Pathophysiology Of Chronic Wounds Research Articles

A low-cost, antimicrobial aloe-alginate hydrogel film containing Australian First Nations remedy ‘lemon myrtle oil’ (Backhousia citriodora) – Potential for incorporation into wound dressings

Chronic wounds pose a global public health challenge, particularly in remote settings where access to specialised wound care and dressings can be limited and cost-prohibitive. First Nations communities in Australia are at a significantly higher risk for developing chronic wounds and this risk further increases for people living in remote regions. There is an urgent need to develop inexpensive but effective wound dressings to improve wound outcomes. Over the past decade, sodium alginate (SA)-based hydrogel polymers have emerged as a cost-effective and biocompatible component in wound dressings, and many have been successfully commercialised. In this study, we have developed and evaluated various prototypes of SA-based hydrogels with the addition of another low-cost component, aloe vera (AV) to further tailor the physicochemical properties of the hydrogel. Since the presence of microbes is a major contributor to the pathophysiology of chronic wounds, we also evaluated the antimicrobial activity of lemon myrtle oil (LMO) (Backhousia citriodora) incorporated into the hydrogel, a remedy used traditionally by First Nations Australians. Novel formulations of AV-SA-LMO hydrogel prototypes in the absence and presence of lemon myrtle oil (at a concentration of 5 μg/mL) were assessed for their physicochemical and antimicrobial properties and compared to a commercially available hydrogel-based dressing. The addition of lemon myrtle oil imparted viscoelastic behaviour for improved processability of AV-SA-LMO hydrogel prototypes, while increasing protein adhesion, enhancing physical properties, and demonstrating antimicrobial activity against the common wound-infecting microbes Staphylococcus epidermidis and Candida albicans. Fourier transmission infrared (FTIR) spectra confirmed the molecular structures of the hydrogel prototypes as predicted. The prototypes also demonstrated biocompatibility with the HaCaT human keratinocyte cell line. This study has provided preliminary evidence that a 25:75 aloe vera:sodium alginate hydrogel with 5 μg/mL lemon myrtle oil has comparable physicochemical characteristics to a commercial hydrogel-based wound dressing and antimicrobial properties against S. epidermidis and C. albicans.

A Detailed Review on Diabetic Wound Healing Activity

Skin damage is known as a wound. Hemostasis, inflammatory, proliferative, and tissue remodelling or resolution are the four perfectly timed and highly planned phases that make up the normal biological process of wound healing in the human body. There are two basic categories of wounds: acute wounds and chronic wounds. Long-term negative effects on one's health are caused by the chronic metabolic condition known as diabetes mellitus, which is becoming more common. 25 percent of those with diabetes mellitus are thought to have poor wound healing due to their diabetes. Oxygenation, infection, hormones related to ageing and sex, stress, diabetes, and obesity, drugs, alcoholism, smoking, and diet are among the factors that affect wound healing. To address their basic medical needs, According to estimates, 80% of people who live in underdeveloped nations need traditional medicines, which are typically made from medicinal plants. Numerous individuals in Africa and other poor nations employ using medicinal herbs to cure diabetic wounds and associated issues due to the abundant supply With therapeutic herbs and enough conventional wisdom regarding wounds healing. Recent developments in functional genomics, nanotechnology, wound healing in diabetics, along with a better knowing the pathophysiology of chronic wounds. In the following review, detailed information about healing of diabetic wounds with mechanism, factors affecting, impairment of wound healing with its pathophysiology, herbal treatments and current advances when treating diabetic wounds are examined.

E-cadherin and aquaporin-3 are downregulated in wound edges of human chronic wounds.

