Therapy Of Chronic Wounds Research Articles

Autologous Stem Cell Therapy for Chronic Lower Extremity Wounds: A Meta-Analysis of Randomized Controlled Trials.

Lower extremity chronic wounds (LECWs) commonly occur in patients with diabetes mellitus (DM) and peripheral arterial disease (PAD). Autologous stem cell therapy (ASCT) has emerged as a promising alternative treatment for those who suffered from LECWs. The purpose of this study was to assess the effects of ASCT on LECWs. Two authors searched three core databases, and independently identified evidence according to predefined criteria. They also individually assessed the quality of the included randomized controlled trials (RCTs), and extracted data on complete healing rate, amputation rate, and outcomes regarding peripheral circulation. The extracted data were pooled using a random-effects model due to clinical heterogeneity among the included RCTs. A subgroup analysis was further performed according to etiology, source of stem cells, follow-up time, and cell markers. A total of 28 RCTs (n = 1096) were eligible for this study. The pooled results showed that patients receiving ASCT had significantly higher complete healing rates (risk ratio (RR) = 1.67, 95% confidence interval (CI) 1.28–2.19) as compared with those without ASCT. In the CD34+ subgroup, ASCT significantly led to a higher complete healing rate (RR = 2.70, 95% CI 1.50–4.86), but there was no significant difference in the CD34− subgroup. ASCT through intramuscular injection can significantly improve wound healing in patients with LECWs caused by either DM or critical limb ischemia. Lastly, CD34+ is an important cell marker for potential wound healing. However, more extensive scale and well-designed studies are necessary to explore the details of ASCT and chronic wound healing.

Spatiotemporal control of myofibroblast activation in acoustically-responsive scaffolds via ultrasound-induced matrix stiffening

Hydrogels are often used to study the impact of biomechanical and topographical cues on cell behavior. Conventional hydrogels are designed a priori, with characteristics that cannot be dynamically changed in an externally controlled, user-defined manner. We developed a composite hydrogel, termed an acoustically-responsive scaffold (ARS), that enables non-invasive, spatiotemporally controlled modulation of mechanical and morphological properties using focused ultrasound. An ARS consists of a phase-shift emulsion distributed in a fibrin matrix. Ultrasound non-thermally vaporizes the emulsion into bubbles, which induces localized, radial compaction and stiffening of the fibrin matrix. In this in vitro study, we investigate how this mechanism can control the differentiation of fibroblasts into myofibroblasts, a transition correlated with substrate stiffness on 2D substrates. Matrix compaction and stiffening was shown to be highly localized using confocal and atomic force microscopies, respectively. Myofibroblast phenotype, evaluated by α-smooth muscle actin (α-SMA) immunocytochemistry, significantly increased in matrix regions proximal to bubbles compared to distal regions, irrespective of the addition of exogenous transforming growth factor-β1 (TGF-β1). Introduction of the TGF-β1 receptor inhibitor SB431542 abrogated the proximal enhancement. This approach providing spatiotemporal control over biophysical signals and resulting cell behavior could aid in better understanding fibrotic disease progression and the development of therapeutic interventions for chronic wounds. Statement of SignificanceHydrogels are used in cell culture to recapitulate both biochemical and biophysical aspects of the native extracellular matrix. Biophysical cues like stiffness can impact cell behavior. However, with conventional hydrogels, there is a limited ability to actively modulate stiffness after polymerization. We have developed an ultrasound-based method of spatiotemporally-controlling mechanical and morphological properties within a composite hydrogel, termed an acoustically-responsive scaffold (ARS). Upon exposure to ultrasound, bubbles are non-thermally generated within the fibrin matrix of an ARS, thereby locally compacting and stiffening the matrix. We demonstrate how ARSs control the differentiation of fibroblasts into myofibroblasts in 2D. This approach could assist with the study of fibrosis and the development of therapies for chronic wounds.

