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Agarwal Lab

Physiomimetic Microsystems Lab, Organ on Chip platforms for development of precision treatments

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Investigator / Contact Person Ashutosh Agarwal

Research

Diabetes affects about 300 million people worldwide and is expected to affect more than 400 million by 2030. In the U.S. alone, the total estimated cost of diagnosed diabetes was $345 billion in 2012, an increase of 41 percent since 2007. Type 1 diabetes mellitus results from the autoimmune destruction of insulin-secreting islets within the human pancreas, and it is one of the most common and costly chronic pediatric diseases. 

The multidisciplinary researchers of Physiomimetic Microsystems Laboratory are developing robust fluidic platforms for evaluation of pancreatic islets that will be critical for diabetes research and therapy. For example, clinical transplantation of islets is developing into a viable therapy for type 1 diabetes mellitus. In fact, the Diabetes Research Institute at University of Miami is one of the leading sites in that effort. It is critically important to consistently and reliably assess the quality of isolated pancreatic islet cells. Since transplanted islets experience a dynamic stimulatory environment and secrete hormones in response to these ongoing stimuli, it is important to test pre-transplant islets in devices that re-create dynamic sequential events, such as changes in glucose and other environmental inputs rather than conventional static wells or plates. Similar testing is important for developing organs on chip platforms that will enable drug and therapy discovery in a manner that is more human relevant than is the use of animals.

A $4.9 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) to Agarwal and his collaborators is currently funding this effort. The research team also participates in the Consortium on Human Islet Biomimetics within the Human Islet Research Network of National Institutes of Health (NIH).
Following the engineering paradigm of Design/Build/Test, fluidic chips are built out of inert plastic materials and micromachined features that promote optimized convective fluid transport. The platform is tested for perfusion interrogation of rodent and human pancreatic islets, dynamic secretion of hormones, concomitant live-cell imaging and optogenetic stimulation of genetically engineered islets. A coupled quantitative fluid dynamics computational model of glucose stimulated insulin secretion and fluid dynamics was first utilized to design device geometries that are optimal for complete perfusion of three-dimensional islets, effective collection of secreted insulin, and minimization of system volumes and associated delays. Fluidic devices were then fabricated through rapid prototyping techniques, such as micromilling and laser engraving, as two interlocking parts from materials that are non-absorbent and inert.

Finally, the assembly was tested for performance using both rodent and human islets with multiple assays conducted in parallel, such as dynamic perfusion, staining and optogenetics on standard microscopes, as well as for integration with commercial perfusion machines. The optimized design of convective fluid flows, use of bio-inert and non-absorbent materials, reversible assembly, manual access for loading and unloading of islets, and straightforward integration with commercial imaging and fluid handling systems proved to be critical for perfusion assay and particularly suited for time-resolved optogenetics studies.

Agarwal's team has reported results of the work in the reputable journal Lab on a Chip. The design features of the chip are protected in a patent application that was converted to full filing by the University of Miami Innovation Office. In addition to the publication and patent application, Agarwal's team is pursuing translational opportunities for the technology, thanks to a recent Wallace H. Coulter Commercialization Grant.