Skin injury rapidly triggers a cascade of hemostatic responses that initiate wound healing. Hemostasis comprises multiple processes, including the cessation of blood flow and clot formation. Vascular injury induces transient vasoconstriction, which reduces blood flow and initiates primary hemostasis. Platelets, predominantly located near the vessel wall, are positioned to respond rapidly to vascular damage. Upon exposure of the subendothelial matrix, platelets are activated and bind to it via collagen receptor Ib-V-IX and glycoprotein VI. Activated platelets adhere to extracellular matrix (ECM) components, including fibronectin, collagen, and von Willebrand factor, aggregate into platelet plugs, and release granules that recruit and activate additional platelets. Within the plugs, platelet stabilization is mediated by αIIbβ3 integrin-dependent interactions that incorporate newly activated platelets (14, 15). The coagulation cascade is triggered through both intrinsic and extrinsic pathways, ultimately generating thrombin. Thrombin then cleaves fibrinogen into fibrin and facilitates its aggregation into fibrin networks. In conjunction with platelet activation, a platelet plug seals the wound, reinforced by the fibrin networks (16, 17). In addition, the fibrin mesh serves as a provisional extracellular matrix that supports cell adhesion, proliferation, and differentiation, while also regulating inflammatory responses and innate immunity (18). Coagulation and innate immunity are tightly linked through reciprocal activation mechanisms at the wound site (16) ( Figure1A ).

Inflammation represents a coordinated immune response to tissue injury, involving a cascade of immune cell activities, with neutrophils and macrophages serving as the primary effector cells. Neutrophils are the earliest responders at this stage. Following injury, they migrate to the wound site and eliminate bacteria, foreign bodies, and necrotic tissue through phagocytosis. Subsequently, circulating monocytes are recruited to the wound, where they differentiate into macrophages that sustain phagocytosis and act as key regulators of the inflammatory response. Macrophages promote the recruitment and activation of additional innate immune cells by secreting mediators such as transforming growth factor-β (TGF-β), platelet-derived growth factor (PDGF), and platelet factor 4 (PF4) (19–21). In addition, macrophages release a range of activating factors, including transforming growth factor-α (TGF-α), fibroblast growth factor (FGF), and collagenase, which stimulate keratinocytes, fibroblasts, and endothelial cells to promote tissue repair and wound closure (22, 23). Through integrin-mediated interactions with the ECM, macrophages migrate into the wound bed and orchestrate local immune responses. Depending on microenvironmental cues, macrophages can polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes: M1 macrophages are primarily responsible for pathogen clearance and propagation of inflammation, whereas M2 macrophages contribute to tissue remodeling, angiogenesis, and resolution of inflammation (24). Other immune cells are also involved in this phase, including mast cells, which originate from hematopoietic progenitors and participate in early immune activation, though their recruitment generally follows that of neutrophils and macrophages (25). Overall, the inflammatory phase of wound healing, as an immune response to external stimuli, not only participates in pathogen clearance but also regu.ates the proliferation of cells involved in tissue repair, whose intensity and duration directly influence the subsequent healing process and final outcome (6, 25, 26) ( Figure 1B ).

The proliferative phase of wound healing follows the hemostatic and inflammatory phases, characterized primarily by re-epithelialization and granulation tissue formation, the latter involving both angiogenesis and fibroplasia (16, 22). Re-epithelialization is a dynamic, complex process governed by an active signaling network among various growth factors (GFs) and multiple cell types. Keratinocytes (KCs) play a central role in this process. At the wound margin, basal keratinocytes differentiate and migrate away from the wound bed, forming an epithelium that covers the exposed region (27). Concurrently, granulation tissue is established through the coordinated actions of newly formed capillaries, fibroblasts, and inflammatory cells, creating a temporary repair matrix that fills the wound defect. Vascular endothelial cells undergo proliferation, migration, and branching in response to various GFs, ultimately forming new blood vessels (28). Fibroblasts, as the primary producers of ECM proteins, are essential for maintaining skin structural integrity and physiological functions. They secrete factors that modulate macrophage inflammatory phenotypes, promote neovascularization, and stimulate the generation of granulation tissue, skin cells, and ECM components, playing a critical role during both the proliferative and remodeling phases of wound healing (29, 30). As new blood vessels form, fibroblasts proliferate and invade the fibrin network, generating contractile granulation tissue. Approximately one week after injury, activated fibroblasts gradually replace the clot, synthesizing and remodeling collagen-rich ECM and thereby transforming the wound environment from an inflammatory to a proliferative state (31). Moreover, macrophages recruited during the inflammatory phase phagocytose ECM components and cellular debris, signaling fibroblasts at the wound site to regulate ECM deposition and remodeling (16, 32). The newly formed ECM ultimately supports capillary ingrowth and connective tissue formation. The functional interplay between immune cells from the inflammatory phase and nascent tissues of the proliferative phase establishes the biological foundation necessary for the subsequent scar remodeling stage of wound healing ( Figure 1C ).

