Frontiers in Bioengineering and Biotechnology

Journal: Frontiers in Bioengineering and Biotechnology

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Front. Bioeng. Biotechnol.

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Frontiers Media

ISSN

2296-4185

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Publications 1 - 10 of 90

Digital twin simulations with a micro-multiphysics agent-based model reveal key drivers of bone loss after denosumab discontinuation
Ledoux, Charles; Kendall, Jack J.; Boaretti, Daniele; et al. (2025)
Frontiers in Bioengineering and Biotechnology
Background: Denosumab is a widely used pharmacological treatment for osteoporosis-related bone fragility; however, its discontinuation is followed by a rapid drop in bone density. Methods: We investigate proposed mechanistic hypotheses from literature for this rapid bone loss using a computational micro-multiphysics agent-based model validated against clinical data. Using a representative selection of iliac crest patient biopsies scanned with micro-computed tomography, this model generates digital twin simulations of denosumab discontinuation after various treatment periods, with ceteris paribus implementations of each mechanistic hypothesis. Results: Our mixed effects linear regression analysis suggests that only the gate-blocking effect (p=0.014) and osteomorphs recycling (p=0.007) explain the rapid bone loss post denosumab discontinuation. In silico cell and cytokine dynamics emphasize that fusion of osteomorphs is more rapid than osteoclast precursor differentiation in the short-term. Conclusion: These findings highlight potential targets for managing fracture risk when discontinuing denosumab and emphasize the importance of personalized treatment strategies based on high-resolution imaging in addition to bone turnover marker measurements.
Subject-Specific Alignment and Mass Distribution in Musculoskeletal Models of the Lumbar Spine
Fasser, Marie-Rosa; Jokeit, Moritz; Kalthoff, Mirjam; et al. (2021)
Frontiers in Bioengineering and Biotechnology
Musculoskeletal modeling is a well-established method in spine biomechanics and generally employed for investigations concerning both the healthy and the pathological spine. It commonly involves inverse kinematics and optimization of muscle activity and provides detailed insight into joint loading. The aim of the present work was to develop and validate a procedure for the automatized generation of semi-subject-specific multi-rigid body models with an articulated lumbar spine. Individualization of the models was achieved with a novel approach incorporating information from annotated EOS images. The size and alignment of bony structures, as well as specific body weight distribution along the spine segments, were accurately reproduced in the 3D models. To ensure the pipeline's robustness, models based on 145 EOS images of subjects with various weight distributions and spinopelvic parameters were generated. For validation, we performed kinematics-dependent and segment-dependent comparisons of the average joint loads obtained for our cohort with the outcome of various published in vivo and in situ studies. Overall, our results agreed well with literature data. The here described method is a promising tool for studying a variety of clinical questions, ranging from the evaluation of the effects of alignment variation on joint loading to the assessment of possible pathomechanisms involved in adjacent segment disease.
Uncertainty in Muscle-Tendon Parameters can Greatly Influence the Accuracy of Knee Contact Force Estimates of Musculoskeletal Models
Hosseini Nasab, Seyyed Hamed; Smith, Colin R.; Maas, Allan; et al. (2022)
Frontiers in Bioengineering and Biotechnology
Understanding the sources of error is critical before models of the musculoskeletal system can be usefully translated. Using in vivo measured tibiofemoral forces, the impact of uncertainty in muscle-tendon parameters on the accuracy of knee contact force estimates of a generic musculoskeletal model was investigated following a probabilistic approach. Population variability was introduced to the routine musculoskeletal modeling framework by perturbing input parameters of the lower limb muscles around their baseline values. Using ground reaction force and skin marker trajectory data collected from six subjects performing body-weight squat, the knee contact force was calculated for the perturbed models. The combined impact of input uncertainties resulted in a considerable variation in the knee contact force estimates (up to 2.1 BW change in the predicted force), especially at larger knee flexion angles, hence explaining up to 70% of the simulation error. Although individual muscle groups exhibited different contributions to the overall error, variation in the maximum isometric force and pathway of the muscles showed the highest impacts on the model outcomes. Importantly, this study highlights parameters that should be personalized in order to achieve the best possible predictions when using generic musculoskeletal models for activities involving deep knee flexion.
An in silico micro-multiphysics agent-based approach for simulating bone regeneration in a mouse femur defect model
Kendall, Jack J.; Ledoux, Charles; Marques, Francisco C.; et al. (2023)
Frontiers in Bioengineering and Biotechnology
