Antimicrobial Strategies for Chronic Cutaneous Ulcers: From Preclinical Nanotechnology to Clinical Practice

Abstract

Chronic cutaneous ulcers represent a growing global public health challenge, affecting an estimated 1–2% of the population in high-income countries and imposing a substantial socioeconomic burden through prolonged hospitalizations, repeated outpatient visits, increased risk of amputation, and significant impairment of patients’ quality of life. Standard wound care centered on debridement, moisture-balancing dressings, and systemic antibiotics fails to resolve a large proportion of cases, particularly those complicated by polymicrobial biofilm infection and antimicrobial resistance, underscoring an urgent need for more effective therapeutic strategies. Despite the growing body of work on individual therapeutic modalities, no prior review has jointly evaluated clinically validated adjunct therapies and preclinical nanoplatform evidence for chronic cutaneous ulcers within a single, biofilm-ecology-centered framework, the gap this review addresses. This review critically evaluates current clinical and preclinical advances in the treatment of chronic cutaneous ulcers, with a focus on novel therapeutic modalities and emerging nanotechnology-based approaches. Clinically, the available evidence indicates that low-intensity ultrasound, electrical microcurrent therapy, photodynamic therapy, regenerative biomaterials, oxygen-based interventions, and advanced topical therapies may improve wound contraction, reduce microbial burden, relieve pain, and enhance tissue repair when used as adjuncts to standard care. At the preclinical level, metallic, polymeric, inorganic, and hybrid nanoplatforms can simultaneously target resistant bacteria and biofilms, stimulate angiogenesis, regulate inflammatory signaling, and support extracellular matrix remodeling. Recent advances in ulcer therapy are moving the field beyond passive wound coverage toward mechanism-driven treatments that actively modulate the chronic wound microenvironment. Despite this progress, current clinical evidence remains inconsistent and is often limited by small patient cohorts and non-standardized protocols. This highlights the pressing need for rigorous translational research to incorporate multifunctional bioactive platforms into well-supported, ulcer-specific therapeutic strategies.

Chronic Cutaneous Ulcers: Definition, Ecology, and Conventional Management

Definition and General Characteristics

Clinically and pathophysiologically, cutaneous ulcers are broadly divided into acute and chronic categories, a separation based on duration, depth, tissue response, and the persistence of damaging stimuli. Acute cutaneous ulcers typically develop rapidly after a discrete skin insult. These insults may include mechanical trauma, brief ischemic episodes, thermal or chemical injury, or transient infection. These lesions are generally shallow, well-defined, and accompanied by localized pain and inflammation, yet they retain intact reparative capacity. When the inciting factor is removed, and appropriate wound care is administered, acute ulcers typically progress through the conventional phases of wound healing and close within a relatively short timeframe, often without notable scarring or functional loss.¹ This burden is compounded by the global rise in diabetes, the leading driver of chronic lower-extremity ulceration: an estimated 529 million people were living with diabetes worldwide in 2021, according to the Global Burden of Disease Study.²

Chronic cutaneous ulcers are defined as localized losses of skin integrity that extend beyond the epidermis into the dermis and, in many cases, the underlying subcutaneous tissue, resulting in a true ulcer rather than a superficial wound. As with other ulcerative disorders, the extent of tissue involvement dictates biological behavior, healing capacity, and the likelihood of recurrence.³

The chronic cutaneous ulcers represent a distinct pathological entity rather than merely a prolonged acute wound. By definition, they persist for more than 6 weeks and infiltrate deeper tissue layers, frequently exhibiting fibrotic or indurated borders, necrotic tissue, and compromised granulation tissue. Such ulcers develop in the setting of ongoing tissue stress: prolonged pressure, repeated mechanical loading, persistent ischemia, metabolic disturbances, or continual infection.⁴ Clinically, they are marked by delayed healing, frequent recurrence, and an elevated risk of complications such as secondary infection and chronic inflammation.⁵

A defining feature of chronic cutaneous ulcers is their propensity to harbor microbial communities organized as biofilms. Unlike fleeting contamination, biofilm‑associated organisms persist within the wound milieu, sustaining a pro‑inflammatory environment and impeding normal tissue repair. This microbial tenacity contributes to therapeutic resistance and sets chronic ulcers apart from acute lesions, which usually resolve once the microbial load is controlled. Consequently, chronic cutaneous ulcers should be viewed as biologically stabilized lesions maintained by ongoing pathological processes rather than as wounds that have simply failed to close.⁶

The mechanisms that perpetuate chronicity are intricate and highly interrelated. Persistent tissue injury (whether from recurrent mechanical stress, sustained ischemia, or continual exposure to microbial virulence factors) prevents the wound bed from stabilizing, trapping the tissue in a prolonged inflammatory phase. Simultaneously, protective and reparative systems are compromised: barrier function is weakened, extracellular matrix production declines, and epithelial migration is impaired, all of which diminish the skin’s capacity to re‑establish integrity.⁷ Fibroblast dysfunction further restricts collagen deposition and wound contraction, while disrupted signaling among keratinocytes, immune cells, and stromal elements undermines coordinated healing, lowering the threshold for additional injury.^8,9

Microvascular dysfunction is among the earliest and most critical contributors to ulcer chronicity. Reduced perfusion limits oxygen and nutrient delivery, creating a hypoxic microenvironment that, when sustained, promotes apoptosis and impairs cellular metabolism. This inadequate circulation hampers both immune defense and regenerative potential, fostering ulcer persistence.⁹

Chronic inflammation amplifies tissue damage by maintaining the recruitment of neutrophils and other inflammatory cells, which generate a continuous stream of reactive oxygen species and proteolytic enzymes. These mediators degrade extracellular matrix components and harm surrounding viable tissue, while excessive protease activity disrupts growth‑factor signaling and impairs fibroblast function, shifting inflammation from a reparative to a destructive role.¹⁰

Biofilm formation at the ulcer surface further stabilizes the chronic state. Biofilms shield resident microorganisms from host immunity and impede antimicrobial penetration, allowing microbes to endure within the wound niche, perpetuate inflammation, and prevent eradication of underlying triggers. The interplay among microbial persistence, immune dysregulation, and defective tissue repair establishes a self‑reinforcing loop that is difficult to disrupt with conventional therapies.⁶

Overall, chronic cutaneous ulcers are sustained by a dynamic interaction of ongoing injury, compromised defense mechanisms, microvascular insufficiency, persistent inflammation, and microbial biofilm formation. This self‑perpetuating cycle of damage and inadequate repair fundamentally separates chronic ulcers from acute, self‑limited wounds and underlies the substantial clinical challenge they present.

Ecology as Influential Actors in Chronic Ulcers

Chronic cutaneous ulcers are now understood as complex ecological systems in which microbial communities, host tissue and immune responses co-evolve, rather than being driven by a single pathogen. Most chronic wounds harbor polymicrobial consortia organized in biofilms that interact dynamically with a hypoxic, inflamed, and metabolically altered microenvironment. This ecological perspective helps explain why standard culture, systemic antibiotics, and conventional dressings often fail to restore healing, and it frames new avenues for targeted, microbiology-informed interventions.

Ecology of Chronically Infected Ulcers

A breach in the skin barrier exposes subcutaneous tissue to the external environment and resident skin microbiota, initiating colonization of the wound bed. In acute wounds with intact host defenses, low-level colonization does not impede orderly progression through hemostasis, inflammation, proliferation, and remodeling, and microbial populations remain relatively sparse and dynamic. By contrast, chronic ulcers, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLU), pressure injuries (PU), and hidradenitis suppurativa lesions, are characterized by prolonged inflammation, persistent microbial colonization and biofilm formation, and failure to re-epithelialize.¹¹

The wound microenvironment is a key ecological driver of microbial composition and behavior. Chronic wounds are typically hypoxic or even anoxic, with steep oxygen gradients from the surface to deeper tissues, high protease activity, accumulated necrotic debris, and variable pH. Hypoxia, in particular, selects for facultative and obligate anaerobes and profoundly alters bacterial metabolism, favoring fermentative and anaerobic respiratory pathways that support long-term survival in nutrient-limited niches. This oxygen limitation also reduces the efficacy of many antibiotics that require active aerobic metabolism or oxygen-dependent uptake, thereby reinforcing persistence.^12,13

Sources of colonizing microorganisms include the surrounding skin microbiota, mucosal sites, the hospital environment, and occasionally hematogenous seeding. The normal skin microbiome is dominated by Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes, with strong site specificity (sebaceous, moist and dry niches), and the foot skin in particular shows low temporal stability and high interindividual variability. These baseline communities are reshaped by tissue damage, exudate, and repeated antimicrobial exposure into a wound-associated microbiota that is often less diverse but enriched in opportunistic pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus spp., Enterobacteriaceae, and a broad range of anaerobes.¹⁴

Chronic wound ecology is also strongly shaped by polymicrobial interactions. Cooperative relationships, such as cross-feeding of metabolic by products, shared exopolysaccharide matrix production, and quorum-sensing crosstalk, can enhance collective fitness and tolerance to host defenses and antimicrobials. Conversely, antagonistic interactions (eg, bacteriocin production, resource competition) may suppress some species while selecting for others better adapted to the inflammatory niche. This dynamic “interactome bed” helps explain why microbiota composition differs between wound types and over time, even within a single patient, and why transitions from colonization to clinically overt infection is difficult to predict based solely on culture results.¹⁵

Microbiota Composition and Biofilm Formation in Chronic Wounds

Microbiota refers to the community of microorganisms that live naturally in a given environment, including bacteria, fungi, and other microbes. In wounds, its composition can shift and contribute to balance, inflammation, or chronicity depending on whether beneficial or pathogenic species predominate.¹⁶

Culture-based studies and, more recently, next-generation sequencing (NGS) have shown that chronic wound microbiota are polymicrobial and structurally complex. Across ulcer types, S. aureus, P. aeruginosa, Proteus mirabilis, Klebsiella pneumoniae, Enterococcus spp., and Escherichia coli are among the most frequently detected pathogens, often co-colonizing the same lesion. Anaerobes such as Anaerococcus, Finegoldia, Peptoniphilus, Prevotella and Bacteroides are highly prevalent, particularly in pressure injuries and deep DFUs, yet are routinely under-detected by standard aerobic culture. NGS-based studies consistently reveal greater richness and evenness than culture alone, highlighting the contribution of fastidious and low-abundance taxa to community structure.¹²

Comparative work suggests that while DFUs, venous ulcers, pressure ulcers and hidradenitis suppurativa lesions share many core taxa, their microbiomes differ in relative abundance patterns, likely reflecting differences in local perfusion, anatomical site, moisture, and host comorbidities. For example, venous leg ulcers and hidradenitis suppurativa lesions often show high loads of Gram-negative rods and anaerobes, whereas superficial pressure injuries may be dominated by skin-derived Gram-positive cocci. The dominance of specific anaerobic genera such as Anaerococcus and Finegoldia has been associated with delayed healing in pressure injuries, underscoring the pathogenic potential of organisms traditionally considered “commensals”.¹⁷

A defining feature of chronic wound microbiota is their organization into biofilms. Histologic and microscopic analyses estimate that biofilms are present in approximately 80% of chronic wounds but only a minority of acute wounds, though these figures likely underestimate true prevalence because biofilms are patchily distributed and sampling methods vary.¹⁸ Bacterial cells within wound biofilms are embedded in a self-produced extracellular polymeric substance (EPS) composed of polysaccharides, proteins, lipids and extracellular DNA (eDNA). eDNA not only contributes to matrix structure and cohesion but also binds antimicrobial agents and cationic host molecules, thereby limiting their activity.¹⁹

Biofilm formation on wounds proceeds through stages: initial attachment of planktonic cells to exposed tissue or devitalized material, microcolony formation, EPS production and maturation into three-dimensional structures with water channels and eventual dispersal of cells or aggregates to seed new sites. In chronic wounds, these stages occur in a highly heterogeneous landscape, producing a mosaic of biofilm “islands” interspersed with more sparsely colonized areas. Mixed-species biofilms are common; for instance, P. aeruginosa can create an anoxic sub environment that benefits obligate anaerobes, while staphylococci and streptococci contribute additional matrix components and immunodulatory factors.²⁰

Clinically, biofilm presence correlates with increased exudate, slough, hypergranulation, malodor, and failure of standard care, even when overt signs of acute infection (erythema, warmth, purulence) are muted. Traditional culture techniques, which dislodge and disperse biofilm aggregates, seldom capture the spatial organization, metabolic heterogeneity, or true taxonomic diversity of biofilm communities. This diagnostic blind spot has contributed to the under recognition of biofilms as central drivers of chronicity.²¹

Persistence of Inflammation and Local Immune Dysregulation

Normal wound healing requires a tightly regulated inflammatory phase, during which neutrophils and monocytes clear contaminants and dead tissue before yielding to proliferative and remodeling processes. In chronic ulcers, this phase becomes stalled: neutrophils and macrophages accumulate in large numbers, pro-inflammatory cytokines remain elevated, and the transition to a reparative milieu fails to occur.²²

Inflammation is a normal and essential component of wound repair, but in the context of chronic wounds it becomes excessive, prolonged, and poorly resolved. Rather than protecting the tissue and promoting clearance, persistent inflammation maintains a hostile local environment that impairs cell migration, matrix repair, and re-epithelialization. In this setting, inflammation is not a sign of effective healing, but a marker of dysregulated host response that contributes to wound chronicity.²³