Scar remodeling represents the final phase of wound healing, during which the primary objective is the dynamic regulation of collagen metabolism and ECM remodeling to optimize the structure and functionality of scar tissue. Following the proliferative phase, fibroblasts remain central players. They secrete growth factors (GFs), cytokines, and chemokines to generate a provisional matrix rich in hyaluronan, fibronectin, and proteoglycans, which gradually replaces the initial fibrin matrix (33, 34). In addition, fibroblasts contribute to tissue remodeling and repair by interacting with immune-active cells and regulating neuropeptides at the injury site. Meanwhile, neovascularization progressively regresses, ECM deposition continues, and granulation tissue undergoes a dynamic balance between remodeling and degradation (35). The ECM is primarily composed of collagen, which is the most abundant structural protein in the human body. Matrix metalloproteinases (MMPs), secreted by fibroblasts, macrophages, and endothelial cells, promote collagen degradation, which not only prevents excessive accumulation of disorganized ECM but maintains its dynamic balance and integrity, thereby facilitating effective wound healing (36–38). Dynamic collagen subtype transitions, such as the gradual replacement of soft type III collagen with rigid type I collagen, form the basis of ECM remodeling. Together with sustained mechanical stress, this process ultimately gives rise to scar formation. In scar tissue, collagen fibers are arranged into smaller, parallel bundles rather than the mesh-like pattern characteristic of healthy dermis. Subsequently, myofibroblasts attach to collagen fibers at multiple sites, generating contractile forces that induce wound contraction and reduce scar surface area (35, 39). Therefore, the success of the remodeling phase relies on the coordinated activities of key cellular populations from the inflammatory and proliferative phases,ultimately culminating in the formation of well-organized scar tissue and complete wound closure ( Figure 1D ).

DFI is a major cause of wound infection and impaired healing in DFU, primarily due to pathogen invasion of the wound. Uncontrolled pathogens in infections can delay wound healing, increase the risk of amputation, and even cause systemic infection (40, 41). According to current statistics, the infectious pathogens are mainly microorganisms, which are divided into bacteria and fungi. Bacteria can be further classified as gram-positive, gram-negative, or anaerobic. Among fungi,Candida albicans (C. albicans) is the most common species, while filamentous fungi, though less frequent, also pose a risk of invasive infection in DFU ( Table 1 ).

