions to Cu²⁺ ions and subsequent release inside the matrix of mitochondria (158). Research indicates that FDX1, metabolic enzymes, and targets of lipoylation proteins within the PDH complex mediate Cu ionophore toxicity. Posttranslational lipoylation adds lipoic acid to mitochondrial proteins, reducing Cu-induced cell death. FDX1-dependent cancer cells require lipoic acid pathway components for survival, and modifications reduce metabolic enzyme lipoylation, making some cells susceptible to elesclomol-induced cuproptosis (157, 159, 160).

Cuproptosis refers to the phenomenon in which mitochondrial Cu undergoes a process of substitution with proteins, hence playing a crucial role in elucidating the physiological significance of Cu in the human body. Cu is often located inside the matrix of mitochondria and is integrated into the assembling process of cytochrome c oxidase. Copper shortages have been shown to be associated with the occurrence of developmental problems. However, it has been observed that the administration of elesclomol can effectively mitigate these defects (161). The use of Cu metalloallostery, a mechanism that governs several cellular processes, such as proliferation and autophagy, has been under scrutiny due to its possible harmful effects. Cuproptosis is a phenomenon characterized by cellular demise, which is intricately associated with copper biology (162, 163).

According to Tsvetkov’s study findings, cuproptosis might potentially play a role in the development of Wilson’s illness, which is defined by an abnormal buildup of Cu in the body. Increased Cu concentrations in liver cells trigger the activation of Cu metalloallostery, which can remove impaired mitochondria and alleviate cuproptosis (157). The buildup of metals generated by ions affects cellular homeostasis, hence impacting the stability of proteins. Histone H3 can attach to Cu and function as a Cu reductase, therefore indicating the presence of many protein binding sites that may accommodate exchangeable Cu ions (164). Cuproptosis has the potential to induce cellular demise via the process of copper-mediated aggregation (162, 165).

Cuproptosis, controlled cell death using copper buildup and reactive oxygen species, is associated with cancer neurological, and cardiovascular problems. Recent research suggests it may aid wound healing (162, 165). Research shows that wound healing may be accelerated by upregulating cuproptosis-related genes and delayed by suppressing it. Cuproptosis is an essential process in the context of wound healing as it facilitates the elimination of impaired cells, recruits inflammatory cells, and governs the orchestration of new tissue generation. Nevertheless, the specific contributions of the subject in question continue to be a topic of continuous scholarly investigation, whereby the possible advantages and disadvantages are contingent upon the particular circumstances (165).

Necrosis takes place when an illness remains untreated or when harm to tissue reaches an irreversible state. The condition can advance into the deeper layers of tissue, impacting the integrity of bone tissue and possibly resulting in the development of bacteremia and sepsis (7). Skin necrosis may be due to either extrinsic causes or vascular blockage. Necrosis is a pathological condition that is distinguished by cellular or tissue demise, often leading to a discoloration of the skin in shades of purple, blue, or black. Frequently seen necrotizing disorders include necrotizing fasciitis, ecthyma, and meningococcemia (166).

The proliferative stage of wound healing is a complicated process that includes the creation of neovascularization, re-epithelialization, granulation tissue, and immune system modulation. This phase of wound healing occurs after the inflammatory stage of wound repair. Granulation tissue is predominantly activated fibroblasts, as described by Alexis Carrel and John Hunter. These fibroblasts produce new ECM, which helps to contract wounds and forms cellular and structural elements (30, 167).

Neovascularization is necessary for the healing of wounds, the transport of nutrients, the preservation of oxygen balance, the multiplication of cells, and the regeneration of tissue (30). During the early stages of embryonic development, endothelial progenitor cells (EPCs), also known as angioblasts, give rise to the first blood vessels. Angiogenesis is the primary process that leads to the development of new blood vessels during adult tissue healing. This process involves the activation of local microvascular ECs in response to hypoxia and growth factors such as PDGF and VEGF. Proliferation, migration, and the development of capillaries are all processes that ECs go through (168).

ECs and pericytes are involved in the angiogenesis procedure. These cells react to hypoxic injury settings by beginning the cycle of angiogenesis, which includes tearing down the ECM and generating blood vessels (169). Pericytes maintain the integrity of these vessels. Granulation tissue may also be formed owing to the participation of circulating progenitor cells and several subtypes of fibroblasts in the formation process. Understanding these systems is necessary for the development of therapeutic strategies for wound healing (6).