Chronic wounds are defined as wounds that fail to proceed through the normal phases of wound healing; a complex process involving different dynamic events including migration of keratinocytes in the epidermis. Chronic wounds are estimated to affect 1-2% of the human population worldwide and are a major socioeconomic burden. The prevalence of chronic wounds is expected to increase with the rising number of elderly and patients with diabetes and obesity, who are at high risk of developing chronic wounds. Since E-cadherin and the water channel aquaporin-3 are important for both skin function and cell migration, and aquaporin-3 is furthermore involved in wound healing of the skin demonstrated by impaired wound healing in aquaporin-3-null mice, we hypothesized that E-cadherin and aquaporin-3 expression may be dysregulated in chronic wounds. Therefore, we investigated the expression of E-cadherin and aquaporin-3 in biopsies from the edges of chronic wounds from human patients. This was accomplished by immunohistochemical stainings of E-cadherin and aquaporin-3 on serial sections followed by qualitative evaluation of staining patterns, which revealed low expression of both E-cadherin and aquaporin-3 at the wound edge. Future studies are needed to reveal if this downregulation is associated with the pathophysiology of chronic wounds.

Molecular Pathophysiology of Chronic Wounds: Current State and Future Directions.

Venous leg ulcers, diabetic foot ulcers, and pressure ulcers are complex chronic wounds with multifactorial etiologies that are associated with high patient morbidity and mortality. Despite considerable progress in deciphering the pathologies of chronic wounds using "omics" approaches, considerable gaps in knowledge remain, and current therapies are often not efficacious. We provide a comprehensive overview of current understanding of the molecular mechanisms that impair healing and current knowledge on cell-specific dysregulation including keratinocytes, fibroblasts, immune cells, endothelial cells and their contributions to impaired reepithelialization, inflammation, angiogenesis, and tissue remodeling that characterize chronic wounds. We also provide a rationale for further elucidation of ulcer-specific pathologic processes that can be therapeutically targeted to shift chronic nonhealing to acute healing wounds.

Mesenchymal Stem Cell-Derived Extracellular Vesicles as an Advanced Therapy for Chronic Wounds.

Chronic wounds are a significant challenge for patients, healthcare providers, and healthcare systems. Chronic wounds develop due to a complex interplay between chronic inflammation, tissue hypoxia, and oxidative stress, often occurring in the setting of advancing age. Ideally, new therapeutics should address all the components of chronic wound pathophysiology. Mesenchymal stem cell (MSC) therapies show significant promise to promote healing of chronic wounds. Extracellular vesicles (EVs) secreted by MSCs mediate many of their beneficial effects. We review the evidence demonstrating that MSC-EVs target the processes leading to chronic wounds. Additionally, we discuss how MSCs can be influenced to generate more potent wound healing EVs. Finally, we highlight the current state of EV clinical trials for wound healing and important preclinical studies that will lead to optimal use of MSC-EVs for patient care.

Human Amniotic Membrane Promotes Angiogenesis in an Oxidative Stress Chronic Diabetic Murine Wound Model.

Objective: The development of animal models, which adequately replicate the pathophysiology of chronic wounds, has been challenging. In this study, we utilized an oxidative stress (OS) murine model, which was previously developed by our group, to study the effect of a human amniotic membrane (AM) on chronic wound healing. Approach: Forty-five diabetic (genetically obese leptin receptor-deficient mice [db/db]) mice were separated into three groups. Thirty mice received an OS regimen and a 1 - × 1 cm2 full-thickness excisional dorsal wound. The wounds were either covered with AM and occlusive dressing (db/dbOS-AM) or occlusive dressing only (db/dbOS). Fifteen mice did not receive the OS regimen, and were covered with AM and occlusive dressing (db/db-AM). The wounds were photographed, and tissue was harvested at various time points. Results: Vascular density was higher in the AM-treated groups (db/dbOS-AM: 34 ± 12; db/db-AM: 37 ± 14; vs. db/dbOS: 19 ± 9 cluster of differentiation 31 [CD31+]/high power field [HPF] photograph; p = 0.04 and p = 0.003). Vessel maturity was lowest in the db/dbOS group (21% ± 4%; vs. db/dbOS-AM: 38% ± 10%, p = 0.004; db/db-AM: 40% ± 11%, p = 0.0005). Leukocyte infiltration was higher in the AM groups (db/dbOS-AM: 15 ± 4; db/db-AM: 16 ± 4 vs. db/dbOS: 8 ± 3 lymphocyte common antigen [CD45+]/HPF; p = 0.005 and p = 0.06). AM upregulated various proangiogenic factors, including vascular endothelial growth factor (VEGF), and downregulated genes involved in chronicity, such as osteopontin, as visualized through proteome analysis and western blotting. Cell death was lower in the AM groups (db/dbOS-AM: 28 ± 10, db/db-AM: 7 ± 5 vs. db/dbOS: 17% ± 9% Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL+]; p = 0.03 and p < 0.0001). Innovation: This study offers new insight on the mechanisms of action of human AM in chronic wound healing. Conclusion: AM treatment promoted healing in mice with complex chronic wounds. The AM stimulated angiogenesis through upregulation of proangiogenic factors, improving the wound milieu by increasing leukocyte and growth factor delivery and decreasing cell death.

