Subject-specific musculoskeletal models of the lower limbs for the prediction of skeletal loads during motion

The determination of skeletal loading conditions in vivo and their relationship to the health of bone tissues, remain an open question. Computational modeling of the musculoskeletal system is the only practicable method providing a valuable approach to muscle and joint loading analyses, although crucial shortcomings limit the translation process of computational methods into the orthopedic and neurological practice. A growing attention focused on subject-specific modeling, particularly when pathological musculoskeletal conditions need to be studied. Nevertheless, subject-specific data cannot be always collected in the research and clinical practice, and there is a lack of efficient methods and frameworks for building models and incorporating them in simulations of motion. The overall aim of the present PhD thesis was to introduce improvements to the state-of-the-art musculoskeletal modeling for the prediction of physiological muscle and joint loads during motion. A threefold goal was articulated as follows: (i) develop state-of-the art subject-specific models and analyze skeletal load predictions; (ii) analyze the sensitivity of model predictions to relevant musculotendon model parameters and kinematic uncertainties; (iii) design an efficient software framework simplifying the effort-intensive phases of subject-specific modeling pre-processing. The first goal underlined the relevance of subject-specific musculoskeletal modeling to determine physiological skeletal loads during gait, corroborating the choice of full subject-specific modeling for the analyses of pathological conditions. The second goal characterized the sensitivity of skeletal load predictions to major musculotendon parameters and kinematic uncertainties, and robust probabilistic methods were applied for methodological and clinical purposes. The last goal created an efficient software framework for subject-specific modeling and simulation, which is practical, user friendly and effort effective. Future research development aims at the implementation of more accurate models describing lower-limb joint mechanics and musculotendon paths, and the assessment of an overall scenario of the crucial model parameters affecting the skeletal load predictions through probabilistic modeling.

Development of musculoskeletal models for the design and the pre-clinical validation of hip resurfacing prosthesis

Background. The surgical treatment of dysfunctional hips is a severe condition for the patient and a costly therapy for the public health. Hip resurfacing techniques seem to hold the promise of various advantages over traditional THR, with particular attention to young and active patients. Although the lesson provided in the past by many branches of engineering is that success in designing competitive products can be achieved only by predicting the possible scenario of failure, to date the understanding of the implant quality is poorly pre-clinically addressed. Thus revision is the only delayed and reliable end point for assessment. The aim of the present work was to model the musculoskeletal system so as to develop a protocol for predicting failure of hip resurfacing prosthesis. Methods. Preliminary studies validated the technique for the generation of subject specific finite element (FE) models of long bones from Computed Thomography data. The proposed protocol consisted in the numerical analysis of the prosthesis biomechanics by deterministic and statistic studies so as to assess the risk of biomechanical failure on the different operative conditions the implant might face in a population of interest during various activities of daily living. Physiological conditions were defined including the variability of the anatomy, bone densitometry, surgery uncertainties and published boundary conditions at the hip. The protocol was tested by analysing a successful design on the market and a new prototype of a resurfacing prosthesis. Results. The intrinsic accuracy of models on bone stress predictions (RMSE < 10%) was aligned to the current state of the art in this field. The accuracy of prediction on the bone-prosthesis contact mechanics was also excellent (< 0.001 mm). The sensitivity of models prediction to uncertainties on modelling parameter was found below 8.4%. The analysis of the successful design resulted in a very good agreement with published retrospective studies. The geometry optimisation of the new prototype lead to a final design with a low risk of failure. The statistical analysis confirmed the minimal risk of the optimised design over the entire population of interest. The performances of the optimised design showed a significant improvement with respect to the first prototype (+35%). Limitations. On the authors opinion the major limitation of this study is on boundary conditions. The muscular forces and the hip joint reaction were derived from the few data available in the literature, which can be considered significant but hardly representative of the entire variability of boundary conditions the implant might face over the patients population. This moved the focus of the research on modelling the musculoskeletal system; the ongoing activity is to develop subject-specific musculoskeletal models of the lower limb from medical images. Conclusions. The developed protocol was able to accurately predict known clinical outcomes when applied to a well-established device and, to support the design optimisation phase providing important information on critical characteristics of the patients when applied to a new prosthesis. The presented approach does have a relevant generality that would allow the extension of the protocol to a large set of orthopaedic scenarios with minor changes. Hence, a failure mode analysis criterion can be considered a suitable tool in developing new orthopaedic devices.

