Cell migration in diabetic wound healing: Molecular mechanisms and therapeutic strategies (Review)

Jielin Song; Tong Zhao; Chuanfu Wang; Xu Sun; Junchao Sun; Zhaohui Zhang

doi:10.3892/ijmm.2025.5567

. 2025 Jun 16;56(2):126. doi: 10.3892/ijmm.2025.5567

Cell migration in diabetic wound healing: Molecular mechanisms and therapeutic strategies (Review)

Jielin Song ^1,^2,³, Tong Zhao ^1,^2,³, Chuanfu Wang ⁴, Xu Sun ^2,^3,⁵, Junchao Sun ^2,^3,^5,^✉, Zhaohui Zhang ^2,^3,^5,^✉

PMCID: PMC12180913 PMID: 40539458

Abstract

Diabetic wounds are among the most prevalent forms of chronic wound and are a prominent clinical challenge in contemporary healthcare. Impaired cell migration represents one of the key mechanisms underlying the difficulty in diabetic wound healing, involving multiple cell types including neutrophils, macrophages, keratinocytes, endothelial cells and fibroblasts. Under the influence of pathological factors, including hyperglycemia, chronic inflammation, oxidative stress and an abnormal microenvironment, the cell migration becomes impaired, leading to delayed wound healing. Key signaling pathways including Rho GTPase, PI3K/Akt, TGF-β/Smad and Wnt/β-catenin are involved in the regulation of cell migration. Non-coding RNAs exert a pivotal influence on diabetic wound healing by modulating these signaling pathways or their downstream targets. Notably, stem cells and their exosomes, growth factor therapy, drug-loaded dressings and traditional Chinese medicine can modulate cell migration via non-coding RNAs and associated signaling pathways, thereby establishing a therapeutic regulatory axis. This review systematically consolidates advances in this field, providing novel insight into the mechanisms of cell migration in diabetic wounds and facilitating the development of innovative therapeutic strategies.

Keywords: diabetic wound, cell migration, signaling pathway, non-coding RNA, mechanism, therapy

1. Introduction

Diabetic wounds are a prevalent and severe complication of diabetes mellitus, characterized by impaired healing, increased infection risk and failure to achieve complete closure (1,2). Among reported cases of diabetes mellitus, ~25% are at risk of developing diabetic wounds (3). Diabetes disrupts wound healing, potentially leading to chronic foot ulcers, lower extremity amputation and increased mortality (4,5). Moreover, the high treatment costs of diabetic wounds place an economic burden on healthcare systems (6). The global prevalence of diabetes was estimated at 529 million cases in 2021, with projections indicating a potential surge to 1.31 billion by 2050 (7). With the increasing prevalence of diabetes, the incidence of diabetic wounds is expected to rise, posing a challenge to public health systems.

The difficulty in diabetic wound healing primarily arises from a multifactorial combination of neuropathy, vasculopathy and infection, which collectively exacerbate the complexity and challenges of wound management (8). At the cellular level, a key factor influencing wound healing is the efficient and rapid migration of cells to the wound center (9). This involves multiple cell types, including neutrophils, macrophages, keratinocytes, fibroblasts and endothelial cells (ECs) (10-14). The diabetic microenvironment impairs the migratory capacity of cells via multiple mechanisms, thereby contributing to delayed wound healing (15,16). Consequently, understanding of cell migration regulatory mechanisms is key to formulate novel therapeutic interventions for diabetic wounds.

The present study aimed to summarize cell migration dysfunction in diabetic wounds and the mechanisms underlying cell migration impairment induced by hyperglycemia, chronic inflammation, oxidative stress and an abnormal microenvironment. Based on key signaling pathways, non-coding RNAs (ncRNAs) and their associated molecular networks that regulate cell migration in diabetic wounds, the present study further explores innovative therapeutic strategies to enhance cell migration, as well as therapeutic challenges and future research directions, offering innovative perspectives to advance diabetic wound clinical management.

2. Cell migration

Cell migration is a synchronized and dynamic phenomenon that generally commences with the polarization of cells (Fig. 1) (17). Cell polarization occurs when migrating cells detect chemotactic signals such as chemokines, growth factors or extracellular matrix (ECM) cues. This process involves coordinated activity of key molecular players, including Rho GTPases, integrins, phosphoinositide 3-kinase (PI3K), microtubules and vesicular transport systems, to establish front-rear polarity and generate distinct functional patterns between the leading and trailing edges (18). Actin polymerization at the leading edge drives membrane protrusion, forming pseudopodial structures such as lamellipodia and filopodia, facilitating cell extension. The extended pseudopodia adhere to the ECM through adhesion molecules such as integrins, forming focal adhesions that mechanically link the cytoskeleton to the extracellular environment (19). Through myosin-mediated contractile forces, the cell body is propelled forward, driving translocation. Disassembly of adhesion complexes at the trailing edge permits tail detachment from the substrate, finalizing the de-adhesion process (20). The coordinated actions of the anterior and posterior regions complete one cycle of migration.

Key stages of cell migration. Polarization involves establishment of front-rear polarity. This is followed by extension of pseudopodial structures at the leading edge and anchorage of pseudopodia to the extracellular matrix via adhesion complexes. Cell body contraction generates traction forces for forward movement. Dissociation of adhesion structures at the trailing edge completes the migration cycle. Created with BioRender.com.

3. Cell migration in normal wound healing

Cell migration is a critical and continuous process in wound healing, integral to every phase of repair. Various cell types facilitate tissue regeneration, notably the migration of neutrophils, macrophages, keratinocytes, vascular ECs and fibroblasts. Through precise migration and functional modulation, these cells contribute to pathogen clearance, angiogenesis promotion, ECM secretion and epidermal barrier reconstruction. Their migration is regulated by signaling molecules and microenvironmental factors to ensure efficient repair (21,22). Investigating these migration mechanisms not only enhances understanding of the physiological principles governing wound healing but also offers a solid theoretical framework for potential therapeutic strategies for managing chronic wounds and impaired repair.

Neutrophil migration

Neutrophils are the initial immune responders during wound healing, rapidly mobilizing to injury sites via intricate migratory mechanisms (Fig. 2A). Neutrophils detect 'find-me' signals, including damage-associated molecular patterns (DAMPs), hydrogen peroxide, lipid mediators and chemokines, via surface receptors such as G protein-coupled receptors (GPCRs), integrins, Fc receptors and pattern recognition receptors. These signals, released from injured tissues, drive neutrophil directed migration to the site of damage and trigger inflammatory responses (23,24). The migration process is coordinated by ~30 distinct neutrophil receptors and multiple signaling pathways. Neutrophils recognize fMet-Leu-Phe (fMLP) released by damaged cells and bacteria through specific formyl peptide receptors (25). Mast cells augment vascular permeability and facilitate neutrophil infiltration via the release of histamine, chemokines and inflammatory mediators. Macrophages identify DAMPs or pathogen-associated molecular patterns, leading to their activation and guidance of neutrophils to the site of injury (26). Local cells and neutrophils release chemokines, including C-C motif ligand 3 (CCL3) and C-X-C motif ligands 1/2 (CXCL1/2). These chemokines interact with their receptors (CCR1, CXCR1, and CXCR2) to guide neutrophil migration (21). Furthermore, neutrophils produce leukotriene B4, which binds leukotriene B4 receptor 1 to drive neutrophil recruitment from distant tissue (27). During migration, neutrophils utilize adhesion molecules (such as CD11b) and downstream signaling pathways (such as Src and Rho GTPases) to drive actin remodeling and membrane extension, enabling transendothelial migration and deep tissue infiltration through ECM degradation (23,28). At the wound site, neutrophils perform essential antimicrobial functions through various mechanisms, including the secretion of toxic granules, production of reactive oxygen species, phagocytosis of invading pathogens and the formation of neutrophil extracellular traps (29,30). Additionally, they secrete proteases to remodel the ECM, recruit immune cells and facilitate tissue repair. While these functions are essential for combating infections, they can also lead to bystander effects, causing tissue damage, particularly in chronic inflammatory conditions (31,32). Upon completion of their task, neutrophils are cleared by macrophages or re-enter the vasculature via reverse migration, thereby contributing to the resolution of inflammation (33). Excessive neutrophil retention or migration defects may sustain inflammatory responses and hinder healing processes, contributing to chronic wound pathogenesis (34). The CXCL12-CXCR4 axis serves a pivotal role in neutrophil retention at inflammatory sites. Inhibition of this pathway may enhance inflammation resolution by inducing neutrophil reverse migration (35).

Monocyte/macrophage migration

Following tissue injury, a coordinated chemokine cascade drives monocyte and macrophage trafficking to the wound site (Fig. 2B). Damaged cells release calcium waves that activate NADPH oxidase, producing hydrogen peroxide, which, together with calcium, serves as an early signal to mobilize immune cells to the injury site (36-38). Additionally, DAMPs such as high-mobility group box 1 and ATP, along with inflammatory cytokines such as IL-1 and IL-33, activate resident macrophages, prompting the release of pro-inflammatory factors that establish a localized inflammatory environment (39). During the initial injury phase, monocytes expressing CCR2 migrate in response to CCL2 signaling. These monocytes simultaneously express and respond to CCL7, promoting the recruitment of myeloid cells (monocytes and macrophages) to the injury site (21). Furthermore, the degranulation of platelets and mast cells releases chemokines such as stromal cell-derived factor 1/CXCL12, while hypoxia-inducible factors (HIFs) amplify chemotactic signals, promoting the recruitment of monocytes (23). The clotting mechanism initiated by blood vessel damage further liberates compounds such as unbound heme, exacerbating the inflammatory reaction and drawing monocytes to the site of injury (40). Upon reaching the wound site, monocytes develop into macrophages and serve essential roles throughout the healing process. Initially, M1-polarized macrophages dominate, displaying potent antimicrobial and inflammatory properties (41). As healing progresses, macrophages transition to the M2 phenotype, facilitating inflammation resolution and angiogenesis while orchestrating collagen deposition and ECM remodeling to promote tissue regeneration and functional recovery (42,43).

Keratinocyte migration

Keratinocyte movement is key for successful wound closure, facilitating re-epithelialization and barrier function recovery (Fig. 2C). Following tissue injury, edge-located keratinocytes respond to inflammatory mediators (IL-1, TNF-α) by adopting a flattened morphology, cellular elongation and forming membrane protrusions such as lamellipodia and filopodia (22). These changes are driven by cytoskeletal reorganization, which provides the structural support and mechanical force required for migration. Fibroblasts promote keratinocyte proliferation, migration and differentiation by secreting growth factors such as keratinocyte and hepatocyte growth factors, thereby driving the re-epithelialization of wounds (44). During motility, keratinocytes engage with the ECM via integrin receptors such as αvβ5 and α5β1 while releasing MMPs to remodel temporary matrix proteins (fibrin, fibronectin), thereby promoting cellular migration (45-48). Dynamic regulation of cell-cell and cell-ECM connections, along with increased gap junction communication, ensures coordinated and efficient migration (49). Keratinocytes employ multiple mechanisms for migration, including the 'leapfrog' and 'sliding' models and suprabasal cell dedifferentiation in collaboration with basal cells (22). The leapfrog mechanism proposes that suprabasal cells roll over the leading edge basal cells, undergo dedifferentiation, and subsequently form new migratory leaders within the cohesive epidermal tongue (50). In the sliding mechanism, keratinocytes from the basal layer move forward as a cohesive block at the leading edge, while the overlying cluster of superficial cells is passively dragged along (51). Suprabasal cell dedifferentiation refers to the reversal of differentiation in committed suprabasal keratinocytes, which regain migratory and proliferative capacity to directly contribute to epidermal regeneration. During migration, keratinocytes proliferate and differentiate to form new epithelium, reestablishing the skin barrier. They also regulate local inflammation, promote ECM remodeling and coordinate the activity of neighboring cells through autocrine and paracrine signaling (52). Additionally, keratinocytes adapt their migratory behavior and functional characteristics to the dynamic wound microenvironment, providing key flexibility and support for effective wound repair.

EC migration

New blood vessel formation (angiogenesis) peaks in the proliferative stage of repair, delivering oxygen and nutrients critical for tissue regeneration and functional restoration (53). EC movement is key for vascular restructuring and necessary for new blood vessel formation, primarily mediated by chemotactic, haptotactic and mechanotactic cues (Fig. 2D) (54). Chemotaxis in angiogenesis involves the directional migration of ECs along chemical gradients of attractants such as VEGF and basic fibroblast growth factor. This migration is initiated when VEGF binds to VEGF receptor (R)-2, activating downstream effectors such as PI3K/Akt and Rho GTPases to remodel the cytoskeleton. VEGFR-2 serves as the primary regulator of this process (55). Through paracrine signaling, VEGF is secreted by repair-associated macrophages, keratinocytes and fibroblasts, driving EC expansion and motility to enhance blood vessel formation (56,57). Haptotaxis refers to the directional movement of ECs during angiogenesis, driven by the interaction of integrins (such as αvβ3 and αvβ5) with ECM components along a ligand gradient (58). Integrin activation triggers downstream signaling pathways, including Ras-related C3 botulinum toxin substrate (Rac) and cell division cycle 42 (Cdc42), which regulate cytoskeletal remodeling and mechanical force generation to propel cell movement (59). Additionally, integrins synergize with growth factor signaling pathways to enhance migratory efficiency. Mechanotaxis is the process by which ECs undergo directed migration in response to mechanical forces, such as shear stress, mediated by integrin activation and cytoskeletal remodeling (60).

Fibroblast migration

As key mediators of tissue regeneration, fibroblasts generate and remodel ECM proteins, including collagen, elastin, fibronectin and laminin, to support structural integrity (61). Chemokines and cytokines secreted by platelets and inflammatory cells guide fibroblasts to the injury site during early wound healing (62,63). Keratinocytes support this process by releasing IL-1 and transforming growth factor (TGF)-β, which enhance fibroblast migration and activation (Fig. 2E) (44). Fibroblasts recruited to the wound site synthesize and secrete ECM components, such as collagen, promoting granulation tissue formation. Under mechanical tension and cytokine stimulation (TGF-β), these fibroblasts differentiate into myofibroblasts. This transition is marked by α-smooth muscle actin expression, which forms stress fibers that generate contractile forces to draw the wound edges together, aiding in closure (64). Additionally, a small population of bone marrow-derived circulating fibroblasts migrates to the wound bed in response to cytokines such as IL-4, IL-13 and IFN-γ and differentiates into myofibroblasts (65); however, their contribution to skin wound healing is relatively minor (66). Persistent fibroblast overproliferation and hyperactivation drive excessive ECM deposition, primarily collagen, promoting hypertrophic scar or keloid formation (67,68). In the final remodeling phase, fibroblasts deposit type I collagen to replace type III collagen, reinforcing the ECM and forming a mature, mechanically stable scar. This process may persist for months to years (69).

In wound healing, although different cell types exhibit distinct migration characteristics, their movement is regulated by signaling molecules such as chemokines and cytokines, as well as microenvironmental factors including hypoxia, mechanical forces and ECM composition (21,23,44,56). These cells sense external cues via surface receptors, facilitate migration through cytoskeletal reorganization and dynamic adhesion molecule interactions and maintain coordinated motility via cell-cell and cell-matrix communications (23,28). Collectively, these mechanisms establish an efficient and orderly repair network that drives the wound healing process.

4. Mechanisms of cellular migration impairment in diabetic wound healing

Diabetic patients exhibit impairment in cell migration function during wound repair (70,71). This impairment may be linked to the interplay of multiple factors, including hyperglycemia, chronic inflammatory responses, oxidative stress and an aberrant wound microenvironment. These factors influence cell migration via complex biological pathways, ultimately leading to the obstruction of wound healing and potentially resulting in prolonged refractory states (Fig. 3).

Mechanisms of cellular migration impairment in diabetic wound healing. High glucose, chronic inflammation, oxidative stress and abnormal wound microenvironment contribute to delayed wound healing in diabetes. Created with BioRender.com. TIMP, tissue inhibitor of metalloproteinases; ROS, reactive oxygen species; PDGF, platelet-derived growth factor; CXCL, C-X-C motif ligand; PAF, ; fMLP, fMet-Leu-Phe; ECM, extracellular matrix; AGE, advanced glycation end-products; KRT, keratin; c-MYB, v-myb avian myeloblastosis viral oncogene homolog; p125FAK, focal adhesion kinase; IRF, interferon regulatory factor.

Effects of high glucose on cell migration

High glucose may impair cell migration by promoting the formation of unstable protrusions, decreasing adhesion maturation, altering RhoA activity to disrupt migration regulation and enhancing glucose uptake and metabolism to activate the mTOR pathway (72). These mechanisms are implicated in various cell types such as neutrophils, macrophages, keratinocytes and endothelial cells. Chronic elevation of blood glucose levels results in the buildup of advanced glycation end products (AGEs) within tissue. AGE-modified proteins disrupt chemotactic signaling, impairing the migration of neutrophils to wound sites (73). Under chronic hyperglycemia, monocyte motility is compromised, resulting in inadequate macrophage infiltration, decreased phagocytic capacity and dysregulated polarization from M1 to M2 phenotypes (74). Inadequate migration of neutrophils and macrophages to the wound site increases the risk of wound infection (75). Additionally, high glucose upregulates STING expression and activates the interferon regulatory factor 3 and NF-κB signaling pathway, thereby inhibiting EC migration and delaying the healing of diabetic wounds (70). Under physiological conditions, keratinocyte proliferation and migration are key for re-epithelialization during cutaneous wound repair. Phosphorylated focal adhesion kinase (p125FAK) is a key regulator of keratinocyte migration. However, hyperglycemia attenuates p125FAK phosphorylation, compromising keratinocyte migration in diabetic wound healing. (76). High glucose also inhibits the PI3K signaling pathway, impairing the function of ClC-2 chloride channels and suppressing the migratory capacity of keratinocytes. Conversely, hyperglycemia-induced upregulation of keratin 17 activates c-MYB/PI3K/AKT signaling, promoting excessive keratinocyte proliferation and migration. This dysregulation contributes to hyperkeratosis and impairs wound healing (77). Thus, high glucose conditions exert a dual effect, both inhibiting and promoting cell migration through distinct mechanisms, leading to delayed diabetic wound healing.

Effects of chronic inflammation on cell migration

Chronic inflammation is a key pathological mechanism underlying diabetic wound healing disorder, exerting its effects on cell migration and delaying the wound repair process through a variety of mechanisms (78-80). Hyperglycemia impedes macrophage polarization from the M1 to M2 phenotype, leading to persistent secretion of pro-inflammatory mediators including IL-6, IL-1 and TNF-α, alongside decreased production of anti-inflammatory factors such as IL-10 and TGF-β (57,80). This persistent pro-inflammatory microenvironment markedly impairs the motility of keratinocytes, fibroblasts and vascular ECs, extending the inflammatory phase and impairing wound repair (81-83). Overproduction of TNF-α from M1-polarized macrophages elevates tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in keratinocytes, suppressing motility and ultimately impairing diabetic wound repair (71). IL-1β is a key contributor to maintaining a pro-inflammatory state. It activates the p38 MAPK pathway to upregulate MMP2 and MMP9 expression while downregulating TIMP1 and TIMP2, thereby altering the levels of ECM remodeling proteins. This suppresses proliferation and motility of dermal fibroblasts, thereby delaying wound repair in diabetic individuals (84).

Effects of oxidative stress on cell migration

Oxidative stress reflects a disrupted equilibrium where oxidation predominates over antioxidant defenses. Tissue in diabetic hyperglycemic wound microenvironments exhibits heightened vulnerability to this oxidative imbalance (85). Reactive oxygen species (ROS) serve a dual role in wound healing: Moderate levels promote tissue repair, while excess accumulation impairs wound closure and delays regenerative processes (86). High concentrations of ROS inhibit cell migration by oxidizing related proteins such as actin and myosin II, disrupting the structure and function of the cytoskeleton and impairing cell contractility (87). High glucose exacerbates oxidative stress, resulting in excessive Rac1 activation. This overactivation promotes the formation of unstable protrusions, disrupts cell polarity and impairs adhesion maturation, collectively decreasing cell migration speed and directionality, ultimately contributing to defective wound healing (72). A study has shown that hyperglycemia exacerbates oxidative stress, impairing the migratory and proliferative capacity of keratinocytes, thereby impairing wound repair in diabetic conditions (88). Moreover, oxidative stress decreases nuclear Nrf2 levels and manganese-superoxide dismutase (Mn-SOD) expression, thereby weakening the cellular antioxidant defense system, exacerbating ROS accumulation, impairing EC proliferation and migration and ultimately delaying tissue regeneration (89). MMP9 impedes diabetic wound repair (90,91). In human keratinocytes, ROS activate NF-κB, upregulating MMP-9 and suppressing keratinocyte migration, thereby delaying wound closure (92,93).

Effects of wound microenvironment on cell migration

Alterations in the wound microenvironment, such as deficiencies in key growth factors, changes in chemokine receptors and abnormal ECM remodeling, disrupt cell migration and impede wound healing. Diminished growth factor secretion in diabetic wounds disrupts cellular migration. During early wound repair, platelet-derived growth factor (PDGF) recruits fibroblasts, neutrophils and monocytes to the injury site (94). However, in diabetic wounds, PDGF and its receptor expression are downregulated, compromising cell migration and delaying wound closure (95). Similarly, hyperglycemia suppresses VEGF secretion by macrophages, fibroblasts and keratinocytes, impairing EC and keratinocyte migration, thereby hindering vascularization and re-epithelialization and delaying wound healing (94,96). TGF-β3 has been shown to facilitate the migration of fibroblasts and keratinocytes; considering the marked downregulation of TGF-β3 in diabetic wounds, restoring its activity locally may represent a viable approach to improving wound regeneration in diabetic patients (97). The alteration of chemokine receptors is also a key factor in impaired cell migration in diabetic wounds. Compared with healthy individuals, neutrophils from diabetic patients exhibit a substantial decrease in chemotaxis towards the chemokines CXCL8/IL-8, platelet-activating factor and fMLP (98). This attenuated chemotactic response may hinder cellular migration to the wound site, disrupting healing progression. Moreover, in chronic diabetic wounds, an imbalance in the regulation of MMPs disrupts ECM remodeling, impairing cell migration and delaying tissue repair (99,100). Normal function of MMP1 in keratinocytes is key for their migration on type I collagen (101). Hyperglycemia may impair keratinocyte migration via inhibition of the p-Stat-1 pathway and α2β1 integrin-dependent MMP1 activation, contributing to delayed diabetic wound healing (102). Hyperglycemia upregulates FOXO1, increasing MMP-9 while decreasing TGF-β1, thereby disrupting ECM homeostasis, impairing keratinocyte migration and delaying diabetic wound healing (100,103,104).

Other effects on cell migration

Complications of diabetes, including vasculopathy and neuropathy, are key pathological factors that impair wound healing by affecting cellular migration. Vascular disease in diabetic patients contributes to the delayed migration of white blood cells to injury sites (105). Diabetic neuropathy may disrupt keratinocyte and immune cell migration by altering neuropeptide release (substance P and calcitonin gene-related peptide), thereby impairing wound healing (106,107). Bacterial biofilms are highly structured, surface-associated microbial aggregates encased in a self-secreted extracellular polymeric substance, which provides mechanical stability and protects against environmental stresses (108). Diabetic wounds exhibit heightened susceptibility to infection and biofilm formation due to hyperglycemia-induced immunosuppression. The presence of these bacteria and their associated biofilms hinders cellular migration and disrupts the normal wound healing process (18,109). In diabetic wounds, aberrant mechanical signals may contribute to impaired cell migration function. Beyond its structural scaffolding role, the ECM also serves as a platform for initiating and integrating mechanotransduction signals. Under diabetic conditions, fibroblasts secrete a thicker and less porous ECM, hindering the migration of normal fibroblasts. Diabetic fibroblasts exhibit increased cellular stiffness yet generate markedly reduced traction and contractile forces within collagen matrices (110). These pathological changes may impair cell migration, disrupting wound contraction and delaying healing. Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the central effectors of the Hippo pathway and serve as the primary nuclear sensors for a variety of extracellular and intrinsic mechanical signals (111,112). Downregulation of Agrin (a key component of the ECM) in diabetic wounds may decrease MMP12 expression by inhibiting the nuclear localization of YAP/TAZ and its positive feedback regulation in keratinocytes (113). This weakens the cell ability to respond to mechanical stress, impairs their migration efficiency and ultimately delays wound healing. Mitochondria serve a crucial role in cell migration by providing ATP and maintaining calcium homeostasis (114). Mitochondrial dysfunction in diabetic wounds may be a key factor impairing cell migration. Sirtuin 3 (SIRT3), a key mitochondrial deacetylase, regulates energy metabolism and oxidative stress (115,116). SIRT3 deficiency in diabetic wounds disrupts mitochondrial structure and function, leading to oxidative stress, necroptosis, impaired migration of skin fibroblasts and delayed wound healing (117).

The impaired wound healing in diabetes arises from multifaceted interactions of various factors that compromise cellular migratory function. Research has predominantly focused on conventional mechanisms including metabolic dysregulation, oxidative stress, inflammatory responses and microenvironmental alterations (70,79,88,95). However, knowledge remains limited regarding regulatory pathways such as neural modulation, mechanical signals, mitochondrial dynamics, epigenetic modification and microbial community regulation (106,113,117). Future investigations should broaden the research scope to elucidate the precise roles of these factors in cellular migration, thereby providing theoretical foundations for developing targeted therapeutic strategies for diabetic wounds.

5. Key signaling pathways regulating cell migration to promote wound healing

During wound healing, cell migration is controlled by multiple signaling cascades, including Rho GTPase, PI3K/Akt, TGF-β/Smad and Wnt/β-catenin pathways (118-121). These signaling axes regulate key migratory processes such as cytoskeletal dynamics, cell polarization and force generation through distinct molecular mechanisms (122-125).

Rho GTPase signaling pathway

Rho GTPases serve as master regulators of cell migration, controlling cytoskeletal dynamics to facilitate directional cell movement (Fig. 4) (122). Rho GTPases are a distinct subclass within the Ras superfamily, serving as molecular switches that cycle between their biologically active GTP-bound conformation and inactive GDP-bound state. The Rho GTPase regulatory cycle is orchestrated by three protein families: Guanine nucleotide exchange factors, which promote GDP-to-GTP exchange to activate Rho GTPases; GTPase-activating proteins, which enhance GTP hydrolysis, inducing inactivation, and GDP dissociation inhibitors, which stabilize the inactive GDP-bound form and sequester Rho GTPases from membranes, thus maintaining quiescence (126).

Recent investigations into cell migration have largely centered on three key Rho GTPases: RhoA, Rac1 and Cdc42 (127-129). RhoA exhibits activity at both the leading and trailing edges of migrating cells, where it orchestrates actomyosin contractility via Rho-associated coiled-coil forming protein kinase (ROCK) and modulates actin polymerization via formin family nucleators (130). Rac1 initiates cytoskeletal remodeling by sequential activation of downstream effectors, first stimulating PAK kinase and the Wiskott-Aldrich syndrome protein (WASP) family verprolin-homologous protein (WAVE) regulatory complex. This signaling cascade induces WAVE-mediated direct activation of the actin-related protein (Arp) 2/3 complex, resulting in the nucleation of highly branched actin filament networks that mechanically drive lamellipodial membrane extension (122). Cdc42 orchestrates a distinct morphological response by specifically activating WASP family proteins, which serve as molecular scaffolds to facilitate precise Arp2/3 complex assembly and generation of parallel actin bundles, thereby promoting filopodial protrusion.

PI3K/Akt signaling pathway

The PI3K/Akt pathway is a central regulator of fundamental cellular functions, such as proliferative signaling, migratory behavior and immune modulation (Fig. 5) (131). Initiation of this pathway occurs through upstream membrane-associated receptors, such as receptor tyrosine kinases, integrins, antigen/cytokine receptors and GPCRs, which trigger PI3K activation (132). Following stimulation, PI3K mediates the phosphorylation of phosphatidylinositol-4,5-bisphosphate, generating the second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3). This lipid product recruits Akt to the membrane via interaction with its pleckstrin homology domain, enabling dual phosphorylation (Thr308/Ser473) and consequent functional activation (133). Once activated, Akt phosphorylates multiple downstream substrates in both the cytoplasm and nucleus, thereby modulating cellular motility.

Previous studies have suggested that the PI3K/Akt axis may contribute to wound repair by modulating the migratory dynamics of target cells (134,135). Through modulation of cytoskeletal component equilibrium, this pathway drives cell migration. Specifically, the PI3K/Akt-mediated signaling cascade activates Rho family small GTPases, including Rac1 and Cdc42, as well as actin-polymerization-promoting factors such as WASP/WAVE-Arp2/3 complexes (136). These components enhance actin nucleation and branched assembly at the advancing front, fostering lamellipodia growth and other protrusions that support cell motility. Secondly, the PI3K/Akt pathway modulates migratory capacity by regulating the dynamics of cell adhesion. Akt kinase activity enhances the formation and turnover of integrin-mediated focal adhesions, thereby allowing migrating cells to maintain traction at the leading edge while efficiently releasing adhesions at the rear (137). This mechanism ensures continuous and coordinated cell movement. Furthermore, this pathway exerts a key influence on chemotactic cell migration. When chemokines bind to GPCRs, the Gβγ subunit rapidly activates PI3K, particularly the PI3Kγ isoform, leading to increased PIP3 accumulation at the cell membrane leading edge. Subsequently, PIP3 recruits and activates Akt at the cell front, locally eliciting downstream pro-migratory effects and guiding the cell toward areas with higher chemokine concentrations (138).

TGF-β/Smad signaling pathway

The TGF-β superfamily signaling cascade regulates a wide range of cell processes, including proliferation, migration and ECM synthesis and reorganization (139). Central to this pathway is the TGF-β/Smad axis, which involves TGF-β ligands, cognate receptors (TGFβRI and TGFβRII) and downstream Smad mediators (Fig. 6). Upon ligand binding, TGFβRII interacts with TGF-β to assemble a heteromeric receptor complex, facilitating the recruitment and phosphorylation of TGFβRI (140). Activated TGFβRI exhibits kinase function, specifically phosphorylating Smad2 and Smad3. These phosphorylated Smads dimerize with Smad4, forming a transcriptionally active oligomeric complex that translocates into the nucleus to modulate target gene expression (141).

The TGF-β/Smad signaling pathway activates ROCK through the stimulation of RhoA (142). ROCK facilitates cell migration by modulating actin cytoskeletal rearrangement and myosin contractility. TGF-β signaling promotes keratinocyte migration and facilitates wound healing through the transcriptional regulation of key ECM-associated molecules. This includes the upregulation of integrin subunits (α5, αv and β5) as well as specific MMPs, particularly MMP3 and MMP9 (143,144). The TGF-β/Smad pathway serves as a key regulator of epithelial-mesenchymal transition (EMT) by downregulating E-cadherin and tight junction proteins, including occludin, claudins and zona occludens-1 (145). Simultaneously, elevated expression of mesenchymal markers, including N-cadherin and vimentin, reinforces cell motility, promoting the advancement of EMT.

Wnt/β-catenin signaling pathway

The Wnt/β-catenin signaling pathway, an evolutionarily conserved regulatory mechanism, governs a spectrum of biological functions including cellular proliferation, differentiation, apoptotic regulation and migratory behavior (Fig. 7) (146). In the absence of Wnt signaling, cytosolic β-catenin undergoes sequential phosphorylation mediated by the multiprotein degradation complex, comprising adenomatous polyposis coli, axin, casein kinase 1 and glycogen synthase kinase-3β, leading to its proteasomal degradation and thus ensuring minimal intracellular concentrations (147). Activation occurs upon binding of Wnt ligands (Wnt3a) to the Frizzled receptor family and its coreceptor low-density lipoprotein receptor-related protein 5/6, which disrupts the destabilization complex (148). This stabilization allows β-catenin to accumulate in the cytoplasm, undergo nuclear translocation and form complexes with T cell factor/lymphoid enhancer factor transcription factors, driving transcription of downstream target genes (149).

