Document Type

Dissertation

Date of Degree

Spring 2015

Degree Name

PhD (Doctor of Philosophy)

Degree In

Biomedical Engineering

First Advisor

James A. Martin

Abstract

Articular cartilage is a complex soft tissue covering the end of moving bones in joints which provide pressure load distribution over the joint surface and smooth lubrication with little friction for establishing movement. Articular cartilage has an intrinsically limited capacity for self-repair when injured due to the lack of nerve and blood supply. Considered that injured cartilage is left untreated, it is likely to undergo progressive cartilage degeneration without pain which may lead to posttraumatic osteoarthritis. Therefore functional and physiologic restoration of injured cartilage back to a normal condition has long been in demand, yet current available repairing methods in clinics have met with limited success. Mechanically applied loads to articular cartilage is necessary for chondrocytes, cartilage cells, since they are responsible for cartilage matrix turnover by synthesizing extracellular matrix (ECM) molecules in response to bio- chemical and mechanical changes in ECM.

Ultrasound has emerged as an anabolic stimulator over the past few decades and a number of studies have proven that ultrasound therapy is beneficial for cartilage repair by synthesizing cartilage ECM components such as type II collagen and proteoglycan. Ultrasound therapy has also proven its potential for the attenuation of progressive cartilage degradation and induction of chondrogenic differentiation of mesenchymal stem cells. The use of ultrasound as an anabolic stimulator would be valuable with respect to cartilage repair since ultrasound as a form of mechanical energy can be non-invasively transferred into a human body. However, understanding the underlying mechanisms has been slow and the mechanisms have been roughly classified into thermal and non-thermal effects. Biologically detailed underlying mechanisms have not been sufficiently studied. That might be the reason why the application of ultrasound as a therapeutic tool has been limitedly available in clinics. In this study, mechanism involved biophysical effects of low intensity ultrasound has been studied for cartilage regeneration. First of all, the effect of ultrasound therapy as a mechanical stimulator on chondrogenic progenitor cell homing toward injured sites in cartilage was investigated with underlying biologic mechanisms. And the feasibility of ultrasound therapy for reactive oxygen species production mediated cartilage energy modulation was evaluated.

There have been extensive preclinical studies about the effects of microbubble mediated ultrasound therapy on the targeted drugs or gene delivery into tissues of interest. Mechanical shock waves are released during ultrasound mediated microbubble destruction and the waves facilitate drug delivery into target tissues through transient blood vessel disruption. However, the clinical use of this technique has been limited through vascular system. In this study, the effects of microbubble mediated low intensity ultrasound therapy on directly delivered mechanical shock waves and controlled drug release were investigated.

In conclusion, low intensity ultrasound therapy accelerates the homing of chondrogeic progenitor cells toward injured sites in cartilage via triggering mechanotransductive cell signaling pathways. This may result in speed up the return to normal cellularity and cartilage integrity by accelerating cartilage matrix repair. Low intensity ultrasound therapy was investigated as an energy modulator for chondrocytes via reactive oxygen species production in articular cartilage; however, little effects of ultrasound therapy driven cartilage energy modulation were found. The strong relationship between microbubbles mediated low intensity ultrasound therapy and the controlled release of drugs and mechanical shock waves was found. This strongly suggests that low intensity ultrasound therapy can play a role as a non-invasive controller for the release of drugs and lethal shock waves upon request.

Public Abstract

Ultrasound is a form of mechanical waves that can be non-invasively transferred into the human body. Ultrasound has extended its application from medical ultrasonography into a variety of fields. In this study, ultrasound was evaluated as a multi-functional therapeutic tool for the orthopaedic rehabilitation. First the low intensity ultrasound therapy was investigated as an anabolic stimulator for cartilage regeneration and as a delivery controller for targeted drugs and mechanical shock waves.

Over the past few decades, ultrasound has been emerged as an anabolic stimulator for the cartilage regeneration; however, understanding of the underlying mechanisms has been slow. In this study, mechanism involved beneficial effects of ultrasound therapy on cartilage regeneration was investigated. We found that low intensity ultrasound stimulates the homing of chondrogenic progenitor cells toward injured sites in cartilage by triggering mechanotransductive cell signaling pathways that may result in faster cartilage regeneration.

Microbubble mediated ultrasound therapy has been frequently studied as a way to enhance the delivery efficiency of intravascular administered drugs or genes to targeted tissues. In this study, the effects of microbubble mediated low intensity ultrasound therapy on the intratumorally delivered lethal shock waves for tumor treatments and the controlled drug release were investigated. We found that ultrasound power dependent release of mechanical shock waves has significant effects on the suppression of tumor growth and controlled drug release.

Keywords

publicabstract, Articular cartilage repair, Microbubbles, Osteoarthritis, Ultrasound therapy

Pages

xv, 140

Bibliography

128-140

Copyright

Copyright 2015 kee woong Jang

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