156 research outputs found
Determining the optimal mechanical requirements for early intervention devices in the knee
No full textInterpositional arthroplasty is a treatment option for isolated medial compartment
osteoarthritis of the knee. No bone resection and no mechanical fixation
are the main advantages of this procedure. However post-operative problems,
such as implant dislocation, swelling and severe knee pain have been generally
observed. Since these problems are related to the motions and loads occurring
at the knee and probably to design factors of the implant, there is a need to
investigate the kinematics and contact mechanics of the knee implanted with an
interpositional spacer and its differences with respect to the normal knee. Although
the knee joint is routinely involved in dynamic activities, to date, no
experimental or numerical studies have investigated the kinematics and contact
mechanics of the normal knee joint during dynamic loading conditions, most of
the experimental and finite element studies are static or quasi-static in nature.
Hence the purpose of this study was to investigate: 1) the behaviour of the
normal knee joint under dynamic loading conditions, 2) the performance of a
knee implanted with an interpositional spacer and 3) the effect of several implant
design parameters on the behaviour of the implanted knee. The kinematics and
contact pressures of the normal knee joint during the activities of walking, stair
ascent and squatting were obtained using dynamic finite element analysis. Higher
contact pressures were predicted when applying more demanding loads, during
the simulation of the squatting and stair ascent activities. Similar ranges of motion
were predicted for the three activities simulated, despite the difference in the
magnitude of the loads applied, due to the restraining function of the ligaments
and the geometry of the surfaces into contact. In the second study, the kinematics
and contact pressures of a knee implanted with a polyurethane interpositional
spacer were obtained and compared to the normal knee. In general, for the three
activities simulated, the implanted knee was able to follow the kinematics of the
normal knee, however higher contact pressures were predicted in the medial side
of the tibial and femoral articular cartilages, which could increase the propensity
for articular cartilage degeneration. In the third study, the influence of implant
material, size, thickness and radii of the bearing surface in anterior/posterior and
medial/lateral directions was assessed. A hard material compared to the menisci,
such as a cobalt-chromium alloy, caused higher contact pressures in both the medial
and lateral side of the knee. Implant size did not affect the kinematics or
contact pressures in the knee, however anterior dislocation of the implant was
observed for a large spacer during the squatting activity. Thickness and radii of
the bearing surface did not show any significant influence on the kinematics or
contact pressures
Influence of an interpositional spacer on the behaviour of the tibiofemoral joint: a finite element study
No full textBackground: interpositional arthroplasty is considered by many surgeons for the treatment of isolated medial compartment osteoarthritis of the knee. In this procedure, an interpositional spacer is inserted into the medial compartment of the joint with no bone resection and no mechanical fixation. Major problems such as implant dislocation, severe pain or need for revision have been reported post-operatively.Methods: in this study, the kinematics of a knee implanted with an interpositional spacer made of either polyurethane or cobalt–chrome during walking, stair ascent and squatting cycles have been predicted and compared to the normal knee using finite element analysis. In addition, articular cartilage stress histories have been examined to obtain distributions of cumulative stress, a measure of the likelihood of articular cartilage degeneration.Findings: the insertion of a polyurethane interpositional spacer in the medial side of the knee did not affect knee kinematics as compared to the normal knee, but caused an increase of articular cartilage cumulative contact stress exposures in the medial compartment of the joint. The knee implanted with the Co–Cr spacer exhibited similar trends in knee kinematics, however significantly different ranges of motion were observed during some periods of the activity cycles, specifically during the first half of the walking cycle where lower ranges of motion were predicted. In addition, higher articular cartilage cumulative contact stress exposures were observed in both compartments of the knee. In both cases, cumulative contact stress exposures of the tibial articular cartilage were more affected than those of the femoral articular cartilage.Interpretation: these results suggest implant material as an important parameter in the design phase of interpositional spacer
Finite element study of fractured mandible in human and sheep
No full textOsteosynthesis is one of the most discussed and investigated subjects in the orthopaedic literature. Mandible fractures are reported as one of the main causes of facial injury and their impact on patient life may bring serious consequences, compromising masticatory function, speech and facial aesthetics.
