In vivo reprogramming of wound-resident cells generates skin epithelial tissue.

Large cutaneous ulcers are, in severe cases, life threatening1,2. As the global population ages, non-healing ulcers are becoming increasingly common1,2. Treatment currently requires the transplantation of pre-existing epithelial components, such as skin grafts, or therapy using cultured cells2. Here we develop alternative supplies of epidermal coverage for the treatment of these kinds of wounds. We generated expandable epithelial tissues using in vivo reprogramming of wound-resident mesenchymal cells. Transduction of four transcription factors that specify the skin-cell lineage enabled efficient and rapid de novo epithelialization from the surface of cutaneous ulcers in mice. Our findings may provide a new therapeutic avenue for treating skin wounds and could be extended to other disease situations in which tissue homeostasis and repair are impaired.

Healing refractory livedoid vasculopathy-related skin ulcers by ozone therapy: a case-based review.

Chronic skin wounds represent a prominent etiological factor in the occurrence of non-traumatic foot amputations on a global scale and pose a substantial threat to the patient's well-being and mortality in the absence of effective treatment strategies. There exists a subset of patients that exhibit an insufficient response to different treatment options, comprising antibiotics, dressings, gauze bandages, debridement, rehabilitation, collagen patch, and vacuum-assisted closure. In this patient group, distinct treatment strategies emerge before surgery and amputation. Ozone therapy is one of them. Ozone exhibits a wide variety of effects such as antimicrobial, anti-inflammatory, antioxidant, and trophic. Its trophic effect is mediated by disinfection, stimulation of granulation tissue, acceleration of the angiogenesis process, and detoxification mechanisms. In this article, we presented the beneficial effect of ozone therapy in a case of chronic skin ulcer associated with livedoid vasculopathy. In this context, we aimed to discuss the role of ozone therapy in the management of chronic skin ulcers. Finally, we focused on ozone therapy as a promising method in inflammatory rheumatic diseases.

The Management of Chronic Graft-Versus-Host Disease Skin Ulcers after Hematopoietic Stem Cell Transplantation: A Case Report.

ABSTRACT: The comprehensive management of a patient with chronic graft-versus-host disease skin ulcers after hematopoietic stem cell transplantation is challenging. This report describes the case of a 53-year-old woman who presented with ulcers on her right leg 140 weeks after a bone marrow transplant. The patient received wound assessment and management based on the Triangle of Wound Assessment and Wound Bed Preparation 2021, respectively. Hydrogel and antibacterial protease dressings were applied along with systemic oral administration of moxifloxacin hydrochloride (two capsules, two times daily) and JiXueGanPian tablets (classic Chinese herbal formula; two capsules, two times daily), hospital-community-home continuous care, and patient-centered education. Finally, after 133 days of nursing, the patient's wound was completely healed without complications or other skin issues. The use of hydrogel combined with the antibacterial protease dressing was a promising technique for handling this type of wound, enhanced by multidisciplinary collaboration. Of course, providing patients with education that focuses on prevention is necessary.

Treatment of Chronic Parastomal Ulceration with Silver Sulfadiazine and Hyaluronic Acid: Two Case Reports.

ABSTRACT: Skin complications in individuals with an ostomy are widely reported and can cause physical and emotional challenges in everyday life. Chronic parastomal skin complications can be difficult to heal and cause significant pain.Two patients presented to the stomal therapy clinic for treatment and were diagnosed with chronic parastomal skin ulceration. Following standard treatment of wound management, topical corticosteroid ointment, and appliance review, the ulcers either were not improving or had reoccurred. Treatment with a combination cream consisting of 0.2% hyaluronic acid and 1% silver sulfadiazine was initiated, and both patients demonstrated complete healing.Treatment of parastomal skin ulceration with dual-action cream 0.2% hyaluronic acid and 1% silver sulfadiazine was successful for these two patients, with a reduction in pain and purulent fluid noted throughout treatment, in addition to a reduced cost of treatment when compared with standard protocols.

Systematic review and quality assessment of clinical and economic evidence for superabsorbent wound dressings in a population with chronic ulcers.

