High Levels of Oxidative Stress and Skin Microbiome are Critical for Initiation and Development of Chronic Wounds in Diabetic Mice.

A balanced redox state is critical for proper healing. Although human chronic wounds are characterized by high levels of oxidative stress (OS), whether OS levels are critical for chronic wound development is not known. For these studies, we used our chronic wound model in diabetic mice that has similar characteristics as human chronic wounds, including naturally developed biofilm. We hypothesize that OS levels in wound tissues are critical for chronic wound initiation and development. We show that increased OS levels in the wound correlate with increased chronicity. Moreover, without increased OS levels, biofilm taken from chronic wounds and placed in new excision wounds do not create chronic wounds. Similarly, high OS levels in the wound tissue in the absence of the skin microbiome do not lead to chronic wounds. These findings show that both high OS levels and bacteria are needed for chronic wound initiation and development. In conclusion, OS levels in the wound at time of injury are critical for biofilm formation and chronic wound development and may be a good predictor of the degree of wound chronicity. Treating such wounds might be accomplished by managing OS levels with antioxidants combined with manipulation of the skin microbiome after debridement

Medicare-VHA Dual Use Is Associated With Poorer Chronic Wound Healing

Veterans who use Veterans Health Affairs (VHA) have the option of enrolling in and obtaining care from other non-VA sources. Dual system use may improve care by increasing options or it may result in poorer outcomes because of fragmented care. Our objective was to assess whether dual system use of VHA and Medicare for wound care was associated chronic wound healing. We conducted a retrospective cohort study of 227 Medicare-enrolled VHA users in the Pacific Northwest who had an incident, chronic lower limb wound between October 1, 2006 and September 30, 2007 identified through VHA chart review. All wounds were followed until resolution or for up to one year. Dual system wound care was identified through Medicare claims during follow-up. We used a proportional hazards model to compare wound healing among VHA-exclusive and dual wound care users, using a time-varying measure of dual use and treating amputation and death as competing risks. 18.1% of subjects were classified as dual wound care users during follow-up. After adjustment using propensity scores, dual use was associated with a significantly lower hazard of wound healing compared to VHA- exclusive use (HR=0.63, 95%CI: 0.39-0.99, p=0.047). Hazards for the competing risks, amputation (HR=4.23,95% CI: 1.61-11.15, p=0.003) and death (HR=3.08, 95%CI: 1.11-8.56, p=0.031), were significantly higher for dual users compared to VHA-exclusive users. Results were similar in inverse probability of treatment weighted analyses and in sensitivity analyses that excluded veterans enrolled in a Medicare managed care plan and that used a revised wound resolution date based on Medicare claims data, but were not always statistically significant. Overall, dual wound care use was associated with substantially poorer wound healing compared to VHA-exclusive wound care use. VHA may need to design programs or policies that support and improve care coordination for veterans needing chronic wound care

Artificial Intelligence-Powered Chronic Wound Management System: Towards Human Digital Twins

Artificial Intelligence (AI) has witnessed increased application and widespread adoption over the past decade. AI applications to medical images have the potential to assist caregivers in deciding on a proper chronic wound treatment plan by helping them to understand wound and tissue classification and border segmentation, as well as visual image synthesis. This dissertation explores chronic wound management using AI methods, such as Generative Adversarial Networks (GAN) and Explainable AI (XAI) techniques. The wound images are collected, grouped, and processed. One primary objective of this research is to develop a series of AI models, not only to present the potential of AI in wound management but also to develop the building blocks of human digital twins. First of all, motivations, contributions, and the dissertation outline are summarized to introduce the aim and scope of the dissertation. The first contribution of this study is to build a chronic wound classification and its explanation utilizing XAI. This model also benefits from a transfer learning methodology to improve performance. Then a novel model is developed that achieves wound border segmentation and tissue classification tasks simultaneously. A Deep Learning (DL) architecture, i.e., the GAN, is proposed to realize these tasks. Another novel model is developed for creating lifelike wounds. The output of the previously proposed model is used as an input for this model, which generates new chronic wound images. Any tissue distribution could be converted to lifelike wounds, preserving the shape of the original wound. The aforementioned research is extended to build a digital twin for chronic wound management. Chronic wounds, enabling technologies for wound care digital twins, are examined, and a general framework for chronic wound management using the digital twin concept is investigated. The last contribution of this dissertation includes a chronic wound healing prediction model using DL techniques. It utilizes the previously developed AI models to build a chronic wound management framework using the digital twin concept. Lastly, the overall conclusions are drawn. Future challenges and further developments in chronic wound management are discussed by utilizing emerging technologies

