Early indicators of healing provide valuable information on the potential benefit of treatment. In patients with hard-to-heal (chronic) diabetic foot ulcers (DFUs), timely intervention is critical. Ulcers that fail to show measurable progress within four weeks of treatment are considered recalcitrant. These ulcers increase the risk of soft tissue infection, osteomyelitis and lower extremity amputation. A prognostic indicator or surrogate marker allows for rapid evaluation of treatment efficacy and safety. An inverse correlation between a percentage area reduction (PAR) of ≤50% at week 4 and complete healing by week 12 has been previously established; however, the data were derived from a standard of care (SoC) arm of clinical trials that are over a decade old. In this post hoc analysis, data from a large multicentre prospective randomised controlled trial were reviewed to assess PAR at week 4 as a prognostic indicator in patients treated with SoC. Overall, 65.4% (17/26) of patients with PAR >50% at week 4 achieved complete closure at week 12. The receiver operating characteristic (ROC) curve for area reduction by week 4 showed strong discrimination for predicting non-healing (area under the ROC curve: 0.92; p<0.001; positive predictive value: 70.6%; negative predictive value: 87.2%). These findings are consistent with previous studies and support the use of four-week PAR as a prognostic indicator.

Background:Pressure injuries (PIs) impose a substantial burden on patients, caregivers, and healthcare systems, affecting an estimated 3 million Americans and costing nearly $18 billion annually. Accurate pressure injury staging remains clinically challenging. Over the last decade, object detection and semantic segmentation have evolved quickly with new methods invented and new application areas emerging. Simultaneous object detection and segmentation paved the way to segment and classify anatomical structures. In this study, we utilize the Mask-R-CNN algorithm for segmentation and classification of stage 1-4 pressure injuries.Methods:Images from the eKare Inc. pressure injury wound data repository were segmented and classified manually by two study authors with medical training. The Mask-R-CNN model was implemented using the Keras deep learning and TensorFlow libraries with Python. We split 969 pressure injury images into training (87.5%) and validation (12.5%) subsets for Mask-R-CNN training.Results:We included 121 random pressure injury images in our test set. The Mask-R-CNN model showed overall classification accuracy of 92.6%, and the segmentation demonstrated 93.0% accuracy. Our F1 scores for stages 1-4 were 0.842, 0.947, 0.907, and 0.944, respectively. Our Dice coefficients for stages 1-4 were 0.92, 0.85, 0.93, and 0.91, respectively.Conclusions:Our Mask-R-CNN model provides levels of accuracy considerably greater than the average healthcare professional who works with pressure injury patients. This tool can be easily incorporated into the clinician's workflow to aid in the hospital setting.

The current public health crisis has highlighted the need to accelerate healthcare innovation. Despite unwavering levels of cooperation among academia, industry, and policy makers, it can still take years to bring a life-saving product to market. There are some obvious limitations, including lack of blinding or masking and small sample size, which render the results less applicable to the real world. Traditional randomized controlled trials (RCTs) are lengthy, expensive, and have a low success rate. There is a growing acknowledgement that the current process no longer fully meets the growing healthcare needs. Advances in technology coupled with proliferation of telehealth modalities, sensors, wearable and connected devices have paved the way for a new paradigm. Virtual randomized controlled trials (vRCTs) have the potential to drastically shorten the clinical trial cycle while maximizing patient-centricity, compliance, and recruitment. This new approach can inform clinical trials in real time and with a holistic view of a patient’s health. This paper provides an overview of virtual clinical trials, addressing critical issues, including regulatory compliance, data security, privacy, and ownership.

Aim: Determine the effectiveness of hypothermically stored amniotic membrane (HSAM) versus standard of care (SOC) in diabetic foot ulcers (DFUs). Methods: A randomized controlled trial was conducted on 76 DFUs analyzed digitally. Results: Cox wound closure for HSAM (38 wounds) was significantly greater (p = 0.04) at weeks 12 (60 vs 38%), and 16 (63 vs 38%). The probability of wound closure increased by 75% (Hazard Ratio = 1.75; 95% CI: 1.16-2.70). HSAM showed >60% reductions in area (82 vs 58%; p = 0.02) and depth (65 vs 39%; p = 0.04) versus SOC. Conclusion: HSAM increased frequency and probability of wound closure in DFUs versus SOC.