Effective exudate management is key for optimal ulcer healing. Superabsorbent dressings are designed to have high fluid handling capacity, reduced risk of exudate leakage, fluid retention under compression, and to sequester harmful exudate components. This study aimed to systematically identify existing evidence for the clinical efficacy and cost-effectiveness of superabsorbent dressings for the treatment of moderate-to-highly exudating chronic ulcers of various etiologies. The aim is focused on examining the 'class' effect of all superabsorbers, not any particular dressing. Clinical and cost effectiveness systematic reviews were conducted, searching Embase, MEDLINE, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature. The Cost Effectiveness Analysis Registry and Econ papers were also searched for the economic review. Outcomes of interest included ulcer closure, dressing properties, hospital- and infection-related outcomes, safety, and economic outcomes. Fourteen studies were included in the clinical systematic review. Eleven were case series, with one randomised controlled trial, one retrospective matched observational study, and one retrospective cohort study. The studies investigated eight superabsorbent dressings and were heterogeneous in their patient population and outcomes. Superabsorbent dressings may result in favourable outcomes, including reductions in frequency of dressing change and pain scores. As most studies were case series, drawing firm conclusions was difficult due to absence of a comparator arm. The economic systematic review identified seven studies, five of which were cost-utility analyses. These suggested superabsorbent dressings are a more cost-effective option for the treatment of chronic ulcers compared with standard dressings. However, the small number and low quality of studies identified in both reviews highlights the need for future research.

The role of split-thickness skin grafting in the treatment of vasculitic and pyoderma gangrenosum ulcers in a multidisciplinary wound centre.

Vasculitic and pyoderma gangrenosum ulcers are traditionally treated with immunosuppressants, and the role of surgery in the treatment of these atypical ulcers remains unclear. This study aimed to investigate the need for surgical intervention as well as the outcome and safety of skin grafting in the treatment of 46 patients with vasculitic ulcers and 34 with pyoderma gangrenosum ulcers using data recorded in the validated Wound Registry. Of the 80 patients with atypical ulcers, 14% (n = 11) were treated surgically; these patients were older (p = 0.039), had lower mobility status (p = 0.002), and more often pulmonary diseases, rheumatoid arthritis, and previous arterial procedures (p = 0.007; p = 0.031; p = 0.031, respectively) than those treated conservatively. Of 181 ulcers, 15% (n = 27) were surgically treated, 78% once and 22% multiple times. During follow-up, 92.3% of both surgically and conservatively treated ulcers with available data healed. Of the surgically treated ulcers, median healing time after first surgical procedure was 96 days, and post-surgical complications were considered mild or unrelated to surgery. Our results suggest that if surgery is indicated, skin grafting is a safe and efficient treatment method provided that multidisciplinary approach is applied.

Treatment of systemic sclerosis-associated digital ulcers: recommendations of the Turkish Society for Rheumatology.

OBJECTIVES: Digital ulcers (DUs) are associated with a significant burden in systemic sclerosis (SSc) by leading to severe pain, physical disability, and reduced quality of life. This effort aimed to develop recommendations of the Turkish Society for Rheumatology (TRD) on the management of DUs associated with SSc. METHODS: In the first meeting held in December 2020 with the participation of a task force consisting of 23 rheumatologists the scope of the recommendations and research questions were determined. A systematic literature review was conducted by 5 fellows and results were presented to the task force during the second meeting. The Oxford system was used to determine the level of evidence. The preliminary recommendations were discussed, modified, and voted by the task force and then by members of TRD via e-mail invitation allowing personalised access to a web-based questionnaire [SurveyMonkey®]. RESULTS: A total of 23 recommendations under 7 main headings were formulated covering non-pharmacological measures for the prevention of DUs and pharmacological treatments including vasodilators, anti-aggregants, antibiotics, wound care, pain control, and interventions including sympathectomy, botulinum toxin, and surgery. Risk factors, poor prognostic factors, prevention of DU and adverse effects of medical treatments were reported as 4 overarching principles. CONCLUSIONS: These evidence-based recommendations for the management of SSc-associated DUs were developed to provide a useful guide to all physicians who are involved in the care of patients with SSc, as well as to point out unmet needs in this field.

