Human on a chip systems to investigate disease comorbidities common in the aged population

Project SummaryBoth older adults and the pharmaceutical industry would benefit from the development of human on a chip systems to be able to systematically investigate disease comorbidities and their response to drug candidates in the aged population at the preclinical stage due to the lack of good multimodal models of disease combinationsWe will investigate diseases that are most prevalent in the aged population including nonalcoholic fatty liver diseaseNAFLDcardiomyopathycachexia sarcopenia and type II diabetesThe influence of metabolic diseasesespecially type II diabeteson aged and diseased patients is well knownbut little studied at the preclinical levelThis proposal will build upon the expertise at Hesperos and their current collaborations with UCF and the Center for Pharmacodynamics at the University of Florida branchlocated in OrlandoWe will use Hesperospatented multi organ functional systems to investigate multiple disease phenotypes to determine how other deficits in organs or modalities enhance or cause diseasehasten progression or limit treatment options in each organIt is also unclear how normal aging is affected by metabolic disordersalthough some correlations have been observedHuman on a chip models composed of multiple organs in recirculating media will provide a controlled reproducible system to evaluate responses to drugsIn additionby comparing acute to chronic effectsthe model will enable prediction of clinical trial success using models to inform clinical disease trial design based on these preclinical studiesWe will build on ongoing initiatives to expand PBPK PD modeling and simulation platforms to geriatrics by accounting for changes in the underlying pathophysiology with ageThese models may also serve as screening tools during early stages of drug development and facilitate decision making with respect to selecting the compound with a more favorable PK and formulation propertiesTo construct a well defined systemwe will use a common serum free medium with functional readouts using microelectrode arrays and cantilevers that are integrated on chip that allow for noninvasive electronic and mechanical readouts for acute drug responses in Phase I and chronic drug tests in Phase IIThe Phase I portion of this proposal will show that three organs can be linked togetherlivercardiac and muscleand that their response to therapeutics can reproduce responses in clinical trialsDrug and drug combinations will then be tested in the multiplexed disease models acutely for altered efficacy and toxicity compared to healthy or non comorbidity systemsAfter the quantitative milestones for Phase I have been achievedthe acute studies will be extended to chronic applications in Phase IIWe will also establish a type II diabetic phenotype in the system by utilizing different concentrations of insulin and glucose in a five organ system developed by integrating the system in Aimwith adipose and pancreasThe disease phenotypes introduced into the system in Phase I and the combined effect of metabolic diseases will be used to evaluate therapeutics in the system Project Narrative We will investigate diseases that are most prevalent in the aged population including non alcoholic fatty liver diseaseNAFLDcardiomyopathycachexia sarcopenia and type II diabetesThe influence of metabolic diseasesespecially type II diabeteson aged and diseased patients is well knownbut little studied at the preclinical levelHespseros will establish a service for commercialgovernment and academic labs to utilize in investigating drug candidates in a comorbidities human on a chip model system