Development of full thickness human skin model for investigating the mechanism(s) of radiation induced skin injuries and therapeutics development

About This Grant

The evolving geopolitical landscape has heightened the risk of radiation-induced skin injuries due to large- scale radiological incidents, including state or terrorist-improvised nuclear devices. Additionally, radiation induced skin injuries are a significant adverse effect of radiotherapy in cancer patients. However, effective countermeasures remain limited, primarily due to the lack of physiologically and anatomically relevant human models for studying radiation-induced injuries.This proposal aims to address this critical gap by developing an extracorporeal human skin perfusion model to investigate radiation injury mechanisms and facilitate the development of effective therapeutics. The long-term goal is to create a fully automated, immune- competent human skin perfusion system that mimics in vivo conditions, enabling precise studies on radiation injury dynamics and therapeutic interventions. The overall objectives of this proposal are to (i) automate perfusion bioreactor and establish parameters to enable immune capability of the skin perfusion system, (ii) determine the utilization of human skin perfusion system to study mechanism(s) of radiation injury and (iii) as a proof-of-principle demonstrate the utilization of human skin perfusion model for developing radiation countermeasure using metformin lotion as an example. Our central hypothesis is that an automated full- thickness human skin perfusion model will provide a robust ex vivo platform for studying radiation-induced skin injuries and developing countermeasures. This hypothesis will be tested through the following three specific aims: 1) Automate perfusion bioreactor and optamize immune capabilities of human skin perfusion model – we will develop a fully automated perfusion bioreactor in collaboration with Daedalus Inc. to improve reproducibility, operational efficiency, and real-time monitoring. Additionally, integrate immune components to enhance the physiological relevance of the model; 2) elucidate the mechanism(s) of radiation induced injuries in human skin - investigate molecular and cellular responses to radiation exposure across diverse human donor samples (sex, age, race) using histological, genomic, and proteomic analyses; and 3) evaluate the use of metformin lotion as a mitigator of radiation induced skin injury – proof -of-principle for employing human skin perfusion model for therapeutics development - as a proof-of-concept, assess metformin lotion efficacy in mitigating radiation- induced skin injuries using the developed perfusion model, demonstrating its potential for therapeutic screening. This project is highly innovative as it will deliver the first-of-its-kind, fully automated, immune-competent human skin perfusion platform, transforming the study of radiation-induced injuries and enabling broader applications for skin-related research. The proposed research is highly significant because it will: i) Provide strong scientific justification for using human skin-based models in radiation injury research; ii) Reduce reliance on animal models, aligning with ethical and regulatory priorities; and iii) accelerate the development and FDA approval process for radiation countermeasures and other skin therapeutics. By successfully achieving these aims, this project will establish a new paradigm in preclinical skin research, bridging the gap between ex vivo modeling and clinical translation to improve radiation injury management and therapeutic development.