Endothelial progenitor cell derived exosomes mediated miR-182-5p delivery accelerate diabetic wound healing via down-regulating PPARG.

Diabetic wound is one of the most common and serious complications of diabetes, which is characterized by abnormal number and quality of wound repair related cells. Previous studies have shown that human endothelial progenitor cells derived exosomes (EPCs-EXO) can promote diabetic wound healing through modulating vascular endothelial cell function. The purpose of this study was to investigate the biological effects and molecular mechanisms of EPCs-EXO on diabetic wound healing. The regulation of EPCs-EXO on human immortalized epidermal cell line HaCaT in high glucose (HG) environment was evaluated. Our data showed that EPCs-EXO promoted the proliferation, migration, while inhibited apoptosis of HaCaTs challenged by HG via elevating miR-182-5p expression level in vitro. Skin wound healing was significantly enhanced by EPCs-EXO in diabetic mice. Moreover, bioinformatics analyses and luciferase reporter assay indicated that exosomal miR-182-5p was bound to PPARG 3' UTR sequence and inhibited the expression of PPARG. Collectively, our findings provided a new role of EPCs-EXO in the clinical treatment of diabetic skin wounds. Diabetic wound is one of the most common and serious complications of diabetes, which is characterized by abnormal number and quality of wound repair related cells. Previous studies have shown that human endothelial progenitor cells derived exosomes (EPCs-EXO) can promote diabetic wound healing through modulating vascular endothelial cell function. The purpose of this study was to investigate the biological effects and molecular mechanisms of EPCs-EXO on diabetic wound healing. The regulation of EPCs-EXO on human immortalized epidermal cell line HaCaT in high glucose (HG) environment was evaluated. Our data showed that EPCs-EXO promoted the proliferation, migration, while inhibited apoptosis of HaCaTs challenged by HG via elevating miR-182-5p expression level in vitro. Skin wound healing was significantly enhanced by EPCs-EXO in diabetic mice. Moreover, bioinformatics analyses and luciferase reporter assay indicated that exosomal miR-182-5p was bound to PPARG 3' UTR sequence and inhibited the expression of PPARG. Collectively, our findings provided a new role of EPCs-EXO in the clinical treatment of diabetic skin wounds.

Immersion Ultrasound Therapy in Combination with Manual Therapy in the Treatment of Ischemic Digital Ulcers in Systemic Sclerosis.

Background and Objectives: Digital ulcers (DUs) are the most common complication in patients with Systemic Sclerosis (SSc). They cause pain with hand dysfunction and negatively impact activities of daily and working life. Our study aims to evaluate the efficacy of a combined treatment of manual therapy and ultrasound therapy in SSc patients with ischemic DU (IDU) compared to manual therapy alone. Materials and Methods: We conducted a before-and-after study (non-randomized study). We enrolled a consecutive series of IDU patients undergoing rehabilitation treatment and divided them into two groups: a treatment group consisting of patients undergoing a combination of manual therapy and US water immersion and a standard care group consisting of patients subjected to manual therapy alone. At the time of the first visit (T0) and at the end of the 4-week rehabilitation period (T1), we evaluated functional capacity, pain intensity, ulcer evolution, and quality of life. Results: In the treatment group, we observed a statistically significant improvement in the functional capacity of the hand (DHI: 28.15 ± 11.0 vs. 19.05 ± 8.83; p < 0.05), pain (NRS: 5.55 ± 1.2 vs. 2.9 ± 1.09; p < 0.05), and PSST score (24.4 ± 4.0 vs. 16.2 ± 2.36; p < 0.05). In the standard care group, we observed a statistically significant improvement only for the functional capacity of the hand (DHI: 28.85 ± 9.72 vs. 22.7 ± 7.68; p < 0.05). Finally, from the comparison between the treatment group and the standard care group, we observed statistically significant improvements in pain (2.9 ± 1.09 vs. 4.5 ± 1.07; p < 0.05) and in the PSST scale (16.2 ± 2.36 vs. 20.4 ± 4.02; p < 0.05). Furthermore, at the end of treatment in the treatment group, 15 ulcers (62.5%) were completely healed, while in the standard care group, only 3 ulcers were completely healed (14.3%). Conclusions: Combined treatment with manual therapy and ultrasound therapy appears to be useful in the management of IDU in patients with scleroderma.