Arginase Signalling as a Key Player in Chronic Wound Pathophysiology and Healing.

Arginase (ARG) represents an important evolutionarily conserved enzyme that is expressed by multiple cell types in the skin. Arg acts as the mediator of the last step of the urea cycle, thus providing protection against excessive ammonia under homeostatic conditions through the production of L-ornithine and urea. L-ornithine represents the intersection point between the ARG-dependent pathways and the urea cycle, therefore contributing to cell detoxification, proliferation and collagen production. The ARG pathways help balance pro- and anti-inflammatory responses in the context of wound healing. However, local and systemic dysfunctionalities of the ARG pathways have been shown to contribute to the hindrance of the healing process and the occurrence of chronic wounds. This review discusses the functions of ARG in macrophages and fibroblasts while detailing the deleterious implications of a malfunctioning ARG enzyme in chronic skin conditions such as leg ulcers. The review also highlights how ARG links with the microbiota and how this impacts on infected chronic wounds. Lastly, the review depicts chronic wound treatments targeting the ARG pathway, alongside future diagnosis and treatment perspectives.

A cut above the rest: oxidative stress in chronic wounds and the potential role of polyphenols as therapeutics

The pathophysiology of chronic wounds typically involves redox imbalance and inflammation pathway dysregulation, often with concomitant microbial infection. Endogenous antioxidants such as glutathione and tocopherols are notably reduced or absent, indicative of significant oxidative imbalance. However, emerging evidence suggests that polyphenols could be effective agents for the amelioration of this condition. This review aims to summarise the current state of knowledge surrounding redox imbalance in the chronic wound environment and the potential use of polyphenols for the treatment of chronic wounds. Polyphenols provide a multi-faceted approach towards the treatment of chronic wounds. Firstly, their antioxidant activity allows direct neutralisation of harmful free radicals and reactive oxygen species, assisting in restoring redox balance. Upregulation of pro-healing and anti-inflammatory gene pathways and enzymes by specific polyphenols further acts to reduce redox imbalance and promote wound healing actions, such as proliferation, extracellular matrix deposition and tissue remodelling. Finally, many polyphenols possess antimicrobial activity, which can be beneficial for preventing or resolving infection of the wound site. Exploration of this diverse group of natural compounds may yield effective and economical options for the prevention or treatment of chronic wounds.

Functional Biomaterials for Treatment of Chronic Wound.

The increasing number of patients with chronic wounds caused by diseases, such as diabetes, malignant tumors, infections, and vasculopathy, has caused severe economic and social burdens. The main clinical treatments for chronic wounds include the systemic use of antibiotics, changing dressings frequently, operative debridement, and flap repair. These routine therapeutic strategies are characterized by a long course of treatment, substantial trauma, and high costs, and fail to produce satisfactory results. Biomaterial dressings targeting the different stages of the pathophysiology of chronic wounds have become an active research topic in recent years. In this review, after providing an overview of the epidemiology of chronic wounds, and the pathophysiological characteristics of chronic wounds, we highlight the functional biomaterials that can enhance chronic wound healing through debridement, anti-infection and antioxidant effects, immunoregulation, angiogenesis, and extracellular matrix remodeling. It is hoped that functional biomaterials will resolve the treatment dilemma for chronic wounds and improve patient quality of life.

