Chronic wounds represent a significant medical challenge affecting millions of patients worldwide, imposing substantial burdens on healthcare systems with estimated costs exceeding US$25 billion annually in the United States alone2. These non-healing wounds are defined as barrier defects that have not healed within 3 months despite appropriate care1. The prevalence of chronic wounds continues to increase alongside rising rates of diabetes, obesity, vascular disorders, and an aging population. An examination of the normal wound healing process, pathophysiology of chronic wounds, and specific approaches to managing venous ulcers, pressure ulcers, arterial ulcers, and diabetic foot ulcers.
Physiological Wound Healing Process
Wound healing under normal circumstances is a complex, highly regulated process involving a coordinated interplay between multiple cell types and molecular signaling pathways. This intricate process occurs in overlapping but distinct phases that must proceed in a synchronized manner to achieve optimal healing.
Inflammatory Phase
The inflammatory phase begins immediately after injury, following hemostasis, and serves to clear pathogens and foreign material from the wound site. Vascular permeability increases with vasodilation, allowing neutrophils and monocytes to migrate to the wound area2. These immune cells are responsible for removing debris and combating potential infection. Monocytes convert to macrophages, often considered the master regulators of the inflammatory phase, as they not only phagocytose tissue debris and neutrophils but also secrete growth factors and cytokines that promote tissue regeneration and cell migration2. This initial inflammatory response is crucial for preparing the wound bed for subsequent healing phases and typically lasts about 3 days in acute wounds.
Proliferative Phase
The proliferative phase commences approximately 3 days after injury and is characterized by fibroblast activity, collagen deposition, and formation of granulation tissue. Fibroblasts produce collagen and ground substance that serve as scaffolding for the healing tissue2. Concurrently, endothelial cells undergo rapid proliferation, leading to angiogenesis within the granulation tissue and creating a rich vascular network that supplies the actively healing area2. Keratinocytes at the wound edges migrate across the wound bed to re-establish the epithelial barrier. This dynamic phase typically spans 2-3 weeks and represents the period of most visible healing progress.
Remodeling Phase
The final phase of wound healing is remodeling or maturation, which can last for months to years. During this phase, type III collagen is gradually replaced by stronger type I collagen, and the collagen fibers align along tension lines to increase wound strength2. The vascular network that had developed during the proliferative phase begins to regress, and cellular activity decreases2. Despite this extensive remodeling process, the healed tissue never regains the full strength of unwounded skin, achieving at best about 70% of its pre-injury tensile strength2.
Pathophysiology of Chronic Wounds
Chronic wounds develop when the normal wound healing cascade becomes disrupted, often due to underlying pathologies that impair one or more phases of the healing process. Understanding these disruptions is essential for developing effective treatment strategies.
Factors Contributing to Chronic Wound Development
A key contributor to wound chronicity is excessive and prolonged inflammation, which perpetuates tissue damage instead of promoting repair3. This pathological inflammation creates a destructive environment characterized by elevated levels of pro-inflammatory cytokines, increased protease activity, and oxidative stress. The imbalance between tissue destruction and synthesis prevents progression to the proliferative phase of healing.
Hypoxia represents another critical factor in chronic wound development. Wound healing requires significant oxygen to support cellular activities, interact with cytokines, and facilitate the neutrophil respiratory burst that fights infection2. Studies have estimated that a minimum tissue oxygen tension of 20 mmHg is necessary for healing, yet chronic wounds often exhibit tensions as low as 5 mmHg2. This oxygen deficit not only impairs cellular proliferation and collagen synthesis but also compromises bacterial defense mechanisms, creating favorable conditions for infection.
Ischemia-reperfusion injury contributes significantly to chronic wound pathology, particularly in arterial and diabetic ulcers. The alternating periods of low and restored blood flow generate damaging reactive oxygen species, perpetuating tissue injury and inflammation4. Additionally, bacterial colonization and biofilm formation represent major barriers to healing. When bacterial load exceeds 10^5 bacteria per gram of tissue, wound healing becomes severely impaired across various types of wounds4.