• Gram-positive bacteria

In diabetic foot infections, several Gram-positive bacteria are frequently isolated, includingStaphylococcus,Streptococcus andEnterococcus. These organisms commonly appear in polymicrobial infections, particularly in chronic wounds (80). This section focuses on common Gram-positive strains such asStaphylococcus aureus(S. aureus), Group BStreptococcus(GBS),Enterococcus faecalism(E. faecalis) and non-pathogenic skin-resident colonizers.S. aureusis one of the most prevalent pathogens in DFI (42), found in both community-and hospital-acquired infections. Research from the University of Pennsylvania using Shotgun Metagenomics revealed thatS. aureus was detected in 94% of 100 DFU patients, and its abundance correlated linearly with healing duration (81). The increasing prevalence of methicillin-resistantS. aureus (MRSA) in DFI is concerning, as MRSA infections are associated with prolonged healing times and elevated amputation risk due to antibiotic resistance (43–45).S. aureus can cause a spectrum of infections in DFU, ranging from superficial epidermal involvement to deep osteomyelitis, often leading to persistent infection that impairs wound healing. Chronic infection prolongs inflammation, disrupts normal tissue repair, and increases the likelihood of severe complications such as osteomyelitis and amputation. Additionally,S. aureus can induce septic shock, particularly in immunocompromised diabetic patients, further complicating management. The biofilm produced byS. aureus protects the bacteria from immune clearance and antibiotic treatment, promoting infection persistence and recurrence (44, 46–49). Its virulence factors—including various proteases, hemolysins, and collagenases—enhance adhesion and invasion of wound tissue, creating a favorable environment for bacterial growth (50). Importantly, infections in DFU are rarely caused by a single organism; polymicrobial communities often coexist and act synergistically to exacerbate pathogenicity (40). GBS, a β-hemolyticStreptococcus, is also frequently reported in DFI. It often co-occurs in polymicrobial infections and is associated with poor healing outcomes and higher amputation rates (82) (51). β-hemolyticStreptococcus species are commonly implicated in necrotizing soft tissue infections (NSTIs) and cellulitis in DFU. These conditions are characterized by severe tissue necrosis, intense inflammation, and high rates of mortality and amputation. Some strains may exhibit antibiotic resistance, particularly to clindamycin, complicating clinical management (83–85). Evidence suggests that GBS often coexists withS. aureus in chronic wound infections, with their synergistic interactions exacerbating ulcer severity (84). In addition toS. aureus and GBS,Enterococcus species, particularlyE. faecalis, is important Gram-positive pathogens in diabetic foot infections. Global meta-analyses indicate thatEnterococcus prevalence ranges from 5.4% in aerobic culture studies to 7.1% when combined aerobic and anaerobic cultures are used, with slightly higher detection rates in high-income countries (52). In Chinese DFU cohorts,E. faecalis accounted for approximately 4.9% of all bacterial isolates, ranking third among Gram-positive bacteria (53).Enterococci frequently co-exist with Gram-negative pathogens such asP. aeruginosa,Escherichia coli (E. coli), andMorganella morganii, contributing to polymicrobial infections in DFU.In vitro studies have further revealed thatE. faecalis can gain a significant growth advantage when co-cultured with Gram-negative bacteria, particularlyP. aeruginosa, under wound-like microenvironments,which may enhance bacterial persistence and promote the chronicity of infection (54). Non-pathogenic skin commensals, including coagulase-negativeStaphylococci,Corynebacterium, andPropionibacterium, are also commonly present in DFU wounds. While generally non-pathogenic, these bacteria may exacerbate chronic wounds by providing niches for pathogenic bacteria or interacting with them within the wound microenvironment (10, 40, 48, 55). Transitioning to the next section, Gram-negative bacteria are another crucial group of pathogens contributing to the complexity of DFI and will be discussed in detail. In addition to the previously discussed Gram-positive bacteria, these pathogens significantly contribute to the complexity of infections by often coexisting with other microorganisms.

• Gram-negative bacteria

Following Gram-positive bacteria, Gram-negative bacteria also play a critical role in DFI and are predominant pathogens in some regions. Studies have shown that Gram-negative bacteria such asPseudomonas aeruginosa (P. aeruginosa) andEnterobacteriaceae are more frequently isolated from DFI than Gram-positive bacteria. Their ability to form biofilms contributes to infection chronicity and enhances resistance to host immune responses and antibiotic therapy. Epidemiological data indicate thatS. aureus is the most prevalent pathogen in DFU in Western countries, whileP. aeruginosa predominates in Asia and Africa (56, 57). DFU involvingP. aeruginosa generally have a poor prognosis if not managed appropriately. Due to its multidrug resistance, including resistance to beta-lactams, treatment often requires combination therapy (58, 59). According to the latest IWGDF 2023 guidelines on the prevention and management of diabetes-related foot disease,P. aeruginosa andS. aureus are commonly involved in chronic and severe DFI, and their symbiotic interaction exacerbates infection severity (60, 86). Both species belong to theEnterococcus faecium,S. aureus,Klebsiella pneumoniae,Acinetobacter baumannii,P. aeruginosa and Enterobacter ssp. (ESKAPE) group of pathogens, which are notorious for multidrug resistance to commonly used antibiotics (61). In vitro experiments have also shown that mixed infections of P. aeruginosa and S. aureus exhibit greater virulence than infections with either species alone, with co-infection potentially protecting them from certain antibiotics (87). P. aeruginosa forms biofilms that enhance its persistence in the wound environment and resistance to immune clearance and antibiotic therapy, making it a key pathogen in chronic, non-healing DFU. It secretes various enzymes and toxins, such as elastase and exotoxin A, which degrade host tissues and exacerbate inflammation (62). In addition,Enterobacteriaceae such asE. coli,Klebsiella pneumoniae, andProteus species are reported in DFI.Klebsiella pneumoniae is particularly concerning due to its broad-spectrum antibiotic resistance and production of extended-spectrum beta-lactamases (ESBLs), complicating treatment and often requiring more aggressive, broad-spectrum antibiotics, especially for severe infections (41, 63).

