Chronic Skin Ulcers Research Articles

649 Hypoxia-pretreatment as a possible approach to stimulate wound healing potentials of dermal fibroblasts in treatment of chronic skin ulcers

The development of new therapeutic approaches to chronic wounds hasn’t lost its relevance. In non-healing diabetic ulcers (diabetic foot) auto-transplantation (a common treatment approach) is not effective due to impaired fibroblast functionality and shifts in synthesis of ECM proteins (COL1, COL3, FN) and certain growth factors. It was shown that HIF1 (hypoxia-induced factor) is a key regulator of ECM remodeling by fibroblasts through control of collagen prolyl hydroxylase (P4HA1, P4HA2 – both required for collagen deposition) and lysylhydroxylase (PLOD2 – modulates collagen fibers strength) expression. Therefore, the use of hypoxia-stimulated fibroblasts (sFbs) may represent a reasonable treatment alternative in the maintenance of chronic diabetic wounds. Here, we evaluated the expression levels of wound healing-related genes and proteins in sFbs after 24h, 48h and 72h exposure to 1% O2. After a short-term (24/48h) exposure to hypoxia, sFbs exhibited a marked increase in expression of a number of genes as compared to 21% O2 culture: Hif1a – 7.4 and 16.9 fold respectively; Vegf1a – 21/60; Egln1 – 9/9; Egln2 – 6.5/5; Egln3 – 53/110; COL1 – 2.4/3; Fn – 3.3/1.7; P4HAa1 - 5.8/7.8; P4ha2 – 6.6/8.5; and Plod2 - 9/25 fold. In contrast, with a longer exposure to hypoxia (72h), activation was significantly diminished (Hif1a – 2 fold; Vegf1a – 6; Egln3 – 2.4) or completely abrogated (Egln1, Egln2, COL1, Fn, P4ha1, P4ha2, and Plod2). Importantly, at protein level, we observed only COLI (2 fold) stimulation by hypoxia. The stimulation of COLIII and Fn synthesis in sFb was detected only after a 6-18h period of their re-oxygenation. Based on our results, we propose that short-term stimulation of dermal fibroblasts (for example, immobilized on a biopolymer scaffold) by hypoxia could be beneficial for chronic diabetic wound treatment. (NRC Kurchatov Institute intramural grant supported research).

Abstract P2021: Cutaneous Wound Healing in Diabetic Mice is Improved by Topical Mineralocorticoid Receptor Blockade

Introduction: Chronic skin ulcers resulting from impaired wound healing are a serious complication of diabetes. Unresolved inflammation, associated with the dysregulation of both the phenotype and function of macrophages, is involved in the poor healing of diabetic wounds. Objective: To investigate the role of the mineralocorticoid receptor in the healing delay and specifically in the impaired angiogenesis and prolonged inflammation of diabetic wounds. Methods: 6 mm wounds were created on the back skin of female streptozotocin (STZ)-induced or db/db mice. Wounds were treated topically with canrenoate (Canre: 0.5mM) or PBS twice a day, for 5 (STZ mice) or 7 (db/db mice) days. Wound area was measured at indicated time post-wounding. Wounded skin was collected for histology and molecular analysis. Results: topical pharmacological inhibition of the MR by Canre can resolve prolonged inflammation to improve delayed skin wound healing in diabetic mouse models. The improvement is demonstrated by increasing of 39% of neo-epidermisation and 62% of epidermal keratinocyte proliferation in db/db wounds treated by Canre. Moreover, Canre could improve the reduced blood vessel density in the wound beds of STZ mice (STZ + PBS: 5.33% ± 0.32 vs STZ + Canre: 8.26% ± 0.64) and of db/db mice (db/db + PBS: 1.32% ± 0.29 vs db/db + Canre: 3.31% ± 0.33). The beneficial effect of Canre is associated with an increased ratio of anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages in diabetic wounds (ratio of M2 to M1 in db/db + PBS vs db/db + Canre: 0.72 ± 0.15 vs 1.72 ± 0.29, respectively). Furthermore, we show that MR blockade leads to downregulated expression of a MR target, lipocalin 2 (Lcn2), which may facilitate macrophage polarization towards the M2 phenotype and promote impaired angiogenesis in diabetic wounds. Indeed, diabetic Lcn2-deficient mice showed improved wound healing, associated with macrophage M2 polarization and angiogenesis. In addition, recombinant Lcn2 protein prevented IL4-induced macrophages switch from M1 to M2 phenotype. Conclusion: topical MR blockade accelerates skin wound healing in diabetic mice via Lcn2 reduction, M2 macrophage polarization, prevention of prolonged inflammation, and induction of angiogenesis.