VEGF-A, PDGF-BB and HB-EGF engineered for promiscuous super affinity to the extracellular matrix improve wound healing in a model of type 1 diabetes

Chronic non-healing wounds, frequently caused by diabetes, lead to lower quality of life, infection, and amputation. These wounds have limited treatment options. We have previously engineered growth factors to bind to exposed extracellular matrix (ECM) in the wound environment using the heparin-binding domain of placental growth factor-2 (PlGF-2123–144), which binds promiscuously to ECM proteins. Here, in the type 1 diabetic (T1D) NOD mouse model, engineered growth factors (eGFs) improved both re-epithelialization and granulation tissue formation. eGFs were even more potent in combination, and the “triple therapy” of vascular endothelial growth factor-A (VEGF-PlGF-2123–144), platelet-derived growth factor-BB (PDGF-BB-PlGF-2123–144), and heparin-binding epidermal growth factor (HB-EGF-PlGF-2123–144) both improved wound healing and remained at the site of administration for significantly longer than wild-type growth factors. In addition, we also found that changes in the cellular milieu of a wound, including changing amounts of M1 macrophages, M2 macrophages and effector T cells, are most predictive of wound-healing success in the NOD mouse model. These results suggest that the triple therapy of VEGF-PlGF-2123–144, PDGF-BB-PlGF-2123–144, and HB-EGF-PlGF-2123–144 may be an effective therapy for chronic non-healing wounds in that occur as a complication of diabetes.

Zeolitic imidazolate framework-67 accelerates infected diabetic chronic wound healing

Chronic wounds in diabetes are often considered as a latent threat to human health, and they can cause persistent pain and even lead to amputation or death. Bacterial infections and insufficient angiogenesis are two important factors resulting in chronic wounds that cannot heal naturally. Currently, most multifunctional biomaterials are manufactured from several types of active components because single ingredients can hardly provide comprehensive and effective therapy for chronic wounds. Herein, a series of zeolitic imidazolate framework-67 (ZIF-67) with different morphologies and sizes was prepared. These nanostructures exhibited remarkable antibacterial activity against Saccharomyces cerevisiae, which was better for the cube-type than for the dodecahedron-type morphology. Simultaneously, these single-component ZIF-67 promoted the proliferation, migration, and tube formation of human umbilical vein endothelial cells in vitro. Furthermore, in vivo evaluation of a C57BL/6 type I diabetic mouse model showed that bioactive ZIF-67 (particularly ZIF-67 nanocubes) accelerated wound healing by promoting angiogenesis, enhancing collagen deposition, and polarizing macrophages. Our results unambiguously demonstrate that such single-component but multifunctional ZIF-67 nanostructures have great potential for integrating other complementary active ingredients for biomedical applications.

A systematic review of ozone therapy for treating chronically refractory wounds and ulcers.

This study aims at evaluating the efficacy and safety of ozone therapy for chronic wounds. The Cochrane Library, PubMed, Ovid Embase, Web of Science, and Chinese Biomedical Literature Database were searched. Randomised controlled trials (RCTs) about participants with chronic wounds were included. Risk of bias assessment was performed by the Cochrane risk‐of‐bias tool. A randomised‐effects model was applied to pool results according to the types of wounds or ulcers. Among 12 included studies, ozone was implemented by topical application (ozone gas bath, ozonated oil, ozone water flushing) and systematic applications including autologous blood immunomodulation and rectal insufflation. The results indicated compared with standard control therapy for diabetic foot ulcers, ozone therapy regardless of monotherapy or combined control treatment markedly accelerated the improvement of the wound area(standardised mean difference(SMD) = 66.54%, 95% confidence interval (CI) = [46.18,86.90], P < .00001) and reduced the amputation rate (risk ration (RR) = 0.36, 95% CI = [0.24,0.54], P < .00001). But there is no improvement in the proportion of participants with completely healed wounds and length of hospital stay. No adverse events associated with ozone treatment have been reported. And the efficacy of ozone therapy for other wound types is still uncertain because of no sufficient studies. More high‐quality randomised controlled trials are needed to confirm the efficacy and safety of ozone therapy for chronic wounds or ulcers.

