What’s New in Wound Healing: Treatment Advances and Microbial Insights

Abstract

Recent advancements in wound healing are reshaping clinical practice by integrating dermatology, cutaneous microbiome research, and technology. This article discusses new diagnostic tools, such as imaging devices and microbial composition analysis, that enhance our understanding of wound environments. It highlights the importance of wound bed preparation and explores innovative treatment methods for optimal wound healing, including debridement techniques like ultrasound-assisted methods, hydrosurgery, and larval therapy. The evolution of wound management is further illustrated through the use of cellular and acellular matrix products and cellular therapies involving whole blood products. We also present the latest insights on the wound microbiome and antimicrobial treatments, including advanced dressings and antibiofilm surfactants. Finally, the potential of gene therapy for complex conditions like epidermolysis bullosa is discussed as a promising model for advancing wound healing. This review synthesizes current research to improve dermatological practices and patient outcomes in wound care.

Key Points

Dermatologists should focus on wound bed preparation by utilizing the TIME framework (Tissue, Inflammation/Infection, Moisture Imbalance, Epithelial Edge Advancement) to maximize healing and improve the success of cellular and acellular matrix products, while also choosing the most effective debridement method.

Understanding the makeup of the skin microbiome is vital in the wound healing process; a balanced microbial community aids in tissue repair, infection prevention, and overall healing, whereas imbalances can result in chronic wounds and hinder recovery.

The future of wound healing will revolve around personalized care, leading to more effective treatments and improved healing outcomes.

Introduction

The field of wound healing is witnessing significant advancements, driven by ongoing research and innovation in dermatology. Understanding emerging treatment options is essential for integrating dermatology, cutaneous microbiome research, and technology into clinical practice. This article provides an overview of innovations in wound healing pertinent to dermatology, including new diagnostic tools like imaging devices and microbial composition analysis, as well as wound bed preparation techniques such as ultrasound-assisted methods, hydrosurgery, and larval therapy. It also discusses the latest data on the microbiology of wounds, focusing on antimicrobial treatments like advanced dressings and antibiofilm surfactants, along with the evolving role of the wound microbiome. Furthermore, it covers advanced options like cellular and acellular matrix products (CAMPs), whole blood therapies, and exosomes and the potential of gene therapy for complex conditions like epidermolysis bullosa (EB) to act as a model to advance personalized wound healing treatments. This article acknowledges limitations in clinical practice, such as product availability, insurance coverage variations, and the distinct characteristics of each wound type. These factors can significantly influence the selection and efficacy of treatments, making it crucial to consider clinical and financial aspects when determining the most appropriate approach for optimal wound healing.

Methodology

A comprehensive literature search was conducted, focusing on the most recent data regarding new therapeutics in wound healing. Keywords like “chronic wounds,” “infected wounds,” “wound healing,” “novel therapies,” and “advanced wound care” were used. The search included peer-reviewed articles, clinical trials, systematic reviews, and meta-analyses relevant to dermatologists in practice. Topics were selected based on emerging treatments that have demonstrated promising results in recent studies or have gained attention for their potential in improving wound healing outcomes. Additional therapies may exist, but their inclusion falls outside the scope of this paper.

Wound Diagnostics

Sampling of Wound Exudate

Advancements in treatment and wound diagnostics can improve the management of acute and chronic wounds. Traditionally, wound exudate (WE) analysis focused on specific proteins linked to healing outcomes [1–3]. However, a recent study by Doerfler et al. examined over 800 exudate samples from healing and nonhealing wounds, developing a cell-based biomarker assay to measure fibroblast proliferation instead. This assay differentiated wound types and monitored their progress, showing a strong correlation between wound chronicity and the inhibitory effects of exudates on fibroblast growth, with diagnostic sensitivity of 76–90%. Treatment testing aligned with clinical observations, highlighting the potential of the assay as a new therapeutic option [4]. Jozic and Tomic-Canic noted that a standardized methodology for analyzing WE could enhance personalized wound care [5].

An ongoing clinical trial (NCT04614038) is evaluating the effectiveness of a portable, disposable, non-invasive, and non-contact device that continuously monitors wound alkalinity in diabetic foot ulcers (DFUs), pressure ulcers (PUs), and venous leg ulcers (VLUs). By analyzing WE collected from freshly discarded dressings of 450 participants over a 12-week period, the device aims to facilitate the early identification of slowly healing or non-healing ulcers, potentially altering their treatment trajectory based on this information [6].

Identification of Wound Microbiota

Recently, advanced next-generation sequencing has been introduced to enhance the personalization of wound care and tackle the limitations of traditional cultures known to underestimate bacterial load [7]. Notably, researchers have utilized 16S ribosomal RNA (rRNA) gene and metagenomic sequencing to monitor how microbial communities change in DFUs after treatments like debridement [8] and topical surfactant gel (SG) [9] as well as during the clearance of infections in burn wounds [10].

The most comprehensive study, which used 16S rRNA sequencing on 2963 chronic wound samples, found that Staphylococcus and Pseudomonas species predominated, along with pathogenic anaerobes, regardless of the underlying cause of the wound [11]. A recent study observed a negative correlation between the abundance of Corynebacterium and Streptococcus in chronic wounds of patients with severe pain [12]. It also found a high prevalence of Streptococcus epidermidis [12], a skin commensal that, depending on the strain, can form biofilms and impair wound closure [13].

