Application of subject-specific adaptive mechanical loading for bone healing in a mouse tail vertebral defect

Abstract

Methods to repair bone defects arising from trauma, resection, or disease, continue to be sought after. Cyclic mechanical loading is well established to influence bone (re)modelling activity, in which bone formation and resorption are correlated to micro-scale strain. Based on this, the application of mechanical stimulation across a bone defect could improve healing. However, if ignoring the mechanical integrity of defected bone, loading regimes have a high potential to either cause damage or be ineffective. This study explores real-time finite element (rtFE) methods that use three-dimensional structural analyses from micro-computed tomography images to estimate effective peak cyclic loads in a subject-specific and time-dependent manner. It demonstrates the concept in a cyclically loaded mouse caudal vertebral bone defect model. Using rtFE analysis combined with adaptive mechanical loading, mouse bone healing was significantly improved over non-loaded controls, with no incidence of vertebral fractures. Such rtFE-driven adaptive loading regimes demonstrated here could be relevant to clinical bone defect healing scenarios, where mechanical loading can become patient-specific and more efficacious. This is achieved by accounting for initial bone defect conditions and spatio-temporal healing, both being factors that are always unique to the patient.

Individualized cyclic mechanical loading improves callus properties during the remodelling phase of fracture healing in mice as assessed from time-lapsed in vivo imaging

“…We addressed this by using our recently developed RTFE based loading approach 26 , which takes into account the individual strain distribution within the callus for determining individual loading settings at weekly post-operative intervals. In a recent study by Malhotra et al 27 individualized cyclic mechanical loading (week 0 – week 4, 3x/week) was shown to significantly increase bone volume fraction in a partial vertebral defect model compared to controls. So far, no study using a complete defect model assessed the effect of local cyclic mechanical loading (e.g.…”

Bone Mechanoregulation Allows Subject-Specific Load Estimation Based on Time-Lapsed Micro-CT and HR-pQCT in Vivo

“…According to previous work, SED was used as a mechanical signal (Christen et al, 2012(Christen et al, , 2013(Christen et al, , 2014. More recent studies (né Betts et al, 2020;Malhotra et al, 2021) have identified an effective strain as a preferred candidate for bone mechanoregulation analysis using multidensity FE analysis. However, previous research has shown that these signals are strongly correlated (Pistoia et al, 2002;Ruimerman et al, 2005).…”

“…More recently, complementary methods have been proposed to computationally monitor 3D bone microstructure changes over time (time-lapse) and calculate local mechanical loading using micro-finite element (micro-FE) analysis. This has been demonstrated in mice (Schulte et al, 2013;né Betts et al, 2020;Malhotra et al, 2021) and patients (Christen et al, 2014;Mancuso and Troy, 2020) at such high spatial resolution that cellular behaviour-in the form of bone remodelling sites-can be studied and the corresponding mechanical loading can be calculated. Subsequently, these methods can be used to investigate bone's underlying mechanoregulated remodelling process, which may be the key to the development of patient-specific therapeutic or pharmacological interventions for various bone diseases.…”

“…Typically, when investigating bone mechanoregulation under controlled experimental conditions, micro-FE models disregard subject-specific variations in external loading conditions using simplified uniaxial compressive displacement boundary conditions (SC) (Schulte et al, 2013;Mancuso and Troy, 2020;né Betts et al, 2020;Malhotra et al, 2021). However, when investigating mechanoregulation in patients, variations in day-to-day external loading are more substantial due to habitual differences and patient-specific variability in the musculoskeletal system's performance.…”

Bone mechanoregulation allows subject-specific load estimation based on time-lapsed micro-CT and HR-pQCT in vivo

“…More recently, complementary methods have been proposed to computationally monitor 3D bone microstructure changes over time (time-lapse) and calculate local mechanical loading using microfinite element (micro-FE) analysis. This has been demonstrated in mice (Schulte et al, 2013;né Betts et al, 2020;Malhotra et al, 2021) and patients (Christen et al, 2014;Mancuso and Troy, 2020) at such high spatial resolution that cellular behaviour -in the form of bone remodelling sites -can be studied and the corresponding mechanical loading can be calculated. Subsequently, these methods can be used to investigate bone's underlying mechanoregulated remodelling process, which may be the key to the development of patient-specific therapeutic or pharmacological interventions for various bone diseases.…”