PACE: randomized, controlled, multicentre, multinational, phase III study of PLX-PAD for critical limb ischaemia in patients unsuitable for revascularization: randomized clinical trial.

BACKGROUND: Revascularization is the primary treatment modality for chronic limb-threatening ischaemia (CLTI), but is not feasible in all patients. PLX-PAD is an off-the-shelf, placental-derived, mesenchymal stromal cell-like cell therapy. This study aimed to evaluate whether PLX-PAD would increase amputation-free survival in people with CLTI who were not candidates for revascularization. METHODS: People with CLTI and minor tissue loss (Rutherford 5) who were unsuitable for revascularization were entered into a randomized, parallel-group, placebo-controlled, multinational, blinded, trial, in which PLX-PAD was compared with placebo (2 : 1 randomization), with 30 intramuscular injections (0.5 ml each) into the index leg on days 0 and 60. Planned follow-up was 12-36 months, and included vital status, amputations, lesion size, pain and quality-of-life assessments, haemodynamic parameters, and adverse events. RESULTS: Of 213 patients enrolled, 143 were randomized to PLX-PAD and 70 to placebo. Demographics and baseline characteristics were balanced. Most patients were Caucasian (96.2%), male (76.1%), and ambulatory (85.9%). Most patients (76.6%) reported at least one adverse event, which were mostly expected events in CLTI, such as skin ulcer or gangrene. The probability of major amputation or death was similar for placebo and PLX-PAD (33 and 28.6% respectively; HR 0.93, 95% c.i. 0.53 to 1.63; P = 0.788). Revascularization and complete wound healing rates were similar in the two groups. A post hoc analysis of a subpopulation of 121 patients with a baseline haemoglobin A1c level below 6.5% showed improved 12-month amputation-free survival (HR 0.46, 0.21 to 0.99; P = 0.048). CONCLUSION: Although there was no evidence that PLX-PAD reduced amputation-free survival in the entire study population, benefit was observed in patients without diabetes mellitus or whose diabetes was well controlled; this requires confirmation in further studies. Trial registration: NCT03006770 (http://www.clinicaltrials.gov); 2015-005532-18 (EudraCT Clinical Trials register - Search for 2015-005532-18).

The Clinical Utility of Powdered and Flowable Matrices in Wound Repair and Tissue Regeneration.

Cellular and matrix-like products come in many forms. Among them, powdered and micronized formulations have become increasingly available and popular owing to their unique properties and advantages. Powders have increased tissue contact which many believe can enhance granulation tissue formation, they fill irregular and deep cavities, and they can be used in concert with sheet-like products and skin grafts for improved healing. Despite their advantages, powdered products do have certain limitations that hinder their use, including poor insurance coverage and a lack of CPT coding for adequate reimbursement in an outpatient setting, making their use primarily limited to the operating room. Also, most published data on powdered products consists of smaller case studies and case series, with few reports evaluating the efficacy and utility of powdered formulations compared to their sheet-like progenitors. In this manuscript, we organize available powdered matrix products by type of substrate: xenograft, allograft, placental-based, and synthetic, and review the data in support of various products in specific wound types. This review of the supporting literature provides the current body of evidence on the utility of powdered matrices in wounds.

Autologous Blood-Derived Products (ABDPs) for the Treatment of Chronic Wounds.

Autologous blood-derived therapies have emerged as a unique and promising treatment option for chronic wounds. From whole blood clots to spun-down clot constituents, these therapies are highly versatile and tend to have a lower cost profile, allow for point-of-service preparation, and inherently carry minimal to no risk of rejection or allergic reaction when compared to many alternative cellular and matrix-like products. Subsequently, a diversity of processing systems, devices, and kits have surfaced on the market for preparing autologous blood-derived products (ABDPs) and many have demonstrated preclinical and clinical efficacy in facilitating chronic wound healing. However, not all ABDPs are created equal, and the lack of standardization among product formulations and cell concentrations as well as varying complexities in preparation protocols has led to unreliable substrate viabilities and overall inconsistent conclusions on efficacy. Additionally, external factors, such as the ease of drawing blood, the health of a patient's blood, and the reimbursement landscape have dissuaded some practitioners from incorporating ABDPs into an algorithm of care for recalcitrant wounds. Here, we attempt to categorize ABDPs into "classes" and examine their efficacy, advantages, and limitations when used as both a primary therapy and an adjunct for treating chronic wounds as well as comment on some potential considerations that may help gear future product development and application.