Using metagenomic shotgun sequencing, Kalan et al. linked multi-drug-resistant Staphylococcus aureus and anaerobes to poorer healing in DFUs, while debridement reduced pathogens and increased microbiota diversity, improving healing outcomes [8]. In contrast to S. aureus, bacteria commonly detected in chronic wounds, Alcaligenes faecalis were associated with decreased wound severity and improved healing [14]. The complexity of chronic wound microbiota supports the notion against empiric use of antibiotics, suggesting that microbiota composition in chronic wounds could guide personalized treatment strategies. Studies have led to polymerase chain reaction-based kits for bacterial identification and antibiotic-resistant markers [15–17], but their clinical utility requires further validation in randomized controlled trials (RCTs).

Ring et al. studied the skin microbiome of individuals with and without hidradenitis suppurativa (HS) using the 16S rRNA sequencing approach. The study found that HS wounds were primarily colonized by Corynebacterium and Porphyromonas/Peptoniphilus species, with the latter absent in healthy controls, suggesting its role in HS pathogenesis [18]. The predominance of anerobic pathogens in HS may also explain the positive effects of ertapenem treatment for severe cases of HS [19]. Understanding microbial composition and functional gene content of HS wounds could lead to new diagnostic, therapeutic, and management strategies, but these approaches have not yet been fully explored.

In contrast to pathogens, multiple studies have shown commensal microbes may promote healing by enhancing antimicrobial peptide (AMP) production. For example, S. epidermidis boosts AMP expression to combat infections from Streptococcus and S. aureus [20–22]. These beneficial microbes not only limit infection but may also enhance the regeneration of skin and tissue, highlighting the potential therapeutic role of the skin microbiome in wound management and healing.

Imaging Devices

A new point-of-care autofluorescence imaging device is useful for digital wound measurement and bacterial load assessment. This handheld device emits light at 405 nm and uses a dual-band filter (590–690 nm) to detect bacteria. Porphyrin-producing bacteria emit red fluorescence, Pseudomonas species emit cyan fluorescence, and collagen and elastin emit green fluorescence signals [7]. In an RCT with 56 patients with non-infected DFUs, the autofluorescence group showed a 40.4% wound area reduction at 4 weeks, compared to 38.6% for controls, and 91.3% versus 72.8% at 12 weeks [23]. This non-invasive device continuously monitors bacterial load and tissue health, providing real-time insights to guide treatment.

Near-infrared spectroscopy (NIRS) assesses tissue health by measuring unbound and oxygen-bound hemoglobin at 750 nm and 850 nm, respectively, calculating the oxygenated-to-deoxygenated ratio [24]. NIRS penetrates deeper, benefiting individuals with darker skin, and allows for multi-angle imaging. In a case of a 38-year-old woman, NIRS showed only 11% oxygen saturation at the post-surgical incision site, below the 40% threshold for healing, indicating a risk of poor outcomes [24]. Additionally, in an RCT of 81 patients with hard-to-heal VLUs, NIRS predicted healing outcomes showing improved tissue oxygenation in healing ulcers undergoing hyperbaric oxygen therapy, but not in non-healing ones [25]. NIRS can help guide proactive tissue management to prevent complications.

Wound Bed Preparation

Dermatologists should prioritize wound bed preparation (WBP) as it is essential for successful integration of advanced cellular therapy and overall healing. The TIME framework (Tissue, Inflammation/Infection, Moisture Imbalance, Epithelial Edge Advancement) offers a systematic approach to WBP, focusing on identifying wound causes, evaluating patient health, and tailoring treatment plans based on whether the wound is healable, requires management, or is non-healable [26–28].

Debridement plays a critical role in the WBP process. Options include mechanical, biological, enzymatic, and autolytic debridement. Surgical debridement (SD) remains the standard for chronic wounds, but challenges like pain, blood loss, level of expertise, and visibility can impact its effectiveness [29]. Choosing the right debridement method(s) is vital for optimal cellular therapy adherence and successful healing in wound care (Table 1). The following sections will highlight the most recent advances and data in WBP.

Table 1.

Different debridement methods by level of evidence, advantages, disadvantages, and setting