Cystic Fibrosis Transmembrane Conductance Regulator: A Possible New Target for Photodynamic Therapy Enhances Wound Healing.

Objective: Cell migration is an essential process in skin wound healing. Photodynamic therapy (PDT) enhances wound healing by photoactivating a photosensitizer with a specific wavelength of light. Cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel expressed in multiple layers of keratinocytes. Recent studies showed that the activation of CFTR-related downstream signaling affects skin wound healing. We examined whether indocyanine green (ICG)-mediated PDT-enhanced cell migration is related to CFTR activation. Approach: The spatial and temporal expression levels of CFTR and proteins involved in focal adhesion, including focal adhesion kinase (FAK) and paxillin, were evaluated during cell migration in vitro and in vivo for wound healing. Results: ICG-PDT-conditioned medium collected from cells exposed to 5 J/cm2 near-infrared light in the presence of 100 μg/mL ICG activated CFTR and enhanced HaCaT cell migration. The expression of phosphorylated FAK Tyr861 and phosphorylated paxillin in focal adhesions was spatially and temporally regulated in parallel by ICG-PDT-conditioned medium. Curcumin, a nonspecific activator of CFTR, further increased PDT-enhanced cell migration, whereas inhibition of CFTR and FAK delayed cell migration. The involvement of CFTR in ICG-PDT-enhanced skin wound healing was confirmed in a mouse back skin wound model. Innovation: CFTR is a potential new therapeutic target in ICG-PDT to enhance wound healing. Conclusion: ICG-PDT-enhanced cell migration may be related to activation of the CFTR and FAK pathway. Conditioned medium collected from ICG-PDT may be useful for treating patients with chronic skin ulcer by regulating CFTR expression in keratinocytes.

MMP-sensitive PEG hydrogel modified with RGD promotes bFGF, VEGF and EPC-mediated angiogenesis.

Traumatic soft tissue defects such as bedsores, chronic skin ulcers, limb necrosis, osteonecrosis and other ischemic orthopedic diseases are the most clinically intractable and common problems in orthopedics due to unsatisfactory conventional treatments. The present study designed poly(ethylene glycol; PEG) hydrogels with covalently binded arginylglycylaspartic acid (RGD). Endothelial progenitor cells (EPCs) were encapsulated in the modified hydrogel along with vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). Results demonstrated that the modified hydrogel displayed good mechanical properties appropriate for a sustained release carrier. RGD modification significantly promoted EPC biocompatibility. VEGF and bFGF encapsulation enhanced the adhesion of EPCs, promoted the production of extracellular matrix and facilitated EPC proliferation. In addition, bFGF and VEGF induced angiogenesis. The combination of growth factors and EPCs in the hydrogel displayed a strong synergy to improve biocompatibility. The present results provided a potential novel treatment approach for soft tissue defects such as bone exposure, chronic skin ulcers, bedsores, limb necrosis, osteonecrosis and other ischemic diseases.

Effect of Ellagic Acid on Wound Healing of Chronic Skin Ulceration in Diabetic Mice and Macrophage Phenotype Transformation

