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Research Interests
- Hepatic Tissue Engineering
We are interested in understanding the structure/function relationship of the liver to improve cell-based therapy for liver disease and develop in vitro models of liver tissue. Because of the complexity of the liver architecture and the inadequate therapies for liver disease, we have focused on a cell-based approach. Progress in development of such therapies has been stymied by the tendency of primary liver cells (hepatocytes) to rapidly lose their viability and phenotype upon isolation from the complex in vivo microenvironment of the liver. We are therefore interested in how the microenvironment around hepatocytes affects cell fate and function. We utilize microfabrication tools (methods developed to manufacture microelectronic circuits) to control and study the role of cell-cell interactions , cell-extracellular matrix interactions, and soluble stimuli (e.g. O2) on hepatocyte function. We are also developing systems to extend our findings in two-dimensional tissues to three-dimensional constructs using photopolymerized hydrogels . Finally, due to the limited growth of hepatocytes in vitro, we are interested in stem cell sources of hepatocytes. Collectively, these studies will provide a rational approach to hepatic tissue engineering.
- BioMEMS
Miniaturizion using microtechnology tools offers key advantages over
current approaches to interrogate cells but also introduces new challenges. The advantages parallel those seen in the semiconductor revolution (faster, cheaper, parallelism, advantageous microscale phenomena); however the challenges arise primarily from the difficulty associated with biological constraints: (1) integrating mammalian cells with synthetic platforms and maintaining viability (2) innocuous manipulation of cells and (3) maintaining cellular phenotypes to mimic in vivo behavior. Towards this end, we have developed new strategies for controlling the phenotype of immobilized cells and characterized several new methods to rapidly array living cells. Specifically, our laboratory has explored the use of electromagnetic fields
(electrophoresis (DC) or dielectrophoresis (AC)), miniaturized optical
tweezers , photochemistry , robotic spotting , and microfabricated wells - all to array living cells for parallel observation. We have extensively characterized the ‘biocompatibility' of this suite of techniques and have found that careful engineering design can serve to minimize exposure to harmful physical and chemical stimuli. In addition, a major emphasis in our technology development has been the seamless integration with conventional biomedical tools (inverted microscopes, aseptic technique, etc) with the goal of developing tools that can be easily disseminated to the biomedical community. We are particularly interested in leveraging this suite of microtechnology tools to dissect the components of the stem cell niche that serve to regulate stem cell fate and function.
- Nanobiotechnology
The unique electromagnetic properties of nanomaterials have already enabled significant advances in molecular detection, long term cellular tracking, and non-invasive imaging of disease in vivo. In collaboration with Dr. Erkki Ruoslahti (Burnham Instiute), our laboratory has shown that CdSe/ZnS ‘ quantum dots' can be functionalized to target tumors in vivo and be actively trafficked to intracellular organelles by living cells. We have also designed superparamagnetic iron oxide nanoparticles that may be proteolytically actuated to self-assemble in the presence of enzymes associated with tumor invasion and are investigating this as a novel means of targeting tumors. Furthermore, using in vitro liver tissue models, we have explored the role of nanoparticle coatings in mitigating their potential cytotoxicity. In collaboration with Dr. Michael Sailor (Chemistry, UCSD), we have explored biomedical applications of nanoporous crystalline silicon. Together, we have explored the biocompatibility of this material with mammalian cells to develop a ‘smart petri dish,' the utility of encoded nanoporous silicon fragments for biomolecular screening, and its function as a template for polymer replicas that can deliver drugs while being monitored remotely. We are actively pursuing both areas of research to develop nanomaterial platforms for biomedical applications.
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