Bone defects represent a challenging clinical problem as they can lead to non-union. In silico models are well suited to study bone regeneration under varying conditions by linking both cellular and systems scales. This paper presents an in silico micro-multiphysics agent-based (micro-MPA) model for bone regeneration following an osteotomy. The model includes vasculature, bone, and immune cells, as well as their interaction with the local environment. The model was calibrated by time-lapsed micro-computed tomography data of femoral osteotomies in C57Bl/6J mice, and the differences between predicted bone volume fractions and the longitudinal in vivo measurements were quantitatively evaluated using root mean square error (RMSE). The model performed well in simulating bone regeneration across the osteotomy gap, with no difference (5.5% RMSE, p = 0.68) between the in silico and in vivo groups for the 5-week healing period - from the inflammatory phase to the remodelling phase - in the volume spanning the osteotomy gap. Overall, the proposed micro-MPA model was able to simulate the influence of the local mechanical environment on bone regeneration, and both this environment and cytokine concentrations were found to be key factors in promoting bone regeneration. Further, the validated model matched clinical observations that larger gap sizes correlate with worse healing outcomes and ultimately simulated non-union. This model could help design and guide future experimental studies in bone repair, by identifying which are the most critical in vivo experiments to perform.
Advancing musculoskeletal shoulder modeling: reflecting glenohumeral translation with bony, ligamentous, and muscular stability constraints
Menze, Johanna; Croci, Eleonora; Andersen, Michael Skipper; et al. (2025)
Frontiers in Bioengineering and Biotechnology
Introduction Glenohumeral (GH) stability is a delicate interplay between bony congruence, muscle contraction, and ligamentous or capsular stability that can be disrupted by pathologies such as rotator cuff (RC) tears. We aimed to develop an advanced musculoskeletal shoulder model that incorporates subject-specific GH joint contact, active and passive muscle stability, and mechanical properties of ligaments to calculate GH translation using force-dependent kinematics (FDK). We hypothesized that inferior-superior GH translation computed using this model are consistent with in vivo GH translation measured by dynamic uniplanar fluoroscopy in healthy shoulders and in shoulders with partial or full RC tears, and that muscle and joint forces computed using the FDK shoulder model are higher than those of the default shoulder model.Methods The AnyBody ShoulderArm model was extended to compute GH translation using FDK, considering joint constraints due to bone congruence and to labrum, ligament and muscle stabilization. The inferior-superior GH translations computed using the FDK model were compared with the translations measured using dynamic uniplanar fluoroscopy in healthy shoulders and shoulders with partial and full RC tears during 0 degrees-30 degrees abduction-adduction cycles with 0-3 kg of handheld weight.Results The FDK model simulations revealed a decrease in median inferior-superior translations, from 2.8 to 1.8 mm with increasing handheld weight (0-3 kg) which was higher than those observed in fluoroscopic imaging (1.4 mm and 1.1 mm at 0 and 2 kg handheld weight). FDK model simulations in abduction with no additional handheld weight revealed greater variations in glenohumeral translations in shoulders with full RC tear. Compressive joint forces and muscle forces were higher in the FDK model than in the default shoulder model, particularly in the infraspinatus in the healthy model and in the deltoid in the full RC tear model.Discussion Distinct differences in muscle and joint forces between the FDK and the default shoulder models confirm that unconstrained translational degrees of freedom of the GH joint are important to advance knowledge of the biomechanical principles of the shoulder. Computed inferior-superior GH translations were greater than in vivo measured GH translations, suggesting that joint stability, particularly through muscle recruitment, could be underestimated.
A graph model to describe the network connectivity of trabecular plates and rods
Walle, Matthias; Yeritsyan, Diana; Abbasian, Mohammadreza; et al. (2024)
Frontiers in Bioengineering and Biotechnology
Introduction: The trabecular network is perceived as a collection of interconnected plate- (P) and rod-like (R) elements. Previous research has highlighted how these elements and their connectivity influence the mechanical properties of bone, yet further work is required to elucidate better the deeply interconnected nature of the trabecular network with distinct element formations conducting forces per their mechanical boundary conditions. Within this network, forces act through elements: a rod or plate with force applied to one end will transmit this force to a component connected to the other end, defining the boundary conditions for the loading of each element. To that end, this study has two aims: First, to investigate the connectivity of individually segmented elements of trabecular bone with respect to their local boundary conditions as defined by the surrounding trabecular network and linking them directly to the bone's overall mechanical response during loading using a mathematical graph model of the plate and rod (PR) Network. Second, we use this model to quantify side artifacts, a known artifact when testing an excised specimen of