In addition to Gram-positive and Gram-negative bacteria, anaerobic bacteria also play a critical role in the occurrence and progression of DFI. In the next section, the types of anaerobic bacteria and their pathogenic mechanisms will be discussed.

• Anaerobic bacteria

Although multiple studies have confirmed the presence of anaerobes in DFI, their pathogenic role has long been underestimated due to the low sensitivity of conventional culture methods and limited research data. In recent years, the application of molecular diagnostic techniques has significantly improved the detection rate of anaerobes, with studies reporting a true detection rate as high as 83.8% in DFI (64–66). A study from Meir Medical Center, demonstrated that in 31 hospitalized DFI patients, anaerobic bacteria were detected in 26% of samples by conventional culture, 59% by 16S rRNA sequencing, and 76% by metagenomic sequencing. Predominant genera includedPeptoniphilus,Bacteroides,Clostridium,Prevotella, withBacteroides andPrevotella being the most common species (67). Notably,Bacteroides abundance was significantly associated with increased amputation risk (59, 68). Moreover, antibiotic resistance is a growing concern, with approximately 40% ofBacteroides isolates resistant to clindamycin, and the recurrence rate of mixed infections being 2.1 times higher than that of pure aerobic infections (66, 69). Anaerobic bacteria exhibit specific pathogenic mechanisms. For instance, both Bacteroides andPrevotella secrete proteases and hyaluronidases that degrade the extracellular matrix (66); Peptoniphilus reinforce biofilm structural stability, impeding antibiotic penetration (70); Clostridium-derived short-chain fatty acids inhibit epithelial cell migration while perpetuating inflammatory responses (71). Interactions among these pathogenic processes disrupt the homeostasis of the wound microenvironment, exacerbating tissue healing disorders. In early-stage ulcers, superficial wounds with sufficient oxygen limit anaerobic growth, so infection is primarily dominated by aerobic or facultative anaerobic bacteria. In deeper tissue infections, anaerobes contribute to cellulitis, lymphangitis, abscesses, gangrene, and involvement of muscles, tendons, and bones, often leading to systemic toxicity with fever. During this stage, the likelihood of isolating anaerobic bacteria is high (48, 66). The abundance of anaerobes is positively correlated with infection severity and poor wound healing outcomes (65, 72). Clinically, anaerobic infections are associated with delayed healing; for example, a high baseline abundance of Peptostreptococcus is directly linked to wound closure disorders (65).

Overall, these findings highlight the critical role of anaerobic bacteria in DFI, their contribution to poor clinical outcomes, and the necessity of molecular detection techniques for accurate diagnosis and management. The following section will focus on recent advances regarding fungal involvement in DFI.

• Fungi

Following the discussion on bacterial pathogens in DFI, this section focuses on the epidemiology and pathogenic role of fungi in diabetic foot infections. Studies have shown that the prevalence and pathogen distribution of fungal infections vary significantly across different regions. In diabetic patients, particularly those with foot complications, the prevalence of cutaneous fungal infections, such as tinea pedis and onychomycosis, is significantly higher than in the general population. These localized infections can compromise the skin barrier, serving as a potential trigger for DFU (73). In addition, a review analyzing data from 112 studies found that the prevalence of fungal infections in DFU was approximately 2.0%, typically occurring as opportunistic infections secondary to prolonged antibiotic use (74). Regional differences in fungal pathogens of the infections are pronounced. For example,Trichophyton rubrum is the predominant cause of skin fungal infections in Iran and Tunisia (78.8% and 80.1%, respectively), commonly presenting asonychomycosis on the foot and only a relatively low percentage of interdigitaltinea, followed byCandida albicans (C. albicans). In contrast, in Croatia, the main pathogenic fungi associated with DFI are found in the genusCandida (such asC. albicans,Candida paraphernata, andCandida tropicalis) (75, 88–90). C. albicans showed cross-regional prevalence in the studies mentioned above and was often associated with bacterial infections, particularly Gram-positive bacteria (such asS. aureus) (76). A significant symbiotic relationship exists betweenC. albicans and bacterial species profoundly influencing infection dynamics. For instance,C. albicans secretes quorum-sensing molecules (such as farnesol) that promote bacterial biofilm formation, whereas bacterial metabolites (such as succinic acid) enhance fungal virulence (48). This polymicrobial interaction complicates treatment by modifying the wound biofilm structure, thereby increasing resistance to both antibiotics and antifungal agents (75). Moreover, the hyperglycemic milieu in diabetic patients creates an optimal environment for fungal proliferation, particularly under moist foot conditions and in the presence of skin barrier disruption caused by diabetic neuropathy, which exacerbates infection severity (77, 78). Experimental studies have demonstrated that hyperglycemia combined with C. albicans infection mediates oxidative stress, activating the NLRP3 inflammasome, which triggers pyroptosis and apoptosis in infected tissues, promoting the release of pro-inflammatory cytokines such as IL-1β and IL-18, thus aggravating DFI (79). Clinically,C. albicans infections manifest as superficial infections, such as interdigital erosions, or as deep invasive infections like osteomyelitis, often accompanied by systemic inflammatory responses (76).

