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.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Wang, Fei
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
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 (2011) Gene therapy for the regeneration of bone. Injury 42:599-604
Evans, Christopher H (2011) Barriers to the clinical translation of orthopedic tissue engineering. Tissue Eng Part B Rev 17:437-41
Nazarian, Ara; Pezzella, Lina; Tseng, Alan et al. (2010) Application of structural rigidity analysis to assess fidelity of healed fractures in rat femurs with critical defects. Calcif Tissue Int 86:397-403
Evans, Christopher H (2010) Gene therapy for bone healing. Expert Rev Mol Med 12:e18
Evans, C H; Liu, F-J; Glatt, V et al. (2009) Use of genetically modified muscle and fat grafts to repair defects in bone and cartilage. Eur Cell Mater 18:96-111
Kwong, Francois N K; Hoyland, Judith A; Freemont, Anthony J et al. (2009) Altered relative expression of BMPs and BMP inhibitors in cartilaginous areas of human fractures progressing towards nonunion. J Orthop Res 27:752-7
Kwong, Francois N K; Hoyland, Judith A; Evans, Christopher H et al. (2009) Regional and cellular localisation of BMPs and their inhibitors'expression in human fractures. Int Orthop 33:281-8
Evans, Christopher H; Ghivizzani, Steven C; Robbins, Paul D (2009) Orthopedic gene therapy in 2008. Mol Ther 17:231-44

Showing the most recent 10 out of 17 publications