Maggot Therapy in Chronic Wounds: New Approaches to Historical Practices

Abstract Blowfly larvae of Lucilia sericata (Meigen) (Diptera: Calliphoridae) are well established as debridement agents in nonhealing wounds. Maggot therapy (MT) experienced reduced application following adoption of Penicillin and other antibiotics, but the advent of antibiotic resistance and the growing global wound burden have boosted demand for new therapies. The mechanisms of action are well accepted, with debridement, disinfection, biofilm destruction, and inhibition, as well as the stimulation of tissue growth uniformly acknowledged as a remarkable biotherapy. The mechanisms of action, while well-recognized, are still being examined. The efforts to understand isolated aspects of a complex system, have resulted in a tendency to approach the field from simplified viewpoints that remove the holistic system of the larvae. Furthermore, clinical studies have conflated wound debridement and healing in definitions of ‘success’. Thus, both in vitro and clinical studies have reported mixed results, presenting some uncertainty regarding the utility of MT that prohibits routine clinical adoption. This review builds from the generally accepted basic mechanisms to justify a future for MT that encompasses larval-bacterial symbioses as the basis to a holistic system. Symbioses are well documented in the Insecta, and literature in MT supports the existence of established symbiotic associations that provide enhanced debridement action. The future of MT requires consideration of a biological system that confers enhanced antimicrobial action on larvae when selective pre-exposure to carefully selected symbionts is adopted. In treating contemporary infections, there is much to be gained from reflecting on the natural biology of the organism, as MT was used with success long before we sterilized the system.

A multi-targeted nanoconjugate for light-driven therapy of chronic wounds

The pathogenic bacteria-induced diabetic ulcer becomes a life-threatening miscellaneous disease and remains a pivotal clinical challenge due to poor healing. To overcome the obstacle, we developed a non-antibiotic strategy based on a three-dimensional multi-targeted nanostructure with near-infrared laser induced photothermal therapy for promoting the healing of diabetic wound infected by Pseudomonas aeruginosa and Staphylococcus aureus. This nanoconjugate was prepared by integrating gold nanorods decorated with bacterial affinitive molecules phenylboronic acid and pH-induced charge-convertible tertiary-amine group. In addition to the binding with the cell wall of bacteria from phenylboronic acid motifs, a dedicated charge conversion of the nanoconjugate from negative charge to positive charge in the acidic microenvironment of bacterial infectious sites further provides robust targeting to negatively charged bacteria. This nanoconjugate could target and kill specific bacterial cells using photothermal ablation. Following excitation by near-infrared light, gold nanorods release energy through nonradioactive decay pathways, locally generating heat that efficiently kills targeted bacterial cells and finally accelerating the wound healing of diabetic rats by down-regulating the expression of proinflammatory factors. Collectively, this nanostructure evolved targeting strategy with the photothermal property is expected to be other kind of treatment programs for repairing chronic wounds of diabetic ulcers infected by multiple bacteria.

An Innovative National Programme for Comprehensive Chronic Wound Therapy and Its Impact on Treatment Outcomes