trabecular bone, where vertical trabeculae lose their load-bearing capacity due to a loss of connectivity, ultimately resulting in a change of the trabecular network topology.Resuts: Connected elements derived from our model predicted apparent elastic modulus by fitting a linear regression (R² = 0.81). In comparison, prediction using conventional bone volume fraction results in a lower accuracy (R² = 0.72), demonstrating the ability of the PR Network to estimate compressive elastic modulus independent of specimen size or loading boundary condition.Discussion: PR Network models are a novel approach to describing connectivity within the trabecular network and incorporating mechanical boundary conditions within the morphological analysis, thus enabling the study of intrinsic material properties of trabecular bone. Ultimately, PR Network models may be an early predictor or provide further insights into osteo-degenerative diseases.
In-Vivo Measurement of Ocular Deformation in Response to Ambient Pressure Modulation
Kling, Sabine (2021)
Frontiers in Bioengineering and Biotechnology
A novel approach is presented for the non-invasive quantification of axial displacement and strain in corneal and anterior crystalline lens tissue in response to a homogenous ambient pressure change. A spectral domain optical coherence tomography (OCT) system was combined with a custom-built set of swimming goggles and a pressure control unit to acquire repetitive cross-sectional scans of the anterior ocular segment before, during and after ambient pressure modulation. The potential of the technique is demonstrated in vivo in a healthy human subject. The quantification of the dynamic deformation response, consisting of axial displacement and strain, demonstrated an initial retraction of the eye globe (−0.43 to −1.22 nm) and a subsequent forward motion (1.99 nm) in response to the pressure change, which went along with a compressive strain induced in the anterior crystalline lens (−0.009) and a tensile strain induced in the cornea (0.014). These mechanical responses appear to be the result of a combination of whole eye motion and eye globe expansion. The latter simulates a close-to-physiologic variation of the intraocular pressure and makes the detected mechanical responses potentially relevant for clinical follow-up and pre-surgical screening. The presented measurements are a proof-of-concept that non-contact low- amplitude ambient pressure modulation induces tissue displacement and strain that is detectable in vivo with OCT. To take full advantage of the high spatial resolution this imaging technique could offer, further software and hardware optimization will be necessary to overcome the current limitation of involuntary eye motions.
From Stoop to Squat: A Comprehensive Analysis of Lumbar Loading Among Different Lifting Styles
von Arx, Michael; Liechti, Melanie; Connolly, Lukas; et al. (2021)
Frontiers in Bioengineering and Biotechnology
Lifting up objects from the floor has been identified as a risk factor for low back pain, whereby a flexed spine during lifting is often associated with producing higher loads in the lumbar spine. Even though recent biomechanical studies challenge these assumptions, conclusive evidence is still lacking. This study therefore aimed at comparing lumbar loads among different lifting styles using a comprehensive state-of-the-art motion capture-driven musculoskeletal modeling approach. Thirty healthy pain-free individuals were enrolled in this study and asked to repetitively lift a 15 kg-box by applying 1) a freestyle, 2) a squat and 3) a stoop lifting technique. Whole-body kinematics were recorded using a 16-camera optical motion capture system and used to drive a full-body musculoskeletal model including a detailed thoracolumbar spine. Continuous as well as peak compressive, anterior-posterior shear and total loads (resultant load vector of the compressive and shear load vectors) were calculated based on a static optimization approach and expressed as factor body weight (BW). In addition, lumbar lordosis angles and total lifting time were calculated. All parameters were compared among the lifting styles using a repeated measures design. For each lifting style, loads increased towards the caudal end of the lumbar spine. For all lumbar segments, stoop lifting showed significantly lower compressive and total loads (−0.3 to −1.0BW) when compared to freestyle and squat lifting. Stoop lifting produced higher shear loads (+0.1 to +0.8BW) in the segments T12/L1 to L4/L5, but lower loads in L5/S1 (−0.2 to −0.4BW). Peak compressive and total loads during squat lifting occurred approximately 30% earlier in the lifting cycle compared to stoop lifting. Stoop lifting showed larger lumbar lordosis range of motion (35.9 ± 10.1°) than freestyle (24.2 ± 7.3°) and squat (25.1 ± 8.2°) lifting. Lifting time differed significantly with freestyle being executed the fastest (4.6 ± 0.7 s), followed by squat (4.9 ± 0.7 s) and stoop (5.9 ± 1.1 s). Stoop lifting produced lower total and compressive lumbar loads than squat lifting. Shear loads were generally higher during stoop lifting, except for the L5/S1 segment, where anterior shear loads were higher during squat lifting. Lifting time was identified as another important factor, considering that slower speeds seem to result in lower loads.
Towards a Platform for Robot-Assisted Minimally-Supervised Therapy of Hand Function: Design and Pilot Usability Evaluation