Debridement method	LOE*/study type	Authors	Explanation	Advantages	Disadvantages	Setting
Autolytic	Level 1 Systematic review of 14 studies (11 RCTs) and meta-analysis of 3 RCTs for autolytic debridement of DFUs [162]		Use of body’s own enzymes and moisture to break down necrotic tissue using moist dressings [159, 160]	Convenient; affordable; non-invasive; painless; suitable for patients who cannot tolerate aggressive methods; maintains moist environment conducive to healing	Slower process; not suitable for infected or deep wounds; requires patient compliance with dressing changes; may lead to periwound maceration	Ideal for long-term care; outpatient and home health care with trained personnel
Biological	Level 1 Systematic review of 8 RCTs and meta-analysis of 4 RCTs for VLUs, DFUs, MLUs, burns, bedsores [68]		Use of living organisms to consume necrotic tissue (e.g., maggots of Lucilia sericata)—can be used as free-range (direct) versus larval bag (indirect) [68, 159, 160]	Highly selective; addresses biofilm and chronic infections; reduces time to debridement; reduces amputation rates [161]	Patient acceptance; may not significantly increase complete healing; limited availability; requires trained personnel	Specialized wound care centers
Mechanical	Level 2 Systematic review and meta-analysis of 11 RCTs for DFUs [43]		Removal of necrotic tissue using force or abrasive techniques (e.g., wet-to-dry dressings, fiber pads, wound irrigation ultrasound, and whirlpool techniques) [160]		May be painful; nonselective—can damage viable tissue; risk of bacterial contamination with prolonged use or maceration of periwound if overusing	Utilized in outpatient or home health care with trained personnel
Ultrasound-assisted			Use of ultrasonic energy to emulsify and remove necrotic tissue (indirect versus direct devices) [54, 159]	Non-invasive/non-contact; quick	Requires specialized equipment and trained personnel; higher cost compared to tradition methods; protective clothing recommended [54]	Advanced wound care centers or hospital-based wound units
Hydrotherapy	Level 2 Systematic review of seven studies (2 RCTs) and meta-analysis of 2 RCTs for DFUs, VLUs, PUs, AUs, dehisced incisions [51]		Combines pressurized water with suction to remove tissue [54, 159]	Quick and precise; minimizes blood loss; access to hard-to-reach areas; suited for larger wounds	Higher cost for equipment; requires trained personnel and sterile environment; may be painful; cross-infection	Surgical settings or outpatient clinics
Monofilament polyester fiber pad	Level 3 Observational study (n = 57) for VLUs, AUs, DFUs, PUs, post-operative wounds [55], and pilot study (n = 11) for DFUs, VLUs, MLUs [56]		Fiber pads that loosen and absorb necrotic tissue [54]	Well-tolerated, gentle, safe, and no shedding of pad; effective with single use and on dry or heavy exudated wounds; suitable for trained patients or caregivers	Higher cost; limited depth of debridement; operator dependent based on pressure applied; not ideal for infected wounds; some slough may remain if not used thoroughly	Outpatient clinics, wound care centers, home care
Enzymatic	Level 1/2 Systematic review of 20 studies (19 RCTs) for PUs, burns, VLUs, DFUs, and pilonidal sinus disease and meta-analysis of 10 RCTs [164] (collagenase based); systematic review of 7 studies (3 RCTs) for burns [70] and RCT by [75] for VLUs (bromelain based)		Topical application of exogenous enzymes to wound surface to remove necrotic tissue (e.g., collagenase-based products, bromelain-based enzymes) [159, 160]	Suitable when surgical debridement not available [164]; spares healthy tissue; minimal to no discomfort; can be done at home	Requires frequent application and monitoring; may cause irritation; not recommended for infected wounds or very deep wounds; slower process; may not be as effective for heavily necrotic wounds; costly long term	Outpatient wound care centers, home care
Surgical/Sharp†	Level 3 Cohort study (n = 53) for VLUs [165]		Removal of non-viable tissue using sharp instruments (e.g., scissors, curette, scalpels, forceps) [159–161]	Fast and effective; removes large amounts of necrotic tissue; can be performed at bedside or in operating room; reduces number of microorganisms and aids in biofilm control [160]	Requires expertise; requires adequate vascular supply; can be painful without proper anesthesia; caution in patients with bleeding disorders or anticoagulation therapy	Common in clinics, hospitals, and home health care with trained personnel

AU arterial ulcer, DFU diabetic foot ulcer, LOE level of evidence, MLU mixed leg ulcer, PU pressure ulcer, RCT randomized controlled trial, VLU venous leg ulcer

*Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence: level 1-systematic review of RCTs; level 2-RCT; level 3-non-randomized controlled cohort/follow-up study; level 4-case-series, case-control, or historically controlled studies; level 5-mechanism-based reasoning

^†Although robust data are lacking, still recommended as “gold” standard

Mechanical Debridement

Ultrasound-Assisted Wound Debridement

Ultrasound energy, initially used for diagnostics, is now used therapeutically in wound care through ultrasound-assisted wound debridement (UAWD). Devices are classified as non-contact low-frequency ultrasound (NLFU) and direct-contact low-frequency ultrasound (DLFU), utilizing cavitation and acoustic streaming to enhance tissue repair [30]. Cavitation is the formation of micron-sized bubbles in a fluid medium that expand, vibrate, and compress under ultrasound energy, promoting cellular activity and tissue dynamics to facilitate the removal of necrotic tissue [30, 31]. Acoustic streaming describes the microscopic movement of fluids induced by ultrasound pressure waves, which enhances circulation and nutrient delivery [30, 31]. NLFU has proven effective for DFUs [30–32], VLUs [31–33], PUs [32, 34, 35], arterial ulcers (AUs) [32, 36], chronic infected wounds [32, 37], and burns [38]. Additionally, success has been reported on digital ulcers secondary to limited cutaneous systemic sclerosis [39], a facial necrotic hemangioma in a 5-month-old [40], a radiation-induced wound [41], and various infected surgical wounds [42].

A 2024 systematic review by Liu et al. found that patients with DFUs treated with UAWD had over double the healing improvements compared to those not treated, with a reduction in healing time by about 12 days and wound size by 14% [43]. UAWD serves as an alternative when standard debridement is not feasible. NLFU treatment has been shown to reduce fibrinogen levels, bacterial burden, and inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-8 at the molecular level, promoting enhanced wound healing in chronic VLUs compared to standard of care (SOC) [33]. UAWD is a valuable and quick option for wound management.

Using a similar acoustic mechanism, acoustic pressure therapy combined with negative pressure therapy led to significant healing in six patients with large, infected surgical wounds, achieving up to 100% reduction in wound volume and surface area, as well as a notable decrease in drainage [42]. This combination therapy is effective in reducing both wound volume and surface area, while also helping to decrease drainage, which can be key factors in improving recovery times and reducing complications in wound care.

Hydrosurgery Debridement

Hydrosurgery, or hydrotherapy, uses a high-speed fluid jet to simultaneously grasp, cut, and remove tissue via a Venturi effect. The angle can be adjusted for aggressive or gentle debridement [44]. Various modalities exist; however, baths are less favored due to contamination risks [45–47]. Hydrotherapy typically has few side effects, though excessive force can damage healthy tissue, leading to the recommended pressure range of 4–15 psi [46, 48].