Objection: To study the effect of modified formulae for ellagic acid (EA) on wound healing and macrophage phenotype transformation in diabetic mice. Materials and Methods: 10 db/m mice regarded as normal group, Dividing 20 db/db mice as the model group and EA group, 10 in every group. Surgical operation on the back was made to prepare experimental wound models. External medicines were applied and changed dressings every other day and measurement. Wound tissues were gained when animals were sacrificed by anesthesia 7 days later. Pathological changes were observed by HE and Masson staining methods, while using RT-PCR and IHC to measure mRNA and protein levels of MI/M2 type cytokines of the wound tissues. Results: Compared with the normal group, the wound area of db/db was greater (P < 0.001), while EA group less (P < 0.001). IL-12 and TNF-α mRNA and proteins levels in model group were higher (P < 0.001, respectively), while VEGF and TGF-βmRNA and proteins were lower. mRNA and protein levels of inflammato cytokines of EA group was all lower (P < 0.001), while the growth factor were significantly higher (P < 0.001). Conclusion: Wound healing of db/db mice was delayed and modified formulae for EA had effects on wound healing. The way by decreasing the Ml type inf1ammatory factors and improving the M2 type growth factors might be one of the mechanisms for wound healing.

Histopathological spectrum of chronic skin ulcers in a tertiary care hospital

<p class="abstract"><strong>Background:</strong> The skin is the largest organ of the body, comprising of epidermis, dermis and hypodermis. Thus, a wide range of diseases can develop from the skin ranging from infectious diseases to malignancy, some of which may present as non-healing ulcers. Skin biopsy forms the fundamental basis for differentiation of similar looking lesions, thus helping the pathologists to make a definitive diagnosis and more so to the clinician for better management of patients. The objective was to study the histopathological spectrum of chronic non healing ulcers of skin for proper management and treatment.</p><p class="abstract"><strong>Methods:</strong> This was a hospital-based study which was conducted in SKIMS, Soura, a tertiary care hospital of Kashmir valley for a period of 1 year extending from January 2018 to December 2018. All the patients who presented with the complaint of non-healing ulcer for more than 4 to 6 weeks were subjected to skin biopsy and histopathological examination.</p><p class="abstract"><strong>Results:</strong> A total of 260 biopsies were examined. Out of 260 patients 146 were males and 114 were females. Ninety out of 260 cases (34.61%) and 170 (65.39%) were diagnosed as malignant and benign ulcers respectively.</p><p class="abstract">Diabetic ulcer was the second most common cause of non-healing ulcers followed by bacterial infections and tuberculosis. Squamous cell carcinoma was the most common neoplastic pathology.</p><p class="abstract"><strong>Conclusions: </strong>It was concluded from the study that non-healing skin ulcers can be encountered at any age in daily medical practice.</p>

Il trattamento topico con una matrice contenente mesoglicano in associazione ad acido ialuronico nella gestione delle ulcere cutanee croniche degli arti inferiori/Topical treatment with a matrix containing mesoglycan in association with hyaluronic acid in the management of chronic skin ulcers of the lower limbs

Un’ulcera cutanea cronica degli arti inferiori rappresenta l’epifenomeno di varie situazioni patologiche che possono coinvolgere, a vari livelli e con diversi gradi di interessamento, i sistemi venoso, arterioso e linfatico della gamba. Recentemente sono state pubblicate numerose evidenze secondo cui i glicosaminoglicani (GAG) svolgono un ruolo importante nella riepitelizzazione delle ulcere cutanee croniche degli arti inferiori, in particolare per quanto riguarda le ulcere ad eziopatogenesi vascolare venosa o mista. In questo articolo riportiamo la nostra esperienza nel trattamento delle ulcere cutanee croniche degli arti inferiori con una metodica che prevede il debridement secondo il protocollo TIME, antisepsi con una soluzione di iodopovidone al 10% la successiva l’applicazione di una medicazione bioattiva contenente GAG e acido ialuronico. Questa metodica è stata confrontata con un’analoga metodica che prevede sempre lo stesso tipo di debridement e di antisepsi con soluzione di iodopovidone al 10% affiancata a una medicazione non bioattiva.
 A chronic skin ulcer in the lower limbs represents the epiphenomenon of pathologies that may involve, at various levels, the venous, arterial, lymphatic and nervous systems of the leg, which must be identified and adequately treated. Recently, there has been increasing evidence that glycosaminoglycans (GAGs) play a role in the re-epithelialization of chronic skin ulcerative wounds of the lower limbs, particularly as regards ulcers of venous and arterial vascular origin. In this paper we report our experience in the treatment of chronic skin ulcers with debridement according to the TIME Wound Bed Preparation protocol with application of a bioactive dressing containing GAGs and hyaluronic acid, compared to a technique using a standard dressing involving the cleansing of the wound with 10% povidone iodine solution.

