Hydro-responsive wound dressings for treating hard-to-heal wounds: a narrative review of the clinical evidence

A break in skin integrity must be repaired as quickly as possible to avoid excess blood and fluid loss, and to minimise the onset of infection. Hard-to-heal wounds, in which the progression of the wound healing response is compromised, present several challenges to healing (for example, the presence of devitalised tissue acting as a physical barrier to healing and as a focus for bacterial contamination with the potential for subsequent infection). The objective of this article is to present, as a narrative review, the clinical evidence supporting the use of a unique hydro-responsive wound dressing (HydroClean, HRWD1, PAUL HARTMANN AG, Germany). The dressing provides a simple treatment option to address a number of clinical challenges clinicians must overcome in order to facilitate wound healing progression. These studies demonstrated that this product supported successful debridement/cleansing of a wide variety of wounds, including hard-to-heal wounds, enabled wound bed preparation, and lead to positive healing outcomes, including in wounds that previously had failed to heal. The simplicity of using HRWD1 as a single dressing can help clinicians overcome a variety of challenges when treating both acute and hard-to-heal wounds, which, with the benefit of proven patient outcomes, could make it an ideal choice for a first-line treatment.

Combined Metallomics/Transcriptomics Profiling Reveals a Major Role for Metals in Wound Repair

Endogenous metals are required for all life, orchestrating the action of diverse cellular processes that are crucial for tissue function. The dynamic wound healing response is underpinned by a plethora of such cellular behaviours, occurring in a time-dependent manner. However, the importance of endogenous metals for cutaneous repair remains largely unexplored. Here we combine ICP-MS with tissue-level RNA-sequencing to reveal profound changes in a number of metals, and corresponding metal-regulated genes, across temporal healing in mice. Wound calcium, magnesium, iron, copper and manganese are elevated at 7 days post-wounding, while magnesium, iron, aluminium, manganese and cobalt increase at 14 days post-wounding. At the level of transcription, wound-induced pathways are independently highly enriched for metal-regulated genes, and vice versa. Moreover, specific metals are linked to distinct wound-induced biological processes and converge on key transcriptional regulators in mice and humans. Finally, we reveal a potential role for one newly identified transcriptional regulator, TNF, in calcium-induced epidermal differentiation. Together, these data highlight potential new and diverse roles for metals in cutaneous wound repair, paving the way for further studies to elucidate the contribution of metals to cellular processes in the repair of skin and other tissues.

The Roles and Mechanisms of lncRNAs in Liver Fibrosis

Long non-coding RNAs (lncRNAs) can potentially regulate all aspects of cellular activity including differentiation and development, metabolism, proliferation, apoptosis, and activation, and benefited from advances in transcriptomic and genomic research techniques and database management technologies, its functions and mechanisms in physiological and pathological states have been widely reported. Liver fibrosis is typically characterized by a reversible wound healing response, often accompanied by an excessive accumulation of extracellular matrix. In recent years, a range of lncRNAs have been investigated and found to be involved in several cellular-level regulatory processes as competing endogenous RNAs (ceRNAs) that play an important role in the development of liver fibrosis. A variety of lncRNAs have also been shown to contribute to the altered cell cycle, proliferation profile associated with the accelerated development of liver fibrosis. This review aims to discuss the functions and mechanisms of lncRNAs in the development and regression of liver fibrosis, to explore the major lncRNAs involved in the signaling pathways regulating liver fibrosis, to elucidate the mechanisms mediated by lncRNA dysregulation and to provide new diagnostic and therapeutic strategies for liver fibrosis.

The Potential Use of Cannabis in Tissue Fibrosis

Fibrosis is a condition characterized by thickening or/and scarring of various tissues. Fibrosis may develop in almost all tissues and organs, and it may be one of the leading causes of morbidity and mortality. It provokes excessive scarring that excels the usual wound healing response to trauma in numerous organs. Currently, very little can be done to prevent tissue fibrosis, and it is almost impossible to reverse it. Anti-inflammatory and immunosuppressive drugs are among the few treatments that may be efficient in preventing fibrosis. Numerous publications suggest that cannabinoids and extracts of Cannabis sativa have potent anti-inflammatory and anti-fibrogenic properties. In this review, we describe the types and mechanisms of fibrosis in various tissues and discuss various strategies for prevention and dealing with tissue fibrosis. We further introduce cannabinoids and their potential for the prevention and treatment of fibrosis, and therefore for extending healthy lifespan.

