A Novel Resolution Strategy for Chronic Inflammation and Impaired Healing of Wounds in Aging

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ABSTRACT Age-related chronic inflammation is a key factor that prevents wound healing, but no effective therapy currently exists to cure non-healing wounds in the aging population. This R21 project, submitted in response to “PA-16- 231 Non-healing Ulcerative Wounds in Aging,” will explore a novel translational strategy for resolving chronic inflammation and restoring healing of non-healing ulcers in aging. Resolution of chronic inflammation is critical for restoration of healing process and appears to require the action of maresin-like lipid mediators (MarLs), which are produced by macrophages (Ms), resolve inflammation, and promote wound healing. Our long- term goal is to overcome the impairment of wound healing in aging. Toward this goal, we discovered that two endogenous wound MarLs (MarL1 and MarL3, derived from ω-3 docosahexaenoic acid) reverse this impairment. Our published data showed that MarL3 enhances diabetic wound healing and promotes the expression of reparative VEGF, PDGF-BB, and IL10, and the switch to reparative Ms and that it is likely to act via PI3K signaling. MarL3 also promotes wound blood-vessel growth and VEGF formation by endothelial cells. By contrast, MarL1 promotes the production of regenerative growth factor HGF and attenuates M production of pro-inflammatory TNFα. MarL1 also enhances M promoted migration of epithelial cells, fibroblasts, and stem cells. Application of MarL1 to wounds of aged mice improves healing. However, the therapeutic potential of MarLs is limited, because topically applied MarLs are eliminated from wounds within a few hours, whereas wound healing takes many days. Wound healing also involves multiple processes across this long time course, and many of these steps could be promoted by MarLs. In preliminary studies, we obtained sustained release of MarL1 to wounds using MarL1 embedded in amino acid (arginine)-based poly(ester amide) protein-mimic (AA-PEA) microparticles (µPs). AA-PEAs are a new generation of biomaterials that are biocompatible, biodegradable, and non-toxic. The MarL1 embedded in AA-PEA-µPs was more effective than MarL1 alone in promoting wound closure in aging. Our hypothesis is that a sustained release of MarLs to wounds will resolve inflammation and overcome the aging-impairment of healing. Our objective is to develop and assess the ability of our innovative µP-sustained release of MarLs to restore wound healing in the aged. Specific Aim 1. A) Develop the MarL-loaded µPs to control and sustain MarL- release to wounds of aged mice and determine kinetics of MarL release in wounds. B) Determine the optimal sustained MarL release from µPs and administration regimens for resolving inflammation and restoring healing (re-epithelialization, blood vessel regeneration, skin breaking-strength) of aged mice. This project will use µPs- sustained-release MarLs to identify an innovative strategy as well as therapeutic leads to overcome the impairment of healing in non-healing wounds of the elderly. It will also provide a new knowledge about the temporal relationship between the resolution of inflammation and healing of wounds in aging.