Stimulation of osteoblast differentiation and mineralization from mesenchymal stemcells is a potential new approach for bone regeneration and repair. Traditionally, large molecule growth factors such as bone morphogenetic proteins (BMPs) have been used in humans and animals to regenerate bone. Unfortunately, the use of these biological factors has shortcomings. Protein instability, cost, immunogenicity, and supraphysiological dosage are the major concerns involving BMPs. There is thus a need to examine alternative growth factors that can reduce or even avoid these limitations. Here we propose a new strategy for bone regeneration via osteoblast differentiation using a stable small molecule. Preliminary data in the P.I.'s group suggest that a newly developed small molecule cAMP analogue, N6-Benzoyladenosine-3',5'- cyclic monophosphate (6-Bnz-cAMP), promotes initial cell adhesion and supports proliferation on biodegradable polymeric poly(lactic acid-co-glycolic acid) scaffolds. Further, it induces differentiation and matrices mineralization of osteoblast-like MC3T3-E1 cells. The objectives of the present research proposal are 1) to evaluate the osteoinductive potential of 6-Bnz-cAMP in rabbit mesenchymal stem cells, 2) to directly compare the osteoinductive effects of 6-Bnz-cAMP and BMP-2, 3) to develop and evaluate a novel bone grafting material system comprising biodegradable PLAGA microspheres matrices with small molecule 6-Bnz-cAMP. The biological performance of the novel 6-Bnz-cAMP loaded microsphere based scaffold will be examined in vivo using a rabbit ulnar critical size defect model. We hypothesize that the bioactivity of the proposed microspheres scaffold system will be significantly improved by the incorporation of the small molecule 6-Bnz-cAMP. We further hypothesize that the use of the small molecule- polymeric matrix system will result in bone tissue regeneration in vivo.

Public Health Relevance

The laboratory has focused on developing engineered alternatives to orthopaedic tissues such as bone, cartilage, and ligament. To achieve these goals, we work with clinicians, cell biologists, and engineers from the University of Connecticut and throughout the world. The innovation of the current proposal is the use of small molecules with polymers for engineering bone tissue.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
3R21AR060480-01A1S1
Application #
8502063
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Wang, Fei
Project Start
2011-09-15
Project End
2013-08-31
Budget Start
2012-07-01
Budget End
2012-08-31
Support Year
1
Fiscal Year
2012
Total Cost
$10,087
Indirect Cost
$3,537
Name
University of Connecticut
Department
Orthopedics
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Lo, Kevin W-H; Kan, Ho Man; Laurencin, Cato T (2016) Short-term administration of small molecule phenamil induced a protracted osteogenic effect on osteoblast-like MC3T3-E1 cells. J Tissue Eng Regen Med 10:518-26
Lo, Kevin W-H; Kan, Ho Man; Gagnon, Keith A et al. (2016) One-day treatment of small molecule 8-bromo-cyclic AMP analogue induces cell-based VEGF production for in vitro angiogenesis and osteoblastic differentiation. J Tissue Eng Regen Med 10:867-875
Ulery, Bret D; Kan, Ho-Man; Williams, Bryce A et al. (2014) Facile fabrication of polyanhydride/anesthetic nanoparticles with tunable release kinetics. Adv Healthc Mater 3:843-7
Lo, Kevin W-H; Ulery, Bret D; Kan, Ho Man et al. (2014) Evaluating the feasibility of utilizing the small molecule phenamil as a novel biofactor for bone regenerative engineering. J Tissue Eng Regen Med 8:728-36
Carbone, Erica J; Jiang, Tao; Nelson, Clarke et al. (2014) Small molecule delivery through nanofibrous scaffolds for musculoskeletal regenerative engineering. Nanomedicine 10:1691-9
Cushnie, Emily K; Ulery, Bret D; Nelson, Stephen J et al. (2014) Simple signaling molecules for inductive bone regenerative engineering. PLoS One 9:e101627
Laurencin, Cato T; Ashe, Keshia M; Henry, Nicole et al. (2014) Delivery of small molecules for bone regenerative engineering: preclinical studies and potential clinical applications. Drug Discov Today 19:794-800
Lo, Kevin W-H; Jiang, Tao; Gagnon, Keith A et al. (2014) Small-molecule based musculoskeletal regenerative engineering. Trends Biotechnol 32:74-81
Lo, Kevin W-H; Ulery, Bret D; Ashe, Keshia M et al. (2012) Studies of bone morphogenetic protein-based surgical repair. Adv Drug Deliv Rev 64:1277-91
Lo, Kevin W-H; Ashe, Keshia M; Kan, Ho Man et al. (2012) The role of small molecules in musculoskeletal regeneration. Regen Med 7:535-49