Biofilm–innate immune interactions are pivotal in this dysregulation. Biofilm bacteria express pathogen-associated molecular patterns (PAMPs) that engage pattern-recognition receptors on neutrophils, macrophages and other cells, eliciting chemotaxis and activation. Once recruited, neutrophils attempt to phagocytose biofilm aggregates but are often unable to ingest the large, matrix-embedded clusters, resulting in “frustrated phagocytosis”. This leads to excessive release of reactive oxygen species (ROS), proteases (eg, elastase, matrix metalloproteinases) and neutrophil extracellular traps into surrounding tissue, causing collateral damage to extracellular matrix, growth factors and viable cells.²⁴

Macrophages in chronic wounds show skewing toward a pro-inflammatory (M1) phenotype, with persistent production of tumor necrosis factor-α, interleukin-1β and other mediators and an insufficient transition to the pro-resolving (M2) phenotype needed for matrix deposition and angiogenesis. Bacterial products, including quorum-sensing molecules and secreted toxins from S. aureus and P. aeruginosa, further modulate macrophage and keratinocyte responses, promoting chronic low-grade inflammation rather than clearance.²⁵

Hypoxia and anaerobic metabolism also influence host immunity. Oxygen limitation in chronic wounds impairs the oxidative killing mechanisms of neutrophils and macrophages and favors anaerobic bacteria, whose fermentation products can modulate local pH and immune cell function. Facultative and obligate anaerobes prevalent in chronic wounds are increasingly recognized as active contributors to inflammation and tissue injury rather than innocent bystanders.²⁶

At the tissue level, this dysregulated inflammatory environment disrupts key healing processes. Excessive protease activity degrades fibrin clots, provisional matrix, and growth factors, while persistent ROS damages cell membranes and DNA, leading to senescent fibroblasts and keratinocytes with reduced proliferative capacity.²⁷ Epigenetic reprogramming of resident cells has also been implicated in sustaining non-resolving inflammation and impaired epithelial-mesenchymal transition in chronic ulcers.²⁸

Collectively, these interactions create a self-reinforcing loop: biofilms provoke an exaggerated but ineffective innate immune response; the resulting tissue damage and nutrient release further support microbial growth and biofilm expansion; and the wound remains trapped in a chronic inflammatory state.

Antimicrobial Resistance and Therapeutic Failure of Conventional Treatments

Antimicrobial resistance (AMR) is the ability of microorganisms to survive or continue multiplying despite exposure to antimicrobial agents that would normally inhibit or kill them, typically through acquired resistance genes or other resistance mechanisms. In chronic wounds, AMR reduces the effectiveness of conventional antibiotics and often coexists with biofilm-associated tolerance, making these infections especially difficult to eradicate.²⁹

Chronic wound microbiota not only exist in protective biofilm structures but also frequently harbor acquired AMR determinants.³⁰ Surveys of chronic ulcers, including venous leg ulcers and hidradenitis suppurativa lesions, reveal high rates of resistance among S. aureus (including methicillin-resistant S. aureus, MRSA), Enterobacteriaceae and non-fermenting Gram-negative rods, often with multidrug-resistant phenotypes.³¹ In one comparative study, both wound types showed substantial colonization with resistant Gram-positive and Gram-negative organisms, emphasizing the need for local resistance surveillance to guide empirical therapy.¹⁷

However, AMR in chronic wounds cannot be understood solely in terms of classical resistance genes. Biofilm growth itself confers a profound tolerance to antibiotics and antiseptics. Within biofilms, limited penetration of drugs through the EPS matrix, binding of cationic agents to eDNA and polysaccharides, steep gradients of nutrients and oxygen, and the presence of metabolically dormant “persisted” cells all reduce the killing efficacy of agents that are active against planktonic bacteria.³² Phenotypic heterogeneity means that a fraction of cells can survive even high antibiotic concentrations, later re-establishing the biofilm once treatment is withdrawn.³³

Systemic antibiotics are frequently prescribed for suspected chronic wound infection, yet they often fail to resolve clinical signs or eradicate colonizing organisms, particularly when biofilms are present.³⁴ A systematic review of topical modalities for managing wound biofilms found that while several antiseptic agents and advanced dressings could reduce microbial load and improve healing metrics, none consistently eradicated biofilm across trials, highlighting the resilience of these communities. Agents such as polyhexanide, hypochlorous acid, and other modern antiseptics can be beneficial components of a multimodal regimen, but their effectiveness is influenced by organic load, biofilm maturity, and application technique.³⁵

Overuse and misuse of systemic antibiotics in chronic wound care contribute to the broader development of AMR. Hurlow and Bowler emphasized that acute and chronic wound infections differ fundamentally in microbial phenotype and host response; applying acute-infection paradigms (immediate systemic antibiotics) to chronic, biofilm-driven infections leads to unnecessary antibiotic exposure with limited clinical benefit. They advocate for antimicrobial stewardship strategies grounded in recognition of biofilm pathology and prioritization of local, non-antibiotic measures (eg, debridement, biofilm-disruptive dressings) whenever systemic sepsis.³⁶

Biofilms also serve as reservoirs and hotspots for horizontal gene transfer, facilitating the dissemination of resistance determinants among co-resident species via plasmids, transposons and phages. In the constrained, high-density environment of a chronic wound biofilm, selection pressure from repeated topical and systemic antimicrobial courses favors the emergence and maintenance of multidrug-resistant strains.³² Thus, therapeutic failure in chronically infected ulcers is often the combined result of intrinsic biofilm tolerance, acquired resistance, and suboptimal treatment strategies that fail to address the infection’s ecology.

Impact of Ecological Conditions on Wound Healing and Transition to Chronicity

The net effect of altered ecological conditions, biofilm formation, immune dysregulation and antimicrobial failure is to derail normal wound healing and drive the transition from acute injury to chronic ulceration. In early wound healing, transient bacterial colonization and a short-lived inflammatory phase can be compatible with successful re-epithelialization, as long as the microbial burden remains low and is effectively cleared. By contrast, when biofilms become established and inflammation fails to resolve, the wound is locked into a pathological steady state.⁶

Microbial products and persistent inflammation interfere with multiple healing processes. Protease-rich exudate degrades growth factors such as platelet-derived growth factor and transforming growth factor β, undermining fibroblast proliferation, collagen deposition and angiogenesis. ROS and proteases damage newly formed granulation tissue, preventing maturation and encouraging the formation of friable, hypergranulating tissue that is easily disrupted. Keratinocyte migration and proliferation at the wound edge are impaired by inflammatory cytokines and bacterial toxins, producing a characteristic “cliff-edge” epithelium with non-advancing margins.³⁷

Microbiota composition also appears to correlate with healing trajectories. Studies of pressure injuries and other chronic ulcers indicate that dominance by certain anaerobic genera (eg, Anaerococcus, Finegoldia, Acinetobacter) is associated with delayed healing and higher complication rates. In DFUs and venous leg ulcers, a high relative abundance of P. aeruginosa and other proteolytic Gram-negative rods has been linked to increased risk of deterioration and amputation, likely due to their robust biofilm formation and tissue-destructive virulence factors. Conversely, some wounds that progress to closure exhibit reduced microbial richness and a shift toward less inflammatory taxa during successful treatment, though no universally “beneficial” taxa have been consistently identified.¹²

Biofilms contribute directly to chronicity by physically shielding bacteria from phagocytosis and antibiotics, by sustaining low-grade inflammation, and by providing reservoirs from which planktonic cells and biofilm fragments can repeatedly disperse, re-seeding the wound or adjacent tissue after partial clearance. Clinically, this manifests as cycles of temporary improvement followed by relapse, often associated with minor trauma or treatment changes.⁶

From an ecological standpoint, chronic ulcers can be viewed as maladapted ecosystems stuck in an alternative stable state. In this state, the combination of a dysbiotic microbiota, a pro-inflammatory immune milieu, and a degraded extracellular matrix maintains conditions favorable for biofilm persistence and unfavorable for tissue repair. Effective therapy, therefore, requires not only reducing microbial load but also perturbing this ecological equilibrium, through repeated debridement to remove biofilm and necrotic tissue, modulation of moisture and oxygenation, restoration of perfusion, and targeted use of antiseptics, novel antimicrobials, or immunomodulatory agents that shift the system back toward a healing trajectory.⁶

Viewing chronically infected ulcers through the lens of microbial ecology and biofilm biology clarifies why these lesions are so difficult to treat and why conventional, pathogen-centric approaches often fail. Chronic wounds harbor polymicrobial, biofilm-associated communities shaped by hypoxia, host comorbidities and repeated antimicrobial exposure. These communities drive persistent, dysregulated inflammation, resist antibiotic therapy through both genetic resistance and biofilm-mediated tolerance, and directly impair the cellular and molecular processes required for healing.³⁷

Future strategies for managing chronically infected ulcers are moving toward integrated, ecology-based approaches: advanced diagnostics that better characterize biofilm presence and community structure; antimicrobial stewardship emphasizing local, biofilm-disruptive therapies; biomaterials and dressings designed to modulate the wound microenvironment and deliver targeted agents; and immunomodulatory or regenerative therapies aimed at resetting the chronic inflammatory state.³⁸ A deeper understanding of the microbiological ecology of chronic wounds, how specific taxa, biofilm architectures and host factors interact over time, will be essential for developing precision therapies that can reliably shift these complex ecosystems from chronicity back to healing.

Consequently, there is a clear need for novel clinical and preclinical therapeutic approaches to be integrated with, rather than replace, established best practice. Major guideline documents increasingly call for high-quality randomized trials of new wound-healing interventions used alongside guideline-based multidisciplinary care, emphasizing that the rising incidence and costs of chronic ulcers demand therapies that are both effective and economically sustainable. Emerging research on diabetic foot and other chronic ulcers underscores that current strategies alone have not sufficiently reduced the global burden of ulcer-related morbidity, amputations and mortality. Innovative technologies -including topical oxygen delivery, cellular and tissue-based products, bioengineered matrices, targeted immunomodulators and various biophysical modalities such as photodynamic and light-based therapies- are being actively explored to overcome the limitations of conventional care. Translational work that rigorously evaluates and integrates these modalities into structured care pathways is a key priority for improving healing trajectories and long-term outcomes across all major types of chronic cutaneous ulcers.

Major Types of Chronic Cutaneous Ulcers and Standard Treatments

The most commonly encountered chronic cutaneous ulcers in clinical practice are DFU, VLU, PU, and arterial (ischemic) ulcers. They share the common characteristic of impaired or arrested healing. Yet, each arises from distinct etiologic mechanisms and therefore requires ulcer-type–specific management, in addition to general wound care principles such as debridement, moisture balance, infection control and optimization of systemic comorbidities.³⁹

DFU are a hallmark complication of diabetes mellitus and result from the convergence of peripheral neuropathy, peripheral artery disease and increased susceptibility to infection. Sensory neuropathy diminishes protective sensation so that repetitive pressure or minor trauma at weight-bearing sites, such as the metatarsal heads, goes unnoticed. Motor neuropathy induces intrinsic muscle imbalance and foot deformities, including claw toes and prominent metatarsal heads, which concentrate plantar pressures and increase focal stress on the skin. Autonomic neuropathy impairs sweating and promotes dry, fissured skin, thereby compromising the epidermal barrier.⁴⁰ Concomitant peripheral artery disease, often distal and below the knee, reduces tissue perfusion and oxygen delivery, further impairing host defense and reparative processes. Hyperglycemia contributes to immune dysfunction and fosters colonization and infection once skin integrity is disrupted.¹⁴

Conventional DFU management, as emphasized in international guidelines, is multidisciplinary and combines systemic optimization, local wound care and mechanical off-loading strategies. Metabolic and risk-factor control, including tight glycemic control, blood pressure and lipid management, and smoking cessation, is fundamental to slowing the progression of neuropathy and vascular disease and to improving healing potential. Regular sharp debridement is recommended to remove necrotic tissue, slough and callus, reduce bioburden and biofilm, and stimulate a fresh, bleeding wound bed. Systemic antibiotics are reserved for clinically infected ulcers, with selection guided by severity, likely pathogens and culture results; deep infection, abscess or necrotizing soft-tissue infection requires urgent surgical intervention in combination with antibiotic therapy. Off-loading of plantar pressure is considered a central intervention: non-removable knee-high devices, such as total contact casts, are preferred, with removable cast walkers or alternative devices used when contraindications exist. In patients with DFU and peripheral artery disease, timely vascular assessment and, when appropriate, endovascular or open surgical revascularization significantly increase the likelihood of healing and limb salvage. Moisture-balancing dressings, such as foams, alginates and hydrofibers, are chosen according to ulcer depth and exudate level, and adjunctive therapies, including negative pressure wound therapy, topical oxygen, bioengineered skin substitutes and platelet-based products, be considered for ulcers that fail to respond to optimal standard care.⁴¹