Angiogenesis refers to the physiological process through which new blood vessels are formed, mainly via the involvement of ECs (170). The initiation of the procedure is influenced by a multitude of variables, such as the presence of proteolytic enzymes and growth factors (171). Enzymes such as these facilitate the migration of ECs via clots that are rich in fibrin and fibronectin, hence promoting the repair of injured regions. ECs also exhibit a response to hypoxia and engage in interactions with perivascular cells, therefore emphasizing the complicated structure of their stimulation. This mechanism has a critical role in both physiological and pathological contexts (172). VEGF, FGF, PDGF-B, TGF, and angiopoietins stimulate EC to migrate and proliferate to start angiogenesis (171–173). Some ECs become lead tip cells and extend filopodia toward pro-angiogenic growth factors, while others become trailing stem cells (174).

The Notch signaling pathway is of significant importance in the determination of ECs as either tip or stalk cells. The regulation of this pathway is governed by VEGF, which is synthesized by several cellular populations inside the wound microenvironment. VEGF-A, which belongs to the VEGF family, plays a crucial role in the process of angiogenesis by directing tip cells towards regions of higher concentration gradients and promoting the proliferation of stalk cells in a concentration-dependent manner. The complicated interaction among ECs, growth factors, and signaling pathways exemplifies the sophisticated and orchestrated nature of vascular development (171, 175, 176).

EPCs have garnered significant scientific attention since their first characterization in 1997. Initial investigations have shown that HSCs, as well as EPCs, are involved in the process of blood vessel regeneration. EPCs undergo a sequential three-step mechanism in order to get into ischemic tissues (177). This process involves their mobilization from the bone marrow, subsequent navigation via the circulatory system, and eventual integration into sprouting endothelium (178). Nevertheless, new research has cast uncertainty on the actual function of EPCs in the processes of ischemia-responsive vasculogenesis and blood vessel restoration (179). In mouse models, it has been shown that circulating progenitor cells do not undergo differentiation into ECs at sites of damage or tumor formation (180).

The identification and characterization of circulating progenitor in blood vessels have posed significant challenges, mostly stemming from the complexities associated with their proper isolation from the circulatory system or the surrounding microenvironment (178, 179, 181). The use of single-cell technologies has excellent potential in elucidating the identification and function of cells involved in the process of wound healing, hence facilitating a more accurate comprehension of the mechanisms behind blood vessel regeneration and repair. The acquisition of this information has the potential to enhance the efficacy of wound healing mechanisms and perhaps facilitate the development of specific therapeutic approaches for vascular restoration (6, 181).

Fibroblasts are an assortment of cells located in the dermal layers, demonstrating notable versatility and serving a range of functions (6, 182). Fibroblasts respond to soluble extracellular signals, including growth factors and cytokines, by undergoing activation, leading to cellular proliferation and the modulation of metalloproteinases. During the process of healing a wound, fibroblasts that have reached maturity move toward the granulation tissue, therefore initiating the production of collagen and substituting the temporary fibrin matrix (183, 184). Myofibroblasts are generated, leading to an increase in the accumulation of collagen and the initiation of contraction of the wound. Fibroblasts possess the ability to perceive both the magnitude and direction of mechanical loads, after which they convert this sensory input into appropriate adaptive responses (183, 185). To illustrate fibroblast behavior, consider the intermediary filament vimentin, which inhibits fibroblast growth, promotes the accumulation of collagen, and stimulates keratinocyte mesenchymal reepithelialization and differentiation. It is essential for the study of wound healing procedures and, possibly, for the development of focused treatments in wound care to have a firm grasp on the complex mechanisms governing fibroblast activity (186).

The process of wound healing encompasses wound contraction. This phenomenon leads to a reduction in the surface area of the wound and an improvement in the mechanical strength of the surrounding tissue. The procedure mentioned above converts migratory fibroblasts into myofibroblasts that express α-SMA, leading to the deposition of ECM and facilitating the process of wound healing (187). Myofibroblasts, which exhibit contractile properties similar to smooth muscle cells, contribute to wound healing by depositing ECM components such as collagen type I and III. They achieve wound contraction by connecting to polymerized fibronectin and collagen fibrils (188). The ability to exhibit alternative protein contractility and induce apoptosis upon the restoration of the integrity of tissues has been observed (6, 189). Nevertheless, under pathological circumstances such as hypertrophic scarring, the presence of myofibroblasts might endure, hence playing a role in the excessive formation of scar tissue. The strategic targeting of myofibroblasts has significant potential in the advancement of therapeutic approaches for fibrosis and damage, rendering them a critical focal point for therapeutic interventions. Comprehending the dynamics and control of myofibroblasts is essential in the progression of wound healing procedures and the formulation of tailored medicines to enhance results in healing wounds and fibrosis management ( Figure 7 ) (6, 189).

