Complex, 3D Skin-like Tissues for Preclinical Testing of Diabetic Ulcer Therapy
We seek to develop more complex and predictive, in vitro, human 3D tissue wound healing models for preclinical drug screening that will effectively test the safety and efficacy of novel therapeutics for Diabetic foot ulcers (DFU). This will help meet the urgent need to develop next generation treatments for these and other complications of diabetes by providing more cost-effective ways of predicting the success or failure of drugs designed to treat DFUs before they enter human clinical trials. To fill this critical need, our immediate goal is to characterize and test diabetes-specific, preclinical wound healing models fabricated as in vitro, 3D tissues. We will develop a novel DFU wound repair platform that will have 3 important, new features: 1- harbor DFU fibroblasts and macrophages from a spectrum of Type II DFU patients, 2- a higher throughput format (24 well) than existing tissues and 3- will eliminate all animal products and incorporate only human cells and tissues. This will improve upon our existing DFU wound healing models by creating more complex tissues that will be an important advance over currently available monolayer, tissue cultures. We expect to learn that novel DFU patient-specific, 3D tissue wound models that mimic chronic wounds like DFU can be optimized as a critical step towards developing high-impact, high-throughput human preclinical drug testing platforms for DFU through two SPECIFIC AIMS: 1- To optimize human, DFU patient-specific 3D tissue models harboring primary DFU-derived fibroblasts and macrophages and 2- To test, characterize and optimize these 3D tissue models of DFU wound re-epithelialization. Our research is based on our previous work showing that: 1- DFU patient-derived fibroblasts generate 3D tissue models that simulate defective wound healing of DFUs in vivo, 2- primary, DFU-derived macrophages retain their M1/M2 polarization states when incorporated into 3D tissue models and 3- 3D skin-like tissues can be fabricated with fibroblasts, macrophages and extracellular matrix in a 24-well, tissue format. The success of our strategy will significantly improve our ability to identify biomarkers of DFU and efficiently screen candidate drug for DFU treatment at an early stage in their development in a reproducible and convenient tissue model. By successfully developing small-format, 3D tissues, we will lay the groundwork to incorporate these tissues into “tissues on chips” formats. This will shift preclinical drug screening for DFU towards the dissemination, scale-up and commercialization of preclinical wound healing models that will prioritize and streamline drug discovery for DFUs so they can safely be used in human clinical trials.