Multifunctional Printed Scaffolds for Enhancing Hepatocyte Viability and Function

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DESCRIPTION (provided by applicant): The long-term career goal of the candidate, Dr. Ramille Shah, is to become an independent investigator and leader at the forefront of the liver regeneration field. Her immediate objective is to gain the knowledge, skill and experience needed to perform relevant and impactful research in the area of liver tissue engineering. Dr. Shah is completely committed to biomedical research, as demonstrated by completion of her Ph.D. involving the development of gene-supplemented collagen scaffolds for articular cartilage regeneration at the Massachusetts Institute of Technology and with two years of post-doctoral research involving the investigation of self-assembling peptide amphiphile nanostructures for regenerative medicine at Northwestern University's Institute for BioNanotechnology in Medicine. Currently, she is an Assistant Professor with joint appointments in the Department of Materials Science and Engineering and Department of Surgery (Transplant Surgery division) at Northwestern University. Dr. Shah's past research had mainly focused on the development of biomaterial systems for musculoskeletal regeneration, and she is now venturing into a new area of liver regeneration. Although her regenerative medicine target has changed, she has an excellent foundation in biomaterials and tissue engineering to apply what she has learned and experienced over the years in musculoskeletal tissue engineering to this new target area. This award will give her the opportunity to receive the research training, institutional support, and mentorship she needs to be able to transition into an independent investigator in the liver regeneration field. Dr. Shah's mentors in this K01 proposal consist of well-established and recognized clinicians (Dr. Janardan Reddy-Pathology and Dr. Richard Green-Hepatology) in the hepatic biology field, as well as a world- renowned researcher (Dr. Samuel Stupp-Materials Science and Engineering, Chemistry and Medicine) in the field of self-assembly and nanomedicine. She has their full support in helping hr develop into a successful independent investigator by providing valuable input on research design and methods, troubleshooting, scientific direction, and guidance in the preparation of manuscripts, grants, and presentations. Through interactions with both her mentors and collaborators she will be able to develop molecular biology and biochemical assay techniques, as well as in vitro and in vivo evaluation methods to characterize the behavior of hepatocytes, assess normal function, and understand the mechanisms behind cell-matrix interactions. With NU's strong research and training programs she will also have opportunities to interact with other faculty in the engineering and medical schools who share similar research interests through seminars, conferences, and journal clubs. NU's state of-the-art research facilities and technical support staff will also help Dr. Shah accomplish her proposed research aims. Furthermore, through formal coursework offered by NU's Graduate Program, Dr. Shah will be able to increase her knowledge in basic cell and molecular biology to help her interpret her research results. In addition, she has the opportunity to participate in seminars and conferences within the Hepatology service in the medical school to increase her knowledge of clinical hepatology. The proposed research aims to use multifunctional 3D bioprinted scaffolds incorporating bioactive agents such peptide nanostructures and support cells to enhance the viability and function of hepatocytes fr liver tissue engineering. The lack of liver donors for patients with end stage liver disease (ESLD) is a major healthcare obstacle. Developing organ replacements or functional liver units using tissue engineering strategies as an alternative treatment is a promising possibility to alleviate this significant need. The interplay between microenvironmental cues and cell behavior in liver tissue engineering, however, is still not well understood. This research hopes to establish and understand trends in 3D scaffold design and bioactive agent delivery to start to identify key components in the microenvironment that can enhance liver cell function and normal liver tissue formation both in vitro and in vivo. The hypothesis is that the viability and function of hepatocytes can be significantly enhanced by: 1) optimizing scaffold architecture, which can alter hepatocyte aggregation and cell-cell contact~ 2) including functional moieties for growth factor delivery via self-assembling peptide amphiphile (PA) nanofibers~ and 3) co-culturing stromal cells and hepatocytes with 3D spatial control. Small "liver units" will be created using 3D bioplotted scaffolds of varying pore size and geometry, peptide- based nanostructures and growth factors for bioactive signaling, and liver cells (primary hepatocytes, induced pluripotent stem cell-derived hepatocytes, and stromal cells) that are spatially patterned in 3D to change microenvironmental cues and determine what conditions promote optimal hepatocyte viability and function. Materials characterization, in vitro evaluation of viability, proliferation, and function, as well as in vivo assessment of angiogenesis, scaffold degradation, and tissue synthesis will be performed to evaluate the potential of these multifunctional scaffolds for liver tissue engineering. The reslts from this research will provide the necessary preliminary data for securing R01 funding that will help establish Dr. Shah as an independent investigator in the liver tissue engineering field.