Objective: Oxygen plays an integral role in all phases of the wound healing process and tissue oxygenation is a key determinant of wound healing. A comprehensive evaluation of patients with hard-to-heal wounds must include measurement of oxygenation in and around the area of skin breakdown. The current gold standard, transcutaneous oxygen measurement (TCOM), has numerous drawbacks and as a result has fallen into disuse. Method: This study compared measurement of tissue oxygenation of near infrared spectroscopy (NIRS) with TCOM in patients with acute and hard-to-heal wounds. The Shapiro-Wilk test was used to evaluate the normality of the data. The level of agreement between NIRS and TCOM was determined using Bland-Altman analysis. The relationship between TCOM and NIRS was examined using Pearson correlation. Results: A total of 24 observations were obtained from 10 patients using TCOM and NIRS. The weighted mean partial pressure of oxygen (pO(2)) in the study population was 39.54mmHg (8.96 standard deviation). Bland-Altman analysis showed that mean difference was positive (18.75), suggesting an overestimation of oxygen measurements using TCOM compared with NIRS. The oxygen levels measured by TCOM and NIRS showed a strong correlation (r=0.74). Conclusion: The wound and hyperbaric community would benefit from a simplified procedure for measuring tissue oxygenation. These findings suggest a strong trend toward correlation between NIRS and TCOM. A further study in a larger population is recommended. NIRS offers several advantages over TCOM. Clinicians have immediate point-of-care visualisation of tissue oxygenation using a handheld device. The procedure takes minutes to perform and is less operator-dependent than TCOM. Finally, NIRS allows measurement of oxygenation in the wound bed, while TCOM does not.

Objective: Punch biopsy is a simple and effective diagnostic technique used in hard-to-heal wound management. Histologic examination can rule out cancer in the wound bed or diagnose vasculitis in a hard-to-heal or suspicious ulcer. A biopsy can determine the level of bacteria in an ulcer when infection is suspected. Despite its use, health professionals practicing in wound clinics hesitate to perform punch biopsies. The reasons vary from the invasive nature of the procedure to a fear of complications. Methods: A multicentre clinical trial evaluated the addition of fluorescence imaging to clinical examination in determining bacterial burden in hard-to-heal wounds. The protocol required a 6mm punch biopsy of any area (up to three) suspected of having moderate-to-high bacteria levels either on clinical examination or fluorescence image. If clinical examination and fluorescence imaging both did not indicate bacteria, the health professional took a biopsy of the centre of the ulcer. The biopsies were performed under local anaesthesia after cleansing the ulcer bed with sterile normal saline. Haemostasis was achieved with direct pressure and the occasional topical clotting agent. All of the patients were followed for 30 days to monitor for adverse events. Results: A total of 350 patientis with wounds (diabetic foot ulcer n=138; venous leg ulcer n=106; pressure ulcer n=22; surgical site infection n=60; other n=24), enrolled by 20 investigators at 14 sites in the US, underwent a total of 412 punch biopsies. Haemostasis was achieved in all 412 biopsies. No biopsy sites required cautery or suture ligation to control bleeding. No subjects returned to the clinic secondary to bleeding. A patient developed an infection three days post-biopsy that could have been due to the punch biopsy. However, the patient was HIV-positive and the quantitative biopsy was positive for infection, biopsy bacterial load of 106 colony forming units (CFU)/g. Conclusion: This trial used a 6mm punch to obtain tissue for culture, histology and additional biomarker research. In daily wound care practice, a smaller 3mm punch suffices. Adverse events were rare despite the larger biopsy. Punch biopsies are a safe procedure for obtaining tissue for histologic or microbiologic analysis.

OBJECTIVE A pandemic afflicts the entire world. The highly contagious SARS-CoV-2 virus originated in Wuhan, China in late 2019 and rapidly spread across the entire globe. According to the World Health Organization (WHO), the novel Coronavirus (COVID-19)has infected more than two million people worldwide, causing over 160,000 deaths. Patients with COVID-19 disease present with a wide array of symptoms, ranging from mild flu-like complaints to life threatening pulmonary and cardiac complications. Older people and patients with underlying disease have an increased risk of developing severe acute respiratory syndrome (SARS) requiring mechanical ventilation. Once intubated, mortality increases exponentially. A number of pharmacologic regimens, including hydroxychloroquine-azithromycin, antiviral therapy (eg, remdesevir), and anti-IL-6 agents (e.g., toclizumab), have been highlighted by investigators over the course of the pandemic, based on the therapy's potential to interrupt the viral life-cycle of SARS-CoV-2 or preventing cytokine storm. At present, there have been no conclusive series of reproducible randomised clinical trials demonstrating the efficacy of any one drug or therapy for COVID-19. CASES COVID-19 positive patients (n=5) at a single institution received hyperbaric oxygen therapy (HBOT) between 13 and 20 April 2020. All the patients had tachypnoea and low oxygen saturation despite receiving high FiO2. HBOT was added to prevent the need for mechanical ventilation. A standard dive profile of 2.0ATA for 90 minutes was employed. Patients received between one and six treatments in one of two dedicated monoplace hyperbaric chambers. RESULTS All the patients recovered without the need for mechanical ventilation. Following HBOT, oxygen saturation increased, tachypnoea resolved and inflammatory markers fell. At the time of writing, three of the five patients have been discharged from the hospital and two remain in stable condition. CONCLUSION This small sample of patients exhibited dramatic improvement with HBOT. Most importantly, HBOT potentially prevented the need for mechanical ventilation. Larger studies are likely to define the role of HBOT in the treatment of this novel disease.