Wnt signaling induces localized activation of Rho family GTPases, including Rac1, at the leading edge of migrating cells. This stimulates actin polymerization, which is essential for driving forward cell motility (150). Wnt signaling promotes EMT through the suppression of E-cadherin and concurrent upregulation of mesenchymal markers such as vimentin and N-cadherin. This shift disrupts intercellular adhesion and augments the migratory potential of cells. In addition, Wnt/β-catenin signaling can upregulate the expression of MMPs, including MMP2, MMP7 and MMP9, thereby promoting the degradation of the ECM and facilitating cell migration (151,152). Activation of Wnt downstream targets serves a crucial role in cell migration, which significantly enhances wound healing processes. For example, Wnt1-inducible signaling pathway protein 1 stimulates proliferation and directional movement of dermal fibroblasts (153), while epidermal growth factor receptor (EGFR) activation is essential for keratinocyte recruitment to wound sites (154). Additionally, VEGF promotes mitogenic activity and chemotactic migration of ECs during neovascularization (155).

Crosstalk between signaling pathways may regulate cell migration during wound healing. Hypoxic conditioned medium from human amniotic fluid-derived mesenchymal stem cells (MSCs) promotes fibroblast migration and accelerates wound healing by modulating the TGF-β/SMAD2 and PI3K/Akt signaling pathways (156). Toraldo et al (157) demonstrated that topical androgen antagonism accelerates keratinocyte migration and promotes skin wound healing by inhibiting β-catenin nuclear translocation and its crosstalk with TGF-β signaling in keratinocytes. Furthermore, the Rho GTPase signaling pathway may serve as a common downstream node for other pathways to regulate cell migration (136,142,150). The types of cell migration regulated by different pathways exhibit distinct characteristics (Table I) (118-121,158-166).

Table I.

Signaling pathways regulating migration of distinct cell types during diabetic wound healing.

First author/s, year	Wound type	Signaling pathway	Type of cell	(Refs.)
Johan et al, 2024	Diabetic	Rho GTPase (ROCK)	Fibroblast	(118)
Wang et al, 2022	Diabetic foot ulcer	Rho GTPase (ROCK1)	Fibroblast, endothelial cell	(158)
Yu et al, 2020	Diabetic	Rho GTPase (Rac1, ROCK)	Fibroblast	(159)
Li et al, 2025	Diabetic	PI3K/Akt	Fibroblast	(119)
Huang et al, 2025	Diabetic	PI3K/Akt	Keratinocyte, endothelial cell	(160)
Xu et al, 2024	Diabetic	PI3K/Akt	Endothelial cell	(161)
Gao et al, 2022	Diabetic	TGF-β/Smad	Keratinocyte	(120)
Peng et al, 2019	Diabetic	TGF-β1/Smad	Fibroblast	(162)
Oyebode and Houreld, 2022	Diabetic	TGF-β1/Smad	Fibroblast	(163)
Dong et al, 2025	Diabetic	Wnt/β-catenin	Fibroblast	(121)
Wang et al, 2024	Diabetic	Wnt/β-catenin	Fibroblast	(164)
Liu et al, 2023	Diabetic	Wnt/β-catenin	Endothelial cell	(165)
Lv et al, 2020	Diabetic cutaneous	Wnt/β-catenin	Keratinocyte	(166)

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ROCK, Rho-associated coiled-coil forming protein kinase; Rac, Ras-related C3 botulinum toxin substrate.

6. ncRNAs of cell migration in diabetic wounds

ncRNAs represent a diverse class of RNA transcripts that lack protein-coding potential yet serve key roles in modulating gene expression and orchestrating cell processes (167). Among these transcripts, distinct subcategories, including long ncRNAs (lncRNAs), microRNAs (miRNAs or miRs) and circular RNAs (circRNAs), have been identified and functionally characterized (168). Emerging evidence underscores the significance of ncRNAs in controlling migratory behaviors of cells and their impact on diabetic wound repair (Table II) (169-171). Given their regulatory versatility, targeting ncRNAs may offer novel therapeutic avenues for improving wound outcomes in diabetic patients.

Table II.

ncRNAs regulating cell migration in diabetic wounds.

First author/s, year	ncRNA	Exosome	Target	Type of cell	Effect on cell migration	(Refs.)
Hong et al, 2024	lncRNA XIST	N/A	miR-126-3p/EGFR	Keratinocyte	Promotion	(174)
Chen et al, 2023	lncRNA SNHG16	N/A	miR-31-5p	Human dermal fibroblast	Inhibition	(169)
He et al, 2022	lncRNA CASC2	N/A	miR-155/HIF-1α	Fibroblast	Promotion	(175)
Li et al, 2021	lncRNA H19	N/A	miR-29b, FBN1	Fibroblast	Promotion	(176)
Hu et al, 2020	lnc-URIDS	N/A	Plod1	Fibroblast	Inhibition	(177)
Li et al, 2020	lncRNA H19	MSC-exos	miR-152-3p, PTEN	Fibroblast	Promotion	(179)
Han et al, 2022	lncRNA KLF3-AS1	BMSCs-exo	miR-383, VEGFA	HUVEC	Promotion	(180)
Fu et al, 2022	LINC01435	Keratinocyte-exos	YY1, HDAC8	HUVEC	Inhibition	(181)
Peng et al, 2024	miR-155	N/A	HIF-1α, SOX2, EGFR/MEK/ERK	Keratinocyte	Inhibition	(170)
Tsai et al, 2024	miR-3138	N/A	PALM2-AKAP2, SNX30, ZNF365	Keratinocyte	Promotion	(184)
Tsai et al, 2024	miR-3679-5p	N/A	DMXL1, PPP2R2A, TTC39C	Keratinocyte	Inhibition	(184)
Zhao et al, 2023	miR-204-3p	N/A	KLF6	Keratinocyte	Promotion	(185)
Zhang et al, 2022	miR-146a	N/A	AKAP12	Keratinocyte	Promotion	(186)
Li et al, 2023	miR-182-5p	EPC-exos	PPARG	Keratinocyte	Promotion	(188)
Lv, et al 2020	miR-21-5p	hASC-exos	Wnt/β-catenin	Keratinocyte	Promotion	(166)
Wang et al, 2018	miR-129, miR-335	N/A	Sp1, MMP9	Keratinocyte	Promotion	(187)
Song et al, 2025	miR-204-5p	ADSC-exos	TGF-β1/Smad	Fibroblast	Promotion	(275)
Zheng et al, 2024	miR-132-3p	Insig1-exos	MMP9, PDGF, VEGF	Dermal fibroblast	Promotion	(195)
Wang et al, 2024	miR-145-5p	N/A	PDGFD	Human foreskin fibroblast	Inhibition	(192)
Wang et al, 2023	miR-185-5p	N/A	IL-6, TNF-α, ICAM-1	Human skin fibroblast	Promotion	(189)
Wu et al, 2023	miR-16-5p	N/A	SP5	Rat fibroblast	Promotion	(190)
Zhao et al, 2022	miR-103	N/A	RCAN1	Dermal fibroblast	Inhibition	(193)
Zhang et al, 2020	miR-27-3p	N/A	NOVA1	Fibroblast	Inhibition	(194)
Wu et al, 2020	miR-21-3p	N/A	SPRY1	Fibroblast	Promotion	(191)
Wang et al, 2022	miR-199a-5p	N/A	VEGFA, ROCK1	Human, foreskin fibroblast HUVEC	Inhibition	(158)
Zuo et al, 2024	miR-488-3p	N/A	MeCP2, CYP1B1, Wnt4/β-catenin	HUVEC	Promotion	(196)
Qiu et al, 2024	miR-221-3p	BMSC-exos	FOXP1/SPRY1	HUVEC	Promotion	(198)
Guo et al, 2024	miR-125b	ADSC-exos	CD34, Ki-67, VEGF, TGFβ1	HUVEC	Promotion	(200)
Che et al, 2024	miR-146a-5p	ADSC-exos	JAZF1	HUVEC	Promotion	(201)
Zhou et al, 2024	miR-146a-5p	BMSC-exos	TRAF6	HUVEC	Promotion	(199)
Huang et al, 2023	miR-204-3p	N/A	HIPK2	HUVEC	Promotion	(197)
Ge et al, 2023	miR-132	ADSC-exos	NF-κB	HUVEC	Promotion	(202)
Yan et al, 2022	miR-31-5p	Milk-exos	HIF1AN	HUVEC	Promotion	(205)
Huang et al, 2024	circCDK13	sEVs	IGF2BP3, CD44, c-MYC	Human dermal fibroblast, human epidermal keratinocyte	Promotion	(213)
Tian et al, 2023	circ_072697	N/A	miR-3150a-3p/KDM2A, MAPK	Keratinocyte	Inhibition	(171)
Fu et al, 2023	circ_0080968	N/A	miR-326, miR-766-3p	Keratinocyte	Inhibition	(209)
Han et al, 2021	circ_PRKDC	N/A	miR-31/FBN1	Keratinocyte	Inhibition	(210)
Wang et al, 2020	hsa_circ_0084443	N/A	PI3K, EGFR and ERK pathways	Keratinocyte	Inhibition	(211)
Wang et al, 2024	circMYO9B	MSCs-exos	hnRNPU/CBL/KDM1A/VEGFA	HUVEC	Promotion	(285)
Liang et al, 2022	mmu_circ_0001052	ADSCs-exos	FGF4/p38MAPK pathway	HUVEC	Promotion	(212)

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FBN1, fibrillin 1; YY1, yin yang 1; HDAC8, histone deacetylase 8; Plod1, procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1; SOX2, sex determining region Y-box 2; PALM2-AKAP2, paralemmin 2-A kinase anchoring protein 2; SNX30, sorting nexin family member 30; ZNF365, zinc finger protein 365; DMXL1, Dmx-like 1; PPP2R2A, protein phosphatase 2; TTC39C, tetratricopeptide repeat domain 39C; KLF6, Kruppel-like factor 6; AKAP12, A-kinase-anchoring protein 12; PPARG, peroxisome proliferator activated receptor γ; Sp1, specificity protein-1; ICAM-1, intercellular adhesion molecule 1; SP5, transacting transcription factor 5; RCAN1, regulator of calcineurin; NOVA1, neuro-oncological ventral antigen 1; SPRY1, protein sprout homolog 1; ROCK1, Rho-associated kinase 1; MeCP2, methyl-CpG-binding protein 2; CYP1B1, cytochrome P450 1B1; FOXP1, forkhead box P1; JAZF1, juxtaposed with another zinc finger 1; TRAF6, tumor necrosis factor receptor-associated factor 6; HIPK2, homeodomain-interacting protein kinase 2; HIF1AN, hypoxia-inducible factor 1 subunit α inhibitor. IGF2BP3, insulin-like growth factor 2 mRNA binding protein 3; KDM2A, lysine demethylase 2 A; N/A, no information available; miR, microRNA; lnc, long non-coding; circ, circular.

lncRNAs

lncRNAs are ncRNAs >200 nucleotides in length (172). These molecules serve as master regulators in key biological activities, spanning cellular proliferation, lineage specification, embryogenesis, programmed cell death and metastatic dissemination. lncRNAs frequently function via the competitive endogenous RNA (ceRNA) network, where they sequester miRNAs to modulate the abundance of miRNA target transcripts (173). Hong et al (174) demonstrated that decreased lncRNA XIST expression in diabetic wounds elevates miR-126-3p levels, which subsequently suppresses EGFR (174). This inhibition impairs keratinocyte proliferation and migration in high-glucose environments, contributing to delayed wound healing. These observations indicate that XIST could serve as a promising therapeutic target to enhance keratinocyte motility during wound repair. lncRNAs CASC2 and H19 accelerate fibroblast migration in diabetic wounds through miRNA modulation, ultimately altering the expression of downstream effector genes (175,176). By contrast, lncRNA SNHG16 and lnc-URIDS have been found to inhibit fibroblast migration and impair wound healing (169,177). Exosomes represent a distinct subclass of extracellular vesicles that serve a pivotal role in cell-to-cell signaling by transporting bioactive cargo, including proteins, lipids and nucleic acids. lncRNAs, which are expressed at low levels in cells, tend to be enriched in exosome secretion (178). lncRNA H19 encapsulated in MSC-derived exosomes alleviates fibroblast apoptosis and inflammatory responses by attenuating miR-152-3p-dependent suppression of PTEN, enhancing fibroblast proliferation and motility to accelerate diabetic wound repair (179). Exosomal lncRNA KLF3-AS1 secreted by bone marrow MSCs (BMSCs) enhances EC proliferation, migration and angiogenic tube formation via the miR-383/VEGFA axis, where KLF3-AS1 competitively sponges miR-383 to decrease its suppression of VEGFA, ultimately accelerating diabetic cutaneous wound regeneration (180). Fu et al revealed that keratinocyte-derived exosomal LINC01435 inhibits the migration of human umbilical vein ECs (HUVECs) via the Yin Yang 1 (YY1)/histone deacetylase 8 (HDAC8) pathway, thereby suppressing angiogenesis and hindering diabetic wound healing (181).

miRNAs

miRNAs, a class of evolutionarily conserved small ncRNAs averaging 21-25 nucleotides in length (182), serve as critical mediators of post-transcriptional regulation, exerting their effects through either mRNA destabilization or translational suppression upon target binding (183). Certain miRNAs, including miR-3138, miR-204-3p, miR-146a, miR-129, and miR-335, promote keratinocyte migration through regulation of downstream targets or key signaling pathways, thereby accelerating wound healing in diabetic models (184-187). By contrast, elevated expression of miR-155 and miR-3679-5p suppresses keratinocyte migratory capacity, contributing to impaired re-epithelialization and protracted wound closure in diabetic conditions (170,184). Exosomes derived from endothelial progenitor cells deliver miR-182-5p, which downregulates PPARG expression, enhances keratinocyte proliferation and migration under hyperglycemic conditions, decreases apoptotic activity and ultimately facilitates diabetic wound repair (188). In addition, loading miR-21-5p into human adipose stem cell-derived exosomes facilitates keratinocyte proliferation and migration by activating the Wnt/β-catenin signaling pathway. This improves diabetic wound repair by concurrently stimulating re-epithelialization, optimizing collagen deposition and organization, boosting neovascularization and fostering functional vascular network maturation (166).

In a high-glucose environment, miR-185-5p, miR-16-5p, and miR-21-3p enhance the migratory capacity of fibroblasts (189-191). By contrast, miR-145-5p, miR-103, miR-27-3p, and miR-199a-5p exert a pronounced inhibitory effect on fibroblast migration in diabetic wounds (192-194,158). Recent research demonstrates that exosomes derived from insulin-induced gene 1 (Insig1)-overexpressing BMSCs (Insig1-exos), which are highly enriched with miR-132-3p, markedly enhance dermal fibroblast migration, proliferation and angiogenic activity under hyperglycemic conditions (195). Mechanistically, Insig1-exos modulate key wound repair mediators, including MMP9, PDGF and VEGF, thereby improving diabetic wound closure in murine models. These results underscore the key contribution of miR-132-3p in facilitating cellular motility and tissue regeneration.

Recent studies have demonstrated that miR-488-3p, miR-199a-5p and miR-204-3p facilitate diabetic wound repair by enhancing EC migration under hyperglycemia (158,196,197). Moreover, BMSCs release miR-221-3p and miR-146a-5p, while exosomes from adipose-derived SCs (ADSCs) deliver miR-125b, miR-146a-5p and miR-132, all of which collaboratively enhance EC migration, proliferation and angiogenic functions. These effects contribute to accelerated wound healing in diabetic models, underscoring their therapeutic promise (198-202). Milk-derived exosomes, obtained from both bovine colostrum and mature milk, present benefits such as excellent safety profiles, cost-effectiveness and high production yields (203). These natural vesicles exhibit remarkable drug-loading capacity and robust biological functionality across both in vitro and in vivo systems, highlighting their potential for pharmaceutical delivery and immunomodulatory applications (204). Notably, Yan et al (205) revealed that milk exosome-encapsulated miR-31-5p exhibits enhanced stability and cellular internalization (compared with free miR-31-5p mimics), stimulates EC proliferation, migration and neovascularization through hypoxia-inducible factor 1 subunit α inhibitor suppression and ultimately promotes diabetic wound repair.

circRNAs

circRNAs are a unique class of ncRNA molecules distinguished by their covalently closed-loop conformation, which confers resistance to exonuclease-mediated degradation (206). circRNAs function as 'sponges' to inhibit specific miRNAs, preventing their binding to target mRNAs, thereby serving as endogenous miRNA regulators (inhibitors) (207). Moreover, circRNAs modulate post-transcriptional gene expression and transcriptional processes through interactions with transcription factors and RNA-binding proteins (208). circ_072697, circ_0080968, circ_PRKDC and hsa_ circ_0084443 exert inhibitory effects on keratinocyte migration and impair diabetic wound healing by suppressing miRNAs or directly modulating target gene expression (171,209-211). ADSC-derived exosomes carrying mmu_circ_0001052 downregulate miR-106a-5p, which elevates fibroblast growth factor 4 (FGF4) levels, triggers the FGF4/p38MAPK signaling cascade and stimulates HUVEC proliferation, migration and angiogenic activity in high-glucose environments, collectively improving diabetic wound healing (212). Huang et al (213) reported that engineered small extracellular vesicles (sEVs) with circCDK13 overexpression bind insulin-like growth factor 2 mRNA-binding protein 3, stabilizing CD44 and c-MYC transcripts to enhance keratinocyte and fibroblast motility and division, thus accelerating wound closure in diabetic mouse models.

ncRNAs modulate cell migration via signaling pathways or downstream targets, presenting a promising intervention strategy for diabetic wounds. Both lncRNAs and circRNAs serve as ceRNAs, sequestering specific miRNAs to prevent their suppressive effects on target mRNAs, thereby indirectly regulating gene expression (171,174). By contrast, miRNAs directly bind to mRNAs to induce degradation or translational inhibition, forming an integrated miRNA-mRNA-functional protein regulatory network (170,186). Future studies should delineate the dynamic ncRNA-mediated regulatory networks in diabetic wound healing to develop precision-based therapeutic approaches for clinical translation.

7. Regulation of cell migration for the treatment of diabetic wounds

SCs and derived exosomes

SCs are undifferentiated cells characterized by their capacity for self-renewal and pluripotency, allowing differentiation into specialized lineages (214). Additionally, they secrete bioactive factors, modulate inflammatory responses, stimulate angiogenesis and enhance tissue remodeling, highlighting their therapeutic potential in regenerative medicine and tissue repair (Table III) (215). Their low immunogenicity and diverse sources enhance clinical potential. A recent investigation revealed that perinatal tissue-derived MSCs potentiate keratinocyte and EC proliferation and migration via PI3K/Akt pathway activation, culminating in accelerated healing of diabetic wounds (160). Furthermore, SCs can serve as carriers for drugs or bioactive molecules, facilitating sustained release while protecting them from degradation. Administration of genetically modified umbilical cord MSCs expressing angiopoietin-1 improves wound vascularization in diabetic murine models by stimulating EC migration and tubulogenesis, leading to faster healing kinetics (216).

Table III.

SCs and exos regulating cell migration in diabetic wounds.

First author/s, year	Type of SC	Exos	Target	Type of cell migration	(Refs.)
Huang et al, 2025	MSCs derived from perinatal tissue	N/A	PI3K/Akt	Keratinocyte, HUVEC	(160)
Deng et al, 2024	MSCs derived from human umbilical cords	N/A	ANG1	HUVEC	(216)
He et al, 2024	ADSC	ADSC-exos	TRIM32/STING	HUVEC	(218)
Liu et al, 2023	GMSC	GMSC-exos	Wnt/β-catenin	HUVEC	(165)

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TRIM32, tripartite motif-containing 32; STING, stimulator of interferon genes; N/A, no information available; MSC, mesenchymal stem cell; exo, exosome; ADSC, adipose-derived stem cell; GMSC, gingival mesenchymal stem cell; ANG, angiopoietin; HUVEC, human umbilical vein endothelial cell.

The application of SCs is limited by several factors, including a low survival rate, difficulty in controlling differentiation direction and the potential for immune rejection (217). By contrast, SC-derived exosomes, characterized by strong targeting ability, well-defined mechanisms of action and high safety profiles, offer a more precise and controllable cell-free therapeutic strategy for tissue repair. Beyond ncRNA-mediated regulation, SC-derived exosomes also promote cell migration and improve diabetic wound repair by targeting key signaling pathways. For example, ADSC-exos enhance EC migration and angiogenesis via the Tripartite motif-containing protein 32 (TRIM32)/STING axis, expediting wound closure in diabetic models (218). Liu et al (165) reported that exosomes isolated from gingival MSCs stimulate EC proliferation, migration and tube formation by activating the Wnt/β-catenin cascade, offering a potential therapeutic strategy for diabetic wound management.

SC therapy has demonstrated substantial therapeutic potential in diabetic wound repair; however, limitations persist (215). The precise mechanistic pathways governing its efficacy remain incompletely characterized, underscoring the need for further exploration of its molecular and cellular regulatory networks. Safety concerns need to be addressed by defining optimal dosages and administration routes to minimize potential adverse effects. Additionally, the complex processes involved in SC collection and pretreatment require simplification to enhance clinical feasibility and efficiency. The preparation and quality control of exosomes require the establishment of a unified standard (219). Additionally, due to the low molecular concentration of natural exosomes and their limited repair capabilities, exploring pretreatment methods, genetically engineered exosomes and the integration of exosomes with biomaterials may represent promising directions for development (220).

Growth factor therapy

Growth factor therapy for diabetic wound healing is based on its ability to coordinate key cellular responses and molecular pathways governing tissue regeneration. Key growth factors, including PDGF, VEGF, EGF, FGF and TGF, demonstrate potent pro-healing effects by stimulating cell migration and other regenerative processes that collectively accelerate wound repair (221). FGF-21 markedly improves EC proliferation, migration and angiogenic tube formation under hyperglycemic conditions, accelerating diabetic wound repair and underscoring its potential as a therapeutic agent for diabetic wounds (222). Tang et al (223) reported that PDGF-loaded nanocapsules with sustained release properties efficiently regulate fibroblast migration, proliferation and neovascularization, contributing to enhanced wound repair in diabetic models. Jeong et al (224) found that EGF encapsulated within gelatin-alginate coacervates enhances keratinocyte migration in vitro and accelerates wound closure in diabetic mice.

Growth factor therapy exhibits potential for promoting tissue regeneration; however, its clinical translation is hindered by rapid degradation, poor diffusion efficiency and insufficient local retention (221). Future studies should prioritize design of advanced biocompatible biomaterials with tunable degradation kinetics, alongside optimization of nanoscale delivery platforms to enable spatiotemporal control of drug release, targeted accumulation at wound sites and improved pharmacokinetic profile, which are key for expanding therapeutic utility in clinical settings.

Drug-loaded dressings

Hydrogel-based drug therapy

Hydrogels are three-dimensional polymeric networks distinguished by high hydration capacity and structural integrity, formed via cross-linked polymer chains. Owing to their biocompatibility, low immunogenicity and ability to retain moisture, hydrogels have gained prominence as an ideal biomaterial for diabetic wound management (Table IV) (225,226). These materials are capable of absorbing excess wound exudate, sustaining a moist microenvironment and preventing anaerobic bacterial proliferation through enhanced oxygen diffusion, facilitating cellular migration, tissue repair mechanisms and an accelerated healing trajectory (227,228). Recent studies have demonstrated that drug-loaded hydrogel dressings accelerate diabetic wound closure by facilitating cell motility and tissue remodeling (229,230). Notably, PDGF and cytokines stimulate ECM production, neovascularization and directed cellular movement, contributing to enhanced tissue repair (231). Xu et al (232) demonstrated that platelet-rich plasma-loaded multifunctional hydrogels exhibit dual therapeutic effects, suppressing excessive inflammation while shifting macrophage differentiation in favor of the regenerative M2 subset. This phenotypical modulation enhances migratory activity in both fibroblasts and vascular ECs, contributing to accelerated wound repair. This approach presents a clinically viable therapeutic paradigm for enhancing diabetic wound repair mechanisms. In addition, the incorporation of engineered sEVs into hydrogels prolongs their residence within the wound microenvironment, establishing them as optimal vehicles for bioactive molecule delivery. Wei et al (233) revealed that miR-17-5p-modified sEVs encapsulated in gelatin methacryloyl hydrogels enhance ECM remodeling via PTEN/p21 pathway modulation, thus stimulating both EC and fibroblast motility. Such a therapeutic strategy markedly improves the healing kinetics of diabetic wounds.

Table IV.

Modulation of cell migration by drug-loaded dressings for diabetic wound healing.

First author/s, year	Dressing type	Name	Components	Type of cell migration	(Refs.)
Bei et al, 2024	Hydrogel	PAN/Ag-PLG hydrogel	Gallic acid; functionalized polylysine; Ag-PLG, oxidized HA, cross-linked polyacrylic acid grafted with N-hydrosuccinimide ester	HUVEC	(229)
Li et al, 2022	Hydrogel	HA-DA/MXene@ PDA hydrogel	HA-DA; PDA; Ti₃C₂ MXene nanosheets	HUVEC	(230)
Xu et al, 2023	Hydrogel	PRP loaded multifunctional hydrogel	PRP; DA-grafted alginate; 6-aminobenzo[c][1,2] oxaborol-1(3H)-ol-conjugated HA	Fibroblast, HUVEC	(232)
Liu et al, 2022	Hydrogel	B-G hydrogel	Methacryloyl-substituted B; G	Fibroblast	(286)
Wu et al, 2022	Hydrogel	Injectable conductive and angiogenic hydrogel	Quaternized chitosan; polyaniline; four-armed aldehyde-terminated polyethylene glycol; deferoxamine	HUVEC	(287)
Wei et al, 2024	Hydrogel	GelMA hydrogel loaded with sEVs^17−OE	sEVs^17−OE; GelMA	Fibroblast, HUVEC	(233)
Wu et al, 2024	Aerogel	TDNP functionalized aerogel	TDNPs	Fibroblast	(242)
John et al, 2023	Aerogel	Nanofiber aerogels with precision macrochannels and LL-37-mimic peptides	Poly(glycolide-co-lactide) (90:10 glycolide: lactide); gelatin; poly-p-dioxanone; LL-37-mimic peptide W379	Keratinocyte, fibroblast	(245)
Yin et al, 2021	Microneedle patch	MN-MOF-GO-Ag	Mg-MOF; poly(γ-glutamic acid) hydrogel; gallic acid; GO-Ag; Mg²⁺	HUVEC	(248)
Wang et al, 2023	Microneedle patch	MN-MgH₂	MgH₂; poly(lactic-co-glycolic acid)	Fibroblast, HUVEC	(249)
Liu et al, 2023	Microneedle patch	Double-layer drug-loaded microneedles (DMN@TH/rh-EGF)	TH; rh-EGF; HA; carboxymethyl chitosan; gelatin	HUVEC	(288)

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PAN, polyacrylic acid grafted with N-hydrosuccinimide ester; PLG, polylysine-gallic acid; HUVEC, human umbilical vein endothelial cell; HA, hyaluronic acid; DA, dopamine; PDA, polydopamine; MXene, two-dimensional transition metal carbides, carbonitrides, and nitrides; PRP, platelet rich plasma; G, gelatin; B, Bletilla Striata polysaccharide; GelMA, Gelatin methacryloyl; sEVs^17−OE, miR-17-5p-engineered small extracellular vesicles; miR, microRNA; TDNP, Turmeric-derived nanoparticle; LL-37, human cathelicidin antimicrobial peptide; MN, microneedle; MOF, magnesium organic framework; GO, graphene oxide; DMN@TH, double-layer microneedle loaded with tetracycline hydrochloride; rh-EGF, recombinant human epidermal growth factor.

Hydrogels face limitations in their application. Due to their time-dependent viscoelastic properties, long-term structural degradation and stress relaxation under load may occur, which can impair cell adhesion, migration and proliferation (234). Additionally, insufficient mechanical strength, challenges in controlling degradation rate and narrow functionality further restrict their practical use. Future integration of artificial intelligence-based screening with advanced 3D bioprinting platforms may simultaneously optimize the biomechanical performance, biofunctional characteristics and therapeutic applicability of next-generation hydrogels (235,236). Combined with personalized customization, these advancements may provide more efficient and precise solutions for wound healing.

Aerogel-based drug therapy

Aerogels are ultra-lightweight nanoporous materials formed by removing the liquid from gel pores to create interconnected porous structures (237). They exhibit rapid absorption of exudate while maintaining a moist wound environment and facilitating efficient gas exchange (238). Compared with conventional hydrogels and standard wound dressings, aerogels demonstrate superior structural characteristics, including ultralow density, minimal thermal conductivity, interconnected macroporosity and an extensive surface-to-volume ratio, which position them as promising alternatives for advanced wound management (Table IV) (239). Emerging evidence highlights the therapeutic potential of aerogel-based drug delivery systems in accelerating cell migration during wound regeneration (240,241). Wu et al (242) developed a turmeric nanoparticle-embedded aerogel dressing that demonstrates controlled drug release kinetics and potent anti-inflammatory and antioxidant activity, alongside enhanced fibroblast migration and proliferation. This formulation exhibited remarkable effectiveness in treating diabetic ulcers. Furthermore, LL-37, a cathelicidin-derived host defense peptide, serves key biological functions beyond its antimicrobial effects, including the modulation of keratinocyte and fibroblast activity to facilitate cutaneous wound closure (243,244). John et al (245) developed a nanofiber aerogel scaffold engineered with tailored macrochannels and LL-37 biomimetic peptides for diabetic wound therapy. The results demonstrated notable stimulation of both keratinocyte and fibroblast migratory activity and mitotic expansion, alongside marked enhancement in neovascularization and epidermal regeneration.

The application of aerogel requires further enhancement. Its intrinsic porous structure results in inadequate mechanical properties, low mechanical strength and susceptibility to fragmentation (238). Moreover, the intricate preparation process and high production costs hinder large-scale manufacturing and clinical adoption (242). In future, it may be feasible to enhance mechanical strength and flexibility through composite material design (by integrating with polymers), while simultaneously optimizing manufacturing processes, reducing expenses and developing more environmentally friendly and sustainable preparation methodologies.

Drug therapy based on microneedle patches

Microneedles are miniature, spine-like structures made from biocompatible materials, typically measuring from tens to hundreds of microns in size. Microneedle technology facilitates the penetration of the stratum corneum, enabling drug delivery, substance extraction or physical therapy targeting deep skin tissue (Table IV) (246). The microneedle patch integrates microneedle technology with a patch format, using tiny needle-like structures distributed on a substrate for transdermal drug delivery. Given their high exudate absorption capacity, robust bioadhesive performance and sustained drug release kinetics, microneedle patches have emerged as a promising therapeutic modality for chronic wound management (247). Yin et al (248) engineered a microneedle system incorporating magnesium-based organic frameworks, enabling efficient transdermal drug transport in diabetic wounds. This platform significantly augments EC migratory activity, stimulates neovascularization and accelerates tissue repair processes. Wang et al (249) developed a biodegradable poly (lactic-co-glycolic acid) microneedle patch loaded with magnesium hydride. This platform effectively scavenges ROS, induces a shift toward pro-regenerative M2 macrophage phenotypes and stimulates the proliferation and motility of fibroblasts and ECs, enhancing the healing trajectory of diabetic wounds.

Microneedle technology encounters several challenges, including limited drug-loading capacity, high production cost and insufficient stability in complex wound environments (246,250). Future advancements are required, such as optimizing materials and structures for the design of novel microneedles, assessing drug stability and enhancing biocompatibility and safety profiles. Additionally, the combination of micromachining and 3D printing techniques may streamline the manufacturing process and decrease production expenses (250).

Traditional chinese medicine (TCM) treatment

Phytochemicals derived from medicinal plants demonstrate multifunctional bioactive properties, including the stimulation of cellular proliferation and migratory capacity, potent antimicrobial effects and the induction of neovascularization, all of which contribute to enhanced tissue regeneration (Table V) (251,252). Recent research has shown that topical administration of Crocus sativus L. (saffron) petal extract markedly accelerates diabetic wound repair by elevating Collagen type I alpha 1 and VEGF levels, stimulating fibroblast and EC motility and enhancing overall re-epithelialization in mice (253). Ginsenoside Rg1 (Rg1), a principal active component derived from Panax ginseng, exerts pro-angiogenic effects by stimulating the proliferation and migration of ECs, thereby facilitating wound repair in diabetic wounds. Mechanistically, Rg1 downregulates miR-48-3p, elevates Sirt1 expression and triggers the PI3K/AKT/endothelial nitric oxide synthase) cascade, collectively enhancing vascular regeneration (254). Similarly, paeoniflorin, a key monoterpene glycoside isolated from Paeoniae alba radix, was demonstrated by Sun et al to attenuate oxidative damage while promoting keratinocyte proliferation and motility (255). These reparative effects are achieved via Nrf2 pathway activation coupled with increased VEGF and TGF-β1 production, expediting diabetic wound closure in rats.