Circulating endothelial precursor cells are associated with a healed diabetic foot ulcer evaluated in a prospective cohort study.

The goal of this multicentre study was to evaluate whether circulating endothelial precursor cells and microparticles can predict diabetic foot ulcer healing by the 16th week of care. We enrolled 207 subjects, and 40.0% (28.4, 41.5) healed by the 16th week of care. Using flow cytometry analysis, several circulating endothelial precursor cells measured at the first week of care were associated with healing after adjustment for wound area and wound duration. For example, CD34+ CD45dim , the univariate odds ratio was 1.19 (95% confidence interval: 0.88, 1.61) and after adjustment for wound area and wound duration, the odds ratio was (1.67 (1.16, 2.42) p = 0.006). A prognostic model using CD34+ CD45dim , wound area, and wound duration had an area under the curve of 0.75 (0.67, 0.82) and CD34+ CD45dim per initial wound area, an area under the curve of 0.72 (0.64, 0.79). Microparticles were not associated with a healed wound. Previous studies have indicated that circulating endothelial precursor cells measured at the first office visit are associated with a healed diabetic foot ulcer. In this multicentred prospective study, we confirm this finding, show the importance of adjusting circulating endothelial precursor cells measurements by wound area, and show circulating endothelial precursor cells per wound area is highly predictive of a healed diabetic foot ulcer by 16th week of care.

Best practice for wound repair and regeneration use of cellular, acellular and matrix-like products (CAMPs).

There are currently over 80 biomaterials derived from autologous, allogeneic, synthetic and xenogeneic sources, or a combination of any or all these types of materials, available for soft-tissue coverage to effect wound closure. Often generically referred to as cellular and/or tissue-based products (CTPs), they are manufactured under various trade names and marketed for a variety of indications.

Median nerve somatosensory evoked potential alarm related to head and neck positioning for carotid surgery.

Head positioning in carotid surgery represents an often overlooked but sensitive period in the surgical plan. A 53-year-old male presented a significant decrement in median nerve somatosensory evoked potential (mSEP) following head and neck positioning for carotid pseudoaneurysm repair before skin incision.Neurophysiological monitoring was performed with mSEP and electroencephalography early during the patient's preparation and surgery. Within five minutes after rotation and extension of the head to properly expose the surgical field, the contralateral m-SEP significantly decreased in both cortical (N20/P25) and subcortical (P14/N18) components. Partial neck correction led to m-SEP improvement, allowing to proceed with the carotid repair. We discuss possible underlying pathophysiological mechanisms responsible for these changes and highlight the relevance of an early start on monitoring to avoid neurological deficits.

Acellular Fish Skin for Tissue Replacement.

In modern practice, xenografts play a crucial role in wound management due to their regenerative properties. Of the various xenografts currently available on the market, acellular fish skin (AFS) grafts have emerged as a more effective alternative to existing xenografts and other standard of care (SOC) treatments for wound healing. Since AFS grafts require minimal processing, they maintain their structural integrity and natural properties, including an abundance of Omega-3 fatty acids, which is a distinctive, pro-regenerative feature. AFS grafts are also unique in that they are not derived from mammalian tissue, so there is no risk of viral transmission and no cultural or religious barriers to use. AFS grafts have been shown to be more cost-effective in the treatment of diabetic foot ulcers (DFUs) and result in a higher percentage of healed wounds, fewer amputations, and better patient quality of life. Several studies and case reports have highlighted the versatility of AFS in not only acute and chronic wound healing, but also for burn wound skin regeneration. Additionally, AFS may have promise as an implantable biologic matrix for suture line reinforcement in hernia repairs or breast and dura reconstruction.