Evidence and consensus-based recommendations for non-pharmacological treatment of fatigue, hand function loss, Raynaud's phenomenon and digital ulcers in patients with systemic sclerosis.

OBJECTIVE: SSc is a complex CTD affecting mental and physical health. Fatigue, hand function loss, and RP are the most prevalent disease-specific symptoms of systemic sclerosis. This study aimed to develop consensus and evidence-based recommendations for non-pharmacological treatment of these symptoms. METHODS: A multidisciplinary task force was installed comprising 20 Dutch experts. After agreeing on the method for formulating the recommendations, clinically relevant questions about patient education and treatments were inventoried. During a face-to-face task force meeting, draft recommendations were generated through a systematically structured discussion, following the nominal group technique. To support the recommendations, an extensive literature search was conducted in MEDLINE and six other databases until September 2020, and 20 key systematic reviews, randomized controlled trials, and published recommendations were selected. Moreover, 13 Dutch medical specialists were consulted on non-pharmacological advice regarding RP and digital ulcers. For each recommendation, the level of evidence and the level of agreement was determined. RESULTS: Forty-one evidence and consensus-based recommendations were developed, and 34, concerning treatments and patient education of fatigue, hand function loss, and RP/digital ulcers-related problems, were approved by the task force. CONCLUSIONS: These 34 recommendations provide guidance on non-pharmacological treatment of three of the most frequently described symptoms in patients with systemic sclerosis. The proposed recommendations can guide referrals to health professionals, inform the content of non-pharmacological interventions, and can be used in the development of national and international postgraduate educational offerings.

Combination of Full-Field and Fractional Erbium: YAG Laser for Nonhealing Wounds.

BACKGROUND: To evaluate the outcomes of a heterogeneous group of patients with chronic ulcer receiving a combination regimen of full-field and fractional erbium-doped yttrium aluminum garnet (erbium: YAG) laser applications. METHODS: Enrolled in this study were patients with chronic ulcer who had received at least 2 erbium: YAG laser sessions. Fractional applications followed the initial full-field application for debridement. The therapeutic outcomes were evaluated by serial photographs. The primary outcome measure was the proportion of patients achieving complete re-epithelialization at the first year. RESULTS: Forty-three treatment regions from 23 patients between 40 and 90 years (F: M = 11:12; age: 60.3 ± 15.5 years, mean ± SD) were eligible. The ulcers' median duration was 24 months (min-max: 2-240 months). The median number of laser sessions was 5 (min-max: 2-12). Of arterial (n = 13), immunologic (n = 9), venous (n = 8), diabetic (n = 8), and mechanical ulcers (n = 5), the primary outcome measure was achieved in 69%, 77.7%, 75%, 88.8%, and 100% of the groups, respectively. CONCLUSION: Full-field erbium: YAG laser applications preserve the vascular architecture and enable delicate debridement. Ongoing maintenance fractional laser sessions promote wound healing. Similar to the previous reports of erbium: YAG laser in venous and diabetic ulcers, arterial ulcers, and ulcers of immunologic origin demonstrated an objective treatment response along with different adjuvant approaches.

Get It Off Your Chest: A Narrative Review of Breast Ulcers.

GENERAL PURPOSE: To provide comprehensive information about breast ulcers to facilitate accurate diagnosis and treatment of these lesions. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Differentiate common wound complications after mastectomy.2. Identify the clinical manifestations of various types of breast ulcers.3. Explain appropriate pharmacologic and nonpharmacologic treatment options for various types of breast ulcers.

Cutaneous breast ulcers are uncommon but important encounters in clinical practice. Myriad causes may introduce ulcers in the breast tissue. Women are more prone to breast ulcers than men because of having heavier breast fatty tissue. Thorough medical history may easily reveal the underlying etiology; however, a tissue biopsy is often required to rule out other potential causes. The clinical presentation varies based on the underlying etiology, but some clues include surgical scars for postoperative wound dehiscence or well-defined violaceous borders with undermined ulcer base in pyoderma gangrenosum. In this article, the authors divide breast cancers into two major groups: with and without underlying mass. Depending on the underlying etiology, treatment may involve topical medications; optimal wound care; systemic medications such as antibiotics, immunosuppressive medications, or biologics; surgery; or a combination of all of the above. This article aims to shed light on a less frequent anatomic location of ulcers and provide advice to clinicians to facilitate accurate diagnosis and treatment.