A prospective randomized study found no significant differences in wound closure, bacterial reduction, or costs between hydrosurgery and traditional SD in 40 patients with chronic wounds, but hydrosurgery resulted in less intraoperative blood loss [49], benefiting patients on anticoagulants. In another RCT, involving 137 patients with burns, hydrosurgery led to lower Patient and Observer Scar Assessment Scale scores and improved scar quality due to better dermal tissue preservation from gentle debridement [50]. Hydrosurgery is effective for DFUs, VLUs, AUs, PUs, and dehisced incisions [51]. A review by Shimada et al. showed that over 70% of cases achieved satisfactory debridement after one session, with the angled handpiece allowing access to hard-to-reach areas [51, 52].

Monofilament Polyester Fiber Pad

Monofilament polyester fiber pad (MPFP) consists of over 18 million polyester fibers in a 10-cm² pad [53, 54]. In an observational study of 57 patients with chronic wounds, successful debridement was achieved in 93.4% of cases with MPFP use, averaging under 3 min per procedure—much faster than the 9 min for SD—with no adverse incidents. It preserved healthy skin, with 45% of patients reporting no pain and 55% experiencing only slight discomfort for about 2 min, without the need for analgesia [55]. A smaller study of 11 participants by Haemmerle et al. found that a single MPFP application effectively debrided chronic leg ulcers with heavy discharge and necrotic layers, highlighting its ease of use and good tolerability [54, 56]. Available in the USA, MPFP is suitable for sensitive areas, can be safely used by non-specialists, and is time efficient, indicating its potential for use in home settings as a form of mechanical debridement.

Biological Debridement

Larval therapy (LT) is a cost-effective biological method for WBP that uses sterilized larvae from green bottle flies (e.g., Lucilia sericata). Approved by the Food and Drug Administration (FDA) in 2004, LT disinfects wounds, promotes granulation tissue growth, and removes necrotic tissue while minimizing tissue loss [57]. Despite its benefits, LT is underused due to patient stigmatization, pain, lack of insurance coverage, and clinician training needs [58, 59]. LT can be applied in two ways: free-range (FR), where larvae are placed directly on the wound, and larval bag (LB), which contains larvae for indirect application [60]. Clinical evidence shows LT improves debridement in VLUs, leg ulcers of mixed etiology, and PUs [61–66]. Dehghan et al. found FR larvae cleaned DFUs in an average of 4 days, compared to 9 days for LB, and removed 1.8 times more dead tissue [60]. Additionally, LT significantly reduced bacteria like S. aureus and Pseudomonas aeruginosa in DFUs [67]. A recent meta-analysis on four RCTs by Lam et al. report that the likelihood of achieving complete debridement was more than twice as high with LT compared to conventional therapy; however, the findings were not statistically significant [68]. Given its efficacy and popularity for chronic, nonhealing wounds [69], LT should not be a last resort.

Enzymatic Debridement

Enzymatic debridement utilizes a range of agents, commonly with bacterial enzymes such as collagenases from Clostridium histolyticum and Bacillus subtilis, and plant-derived enzymes like papain and bromelain [70]. These products are available in the clinical setting and pharmacies, with insurance coverage typically requiring documentation of medical necessity and prior authorization. Bromelain-based enzymes (BBE), extracted from the pineapple plant (Ananas comosus), were initially used for burns and are now approved for chronic wounds [71, 72]. In a study of 30 patients with burns, those receiving a BBE mixture avoided a split-thickness skin graft in 47% of cases [73]. However, caution is warranted for foot burns in diabetic patients, as Berner et al. reported that four patients worsened after BBE treatment, necessitating surgery [71].

In 2018, Shoham et al. assessed the safety and efficacy of BBE in 24 patients with DFUs, VLUs, and post-surgical wounds, noting an average debridement rate of 68% after 3.5 sessions, with 17 wounds achieving 85% debridement after 3.2 sessions [72]. Later, a 2021 multicenter RCT by Shoham et al. found that bromelain led to a significantly higher complete debridement rate than its gel vehicle (55% vs. 29%, p = 0.047) [74]. A new formulation (EX-02) achieved complete debridement in 63% of patients with VLUs, compared to 30.2% for the gel vehicle and 13.3% for non-surgical SOC (p < 0.001) [75]. A more recent systematic review by Salehi et al. evaluated clinical trials on debriding agents for burn wounds and found that collagenase is effective for burns covering less than 25% of total body surface area. However, BBE were more effective for deep burns, reducing the need for grafting without significant adverse effects [70]. BBE presents a versatile option for various wound types, including post-surgical wounds.

Infection Control and Antimicrobial Guidance

Chronic wounds promote microbial growth and biofilm formation, leading to antimicrobial resistance [76]. A 2017–2019 study of 239 infected wound samples, including surgical wounds, found that 57.9% contained Gram-negative bacteria, with P. aeruginosa (40.2%) and Escherichia coli (20.7%) as the most prevalent. Among Gram-positive bacteria, S. aureus was the most common (79.4%). Alarmingly, 88.2% of the isolates were antibiotic resistant [77]. Systemic antibiotics may be ineffective in biofilm-resistant wounds or poorly perfused tissues, requiring alternative treatments [78].