Implantable Biologics for Soft Tissue Surgery Reinforcement.

Soft tissue reinforcement focuses on medical grafts that are designed to support and regenerate soft tissue under or near suture lines. Soft tissue is defined as areas of similarly specialized cells that function to connect, support, and surround other structures and organs of the body. These tissues include skin, subcutaneous tissue, fascia, ligaments, tendons, fibrous tissues, fat, synovial membranes, and muscle. Most of the implantable devices used for this purpose are made of collagen, the most abundant protein in mammals and a key component of the extracellular matrix of soft tissues that allows for tissue repair. For suture line reinforcement, exogenous collagen from various sources is implanted under or in continuity with the suture line to allow for increased strength and better healing. First introduced in the field of breast reconstruction, this practice is now also used in hernia repair, dural repair, vaginal slings, amputation reinforcement, tendon repair reinforcement, and even dental soft tissue regeneration.

The Shift to Synthetics: A Review of Novel Synthetic Matrices for Wound Closure.

Since the late 1990s, a growing number of "skin substitutes" have become available to practitioners seeking to heal large surface wounds. These extracellular matrices were originally from xenograft sources, and then from very highly engineered living human cellular tissues. More recently, they consist of biosynthetic materials that are combinations of silicone, collagen and chondroitin. The list of xenograft materials as well as minimally manipulated human tissues, such as human skin-, amniotic- and placental-based products, has grown exponentially. Over the last 5 years, truly synthetic materials have become part of the armamentarium available for closing large wounds. The first notable product in this category was made of polyurethane. These purely synthetic products do not have any components made of naturally occurring structures, such as collagen. In this review, we seek to create a rudimentary framework in which to understand these synthetic products and to review the current literature that supports the use of these novel yet intriguing therapies.

Further evidence that wound size and duration are strong prognostic markers of diabetic foot ulcer healing.

Diabetic foot ulcers (DFU) are a critical problem for those with diabetes mellitus. Predicting the healing likelihood of a DFU is important to implementing appropriate care, allocating resources, having access to advanced therapies, having successful clinical trials, calibrating clinical trial results, and providing information to administrative entities on patient and provider outcomes. Prognostic modelling can also be important when attempting to compare results across trials or care centres. In a prospective cohort study, we demonstrate and replicate that simple wound characteristics like wound area and wound duration can be used to predict wound healing by the 16th week of care. The models were based on previous literature and replicated using a machine learning algorithm. The use of wound duration and wound area in a prognostic model continues to be important when comparing study results, centre-based outcomes, as well as designing clinical trials.

The impact of the SARS-CoV-2 pandemic on the management of chronic limb-threatening ischemia and wound care.

In the wake of the coronavirus pandemic, the critical limb ischemia (CLI) Global Society aims to develop improved clinical guidance that will inform better care standards to reduce tissue loss and amputations during and following the new SARS-CoV-2 era. This will include developing standards of practice, improve gaps in care, and design improved research protocols to study new chronic limb-threatening ischemia treatment and diagnostic options. Following a round table discussion that identified hypotheses and suppositions the wound care community had during the SARS-CoV-2 pandemic, the CLI Global Society undertook a critical review of literature using PubMed to confirm or rebut these hypotheses, identify knowledge gaps, and analyse the findings in terms of what in wound care has changed due to the pandemic and what wound care providers need to do differently as a result of these changes. Evidence was graded using the Oxford Centre for Evidence-Based Medicine scheme. The majority of hypotheses and related suppositions were confirmed, but there is noticeable heterogeneity, so the experiences reported herein are not universal for wound care providers and centres. Moreover, the effects of the dynamic pandemic vary over time in geographic areas. Wound care will unlikely return to prepandemic practices. Importantly, Levels 2-5 evidence reveals a paradigm shift in wound care towards a hybrid telemedicine and home healthcare model to keep patients at home to minimize the number of in-person visits at clinics and hospitalizations, with the exception of severe cases such as chronic limb-threatening ischemia. The use of telemedicine and home care will likely continue and improve in the postpandemic era.

