Laboratory for Biomaterials and Tissue Engineering
The successful design of tissue-engineered constructs drives the
need to design novel biocompatible materials and study their
interactions with living cells. The field of tissue
engineering is highly interdisciplinary and brings together people
with knowledge in materials science, chemical engineering,
chemistry, cell and developmental biology, immunology, and surgical
expertise to solve a range of open problems.
My research focuses on the development of model tissue
constructs or functional tissue units and the study of
cell-substratum interactions. A primary goal of my research group is
to design tissue constructs that mimic the native structure of
tissues in vivo and to systematically probe cellular
response to a variety of cues. This involves the fabrication of
biocompatible scaffolds and templates, and more importantly
tailoring surface and bulk properties. Another research interest of
our group is to quantify cell-substratum interactions.
Specifically, our studies focus on how chemical and mechanical
properties of an underlying substratum affect cellular motility and
contractility. An increasing focus of my research is to utilize
computationally-driven tissue engineering to develop models to
predict tissue function, for example, to understand basic liver
biology and to study the toxic effects of environmental chemicals on
Funding We gratefully acknowledge funding from the NSF
(CBET, CMMI, DBI, DMR), NIH (NIDDK), U.S. EPA, the Jeffress Memorial
Trust, and the Institute for
Critical Technology and Applied Science, Virginia Tech.
3D Liver Mimetic Architectures
The liver is one of the most important organs in our bodies, with functions such as metabolism and detoxification, and it mediates the body's complex defense mechanisms. We have successfully designed 3D liver mimics that recapitulate the cellular structure at the interface of hepatocytes and the vasculature. These model hepatic constructs are comprised of primary hepatocytes, liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs). The LSECs and KCs are separated from the hepatocytes by an intermediate nano-scale biocompatible polyelectrolyte multilayer (PEM). The PEM mimics the Space of Disse, a protein-enriched, charged interface that separates these cells in the liver. We have demonstrated maintenance of phenotype and function of all cell types in the 3D models. These 3D models have been utilized for toxicity evaluations of a prototypic drug, acetaminophen. We have demonstrated that the response of each cell type was nearly identical to in vivo.
Self-Assembled Polymer Scaffolds
We are currently designing detachable collagen-hyaluronic acid PEMs with controlled properties that can be used for multiple functions. These PEMs are biocompatible, composed purely of polyelectrolytes, optically transparent, stable in aqueous solutions and do not require post-assembly modifications to enable detachment. These PEMs have been used for the 3D liver models and antimicrobial patches. The antimicrobial patches use conjugated LL37, an anti-microbial peptide, to prevent E. coli adhesion and increase bacterial death. Our current efforts are aimed towards the design and assembly of PEMs with varying stiffness to model the transition between healthy and diseased tissue.
Integrated Gastrointestinal and Liver Models
Previous in vitro models of the liver and the gastrointestinal tract have been developed independently. Limited studies have been conducted to integrate these organs to model the first-pass metabolism of xenobiotics. Previously developed systems use cell lines to model each organ that are known to have reduced biotransformation capabilities. We have integrated the caco-2 cell line with primary rat hepatocytes to assess the transport, metabolism and toxicity of acetaminophen. Ongoing efforts are focused on the complete integration of gastrointestinal explants with the 3D liver models. These models would allow for a more detailed analysis of the simultaneous effects of each of these organs on the other.
Macrophage Phenotype and Migratory Behavior in 2D and 3D Co-cultures
Cell migration is an integral component of tissue engineering and plays crucial roles in wound healing and cancer metastasis. Macrophages are central regulators of the inflammatory response and can be found in a pro-inflammatory or anti-inflammatory state depending on the cellular and chemical composition, as well as the mechanical properties and dimensionality of their surroundings. Our prior and ongoing research is focused upon the investigation of macrophage phenotype and their ability to translocate when co-cultured with other cell types important to the wound healing process and the progression of cancer while also modulating the chemical and mechanical properties of their environment.
Systems Biology of Engineered Tissues
Our goal is to use the 3D liver mimic to obtain insights into the communications between the four main cell types in the liver: hepatocytes, LSECs, KCs, and hepatic stellate cells (HSCs). The primary question that we aim to address is "Which transcriptional signatures arise from communications between these cell types and result in optimal hepatic phenotypic function?" We are combining tissue engineering, DNA microarrays and computational biology to unearth the spectrum of biological pathways and processes (and linkages between them) perturbed as a result of intercellular communications in the liver mimic.