The focus of this proposal is to develop new strategies to promote the growth of mature microvascular networks by therapeutic induction of arteriogenesis. Arteriogenesis is the process by which new arterioles form and existing arterioles structurally enlarge, effectively increasing the number and diameter of resistance microvessels that are critical to the preservation of tissues after surgical transplantation or ischemic injury. Preliminary studies show that sustained delivery of sphingosine-1-phosphate (S1P) from biodegradable polymers significantly enhances lumenal diameter enlargement of arterioles in vivo;one is one hallmark of arteriogenesis. S1P is a pleiotropic autocrine and paracrine signaling small molecule that regulates the behavior of endothelial cells (ECs) and smooth muscle cells (SMCs) through a family of high-affinity G protein- coupled receptors (S1P1, S1P2, S1P3). The motivation for the proposed activities stems from exciting new advances in the synthesis of pharmacological agonists and antagonists of S1P receptors. Recently, we demonstrated that in vivo delivery of selective pharmacological agonists of S1P1 significantly increases arteriolar diameter enlargement and vessel maintenance over S1P itself. The results of S1P1-induced arteriogenesis suggest exciting new possibilities for locally delivering S1P receptor targeted drugs to improve healing outcomes in tissue engineering and regenerative medicine. To this end, exploratory experiments now demonstrate that implantation of biodegradable three-dimensional (3D) scaffolds delivering S1P1 selective compounds to critical size calvarial bone defects significantly increases osseous tissue ingrowth and the proportion of SMC-invested microvessels in boney repair tissues.
AIM 1 will quantify local regulation of SMC proliferation and lumenal diameter enlargement in microvascular networks in vivo via the sustained release of S1P from synthetic biodegradable polymers.
AIM 2 tests the hypothesis that S1P-induced arteriolar diameter enlargement requires activation of S1P1 in SMCs.
AIM 3 tests the hypothesis that S1P1-induced regulation of microvessel remodeling will enhance bone healing outcomes.

Public Health Relevance

The replacement or restoration of function to traumatized, damaged, or lost organs and tissues is an increasingly significant clinical problem. It is estimated that only 24,422 received organ transplants of a possible 79,512 patients on the transplantation wait list in 2002. In addition, it is currently estimated that over 1.5 million musculoskeletal injuries alone will require tissue graft reconstruction in the US each year, and these numbers will continue to grow as the life expectancy of the population increases. Thus, the development of effective strategies to vascularize new tissue engineering organ and tissues to sustain their viability in vivo is a significant medical need.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
7R01AR056445-04
Application #
8291437
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Wang, Fei
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$292,521
Indirect Cost
$78,681
Name
Georgia Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
097394084
City
Atlanta
State
GA
Country
United States
Zip Code
30332
Das, Anusuya; Barker, Daniel A; Wang, Tiffany et al. (2014) Delivery of bioactive lipids from composite microgel-microsphere injectable scaffolds enhances stem cell recruitment and skeletal repair. PLoS One 9:e101276
Ogle, Molly E; Sefcik, Lauren S; Awojoodu, Anthony O et al. (2014) Engineering in vivo gradients of sphingosine-1-phosphate receptor ligands for localized microvascular remodeling and inflammatory cell positioning. Acta Biomater 10:4704-14
Awojoodu, Anthony O; Ogle, Molly E; Sefcik, Lauren S et al. (2013) Sphingosine 1-phosphate receptor 3 regulates recruitment of anti-inflammatory monocytes to microvessels during implant arteriogenesis. Proc Natl Acad Sci U S A 110:13785-90
Das, Anusuya; Segar, Claire E; Hughley, Brian B et al. (2013) The promotion of mandibular defect healing by the targeting of S1P receptors and the recruitment of alternatively activated macrophages. Biomaterials 34:9853-62
Segar, Claire E; Ogle, Molly E; Botchwey, Edward A (2013) Regulation of angiogenesis and bone regeneration with natural and synthetic small molecules. Curr Pharm Des 19:3403-19
Huang, Cynthia; Das, Anusuya; Barker, Daniel et al. (2012) Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation. Cell Tissue Res 347:553-66
Sefcik, Lauren S; Aronin, Caren E Petrie; Awojoodu, Anthony O et al. (2011) Selective activation of sphingosine 1-phosphate receptors 1 and 3 promotes local microvascular network growth. Tissue Eng Part A 17:617-29
Cui, Quanjun; Botchwey, Edward A (2011) Emerging ideas: treatment of precollapse osteonecrosis using stem cells and growth factors. Clin Orthop Relat Res 469:2665-9
Petrie Aronin, Caren E; Sefcik, Lauren S; Tholpady, Sunil S et al. (2010) FTY720 promotes local microvascular network formation and regeneration of cranial bone defects. Tissue Eng Part A 16:1801-9
Petrie Aronin, Caren E; Shin, Soo J; Naden, Kimberly B et al. (2010) The enhancement of bone allograft incorporation by the local delivery of the sphingosine 1-phosphate receptor targeted drug FTY720. Biomaterials 31:6417-24