Treatment with Regenerating Agent Cacicol�

The importance of extracellular matrix (ECM) integrity in maintaining normal tissue function is demonstrated by numerous pathologies of acute or chronic injury associated with destruction or disruption of its components. Regenerating agent therapy (RGTA) showed a strong anti-oxidative and protective effect resulting in reduced inflammation in chronic periodontitis, corneal lesions, oral and skin ulcers [1-5].Two cases of corneal healing with Cacicol�. The first one was a chemical corneal burn with persistent lesions which resulted in restitutio ad integrum after treatment with Cacicol�. The second case was a contact lens wearer whose cornea had an ulcer with profuse lesions within the stromal layer and the evolution under conventional treatment for 2 weeks was insignificant and after the use of Cacicol� the lesions improved. Cacicol� is an innovative treatment that can be used in non-healing corneal lesions, eg: unresponsive corneal burns with conventional treatment.

Patterns of multimorbidity associated with 30-day readmission: a multinational study

BackgroundMultimorbidity is associated with higher healthcare utilization; however, data exploring its association with readmission are scarce. We aimed to investigate which most important patterns of multimorbidity are associated with 30-day readmission.MethodsWe used a multinational retrospective cohort of 126,828 medical inpatients with multimorbidity defined as ≥2 chronic diseases. The primary and secondary outcomes were 30-day potentially avoidable readmission (PAR) and 30-day all-cause readmission (ACR), respectively. Only chronic diseases were included in the analyses. We presented the OR for readmission according to the number of diseases or body systems involved, and the combinations of diseases categories with the highest OR for readmission.ResultsMultimorbidity severity, assessed as number of chronic diseases or body systems involved, was strongly associated with PAR, and to a lesser extend with ACR. The strength of association steadily and linearly increased with each additional disease or body system involved. Patients with four body systems involved or nine diseases already had a more than doubled odds for PAR (OR 2.35, 95%CI 2.15–2.57, and OR 2.25, 95%CI 2.05–2.48, respectively). The combinations of diseases categories that were most strongly associated with PAR and ACR were chronic kidney disease with liver disease or chronic ulcer of skin, and hematological malignancy with esophageal disorders or mood disorders, respectively.ConclusionsReadmission was associated with the number of chronic diseases or body systems involved and with specific combinations of diseases categories. The number of body systems involved may be a particularly interesting measure of the risk for readmission in multimorbid patients.

Biostimulation of venous chronic ulcers with platelet-rich plasma gel and biocompatible membranes of chitosan and alginate: A pilot study

Abstract Venous ulcers are a common disease caused by circulatory insufficiency, having as characteristics slow healing and therefore a difficult treatment. Consequently, this disease has a high impact at personal, professional and social levels, representing large costs for both patients and healthcare system. The aim of the present pilot study was to evaluate the effectiveness of an alternative treatment for this specific type of wound, based on the use of autologous platelet-rich plasma gel (PRP) combined with biocompatible porous membranes produced with the polysaccharides chitosan (C) and alginate (A). The applicability, security and healing efficacy of this treatment was evaluated in four patients suffering from venous ulcers with an at least 6-month of evolution that did not heal after conventional treatments. The clinical evolution analysis during the treatment was performed by periodic measurement of the lesions area for an average of 5.4 months. The results attained showed that the use of this treatment led to completed reduction in the ulcers area as well as to pain decrease. Hence, the combination between autologous PRP gel and chitosan-alginate (CA) porous membranes could be a useful alternative to treat chronic skin ulcers in humans.

The healing effect of Wharton's jelly stem cells seeded on biological scaffold in chronic skin ulcers: A randomized clinical trial.