Aspects of Nanomaterials in Wound Healing.

Wound infections impose a remarkable clinical challenge that has a considerable influence on morbidity and mortality of patients, influencing the cost of treatment. The unprecedented advancements in molecular biology have come up with new molecular and cellular targets that can be successfully applied to develop smarter therapeutics against diversified categories of wounds such as acute and chronic wounds. However, nanotechnology-based diagnostics and treatments have achieved a new horizon in the arena of wound care due to its ability to deliver a plethora of therapeutics into the target site, and to target the complexity of the normal wound-healing process, cell type specificity, and plethora of regulating molecules as well as pathophysiology of chronic wounds. The emerging concepts of nanobiomaterials such as nanoparticles, nanoemulsion, nanofibrous scaffolds, graphene-based nanocomposites, etc., and nano-sized biomaterials like peptides/proteins, DNA/RNA, oligosaccharides have a vast application in the arena of wound care. Multi-functional, unique nano-wound care formulations have acquired major attention by facilitating the wound healing process. In this review, emphasis has been given to different types of nanomaterials used in external wound healing (chronic cutaneous wound healing); the concepts of basic mechanisms of wound healing process and the promising strategies that can help in the field of wound management.

Biological wound matrices with native dermis-like collagen efficiently modulate protease activity.

When the delicate balance between catabolic and anabolic processes is disturbed for any reason, the healing process can stall, resulting in chronic wounds. In chronic wound pathophysiology, proteolytic imbalance is implicated due to elevated protease levels mediating tissue damage. Hence, it is important to design appropriate wound treatments able to control and modulate protease activity directly at the host/biomaterial interface. Here, we investigate collagen-based wound dressings with the focus on their potential to adsorb and inactivate tissue proteases. We examined the effect of six collagen-based dressings on their ability to adsorb and inactivate different granulocyte proteases, plasmin, human neutrophil elastase (HLE), and matrix metalloproteases (MMP)-1, -2, -8, and -9, by an integrated approach including immunoelectron microscopy. We observed a reduction of the proteolytic activities of plasmin, HLE, and MMP-1, -2, -8, and -9, both on the biomaterial surface and in human chronic wound fluid. The most pronounced effect was observed in collagen-based dressings, with the highest content of native collagen networks resembling dermis structures. Our data suggest that this treatment strategy might be beneficial for the chronic wound environment, with the potential to promote improved wound healing.

Drug delivery systems and materials for wound healing applications.

Chronic, non-healing wounds place a significant burden on patients and healthcare systems, resulting in impaired mobility, limb amputation, or even death. Chronic wounds result from a disruption in the highly orchestrated cascade of events involved in wound closure. Significant advances in our understanding of the pathophysiology of chronic wounds have resulted in the development of drugs designed to target different aspects of the impaired processes. However, the hostility of the wound environment rich in degradative enzymes and its elevated pH, combined with differences in the time scales of different physiological processes involved in tissue regeneration require the use of effective drug delivery systems. In this review, we will first discuss the pathophysiology of chronic wounds and then the materials used for engineering drug delivery systems. Different passive and active drug delivery systems used in wound care will be reviewed. In addition, the architecture of the delivery platform and its ability to modulate drug delivery are discussed. Emerging technologies and the opportunities for engineering more effective wound care devices are also highlighted.