In summary, fungi, particularlyC. albicans, play a critical role in diabetic foot infections pathogenesis. Their interactions with bacterial pathogens, along with hyperglycemic conditions and impaired skin barriers, contribute to increased infection severity and complicate treatment strategies.

In DFU, microbial infection disrupts immune cell functions, particularly macrophage polarization, leading to an exaggerated inflammatory phase. The imbalance between pro-inflammatory M1 and reparative M2 macrophages is central to chronic inflammation pathogenesis (133). The hyperglycemia in the diabetic milieu exacerbates the imbalance (134, 135), while infection further amplifies this imbalance through pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). These molecules activate multiple signaling cascades, thereby promoting excessive M1 macrophage polarization (136). Additionally, infection enhances reactive oxygen species (ROS) production via NADPH oxidase and activates CD38–NAADP signaling, promoting M1 polarization independently of TLR pathways (137). Signal transducers and activators of transcription (STATs) also critically regulate macrophage polarization. STAT1 sustains M1 macrophage polarization, whereas STAT6 promotes M2 macrophage polarization. Their mutual exclusivity under infection favors STAT1 dominance, disrupting the balance (138). Fungal pathogens exacerbate inflammation through NLRP3 inflammasome activation, and inhibition of NLRP3 and downstream inflammatory mediators offers a promising therapeutic target (139) (140). During infection, metabolic changes reduce the expression of chemokines, impairing the recruitment of neutrophils and macrophages, leading to their prolonged retention in local tissues. The latter prolongs the inflammatory response phase and impairs tissue repair (141). Neutrophils activated by pathogens release neutrophil extracellular traps (NETs), which are web-like chromatin structures coated with nuclear proteins. These structures physically trap pathogens, triggering NETosis and robust ROS release. A high level of ROS ultimately damages endothelial cells and fibroblasts, which inhibits angiogenesis and delays wound healing (142) ( Figure 2A ).

During the proliferative phase, the dual pathological challenges of diabetes and microbial infection exacerbate extracellular matrix (ECM) degradation and impair angiogenesis ( Figure 2B ).

Microbial imbalance drives ECM degradation——During wound healing, anaerobes and gram-negative bacteria infecting the wound (such asBacteroides andProteobacteria) activate inflammation signaling pathways, including toll-like receptor 2 (TLR2), which stimulates the release of pro-inflammation cytokines. The cascade further upregulates matrix metalloproteinases (MMPs), resulting in aberrant degradation of ECM components (143, 144). Studies have revealed that infections in DFU, particularly those involving biofilm-forming bacteria, induce elevated levels of active MMP-9, impairing physiological ECM formation (145). Moreover, decreased expression of diabetes-associated heat shock proteins may compromise cellular repair mechanisms and exacerbate ECM metabolic imbalance (143). Accumulated reactive oxygen species (ROS) within the wound microenvironment suppress fibroblast function by inhibiting the activation of the TGF-β/Smad signaling pathway, leading to reduced procollagen synthesis and impaired ECM deposition (146). The dysregulated inflammatory response in diabetic patients further aggravates the imbalance of angiogenic factors (147), with microbial infections promoting pro-inflammatory cytokine release, worsening this effect (148).

