Computer Models Suggest Treatments for Fractures That Won't Heal

Researchers at the Katholieke Universiteit Leuven (Belgium), the University of Liège (Belgium), Edinburgh University (United Kingdom), and Oxford University (United Kingdom randomized 28 adult female Wistar rats into a nonunion and healing groups. A standardized circular frame external fixator was applied to the right tibia under general anaesthesia (GA) and with aseptic conditions. The fibula was then fractured manually using a three-point bending method, and a 1 mm gap was introduced at the site.

In 14 of the 28 animals, the periosteum was stripped and the intramedullary canal was curetted, both proximally and distally, for a distance equivalent to 1 tibial diameter, to induce atrophic nonunion. The rats were sacrificed at 1, 3, 8, and 16 weeks, and the right (operated) tibia was prepared for histological examination, and two independent senior orthopedic trainees assessed standardized radiographs obtained after operation and every two weeks thereafter, and categorized the fractures as healing or not.

At the same time, a mathematical model was developed to describe normal fracture healing, which expressed the change of a number of continuum-type variables--growth factor concentrations, cell densities and matrix densities--as a function of time and spatial coordinates; it also accounted for various key processes of bone regeneration. The model was adapted as a clinical tool to investigate the etiology and treatment of atrophic nonunions. The researchers found that despite a number of deviations, mainly due to simplifications in the model, the mathematical model was able to capture essential aspects of the atrophic nonunion as observed experimentally in vivo. The study was published on the September 2, 2010, in the open-access journal PLoS Computational Biology.

"The model can be used to design treatment strategies, assist in the interpretation of experimental observations, and test in silico various hypotheses in order to explain unexpected experimental results,” concluded lead author Liesbet Geris, Ph.D., of the department of mechanical engineering at Katholieke Universiteit Leuven, and colleagues. "Following such a combined in silico-in vivo approach may help to optimize experimental and clinical studies in this area.”

After showing that the mathematical model was able to simulate key aspects of the nonunion formation, the researchers used it to investigate several treatment strategies. One of these strategies, the treatment of a nonunion involving a transplantation of mesenchymal stem cells (MSCs) from the bone marrow to the fracture site, was also tested in a pilot animal experiment. Both the simulations and the experiments showed the formation of a bony union between the fractured bone ends.

Related Links:
Katholieke Universiteit Leuven
University of Liège
Edinburgh University
Oxford University