Bioengineering of exercise: biomechanical and metabolic aspects

The field of research of this dissertation concerns the bioengineering of exercise, in particular the relationship between biomechanical and metabolic knowledge. This relationship can allow to evaluate exercise in many different circumstances: optimizing athlete performance, understanding and helping compensation in prosthetic patients and prescribing exercise with high caloric consumption and minimal joint loading to obese subjects. Furthermore, it can have technical application in fitness and rehabilitation machine design, predicting energy consumption and joint loads for the subjects who will use the machine. The aim of this dissertation was to further understand how mechanical work and metabolic energy cost are related during movement using interpretative models. Musculoskeletal models, when including muscle energy expenditure description, can be useful to address this issue, allowing to evaluate human movement in terms of both mechanical and metabolic energy expenditure. A whole body muscle-skeletal model that could describe both biomechanical and metabolic aspects during movement was identified in literature and then was applied and validated using an EMG-driven approach. The advantage of using EMG driven approach was to avoid the use of arbitrary defined optimization functions to solve the indeterminate problem of muscle activations. A sensitivity analysis was conducted in order to know how much changes in model parameters could affect model outputs: the results showed that changing parameters in between physiological ranges did not influence model outputs largely. In order to evaluate its predicting capacity, the musculoskeletal model was applied to experimental data: first the model was applied in a simple exercise (unilateral leg press exercise) and then in a more complete exercise (elliptical exercise). In these studies, energy consumption predicted by the model resulted to be close to energy consumption estimated by indirect calorimetry for different intensity levels at low frequencies of movement. The use of muscle skeletal models for predicting energy consumption resulted to be promising and the use of EMG driven approach permitted to avoid the introduction of optimization functions. Even though many aspects of this approach have still to be investigated and these results are preliminary, the conclusions of this dissertation suggest that musculoskeletal modelling can be a useful tool for addressing issues about efficiency of movement in healthy and pathologic subjects.

Musculoskeletal tissue regeneration by human non-embryonic stem cells

The aim of this thesis was to investigate the regenerative potential of alternative sources of stem cells, derived from human dental pulp (hDPSCs) and amniotic fluid (hAFSCs) and, specifically, to evaluate their capability to be committed towards osteogenic and myogenic lineages, for the eventual applicability of these stem cells to translational strategies in regenerative medicine of bone and skeletal muscle tissues. The in vitro bone production by stem cells may represent a radical breakthrough in the treatment of pathologies and traumas characterized by critical bone mass defects, with no medical or surgical solution. Human DPSCs and AFSCs were seeded and pre-differentiated on different scaffolds to test their capability to subsequently reach the osteogenic differentiation in vivo, in order to recover critical size bone defects. Fibroin scaffold resulted to be the best scaffold promoting mature bone formation and defect correction when combined to both hDPSCs and hAFSCs. This study also described a culture condition that might allow human DPSCs to be used for human cell therapy in compliance with good manufacturing practices (GMPs): the use of human serum (HS) promoted the expansion and the osteogenic differentiation of hDPSCs in vitro and, furthermore, allowed pre-differentiated hDPSCs to regenerate critical size bone defects in vivo. This thesis also showed that hDPSCs and hAFSCs can be differentiated towards the myogenic lineage in vitro, either when co-cultured with murine myoblasts and when differentiated alone after DNA demethylation treatment. Interestingly, when injected into dystrophic muscles of SCID/mdx mice - animal model of Duchenne Muscular Dystrophy (DMD) - hDPSCs and hAFSCs pre-differentiated after demethylating treatment were able to regenerate the skeletal muscle tissue and, particularly, to restore dystrophin expression. These observations suggest that human DPSCs and AFSCs might be eventually applied to translational strategies, in order to enhance the repair of injured skeletal muscles in DMD patients.

