The goal of this proposal is the development of polymeric scaffolds for cardiovascular tissue engineering which will lead to the production of tissue-based small diameter vascular grafts. Hydrogel polymer scaffolds will be formed by rapid photopolymerization of aqueous precursors which allows for the incorporation of cell suspensions within the final product. Cell viability is maintained during this process, and the focus will be on the use of genetically engineered smooth muscle and endothelial cells. The incorporation of a variety of bioactive domains within the structure of the hydrogel matrices will be investigated to promote cell adhesion, growth, and extracellular matrix synthesis. Bioactive domains to be incorporated will include cell adhesion peptides and peptide growth factors. Cells will be transduced with genes that encode NO synthase for NO production (a proven anti-thrombotic agent), an endothelial cell-specific growth factor (VEGF), lysyl oxidase to enhance matrix crosslinking, and protease inhibitors (TIMPs) to reduce matrix degradation. In vitro assessment of cell viability and proliferation, extracellular matrix synthesis, and transgene expression will be performed under conditions of flow and static culture. Polymer preparations and polymer/cell composites will be tested using small animal in vivo vascular injury models for the recruitment of endothelial cells and the maintenance of homeostasis. Coating of Dacron grafts with polymers and polymer/cell composites will be investigated both in vitro and in vivo in canine arteriograft modalities. The ultimate focus of this proposal is to develop polymers which are biodegradable and can be used to support cell growth and deposition of extensive extracellular matrix material for de novo synthesis of vascular tissue. Populations of vascular cells (smooth muscle and endothelial cells) will be introduced as suspensions to the polymer environment prior to crosslinking of the hydrogel. Genetic engineering of cells will be used to optimize their production of matrix materials for the formation of tissue structures with mechanical integrity and to introduce anti- thrombotic properties to the newly formed tissue. The proposal seeks to develop vascular tissue grafts based on the provision of a biodegradable structure which will serve as a temporary scaffold and which will promote the proliferation and extracellular matrix elaboration of normal and genetically enhanced cell populations.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060485-04
Application #
6389937
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M2))
Program Officer
Kelley, Christine A
Project Start
1998-07-10
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
4
Fiscal Year
2001
Total Cost
$261,922
Indirect Cost
Name
Rice University
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Lau, Ying-Ka Ingar; Gobin, Andre M; West, Jennifer L (2006) Overexpression of lysyl oxidase to increase matrix crosslinking and improve tissue strength in dermal wound healing. Ann Biomed Eng 34:1239-46
Elbjeirami, Wafa M; West, Jennifer L (2006) Angiogenesis-like activity of endothelial cells co-cultured with VEGF-producing smooth muscle cells. Tissue Eng 12:381-90
Gonzalez, Anjelica L; Gobin, Andrea S; West, Jennifer L et al. (2004) Integrin interactions with immobilized peptides in polyethylene glycol diacrylate hydrogels. Tissue Eng 10:1775-86
Jun, Ho-Wook; West, Jennifer (2004) Development of a YIGSR-peptide-modified polyurethaneurea to enhance endothelialization. J Biomater Sci Polym Ed 15:73-94
Elbjeirami, Wafa M; Yonter, Edward O; Starcher, Barry C et al. (2003) Enhancing mechanical properties of tissue-engineered constructs via lysyl oxidase crosslinking activity. J Biomed Mater Res A 66:513-21
Mann, Brenda K; West, Jennifer L (2002) Cell adhesion peptides alter smooth muscle cell adhesion, proliferation, migration, and matrix protein synthesis on modified surfaces and in polymer scaffolds. J Biomed Mater Res 60:86-93
Mann, B K; Schmedlen, R H; West, J L (2001) Tethered-TGF-beta increases extracellular matrix production of vascular smooth muscle cells. Biomaterials 22:439-44
Mann, B K; Gobin, A S; Tsai, A T et al. (2001) Smooth muscle cell growth in photopolymerized hydrogels with cell adhesive and proteolytically degradable domains: synthetic ECM analogs for tissue engineering. Biomaterials 22:3045-51
Mann, B K; Tsai, A T; Scott-Burden, T et al. (1999) Modification of surfaces with cell adhesion peptides alters extracellular matrix deposition. Biomaterials 20:2281-6