Knee joint biomechanics after anterior cruciate ligament reconstruction

Anterior cruciate ligament (ACL) is an important stabilizer of the knee joint. After ACL rupture, the knee joint has difficulty maintaining its stability; thus the patient often has to receive an ACL-reconstructive surgery to regain the knee joint functions. Unfortunately, traditional transtibial surgical techniques could not fully restore the normal knee joint kinematics during daily activities. Moreover, a higher rate of osteoarthritis was found from the ACL-reconstructed knees compared to the knees without a history of ACL-injuries. The reason for the increased risk of knee osteoarthritis is still unclear, and the pathologies due to abnormal knee joint kinematics remain controversial. The dissertation was to delineate the knee joint motion and loading after ACL-reconstruction. Thirty patients who received ACL-reconstructive surgeries using the traditional transtibial technique and 14 using the recently developed anteromedial portal technique were recruited from the same center (OrthoCarolina). Twenty healthy subjects without history of knee injuries were recruited as the control group. Human motion data and ground reaction force data were collected during level walking and downstairs pivoting using an optical motion capture system. Three-dimensional (3D) knee joint motions were determined from redundant markers using an optimization approach. The 3D knee joint moments and forces were calculated from motion data, ground reaction data by using an inverse dynamics model of the lower extremity. A finite element model was created, and the distributions of stress/strain within articular cartilage under physiological loading were estimated. The results from two groups of patients using different reconstruction techniques were compared. In the transtibial group, excessive internal tibial rotation (2° on average during stance phase), varus rotation and anterior femur translation (swing phase) were observed in the ACL-reconstructed knees when compared to the control group during level walking. The 3D knee joint motion following ACL-reconstruction was found to be influenced by the leg dominance. The motion and load in the uninjured contralateral knee were also affected. During downstairs pivoting, the normal varus rotation and adduction moment were not fully restored by the transtibial technique. Overall, the anteromedial portal technique improved the postsurgical knee joint kinematics by reducing the offsets in the internal tibial rotation, varus rotation and anterior femur translation during level walking. It also improved the adduction moment during downstairs pivoting. At the same time, the anteromedial portal technique may cause a flexion/extension deficit during the stance phase of walking. Results of finite element analysis demonstrated higher pressures within the medial femoral cartilage during the stance phase of walking; it also demonstrated that there is an increased knee joint laxity after ACL-reconstruction. The anteromedial portal technique was overall better than the traditional transtibial technique in respect to postsurgical knee joint compressive loading and contact pressure. The study provides evidence of the possibility by using anatomical single-bundle ACL-reconstruction technique to fight the knee joint osteoarthritis after ligament injury

Precision Medicine for the Intervertebral Disc: Image Processing and Computational Modeling of Disc Degeneration to Inform Patient-Specific Therapies

The human intervertebral disc is a deceptively simple structure which plays an essential role in human movement. Even slight changes to the disc microenvironment can have far reaching consequences, particularly when these changes result in disc degeneration and herniation. Degeneration is increasingly tied to lower back pain; better understanding this complex relationship could enable more informed treatments and better outcomes for patients suffering from low back pain. The overall aim of the work presented here is to investigate tools and techniques which might aid in patient evaluation, for use in both research and clinical settings. Specifically, this includes (1) development of a patient-specific finite element model of nutrient transport in the disc, and (2) quantitative comparison of a novel imaging modality (apparent diffusion coefficient mapping) to established modalities for disc visualization. In the first investigation, results of the patient-specific model showed distinct diffusion behavior between patients, even within discs of the same degeneration grade, indicating the importance of the patient-specific diffusivities to the accurate prediction of nutrient availability in the disc. In the second investigation, the results indicated a general sensitivity of both modalities to degeneration of the NP. However, significant differences were found between the modalities at measuring the same features, indicating that the two modalities have fundamentally different capabilities for IVD visualization and implying that one is more accurate than the other. Validating this will be the focus of future work