How to Decide Upon an Appropriate Post-Operative Dressing: 2022.

In the current era, there are numerous advanced postoperative dressings. The ideal postoperative dressing is one that is thought to improve patient comfort, manage postoperative drainage, potentially allow for visualization of the wound, improve postoperative healing, and possibly reduce bacterial invasion. However, many advanced surgical dressings have shown increased ease of handling and increased patient comfort, but have not shown true superiority with regard to objective criteria. To ease the overall evaluation of such products, we have categorized them as standard of care dressings, engineered dressings, antimicrobial engineered dressings, skin glues and adhesives, and closed incisional negative pressure wound therapy. Among these categories, closed incisional negative pressure wound therapy has repeatedly shown superior subjective and objective outcomes. However, due to cost constraints, this therapy is not ideal for everyone. In many cases, the postoperative dressing should be dictated by the type of surgery, the location of the surgery, and the comorbidities of the patient. The authors will review the appropriate indications for the use of all categories of postoperative dressing and identify specific items that have shown great promise. The current guidelines will also be reviewed.

Skin Expansion Technology in Acute Burns and Chronic Wounds.

The ability to grow skin has long been a topic of study and therapeutic interest. Currently, the main ways of doing this are 1) by placing tissue-expansion devices in the subcutaneous space and expanding skin over time, which can then be moved to cover contiguous structures, and 2) via processes that require relatively long (30 days) incubation periods to grow the patient's autogenous skin into laminar sheets. Over the past five years, there have been significant developments in the ability to expand skin cells, either at the bedside or in the laboratory, but much more rapidly than with previous methods. We explore and discuss the current skin cell-expansion techniques, focusing on point-of-care therapeutic interventions that can be used in the burn population as well as the chronic wound population, hair follicle stem-cell incubation techniques and studies supporting this therapy, as well as micro bullae grafting, and morcellated skin cell therapy. The current data supporting these therapeutic interventions and their current direction are outlined in detail.

Endotheliitis in Coronavirus Disease 2019-Positive Patients After Extremity Amputation for Acute Thrombotic Events.

BACKGROUND: Both arterial and venous thrombotic events of the extremities occur in coronavirus disease 2019 (COVID-19) infection, but the etiology of these events remains unclear. This study sought to evaluate pathology specimens of COVID-19-positive patients postamputation, who were found to have Rutherford 3 acute limb ischemia requiring amputation. METHODS: A retrospective review was performed of all vascular surgery emergency room and inpatient consultations in patients who presented to the Mount Sinai Health System from March 26, 2020, to May 10, 2020. Pathology specimens were examined using hematoxylin and eosin stain. The specimens were assessed for the following: inflammatory cells associated with endothelium/apoptotic bodies, mononuclear cells, small vessel congestion, and lymphocytic endotheliitis. Of the specimens evaluated, 2 patients with a known history of peripheral vascular disease were excluded. RESULTS: Inflammatory cells associated with endothelium/apoptotic bodies were seen in all 4 patients and in 4 of 5 specimens. Mononuclear cells were found in 2 of 4 patients. Small vessel congestion was seen in all patients. Lymphocytic endotheliitis was seen in 1 of 4 patients. CONCLUSIONS: This study shows endotheliitis in amputation specimens of four patients with COVID-19 disease and Rutherford Class 3 acute limb ischemia. The findings in these patients is more likely an infectious angiitis because of COVID-19.

