Methods to Validate Tooth-Supporting Regenerative Therapies
In humans, microbially induced inflammatory periodontal diseases are the primary initiators that disrupt the functional and structural integrity of the periodontium (i.e., the alveolar bone, the periodontal ligament, and the cementum). The reestablishment of its original structure, properties, and function constitutes a significant challenge in the development of new therapies to regenerate tooth-supporting defects. Preclinical models represent an important in vivo tool to critically evaluate and analyze the key aspects of novel regenerative therapies, including (1) safety, (2) effectiveness, (3) practicality, and (4) functional and structural stability over time. Therefore, these models provide foundational data that supports the clinical validation and the development of novel innovative regenerative periodontal technologies. Steps are provided on the use of the root fenestration animal model for the proper evaluation of periodontal outcome measures using the following parameters: descriptive histology, histomorphometry, immunostaining techniques, three-dimensional imaging, electron microscopy, gene expression analyses, and safety assessments. These methods will prepare investigators and assist them in identifying the key end points that can then be adapted to later stage human clinical trials.
Key wordsGuided tissue regeneration Regenerative medicine Bone regeneration Tissue engineering Animal models Periodontal diseases Periodontal engineering
The authors appreciate Sarah L. Volk for assisting with the preparation of the manuscript. We also acknowledge the technical contributions of Chan Ho Park, Scott Lim, and Jim Sugai. This work was supported by the NIH Grants K23DE019872 (HFR) and DE13397 (WVG). MPM was also supported by the Talentia Scholarship Program from the Regional Ministry for Innovation, Science and Enterprise, Junta de Andalusia (Spain). The authors report no conflicts of interest.
- 4.Rios, H. F., Lin, Z., Oh, B., Park, C. H., and Giannobile, W. V. (2011) Cell- and gene-based therapeutic strategies for periodontal regenerative medicine. J Periodontol 82, 1223–1237.Google Scholar
- 7.Kaigler, D., Fuller, K., and Giannobile, W. V. (2010) Regulatory process for the evaluation of dental drugs, devices and biologics (Chapter 4). In: Giannobile, W. V., Burt, B. A., and Genco, R. J., Eds. Clinical Research in Oral Health 1 ed., Wiley-Blackwell, Ames, pp 55–78.Google Scholar
- 12.Chang, P. C., Cirelli, J. A., Jin, Q., Seol, Y. J., Sugai, J. V., D’Silva, N. J., Danciu, T. E., Chandler, L. A., Sosnowski, B. A., and Giannobile, W. V. (2009) Adenovirus encoding human platelet-derived growth factor-B delivered to alveolar bone defects exhibits safety and biodistribution profiles favorable for clinical use. Hum Gene Ther 20, 486–496.PubMedCrossRefGoogle Scholar
- 14.Wood, M., Perrotte, P., Onishi, E., Harper, M. E., Dinney, C., Pagliaro, L., and Wilson, D. R. (1999) Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse. Cancer Gene Ther 6, 367–372.PubMedCrossRefGoogle Scholar
- 16.Howell, T. H., Fiorellini, J. P., Paquette, D. W., Offenbacher, S., Giannobile, W. V., and Lynch, S. E. (1997) A phase I/II clinical trial to evaluate a combination of recombinant human platelet-derived growth factor-BB and recombinant human insulin-like growth factor-I in patients with periodontal disease. J Periodontol 68, 1186–1193.PubMedCrossRefGoogle Scholar
- 30.Rios, H. F., and Giannobile, W. V. (2011) Preclinical protocols for periodontal regeneration (Chapter 7). In: Osteology Guidelines for oral and maxillofacial regeneration: Preclinical models for translational research. Giannobile, W. V. and Nevins, M. Eds. Berlin: Quintessence Publishing Co, Inc, pp 77–104. ISBN: 9781850972112.Google Scholar
- 33.Park, C. H., Abramson, Z. R., Taba Jr, M., Jin, Q., Chang, J., Kreider, J. M., Goldstein, S. A., and Giannobile, W. V. (2007) Threedimensional micro-computed tomographic imaging of alveolar bone in experimental bone loss or repair. J Periodontol 78, 273–281.Google Scholar