Table V.

Regulation of cell migration in diabetic wound healing by traditional Chinese medicine.

First author/s, year	Drug category	Name	Target	Type of cell migration	(Refs.)
Soheilifar et al, 2024	Natural product	Saffron (Crocus Sativus L.) petal extract	COL1A1, VEGF	Fibroblast, HUVEC	(253)
Xiong et al, 2024	Natural product	Astragaloside IV	PIK3R2, VEGF/PI3K/AKT	HUVEC	(289)
Lei et al, 2022	Natural product	Panax notoginseng saponins	GSK-3β/β-catenin/VEGF	HUVEC	(290)
Huang et al, 2021	Natural product	Ginsenoside Rg1	miR-489-3p/Sirt1, PI3K/AKT/eNOS	HUVEC	(254)
Sun et al, 2020	Natural product	Paeoniflorin	Nrf2, VEGF, TGF-β1	Keratinocyte	(255)
Lu et al, 2021	Herbal formula	Quyu Shengji formula	PGT	Human dermal microvascular endothelial cell	(291)
Zhang et al, 2024	Herbal formula	Dang-Gui-Si-Ni decoction	AGE/RAGE/TGF-β/Smad2/3	Fibroblast	(256)
Gong et al, 2022	Herbal formula	Moist exposed burn ointment	N/A	Keratinocyte	(257)
Liu et al, 2023	Herbal formula	Pien-tze-huang	Nrf2/ARE	HUVEC	(292)

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COL1A1, collagen type I α1; PIK3R2, phosphoinositol-3 kinase regulatory subunit 2; GSK-3β, glycogen synthase kinase-3β; PGT, prostaglandin transporter; ARE, antioxidant response element; N/A, no information available; HUVEC, human umbilical vein endothelial cell; miR, microRNA; Sirt, Sirtuin; eNOS, endothelial nitric oxide synthase; RAGE, receptor for advanced glycation end-products.

Chinese herbal formulas have potential in facilitating cell migration in diabetic wound healing (256,257). Danggui Sini decoction (DSD), a TCM formulation, exhibits multi-target pharmacological actions such as vasodilatory, anti-inflammatory and antioxidant activity (258). Mechanistic study has revealed that DSD facilitates diabetic wound repair by augmenting fibroblast proliferation and migratory capacity, mediated via regulation of the AGE/RAGE (Receptor for advanced glycation end-products)/TGF-β/Smad2/3 signaling axis in diabetic foot ulcer rats (256). Moist exposed burn ointment, a herbal oil-based preparation, is utilized for burn management and chronic refractory wound care due to its clinical effectiveness (259). When applied to diabetic wounds, as demonstrated by Gong et al (257), this formulation accelerates tissue regeneration by stimulating keratinocyte migration, promoting granulation tissue development and collagen reorganization and enhancing re-epithelialization.

While TCM demonstrates therapeutic promise in enhancing diabetic wound repair, several challenges remain to be resolved, including poorly characterized molecular mechanisms, intricate multi-component formulations and restricted administration options. Overcoming these limitations requires systematic research strategies to elucidate fundamental mechanisms, optimize bioactive compound extraction protocols, develop novel delivery systems and validate therapeutic effects through multicenter clinical studies.

Additional treatment options

Diabetic foot ulcers are frequently attributed to inadequate blood supply to the lower limb vessels, leading to localized hypoxia in the wound and consequently impairing the healing process. Hyperbaric oxygen therapy (HBOT) serves as an adjunctive therapy that elevates oxygen concentrations in arterial blood and tissues (260). This therapeutic intervention involves the administration of 100% oxygen in a pressurized chamber, elevating environmental pressure to 2-3 atmospheres absolute (261). Under hyperbaric conditions, tissue hypoxia is alleviated, improving oxygenation for key metabolic processes, cellular proliferation and wound repair. HBOT stimulates fibroblast and EC activity via HIF-1α pathway activation, which enhances vascularization and accelerates healing of diabetic wounds (262).

Negative pressure wound therapy (NPWT) is a non-surgical therapeutic approach utilizing an airtight dressing system to achieve localized sub-atmospheric pressure at the wound bed, facilitating enhanced tissue perfusion and wound closure. This therapy effectively removes wound exudate and necrotic tissue, decreases tissue edema, promotes the growth of granulation tissue and angiogenesis, thereby providing optimal conditions for wound healing (263,264). Huang et al (265) revealed that NPWT promotes human dermal fibroblast proliferation and migration via miR-155 downregulation in diabetic wound granulation tissue, concurrently augmenting FGF7 expression to accelerate wound repair (265). Liu et al (266) demonstrated that NPWT stimulates keratinocyte proliferation and migration by suppressing hsa-miR-203, which elevates p63 protein levels in both peripheral blood and wound edge tissue, contributing to enhanced diabetic wound healing.

Photobiomodulation (PBM), commonly known as low-intensity laser therapy, is a non-interventional treatment approach that employs low-power optical radiation, typically delivered via lasers or light-emitting diodes (267). PBM enhances wound closure and tissue regeneration, with optimal therapeutic outcomes depend on precise selection of wavelength and fluence parameters (268,269). PBM at 830 nm (5 J/cm² fluence) significantly boosts fibroblast viability, migration and proliferative capacity via activation of the TGF-β1/Smad pathway, leading to accelerated healing of diabetic wounds (163). Cai et al (270) examined dual-wavelength (red/blue) phototherapy in diabetic rats, observing substantial decreases in inflammatory markers and ROS accumulation alongside enhanced EC activity. This combined approach promotes NO synthesis and markedly improves wound closure rates.

Filgrastim, a recombinant human granulocyte colony-stimulating factor analog, promotes both neutrophil progenitor differentiation and functional maturation (271). Additionally, this cytokine directs neutrophil trafficking toward inflammatory and infectious foci, amplifying localized immune defenses via targeted cellular recruitment. A retrospective analysis of patients with infectious diabetic wounds demonstrated that those treated with filgrastim exhibited significantly faster recovery times (272). This indicates the potential therapeutic value of filgrastim in enhancing infection control and promoting wound healing via increased neutrophil production and migration, bolstered immune response and accelerated tissue repair.

There are limitations in the application of the aforementioned therapies. The high cost of treatment and reliance on specialized equipment restrict the widespread adoption of HBOT. Future research should focus on optimizing treatment parameters, decreasing cost and investigating combination therapies. NPWT may induce pain and skin damage, with limited efficacy for infected wounds. Advances in dressing materials and refined control of negative pressure are required to minimize adverse reactions (273). PBM lacks standardized therapeutic parameters, such as wavelength and fluence, and its efficacy varies between individuals (268,269). Large-scale clinical trials are necessary to establish optimal parameters and indications. Filgrastim may lead to overactivation of neutrophils, potentially causing increased inflammation and other adverse reactions (274). Future studies should aim to optimize dosing regimens and develop novel drugs to enhance therapeutic outcomes.

8. Conclusion

The present review summarizes cell migration dynamics in diabetic wounds, with a focus on cellular mechanisms, signaling cascades, ncRNA-mediated regulation and their translational implications for targeted therapies. Emerging therapies, such as SCs, exosomes, drug-loaded dressings and TCM, enhance cell migration via ncRNA-mediated signaling (160,275). This establishes regulatory axes of drug/therapy-ncRNA-signaling pathway/downstream target-cell migration (166,254). These breakthroughs substantially enhance understanding of diabetic wound pathological mechanisms while establishing a framework for targeted therapeutic development.

Although the mechanisms underlying abnormal cell migration in diabetic wounds and targeted therapeutic approaches have seen advancements, notable gaps remain. The majority of studies emphasize the regulation of individual cell types or specific signaling pathways, with limited exploration of cellular interactions and signaling crosstalk (160,165,166,275). Research on the regulation of cell migration primarily focuses on ncRNAs, whereas other epigenetic modifications, such as DNA methylation and histone modification, warrant further investigation (170,177,192,211). Most studies rely on in vitro experiments or animal models, which differ from the complex pathological environment of the human body, limiting their clinical translation and necessitating further validation (170,253). Despite their growing use, SC/exosome and growth factor therapy, advanced drug-loaded dressings and TCM intervention lack comprehensive clinical trial data to confirm their long-term safety and therapeutic efficacy. Furthermore, given the high heterogeneity of patients, there is a lack of research on personalized treatment approaches in existing studies, which restricts broader clinical application (276-278).

Future research should explore crosstalk between immune cells, fibroblasts, keratinocytes and ECs in diabetic wounds, focusing on key pathways. The application of organoids or 3D-printed tissue models may facilitate the development of more accurate models that closely mimic the human pathological environment (279,280). It is essential to refine the preparation and delivery technologies for SCs and exosomes, enhance the manufacturing processes of drug-loaded dressings and design intelligent dressing delivery systems to improve the precision and control of therapeutic interventions (281-283). The integration of topical TCM agents with advanced wound dressings may enhance therapeutic efficacy, presenting a potential strategy for diabetic wound management. Large-scale, multi-center clinical trials are required to validate the efficacy of existing treatments. Integrating multi-omics techniques with artificial intelligence-based analysis to explore personalized treatment strategies will aid in achieving precise intervention tailored to individual patient characteristics (284). Ultimately, it is essential to enhance multi-disciplinary collaboration between basic research and clinical practice, thereby facilitating the translation of research findings into practical applications and providing more efficient and safer solutions for the treatment of diabetic wounds.

Acknowledgments

Not applicable.

Funding Statement

The present study was supported by the Construction Project of the TCM Institute of Sore and Ulcer, Tianjin University of Traditional Chinese Medicine (grant no. 202206), the Construction Project of the Institute of Traditional Chinese Medicine and Integrated Chinese and Western Medicine under the Tianjin Municipal Health Commission (grant no. 202455) and the Research Planning Projects of the Tianjin Municipal Education Commission (grant no. 2024ZD014).

Availability of data and materials

Not applicable.