Wound care during the COVID-19 pandemic: improving outcomes through the integration of telemedicine.

COVID-19 is highly contagious and its rapid spread burdens the healthcare system. As the number of confirmed cases goes up, the shortage of medical resources has become a challenge. To avoid the collapse of the healthcare system during the fight with COVID-19, all healthcare workers, including wound care practitioners, should adapt to new roles and use any appropriate methods available to slow the spread of the virus. Integrating telemedicine into wound care during the outbreak helps maintain social distancing, preserve personal protective equipment and medical resources, and eliminate unnecessary exposure for both vulnerable patients and high-risk healthcare workers.

Topical oxygen therapy in the treatment of diabetic foot ulcers: a multicentre, open, randomised controlled clinical trial.

OBJECTIVES: Perfusion and blood oxygen levels are frequently insufficient in patients with hard-to-heal wounds due to poor circulation, vascular disruption and vasoconstriction, reducing the wound's capacity to heal. This study aimed to investigate the effect of topical oxygen on healing rates in patients with hard-to-heal diabetic foot ulcers (DFUs) (i.e., non-responsive over four weeks). METHOD: This multicentre, open-label, community-based randomised clinical trial compared standard care (SOC) with or without continuous topical oxygen therapy (TOT) for 12 weeks in patients with DFUs or minor amputation wounds. SOC included debridement, offloading with total contact casting (TCC) and appropriate moisture balance. Primary endpoints were the number of patients to achieve complete wound closure and percentage change in ulcer size. Secondary endpoints were pain levels and adverse events. RESULTS: For the study, 145 patients were randomised with index ulcers graded Infectious Diseases Society of America (IDSA) 1 or 2, or Wagner 1 or 2. In the intention-to-treat analysis, 18/64 (28.1%) patients healed in the SOC group at 12 weeks compared with 36/81 (44.4%) in the SOC plus TOT group (p=0.044). There was a statistically significant reduction in wound area between the groups: SOC group mean reduction: 40% (standard deviation (SD) 72.1); SOC plus TOT group mean reduction: 70% (SD 45.5); per protocol p=0.005). There were no significant differences in changes to pain levels or adverse events. CONCLUSION: This study suggests that the addition of TOT to SOC facilitates wound closure in patients with hard-to-heal DFUs.

Fetal bovine acellular dermal matrix for the closure of diabetic foot ulcers: a prospective randomised controlled trial.

AIM: The purpose of this clinical trial was to evaluate the safety and efficacy of a fetal bovine acellular dermal matrix (FBADM) plus standard of care (SOC) for treating hard-to-heal diabetic foot ulcers (DFUs). METHOD: A prospective, multi-centre, randomised controlled trial was carried out. The study included a 2-week run-in period, a 12-week treatment phase and a 4-week follow-up phase. The primary endpoint was complete wound closure at 12 weeks. RESULTS: Twenty-one US sites enrolled and randomised 226 patients with hard-to-heal DFUs. The study was terminated early due to the COVID-19 pandemic, which led to a modified intent-to-treat (mITT) population of 207 patients, with 103 in the FBADM group and 104 in the SOC group. Of these participants, 161 completed the study per protocol (mPP population), with 79 receiving FBADM, and 82 without. At the first analysis point, patients treated with FBADM were found to be significantly more likely to achieve complete wound closure compared with SOC alone (mITT: 45.6% versus 27.9% p=0.008; mPP: 59.5% versus 35.6% p=0.002). The difference in outcome yielded an odds ratio of 2.2 (95% confidence interval (CI): 1.2, 3.9; p=0.008). Median time to closure within 12 weeks was 43 days for the FBADM group compared to 57 days for the SOC group (p=0.36). The median number of applications of FBADM to achieve closure was one. Adverse events were similar between groups and no product-related serious adverse events occurred. CONCLUSIONS: These results indicate that in many cases a single application of FBADM in conjunction with SOC offers a safe, faster and more effective treatment of DFUs than SOC alone.