Nanoparticle Antimicrobial Dressings

Nanotechnology has led to the development of silver nanoparticle (AgNP) dressings, which enhance drug delivery and activate effectively in biofilm environments [79]. Unlike silver sulfadiazine, which can cause systemic toxicity, AgNPs allow for controlled release, though mild side effects like contact dermatitis may occur [80–82]. AgNPs are effective against various bacteria, including E. coli, S. aureus, Streptococcus pyogenes, and Klebsiella pneumoniae, and are especially useful for infected wounds [83–85]. However, they do not benefit clean, non-infected wounds, may slow healing, and have been associated with the emergence of silver resistance in clinical settings [80, 86–88]. In contrast, copper dressings have been shown to reduce wound area more effectively than silver in some non-infected wounds [89]. For burn injuries, AgNP dressings lower infection rates, reduce pain, and decrease costs [90]. A new silver-based dressing with two antimicrobial layers (TLG-Ag) is available in the USA and has demonstrated a 57.4% median area reduction in chronic wounds at risk for local infection in an observational study of 2270 patients [91].

Emerging Antimicrobial Dressings

There are many antimicrobial dressings available; however, their necessity in general dermatology practice has not been thoroughly examined. In conditions like HS, where dysbiosis is a contributing factor, these dressings may help manage microbial colonization, which in turn reduces inflammation and odor [92]. A prospective cohort pilot study showed that patients with HS experienced significant improvements in quality-of-life (QOL) scores when provided with a kit of wound dressings containing dialkylcarbamoyl chloride (DACC) that traps bacteria in the dressing through hydrophobic interaction [93]. Recent coverage denials for antimicrobial dressings in the EU, particularly in Germany where outpatient care budgets are fixed, led to a study showing that DACC dressings reduce costs by 21% [94]. These findings highlight the potential of DACC to improve both clinical outcomes and cost-efficiency in managing HS and other chronic wounds.

Bioelectric wound dressing (BEWD) is a novel dressing that was recently introduced to the market. A BEWD offers a unique mechanism of action for wound management, using electrical stimulation to promote healing and reduce infection and inflammation [95]. In a study by Yaghi et al., seven patients with moderate to severe HS treated with BEWD showed a 57% reduction in wound area after 4 weeks, compared to 43% with standard petrolatum and gauze (i.e., standard wound care (SWC)). Among those treated for 8 weeks, recurrence occurred in two of four SWC patients, while none recurred with BEWD [96]. Further studies are needed; however, BEWD may emerge as an alternative solution for acute and chronic wound management.

Antibiofilm Surfactants

To further address the challenges of biofilms in wound care, antibiofilm surfactants offer a promising avenue for improving treatment efficacy. The primary surfactants utilized in wound care are betaines and poloxamers [97]. These agents are effective in loosening cellular debris, which helps to disrupt and prevent biofilm formation. Additionally, they can mobilize materials that would otherwise remain unmixed due to molecular incompatibility [97–99]. Some potential limitations include the ingredients of the gel interfering with other antibacterial technologies, like silver [7].

Malone et al. studied a concentrated SG combined with SWC for chronic biofilm infections in DFUs. Over 6 weeks, SG reduced microbial load by 84% in seven of ten samples [100]. Similarly, Ratliff found SG effective in cleaning slough and necrotic debris in 18 patients with VLUs and AUs over 4 weeks, leading to improved healing [101]. Prioritizing biofilm prevention can enhance healing, reduce infections, and improve overall patient QOL [102].

Advanced Wound Care Technologies

Cellular and Acellular Matrix Products

There are more than 70 CAMPs available on the market, which can be classified as cellular, containing living cells, or acellular, which do not [103]. This section provides an overview of the most clinically relevant information, highlighting the CAMPs with the most high-quality data and those most readily available to clinicians, along with an introduction to the relatively newer placenta-derived tissue, while recognizing that a wealth of additional data exists beyond the scope of this paper. For all CAMPs, in addition to evidence, pragmatic considerations such as shelf life and cost should be considered. Prior authorization and documentation of chronicity are often required for insurance coverage.

Among cellular CAMPs, the bilayered living cellular construct (BLCC) remains widely used and most studied [104–106], but is costly (over US$30/cm²) [107]. In a study with 120 patients with hard-to-heal VLUs, BLCC treatment plus compression therapy led to almost half of the ulcers achieving complete closure by 6 months (p < 0.005) (Table 2) [106]. Importantly, the mechanism of BLCC is based on shifting the trajectory of the wound healing process from chronic to acute physiological healing [108]. BLCC has also shown effectiveness for EB [109] and pyoderma gangrenosum [110].

Table 2.