VLU are the most frequent chronic ulcers of the lower limb in the general population and represent an advanced manifestation of chronic venous insufficiency and ambulatory venous hypertension.⁴² Venous valve incompetence and/or venous obstruction led to reflux and stasis, resulting in sustained elevation of venous pressure in the lower leg. This results in capillary hypertension, leukocyte trapping, microvascular damage, fibrin cuff formation and tissue hypoxia, particularly in the gaiter region, ultimately culminating in ulceration.⁴³

Standard management of VLUs centers on correcting venous hypertension and providing appropriate local wound care. Compression-based therapy is identified as the cornerstone of treatment, provided that arterial inflow is adequate. Multilayer compression bandages or graduated compression stockings improve venous return, reduce edema and enhance microcirculatory perfusion. Regular leg elevation above heart level and calf-muscle activation through walking or exercises complement compression by further lowering venous pressure. Local wound care strategies focus on the use of absorbent dressings to manage often copious exudate, maintain a moist wound environment and protect periwound skin; debridement of slough or necrotic tissue is performed when indicated. In selected patients with correctable superficial venous reflux or iliac obstruction, venous interventions such as endogenous ablation, sclerotherapy or venous surgery can reduce venous hypertension, promote ulcer healing and diminish recurrence risk.⁴⁴

PU, also termed pressure injuries, develop when sustained external pressure and shear forces exceed capillary closing pressure, most commonly over bony prominences in patients with immobility, sensory impairment or severe systemic illness. They are highly prevalent in acute care hospitals, rehabilitation centers and long-term care facilities and are associated with substantial morbidity, impaired quality of life, and increased healthcare costs.⁴⁵

International consensus guidelines guide management of PUs and focus on pressure redistribution and meticulous local care. Scheduled repositioning and turning, tailored to individual risk, comfort and tissue tolerance, are fundamental to reducing the duration and magnitude of pressure. High-specification foam mattresses, reactive or alternating pressure surfaces and specialized cushions are used to redistribute pressure and reduce shear at vulnerable sites. Debridement of necrotic tissue, using sharp, enzymatic, autolytic or mechanical methods, is generally indicated, although stable, dry eschar on the heel without signs of infection or ischemia may be left intact as a biologic cover. Dressings are selected based on ulcer depth, exudate volume and presence or absence of infection, with the dual goal of maintaining a moist environment and preventing maceration of the surrounding skin. Effective management of moisture, including incontinence, is essential to prevent further skin breakdown. Systemic optimization -adequate nutrition, pain control, management of spasticity and contractures, and treatment of systemic infection- supports local interventions and contributes to both healing and prevention of new lesions.⁴⁶

Arterial ulcers are a manifestation of advanced peripheral arterial disease and critical limb ischemia, most often due to atherosclerosis and frequently occurring in patients with diabetes, smoking and other cardiovascular risk factors. They typically occur on the distal foot, toes or lateral malleolus and are characterized by punched-out, sharply demarcated, painful lesions with pale or necrotic bases, scant granulation tissue, cool atrophic surrounding skin and diminished or absent peripheral pulses.⁴⁷

Standard management of arterial ulcers is defined by three priorities: restoration of blood flow, aggressive cardiovascular risk reduction and careful local wound protection. When anatomically feasible, endovascular procedures, such as balloon angioplasty and stenting, or open surgical bypass, are recommended to re-establish in-line flow to the foot. Successful revascularization is a major determinant of wound healing and limb preservation. Concurrently, comprehensive risk-factor modification is mandatory, including smoking cessation, glycemic control optimization, treatment of hypertension and dyslipidemia, and initiation of antiplatelet and statin therapy, according to peripheral arterial disease guidelines. Locally, ischemic tissue is protected with non-adhesive dressings and appropriate off-loading. Extensive debridement of devitalized tissue is generally deferred until perfusion is improved, as aggressive debridement in a severely ischemic limb may exacerbate tissue loss. Infection is treated with systemic antibiotics when present, but therapeutic response is often limited until adequate perfusion is restored.⁴⁸

Limitations of Conventional Treatments

Despite adherence to evidence-based guidelines and advances in multidisciplinary care, outcomes for chronic cutaneous ulcers remain suboptimal. Across etiologies, there are substantial rates of delayed or non-healing, recurrence, infection and amputation, which translate into high economic and human costs. Many diabetic, venous and arterial ulcers remain unhealed after months of optimal standard care, and even when closure is achieved, recurrence is frequent. The duration of chronic wounds often exceeds one year, and recurrence rates for venous leg ulcers and diabetic foot ulcers can reach very high levels in some cohorts, particularly when long-term compression or off-loading is not consistently maintained. In frail older adults and individuals with spinal cord injury, pressure ulcers may persist for prolonged periods and recur at the same anatomical sites despite best practice in repositioning and use of appropriate support surfaces.⁴⁹

Chronic cutaneous ulcers also confer an increased risk of severe infection and amputation. Diabetic foot ulcers are a leading cause of non-traumatic lower-extremity amputation worldwide, and infection, frequently occurring on a background of ischemia, is the main precipitating factor.⁵⁰ Conventional management combining debridement, systemic antibiotics, and off-loading reduces but does not eliminate the risk of deep infection, osteomyelitis and limb loss, especially in patients with severe peripheral arterial disease, end-stage renal disease or poor adherence. Similarly, infection of arterial ulcers in the setting of critical ischemia can rapidly progress to gangrene when revascularization is not feasible or fails, necessitating major amputation.⁴⁸ Chronic venous leg ulcers and pressure ulcers are also prone to recurrent infection, sepsis and repeated hospitalizations, particularly in older and multimorbid patients, adding further burden to patients, caregivers and health systems.⁵¹

A further limitation is that conventional strategies address only part of the complex underlying pathophysiology of chronic wounds. Interventions such as off-loading, compression, repositioning and revascularization predominantly target mechanical and hemodynamic factors but do not directly correct chronic inflammation, biofilm-mediated infection, cellular senescence and immune dysregulation, all of which are now recognized as key drivers of non-healing. Standard dressings largely provide passive moisture control and physical protection rather than actively modulating the wound microenvironment, microbiota or host response, and many advanced products that claim biological activity still lack robust, cost-effective evidence in routine practice.

Building on this ecological and clinical background, this review has two aims. First, it critically evaluates the current clinical evidence for adjunct physical, photodynamic, regenerative, oxygen-based, and topical therapies in chronic cutaneous ulcers (Innovative Therapies for Ulcer Management: Clinical Evidence in Patients). Second, it examines preclinical evidence for metallic, polymeric, inorganic, and hybrid nanoplatforms that target the same drivers of chronicity biofilm persistence, antimicrobial resistance, impaired angiogenesis, and dysregulated matrix remodeling (Promising Preclinical Evidence and Mechanisms for Chronic Cutaneous Ulcers Elimination). To our knowledge, this is the first review to place both evidence streams within a single wound-ecology framework, allowing direct comparison of clinical readiness across modalities.

Innovative Therapies for Ulcer Management: Clinical Evidence in Patients

In this section, therapies are presented that act as disruptive agents of the chronic wound ecology by directly targeting the organization and functionality of the biofilm. These approaches extend beyond simple tissue repair, actively interfering with the extracellular polymeric matrix, microbial communication pathways, and resistance mechanisms, thereby reshaping the microenvironment that supports persistent infection.⁵² This strategy is particularly relevant given that the complex ecology of biofilms significantly limits the effectiveness of standard treatments based on wound dressings, which generally fail to account for microbial interactions and structural dynamics.²¹ Consequently, the limited efficacy of conventional therapies arises from their predominantly passive approach, whereas the therapies discussed herein provide a more active and targeted intervention aligned with the ecological nature of the wound microenvironment.

Innovative Physical Therapies

Physical modalities have emerged as relevant adjunctive interventions in the management of chronic cutaneous ulcers, exploiting biophysical mechanisms to modulate wound microenvironments and accelerating tissue repair.⁵³ Low-intensity ultrasound, administered either as a standalone therapy or in conjunction with microbubbles, exerts mechanical and biological effects that enhance microvascular perfusion, promote angiogenic signaling, and facilitate the selective removal of devitalized tissue.⁵⁴ In parallel, electrical microcurrent therapy re-establishes endogenous bioelectric fields that orchestrate cellular migration and proliferation, stimulate extracellular matrix deposition, and support the structural remodeling of regenerating tissue.⁵⁵

Emerging Innovations: Low-Intensity Diagnostic Ultrasound with Microbubbles (LIDUS+MB)

Therapeutic ultrasound has increasingly been recognized as a valuable adjunct in the management of chronic ulcers, where wound repair is often hindered by complex and multifactorial pathophysiology. Its therapeutic efficacy is mediated through the propagation of mechanical waves that generate microvibrations within tissues, triggering a cascade of biological effects that promote healing.⁵⁶ These include stimulation of cell proliferation and angiogenesis, enhancement of local blood flow, reduction of microbial load, and facilitation of gentle debridement of necrotic tissue. Ultrasound therapy also modulates chronic inflammation by downregulating pro-inflammatory cytokines and matrix metalloproteinases, thereby fostering a microenvironment conducive to wound closure (Figure 1). The modality is non-invasive, safe, and generally well tolerated by patients.⁵⁷

Figure 1.

(a) Healing progression of a chronic diabetic ulcer under low-intensity diagnostic ultrasound combined with microbubbles (i–vi). (b) Sequential clinical progression of a chronic plantar ulcer treated with photodynamic therapy (PDT). (i) Baseline image showing a chronic ulcer located on the plantar surface of the foot. (ii) Application of photodynamic therapy with topical 20% 5-aminolevulinic acid (ALA) after a 4-hour incubation, followed by 630 nm laser irradiation at 80 J/cm² and 80–100 mW/cm² power output. (iii) Clinical outcome after treatment, demonstrating complete ulcer closure and re-epithelialization. (c) Clinical outcome of autologous regenerative therapy (PRP ± adipose-derived stem cells) in chronic lower-limb ulcer: (i) before treatment and (ii) after treatment. Reproduced from Zhang et al⁵⁶ Krupka et al⁵⁸ and Riza et al⁵⁹ under a Creative Commons Attribution License.

Clinical outcomes, however, remain heterogeneous. In Germany, a randomized trial involving 24 patients with venous leg ulcers treated with ultrasound at 1 MHz and 0.5 W/cm² for 12 weeks reported significant reductions in ulcer size, with some cases achieving complete closure.⁵⁴ Similarly, in Poland, Taradaj et al⁵³ ported daily sonotherapy over 7 weeks in 24 patients, observing reductions in ulcer area ranging from 53% to 69%, although differences between treatment groups did not reach statistical significance. By contrast, a large multicenter trial in the United Kingdom enrolling 337 patients found no meaningful differences in healing rates between ultrasound and standard care, suggesting that efficacy may be influenced by ulcer etiology, treatment frequency, and the ultrasound modality applied.⁶⁰

More recent studies have reported encouraging results. In Boston, a pilot trial with 12 patients suffering from neuropathic diabetic foot ulcers treated with non-contact low-frequency ultrasound (40 kHz, 0.2–0.6 W/cm²) demonstrated that patients receiving more frequent sessions achieved up to an 86% reduction in wound area within five weeks, accompanied by decreased concentrations of inflammatory mediators in wound exudates.⁶¹ In the United Kingdom, a case study using MIST Therapy documented substantial improvement in a chronic ulcer of five years’ duration, with significant reductions in both wound size and pain after eight weeks of regular treatment.⁶²

The most innovative contribution comes from Zhang et al⁶³ who applied low-intensity diagnostic ultrasound combined with microbubbles (LIDUS+MB) in two patients with chronic, refractory diabetic foot ulcers. This technique employed a conventional diagnostic ultrasound system in contrast mode, together with intravenous administration of microbubbles, SonoVue^® (sulfur hexafluoride microbubbles). The interaction between ultrasound waves and microbubbles induces stable cavitation, which decreases peripheral vascular resistance, enhances microcirculatory perfusion, and promotes the release of nitric oxide, prostaglandins, and angiogenic factors such as Vascular Endothelial Growth Factors (VEGF), thereby supporting neovascularization and tissue regeneration.

The treatment protocol involved daily 20-minute sessions for seven consecutive days, using a frequency of 4 MHz, a mechanical index of 0.86, and a penetration depth of 4 cm. Outcomes were remarkable: one patient with an infected ulcer measuring 3.0×2.0 cm achieved complete closure within 60 days (Figure 1a), while another with an extensive heel ulcer of 7.5×4.6 cm (initially considered for skin grafting but deemed inoperable due to comorbidities) achieved full healing after 150 days. Both patients remained recurrence-free during more than one year of follow-up.

The discrepancy between these outcomes is plausibly explained by differences in study design rather than a true absence of effect: the German and Polish trials enrolled small, single-etiology cohorts (n=24) with fixed ultrasound parameters, whereas the UK multicenter trial (n=337) pooled multiple ulcer etiologies and did not standardize treatment frequency, which may have diluted a true treatment effect present in more homogeneous subgroups.⁵³

Therapeutic ultrasound is emerging as a promising adjunctive modality in the management of chronic ulcers, owing to its ability to induce mechanotransductive effects that enhance tissue repair, modulate inflammation, and reduce microbial burden. However, clinical evidence remains heterogeneous, indicating that its efficacy is influenced by ulcer a etiology as well as treatment parameters and application frequency. In this context, the combination of low-intensity ultrasound with LIDUS+MB represents a significant advancement, as it improves microvascular perfusion and stimulates regenerative processes through cavitation-mediated mechanisms. Although preliminary findings are encouraging, further robust clinical studies are required to validate its efficacy and optimize therapeutic protocols.