Multifunctional enzymatically generated hydrogels for chronic wound application

The healing of chronic wounds requires intensive medical intervention at huge healthcare costs. Dressing materials should consider the multifactorial nature of these wounds comprising deleterious proteolytic and oxidative enzymes and high bacterial load. In this work, multifunctional hydrogels for chronic wound application were produced by enzymatic cross- linking of thiolated chitosan and gallic acid. The hydrogels combine several beneficial to wound healing properties, controlling the matrix metalloproteinases (MMPs) and myeloperoxidase (MPO) activities, oxidative stress, and bacterial contamination. In vitro studies revealed above 90% antioxidant activity, and MPO and collagenase inhibition by up to 98 and 23%, respectively. Ex vivo studies with venous leg ulcer exudates confirmed the inhibitory capacity of the dressings against MPO and MMPs. Additionally, the hydrogels reduced the population of the most frequently encountered in nonhealing wounds bacterial strains. The stable at physiological conditions and resistant to lysozyme degradation hydrogels showed high biocompatibility with human skin fibroblastsPeer ReviewedPostprint (author's final draft

Challenges in the management of chronic wound infections.

ABSTRACT Objectives Chronic wound infections may delay the healing process and are responsible for a significant burden on healthcare systems. Since inappropriate management may commonly occur in the care of these patients, this review aims to provide a practical guide underlining actions to avoid in the management of chronic wound infections. Methods We performed a systematic review of the literature available in PubMed in the last 10 years, identifying studies regarding the management of patients with chronic wound infections. A panel of experts discussed the potential malpractices in this area. A list of 'Don'ts', including the main actions to be avoided, was drawn up using the 'Choosing Wisely' methodology. Results In this review, we proposed a list of actions to avoid for optimal management of patients with chronic wound infections. Adequate wound bed preparation and wound antisepsis should be combined, as the absence of one of them leads to delayed healing and a higher risk of wound complications. Moreover, avoiding inappropriate use of systemic antibiotics is an important point because of the risk of selection of multidrug-resistant organisms as well as antibiotic-related adverse events. Conclusion A multidisciplinary team of experts in different fields (surgeon, infectious disease expert, microbiologist, pharmacologist, geriatrician) is required for the optimal management of chronic wound infections. Implementation of this approach may be useful to improve the management of patients with chronic wound infections

Preoperative Skin Conditioning: Extracellular Matrix Clearance and Skin Bed Preparation, A New Paradigm.

This paper introduces the concept of "skin bed preparation" prior to surgical procedures. Following the theory of chronic wound bed preparation and adapting the skin model to one of chronic wound changes related to extrinsic and intrinsic factors, a topical formulation aimed at recycling the extracellular matrix (ECM) from accumulated waste products is evaluated and discussed. The clearance of these products and stimulation of new replacements has the potential to change the regenerative milieu of the skin so that when procedures are carried out, cellular signaling and cross-talk at the dermal level are improved and healing is optimized. By introducing a combination of peptides and other synergistic active agents, a sequence of clearance, regeneration, and remodeling is initiated. This is confirmed and validated by a series of biopsies and clinical studies that demonstrate changes in the ECM as early as 2 to 3 weeks after application. Clinical studies related to resurfacing procedures show accelerated healing and improved symptomatic relief compared with standard of care by preconditioning the skin 2 weeks prior to the procedure. A similar approach is suggested as a potential advantage for invasive surgical procedures based on similar scientific principles elucidated on in the text

Improving chronic wound treatment

Wunden, die über eine Zeit von mehreren Monaten nicht abheilen, werden als chronische Wunden bezeichnet. Vor allem ältere Menschen sind betroffen. Infektionen mit Antibiotika-resistenten Bakterien können weitere Schwierigkeiten bei der Behandlung und Heilung hervorrufen. Zur Behandlung von chronischen Wunden entwickeln wir daher eine Hydrogel-basierte Wundauflage, welche heilungsfördernde Substanzen in die Wunde abgibt. Diese sind zum einen Bakteriophagen, also Viren, die Bakterien befallen und so die Infektion bekämpfen und zum anderen Wachstumsfaktoren, welche die Bildung von gesundem Gewebe anregen. Das Hydrogel wird mit diesen angereichert und reagiert mit Proteasen in der Wunde, sodass es sich teilweise auflöst und die Substanzen freigesetzt werden. Das Hydrogel basiert auf dem Polymer starPEG, welches gut verträglich ist. An einigen Stellen werden Peptide in das Hydrogel eingebaut, die von den Proteasen, welche von Bakterien oder dem Immunsystem produziert werden, zerschnitten werden. Die menschlichen Wachstumsfaktoren werden in Hefe produziert, indem die entsprechende DNA per Plasmid in diese eingebaut wird. Ein System zur effizienten Sekretion der Wachstumsfaktoren wird getestet, wodurch die Reinigung dieser für den medizinischen Einsatz erleichtert werden soll. Weiterhin wird eine computergestützte Design-Pipeline entwickelt, die es erlauben soll, verschiedene Hydrogel-Kompositionen in-silico zu testen. Damit sollen Kosten und Aufwand für Entwicklung und Anpassungen reduziert werden. Das Projekt findet im Rahmen des iGEM-Wettbewerbs im Bereich der Synthetischen Biologie statt und läuft bis zum Oktober 2022. Ziel ist es, bis dahin die einzelnen Bestandteile des Produkts zu entwickeln und im Labor getrennt zu testen. Es soll gezeigt werden, dass Bakteriophagen vom Hydrogel abgegeben werden und immer noch in der Lage sind, Bakterien abzutöten. Weiterhin soll die Diffusion der produzierten Wachstumsfaktoren aus dem Hydrogel quantifiziert werden.:Chronic wounds A new dressing for treating chronic wounds Result

