User:Eric J Gomez/Notebook/Mod3 : Research Proposal/Entry Base

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Mod 3 Research Proposal
Topic: 3D Vascularized cell sheet/polymer hydrogel for Tissue Engineering

Background: Cell Sheet Engineering is a type of tissue engineering that avoids the limitations of biodegradable scaffolds or single cell suspension injections, such as: inefficient transport of cells, inflammation/toxicity upon degradation, difficulty in maintaining unique tissue qualities i.e. beating of cardiac tissue, optical transparency of ocular tissue. Cell sheets are prepared using temperature-responsive culture dishes with covalently grafted temperature-responsive polymers, allowing various types of cells to adhere and proliferate at 37°C. The cells spontaneously detach when the temperature is reduced below 32°C without the need for proteolytic enzymes (such as trypsin, which is toxic to cells), because the polymer becomes hydrophillic and swells. The confluent cells are noninvasively harvested as single, contiguous cell sheets with intact cell-cell junctions and deposited extracellular matrix(ECM).Various tissue reconstructions, including ocular surfaces, periodontal ligaments, cardiac patches, and bladder augmentation, have been achieved through cell sheet engineering.

Problem: A key restriction on scaffold-based designs is the limits on passive diffusion that prevent the delivery of nutrients and cause an accumulation of metabolic wastes. With cell sheet engineering, the number of cell sheets that can be effectively layered without core ischemia or hypoxia is therefore also limited. Methods to resolve this problem still remain a significant obstacle in the effective reconstruction of thick, viable, 3-D tissues even when scaffold-based technologies are avoided.

Proposal: We hope to overcome the critical problem of cell-sheet engineering and help the field of tissue engineering progress more smoothly by developing a three dimensional composite material consisting of layers of cell sheets and slices of biocompatible polymers such as (but not limited to): hyaluronic acid, hyaluronic acid/collagen interpenetrating networks, and collagen-chondroitin sulfate. The diffusivity already proven in the aforementioned materials would not drastically hinder nutrients and O2 from reaching cells in the middle of the construct (especially because they would be thin layers ~50-150 microns thick), but would allow for larger and more useful construct size. Also, by incorporating endothelial cells into cell sheets comprising of other major cell types (cardiomyocite, chondrocyte, fibroblast, etc), we can possibly induce vascularization within the constructs, for improved flow of nutrients and O2.

Objectives:
 * Enable the engineering of thicker tissues by providing more uniform oxygen and nutrition supply to the interior of the material with use of biomaterials and HUVECs
 * Provide a method for use with cell sheet engineering that can modify mechanical properties of desired tissue construct (type of polymer embedded between cell sheets), and modify size/dimensions for an easily processable material
 * Help advance the field of tissue and biomaterial engineering.

Very Helpful Sources in Our Process of Designing a Proposal

"Cell Sheet Engineering" by Masayuki Yamato and Teruo Okano. MaterialsToday Magazine. (pages 42-47, May 2004)

"Cell Sheet Engineering: Recreating Tissues Without Biodegradable Scaffolds" Yang et al. Biomaterials. (pages 6415-6422, November 2005)

"A thermoresponsive, microtextured substrate for cell sheet engineering with defined structural organization" Isenberg et al. Biomaterials. (pages 2565-2574, February 2008)


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