Effects of mechanical loading on cortical defect repair using a novel mechanobiological model of bone healing

Abstract

Mechanical loading is an important aspect of post-surgical care. The timing of load application relative to the injury event is thought to differentially regulate repair depending on the stage of healing. Here, we show using a novel mechanobiological model of cortical defect repair that daily loading (5 N peak load, 2 Hz, 60 cycles, 4 consecutive days) during hematoma consolidation and inflammation disrupts the injury site and activates cartilage formation on the periosteal surface adjacent to the defect. We also show that daily loading during the matrix deposition phase enhances both bone and cartilage formation at the defect site, while loading during the remodeling phase results in an enlarged woven bone regenerate. All loading regimens resulted in abundant cellular proliferation within the regenerate and at the periosteal surface and fibrous tissue formation directly above the defect. Stress was concentrated at the edges of the defect during exogenous loading, and finite element (FE)-modeled longitudinal strain (εzz) values along the anterior and posterior borders of the defect (~2200 με) were an order of magnitude larger than strain values on the proximal and distal borders (~50-100 με). These findings demonstrate that all phases of cortical defect healing are sensitive to physical stimulation. In addition, the proposed novel mechanobiological model offers several advantages including its technical simplicity and its well-characterized and spatially confined repair program, making effects of physical and biological interventions more easily assessed.

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

“…Bilateral tibial cortical defects were created in all mice. This repair model produces a consistent pattern of angiogenesis and revascularization in addition to bone matrix deposition . This model consists of a 1‐mm‐diameter circular defect on the anterior medial surface of the tibia, created with a precision surgical drill at 23,000 rpm.…”

“…All tibias were collected on PSD 10. Strain within cortical bone surrounding the defect is tensile in nature, is oriented in the direction of the long‐axis of the bone (direction of loading), and has been estimated to be 400 to 1000 microstrain (μϵ) …”

“…In bone, mechanical loading regulates bone structure as well as collagen fiber orientation under homeostatic conditions. In a healing defect, mechanical loading in the form of weight‐bearing and cyclic axial compressive loading have been shown to enhance repair when applied during the matrix deposition phase, while loading at the hematoma and cell invasion phases of bone repair inhibit the healing process . In addition, mechanical cues can directly influence the assembly, composition, and architecture of the extracellular matrix, which can have a significant impact on cell‐matrix interactions.…”

“…Bone formation is first observed 5 to 7 days after surgery with complete mineralized bridging by day 14. This model also allows for controlled dynamic compressive mechanical loading . We utilized a three‐dimensional (3D), high‐resolution imaging platform to observe and quantify the spatiotemporal profile of vascular and osteogenic progenitor cell distributions during healing in 3D space.…”

“…This experimental approach allows quantification of 3D vessel geometry, the distribution of osteoprogenitors in relation to vessels, and osteoprogenitor and endothelial‐progenitor proliferation at the site of repair. Here we utilize an established mechanobiological model of bone repair that makes use of sinusoidal compressive force in the osteogenic range . We hypothesize that mechanical loading induces expansion of the OPC population within the healing bone defect, leading to greater numbers of osteogenic cells, which preferentially co‐localize with vessels during the long bone repair process.…”