Survey of bacterial diversity in chronic wounds using Pyrosequencing, DGGE, and full ribosome shotgun sequencing

<p>Abstract</p> <p>Background</p> <p>Chronic wound pathogenic biofilms are host-pathogen environments that colonize and exist as a cohabitation of many bacterial species. These bacterial populations cooperate to promote their own survival and the chronic nature of the infection. Few studies have performed extensive surveys of the bacterial populations that occur within different types of chronic wound biofilms. The use of 3 separate16S-based molecular amplifications followed by pyrosequencing, shotgun Sanger sequencing, and denaturing gradient gel electrophoresis were utilized to survey the major populations of bacteria that occur in the pathogenic biofilms of three types of chronic wound types: diabetic foot ulcers (D), venous leg ulcers (V), and pressure ulcers (P).</p> <p>Results</p> <p>There are specific major populations of bacteria that were evident in the biofilms of all chronic wound types, including <it>Staphylococcus, Pseudomonas, Peptoniphilus, Enterobacter, Stenotrophomonas, Finegoldia</it>, and <it>Serratia </it>spp. Each of the wound types reveals marked differences in bacterial populations, such as pressure ulcers in which 62% of the populations were identified as obligate anaerobes. There were also populations of bacteria that were identified but not recognized as wound pathogens, such as <it>Abiotrophia para-adiacens </it>and <it>Rhodopseudomonas </it>spp. Results of molecular analyses were also compared to those obtained using traditional culture-based diagnostics. Only in one wound type did culture methods correctly identify the primary bacterial population indicating the need for improved diagnostic methods.</p> <p>Conclusion</p> <p>If clinicians can gain a better understanding of the wound's microbiota, it will give them a greater understanding of the wound's ecology and will allow them to better manage healing of the wound improving the prognosis of patients. This research highlights the necessity to begin evaluating, studying, and treating chronic wound pathogenic biofilms as multi-species entities in order to improve the outcomes of patients. This survey will also foster the pioneering and development of new molecular diagnostic tools, which can be used to identify the community compositions of chronic wound pathogenic biofilms and other medical biofilm infections.</p

Wound healing and hyper-hydration - a counter intuitive model

Winters seminal work in the 1960s relating to providing an optimal level of moisture to aid wound healing (granulation and re-epithelialisation) has been the single most effective advance in wound care over many decades. As such the development of advanced wound dressings that manage the fluidic wound environment have provided significant benefits in terms of healing to both patient and clinician. Although moist wound healing provides the guiding management principle confusion may arise between what is deemed to be an adequate level of tissue hydration and the risk of developing maceration. In addition, the counter-intuitive model ‘hyper-hydration’ of tissue appears to frustrate the moist wound healing approach and advocate a course of intervention whereby tissue is hydrated beyond what is a normally acceptable therapeutic level. This paper discusses tissue hydration, the cause and effect of maceration and distinguishes these from hyper-hydration of tissue. The rationale is to provide the clinician with a knowledge base that allows optimisation of treatment and outcomes and explains the reasoning behind wound healing using hyper-hydration

Microbial predictors of healing and short-term effect of debridement on the microbiome of chronic wounds.

Chronic wounds represent a large and growing disease burden. Infection and biofilm formation are two of the leading impediments of wound healing, suggesting an important role for the microbiome of these wounds. Debridement is a common and effective treatment for chronic wounds. We analyzed the bacterial content of the wound surface from 20 outpatients with chronic wounds before and immediately after debridement, as well as healthy skin. Given the large variation observed among different wounds, we introduce a Bayesian statistical method that models patient-to-patient variability and identify several genera that were significantly enriched in wounds vs. healthy skin. We found no difference between the microbiome of the original wound surface and that exposed by a single episode of sharp debridement, suggesting that this debridement did not directly alter the wound microbiome. However, we found that aerobes and especially facultative anaerobes were significantly associated with wounds that did not heal within 6 months. The facultative anaerobic genus Enterobacter was significantly associated with lack of healing. The results suggest that an abundance of facultative anaerobes is a negative prognostic factor in the chronic wound microbiome, possibly due to the increased robustness of such communities to different metabolic environments