Large Eddy Simulations applied to wind loading and pollutant dispersion

The application of Computational Fluid Dynamics based on the Reynolds-Averaged Navier-Stokes equations to the simulation of bluff body aerodynamics has been thoroughly investigated in the past. Although a satisfactory accuracy can be obtained for some urban physics problems their predictive capability is limited to the mean flow properties, while the ability to accurately predict turbulent fluctuations is recognized to be of fundamental importance when dealing with wind loading and pollution dispersion problems. The need to correctly take into account the flow dynamics when such problems are faced has led researchers to move towards scale-resolving turbulence models such as Large Eddy Simulations (LES). The development and assessment of LES as a tool for the analysis of these problems is nowadays an active research field and represents a demanding engineering challenge. This research work has two objectives. The first one is focused on wind loads assessment and aims to study the capabilities of LES in reproducing wind load effects in terms of internal forces on structural members. This differs from the majority of the existing research, where performance of LES is evaluated only in terms of surface pressures, and is done with a view of adopting LES as a complementary design tools alongside wind tunnel tests. The second objective is the study of LES capabilities in calculating pollutant dispersion in the built environment. The validation of LES in this field is considered to be of the utmost importance in order to conceive healthier and more sustainable cities. In order to validate the numerical setup adopted, a systematic comparison between numerical and experimental data is performed. The obtained results are intended to be used in the drafting of best practice guidelines for the application of LES in the urban physics field with a particular attention to wind load assessment and pollution dispersion problems.

Preventing worker’s musculoskeletal disorders with wearable inertial sensors: ergonomics and modelling of physical human-robot interactions

The most widespread work-related diseases are musculoskeletal disorders (MSD) caused by awkward postures and excessive effort to upper limb muscles during work operations. The use of wearable IMU sensors could monitor the workers constantly to prevent hazardous actions, thus diminishing work injuries. In this thesis, procedures are developed and tested for ergonomic analyses in a working environment, based on a commercial motion capture system (MoCap) made of 17 Inertial Measurement Units (IMUs). An IMU is usually made of a tri-axial gyroscope, a tri-axial accelerometer, and a tri-axial magnetometer that, through sensor fusion algorithms, estimates its attitude. Effective strategies for preventing MSD rely on various aspects: firstly, the accuracy of the IMU, depending on the chosen sensor and its calibration; secondly, the correct identification of the pose of each sensor on the worker’s body; thirdly, the chosen multibody model, which must consider both the accuracy and the computational burden, to provide results in real-time; finally, the model scaling law, which defines the possibility of a fast and accurate personalization of the multibody model geometry. Moreover, the MSD can be diminished using collaborative robots (cobots) as assisted devices for complex or heavy operations to relieve the worker's effort during repetitive tasks. All these aspects are considered to test and show the efficiency and usability of inertial MoCap systems for assessing ergonomics evaluation in real-time and implementing safety control strategies in collaborative robotics. Validation is performed with several experimental tests, both to test the proposed procedures and to compare the results of real-time multibody models developed in this thesis with the results from commercial software. As an additional result, the positive effects of using cobots as assisted devices for reducing human effort in repetitive industrial tasks are also shown, to demonstrate the potential of wearable electronics in on-field ergonomics analyses for industrial applications.

Numerical simulations of the spine for patient-specific models of severe scoliosis

In silico methods, such as musculoskeletal modelling, may aid the selection of the optimal surgical treatment for highly complex pathologies such as scoliosis. Many musculoskeletal models use a generic, simplified representation of the intervertebral joints, which are fundamental to the flexibility of the spine. Therefore, to model and simulate the spine, a suitable representation of the intervertebral joint is crucial. The aim of this PhD was to characterise specimen-specific models of the intervertebral joint for multi-body models from experimental datasets. First, the project investigated the characterisation of a specimen-specific lumped parameter model of the intervertebral joint from an experimental dataset of a four-vertebra lumbar spine segment. Specimen-specific stiffnesses were determined with an optimisation method. The sensitivity of the parameters to the joint pose was investigate. Results showed the stiffnesses and predicted motions were highly depended on both the joint pose. Following the first study, the method was reapplied to another dataset that included six complete lumbar spine segments under three different loading conditions. Specimen-specific uniform stiffnesses across joint levels and level-dependent stiffnesses were calculated by optimisation. Specimen-specific stiffness show high inter-specimen variability and were also specific to the loading condition. Level-dependent stiffnesses are necessary for accurate kinematic predictions and should be determined independently of one another. Secondly, a framework to create subject-specific musculoskeletal models of individuals with severe scoliosis was developed. This resulted in a robust codified pipeline for creating subject-specific, severely scoliotic spine models from CT data. In conclusion, this thesis showed that specimen-specific intervertebral joint stiffnesses were highly sensitive to joint pose definition and the importance of level-dependent optimisation. Further, an open-source codified pipeline to create patient-specific scoliotic spine models from CT data was released. These studies and this pipeline can facilitate the specimen-specific characterisation of the scoliotic intervertebral joint and its incorporation into scoliotic musculoskeletal spine models.