Ranzani, Raffaele; Eicher, Lucas; Viggiano, Federica; et al. (2021)
Frontiers in Bioengineering and Biotechnology
Background: Robot-assisted therapy can increase therapy dose after stroke, which is often considered insufficient in clinical practice and after discharge, especially with respect to hand function. Thus far, there has been a focus on rather complex systems that require therapist supervision. To better exploit the potential of robot-assisted therapy, we propose a platform designed for minimal therapist supervision, and present the preliminary evaluation of its immediate usability, one of the main and frequently neglected challenges for real-world application. Such an approach could help increase therapy dose by allowing the training of multiple patients in parallel by a single therapist, as well as independent training in the clinic or at home. Methods: We implemented design changes on a hand rehabilitation robot, considering aspects relevant to enabling minimally-supervised therapy, such as new physical/graphical user interfaces and two functional therapy exercises to train hand motor coordination, somatosensation and memory. Ten participants with chronic stroke assessed the usability of the platform and reported the perceived workload during a single therapy session with minimal supervision. The ability to independently use the platform was evaluated with a checklist. Results: Participants were able to independently perform the therapy session after a short familiarization period, requiring assistance in only 13.46 (7.69–19.23)% of the tasks. They assigned good-to-excellent scores on the System Usability Scale to the user-interface and the exercises [85.00 (75.63–86.88) and 73.75 (63.13–83.75) out of 100, respectively]. Nine participants stated that they would use the platform frequently. Perceived workloads lay within desired workload bands. Object grasping with simultaneous control of forearm pronosupination and stiffness discrimination were identified as the most difficult tasks. Discussion: Our findings demonstrate that a robot-assisted therapy device can be rendered safely and intuitively usable upon first exposure with minimal supervision through compliance with usability and perceived workload requirements. The preliminary usability evaluation identified usability challenges that should be solved to allow real-world minimally-supervised use. Such a platform could complement conventional therapy, allowing to provide increased dose with the available resources, and establish a continuum of care that progressively increases therapy lead of the patient from the clinic to the home.
Accounting for Biomechanical Measures from Musculoskeletal Simulation of Upright Posture Does Not Enhance the Prediction of Curve Progression in Adolescent Idiopathic Scoliosis
Bassani, Tito; Cina, Andrea; Ignasiak, Dominika; et al. (2021)
Frontiers in Bioengineering and Biotechnology
A major clinical challenge in adolescent idiopathic scoliosis (AIS) is the difficulty of predicting curve progression at initial presentation. The early detection of progressive curves can offer the opportunity to better target effective non-operative treatments, reducing the need for surgery and the risks of related complications. Predictive models for the detection of scoliosis progression in subjects before growth spurt have been developed. These models accounted for geometrical parameters of the global spine and local descriptors of the scoliotic curve, but neglected contributions from biomechanical measurements such as trunk muscle activation and intervertebral loading, which could provide advantageous information. The present study exploits a musculoskeletal model of the thoracolumbar spine, developed in AnyBody software and adapted and validated for the subject-specific characterization of mild scoliosis. A dataset of 100 AIS subjects with mild scoliosis and in pre-pubertal age at first examination, and recognized as stable (60) or progressive (40) after at least 6-months follow-up period was exploited. Anthropometrical data and geometrical parameters of the spine at first examination, as well as biomechanical parameters from musculoskeletal simulation replicating relaxed upright posture were accounted for as predictors of the scoliosis progression. Predicted height and weight were used for model scaling because not available in the original dataset. Robust procedure for obtaining such parameters from radiographic images was developed by exploiting a comparable dataset with real values. Six predictive modelling approaches based on different algorithms for the binary classification of stable and progressive cases were compared. The best fitting approaches were exploited to evaluate the effect of accounting for the biomechanical parameters on the prediction of scoliosis progression. The performance of two sets of predictors was compared: accounting for anthropometrical and geometrical parameters only; considering in addition the biomechanical ones. Median accuracy of the best fitting algorithms ranged from 0.76 to 0.78. No differences were found in the classification performance by including or neglecting the biomechanical parameters. Median sensitivity was 0.75, and that of specificity ranged from 0.75 to 0.83. In conclusion, accounting for biomechanical measures did not enhance the prediction of curve progression, thus not supporting a potential clinical application at this stage.

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