Comorbid Conditions and Chronicity
Several systemic conditions predispose patients to chronic wounds. Diabetes mellitus affects wound healing through multiple mechanisms, including impaired cellular function, neuropathy, microvascular disease, and accumulation of advanced glycation end products2. Uncontrolled hyperglycemia significantly compromises immune function, cellular migration, and angiogenesis, while diabetic neuropathy leads to loss of protective sensation and subsequent injury.
Age-related changes also contribute to delayed healing. Elderly patients experience decreased inflammatory responses, reduced collagen production, diminished angiogenesis, and impaired cellular proliferation and migration4. Malnutrition, particularly protein deficiency, further impedes healing by limiting the availability of essential building blocks for tissue repair.
Venous Leg Ulcers
Venous leg ulcers represent a common type of chronic wound, primarily resulting from venous hypertension and associated venous insufficiency. These ulcers typically develop in the gaiter area of the leg and often present with characteristic features including edema, hyperpigmentation, and lipodermatosclerosis.
Treatment Approaches for Venous Ulcers
The cornerstone of venous ulcer management is compression therapy, which addresses the underlying venous hypertension by improving venous return and reducing edema. With appropriate treatment including compression, venous leg ulcers often heal within 6 months5. Treatment should be administered by healthcare professionals trained in compression therapy, usually practice or district nurses.
Compression therapy involves the application of firm bandages or stockings designed to squeeze the legs and promote upward blood flow toward the heart. Various compression systems exist, including two, three, or four-layer bandages5. These are typically changed 1-3 times weekly, coinciding with dressing changes. While initially painful, particularly with active ulceration, the discomfort generally diminishes as healing progresses. Proper patient education regarding compression use is essential, as incorrect application or removal can impede healing or cause additional complications.
Before applying compression, proper wound bed preparation is necessary. This involves cleaning the ulcer to remove debris and dead tissue, followed by the application of an appropriate non-adhesive dressing5. Simple non-sticky dressings are generally preferred and require changing 1-3 times weekly. Many patients can eventually manage their own wound cleaning and dressing under nursing supervision, which promotes self-care and may improve adherence to treatment.
Pressure Ulcers
Pressure ulcers develop when prolonged pressure impairs blood flow to tissues, typically over bony prominences such as the sacrum, heels, and ischial tuberosities. These ulcers represent a significant challenge, particularly in immobile or hospitalized patients.
Evidence-Based Interventions for Pressure Ulcers
A systematic review of pressure ulcer treatments identified several interventions with moderate-strength evidence supporting their efficacy. Air-fluidized beds significantly improved healing compared to standard care, demonstrating high consistency across five studies involving 908 patients6. These specialized support surfaces redistribute pressure and reduce shear forces, creating optimal conditions for healing.
Protein supplementation represents another effective intervention, with moderate-strength evidence from 12 studies involving 562 participants showing improved healing outcomes6. This finding underscores the importance of nutritional status in wound healing, particularly protein intake which provides essential amino acids for tissue repair and immune function.
Additional interventions with moderate-strength evidence include radiant heat dressings and electrical stimulation6. Radiant heat dressings maintain an optimal wound temperature that enhances cellular activity and local blood flow, while electrical stimulation appears to promote healing through multiple mechanisms including enhanced cellular migration, increased protein synthesis, and improved blood flow.
Interventions with low-strength evidence include alternating-pressure surfaces, hydrocolloid dressings, platelet-derived growth factor, and light therapy6. While these approaches show promise, additional research with larger sample sizes and more rigorous methodologies is needed to establish their efficacy conclusively.
Arterial Ulcers
Arterial ulcers result from insufficient arterial blood supply to tissues, most commonly due to peripheral arterial disease. These ulcers typically present with distinct characteristics including well-demarcated wound edges, pale wound bed, minimal exudate, and significant pain, particularly when the affected limb is elevated.
Management Challenges and Options
The treatment of arterial ulcers presents unique challenges, as the underlying vascular insufficiency must be addressed for healing to occur. While revascularization procedures represent the cornerstone of management, these interventions are not always feasible or successful, necessitating alternative approaches.
