The Role of Biomechanics in Liver Tissue Engineering

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Abstract

The field of liver bioengineering aims to generate functioning liver tissue in the laboratory in order to study complicated processes such as development, disease, cancer, drug metabolism, or even to engineer organs that can be implanted in patients. One approach in liver tissue engineering is to use the process of decellularization to create acellular liver scaffolds that retain the native tissue’s extracellular matrix and architecture. These scaffolds can then be repopulated with a variety of hepatic and nonhepatic cell-types depending on the application, or in the case of human transplantation, the patient’s own cells. While there has been some success in transplanting these constructs in animals and applying them towards simplistic models, we are still far away from achieving physiological liver structure and function. In order to achieve this, seeded cells need to be placed within the proper environment and given particular biological cues in order to function as they would physiologically. One important aspect of this process is the mechanical environment and signaling that cells experience within the acellular liver scaffolds. This thesis aims to investigate the role of biomechanics in liver tissue engineering so that we can better understand how to deliver the proper mechanical stimuli to cells in order to optimize their growth and function. To this end, we first characterized changes in liver biomechanics with tissue decellularization, finding that this process increases scaffold permeability and lowers matrix stiffness. Next, we investigated the impact of fluid flow-driven forces on cell seeding, tissue growth and cellular organization in a bioengineered liver with capabilities of modeling liver development and disease. Finally, we developed a bioengineered liver model of colon cancer metastasis in which we analyzed the influence of fluid flow and matrix stiffness on tumor behavior. Overall, the findings of this thesis demonstrate the importance of the biomechanical environment in creating successful bioengineered liver models.

Cited Works (19)

Year	Entry
1992	Simon BR. Multiphase poroelastic finite element models for soft tissue structures. Appl Mech Rev. June 1992;45(6):191-218.
1998	Wu JZ, Herzog W, Epstein M. Evaluation of the finite element software ABAQUS for biomechanical modelling of biphasic tissues. J Biomech. February 1998;31(2):165-169.
2001	Huang C-Y, Mow VC, Ateshian GA. The role of flow-independent viscoelasticity in the biphasic tensile and compressive responses of articular cartilage. J Biomech Eng. October 2001;123(5):410-417.
2005	Discher DE, Janmey P, Wang Y-l. Tissue cells feel and respond to the stiffness of their substrate. Science. November 18, 2005;310(5751):1139-1143.
2006	Ingber DE. Cellular mechanotransduction: putting all the pieces together again. FASEB J. May 2006;20(7):811-827.
1986	Mak AF. The apparent viscoelastic behavior of articular cartilage: the contributions from the intrinsic matrix viscoelasticity and interstitial fluid flows. J Biomech Eng. May 1986;108(2):123-130.
1980	Mow VC, Kuei SC, Lai WM, Armstrong CG. Biphasic creep and stress relaxation of articular cartilage in compression: theory and experiments. J Biomech Eng. February 1980;102(1):73-84.
2007	Cheng S, Bilston LE. Unconfined compression of white matter. J Biomech. 2007;40(2):117-124.
2001	Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2^−ΔΔCT method. Methods. December 2001;25(4):402-408.
1976	Mansour JM, Mow VC. The permeability of articular cartilage under compressive strain and at high pressures. J Bone Joint Surg. June 1976;58A(4):509-516.
2001	DiSilvestro MR, Zhu Q, Wong M, Jurvelin JS, Suh J-KF. Biphasic poroviscoelastic simulation of the unconfined compression of articular cartilage, I: simultaneous prediction of reaction force and lateral displacement. J Biomech Eng. April 2001;123(2):191-197.
1998	Suh J-K, Bai S. Finite element formulation of biphasic poroviscoelastic model for articular cartilage. J Biomech Eng. April 1998;120(2):195-201.
2006	Kerdok AE, Ottensmeyer MP, Howe RD. Effects of perfusion on the viscoelastic characteristics of liver. J Biomech. 2006;39(12):2221-2231.
2001	DiSilvestro MR, Zhu Q, Suh J-KF. Biphasic poroviscoelastic simulation of the unconfined compression of articular cartilage, II: effect of variable strain rates. J Biomech Eng. April 2001;123(2):198-200.
1990	Spilker RL, Suh J-K, Mow VC. Effects of friction on the unconfined compressive response of articular cartilage: a finite element analysis. J Biomech Eng. May 1990;112(2):138-146.
2006	Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. August 25, 2006;126(4):P677-P689.
1999	Gu WY, Mao XG, Foster RJ, Weidenbaum M, Mow VC, Rawlins BA. The anisotropic hydraulic permeability of human lumbar anulus fibrosus: influence of age, degeneration, direction, and water content. Spine. December 1, 1999;24(23):2449-2455.
2011	Evans DW. A Nanoindentation Device and the Scale-Dependent Mechanical Properties of Native and Decellularized Liver Tissue [Master's thesis]. Winston-Salem, NC: Wake Forest University; December 2011.
2007	Anderson AE, Ellis BJ, Weiss JA. Verification, validation and sensitivity studies in computational biomechanics. Comput Methods Biomech Biomed Eng. June 2007;10(3):171-184.