The Role of Antioxidants on Wound Healing: A Review of the Current Evidence

(1) Background: Reactive oxygen species (ROS) play a crucial role in the preparation of the normal wound healing response. Therefore, a correct balance between low or high levels of ROS is essential. Antioxidant dressings that regulate this balance are a target for new therapies. The purpose of this review is to identify the compounds with antioxidant properties that have been tested for wound healing and to summarize the available evidence on their effects. (2) Methods: A literature search was conducted and included any study that evaluated the effects or mechanisms of antioxidants in the healing process (in vitro, animal models or human studies). (3) Results: Seven compounds with antioxidant activity were identified (Curcumin, N-acetyl cysteine, Chitosan, Gallic Acid, Edaravone, Crocin, Safranal and Quercetin) and 46 studies reporting the effects on the healing process of these antioxidants compounds were included. (4) Conclusions: this review offers a map of the research on some of the antioxidant compounds with potential for use as wound therapies and basic research on redox balance and oxidative stress in the healing process. Curcumin, NAC, quercetin and chitosan are the antioxidant compounds that shown some initial evidence of efficacy, but more research in human is needed.

Mammals fail to regenerate organs when wound contraction drives scar formation

To understand why mammals generally do not regenerate injured organs, we considered the exceptional case of spontaneous skin regeneration in the early lamb fetus. Whereas during the early fetal stage skin wounds heal by regeneration, in the late fetal stage, and after birth, skin wounds close instead by scar formation. We review independent evidence that this switch in wound healing response coincides with the onset of wound contraction, which is also enabled during late fetal gestation. The crucial role of wound contraction in determining the wound healing outcome in adults has been demonstrated in three mammalian models of severe injury (excised guinea pig skin, transected rat sciatic nerve, excised rabbit conjunctival stroma) where grafting the injury with DRT, a contraction-blocking scaffold of highly-specific structure, altered significantly the wound healing outcome. While spontaneous healing resulted in scar formation in these animal models, DRT grafting significantly reduced the extent of wound contraction, prevented scar synthesis, and resulted in partial regeneration. These findings, as well as independent data from species that heal spontaneously via regeneration, point to a striking hypothesis: The process of regeneration lies dormant in mammals until appropriately activated by injury. In spontaneous wound healing of the late fetus and in adult mammals, wound contraction impedes such endogenous regeneration mechanisms. However, engineered treatments, such as DRT, that block wound contraction can cancel its effects and favor wound healing by regeneration instead of scar formation.

Elastomeric Cardiowrap Scaffolds Functionalized with Mesenchymal Stem Cells-Derived Exosomes Induce a Positive Modulation in the Inflammatory and Wound Healing Response of Mesenchymal Stem Cell and Macrophage

A challenge in contractile restoration of myocardial scars is one of the principal aims in cardiovascular surgery. Recently, a new potent biological tool used within healing processes is represented by exosomes derived from mesenchymal stem cells (MSCs). These cells are the well-known extracellular nanovesicles released from cells to facilitate cell function and communication. In this work, a combination of elastomeric membranes and exosomes was obtained and tested as a bioimplant. Mesenchymal stem cells (MSCs) and macrophages were seeded into the scaffold (polycaprolactone) and filled with exosomes derived from MSCs. Cells were tested for proliferation with an MTT test, and for wound healing properties and macrophage polarization by gene expression. Moreover, morphological analyses of their ability to colonize the scaffolds surfaces have been further evaluated. Results confirm that exosomes were easily entrapped onto the surface of the elastomeric scaffolds, increasing the wound healing properties and collagen type I and vitronectin of the MSC, and improving the M2 phenotype of the macrophages, mainly thanks to the increase in miRNA124 and decrease in miRNA 125. We can conclude that the enrichment of elastomeric scaffolds functionalized with exosomes is as an effective strategy to improve myocardial regeneration.

Soft limbal niche maintains stem cell compartmentalization and function through YAP

Stem cells (SCs) decision to self-renew or differentiate largely depends on the extracellular environment and elasticity of their niche. A well-described mediator of the mechanotransduction pathway is the co-transcriptional activator Yes-associated protein (YAP), known to shuttle into the nucleus of cells grown on stiff matrices. YAP is also known to be essential for stemness, but confusingly, SCs often reside in soft niches. Furthermore, the role of matrix rigidity in niche formation and SC function in vivo is poorly understood. Here we report that the post-natal development of the murine corneal epithelium involves matrix stiffening and loss of YAP activity that is associated with the formation of differentiation compartment. Importantly, manipulating the matrix crosslinking enzyme, Lox, perturbed SC mark expression and resulted in loss of corneal transparency. In agreement, we found that YAP and mechanotransduction pathways are essential for stemness in the soft niche compartment, wound healing response, and dedifferentiation of committed cells into SCs following SC depletion. In vitro experiments revealed that stiffer substrates induced cytoplasmic YAP localization through activation of LATS1/2, facilitating SMAD2/3-mediated cell differentiation. Taken together, we propose that the soft environment of the corneal SC niche maintains YAP activity to support SC regulation during morphogenesis, adult homeostasis and regeneration by the niche.