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Local Sustained Delivery of Osteoprotegerin via Hydroxyapatite Microparticles to Enhance Post-Orthodontic Tooth Stability

Award Number: F30DE031158
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Local Sustained Delivery of Osteoprotegerin via Hydroxyapatite Microparticles to Enhance Post-Orthodontic Tooth Stability - PROJECT SUMMARY/ABSTRACT Post-treatment relapse is one of the most unpredictable limitations of orthodontic therapy. Relapse results in patient's teeth reverting towards their pretreatment positions, which increases the susceptibility to functional problems, dental disease, and substantially increases the financial burden for retreatment. Currently, patient compliance-based retention is the primary method for maintaining post-orthodontic tooth stability, which due to its variable use results in a significant proportion of patients experiencing relapse. Therefore, the objective of this application is to address the clinical need for a translational and clinically relevant approach to increase post-orthodontic tooth stability using approaches that minimize the need for patient compliance. Orthodontic relapse is strongly associated with increased bone-resorbing osteoclast activity and immature bone quality surrounding the teeth. As such, a promising approach to this adverse outcome is to produce a response of net bone accretion by synergistically inducing osteogenesis and inhibiting osteoclastic activity. However, a strategy to produce such synergistic responses in bone has never been explored for this purpose. Our group has found that multiple and single submucosal injections of anti-osteoclastic recombinant OPG protein (OPG-Fc) reduced relapse by 60-70% in a rat model of orthodontic relapse. These biological methods have not been adopted for clinical use presumably due to the lack of effective drug delivery systems that mitigate the need for large bolus doses over long durations that may produce systemic effects. This application aims to develop a clinically relevant osteoconductive hydroxyapatite (HAP)-based drug delivery system for local and sustained release of OPG to mitigate post-orthodontic relapse that will also enhance our understanding of bone regeneration/maturation following mechanically mediated bone turnover through modulation of these responses by HAP and OPG. This project will test the central hypothesis that sustained release of recombinant OPG from hollow hydroxyapatite (HHAP) microparticles will inhibit orthodontic relapse by decreasing osteolysis and promoting bone anabolism. Aim 1 will build on our preliminary data to engineer HHAP microparticles for sustained release of OPG at desired concentrations and validate this system in vitro with OPG and osteoclast activity assays. Aim 2 will validate the use of OPG administered for local and sustained release via HHAP drug delivery microparticles to mitigate relapse in our animal model of orthodontic relapse with minimal systemic effects. Furthermore, this study will characterize potential molecular pathways by which the periodontal tissues and cellular responses result in enhancing bone regeneration and maturation. The successful completion of this project will lead to a translatable method to improve post-orthodontic tooth stability outcomes and provide significant insight into enhancing bone regeneration/maturation following mechanically mediated bone turnover.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $55,338 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	5	7/11/2025	NON-COMPETING CONTINUATION	$55,338
														Subtotal = $55,338

Issue Date FY: 2024 ( Subtotal = $54,774 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	4	5/21/2024	NON-COMPETING CONTINUATION	$54,774
														Subtotal = $54,774

Issue Date FY: 2023 ( Subtotal = $53,494 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	3	5/18/2023	NON-COMPETING CONTINUATION	$53,494
														Subtotal = $53,494

Issue Date FY: 2022 ( Subtotal = $45,328 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	2	5/24/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	2	5/5/2022	NON-COMPETING CONTINUATION	$45,329
														Subtotal = $45,328

Issue Date FY: 2021 ( Subtotal = $43,360 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	000	1	6/1/2021	NEW	$43,360
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Oral Diseases and Disorders Research	001	1	6/1/2021	NEW	$0
														Subtotal = $43,360

Grand Total All Awards = $252,294

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Local Sustained Delivery of Osteoprotegerin via Hydroxyapatite Microparticles to Enhance Post-Orthodontic Tooth Stability

Award Number: F30DE031158

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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