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 ... read morelimitations 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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