Chronic wound or nonhealing ulcer is essentially a wound that does not progress normally through the wound healing process. This study assessed the healing effect of umbilical cord Wharton's jelly stem cells seeded on biological scaffold in chronic skin ulcers. In a randomized clinical trial, five patients between 30 and 60years with chronic diabetic wounds were enrolled. To cover the wounds, acellular amniotic membrane seeded with Wharton's jelly mesenchymal stem cells (WJSCs) was used for 9days, every 3days with a follow-up of 1month. The percentage and time of wound healing and the size of wound were recorded for each patient. In treated patients, the wound healing time and wound size significantly decreased, and after 6 and 9days, the wound size significantly declined (P<0.002). As WJSCs seeded on amniotic membrane could significantly accelerate the healing effect in chronic diabetic wounds, they can be an alternative source in tissue engineering and repair of chronic ulcers.

May-Thurner Syndrome in Pregnancy [7K

INTRODUCTION: Thromboembolic disease is responsible for approximately 11% of maternal deaths in the United States. May-Thurner syndrome occurs when compression by the right common iliac artery against the fifth lumbar vertebra causes left common iliac vein obstruction and thrombosis. The incidence is 22-24%. It increases the risk for deep vein thrombosis. Pregnancy and oral contraceptives are risk factors. Diagnosis is by CT, MRI and venography. If anticoagulation therapy is not effective, angioplasty and endovascular stenting are needed. If undiagnosed and untreated, the patient can develop post-thrombotic syndrome with chronic edema, pain, hyperpigmentation, varicosities and skin ulcerations. METHODS: A 34 year old female G3 P0020 at 27 weeks gestation presented with left thigh, groin and gluteal region swelling and pain. Doppler studies were negative. Symptoms persisted and MRI/MRV diagnosed thrombosis of the left common and external iliac veins. The only antecedent precipitating event was a 2.5 hour plane flight 10 days prior. Screening for hypercoagulable disorders was negative. The patient was placed on Lovenox antepartum, anti Xa levels followed and continued postpartum for 6 weeks. MRV 2 months postdelivery revealed partial recanalization of vessels. In her second uneventful pregnancy, the patient initiated early care, was started on Lovenox, and delivered vaginally. CONCLUSION: May-Thurner syndrome is a rare condition with significant morbidity and mortality. Apart from pregnancy, this patient had no risk factors. The continuing symptoms prompted an appropriate diagnosis by MRV. Immediate anticoagulant treatment helped to prevent post-thrombotic syndrome. A high index of suspicion is needed to avoid misdiagnosis.

Canine neuropathies: powerful spontaneous models for human hereditary sensory neuropathies.

In humans, hereditary sensory neuropathies (HSN), also known as hereditary sensory and autonomic neuropathies (HSAN), constitute a clinically and genetically heterogeneous group of disorders characterized by progressive sensory loss, often accompanied by chronic skin ulcerations and nail dystrophic changes. To date, although around 20 genes have already been discovered, they do not explain the genetic causes of all patients. In dogs, similar neuropathies are also diagnosed, several breeds being predisposed to specific forms of the disease. Indeed, the breed specificity of most canine genetic diseases is due to the small numbers of founders and high levels of inbreeding. Recent knowledge and tools developed to study the canine genome efficiently allows deciphering the genetic bases of such diseases. To date, a dozen breeds are recognized to develop specific HSN. For the Border collie and hunting dog breeds, the genes involved have recently been discovered. Other affected breeds thus constitute potential genetic models, with new genes to be found in dogs that can be considered as candidate genes for human HSAN/HSN. Here, we review the different forms of human and canine HSAN/HSN and we present a novel form in Fox terrier cases, highlighting the advantages of the dog model for such rare human diseases.

Prolotherapy: Potential for the Treatment of Chronic Wounds?

