Occurrence and Treatment of Bone Atrophic Non-Unions Investigated by an Integrative Approach

Philip E Bourne,Jos Vander Sloten,Liesbet Geris,Hans Van Oosterwyck,Anita A C Reed,A Hamish R W Simpson

doi:10.1371/journal.pcbi.1000915

Abstract

Recently developed atrophic non-union models are a good representation of the clinical situation in which many non-unions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures.

Highlights

Atrophic non-unions, a class of non-healing fractures that display only limited external callus formation, were thought to occur as a result of impaired local blood supply [1,2]
All models demonstrate established non-unions. These animal models are a good representation of the clinical situation in which most atrophic nonunions develop [8]
In this study we used a combination of an animal model mimicking a clinical non-union situation and a mathematical model developed for normal fracture healing to investigate both the causes of non-union formation and potential therapeutic strategies that can be applied to restart the healing process

Summary

Introduction

Atrophic non-unions, a class of non-healing fractures that display only limited external callus formation, were thought to occur as a result of impaired local blood supply [1,2]. Several animal models were developed to investigate the etiology of atrophic nonunions [6,7,8,9]. In these animal models, the periosteum disruption and reaming of the marrow canal is combined with adequate stabilization of the osteotomy site. These animal models are a good representation of the clinical situation in which most atrophic nonunions develop [8]. Previous non-union models often utilized large segmental bone defects [10,11,12,13] where non-unions developed due to the size of the defect rather than the altered biology of the fracture site [8]

Methods

Results

Conclusion