Introduction: Blood has become a major source for wound care products due to its primary role in wound healing. The blood clot provides a fibrin scaffold that serves as a protective, provisional extracellular matrix. The clot dries out and becomes a protective scab, under which a moist wound environment can be maintained. In this study, the safety of an autologous whole blood clot product was evaluated in porcine models. Methods: A total of 24 full thickness dermal wounds were analyzed (6 wounds on each of the 4 porcine models). Eighteen wounds received the whole blood clot product and 6 were treated with saline soaked gauze for 18 days. Reapplications occurred on days 6 and 12. Histological evaluations were carried out to detect the presence of kaolin. Percentage area reduction and adverse events related to the whole blood clot product were assessed. Results: Microscopic evaluation revealed that the whole blood clot product was associated with partial to complete wound reepithelialization, whereas minimal reepithelialization was present with the control. The mean reepithelialization score for the control wounds was 1.0, or 2.3 times less than the mean score for the intervention group. By day 18, the mean reduction in wound area was 41% (SD: 3.8) for the control wounds versus 66% (SD: 6.4) for the wounds treated with the whole blood clot product (P<0.0001).

OBJECTIVE Clinical evaluation of signs and symptoms (CSS) of infection is imperative to the diagnostic process. However, patients with heavily colonised and infected wounds are often asymptomatic, leading to poor diagnostic accuracy. Point-of-care fluorescence imaging rapidly provides information on the presence and location of bacteria. This clinical trial (#NCT03540004) aimed to evaluate diagnostic accuracy when bacterial fluorescence imaging was used in combination with CSS for identifying wounds with moderate-to-heavy bacterial loads. METHODS Wounds were assessed by study clinicians using NERDS and STONEES CSS criteria to determine the presence or absence of moderate-to-heavy bacterial loads, after which the clinician prescribed and reported a detailed treatment plan. Only then were fluorescence images of the wound acquired, bacterial fluorescence determined to be present or absent and treatment plan adjusted if necessary. RESULTS We examined 17 VLUs/2 DFUs. Compared with CSS alone, use of bacterial fluorescence imaging in combination with CSS significantly improved sensitivity (22% versus 72%) and accuracy (26% versus 74%) for identifying wounds with moderate-to-heavy bacterial loads (≥104 CFU/g, p=0.002). Clinicians reported added value of fluorescence images in >90% of study wounds, including identification of wounds incorrectly diagnosed by CSS (47% of study wounds) and treatment plan modifications guided by fluorescence (73% of study wounds). Modifications included image-guided cleaning, treatment selection, debridement and antimicrobial stewardship. CONCLUSION Findings from this pilot study suggest that when used in combination with CSS, bacterial fluorescence may: (1) improve the diagnostic accuracy of identifying patients with wounds containing moderate-to-heavy bacterial loads and (2) guide more timely and appropriate treatment decisions at the point-of-care.

outcomes were evaluated in patients receiving HSAM for the treatment of chronic nonhealing ulcers. Relevant medical history was captured in addition to data on wound characteristics and measurements. Two venous leg ulcers and one postsurgical wound were treated with HSAM. Findings: A significant reduction in wound size was observed for patients treated with HSAM. Overall, HSAM demonstrated a wound size reduction of 93.94% in 42 days. These results provide evidence that HSAM may reduce the long-term costs associated with the care of chronic ulcers by increasing the healing rate and lowering the risk of infection and complications.

