The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness that potential are rare. In fact, the current clinical practice with an initially partial or non-weight-bearing approach appears to contradict the findings from animal experiments that early mechanical stimulation is critical. Therefore, we posed the question as to whether optimizing the mechanical environment over the course of healing can deliver a clinically significant reduction in fracture healing time. In reviewing the evidence from pre-clinical studies that investigate the influence of mechanics on bone healing, we formulate a hypothesis for the stimulation protocol which has the potential to shorten healing time. The protocol involves confining stimulation predominantly to the proliferative phase of healing and including adequate rest periods between applications of stimulation.

It is well known that mechanical stimulation promotes indirect fracture healing by triggering callus formation. We investigated the short-term response of healing tissue to mechanical stimulation to compare the changes in tissue stiffness during stimulation and resting phases in a preclinical case-series. Four sheep underwent a tibial osteotomy and were instrumented with a custom-made active fixator which applied a mechanical stimulation protocol of 1000 cycles/day, equally distributed over 12 h, followed by 12 h of rest. During each cycle, a surrogate metric for tissue stiffness was measured, enabling a continuous real-time monitoring of the healing progression. A daily stiffness increase during stimulation and an increase during resting were evaluated for each animal. One animal had to be excluded from the evaluation due to technical reasons. For all included animals, the stiffness began to increase within the second week post-op. A characteristic pattern was observed during daily measurements: the stiffness dropped considerably within the first stimulation cycles followed by a steady rise throughout the rest of the stimulation phase. However, for all included animals, the average daily stiffness increase within the first three weeks post operation was larger during resting than during stimulation (Sheep I: 16.9% vs. −5.7%; Sheep II: 14.7% vs. −1.8%; Sheep III: 8.9% vs. 1.6%). A continuous measurement of tissue stiffness together with a controlled fracture stimulation enabled the investigation of the short-term effects of specific stimulatory parameters, such as resting periods. Resting was identified as a potentially determining factor for bone healing progression. Optimizing the ratio between stimulation and resting may contribute to more robust fracture healing in the future.

This manuscript introduces a programable active bone fixator system that enables systematic investigation of bone healing processes in a sheep animal model. In contrast to previous systems, this solution combines the ability to precisely control the mechanical conditions acting within a fracture with continuous monitoring of the healing progression and autonomous operation of the system throughout the experiment. The active fixator system was implemented on a double osteotomy model that shields the experimental fracture from the influence of the animal’s functional loading. A force sensor was integrated into the fixator to continuously measure stiffness of the repair tissue as an indicator for healing progression. A dedicated control unit was developed that allows programing of different loading protocols which are later executed autonomously by the active fixator. To verify the feasibility of the system, it was implanted in two sheep with different loading protocols, mimicking immediate and delayed weight-bearing, respectively. The implanted devices operated according to the programmed protocols and delivered seamless data over the whole course of the experiment. The in vivo trial confirmed the feasibility of the system. Hence, it can be applied in further preclinical studies to better understand the influence of mechanical conditions on fracture healing.

Secondary bone healing is impacted by the extent of interfragmentary motion at the fracture site. It provides mechanical stimulus that is required for the formation of fracture callus. In clinical settings, interfragmentary motion is induced by physiological loading of the broken bone – for example, by weight-bearing. However, there is no consensus about when mechanical stimuli should be applied to achieve fast and robust healing response. Therefore, this study aims to identify the effect of the immediate and delayed application of mechanical stimuli on secondary bone healing.A partial tibial osteotomy was created in twelve Swiss White Alpine sheep and stabilized using an active external fixator that induced well-controlled interfragmentary motion in form of a strain gradient. Animals were randomly assigned into two groups which mimicked early (immediate group) and late (delayed group) weight-bearing. The immediate group received daily stimulation (1000 cycles/day) from the first day post-op and the delayed group from the 22nd day post-op. Healing progression was evaluated by measurements of the stiffness of the repair tissue during mechanical stimulation and by quantifying callus area on weekly radiographs. At the end of the five weeks period, callus volume was measured on the post-mortem high-resolution computer tomography (HRCT) scan.Stiffness of the repair tissue (p<0.05) and callus progression (p<0.01) on weekly radiographs were significantly larger for the immediate group compared to the delayed group. The callus volume measured on the HRCT was nearly 3.2 times larger for the immediate group than for the delayed group (p<0.01).This study demonstrates that the absence of immediate mechanical stimuli delays callus formation, and that mechanical stimulation already applied in the early post-op phase promotes bone healing.