Dissertation/Thesis Abstract

Using Development and Natural Healing as a Paradigm to Improve Tendon Repair
by Dyment, Nathaniel, Ph.D., University of Cincinnati, 2011, 167; 3490866
Abstract (Summary)

Tendon and ligament injuries present a significant socioeconomic problem. Tissue engineering has become an attractive option for improving repair of these injuries. Our lab has previously shown success utilizing stem-cell based therapies but we have yet to produce repairs that functionally match normal tendon mechanical properties for more strenuous activities of daily living. This dissertation focuses on using the differences between normal embryonic development and natural adult healing as a strategy to improve repair outcome of tendon injuries.

We first analyzed the biology and mechanics of natural healing in the mouse patellar tendon and how these processes compared to normal tendon development. Understanding the differences between these processes may provide therapeutic targets to modulate during the healing process. We found that natural healing of a central patellar tendon defect followed a traditional healing response with inflammation at 1 week, repair at 2 weeks, and remodeling at 3 weeks and greater. The healing tissue yielded a non-functional repair with stiffnesses and ultimate loads that plateaued at 60% of normal PT after 5 weeks of healing.

We found in the second study that the healing tendons exhibited reduced expression of known tenogenic transcription factors and fibrillogenic genes during healing. Type-I and type-III collagen gene expression was elevated during healing of both the injury and sham tendons; however, the reduced expression of tenogenic and fibrillogenic markers suggests that the matrix was not properly assembled, leading to a non-functional scar.

In order to promote tendon differentiation during repair, we then stimulated mesenchymal progenitor cell collagen constructs with myogenic (myoblasts) and tenogenic (tendon fibroblasts) signals in culture. We found that myoblast- and Achilles tendon fibroblast-conditioned media did not promote differentiation of the constructs as gene expression of tenogenic markers was unchanged.

While the central patellar tendon defect is a reproducible model, it is not clinically relevant as it does not display degeneration, which is seen in over 90% of clinical injuries. Therefore, the next study compared the effect of prostaglandin-E2 and collagenase delivery on creating degenerative aspects in the rabbit patellar tendon. We found that collagenase yielded reduced mechanical properties and histological aspects of degeneration at 4 weeks but did not sustain these changes at 16 weeks.

The final study of this dissertation applied the methodologies used in our previous tendon healing studies to understand fracture healing in the mouse as our lab transitions into developing tissue engineered strategies for improving bone repair. We compared sub-critical vs. critical femoral defects and found that the sub-critical defects healed with successful periosteal bridging while the critical defects yielded impaired healing with capping of the ends of the bone.

Future studies need to determine the lineage of the cells that contribute to healing and if these cells can be modulated to improve repair. Mechanistic studies that alter expression of these tenogenic markers are needed to further understand the molecular signaling that drives healing. Further understanding of the healing process will provide tissue engineers with potential treatment modalities to ultimately improve repair outcome and the patient's quality of life.

Indexing (document details)
Advisor: Butler, David
Commitee: Galloway, Marc, Rao, Marepalli, Shearn, Jason
School: University of Cincinnati
Department: Biomedical Engineering
School Location: United States -- Ohio
Source: DAI-B 73/04, Dissertation Abstracts International
Subjects: Biomedical engineering
Keywords: Development, Healing processes, Regeneration, Tendon repair, Tissue engineering
Publication Number: 3490866
ISBN: 9781267120953
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