An update and review of cell-based wound dressings and their integration into clinical practice

Chronic wounds affect over 4 million individuals and pose a significant burden to the US healthcare system. Diabetes, venous stasis, radiation or paralysis are common risk factors for chronic wounds. Unfortunately, the current standard of care (SOC) has a high relapse rate and these wounds continue to adversely affect patients' quality of life. Fortunately, advances in tissue engineering have allowed for the development of cell-based wound dressings that promote wound healing by improving cell migration and differentiation. As the available options continue to increase in quantity and quality, physicians should have a user-friendly guide to reference when deciding which dressing to use. The objective of this review is to identify the currently available biologic dressings, describe their indications, and provide a framework for integration into clinical practice. This review included 53 studies consisting of prospective and retrospective cohorts as well as several randomized control trials. Three general categories of cell-based biologic dressings were identified and nine brands were included. Cell-based biologic dressings have shown efficacy in a broad range of scenarios, and studies examining their efficacy have improved our understanding of the pathophysiology of chronic wounds. Amniotic and placental membranes have the widest scope and can be used to treat all subtypes of chronic wounds. Human skin allografts and bioengineered skin substitutes can be used for chronic ulcers but generally require a vascularized wound bed. Autologous platelet rich plasma (PRP) has shown promise in venous stasis ulcers and decubitus ulcers that have failed conventional treatment. Overall, more research is necessary to determine if these novel therapeutic options will change the current SOC, but current studies demonstrate encouraging results in the treatment of chronic wounds.

Matrix metalloproteinases in the wound microenvironment: therapeutic perspectives

Matrix metalloproteinases in the wound microenvironment: therapeutic perspectives Alicja Krejner,1 Malgorzata Litwiniuk,1&ndash;3 Tomasz Grzela11Laboratory of Cell Molecular Biology, Department of Histology and Embryology, Biostructure Research Center, Medical University of Warsaw, Warsaw, Poland; 2Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland; 3Department of Otolaryngology, Medical University of Warsaw, Warsaw, PolandAbstract: Matrix metalloproteinases (MMPs) are key effector molecules responsible for extracellular matrix (ECM) turnover. They are involved in tissue remodeling and regeneration. Although the main targets for MMPs are ECM components, they are also able to digest a variety of non-ECM molecules including cytokines, their receptors, or carriers. Therefore, the activity of the MMPs remains under tight control. However, when controlling mechanisms are ineffective, MMPs may become highly dangerous molecules, which have a strong destructive effect on affected tissues. Apart from cancer metastasis, aneurysm formation, or airway remodeling in asthma, MMPs have also been identified as main detrimental factors in delayed healing of chronic wounds. In this short review, we describe main representatives of MMPs family, their role in pathophysiology of chronic wounds, as well as current and possible therapeutic strategies for modulation of MMPs&rsquo; activity, which may be useful in management of chronic wounds.Keywords: chronic wound, MMPs, MMP inhibitors, wound treatment

Filamin A Mediates Wound Closure by Promoting Elastic Deformation and Maintenance of Tension in the Collagen Matrix

Fibroblasts have a central role in wound healing via matrix production, remodeling, and contraction. Their role as mechanoresponsive cells during tissue repair is evident, but the molecular mechanisms of this process remain uncertain. Filamin A, an intracellular protein that stabilizes the actin cytoskeleton regulates fibroblast-matrix interactions. Fibroblast defects in cytoskeletal dynamics may underlie key aspects of chronic wound pathophysiology.

Beneficial and deleterious bacterial&amp;ndash;host interactions in chronic wound pathophysiology

Abstract : Chronic wounds represent a major health and financial burden. Although incredible advancements in wound management have been made in the last decade, the incidences of chronic wounds continue to increase due to a rise in biofilm-associated infections. The presence of biofilm causes chronic inflammation, leading to impaired healing rates and host mortality. This review describes the deleterious bacterialhost interactions, as well as the beneficial role of pH and probiotics in chronic wound infections.

Loss of keratinocyte focal adhesion kinase stimulates dermal proteolysis through upregulation of MMP9 in wound healing.