Although the lifetime prevalence of chronic ulcers tends to be approximately 2.2-10 per 1000 population, no systemic solutions for this problem have been implemented in many countries. It is still not fully agreed whether treatment of chronic wounds requires hospitalization, which incurs high costs, or whether the therapy can be carried out entirely in an outpatient setting. Therefore, the aim of this study was to evaluate the 5-year activity and effectiveness of a national programme for the comprehensive treatment of chronic wounds based on hybrid care for patients. Treatment of nonhealing chronic wounds begins in the hospital, where necessary diagnostic actions are carried out, followed by surgical cleansing of the wound and selection of appropriate dressings. Then, the treatment is continued in the outpatient setting with a continuous patient education. The programme is divided into four subsequent stages. In addition, the present study compared the effectiveness of chronic wound treatment with that in the period before implementation of the programme. From January 2015 to December 2019, 383 patients were treated at a centre for chronic wounds. We analysed the outcomes in 227 individuals with chronic venous ulceration or diabetic foot syndrome. The mean wound area at the time of introduction of treatment was 36 cm2 (1-290; SD 34). After three stages of treatment, wounds were completely healed in 139 patients (61.2%), 78 patients with venous ulcers (55.3%) and 61 patients with diabetic foot (70.9%). In an additional 67 cases (29.5%), a significant reduction in wound area and depth was achieved, and the treatment was continued beyond the actual treatment programme. No significant effect was achieved in 21 patients (9.2%). In the group of patients treated without systematic application of the guidelines of the programme, wound healing occurred only in 19 cases (26.8%), reduction in the wound area occurred in 27 patients (38.0%), and lack of any healing progress or even worsening of the wound status was found in the remaining 25 cases (35.2%); these differences were statistically significant (p < 0.001). Treatment of chronic wounds based on a systematic dedicated programme using an experienced multidisciplinary team of professionals allows to obtain better results in terms of reduction in wound area and might be an effective procedure. The combination of frequent, scheduled outpatient visits, access to inpatient treatment, and regular education of patients based on a standard form improves treatment outcomes.

LncRNA MALAT1 promotes wound healing via regulating miR-141-3p/ZNF217 axis.

BackgroundThe process of wound healing is complex. Increasing evidences have shown that lncRNA MALAT1 is abundant in fibroblasts and may be engaged in wound healing process. Therefore, we explored the mechanism of MALAT1 affecting wound healing.MethodsThe expression levels of MALAT1, miR-141-3p as well as ZNF217 in human fibroblast cells (HFF-1) were quantified by qRT-PCR. HFF-1 proliferation was measured by MTT, while migration was detected by wound healing assay. SMAD2 activation and matrix proteins expression were detected by western blotting. The interaction between miR-141-3p and MALAT1 or ZNF217 was further confirmed using the luciferase reporter gene assay. In vivo wound healing was assessed by full-thickness wound healing model on C57BL/6 mice.ResultKnockdown of MALAT1 as well as overexpression miR-141-3p remarkably inhibited the proliferation, migration and matrix protein expression in HFF-1 cells. MALAT1 directly targeted and inhibited the expression of miR-141-3p. MiR-141-3p suppressed the activation of TGF-β2/SMAD2 signaling pathway by targeting ZNF217. Knockdown of MALAT1 inhibited wound healing process in mice.ConclusionsMALAT1 up-regulates ZNF217 expression by targeting miR-141-3p, thus enhances the activity of TGF-β2/SMAD2 signaling pathway and promotes wound healing process. This investigation shed new light on the understanding of the role of MALAT1 in wound healing, and may provide potential target for the diagnosis or therapy of chronic wounds.

A Concise Review on Tissue Engineered Artificial Skin Grafts for Chronic Wound Treatment: Can We Reconstruct Functional Skin Tissue In Vitro?

Chronic wounds occur as a consequence of a prolonged inflammatory phase during the healing process, which precludes skin regeneration. Typical treatment for chronic wounds includes application of autografts, allografts collected from cadaver, and topical delivery of antioxidant, anti-inflammatory, and antibacterial agents. Nevertheless, the mentioned therapies are not sufficient for extensive or deep wounds. Moreover, application of allogeneic skin grafts carries high risk of rejection and treatment failure. Advanced therapies for chronic wounds involve application of bioengineered artificial skin substitutes to overcome graft rejection as well as topical delivery of mesenchymal stem cells to reduce inflammation and accelerate the healing process. This review focuses on the concept of skin tissue engineering, which is a modern approach to chronic wound treatment. The aim of the article is to summarize common therapies for chronic wounds and recent achievements in the development of bioengineered artificial skin constructs, including analysis of biomaterials and cells widely used for skin graft production. This review also presents attempts to reconstruct nerves, pigmentation, and skin appendages (hair follicles, sweat glands) using artificial skin grafts as well as recent trends in the engineering of biomaterials, aiming to produce nanocomposite skin substitutes (nanofilled polymer composites) with controlled antibacterial activity. Finally, the article describes the composition, advantages, and limitations of both newly developed and commercially available bioengineered skin substitutes.

