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Jaison Marks MSE Thesis FINAL CORRECTED1,016.86 kB
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Thesis
Sustained release of Amobarbital: a prospective therapy for the prevention of post-traumatic osteoarthritis
University of Iowa
Master of Science (MS), University of Iowa
Spring 2021
DOI: 10.25820/etd.007886
Abstract
Articular chondrocytes exposed to excessive mechanical stresses, arising from multiple joint injuries, accumulate defects in mitochondrial function that contribute to the progression of post-traumatic osteoarthritis (PTOA). At present, there are no disease-modifying treatments before terminal joint replacement, and current standard-of-care interventions fail to prevent PTOA in injured joints. Therefore, there is an immediate unmet need for strategies to prevent PTOA following joint trauma.
It has been previously shown that mitochondrial damage is caused by overproduction of oxidants and that a single dose of amobarbital, a barbiturate that reversibly inhibits mitochondrial electron transport, blocked oxidant overproduction and mitigated PTOA following an intra-articular fracture. Medial meniscus tears are the most common orthopedic injury concomitant with articular cartilage damage. This injury has been characterized as pathogenic due to chronically elevated mechanical stress which leads to prolonged oxidative stress. Such conditions are unlikely to be countered by a single amobarbital dose.
To address this problem, an implantable, PLGA-based dosage form providing sustained administration of amobarbital has been developed. The hypothesis is that this strategy can moderate oxidant overproduction over longer timeframes and subsequently block PTOA development following less severe joint trauma. To date, a formulation has been developed which elutes amobarbital at a targeted rate to achieve a localized, therapeutic concentration. Further optimization of the formulation will be conducted. This effort will focus on prolonging the duration of the amobarbital release. This project will culminate in an in vivo proof-of-concept study in a well characterized medial meniscus destabilization rabbit model.
Details
- Title: Subtitle
- Sustained release of Amobarbital: a prospective therapy for the prevention of post-traumatic osteoarthritis
- Creators
- Jaison Marks
- Contributors
- James Martin (Advisor)Aliasger Salem (Committee Member)Edward Sander (Committee Member)James Ankrum (Committee Member)Nicole Grosland (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Biomedical Engineering
- Date degree season
- Spring 2021
- DOI
- 10.25820/etd.007886
- Publisher
- University of Iowa
- Number of pages
- vii, 39 pages
- Copyright
- Copyright 2021 Jaison Marks
- Language
- English
- Date submitted
- 04/27/2021
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 36-39).
- Public Abstract (ETD)
- Post-traumatic osteoarthritis (PTOA), a progressively degenerative orthopedic disease that occurs after joint injury and results in quality-of-life issues comparable to those of congestive heart failure or kidney disease. PTOA affects more than six million Americans and is associated with healthcare costs greater than $12 billion annually. There are no existing disease- modifying treatments other than terminal joint replacement, and current standard of care interventions fail to prevent PTOA in injured joints. Therefore, there is an immediate unmet need for strategies to prevent PTOA following joint trauma. In this research project I have looked to expand on current knowledge to develop a strategy to prevent PTOA following a soft-tissue joint injury, such as ligament rupture or meniscal tear. Specifically, I have developed such a strategy and obtained evidence that this approach would allow for targeted administration of a disease-modifying drug product. Therefore, this prospective technology could have the direct benefit of preventing PTOA and improving patient outcomes. Future directions will include further optimization of the technology and a proof-of-concept study in a small animal model.
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Craniofacial Anomalies Research Center
- Record Identifier
- 9984831231902771
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