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MedTech Outlook | Wednesday, May 24, 2023
Chronic wounds are reclassified as acute wounds when they do not go through the expected stages of inflammation, proliferation/repair, and remodelling. Instead, they persist in a dysregulated inflammatory state.
FREMONT, CA: Clinically, chronic wounds are managed with non-specific wound dressings and initial and ongoing thorough debridement to remove devitalized tissue. These commercially available wound dressings (wet gauze, hydrogels, hydrocolloids, foam dressings and films) facilitate wound healing by offering moisture, gas exchange, thermal insulation, exudate drainage, an infection-resistance barrier, and a reduction in skin irritation or friction between the wound and objects like wheelchairs. Debriding or antibacterial chemicals may also be delivered by some commercial bandages. More expensive and typically utilised in specialised settings are more complex commercial dressings like acellular and cellular skin substitutes.
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These skin substitutes serve as a growth factor store, stromal cell reservoir, and temporary extracellular matrix (ECM) replacement for cell anchoring. Cellular skin substitutes also serve these functions. Currently, a clinical evaluation of the patient's wound is used to determine the best wound dressing. The choice of the wound dressing in clinical practice is made more difficult by the large range of wound dressings and a general dearth of high-quality evidence.
The understanding of the pathophysiology of chronic wounds has grown during the last 20 years. It is now widely acknowledged that the inflammatory stage of chronic wounds is probably the most dysregulated mechanism. With high levels of pro-inflammatory chemokines, cytokines, reactive oxygen species (ROS), and matrix metalloproteinases (MMPs), chronic wounds display a persistent pro-inflammatory milieu.
The constant attraction of neutrophils and monocytes, the polarisation of macrophages into the pro-inflammatory M1 phenotype, and the subsequent release of pro-inflammatory and leukocyte-attracting chemokines and cytokines make this pro-inflammatory environment a positive feedback loop. This atmosphere hinders the advancement of wound healing into the proliferation and remodelling phases as well as key regeneration activities such as angiogenesis, granulation tissue creation, and re-epithelialization.
Modulating neutrophil and monocyte recruitment as well as macrophage polarisation can be used to target the persistent, low-grade inflammation in chronic wounds. The cycle of leukocyte influx and leukocyte-recruiting chemokine release is broken in chronic wounds by neutralising pro-inflammatory chemokines and cytokines. In contrast, re-epithelialisation and angiogenesis are enhanced by administering anti-inflammatory M2 macrophages to chronic wounds. New research on diabetic wounds supports the incredible theory that inducing acute inflammation can reduce chronic inflammation and boost wound healing. Chronic wounds that are not diabetic may benefit from the local application of acutely pro-inflammatory chemicals.
Immune cells also release substances like ROS and MMPs that directly hinder the proliferative and remodelling stages of regeneration in addition to chemokines and cytokines.) The high ROS concentrations found in chronic wounds cause lipid peroxidation, protein modification, and DNA damage, even though ROS have physiological roles in wound healing. This oxidative stress inhibits angiogenesis, granulation tissue development, and re-epithelialization and causes stromal cells to undergo death. Small compounds can control ROS metabolism to lower ROS concentration. For instance, the iron(II)-sequestering substance deferoxamine prevents iron(II) from producing the extremely deadly hydroxyl radical. Other intriguing approaches use nucleic acid therapies that either increase the expression of ROS-degrading enzymes or suppress the genes of ROS-generating enzymes.
Endopeptidases known as MMPs break down the ECM as well as other substrates (growth factors, cytokines, and chemokines). During physiological wound healing, a careful equilibrium between the production of MMPs and their inhibitors causes a controlled breakdown of the ECM, allowing stromal cell migration, angiogenesis, and remodelling of the wounded tissue.
The elevated MMP levels found in chronic wounds cause excessive ECM breakdown and growth factor degradation, which hinders angiogenesis and re-epithelialisation. Low-molecular-weight MMP inhibitors and nucleic acid medications that quiet MMP genes or express tissue inhibitors of metalloproteinases can both target MMP activity. High MMP subtype specificity is crucial for these therapies since some MMPs, like MMP8 in diabetic wounds, are helpful for wound healing. The systemic bioavailability of ROS- and MMP-targeting medicines is a crucial factor to take into account as systemic exposure may impair physiologic ROS and MMP functioning in other tissues.
The ECM in chronic wounds cannot frequently give stromal cells pro-healing cues, which hinders entry into the proliferative and remodelling phase. Fibroblasts, keratinocytes, and endothelial cells may be directly engaged with and given anchors by polymeric ECM-imitating dressings embellished with ECM-derived peptides. They can also act as a reservoir for the gradual release of growth substances that promote healing. These dressings composed of polymers and peptides would possibly be easier to make, more stable, and less immunogenic than biological skin replacements when compared to the clinically employed skin substitutes previously described.
The treatment targets might also develop into helpful biomarkers that could shed light on a chronic wound's prognosis. Since chronic wounds are categorised using macroscopic and general criteria (wound size, depth), new molecular diagnostics are required to comprehend the underlying molecular pathophysiology, predict healing rates, and assess the effectiveness of treatment. The ideal diagnostic bandages detect these indicators in real-time and give the practitioner prognostic information right at the point of care.
Markers of inflammation, oxidative stress, MMP activity, bacterial infection, and mechanical stress are among the biomarkers of interest. Once molecular therapies are made available for chronic wounds, such molecular fingerprinting will also allow evidence-based treatment selection. Therefore, diagnostic wound dressings offer to open the door to individualised therapy for chronic wounds. The ultimate goal of a bandage is for it to autonomously release the appropriate medication at the appropriate moment after sensing the molecular makeup of a wound (theranostic wound dressing).
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