Advanced wound care technologies

Category	Subgroup	LOE*/study type	Authors	Indications	Study outcomes		Advantages	Disadvantages
CAMPs	Cellular BLCC	Level 1 Systematic review of RCTs for DFUs and VLUs [104]		Non-infected partial and full-thickness VLUs > 1 month and full-thickness neuropathic DFUs > 3 weeks without tendon, muscle, capsule, or bone exposure that have not adequately responded to conventional ulcer therapy [107, 166]	DFU 56% of patients treated with BLCC achieved wound closure at 12 weeks, compared to 38% with SOC in an RCT (n = 208) [105]	VLU 47% of patients treated with BLCC achieved wound closure at 24 weeks, compared to 18% with SOC in an RCT (n = 120) [106]	Presence of living keratinocytes and fibroblasts with collagen matrix [166]	Cost; multiple applications required; may not be superior to other advanced therapies; cannot be used in infected wounds; pH range of 6.8–7.7 required for use [166]
	Acellular PSIS	Level 1 Systematic review of RCTs for VLUs [163]		Partial- and full-thickness wounds, including DFUs, VLUs, PUs, peripheral vascular ulcers, second-degree burns, tunneled or undermined wounds, draining wounds, surgical wounds [107, 167]	DFU 54% wound closure at 12 weeks with tri-layered PSIS, compared to 32% with SOC in an RCT (n = 82) [112]	VLU 55% wound healing at 12 weeks with PSIS, compared to 34% in SOC in an RCT (n = 120) [111]	Easy to trim to size/shape of wound; comes ready to apply; can be used in wide range of wound types	Not for patients with known sensitivity to porcine material or for third-degree burns; thin and lightweight can easily blow away while applying [167]
Cellular therapy	AWBCT	Level 2 RCT for DFUs [122]		Exuding cutaneous wounds, such as leg ulcers, PUs, DFUs, and mechanically or surgically debrided wounds [168]	41% healing rate in AWBCT group at 12 weeks, compared to 15% in control for DFUs [122]		Minimal handling of wound	Requires patient blood; not for malignant or infected wounds; not verified to be used with other products [168]
	ASCS	Level 1 Systematic review and meta-analysis of RCTs for DFUs and VLUs [169]		Acute partial-thickness thermal burn wounds in adults; in combination with meshed autografting for acute full-thickness thermal burn wounds in pediatric and adult patients [170]	ASCS group, which included DFUs and VLUs, compared to SOC or placebo had significantly reduced healing time, size of donor site for treatment, operation time, pain scores, and complications. No difference for size of treatment area, repigmentation, scar scale scores and satisfaction scores [169]		Clinic setting use; allows for dispersion of cells across larger surfaces [124]	Requires small (1.5–2.0 cm2), thin skin sample (0.15–0.20 mm) [128]
Platelet-derived therapy	PDGF	Level 1 Meta-analysis of RCTs for DFUs [132]		Deep neuropathic DFUs that extend into the subcutaneous tissue or beyond and have an adequate blood supply [130]	Use of recombinant human PDGF-BB gel for DFUs were 1.53 times more likely to achieve complete healing compared to those not receiving the treatment [132]		FDA approval for DFUs [130]	Not for malignant wounds or known hypersensitivity to components of product; not established treatment for PUs or VLUs [130]
	PRP	Level 1 Systematic review and meta-analysis of RCTs for DFUs, VLUs and MLUs [134]		Been used in DFUs, VLUs, AUs, and pilonidal disease [134]	29 RCTs involving a total of 2198 wounds of DFUs, VLUs, AUs, or MLUs found that the likelihood of complete closure was more than five times higher in the PRP group compared to the control group [134]		High number of platelets, growth factors, and cytokines [134]	Mixed results for PUs or VLUs
Extracellular vesicle therapy	Exosomes	Level 2/3 RCT in healthy controls [140] and pilot study for VLUs [141]		No FDA approval but used in various specialties including chronic wounds [136]	11 skin biopsies to healthy controls followed by injection of allogeneic platelet-derived EVs—no difference in mean healing time compared to placebo [140, 142]. Six doses over 2 weeks of topical serum-derived EVs for VLUs (n = 4) in a case-controlled pilot study—reduction in mediation surface area after 30 days compared to SOC [141, 142]		Robust pre-clinical data, multiple delivery modalities (IV, injection, or topical) [136]	None have FDA approval; high heterogeneity in manufacturing/isolation; no standardized data reporting method [136, 139]

ASCS autologous skin cell suspension, AU arterial ulcer, AWBCT autologous whole blood clot therapy, BLCC bilayered living cellular construct, CAMP cellular and acellular matrix product, DFU diabetic foot ulcer, EV extracellular vesicle, FDA Food and Drug Administration, IV intravenous, LOE level of evidence, MLU mixed leg ulcer, PDGF platelet-derived growth factor, PRP platelet-rich plasma, PSIS porcine small intestine, PU pressure ulcer, RCT randomized controlled trial, SOC standard of care, VLU venous leg ulcer

*Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence: level 1-systematic review of RCTs; level 2-RCT; level 3-non-randomized controlled cohort/follow-up study; level 4-case-series, case-control, or historically controlled studies; level 5-mechanism-based reasoning

For acellular options, porcine small intestine mucosa (PSIS) combined with compression improved healing rates in VLUs to 55% compared to 34% with compression alone [107, 111]. Cazzell et al. reported 54% wound closure at 12 weeks with tri-layered PSIS for DFUs, compared to 32% with SOC in an RCT of 82 participants (Table 2) [112]. PSIS is more affordable, costing about US$100 for the smaller size (3 × 3.5 cm, about US$9.5/cm²) and about US$200 for the larger size (3 × 7 cm, about US$9.5/cm²) [107]. In a single-center, moderate-size RCT, Tchanque-Fossuo et al. found no significant differences in DFU healing between cellular and acellular products after 12 and 28 weeks, suggesting advanced cellular products may not be essential for effective healing [107, 113].

Dehydrated human amnion/chorion membrane (dHACM) is rich in extracellular matrix components (ECM) and is primarily used for DFUs and VLUs [107]. In a multicenter RCT, 62% of patients with VLUs treated with dHACM achieved over 40% closure at 4 weeks, with average wound size reduction of 48% versus 19% [114]. In a separate 12-week study, 92.5% of DFUs healed completely, with weekly applications resulting in a mean healing time of 2.4 weeks compared to 4.1 weeks for biweekly applications. By week 4, 90% of wounds in the weekly group were healed versus 50% in the biweekly group, suggesting weekly applications may enhance healing and lower complications [115]. Lastly, cryopreserved placental membrane (CPM) costs around US$1100 and is effective for DFUs, leading to 62% complete closure compared to 21% in controls (p = 0.0001) [107, 116, 117].