Electrical Microcurrent Therapy as a Novel Strategy in Chronic Wound Management

Electrical microcurrent therapy (EMT) has gained recognition as a promising adjunctive approach for the treatment of chronic ulcers, in which the physiological healing process is frequently impaired by complex and multifactorial pathophysiology. Its therapeutic rationale lies in restoring endogenous bioelectrical fields naturally generated at wound margins, which are essential for initiating and sustaining the reparative cascade. At the cellular level, EMT promotes fibroblast and keratinocyte migration and proliferation, enhances angiogenesis, stimulates collagen synthesis, and improves microvascular perfusion.⁶⁴ In addition, it reduces bacterial load and downregulates persistent inflammatory responses, thereby creating a local environment conducive to tissue regeneration. Modality is non-invasive, painless, and generally well tolerated, which facilitates its clinical translation.⁶⁵

Early clinical investigations provided encouraging preliminary data. Ivandra et al⁶⁶ conducted a controlled trial involving 14 patients with venous leg ulcers: eight received EMT and six served as controls. After 4 weeks, patients in the EMT group reported a significant reduction in pain (VAS score from 8.5 to 3.5), whereas no appreciable change was observed in controls. Although the reduction in ulcer area did not achieve statistical significance, the study demonstrated a reproducible analgesic benefit and suggested a potential role of EMT in improving treatment adherence.

Further evidence has consolidated these observations. Kurz et al⁵⁵ investigated 39 patients with 40 hard-to-heal wounds (including venous, arterial, pressure, and diabetic foot ulcers) treated for 12 days with a portable automated microcurrent device (Accel-Heal^®). Among these patients, 78% of wounds demonstrated a favorable clinical response, while 96% reported pain relief within the first 48 hours. Pain intensity decreased by an average of 45% after the first week and by 67% after the second week, reflecting both rapid analgesia and early activation of reparative processes.

Notably, the randomized, double-blind, crossover trial conducted in Japan by Yoshikawa et al⁶⁷ enrolled 12 elderly patients with stage ≥3 pressure ulcers presenting with undermining, representing clinically complex, high-risk wounds. The intervention protocol consisted of monophasic pulsed microcurrent (200 µA, 2 Hz, 50% duty cycle) administered over two weeks, compared with sham stimulation. EMT-treated patients exhibited significantly greater wound contraction and accelerated healing rates compared to controls (p=0.008 and p=0.002, respectively). In addition, qualitative improvements were documented in wound bed characteristics, including increased viable granulation tissue, reduced exudate, and attenuation of local inflammatory signs. The therapy was well tolerated, with no adverse events reported, supporting its safety in frail geriatric patients with multiple comorbidities. Collectively, these findings indicate that EMT not only accelerates wound closure but also enhances the quality of reparative tissue, which is critical for reducing recurrence and long-term complications.

Electrical microcurrent therapy emerges as a promising therapeutic modality in the management of chronic ulcers by restoring endogenous bioelectrical fields and promoting key processes involved in tissue repair. Available clinical evidence indicates consistent benefits in pain reduction and accelerated wound healing, even in complex cases. However, further studies with larger sample sizes and standardized protocols are required to support its broader clinical implementation.

Photodynamic Therapy

Photodynamic therapy (PDT) has emerged as a promising adjuvant modality for the management of chronic ulcers, as shown in Table 1, particularly those complicated by persistent infection or colonization with multidrug-resistant microorganisms. The therapeutic principle involves administration of a photosensitizer (such as 5-aminolevulinic acid (ALA), methylene blue, or phthalocyanine derivatives) followed by irradiation with a light source at a defined wavelength, most commonly in the red spectrum (630–635 nm).⁵⁸ Upon activation, the photosensitizer generates ROS, predominantly singlet oxygen, which exerts a dual effect: potent antimicrobial activity against planktonic bacteria and biofilms, and bio-stimulatory effects that enhance angiogenesis, fibroblast proliferation, collagen synthesis, and epithelialization.⁶⁸ This dual mechanism distinguishes PDT from conventional antimicrobial strategies, offering both infection control and stimulation of endogenous repair without fostering microbial resistance.⁶⁹

Table 1.

Representative Clinical Evidence on Photodynamic Therapy Protocols and Outcomes in Chronic Cutaneous Ulcers

Ulcer Type	Light (λ/Dosimetry)	Photosensitizer	Patients	Duration/Protocol	Key Outcomes	Status	Reference
Venous ulcers (cohort)	630 nm, 80 J/cm2 weekly + standard care	Topical ALA	19	≈3–4 months (12 weeks of weekly PDT)	Improved healing with adjuvant PDT	Investigational	[68]
Chronic infected ulcers (case)	630 nm Aktilite, ~37 J/cm2	Methylene blue 1%	1	Weeks (multiple sessions in short intervals)	Complete clinical and microbiological healing	Investigational	[58]
Complex chronic ulcers (series)	Red 630 nm, standard clinical parameters	Methylene blue 10 mg/mL	3	Weeks (3 sessions in series)	Improved healing in lesions >40 cm2	Investigational	[70]
Chronic ulcers (multicenter study)	630 nm, 80 J/cm2; 10 sessions/14 days; cycles every 3 weeks	Topical ALA 20%	10	≈2–3 months (3–5 cycles)	40% complete closure; 40% partial reduction; 20% no change	Investigational	[71]
Diabetic foot ulcers	Red LED 630 nm, 60 J/cm2; 8 sessions in 4 weeks	RLP068 (Zn-phthalocyanine derivative)	18	1 month (8 sessions in 4 weeks)	Wound area reduction, re-epithelialization 50–80%; bacterial load reduction	Investigational	[72]
Lower limb ulcers (venous/mixed)	Red light with activable gel, repeated sessions	Phthalocyanine (light-activated gel)	34	Several weeks	Reduction of bacterial load, improved graft acceptance	Investigational	[69]
Chronic ulcers (2 cases)	630 nm Aktilite, ~37 J/cm2; multiple sessions	Methylene blue 1%	2	≈3 weeks	Complete clinical and microbiological healing	Investigational	[73]

Abbreviations: PDT, photodynamic therapy; ALA, 5-aminolevulinic acid; LED, light-emitting diode; OLED, organic light-emitting diode; Zn, zinc; J/cm², joules per square centimeter; mW/cm², milliwatts per square centimeter; nm, nanometers; MRSA, methicillin-resistant Staphylococcus aureus.

In China, Chen et al⁶⁸ treated 10 patients with chronic infected ulcers refractory to standard therapies. The protocol comprised surgical debridement, topical application of 5% ALA under occlusion for 3 hours, and subsequent irradiation with a 635 ± 5 nm red LED at 60–80 mW/cm², delivering 80–96 J/cm² over 20 minutes. Three cycles were administered at two-week intervals. Outcomes were highly favorable, with 9 of 10 patients achieving complete wound closure, accompanied by marked reductions in microbial load and improved tissue perfusion confirmed by Doppler imaging. Adverse effects were limited to mild, transient erythema and localized discomfort.

In Poland, Krupka et al⁵⁸ investigated 10 patients with chronic venous and mixed-etiology leg ulcers. Treatment involved 20% topical ALA with a 4-hour incubation, followed by 630 nm laser irradiation at 80 J/cm² and 80–100 mW/cm². Patients underwent 10 sessions over 14 days, repeated every 3 weeks for a total of 3 to 5 cycles. After eight months of follow-up, 4 patients achieved complete closure (Figure 1b), 4 demonstrated >50% reduction in ulcer area, and 2 showed no improvement (Figure 1b i–iii). Clinical response was most pronounced in patients with shorter ulcer duration and fewer vascular comorbidities, underscoring the importance of patient selection.

In Canada, Yu et al⁷⁰ described a 75-year-old woman with a chronic chest wall ulcer secondary to post-mastectomy radiotherapy, persisting for over five years despite multiple treatments including hyperbaric oxygen therapy. The protocol involved 5% ALA in cream with a 5-hour incubation, followed by irradiation with a 630 nm red LED (54 J/cm², 30 minutes). Clinical improvement was evident after the first session, with reduced exudation and granulation tissue formation. After three biweekly sessions, the ulcer progressively contracted until complete closure was achieved, maintained over 14 months of follow-up.

In Italy, Mancusi et al⁷² reported a series of 17 diabetic patients with chronic foot ulcers treated with RLP068, a zi(II) phthalocyanine derivative. The photosensitizer was applied topically and activated with a 630 nm red LED (fluence 60 J/cm², 8 minutes per session), delivered twice weekly for four weeks. All patients exhibited rapid reductions in bacterial burden, pain, and local inflammation. In 10 cases, re-epithelialization reached 50–80%, and in several, PDT was combined with skin grafting or transcutaneous magnetic stimulation, further accelerating healing. Treatment was well tolerated, with no adverse events reported.

In a complementary line of investigation, Piksa et al⁶⁹ employed OLED-based antimicrobial PDT on wound isolates from 10 patients with diabetic foot ulcers. The protocol utilized methylene blue (16 µM) as a photosensitizer, followed by blue OLED irradiation at a fluence of 30 J/cm². PDT achieved substantial reductions in opportunistic and resistant pathogens, including MRSA, with decreases of up to 5 log units. Although performed in vitro on clinical samples rather than directly in patients, these findings highlight the translational potential of compact, low-cost PDT devices for real-world chronic wound management.

Photodynamic therapy represents a therapeutic approach with a distinctive mechanism of action, combining antimicrobial activity with stimulation of tissue regeneration. Clinical evidence indicates favorable outcomes in reducing microbial burden and promoting wound healing, even in chronic ulcers. Its safety profile and the absence of induced microbial resistance further support its potential. However, variability in protocols and patient characteristics underscores the need for standardization to optimize its clinical application.

Biological and Regenerative Therapies

Biological and regenerative therapies have emerged as innovative strategies for the management of chronic ulcers, designed to re-establish a microenvironment conducive to tissue repair by combining structural scaffolds with bioactive stimuli.⁵⁹ Regenerative therapy broadly encompasses the use of biomaterials and cellular-based approaches aimed at restoring tissue structure and function, including the application of biological membranes such as amniotic membranes, as well as extracellular matrix substitutes and stem cell-based constructs.⁷⁴ In parallel, biological therapies may also involve the use of biologically derived products, including platelet concentrates, growth factors, and other bioactive molecules, although they do not necessarily rely on conventional pharmacological agents but rather on biologically active components that modulate the healing response.⁷⁵ Key modalities include amniotic membranes, extracellular matrix–derived biomaterials, platelet concentrates, and autologous grafts enriched with stem cells. Their therapeutic effects are mediated through three principal mechanisms: (i) provision of a biological scaffold that supports tissue regeneration and angiogenesis, (ii) sustained release of growth factors and cytokines that promote fibroblast, keratinocyte, and endothelial cell proliferation, and (iii) modulation of chronic inflammation and reduction of microbial burden, thereby accelerating wound closure and enhancing long-term tissue stability.⁷⁶

Clinical evidence demonstrates consistent benefits across diverse contexts. In a multicenter randomized controlled trial involving 84 patients with venous leg ulcers, the use of one or two dehydrated human amnion/chorion membrane (dHACM) grafts combined with compression therapy was compared to compression alone.⁷⁵ After 4 weeks, 62% of patients in the dHACM group achieved ≥40% reduction in wound area, compared with 32% in controls, confirming a significant acceleration of early healing.⁵⁹ Likewise, a prospective study in 16 patients with chronic ulcers of varying etiologies, with wound duration ranging from two months to eleven years, reported that treatment with lyophilized amniotic membrane (Amnioderm^®) achieved complete healing in 50% of cases, while an additional 37% exhibited substantial wound size reduction.⁷⁷

A further approach explored the use of a collagen dermal substitute combined with delayed split-thickness skin grafting. In a series of 35 patients with vasculogenic ulcers, the treatment protocol involved initial placement of the collagen scaffold (Nevelia^®), followed by autologous dermo epidermal grafting approximately 28 days later. Histological evaluation revealed active angiogenesis, organized collagen deposition, and progressive re-epithelialization, while clinical outcomes demonstrated improved scar quality, as assessed using the Manchester Scar Scale.⁷⁶

Autologous biologic therapies have also shown promising results. In a prospective cohort of 31 patients with chronic lower-limb ulcers, platelet-rich plasma (PRP) was administered in most cases (82.9%), while in 17% it was combined with autologous fat grafts enriched with adipose-derived stem cells. This strategy resulted in complete closure (Figure 1c) in 45.7% of patients and an overall clinical response rate approaching 90%, without prolonging the average healing time compared with conventional care, which remained approximately 35 days.⁵⁹

Biological and regenerative therapies constitute a comprehensive therapeutic approach aimed at restoring the structural and functional integrity of chronic wounds through the integration of biomaterials and bioactive signals. Current clinical evidence supports their capacity to enhance tissue regeneration, promote angiogenesis, and improve healing outcomes across diverse ulcer types, including long-standing and complex cases. Moreover, their ability to modulate the wound microenvironment and support the formation of stable, high-quality tissue highlights their relevance in reducing recurrence and long-term complications. Nonetheless, variability in therapeutic strategies and patient responses indicates the need for further standardization and well-controlled studies to optimize their clinical application.