Chronic wounds (ie, wounds that fail to progress through a normal, orderly, timely sequence of repair) continue to pose significant clinical and economic burdens. A prospective, descriptive, 3-week post-marketing surveillance study was conducted across 3 wound care centers in the United States to evaluate the effectiveness of a collagen calcium alginate dressing on chronic wounds in conjunction with standard care (SC) practices (eg, offloading, debridement, compression) to support healing. Eligible participants had to be >18 years of age, have at least 1 chronic wound, and no known sensitivity to collagen. Demographic characteristics were recorded at the screening visit on case report forms. At each visit, wound-related pain was assessed using the Visual Analog Scale along with wound characteristics including size (using digital planimetry), wound exudate (minimal, moderate, heavy), and odor (none, mild). Participants were monitored for adverse events as well as infection based on signs and symptoms in and around the local wound bed, the deeper structures, and the surrounding skin. An intention-to-treat approach was used for all analyses. If an observation was missing, the last observation carried forward principle was used. For wounds that healed, pain and exudate were set to 0 (no pain/exudate) at visit 4. Descriptive, paired t tests and the Wilcoxon signed rank test were used to analyze the data. Of the 31 participants (15 men, 16 women, mean age 66.6 years), most (13, 42%) had a diabetic foot ulcer or venous leg ulcer (10, 32%); median duration of all wounds was 148 days. Thirty (30) patients completed the study. The mean number of comorbidities was 10.6 ± 6.3, and patients used a mean of 9.3 ± 5.64 prescription or over-the-counter medications. For all wounds combined, mean wound area was 4.8 ± 8.38 cm2 at baseline. At week 3, a decrease in wound area of 38.1% was noted (median: 45% ± 42.54; P = .006); 3 wounds healed completely. The change in wound exudate level from visit 1 to visit 4 was statistically significant (P = .006). No adverse events or infections occurred. In this population, the use of etiology-appropriate SC and a collagen calcium alginate dressing resulted in a decrease in wound area after 3 weeks of care. Longer-term studies to confirm these observations and controlled clinical studies to compare the effects of this dressing to other nongauze dressing treatments are needed.

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The term epidermolysis bullosa describes a group of rare genetic mechanicobullous disorders. The disease has several modes of inheritance with various degrees of severity and expression. A patient with simplex epidermolysis bullosa had typical cutaneous lesions and dental involvement. The teeth were severely affected by hypoplasia. Dental therapy consisted of placement of amalgam restorations and topical applications of fluoride. The need for, and advantages of, early preventive and restorative dental care are illustrated by the case presented.

The disparity between ideal evidence from randomized controlled trials and real-world evidence in medical research has prompted the United States Food and Drug Administration to consider the use of real-world data to better understand safety and effectiveness of new devices for a broader patient population and to prioritize real-world data in regulatory decision making. As the healthcare system transitions from volume- to value-based care, there is a growing need to harness the power of real-world data to change the paradigm for wound care clinical research and enable more generalizable clinical trials. This paper describes the implementation of a network-based learning healthcare system by a for-profit consortium of wound care clinics that integrates wound care management, quality improvement, and comparative effectiveness research, by harnessing structured real-world data within a purpose-built electronic health record at the point of care. Centers participating in the consortium submit their clinical data and quality measures to a qualified clinical data registry for wound care, enabling benchmarking of their data across this national network. The common definitional framework of the purpose-built electronic health record and the 21 wound-specific quality measures help to standardize the potential sources of bias in real-world data, making the consortium data useful for comparative effectiveness research. This consortium can transform wound care clinical research and raise the standards of care, while helping physicians achieve success with the Merit-Based Incentive Payment System.

OBJECTIVE: To assess healing outcomes in venous leg ulcers (VLUs) treated with a combination of collagen, oxidized regenerated cellulose, and silver in conjunction with standard of care (SOC; intervention group) compared with SOC alone (control group). Standard of care included ADAPTIC nonadhering dressing (Acelity, San Antonio, Texas) and compression. DESIGN AND SETTING: Randomized controlled trial that followed patients in 3 US facilities for 12 weeks or until complete healing. PATIENTS AND INTERVENTION: Forty-nine patients with VLUs were randomized to either the intervention group (n = 22) or the control group (n = 27). MAIN OUTCOME MEASURE: Wound healing over 12 weeks. MAIN RESULTS: Intent-to-treat analysis showed a mean percentage wound area reduction at 12 weeks of 85.6% (SD, 28.6%) for the intervention group and 72.5% (SD, 77.8%) for the control group. There was a higher healing rate in the intervention group compared with patients who received SOC only at both week 4 (23% vs 11%) and week 12 (64% vs 59%). There were no adverse events related to the study therapy. CONCLUSIONS: Although the results were not significant, there was a trend toward faster healing in the intervention group. The results of this study indicate that collagen/oxidized regenerated cellulose/silver is a suitable and safe adjunctive intervention for use with SOC to manage VLUs.