Research on non-surgical treatments for arterial ulcers remains limited. A review identified only two small studies with data on 49 participants with arterial leg ulcers, both with methodological limitations and short follow-up periods insufficient to measure complete healing7. One study investigated 2% ketanserin ointment in polyethylene glycol (PEG) versus PEG alone, reporting accelerated wound healing in the ketanserin group, though it should be noted that ketanserin is not licensed for use in humans in all countries7.
A second study examined concentrated growth factors (CGF) derived from the patient’s blood compared to standard dressings. In participants with diabetic arterial ulcers, 66.6% of those treated with CGF showed more than 50% reduction in ulcer size, compared to only 6.7% in the standard dressing group7. However, the small sample size and methodological limitations preclude definitive conclusions.
Additional evidence suggests potential benefits from systemic prostanoids, ultrasound therapy, and pneumatic compression for arterial ulcers10. However, these options have limitations including side effects, patient tolerance issues related to pain, and limited availability in clinical practice. Further research is urgently needed to improve treatment options for this complex patient population.
Diabetic Foot Ulcers
Diabetic foot ulcers (DFUs) represent a significant complication of diabetes mellitus, with complex pathophysiology involving neuropathy, vascular disease, altered immune function, and biomechanical abnormalities. The management of DFUs requires a multidisciplinary approach addressing multiple factors simultaneously.
Comprehensive Management Approaches
The main components of effective DFU management include education, glycemic control, wound debridement, advanced dressings, offloading, surgical interventions when necessary, and advanced therapies8. This multifaceted approach is essential due to the complex nature of these ulcers and the numerous comorbidities typically present in affected patients.
Offloading techniques, or pressure modulation, represent the most critical component in managing neuropathic ulcers in diabetic patients8. These interventions redistribute pressure away from the ulcer site, creating favorable conditions for healing. Multiple studies have demonstrated that proper offloading significantly promotes DFU healing8.
Various offloading modalities exist, including casting techniques, footwear-related approaches, surgical interventions, and other methods8. Total contact casts (TCCs) are considered the most effective offloading technique for neuropathic DFUs8. TCCs are minimally padded and carefully molded to the foot’s shape, redistributing pressure over the entire foot surface while protecting the wound site. Clinical trials have demonstrated that TCCs heal a higher percentage of plantar ulcers at a faster rate compared to standard treatments8.
Despite their efficacy, TCCs remain underutilized in practice, with one study showing only 16% of DFU patients received this intervention8. Barriers to TCC use include the need for specialized expertise in application, potential skin irritation from improper application, time and material expenses, limitations on daily activities, and inability to perform daily wound assessment8. Alternative options include removable cast walkers (RCWs) and instant TCCs (iTCCs), which may offer greater convenience while still providing offloading benefits.
Appropriate wound dressings represent another crucial component of DFU management. Ideal dressings should maintain moisture balance, sequester proteases, stimulate growth factors, provide antimicrobial activity, allow oxygen permeability, and promote autolytic debridement8. No single dressing fulfills all requirements, and selection should be based on wound characteristics including cause, location, depth, exudate amount, presence of infection, and need for conformability8.
Dressings for DFUs can be categorized as passive, active, or interactive. Passive dressings serve primarily protective functions and are suitable for acute wounds. Active and interactive dressings modify wound physiology by stimulating cellular activity and growth factor release, making them appropriate for chronic wounds8. Common dressing categories include films, hydrogels, hydrocolloids, alginates, foams, and silver-impregnated dressings, each with specific indications based on wound characteristics.
Growth factors represent an advanced therapeutic option for recalcitrant DFUs. While multiple growth factors show theoretical benefits, only recombinant human platelet-derived growth factor (rhPDGF, Becaplermin or Regranex) has demonstrated sufficient efficacy in clinical trials to gain FDA approval8. In randomized controlled trials, Becaplermin showed a 43% increase in complete closure compared to placebo gel (50% vs. 35%)8. This treatment option should be considered for wounds that fail to respond to standard interventions.
