Thrombopoietin in Cranial Regeneration
Dr. Tien-Min Chu received his DDS degree from Kaohsiung Medical College in Taiwan. He later received his PhD in materials science and engineering from the University of Michigan in 1999. He is currently an Associate Professor of Dental Biomaterials at the Indiana University School of Dentistry. Dr. Chu’s current research activities mainly focus on cranial bone tissue engineering and the in vivo dental implant evaluations.
When large bone loss in the craniofacial area occurs, oral surgeons are faced with a very challenging reconstruction task to address both the functional and the esthetical needs for the patient. To accomplish this, they often use a combination of biological factors and graft materials. In the past, tissue engineering approach of using a three-dimensional (3D) scaffold conforming to the shape of the missing bone, loaded with mesenchymal stem cells (MSCs) and bone morphogenetic protein (BMP) has shown great promise. However, several papers since 2011 revealed serious health risks in association with the use of BMP-2. Recently, we have shown that thrombopoietin (TPO) can indirectly promote the osteogenic differentiation of MSCs and stimulate osteoblast proliferation through its action on megakaryocytes (MKs). Others have shown that TPO can potentially promote angiogenesis and endochondral ossification indirectly through MSCs. In our pilot studies, we demonstrated that TPO can induce bridging callus formation in critical-size femoral defects and can induce bone formation in cranial defects. Combined with our prior success in fabricating 3D scaffolds to carry MSCs, we hypothesize that TPO can indirectly stimulate MSCs delivered by 3D scaffolds to induce complete regeneration in critical-size cranial defects. We will first study the effects of stem cell source (bone marrow versus dental pulp), seeding density and pre-culture condition combinations on bone regeneration from stem cells seeded on scaffold and stimulated by TPO. The best combinations will then be used to investigate the dose-response of TPO in vivo. Finally, the best dose from the dose-response study will be used to study the time-response of TPO and compare that to BMP-2 in vivo. The success of this project will provide preliminary data to secure funding to allow a more comprehensive evaluation on the potentials of using TPO in this challenging task of large cranial defect regeneration.
1. AM Emmakah1, 4, HE Arman2, JC Bragg3, T Greene3, MB Alvarez2, PJ Childress2, WS Goebel4,MA Kacena2, CC Lin1, 3, and TM Chu. A Fast-Degrading Thiol-Acrylate based Hydrogel for Cranial Regeneration, Journal of Biomaterials., at press: 2017. Abstract
1. Emmakah, A.; Alvarez, M.; Childress, P.; Goebel, S.; Kacena, M.; Lin, C.;Chu, T.G., “A Fast-degrading Thiol-acrylate Hydrogel as a Cell Carrier for Craniofacial Bone Regeneration”, Society for Biomaterials, Minneapolis, MN, April 5-8, 2017
2. Emmakah, A.; Greene, T.; Bragg, J.; Lin, C.; Alvarez, M.; Childress, P.; Goebel, S.; Kacena, M.; Chu, T.G., “Cranial regeneration using Stem cells encapsulated in fast-degrading thiol-acrylate hydrogel”, Annual Meeting of the International Association for Dental Research, San Francisco, CA, March 22-25, 2017
3. Emmakah, A.; Alvarez, M.; Childress, P.; Goebel, S.; Kacena, M.; Lin, C.;Chu, T.G., “A fast-degrading thiol-acrylate hydrogel shows promise as a cell carrier for stem-cell assisted cranial regeneration”, Annual Meeting of the Orthopedic Research Society, San Diego CA, March 19-22, 2017
4. Ballenger, B.; Emmakah, A.; Lin, C.; Chu, T.G., “Degradation and Cell Proliferation in a Fast-Degrading Thiol-Acrylate based Hydrogel for Cranial Regeneration”, Annual Meeting of the American Association for Dental Research, Los Angeles, CA, March 16-19, 2016
5. Emmakah, A.; Cheng, Y.; Alvare, B.; Kacena, M.; Chu, T.G., “Proliferation and Differentiation of Stem Cells Co-Cultured with Megakaryocytes”, Annual Meeting of the American Association for Dental Research, Los Angeles, CA, March 16-19, 2016
6. Emmakah, A.; Greene, T.; Bragg, J.; Lin, C.; Chu, T.G., “A Fast-Degrading Thiol-Acrylate based Hydrogel for Cranial Regeneration”, Annual Meeting of the International Association for Dental Research, Seoul Republic of Korea, June 22-25, 2016
7. Emmakah, A.; Cheng, Y.; Alvare, M.; Kacena, M.; Chu, T.G., “Megakaryocytes Enhances Proliferation but Delayed Differentiation in Stem Cells” Annual Meeting of the World Biomaterials Congress, Montreal, QC Canada, May 17-22, 2016
8. Emmakah, A.; Lin, C.; Chu, T.G., “Degradation and Cell Proliferation in a Fast-Degrading Thio-Acrylate based Hydrogel for Cranial Regeneration” Annual Meeting of the World Biomaterials Congress, Montreal, QC Canada, May 17-22, 2016
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