Unveiling the prospects of point-of-care 3D printing of Polyetheretherketone (PEEK) patient-specific implants

Additive manufacturing (AM) or three-dimensional (3D) printing is rapidly gaining acceptance in the healthcare sector. With the availability of low-cost desktop 3D printers and inexpensive materials, in-hospital or point-of-care (POC) manufacturing has gained considerable attention in personalized medicine. Material extrusion-based [Fused Filament Fabrication (FFF)] 3D printing of low-temperature thermoplastic polymer is the most commonly used 3D printing technology in hospitals due to its ease of operability and availability of low-cost machines. However, this technology has been limited to the production of anatomical biomodels, surgical guides, and prosthetic aids and has not yet been adopted into the mainstream production of patient-specific or customized implants. Polyetheretherketone (PEEK), a high-performance thermoplastic polymer, has been used mainly in reconstructive surgeries as a reliable alternative to other alloplastic materials to fabricate customized implants. With advancements in AM systems, prospects for customized 3D printed surgical implants have emerged, increasing attention for POC manufacturing. A customized implant may be manufactured within few hours using 3D printing, allowing hospitals to become manufacturers. However, manufacturing customized implants in a hospital environment is challenging due to the number of actions necessary to design and fabricate the implants. The focus of this thesis relies on material extrusion-based 3D printing of PEEK patient-specific implants (PSIs). The ambitious challenge was to bridge the performance gap between 3D printing of PEEK PSIs for reconstructive surgery and the clinical applicability at the POC by taking advantage of recent developments in AM systems. The main reached milestones of this project include: (i) assessment of the fabrication feasibility of PEEK surgical implants using material extrusion-based 3D printing technology, (ii) incorporation of a digital clinical workflow for POC manufacturing, (iii) assessment of the clinical applicability of the POC manufactured patient-specific PEEK scaphoid prosthesis, (iv) visualization and quantification of the clinical reliability of the POC manufactured patient-specific PEEK cranial implants, and (v) assessment of the clinical performance of the POC manufactured porous patient-specific PEEK orbital implants. During this research work, under the first study, we could demonstrate the prospects of FFF 3D printing technology for POC PEEK implant manufacturing. It was established that FFF 3D printing of PEEK allows the construction of complex anatomical geometries which cannot be manufactured using other technologies. With a clinical digital workflow implementation at the POC, we could further illustrate a smoother integration and faster implant production (within two hours) potential for a complex-shaped, patented PEEK patient-specific scaphoid prosthesis. Our results revealed some key challenges during the FFF printing process, exploring the applicability of POC manufactured FFF 3D printed PEEK customized implants in craniofacial reconstructions. It was demonstrated that optimal heat distribution around the cranial implants and heat management during the printing process are essential parameters that affect crystallinity, and thus the quality of the FFF 3D printed PEEK cranial implants. At this stage of the investigation, it was observed that the root mean square (RMS) values for dimensional accuracy revealed higher deviations in large-sized cranial prostheses with “horizontal lines” characteristics. Further optimization of the 3D printer, a layer-by-layer increment in the airflow temperature was done, which improved the performance of the FFF PEEK printing process for large-sized cranial implants. We then evaluated the potential clinical reliability of the POC manufactured 3D printed PEEK PSIs for cranial reconstruction by quantitative assessment of geometric, morphological, and biomechanical characteristics. It was noticed that the 3D printed customized cranial implants had high dimensional accuracy and repeatability, displaying clinically acceptable morphologic similarity concerning fit and contours continuity. However, the tested cranial implants had variable peak load values with discrete fracture patterns from a biomechanical standpoint. The implants with the highest peak load had a strong bonding with uniform PEEK fusion and interlayer connectivity, while air gaps and infill fusion lines were observed in implants with the lowest strength. The results of this preclinical study were in line with the clinical applicability of cranial implants; however, the biomechanical attribute can be further improved. It was noticed that each patient-specific reconstructive implant required a different set of manufacturing parameters. This was ascertained by manufacturing a porous PEEK patient-specific orbital implant. We evaluated the FFF 3D printed PEEK orbital mesh customized implants with a metric considering the design variants, biomechanical, and morphological parameters. We then studied the performance of the implants as a function of varying thicknesses and porous design constructs through a finite element (FE) based computational model and a decision matrix based statistical approach. The maximum stress values achieved in our results predicted the high durability of the implants. In all the implant profile configurations, the maximum deformation values were under one-tenth of a millimeter (mm) domain. The circular patterned design variant implant revealed the best performance score. The study further demonstrated that compounding multi-design computational analysis with 3D printing can be beneficial for the optimal restoration of the orbital floor. In the framework of the current thesis, the potential clinical application of material extrusion-based 3D printing for PEEK customized implants at the POC was demonstrated. We implemented clinical experience and engineering principles to generate a technical roadmap from preoperative medical imaging datasets to virtual surgical planning, computer-aided design models of various reconstructive implant variants, to the fabrication of PEEK PSIs using FFF 3D printing technology. The integration of 3D printing PEEK implants at the POC entails numerous benefits, including a collaborative team approach, quicker turnaround time of customized implants, support in pre-surgical and intraoperative planning, improved patient outcomes, and decreased overall healthcare cost. We believe that FFF 3D printing of customized PEEK implants could become an integral part of the hospitals and holds potential for various reconstructive surgery applications