Current treatments for mandibular simple fractures include the use of load-sharing devices such as titanium miniplates and screws, which have the role of fixing the fracture ends and restore the facial continuity. Fixation systems ultimately aim to
generate the optimum mechanical strains within the fracture region, which will promote the bone healing process. However, there is not a clear understanding of the influence of fixation stability on the biomechanics of stabilized mandibular
fractures, particularly when using biomaterials different from titanium. The aim of this study is to investigate the biomechanical response of fractured mandible using traditional titanium miniplates and alternative fixation systems made of magnesium alloys. With a view on future preclinical evaluation of these new devices, both human and sheep models are investigated
On the role of mechanical signals on sprouting angiogenesis through computer modeling approaches
No full textSprouting angiogenesis, the formation of new vessels from preexisting vasculature, is an essential process in the regeneration of new tissues as well as in the development of some diseases like cancer. Although early studies identified chemical signaling as the main driver of this process, many recent studies have shown a strong role of mechanical signals in the formation of new capillaries. Different types of mechanical signals (e.g., external forces, cell traction forces, and blood flow-induced shear forces) have been shown to play distinct roles in the process; however, their interplay remains still largely unknown. During the last decades, mathematical and computational modeling approaches have been developed to investigate and better understand the mechanisms behind mechanically driven angiogenesis. In this manuscript, we review computational models of angiogenesis with a focus on models investigating the role of mechanics on the process. Our aim is not to provide a detailed review on model methodology but to describe what we have learnt from these models. We classify models according to the mechanical signals being investigated and describe how models have looked into their role on the angiogenic process. We show that a better understanding of the mechanobiology of the angiogenic process will require the development of computer models that incorporate the interactions between the multiple mechanical signals and their effect on cellular responses, since they all seem to play a key in sprout patterning. In the end, we describe some of the remaining challenges of computational modeling of angiogenesis and discuss potential avenues for future research
Multiscale agent-based computer models in skeletal tissue regeneration
No full textBone regeneration is a fascinating process in which, after injury, bone is able to regain full functionality without scar formation. Although the process is successful in most cases, there are conditions in which the bone fails to heal leading to delayed or nonunions (e.g., large segmental defects due to trauma or cancer). The treatment of those conditions remains a clinical challenge; therefore, a full understanding of the regeneration process is needed to develop new treatment strategies. Bone regeneration involves many different processes at multiple length and time scales (intracellular, cellular, tissue, organ). Understanding the process as a whole requires assessing how individual events interact within and across the different scales. Experimental approaches are usually focused on understanding specific processes occurring at a single scale, making it difficult to assess their relevance to the overall process. Computer modeling techniques are a powerful tool to investigate across scales processes. In particular, agent-based modeling approaches are especially well suited to study the bone regeneration response. In this chapter, we describe the main components of agent-based models, how they can be used to investigate bone regeneration at the different time and length scales, and provide simple examples of the integration between the different scales
Computer-aided scaffold design optimization towards enhanced bone regeneration
No full textLarge bone defects remain a clinical challenge, with a gold standard treatment - autologous bone graft - that presents many drawbacks. Design optimized scaffolds appear as a promising alternative [1]; however, bone scaffold design remains a trial and error approach where some specific properties (porosity, mechanical properties, etc) are individually optimized. Thus, the aim of this study was to develop a computer-aided scaffold design optimisation framework towards enhanced bone regeneration, taking into account the dynamics of the bone regeneration process.
A computer model of scaffold-guided bone regeneration was developed and tested against different experimental setups that have used different scaffold designs for large bone defect healing in large animal models [2,3]. The model takes into account the scaffold design (architecture and material properties) as well as its interaction with different cellular processes (e.g. migration). Computer model predictions of bone tissue formation within the scaffold pores were compared against in vivo experimental data. The validated model was then used to develop a computer framework that allow us to optimize the scaffold design with the objective of achieving maximum bone regeneration.