Telehealth-guided home-based maggot debridement therapy for chronic complex wounds: Peri- and post-pandemic potential.

Patients with complex chronic lower extremity wounds require a great deal of interaction with outpatient and inpatient services. Paradoxically, these are the very patients that, because of their chronic comorbidities, are at greatest risk for COVID-related morbidity and mortality. Disinfected Phaenicia (Lucilia) sericata (Medical Maggots; Monarch Labs, Irvine, California) were applied in a standardised fashion by a home-health nurse with direct monitoring, guidance, and collaboration of the attending surgeon. A family member was able to change the outer dressing daily based on normal wound exudate. The inner maggot debridement therapy (MDT) dressing was changed at 2 days showing dramatic reduction in necrotic tissue, elimination of profound malodor, and no evidence of local or advancing infection. The entire initial telehealth-guided application took approximately 20 minutes. The first telehealth-guided MDT dressing change took 14 minutes. We used an artificial-intelligence-based algorithm to measure changes in wound characteristics. At day 0, 46% of the total surface area was covered in malodorous black, necrotic tissue. The first dressing change saw an elimination in assessed malodor with necrotic tissue constituting 14% of total surface area. The second dressing change at 5 days showed a greater than 99% reduction in necrotic tissue. This manuscript constitutes what we believe to be the first telehealth-guided MDT conducted during a resource-limited peri-pandemic period. We believe that MDT, which is an extension of efforts regularly performed in clinic and hospital, may have the potential to reduce resource usage while potentially improving care and quality of life for people with limb and life-threatening complications of diabetes and other chronic diseases.

Application of Easy Wet Healing Therapy for Chronic Noninfectious Wounds in Limbs.

Chronic wounds in limbs without infection are common. This study was to identify an economical, simple, and useful wet healing therapy for patients with chronic noninfectious wounds in the limbs, especially for low-income patients. In total, 56 patients with chronic limb wounds without infection from April 2018 to March 2019 were included. They underwent wound cleaning by iodine and wound covering by recombinant human epidermal growth factor gel, zinc oxide ointment, and erythromycin eye ointment at a 1:1:1 ratio and thickness of 0.8 cm. After applying the drug, a slight-pressure dressing was applied to the wound with a cotton pad and bandage, and the dressing was changed every 3 days. All the wounds completely healed within 12 to 45 days (26.2 ± 11.9 days). The healing time showed a positive correlation with the area of the wound (r = 0.328, P < .05) and the course of disease (r = 0.485, P < .01). The healing time of deep second-degree wounds was 17.2 ± 3.3 days, which was shorter than that of deep third-degree wounds (34.8 ± 8.4 days; P < .05). There was no significant difference in the healing time according to sex. Upper limb wounds healed faster than lower limb wounds (16 ± 2.7 days versus 31.7 ± 9.7 days, P < .05). The simple therapy required a low cost of 0.07 dollars per square centimeter for each dressing change. This wet healing therapy is easy, effective, relatively safe, and affordable, with no obvious side effects.

Antioxidant dressing therapy versus standard wound care in chronic wounds (the REOX study): study protocol for a randomized controlled trial