Angiogenesis disorder——Research indicates that extracellular DNA and toxins produced by bacterial infections, such asS. aureus alpha-toxin, directly damage vascular endothelial cell membranes, inhibit VEGF and bFGF expression, and hinder angiogenesis (149). Upregulation of PCSK9 in diabetic wounds promotes VEGFR2 ubiquitination and degradation, causing failure of angiogenic factors (150). Concurrently, ROS accumulation is a key factor in diabetic endothelial dysfunction, and ROS generated in the microbial environment further exacerbate this process (151). Tissue ischemia and hypoxia in wounds decrease oxygen partial pressure, leading to increased HIF levels that promote facultative anaerobe proliferation. Anaerobic infection favors local biofilm formation, which, combined with hypoxia, inhibits angiogenesis (91, 143, 152). Recent studies indicate that during diabetic wound healing, senescent fibroblasts exhibit impaired proliferative capacity and are unable to synthesize essential ECM components; meanwhile (153), the accumulation of senescent cells releases SASP factors that inhibit endothelial cell proliferation and migration, whereas clearance of senescent cells can accelerate healing (154).

Cross-phase dynamics in wound healing of DFU——Regardless of wound type, healing stages temporally overlap and interact dynamically. The hemostasis and remodeling phases are not discussed separately here because the hemostasis phase occurs immediately post-injury (0–2 hours), focusing on hemostasis and growth factor release (155). Infection control depends on neutrophil and macrophage infiltration during the subsequent inflammatory phase (6–48 hours post-injury) (156), initiated after hemostasis. Prolonged inflammation and impaired proliferation disrupt transition to the remodeling phase (157). The persistent non-healing of DFU centers on chronic hyperinflammation and vascular regeneration deficits, emphasizing the need to reconstruct microvascular networks while inhibiting pathological inflammatory cascades, highlighting their significant impact on healing.

• Glycemic control

Maintaining appropriate blood glucose levels is a cornerstone in the management of DFU. Hyperglycemia not only exacerbates tissue injury but also suppresses immune responses, thereby impairing the body’s ability to fight infections and repair wounds. Sustained and moderate glycemic control can improve endothelial function and create a more favorable microenvironment for wound healing. While some recent reviews have reported inconsistent outcomes with intensive glycemic control, observational studies consistently support its role in enhancing immune function and reducing complication risks (5, 158, 159). Research has shown that hyperglycemia activates the polyol pathway, leading to microcirculatory dysfunction (5), and that a rapid decrease in HbA1c (2% over 3 months) may result in treatment-induced neuropathy (160). Diabetic peripheral neuropathy (DPN), a major risk factor for DFU, can be alleviated by optimal glycemic control (161, 162). Therefore, clinical guidelines recommend maintaining inpatient blood glucose levels between 140–200 mg/dL to balance wound healing promotion while minimizing the risk of hypoglycemia (163).

In conclusion, precise glycemic control strategies are fundamental to the success of DFU treatment and form the foundation for subsequent infection control, vascular restoration, and local wound care.

• Antimicrobial therapy

Antimicrobial therapy is an essential component of the systematic management of DFI, particularly in the context of polymicrobial colonization and antimicrobial resistance. The most common pathogens includeS. aureus (including MRSA), Pseudomonas aeruginosa, and various anaerobes (164). The choice of antimicrobial therapy is primarily guided by authoritative recommendations such as the International Working Group on the Diabetic Foot (IWGDF) infection guideline and the Infectious Diseases Society of America (IDSA) guideline, which recommend tailoring antibiotic regimens according to infection severity, clinical manifestations, and microbiological findings: narrow-spectrum agents such as cephalexin are suggested for mild infections, whereas broad-spectrum antibiotics such as piperacillin-tazobactam or vancomycin are indicated for moderate to severe or extensive infections (165); in the absence of clinical evidence of soft tissue or bone infection, antibiotic use is not recommended (166). Furthermore, in cases of severe DFI, or moderate infection complicated by extensive gangrene, necrosis, deep abscesses, compartment syndrome, or severe limb ischemia, urgent surgical consultation is advised (167). Recent studies have shown that selecting antibiotics based on microbiological culture results prior to initiating therapy can significantly improve treatment outcomes (168), a practice that has been endorsed in the previous guidelines. Collectively, these findings highlight that balancing “avoiding undertreatment” with “minimizing resistance and adverse effects” remains a key clinical challenge, requiring further high-quality evidence. Furthermore, a systematic review published the same year found no significant differences in amputation or remission rates between short-course (<6 weeks) and long-course (>6 weeks) regimens in diabetic foot osteomyelitis (DFO), with fewer adverse events in the short-course group (169). A 2025 expert review further noted that for DFO without surgical debridement, antimicrobial therapy beyond 6 weeks is unnecessary; in patients who have undergone debridement, a 3-week course is not inferior to a 6-week course (170). Another review supports that antimicrobial therapy for soft tissue infections should not exceed 2 weeks, and extending the course does not reduce microbiological failure or recurrence risk (171).