A dual pressure indicator, two-layer compression system for treatment of venous leg ulcers: a review.

OBJECTIVE: Venous leg ulcers (VLUs) are considered the most frequent category of hard-to-heal limb ulcers. Although evidence-based care of VLUs suggests that compression therapy plays a pivotal role in the standard of care, patient adherence is considered low, with at least 33% non-compliance, either due to perceived problems from clinicians regarding their own competency in applying the bandages, or from the patient finding the wrapping bothersome. For many years, four-layer bandaging has been considered the 'gold standard', but application can be difficult and may also prove uncomfortable for patients. Accurate application may be facilitated by a stretch indicator which has been engineered to act as a surrogate for appropriate pressure application that can address the skill concern, while fewer layers can save clinicians' time and improve the quality of life of patients. Here, we review the literature supporting a two-layer system which combines elastic (long stretch) and inelastic (short stretch) components as well as both layers having graphic markers to define that the dressing has been applied at the proper tension. METHOD: An initial search was conducted on PubMed and then followed up by a manual search of Google Scholar to retrieve evidence of different levels, in order to evaluate the outcomes of use of the specific two-layer compression system with pressure indicators in the management of patients presenting with VLUs. RESULTS: A total of four papers discussing the specific compression system in question were identified from 32 publications retrieved from PubMed, while a further six were retrieved from Google Scholar. These 10 publications were considered relevant to the two-layer system and were analysed for the outcomes of care, including wound healing, appropriate application, time-saving and better patient acceptance and adherence. CONCLUSION: Previous authors have demonstrated that two-layer systems are equivalent to four-layer systems. However, the ability to reproducibly apply appropriate compression has remained a question. The papers reviewed demonstrate that evidence suggests that the two-layer compression bandage system with indicators provides continuous, consistent and comfortable treatment that may be easier to apply with accurate pressure levels due to their indicator systems, and therefore, is a procedure that may increase patient adherence and acceptability to the wound therapy.

Effect of Topical Oxygen Therapy on Chronic Wounds.

Over the past three decades, there has been a growing interest in the use of oxygen therapy to promote wound healing. Although the most commonly recognized oxygen therapy for the treatment of chronic wounds is hyperbaric oxygen therapy, topical oxygen therapy has a greater level of evidence supporting its use in chronic wound care. Still, it is imperative that these two treatment modalities be recognized not merely as competitors, but as distinct therapeutic entities. Through personal experience and a thorough literature review, we investigated the use of topical oxygen therapy in the management of chronic wounds. The benefits of using topical oxygen therapy have been demonstrated in patients with diabetic foot ulcers, ischemic ulcers, post-revascularization ulcers, and pressure ulcers. There are several topical oxygen devices currently on the market that are versatile, relatively low-risk, and generally well-tolerated by patients. While these devices have been used in the treatment of chronic wounds at different locations and of different etiologies, other uses of these devices are still being investigated. Topical oxygen therapy is yet another tool in our arsenal to be used in treating difficult to heal chronic wounds and could potentially be used more readily.

The Evidence for Antimicrobial and Hard to Infect Regenerative Matrices.

Preparation of the wound bed is a key step in the use of cell- and tissue-based therapy (CTP). In particular, good pre-application debridement is an essential component of CTP. However, there are many situations in which the wound bed is not adequately debrided, including trauma, burn, and in cases of chronic wounds with significant biofilm. In the setting of inadequate wound bed preparation, the use of a CTP that has either added or intrinsic antimicrobial properties is attractive. Some CTPs include added antimicrobial agents such as PHMB or silver, while others have intrinsic antimicrobial components, such as Omega 3 fatty acids. In addition, some wound-covering dressings are completely synthetic, and therefore simply do not become infected. A full understanding of the basic science and clinical data supporting the use of these therapies is important for the advanced wound care practitioner.