Engineering a Novel Bio-Scaffold for Hepatic Tissue Restoration and Drug Screening

Health issues associated with liver diseases afflict millions of individuals and account for over 70,000 deaths
annually in the United States. Due in part to an aging population, liver diseases are expected to rise
significantly over the next two decades, increasing the need for more effective treatment therapies and
increased success rates with transplants. Unfortunately, there are no effective treatments to curb the pathology
and there remains a shortage of available livers for transplantation. This challenge is further compounded with
alloreactive responses leading to transplant rejection. However, a viable solution is the use of a model liver
systems that accurately mimic the biomechanical and biochemical functioning of in vivo liver tissue.
Additionally, alternative methods to expand recipient autologous hepatic cells while maintaining function would
serve as efficient methods to generate liver systems for transplantation. However, while liver models for in vivo
use have been attempted, none have yet successfully expanded autologous hepatic cells in vitro followed by
successful implantation to alleviate liver failure in recipients using an in vivo model system. My laboratory has
recently demonstrated success in this approach, where we have established an effective in vitro 3D hepatocyte
culture system for rapid expansion. Furthermore our preliminary work shows great promise in applying the
system for in vivo adoptive implantation using our innovative in-house designed 3D scaffold system. Therefore,
this proposal's objective is to develop a method for rapid expansion of hepatic cells in a novel 3D printed
bioscaffold for assembly of a liver organoid for in vivo tissue restoration and ex vivo drug screening. The
central hypothesis is that primary hepatic cells seeded in a novel biomaterial scaffold will display similar
metabolic function, structure, and biomechanical properties to that of the original liver tissues. The success of
this approach will restore liver function following transplantation in a liver-damaged mouse model. The
innovative combination of rheological biomaterial tuning, 3D bioprinting, and culture methods that utilize a
novel bioscaffold will be applied in pursuit of two specific aims: 1) Engineering an ex vivo model for screening
therapeutic drugs targeting hepatocytes through 3D printed bioscaffolds and 2) Development of an implantable
hepatic organoid for in vivo tissue restoration to alleviate liver failure in a mouse model. These investigations
will establish a platform for novel 3D culture systems for both rigorous in vitro diagnostic screening and for in
vivo adoptive transfer approaches to physiologically restore failed liver function. The proposed work is
significant as the anticipated results will establish a platform for future investigations utilizing the biomaterial for
engineering cell seeded scaffolds to restore tissue function and in pursuit of drug discovery.

Grant Number: 5R16GM145595-04
NIH Institute/Center: NIH
Principal Investigator: Jamel Ali