Abstract
The link between mechanics and biology in the generation and the adaptation of bone has been well studied in context of skeletal development and fracture healing. Yet, the prediction of tissue genesis within - and the spatiotemporal healing of - postnatal defects, necessitates a quantitative evaluation of mechano-biological interactions using experimental and clinical parameters. To address this current gap in knowledge, this study aims to develop a mechanistic mathematical model of tissue genesis using bone morphogenetic protein (BMP) to represent of a class of factors that may coordinate bone healing. Specifically, we developed a mechanistic, mathematical model to predict the dynamics of tissue genesis by periosteal progenitor cells within a long bone defect surrounded by periosteum and stabilized via an intramedullary nail. The emergent material properties and mechanical environment associated with nascent tissue genesis influence the strain stimulus sensed by progenitor cells within the periosteum. Using a mechanical finite element model, periosteal surface strains are predicted as a function of emergent, nascent tissue properties. Strains are then input to a mechanistic mathematical model, where mechanical regulation of BMP-2 production mediates rates of cellular proliferation, differentiation and tissue production, to predict healing outcomes. A parametric approach enables the spatial and temporal prediction of endochondral tissue regeneration, assessed as areas of cartilage and mineralized bone, as functions of radial distance from the periosteum and time. Comparing model results to histological outcomes from two previous studies of periosteum-mediated bone regeneration in a common ovine model, it was shown that mechanistic models incorporating mechanical feedback successfully predict patterns (spatial) and trends (temporal) of bone tissue regeneration. The novel model framework presented here integrates a mechanistic feedback system based on the mechanosensitivity of periosteal progenitor cells, which allows for modeling and prediction of tissue regeneration on multiple length and time scales. Through combination of computational, physical and engineering science approaches, the model platform provides a means to test new hypotheses in silico and to elucidate conditions conducive to endogenous tissue genesis. Next generation models will serve to unravel intrinsic differences in bone genesis by endochondral and intramembranous mechanisms.
Highlights
Critical-sized long bone defects pose a currently intractable challenge in orthopaedics as they do not heal spontaneously without surgical intervention and they are associated with significant disability and health care costs
New surgical approaches harness the regenerative power of the periosteum, a tissue membrane covering most bones, which provides a niche for stem cells and plays a key role in healing after injury
The interplay of mechanical, cellular and biochemical mechanisms involved in periosteum-mediated tissue genesis and healing remains elusive, providing the impetus for the current study
Summary
Critical-sized long bone defects pose a currently intractable challenge in orthopaedics as they do not heal spontaneously without surgical intervention and they are associated with significant disability and health care costs. The one-stage bone transport technique introduces a new defect, enveloped in situ by the periosteum, by osteotomizing the underlying cortical bone and transporting it distally into the original defect site (Fig. 1A, B). Tested in a 16-week ovine femoral defect model, bridging does not occur in absence of the periosteum (control group), which confirms the critical size of the defect. All treated groups (periosteum 6 bone graft) exhibit de novo bone tissue genesis within and bridging across the defect. Infilling is facilitated in the absence of bone graft within the defect [1]. Using a similar in vivo ovine model, a follow on study was conducted to determine which periosteal factors
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