Oxygen-Based Therapies

Persistent tissue hypoxia is a critical determinant in the chronicity of cutaneous ulcers, as it disrupts the cellular and biochemical pathways essential for repair. Oxygen-based therapies are designed to overcome this condition by controlling exposure to elevated oxygen concentrations, thereby enhancing diffusion into ischemic tissues and promoting wound healing through multiple physiological mechanisms.⁷⁸ These include stimulation of angiogenesis and neovascularization, increased fibroblast proliferation and collagen deposition, enhancement of neutrophil and macrophage bactericidal activity, and modulation of inflammatory mediators.⁷⁹ On this basis, both systemic hyperbaric oxygen therapy (HBOT) and topical oxygen delivery have been implemented across various clinical contexts with encouraging results.⁸⁰

In pressure ulcers, a patient with cervical spinal cord injury (C6) and a chronic stage IV gluteal ulcer underwent treatment in a soft hyperbaric chamber at 1.3 ATA (Atmospheres Absolute, the standard unit of absolute pressure), receiving oxygen at 10 L/min via face mask for 60 minutes, three times per week over 14 weeks. This protocol resulted in a marked reduction in wound area, a significant decrease in C-reactive protein, and improved patient-reported quality of life, underscoring.⁸¹

In diabetic foot ulcers, a 62-year-old man with an 18-month history of a chronic lateral foot ulcer complicated by fifth metatarsal osteomyelitis was treated with HBOT at 2.4 ATA for 90 minutes per session (Figure 2a). After multiple treatment cycles, progressive re-epithelialization and resolution of osteomyelitis were achieved, thereby preventing the major amputation initially indicated. This case illustrates the potential of HBOT as a limb-salvaging strategy in refractory ulcers complicated by ischemia and infection.⁸²

Figure 2.

(a) Sequential clinical documentation (i–vii) of a chronic diabetic foot ulcer with fifth metatarsal osteomyelitis in a 62-year-old patient, demonstrating progressive wound contraction, re-epithelialization, and resolution of infection following multiple cycles of hyperbaric oxygen therapy (HBOT, 2.4 ATA, 90 min/session). The composite series (circles in red) illustrates the role of HBOT as an effective limb-salvaging strategy in refractory ischemic and infected diabetic ulcers. (b) Clinical evolution of a chronic ulcer treated with autologous platelet concentrates (PRP/PRF), showing progressive tissue regeneration, angiogenesis, and wound closure over the treatment period (i–iv). Reproduced from Jeffrey et al⁸² and Edek et al,⁸³ under a Creative Commons Attribution License.

In systemic sclerosis, where microangiopathy and cutaneous fibrosis contribute to chronic, non-healing ulcers, two patients were treated with regimens ranging from 20 to 40 sessions at 2.4 ATA for 90 minutes daily. Treatment resulted in scab formation, reduction in ulcer size, and alleviation of pain. These outcomes are consistent with broader evidence, which reports response rates of up to 80%, reinforcing the therapeutic role of HBOT in autoimmune disorders with vascular compromise.⁷⁸

In pyoderma gangrenosum, a neutrophilic dermatosis associated with painful ulcerations, HBOT has also demonstrated clinical benefit. A 54-year-old woman, refractory to multiple immunosuppressive regimens (prednisone, infliximab, mycophenolate, and intravenous immunoglobulin), received 50 sessions at 2.4 ATA for 90 minutes over three months. The intervention induced complete remission of the lesions, highlighting the value of HBOT as an effective adjuvant therapy in complex and treatment-resistant cases.⁷⁹

In radiation-induced injuries, a 74-year-old woman with a history of radical mastectomy and radiotherapy developed a late-onset thoracic ulcer complicated by costal osteomyelitis, 25 years after oncological treatment. She underwent 101 sessions of HBOT at 2.5 ATA, each lasting 60 minutes over the course of one year. Complete wound closure and resolution of osteomyelitis were achieved, demonstrating that extended HBOT protocols, exceeding the conventional number of sessions, can remain both safe and effective in the management of long-term radiation-related complications.⁸⁰

Advanced Topical Therapies

Advanced topical therapies have emerged as valuable adjuvant strategies for the management of chronic cutaneous ulcers, which are typically characterized by a hostile microenvironment marked by persistent inflammation, hypoxia, microbial colonization, and a deficiency of reparative mediators. These approaches aim to directly modulate the wound bed by locally applying pharmacological agents, biomolecules, or autologous concentrates that target specific biological pathways. Their main mechanisms of action include stimulation of keratinocyte migration and proliferation, activation of fibroblasts with enhanced collagen and extracellular matrix synthesis, promotion of angiogenesis, modulation of pro-inflammatory cytokines, and improved local bacterial control.

Topical phenytoin, an antiepileptic drug with well-documented wound-healing properties, enhances fibroblast proliferation and collagen production. In a controlled clinical trial involving 104 patients with chronic venous ulcers, the group treated with phenytoin-impregnated dressings achieved a complete-healing rate of 64.8%, compared with 52% in the saline-treated control group. Moreover, the rate of wound area reduction was significantly greater in the experimental group, with only minor, well-tolerated adverse effects, such as localized burning sensations reported in a small subset of patients.⁸⁴

Topical timolol, a β-adrenergic antagonist, has been investigated for its ability to block β2 receptor signaling in keratinocytes, thereby facilitating cell migration and re-epithelialization. In a prospective study enrolling 60 patients with chronic venous and diabetic ulcers, daily application of 0.5% timolol, in conjunction with conventional wound care, produced a significantly greater reduction in ulcer area than controls. After 12 weeks of follow-up, the mean reduction was approximately 62% in the timolol group versus 30in the control group, underscoring its potential as an effective adjuvant therapy for non-healing ulcers.⁸⁵

Topical nitroglycerin, owing to its vasodilatory effect mediated by increased intracellular cGMP, has been applied in cases where local ischemia impairs tissue repair. In a clinical case report, administration of nitroglycerin in a patient with symmetrical peripheral gangrene led to marked improvement in tissue perfusion and progressive regression of ischemic lesions, without relevant adverse events. These findings highlight the therapeutic promise of nitroglycerin as a local intervention in severe ischemic conditions.⁸⁶

Autologous platelet concentrates such as platelet-rich plasma (PRP) and platelet-rich fibrin (PRF) have demonstrated strong regenerative potential by delivering high local concentrations of growth factors, including PDGF, TGF-β, and VEGF, which are essential for angiogenesis, cellular proliferation, and extracellular matrix remodeling. In a clinical series of 24 patients with chronic ulcers of diverse etiologies, the use of autologous PRP (administered both as a gel and via perilesional injections) resulted in complete healing within an average of 8 weeks, with significant wound size reduction and no associated complications.⁸⁷ Additionally, reports have described the use of PRF in combination with skin grafting for Wagner grade 4 diabetic foot ulcers, achieving successful graft integration and resolution of advanced gangrenous lesions (Figure 2b).⁸³

Promising Preclinical Evidence and Mechanisms for Chronic Cutaneous Ulcers Elimination

Metallic Nanoparticles as Bioactive Agents

The therapeutic rationale for metallic nanoparticles (MNPs) follows directly from the wound ecology described in Ecology as Influential Actors in Chronic Ulcers: biofilm-embedded microbial communities that conventional dressings cannot penetrate.⁸⁸ MNPs address this gap through nanometric penetration into the biofilm matrix and multimodal antimicrobial mechanisms, ROS generation, membrane disruption, and sustained ion release, that simultaneously target multiple structural and metabolic components of the microbial community.⁸⁸

Potent Antimicrobial Activity Against Resistant Bacteria

Bacterial infection is one of the main reasons ulcers become chronic and difficult to treat. Pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa can form biofilms, which are organized bacterial communities protected by an extracellular matrix.⁸⁹ Biofilms reduce antibiotic penetration and help bacteria tolerate stress.⁸⁸ Because of this, many preclinical nanoplatforms have been developed, prioritizing rapid bacterial control before targeting angiogenesis and remodeling (Table 2).

Table 2.

Representative Preclinical Studies on Nanomaterial-Based Strategies for Chronic Cutaneous Ulcers According to Therapeutic Application

Material/Formulation	Application	In vitro/Model	Main Result	References
AuNPs/Au–Ag NPs	Antimicrobial activity against resistant bacteria	Pseudomonas, E. coli, P. aeruginosa, E. faecalis, S. aureus, including biofilms	Broad antibacterial activity: Au–Ag systems were active against both planktonic and biofilm-associated pathogens.	[83,88,90,91]
Chitosan- and alginate-based polymeric systems: CeNPs-CS NPs; streptomycin-CS NPs; ALG/MgO systems; CS/ALG-encapsulated extract.	Antimicrobial activity against resistant bacteria	S. aureus, MRSA, S. agalactiae, K. pneumoniae, diabetic rat wound model	Improved antibacterial efficacy and antibiofilm activity; some systems also promoted wound repair, including >95% healing in diabetic rats.	[92–96]
Inorganic antibacterial systems: SiO2 NPs; Ag/AgBr-mesoporous silica; TiO2–AgNPs; TiO2/ZnO2-zeolite	Antimicrobial activity against resistant bacteria	MDR bacteria, E. coli, S. aureus, infected wound models	Strong bactericidal activity: silica-silver systems also accelerated wound healing in vivo within 14 days.	[97–101]
CuNPs/CuO2 nanodots	Promotion of angiogenesis	Rat skin defect model, chick embryo model, HUVECs	Accelerated healing, increased cell migration and neovascularization, and upregulated HIF-1α/VEGF signaling.	[91,102–104]
AgNPs/AuNPs/CeNPs	Promotion of angiogenesis	Endothelial in vitro assays, mouse wound models and fibroblast migration assays	Promoted tube formation, VEGF/NO signaling, endothelial infiltration, and fibroblast migration; angiogenic effects were dose-dependent in some AgNP systems.	[105–112]
Polymeric pro-angiogenic nanocarriers: mPEG-PLGA NO-releasing NPs; PLGA-poloxamer nanocapsules; poly(β-amino ester)-DNA NPs	Promotion of angiogenesis	Vascular sprouting and ischemic in vivo models	Sustained release and gene delivery strategies enhanced angiogenic signaling and supported restoration of blood supply.	[113–115]
AgNPs/MMP9-siRNA chitosan NPs/alginate-HA-Ag membranes	Regulation of MMPs and tissue remodeling	Human skin cells, diabetic rat wound model, bacteria/biofilm-related wound models	Reduced MMP-3 or MMP-9, lowered inflammatory cytokines, preserved extracellular matrix, and improved wound stability.	[116–118]
ZnO NPs/Laponite®-VEGF/EGF nanocomposite	Regulation of MMPs and tissue remodeling	A. baumannii-infected rat burn model; growth factor retention model	Reduced TNF-α and IL-6, improved re-epithelialization, and enhanced localized tissue remodeling signals.	[101,119]
Functionalized hydrogels: CuNPs@CMCS–PCA; CuS/HA hydrogel; CDs-based hydrogel	Multifunctional healing platform	Diabetic rat and wound-healing models	Combined antibacterial, anti-inflammatory, angiogenic, and collagen-promoting effects; one system reached 86.5% healing.	[120–122]
Nanofibers/nanosheets: Ag/rGO-curcumin mats; CNT-curcumin nanofibers	Multifunctional healing platform	In vivo histological healing and fibroblast viability models	Improved histological repair and fibroblast viability, although some carbon-based systems required caution due to fibrosis/inflammation risk.	[123–125]
Graphene and hybrid graphene platforms: GO; MnS2/rGO; CuS/GO; GO-cellulose	Antimicrobial and regenerative activity	S. aureus-infected mouse wound model, MRSA-infected rat model, skin wound models	Complete antibacterial inhibition in some models; accelerated wound closure, collagen deposition, re-epithelialization, and neovascularization.	[126–130]
Quantum dots: EGCG-ZnO QDs; CDs-ε-polylysine hydrogel; GQDs-cellulose hydrogel	Antimicrobial and pro-angiogenic/pro-healing activity	Diabetic infected wound models, infected mouse models and resistant bacterial models	Combined antibacterial action with VEGF/EGF upregulation, inflammation reduction, and high healing rates (>90% in some infected models).	[131–135]

Abbreviations: AuNPs, gold nanoparticles; Au-AgNPs, gold-silver nanoparticles; CuNPs, copper nanoparticles; CuO₂ nanodots, Copper dioxide nanodots; CeNPs, cerium nanoparticles; AgNPs, Silver nanoparticles; mPEG-PLGA NO-releasing NPs, Nitric oxide-releasing poly(ethylene glycol)-poly(lactic-co-glycolic acid) nanoparticles; MMP9-siRNA, small interfering RNA targeting matrix metalloproteinase 9; Alginate-HA-Ag, Alginate, hyaluronic acid, and silver; ZnO NPs, zinc oxide nanoparticles; VEGF/EGF, vascular endothelial growth factor/epidermal growth factor; CuNPs@CMCS-PCA, Copper nanoparticles incorporated into carboxymethyl chitosan cross-linked with polycarboxylic acid; CuS/HA hydrogel, Copper sulfide and hyaluronic acid hydrogel; Ag/rGO, Silver/reduced graphene oxide; CNT, Carbon nanotube; CS, chitosan; ALG, alginate; GO, graphene oxide; rGO, reduced graphene oxide; MnS₂/rGO, Manganese sulfide supported on reduced graphene oxide; CuS/GO, Copper sulfide supported on graphene oxide; QDs, quantum dots; MRSA, methicillin-resistant Staphylococcus aureus; HUVECs, human umbilical vein endothelial cells; TNF-α, tumor necrosis factor alpha; IL-6, interleukin-6.

