Title

The conceptual development of a predictive model system to test pediatric musculo-skeletal sarcoma therapies in growing bone

Date of Award

2007

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical and Chemical Engineering

Advisor(s)

Timothy A. Damron

Keywords

Pediatric, Bone, Musculoskeletal sarcoma

Subject Categories

Biomedical Engineering and Bioengineering | Engineering

Abstract

The long term objective of this work is to generate a predicative mathematical model that will allow radiation therapy and different combinations of chemotherapy to be tested against pediatric bone sarcomas. An important component of this goal is to develop treatment strategies that preserve near normal bone growth following irradiation or attempt to recoup growth function from the surviving population of bone cells. For these treatment strategies to be clinically viable they must selectively protect or promote growth in non-tumor cells while not conferring any treatmentassociated benefit on the tumor. The following questions were addressed: First, what is the temporal progression of irradiation injury in the growth plate and what is the spatial-temporal progression of post-irradiation survival and regeneration? Second, what are the differential effects of irradiation on non-tumor bone cells and pediatric tumor cells? Finally, will chemotherapeutic agents that either protect growing bone from the negative effects of irradiation or recoup growth function following irradiation selectively benefit non-tumor cells while providing no treatment-associated benefit for the tumor? Using a both rat and mouse animal models in parallel with an in vitro culture model the temporal progression of the negative radiation effects on bone and the relevant postradiation survival associated pathways have been observed. Further, radio-protective and radio-recovery therapies were shown to provide selective protection to non-tumor cells while providing no apparent treatment-associated benefit to the tumor. Finally, a preliminary model of irradiation-induced growth plate injury was developed as a proof that a predictive model system to test pediatric musculo-skeletal sarcoma therapies in growing bone could be generated in future work.

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