The computer model of scaffold-supported bone regeneration is able to explain experimental observations of bone tissue formation within a honeycomb titanium scaffold and a strut-based PCL-βTCP scaffold. In both experimental settings, scaffold surface guidance was predicted to play a key role on the regulation of cellular activity. Computer-aided optimization resulted in a scaffold design which was predicted to achieve almost complete bone regeneration within a large bone defect.
We have developed a framework that allows 1) to investigate the mechanisms behind scaffold-supported bone regeneration and 2) to optimize the scaffold design to achieve maximum bone regeneration. Although, the computer model of bone regeneration has shown promising results in different experimental settings, further testing of the model and validation against experimental data is needed to ensure model robustness. The optimization framework allows shape optimization of specific scaffold designs. Future studies will focus on the validation of the optimization framework
Mehrskalen In Silico Modell zur Untersuchung von beeinträchtigter Knochenheilung
No full textMechanics plays a key role in bone regeneration as it modulates the biological events taking place during the process. Extensive research has been done on elucidating the mechanical “rules” driving bone regeneration in uneventful healing conditions. However, under compromised healing conditions (e.g. aging, large bone defects) the mechanical regulation of healing might be altered and result in delayed healing or non-unions. The aim of this thesis was to investigate to what degree the mechano-regulation rules that have been identified for regular, uneventful healing still play a role in more challenging conditions. Among these conditions, aging and large bone defects were the focus of this study. The influence of mechanics on therapeutic solutions, as bone morphogenetic protein 2 (BMP-2), was also investigated to understand its role in the treatment of critical healing conditions.
A multiscale in silico approach that combined finite element analysis and agent-based computer models was used to simulate the bone healing process. The mechanical signals within the bone healing region were investigated using finite element techniques. Agent-based computer models simulated the cellular dynamics and BMP-2 concentration patterning within the callus. Computer model predictions were then compared to in vivo micro CT and histological data at several time points over the course of healing. Aging effects on the mechano-regulation of healing was investigated in silico by using a design of experiment approach. The mechanobiological regulation of large bone defect healing was investigated in untreated conditions, under BMP-2 provision, under additional mechanical stimulation and under the combination of the two treatments.
The bone healing response to mechanical stimulation was observed to change with age. Reduction of cell mechano-response with aging could explain the differences on bone healing outcomes between adult and elderly mice under different mechanical stability. Limited cellular activity could explain non unions within untreated large bone defects. Furthermore, encapsulation of the medullary cavity was predicted in large defects due to an adverse mechanical environment. BMP-2 stimulated healing could be explained by its capacity to attract mesenchymal cells to migrate to the center of the fracture. Under BMP-2 treatment, the formation of a rigid callus since the first stages of healing was observed to weaken the contribution of additional mechanical stimulation on bone defect healing.
This study shows that mechanics plays a key role also in compromised healing conditions. Age-related reduction of cellular mechano-response points out the importance of mechanical stimulation as potential rehabilitative therapy for elderly patients. Under the mechanical environment that characterizes large bone defects, limited migration of mesenchymal cells was observed to lead to marrow encapsulation. Dose-Regulated chemotaxis was identified as a strong promoter to bridge the defect extremities and guarantee successful healing in critical conditions.Die Mechanik spielt eine Schlüsselrolle bei der Knochenregeneration, indem sie die biologischen Vorgänge dieses Prozesses beeinflusst. Umfangreiche Studien zur Aufklärung der mechanischen „Regeln“, die die Knochenregeneration unter komplikationslosen Heilungsbedingungen erforschen, wurden bereits durchgeführt. Allerdings kann unter beeinträchtigten Heilungsbedingungen (z.B. Alterung, große Knochendefekte) die mechanische Regulation der Heilung verändert werden und zu verzögerter Heilung oder Pseudoarthrose führen. Das Ziel dieser Doktorarbeit war zu untersuchen, inwiefern mechanisch-regulierende Regeln, die bei normaler, komplikationsloser Heilung identifiziert wurden, noch eine Rolle unter beeinträchtigten Bedingungen spielen. Unter diesen Bedingungen standen das Altern und große Knochendefekte im Mittelpunkt dieser Studie. Der Einfluss der Mechanik auf therapeutische Lösungen, wie die Anwendung des knochenmorphogenetischen Protein 2 (BMP-2), wurde ebenfalls untersucht, um deren Rolle in der Behandlung kritischer Heilungsbedingungen zu verstehen.