ABSTRACTBackgroundA wound that does not heal in the orderly stages of the healing process or does not heal within 3 months is considered a chronic wound. Wound healing is impaired when the wound remains in the inflammatory stage for too long. A range of factors can delay the healing process: imbalance between proteases and protease inhibitors in the wound bed; bacterial colonization and the presence of biofilm; and oxidative stress. Recently, wound management has improved significantly. A new antioxidant dressing has been developed, which combines an absorbent matrix obtained from locust bean gum galactomannan and a hydration solution with curcumin and N-acetylcysteine. This dressing combines the advantages of moist healing in exudate management and free radical neutralization, achieving wound reactivation. The primary aim of this study is to compare the effect of the antioxidant dressing on chronic wound healing against the use of a standard wound dressing in patients with hard-to-heal wounds.MethodsWe will conduct a multicentre, single-blind, randomized controlled trial with parallel groups. Participants will be selected from three primary public health care centres located in Andalucía (southern Spain). Patients will be randomized into an intervention group (antioxidant dressing) or a control group (standard wound dressing). Assessments will be carried out at weeks 2, 4, 6 and 8. Follow-up will be for a period of 8 weeks or until complete healing if this occurs earlier.DiscussionThe findings from this study should provide scientific evidence on the efficacy of the antioxidant dressing as an alternative for the treatment of chronic wounds. This study fills some of the gaps in the existing knowledge about patients with hard-to-heal wounds.Trial registrationClinicalTrials.gov: NCT03934671. Registered on 2 May 2019.

Mesenchymal Stem Cells for Chronic Wound Healing: Current Status of Preclinical and Clinical Studies.

Healing skin wounds with anatomic and functional integrity, especially under chronic pathological conditions, remain an enormous challenge. Due to their outstanding regenerative potential, mesenchymal stem cells (MSCs) have been explored in many studies to determine the healing ability for difficult-to-treat diseases. In this article, we review current animal studies and clinical trials of MSC-based therapy for chronic wounds, and discuss major challenges that confront future clinical applications. We found that a wealth of animal studies have revealed the versatile roles and the benefits of MSCs for chronic wound healing. MSC treatment results in enhanced angiogenesis, facilitated reepithelialization, improved granulation, and accelerated wound closure. There are some evidences of the transdifferentiation of MSCs into skin cells. However, the healing effect of MSCs depends primarily on their paracrine actions, which alleviate the harsh microenvironment of chronic wounds and regulate local cellular responses. Consistent with the findings of preclinical studies, some clinical trials have shown improved wound healing after transplantation of MSCs in chronic wounds, mainly lower extremity ulcers, pressure sores, and radiation burns. However, there are some limitations in these clinical trials, especially a small number of patients and imperfect methodology. Therefore, to better define the safety and efficiency of MSC-based wound therapy, large-scale controlled multicenter trials are needed in the future. In addition, to build a robust pool of clinical evidence, standardized protocols, especially the cultivation and quality control of MSCs, are recommended. Altogether, based on current data, MSC-based therapy represents a promising treatment option for chronic wounds. Impact statement Chronic wounds persist as a significant health care problem, particularly with increasing number of patients and the lack of efficient treatments. The main goal of this article is to provide an overview of current status of mesenchymal stem cell (MSC)-based therapy for chronic wounds. The roles of MSCs in skin wound healing, as revealed in a large number of animal studies, are detailed. A critical view is made on the clinical application of MSCs for lower extremity ulcers, pressure sores, and radiation burns. Main challenges that confront future clinical applications are discussed, which hopefully contribute to innovations in MSC-based wound treatment.

Prevention and therapy of acute and chronic wounds using NPWT devices during the COVID-19 pandemic, recommendation from The NPWT Working Group

Recent SARS-CoV-2 pandemic leading to a rapidly increasing number of hospitalizations enforced reevaluation of wound management strategies.&#x0D; The optimal treatment strategy for patients with chronic wounds and those recovering from emergency and urgent oncological surgery should aim to minimize the number of hospital admissions, as well as the number of surgical procedures and decrease the length of stay to disburden the hospital staff and to minimize viral infection risk.&#x0D; One of the potential solutions that could help to achieve these goals may be the extensive and early use of NPWT devices in the prevention of wound healing complications.&#x0D; Single-use NPWT devices are helpful in outpatient wound treatment and SSI prevention (ciNPWT) allowing to minimize in-person visits to the health care center while still providing the best possible wound-care. Stationary NPWT should be used in deep SSI and perioperative wound healing disorders as soon as possible. Patient’s education and telemedical support with visual wound healing monitoring and video conversations have the potential to minimize the number of unnecessary in-person visits in patients with wounds and therefore substantially increase the level of care.

