The Development of an In-Vitro System for the Study of Osteoarthritis in a Mouse Model
Nehme, Christopher.
2017
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Abstract: Osteoarthritis (OA) is a painful and debilitating disease of the human joints. Sufferers of OA face a lifelong struggle with the chronic disease. Current treatment options are directed at pain and inflammation management, occasionally culminating in total joint replacements for qualifying patients. To date, no comprehensive treatments have been developed, partially attributed to limitati... read moreons in current OA research models. With the incidence of OA constantly on the rise, in part due to our aging population and increasing life spans, the necessity of comprehensive treatment options is becoming inevitable. A novel model for studying OA in a mouse model was developed. A first generation system capable of actuating and culturing amputated murine stifle joints was designed, fabricated and tested. The system comprises of: a mechanical device that maintains a stifle joint in a culture medium reservoir and actuates the joint through a controlled flexion-extension profile; and a microcontroller board used to run an open-loop controller supporting the device's function. The system was used to investigate the effects of actuation and culture medium glucose concentration on the articular cartilage of stifle joints harvested from eight-week-old NFκB/Balb C mice. Results suggest that a high concentration of glucose (9.0 mg/ml) in Dulbecco's Modified Eagle's Medium (DMEM) used to culture dynamically actuated joints promotes a higher degree of joint damage as measured by quantification of Safranin-O staining loss, as opposed to moderate (4.5 mg/ml) and low (1.0 mg/ml) glucose concentrations. A second-generation system was then developed, addressing limitations identified in the first-generation system related to repeatability, reliability and usability. The design process focused on developing a pair of robust coupled four bar linkage systems with the ability to repeatedly actuate the joint through a well-defined and repeatable flexion extension cycle. A novel joint clamping and mounting system was also developed to minimize user uncertainty associated with experimental set ups. The device's function is supported by a closed-loop speed control system combining proportional-integral (PI) action with an iterative feed forward controller. The superior controllability of this system allowed investigation into the effects of actuation cycle rate and relative activity-rest durations on joint health. Results demonstrate that the system is capable of causing a range of damage as measured by Safranin-O staining loss on joint samples by varying activity cycle durations. Finally, substantial work was directed towards extending the functionality of the second-generation system to implement active loading control, effectively allowing the device to control the loads at a mounted stifle joint as function of the cycle position. A second PI control system was developed to control load by sensing bending torque in a system link. Extensive experimental and analytical modeling was performed to develop a working control system. Several limitations of the controllability were determined due to the system geometry and assumptions made during the design process. Nevertheless, it was successfully demonstrated that with proper loading profile considerations, accurate control could be achieved, opening the door for a plethora of future research.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Mechanical Engineering.
Advisor: William Messner.
Committee: Li Zeng, Robert White, and Alan Grodzinsky.
Keywords: Mechanical engineering, Biomedical engineering, and Biology.read less - ID:
- 3r075589w
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