Integrated Approach to DFU Management
Successful management of DFUs requires not only addressing the wound itself but also optimizing numerous contributing factors. Glycemic control represents a fundamental component, as hyperglycemia adversely affects multiple aspects of wound healing9. Studies have demonstrated impaired neutrophil function in poorly controlled diabetic patients, particularly those with markedly elevated hemoglobin A1c levels2.
A multidisciplinary team approach is essential due to the multifaceted nature of foot ulcers and the numerous comorbidities present in affected patients9. Treatment selection should consider both patient characteristics and ulcer features, as well as the patient’s ability to comply with recommended interventions. Early intervention is crucial to prevent exacerbation and potential need for amputation.
Management strategies should be tailored based on ulcer severity, vascular status, and presence of infection9. Rest, elevation, and pressure removal (off-loading) represent essential components that should be initiated at first presentation. Ill-fitting footwear should be discarded and replaced with appropriate offloading devices to mitigate pressure at the ulceration site9.
Advances in Chronic Wound Management
Recent years have witnessed significant advances in understanding the cellular and molecular mechanisms underlying chronic wounds, leading to novel therapeutic approaches. These innovations aim to address specific pathophysiological abnormalities and promote progression through the normal healing cascade.
Molecular and Cellular Therapies
Growth factors have emerged as promising interventions for recalcitrant chronic wounds. These naturally occurring proteins regulate various aspects of the wound healing process, including cell proliferation, migration, and matrix synthesis. While multiple growth factors have theoretical benefits, clinical evidence supporting their use varies considerably.
Platelet-derived growth factor (PDGF) has the strongest evidence base, with FDA approval for treating diabetic foot ulcers8. Fibroblast growth factor, vascular endothelial growth factor, insulin-like growth factors, epidermal growth factor, and transforming growth factor β have also demonstrated potential benefits in preclinical studies, though their clinical utility requires further investigation8.
Inflammation modulation represents another therapeutic target, as excessive inflammation contributes significantly to wound chronicity. Approaches to address pathological inflammation include anti-inflammatory agents, protease inhibitors, and immunomodulatory compounds. By restoring the balance between pro-inflammatory and anti-inflammatory signals, these interventions aim to facilitate progression from the inflammatory to proliferative phase.
Conclusion
Chronic wounds represent a significant healthcare challenge that requires a comprehensive understanding of normal healing processes and the pathophysiological factors that lead to healing impairment. Venous ulcers, pressure ulcers, arterial ulcers, and diabetic foot ulcers each present unique management challenges requiring tailored approaches addressing specific underlying pathologies.
Successful management of chronic wounds demands a multidisciplinary approach integrating wound care specialists, vascular surgeons, endocrinologists, nutritionists, and other healthcare professionals. Treatment strategies must address not only the wound itself but also contributing factors including vascular insufficiency, pressure, infection, nutritional status, and glycemic control in diabetic patients.
Despite advances in understanding wound healing biology and developing novel therapeutic approaches, significant knowledge gaps remain. Further research is needed to elucidate the complex interplay between cellular processes, molecular signals, and systemic factors in chronic wound development and healing. Such insights will facilitate the development of more effective interventions targeting specific pathophysiological mechanisms, ultimately improving outcomes for the millions of patients affected by chronic wounds worldwide.
References
- https://academic.oup.com/bjd/article/173/2/370/6616578
- https://pmc.ncbi.nlm.nih.gov/articles/PMC5350204/
- https://royalsocietypublishing.org/doi/10.1098/rsob.200223
- https://www.mdpi.com/1422-0067/17/12/2085
- https://www.nhs.uk/conditions/leg-ulcer/treatment/
- https://pubmed.ncbi.nlm.nih.gov/23817703/
- https://pmc.ncbi.nlm.nih.gov/articles/PMC6984409/
- https://www.wjgnet.com/1948-9358/full/v6/i1/37.htm
- https://pmc.ncbi.nlm.nih.gov/articles/PMC6368931/
- https://pubmed.ncbi.nlm.nih.gov/36367798/