Despite its pivotal role in DFI management, antimicrobial therapy still faces major challenges, including the high prevalence of MRSA and multidrug-resistant Gram-negative bacteria, as well as the polymicrobial and recurrent nature of infections. Therefore, rational, evidence-based selection of antimicrobial agents and treatment duration, combined with surgery and comprehensive care, remains central to the effective management of DFI.

• Offloading for pressure relief

Offloading is a critical component of DFU management, essential for promoting ulcer healing and preventing disease progression. Prolonged mechanical pressure impairs local blood flow and induces tissue damage, significantly delaying wound repair (172) (173). Common offloading strategies include casts, therapeutic footwear, orthotics, felt padding, and foam dressings (174). For neuropathic foot ulcers, total contact casts or non-removable knee-high offloading braces are considered the gold standard, as they offer consistent and effective pressure redistribution (173). Studies have demonstrated that non-removable devices significantly outperform their removable counterparts with equivalent mechanical design, improving overall DFU healing rates by 43% (RR = 1.43, 95% CI: 1.11–1.84) and reducing average healing time by 8–12 days (175). More recently, personalized offloading devices incorporating modular mechanical features—such as rocker soles, knee-high shells, and adjustable struts—have emerged as innovative solutions tailored to individual patient needs (176).

• Wound debridement and revascularization

Wound debridement and revascularization are essential components of DFU management, aimed at establishing a viable wound bed and restoring adequate blood supply.

Debridement involves the removal of necrotic and non-viable tissue from the wound site, thereby facilitating the healing process (166). Surgical debridement remains a cornerstone in DFU treatment, particularly in cases involving severe infections or osteomyelitis, as it effectively reduces bacterial burden and promotes tissue recovery (159). It is generally recommended to perform debridement every 1 to 4 weeks, depending on wound progression (177). Combining debridement with negative pressure wound therapy (NPWT) has been shown to enhance necrotic tissue removal and promote granulation tissue formation (178). Additionally, debridement plays a critical role in infection control by eliminating biofilm-laden foci, disrupting barriers to antibiotic penetration, and restoring immune function (179).

Adequate tissue perfusion is equally critical to ensure healing and prevent progression to severe infection. Therefore, comprehensive screening for peripheral artery disease (PAD) and vascular assessment should be standard in DFU management protocols (180). For patients with PAD, revascularization procedures—such as angioplasty—can significantly improve limb perfusion (181). Even in the presence of high biomechanical stress, extensive tissue loss, or severe infection, revascularization remains a feasible strategy when guided by the Wound, Ischemia, and foot Infection (WIfI) classification system, which supports clinical decision-making through stratified risk assessment (182).

In conclusion, integrating regular debridement and vascular intervention into DFU management is vital to enhance wound healing, control infection, and reduce the risk of limb amputation.

In the management of DFU, individualized topical dressing therapy plays a crucial role. These dressings not only provide a physical barrier for wound protection but also help maintain a moist environment and facilitate exudate drainage (183). Traditional dressings, such as gauze, can absorb wound exudate and provide basic coverage, but they are limited in addressing infection or adapting to the dynamic wound microenvironment (184). This review focuses on literature published in the past five years to highlight the latest innovations in personalized DFU dressings and their potential clinical relevance. The rationale for focusing on this period is that the DFU dressing field has experienced rapid technological development, particularly in the emergence of smart responsive hydrogels, multifunctional nanofiber membranes, and oxygen-releasing or bioactive composite dressings. These recent studies also provide the most clinically relevant evidence for practice and future research. Furthermore, bibliometric analysis indicates that approximately 70% of innovative DFU dressing studies were published within the past five years (PubMed search using keywords “DFU” and “dressing”), highlighting that the latest scientific findings and technological advances are concentrated in this period. Over this period, notable advances have been made in intelligent dressings that combine controlled drug delivery, multifunctional components, and microenvironment modulation. For clarity, these dressings can be broadly described under three categories, though many modern designs integrate multiple functions.