To investigate how epithelial mechanotransduction pathways impact wound repair. Mechanical forces are increasingly recognized to influence tissue repair, but their role in chronic wound pathophysiology remains unknown. Studies have shown that chronic wounds exhibit high levels of matrix metalloproteinase 9 (MMP9), a key proteolytic enzyme that regulates wound remodeling. We hypothesized that epithelial mechanosensory pathways regulated by keratinocyte-specific focal adhesion kinase (FAK) control dermal remodeling via MMP9. A standard wound model was applied to keratinocyte-specific FAK knockout (KO) and control mice. Rates of wound healing were measured and tissue was obtained for histologic and molecular analyses. Transcriptional and immunoblot assays were used to assess the activation of FAK, intracellular kinases, and MMP9 in vitro. A cell suspension model was designed to validate the importance of FAK mechanosensing, p38, and MMP9 secretion in human cells. Biomechanical testing was utilized to evaluate matrix tensile properties in FAK KO and control wounds. Wound healing in FAK KO mice was significantly delayed compared with controls (closure at 15 days compared with 20 days, P = 0.0003). FAK KO wounds demonstrated decreased dermal thickness and collagen density. FAK KO keratinocytes exhibited overactive p38 and MMP9 signaling in vitro, findings recapitulated in human keratinocytes via the deactivation of FAK in the cell suspension model. Functionally, FAK KO wounds were significantly weaker and more brittle than control wounds, results consistent with the histologic and molecular analyses. Keratinocyte FAK is highly responsive to mechanical cues and may play a critical role in matrix remodeling via regulation of p38 and MMP9. These findings suggest that aberrant epithelial mechanosensory pathways may contribute to pathologic dermal proteolysis and wound chronicity.

Targeting homeostasis in drug delivery using bioresponsive hydrogel microforms

A drug delivery platform comprising a biocompatible, bioresponsive hydrogel and possessing a covalently tethered peptide-drug conjugate was engineered to achieve stasis, via a closed control loop, of the external biochemical activity of the actuating protease. The delivery platform contains a peptide-drug conjugate covalently tethered to the hydrogel matrix, which in the presence of the appropriate protease, was cleaved and the drug released into the bathing environment. This platform was developed and investigated in silico using a finite element modeling (FEM) approach. Firstly, the primary governing phenomena guiding drug release profiles were investigated, and it was confirmed that under transport-limited conditions, the diffusion of the enzyme within the hydrogel and the coupled enzyme kinetics accurately model the system and are in agreement with published results. Secondly, the FEM model was used to investigate the release of a competitive protease inhibitor, MAG283, via cleavage of Acetyl-Pro-Leu-Gly|Leu-MAG-283 by MMP9 in order to achieve targeted homeostasis of MMP-9 activity, such as in the pathophysiology of chronic wounds, via closed-loop feedback control. The key engineering parameters for the delivery device are the radii of the hydrogel microspheres and the concentration of the peptide-inhibitor conjugate. Homeostatic drug delivery, where the focus turns away from the drug release rate and turns toward achieving targeted control of biochemical activity within a biochemical pathway, is an emerging approach in drug delivery methodologies for which the potential has not yet been fully realized.

Current and future developments in the treatment of chronic wounds

Chronic wounds are common and their incidence has been on the increase. They place an enormous burden on health care services and have a major impact on several aspects of patients' wellbeing. It is vital for clinicians to recognize the complexity of the underlying processes leading to the development of a chronic wound. With this knowledge, the key factors that led to their development in each patient can be identified and appropriate steps taken to address modifiable factors. There is currently a wide range of treatments available for treatment of chronic wounds, with a range of exciting new treatments being developed. This paper aims to give an overview of the common etiology and pathophysiology of chronic wounds followed by a discussion of a range of current and future developments in their treatment.

Current Aspects in the Pathophysiology and Treatment of Chronic Wounds in Diabetes Mellitus

Impaired wound healing is a frequent and very severe problem in patients with diabetes mellitus, yet little is known about the underlying pathomechanisms. In this paper we review the biology of wound healing with particular attention to the pathophysiology of chronic wounds in diabetic patients. The standard treatment of diabetic ulcers includes measures to optimize glycemic control as well as extensive debridement, infection elimination by antibiotic therapy based on wound pathogen cultures, the use of moisture dressings, and offloading high pressure from the wound bed. In this paper we discuss novel adjuvant therapies with particular reference to the use of autologous skin transplants for the treatment of diabetic foot ulcers which do not respond to standard care.