The biting performance of Homo sapiens and Homo heidelbergensis

Modern humans have smaller faces relative to Middle and Late Pleistocene members of the genus Homo. While facial reduction and differences in shape have been shown to increase biting efficiency in Homo sapiens relative to these hominins, facial size reduction has also been said to decrease our ability to resist masticatory loads. This study compares crania of Homo heidelbergensis and H. sapiens with respect to mechanical advantages of masticatory muscles, force production efficiency, strains experienced by the cranium and modes of deformation during simulated biting. Analyses utilize X-ray computed tomography (CT) scan-based 3D models of a recent modern human and two H. heidelbergensis. While having muscles of similar cross-sectional area to H. heidelbergensis, our results confirm that the modern human masticatory system is more efficient at converting muscle forces into bite forces. Thus, it can produce higher bite forces than Broken Hill for equal muscle input forces. This difference is the result of alterations in relative in and out-lever arm lengths associated with well-known differences in midfacial prognathism. Apparently at odds with this increased efficiency is the finding that the modern human cranium deforms more, resulting in greater strain magnitudes than Broken Hill when biting at the equivalent tooth. Hence, the facial reduction that characterizes modern humans may not have evolved as a result of selection for force production efficiency. These findings provide further evidence for a degree of uncoupling between form and function in the masticatory system of modern humans. This may reflect the impact of food preparation technologies. These data also support previous suggestions that differences in bite force production efficiency can be considered a spandrel, primarily driven by the midfacial reduction in H. sapiens that occurred for other reasons. Midfacial reduction plausibly resulted in a number of other significant changes in morphology, such as the development of a chin, which has itself been the subject of debate as to whether or not it represents a mechanical adaptation or a spandrel

Linking quantitative radiology to molecular mechanism for improved vascular disease therapy selection and follow-up