Authors' contributions

JLS designed the study, wrote the manuscript and constructed figures. TZ and CW performed the literature review and created figures. XS, JCS and ZZ revised the manuscript. JCS and ZZ supervised the study and acquired funding. Data authentication is not applicable. All authors have read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1.Dwivedi J, Sachan P, Wal P, Wal A, Rai AK. Current state and future perspective of diabetic wound healing treatment: Present evidence from clinical trials. Curr Diabetes Rev. 2024;20:e280823220405. doi: 10.2174/1573399820666230828091708. [DOI] [PubMed] [Google Scholar]
2.Sun H, Pulakat L, Anderson DW. Challenges and new therapeutic approaches in the management of chronic wounds. Curr Drug Targets. 2020;21:1264–1275. doi: 10.2174/1389450121666200623131200. [DOI] [PubMed] [Google Scholar]
3.Burgess JL, Wyant WA, Abujamra BA, Kirsner RS, Jozic I. Diabetic wound-healing science. Medicina (Kaunas) 2021;57:1072. doi: 10.3390/medicina57101072. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Vijayakumar V, Samal SK, Mohanty S, Nayak SK. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int J Biol Macromol. 2019;122:137–148. doi: 10.1016/j.ijbiomac.2018.10.120. [DOI] [PubMed] [Google Scholar]
5.Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic foot ulcers: A review. JAMA. 2023;330:62–75. doi: 10.1001/jama.2023.10578. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Dasari N, Jiang A, Skochdopole A, Chung J, Reece EM, Vorstenbosch J, Winocour S. Updates in diabetic wound healing, inflammation, and scarring. Semin Plast Surg. 2021;35:153–158. doi: 10.1055/s-0041-1731460. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.GBD 2021 Diabetes Collaborators Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the global burden of disease study 2021. Lancet. 2023;402:203–234. doi: 10.1016/S0140-6736(23)01301-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Feng J, Yao Y, Wang Q, Han X, Deng X, Cao Y, Chen X, Zhou M, Zhao C. Exosomes: Potential key players towards novel therapeutic options in diabetic wounds. Biomed Pharmacother. 2023;166:115297. doi: 10.1016/j.biopha.2023.115297. [DOI] [PubMed] [Google Scholar]
9.Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. 2024;25:599–616. doi: 10.1038/s41580-024-00715-1. [DOI] [PubMed] [Google Scholar]
10.Hanson AJ, Quinn MT. Effect of fibrin sealant composition on human neutrophil chemotaxis. J Biomed Mater Res. 2002;61:474–481. doi: 10.1002/jbm.10196. [DOI] [PubMed] [Google Scholar]
11.Liu C, Lu Y, Du P, Yang F, Guo P, Tang X, Diao L, Lu G. Mesenchymal stem cells pretreated with proinflammatory cytokines accelerate skin wound healing by promoting macrophages migration and M2 polarization. Regen Ther. 2022;21:192–200. doi: 10.1016/j.reth.2022.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Wang S, Wang K, Xin Y, Lv D. Maggot excretions/secretions induces human microvascular endothelial cell migration through AKT1. Mol Biol Rep. 2010;37:2719–2725. doi: 10.1007/s11033-009-9806-x. [DOI] [PubMed] [Google Scholar]
13.Xia W, Li M, Jiang X, Huang X, Gu S, Ye J, Zhu L, Hou M, Zan T. Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing. J Nanobiotechnology. 2022;20:144. doi: 10.1186/s12951-022-01348-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
14.Fang PH, Lai YY, Chen CL, Wang HY, Chang YN, Lin YC, Yan YT, Lai CH, Cheng B. Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions. Mol Med. 2022;28:71. doi: 10.1186/s10020-022-00499-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
15.Huang SM, Wu CS, Chiu MH, Yang HJ, Chen GS, Lan CCE. High-glucose environment induced intracellular O-GlcNAc glycosylation and reduced galectin-7 expression in keratinocytes: Implications on impaired diabetic wound healing. J Dermatol Sci. 2017;87:168–175. doi: 10.1016/j.jdermsci.2017.04.014. [DOI] [PubMed] [Google Scholar]
16.Song Q, An X, Li D, Sodha NR, Boodhwani M, Tian Y, Sellke FW, Li J. Hyperglycemia attenuates angiogenic capability of survivin in endothelial cells. Microvasc Res. 2009;78:257–264. doi: 10.1016/j.mvr.2009.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Huttenlocher A. Cell polarization mechanisms during directed cell migration. Nat Cell Biol. 2005;7:336–337. doi: 10.1038/ncb0405-336. [DOI] [PubMed] [Google Scholar]
18.Brothers KM, Stella NA, Hunt KM, Romanowski EG, Liu X, Klarlund JK, Shanks RMQ. Putting on the brakes: Bacterial impediment of wound healing. Sci Rep. 2015;5:14003. doi: 10.1038/srep14003. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Carragher NO, Fincham VJ, Riley D, Frame MC. Cleavage of focal adhesion kinase by different proteases during SRC-regulated transformation and apoptosis. Distinct roles for calpain and caspases. J Biol Chem. 2001;276:4270–4275. doi: 10.1074/jbc.M008972200. [DOI] [PubMed] [Google Scholar]
20.Zhao Y, Wang Y, Sarkar A, Wang X. Keratocytes generate high integrin tension at the trailing edge to mediate rear de-adhesion during rapid cell migration. iScience. 2018;9:502–512. doi: 10.1016/j.isci.2018.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Clayton SM, Shafikhani SH, Soulika AM. Macrophage and neutrophil dysfunction in diabetic wounds. Adv Wound Care (New Rochelle) 2024;13:463–484. doi: 10.1089/wound.2023.0149. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Rousselle P, Braye F, Dayan G. Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2019;146:344–365. doi: 10.1016/j.addr.2018.06.019. [DOI] [PubMed] [Google Scholar]
23.Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: A cellular perspective. Physiol Rev. 2019;99:665–706. doi: 10.1152/physrev.00067.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]
24.Su Y, Richmond A. Chemokine regulation of neutrophil infiltration of skin wounds. Adv Wound Care (New Rochelle) 2015;4:631–640. doi: 10.1089/wound.2014.0559. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Dahlgren C, Gabl M, Holdfeldt A, Winther M, Forsman H. Basic characteristics of the neutrophil receptors that recognize formylated peptides, a danger-associated molecular pattern generated by bacteria and mitochondria. Biochem Pharmacol. 2016;114:22–39. doi: 10.1016/j.bcp.2016.04.014. [DOI] [PubMed] [Google Scholar]
26.Mamun AA, Shao C, Geng P, Wang S, Xiao J. Recent advances in molecular mechanisms of skin wound healing and its treatments. Front Immunol. 2024;15:1395479. doi: 10.3389/fimmu.2024.1395479. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Lämmermann T, Afonso PV, Angermann BR, Wang JM, Kastenmüller W, Parent CA, Germain RN. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature. 2013;498:371–375. doi: 10.1038/nature12175. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Lee WL, Harrison RE, Grinstein S. Phagocytosis by neutrophils. Microbes Infect. 2003;5:1299–1306. doi: 10.1016/j.micinf.2003.09.014. [DOI] [PubMed] [Google Scholar]
29.McLeish KR, Fernandes MJ. Understanding inhibitory receptor function in neutrophils through the lens of CLEC12A. Immunol Rev. 2023;314:50–68. doi: 10.1111/imr.13174. [DOI] [PubMed] [Google Scholar]
30.Fetz AE, Bowlin GL. Neutrophil extracellular traps: Inflammation and biomaterial preconditioning for tissue engineering. Tissue Eng Part B Rev. 2022;28:437–450. doi: 10.1089/ten.teb.2021.0013. [DOI] [PubMed] [Google Scholar]
31.Bratton DL, Henson PM. Neutrophil clearance: When the party is over, clean-up begins. Trends Immunol. 2011;32:350–357. doi: 10.1016/j.it.2011.04.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
32.Guo S, DiPietro LA. Factors affecting wound healing. J Dent Res. 2010;89:219–229. doi: 10.1177/0022034509359125. [DOI] [PMC free article] [PubMed] [Google Scholar]
33.de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: Going forward in reverse. Nat Rev Immunol. 2016;16:378–391. doi: 10.1038/nri.2016.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
34.Chen WYJ, Rogers AA. Recent insights into the causes of chronic leg ulceration in venous diseases and implications on other types of chronic wounds. Wound Repair Regen. 2007;15:434–449. doi: 10.1111/j.1524-475X.2007.00250.x. [DOI] [PubMed] [Google Scholar]
35.Isles HM, Herman KD, Robertson AL, Loynes CA, Prince LR, Elks PM, Renshaw SA. The CXCL12/CXCR4 signaling axis retains neutrophils at inflammatory sites in zebrafish. Front Immunol. 2019;10:1784. doi: 10.3389/fimmu.2019.01784. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Wood W. Wound healing: Calcium flashes illuminate early events. Curr Biol. 2012;22:R14–R16. doi: 10.1016/j.cub.2011.11.019. [DOI] [PubMed] [Google Scholar]
37.Niethammer P, Grabher C, Look AT, Mitchison TJ. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature. 2009;459:996–999. doi: 10.1038/nature08119. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Razzell W, Evans IR, Martin P, Wood W. Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release. Curr Biol. 2013;23:424–429. doi: 10.1016/j.cub.2013.01.058. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Minutti CM, Knipper JA, Allen JE, Zaiss DM. Tissue-specific contribution of macrophages to wound healing. Semin Cell Dev Biol. 2017;61:3–11. doi: 10.1016/j.semcdb.2016.08.006. [DOI] [PubMed] [Google Scholar]
40.Dutra FF, Bozza MT. Heme on innate immunity and inflammation. Front Pharmacol. 2014;5:115. doi: 10.3389/fphar.2014.00115. [DOI] [PMC free article] [PubMed] [Google Scholar]
41.Sindrilaru A, Scharffetter-Kochanek K. Disclosure of the culprits: Macrophages-versatile regulators of wound healing. Adv Wound Care (New Rochelle) 2013;2:357–368. doi: 10.1089/wound.2012.0407. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–321. doi: 10.1038/nature07039. [DOI] [PubMed] [Google Scholar]
43.Zhang T, Tai Z, Miao F, Zhao Y, Wang W, Zhu Q, Chen Z. Bioinspired nanovesicles derived from macrophage accelerate wound healing by promoting angiogenesis and collagen deposition. J Mater Chem B. 2024;12:12338–12348. doi: 10.1039/D3TB02158K. [DOI] [PubMed] [Google Scholar]
44.Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007;127:998–1008. doi: 10.1038/sj.jid.5700786. [DOI] [PubMed] [Google Scholar]
45.Rousselle P, Montmasson M, Garnier C. Extracellular matrix contribution to skin wound re-epithelialization. Matrix Biol. 2019;75-76:12–26. doi: 10.1016/j.matbio.2018.01.002. [DOI] [PubMed] [Google Scholar]
46.Rousselle P, Beck K. Laminin 332 processing impacts cellular behavior. Cell Adh Migr. 2013;7:122–134. doi: 10.4161/cam.23132. [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Hamill KJ, McLean WHI. The alpha-3 polypeptide chain of laminin 5: Insight into wound healing responses from the study of genodermatoses. Clin Exp Dermatol. 2005;30:398–404. doi: 10.1111/j.1365-2230.2005.01842.x. [DOI] [PubMed] [Google Scholar]
48.Rousselle P, Lunstrum GP, Keene DR, Burgeson RE. Kalinin: An epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J Cell Biol. 1991;114:567–576. doi: 10.1083/jcb.114.3.567. [DOI] [PMC free article] [PubMed] [Google Scholar]
49.Theveneau E, Mayor R. Collective cell migration of epithelial and mesenchymal cells. Cell Mol Life Sci. 2013;70:3481–3492. doi: 10.1007/s00018-012-1251-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Krawczyk WS. A pattern of epidermal cell migration during wound healing. J Cell Biol. 1971;49:247–263. doi: 10.1083/jcb.49.2.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Headon D. Reversing stratification during wound healing. Nat Cell Biol. 2017;19:595–597. doi: 10.1038/ncb3545. [DOI] [PubMed] [Google Scholar]
52.Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M. Keratins and the keratinocyte activation cycle. J Invest Dermatol. 2001;116:633–640. doi: 10.1046/j.1523-1747.2001.01327.x. [DOI] [PubMed] [Google Scholar]
53.Veith AP, Henderson K, Spencer A, Sligar AD, Baker AB. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv Drug Deliv Rev. 2019;146:97–125. doi: 10.1016/j.addr.2018.09.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Velnar T, Gradisnik L. Tissue augmentation in wound healing: The role of endothelial and epithelial cells. Med Arch. 2018;72:444–448. doi: 10.5455/medarh.2018.72.444-448. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Lamalice L, Le Boeuf F, Huot J. Endothelial cell migration during angiogenesis. Circ Res. 2007;100:782–794. doi: 10.1161/01.RES.0000259593.07661.1e. [DOI] [PubMed] [Google Scholar]
56.Al Sadoun H. Macrophage phenotypes in normal and diabetic wound healing and therapeutic interventions. Cells. 2022;11:2430. doi: 10.3390/cells11152430. [DOI] [PMC free article] [PubMed] [Google Scholar]
57.Song J, Wu Y, Chen Y, Sun X, Zhang Z. Epigenetic regulatory mechanism of macrophage polarization in diabetic wound healing (Review) Mol Med Rep. 2025;31:2. doi: 10.3892/mmr.2024.13367. [DOI] [PMC free article] [PubMed] [Google Scholar]
58.Morbidelli L, Genah S, Cialdai F. Effect of microgravity on endothelial cell function, angiogenesis, and vessel remodeling during wound healing. Front Bioeng Biotechnol. 2021;9:720091. doi: 10.3389/fbioe.2021.720091. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Hsu S, Thakar R, Liepmann D, Li S. Effects of shear stress on endothelial cell haptotaxis on micropatterned surfaces. Biochem Biophys Res Commun. 2005;337:401–409. doi: 10.1016/j.bbrc.2005.08.272. [DOI] [PubMed] [Google Scholar]
60.Li S, Huang NF, Hsu S. Mechanotransduction in endothelial cell migration. J Cell Biochem. 2005;96:1110–1126. doi: 10.1002/jcb.20614. [DOI] [PubMed] [Google Scholar]
61.Lynch MD, Watt FM. Fibroblast heterogeneity: Implications for human disease. J Clin Invest. 2018;128:26–35. doi: 10.1172/JCI93555. [DOI] [PMC free article] [PubMed] [Google Scholar]
62.Talbott HE, Mascharak S, Griffin M, Wan DC, Longaker MT. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. 2022;29:1161–1180. doi: 10.1016/j.stem.2022.07.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
63.Bussone G. Subjectivity in primary headaches: Insight the causes. Neurol Sci. 2017;38:1–2. doi: 10.1007/s10072-017-2949-y. [DOI] [PubMed] [Google Scholar]
64.Younesi FS, Miller AE, Barker TH, Rossi FMV, Hinz B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol. 2024;25:617–638. doi: 10.1038/s41580-024-00716-0. [DOI] [PubMed] [Google Scholar]
65.Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D. Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol. 2008;83:1323–1333. doi: 10.1189/jlb.1107782. [DOI] [PMC free article] [PubMed] [Google Scholar]
66.Grieb G, Steffens G, Pallua N, Bernhagen J, Bucala R. Circulating fibrocytes-biology and mechanisms in wound healing and scar formation. Int Rev Cell Mol Biol. 2011;291:1–19. doi: 10.1016/B978-0-12-386035-4.00001-X. [DOI] [PubMed] [Google Scholar]
67.Park JG, Lim DC, Park JH, Park S, Mok J, Kang KW, Park J. Benzbromarone induces targeted degradation of HSP47 protein and improves hypertrophic scar formation. J Invest Dermatol. 2024;144:633–644. doi: 10.1016/j.jid.2023.09.279. [DOI] [PubMed] [Google Scholar]
68.Kohlhauser M, Mayrhofer M, Kamolz LP, Smolle C. An update on molecular mechanisms of scarring-A narrative review. Int J Mol Sci. 2024;25:11579. doi: 10.3390/ijms252111579. [DOI] [PMC free article] [PubMed] [Google Scholar]
69.Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol. 2007;127:526–537. doi: 10.1038/sj.jid.5700613. [DOI] [PubMed] [Google Scholar]
70.Luo L, An Y, Geng K, Wan S, Zhang F, Tan X, Jiang Z, Xu Y. High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis. Biochem Biophys Res Commun. 2023;668:82–89. doi: 10.1016/j.bbrc.2023.05.081. [DOI] [PubMed] [Google Scholar]
71.Huang SM, Wu CS, Chiu MH, Wu CH, Chang YT, Chen GS, Lan CCE. High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-α: An important mechanism to delay the diabetic wound healing. J Dermatol Sci. 2019;96:159–167. doi: 10.1016/j.jdermsci.2019.11.004. [DOI] [PubMed] [Google Scholar]
72.Lamers ML, Almeida MES, Vicente-Manzanares M, Horwitz AF, Santos MF. High glucose-mediated oxidative stress impairs cell migration. PLoS One. 2011;6:e22865. doi: 10.1371/journal.pone.0022865. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Brubaker AL, Rendon JL, Ramirez L, Choudhry MA, Kovacs EJ. Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J Immunol. 2013;190:1746–1757. doi: 10.4049/jimmunol.1201213. [DOI] [PMC free article] [PubMed] [Google Scholar]
74.den Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing. Transl Res. 2019;204:39–50. doi: 10.1016/j.trsl.2018.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
75.Kasuya A, Tokura Y. Attempts to accelerate wound healing. J Dermatol Sci. 2014;76:169–172. doi: 10.1016/j.jdermsci.2014.11.001. [DOI] [PubMed] [Google Scholar]
76.Lan CCE, Liu IH, Fang AH, Wen CH, Wu CS. Hyperglycaemic conditions decrease cultured keratinocyte mobility: Implications for impaired wound healing in patients with diabetes. Br J Dermatol. 2008;159:1103–1115. doi: 10.1111/j.1365-2133.2008.08789.x. [DOI] [PubMed] [Google Scholar]
77.Zhou P, Feng H, Qin W, Li Q. KRT17 from skin cells with high glucose stimulation promotes keratinocytes proliferation and migration. Front Endocrinol (Lausanne) 2023;14:1237048. doi: 10.3389/fendo.2023.1237048. [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Worsley AL, Lui DH, Ntow-Boahene W, Song W, Good L, Tsui J. The importance of inflammation control for the treatment of chronic diabetic wounds. Int Wound J. 2023;20:2346–2359. doi: 10.1111/iwj.14048. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Li M, Wang T, Tian H, Wei G, Zhao L, Shi Y. Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model. Artif Cells Nanomed Biotechnol. 2019;47:3793–3803. doi: 10.1080/21691401.2019.1669617. [DOI] [PubMed] [Google Scholar]
80.Nirenjen S, Narayanan J, Tamilanban T, Subramaniyan V, Chitra V, Fuloria NK, Wong LS, Ramachawolran G, Sekar M, Gupta G, et al. Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes. Front Immunol. 2023;14:1216321. doi: 10.3389/fimmu.2023.1216321. [DOI] [PMC free article] [PubMed] [Google Scholar]
81.Goren I, Müller E, Schiefelbein D, Christen U, Pfeilschifter J, Mühl H, Frank S. Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages. J Invest Dermatol. 2007;127:2259–2267. doi: 10.1038/sj.jid.5700842. [DOI] [PubMed] [Google Scholar]
82.Mirza RE, Fang MM, Ennis WJ, Koh TJ. Blocking interleukin-1β induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes. 2013;62:2579–2587. doi: 10.2337/db12-1450. [DOI] [PMC free article] [PubMed] [Google Scholar]
83.Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. Biomed Res Int. 2013;2013:754802. doi: 10.1155/2013/754802. [DOI] [PMC free article] [PubMed] [Google Scholar]
84.Dai J, Shen J, Chai Y, Chen H. IL-1β impaired diabetic wound healing by regulating MMP-2 and MMP-9 through the p38 pathway. Mediators Inflamm. 2021;2021:6645766. doi: 10.1155/2021/6645766. [DOI] [PMC free article] [PubMed] [Google Scholar]
85.Lan CCE, Wu CS, Huang SM, Wu IH, Chen GS. High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: New insights into impaired diabetic wound healing. Diabetes. 2013;62:2530–2538. doi: 10.2337/db12-1714. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Wang G, Yang F, Zhou W, Xiao N, Luo M, Tang Z. The initiation of oxidative stress and therapeutic strategies in wound healing. Biomed Pharmacother. 2023;157:114004. doi: 10.1016/j.biopha.2022.114004. [DOI] [PubMed] [Google Scholar]
87.Xu Q, Huff LP, Fujii M, Griendling KK. Redox regulation of the actin cytoskeleton and its role in the vascular system. Free Radic Biol Med. 2017;109:84–107. doi: 10.1016/j.freeradbiomed.2017.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
88.Long M, de la Vega MR, Wen Q, Wen Q, Bharara M, Jiang T, Zhang R, Zhou S, Wong PK, Wondrak GT, et al. An essential role of NRF2 in diabetic wound healing. Diabetes. 2016;65:780–793. doi: 10.2337/db15-0564. [DOI] [PMC free article] [PubMed] [Google Scholar]
89.Zhou X, Ruan Q, Ye Z, Chu Z, Xi M, Li M, Hu W, Guo X, Yao P, Xie W. Resveratrol accelerates wound healing by attenuating oxidative stress-induced impairment of cell proliferation and migration. Burns. 2021;47:133–139. doi: 10.1016/j.burns.2020.10.016. [DOI] [PubMed] [Google Scholar]
90.Gao M, Nguyen TT, Suckow MA, Wolter WR, Gooyit M, Mobashery S, Chang M. Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy. Proc Natl Acad Sci USA. 2015;112:15226–15231. doi: 10.1073/pnas.1517847112. [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Jones JI, Nguyen TT, Peng Z, Chang M. Targeting MMP-9 in diabetic foot ulcers. Pharmaceuticals (Basel) 2019;12:79. doi: 10.3390/ph12020079. [DOI] [PMC free article] [PubMed] [Google Scholar]
92.Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology (Bethesda) 2013;28:391–403. doi: 10.1152/physiol.00029.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Ambrozova N, Ulrichova J, Galandakova A. Models for the study of skin wound healing. The role of Nrf2 and NF-κB. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017;161:1–13. doi: 10.5507/bp.2016.063. [DOI] [PubMed] [Google Scholar]
94.Zubair M, Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord. 2019;20:207–217. doi: 10.1007/s11154-019-09492-1. [DOI] [PubMed] [Google Scholar]
95.Papanas N, Maltezos E. Growth factors in the treatment of diabetic foot ulcers: New technologies, any promises? Int J Low Extrem Wounds. 2007;6:37–53. doi: 10.1177/1534734606298416. [DOI] [PubMed] [Google Scholar]
96.Ong HT, Dilley RJ. Novel non-angiogenic role for mesenchymal stem cell-derived vascular endothelial growth factor on keratinocytes during wound healing. Cytokine Growth Factor Rev. 2018;44:69–79. doi: 10.1016/j.cytogfr.2018.11.002. [DOI] [PubMed] [Google Scholar]
97.Ou MY, Tan PC, Xie Y, Liu K, Gao YM, Yang XS, Zhou SB, Li QF. Dedifferentiated Schwann cell-derived TGF-β3 is essential for the neural system to promote wound healing. Theranostics. 2022;12:5470–5487. doi: 10.7150/thno.72317. [DOI] [PMC free article] [PubMed] [Google Scholar]
98.R AS, Nambi N, Radhakrishnan L, Prasad MK, Ramkumar KM. Neutrophil migration is a crucial factor in wound healing and the pathogenesis of diabetic foot ulcers: Insights into pharmacological interventions. Curr Vasc Pharmacol. 2024;30 doi: 10.2174/0115701611308960241014155413. [DOI] [PubMed] [Google Scholar]
99.Michopoulou A, Montmasson M, Garnier C, Lambert E, Dayan G, Rousselle P. A novel mechanism in wound healing: Laminin 332 drives MMP9/14 activity by recruiting syndecan-1 and CD44. Matrix Biol. 2020;94:1–17. doi: 10.1016/j.matbio.2020.06.004. [DOI] [PubMed] [Google Scholar]
100.Fang WC, Lan CCE. The epidermal keratinocyte as a therapeutic target for management of diabetic wounds. Int J Mol Sci. 2023;24:4290. doi: 10.3390/ijms24054290. [DOI] [PMC free article] [PubMed] [Google Scholar]
101.Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol. 1997;137:1445–1457. doi: 10.1083/jcb.137.6.1445. [DOI] [PMC free article] [PubMed] [Google Scholar]
102.Lan CCE, Wu CS, Kuo HY, Huang SM, Chen GS. Hyperglycaemic conditions hamper keratinocyte locomotion via sequential inhibition of distinct pathways: New insights on poor wound closure in patients with diabetes. Br J Dermatol. 2009;160:1206–1214. doi: 10.1111/j.1365-2133.2009.09089.x. [DOI] [PubMed] [Google Scholar]
103.Zhang C, Ponugoti B, Tian C, Xu F, Tarapore R, Batres A, Alsadun S, Lim J, Dong G, Graves DT. FOXO1 differentially regulates both normal and diabetic wound healing. J Cell Biol. 2015;209:289–303. doi: 10.1083/jcb.201409032. [DOI] [PMC free article] [PubMed] [Google Scholar]
104.Wang Y, Graves DT. Keratinocyte function in normal and diabetic wounds and modulation by FOXO1. J Diabetes Res. 2020;2020:3714704. doi: 10.1155/2020/3714704. [DOI] [PMC free article] [PubMed] [Google Scholar]
105.Kaussikaa S, Prasad MK, Ramkumar KM. Nrf2 activation in keratinocytes: A central role in diabetes-associated wound healing. Exp Dermatol. 2024;33:e15189. doi: 10.1111/exd.15189. [DOI] [PubMed] [Google Scholar]
106.da Silva L, Carvalho E, Cruz MT. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin Biol Ther. 2010;10:1427–1439. doi: 10.1517/14712598.2010.515207. [DOI] [PubMed] [Google Scholar]
107.Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: The connection in diabetic wound healing. Expert Rev Mol Med. 2009;11:e2. doi: 10.1017/S1462399409000945. [DOI] [PMC free article] [PubMed] [Google Scholar]
108.Grande R, Puca V, Muraro R. Antibiotic resistance and bacterial biofilm. Expert Opin Ther Pat. 2020;30:897–900. doi: 10.1080/13543776.2020.1830060. [DOI] [PubMed] [Google Scholar]
109.Marano RJ, Wallace HJ, Wijeratne D, Fear MW, Wong HS, O'Handley R. Secreted biofilm factors adversely affect cellular wound healing responses in vitro. Sci Rep. 2015;5:13296. doi: 10.1038/srep13296. [DOI] [PMC free article] [PubMed] [Google Scholar]
110.Xing H, Huang Y, Kunkemoeller BH, Dahl PJ, Muraleetharan O, Malvankar NS, Murrell MP, Kyriakides TR. Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction. Sci Rep. 2022;12:22474. doi: 10.1038/s41598-022-26337-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
111.Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011;474:179–183. doi: 10.1038/nature10137. [DOI] [PubMed] [Google Scholar]
112.Brusatin G, Panciera T, Gandin A, Citron A, Piccolo S. Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour. Nat Mater. 2018;17:1063–1075. doi: 10.1038/s41563-018-0180-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Lin MO, Sampath D, Bosykh DA, Wang C, Wang X, Subramaniam T, Han W, Hong W, Chakraborty S. YAP/TAZ drive agrin-matrix metalloproteinase 12-mediated diabetic skin wound healing. J Invest Dermatol. 2025;145:155–170.e2. doi: 10.1016/j.jid.2024.05.005. [DOI] [PubMed] [Google Scholar]
114.Majumdar R, Steen K, Coulombe PA, Parent CA. Non-canonical processes that shape the cell migration landscape. Curr Opin Cell Biol. 2019;57:123–134. doi: 10.1016/j.ceb.2018.12.013. [DOI] [PMC free article] [PubMed] [Google Scholar]
115.Xie L, Feng H, Li S, Meng G, Liu S, Tang X, Ma Y, Han Y, Xiao Y, Gu Y, et al. SIRT3 mediates the antioxidant effect of hydrogen sulfide in endothelial cells. Antioxid Redox Signal. 2016;24:329–343. doi: 10.1089/ars.2015.6331. [DOI] [PMC free article] [PubMed] [Google Scholar]
116.Meng G, Liu J, Liu S, Song Q, Liu L, Xie L, Han Y, Ji Y. Hydrogen sulfide pretreatment improves mitochondrial function in myocardial hypertrophy via a SIRT3-dependent manner. Br J Pharmacol. 2018;175:1126–1145. doi: 10.1111/bph.13861. [DOI] [PMC free article] [PubMed] [Google Scholar]
117.Yang S, Xu M, Meng G, Lu Y. SIRT3 deficiency delays diabetic skin wound healing via oxidative stress and necroptosis enhancement. J Cell Mol Med. 2020;24:4415–4427. doi: 10.1111/jcmm.15100. [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Johan MZ, Pyne NT, Kolesnikoff N, Poltavets V, Esmaeili Z, Woodcock JM, Lopez AF, Cowin AJ, Pitson SM, Samuel MS. Accelerated closure of diabetic wounds by efficient recruitment of fibroblasts upon inhibiting a 14-3-3/ROCK regulatory axis. J Invest Dermatol. 2024;144:2562–2573.e4. doi: 10.1016/j.jid.2024.03.032. [DOI] [PubMed] [Google Scholar]
119.Li Z, Zhang C, Wang L, Zhang Q, Dong Y, Sha X, Wang B, Zhu Z, Wang W, Wang Y, et al. Chitooligosaccharides promote diabetic wound healing by mediating fibroblast proliferation and migration. Sci Rep. 2025;15:556. doi: 10.1038/s41598-024-84398-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
120.Gao Q, Pan L, Li Y, Zhang X. Astragaloside IV attenuates high glucose-induced human keratinocytes injury via TGF-β/Smad signaling pathway. J Tissue Viability. 2022;31:678–686. doi: 10.1016/j.jtv.2022.08.002. [DOI] [PubMed] [Google Scholar]
121.Dong M, Ma X, Li F. Dedifferentiated fat cells-derived exosomes (DFATs-Exos) loaded in GelMA accelerated diabetic wound healing through Wnt/β-catenin pathway. Stem Cell Res Ther. 2025;16:103. doi: 10.1186/s13287-025-04205-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
122.Ridley AJ. Rho GTPase signalling in cell migration. Curr Opin Cell Biol. 2015;36:103–112. doi: 10.1016/j.ceb.2015.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
123.Wu M, Zhang S, Zhang W, Zhou Y, Guo Z, Fang Y, Yang Y, Shen Z, Lian D, Shen A, Peng J. Qingda granule ameliorates vascular remodeling and phenotypic transformation of adventitial fibroblasts via suppressing the TGF-β1/Smad2/3 pathway. J Ethnopharmacol. 2023;313:116535. doi: 10.1016/j.jep.2023.116535. [DOI] [PubMed] [Google Scholar]
124.Fang H, Yang S, Luo Y, Zhang C, Rao Y, Liu R, Feng Y, Yu J. Notoginsenoside R1 inhibits vascular smooth muscle cell proliferation, migration and neointimal hyperplasia through PI3K/Akt signaling. Sci Rep. 2018;8:7595. doi: 10.1038/s41598-018-25874-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Carvalho JR, Fortunato IC, Fonseca CG, Pezzarossa A, Barbacena P, Dominguez-Cejudo MA, Vasconcelos FF, Santos NC, Carvalho FA, Franco CA. Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration. Elife. 2019;8:e45853. doi: 10.7554/eLife.45853. [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Van den Broeke C, Favoreel HW. Actin' up: Herpesvirus Interactions with Rho GTPase signaling. Viruses. 2011;3:278–292. doi: 10.3390/v3040278. [DOI] [PMC free article] [PubMed] [Google Scholar]
127.Qian W, Yamaguchi N, Lis P, Cammer M, Knaut H. Pulses of RhoA signaling stimulate actin polymerization and flow in protrusions to drive collective cell migration. Curr Biol. 2024;34:245–259.e8. doi: 10.1016/j.cub.2023.11.044. [DOI] [PMC free article] [PubMed] [Google Scholar]
128.Takaya K, Imbe Y, Wang Q, Okabe K, Sakai S, Aramaki-Hattori N, Kishi K. Rac1 inhibition regenerates wounds in mouse fetuses via altered actin dynamics. Sci Rep. 2024;14:27213. doi: 10.1038/s41598-024-78395-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
129.Shih PC, Tzeng IS, Chen YC, Chen ML. Gastrodin mitigates ketamine-induced inhibition of F-actin remodeling and cell migration by regulating the rho signaling pathway. Biomedicines. 2025;13:649. doi: 10.3390/biomedicines13030649. [DOI] [PMC free article] [PubMed] [Google Scholar]
130.Lawson CD, Ridley AJ. Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol. 2018;217:447–457. doi: 10.1083/jcb.201612069. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Xue C, Li G, Lu J, Li L. Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 2021;6:400. doi: 10.1038/s41392-021-00788-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Teng Y, Fan Y, Ma J, Lu W, Liu N, Chen Y, Pan W, Tao X. The PI3K/Akt pathway: Emerging roles in skin homeostasis and a group of non-malignant skin disorders. Cells. 2021;10:1219. doi: 10.3390/cells10051219. [DOI] [PMC free article] [PubMed] [Google Scholar]
133.Zhang X, Shi L, Xing M, Li C, Ma F, Ma Y, Ma Y. Interplay between lncRNAs and the PI3K/AKT signaling pathway in the progression of digestive system neoplasms (Review) Int J Mol Med. 2024;55:15. doi: 10.3892/ijmm.2024.5456. [DOI] [PMC free article] [PubMed] [Google Scholar]
134.Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51. doi: 10.3389/fnmol.2011.00051. [DOI] [PMC free article] [PubMed] [Google Scholar]
135.Wu X, Sun Q, He S, Wu Y, Du S, Gong L, Yu J, Guo H. Ropivacaine inhibits wound healing by suppressing the proliferation and migration of keratinocytes via the PI3K/AKT/mTOR pathway. BMC Anesthesiol. 2022;22:106. doi: 10.1186/s12871-022-01646-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
136.Deng S, Leong HC, Datta A, Gopal V, Kumar AP, Yap CT. PI3K/AKT signaling tips the balance of cytoskeletal forces for cancer progression. Cancers (Basel) 2022;14:1652. doi: 10.3390/cancers14071652. [DOI] [PMC free article] [PubMed] [Google Scholar]
137.Hsu JW, Bai M, Li K, Yang JS, Chu N, Cole PA, Eck MJ, Li J, Hsu VW. The protein kinase Akt acts as a coat adaptor in endocytic recycling. Nat Cell Biol. 2020;22:927–933. doi: 10.1038/s41556-020-0530-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
138.Hannigan M, Zhan L, Li Z, Ai Y, Wu D, Huang CK. Neutrophils lacking phosphoinositide 3-kinase gamma show loss of directionality during N-formyl-Met-Leu-Phe-induced chemotaxis. Proc Natl Acad Sci USA. 2002;99:3603–3608. doi: 10.1073/pnas.052010699. [DOI] [PMC free article] [PubMed] [Google Scholar]
139.Najafi M, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 2019;120:2782–2790. doi: 10.1002/jcb.27681. [DOI] [PubMed] [Google Scholar]
140.Nakerakanti S, Trojanowska M. The role of TGF-β receptors in fibrosis. Open Rheumatol J. 2012;6:156–162. doi: 10.2174/1874312901206010156. [DOI] [PMC free article] [PubMed] [Google Scholar]
141.Tu S, Huang W, Huang C, Luo Z, Yan X. Contextual regulation of TGF-β signaling in liver cancer. Cells. 2019;8:1235. doi: 10.3390/cells8101235. [DOI] [PMC free article] [PubMed] [Google Scholar]
142.Zhang K, Zhang H, Xiang H, Liu J, Liu Y, Zhang X, Wang J, Tang Y. TGF-β1 induces the dissolution of tight junctions in human renal proximal tubular cells: role of the RhoA/ROCK signaling pathway. Int J Mol Med. 2013;32:464–468. doi: 10.3892/ijmm.2013.1396. [DOI] [PubMed] [Google Scholar]
143.Gailit J, Welch MP, Clark RA. TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds. J Invest Dermatol. 1994;103:221–227. doi: 10.1111/1523-1747.ep12393176. [DOI] [PubMed] [Google Scholar]
144.Ponugoti B, Xu F, Zhang C, Tian C, Pacios S, Graves DT. FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress. J Cell Biol. 2013;203:327–343. doi: 10.1083/jcb.201305074. [DOI] [PMC free article] [PubMed] [Google Scholar]
145.Weber CE, Li NY, Wai PY, Kuo PC. Epithelial-Mesenchymal transition, TGF-β, and osteopontin in wound healing and tissue remodeling after injury. J Burn Care Res. 2012;33:311–318. doi: 10.1097/BCR.0b013e318240541e. [DOI] [PMC free article] [PubMed] [Google Scholar]
146.Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol. 2024;17:46. doi: 10.1186/s13045-024-01563-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
147.Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: Diseases and therapies. Nat Rev Genet. 2004;5:691–701. doi: 10.1038/nrg1427. [DOI] [PubMed] [Google Scholar]
148.Nusse R, Clevers H. Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–999. doi: 10.1016/j.cell.2017.05.016. [DOI] [PubMed] [Google Scholar]
149.Schaale K, Neumann J, Schneider D, Ehlers S, Reiling N. Wnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur J Cell Biol. 2011;90:553–559. doi: 10.1016/j.ejcb.2010.11.004. [DOI] [PubMed] [Google Scholar]
150.Sedgwick AE, D'Souza-Schorey C. Wnt signaling in cell motility and invasion: Drawing parallels between development and cancer. Cancers (Basel) 2016;8:80. doi: 10.3390/cancers8090080. [DOI] [PMC free article] [PubMed] [Google Scholar]
151.Wu B, Crampton SP, Hughes CCW. Wnt signaling induces MMP expression and regulates T cell transmigration. Immunity. 2007;26:227–239. doi: 10.1016/j.immuni.2006.12.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
152.Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell Mol Life Sci. 2024;81:79. doi: 10.1007/s00018-023-05099-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
153.Ono M, Masaki A, Maeda A, Kilts TM, Hara ES, Komori T, Pham H, Kuboki T, Young MF. CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα. Matrix Biol. 2018;68-69:533–546. doi: 10.1016/j.matbio.2018.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
154.Repertinger SK, Campagnaro E, Fuhrman J, El-Abaseri T, Yuspa SH, Hansen LA. EGFR enhances early healing after cutaneous incisional wounding. J Invest Dermatol. 2004;123:982–989. doi: 10.1111/j.0022-202X.2004.23478.x. [DOI] [PubMed] [Google Scholar]
155.Wang Y, Wu Z, Tian J, Mi Y, Ren X, Kang J, Zhang W, Zhou X, Wang G, Li R. Intermedin protects HUVECs from ischemia reperfusion injury via Wnt/β-catenin signaling pathway. Ren Fail. 2019;41:159–166. doi: 10.1080/0886022X.2019.1587468. [DOI] [PMC free article] [PubMed] [Google Scholar]
156.Jun EK, Zhang Q, Yoon BS, Moon JH, Lee G, Park G, Kang PJ, Lee JH, Kim A, You S. Hypoxic conditioned medium from human amniotic fluid-derived mesenchymal stem cells accelerates skin wound healing through TGF-β/SMAD2 and PI3K/Akt pathways. Int J Mol Sci. 2014;15:605–628. doi: 10.3390/ijms15010605. [DOI] [PMC free article] [PubMed] [Google Scholar]
157.Toraldo G, Bhasin S, Bakhit M, Guo W, Serra C, Safer JD, Bhawan J, Jasuja R. Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking β-catenin nuclear translocation and cross-talk with TGF-β signaling in keratinocytes. Wound Repair Regen. 2012;20:61–73. doi: 10.1111/j.1524-475X.2011.00757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
158.Wang H, Wang X, Liu X, Zhou J, Yang Q, Chai B, Chai Y, Ma Z, Lu S. miR-199a-5p plays a pivotal role on wound healing via suppressing VEGFA and ROCK1 in diabetic ulcer foot. Oxid Med Cell Longev. 2022;2022:4791059. doi: 10.1155/2022/4791059. [DOI] [PMC free article] [PubMed] [Google Scholar]
