Biology subjects

Paul, G. R.

Publications and source records attributed to Paul, G. R..

7 recordsLinked to original sources

bioRxiv2026

The Mechanosensitivity of the Regenerative Response in Bone is Retained with Aging in a Mouse Model of Premature Aging.

Aging impairs the regenerative capacity of bone and is associated with poor healing outcomes. The mechanical environment is of fundamental importance to the regenerative response in bone - yet the effect of aging on the mechano-responsive capacity of bone regeneration remains largely unresolved. To investigate age-dependent mechanobiological responses in bone regeneration, we established an experimental framework consisting of: (i) an established femur defect mouse model, (ii) the use of PolgAD257A/D257A (PolgA) mice - a mouse model of premature aging, and (iii) our recently established spatial transcriptomics-based "mechanomics" platform which permits gene expression to be analyzed as a function of the local in vivo mechanical environment. Aging impaired the regenerative response in PolgA mice, resulting in an increased occurrence of delayed and non-unions, delayed bone formation / resorption responses, impaired osteogenesis and delayed mineralization of new bone. Cyclic mechanical loading significantly enhanced the regenerative response in young PolgA mice inducing sustained bone formation, suppressing bone resorption, and enhancing mineralization, with the strongest effects observed in peripheral regions of the fracture site. In aged PolgA mice, the mechanosensitivity of the regenerative response was retained with an anabolic response localized to the defect center. Cyclic mechanical loading applied during the reparative and remodelling phases of fracture healing thus represents a potential translational strategy to harness the mechanosensitivity of aged bone.

physiology↗

bioRxiv2020

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

Fracture healing is regulated by mechanical loading. Understanding the underlying mechanisms during the different healing phases is required for targeted mechanical intervention therapies. Here, the influence of individualized cyclic mechanical loading on the remodelling phase of fracture healing was assessed in a mouse femur defect model. After bridging of the defect, a loading group (n=10) received individualized cyclic mechanical loading (8-16 N, 10 Hz, 5 min, 3x/week) based on computed strain distribution in the callus using animal-specific real-time micro-finite element analysis. Controls (n=10) received 0 N treatment at the same post-operative time-points. By registration of consecutive scans, structural and dynamic callus morphometric parameters were followed in three callus sub-volumes and the adjacent cortex showing that the remodelling phase of fracture healing is highly responsive to cyclic mechanical loading with changes in dynamic parameters leading to significantly larger callus formation and mineralization. Loading-mediated maintenance of callus remodelling was associated with distinct effects on Wnt-signalling-associated molecular targets Sclerostin and RANKL in callus sub-regions and the adjacent cortex. Given these distinct local protein expression patterns induced by cyclic mechanical loading, the femur defect loading model with individualized load application seems suitable to understand the local spatio-temporal mechano-molecular regulation of the different fracture healing phases.

bioengineering↗

bioRxiv2020

Subject-specific mechanical loading of bones: Improved healing of mouse vertebral defects using adaptive loading regimes.

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.

bioengineering↗

bioRxiv2020

Development of a micro-CT mouse holder for a femur defect mouse model

Correct fixation of an object is essential for accurate micro computed tomography scanning. In this document, we provide a motivation for, description of, and use cases for a mouse holder appropriate for holding an externally fixated mouse in femur fracture/defect healing experiments. In addition to rigid fixation, the holder provides heating and anaesthetic gas to ensure correct anaesthetic conditions for the animal. We provide the description and design files for a Scanco viva40 scanner, but with small changes, the holder can be used with other scanners.

systems biology↗

bioRxiv2020

Reducing variance in a mouse defect healing model: Real-time Finite Element Analysis allows homogenization of tissue scale strains

Mechanical loading allows both investigation into the mechano-regulation of fracture healing as well as interventions to improve fracture-healing outcomes such as delayed healing or non-unions. However, loading is seldom individualised or even targeted to an effective mechanical stimulus level within the bone tissue. In this study, we use micro-finite element analysis to demonstrate the result of using a constant loading assumption for all mouse femurs in a given group. We then contrast this with the application of an adaptive loading approach, denoted real time Finite Element (rtFE) adaptation, in which micro-computed tomography images provide the basis for micro-FE based simulations and the resulting strains are manipulated and targeted to a reference distribution. Using this approach, we demonstrate that individualised femoral loading leads to a better-specified strain distribution and lower variance in tissue mechanical stimulus across all mice, both longitudinally and cross-sectionally, while making sure that no overloading is occurring leading to refracture of the femur bones.

systems biology↗

bioRxiv2020

Mechano-regulation of bone adaptation is controlled by the local in vivo environment and logarithmically dependent on loading frequency

It is well established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether bone mechano-regulation is controlled by mechanical signals in the local in vivo environment and dependent on loading frequency. Specifically, by combining in vivo micro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanical in vivo environment (strain energy density (SED) and SED gradient) of mouse caudal vertebrae over 4 weeks of either cyclic loading at varying frequencies of 2Hz, 5Hz, or 10Hz, respectively or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of bone formation and a decreased probability of bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net remodeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2Hz, 5Hz and 10Hz (+15%, +21% and +24%, p<0.0001), while static loading led to a decrease in bone volume fraction (-9%, p[≤]0.001). Furthermore, regression analysis revealed a logarithmic relationship between loading frequency and the net change in bone volume fraction over the four week observation period (R2=0.74). In conclusion, these results suggest that bone adaptation is regulated by mechanical signals in the local in vivo environment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights towards a better understanding of the mechanical signals influencing bone formation and resorption in the local in vivo environment.

physiology↗

bioRxiv2019

The association between mineralised tissue formation and the mechanical local in vivo environment: Time-lapsed quantification of a mouse defect healing model

An improved understanding of how local mechanical stimuli guide the fracture healing process has the potential to enhance clinical treatment of bone injury. Recent preclinical studies of bone defect in animal models have used cross-sectional data to examine this phenomenon indirectly. In this study, a direct time-lapsed imaging approach was used to investigate the local mechanical strains that precede the formation of mineralised tissue at the tissue scale. The goal was to test two hypotheses: 1) the local mechanical signal that precedes the onset of tissue mineralisation is higher in areas which mineralise, and 2) this local mechanical signal is independent of the magnitude of global mechanical loading of the tissue in the defect. Two groups of mice with femoral defects of length 0.85 mm (n=10) and 1.45 mm (n=9) were studied, allowing for distinct distributions of tissue scale strains in the defects. The regeneration and (re)modelling of mineralised tissue was observed weekly using in vivo micro-computed tomography (micro-CT), which served as a ground truth for resolving areas of mineralised tissue formation. The mechanical environment was determined using micro-finite element analysis (micro-FE) on baseline images. The formation of mineralised tissue showed strong association with areas of higher mechanical strain (area-under-the-curve: 0.91{+/-}0.04, true positive rate: 0.85{+/-}0.05) while surface based strains could correctly classify 43% of remodelling events. These findings support our hypotheses by showing a direct association between the local mechanical strains and the formation of mineralised tissue.

bioengineering↗