Complete Modeling of the Chondrogenic Environment under Continuous Low-Intensity Ultrasound

Articular cartilage is an avascular tissue that requires therapeutic intervention methods. This work answers the following: determine transducer operation to optimize the bioeffects; calculate the magnitude of pressure exerted on chondrocytes at an injury site; and confirm the theoretical findings by an animal model. Earlier work has shown that cellular response to US is maximized at the resonance frequency of the cells. Resonance frequencies were calculated for chondrocytes in various layers. The latter configuration closest resembles in vivo conditions and the resonance occurred at 3.8±0.3 . The 3D model of US propagation in a rabbit knee was constructed from MRIs to produce anatomically correct domains. US attenuates in cartilage and 3D results showed that pressure is maximized at an injury site when the transducer is placed in line with the site. Transducer positions that causes US waves to traverse cartilage before reaching the injury site must be avoided. The 3D model is time-consuming, and impractical for routine clinical usage. The average pressure delivered is lower in pulsed low-intensity US compared to cLIUS. A 1D model, which captured all the key results of the 3D model, was used to calculate the temperature rise due to US dissipation – the cLIUS protocol produces negligible increases in temperature. US attenuation can be overcome if the injury site lies in the near-field of the transducer, where constructive interference tends to not only cancel attenuation but delivers pressures higher than the transducer value – confirmed by both 3D and 1D models. Rabbit studies confirmed that cLIUS treatment significantly improved healing of damaged cartilages, and defect sites filled, in contrast to fibrous filling in untreated defects. Finally, a model that involves three intracellular pathways was used to investigate mechanochemical response of a mesenchymal stem cell (MSC). Results showed that MSCs could be prompted towards the condensation step by mechanical stimulation at the resonance frequencies without any exogeneous chemical prompting, and the key proteins formed much earlier than in in vitro experiments. Adviser: Hendrik J. Viljoe