Ein skalenübergreifender in silico Ansatz, der Finite-Elemente-Analyse mit agentenbasierten Computermodellen kombiniert, wurde verwendet, um den Knochenheilungsprozess zu simulieren. Die mechanischen Signale in der Region der Knochenheilung wurden mit Finite-Elemente-Methoden untersucht. Agentenbasierte Computermodelle simulierten die Zelldynamik und BMP-2-Konzentrationsmuster innerhalb des Kallus. Die Vorhersagen des Computermodells wurden dann mit in vivo Mikro-CT und histologischen Daten an mehreren Zeitpunkten im Verlauf der Heilung verglichen. Der Einfluss von Alter auf die mechanische Regulierung der Heilung wurde anhand eines Design of Experiment Ansatzes in silico untersucht. Die mechanobiologische Regulierung der Heilung großer Knochendefekte wurde unter unbehandelten Bedingungen, unter BMP-2-Versorgung, unter zusätzlicher mechanischer Stimulierung und unter der Kombination der beiden Behandlungen untersucht.
Es wurde beobachtet, dass sich die Reaktion der Knochenheilung auf mechanische Stimulierung mit dem Alter verändert. Eine altersbedingte Reduzierung der mechanischen Reaktion der Zellen könnte die Unterschiede des Knochenheilungsergebnisses zwischen erwachsenen und älteren Mäusen bei unterschiedlicher mechanischer Stabilität erklären. Beschränkte Zellaktivität in dieser Population könnte hingegen Pseudoarthrose in großen Knochendefekten begründen. Darüber hinaus wurde die Verkapselung der Markhöhle in großen Defekten aufgrund einer ungünstigen mechanischen Umgebung vorhergesagt. BMP-2-stimulierte Heilung konnte dadurch erklärt werden, dass dieser Wachstumsfaktor die Migration mesenchymaler Zellen in die Frakturmitte bewirkt. Unter BMP-2 Behandlung wurde beobachtet, dass die Bildung eines rigiden Kallus in der initialen Heilungsphase den Beitrag zusätzlicher mechanischer Stimulierung zur Knochendefektheilung schwächt.
Diese Studie zeigt, dass die Mechanik auch unter beeinträchtigten Heilungsbedingungen eine Schlüsselrolle spielt. Die altersbedingte Reduzierung der zellulären Mechano-Reaktion weist auf die Bedeutung der mechanischen Stimulation als mögliche rehabilitative Therapie für ältere Patienten hin. Unter der für große Knochendefekte spezifischen mechanischen Umgebung wurde beobachtet, dass eine begrenzte Migration von mesenchymalen Zellen zu einer Verkapselung des Knochenmarks führte. Es wurde festgestellt, dass eine dosisregulierte Chemotaxis die Überbrückung der defekten Extremitäten stark fördert und eine erfolgreiche Heilung unter kritischen Bedingungen gewährleistet
Computational modeling to quantify the contributions of VEGFR1, VEGFR2, and lateral inhibition in sprouting angiogenesis
No full textSprouting angiogenesis is a necessary process in regeneration and development as well as in tumorigenesis. VEGF-A is the main pro-angiogenic chemoattractant and it can bind to the decoy receptor VEGFR1 or to VEGFR2 to induce sprouting. Active sprout cells express Dll4, which binds to Notch1 on neighboring cells, in turn inhibiting VEGFR2 expression. It is known that the balance between VEGFR2 and VEGFR1 determines tip selection and network architecture, however the quantitative interrelationship of the receptors and their interrelated balances, also with relation to Dll4-Notch1 signaling, remains yet largely unknown. Here, we present an agent-based computer model of sprouting angiogenesis, integrating VEGFR1 and VEGFR2 in a detailed model of cellular signaling. Our model reproduces experimental data on VEGFR1 knockout. We show that soluble VEGFR1 improves the efficiency of angiogenesis by directing sprouts away from existing cells over a wide range of parameters. Our analysis unravels the relevance of the stability of the active notch intracellular domain as a dominating hub in this regulatory network. Our analysis quantitatively dissects the regulatory interactions in sprouting angiogenesis. Because we use a detailed model of intracellular signaling, the results of our analysis are directly linked to biological entities. We provide our computational model and simulation engine for integration in complementary modeling approaches
