Currently there is a paucity of objective means to gauge the probability for non-healing of diabetic foot ulcers (DFUs), which ultimately impedes the clinician's timely decision in selecting the best treatment. Resolving chronic inflammation is pivotal in overcoming this impairment and is attributable to specialized pro-resolving lipid mediators (SPMs) in the restoration of healing of DFUs. We identified endogenous SPMs, SPM1 and neuroprotection D1 (NPD1) in normal healing wounds. SPM1 and NPD1 were deficient in diabetic wounds. Compensation for the SPM deficiency restored the healing and resolved chronic inflammation, suggesting that SPM deficiency is an important contributor to the impairment of healing. Our data showed that these SPMs were diminished in the blood plasma of humans with nonhealing DFUs compared to healing DFUs, implying an impaired reparative and inflammation-resolving system throughout the whole body of nonhealing humans. Thus, blood SPMs could be used to identify the current healing status and to forecast future healing outcome. Our hypothesis is that the diminished level of SPM1 or NPD1 in blood plasma is a biomarker of a nonhealing risk of DFUs and that the SPM levels in blood represent the healing status. The goal of this phase-1 feasibility project is to further develop the commercially viable SPM-biomarker diagnosis system for objective prediction of DFU nonhealing outcome and measurement of DFU status. Our Aim is to: A) advance a novel commercially viable method with doubled throughput for SPM analysis in blood plasma using acLC-MS/MS; B) validate the diminished plasma level of SPMs of patients with nonhealing DFUs compared to healing DFUs; C) examine whether the SPM levels in blood plasma are correlated with the healing status of DFUs at each time point; and D) further validate that early in the standard care of DFUs the plasma SPM levels can be used to predict the later outcome of healing. We will pursue the protection of created intellectual properties (IP). Overall impact: This phase-1 feasibility project will develop a commercially viable and effective diagnostic system based on SPM plasma levels measured by the novel LC-MS/MS based method, and will offer a near- noninvasive, objective prediction of DFU nonhealing-wound outcomes and measurement of DFU status. It will further advance the IP and enhance the collaboration between the SBC and institute in future commercialization of this system. It will build the basis for the phase 2 of this project, where we will advance the SPM biomarker system in infected DFUs. Down the line, we envision clinical trials, filing for FDA approval, and commercialization of this system. The established SPM biomarker system will provide high-demand objective measures for guiding clinicians in making decisions on whether to implement more aggressive or adjunctive treatments early on when treatment can be more effective to achieve healing and avoid the need for amputation due to nonhealing in DFUs. It may be used to measure DFU early response to intervention and serve as surrogate end-points for clinical outcomes that may take many months to occur.
Project Terms: Affect; American; Amputation; Animals; aqueous; barrier to care; base; Biological Markers; Blood; care costs; Caring; Chronic; chronic wound; Clinical; clinical application; Clinical Research; Clinical Trials; Collaborations; commercialization; Data; Decision Making; diabetic; Diabetic Foot Ulcer; Diabetic mouse; Diabetic wound; Diagnosis; Diagnostic; Early treatment; Endogenous Factors; Financial compensation; Future; Goals; healing; high throughput analysis; Human; Human body; Impaired wound healing; Impairment; Inflammation; Institutes; Intellectual Property; Intervention; Lead; lipid mediator; Liquid Chromatography; Lower Extremity; Measurement; Measures; Methodology; Methods; Morbidity - disease rate; Mus; neuroprotectin D1; neuroprotection; non-healing wounds; novel; Outcome; Patients; Peripheral; Phase; Pilot Projects; Plasma; Polyunsaturated Fatty Acids; predictive tools; Probability; Protocols documentation; Resolution; response; restoration; Risk; Skin Ulcer; standard care; Surrogate Endpoint; System; tandem mass spectrometry; Testing; therapy development; Time; Ulcer; Veins; wound; Wound Healing;