MNPs can attack bacteria via multiple parallel mechanisms rather than a single drug target, making them potential.⁹⁰ Key mechanisms include ROS generation, which damages cellular components; membrane disruption upon attachment; and the release of metal ions, which interfere with essential cellular processes.⁹⁰ This multi-mechanism behavior explains why metal-based NPs can reduce biofilm viability and remain effective even when conventional antibiotics fail.

This ability of NPs to target complex bacterial defenses is vital for treating external ulcers complicated by biofilms. Gold nanoparticles (AuNPs), either alone or combined with other metals, exhibit excellent antibacterial properties. For instance, Rizwana et al⁹¹ biosynthesized AuNPs from Panchagavya, which showed stronger activity against Gram-negative pathogens such as Pseudomonas, which are common in ulcers (Figure 3a and b). Similarly, Ramasamy et al¹⁰³ developed gold-silver nanoparticles (Au-Ag NPs) effective against E. coli, P. aeruginosa, E. faecalis, and S. aureus, including those in biofilms. These results indicated that Au-Ag-NPs enhance cellular internalization, leading to pathogen inactivation and highlighting their potential as nanoantibiotics against resistant bacteria.

Figure 3.

(a) Schematic illustration of the green synthesis of AuNPs. (b) Antibacterial activity of AuNPs against B. subtilis, K. pneumoniae, and E. coli at different tested volumes: 10 µL (i), 20 µL (ii), 30 µL (iii), and 40 µL (iv); the central circle in yellow corresponds to the control. (c) Schematic representation of the preparation of Ni-NPs. (d) Time-dependent bacterial count (%) of S. aureus and E. coli in the presence of Ni-NPs. (e and f) Representative colony-forming unit (CFU) plates of S. aureus and E. coli in the absence (control) and presence of Ni-NPs after 24 h of exposure. Reproduced from Rizwana et al⁹¹ and Ahghari et al¹⁰² under Attribution-NonCommercial 4.0 International License.

Additionally, Copper nanoparticles (CuNPs) have been reported to inhibit multiple bacteria, including P. aeruginosa and MRSA, while also demonstrating antioxidant and wound-healing effects in vivo.¹³⁶ Nickel nanoparticles (Ni-NPs) have also shown antibacterial properties; Ahghari et al¹⁰² reported over 80% inhibition of S. aureus and E. coli after 18 hours (Figure 3c–f).

However, despite strong antibacterial activity, MNPs must be interpreted with caution. Antimicrobial performance depends on size, surface chemistry, and dose. The same mechanisms that inactivate bacteria, such as ROS generation and ion release, can also stress healthy cells if not controlled.^102,103,136 Therefore, many authors argue that the priority is not “more metal”, but smarter design, green synthesis, coatings, targeted delivery, or matrix embedding to concentrate activity at the ulcer site while limiting systemic exposure.

Promotion of Angiogenesis

For most chronic ulcers, killing bacteria is necessary but not sufficient. A major obstacle is poor blood supply, which hinders the delivery of oxygen and nutrients. This highlights the importance of angiogenesis, the physiological process by which new blood vessels form from pre-existing ones.¹⁰⁴ MNPs, specifically copper, silver and gold, can promote angiogenesis by stimulating endothelial cell migration, modulating growth factors, and regulating the local inflammatory environment (Table 2).

Critically, angiogenesis is not merely a circulatory event: the restoration of microvascular density is a prerequisite for re-epithelialization, the process by which keratinocytes migrate from wound margins and residual follicular structures to regenerate the overlying epidermis and form new skin. Adequate neovascularization delivers oxygen, keratinocyte growth factor (KGF), epidermal growth factor (EGF), and transforming growth factor-β (TGF-β) signaling molecules indispensable for keratinocyte proliferation and directed migration across the wound bed.¹⁰⁴ In the hypoxic environment of a chronic ulcer, the absence of functional vasculature suppresses keratinocyte activity and stalls epidermal closure even when the bacterial burden has been controlled. This mechanistic link between vascularization and re-epithelialization explains why promoting angiogenesis is not simply a supportive measure, but a central therapeutic target for achieving definitive wound closure.¹⁰⁵

Among metallic nanomaterials, CuNPs are widely recognized for promoting wound repair because copper ions interact with the angiogenic pathway, including VEGF and Fibroblast Growth Factors (FGF), which are crucial growth factors. A key in vivo study by Alizadeh et al¹⁰⁵ demonstrated that CuNPs accelerated healing in a rat skin defect model. They attributed this faster closure to increased cell migration, proliferation, and neovascularization, specifically at a size-dose condition of 80 nm at 1 μM. Similarly, Mroczek-Sosnowska et al¹⁰⁶ highlighted the pro-angiogenic effect of CuNPs in a chicken embryo model, with superior efficacy compared to copper sulfate. Additionally, Zhang et al¹³⁶ confirmed that copper oxide (CuO₂) nanodots CuO2 possess dual capabilities: bactericidal activity against MRSA, S. aeruginosa, and E. coli, and pro-angiogenic via the expression of Hypoxia-induced factors (HIF-1α) and VEGF in endothelial cells (HUVECs), promoting cell migration and tube formation for angiogenesis. These studies demonstrate that CuNPs are not only antibacterial, but also “repair-active”, helping the transition from inflammatory/infected state to the proliferative phase and tissue regeneration.

Beyond copper, other metallic agents commonly used in infection control also demonstrated regenerative properties, including AgNPs and AuNPs. Preclinical evidence demonstrated that AgNPs can promote angiogenesis. For instance, Kang et al¹⁰⁷ and Palanisamy et al¹⁰⁸ showed AgNPs induced endothelial tube formation, increased ROS generation, and increased angiogenic factors such as VEGF and NO in vitro. In vivo studies in mice confirmed this response, showing increased endothelial infiltration and hemoglobin content. However, the pro-angiogenic effect of AgNPs depends on the dose and coating. Low doses generate moderate oxidative signals for repair, but high doses cause excessive stress (ROS) that damages cells. For this reason, AgNPs work best when incorporated into polymer coatings such as polyvinylpyrrolidone to control release rather than as freely diffusing particles.¹⁰⁷ Similarly, Gold nanoparticles are widely recognized for their biocompatibility and their ability to promote angiogenesis. Ngernyuang et al¹⁰⁹ developed green-synthesized apigenin-conjugated AuNPs, demonstrating enhanced endothelial tube formation and cell motility in vitro. Additionally, Poomrattanangoon et al¹¹⁰ used collagen I-coated AuNPs to stimulate VEGF and FGF expression, promoting fibroblast migration and wound closure.

In a similar line, Zinc nanoparticles (ZnNPs) and lanthanide hydroxide nanoparticles (Europium and Terbium) have also proved effective in vivo, but with a specific mechanism to enhance angiogenesis: activation via ROS and Nitric Oxide (NO) generation. These metals promote new blood vessel growth and higher cell density in scaffolds.^111,112,137

A different strategy involves nanoparticles such as Cerium nanoparticles (CNPs) and Cobalt NPs (CoNPs) that promote angiogenesis by modulating the cellular oxygen environment. In the case of CNPs, Das et al¹³⁸ demonstrated that they stabilize Hypoxia-Inducible factor (HIF-1α) by regulating the oxygen environment through their surface Ce³⁺/Ce⁴⁺ ions. Similarly, CoNPs induce a pro-angiogenic response by releasing Co²⁺ ions; these ions mimic hypoxia, induce VEGF expression and enhance endothelial tubule formation.

Regulation of Matrix Metalloproteinases (MMPs) and Tissue Remodeling

The chronic ulcer wound bed harbors numerous inflammatory mediators including pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), ROS, and a diverse array of proteolytic enzymes all of which contribute to the failure of wound closure.¹¹⁶ Among these, MMPs warrant particular attention for two fundamental reasons. First, MMPs are the direct biochemical executors of ECM destruction: unlike cytokines or ROS, which act through cell signaling cascades, overactivated MMPs physically cleave structural proteins collagen, fibronectin, vitronectin, and laminin the very scaffold upon which all regenerative processes depend.¹¹⁶ Second, elevated MMPs also inactivate growth factors (VEGF, EGF, TGF-β) and disrupt cell-matrix interactions, creating a compounding deficit in the reparative signaling network. This means that controlling upstream inflammatory signals alone is insufficient if MMP hyperactivity remains unchecked: the wound bed will continue to self-destruct regardless of antimicrobial or anti-inflammatory interventions.¹³⁹ For these reasons, MMP regulation represents a uniquely direct and structurally irreversible checkpoint in the transition from chronic inflammation to tissue regeneration, justifying its central role in preclinical therapeutic research.

MNPs can help correct this destructive state. For instance, Franková et al demonstrated, using human skin cells, that AgNPs significantly reduced MMP production (specifically MMP-3) and lowered proinflammatory cytokine signals (TNF-α and IL-12). These results suggest that AgNPs can mitigate tissue destruction, improving the wound microenvironment from a chronic inflammatory state toward regeneration.

Conversely, MNPs can prevent healing if they cause to much oxidative stress. For instance, Wan et al¹⁴⁰ showed that CoNPs increased the levels of destructive enzymes (MMP-2 and MMP-9), leading to tissue breakdown. This presents a significant challenge: it is necessary to kill bacteria without generating a high-ROS environment. Therefore, it is essential to design MNP systems that carefully modulate MMPs, reducing inflammation without stimulating the excessive enzymatic activity that damages tissue.

Overall, these preclinical studies suggest that MNPs influence tissue remodeling by modulating inflammatory mediators and MMPs behavior, sometimes in a pro-healing direction (eg, reduced MMP-3 and cytokines with AgNPs), but sometimes in a harmful direction when oxidative stress dominates (eg, CoNPs).

Polymers as Drug Delivery System

Polymeric nanocarriers are polymer-based materials produced by the polymerization of many monomer units, and, under certain conditions, they can be organized and self-assemble into nanometric structures 10–100 nm.⁹² The use of these nanomaterials offers significant advantages, including protection of therapeutic agents, prolonged residence time at the wound site, and controlled release. These properties are particularly relevant for chronic cutaneous ulcers, where infection, inflammation, impaired vascularization, and delayed tissue remodeling often coexist (Table 2).⁹³

As in Metallic Nanoparticles as Bioactive Agents, the ecological barrier posed by biofilm-associated resistance (Ecology as Influential Actors in Chronic Ulcers) motivates polymer-based delivery: their nanometric architecture allows therapeutic agents to reach the biofilm microenvironment that standard dressings cannot access.⁹³ Conventional dressings cannot penetrate or structurally disrupt the biofilm community, addressing only its surface manifestations while leaving the underlying microbial ecology intact. Polymeric nanocarriers are designed precisely to overcome these ecological barriers: their nanometric architecture enables delivery of therapeutic agents directly into the biofilm microenvironment, disrupting the microbial community structure that standard care is unable to reach.⁹³

Potent Antimicrobial Activity Against Resistant Bacteria

Polymers such as Chitosan (CS), alginate (ALG) and polyesters have been widely explored to improve antimicrobial delivery against wound-associated pathogens and biofilm-related infections. For instance, Cerium Nanoparticles (CeNPs) were encapsulated in CS NPs to improve high antibacterial performance against S. aureus (>90%) and to promote cell migration. Additionally, in vivo experiments in a diabetic rat model showed a significantly increased repair rate (>95%).⁹⁴ Similarly, Streptomycin-loaded chitosan nanoparticles were developed as a controlled -release system and showed marked in vitro activity against resistant pathogens, with growth inhibition rates exceeding 98% (Figure 4a and b).⁹⁵

Figure 4.

Effect of streptomycin-loaded, chitosan-coated magnetic nanoparticles on the inhibition of microbial growth using the plate colony counting method at two concentrations: (a) 1 mg and (b) 2 mg (**:p < 0.01; ***: p < 0.001; ****: p < 0.0001). Polyester Fiber: (c) without AgNPs (d) with AgNPs. The Clear Zone of Polyester Fiber Before and After Modification against: (e) S. aureus and (f) E coli. Reproduced from El-Zowalaty et al⁹⁵ and Rohaeti et al¹¹³ under Attribution-NonCommercial 4.0 International License.