159.Yu J, Nam D, Park KS. Substance P enhances cellular migration and inhibits senescence in human dermal fibroblasts under hyperglycemic conditions. Biochem Biophys Res Commun. 2020;522:917–923. doi: 10.1016/j.bbrc.2019.11.172. [DOI] [PubMed] [Google Scholar]
160.Huang J, Deng Q, Tsang LL, Chang G, Guo J, Ruan YC, Wang CC, Li G, Chan HF, Zhang X, Jiang X. Mesenchymal stem cells from perinatal tissues promote diabetic wound healing via PI3K/AKT activation. Stem Cell Res Ther. 2025;16:59. doi: 10.1186/s13287-025-04141-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
161.Xu S, Jiang C, Yu T, Chen K. A multi-purpose dressing based on resveratrol-loaded ionic liquids/gelatin methacryloyl hydrogel for enhancing diabetic wound healing. Int J Biol Macromol. 2024;283:136773. doi: 10.1016/j.ijbiomac.2024.136773. [DOI] [PubMed] [Google Scholar]
162.Peng Y, Wu S, Tang Q, Li S, Peng C. KGF-1 accelerates wound contraction through the TGF-β1/Smad signaling pathway in a double-paracrine manner. J Biol Chem. 2019;294:8361–8370. doi: 10.1074/jbc.RA118.006189. [DOI] [PMC free article] [PubMed] [Google Scholar]
163.Oyebode OA, Houreld NN. Photobiomodulation at 830 nm stimulates migration, survival and proliferation of fibroblast cells. Diabetes Metab Syndr Obes. 2022;15:2885–2900. doi: 10.2147/DMSO.S374649. [DOI] [PMC free article] [PubMed] [Google Scholar]
164.Wang L, Chen J, Song J, Xiang Y, Yang M, Xia L, Yang J, Hou X, Chen L, Wang L. Activation of the Wnt/β-catenin signalling pathway enhances exosome production by hucMSCs and improves their capability to promote diabetic wound healing. J Nanobiotechnology. 2024;22:373. doi: 10.1186/s12951-024-02650-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
165.Liu Z, Yang S, Li X, Wang S, Zhang T, Huo N, Duan R, Shi Q, Zhang J, Xu J. Local transplantation of GMSC-derived exosomes to promote vascularized diabetic wound healing by regulating the Wnt/β-catenin pathways. Nanoscale Adv. 2023;5:916–926. doi: 10.1039/D2NA00762B. [DOI] [PMC free article] [PubMed] [Google Scholar]
166.Lv Q, Deng J, Chen Y, Wang Y, Liu B, Liu J. Engineered human adipose stem-cell-derived exosomes loaded with miR-21-5p to promote diabetic cutaneous wound healing. Mol Pharm. 2020;17:1723–1733. doi: 10.1021/acs.molpharmaceut.0c00177. [DOI] [PubMed] [Google Scholar]
167.Yang Y, GuangXuan H, GenMeng W, MengHuan L, Bo C, XueJie Y. Idiopathic inflammatory myopathy and non-coding RNA. Front Immunol. 2023;14:1227945. doi: 10.3389/fimmu.2023.1227945. [DOI] [PMC free article] [PubMed] [Google Scholar]
168.Ballarino M, Morlando M, Fatica A, Bozzoni I. Non-coding RNAs in muscle differentiation and musculoskeletal disease. J Clin Invest. 2016;126:2021–2030. doi: 10.1172/JCI84419. [DOI] [PMC free article] [PubMed] [Google Scholar]
169.Chen L, Shen S, Wang S. LncRNA SNHG16 knockdown promotes diabetic foot ulcer wound healing via sponging MiR-31-5p. Tohoku J Exp Med. 2023;261:283–289. doi: 10.1620/tjem.2023.J078. [DOI] [PubMed] [Google Scholar]
170.Peng J, Zhu H, Ruan B, Duan Z, Cao M. miR-155 promotes m6A modification of SOX2 mRNA through targeted regulation of HIF-1α and delays wound healing in diabetic foot ulcer in vitro models. J Diabetes Investig. 2024;16:60–71. doi: 10.1111/jdi.14327. [DOI] [PMC free article] [PubMed] [Google Scholar]
171.Tian M, Tang J, Huang R, Dong J, Jia H. Circ_072697 knockdown promotes advanced glycation end products-induced cell proliferation and migration in HaCaT cells via miR-3150a-3p/KDM2A axis. BMC Endocr Disord. 2023;23:200. doi: 10.1186/s12902-023-01430-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
172.Wang F, Mei X, Yang Y, Zhang H, Li Z, Zhu L, Deng S, Wang Y. Non-coding RNA and its network in the pathogenesis of myasthenia gravis. Front Mol Biosci. 2024;11:1388476. doi: 10.3389/fmolb.2024.1388476. [DOI] [PMC free article] [PubMed] [Google Scholar]
173.Bhan A, Mandal SS. Long noncoding RNAs: Emerging stars in gene regulation, epigenetics and human disease. ChemMedChem. 2014;9:1932–1956. doi: 10.1002/cmdc.201300534. [DOI] [PubMed] [Google Scholar]
174.Hong W, Xiong Z, Wang X, Liao X, Liu M, Jiang Z, Min D, Li J, Guo G, Fu Z. Long noncoding RNA XIST promotes cell proliferation and migration in diabetic foot ulcers through the miR-126-3p/EGFR axis. Diabetol Metab Syndr. 2024;16:35. doi: 10.1186/s13098-024-01260-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
175.He M, Tu L, Shu R, Meng Q, Du S, Xu Z, Wang S. Long noncoding RNA CASC2 facilitated wound healing through miRNA-155/HIF-1α in diabetic foot ulcers. Contrast Media Mol Imaging. 2022;2022:6291497. doi: 10.1155/2022/6291497. [DOI] [PMC free article] [PubMed] [Google Scholar]
176.Li B, Zhou Y, Chen J, Wang T, Li Z, Fu Y, Zhai A, Bi C. Long noncoding RNA H19 acts as a miR-29b sponge to promote wound healing in diabetic foot ulcer. FASEB J. 2021;35:e20526. doi: 10.1096/fj.201900076RRRRR. [DOI] [PubMed] [Google Scholar]
177.Hu M, Wu Y, Yang C, Wang X, Wang W, Zhou L, Zeng T, Zhou J, Wang C, Lao G, et al. Novel long noncoding RNA lnc-URIDS delays diabetic wound healing by targeting Plod1. Diabetes. 2020;69:2144–2156. doi: 10.2337/db20-0147. [DOI] [PubMed] [Google Scholar]
178.Gezer U, Özgür E, Cetinkaya M, Isin M, Dalay N. Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int. 2014;38:1076–1079. doi: 10.1002/cbin.10301. [DOI] [PubMed] [Google Scholar]
179.Li B, Luan S, Chen J, Zhou Y, Wang T, Li Z, Fu Y, Zhai A, Bi C. The MSC-derived exosomal lncRNA H19 promotes wound healing in diabetic foot ulcers by upregulating PTEN via MicroRNA-152-3p. Mol Ther Nucleic Acids. 2020;19:814–826. doi: 10.1016/j.omtn.2019.11.034. [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Han ZF, Cao JH, Liu ZY, Yang Z, Qi RX, Xu HL. Exosomal lncRNA KLF3-AS1 derived from bone marrow mesenchymal stem cells stimulates angiogenesis to promote diabetic cutaneous wound healing. Diabetes Res Clin Pract. 2022;183:109126. doi: 10.1016/j.diabres.2021.109126. [DOI] [PubMed] [Google Scholar]
181.Fu W, Liang D, Wu X, Chen H, Hong X, Wang J, Zhu T, Zeng T, Lin W, Chen S, et al. Long noncoding RNA LINC01435 impedes diabetic wound healing by facilitating YY1-mediated HDAC8 expression. iScience. 2022;25:104006. doi: 10.1016/j.isci.2022.104006. [DOI] [PMC free article] [PubMed] [Google Scholar]
182.Roso-Mares A, Andújar I, Corpas TD, Sun BK. Non-coding RNAs as skin disease biomarkers, molecular signatures, and therapeutic targets. Hum Genet. 2024;143:801–812. doi: 10.1007/s00439-023-02588-4. [DOI] [PubMed] [Google Scholar]
183.Shirley SN, Watson AE, Yusuf N. Pathogenesis of inflammation in skin disease: From molecular mechanisms to pathology. Int J Mol Sci. 2024;25:10152. doi: 10.3390/ijms251810152. [DOI] [PMC free article] [PubMed] [Google Scholar]
184.Tsai HC, Chang GRL, Tung MC, Tu MY, Chen IC, Liu YH, Cidem A, Chen CM. MicroRNA signature in an in vitro keratinocyte model of diabetic wound healing. Int J Mol Sci. 2024;25:10125. doi: 10.3390/ijms251810125. [DOI] [PMC free article] [PubMed] [Google Scholar]
185.Zhao X, Xu M, Tang Y, Xie D, Deng L, Chen M, Wang Y. Decreased expression of miR-204-3p in peripheral blood and wound margin tissue associated with the onset and poor wound healing of diabetic foot ulcers. Int Wound J. 2023;20:413–429. doi: 10.1111/iwj.13890. [DOI] [PMC free article] [PubMed] [Google Scholar]
186.Zhang HC, Wen T, Cai YZ. Overexpression of miR-146a promotes cell proliferation and migration in a model of diabetic foot ulcers by regulating the AKAP12 axis. Endocr J. 2022;69:85–94. doi: 10.1507/endocrj.EJ21-0177. [DOI] [PubMed] [Google Scholar]
187.Wang W, Yang C, Wang XY, Zhou LY, Lao GJ, Liu D, Wang C, Hu MD, Zeng TT, Yan L, Ren M. MicroRNA-129 and -335 promote diabetic wound healing by inhibiting Sp1-mediated MMP-9 expression. Diabetes. 2018;67:1627–1638. doi: 10.2337/db17-1238. [DOI] [PubMed] [Google Scholar]
188.Li P, Hong G, Zhan W, Deng M, Tu C, Wei J, Lin H. Endothelial progenitor cell derived exosomes mediated miR-182-5p delivery accelerate diabetic wound healing via down-regulating PPARG. Int J Med Sci. 2023;20:468–481. doi: 10.7150/ijms.78790. [DOI] [PMC free article] [PubMed] [Google Scholar]
189.Wang KX, Zhao LL, Zheng LT, Meng LB, Jin L, Zhang LJ, Kong FL, Liang F. Accelerated wound healing in diabetic rat by miRNA-185-5p and its anti-inflammatory activity. Diabetes Metab Syndr Obes. 2023;16:1657–1667. doi: 10.2147/DMSO.S409596. [DOI] [PMC free article] [PubMed] [Google Scholar]
190.Wu M, Tu J, Huang J, Wen H, Zeng Y, Lu Y. Exosomal IRF1-loaded rat adipose-derived stem cell sheet contributes to wound healing in the diabetic foot ulcers. Mol Med. 2023;29:60. doi: 10.1186/s10020-023-00617-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Wu Y, Zhang K, Liu R, Zhang H, Chen D, Yu S, Chen W, Wan S, Zhang Y, Jia Z, et al. MicroRNA-21-3p accelerates diabetic wound healing in mice by downregulating SPRY1. Aging (Albany NY) 2020;12:15436–15445. doi: 10.18632/aging.103610. [DOI] [PMC free article] [PubMed] [Google Scholar]
192.Wang C, Huang L, Li J, Liu D, Wu B. MicroRNA miR-145-5p inhibits cutaneous wound healing by targeting PDGFD in diabetic foot ulcer. Biochem Genet. 2024;62:2437–2454. doi: 10.1007/s10528-023-10551-1. [DOI] [PubMed] [Google Scholar]
193.Zhao X, Xu M, Tang Y, Xie D, Wang Y, Chen M. Changes in miroRNA-103 expression in wound margin tissue are related to wound healing of diabetes foot ulcers. Int Wound J. 2022;20:467–483. doi: 10.1111/iwj.13895. [DOI] [PMC free article] [PubMed] [Google Scholar]
194.Zhang P, Song X, Dong Q, Zhou L, Wang L. miR-27-3p inhibition restore fibroblasts viability in diabetic wound by targeting NOVA1. Aging (Albany NY) 2020;12:12841–12849. doi: 10.18632/aging.103266. [DOI] [PMC free article] [PubMed] [Google Scholar]
195.Zheng L, Song H, Li Y, Li H, Lin G, Cai Z. Insulin-Induced gene 1-enhance secretion of BMSC exosome enriched in miR-132-3p promoting wound healing in diabetic mice. Mol Pharm. 2024;21:4372–4385. doi: 10.1021/acs.molpharmaceut.4c00322. [DOI] [PubMed] [Google Scholar]
196.Zuo C, Fan P, Yang Y, Hu C. MiR-488-3p facilitates wound healing through CYP1B1-mediated Wnt/β-catenin signaling pathway by targeting MeCP2. J Diabetes Investig. 2024;15:145–158. doi: 10.1111/jdi.14099. [DOI] [PMC free article] [PubMed] [Google Scholar]
197.Huang H, Zhu W, Huang Z, Zhao D, Cao L, Gao X. Adipose-derived stem cell exosome NFIC improves diabetic foot ulcers by regulating miR-204-3p/HIPK2. J Orthop Surg Res. 2023;18:687. doi: 10.1186/s13018-023-04165-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
198.Qiu ZY, Xu WC, Liang ZH. Bone marrow mesenchymal stem cell-derived exosomal miR-221-3p promotes angiogenesis and wound healing in diabetes via the downregulation of forkhead box P1. Diabet Med. 2024;41:e15386. doi: 10.1111/dme.15386. [DOI] [PubMed] [Google Scholar]
199.Zhou X, Ye C, Jiang L, Zhu X, Zhou F, Xia M, Chen Y. The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization. Mol Cell Endocrinol. 2024;579:112089. doi: 10.1016/j.mce.2023.112089. [DOI] [PubMed] [Google Scholar]
200.Guo E, Wang L, Wu J, Chen Q. Exosomes from MicroRNA-125b-modified adipose-derived stem cells promote wound healing of diabetic foot ulcers. Curr Stem Cell Res Ther. 2024;20:409–420. doi: 10.2174/011574888X287173240415050555. [DOI] [PubMed] [Google Scholar]
201.Che D, Xiang X, Xie J, Chen Z, Bao Q, Cao D. exosomes derived from adipose stem cells enhance angiogenesis in diabetic wound via miR-146a-5p/JAZF1 axis. Stem Cell Rev Rep. 2024;20:1026–1039. doi: 10.1007/s12015-024-10685-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
202.Ge L, Wang K, Lin H, Tao E, Xia W, Wang F, Mao C, Feng Y. Engineered exosomes derived from miR-132-overexpresssing adipose stem cells promoted diabetic wound healing and skin reconstruction. Front Bioeng Biotechnol. 2023;11:1129538. doi: 10.3389/fbioe.2023.1129538. [DOI] [PMC free article] [PubMed] [Google Scholar]
203.Sedykh S, Kuleshova A, Nevinsky G. Milk exosomes: Perspective agents for anticancer drug delivery. Int J Mol Sci. 2020;21:6646. doi: 10.3390/ijms21186646. [DOI] [PMC free article] [PubMed] [Google Scholar]
204.Munagala R, Aqil F, Jeyabalan J, Gupta RC. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016;371:48–61. doi: 10.1016/j.canlet.2015.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]
205.Yan C, Chen J, Wang C, Yuan M, Kang Y, Wu Z, Li W, Zhang G, Machens HG, Rinkevich Y. Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis. Drug Deliv. 2022;29:214–228. doi: 10.1080/10717544.2021.2023699. [DOI] [PMC free article] [PubMed] [Google Scholar]
206.Liu R, Zhang L, Zhao X, Liu J, Chang W, Zhou L, Zhang K. circRNA: Regulatory factors and potential therapeutic targets in inflammatory dermatoses. J Cell Mol Med. 2022;26:4389–4400. doi: 10.1111/jcmm.17473. [DOI] [PMC free article] [PubMed] [Google Scholar]
207.Beňačka R, Szabóová D, Guľašová Z, Hertelyová Z. Non-Coding RNAs in breast cancer: Diagnostic and therapeutic implications. Int J Mol Sci. 2024;26:127. doi: 10.3390/ijms26010127. [DOI] [PMC free article] [PubMed] [Google Scholar]
208.Zhang Y, Wu Y, Liu Z, Yang K, Lin H, Xiong K. Non-coding RNAs as potential targets in metformin therapy for cancer. Cancer Cell Int. 2024;24:333. doi: 10.1186/s12935-024-03516-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
209.Fu Z, Jiang Z, Liao X, Liu M, Guo G, Wang X, Yang G, Zhou Z, Hu L, Xiong Z. Upregulation of circ_0080968 in diabetic foot ulcer inhibits wound healing via repressing the migration and promoting proliferation of keratinocytes. Gene. 2023;883:147669. doi: 10.1016/j.gene.2023.147669. [DOI] [PubMed] [Google Scholar]
210.Han D, Liu W, Li G, Liu L. Circ_PRKDC knockdown promotes skin wound healing by enhancing keratinocyte migration via miR-31/FBN1 axis. J Mol Histol. 2021;52:681–691. doi: 10.1007/s10735-021-09996-8. [DOI] [PubMed] [Google Scholar]
211.Wang A, Toma MA, Ma J, Li D, Vij M, Chu T, Wang J, Li X, Landén NX. Circular RNA hsa_circ_0084443 is upregulated in diabetic foot ulcer and modulates keratinocyte migration and proliferation. Adv Wound Care (New Rochelle) 2020;9:145–160. doi: 10.1089/wound.2019.0956. [DOI] [PMC free article] [PubMed] [Google Scholar]
212.Liang ZH, Pan NF, Lin SS, Qiu ZY, Liang P, Wang J, Zhang Z, Pan YC. Exosomes from mmu_circ_0001052-modified adipose-derived stem cells promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway. Stem Cell Res Ther. 2022;13:336. doi: 10.1186/s13287-022-03015-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
213.Huang Q, Chu Z, Wang Z, Li Q, Meng S, Lu Y, Ma K, Cui S, Hu W, Zhang W, et al. circCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models. Nat Commun. 2024;15:3904. doi: 10.1038/s41467-024-48284-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
214.Chen M, Przyborowski M, Berthiaume F. Stem cells for skin tissue engineering and wound healing. Crit Rev Biomed Eng. 2009;37:399–421. doi: 10.1615/CritRevBiomedEng.v37.i4-5.50. [DOI] [PMC free article] [PubMed] [Google Scholar]
215.Xu ZH, Ma MH, Li YQ, Li LL, Liu GH. Progress and expectation of stem cell therapy for diabetic wound healing. World J Clin Cases. 2023;11:506–513. doi: 10.12998/wjcc.v11.i3.506. [DOI] [PMC free article] [PubMed] [Google Scholar]
216.Deng Q, Pan S, Du F, Sang H, Cai Z, Xu X, Wei Q, Yu S, Zhang J, Li C. The Effect of conditioned medium from angiopoietin-1 gene-modified mesenchymal stem cells on wound healing in a diabetic mouse model. Bioengineering (Basel) 2024;11:1244. doi: 10.3390/bioengineering11121244. [DOI] [PMC free article] [PubMed] [Google Scholar]
217.Liu Z, Wen X, Wang H, Zhou J, Zhao M, Lin Q, Wang Y, Li J, Li D, Du Z, et al. Molecular imaging of induced pluripotent stem cell immunogenicity with in vivo development in ischemic myocardium. PLoS One. 2013;8:e66369. doi: 10.1371/journal.pone.0066369. [DOI] [PMC free article] [PubMed] [Google Scholar]
218.He L, Cai Y, Du H, Shu M, Zhu C. Adipose stem cell-derived exosomes promote high glucose-induced wound healing by regulating the TRIM32/STING axis. Arch Dermatol Res. 2024;316:323. doi: 10.1007/s00403-024-03065-2. [DOI] [PubMed] [Google Scholar]
219.Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: Roles, opportunities and challenges. Mil Med Res. 2023;10:36. doi: 10.1186/s40779-023-00472-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
220.Li Y, Zhu Z, Li S, Xie X, Qin L, Zhang Q, Yang Y, Wang T, Zhang Y. Exosomes: Compositions, biogenesis, and mechanisms in diabetic wound healing. J Nanobiotechnology. 2024;22:398. doi: 10.1186/s12951-024-02684-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
221.Laiva AL, O'Brien FJ, Keogh MB. Innovations in gene and growth factor delivery systems for diabetic wound healing. J Tissue Eng Regen Med. 2018;12:e296–e312. doi: 10.1002/term.2443. [DOI] [PMC free article] [PubMed] [Google Scholar]
222.Li Z, Qiu X, Guan G, Shi K, Chen S, Tang J, Xiao M, Tang S, Yan Y, Zhou J, Xie H. The role of FGF-21 in promoting diabetic wound healing by modulating high glucose-induced inflammation. Heliyon. 2024;10:e30022. doi: 10.1016/j.heliyon.2024.e30022. [DOI] [PMC free article] [PubMed] [Google Scholar]
223.Tang L, Cai S, Lu X, Wu D, Zhang Y, Li X, Qin X, Guo J, Zhang X, Liu C. Platelet-Derived growth factor nanocapsules with tunable controlled release for chronic wound healing. Small. 2024;20:e2310743. doi: 10.1002/smll.202310743. [DOI] [PubMed] [Google Scholar]
224.Jeong S, Kim B, Park M, Ban E, Lee SH, Kim A. Improved diabetic wound healing by EGF encapsulation in gelatin-alginate coacervates. Pharmaceutics. 2020;12:334. doi: 10.3390/pharmaceutics12040334. [DOI] [PMC free article] [PubMed] [Google Scholar]
225.Wang H, Xu Z, Zhao M, Liu G, Wu J. Advances of hydrogel dressings in diabetic wounds. Biomater Sci. 2021;9:1530–1546. doi: 10.1039/D0BM01747G. [DOI] [PubMed] [Google Scholar]
226.Serpico L, Iacono SD, Cammarano A, De Stefano L. Recent advances in stimuli-responsive hydrogel-based wound dressing. Gels. 2023;9:451. doi: 10.3390/gels9060451. [DOI] [PMC free article] [PubMed] [Google Scholar]
227.Liang Y, He J, Guo B. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano. 2021;15:12687–12722. doi: 10.1021/acsnano.1c04206. [DOI] [PubMed] [Google Scholar]
228.Miguel SP, Ribeiro MP, Brancal H, Coutinho P, Correia IJ. Thermoresponsive chitosan-agarose hydrogel for skin regeneration. Carbohydr Polym. 2014;111:366–373. doi: 10.1016/j.carbpol.2014.04.093. [DOI] [PubMed] [Google Scholar]
229.Bei Z, Zhang L, Li J, Tong Q, Shi K, Chen W, Yu Y, Sun A, Xu Y, Liu J, Qian Z. A smart stimulation-deadhesion and antimicrobial hydrogel for repairing diabetic wounds infected with methicillin-resistant staphylococcus aureus. Adv Healthc Mater. 2024;13:e2303042. doi: 10.1002/adhm.202303042. [DOI] [PubMed] [Google Scholar]
230.Li Y, Fu R, Duan Z, Zhu C, Fan D. Artificial nonenzymatic antioxidant MXene Nanosheet-anchored injectable hydrogel as a mild photothermal-controlled oxygen release platform for diabetic wound healing. ACS Nano. 2022;16:7486–7502. doi: 10.1021/acsnano.1c10575. [DOI] [PubMed] [Google Scholar]
231.Şeker Ş, Elçin AE, Elçin YM. Current trends in the design and fabrication of PRP-based scaffolds for tissue engineering and regenerative medicine. Biomed Mater. 2025;20:20. doi: 10.1088/1748-605X/ada83f. [DOI] [PubMed] [Google Scholar]
232.Xu K, Deng S, Zhu Y, Yang W, Chen W, Huang L, Zhang C, Li M, Ao L, Jiang Y, et al. Platelet rich plasma loaded multifunctional hydrogel accelerates diabetic wound healing via regulating the continuously abnormal microenvironments. Adv Healthc Mater. 2023;12:e2301370. doi: 10.1002/adhm.202301370. [DOI] [PubMed] [Google Scholar]
233.Wei Q, Su J, Meng S, Wang Y, Ma K, Li B, Chu Z, Huang Q, Hu W, Wang Z, et al. MiR-17-5p-engineered sEVs encapsulated in GelMA hydrogel facilitated diabetic wound healing by targeting PTEN and p21. Adv Sci (Weinh) 2024;11:e2307761. doi: 10.1002/advs.202307761. [DOI] [PMC free article] [PubMed] [Google Scholar]
234.Alberts A, Bratu AG, Niculescu AG, Grumezescu AM. New perspectives of hydrogels in chronic wound management. Molecules. 2025;30:686. doi: 10.3390/molecules30030686. [DOI] [PMC free article] [PubMed] [Google Scholar]
235.Negut I, Bita B. Exploring the potential of artificial intelligence for hydrogel development-a short review. Gels. 2023;9:845. doi: 10.3390/gels9110845. [DOI] [PMC free article] [PubMed] [Google Scholar]
236.Tan CT, Liang K, Ngo ZH, Dube CT, Lim CY. Application of 3D bioprinting technologies to the management and treatment of diabetic foot ulcers. Biomedicines. 2020;8:441. doi: 10.3390/biomedicines8100441. [DOI] [PMC free article] [PubMed] [Google Scholar]
237.Wang M, Song Y, Bisoyi HK, Yang JF, Liu L, Yang H, Li Q. A liquid crystal elastomer-based unprecedented two-way shape-memory aerogel. Adv Sci (Weinh) 2021;8:e2102674. doi: 10.1002/advs.202102674. [DOI] [PMC free article] [PubMed] [Google Scholar]
238.Jeong Y, Patel R, Patel M. Biopolymer-Based biomimetic aerogel for biomedical applications. Biomimetics (Basel) 2024;9:397. doi: 10.3390/biomimetics9070397. [DOI] [PMC free article] [PubMed] [Google Scholar]
239.Guo N, Xia Y, Zeng W, Chen J, Wu Q, Shi Y, Li G, Huang Z, Wang G, Liu Y. Alginate-based aerogels as wound dressings for efficient bacterial capture and enhanced antibacterial photodynamic therapy. Drug Deliv. 2022;29:1086–1099. doi: 10.1080/10717544.2022.2058650. [DOI] [PMC free article] [PubMed] [Google Scholar]
240.Wang X, Yuan Z, Shafiq M, Cai G, Lei Z, Lu Y, Guan X, Hashim R, El-Newehy M, Abdulhameed MM, et al. Composite aerogel scaffolds containing flexible silica nanofiber and tricalcium phosphate enable skin regeneration. ACS Appl Mater Interfaces. 2024;16:25843–25855. doi: 10.1021/acsami.4c03744. [DOI] [PubMed] [Google Scholar]
241.Vaseghi A, Sadeghizadeh M, Herb M, Grumme D, Demidov Y, Remmler T, Maleki HH. 3D printing of biocompatible and antibacterial silica-silk-chitosan-based hybrid aerogel scaffolds loaded with propolis. ACS Appl Bio Mater. 2024;7:7917–7935. doi: 10.1021/acsabm.4c00697. [DOI] [PubMed] [Google Scholar]
242.Wu B, Pan W, Luo S, Luo X, Zhao Y, Xiu Q, Zhong M, Wang Z, Liao T, Li N, et al. Turmeric-Derived nanoparticles functionalized aerogel regulates multicellular networks to promote diabetic wound healing. Adv Sci (Weinh) 2024;11:e2307630. doi: 10.1002/advs.202307630. [DOI] [PMC free article] [PubMed] [Google Scholar]
243.Ramos R, Silva JP, Rodrigues AC, Costa R, Guardão L, Schmitt F, Soares R, Vilanova M, Domingues L, Gama M. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011;32:1469–1476. doi: 10.1016/j.peptides.2011.06.005. [DOI] [PubMed] [Google Scholar]
244.Grönberg A, Mahlapuu M, Ståhle M, Whately-Smith C, Rollman O. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: A randomized, placebo-controlled clinical trial. Wound Repair Regen. 2014;22:613–621. doi: 10.1111/wrr.12211. [DOI] [PubMed] [Google Scholar]
245.John JV, Sharma NS, Tang G, Luo Z, Su Y, Weihs S, Shahriar SMS, Wang G, McCarthy A, Dyke J, et al. Nanofiber aerogels with precision macrochannels and LL-37-mimic peptides synergistically promote diabetic wound healing. Adv Funct Mater. 2023;33:2206936. doi: 10.1002/adfm.202206936. [DOI] [PMC free article] [PubMed] [Google Scholar]
246.Zhao C, Wu Z, Pan B, Zhang R, Golestani A, Feng Z, Ge Y, Yang H. Functional biomacromolecules-based microneedle patch for the treatment of diabetic wound. Int J Biol Macromol. 2024;267:131650. doi: 10.1016/j.ijbiomac.2024.131650. [DOI] [PubMed] [Google Scholar]
247.Hu F, Gao Q, Liu J, Chen W, Zheng C, Bai Q, Sun N, Zhang W, Zhang Y, Lu T. Smart microneedle patches for wound healing and management. J Mater Chem B. 2023;11:2830–2851. doi: 10.1039/D2TB02596E. [DOI] [PubMed] [Google Scholar]
248.Yin M, Wu J, Deng M, Wang P, Ji G, Wang M, Zhou C, Blum NT, Zhang W, Shi H, et al. Multifunctional magnesium organic framework-based microneedle patch for accelerating diabetic wound healing. ACS Nano. 2021;15:17842–17853. doi: 10.1021/acsnano.1c06036. [DOI] [PubMed] [Google Scholar]
249.Wang P, Wu J, Yang H, Liu H, Yao T, Liu C, Gong Y, Wang M, Ji G, Huang P, Wang X. Intelligent microneedle patch with prolonged local release of hydrogen and magnesium ions for diabetic wound healing. Bioact Mater. 2023;24:463–476. doi: 10.1016/j.bioactmat.2023.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
250.Avcil M, Çelik A. Microneedles in drug delivery: Progress and challenges. Micromachines (Basel) 2021;12:1321. doi: 10.3390/mi12111321. [DOI] [PMC free article] [PubMed] [Google Scholar]
251.Alsarayreh AZ, Oran SA, Shakhanbeh JM, Khleifat KM, Al Qaisi YT, Alfarrayeh II, Alkaramseh AM. Efficacy of methanolic extracts of some medicinal plants on wound healing in diabetic rats. Heliyon. 2022;8:e10071. doi: 10.1016/j.heliyon.2022.e10071. [DOI] [PMC free article] [PubMed] [Google Scholar]
252.Wu JR, Lu YC, Hung SJ, Lin JH, Chang KC, Chen JK, Tsai WT, Ho TJ, Chen HP. Antimicrobial and immunomodulatory activity of herb extracts used in burn wound healing: 'San Huang Powder'. Evid Based Complement Alternat Med. 2021;2021:2900060. doi: 10.1155/2021/2900060. [DOI] [PMC free article] [PubMed] [Google Scholar]
253.Soheilifar MH, Dastan D, Masoudi-Khoram N, Neghab HN, Nobari S, Tabaie SM, Amini R. In vitro and in vivo evaluation of the diabetic wound healing properties of Saffron (Crocus Sativus L.) petals. Sci Rep. 2024;14:19373. doi: 10.1038/s41598-024-70010-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
254.Huang L, Cai HA, Zhang MS, Liao RY, Huang X, Hu FD. Ginsenoside Rg1 promoted the wound healing in diabetic foot ulcers via miR-489-3p/Sirt1 axis. J Pharmacol Sci. 2021;147:271–283. doi: 10.1016/j.jphs.2021.07.008. [DOI] [PubMed] [Google Scholar]
255.Sun X, Wang X, Zhao Z, Chen J, Li C, Zhao G. Paeoniflorin accelerates foot wound healing in diabetic rats though activating the Nrf2 pathway. Acta Histochem. 2020;122:151649. doi: 10.1016/j.acthis.2020.151649. [DOI] [PubMed] [Google Scholar]
256.Zhang S, Xu Y, Junior CZ, Chen X, Zhu J. Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3. Arch Dermatol Res. 2024;316:338. doi: 10.1007/s00403-024-03021-0. [DOI] [PubMed] [Google Scholar]
257.Gong Y, Jiang Y, Huang J, He Z, Tang Q. Moist exposed burn ointment accelerates diabetes-related wound healing by promoting re-epithelialization. Front Med (Lausanne) 2022;9:1042015. doi: 10.3389/fmed.2022.1042015. [DOI] [PMC free article] [PubMed] [Google Scholar]
258.Ding R, Wang Y, Zhu JP, Lu WG, Wei GL, Gu ZC, An ZT, Huo JG. Danggui Sini decoction protects against oxaliplatin-induced peripheral neuropathy in rats. J Integr Neurosci. 2020;19:663–671. doi: 10.31083/j.jin.2020.04.1154. [DOI] [PubMed] [Google Scholar]
259.Mabvuure NT, Brewer CF, Gervin K, Duffy S. The use of moist exposed burn ointment (MEBO) for the treatment of burn wounds: A systematic review. J Plast Surg Hand Surg. 2020;54:337–343. doi: 10.1080/2000656X.2020.1813148. [DOI] [PubMed] [Google Scholar]
260.Zhao D, Luo S, Xu W, Hu J, Lin S, Wang N. Efficacy and safety of hyperbaric oxygen therapy used in patients with diabetic foot: A meta-analysis of randomized clinical trials. Clin Ther. 2017;39:2088–2094.e2. doi: 10.1016/j.clinthera.2017.08.014. [DOI] [PubMed] [Google Scholar]
261.Damineni U, Divity S, Gundapaneni SRC, Burri RG, Vadde T. Clinical outcomes of hyperbaric oxygen therapy for diabetic foot ulcers: A systematic review. Cureus. 2025;17:e78655. doi: 10.7759/cureus.78655. [DOI] [PMC free article] [PubMed] [Google Scholar]
262.Huang X, Liang P, Jiang B, Zhang P, Yu W, Duan M, Guo L, Cui X, Huang M, Huang X. Hyperbaric oxygen potentiates diabetic wound healing by promoting fibroblast cell proliferation and endothelial cell angiogenesis. Life Sci. 2020;259:118246. doi: 10.1016/j.lfs.2020.118246. [DOI] [PubMed] [Google Scholar]
263.Borys S, Hohendorff J, Koblik T, Witek P, Ludwig-Slomczynska AH, Frankfurter C, Kiec-Wilk B, Malecki MT. Negative-pressure wound therapy for management of chronic neuropathic noninfected diabetic foot ulcerations-short-term efficacy and long-term outcomes. Endocrine. 2018;62:611–616. doi: 10.1007/s12020-018-1707-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
264.Chen L, Zhang S, Da J, Wu W, Ma F, Tang C, Li G, Zhong D, Liao B. A systematic review and meta-analysis of efficacy and safety of negative pressure wound therapy in the treatment of diabetic foot ulcer. Ann Palliat Med. 2021;10:10830–10839. doi: 10.21037/apm-21-2476. [DOI] [PubMed] [Google Scholar]
265.Huang Y, Yu Z, Xu M, Zhao X, Tang Y, Luo L, Deng D, Chen M. Negative pressure wound therapy promotes wound healing by down-regulating miR-155 expression in granulation tissue of diabetic foot ulcers. Sci Rep. 2025;15:6733. doi: 10.1038/s41598-025-90643-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
266.Liu L, Chen R, Jia Z, Li X, Tang Y, Zhao X, Zhang S, Luo L, Fang Z, Zhang Y, Chen M. Downregulation of hsa-miR-203 in peripheral blood and wound margin tissue by negative pressure wound therapy contributes to wound healing of diabetic foot ulcers. Microvasc Res. 2022;139:104275. doi: 10.1016/j.mvr.2021.104275. [DOI] [PubMed] [Google Scholar]
267.Houreld NN. Shedding light on a new treatment for diabetic wound healing: A review on phototherapy. ScientificWorldJournal. 2014;2014:398412. doi: 10.1155/2014/398412. [DOI] [PMC free article] [PubMed] [Google Scholar]
268.Houreld N, Abrahamse H. Low-intensity laser irradiation stimulates wound healing in diabetic wounded fibroblast cells (WS1) Diabetes Technol Ther. 2010;12:971–978. doi: 10.1089/dia.2010.0039. [DOI] [PubMed] [Google Scholar]
269.Gupta A, Dai T, Hamblin MR. Effect of red and near-infrared wavelengths on low-level laser (light) therapy-induced healing of partial-thickness dermal abrasion in mice. Lasers Med Sci. 2014;29:257–265. doi: 10.1007/s10103-013-1319-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
270.Cai W, Hamushan M, Zhang Y, Xu Z, Ren Z, Du J, Ju J, Cheng P, Tan M, Han P. Synergistic effects of photobiomodulation therapy with combined wavelength on diabetic wound healing in vitro and in vivo. Photobiomodul Photomed Laser Surg. 2022;40:13–24. doi: 10.1089/photob.2021.0068. [DOI] [PubMed] [Google Scholar]
271.Frampton JE, Lee CR, Faulds D. Filgrastim. A review of its pharmacological properties and therapeutic efficacy in neutropenia. Drugs. 1994;48:731–760. doi: 10.2165/00003495-199448050-00007. [DOI] [PubMed] [Google Scholar]
272.Edmonds M, Gough A, Solovera J, Standaert B. Filgrastim in the treatment of infected diabetic foot ulcers. Clin Drug Investig. 1999;17:275–286. doi: 10.2165/00044011-199917040-00003. [DOI] [Google Scholar]
273.Orgill DP, Bayer LR. Negative pressure wound therapy: Past, present and future. Int Wound J. 2013;10:15–19. doi: 10.1111/iwj.12170. [DOI] [PMC free article] [PubMed] [Google Scholar]
274.Yoon D, Byun HJ, Oh SJ, Park JH, Lee DY. A case of cutaneous leukocytoclastic vasculitis associated with granulocyte colony-stimulating factor: An unusual presentation. Ann Dermatol. 2020;32:164–167. doi: 10.5021/ad.2020.32.2.164. [DOI] [PMC free article] [PubMed] [Google Scholar]
275.Song P, Liang Q, Ge X, Zhou D, Yuan M, Chu W, Xu J. Adipose-derived stem cell exosomes promote scar-free healing of diabetic wounds via miR-204-5p/TGF-β1/Smad pathway. Stem Cells Int. 2025;2025:6344844. doi: 10.1155/sci/6344844. [DOI] [PMC free article] [PubMed] [Google Scholar]
276.Van Netten JJ, Woodburn J, Bus SA. The future for diabetic foot ulcer prevention: A paradigm shift from stratified healthcare towards personalized medicine. Diabetes Metab Res Rev. 2020;36(Suppl 1):e3234. doi: 10.1002/dmrr.3234. [DOI] [PubMed] [Google Scholar]
277.Ng GW, Gan KF, Liew H, Ge L, Ang G, Molina J, Sun Y, Prakash PS, Harish KB, Lo ZJ. A Systematic review and classification of factors influencing diabetic foot ulcer treatment adherence, in accordance with the WHO dimensions of adherence to long-term therapies. Int J Low Extrem Wounds. 2024;20:15347346241233962. doi: 10.1177/15347346241233962. [DOI] [PubMed] [Google Scholar]
278.Zhang YW, Sun L, Wang YN, Zhan SY. Role of macrophage polarization in diabetic foot ulcer healing: A bibliometric study. World J Diabetes. 2025;16:99755. doi: 10.4239/wjd.v16.i1.99755. [DOI] [PMC free article] [PubMed] [Google Scholar]
279.Choudhury S, Dhoke NR, Chawla S, Das A. Bioengineered MSCCxcr2 transdifferentiated keratinocyte-like cell-derived organoid potentiates skin regeneration through ERK1/2 and STAT3 signaling in diabetic wound. Cell Mol Life Sci. 2024;81:172. doi: 10.1007/s00018-023-05057-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
280.de Souza A, Martignago CCS, Santo GDE, Sousa KDSJ, Cruz MA, Amaral GO, Parisi JR, Estadella D, Ribeiro DA, Granito RN, et al. 3D printed wound constructs for skin tissue engineering: A systematic review in experimental animal models. J Biomed Mater Res B Appl Biomater. 2023;111:1419–1433. doi: 10.1002/jbm.b.35237. [DOI] [PubMed] [Google Scholar]
281.Yuan T, Tan M, Xu Y, Xiao Q, Wang H, Wu C, Li F, Peng L. All-in-one smart dressing for simultaneous angiogenesis and neural regeneration. J Nanobiotechnology. 2023;21:38. doi: 10.1186/s12951-023-01787-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
282.Mirani B, Hadisi Z, Pagan E, Dabiri SMH, van Rijt A, Almutairi L, Noshadi I, Armstrong DG, Akbari M. Smart dual-sensor wound dressing for monitoring cutaneous wounds. Adv Healthc Mater. 2023;12:e2203233. doi: 10.1002/adhm.202203233. [DOI] [PMC free article] [PubMed] [Google Scholar]
283.Su R, Wang L, Han F, Bian S, Meng F, Qi W, Zhai X, Li H, Wu J, Pan X, et al. A highly stretchable smart dressing for wound infection monitoring and treatment. Mater Today Bio. 2024;26:101107. doi: 10.1016/j.mtbio.2024.101107. [DOI] [PMC free article] [PubMed] [Google Scholar]
284.Lin B, Ma Y, Wu S. Multi-Omics and artificial intelligence-guided data integration in chronic liver disease: Prospects and challenges for precision medicine. OMICS. 2022;26:415–421. doi: 10.1089/omi.2022.0079. [DOI] [PubMed] [Google Scholar]
285.Wang Z, Xu H, Xue B, Liu L, Tang Y, Wang Z, Yao K. MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis. Commun Biol. 2024;7:1700. doi: 10.1038/s42003-024-07367-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
286.Liu J, Qu M, Wang C, Xue Y, Huang H, Chen Q, Sun W, Zhou X, Xu G, Jiang X. A dual-cross-linked hydrogel patch for promoting diabetic wound healing. Small. 2022;18:e2106172. doi: 10.1002/smll.202106172. [DOI] [PubMed] [Google Scholar]
287.Wu C, Long L, Zhang Y, Xu Y, Lu Y, Yang Z, Guo Y, Zhang J, Hu X, Wang Y. Injectable conductive and angiogenic hydrogels for chronic diabetic wound treatment. J Control Release. 2022;344:249–260. doi: 10.1016/j.jconrel.2022.03.014. [DOI] [PubMed] [Google Scholar]
288.Liu W, Zhai X, Zhao X, Cai Y, Zhang X, Xu K, Weng J, Li J, Chen X. Multifunctional double-layer and dual drug-loaded microneedle patch promotes diabetic wound healing. Adv Healthc Mater. 2023;12:e2300297. doi: 10.1002/adhm.202300297. [DOI] [PubMed] [Google Scholar]
289.Xiong W, Zhang X, Zhou J, Chen J, Liu Y, Yan Y, Tan M, Huang H, Si Y, Wei Y. Astragaloside IV promotes exosome secretion of endothelial progenitor cells to regulate PI3KR2/SPRED1 signaling and inhibit pyroptosis of diabetic endothelial cells. Cytotherapy. 2024;26:36–50. doi: 10.1016/j.jcyt.2023.08.013. [DOI] [PubMed] [Google Scholar]
290.Lei T, Gao Y, Duan Y, Cui C, Zhang L, Si M. Panax notoginseng saponins improves healing of high glucose-induced wound through the GSK-3β/β-catenin pathway. Environ Toxicol. 2022;37:1867–1877. doi: 10.1002/tox.23533. [DOI] [PubMed] [Google Scholar]
291.Lu Y, Ding X, Qi F, Ru Y, Kuai L, Chen S, Yang Y, Li X, Li F, Li B, et al. Quyu Shengji formula facilitates diabetic wound healing via inhibiting the expression of prostaglandin transporter. Evid Based Complement Alternat Med. 2021;2021:8849935. doi: 10.1155/2021/8849935. [DOI] [PMC free article] [PubMed] [Google Scholar]
292.Liu Y, Mo J, Liang F, Jiang S, Xiong J, Meng X, Mo Z. Pien-tze-huang promotes wound healing in streptozotocin-induced diabetes models associated with improving oxidative stress via the Nrf2/ARE pathway. Front Pharmacol. 2023;14:1062664. doi: 10.3389/fphar.2023.1062664. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[b1-ijmm-56-02-05567] 1.Dwivedi J, Sachan P, Wal P, Wal A, Rai AK. Current state and future perspective of diabetic wound healing treatment: Present evidence from clinical trials. Curr Diabetes Rev. 2024;20:e280823220405. doi: 10.2174/1573399820666230828091708. [DOI] [PubMed] [Google Scholar]