CAMPs are well-known for treating chronic wounds, but they may also be useful for acute surgical wounds from Mohs micrographic surgery (MMS). Wisco presented three cases of lower eyelid defects from basal cell carcinoma (BCC) treated with dHACM, with healing times of 45 days for a 2.5 × 1.5-cm defect, 15 days for a 0.6 × 0.6-cm defect, and 18 days for a 1.2 × 1.1-cm defect [118]. In another study, four applications of dHACM facilitated healing of a 15.75-cm² scalp defect with exposed bone after MMS, resulting in complete healing within 2.5 months [119, 120]. Commercially available CAMPs can be found here [121].

Complementary Therapies

Cellular Therapy

Autologous Whole Blood Clot Therapy

Autologous whole blood clot therapy (AWBCT) is a bedside treatment that creates a provisional ECM using a patient’s whole blood. Blood is collected in an anticoagulant solution and activated with calcium gluconate and kaolin. In a recent RCT with 119 participants suffering from DFUs, AWBCT showed significantly higher healing rates (41% vs. 15%) and faster healing over 12 weeks compared to controls (Table 2) [122]. In another study, with 14 patients with complex surgical wounds, AWBCT resulted in a mean wound area reduction of 72.33% at 4 weeks, with 33.33% achieving complete closure by then, and a total closure rate of 78.54% by week 12 [123]. This method is particularly effective for challenging wound types due to compromised ECM, offering a promising biologically compatible treatment alternative with minimal handling of the wound itself.

Autologous Skin Cell Suspension (ASCS)

Autologous skin cell suspension (ASCS) is a commercially available kit that uses a “spray-on” technique with autologous skin cells, effective for treating VLUs, scars, burns, and DFUs [124–126]. In a study of 52 patients, VLUs treated with ASCS and compression therapy significantly reduced in size compared to compression alone (8.94 cm² vs. 1.23 cm²) after 14 weeks, with larger ulcers showing the most improvement, resulting in better healing, less pain, and improved QOL [124]. Gilleard et al. also demonstrated the successful use of ASCS for reconstructing donor sites from surgical flaps for BCC and for primary surgical defects after melanoma excision, highlighting its potential for utility in skin cancer reconstruction [127]. This technique can be performed in the clinic and enables effective cell dispersion across larger surfaces up to 1920 cm²; however, it does require a small (1.5–2.0 cm²), thin skin sample from patients (0.15–0.20 mm) (Table 2) [124, 128].

Platelet-Derived Therapy

Platelet-Derived Growth Factor

Becaplermin is a recombinant protein produced by introducing the gene for the B chain of platelet-derived growth factor (PDGF) into the yeast Saccharomyces cerevisiae. It exhibits biological activity like that of natural PDGF [129]. While it is FDA-approved for DFUs [130], it has also been used successfully off-label for flaps, grafts, and MMS wounds [131]. A meta-analysis indicated that patients treated with recombinant human PDGF-BB gel for DFUs were 1.53 times more likely to achieve complete healing compared to those not receiving the treatment (Table 2) [132]. The RCT of Cohen and Eaglstein showed PDGF gel-treated acute wounds healed significantly faster than antibiotic-treated wounds: 71% vs. 28% by day 10 (p = 0.0005) and 92.9% vs. 50% by day 22 (p = 0.0313). Both treatments achieved full healing by day 29, but PDGF gel also reduced wound depth more effectively at days 8 and 10 [131]. PDGF is not indicated for malignant wounds or for wounds with known hypersensitivity to any of its components, and its efficacy for treating PUs or VLUs has not been established.

Platelet-Rich Plasma

Platelet-rich plasma (PRP) uses the patient’s own blood to boost growth factor production, reducing risks of rejection and infection in acute and chronic wounds [133]. Menznerics et al. reviewed 29 RCTs involving a total of 2198 wounds of diabetic, venous, arterial, or mixed origin and found that the likelihood of complete closure was more than five times higher in the PRP group compared to the control group (Table 2) [134]. Interestingly, in pilonidal disease (PD), PRP-treated patients healed in 24 days versus 30+ days for controls, returned to normal activities faster (day 17 vs. 25), and reported better QOL scores (75 vs. 62) [133]. PRP is generally supported for enhancing wound healing, though some studies have shown mixed results or insufficient evidence for VLUs and PUs [135]. Additional data exist beyond the scope of this paper [134].

Exosome Therapies

Extracellular vesicles (EVs) are lipid bilayered vesicles secreted from cells, varying by source cell, size, cargo, and biologic activity. “Exosomes” commonly refers to vesicles sized 50–150 nm, though the terminology can be inconsistent [136]. EVs derived from mesenchymal stem cells show promise in wound healing due to their benefits on proliferation, inflammation, and remodeling as supported by pre-clinical [136] and clinical studies [137]. They are also affordable and customizable for specific wound types [136]. However, challenges like batch-to-batch variability, dosing inconsistencies, and isolation methods hinder their clinical application, affecting safety and efficacy [136, 138]. The FDA regulates EV and exosome therapies, but no products have been approved, and misleading claims exist in the market [139]. Clinicians should inform patients about the premature state of the field. A study by Johnson et al. found no difference in healing time for allogeneic platelet-derived EVs compared to placebo, while Gibello et al. reported a reduction in ulcer size with topical serum-derived EVs in a pilot study for VLUs (Table 2) [140–142]. More research is needed to standardize protocols and confirm the safety and efficacy of EVs in broader applications. Table 3 summarizes ongoing exosome trials in wound healing.

Table 3.