Alginate-based formulations have also shown promising antimicrobial performance. In a study, sodium alginate-stabilized antibiotic/MgO NPs systems significantly enhanced activity against S. agalactiae and K. pneumoniae, two relevant resistant pathogens. This formulation produced the greatest increase in inhibition zones, reaching 59.09% and 56.25% higher values than the control. In another study, CS/ALG-encapsulated Echinacea angustifolia extract showed markedly improved activity against multidrug-resistant S. aureus, reducing MIC values by 4- to 32-fold compared with the free extract. These nanoparticles also significantly downregulated the biofilm-associated genes icaA, icaC, and icaD, while maintaining high cell viability (90% at 256 µg/mL), highlighting their strong antibacterial and antibiofilm potential.⁹⁶

Aliphatic polyesters such as PLA, PCL, and PLGA also have emerged as valuable antimicrobial matrices, particularly when combined with active nanofillers.¹¹³ Although these polymers are intrinsically bioinert toward bacteria, their functionalization with Silver Nanoparticles (AgNPs) or Graphene Oxide functionalized with Silver Nanoparticles (AgNPs–GO) can convert them into effective antimicrobial nanocomposites. In comparative analyses, AgNP-containing polyester systems were more effective than GO-loaded counterparts because silver ions could be released from the matrix and directly damage bacterial cells, whereas immobilized GO largely lost its membrane-disruptive mechanisms (Figure 4c and d). As a result, polyester nanocomposites containing AgNPs or AgNPs–GO hybrids showed significant activity against multidrug-resistant bacteria associated with medical device-related infections (Figure 4e and f).¹¹³ Although some of these studies were not performed in ulcer-specific models, their findings are highly relevant to chronic cutaneous ulcers, where resistant bacteria and biofilm persistence are major barriers to healing.¹¹⁴

Overall, polymers are more than just carriers; they are active enablers of therapy. Their ability to protect drugs and control their release allows us to revitalize classical antibiotics and natural compounds, offering new hope for treating chronic and resistant ulcers.

Promotion of Angiogenesis and Re-Epithelialization

In chronic ulcers, enhanced microcirculation is vital for angiogenesis and tissue regeneration; polymeric nanosystems offer an advantage by delivering therapeutic agents with greater control than free molecules. For instance, methoxy poly(ethylene glycol) and poly(D,L-lactide-co-glycolide) amphiphilic copolymer (mPEG-PLGA) nanoparticles that release nitric oxide (NO) have been shown to directly stimulate vascular sprouting.

NO is a gaseous signaling molecule physiologically produced by endothelial nitric oxide synthase (eNOS) that plays a central role in vascular biology. At the cellular level, NO activates soluble guanylate cyclase (sGC) in endothelial cells, elevating intracellular cyclic GMP (cGMP) levels, which in turn activates protein kinase G (PKG) and promotes endothelial cell migration, proliferation, and three-dimensional tube formation the cellular events that constitute angiogenic sprouting. Additionally, NO upregulates VEGF expression in the wound microenvironment and relaxes smooth muscle cells to increase local perfusion. The controlled, sustained delivery of NO from mPEG-PLGA nanoparticles is critical because free NO donors (such as N-diazeniumdiolates or S-nitrosothiols) have very short half-lives in biological environments and produce burst-release profiles that are poorly suited for wound bed vascularization.^115,117

Moreover, PLGA-poloxamer nanocapsules allow for the sustained release of growth factors such as FLF-2 and Platelet Derived Growth Factor BB (PDGF-BB) for over a month, protecting them for rapid degradation in the wound environment.^115,117 Furthermore, Poly(β-amino ester)-DNA nanoparticle-based gene delivery techniques can effectively modify stem cells to express VEGF, promoting robust angiogenesis and tissue regeneration in vivo (ischemic model).¹¹⁸ Collectively, these results demonstrate that polymers are essential to delivering and expressing pro-angiogenic signals and successfully restoring blood flow.

Beyond these strategies, chitosan-based nanoparticles loaded with copper ions have also demonstrated capacity to upregulate VEGF and HIF-1α expression in endothelial cells, accelerating neovascularization in full-thickness wound models.¹⁴¹ Similarly, gelatin methacryloyl (GelMA) hydrogels incorporating PLGA microspheres have been used to achieve spatiotemporally controlled release of bFGF and PDGF, resulting in significantly enhanced capillary density and accelerated wound closure compared to single-factor delivery systems.¹⁴² These findings underscore that the combined or sequential release of multiple pro-angiogenic factors through polymeric platforms is more effective than single-agent approaches for restoring vascular networks in chronic wounds.

Regulation of Matrix Metalloproteinases and Tissue Remodeling

A key advantage of polymer nanoparticles is their ability to be designed not only to kill bacteria and stimulate blood vessels, but also to modulate the wound’s biochemical microenvironment.¹¹⁶ In clinical practice, this means local delivery of therapeutic modulators (eg, anti-inflammatory agents or nucleic acids) while maintaining a protective, moist interface. A relevant study was reported by Tarusha et al¹⁴³ who developed alginate membranes loaded with hyaluronic acid and silver nanoparticles. In addition to their strong antimicrobial performance against bacteria and biofilms, this formulation demonstrated a significant inhibitory effect on MMP-9 expression. This reinforces the concept that polymeric systems can simultaneously address infection control and proteolytic regulation, thereby facilitating wound stability, preserving the extracellular matrix (ECM) and mitigating tissue degradation.

Complementing these findings, chitosan nanoparticles loaded with curcumin have been reported to selectively downregulate MMP-2 and MMP-9 expression while simultaneously reducing TNF-α and IL-6 levels in diabetic wound models, accelerating closure through a dual anti-protease and anti-inflammatory mechanism.¹⁴⁴ Furthermore, PLGA microspheres encapsulating a TIMP-1 gene construct have demonstrated the ability to restore the MMP/TIMP balance in chronic wound fibroblasts, promoting organized collagen deposition and significantly improving tensile strength of the regenerated tissue.⁹⁷ Together, these results strengthen the argument that polymeric nanocarriers are uniquely suited to orchestrate MMP regulation in a spatiotemporally controlled manner, addressing a key bottleneck in chronic ulcer healing that neither topical dressings nor systemic agents can effectively resolve.

Inorganic Nanoparticles

Inorganic nanoparticles are nanoscale materials made from stable inorganic solids such as metal oxides (ZnO, TiO2, CuO), silica or nanoclays.⁹⁸ These nanoparticles have been studied for ulcer treatment because they are chemically stable, easy to functionalize and can provide strong bioactivity through ion release (eg, Zn²⁺, Ag⁺) or ROS generation (especially under light).⁹⁸ In the following section, inorganic nanoparticles enhance ulcer therapy through three primary mechanisms: antibacterial action, pro-angiogenic signaling, and the indirect facilitation of tissue remodeling via microenvironmental modulation (Table 2). This therapeutic potential is especially significant given the ecological limitations of conventional wound dressings, which cannot penetrate the self-organized architecture of established biofilms and therefore leave the microbial community structurally intact. Inorganic nanoparticles, through their ion-release capacities and ROS-generating properties, actively destabilize this biofilm ecology disrupting the microbial niche that passive wound coverings consistently fail to address.⁹⁸

Potent Antimicrobial Activity Against Resistant Bacteria

Inorganic nanoparticles have proven effective for chronic skin infection ulcers. Silica nanoparticles (SiO₂) derived from Punica granatum and Citrus limon demonstrated antibacterial activity against MDR bacteria (eg, Salmonella, E. coli) and B. subtilis.^99,100 This efficacy is further enhanced when combined with silver: AgNPs and AgBr-loaded mesoporous silica nanoparticles showed high inhibition rates against E. coli and S. aureus and accelerated wound healing in vivo within 14 days.^101,145

Similarly, Titanium dioxide nanoparticles (TiO₂-NPs) combined with AgNPs exhibited superior antibacterial effects compared to controls, confirming that hybridizing metals with inorganic oxides enhances bactericidal activity.¹¹⁹ Furthermore, the combination of TiO₂/ZnO₂ supported on zeolite (4A) showed that these materials attack bacteria through two main routes: releasing toxic ions and generating oxidative stress (ROS).¹⁴⁶

Promotion of Angiogenesis and Re-Epithelialization

After infection control, rebuilding the blood supply is the next priority. Inorganic nanoparticles have demonstrated the ability to support endothelial function and stimulate.⁹⁸ For instance, Zn-doped TiO2 nanoparticles enhanced endothelial cell viability and proliferation, promoting angiogenesis in a chick embryo model. This study revealed that the effect was mediated by increased intracellular messengers (ROS/NO) and a p38/STAT3-linked signaling pathways.¹¹¹ Likewise, ZnO nanoparticles increased the expression of growth factors (FGF and VEGF) and improved fibroblasts proliferation in guinea pig models.¹¹² This is crucial because fibroblast and endothelial cells are the central units for new tissue formation.

Additionally, Cerium oxide nanoparticles (CeO-NPs) have proved effective for their pro-angiogenic properties; Chigurupati et al¹⁴⁷ confirmed in vivo that CeO-NPs reduce oxidative stress, protecting tissue and stimulating cell migration of keratinocytes and epithelial cells, accelerating repair in mice. Collectively, these findings highlight that inorganic nanoparticles are active drivers of repair rather than merely passive carriers. By stimulating angiogenesis through chemical signaling, they successfully restore the blood supply needed to close chronic wounds.

Regulation of Matrix Metalloproteinases (MMPs) and Tissue Remodeling

The application of inorganic nanoparticles for MMP strategies is limited compared with that of polymeric platforms. However, inorganic nanoparticles can still support tissue remodeling indirectly by improving the wound microenvironment in two practical ways. First, by reducing bacterial burden, which lowers persistent inflammation and prevents continuous ECM degradation.¹¹⁶ For instance, ZnO NPs significantly reduced inflammatory markers (TNF-α and IL-6) and improved re-epithelization in an A. baumannii-infected rat burn model, supporting the idea that lowering bacterial burden helps resolve persistent inflammation and reduces ongoing ECM damage.¹²⁰ Second, balancing oxidative stress is critical; while ROS generation (especially light-activated Ag/AgBr-SiO₂ or TiO₂-based platform)¹⁰¹ effectively kills bacteria, excessive exposure can damage host cells. To address this balance, Cidonio et al¹²¹ synthesized a synthetic layered silicate nanoclay, Laponite^®-nanocomposite loaded with VEGF/EGF factors, thereby improving vessel penetration and growth-factor retention. Thus, inorganic nanoparticles are most effective when their activity is localized and controlled to enhance MMP regulation and tissue remodeling.

Hybrid Systems and Emerging Nanoplatforms

Hybrid systems combine two or more components, such as metal or carbon nanomaterials within a polymer matrix, to solve a key challenge in ulcer therapy: balancing strong antibacterial power with safety and healing support.¹³⁹ In clinical settings, each part serves a distinct role. The polymer matrix acts as a scaffold that keeps nanoparticles at the ulcer site, maintains moisture and reduces toxicity. Simultaneously, the nanocomponent provides the active bioactive signals needed to fight infection, reduce oxidation, and stimulate angiogenesis (Table 2).¹²²

Functionalized Hydrogels

Hydrogels are highly cross-linked polymer networks heavily swollen with water. In ulcers therapy, they mimic soft tissue, keep the wound hydrated, and ensure localized drug delivery.¹⁴⁸ Metals-based hydrogels have emerged as multifunctional platforms that combine infection control with angiogenesis support, and inflammation regulation. For instance, Carboxymethyl chitosan-protocatechualdehyde hydrogel loaded with CuNPs (CuNPs@CMCS–PCA), which prevented bacterial growth and reduced inflammation in diabetic rats resulting in an 86.5% healing rate.¹²³ Another effective, the injectable CuS/HA hydrogel, promoted healing by increasing VEGF expression and collagen deposition.¹²⁴ Beyond metals, polymers networks can also empower carbon-based nanomaterials; for example, Yu et al¹²⁵ developed a CDs-based hydrogel EPL@poly(NVP-co-NMA)@AAB-CDs, using N-vinyl-2-pyrrolidinone (NVP), N-(hydroxymethyl) acrylamide (NMA), and ε-poly(L-lysine) (EPL), were was reported robust antibacterial and anti-inflammatory activity, highlighting that carbon dots act as active healing modulators rather than simple additive. Collectively, incorporating metals or carbon nanomaterials into hydrogels transforms them into active, multifunctional platforms. These hybrid systems accelerate tissue repair by simultaneously addressing infection, inflammation, and the angiogenic stimulus required for chronic ulcers.

Nanofibers and Nanosheets

Nanofibers and nanosheets are attractive candidates for ulcer therapy because they structurally resemble the fibrous structure of ECM and offer high drug-loading capacity.¹²⁶ A prime example of synergistic design is the study by Esmaeili et al¹²⁷ who combined Ag/rGO (for infection control) with curcumin (for tissue repair) in cellulose/polyurethane nanofibrous mats, achieving significant histological healing in vivo. Similarly, Shakiba et al¹²⁸ demonstrated that carbon nanotubes (MWCNT) and curcumin loaded into a PVA nanofibrous composite (PA6/PVA/CMWCNT-Cur) enhanced fibroblast viability, a critical factor for tissue formation. However, the use of carbon nanomaterials requires caution; Kittana et al¹²⁹ noted that while chitosan-MWCNT nanofibers accelerated re-epithelialization, they also increased fibrosis and inflammation. This finding highlights a critical nuance in ulcer therapy because nanofiber/nanosheet platforms can accelerate closure and support regeneration, but carbon nanomaterials require careful dose and design control to avoid adverse effects.

