The treatment of skeletal diseases, the central goal of orthopaedic surgery, is greatly dependent upon a clear understanding of normal and pathologic skeletal biology. However, the number of scientifically well-trained orthopaedic surgeons actively engaged in basic research is quite small. In order to provide orthopaedic surgeons with the necessary training to pursue meaningful investigations in clinically relevant basic science topics, the Department of Orthopedic Surgery has designed an unique integrated program, such that an orthopaedic surgery resident is also enrolled as a full-time graduate student in the Department of Biochemistry and Molecular Biology. Phase I of the training will involve completing afl the usual course requirements for the Ph.D. degree and satisfactory performance in preliminary examinations. Additional activities also include attendance at research seminars and regular journal club presentations. during phase II, the candidate will be involved in full-time research in the Orthopaedic Research Laboratory towards completion of the Ph. D. thesis. The proposed project will characterize and analyze the adhesion of primary human osteoblasts to different substrate materials commonly used in orthopaedic implant components, to specifically determine whether initial cell adhesion is a predictive factor in the eventual success of long-term osseointegration. A technique for quantifying the strength of cell adhesion to various substrates will be developed using laminar flow system which subjects the cell-substrate interface to controlled shear stress, thus determining the relative strength of attachment of cells. Once various materials are tested, it should be possible to determine which substrates allow for better initial adhesion, and whether cellular adhesion may be improved by alterations in the surface or chemical or chemical characteristics of the substrate, e.g. porous coating, or coating with collagen type I, fibronectin, hydroxyapatite, and basic polycations. In addition, the effect of exposure to various calcitropic hormones (e.g. vitamin D) and growth factors (e.g. TGF-beta) on subsequent cell adhesion will also be assessed. The nature and mechanistic basis of adhesion will be analyzed at both a molecular level, i.e. expression of integrins, as well as at a physical level, i.e. changes in contact angle and surface charge density. In addition, the ability of cells to grow upon such substrates will be determined. Parameters such as extracellular matrix elaboration, degree of mineralization, alkaline phosphatase activity, and kinetics of cell growth will be measured. Also, histomorphometric studies and SEM of the interface will garner information regarding its anatomy. These investigations are clinically relevant since they will provide greater understanding of the interactions at the bone-metal interface which can allow for improved design of orthopaedic implant components as well as modifications in patient treatment protocols. Once the dissertation project is complete, the candidate will resume and complete clinical residency training in orthopaedic surgery, as well as attend seminars, professional meetings and conduct follow-up research. The long-term goal of the applicant, to become a qualified physician scientist capable in both clinical and basic research fields of orthopaedic surgery, can be realized through this unique program.
| Shah, A K; Lazatin, J; Sinha, R K et al. (1999) Mechanism of BMP-2 stimulated adhesion of osteoblastic cells to titanium alloy. Biol Cell 91:131-42 |
| Shah, A K; Sinha, R K; Hickok, N J et al. (1999) High-resolution morphometric analysis of human osteoblastic cell adhesion on clinically relevant orthopedic alloys. Bone 24:499-506 |
| Sinha, R K; Tuan, R S (1996) Regulation of human osteoblast integrin expression by orthopedic implant materials. Bone 18:451-7 |
| Sinha, R K; Morris, F; Shah, S A et al. (1994) Surface composition of orthopaedic implant metals regulates cell attachment, spreading, and cytoskeletal organization of primary human osteoblasts in vitro. Clin Orthop Relat Res :258-72 |