Exosome trials for wound healing

NCT#	Start year	Title	Status	N	Phase	Country	Primary outcome measure
NCT06391307	2024	The Role of Mesenchymal Stem Cell and Exosome in Treating Pilonidal Sinus Disease in Children	Recruiting	120	N/A	Turkey	Wound healing time at 3 weeks, cosmetic results at 2 months, skin burn rate at 2 weeks, average time to full daily activities at 1 week, pain score at 7 weeks, success rate at 7 weeks, recurrence rate at 7 weeks
NCT04173650	2024	MSC EVs in Dystrophic Epidermolysis Bullosa	Recruiting	10	2	USA	Treatment-emergent adverse events at 22 weeks, and wound healing improvement at 10 weeks
NCT04664738	2021	PEP on a Skin Graft Donor Site Wound	Active, not recruiting	8	1	USA	Acute dosing-limiting toxicities and maximum tolerated dose within the first 14 days
NCT05475418	2022	Pilot Study of Human Adipose Tissue Derived Exosomes Promoting Wound Healing	Completed	5	N/A	China	Percentage of wound healing in each group at 4 weeks
NCT02565264	2015	Effect of Plasma Derived Exosomes on Cutaneous Wound Healing	Unknown status	5	Early 1	Japan	Ulcer size and pain at 28 days

Accessed February 2, 2025. https://clinicaltrials.gov/search?cond=Exosomes&term=Wounds%20and%20Injuries

EV extracellular vesicle, MSC mesenchymal stem cell, N/A not applicable, PEP purified exosome product

Low-Level Light Therapy

Low-level light therapy (LLLT), or photobiomodulation (PBM), uses lasers and light-emitting diodes (LEDs) to non-invasively stimulate cellular processes and promote healing. By enhancing light absorption in enzymes like cytochrome c oxidase, LLLT boosts ATP production and cellular activity [143, 144]. LLLT specifically employs red light (RL, 620–700 nm) or near-infrared (NIR, 700–1440 nm) lasers [144]. A review of 13 RCTs with 361 patients indicated a 23% reduction in DFU size with LLLT, identifying optimal parameters of 632.8–685-nm wavelengths, 50 mW/cm² power, and 3–6 J/cm² energy densities, applied three times weekly for 1 month [145]. Marthur et al. found that LLLT (diode laser at 660 ± 20 nm) as an adjunct to moist dressings significantly improved DFU area reduction (37 ± 9% vs. 15 ± 5.4%) [146]. The integration of LLLT in both office and home settings enhances wound treatment accessibility. For instance, an RCT showed home-based RL and NIR LEDs effectively reduced DFU area [147], and a dual-wavelength LED device improved healing and reduced inflammation in chronic infected wounds [148]. While LEDs have addressed cost and safety challenges, the lack of standardized settings for LLLT requires expert adjustments, complicating use for non-expert clinicians and potentially impacting healing outcomes [144].

Electrical Stimulation Therapy

Electrical stimulation therapy (EST) delivers controlled electrical currents to the wound area through electrodes, mimicking the natural electrical signals of the body. These signals, generated by sodium ions moving through Na+/K+ ATPase pumps in the epidermis, help increase blood flow, tissue oxygenation, collagen organization, wound contraction, and migration and stimulation of fibroblasts essential for wound healing [149]. Modalities include direct current, alternating current, high-voltage pulsed current, low-intensity direct current, frequency rhythmic electrical modulation system (FREMS), and transcutaneous electrical nerve stimulation [149, 150]. A review of eight RCTs on EST for VLUs found significant healing improvements in five studies. For example, Santamato et al. used FREMS on 20 patients with VLUs, resulting in a 58% reduction in ulcer size after 3 weeks, compared to 24% in the control group (p < 0.01) [151]. Jankovic and Binic found FREMS significantly reduced pain levels from 8 to 2 in the treatment group, versus 7 to 5 in controls (p < 0.001) [152]. EST should be considered for chronic, painful wounds and in patients who are not surgical candidates.

Extracorporeal Shock Wave Therapy

Extracorporeal shock wave therapy (ESWT) uses high-energy acoustic waves in two primary forms: radial and focused, with some authors citing a third, defocused type [153]. In an RCT by Ottomann et al., 28 patients with acute burns needing skin grafts showed faster healing with ESWT—13.9 days vs. 16.7 days in the control group (p = 0.0001), with no complications [153, 154]. Another RCT, one with 30 patients suffering from neuropathic DFUs, found that SWC combined with ESWT led to higher closure rates (53.33% vs. 33.33%) and faster healing (60.8 ± 4.7 days vs. 82.2 ± 4.7 days; p < 0.001), with minor adverse effects resolving within a week [155].

The Role of Gene Therapy in Epidermolysis Bullosa

In May 2023, the FDA approved beremagene geperpavec (B-VEC), a non-replicating herpes simplex virus-1 vector gene therapy for treating wounds in patients 6 months and older with dystrophic EB due to collagen type VII alpha 1 chain mutations [156]. B-VEC delivers normal type VII collagen to wounds in the form of a gel mixture, promoting anchoring fibril formation [157]. In a phase III trial with 31 participants, 67% of B-VEC-treated wounds closed completely after 26 weeks, compared to 22% for placebo [158]. Advancements in similar targeted therapies may lead to new wound healing treatment options.

Conclusion

Wound healing in dermatology is rapidly advancing through new approaches and a deeper understanding of wound microbiology. By adopting the latest advancements, dermatologists can improve patient wound outcomes and healing. Ongoing research and clinical application will be key to addressing wound challenges and enhancing care quality, with the future of wound healing focused on personalized care for more effective treatments and improved recovery outcomes.

Declarations

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