Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Bioengineering

First Advisor

Louis J. Soslowsky

Abstract

Tendons are hypovascular tissues, undergoing angiogenesis only during development, wound healing, and pathogenesis. Injured tendons exhibit a healing response with vascular ingrowth during the proliferative phase and vascular regression during remodeling. Despite this normal healing response, tendons never fully regain their original structure or composition. Additionally, aging further increases tendon risk of rupture and impairs healing response. Since the optimal vascularization level and timing during tendon healing is currently unknown, modulating the vascular response during healing could elucidate the role of angiogenesis in tendon injury and ultimately improve the tendon healing outcome. Furthermore, new ultrasound technologies allow for the evaluation of vascular response after injury, which could provide a measure for evaluating tendon healing in vivo. Therefore, the objective of this study is to develop methods for, and evaluate the effect of, vascular modulation in adult and aged rat Achilles tendons during healing using both in vivo ultrasound imaging measures of vascularity and structure and ex vivo measures of tendon compositional and mechanical properties. In Specific Aim 1, we will validate the use of in vivo high-frequency ultrasound technologies to measure vascular changes in rat Achilles tendons. In Specific Aim 2, we will develop methodologies for vascular modulation in an Achilles tendon injury model using the delivery of pro- and anti-angiogenic factors. Finally, in Specific Aim 3, we will apply methods of vascular modulation and ultrasound imaging to determine the role of angiogenesis in adult and aged Achilles tendon healing models. To achieve these goals, we will perform bilateral partial-rupture injuries in the Achilles tendons of adult and aged rats, followed by injections to modulate their vascular response after injury. The animals will receive vascular endothelial growth factor (VEGF), anti-VEGF antibody (B20.4-1-1, Genentech), or saline injections following injury. They will be evaluated using B-mode, color Doppler, photoacoustic, and contrast-enhanced ultrasound imaging weekly post-injury. Additionally, they will undergo in vivo functional assays to assess gait and passive ankle motion. Animals will be sacrificed for histological and mechanical analyses. This study will validate new in vivo methods for evaluating vascularity in tendon injury models, develop potential angiogenic therapies for improved healing outcome, and elucidate the differences in vascular response with age after tendon injury and vascular modulation.

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