The ultimate goal of this research project is to develop novel biologically based, dental and craniofacial skeletal repair and regeneration therapies in humans. We hypothesize that improved knowledge of dental stem cell (DSC) properties, and characteristics, combined with improved knowledge of tissue engineering strategies to reliably generate mineralized dental and craniofacial tissues of predictable size and shape, will result in the development of novel and effective, clinically relevant therapies for humans. To address this hypothesis, four specific aims are proposed, all of which will exclusively use human DSCs harvested from extracted human teeth. First, we will characterize the properties of individually harvested human dental tissues, to establish the normal range of DSC properties, to correlate DSC properties with the age and overall health of the donor, and to correlate these properties with the ability to successfully use harvested dental stem cells for dental tissue regeneration therapies. Next, we will test four different scaffold materials, carefully chosen for their defined physical properties, for their ability to generate bioengineered human tooth crowns of predictable size and shape. Third, we will expand upon our results demonstrating that silk scaffolds can be used to generate osteodentin of predicted size and shape, to bioengineer full sized, functional human tooth root equivalents that can support a synthetic or bioengineered tooth crown. Silk scaffold fabrication methods, porosity, degradation rates, and added growth factor peptides, will be systematically evaluated. As recommended in prior review, Aims 2 and 3 will be performed in both subcutaneous and minipig mandibular implant models. Finally, in Aim 4, we will combine our tooth crown, root, and craniofacial skeletal regenerative strategies, again using the Yucatan mini pig mandibular implant model, to generate successive 1st, 2nd and 3rd generation replacement teeth. For each of the proposed aims, detailed developmental analyses of bioengineered dental implant tissues will be performed in order to better understand, and devise strategies to improve dental tissue regeneration. Our novel approach to tooth repair and regeneration, using human DSCs, and state of the art scaffold fabrication methods, combined with our extensive expertise in Developmental Biology and Tissue Engineering, have the potential to provide new and improved, biologically based repair and regeneration strategies, using autologous tissues. The successful accomplishment of the proposed studies would dramatically alter the field of dentistry as it currently exists, extending clinically relevant dental repair therapies to include biologically based dental materials with properties closely matching those of naturally formed dental tissues.

Public Health Relevance

Due to the severely limited ability for craniofacial and dental tissues to repair themselves, these defects remain a significant clinical problem that affects millions of people worldwide, including both children and adults. Tooth decay, periodontal disease, craniofacial birth defects, trauma, and cancer, all contribute to compromised oral health, and correspondingly to reduced overall health and quality of life. At the present time, synthetic material based repair methods, or autologous grafts which often result in donor site morbidity, are exclusively being used to repair human craniofacial skeletal and tooth defects. The studies proposed here will expand on our prior published studies, to devise methods to repair and regenerate craniofacial skeletal and tooth defects using biologically based tissue engineering approaches, and human dental stem cells. We anticipate that the successful development of alternative biologically based tissue repair methods will provide significantly improved therapies for individuals requiring repair/regeneration of craniofacial skeletal and tooth defects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE016132-08
Application #
8268319
Study Section
Special Emphasis Panel (ZRG1-MOSS-F (02))
Program Officer
Lumelsky, Nadya L
Project Start
2004-07-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$715,492
Indirect Cost
$281,860
Name
Tufts University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
Duailibi, Monica Talarico; Kulikowski, Leslie Domenici; Duailibi, Silvio Eduardo et al. (2012) Cytogenetic instability of dental pulp stem cell lines. J Mol Histol 43:89-94
Traphagen, Samantha B; Fourligas, Nikos; Xylas, Joanna F et al. (2012) Characterization of natural, decellularized and reseeded porcine tooth bud matrices. Biomaterials 33:5287-96
Duailibi, Monica Talarico; Duailibi, Silvio Eduardo; Duailibi Neto, Eduardo Felippe et al. (2011) Tooth tissue engineering: optimal dental stem cell harvest based on tooth development. Artif Organs 35:E129-35
Zhang, Weibo; Ahluwalia, Ivy Pruitt; Literman, Robert et al. (2011) Human dental pulp progenitor cell behavior on aqueous and hexafluoroisopropanol based silk scaffolds. J Biomed Mater Res A 97:414-22
Lin, Y; Gallucci, G O; Buser, D et al. (2011) Bioengineered periodontal tissue formed on titanium dental implants. J Dent Res 90:251-6
Zhang, Weibo; Ahluwalia, Ivy P; Yelick, Pamela C (2010) Three dimensional dental epithelial-mesenchymal constructs of predetermined size and shape for tooth regeneration. Biomaterials 31:7995-8003
Abukawa, Harutsugi; Zhang, Weibo; Young, Conan S et al. (2009) Reconstructing mandibular defects using autologous tissue-engineered tooth and bone constructs. J Oral Maxillofac Surg 67:335-47
Traphagen, Samantha; Yelick, Pamela C (2009) Reclaiming a natural beauty: whole-organ engineering with natural extracellular materials. Regen Med 4:747-58
Xu, Wan-Peng; Zhang, Weibo; Asrican, Rose et al. (2008) Accurately shaped tooth bud cell-derived mineralized tissue formation on silk scaffolds. Tissue Eng Part A 14:549-57
Duailibi, S E; Duailibi, M T; Zhang, W et al. (2008) Bioengineered dental tissues grown in the rat jaw. J Dent Res 87:745-50

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