[b2-ijmm-56-02-05567] 2.Sun H, Pulakat L, Anderson DW. Challenges and new therapeutic approaches in the management of chronic wounds. Curr Drug Targets. 2020;21:1264–1275. doi: 10.2174/1389450121666200623131200. [DOI] [PubMed] [Google Scholar]

[b3-ijmm-56-02-05567] 3.Burgess JL, Wyant WA, Abujamra BA, Kirsner RS, Jozic I. Diabetic wound-healing science. Medicina (Kaunas) 2021;57:1072. doi: 10.3390/medicina57101072. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b4-ijmm-56-02-05567] 4.Vijayakumar V, Samal SK, Mohanty S, Nayak SK. Recent advancements in biopolymer and metal nanoparticle-based materials in diabetic wound healing management. Int J Biol Macromol. 2019;122:137–148. doi: 10.1016/j.ijbiomac.2018.10.120. [DOI] [PubMed] [Google Scholar]

[b5-ijmm-56-02-05567] 5.Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic foot ulcers: A review. JAMA. 2023;330:62–75. doi: 10.1001/jama.2023.10578. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b6-ijmm-56-02-05567] 6.Dasari N, Jiang A, Skochdopole A, Chung J, Reece EM, Vorstenbosch J, Winocour S. Updates in diabetic wound healing, inflammation, and scarring. Semin Plast Surg. 2021;35:153–158. doi: 10.1055/s-0041-1731460. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b7-ijmm-56-02-05567] 7.GBD 2021 Diabetes Collaborators Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: A systematic analysis for the global burden of disease study 2021. Lancet. 2023;402:203–234. doi: 10.1016/S0140-6736(23)01301-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b8-ijmm-56-02-05567] 8.Feng J, Yao Y, Wang Q, Han X, Deng X, Cao Y, Chen X, Zhou M, Zhao C. Exosomes: Potential key players towards novel therapeutic options in diabetic wounds. Biomed Pharmacother. 2023;166:115297. doi: 10.1016/j.biopha.2023.115297. [DOI] [PubMed] [Google Scholar]

[b9-ijmm-56-02-05567] 9.Peña OA, Martin P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. 2024;25:599–616. doi: 10.1038/s41580-024-00715-1. [DOI] [PubMed] [Google Scholar]

[b10-ijmm-56-02-05567] 10.Hanson AJ, Quinn MT. Effect of fibrin sealant composition on human neutrophil chemotaxis. J Biomed Mater Res. 2002;61:474–481. doi: 10.1002/jbm.10196. [DOI] [PubMed] [Google Scholar]

[b11-ijmm-56-02-05567] 11.Liu C, Lu Y, Du P, Yang F, Guo P, Tang X, Diao L, Lu G. Mesenchymal stem cells pretreated with proinflammatory cytokines accelerate skin wound healing by promoting macrophages migration and M2 polarization. Regen Ther. 2022;21:192–200. doi: 10.1016/j.reth.2022.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b12-ijmm-56-02-05567] 12.Wang S, Wang K, Xin Y, Lv D. Maggot excretions/secretions induces human microvascular endothelial cell migration through AKT1. Mol Biol Rep. 2010;37:2719–2725. doi: 10.1007/s11033-009-9806-x. [DOI] [PubMed] [Google Scholar]

[b13-ijmm-56-02-05567] 13.Xia W, Li M, Jiang X, Huang X, Gu S, Ye J, Zhu L, Hou M, Zan T. Young fibroblast-derived exosomal microRNA-125b transfers beneficial effects on aged cutaneous wound healing. J Nanobiotechnology. 2022;20:144. doi: 10.1186/s12951-022-01348-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b14-ijmm-56-02-05567] 14.Fang PH, Lai YY, Chen CL, Wang HY, Chang YN, Lin YC, Yan YT, Lai CH, Cheng B. Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions. Mol Med. 2022;28:71. doi: 10.1186/s10020-022-00499-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b15-ijmm-56-02-05567] 15.Huang SM, Wu CS, Chiu MH, Yang HJ, Chen GS, Lan CCE. High-glucose environment induced intracellular O-GlcNAc glycosylation and reduced galectin-7 expression in keratinocytes: Implications on impaired diabetic wound healing. J Dermatol Sci. 2017;87:168–175. doi: 10.1016/j.jdermsci.2017.04.014. [DOI] [PubMed] [Google Scholar]

[b16-ijmm-56-02-05567] 16.Song Q, An X, Li D, Sodha NR, Boodhwani M, Tian Y, Sellke FW, Li J. Hyperglycemia attenuates angiogenic capability of survivin in endothelial cells. Microvasc Res. 2009;78:257–264. doi: 10.1016/j.mvr.2009.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b17-ijmm-56-02-05567] 17.Huttenlocher A. Cell polarization mechanisms during directed cell migration. Nat Cell Biol. 2005;7:336–337. doi: 10.1038/ncb0405-336. [DOI] [PubMed] [Google Scholar]

[b18-ijmm-56-02-05567] 18.Brothers KM, Stella NA, Hunt KM, Romanowski EG, Liu X, Klarlund JK, Shanks RMQ. Putting on the brakes: Bacterial impediment of wound healing. Sci Rep. 2015;5:14003. doi: 10.1038/srep14003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b19-ijmm-56-02-05567] 19.Carragher NO, Fincham VJ, Riley D, Frame MC. Cleavage of focal adhesion kinase by different proteases during SRC-regulated transformation and apoptosis. Distinct roles for calpain and caspases. J Biol Chem. 2001;276:4270–4275. doi: 10.1074/jbc.M008972200. [DOI] [PubMed] [Google Scholar]

[b20-ijmm-56-02-05567] 20.Zhao Y, Wang Y, Sarkar A, Wang X. Keratocytes generate high integrin tension at the trailing edge to mediate rear de-adhesion during rapid cell migration. iScience. 2018;9:502–512. doi: 10.1016/j.isci.2018.11.016. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b21-ijmm-56-02-05567] 21.Clayton SM, Shafikhani SH, Soulika AM. Macrophage and neutrophil dysfunction in diabetic wounds. Adv Wound Care (New Rochelle) 2024;13:463–484. doi: 10.1089/wound.2023.0149. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b22-ijmm-56-02-05567] 22.Rousselle P, Braye F, Dayan G. Re-epithelialization of adult skin wounds: Cellular mechanisms and therapeutic strategies. Adv Drug Deliv Rev. 2019;146:344–365. doi: 10.1016/j.addr.2018.06.019. [DOI] [PubMed] [Google Scholar]

[b23-ijmm-56-02-05567] 23.Rodrigues M, Kosaric N, Bonham CA, Gurtner GC. Wound healing: A cellular perspective. Physiol Rev. 2019;99:665–706. doi: 10.1152/physrev.00067.2017. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b24-ijmm-56-02-05567] 24.Su Y, Richmond A. Chemokine regulation of neutrophil infiltration of skin wounds. Adv Wound Care (New Rochelle) 2015;4:631–640. doi: 10.1089/wound.2014.0559. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b25-ijmm-56-02-05567] 25.Dahlgren C, Gabl M, Holdfeldt A, Winther M, Forsman H. Basic characteristics of the neutrophil receptors that recognize formylated peptides, a danger-associated molecular pattern generated by bacteria and mitochondria. Biochem Pharmacol. 2016;114:22–39. doi: 10.1016/j.bcp.2016.04.014. [DOI] [PubMed] [Google Scholar]

[b26-ijmm-56-02-05567] 26.Mamun AA, Shao C, Geng P, Wang S, Xiao J. Recent advances in molecular mechanisms of skin wound healing and its treatments. Front Immunol. 2024;15:1395479. doi: 10.3389/fimmu.2024.1395479. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b27-ijmm-56-02-05567] 27.Lämmermann T, Afonso PV, Angermann BR, Wang JM, Kastenmüller W, Parent CA, Germain RN. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature. 2013;498:371–375. doi: 10.1038/nature12175. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b28-ijmm-56-02-05567] 28.Lee WL, Harrison RE, Grinstein S. Phagocytosis by neutrophils. Microbes Infect. 2003;5:1299–1306. doi: 10.1016/j.micinf.2003.09.014. [DOI] [PubMed] [Google Scholar]

[b29-ijmm-56-02-05567] 29.McLeish KR, Fernandes MJ. Understanding inhibitory receptor function in neutrophils through the lens of CLEC12A. Immunol Rev. 2023;314:50–68. doi: 10.1111/imr.13174. [DOI] [PubMed] [Google Scholar]

[b30-ijmm-56-02-05567] 30.Fetz AE, Bowlin GL. Neutrophil extracellular traps: Inflammation and biomaterial preconditioning for tissue engineering. Tissue Eng Part B Rev. 2022;28:437–450. doi: 10.1089/ten.teb.2021.0013. [DOI] [PubMed] [Google Scholar]

[b31-ijmm-56-02-05567] 31.Bratton DL, Henson PM. Neutrophil clearance: When the party is over, clean-up begins. Trends Immunol. 2011;32:350–357. doi: 10.1016/j.it.2011.04.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b32-ijmm-56-02-05567] 32.Guo S, DiPietro LA. Factors affecting wound healing. J Dent Res. 2010;89:219–229. doi: 10.1177/0022034509359125. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b33-ijmm-56-02-05567] 33.de Oliveira S, Rosowski EE, Huttenlocher A. Neutrophil migration in infection and wound repair: Going forward in reverse. Nat Rev Immunol. 2016;16:378–391. doi: 10.1038/nri.2016.49. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b34-ijmm-56-02-05567] 34.Chen WYJ, Rogers AA. Recent insights into the causes of chronic leg ulceration in venous diseases and implications on other types of chronic wounds. Wound Repair Regen. 2007;15:434–449. doi: 10.1111/j.1524-475X.2007.00250.x. [DOI] [PubMed] [Google Scholar]

[b35-ijmm-56-02-05567] 35.Isles HM, Herman KD, Robertson AL, Loynes CA, Prince LR, Elks PM, Renshaw SA. The CXCL12/CXCR4 signaling axis retains neutrophils at inflammatory sites in zebrafish. Front Immunol. 2019;10:1784. doi: 10.3389/fimmu.2019.01784. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b36-ijmm-56-02-05567] 36.Wood W. Wound healing: Calcium flashes illuminate early events. Curr Biol. 2012;22:R14–R16. doi: 10.1016/j.cub.2011.11.019. [DOI] [PubMed] [Google Scholar]

[b37-ijmm-56-02-05567] 37.Niethammer P, Grabher C, Look AT, Mitchison TJ. A tissue-scale gradient of hydrogen peroxide mediates rapid wound detection in zebrafish. Nature. 2009;459:996–999. doi: 10.1038/nature08119. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b38-ijmm-56-02-05567] 38.Razzell W, Evans IR, Martin P, Wood W. Calcium flashes orchestrate the wound inflammatory response through DUOX activation and hydrogen peroxide release. Curr Biol. 2013;23:424–429. doi: 10.1016/j.cub.2013.01.058. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b39-ijmm-56-02-05567] 39.Minutti CM, Knipper JA, Allen JE, Zaiss DM. Tissue-specific contribution of macrophages to wound healing. Semin Cell Dev Biol. 2017;61:3–11. doi: 10.1016/j.semcdb.2016.08.006. [DOI] [PubMed] [Google Scholar]

[b40-ijmm-56-02-05567] 40.Dutra FF, Bozza MT. Heme on innate immunity and inflammation. Front Pharmacol. 2014;5:115. doi: 10.3389/fphar.2014.00115. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b41-ijmm-56-02-05567] 41.Sindrilaru A, Scharffetter-Kochanek K. Disclosure of the culprits: Macrophages-versatile regulators of wound healing. Adv Wound Care (New Rochelle) 2013;2:357–368. doi: 10.1089/wound.2012.0407. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b42-ijmm-56-02-05567] 42.Gurtner GC, Werner S, Barrandon Y, Longaker MT. Wound repair and regeneration. Nature. 2008;453:314–321. doi: 10.1038/nature07039. [DOI] [PubMed] [Google Scholar]

[b43-ijmm-56-02-05567] 43.Zhang T, Tai Z, Miao F, Zhao Y, Wang W, Zhu Q, Chen Z. Bioinspired nanovesicles derived from macrophage accelerate wound healing by promoting angiogenesis and collagen deposition. J Mater Chem B. 2024;12:12338–12348. doi: 10.1039/D3TB02158K. [DOI] [PubMed] [Google Scholar]

[b44-ijmm-56-02-05567] 44.Werner S, Krieg T, Smola H. Keratinocyte-fibroblast interactions in wound healing. J Invest Dermatol. 2007;127:998–1008. doi: 10.1038/sj.jid.5700786. [DOI] [PubMed] [Google Scholar]

[b45-ijmm-56-02-05567] 45.Rousselle P, Montmasson M, Garnier C. Extracellular matrix contribution to skin wound re-epithelialization. Matrix Biol. 2019;75-76:12–26. doi: 10.1016/j.matbio.2018.01.002. [DOI] [PubMed] [Google Scholar]

[b46-ijmm-56-02-05567] 46.Rousselle P, Beck K. Laminin 332 processing impacts cellular behavior. Cell Adh Migr. 2013;7:122–134. doi: 10.4161/cam.23132. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b47-ijmm-56-02-05567] 47.Hamill KJ, McLean WHI. The alpha-3 polypeptide chain of laminin 5: Insight into wound healing responses from the study of genodermatoses. Clin Exp Dermatol. 2005;30:398–404. doi: 10.1111/j.1365-2230.2005.01842.x. [DOI] [PubMed] [Google Scholar]

[b48-ijmm-56-02-05567] 48.Rousselle P, Lunstrum GP, Keene DR, Burgeson RE. Kalinin: An epithelium-specific basement membrane adhesion molecule that is a component of anchoring filaments. J Cell Biol. 1991;114:567–576. doi: 10.1083/jcb.114.3.567. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b49-ijmm-56-02-05567] 49.Theveneau E, Mayor R. Collective cell migration of epithelial and mesenchymal cells. Cell Mol Life Sci. 2013;70:3481–3492. doi: 10.1007/s00018-012-1251-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b50-ijmm-56-02-05567] 50.Krawczyk WS. A pattern of epidermal cell migration during wound healing. J Cell Biol. 1971;49:247–263. doi: 10.1083/jcb.49.2.247. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b51-ijmm-56-02-05567] 51.Headon D. Reversing stratification during wound healing. Nat Cell Biol. 2017;19:595–597. doi: 10.1038/ncb3545. [DOI] [PubMed] [Google Scholar]

[b52-ijmm-56-02-05567] 52.Freedberg IM, Tomic-Canic M, Komine M, Blumenberg M. Keratins and the keratinocyte activation cycle. J Invest Dermatol. 2001;116:633–640. doi: 10.1046/j.1523-1747.2001.01327.x. [DOI] [PubMed] [Google Scholar]

[b53-ijmm-56-02-05567] 53.Veith AP, Henderson K, Spencer A, Sligar AD, Baker AB. Therapeutic strategies for enhancing angiogenesis in wound healing. Adv Drug Deliv Rev. 2019;146:97–125. doi: 10.1016/j.addr.2018.09.010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b54-ijmm-56-02-05567] 54.Velnar T, Gradisnik L. Tissue augmentation in wound healing: The role of endothelial and epithelial cells. Med Arch. 2018;72:444–448. doi: 10.5455/medarh.2018.72.444-448. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b55-ijmm-56-02-05567] 55.Lamalice L, Le Boeuf F, Huot J. Endothelial cell migration during angiogenesis. Circ Res. 2007;100:782–794. doi: 10.1161/01.RES.0000259593.07661.1e. [DOI] [PubMed] [Google Scholar]

[b56-ijmm-56-02-05567] 56.Al Sadoun H. Macrophage phenotypes in normal and diabetic wound healing and therapeutic interventions. Cells. 2022;11:2430. doi: 10.3390/cells11152430. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b57-ijmm-56-02-05567] 57.Song J, Wu Y, Chen Y, Sun X, Zhang Z. Epigenetic regulatory mechanism of macrophage polarization in diabetic wound healing (Review) Mol Med Rep. 2025;31:2. doi: 10.3892/mmr.2024.13367. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b58-ijmm-56-02-05567] 58.Morbidelli L, Genah S, Cialdai F. Effect of microgravity on endothelial cell function, angiogenesis, and vessel remodeling during wound healing. Front Bioeng Biotechnol. 2021;9:720091. doi: 10.3389/fbioe.2021.720091. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b59-ijmm-56-02-05567] 59.Hsu S, Thakar R, Liepmann D, Li S. Effects of shear stress on endothelial cell haptotaxis on micropatterned surfaces. Biochem Biophys Res Commun. 2005;337:401–409. doi: 10.1016/j.bbrc.2005.08.272. [DOI] [PubMed] [Google Scholar]

[b60-ijmm-56-02-05567] 60.Li S, Huang NF, Hsu S. Mechanotransduction in endothelial cell migration. J Cell Biochem. 2005;96:1110–1126. doi: 10.1002/jcb.20614. [DOI] [PubMed] [Google Scholar]

[b61-ijmm-56-02-05567] 61.Lynch MD, Watt FM. Fibroblast heterogeneity: Implications for human disease. J Clin Invest. 2018;128:26–35. doi: 10.1172/JCI93555. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b62-ijmm-56-02-05567] 62.Talbott HE, Mascharak S, Griffin M, Wan DC, Longaker MT. Wound healing, fibroblast heterogeneity, and fibrosis. Cell Stem Cell. 2022;29:1161–1180. doi: 10.1016/j.stem.2022.07.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b63-ijmm-56-02-05567] 63.Bussone G. Subjectivity in primary headaches: Insight the causes. Neurol Sci. 2017;38:1–2. doi: 10.1007/s10072-017-2949-y. [DOI] [PubMed] [Google Scholar]

[b64-ijmm-56-02-05567] 64.Younesi FS, Miller AE, Barker TH, Rossi FMV, Hinz B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol. 2024;25:617–638. doi: 10.1038/s41580-024-00716-0. [DOI] [PubMed] [Google Scholar]

[b65-ijmm-56-02-05567] 65.Shao DD, Suresh R, Vakil V, Gomer RH, Pilling D. Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation. J Leukoc Biol. 2008;83:1323–1333. doi: 10.1189/jlb.1107782. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b66-ijmm-56-02-05567] 66.Grieb G, Steffens G, Pallua N, Bernhagen J, Bucala R. Circulating fibrocytes-biology and mechanisms in wound healing and scar formation. Int Rev Cell Mol Biol. 2011;291:1–19. doi: 10.1016/B978-0-12-386035-4.00001-X. [DOI] [PubMed] [Google Scholar]

[b67-ijmm-56-02-05567] 67.Park JG, Lim DC, Park JH, Park S, Mok J, Kang KW, Park J. Benzbromarone induces targeted degradation of HSP47 protein and improves hypertrophic scar formation. J Invest Dermatol. 2024;144:633–644. doi: 10.1016/j.jid.2023.09.279. [DOI] [PubMed] [Google Scholar]

[b68-ijmm-56-02-05567] 68.Kohlhauser M, Mayrhofer M, Kamolz LP, Smolle C. An update on molecular mechanisms of scarring-A narrative review. Int J Mol Sci. 2024;25:11579. doi: 10.3390/ijms252111579. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b69-ijmm-56-02-05567] 69.Hinz B. Formation and function of the myofibroblast during tissue repair. J Invest Dermatol. 2007;127:526–537. doi: 10.1038/sj.jid.5700613. [DOI] [PubMed] [Google Scholar]

[b70-ijmm-56-02-05567] 70.Luo L, An Y, Geng K, Wan S, Zhang F, Tan X, Jiang Z, Xu Y. High glucose-induced endothelial STING activation inhibits diabetic wound healing through impairment of angiogenesis. Biochem Biophys Res Commun. 2023;668:82–89. doi: 10.1016/j.bbrc.2023.05.081. [DOI] [PubMed] [Google Scholar]

[b71-ijmm-56-02-05567] 71.Huang SM, Wu CS, Chiu MH, Wu CH, Chang YT, Chen GS, Lan CCE. High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-α: An important mechanism to delay the diabetic wound healing. J Dermatol Sci. 2019;96:159–167. doi: 10.1016/j.jdermsci.2019.11.004. [DOI] [PubMed] [Google Scholar]

[b72-ijmm-56-02-05567] 72.Lamers ML, Almeida MES, Vicente-Manzanares M, Horwitz AF, Santos MF. High glucose-mediated oxidative stress impairs cell migration. PLoS One. 2011;6:e22865. doi: 10.1371/journal.pone.0022865. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b73-ijmm-56-02-05567] 73.Brubaker AL, Rendon JL, Ramirez L, Choudhry MA, Kovacs EJ. Reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age. J Immunol. 2013;190:1746–1757. doi: 10.4049/jimmunol.1201213. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b74-ijmm-56-02-05567] 74.den Dekker A, Davis FM, Kunkel SL, Gallagher KA. Targeting epigenetic mechanisms in diabetic wound healing. Transl Res. 2019;204:39–50. doi: 10.1016/j.trsl.2018.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b75-ijmm-56-02-05567] 75.Kasuya A, Tokura Y. Attempts to accelerate wound healing. J Dermatol Sci. 2014;76:169–172. doi: 10.1016/j.jdermsci.2014.11.001. [DOI] [PubMed] [Google Scholar]

[b76-ijmm-56-02-05567] 76.Lan CCE, Liu IH, Fang AH, Wen CH, Wu CS. Hyperglycaemic conditions decrease cultured keratinocyte mobility: Implications for impaired wound healing in patients with diabetes. Br J Dermatol. 2008;159:1103–1115. doi: 10.1111/j.1365-2133.2008.08789.x. [DOI] [PubMed] [Google Scholar]

[b77-ijmm-56-02-05567] 77.Zhou P, Feng H, Qin W, Li Q. KRT17 from skin cells with high glucose stimulation promotes keratinocytes proliferation and migration. Front Endocrinol (Lausanne) 2023;14:1237048. doi: 10.3389/fendo.2023.1237048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b78-ijmm-56-02-05567] 78.Worsley AL, Lui DH, Ntow-Boahene W, Song W, Good L, Tsui J. The importance of inflammation control for the treatment of chronic diabetic wounds. Int Wound J. 2023;20:2346–2359. doi: 10.1111/iwj.14048. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b79-ijmm-56-02-05567] 79.Li M, Wang T, Tian H, Wei G, Zhao L, Shi Y. Macrophage-derived exosomes accelerate wound healing through their anti-inflammation effects in a diabetic rat model. Artif Cells Nanomed Biotechnol. 2019;47:3793–3803. doi: 10.1080/21691401.2019.1669617. [DOI] [PubMed] [Google Scholar]

[b80-ijmm-56-02-05567] 80.Nirenjen S, Narayanan J, Tamilanban T, Subramaniyan V, Chitra V, Fuloria NK, Wong LS, Ramachawolran G, Sekar M, Gupta G, et al. Exploring the contribution of pro-inflammatory cytokines to impaired wound healing in diabetes. Front Immunol. 2023;14:1216321. doi: 10.3389/fimmu.2023.1216321. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b81-ijmm-56-02-05567] 81.Goren I, Müller E, Schiefelbein D, Christen U, Pfeilschifter J, Mühl H, Frank S. Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages. J Invest Dermatol. 2007;127:2259–2267. doi: 10.1038/sj.jid.5700842. [DOI] [PubMed] [Google Scholar]

[b82-ijmm-56-02-05567] 82.Mirza RE, Fang MM, Ennis WJ, Koh TJ. Blocking interleukin-1β induces a healing-associated wound macrophage phenotype and improves healing in type 2 diabetes. Diabetes. 2013;62:2579–2587. doi: 10.2337/db12-1450. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b83-ijmm-56-02-05567] 83.Xu F, Zhang C, Graves DT. Abnormal cell responses and role of TNF-α in impaired diabetic wound healing. Biomed Res Int. 2013;2013:754802. doi: 10.1155/2013/754802. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b84-ijmm-56-02-05567] 84.Dai J, Shen J, Chai Y, Chen H. IL-1β impaired diabetic wound healing by regulating MMP-2 and MMP-9 through the p38 pathway. Mediators Inflamm. 2021;2021:6645766. doi: 10.1155/2021/6645766. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b85-ijmm-56-02-05567] 85.Lan CCE, Wu CS, Huang SM, Wu IH, Chen GS. High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: New insights into impaired diabetic wound healing. Diabetes. 2013;62:2530–2538. doi: 10.2337/db12-1714. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b86-ijmm-56-02-05567] 86.Wang G, Yang F, Zhou W, Xiao N, Luo M, Tang Z. The initiation of oxidative stress and therapeutic strategies in wound healing. Biomed Pharmacother. 2023;157:114004. doi: 10.1016/j.biopha.2022.114004. [DOI] [PubMed] [Google Scholar]

[b87-ijmm-56-02-05567] 87.Xu Q, Huff LP, Fujii M, Griendling KK. Redox regulation of the actin cytoskeleton and its role in the vascular system. Free Radic Biol Med. 2017;109:84–107. doi: 10.1016/j.freeradbiomed.2017.03.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b88-ijmm-56-02-05567] 88.Long M, de la Vega MR, Wen Q, Wen Q, Bharara M, Jiang T, Zhang R, Zhou S, Wong PK, Wondrak GT, et al. An essential role of NRF2 in diabetic wound healing. Diabetes. 2016;65:780–793. doi: 10.2337/db15-0564. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b89-ijmm-56-02-05567] 89.Zhou X, Ruan Q, Ye Z, Chu Z, Xi M, Li M, Hu W, Guo X, Yao P, Xie W. Resveratrol accelerates wound healing by attenuating oxidative stress-induced impairment of cell proliferation and migration. Burns. 2021;47:133–139. doi: 10.1016/j.burns.2020.10.016. [DOI] [PubMed] [Google Scholar]

[b90-ijmm-56-02-05567] 90.Gao M, Nguyen TT, Suckow MA, Wolter WR, Gooyit M, Mobashery S, Chang M. Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy. Proc Natl Acad Sci USA. 2015;112:15226–15231. doi: 10.1073/pnas.1517847112. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b91-ijmm-56-02-05567] 91.Jones JI, Nguyen TT, Peng Z, Chang M. Targeting MMP-9 in diabetic foot ulcers. Pharmaceuticals (Basel) 2019;12:79. doi: 10.3390/ph12020079. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b92-ijmm-56-02-05567] 92.Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: Many shades of function in cardiovascular disease. Physiology (Bethesda) 2013;28:391–403. doi: 10.1152/physiol.00029.2013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b93-ijmm-56-02-05567] 93.Ambrozova N, Ulrichova J, Galandakova A. Models for the study of skin wound healing. The role of Nrf2 and NF-κB. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2017;161:1–13. doi: 10.5507/bp.2016.063. [DOI] [PubMed] [Google Scholar]

[b94-ijmm-56-02-05567] 94.Zubair M, Ahmad J. Role of growth factors and cytokines in diabetic foot ulcer healing: A detailed review. Rev Endocr Metab Disord. 2019;20:207–217. doi: 10.1007/s11154-019-09492-1. [DOI] [PubMed] [Google Scholar]

[b95-ijmm-56-02-05567] 95.Papanas N, Maltezos E. Growth factors in the treatment of diabetic foot ulcers: New technologies, any promises? Int J Low Extrem Wounds. 2007;6:37–53. doi: 10.1177/1534734606298416. [DOI] [PubMed] [Google Scholar]

[b96-ijmm-56-02-05567] 96.Ong HT, Dilley RJ. Novel non-angiogenic role for mesenchymal stem cell-derived vascular endothelial growth factor on keratinocytes during wound healing. Cytokine Growth Factor Rev. 2018;44:69–79. doi: 10.1016/j.cytogfr.2018.11.002. [DOI] [PubMed] [Google Scholar]

[b97-ijmm-56-02-05567] 97.Ou MY, Tan PC, Xie Y, Liu K, Gao YM, Yang XS, Zhou SB, Li QF. Dedifferentiated Schwann cell-derived TGF-β3 is essential for the neural system to promote wound healing. Theranostics. 2022;12:5470–5487. doi: 10.7150/thno.72317. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b98-ijmm-56-02-05567] 98.R AS, Nambi N, Radhakrishnan L, Prasad MK, Ramkumar KM. Neutrophil migration is a crucial factor in wound healing and the pathogenesis of diabetic foot ulcers: Insights into pharmacological interventions. Curr Vasc Pharmacol. 2024;30 doi: 10.2174/0115701611308960241014155413. [DOI] [PubMed] [Google Scholar]

[b99-ijmm-56-02-05567] 99.Michopoulou A, Montmasson M, Garnier C, Lambert E, Dayan G, Rousselle P. A novel mechanism in wound healing: Laminin 332 drives MMP9/14 activity by recruiting syndecan-1 and CD44. Matrix Biol. 2020;94:1–17. doi: 10.1016/j.matbio.2020.06.004. [DOI] [PubMed] [Google Scholar]

[b100-ijmm-56-02-05567] 100.Fang WC, Lan CCE. The epidermal keratinocyte as a therapeutic target for management of diabetic wounds. Int J Mol Sci. 2023;24:4290. doi: 10.3390/ijms24054290. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b101-ijmm-56-02-05567] 101.Pilcher BK, Dumin JA, Sudbeck BD, Krane SM, Welgus HG, Parks WC. The activity of collagenase-1 is required for keratinocyte migration on a type I collagen matrix. J Cell Biol. 1997;137:1445–1457. doi: 10.1083/jcb.137.6.1445. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b102-ijmm-56-02-05567] 102.Lan CCE, Wu CS, Kuo HY, Huang SM, Chen GS. Hyperglycaemic conditions hamper keratinocyte locomotion via sequential inhibition of distinct pathways: New insights on poor wound closure in patients with diabetes. Br J Dermatol. 2009;160:1206–1214. doi: 10.1111/j.1365-2133.2009.09089.x. [DOI] [PubMed] [Google Scholar]

[b103-ijmm-56-02-05567] 103.Zhang C, Ponugoti B, Tian C, Xu F, Tarapore R, Batres A, Alsadun S, Lim J, Dong G, Graves DT. FOXO1 differentially regulates both normal and diabetic wound healing. J Cell Biol. 2015;209:289–303. doi: 10.1083/jcb.201409032. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b104-ijmm-56-02-05567] 104.Wang Y, Graves DT. Keratinocyte function in normal and diabetic wounds and modulation by FOXO1. J Diabetes Res. 2020;2020:3714704. doi: 10.1155/2020/3714704. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b105-ijmm-56-02-05567] 105.Kaussikaa S, Prasad MK, Ramkumar KM. Nrf2 activation in keratinocytes: A central role in diabetes-associated wound healing. Exp Dermatol. 2024;33:e15189. doi: 10.1111/exd.15189. [DOI] [PubMed] [Google Scholar]

[b106-ijmm-56-02-05567] 106.da Silva L, Carvalho E, Cruz MT. Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing. Expert Opin Biol Ther. 2010;10:1427–1439. doi: 10.1517/14712598.2010.515207. [DOI] [PubMed] [Google Scholar]

[b107-ijmm-56-02-05567] 107.Pradhan L, Nabzdyk C, Andersen ND, LoGerfo FW, Veves A. Inflammation and neuropeptides: The connection in diabetic wound healing. Expert Rev Mol Med. 2009;11:e2. doi: 10.1017/S1462399409000945. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b108-ijmm-56-02-05567] 108.Grande R, Puca V, Muraro R. Antibiotic resistance and bacterial biofilm. Expert Opin Ther Pat. 2020;30:897–900. doi: 10.1080/13543776.2020.1830060. [DOI] [PubMed] [Google Scholar]

[b109-ijmm-56-02-05567] 109.Marano RJ, Wallace HJ, Wijeratne D, Fear MW, Wong HS, O'Handley R. Secreted biofilm factors adversely affect cellular wound healing responses in vitro. Sci Rep. 2015;5:13296. doi: 10.1038/srep13296. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b110-ijmm-56-02-05567] 110.Xing H, Huang Y, Kunkemoeller BH, Dahl PJ, Muraleetharan O, Malvankar NS, Murrell MP, Kyriakides TR. Dysregulation of TSP2-Rac1-WAVE2 axis in diabetic cells leads to cytoskeletal disorganization, increased cell stiffness, and dysfunction. Sci Rep. 2022;12:22474. doi: 10.1038/s41598-022-26337-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b111-ijmm-56-02-05567] 111.Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M, Zanconato F, Le Digabel J, Forcato M, Bicciato S, et al. Role of YAP/TAZ in mechanotransduction. Nature. 2011;474:179–183. doi: 10.1038/nature10137. [DOI] [PubMed] [Google Scholar]

[b112-ijmm-56-02-05567] 112.Brusatin G, Panciera T, Gandin A, Citron A, Piccolo S. Biomaterials and engineered microenvironments to control YAP/TAZ-dependent cell behaviour. Nat Mater. 2018;17:1063–1075. doi: 10.1038/s41563-018-0180-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b113-ijmm-56-02-05567] 113.Lin MO, Sampath D, Bosykh DA, Wang C, Wang X, Subramaniam T, Han W, Hong W, Chakraborty S. YAP/TAZ drive agrin-matrix metalloproteinase 12-mediated diabetic skin wound healing. J Invest Dermatol. 2025;145:155–170.e2. doi: 10.1016/j.jid.2024.05.005. [DOI] [PubMed] [Google Scholar]