Graphene and Hybrid Platforms

Graphene and its derivatives, Graphene Oxide (GO), and reduced Graphene Oxide (rGO), are two-dimensional carbon lattices characterized by high surface area, mechanical stability, and functional groups that facilitate aqueous dispersion and cell interaction.¹³⁰ In ulcer therapy, graphene serves as a reinforcing bioactive scaffold that promotes cell adhesion while enhancing antimicrobial effects through oxidative stress and membrane disruption. For instance, Fadhil et al¹⁴⁹ demonstrated complete bacterial inhibition in a S. aureus-infected mouse wound model using GO. However, the biological response is dependent on concentration. Mukherjee et al¹⁵⁰ observed that while low concentrations of GO and rGO promote angiogenesis, higher concentrations can be inhibitory. This highlights a critical translational challenge: hybrid platforms must be carefully tuned to balance antimicrobial efficacy with cellular tolerance.

In hybrid systems, graphene combined with MNPs (eg, CuNPs, MnS₂) or polymers (eg, cellulose) acts as a stabilizer, improving bacterial targeting and facilitating ion release to enhance toxicity. Fakhri et al¹³¹ proved the higher antibacterial properties of MnS2/rGO nanocomposites against E. coli. Likewise, Wang et al¹³² evaluated a CuS/GO nanocomposite in an MRSA-infected rat model; this material demonstrated strong biocompatibility, antibacterial activity, and accelerated wound healing within 14 days, enhancing cell migration and collagen production.

Additionally, combining graphene with biopolymers like cellulose offers significant regenerative benefits. Studies on GO-c cellulose nanocomposites in rat skin wound models showed that re-epithelialization and neovascularization were significantly accelerated in the treatment groups. These results confirm that integrating GO with polymers effectively promotes skin wound healing, suggesting a promising potential for tissue regeneration applications.¹³³

Quantum Dots

Quantum dots (QDs) are ultrasmall nanoparticles (<10 nm) with very high surface area and reactive surface.¹³⁴ Their main advantage in chronic ulcers is that they can provide strong antibacterial action and, at the same time, support healing signals often through controlled ROS/photothermal effects and local microenvironment modulation.¹³⁵ In diabetic wound therapy, ZnO QDs functionalized with Epigallocatechin Gallate (EGCG) showed high antibacterial activity against MRSA and ampicillin-resistant E. coli, while also reducing inflammation. Furthermore, the platform increased repair through the expression of growth factors (VEGF and EGF) and achieve higher wound closure by day 15, suggesting that infection control and immunomodulation can work together to unlock healing in chronic ulcers.¹⁵¹ Similarly, an Ag₂S QD activated by near-infrared light combined hyperthermia/ROS effects with Ag⁺-Mediated antibacterial action, achieving complete inhibition of E. coli and MRSA. Also, it was reported to be pro-angiogenesis with increased collagen deposition and higher VEGF expression. Additionally, Black phosphorus QDs (BPQDs) have been tested in in vivo models of MRSA-infected diabetic wounds, where their photothermal and photodynamic activities enabled a combined antibacterial mechanism. This study is relevant for chronic ulcers because it targets the infection-inflammation lock, helping the wound move toward re-epithelialization and tissue regeneration once bacterial control is achieved.

Carbon dots (CDs) and graphene quantum dots (GQDs) are carbon-based nanomaterials that are often water-dispersible and generally biocompatible and can be engineered to provide antimicrobial and pro-healing activity within dressings or hydrogels.¹⁵² For instance, Mou et al¹⁵³ synthesized CDs-loaded ε-polylysine hydrogels (CD-Plys), which demonstrated significant antimicrobial effect against E. coli and S. aureus and achieved a remarkable healing rate (>90%) in infected mouse models. These results were corroborated by Wang et al¹⁵⁴ who showed that CDs accelerated cutaneous wound healing by activating the Transforming growth factor (TGF-β), which promoted epithelial cell motility and faster re-epithelialization in full-thickness wounds; as a result, barrier recovery improved and reduced scarring.¹⁵⁴

Research on GQDs also shows promise; GQDs-loaded in cellulose hydrogel demonstrated antibacterial activity against resistant pathogens (including MRSA) and upregulated fibroblast genes associated with angiogenesis (eNOS and VEGF), supporting a microenvironment favorable for vascular formation and wound closure.¹⁵⁵ Together, these studies suggest that carbon-based quantum dots act as active biological modulators rather than passive additives, helping infected or chronic wounds transition toward effective regeneration.

Translational Barriers to Clinical Adoption

Despite consistent preclinical efficacy, several barriers currently limit the translation of nanomaterial-based ulcer therapies into clinical practice. Manufacturing reproducibility remains a central obstacle: batch-to-batch variability in nanoparticle size, surface functionalization, and drug-loading efficiency is a recurring limitation across nanomedicine platforms, including polymer-based dressings developed specifically for diabetic foot ulcers.^156–159 Regulatory pathways compound this problem: combination products that embed a nanomaterial within a dressing or device are not classified uniformly across regulatory agencies, and current reviews of nanomedicine translation describe this regulatory-standardization gap as a persistent bottleneck rather than a solved issue.^157–159

Economic evidence adds a further constraint. In chronic wound care generally, nursing time and hospital costs not the dressing itself account for roughly 80–85% of total treatment cost, meaning that a nanomaterial’s price is only one part of its economic case.¹⁶⁰ Formal cost-effectiveness modeling exists for individual clinically established adjuncts, such as dehydrated human amnion/chorion membrane for venous leg ulcers,¹⁶¹ but comparable economic analyses for the metallic, polymeric, inorganic, and hybrid nanoplatforms discussed in Promising Preclinical Evidence and Mechanisms for Chronic Cutaneous Ulcers Elimination are essentially absent from the literature reviewed here, leaving their real-world cost-effectiveness an open question.

These manufacturing and economic constraints compound a clinical-evidence problem already visible in Emerging Innovations: Low-Intensity Diagnostic Ultrasound with Microbubbles (LIDUS+MB): even the best-studied adjunct modality, therapeutic ultrasound, shows inconsistent outcomes across small, single-center cohorts (n=24)^6,53 and a larger multicenter trial (n=337) that pooled multiple ulcer etiologies without standardizing treatment frequency,⁶¹ underscoring how methodological heterogeneity, not necessarily a true absence of effect, currently limits cross-study comparison. Addressing these barriers will require standardized biofilm and healing-outcome assays, larger multicenter trials with harmonized protocols, transparent reporting of manufacturing and scale-up data, and early engagement with regulatory bodies during preclinical development.

Conclusion

Chronic cutaneous ulcers are among the most challenging conditions in wound care because they persist within a pathological microenvironment characterized by biofilm formation, chronic inflammation, hypoxia, impaired angiogenesis, extracellular matrix degradation, and defective tissue remodeling. The evidence reviewed in this manuscript indicates that this complexity cannot be adequately addressed through a single therapeutic pathway.

Clinical research suggests that, when combined with standard treatment, adjunctive techniques such as low-intensity ultrasound, electrical microcurrent therapy, photodynamic therapy, oxygen-based interventions, regenerative biomaterials, and advanced topical treatments may enhance wound contraction, infection control, pain relief, and tissue regeneration. Preclinical research indicates that nanotechnology-based systems, such as metallic, polymeric, inorganic, and hybrid platforms, can simultaneously target biofilms and resistant bacteria, promote angiogenic signaling, and alter matrix remodeling. These results support the use of active, mechanism-based therapeutic approaches to replace passive wound care and alter the chronic ulcer microenvironment, thereby restoring healing potential.

From a medical practice perspective, the current evidence suggests that innovative therapies should be understood as adjuvant tools rather than replacements for established multidisciplinary management. Debridement, infection control, compression therapy, offloading, revascularization, and systemic optimization remain the foundation of care for chronic cutaneous ulcers. However, the studies analyzed here suggest that certain supplemental therapies may offer significant therapeutic advantage in refractory wounds, particularly those complicated by persistent infection, ischemia, biofilm burden, or delayed granulation. In this context, photodynamic therapy appears especially promising for infected ulcers and wounds colonized by multidrug-resistant microorganisms, oxygen-based therapies may offer particular value in hypoxic and ischemic lesions, and regenerative or topical bioactive therapies may improve local tissue restoration. Nevertheless, clinical translation must proceed with caution, as much of the available evidence remains limited by small sample sizes, heterogeneous protocols, mixed ulcer etiologies, and a lack of robust comparative trials with long-term follow-up.

Future translational research should focus on bridging the divide between promising mechanistic findings and clinically reproducible, ulcer-specific applications. More emphasis should be placed on well-designed randomized controlled trials with larger cohorts, standardized endpoints, and extended follow-up periods capable of clarifying which emerging interventions provide real benefit beyond optimized conventional care. Simultaneously, preclinical development should advance toward multifunctional platforms with demonstrated biocompatibility, controlled release, reproducibility, manufacturability, and long-term safety. Particular attention should be paid to therapies that can disrupt biofilms, modulate chronic inflammation, enhance angiogenesis, and preserve extracellular matrix integrity in a coordinated manner. In the end, the best future strategies will likely be multimodal and precision focused. They will use advanced biomaterials and targeted bioactive systems within evidence-based clinical pathways to transform chronic ulcers from persistent pathological conditions into stable regenerative environments.

Future Perspectives

The evidence reviewed here reveals a consistent pattern: therapies with a longer clinical history (ultrasound, electrical microcurrent, photodynamic therapy, biological scaffolds, oxygen-based interventions, advanced topicals) have already reached patients, even if only in small, single-center studies, whereas the nanoplatforms discussed in Promising Preclinical Evidence and Mechanisms for Chronic Cutaneous Ulcers Elimination, metallic, polymeric, inorganic, and hybrid systems alike, remain confined to in vitro assays and animal models such as mice, rats, and chick embryos. No human data currently exist for any of the nanoplatforms reviewed. Closing this gap, rather than simply generating more preclinical data, should be the organizing priority for the field over the next several years.

Standardizing the clinical evidence that already exists; even among the more mature modalities, study designs vary too much to compare directly. Ultrasound illustrates this well: a German trial with 24 patients and fixed treatment parameters, a Polish trial with the same sample size but daily dosing, and a UK multicenter trial with 337 patients that mixed several ulcer etiologies all reported different outcomes, and the difference likely reflects protocol design as much as biological effect. The same pattern of small, non-randomized cohorts with inconsistent follow-up appears across electrical microcurrent, photodynamic therapy, and biological scaffold studies. Before any of these modalities can be recommended as standard adjuncts, the field needs multicenter randomized trials that fix ulcer etiology, treatment frequency, and outcome measures (wound-area reduction at a defined time point, complete closure rate, recurrence at one year) so that results from different centers can actually be compared.

Choosing realistic first candidates for human testing. Not every nanoplatform reviewed here is equally close to a first-in-human study. Metal-ion-releasing systems such as silver- or copper-loaded hydrogels build directly on materials already used in approved wound dressings, which makes them a more realistic near-term candidate for controlled clinical pilot studies than more complex or novel materials such as graphene-hybrid composites or quantum dots, which have only been tested in vitro or in short-term animal models. A staged approach topical, low-complexity nanoplatforms first, more complex hybrid and carbon-based systems later, once manufacturing and safety data mature is more likely to succeed than attempting to advance every material class at the same pace.

Resolving the dose–safety trade-off before moving to patients. This review’s own preclinical evidence shows that the same mechanisms that make nanoplatforms effective can also cause harm at the wrong dose. Cobalt nanoparticles increase tissue-degrading MMP-2 and MMP-9 activity even as they stimulate blood vessel growth. Silver nanoparticles and graphene oxide promote healing at low concentrations but become inhibitory or cytotoxic at higher ones. Chitosan–carbon nanotube nanofibers speed up wound closure while also increasing fibrosis. These findings are not a reason to abandon nanoplatform development; they are a reason to make dose-response and long-term biocompatibility studies a mandatory step before any nanoplatform proceeds to human testing, rather than an optional add-on late in development.

Building manufacturing and regulatory readiness in parallel, not afterward. As discussed in Translational Barriers to Clinical Adoption, batch-to-batch reproducibility and unclear regulatory classification are already limiting translation for nanomedicine broadly, and nothing in the wound-care literature reviewed here suggests chronic ulcer nanoplatforms are an exception. Manufacturing and regulatory strategy should be planned alongside efficacy studies, not after a platform has already shown promise in animals, since retrofitting a laboratory-scale synthesis method for GMP-compliant production is often what stalls translation in practice.

Generating the cost data that do not yet exist. With the exception of a small number of economic analyses for established biological therapies, no cost-effectiveness data exist for any of the nanoplatforms discussed in this review. Given that nursing time and hospital stay, not the material itself, drive most of the cost of chronic wound care, future studies should report cost alongside efficacy from the earliest clinical pilot stage, rather than treating economic evaluation as a separate, later exercise.

Taken together, these priorities point toward a coordinated agenda rather than isolated technical improvements: harmonized clinical trial protocols for existing adjunct therapies, a staged and safety-first path from animal models to first-in-human studies for nanoplatforms, and manufacturing, regulatory, and economic planning built into the development process from the start. Progress on any one of these fronts alone will not be enough to move chronic cutaneous ulcer therapy from mechanistic promise to standard clinical practice.

Disclosure

The authors report no conflicts of interest in this work.