Raynaud's phenomenon and digital ulcers: advances in evaluation and management.

PURPOSE OF REVIEW: The aim of this review is to give an update on advances in evaluation and management of systemic sclerosis (SSc)-related Raynaud's phenomenon and digital ulceration, focusing on reports from the last 18 months. The increasing recognition of the huge impact of Raynaud's phenomenon and of digital ulceration on the everyday lives of patients with SSc has sparked enthusiasm internationally to develop better outcome measures and better treatments, and so a review is timely. RECENT FINDINGS: There have been recent advances in the development of patient reported outcome instruments [e.g. the Hand Disability in Systemic Sclerosis-Digital Ulcers (HDISS-DU) instrument] and also in noninvasive imaging techniques, including thermography and laser Doppler methods. Improved outcome measures will facilitate future clinical trials, both early phase proof-of-concept and later phase trials. New insights have been gained into mechanisms of action and methods of administration of 'conventional' therapies, for example phosphodiesterase inhibitors and intravenous prostanoids. New treatment approaches are being investigated, including topical and procedural therapies. SUMMARY: Clinicians can look forward to seeing these advances translating into clinical benefit over the next 5 years. To help ensure this, they should strive whenever possible to recruit patients with SSc-related digital vasculopathy into observational studies and clinical trials.

Color Doppler Ultrasonography of digital arteries and digital ulcers development in systemic sclerosis.

BACKGROUND: The aim of this study was to evaluate the role of Color Doppler Ultrasonography (CDUS) of proper palmar digital arteries (PPDA) as predictive marker of new digital ulcers (DUs) in systemic sclerosis (SSc) patients during 5 years follow-up. METHODS: 36 SSc patients were examined using nailfold videocapillaroscopy (NVC) and CDUS of PPDA. RESULTS: Fourteen (38.9%) patients had chronic or acute occlusions (C and D pattern) on CDUS evaluation. Using a cut-off of 0.70, 21 (58.3%) patients had a Resistive Index (RI) ≥0.70. Nineteen (52.8%) patients developed new DUs during the follow-up. The median value of RI was higher in SSc patients with DUs than in SSc patients without DUs [0.73 (IQR 0.70-0.81) vs 0.67 (IQR 0.57-0.70), p < 0.0001]. The Kaplan-Meier analysis showed a free survival from new DUs higher (p < 0.01) in SSc patients with Pattern A and B than SSc patients with Pattern C and D. The Kaplan-Meier curves showed that free survival from new DUs is lower (p < 0.001) in SSc patients with increased RI (≥0.70) than in SSc patients with normal RI. In multivariate analysis with two co-variates, RI ≥ 0.70 [HR 5.197 (1.471-18.359), p < 0.01] and NVC late scleroderma pattern [HR 7.087 (1.989-25.246), p < 0.01] were predictive markers of new DUs. CONCLUSIONS: RI of PPDA in association with NVC could be used to evaluate SSc patients with increased risk of new DUs development.

Use of cryopreserved human amniotic membrane in the treatment of skin ulcers secondary to calciphylaxis.

Calciphylaxis is a rare condition characterized by skin ulceration and necrosis as a result of vascular calcification of the small and medium blood vessels of skin and subcutaneous tissues. It mainly occurs in patients with advanced chronic kidney disease and sometimes leads to complications with a fatal outcome. In this report, we describe the case of a 67-year-old male patient with end stage renal disease presenting painful skin ulcers on his lower limbs. The lesions had progressively grown and were associated to severe pain and decreased quality of life. The ulcers did not respond to conventional treatments and the patient underwent skin biopsy of these lesions obtaining anatomopathological findings compatible with calciphylaxis. In this report, we present an innovative treatment for skin ulcers secondary to calciphylaxis using cryopreserved amniotic membrane (AM) as a dressing in order to promote epithelialization of the wounds. After four applications, healing of the main ulcer and reduction in pain was achieved. In summary, applying cryopreserved AM probed to be a promising strategy to reduce pain and to enhance epithelialization and healing of chronic non-responsive ulcers in calciphylaxis.