[b114-ijmm-56-02-05567] 114.Majumdar R, Steen K, Coulombe PA, Parent CA. Non-canonical processes that shape the cell migration landscape. Curr Opin Cell Biol. 2019;57:123–134. doi: 10.1016/j.ceb.2018.12.013. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b115-ijmm-56-02-05567] 115.Xie L, Feng H, Li S, Meng G, Liu S, Tang X, Ma Y, Han Y, Xiao Y, Gu Y, et al. SIRT3 mediates the antioxidant effect of hydrogen sulfide in endothelial cells. Antioxid Redox Signal. 2016;24:329–343. doi: 10.1089/ars.2015.6331. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b116-ijmm-56-02-05567] 116.Meng G, Liu J, Liu S, Song Q, Liu L, Xie L, Han Y, Ji Y. Hydrogen sulfide pretreatment improves mitochondrial function in myocardial hypertrophy via a SIRT3-dependent manner. Br J Pharmacol. 2018;175:1126–1145. doi: 10.1111/bph.13861. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b117-ijmm-56-02-05567] 117.Yang S, Xu M, Meng G, Lu Y. SIRT3 deficiency delays diabetic skin wound healing via oxidative stress and necroptosis enhancement. J Cell Mol Med. 2020;24:4415–4427. doi: 10.1111/jcmm.15100. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b118-ijmm-56-02-05567] 118.Johan MZ, Pyne NT, Kolesnikoff N, Poltavets V, Esmaeili Z, Woodcock JM, Lopez AF, Cowin AJ, Pitson SM, Samuel MS. Accelerated closure of diabetic wounds by efficient recruitment of fibroblasts upon inhibiting a 14-3-3/ROCK regulatory axis. J Invest Dermatol. 2024;144:2562–2573.e4. doi: 10.1016/j.jid.2024.03.032. [DOI] [PubMed] [Google Scholar]

[b119-ijmm-56-02-05567] 119.Li Z, Zhang C, Wang L, Zhang Q, Dong Y, Sha X, Wang B, Zhu Z, Wang W, Wang Y, et al. Chitooligosaccharides promote diabetic wound healing by mediating fibroblast proliferation and migration. Sci Rep. 2025;15:556. doi: 10.1038/s41598-024-84398-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b120-ijmm-56-02-05567] 120.Gao Q, Pan L, Li Y, Zhang X. Astragaloside IV attenuates high glucose-induced human keratinocytes injury via TGF-β/Smad signaling pathway. J Tissue Viability. 2022;31:678–686. doi: 10.1016/j.jtv.2022.08.002. [DOI] [PubMed] [Google Scholar]

[b121-ijmm-56-02-05567] 121.Dong M, Ma X, Li F. Dedifferentiated fat cells-derived exosomes (DFATs-Exos) loaded in GelMA accelerated diabetic wound healing through Wnt/β-catenin pathway. Stem Cell Res Ther. 2025;16:103. doi: 10.1186/s13287-025-04205-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b122-ijmm-56-02-05567] 122.Ridley AJ. Rho GTPase signalling in cell migration. Curr Opin Cell Biol. 2015;36:103–112. doi: 10.1016/j.ceb.2015.08.005. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b123-ijmm-56-02-05567] 123.Wu M, Zhang S, Zhang W, Zhou Y, Guo Z, Fang Y, Yang Y, Shen Z, Lian D, Shen A, Peng J. Qingda granule ameliorates vascular remodeling and phenotypic transformation of adventitial fibroblasts via suppressing the TGF-β1/Smad2/3 pathway. J Ethnopharmacol. 2023;313:116535. doi: 10.1016/j.jep.2023.116535. [DOI] [PubMed] [Google Scholar]

[b124-ijmm-56-02-05567] 124.Fang H, Yang S, Luo Y, Zhang C, Rao Y, Liu R, Feng Y, Yu J. Notoginsenoside R1 inhibits vascular smooth muscle cell proliferation, migration and neointimal hyperplasia through PI3K/Akt signaling. Sci Rep. 2018;8:7595. doi: 10.1038/s41598-018-25874-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b125-ijmm-56-02-05567] 125.Carvalho JR, Fortunato IC, Fonseca CG, Pezzarossa A, Barbacena P, Dominguez-Cejudo MA, Vasconcelos FF, Santos NC, Carvalho FA, Franco CA. Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration. Elife. 2019;8:e45853. doi: 10.7554/eLife.45853. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b126-ijmm-56-02-05567] 126.Van den Broeke C, Favoreel HW. Actin' up: Herpesvirus Interactions with Rho GTPase signaling. Viruses. 2011;3:278–292. doi: 10.3390/v3040278. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b127-ijmm-56-02-05567] 127.Qian W, Yamaguchi N, Lis P, Cammer M, Knaut H. Pulses of RhoA signaling stimulate actin polymerization and flow in protrusions to drive collective cell migration. Curr Biol. 2024;34:245–259.e8. doi: 10.1016/j.cub.2023.11.044. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b128-ijmm-56-02-05567] 128.Takaya K, Imbe Y, Wang Q, Okabe K, Sakai S, Aramaki-Hattori N, Kishi K. Rac1 inhibition regenerates wounds in mouse fetuses via altered actin dynamics. Sci Rep. 2024;14:27213. doi: 10.1038/s41598-024-78395-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b129-ijmm-56-02-05567] 129.Shih PC, Tzeng IS, Chen YC, Chen ML. Gastrodin mitigates ketamine-induced inhibition of F-actin remodeling and cell migration by regulating the rho signaling pathway. Biomedicines. 2025;13:649. doi: 10.3390/biomedicines13030649. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b130-ijmm-56-02-05567] 130.Lawson CD, Ridley AJ. Rho GTPase signaling complexes in cell migration and invasion. J Cell Biol. 2018;217:447–457. doi: 10.1083/jcb.201612069. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b131-ijmm-56-02-05567] 131.Xue C, Li G, Lu J, Li L. Crosstalk between circRNAs and the PI3K/AKT signaling pathway in cancer progression. Signal Transduct Target Ther. 2021;6:400. doi: 10.1038/s41392-021-00788-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b132-ijmm-56-02-05567] 132.Teng Y, Fan Y, Ma J, Lu W, Liu N, Chen Y, Pan W, Tao X. The PI3K/Akt pathway: Emerging roles in skin homeostasis and a group of non-malignant skin disorders. Cells. 2021;10:1219. doi: 10.3390/cells10051219. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b133-ijmm-56-02-05567] 133.Zhang X, Shi L, Xing M, Li C, Ma F, Ma Y, Ma Y. Interplay between lncRNAs and the PI3K/AKT signaling pathway in the progression of digestive system neoplasms (Review) Int J Mol Med. 2024;55:15. doi: 10.3892/ijmm.2024.5456. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b134-ijmm-56-02-05567] 134.Karar J, Maity A. PI3K/AKT/mTOR pathway in angiogenesis. Front Mol Neurosci. 2011;4:51. doi: 10.3389/fnmol.2011.00051. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b135-ijmm-56-02-05567] 135.Wu X, Sun Q, He S, Wu Y, Du S, Gong L, Yu J, Guo H. Ropivacaine inhibits wound healing by suppressing the proliferation and migration of keratinocytes via the PI3K/AKT/mTOR pathway. BMC Anesthesiol. 2022;22:106. doi: 10.1186/s12871-022-01646-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b136-ijmm-56-02-05567] 136.Deng S, Leong HC, Datta A, Gopal V, Kumar AP, Yap CT. PI3K/AKT signaling tips the balance of cytoskeletal forces for cancer progression. Cancers (Basel) 2022;14:1652. doi: 10.3390/cancers14071652. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b137-ijmm-56-02-05567] 137.Hsu JW, Bai M, Li K, Yang JS, Chu N, Cole PA, Eck MJ, Li J, Hsu VW. The protein kinase Akt acts as a coat adaptor in endocytic recycling. Nat Cell Biol. 2020;22:927–933. doi: 10.1038/s41556-020-0530-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b138-ijmm-56-02-05567] 138.Hannigan M, Zhan L, Li Z, Ai Y, Wu D, Huang CK. Neutrophils lacking phosphoinositide 3-kinase gamma show loss of directionality during N-formyl-Met-Leu-Phe-induced chemotaxis. Proc Natl Acad Sci USA. 2002;99:3603–3608. doi: 10.1073/pnas.052010699. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b139-ijmm-56-02-05567] 139.Najafi M, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 2019;120:2782–2790. doi: 10.1002/jcb.27681. [DOI] [PubMed] [Google Scholar]

[b140-ijmm-56-02-05567] 140.Nakerakanti S, Trojanowska M. The role of TGF-β receptors in fibrosis. Open Rheumatol J. 2012;6:156–162. doi: 10.2174/1874312901206010156. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b141-ijmm-56-02-05567] 141.Tu S, Huang W, Huang C, Luo Z, Yan X. Contextual regulation of TGF-β signaling in liver cancer. Cells. 2019;8:1235. doi: 10.3390/cells8101235. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b142-ijmm-56-02-05567] 142.Zhang K, Zhang H, Xiang H, Liu J, Liu Y, Zhang X, Wang J, Tang Y. TGF-β1 induces the dissolution of tight junctions in human renal proximal tubular cells: role of the RhoA/ROCK signaling pathway. Int J Mol Med. 2013;32:464–468. doi: 10.3892/ijmm.2013.1396. [DOI] [PubMed] [Google Scholar]

[b143-ijmm-56-02-05567] 143.Gailit J, Welch MP, Clark RA. TGF-beta 1 stimulates expression of keratinocyte integrins during re-epithelialization of cutaneous wounds. J Invest Dermatol. 1994;103:221–227. doi: 10.1111/1523-1747.ep12393176. [DOI] [PubMed] [Google Scholar]

[b144-ijmm-56-02-05567] 144.Ponugoti B, Xu F, Zhang C, Tian C, Pacios S, Graves DT. FOXO1 promotes wound healing through the up-regulation of TGF-β1 and prevention of oxidative stress. J Cell Biol. 2013;203:327–343. doi: 10.1083/jcb.201305074. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b145-ijmm-56-02-05567] 145.Weber CE, Li NY, Wai PY, Kuo PC. Epithelial-Mesenchymal transition, TGF-β, and osteopontin in wound healing and tissue remodeling after injury. J Burn Care Res. 2012;33:311–318. doi: 10.1097/BCR.0b013e318240541e. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b146-ijmm-56-02-05567] 146.Song P, Gao Z, Bao Y, Chen L, Huang Y, Liu Y, Dong Q, Wei X. Wnt/β-catenin signaling pathway in carcinogenesis and cancer therapy. J Hematol Oncol. 2024;17:46. doi: 10.1186/s13045-024-01563-4. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b147-ijmm-56-02-05567] 147.Moon RT, Kohn AD, De Ferrari GV, Kaykas A. WNT and beta-catenin signalling: Diseases and therapies. Nat Rev Genet. 2004;5:691–701. doi: 10.1038/nrg1427. [DOI] [PubMed] [Google Scholar]

[b148-ijmm-56-02-05567] 148.Nusse R, Clevers H. Wnt/β-Catenin signaling, disease, and emerging therapeutic modalities. Cell. 2017;169:985–999. doi: 10.1016/j.cell.2017.05.016. [DOI] [PubMed] [Google Scholar]

[b149-ijmm-56-02-05567] 149.Schaale K, Neumann J, Schneider D, Ehlers S, Reiling N. Wnt signaling in macrophages: Augmenting and inhibiting mycobacteria-induced inflammatory responses. Eur J Cell Biol. 2011;90:553–559. doi: 10.1016/j.ejcb.2010.11.004. [DOI] [PubMed] [Google Scholar]

[b150-ijmm-56-02-05567] 150.Sedgwick AE, D'Souza-Schorey C. Wnt signaling in cell motility and invasion: Drawing parallels between development and cancer. Cancers (Basel) 2016;8:80. doi: 10.3390/cancers8090080. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b151-ijmm-56-02-05567] 151.Wu B, Crampton SP, Hughes CCW. Wnt signaling induces MMP expression and regulates T cell transmigration. Immunity. 2007;26:227–239. doi: 10.1016/j.immuni.2006.12.007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b152-ijmm-56-02-05567] 152.Xue W, Yang L, Chen C, Ashrafizadeh M, Tian Y, Sun R. Wnt/β-catenin-driven EMT regulation in human cancers. Cell Mol Life Sci. 2024;81:79. doi: 10.1007/s00018-023-05099-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b153-ijmm-56-02-05567] 153.Ono M, Masaki A, Maeda A, Kilts TM, Hara ES, Komori T, Pham H, Kuboki T, Young MF. CCN4/WISP1 controls cutaneous wound healing by modulating proliferation, migration and ECM expression in dermal fibroblasts via α5β1 and TNFα. Matrix Biol. 2018;68-69:533–546. doi: 10.1016/j.matbio.2018.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b154-ijmm-56-02-05567] 154.Repertinger SK, Campagnaro E, Fuhrman J, El-Abaseri T, Yuspa SH, Hansen LA. EGFR enhances early healing after cutaneous incisional wounding. J Invest Dermatol. 2004;123:982–989. doi: 10.1111/j.0022-202X.2004.23478.x. [DOI] [PubMed] [Google Scholar]

[b155-ijmm-56-02-05567] 155.Wang Y, Wu Z, Tian J, Mi Y, Ren X, Kang J, Zhang W, Zhou X, Wang G, Li R. Intermedin protects HUVECs from ischemia reperfusion injury via Wnt/β-catenin signaling pathway. Ren Fail. 2019;41:159–166. doi: 10.1080/0886022X.2019.1587468. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b156-ijmm-56-02-05567] 156.Jun EK, Zhang Q, Yoon BS, Moon JH, Lee G, Park G, Kang PJ, Lee JH, Kim A, You S. Hypoxic conditioned medium from human amniotic fluid-derived mesenchymal stem cells accelerates skin wound healing through TGF-β/SMAD2 and PI3K/Akt pathways. Int J Mol Sci. 2014;15:605–628. doi: 10.3390/ijms15010605. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b157-ijmm-56-02-05567] 157.Toraldo G, Bhasin S, Bakhit M, Guo W, Serra C, Safer JD, Bhawan J, Jasuja R. Topical androgen antagonism promotes cutaneous wound healing without systemic androgen deprivation by blocking β-catenin nuclear translocation and cross-talk with TGF-β signaling in keratinocytes. Wound Repair Regen. 2012;20:61–73. doi: 10.1111/j.1524-475X.2011.00757.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b158-ijmm-56-02-05567] 158.Wang H, Wang X, Liu X, Zhou J, Yang Q, Chai B, Chai Y, Ma Z, Lu S. miR-199a-5p plays a pivotal role on wound healing via suppressing VEGFA and ROCK1 in diabetic ulcer foot. Oxid Med Cell Longev. 2022;2022:4791059. doi: 10.1155/2022/4791059. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b159-ijmm-56-02-05567] 159.Yu J, Nam D, Park KS. Substance P enhances cellular migration and inhibits senescence in human dermal fibroblasts under hyperglycemic conditions. Biochem Biophys Res Commun. 2020;522:917–923. doi: 10.1016/j.bbrc.2019.11.172. [DOI] [PubMed] [Google Scholar]

[b160-ijmm-56-02-05567] 160.Huang J, Deng Q, Tsang LL, Chang G, Guo J, Ruan YC, Wang CC, Li G, Chan HF, Zhang X, Jiang X. Mesenchymal stem cells from perinatal tissues promote diabetic wound healing via PI3K/AKT activation. Stem Cell Res Ther. 2025;16:59. doi: 10.1186/s13287-025-04141-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b161-ijmm-56-02-05567] 161.Xu S, Jiang C, Yu T, Chen K. A multi-purpose dressing based on resveratrol-loaded ionic liquids/gelatin methacryloyl hydrogel for enhancing diabetic wound healing. Int J Biol Macromol. 2024;283:136773. doi: 10.1016/j.ijbiomac.2024.136773. [DOI] [PubMed] [Google Scholar]

[b162-ijmm-56-02-05567] 162.Peng Y, Wu S, Tang Q, Li S, Peng C. KGF-1 accelerates wound contraction through the TGF-β1/Smad signaling pathway in a double-paracrine manner. J Biol Chem. 2019;294:8361–8370. doi: 10.1074/jbc.RA118.006189. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b163-ijmm-56-02-05567] 163.Oyebode OA, Houreld NN. Photobiomodulation at 830 nm stimulates migration, survival and proliferation of fibroblast cells. Diabetes Metab Syndr Obes. 2022;15:2885–2900. doi: 10.2147/DMSO.S374649. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b164-ijmm-56-02-05567] 164.Wang L, Chen J, Song J, Xiang Y, Yang M, Xia L, Yang J, Hou X, Chen L, Wang L. Activation of the Wnt/β-catenin signalling pathway enhances exosome production by hucMSCs and improves their capability to promote diabetic wound healing. J Nanobiotechnology. 2024;22:373. doi: 10.1186/s12951-024-02650-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b165-ijmm-56-02-05567] 165.Liu Z, Yang S, Li X, Wang S, Zhang T, Huo N, Duan R, Shi Q, Zhang J, Xu J. Local transplantation of GMSC-derived exosomes to promote vascularized diabetic wound healing by regulating the Wnt/β-catenin pathways. Nanoscale Adv. 2023;5:916–926. doi: 10.1039/D2NA00762B. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b166-ijmm-56-02-05567] 166.Lv Q, Deng J, Chen Y, Wang Y, Liu B, Liu J. Engineered human adipose stem-cell-derived exosomes loaded with miR-21-5p to promote diabetic cutaneous wound healing. Mol Pharm. 2020;17:1723–1733. doi: 10.1021/acs.molpharmaceut.0c00177. [DOI] [PubMed] [Google Scholar]

[b167-ijmm-56-02-05567] 167.Yang Y, GuangXuan H, GenMeng W, MengHuan L, Bo C, XueJie Y. Idiopathic inflammatory myopathy and non-coding RNA. Front Immunol. 2023;14:1227945. doi: 10.3389/fimmu.2023.1227945. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b168-ijmm-56-02-05567] 168.Ballarino M, Morlando M, Fatica A, Bozzoni I. Non-coding RNAs in muscle differentiation and musculoskeletal disease. J Clin Invest. 2016;126:2021–2030. doi: 10.1172/JCI84419. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b169-ijmm-56-02-05567] 169.Chen L, Shen S, Wang S. LncRNA SNHG16 knockdown promotes diabetic foot ulcer wound healing via sponging MiR-31-5p. Tohoku J Exp Med. 2023;261:283–289. doi: 10.1620/tjem.2023.J078. [DOI] [PubMed] [Google Scholar]

[b170-ijmm-56-02-05567] 170.Peng J, Zhu H, Ruan B, Duan Z, Cao M. miR-155 promotes m6A modification of SOX2 mRNA through targeted regulation of HIF-1α and delays wound healing in diabetic foot ulcer in vitro models. J Diabetes Investig. 2024;16:60–71. doi: 10.1111/jdi.14327. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b171-ijmm-56-02-05567] 171.Tian M, Tang J, Huang R, Dong J, Jia H. Circ_072697 knockdown promotes advanced glycation end products-induced cell proliferation and migration in HaCaT cells via miR-3150a-3p/KDM2A axis. BMC Endocr Disord. 2023;23:200. doi: 10.1186/s12902-023-01430-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b172-ijmm-56-02-05567] 172.Wang F, Mei X, Yang Y, Zhang H, Li Z, Zhu L, Deng S, Wang Y. Non-coding RNA and its network in the pathogenesis of myasthenia gravis. Front Mol Biosci. 2024;11:1388476. doi: 10.3389/fmolb.2024.1388476. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b173-ijmm-56-02-05567] 173.Bhan A, Mandal SS. Long noncoding RNAs: Emerging stars in gene regulation, epigenetics and human disease. ChemMedChem. 2014;9:1932–1956. doi: 10.1002/cmdc.201300534. [DOI] [PubMed] [Google Scholar]

[b174-ijmm-56-02-05567] 174.Hong W, Xiong Z, Wang X, Liao X, Liu M, Jiang Z, Min D, Li J, Guo G, Fu Z. Long noncoding RNA XIST promotes cell proliferation and migration in diabetic foot ulcers through the miR-126-3p/EGFR axis. Diabetol Metab Syndr. 2024;16:35. doi: 10.1186/s13098-024-01260-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b175-ijmm-56-02-05567] 175.He M, Tu L, Shu R, Meng Q, Du S, Xu Z, Wang S. Long noncoding RNA CASC2 facilitated wound healing through miRNA-155/HIF-1α in diabetic foot ulcers. Contrast Media Mol Imaging. 2022;2022:6291497. doi: 10.1155/2022/6291497. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b176-ijmm-56-02-05567] 176.Li B, Zhou Y, Chen J, Wang T, Li Z, Fu Y, Zhai A, Bi C. Long noncoding RNA H19 acts as a miR-29b sponge to promote wound healing in diabetic foot ulcer. FASEB J. 2021;35:e20526. doi: 10.1096/fj.201900076RRRRR. [DOI] [PubMed] [Google Scholar]

[b177-ijmm-56-02-05567] 177.Hu M, Wu Y, Yang C, Wang X, Wang W, Zhou L, Zeng T, Zhou J, Wang C, Lao G, et al. Novel long noncoding RNA lnc-URIDS delays diabetic wound healing by targeting Plod1. Diabetes. 2020;69:2144–2156. doi: 10.2337/db20-0147. [DOI] [PubMed] [Google Scholar]

[b178-ijmm-56-02-05567] 178.Gezer U, Özgür E, Cetinkaya M, Isin M, Dalay N. Long non-coding RNAs with low expression levels in cells are enriched in secreted exosomes. Cell Biol Int. 2014;38:1076–1079. doi: 10.1002/cbin.10301. [DOI] [PubMed] [Google Scholar]

[b179-ijmm-56-02-05567] 179.Li B, Luan S, Chen J, Zhou Y, Wang T, Li Z, Fu Y, Zhai A, Bi C. The MSC-derived exosomal lncRNA H19 promotes wound healing in diabetic foot ulcers by upregulating PTEN via MicroRNA-152-3p. Mol Ther Nucleic Acids. 2020;19:814–826. doi: 10.1016/j.omtn.2019.11.034. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b180-ijmm-56-02-05567] 180.Han ZF, Cao JH, Liu ZY, Yang Z, Qi RX, Xu HL. Exosomal lncRNA KLF3-AS1 derived from bone marrow mesenchymal stem cells stimulates angiogenesis to promote diabetic cutaneous wound healing. Diabetes Res Clin Pract. 2022;183:109126. doi: 10.1016/j.diabres.2021.109126. [DOI] [PubMed] [Google Scholar]

[b181-ijmm-56-02-05567] 181.Fu W, Liang D, Wu X, Chen H, Hong X, Wang J, Zhu T, Zeng T, Lin W, Chen S, et al. Long noncoding RNA LINC01435 impedes diabetic wound healing by facilitating YY1-mediated HDAC8 expression. iScience. 2022;25:104006. doi: 10.1016/j.isci.2022.104006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b182-ijmm-56-02-05567] 182.Roso-Mares A, Andújar I, Corpas TD, Sun BK. Non-coding RNAs as skin disease biomarkers, molecular signatures, and therapeutic targets. Hum Genet. 2024;143:801–812. doi: 10.1007/s00439-023-02588-4. [DOI] [PubMed] [Google Scholar]

[b183-ijmm-56-02-05567] 183.Shirley SN, Watson AE, Yusuf N. Pathogenesis of inflammation in skin disease: From molecular mechanisms to pathology. Int J Mol Sci. 2024;25:10152. doi: 10.3390/ijms251810152. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b184-ijmm-56-02-05567] 184.Tsai HC, Chang GRL, Tung MC, Tu MY, Chen IC, Liu YH, Cidem A, Chen CM. MicroRNA signature in an in vitro keratinocyte model of diabetic wound healing. Int J Mol Sci. 2024;25:10125. doi: 10.3390/ijms251810125. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b185-ijmm-56-02-05567] 185.Zhao X, Xu M, Tang Y, Xie D, Deng L, Chen M, Wang Y. Decreased expression of miR-204-3p in peripheral blood and wound margin tissue associated with the onset and poor wound healing of diabetic foot ulcers. Int Wound J. 2023;20:413–429. doi: 10.1111/iwj.13890. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b186-ijmm-56-02-05567] 186.Zhang HC, Wen T, Cai YZ. Overexpression of miR-146a promotes cell proliferation and migration in a model of diabetic foot ulcers by regulating the AKAP12 axis. Endocr J. 2022;69:85–94. doi: 10.1507/endocrj.EJ21-0177. [DOI] [PubMed] [Google Scholar]

[b187-ijmm-56-02-05567] 187.Wang W, Yang C, Wang XY, Zhou LY, Lao GJ, Liu D, Wang C, Hu MD, Zeng TT, Yan L, Ren M. MicroRNA-129 and -335 promote diabetic wound healing by inhibiting Sp1-mediated MMP-9 expression. Diabetes. 2018;67:1627–1638. doi: 10.2337/db17-1238. [DOI] [PubMed] [Google Scholar]

[b188-ijmm-56-02-05567] 188.Li P, Hong G, Zhan W, Deng M, Tu C, Wei J, Lin H. Endothelial progenitor cell derived exosomes mediated miR-182-5p delivery accelerate diabetic wound healing via down-regulating PPARG. Int J Med Sci. 2023;20:468–481. doi: 10.7150/ijms.78790. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b189-ijmm-56-02-05567] 189.Wang KX, Zhao LL, Zheng LT, Meng LB, Jin L, Zhang LJ, Kong FL, Liang F. Accelerated wound healing in diabetic rat by miRNA-185-5p and its anti-inflammatory activity. Diabetes Metab Syndr Obes. 2023;16:1657–1667. doi: 10.2147/DMSO.S409596. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b190-ijmm-56-02-05567] 190.Wu M, Tu J, Huang J, Wen H, Zeng Y, Lu Y. Exosomal IRF1-loaded rat adipose-derived stem cell sheet contributes to wound healing in the diabetic foot ulcers. Mol Med. 2023;29:60. doi: 10.1186/s10020-023-00617-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b191-ijmm-56-02-05567] 191.Wu Y, Zhang K, Liu R, Zhang H, Chen D, Yu S, Chen W, Wan S, Zhang Y, Jia Z, et al. MicroRNA-21-3p accelerates diabetic wound healing in mice by downregulating SPRY1. Aging (Albany NY) 2020;12:15436–15445. doi: 10.18632/aging.103610. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b192-ijmm-56-02-05567] 192.Wang C, Huang L, Li J, Liu D, Wu B. MicroRNA miR-145-5p inhibits cutaneous wound healing by targeting PDGFD in diabetic foot ulcer. Biochem Genet. 2024;62:2437–2454. doi: 10.1007/s10528-023-10551-1. [DOI] [PubMed] [Google Scholar]

[b193-ijmm-56-02-05567] 193.Zhao X, Xu M, Tang Y, Xie D, Wang Y, Chen M. Changes in miroRNA-103 expression in wound margin tissue are related to wound healing of diabetes foot ulcers. Int Wound J. 2022;20:467–483. doi: 10.1111/iwj.13895. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b194-ijmm-56-02-05567] 194.Zhang P, Song X, Dong Q, Zhou L, Wang L. miR-27-3p inhibition restore fibroblasts viability in diabetic wound by targeting NOVA1. Aging (Albany NY) 2020;12:12841–12849. doi: 10.18632/aging.103266. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b195-ijmm-56-02-05567] 195.Zheng L, Song H, Li Y, Li H, Lin G, Cai Z. Insulin-Induced gene 1-enhance secretion of BMSC exosome enriched in miR-132-3p promoting wound healing in diabetic mice. Mol Pharm. 2024;21:4372–4385. doi: 10.1021/acs.molpharmaceut.4c00322. [DOI] [PubMed] [Google Scholar]

[b196-ijmm-56-02-05567] 196.Zuo C, Fan P, Yang Y, Hu C. MiR-488-3p facilitates wound healing through CYP1B1-mediated Wnt/β-catenin signaling pathway by targeting MeCP2. J Diabetes Investig. 2024;15:145–158. doi: 10.1111/jdi.14099. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b197-ijmm-56-02-05567] 197.Huang H, Zhu W, Huang Z, Zhao D, Cao L, Gao X. Adipose-derived stem cell exosome NFIC improves diabetic foot ulcers by regulating miR-204-3p/HIPK2. J Orthop Surg Res. 2023;18:687. doi: 10.1186/s13018-023-04165-x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b198-ijmm-56-02-05567] 198.Qiu ZY, Xu WC, Liang ZH. Bone marrow mesenchymal stem cell-derived exosomal miR-221-3p promotes angiogenesis and wound healing in diabetes via the downregulation of forkhead box P1. Diabet Med. 2024;41:e15386. doi: 10.1111/dme.15386. [DOI] [PubMed] [Google Scholar]

[b199-ijmm-56-02-05567] 199.Zhou X, Ye C, Jiang L, Zhu X, Zhou F, Xia M, Chen Y. The bone mesenchymal stem cell-derived exosomal miR-146a-5p promotes diabetic wound healing in mice via macrophage M1/M2 polarization. Mol Cell Endocrinol. 2024;579:112089. doi: 10.1016/j.mce.2023.112089. [DOI] [PubMed] [Google Scholar]

[b200-ijmm-56-02-05567] 200.Guo E, Wang L, Wu J, Chen Q. Exosomes from MicroRNA-125b-modified adipose-derived stem cells promote wound healing of diabetic foot ulcers. Curr Stem Cell Res Ther. 2024;20:409–420. doi: 10.2174/011574888X287173240415050555. [DOI] [PubMed] [Google Scholar]

[b201-ijmm-56-02-05567] 201.Che D, Xiang X, Xie J, Chen Z, Bao Q, Cao D. exosomes derived from adipose stem cells enhance angiogenesis in diabetic wound via miR-146a-5p/JAZF1 axis. Stem Cell Rev Rep. 2024;20:1026–1039. doi: 10.1007/s12015-024-10685-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b202-ijmm-56-02-05567] 202.Ge L, Wang K, Lin H, Tao E, Xia W, Wang F, Mao C, Feng Y. Engineered exosomes derived from miR-132-overexpresssing adipose stem cells promoted diabetic wound healing and skin reconstruction. Front Bioeng Biotechnol. 2023;11:1129538. doi: 10.3389/fbioe.2023.1129538. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b203-ijmm-56-02-05567] 203.Sedykh S, Kuleshova A, Nevinsky G. Milk exosomes: Perspective agents for anticancer drug delivery. Int J Mol Sci. 2020;21:6646. doi: 10.3390/ijms21186646. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b204-ijmm-56-02-05567] 204.Munagala R, Aqil F, Jeyabalan J, Gupta RC. Bovine milk-derived exosomes for drug delivery. Cancer Lett. 2016;371:48–61. doi: 10.1016/j.canlet.2015.10.020. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b205-ijmm-56-02-05567] 205.Yan C, Chen J, Wang C, Yuan M, Kang Y, Wu Z, Li W, Zhang G, Machens HG, Rinkevich Y. Milk exosomes-mediated miR-31-5p delivery accelerates diabetic wound healing through promoting angiogenesis. Drug Deliv. 2022;29:214–228. doi: 10.1080/10717544.2021.2023699. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b206-ijmm-56-02-05567] 206.Liu R, Zhang L, Zhao X, Liu J, Chang W, Zhou L, Zhang K. circRNA: Regulatory factors and potential therapeutic targets in inflammatory dermatoses. J Cell Mol Med. 2022;26:4389–4400. doi: 10.1111/jcmm.17473. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b207-ijmm-56-02-05567] 207.Beňačka R, Szabóová D, Guľašová Z, Hertelyová Z. Non-Coding RNAs in breast cancer: Diagnostic and therapeutic implications. Int J Mol Sci. 2024;26:127. doi: 10.3390/ijms26010127. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b208-ijmm-56-02-05567] 208.Zhang Y, Wu Y, Liu Z, Yang K, Lin H, Xiong K. Non-coding RNAs as potential targets in metformin therapy for cancer. Cancer Cell Int. 2024;24:333. doi: 10.1186/s12935-024-03516-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b209-ijmm-56-02-05567] 209.Fu Z, Jiang Z, Liao X, Liu M, Guo G, Wang X, Yang G, Zhou Z, Hu L, Xiong Z. Upregulation of circ_0080968 in diabetic foot ulcer inhibits wound healing via repressing the migration and promoting proliferation of keratinocytes. Gene. 2023;883:147669. doi: 10.1016/j.gene.2023.147669. [DOI] [PubMed] [Google Scholar]