The epidermis, an integral layer of the skin, serves as a vital protective barrier from external factors and plays a critical role in the process of wound healing. The structure in question is comprised of many distinct layers, including the basal, granular, spinous, and stratum corneum layers. Its main constituents are keratinocytes, which are interconnected by desmosomes. The basal layer is in direct association with the basement membrane, housing many components such as hair follicles, immune cells, sebaceous, and sweat glands. The presence of stem cells inside the epidermis plays a vital role in the processes of repair and maintenance (6, 43, 190). Lineage tracing investigations have been conducted to discern the presence of stem cell populations inside different skin structures, such as the interfollicular epidermis (IFE), hair follicles, sebaceous glands, sweat glands, and melanocytes. The concept known as the EPU explains the processes of regeneration and repair. In this model, slow-cycling stem cells located in the basal layer of the epidermis generate transit-amplifying cells via a process of asymmetric proliferation (191). iPSCs exhibit a phenomenon known as inflammatory memory, which facilitates their ability to mount rapid reactions when encountering subsequent challenges. The turnover of epidermal appendages, such as sebaceous glands, hair follicles, and sweat glands, is a continuous process that involves lineage-restricted stem cells dedicated to the maintenance of their respective cell types. Gaining a comprehensive understanding of the dynamics and characteristics of these cells provides valuable insights into the processes behind wound healing. Such insights have the potential to pave the way for the development of precise wound-healing techniques and regenerative medicines (6, 43, 192–194).

When a person has traumatic damage to a peripheral nerve, the homeostatic function of their skin is disrupted. Collateral reinnervation and nerve regeneration are both necessary steps in the procedure of repairing neurological functionality (195). The peripheral nervous system in adults is capable of regenerating nerve activity via the process of growing back the terminals of myelinated nerve and rejoining the wounded nerve (196). Schwann cells, monocytes, macrophages, and fibroblasts are essential players in the process of regenerating nerves. Schwann cells are distinguished by their exceptional plasticity, which enables them to redifferentiate into progenitor-like cells after damage. This facilitates the rebuilding of axons (39, 195, 197).

The process of Schwann cell differentiation initiates the secretion of monocyte chemoattractant protein-1, PAP-III, IL-1α, and IL-1β, which in turn pull monocytes/macrophages to the location of damage. Macrophages are known to secrete VEGF and HIF, hence facilitating the process of angiogenesis (198). The newly reorganized vasculature functions as a supportive structure for Schwann cell cords, reducing the guidance of axon development. The complex nature of this process guarantees the restoration of nerve function after an injury, and comprehending these processes is of utmost importance in the development of specific therapeutic approaches for traumatic damage to the peripheral nerve (199).

In response to injuries, the human body undergoes a series of physiological processes that include wound healing and the subsequent creation of scars. Scars are tissue characterized by an effective neo-formation process, which involves the replacement of lost tissue with an ECM that is mainly composed of fibronectin and collagen types I and III. Specific components of the skin, including hair follicles, subepidermal appendages, and glands, have little or no regenerative capacity after significant damage (203). The scar tissue matrix, which is denoted by granulation tissue, is distinguished by a considerable concentration of fibroblasts, capillaries, macrophages, granulocytes, and collagen fibers (204). During the first stage of scar formation, known as the primordial scar tissue phase, the process of angiogenesis is still ongoing but not fully developed. The predominant cell type during this phase is fibroblasts (205). The process of scar development concludes during the remodeling phase, commencing on day 21 and continuing for one year subsequent to the occurrence of an injury. During this particular stage, the ECM constituents experience continuous modifications, characterized by the replacement of collagen III with type I collagen and the involvement of myofibroblasts in the process of wound contraction. Excessive use of scarring results in a disruption of the equilibrium between the processes of biosynthesis and degradation, which subsequently gives rise to a prolonged inflammatory phase, an extended proliferative phase, and a diminished remodeling process (204–206). Abundant microvessels are present in hypertrophic scars, and aberrant scarring is also characterized by alterations in the ECM and epithelial tissue (7).