Abstract 175: Single Cell RNA-Seq Reveals Molecular Signatures Of Heterogeneous Populations Of Dendritic Cells And Macrophages In Murine Wound Healing And Hypertrophic Scarring

Purpose: Defining cellular sub-populations within the skin is critical to understand wound healing and scarring and develop novel therapeutic approaches. Dendritic cells (DC) and macrophages (MF) are mediators of the inflammatory response to skin injury and are involved in tissue homeostasis, wound healing and fibrosis. However, their cellular sub-populations in the skin remain poorly characterized. Here, we use single-cell RNA sequencing to analyze sub-populations of DCs and MFs in murine excisional wounds and hypertrophic scars over time. Methods: Cells were isolated from stented excisional wounds in C57/BL6J mice 7 and 14 days after wounding as well as from a murine hypertrophic scar (HTS) model 14 days after external mechanical loading. Unwounded skin and scars without mechanical loading served as controls. DCs and MFs were enriched in single cell suspensions using flow cytometry, gating for live, CD45+ cells and excluding B cells, T cells, NK cells and granulocytes. Cells were further processed for droplet-based microfluidic single cell analysis using the 10X Genomics platform, in which individual cells are barcoded, lysed, and sequenced. Read depth was 50,000 reads per cell. Data were log-normalized and partitioned using UMAP based density mappings. Results: We identified 7 distinct clusters of DCs, MFs and tissue monocytes. Two MF sub-populations (MHCII+,CD11cLo,CD11b+,CD103- and MHCII+,CD115+F4/80Int) were most abundant in excisional wounds, whereas HTS and control scars exhibited an enrichment of CD103-CD11b+CD24+ DCs and tissue monocytes which were specifically enriched in HTS. Unwounded skin showed an abundance of CD11c+CD11b+ DCs and B220-F4/80Lo,CD115+MHCII+ macrophages. An enrichment of transcriptomic signatures of hypertrophy, fibrosis, and cytokine signaling was found in DC and MF subpopulations which were identified in wounds and HTS. Conclusion: Our study demonstrates that wound healing and scarring induces a high degree of heterogeneity among sub-populations of DCs and MFs and thus expands our knowledge on cellular diversity of these cell types identifying novel targets for the development of therapies for chronic wounds and hypertrophic scars.

Bacteriophages for Chronic Wound Treatment: from Traditional to Novel Delivery Systems.

The treatment and management of chronic wounds presents a massive financial burden for global health care systems, with significant and disturbing consequences for the patients affected. These wounds remain challenging to treat, reduce the patients’ life quality, and are responsible for a high percentage of limb amputations and many premature deaths. The presence of bacterial biofilms hampers chronic wound therapy due to the high tolerance of biofilm cells to many first- and second-line antibiotics. Due to the appearance of antibiotic-resistant and multidrug-resistant pathogens in these types of wounds, the research for alternative and complementary therapeutic approaches has increased. Bacteriophage (phage) therapy, discovered in the early 1900s, has been revived in the last few decades due to its antibacterial efficacy against antibiotic-resistant clinical isolates. Its use in the treatment of non-healing wounds has shown promising outcomes. In this review, we focus on the societal problems of chronic wounds, describe both the history and ongoing clinical trials of chronic wound-related treatments, and also outline experiments carried out for efficacy evaluation with different phage-host systems using in vitro, ex vivo, and in vivo animal models. We also describe the modern and most recent delivery systems developed for the incorporation of phages for species-targeted antibacterial control while protecting them upon exposure to harsh conditions, increasing the shelf life and facilitating storage of phage-based products. In this review, we also highlight the advances in phage therapy regulation.

Light-Activatable Synergistic Therapy of Drug-Resistant Bacteria-Infected Cutaneous Chronic Wounds and Nonhealing Keratitis by Cupriferous Hollow Nanoshells.

