Mechanistic Studies and Modeling of Drug Delivery
Currently, our focus is on enabling the prediction of the impact of lipids, either in drug delivery systems or food, on transport in the intestinal environment and absorption of drugs. Lipids have a significant yet poorly understood impact on the absorption and bioavailability of water-insoluble compounds (including drugs, dietary supplements, nutrients, and toxins). We are working to enable mechanistic understanding and quantitative prediction of the influence of ingested lipids in drug delivery systems or food on orally delivered compound absorption. We employ a systems-based approach, considering multiple parallel, dynamic processes (compound dissolution, digestion, partitioning into colloidal phases, absorption). These processes are studied in isolation to develop appropriate mathematical expressions which are then integrated within a theoretical framework. The mechanistic and predictive models developed in this project will be useful in streamlining the drug development process, enabling efficient design of oral delivery systems and enhancing understanding of the significance of food matrix in absorption of compounds, including drugs as well as nutrients.
Engineering the Intestinal Environment
Engineered models of the microbiome-epithelium-immune axis
The intestinal mucosal barrier is highly significant to effective oral drug delivery, nutrient absorption, and interactions between microbes and underlying tissues. One limitation to studying the intestinal mucosal barrier is lack of appropriate in vitro experimental models. Our laboratory is working to develop engineered intestinal models incorporating microbiota in homeostasis with intestinal epithelium and immune cells for studying the links between ingested material and intestinal homeostasis/inflammation. Such models can be useful for studying mucosal transport in a physiological context, and for understanding how changes in mucosal barrier properties may contribute to disruptions in homeostasis of the microbiome-epithelium-immune axis. Use of microfluidic systems for building these models enables prolonged stable bacteria-mammalian cell co-culture.
The mucosa is exposed each day to dynamic and variable intestinal lumen contents, yet the impact of these contents on the mucosal barrier is not well understood. Our laboratory is studying the impact of ingested materials, such as lipids in drug delivery systems or food, on transport through the intestinal mucosa of molecules (e.g., drugs and nutrients), particulates (e.g., drug carrier systems), and microbes. Results indicate that mild stimuli, such as those presented by food, can modulate the intestinal barrier, for example to impact oral drug delivery or microbial invasion, and that permeation through mucus is highly dependent on the physical and chemical properties of the penetrating material (drug, particle, microbe). We hypothesize, given the crucial role of intestinal mucus in modulating interactions between intestinal contents and underlying tissues, that ingested materials directly impact the mucus barrier in vivo, and that an altered mucus barrier modifies interactions of microbes and other lumen contents (e.g., drugs, signaling molecules including bile acids) with underlying tissues.
Biomaterials for Retinal Tissue Engineering
Cell transplantation therapy offers tremendous promise as a treatment for retinal degeneration resulting from diseases such as age-related macular degeneration, but a major hurdle to clinical translation of these therapies is that the vast majority of implanted cells fail to survive and integrate. We are seeking to understand: a. why transplanted cells die, and b. what physical and chemical cues, presented by a hydrogel biomaterial carrier, may promote the survival and integration of transplanted cells in the retinal microenvironment. In addition, we are working to develop retinal organoid models useful for studying retinal development and disease. Specifically, we are exploring the ability of hydrogels presenting specific physical and chemical cues to aid in appropriate cellular organization during retinal organoid development, and working to develop a microfluidic vascularized retinal organoid model.