The predominant kind of stem cells used in medical applications are adult stem cells, which are obtained from several sources, such as bone marrow and adipose tissue (207). According to previous research, MSCs exhibit anti-inflammatory and immunomodulatory characteristics during the inflammation phase while also promoting the activation of fibroblasts, keratinocytes, and ECs during the proliferative phase. This cellular response ultimately leads to an expedited healing of wounds (207). Research has shown that the use of MSC treatment has the potential to decrease the duration of wound healing, minimize wound contraction, enhance the formation of new blood vessels (angiogenesis), and expedite the process of epithelialization (208, 209). The administration of stem cell treatment may occur by topical or systemic means. Topically, MSCs can be applied in the kind of spray, aiding in the retention of these cells throughout the wound (210). In order to enhance the retention of stem cells inside a wound, it has become common practice to provide these cells with suitable support or scaffold material, such as collagen or skin substitutes. This phenomenon contributes to the preservation of cellular functionality and promotes the movement of cells inside the wound site (35, 211).

Negative pressure wound treatment (NPWT) is a wound healing technique that leverages the application of differential vacuum or suction to augment the healing process. The use of this treatment modality is often seen in the management of both acute and chronic wounds, including pressure ulcers, diabetic foot ulcers (DFUs), postoperative incisions, lower extremity wounds, traumatic wounds, infected wounds, burns, necrotizing fasciitis, infected sternal injuries, and post-skin grafting interventions. Significant advancements have been seen in individuals suffering from vascular lower leg ulcers and DFUs who possess adequate blood circulation (241, 242). NPWT devices are comprised of three essential components, as described in the literature (243). These components include a porous substance that fills the wound site, a drainage port that is coupled to a vacuum pump under regulated conditions, and an adhesive film dressing that effectively seals the wound. The porous substance often used is polyurethane foam, while the adhesive dressing is composed of polyurethane owing to its occlusive qualities (241, 244, 245).

NPWT facilitates the process of wound healing by using four main mechanisms: microdeformation, macrodeformation, elimination of wound fluid and decrease of edema, and modification of the wound microenvironment (242). Notwithstanding its efficacy, the use of this intervention has inherent dangers and possible consequences. There are three primary problems associated with this condition, including infection, bleeding, and the retention of foam dressing (241, 246). Bleeding occurs as a result of physical trauma to the underlying tissues, a condition that may be further exacerbated by factors such as necrotic tissue, infection, or coagulopathy. The use of NPWT in near proximity to accessible blood vessels, nerves, organs, or anastomotic sites is discouraged due to the heightened likelihood of fistulae development (245, 246). It is recommended to provide treatment for infections prior to the administration of NPWT. Additionally, it is essential to note that the non-dissolving nature of the dressing materials used in NPWT may potentially lead to complications such as bleeding or infection caused by foam retention. Additional concerns include the presence of discomfort during dressing changes and the occurrence of patient allergies to the adhesive bandage or foam substance (241, 243, 245, 247).

Enterocutaneous fistulas, which were formerly regarded as contraindications for non-operative percutaneous wound closure, are currently being managed with favorable outcomes. The device achieved fistula closure in a majority of the documented patients, namely those with low-output fistulas, comprising almost two-thirds of the total sample size of forty (248). Trauma patients, as well as those with abdominal compartment syndrome, are managed by using an open abdomen technique with the use of a negative pressure wound therapy device. This approach serves as a temporary measure by providing coverage, eliminating intraabdominal contaminants and exudates, and reducing visceral edema (249).

The use of NPWD closure has yielded substantial advancements in the management of severe orthopedic injuries. In the past, significant injuries to the extremities were managed by the use of extensive debridement, which necessitated the use of free flaps for rapid wound covering. The NPWD generates a hermetically sealed and safeguarded environment that effectively eliminates swelling and accumulation of blood outside blood vessels, hence enhancing blood flow and optimizing the preservation of the area around the wound. Serial debridements are conducted, and ultimate rebuilding is carried out in a stable wound in a planned manner (250). The contraindication of exposed tendons, joints, or bones has been reconsidered due to the formation of granulation tissue over these structures, which enables the possibility of skin grafting if deemed essential (251).

Historically, the two most critical oxygen-based treatments for wound care were known as hyperbaric oxygen therapy and topical hyperbaric oxygen therapy. However, recent developments in CDOT and Transdermal Oxygen Therapy have led to the introduction of a novel category of oxygen-based wound healing devices. These devices provide persistent treatment of wounds with oxygenation and are part of the oxygen-based wound care industry. Although these techniques promote wound healing in a manner that is analogous to one another, there are significant technical and medical distinctions between them (252).