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Mary Beth Wilson — 2010-11 Fellow

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The ability to create new functional systems that can be interfaced with medical applications is often limited by the materials that are available. One particular area of interest in biologically integrated materials are polymers due to their ability to be altered for diverse advantageous characteristics. In the areas of tissue engineering and regenerative medicine, polymers are mainly used as biodegradable scaffold materials that provide the structural basis for engineered tissue constructs.1 Our goal is to take a quite different approach and focus on non-obvious functionality of polymers, which can provide a significant advantage. Here we focus on thermally activated polymers, which exhibit reversible liquid-to-gel transition as temperature increases from room to body temperature. These innovative gels will enable the ability to create three-dimensional synthetic vasculature networks that are one of the most significant roadblocks in tissue engineering and regenerative medicine. Integrated vasculature in tissue engineered constructs is imperative for the continual delivery of nutrients to and removal of waste from the tissue, but is lacking in almost all current tissue engineered systems.2 We believe that our approach with thermally reversible polymers combined with microfluidics is well-suited for engineering microvasculature, which is a crucial, yet unsolved, component required for the advancement of regenerative medicine.

Tissue engineering is an evolving interdisciplinary field that has already produced artificial life-saving tissues. Functional tissue-engineered constructs have been developed and implanted in vivo to replace tissues such as skin, bone, and bladder.3 However, these products are not vital organs with high metabolic demands. Artificial vasculature would provide an enabling technology for vital organ engineering. There are current engineering approaches such as microfabrication, cell printing, and growth factory delivery, which have made progress in areas of vascular engineering, but while each has its advantages, existing approaches to address this challenge are inadequate.4

In addressing this issue, we propose to develop artificial capillary networks with close parenchymal contacts by combining the advantages of three separate approaches: high-resolution control using direct cell placement with thermally responsive polymers, microfluidic technology, and biochemical regulation. The ability to engineer micropatterned cell co-cultures by combining reversible thermal gels with micromachining is a novel and transformative approach to engineering vasculature. Because the microvasculature of every organ is unique, it is important to focus on a defined physiological system. For this proposal, liver is targeted due to its high vascularity and discrete functional units. To accomplish our ultimate goal of engineering a vascularized liver module in which capillaries are completely surrounded by hepatocytes, the following aims will be pursued:

Objective 1: Construct synthetic vascular networks with thermally reversible polymers and microfluidics
Objective 2: Assemble alternating vascular and hepatocyte layers towards 3D synthetic vascularized liver construct

These novel approaches address a critical challenge in tissue engineering. Successful completion of these aims will yield in-depth knowledge of the interactions between endothelial cells and hepatocytes in a biomimetic 3D environment. This project will be transformative by producing a significant advance in regenerative medicine, as we expect this approach to be applicable to other systems such as the kidney, heart, lung, and brain with modest adjustments. The scientific discoveries generated would ultimately impact the care of the millions of Americans that suffer terminal organ failure by engineering vascularized organs that can readily integrate with host vasculature or provide a bridge prior to transplantation.

[1] Karp & Langer, Curr Opin Biotech. 18, 454 (2007)
[2] Jain et al., Nature Biotechnol. 23, 821 (2005)
[3] Bettinger et al., Adv Mater. 18, 165 (2006)
[4] Perets et al., J Biomed Mater A. 15, 489 (2003)
[5] Kim et al., Lab Chip. 9, 2603 (2009)
[6] Ross et al., Hepatology. 34, 1135 (2001)