Topical Application of Virus-Derived Immunomodulating Proteins and Peptides to Promote Wound Healing in Mouse Models
Immune modulators play critical roles in the progression of wounds to normal or conversely delayed healing, through the regulation of normal tissue regrowth, scarring, inflammation, and growth factor expression. Many immune modulator recombinants are unde
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Introduction Large surface wounds remain a major health issue, after trauma and burns, often increasing mortality and prolonging morbidity. With poor healing, large wounds impair skin function and increase risk of hemorrhage, infection, sepsis, and death. Diabetic wounds are at particularly high risk for chronic infections and poor healing, requiring surgical debridement or even amputations. The wound healing process generally includes three steps: [1] hemostasis and inflammation, [2] new tissue generation, and [3] remodeling.
Alexandra R. Lucas (ed.), Viruses as Therapeutics: Methods and Protocols, Methods in Molecular Biology, vol. 2225, https://doi.org/10.1007/978-1-0716-1012-1_12, © Springer Science+Business Media, LLC, part of Springer Nature 2021
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Liqiang Zhang et al.
Wound healing is affected by many factors, such as infection and advanced age, as well as diabetes and other related diseases with suppressed immunity. Multiple inflammatory, immune, and fibrotic pathways are sequentially activated in wound repair beginning from the time of injury to new tissue regeneration. Among these are the coagulation (thrombotic) and hemorrhagic (thrombolytic) serine protease pathways, chemokines, inflammasomes, and apoptotic pathway activation. On the other hand, although inflammation is necessary for early wound healing, sustained and excess inflammation and immune cell activation after severe wound can also prolong healing and cause excess scarring. The Lucas lab and other research teams have developed a series of highly active biological therapeutics, immune-modulating proteins, and peptides derived from virus where these proteins have evolved over millions of years to a high level of efficacy for modulating key immune and inflammatory pathways [1]. Several of these new biologics have proven beneficial in animal models of wound healing, including Serp-1 [2], viral IL-10 (vIL-10), and viral VEGF (VEGF-E) [3]. Based on our work and prior experience in studying new therapeutic approaches, specifically virus-derived immune-modulating protein biologics, we will use myxoma virus-derived Serp-1 as a typical protein to demonstrate the method of preclinical testing on a full-thickness wound healing mouse model. The development of a hydrogel for delivery in these immunomodulating proteins as topical treatments for wound healing is also discussed. The mouse full-thickness excisional wound model has apparent advantages over other larger animal models, including lower cost, easier maintenance, and ability to standardize the experimental conditions and analyses, and additionally transgenic strains available for analysis of mechanism studies [4, 5]. Considering the distinct and overlapping phases of highly complex cellular and molecular events, wound healing is considered to be similar in humans and mice. One major difference or problem in the mouse model with the use of a full-thickness excisional model is the marked contraction of the skin caused by the mouse panniculus carnosus which differs from human wounds and d
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