Focused Ultrasound-Induced Bioeffects in Elastic, Anisotropic Tissues
Restricted (Penn State Only)
- Author:
- Elliott, Jacob
- Graduate Program:
- Acoustics
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 13, 2024
- Committee Members:
- Andrew Barnard, Program Head/Chair
Meghan Vidt, Outside Unit & Field Member
Julianna Simon, Chair & Dissertation Advisor
Andrea Arguelles, Major Field Member
Yun Jing, Major Field Member - Keywords:
- Focused ultrasound
Histotripsy
Cavitation
Neurostimulation
Passive cavitation imaging
Doppler ultrasound
Elastic tissue
Anisotropic tissue
Tendon
Muscle
Mechanical testing
Numerical modeling
Hydrogels
Therapeutic ultrasound - Abstract:
- Focused ultrasound (fUS) is a non-invasive therapy capable of treating small tissue volumes deep within the body without disrupting intervening tissues. The interaction of the ultrasound field with treated tissue results in therapeutic mechanical and thermal bioeffects. fUS has had pre-clinical and clinical success mechanically fractionating tissue through the creation, oscillation, and collapse of bubble clouds in a modality termed histotripsy. However, histotripsy is currently limited to soft tissues, as elastic, anisotropic tissues such as tendon are resistant to mechanical fractionation despite the presence of fUS-induced bubbles. Additionally, the effects of fUS-induced nerve stimulation on mechanical properties of anisotropic muscle tissue are currently unknown. This work provides insight into the acoustic fundamentals of fUS-induced mechanical bioeffects in elastic, anisotropic tissues. To better understand bubble activity in elastic tissues, collagen hydrogels and novel varieties of fibrin gels, including dehydrated fibrin, were fabricated to better mimic elastic tissues than commonly used soft tissue phantoms. These gels underwent 1.5-MHz fUS exposure to be monitored with simultaneous high-speed photography and passive cavitation imaging (PCI). Unlike soft tissue-mimicking phantoms, dehydrated fibrin was found to exhibit similar bubble dynamics to ex vivo bovine tendon, with peak cavitation emissions within 7.5% of one another. Dehydrated fibrin gels were further characterized using scanning electron microscopy (SEM), confirming the presence of organized fibrous structures. In addition to fibrin gel parameters, ex vivo cervine tendons of varying elasticities were input into a modified Rayleigh-Plesset model to assess radial bubble dynamics in the presence of parallel, viscoelastic layers. The fibrin gel model confirmed a 17% increase in radial bubble expansion when increasing fiber spacing by an order of magnitude from those measured with SEM. Additionally, the cervine tendon model showed that fiber spacing, rather than elastic modulus, dominated radial bubble expansion. In addition to PCI, a cavitation monitoring technique employing 5.2-MHz Doppler ultrasound was evaluated in collagen hydrogels and ex vivo bovine tendon. Here, a Doppler ultrasound pulse was delivered to the sample following each fUS pulse in order to assess bubble-induced motion in the treated gel or tissue region. Using this method, termed bubble-induced color Doppler (BCD), Doppler power associated with bubble-induced motion was found to correlate more strongly with mechanical fractionation of gel and tendon samples than PCI amplitude. Bubble-induced Doppler power evaluated at 6.7 milliseconds following the fUS pulse was therefore shown to be a strong predictor of mechanical fractionation over the course of fUS treatment. Finally, a stimulation-based therapy was explored in an in vivo murine model to evaluate effects of fUS-induced peripheral nerve stimulation on muscle mechanical properties. Trends in mechanical properties of stimulated muscle emerged when compared to contralateral control samples. Namely, elastic modulus and percent relaxation were found to increase in stimulated muscle samples, whereas stiffness decreased. Additionally, this fUS therapy produced no observable damage in treated tissue. These studies provide a further understanding of fUS cavitation- and stimulation-based mechanical bioeffects in elastic tissues, making progress in developing fUS as a versatile therapy for all tissues.