This proposal uses the BIRT mechanism to initiate a collaboration between the PI of the parent R01, a biologist who studies bone healing, and the Co-PI, a physicist with expertise in medical imaging and computational image analysis. It addresses a major clinical problem: our inability to determine with precision when bone has healed. This has important implications both for the clinical management of trauma patients and for the implementation of randomized, controlled studies to evaluate new bone-healing methods. For the parent R01, the PI utilizes a rat, femoral, segmental defect model. This is well characterized and has generated a wealth of historical data, including radiographs, microCT and mechanical testing, concerning defects that healed, did not heal or partially healed.
In Specific Aim one, the Co-PI will use the historical microCT data and a software simulation technique to generate virtual radiographic images of the bone from different orientations. Using bone samples with known outcomes, the image acquisition geometry and software algorithms will be optimized to provide the maximum accuracy for detecting fractures, producing a metric that provides an accurate measure of bone healing probability. This will produce an algorithm that allows healing to be assessed on the basis of just two plain radiographs taken at different angles. Receiver operating characteristic (ROC) analysis will be used to quantify performance.
In Specific Aim 2, this metric will be tested empirically using data obtained from fresh rats whose defects are given different doses of BMP-2 that result in different degrees of healing, ranging from no healing to full healing. The performance of the metric will be evaluated by comparison with "bridging" healing, as measured independently by microCT, and "mechanical" healing, as measured by mechanical testing. If this project is successful, it will provide the trauma surgeon with a reliable, quantitative, objective, and inexpensive method for assessing bone healing. Although the algorithms involve sophisticated mathematical analyses, they run automatically and can be incorporated into digital radiography system equipment found commonly in most radiology departments. Because the technology uses existing hardware, clinical translation should be straightforward.

Public Health Relevance

Surgeons are often unable to tell when a broken bone has healed. This can compromise clinical care and slow the development of better ways to heal bone. The proposed research will provide a new, reliable and inexpensive way to determine when bones have healed. Due to its accurate, inexpensive and easy to use mechanism, it should become widely available for clinical care efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
3R01AR050243-09S1
Application #
8581959
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Wang, Fei
Project Start
2003-08-01
Project End
2014-06-30
Budget Start
2013-09-23
Budget End
2014-06-30
Support Year
9
Fiscal Year
2013
Total Cost
$167,436
Indirect Cost
$50,225
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Evans, Christopher H (2015) Native, living tissues as cell seeded scaffolds. Ann Biomed Eng 43:787-95
Evans, Christopher H; Huard, Johnny (2015) Gene therapy approaches to regenerating the musculoskeletal system. Nat Rev Rheumatol 11:234-42
Liu, F; Ferreira, E; Porter, R M et al. (2015) Rapid and reliable healing of critical size bone defects with genetically modified sheep muscle. Eur Cell Mater 30:118-30; discussion 130-1
Evans, Christopher (2014) Using genes to facilitate the endogenous repair and regeneration of orthopaedic tissues. Int Orthop 38:1761-9
Ferreira, Elisabeth; Porter, Ryan M; Wehling, Nathalie et al. (2013) Inflammatory cytokines induce a unique mineralizing phenotype in mesenchymal stem cells derived from human bone marrow. J Biol Chem 288:29494-505
Evans, Christopher H (2013) Advances in regenerative orthopedics. Mayo Clin Proc 88:1323-39
Evans, C H; Ghivizzani, S C; Robbins, P D (2012) Orthopedic gene therapy--lost in translation? J Cell Physiol 227:416-20
Evans, C H (2012) Gene delivery to bone. Adv Drug Deliv Rev 64:1331-40
Liu, Fangjun; Porter, Ryan M; Wells, James et al. (2012) Evaluation of BMP-2 gene-activated muscle grafts for cranial defect repair. J Orthop Res 30:1095-102
Evans, Christopher H; Liu, Fangjun; Porter, Ryan M et al. (2012) EWS-FLI-1-targeted cytotoxic T-cell killing of multiple tumor types belonging to the Ewing sarcoma family of tumors. Clin Cancer Res 18:5341-51

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