Significance: Chronic skin ulcers, including venous, diabetic, and pressure ulcers, constitute a major health care burden, affecting 2-6 million people in the United States alone, with projected increases in incidence owing to the aging population and rising epidemic of diabetes. The ulcers are often accompanied by pain. Standard of care fails to heal ∼50% of diabetic foot ulcers and 25% of venous leg ulcers. Even advanced therapies do not heal >60%. Thus there is an unmet need for novel therapies that promote healing and also address the concomitant pain issue. Recent Advances: Prolotherapy involves injection of small amounts of an irritant material to the site of degenerated or painful joints, ligaments, and tendons. Multiple irritants are reported to be efficacious, but the focus here is on dextrose prolotherapy. In vitro and in vivo studies support translation to clinical use. Concentrations as low as 5% dextrose have resulted in production of growth factors that have critical roles in repair. Numerous clinical trials report pro-reparative effects of dextrose prolotherapy in joint diseases, tendon, and ligament damage, and for painful musculoskeletal issues. However, most of the studies have limitations that result in low-quality evidence. Critical Issues: The preclinical data support a role for dextrose prolotherapy in promoting tissue repair that is required for healing chronic wounds and ameliorating the associated pain. Critical issues include provision of evidence of efficacy in human chronic wounds. Another potential obstacle is limitation of reimbursement by third-party payers for a therapy with as yet limited evidence. Future Directions: Preclinical studies in models of chronic wounds would support clinical translation. As dextrose prolotherapy has some mechanistic similarities to already approved honey therapies, it may have a shortened pathway for clinical translation. The gold standard for widespread adoption would be a well-designed clinical trial.

Chronic skin ulcers incur substantial healthcare costs

Chronic skin ulcers incur substantial healthcare costs

Buruli Ulcer (Acha-ere): Pathogenesis and Manifestation

Infection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. It has been reported in over 33 countries around the world, the greatest burden of disease is in the tropical regions of West and Central Africa, Australia, and Japan. It primarily affects children aged 5-15 years. Buruli ulcers generally begin as a painless dermal papule or subcutaneous edematous nodule, which over a period of weeks to months, breaks down to form an extensive necrotic ulcer with undermined edges. The pathogenesis of this neglected tropical disease is dependent on a lipidlike toxin, mycolactone, which diffuses through tissue away from the infecting organisms and elucidate its cytotoxic and immunosuppressive properties. The underlying molecular targets for mycolactone are: First, it can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and therefore lead to detachment and cell death. Second, it prevents the co-translational translocation (and therefore production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. Treatment includes a prolonged course of antibiotics and surgical debridement. Early identification and treatment are key, as lesions heal with scarring that can be a significant source of morbidity.

Botulinum Toxin A Injection for Treatment of Chronic Skin Ulcer: A Case Series and Literature Review.

Chronic skin ulcer (CSU) often combines with a variety of refractory factors that respond poorly to routine treatments. Botulinum toxin A (BTX-A) can be injected subcutaneously to improve the local blood supply, to reduce pain, and to promote wound healing. At present, few reports have mentioned BTX-A injection for chronic skin ulcer treatment. We observed the effect of four cases that used BTX-A to treat CSU and provided a brief review of the literature. Four cases of CSUs with 4 different causes were treated with BTX-A injection (4 U/cm2). The specific operation is as follows: local, multipoint, cyclic, equidistant, and subcutaneous injections with a depth of 6 to 8 mm. The ulcer area was significantly reduced. Subsequently, the ulcer healed within 20 to 48 days. Botulinum toxin A is recommended as an important treatment for chronic skin ulcer that can improve healing of skin ulcers with various etiologies.

Comparative study of topical mupirocin versus mupirocin with sucralfate combination in treatment of chronic skin ulcers

Comparative study of topical mupirocin versus mupirocin with sucralfate combination in treatment of chronic skin ulcers

Chronic Skin Ulcer due to Mycobacterium Simiae in an Immunocompetent Lady

Skin and soft tissue infections (SSTIs) with Nontuberculous Mycobacteria (NTMs) are increasingly encountered in recent times. We describe a case of a chronic non-healing ulcer on the foot of a young immunocompetent lady caused by Mycobacterium simiae. The diagnostic approach and successful management of the case have been reviewed. This is probably the first case report SSTI due to M. simiae from India.

Advancement in phodynamic therapy for non-neoplastic skin diseases

Photodynamic therapy is mainly used in dermatology to treat skin tumors, precancerous lesions, and condyloma acuminatum. Due to its excellent tissue selectivity, easy operation and good cosmetic effect, it has been gradually applied to the treatment of various non-neoplastic skin diseases, such as verruca acuminata, acne, rosacea, chronic skin ulcer, fungal diseases, keloid, and so on. Here is the review on the advancement in photodynamic therapy for non-neoplastic skin diseases.