Soluble growth factors play a vital role in virtually all tissue development and regeneration processes, and inductive growth factors are critical components of many emerging tissue engineering strategies. However, approaches used to design biomaterials have not yet achieved a high level of control over growth factor signaling during development of engineered tissues. We propose to develop a new class of biomaterials capable of locally regulating growth factor signaling. Our approach uses low molecular weight ligands, including peptide and oligonucleotide ligands, to specifically and reversibly sequester growth factors upon and within biomaterials. We hypothesize that these specific, variable affinity interactions will control local growth factor availability, resulting in up- or down-regulated growth factor activity. This approach will initially be used to regulate the effects of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF2) on endothelial cells in 2-dimensional and 3-dimensional culture environments. This signaling system is ideal for the proposed studies, as VEGF and FGF2 have well-characterized and pronounced effects on survival, proliferation, and differentiated function of endothelial cells in vitro and in vivo. Furthermore, regulation of endothelial cell behavior has significant implications for clinical applications that require highly regulated vascular tissue growth, including regenerative medicine. We specifically aim to: 1) develop and characterize tailored cell culture substrates for localized, controlled sequestering of FGF2 and VEGF;2) characterize the combinatorial influence of non-covalent growth factor sequestering and cell adhesion on growth factor signaling and, in turn, survival, proliferation, and organization of endothelial cells in vitro;and 3) scale the growth factor sequestering approach to a well-defined hydrogel matrix, and characterize regulated growth factor signaling during capillary morphogenesis and ex vivo aortic sprouting. Alkanethiolate self-assembled monolayer substrates and PEG hydrogels will be used as initial model biomaterials to address the hypothesis guiding this proposal. Cells and proteins exhibit little or no intrinsic interaction with these materials, and they therefore serve as well-defined model systems to explore affinity- based growth factor regulation. We anticipate that the proposed approach can ultimately be applied to a broad range of common biomaterials, and may represent a new direction in biomaterials design. Development of all tissue types requires the coordinated action of particular proteins called growth factors. Current strategies that attempt to "engineer" new tissues are unable to control the effects of growth factors, and it is therefore difficult to mimic tissue development and form functional tissues for transplantation. This proposed research program will develop a new class of materials that can be used to control the effects of growth factors during engineered tissue development, particularly vascular tissue development.

Public Health Relevance

Murphy, William, L. Development of all tissue types requires the coordinated action of particular proteins called growth factors. Current strategies that attempt to engineer new tissues are unable to control the effects of growth factors, and it is therefore difficult to mimic tissue development and form functional tissues for transplantation. This proposed research program will develop a new class of materials that can be used to control the effects of growth factors during engineered tissue development, particularly vascular tissue development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093282-05
Application #
8502738
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2009-07-15
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$341,339
Indirect Cost
$105,719
Name
University of Wisconsin Madison
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Murphy, William L; McDevitt, Todd C; Engler, Adam J (2014) Materials as stem cell regulators. Nat Mater 13:547-57
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Belair, David G; Le, Ngoc Nhi; Murphy, William L (2014) Design of growth factor sequestering biomaterials. Chem Commun (Camb) 50:15651-68
Musah, Samira; Wrighton, Paul J; Zaltsman, Yefim et al. (2014) Substratum-induced differentiation of human pluripotent stem cells reveals the coactivator YAP is a potent regulator of neuronal specification. Proc Natl Acad Sci U S A 111:13805-10
Nguyen, Eric H; Zanotelli, Matthew R; Schwartz, Michael P et al. (2014) Differential effects of cell adhesion, modulus and VEGFR-2 inhibition on capillary network formation in synthetic hydrogel arrays. Biomaterials 35:2149-61
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Suárez-González, Darilis; Lee, Jae Sung; Diggs, Alisha et al. (2014) Controlled multiple growth factor delivery from bone tissue engineering scaffolds via designed affinity. Tissue Eng Part A 20:2077-87
Yu, Xiaohua; Takayama, Toshio; Goel, Shakti A et al. (2014) A rapamycin-releasing perivascular polymeric sheath produces highly effective inhibition of intimal hyperplasia. J Control Release 191:47-53
Hansen, Tyler D; Koepsel, Justin T; Le, Ngoc Nhi et al. (2014) Biomaterial arrays with defined adhesion ligand densities and matrix stiffness identify distinct phenotypes for tumorigenic and nontumorigenic human mesenchymal cell types. Biomater Sci 2:745-756
Khalil, Andrew S; Xie, Angela W; Murphy, William L (2014) Context clues: the importance of stem cell-material interactions. ACS Chem Biol 9:45-56

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