It is widely known that pain frequently accompanies certain types of chronic wounds, most notably arterial insufficiency ulcers, venous leg ulcers, and diabetic foot ulcers; however, until recently, pain associated with chronic wounds has not received much attention. A limited number of studies have explored the impact of painful wounds on the quality of life. Nonetheless, these early works have brought wound-related pain (WRP) to the forefront and highlighted the importance of pain assessment and management in enhancing the quality of life and improving wound healing outcomes. This review of the current literature on WRP presents an overview of pain pathophysiology, clinical features of WRP, and the limitations of pain assessment methods, and offers clinical pearls on preventing, managing, and minimizing WRP.

It is widely accepted that elevated protease activity (EPA) in chronic wounds impedes healing. However, little progress has occurred in quantifying the level of protease activity that is detrimental for healing. The aim of this study was to determine the relationship between inflammatory protease activity and wound healing status, and to establish the level of EPA above which human neutrophil-derived elastase (HNE) and matrix metalloproteases (MMP) activities correlate with nonhealing wounds. Chronic wound swab samples (n = 290) were collected from four wound centers across the USA to measure HNE and MMP activity. Healing status was determined according to percentage reduction in wound area over the previous 2-4 weeks; this was available for 211 wounds. Association between protease activity and nonhealing wounds was determined by receiver operating characteristic analysis (ROC), a statistical technique used for visualizing and analyzing the performance of diagnostic tests. ROC analysis showed that area under the curve (AUC) for HNE were 0.69 for all wounds and 0.78 for wounds with the most reliable wound trajectory information, respectively. For MMP, the corresponding AUC values were 0.70 and 0.82. Analysis suggested that chronic wounds having values of HNE >5 and/or MMP ≥13, should be considered wound healing impaired. EPA is indicative of nonhealing wounds. Use of a diagnostic test to detect EPA in clinical practice could enable clinicians to identify wounds that are nonhealing, thus enabling targeted treatment with protease modulating therapies.

ABSTRACT Introduction The prevalence of diabetes has been rising sharply and the rise in chronic wounds parallels this trend. Lower extremity ulcers present a serious complication for people with diabetes. While debridement of necrotic tissue and off-loading plays an important role in wound healing, many patients with diabetic foot ulcers (DFUs) fail to heal with standard of care (SOC) alone. Unresolved ulcers can lead to complications, such as osteomyelitis and amputation. There continues to be a need for the evaluation of novel wound therapies that can accelerate wound healing and lower the cost of care associated with DFUs. This paper presents recent evidence for the use of cellular and/or tissue-based products (CTPs) and offers an approach for selecting an appropriate CTP. Materials and methods A systematic literature search was conducted using PubMed, Embase, Medline, Cochrane library, and NHS Economic Evaluation Database. Full-length articles in English were assessed for relevance to select studies on effectiveness and economic evaluations. Additionally, Google Scholar was used to gather relevant literature on commonly used CTPs, including Apligraf®, EpiFix®, and Dermagraft®. Findings Results from randomized controlled trials (RCTs) provided evidence for the superior efficacy of CTPs over SOC alone in treatment of chronic DFUs. In recent studies evaluating commonly used CTPs, significantly higher number of DFUs achieved complete closure with EpiFix® when compared to either Apligraf® or Dermagraft®. While cost-effectiveness studies continue to be limited, current literature suggests that CTPs can decrease the long-term costs associated with the care of DFUs by increasing the healing rate, reducing recovery time, and lowering the risk of infection and complications. Cellular and/or tissue-based products (CTPs) may result in higher average number of ulcer-free months and lower average number of amputations or resections compared to SOC alone. How to cite this article Serena TE, Yaakov RA, Mostow EN. Use of Cellular and Tissue-based Product in the Treatment of Diabetic Foot Ulcers. J Foot Ankle Surg (Asia-Pacific) 2016;3(2):92-96.

The prevalence of chronic wounds is sharply rising throughout the world due to an aging population and increases in the incidence of obesity, diabetes, and cardiovascular diseases. People with diabetes, hypertension, and hyperlipidemia are at increased risk for developing peripheral arterial disease (PAD). PAD affects 8 to 12 million people over the age of 40 years in the United States and it is a major contributing factor to the development of lower extremity ulcers. Although a number of noninvasive diagnostic tests are available to detect PAD in lower extremities, they have several clinical limitations. In this review, current understanding of the pathophysiology of commonly seen lower extremity ulcers is described and vascular assessments typically used in practice are evaluated. In addition, application of the LUNA Fluorescence Angiography System (Novadaq, Bonita Springs, FL) for the screening and treatment of complex nonhealing wounds in patients with PAD is discussed.