Requested revision of the ABSTRACT of 2R01DK087800-06A1: Many patients with type-2 diabetes (T2D) suffer from repeated injury and nonhealing linked with T2D damage to nerves and nerve function. T2D impedes macrophage (M[phi]) functions needed for repair of wounded skin, nerves, and other tissues. Our long-term goal is to elucidate mechanisms of diabetic wound nerve recovery and healing, and thereby identify associated targets for development of improved treatments. We have preliminarily identified prohealing lipid autocrine/paracrine of M[phi]s & nerves (PLAMNs) that are necessary for the recovery of healing and nerve regeneration in diabetic wounds. However in wounds, PLAMNs degrade within hours, which restrains the efficient usage of PLAMNs for wound healing and nerve regeneration. Available formulations can only sustain lipid mediator delivery for hours. To overcome the hurdle posed by the short half-life of PLAMNs, we will further develop novel nanoparticle-sustained release PLAMNs (sPLAMNs), which will sustain bioactive PLAMN levels in wounds and have the potential to sustain the PLAMN neurotrophic functions. So far no other formulations or stable analogs can sustain lipid mediators in tissue for more than a day. To test the hypothesis that PLAMNs can be released from specific nanoparticles to provide sustained compensation of T2D caused PLAMN deficits in wounds. We will develop nanoparticles from amino-acid based polyesteramides (AA-PEAs) to control PLAMN release at sustained durations (days) and levels. We will optimize sPLAMNs and assess their kinetics in T2D wounds. AA-PEAs are a new generation of biocompatible, biodegradable, and non-toxic biomaterials. To implement the proposed studies, we will mainly use the splinted excisional wound model of mice with gene-knockout generated T2D hyperglycemia, hyperlipidemia, poor healing, and neuropathy, as well as use the state-of-the-art system of aqueous reversed-phase chiral liquid chromatography-ultraviolet spectrometry-tandem mass spectrometry. OVERALL IMPACT: This two-year project will develop innovative sustained release PLAMNs to compensate T2D-caused PLAMN deficits in wounds, and it will lead to a new direction for the development of efficient therapy for diabetic wound healing and re-innervation. It also will lay a solid foundation for studying the mechanisms of PLAMNs in diabetic wound re-innervation.