Due to the inability to spontaneously heal and vulnerability to bacterial infection, diabetic patients are frustrated by unexpected epithelium injuries in daily life. Notably, a drug-resistant bacterial infection may result in a long-term impact to the natural function of damaged organs. It is imperative to develop strategies that promote injury recovery and eradicate drug-resistant infection simultaneously. Here, we present a composite structured cupriferous hollow nanoshell (AuAgCu2O NS) that consists of a hollow gold-silver (AuAg) core and Cu2O shell as a photothermal therapeutic agent for a cutaneous chronic wound and nonhealing keratitis with drug-resistant bacterial infection. The controllable photothermal therapeutic effect and released silver ion from the hollow AuAg core possess a synergistic effect to eradicate multi-drug-resistant bacteria, including extended-spectrum β-lactamase Escherichia coli (ESBL E. coli) and methicillin-resistant Staphylococcus aureus (MRSA). Meanwhile, the released copper ion from the Cu2O shell could expedite endothelial cell angiogenesis and fibroblast cell migration, thus boosting wound-healing effects. In both infection-complicated disease models, the ophthalmic clinical score, wound closure rates, and histopathology analysis demonstrate that the AuAgCu2O NSs could facilitate the re-epithelialization at the wound area and eliminate the complicated bacterial infection from diabetic mice. A primary signal path involved in the promoted healing effect was further illustrated by comprehensive assays of immunohistochemical evaluation, Western blot, and quantitative polymerase chain reaction. Taken together, our AuAgCu2O NSs are shown to be potent candidates for clinical utilization in the treatment of diabetic epithelium injuries.

Titanium Incorporation into Zr-Porphyrinic Metal-Organic Frameworks with Enhanced Antibacterial Activity against Multidrug-Resistant Pathogens.

This study uses metal-organic frameworks (MOFs) alone without any added antibacterial ingredients as the nonantibiotic agent for photodynamic therapy (PDT) of chronic wounds infected by multidrug-resistant (MDR) bacteria. Nanoparticles (NPs) of MOFs (PCN-224) are incorporated with titanium through a facile cation exchange strategy. The obtained bimetallic PCN-224(Zr/Ti) shows greatly enhanced photocatalytic performance for the generation of reactive oxygen species under visible light, which is responsible for the effective antibacterial activities. The PCN-224(Zr/Ti) NPs are loaded onto lactic-co-glycolic acid nanofibers to prepare a wound dressing, which shows high biocompatibility and minimal cytotoxicity. The wound dressing is efficient for PDT-based in vivo healing of the chronic wound infected by MDR bacteria. Most importantly, this work does not involve any additional antibacterial agents, which is facile, low cost, and in particular, greatly explores the potential of MOFs as a powerful nonantibiotic agent in PDT.

Biomarker directed chronic wound therapy – A new treatment paradigm

AimTo develop a treatment paradigm for chronic leg ulcers that incorporates new biomarkers of wound healing with currently available therapies. MethodsRecently published data on GM-CSF and MMP-13 as biomarkers of venous leg ulcer (VLU) healing status with accuracies of 92% and 78% respectively, was reviewed along with the wound bed preparation (WBP) theoretical framework for treatment of chronic wounds. The broad categories of wound treatments that align with the WBP concepts were identified. These were then considered in a hierarchical order that initially improves the wound bed and subsequently incorporates more complex advanced wound therapies. Identification of the non-healing status of the wound is the driver to advance through the different treatments. ResultsA point of care test of wound healing status is the key to the systematic use of currently available therapies for chronic leg ulcers in a timely fashion. The different therapies address – debridement, moisture control, bacterial contamination, protease inhibition, formation of granulation tissue, application of growth factors, application of matrix constructs, and application of cellular components. Progression through this hierarchical order of therapies is directed by the leg ulcer remaining in a non-healing state with the previous therapies having been implemented. ConclusionCombining a validated point of care test of wound healing with a systematic approach to wound therapies, has the potential to create a new paradigm of chronic leg ulcer treatment - biomarker directed wound therapy.