Objective: Therapeutic advancements in atherosclerotic cardiovascular disease have improved the prevention of ischemic stroke and myocardial infarction. However, diagnostic methods for atherosclerotic plaque phenotyping to aid individualized therapy are lacking. In this thesis, we aimed to elucidate plaque biology through the analysis of computed-tomography angiography (CTA) with sufficient sensitivity and specificity to capture the differentiated drivers of the disease. We then aimed to use such data to calibrate a systems biology model of atherosclerosis with adequate granularity to be clinically relevant. Such development may be possible with computational modeling, but given, the multifactorial biology of atherosclerosis, modeling must be based on complete biological networks that capture protein-protein interactions estimated to drive disease progression. Approach and Results: We employed machine intelligence using CTA paired with a molecular assay to determine cohort-level associations and individual patient predictions. Examples of predicted transcripts included ion transporters, cytokine receptors, and a number of microRNAs. Pathway analyses elucidated enrichment of several biological processes relevant to atherosclerosis and plaque pathophysiology. The ability of the models to predict plaque gene expression from CTAs was demonstrated using sequestered patients with transcriptomes of corresponding lesions. We further performed a case study exploring the relationship between biomechanical quantities and plaque morphology, indicating the ability to determine stress and strain from tissue characteristics. Further, we used a uniquely constituted plaque proteomic dataset to create a comprehensive systems biology disease model, which was finally used to simulate responses to different drug categories in individual patients. Individual patient response was simulated for intensive lipid-lowering, anti-inflammatory drugs, anti-diabetic, and combination therapy. Plaque tissue was collected from 18 patients with 6735 proteins at two locations per patient. 113 pathways were identified and included in the systems biology model of endothelial cells, vascular smooth muscle cells, macrophages, lymphocytes, and the integrated intima, altogether spanning 4411 proteins, demonstrating a range of 39-96% plaque instability. Simulations of drug responses varied in patients with initially unstable lesions from high (20%, on combination therapy) to marginal improvement, whereas patients with initially stable plaques showed generally less improvement, but importantly, variation across patients. Conclusion: The results of this thesis show that atherosclerotic plaque phenotyping by multi-scale image analysis of conventional CTA can elucidate the molecular signatures that reflect atherosclerosis. We further showed that calibrated system biology models may be used to simulate drug response in terms of atherosclerotic plaque instability at the individual level, providing a potential strategy for improved personalized management of patients with cardiovascular disease. These results hold promise for optimized and personalized therapy in the prevention of myocardial infarction and ischemic stroke, which warrants further investigations in larger cohorts

The development of bite force resistance and cranial form in Neanderthals and modern humans

The general aim of the thesis is to understand how biting mechanics interact with cranial form to impact post-natal craniofacial ontogeny in modern humans and Neander-thals. To this end, CT scans of ontogenetic samples of 12 Neanderthal and 63 modern human crania were collected and a series of reconstructions of Neanderthal crania were carried out. Geometric morphometric and multivariate regression approaches were used to create a craniofacial growth model for each species. Using these two models, 3D virtual crania representing the mean adult, juvenile, and infant were extracted in each species. These 6 mean crania were then converted into finite element models and used to conduct two biting simulations: at the right second premolar or second deciduous molar (RP2/RdM2) and right first incisor (RI1), applying the same muscle forces for all models because these are unknown especially for Neanderthals. This study compared modes and magnitudes of deformation, and the distribution and magnitude of tensile and compres-sive strains between the mean infant, juvenile, and adult models within each species and between the two species at each age stage.The morphometric analyses indicate that cranial ontogenetic trajectories differ be-tween modern humans and Neanderthals. The finite element analyses (FEA) in both bit-ing simulations indicate that, within each species, the mean infant juvenile and adult mod-els deform differently. Further, in both biting simulations, the highest strains are localised over similar regions of the cranium; over the anterior maxilla, orbits, and anterior subna-sal surface. Modern humans and Neanderthals deform differently and show differences in the development of biting forces during RI1 and RP2/RdM2 biting simulations at each stage. These findings confirm that modern human and Neanderthal crania have divergent postnatal developmental trajectories and manifest differences in the resistance of masti-catory system loadings throughout life. Differences in modes of deformation and so, strain distributions are considered in light of known differences in craniofacial bone growth remodeling between Neanderthals and modern humans. The findings show some correspondence with the remodeling maps for both species, particularly during RP2/RdM2 biting simulations. They do not falsify the hypothesis that facial remodeling differences arise because of differences in load resistance, and so, in the strain environment during post-natal development. As such, how differences among adult crania arise through post-natal interactions between form and functional loadings merits further investigation through more detailed analyses of a wider range of loading scenarios