Wind loading predictions using computational fluid dynamics

Using Computational Wind Engineering, CWE, for solving wind-related problems is still a challenging task today, mainly due to the high computational cost required to obtain trustworthy simulations. In particular, the Large Eddy Simulation, LES, has been widely used for evaluating wind loads on buildings. The present thesis assesses the capability of LES as a design tool for wind loading predictions through three cases. The first case is using LES for simulating the wind field around a ground-mounted rectangular prism in Atmospheric Boundary Layer (ABL) flow. The numerical results are validated with experimental results for seven wind attack angles, giving a global understanding of the model performance. The case with the worst model behaviour is investigated, including the spatial distribution of the pressure coefficients and their discrepancies with respect to experimental results. The effects of some numerical parameters are investigated for this case to understand their effectiveness in modifying the obtained numerical results. The second case is using LES for investigating the wind effects on a real high-rise building, aiming at validating the performance of LES as a design tool in practical applications. The numerical results are validated with the experimental results in terms of the distribution of the pressure statistics and the global forces. The mesh sensitivity and the computational cost are discussed. The third case is using LES for studying the wind effects on the new large-span roof over the Bologna stadium. The dynamic responses are analyzed and design envelopes for the structure are obtained. Although it is a numerical simulation before the traditional wind tunnel tests, i.e. the validation of the numerical results are not performed, the preliminary evaluations can effectively inform later investigations and provide the final design processes with deeper confidence regarding the absence of potentially unexpected behaviours.

Musculoskeletal disorders, research quality, and pelvic floor health in sports: exploring current evidence and new perspectives

Background. Pelvic floor dysfunction (PFD) is an umbrella term that includes a myriad of conditions such as urinary (UI) and anal incontinence, pelvic organ prolapse, pelvic pain, and sexual dysfunction. Literature showed high prevalence rates of PFD among athletes, especially UI, with high-impact sports have been linked with an increased risk of developing symptoms. However, comprehensive research summarising PFD prevalence across sexes, exploring treatment options, and the absence of a standardised referral screening tool are notable gaps. Misinformation is also prevalent in the sports medicine field. Methods. This doctoral project comprises four studies addressing different aspects of pelvic health in athletes. The first two studies were scoping reviews of epidemiological PFD data in male and female athletes, as well as available interventions. Study 3 concerned the development of a new screening tool for PFD in female athletes, aiming to guide sports medicine clinicians in referring patients to PFD specialists through a worldwide Delphi consensus. Study 4 summarised all previous findings, integrating data into an infographic. Results and conclusions. In Study 1, the findings of 100 articles on PFD in both sexes have been collected, highlighting a higher prevalence of studies on female athletes evaluating UI across multiple sports. Other conditions remain rarely investigated. Study 2 found a diverse range of interventions for female PFD, with a notable emphasis on conservative approaches. Recommendations for clinical practice often relied on the transferability of results from the nonathlete population or expert opinions. In Study 3, 41 international experts took part in the consensus development of the Pelvic Floor Dysfunction-ScrEeNing Tool IN fEmale athLetes (PFD-SENTINEL). It incorporates a cluster of PFD symptoms, items (risk factors, clinical, and sports-related characteristics), and a clinical algorithm. Lastly, Study 4 included ten evidence-based information with a relative description concerning pelvic floor health in athletes.