Locoregional Treatments for Digital Ulcers in Systemic Sclerosis: A Systematic Review.

The management of digital ulcers in systemic sclerosis is difficult. While the 2017 European League Against Rheumatism (EULAR) guidelines clearly defined the use of systemic therapies for digital ulcers, little is known about the efficacy of locoregional treatments. The aim of this review is to systematically assess the spectrum of published locoregional therapies for digital ulcers. A total of 58 studies were included. Among the different locoregional treatment strategies described, injections of fat-derived cells and botulinum toxin showed promising results in the reduction of pain and the number of digital ulcers. By contrast, this review found that sympathectomy yielded disappointing results, with low rates of effectiveness and frequent recurrence. For other treatments, such as hyperbaric oxygen therapy, phototherapy (ultraviolet A), low-level light therapy, intermittent compression, Waon therapy, extracorporeal shockwave, vitamin E gel, and topical dimethyl sulphoxide, the conflicting results or limited published data reflected the low level of evidence. Larger randomized clinical trials are required to confirm the validity of promising techniques.

Smart Dressings for Wound Healing: A Review.

OBJECTIVE: To provide an overview of sensors incorporated into wound dressings that can be used to assess and manage healing parameters. DATA SOURCES: Authors conducted an extensive literature search of the Science Direct, Scopus, MEDLINE-PubMed, and Web of Science databases. STUDY SELECTION: A total of 587 studies that evaluated dressings used to manage wound healing parameters were identified in the search, but only 16 met all of the review criteria and were included in the final analysis. DATA EXTRACTION: Chronic wounds were the most common type of injury among studies. Six articles involved a wireless transmission system. DATA SYNTHESIS: All studies evaluated the physical and chemical characteristics of the dressings. CONCLUSIONS: This review demonstrates the lack of studies examining wound dressing sensors. New studies are required to assess sensors that allow not only wound monitoring, but also the application of drugs in a single dressing, providing a better and more cost-effective treatment for wounds.

Impaired Wound Healing with Imatinib Mesylate Therapy.

ABSTRACT: Medication-induced ulcers are generally rare. Although the tyrosine kinase inhibitor imatinib mesylate is frequently prescribed, the occurrence of ulcers related to the medication has not been previously described. Herein, the authors report a case of a patient with impaired wound healing that was attributed to imatinib mesylate treatment. Providers should maintain suspicion for medication-induced ulcers, particularly if treatment for the presumed underlying cause of an ulcer fails.

Frontiers in translational systemic sclerosis research: A focus on the unmet 'cutaneous' clinical needs (Viewpoint).

This viewpoint considers four cutaneous unmet clinical needs of patients with systemic sclerosis (SSc), namely the rapidly progressive skin thickening (scleroderma) which occurs early on in diffuse cutaneous disease; digital (finger and toe) ulcers; calcinosis; and cutaneous telangiectases. All four problems cause pain, disability and/or disfigurement, all impact on quality of life, and for each, we require effective treatments. For each unmet need, we give a brief description of the clinical problem (including clinical burden), pathophysiology and current treatment, followed by a personal viewpoint of the key questions which research must address. For the painful, debilitating skin thickening of early diffuse cutaneous SSc, studies are required to decide whether corticosteroids are effective and safe (current opinion is divided) and whether phototherapy approaches have a role. Also, we need to develop and validate reliable outcome measures for clinical trials of promising new therapies: these could be composite indices, novel non-invasive imaging methods and patient-reported outcome measures, possibly in combination as they provide complementary information. For digital ulcers, again we require validated outcome measures for clinical trials. We also need to explore local (including topical) treatments, which are free from systemic adverse effects, and preventative strategies for high-risk patients. For calcinosis, we need to better understand pathophysiology, to validate outcome measures and to develop topical treatments. For telangiectases, we need to "use" these highly accessible lesions to help unravel the vascular pathophysiology of SSc and explore their different properties as potential biomarkers.