[b210-ijmm-56-02-05567] 210.Han D, Liu W, Li G, Liu L. Circ_PRKDC knockdown promotes skin wound healing by enhancing keratinocyte migration via miR-31/FBN1 axis. J Mol Histol. 2021;52:681–691. doi: 10.1007/s10735-021-09996-8. [DOI] [PubMed] [Google Scholar]

[b211-ijmm-56-02-05567] 211.Wang A, Toma MA, Ma J, Li D, Vij M, Chu T, Wang J, Li X, Landén NX. Circular RNA hsa_circ_0084443 is upregulated in diabetic foot ulcer and modulates keratinocyte migration and proliferation. Adv Wound Care (New Rochelle) 2020;9:145–160. doi: 10.1089/wound.2019.0956. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b212-ijmm-56-02-05567] 212.Liang ZH, Pan NF, Lin SS, Qiu ZY, Liang P, Wang J, Zhang Z, Pan YC. Exosomes from mmu_circ_0001052-modified adipose-derived stem cells promote angiogenesis of DFU via miR-106a-5p and FGF4/p38MAPK pathway. Stem Cell Res Ther. 2022;13:336. doi: 10.1186/s13287-022-03015-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b213-ijmm-56-02-05567] 213.Huang Q, Chu Z, Wang Z, Li Q, Meng S, Lu Y, Ma K, Cui S, Hu W, Zhang W, et al. circCDK13-loaded small extracellular vesicles accelerate healing in preclinical diabetic wound models. Nat Commun. 2024;15:3904. doi: 10.1038/s41467-024-48284-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b214-ijmm-56-02-05567] 214.Chen M, Przyborowski M, Berthiaume F. Stem cells for skin tissue engineering and wound healing. Crit Rev Biomed Eng. 2009;37:399–421. doi: 10.1615/CritRevBiomedEng.v37.i4-5.50. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b215-ijmm-56-02-05567] 215.Xu ZH, Ma MH, Li YQ, Li LL, Liu GH. Progress and expectation of stem cell therapy for diabetic wound healing. World J Clin Cases. 2023;11:506–513. doi: 10.12998/wjcc.v11.i3.506. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b216-ijmm-56-02-05567] 216.Deng Q, Pan S, Du F, Sang H, Cai Z, Xu X, Wei Q, Yu S, Zhang J, Li C. The Effect of conditioned medium from angiopoietin-1 gene-modified mesenchymal stem cells on wound healing in a diabetic mouse model. Bioengineering (Basel) 2024;11:1244. doi: 10.3390/bioengineering11121244. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b217-ijmm-56-02-05567] 217.Liu Z, Wen X, Wang H, Zhou J, Zhao M, Lin Q, Wang Y, Li J, Li D, Du Z, et al. Molecular imaging of induced pluripotent stem cell immunogenicity with in vivo development in ischemic myocardium. PLoS One. 2013;8:e66369. doi: 10.1371/journal.pone.0066369. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b218-ijmm-56-02-05567] 218.He L, Cai Y, Du H, Shu M, Zhu C. Adipose stem cell-derived exosomes promote high glucose-induced wound healing by regulating the TRIM32/STING axis. Arch Dermatol Res. 2024;316:323. doi: 10.1007/s00403-024-03065-2. [DOI] [PubMed] [Google Scholar]

[b219-ijmm-56-02-05567] 219.Ding JY, Chen MJ, Wu LF, Shu GF, Fang SJ, Li ZY, Chu XR, Li XK, Wang ZG, Ji JS. Mesenchymal stem cell-derived extracellular vesicles in skin wound healing: Roles, opportunities and challenges. Mil Med Res. 2023;10:36. doi: 10.1186/s40779-023-00472-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b220-ijmm-56-02-05567] 220.Li Y, Zhu Z, Li S, Xie X, Qin L, Zhang Q, Yang Y, Wang T, Zhang Y. Exosomes: Compositions, biogenesis, and mechanisms in diabetic wound healing. J Nanobiotechnology. 2024;22:398. doi: 10.1186/s12951-024-02684-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b221-ijmm-56-02-05567] 221.Laiva AL, O'Brien FJ, Keogh MB. Innovations in gene and growth factor delivery systems for diabetic wound healing. J Tissue Eng Regen Med. 2018;12:e296–e312. doi: 10.1002/term.2443. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b222-ijmm-56-02-05567] 222.Li Z, Qiu X, Guan G, Shi K, Chen S, Tang J, Xiao M, Tang S, Yan Y, Zhou J, Xie H. The role of FGF-21 in promoting diabetic wound healing by modulating high glucose-induced inflammation. Heliyon. 2024;10:e30022. doi: 10.1016/j.heliyon.2024.e30022. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b223-ijmm-56-02-05567] 223.Tang L, Cai S, Lu X, Wu D, Zhang Y, Li X, Qin X, Guo J, Zhang X, Liu C. Platelet-Derived growth factor nanocapsules with tunable controlled release for chronic wound healing. Small. 2024;20:e2310743. doi: 10.1002/smll.202310743. [DOI] [PubMed] [Google Scholar]

[b224-ijmm-56-02-05567] 224.Jeong S, Kim B, Park M, Ban E, Lee SH, Kim A. Improved diabetic wound healing by EGF encapsulation in gelatin-alginate coacervates. Pharmaceutics. 2020;12:334. doi: 10.3390/pharmaceutics12040334. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b225-ijmm-56-02-05567] 225.Wang H, Xu Z, Zhao M, Liu G, Wu J. Advances of hydrogel dressings in diabetic wounds. Biomater Sci. 2021;9:1530–1546. doi: 10.1039/D0BM01747G. [DOI] [PubMed] [Google Scholar]

[b226-ijmm-56-02-05567] 226.Serpico L, Iacono SD, Cammarano A, De Stefano L. Recent advances in stimuli-responsive hydrogel-based wound dressing. Gels. 2023;9:451. doi: 10.3390/gels9060451. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b227-ijmm-56-02-05567] 227.Liang Y, He J, Guo B. Functional hydrogels as wound dressing to enhance wound healing. ACS Nano. 2021;15:12687–12722. doi: 10.1021/acsnano.1c04206. [DOI] [PubMed] [Google Scholar]

[b228-ijmm-56-02-05567] 228.Miguel SP, Ribeiro MP, Brancal H, Coutinho P, Correia IJ. Thermoresponsive chitosan-agarose hydrogel for skin regeneration. Carbohydr Polym. 2014;111:366–373. doi: 10.1016/j.carbpol.2014.04.093. [DOI] [PubMed] [Google Scholar]

[b229-ijmm-56-02-05567] 229.Bei Z, Zhang L, Li J, Tong Q, Shi K, Chen W, Yu Y, Sun A, Xu Y, Liu J, Qian Z. A smart stimulation-deadhesion and antimicrobial hydrogel for repairing diabetic wounds infected with methicillin-resistant staphylococcus aureus. Adv Healthc Mater. 2024;13:e2303042. doi: 10.1002/adhm.202303042. [DOI] [PubMed] [Google Scholar]

[b230-ijmm-56-02-05567] 230.Li Y, Fu R, Duan Z, Zhu C, Fan D. Artificial nonenzymatic antioxidant MXene Nanosheet-anchored injectable hydrogel as a mild photothermal-controlled oxygen release platform for diabetic wound healing. ACS Nano. 2022;16:7486–7502. doi: 10.1021/acsnano.1c10575. [DOI] [PubMed] [Google Scholar]

[b231-ijmm-56-02-05567] 231.Şeker Ş, Elçin AE, Elçin YM. Current trends in the design and fabrication of PRP-based scaffolds for tissue engineering and regenerative medicine. Biomed Mater. 2025;20:20. doi: 10.1088/1748-605X/ada83f. [DOI] [PubMed] [Google Scholar]

[b232-ijmm-56-02-05567] 232.Xu K, Deng S, Zhu Y, Yang W, Chen W, Huang L, Zhang C, Li M, Ao L, Jiang Y, et al. Platelet rich plasma loaded multifunctional hydrogel accelerates diabetic wound healing via regulating the continuously abnormal microenvironments. Adv Healthc Mater. 2023;12:e2301370. doi: 10.1002/adhm.202301370. [DOI] [PubMed] [Google Scholar]

[b233-ijmm-56-02-05567] 233.Wei Q, Su J, Meng S, Wang Y, Ma K, Li B, Chu Z, Huang Q, Hu W, Wang Z, et al. MiR-17-5p-engineered sEVs encapsulated in GelMA hydrogel facilitated diabetic wound healing by targeting PTEN and p21. Adv Sci (Weinh) 2024;11:e2307761. doi: 10.1002/advs.202307761. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b234-ijmm-56-02-05567] 234.Alberts A, Bratu AG, Niculescu AG, Grumezescu AM. New perspectives of hydrogels in chronic wound management. Molecules. 2025;30:686. doi: 10.3390/molecules30030686. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b235-ijmm-56-02-05567] 235.Negut I, Bita B. Exploring the potential of artificial intelligence for hydrogel development-a short review. Gels. 2023;9:845. doi: 10.3390/gels9110845. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b236-ijmm-56-02-05567] 236.Tan CT, Liang K, Ngo ZH, Dube CT, Lim CY. Application of 3D bioprinting technologies to the management and treatment of diabetic foot ulcers. Biomedicines. 2020;8:441. doi: 10.3390/biomedicines8100441. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b237-ijmm-56-02-05567] 237.Wang M, Song Y, Bisoyi HK, Yang JF, Liu L, Yang H, Li Q. A liquid crystal elastomer-based unprecedented two-way shape-memory aerogel. Adv Sci (Weinh) 2021;8:e2102674. doi: 10.1002/advs.202102674. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b238-ijmm-56-02-05567] 238.Jeong Y, Patel R, Patel M. Biopolymer-Based biomimetic aerogel for biomedical applications. Biomimetics (Basel) 2024;9:397. doi: 10.3390/biomimetics9070397. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b239-ijmm-56-02-05567] 239.Guo N, Xia Y, Zeng W, Chen J, Wu Q, Shi Y, Li G, Huang Z, Wang G, Liu Y. Alginate-based aerogels as wound dressings for efficient bacterial capture and enhanced antibacterial photodynamic therapy. Drug Deliv. 2022;29:1086–1099. doi: 10.1080/10717544.2022.2058650. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b240-ijmm-56-02-05567] 240.Wang X, Yuan Z, Shafiq M, Cai G, Lei Z, Lu Y, Guan X, Hashim R, El-Newehy M, Abdulhameed MM, et al. Composite aerogel scaffolds containing flexible silica nanofiber and tricalcium phosphate enable skin regeneration. ACS Appl Mater Interfaces. 2024;16:25843–25855. doi: 10.1021/acsami.4c03744. [DOI] [PubMed] [Google Scholar]

[b241-ijmm-56-02-05567] 241.Vaseghi A, Sadeghizadeh M, Herb M, Grumme D, Demidov Y, Remmler T, Maleki HH. 3D printing of biocompatible and antibacterial silica-silk-chitosan-based hybrid aerogel scaffolds loaded with propolis. ACS Appl Bio Mater. 2024;7:7917–7935. doi: 10.1021/acsabm.4c00697. [DOI] [PubMed] [Google Scholar]

[b242-ijmm-56-02-05567] 242.Wu B, Pan W, Luo S, Luo X, Zhao Y, Xiu Q, Zhong M, Wang Z, Liao T, Li N, et al. Turmeric-Derived nanoparticles functionalized aerogel regulates multicellular networks to promote diabetic wound healing. Adv Sci (Weinh) 2024;11:e2307630. doi: 10.1002/advs.202307630. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b243-ijmm-56-02-05567] 243.Ramos R, Silva JP, Rodrigues AC, Costa R, Guardão L, Schmitt F, Soares R, Vilanova M, Domingues L, Gama M. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011;32:1469–1476. doi: 10.1016/j.peptides.2011.06.005. [DOI] [PubMed] [Google Scholar]

[b244-ijmm-56-02-05567] 244.Grönberg A, Mahlapuu M, Ståhle M, Whately-Smith C, Rollman O. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: A randomized, placebo-controlled clinical trial. Wound Repair Regen. 2014;22:613–621. doi: 10.1111/wrr.12211. [DOI] [PubMed] [Google Scholar]

[b245-ijmm-56-02-05567] 245.John JV, Sharma NS, Tang G, Luo Z, Su Y, Weihs S, Shahriar SMS, Wang G, McCarthy A, Dyke J, et al. Nanofiber aerogels with precision macrochannels and LL-37-mimic peptides synergistically promote diabetic wound healing. Adv Funct Mater. 2023;33:2206936. doi: 10.1002/adfm.202206936. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b246-ijmm-56-02-05567] 246.Zhao C, Wu Z, Pan B, Zhang R, Golestani A, Feng Z, Ge Y, Yang H. Functional biomacromolecules-based microneedle patch for the treatment of diabetic wound. Int J Biol Macromol. 2024;267:131650. doi: 10.1016/j.ijbiomac.2024.131650. [DOI] [PubMed] [Google Scholar]

[b247-ijmm-56-02-05567] 247.Hu F, Gao Q, Liu J, Chen W, Zheng C, Bai Q, Sun N, Zhang W, Zhang Y, Lu T. Smart microneedle patches for wound healing and management. J Mater Chem B. 2023;11:2830–2851. doi: 10.1039/D2TB02596E. [DOI] [PubMed] [Google Scholar]

[b248-ijmm-56-02-05567] 248.Yin M, Wu J, Deng M, Wang P, Ji G, Wang M, Zhou C, Blum NT, Zhang W, Shi H, et al. Multifunctional magnesium organic framework-based microneedle patch for accelerating diabetic wound healing. ACS Nano. 2021;15:17842–17853. doi: 10.1021/acsnano.1c06036. [DOI] [PubMed] [Google Scholar]

[b249-ijmm-56-02-05567] 249.Wang P, Wu J, Yang H, Liu H, Yao T, Liu C, Gong Y, Wang M, Ji G, Huang P, Wang X. Intelligent microneedle patch with prolonged local release of hydrogen and magnesium ions for diabetic wound healing. Bioact Mater. 2023;24:463–476. doi: 10.1016/j.bioactmat.2023.01.001. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b250-ijmm-56-02-05567] 250.Avcil M, Çelik A. Microneedles in drug delivery: Progress and challenges. Micromachines (Basel) 2021;12:1321. doi: 10.3390/mi12111321. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b251-ijmm-56-02-05567] 251.Alsarayreh AZ, Oran SA, Shakhanbeh JM, Khleifat KM, Al Qaisi YT, Alfarrayeh II, Alkaramseh AM. Efficacy of methanolic extracts of some medicinal plants on wound healing in diabetic rats. Heliyon. 2022;8:e10071. doi: 10.1016/j.heliyon.2022.e10071. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b252-ijmm-56-02-05567] 252.Wu JR, Lu YC, Hung SJ, Lin JH, Chang KC, Chen JK, Tsai WT, Ho TJ, Chen HP. Antimicrobial and immunomodulatory activity of herb extracts used in burn wound healing: 'San Huang Powder'. Evid Based Complement Alternat Med. 2021;2021:2900060. doi: 10.1155/2021/2900060. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b253-ijmm-56-02-05567] 253.Soheilifar MH, Dastan D, Masoudi-Khoram N, Neghab HN, Nobari S, Tabaie SM, Amini R. In vitro and in vivo evaluation of the diabetic wound healing properties of Saffron (Crocus Sativus L.) petals. Sci Rep. 2024;14:19373. doi: 10.1038/s41598-024-70010-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b254-ijmm-56-02-05567] 254.Huang L, Cai HA, Zhang MS, Liao RY, Huang X, Hu FD. Ginsenoside Rg1 promoted the wound healing in diabetic foot ulcers via miR-489-3p/Sirt1 axis. J Pharmacol Sci. 2021;147:271–283. doi: 10.1016/j.jphs.2021.07.008. [DOI] [PubMed] [Google Scholar]

[b255-ijmm-56-02-05567] 255.Sun X, Wang X, Zhao Z, Chen J, Li C, Zhao G. Paeoniflorin accelerates foot wound healing in diabetic rats though activating the Nrf2 pathway. Acta Histochem. 2020;122:151649. doi: 10.1016/j.acthis.2020.151649. [DOI] [PubMed] [Google Scholar]

[b256-ijmm-56-02-05567] 256.Zhang S, Xu Y, Junior CZ, Chen X, Zhu J. Dang-Gui-Si-Ni decoction facilitates wound healing in diabetic foot ulcers by regulating expression of AGEs/RAGE/TGF-β/Smad2/3. Arch Dermatol Res. 2024;316:338. doi: 10.1007/s00403-024-03021-0. [DOI] [PubMed] [Google Scholar]

[b257-ijmm-56-02-05567] 257.Gong Y, Jiang Y, Huang J, He Z, Tang Q. Moist exposed burn ointment accelerates diabetes-related wound healing by promoting re-epithelialization. Front Med (Lausanne) 2022;9:1042015. doi: 10.3389/fmed.2022.1042015. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b258-ijmm-56-02-05567] 258.Ding R, Wang Y, Zhu JP, Lu WG, Wei GL, Gu ZC, An ZT, Huo JG. Danggui Sini decoction protects against oxaliplatin-induced peripheral neuropathy in rats. J Integr Neurosci. 2020;19:663–671. doi: 10.31083/j.jin.2020.04.1154. [DOI] [PubMed] [Google Scholar]

[b259-ijmm-56-02-05567] 259.Mabvuure NT, Brewer CF, Gervin K, Duffy S. The use of moist exposed burn ointment (MEBO) for the treatment of burn wounds: A systematic review. J Plast Surg Hand Surg. 2020;54:337–343. doi: 10.1080/2000656X.2020.1813148. [DOI] [PubMed] [Google Scholar]

[b260-ijmm-56-02-05567] 260.Zhao D, Luo S, Xu W, Hu J, Lin S, Wang N. Efficacy and safety of hyperbaric oxygen therapy used in patients with diabetic foot: A meta-analysis of randomized clinical trials. Clin Ther. 2017;39:2088–2094.e2. doi: 10.1016/j.clinthera.2017.08.014. [DOI] [PubMed] [Google Scholar]

[b261-ijmm-56-02-05567] 261.Damineni U, Divity S, Gundapaneni SRC, Burri RG, Vadde T. Clinical outcomes of hyperbaric oxygen therapy for diabetic foot ulcers: A systematic review. Cureus. 2025;17:e78655. doi: 10.7759/cureus.78655. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b262-ijmm-56-02-05567] 262.Huang X, Liang P, Jiang B, Zhang P, Yu W, Duan M, Guo L, Cui X, Huang M, Huang X. Hyperbaric oxygen potentiates diabetic wound healing by promoting fibroblast cell proliferation and endothelial cell angiogenesis. Life Sci. 2020;259:118246. doi: 10.1016/j.lfs.2020.118246. [DOI] [PubMed] [Google Scholar]

[b263-ijmm-56-02-05567] 263.Borys S, Hohendorff J, Koblik T, Witek P, Ludwig-Slomczynska AH, Frankfurter C, Kiec-Wilk B, Malecki MT. Negative-pressure wound therapy for management of chronic neuropathic noninfected diabetic foot ulcerations-short-term efficacy and long-term outcomes. Endocrine. 2018;62:611–616. doi: 10.1007/s12020-018-1707-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b264-ijmm-56-02-05567] 264.Chen L, Zhang S, Da J, Wu W, Ma F, Tang C, Li G, Zhong D, Liao B. A systematic review and meta-analysis of efficacy and safety of negative pressure wound therapy in the treatment of diabetic foot ulcer. Ann Palliat Med. 2021;10:10830–10839. doi: 10.21037/apm-21-2476. [DOI] [PubMed] [Google Scholar]

[b265-ijmm-56-02-05567] 265.Huang Y, Yu Z, Xu M, Zhao X, Tang Y, Luo L, Deng D, Chen M. Negative pressure wound therapy promotes wound healing by down-regulating miR-155 expression in granulation tissue of diabetic foot ulcers. Sci Rep. 2025;15:6733. doi: 10.1038/s41598-025-90643-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b266-ijmm-56-02-05567] 266.Liu L, Chen R, Jia Z, Li X, Tang Y, Zhao X, Zhang S, Luo L, Fang Z, Zhang Y, Chen M. Downregulation of hsa-miR-203 in peripheral blood and wound margin tissue by negative pressure wound therapy contributes to wound healing of diabetic foot ulcers. Microvasc Res. 2022;139:104275. doi: 10.1016/j.mvr.2021.104275. [DOI] [PubMed] [Google Scholar]

[b267-ijmm-56-02-05567] 267.Houreld NN. Shedding light on a new treatment for diabetic wound healing: A review on phototherapy. ScientificWorldJournal. 2014;2014:398412. doi: 10.1155/2014/398412. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b268-ijmm-56-02-05567] 268.Houreld N, Abrahamse H. Low-intensity laser irradiation stimulates wound healing in diabetic wounded fibroblast cells (WS1) Diabetes Technol Ther. 2010;12:971–978. doi: 10.1089/dia.2010.0039. [DOI] [PubMed] [Google Scholar]

[b269-ijmm-56-02-05567] 269.Gupta A, Dai T, Hamblin MR. Effect of red and near-infrared wavelengths on low-level laser (light) therapy-induced healing of partial-thickness dermal abrasion in mice. Lasers Med Sci. 2014;29:257–265. doi: 10.1007/s10103-013-1319-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b270-ijmm-56-02-05567] 270.Cai W, Hamushan M, Zhang Y, Xu Z, Ren Z, Du J, Ju J, Cheng P, Tan M, Han P. Synergistic effects of photobiomodulation therapy with combined wavelength on diabetic wound healing in vitro and in vivo. Photobiomodul Photomed Laser Surg. 2022;40:13–24. doi: 10.1089/photob.2021.0068. [DOI] [PubMed] [Google Scholar]

[b271-ijmm-56-02-05567] 271.Frampton JE, Lee CR, Faulds D. Filgrastim. A review of its pharmacological properties and therapeutic efficacy in neutropenia. Drugs. 1994;48:731–760. doi: 10.2165/00003495-199448050-00007. [DOI] [PubMed] [Google Scholar]

[b272-ijmm-56-02-05567] 272.Edmonds M, Gough A, Solovera J, Standaert B. Filgrastim in the treatment of infected diabetic foot ulcers. Clin Drug Investig. 1999;17:275–286. doi: 10.2165/00044011-199917040-00003. [DOI] [Google Scholar]

[b273-ijmm-56-02-05567] 273.Orgill DP, Bayer LR. Negative pressure wound therapy: Past, present and future. Int Wound J. 2013;10:15–19. doi: 10.1111/iwj.12170. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b274-ijmm-56-02-05567] 274.Yoon D, Byun HJ, Oh SJ, Park JH, Lee DY. A case of cutaneous leukocytoclastic vasculitis associated with granulocyte colony-stimulating factor: An unusual presentation. Ann Dermatol. 2020;32:164–167. doi: 10.5021/ad.2020.32.2.164. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b275-ijmm-56-02-05567] 275.Song P, Liang Q, Ge X, Zhou D, Yuan M, Chu W, Xu J. Adipose-derived stem cell exosomes promote scar-free healing of diabetic wounds via miR-204-5p/TGF-β1/Smad pathway. Stem Cells Int. 2025;2025:6344844. doi: 10.1155/sci/6344844. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b276-ijmm-56-02-05567] 276.Van Netten JJ, Woodburn J, Bus SA. The future for diabetic foot ulcer prevention: A paradigm shift from stratified healthcare towards personalized medicine. Diabetes Metab Res Rev. 2020;36(Suppl 1):e3234. doi: 10.1002/dmrr.3234. [DOI] [PubMed] [Google Scholar]

[b277-ijmm-56-02-05567] 277.Ng GW, Gan KF, Liew H, Ge L, Ang G, Molina J, Sun Y, Prakash PS, Harish KB, Lo ZJ. A Systematic review and classification of factors influencing diabetic foot ulcer treatment adherence, in accordance with the WHO dimensions of adherence to long-term therapies. Int J Low Extrem Wounds. 2024;20:15347346241233962. doi: 10.1177/15347346241233962. [DOI] [PubMed] [Google Scholar]

[b278-ijmm-56-02-05567] 278.Zhang YW, Sun L, Wang YN, Zhan SY. Role of macrophage polarization in diabetic foot ulcer healing: A bibliometric study. World J Diabetes. 2025;16:99755. doi: 10.4239/wjd.v16.i1.99755. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b279-ijmm-56-02-05567] 279.Choudhury S, Dhoke NR, Chawla S, Das A. Bioengineered MSCCxcr2 transdifferentiated keratinocyte-like cell-derived organoid potentiates skin regeneration through ERK1/2 and STAT3 signaling in diabetic wound. Cell Mol Life Sci. 2024;81:172. doi: 10.1007/s00018-023-05057-3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b280-ijmm-56-02-05567] 280.de Souza A, Martignago CCS, Santo GDE, Sousa KDSJ, Cruz MA, Amaral GO, Parisi JR, Estadella D, Ribeiro DA, Granito RN, et al. 3D printed wound constructs for skin tissue engineering: A systematic review in experimental animal models. J Biomed Mater Res B Appl Biomater. 2023;111:1419–1433. doi: 10.1002/jbm.b.35237. [DOI] [PubMed] [Google Scholar]

[b281-ijmm-56-02-05567] 281.Yuan T, Tan M, Xu Y, Xiao Q, Wang H, Wu C, Li F, Peng L. All-in-one smart dressing for simultaneous angiogenesis and neural regeneration. J Nanobiotechnology. 2023;21:38. doi: 10.1186/s12951-023-01787-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b282-ijmm-56-02-05567] 282.Mirani B, Hadisi Z, Pagan E, Dabiri SMH, van Rijt A, Almutairi L, Noshadi I, Armstrong DG, Akbari M. Smart dual-sensor wound dressing for monitoring cutaneous wounds. Adv Healthc Mater. 2023;12:e2203233. doi: 10.1002/adhm.202203233. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b283-ijmm-56-02-05567] 283.Su R, Wang L, Han F, Bian S, Meng F, Qi W, Zhai X, Li H, Wu J, Pan X, et al. A highly stretchable smart dressing for wound infection monitoring and treatment. Mater Today Bio. 2024;26:101107. doi: 10.1016/j.mtbio.2024.101107. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b284-ijmm-56-02-05567] 284.Lin B, Ma Y, Wu S. Multi-Omics and artificial intelligence-guided data integration in chronic liver disease: Prospects and challenges for precision medicine. OMICS. 2022;26:415–421. doi: 10.1089/omi.2022.0079. [DOI] [PubMed] [Google Scholar]

[b285-ijmm-56-02-05567] 285.Wang Z, Xu H, Xue B, Liu L, Tang Y, Wang Z, Yao K. MSC-derived exosomal circMYO9B accelerates diabetic wound healing by promoting angiogenesis through the hnRNPU/CBL/KDM1A/VEGFA axis. Commun Biol. 2024;7:1700. doi: 10.1038/s42003-024-07367-z. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b286-ijmm-56-02-05567] 286.Liu J, Qu M, Wang C, Xue Y, Huang H, Chen Q, Sun W, Zhou X, Xu G, Jiang X. A dual-cross-linked hydrogel patch for promoting diabetic wound healing. Small. 2022;18:e2106172. doi: 10.1002/smll.202106172. [DOI] [PubMed] [Google Scholar]

[b287-ijmm-56-02-05567] 287.Wu C, Long L, Zhang Y, Xu Y, Lu Y, Yang Z, Guo Y, Zhang J, Hu X, Wang Y. Injectable conductive and angiogenic hydrogels for chronic diabetic wound treatment. J Control Release. 2022;344:249–260. doi: 10.1016/j.jconrel.2022.03.014. [DOI] [PubMed] [Google Scholar]

[b288-ijmm-56-02-05567] 288.Liu W, Zhai X, Zhao X, Cai Y, Zhang X, Xu K, Weng J, Li J, Chen X. Multifunctional double-layer and dual drug-loaded microneedle patch promotes diabetic wound healing. Adv Healthc Mater. 2023;12:e2300297. doi: 10.1002/adhm.202300297. [DOI] [PubMed] [Google Scholar]

[b289-ijmm-56-02-05567] 289.Xiong W, Zhang X, Zhou J, Chen J, Liu Y, Yan Y, Tan M, Huang H, Si Y, Wei Y. Astragaloside IV promotes exosome secretion of endothelial progenitor cells to regulate PI3KR2/SPRED1 signaling and inhibit pyroptosis of diabetic endothelial cells. Cytotherapy. 2024;26:36–50. doi: 10.1016/j.jcyt.2023.08.013. [DOI] [PubMed] [Google Scholar]

[b290-ijmm-56-02-05567] 290.Lei T, Gao Y, Duan Y, Cui C, Zhang L, Si M. Panax notoginseng saponins improves healing of high glucose-induced wound through the GSK-3β/β-catenin pathway. Environ Toxicol. 2022;37:1867–1877. doi: 10.1002/tox.23533. [DOI] [PubMed] [Google Scholar]

[b291-ijmm-56-02-05567] 291.Lu Y, Ding X, Qi F, Ru Y, Kuai L, Chen S, Yang Y, Li X, Li F, Li B, et al. Quyu Shengji formula facilitates diabetic wound healing via inhibiting the expression of prostaglandin transporter. Evid Based Complement Alternat Med. 2021;2021:8849935. doi: 10.1155/2021/8849935. [DOI] [PMC free article] [PubMed] [Google Scholar]

[b292-ijmm-56-02-05567] 292.Liu Y, Mo J, Liang F, Jiang S, Xiong J, Meng X, Mo Z. Pien-tze-huang promotes wound healing in streptozotocin-induced diabetes models associated with improving oxidative stress via the Nrf2/ARE pathway. Front Pharmacol. 2023;14:1062664. doi: 10.3389/fphar.2023.1062664. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Cell migration in diabetic wound healing: Molecular mechanisms and therapeutic strategies (Review)

Jielin Song

Tong Zhao

Chuanfu Wang

Xu Sun

Junchao Sun

Zhaohui Zhang

Abstract

1. Introduction

2. Cell migration

Figure 1.

3. Cell migration in normal wound healing

Neutrophil migration

Figure 2.

Monocyte/macrophage migration

Keratinocyte migration

EC migration

Fibroblast migration

4. Mechanisms of cellular migration impairment in diabetic wound healing

Figure 3.

Effects of high glucose on cell migration

Effects of chronic inflammation on cell migration

Effects of oxidative stress on cell migration

Effects of wound microenvironment on cell migration

Other effects on cell migration

5. Key signaling pathways regulating cell migration to promote wound healing

Rho GTPase signaling pathway

Figure 4.

PI3K/Akt signaling pathway

Figure 5.

TGF-β/Smad signaling pathway

Figure 6.

Wnt/β-catenin signaling pathway

Figure 7.

Table I.

6. ncRNAs of cell migration in diabetic wounds

Table II.

lncRNAs

miRNAs

circRNAs

7. Regulation of cell migration for the treatment of diabetic wounds

SCs and derived exosomes

Table III.

Growth factor therapy

Drug-loaded dressings

Hydrogel-based drug therapy

Table IV.

Aerogel-based drug therapy

Drug therapy based on microneedle patches

Traditional chinese medicine (TCM) treatment

Table V.

Additional treatment options

8. Conclusion

Acknowledgments

Funding Statement

Availability of data and materials

Authors' contributions

Ethics approval and consent to participate

Patient consent for publication

Competing interests

References

Associated Data

Data Availability Statement

ACTIONS

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