The inflammasome is a multiprotein complex critical for the innate immune response to injury. Inflammasome activation initiates healthy wound healing, but comorbidities with poor healing, including diabetes, exhibit pathologic, sustained activation with delayed resolution that prevents healing progression. In prior work, we reported the allosteric P2X7 antagonist A438079 inhibits extracellular ATP-evoked NLRP3 signaling by preventing ion flux, mitochondrial reactive oxygen species generation, NLRP3 assembly, mature IL-1β release, and pyroptosis. However, the short half-life
- NSF-PAR ID:
- 10391533
- Date Published:
- Journal Name:
- Soft Science
- Volume:
- 2
- Issue:
- 2
- ISSN:
- 2769-5441
- Page Range / eLocation ID:
- 9
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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in vivo limits clinical translation of this promising molecule. Here, we develop a controlled release scaffold to deliver A438079 as an inflammasome-modulating wound dressing for applications in poorly healing wounds. We fabricated and characterized tunable thickness, long-lasting silk fibroin dressings and evaluated A438079 loading and release kinetics. We characterized A438079-loaded silk dressingsin vitro by measuring IL-1β release and inflammasome assembly by perinuclear ASC speck formation. We further evaluated the performance of A438079-loaded silk dressings in a full-thickness model of wound healing in genetically diabetic mice and observed acceleration of wound closure by 10 days post-wounding with reduced levels of IL-1β at the wound edge. This work provides a proof-of-principle for translating pharmacologic inhibition of ATP-induced inflammation in diabetic wounds and represents a novel approach to therapeutically targeting a dysregulated mechanism in diabetic wound impairment. -
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Abstract Dermal wounds are a major global health burden made worse by common comorbidities such as diabetes and infection. Appropriate wound closure relies on a highly coordinated series of cellular events, ultimately bridging tissue gaps and regenerating normal physiological structures. Wound dressings are an important component of wound care management, providing a barrier against external insults while preserving the active reparative processes underway within the wound bed. The development of wound dressings with biomaterial constituents has become an attractive design strategy due to the varied functions intrinsic in biological polymers, such as cell instructiveness, growth factor binding, antimicrobial properties, and tissue integration. Using photosensitive agents to generate crosslinked or photopolymerized dressings in situ provides an opportunity to develop dressings rapidly within the wound bed, facilitating robust adhesion to the wound bed for greater barrier protection and adaptation to irregular wound shapes. Despite the popularity of this fabrication approach, relatively few experimental wound dressings have undergone preclinical translation into animal models, limiting the overall integrity of assessing their potential as effective wound dressings. Here, we provide an up‐to‐date narrative review of reported photoinitiator‐ and wavelength‐guided design strategies for in situ light activation of biomaterial dressings that have been evaluated in preclinical wound healing models.
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Abstract Diabetic foot ulcers are chronic wounds that affect millions and increase the risk of amputation and mortality, highlighting the critical need for their early detection. Recent demonstrations of wearable sensors enable real‐time wound assessment, but they rely on bulky electronics, making them difficult to interface with wounds. Herein, a miniaturized, wireless, battery‐free wound monitor that measures lactate in real‐time and seamlessly integrates with bandages for conformal attachment to the wound bed is introduced. Lactate is selected due to its multifaceted role in initiating healing. Studies in healthy and diabetic mice reveal distinct lactate profiles for normal and impaired healing wounds. A mathematical model based on the sensor data predicts wound closure rate within the first 3 days post‐injury with ≈76% accuracy, which increases to ≈83% when pH is included. These studies underscore the significance of monitoring biomarkers during the inflammation phase, which can offer several benefits, including short‐term use of wound monitors and their easy removal, resulting in lower risks of injury and infection at the wound site. Improvements in prediction accuracy can be achieved by designing mathematical models that build on multiple wound parameters such as pro‐inflammatory and metabolic markers. Achieving this goal will require designing multi‐analyte wound monitors.
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Abstract Chronic wounds are one of the most devastating complications of diabetes and are the leading cause of nontraumatic limb amputation. Despite the progress in identifying factors and promising in vitro results for the treatment of chronic wounds, their clinical translation is limited. Given the range of disruptive processes necessary for wound healing, different pharmacological agents are needed at different stages of tissue regeneration. This requires the development of wearable devices that can deliver agents to critical layers of the wound bed in a minimally invasive fashion. Here, for the first time, a programmable platform is engineered that is capable of actively delivering a variety of drugs with independent temporal profiles through miniaturized needles into deeper layers of the wound bed. The delivery of vascular endothelial growth factor (VEGF) through the miniaturized needle arrays demonstrates that, in addition to the selection of suitable therapeutics, the delivery method and their spatial distribution within the wound bed is equally important. Administration of VEGF to chronic dermal wounds of diabetic mice using the programmable platform shows a significant increase in wound closure, re‐epithelialization, angiogenesis, and hair growth when compared to standard topical delivery of therapeutics.
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Abstract Impaired wound healing after trauma, disorders, and surgeries impact millions of people globally every year. Dysregulation in orchestrated healing mechanisms and underlying medical complications make chronic wound management extremely challenging. Besides standard‐of‐care treatments including broad spectrum antibiotics and wound‐debridement, novel adjuvant therapies are clinically tested and commercialized. These include topical agents, skin substitutes, growth factor delivery, and stem cell therapies. With a goal to overcome factors playing pivotal role in delayed wound healing, researchers are exploring novel approaches to elicit desirable healing outcomes in chronic wounds. Although recent innovations in wound care products, therapies, and devices are extensively reviewed in past, a comprehensive review summarizing their clinical outcomes is surprisingly lacking. Herein, this work reviews the commercially available wound care products and their performance in clinical trials to provide a statistically comprehensive understanding of their safety and efficacy. The performance and suitability of various commercial wound care platforms, including xenogeneic and allogenic products, wound care devices, and novel biomaterials, are discussed for chronic wounds. The current clinical evaluation will provide a comprehensive understanding of the benefits and drawbacks of the most‐recent approaches and will enable researchers and healthcare providers to develop next‐generation technologies for chronic wound management.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.20517/ss.2022.13