1st EFORT European Consensus: Medical & Scientific Research Requirements for the Clinical Introduction of Artificial Joint Arthroplasty Devices

Innovations in Orthopaedics and Traumatology have contributed to the achievement of a high-quality level of care in musculoskeletal disorders and injuries over the past decades. The applications of new implants as well as diagnostic and therapeutic techniques in addition to implementation of clinical research, have significantly improved patient outcomes, reduced complication rates and length of hospital stay in many areas. However, the regulatory framework is extensive, and there is a lack of understanding and clarity in daily practice what the meaning of clinical & pre‐clinical evidence as required by the MDR is. Thus, understanding and clarity are of utmost importance for introduction of new implants and implant-related instrumentation in combination with surgical technique to ensure a safe use of implants and treatment of patients. Therefore EFORT launched IPSI, The Implant and Patient Safety Initiative, which starting from an inaugural workshop in 2021 issued a set of recommendations, notably through a subsequent Delphi Process involving the National Member Societies of EFORT, European Specialty Societies as well as International Experts. These recommendations provide surgeons, researchers, implant manufacturers as well as patients and health authorities with a consensus of the development, implementation, and dissemination of innovation in the field of arthroplasty. The intended key outcomes of this 1st EFORT European Consensus on “Medical & Scientific Research Requirements for the Clinical Introduction of Artificial Joint Arthroplasty Devices”are consented, practical pathways to maintain innovation and optimisation of orthopaedic products and workflows within the boundaries of MDR 2017/745. Open Access practical guidelines based on adequate, state of the art pre-clinical and clinical evaluation methodologies for the introduction of joint replacements and implant-related instrumentation shall provide hands-on orientation for orthopaedic surgeons, research institutes and laboratories, orthopaedic device manufacturers, Notified Bodies but also for National Institutes and authorities, patient representatives and further stakeholders. We would like to acknowledge and thank the Scientific Committee members, all International Expert Delegates, the Delegates from European National & Specialty Societies and the Editorial Team for their outstanding contributions and support during this EFORT European Consensus

Doctor of Philosophy

dissertationComputational simulation has become an indispensable tool in the study of both basic mechanisms and pathophysiology of all forms of cardiac electrical activity. Because the heart is comprised of approximately 4 billion electrically active cells, it is not possible to geometrically model or computationally simulate each individual cell. As a result computational models of the heart are, of necessity, abstractions that approximate electrical behavior at the cell, tissue, and whole body level. The goal of this PhD dissertation was to evaluate several aspects of these abstractions by exploring a set of modeling approaches in the field of cardiac electrophysiology and to develop means to evaluate both the amplitude of these errors from a purely technical perspective as well as the impacts of those errors in terms of physiological parameters. The first project used subject specific models and experiments with acute myocardial ischemia to show that one common simplification used to model myocardial ischemia-the simplest form of the border zone between healthy and ischemic tissue-was not supported by the experimental results. We propose a alternative approximation of the border zone that better simulates the experimental results. The second study examined the impact of simplifications in geometric models on simulations of cardiac electrophysiology. Such models consist of a connected mesh of polygonal elements and must often capture complex external and internal boundaries. A conforming mesh contains elements that follow closely the shapes of boundaries; nonconforming meshes fit the boundaries only approximately and are easier to construct but their impact on simulation accuracy has, to our knowledge, remained unknown. We evaluated the impact of this simplification on a set of three different forms of bioelectric field simulations. The third project evaluated the impact of an additional geometric modeling error; positional uncertainty of the heart in simulations of the ECG. We applied a relatively novel and highly efficient statistical approach, the generalized Polynomial Chaos-Stochastic Collocation method (gPC-SC), to a boundary element formulation of the electrocardiographic forward problem to carry out the necessary comprehensive sensitivity analysis. We found variations large enough to mask or to mimic signs of ischemia in the ECG