Simulation of angiogenesis and cell differentiation in a CaP scaffold subjected to compressive strains using a lattice modeling approach
No full textMechanical stimuli are one of the factors that influence tissue differentiation. In the development of biomaterials for bone tissue engineering, mechanical stimuli and formation of a vascular network that transport oxygen to cells within the pores of the scaffolds are essential. Angiogenesis and cell differentiation have been simulated in scaffolds of regular porosity; however, the dynamics of differentiation can be different when the porosity is not uniform. The objective of this study was to investigate the effect of the mechanical stimuli and the capillary network formation on cell differentiation within a scaffold of irregular morphology. A porous scaffold of calcium phosphate based glass was used. The pores and the solid phase were discretized using micro computed tomography images. Cell activity was simulated within the interconnected pore domain of the scaffold using a lattice modeling approach. Compressive strains of 0.5 and 1% of total deformation were applied and two cases of mesenchymal stem cells initialization (in vitro seeding and in vivo) were simulated. Similar capillary networks were formed independently of the cell initialization mode and the magnitude of the mechanical strain applied. Most of vessels grew in the pores at the periphery of the scaffolds and were blocked by the walls of the scaffold. When 0.5% of strain was applied, 70% of the pore volume was affected by mechano-regulatory stimuli corresponding to bone formation; however, because of the lack of oxygen, only 40% of the volume was filled with osteoblasts. 40% of volume was filled with chondrocytes and 3% with fibroblasts. When the mechanical strain was increased to 1%, 11% of the pore volume was filled with osteoblasts, 59% with chondrocytes, and 8% with fibroblasts. This study has shown the dynamics of the correlation between mechanical load, angiogenesis and tissue differentiation within a scaffold with irregular morphology
Examining tissue composition, whole-bone morphology and mechanical behavior of GorabPrx1 mice tibiae: A mouse model of premature aging
No full textGerodermia osteodysplastica (GO) is a segmental progeroid disorder caused by loss-of-function mutations in the GORAB gene, associated with early onset osteoporosis and bone fragility. A conditional mouse model of GO (GorabPrx1) was generated in which the Gorab gene was deleted in long bones. We examined the biomechanical/functional relevance of the GorabPrx1 mutants as a premature aging model by characterizing bone composition, tissue-level strains, and whole-bone morphology and mechanical properties of the tibia. MicroCT imaging showed that GorabPrx1 tibiae had an increased anterior convex curvature and decreased cortical cross-sectional area, cortical thickness and moments of inertia, compared to littermate control (LC) tibiae. Fourier transform infrared (FTIR) imaging indicated a 34% decrease in mineral/matrix ratio and a 27% increase in acid phosphate content in the posterior metaphyseal cortex of the GorabPrx1 tibiae (p <.05), suggesting delayed mineralization. In vivo strain gauge measurement and finite element analysis showed ∼two times higher tissue-level strains within the GorabPrx1 tibiae relative to LC tibiae when subjected to axial compressive loads of the same magnitude. Three-point bending tests suggested that GorabPrx1 tibiae were weaker and more brittle, as indicated by decreasing whole-bone strength (46%), stiffness (55%), work-to-fracture (61%) and post-yield displacement (47%). Many of these morphological and biomechanical characteristics of the GorabPrx1 tibia recapitulated changes in other animal models of skeletal aging. Future studies are necessary to confirm how our observations might guide the way to a better understanding and treatment of GO
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