Biomechanical evaluation of CAD/CAM magnesium miniplates as a fixation strategy for the treatment of segmental mandibular reconstruction with a fibula free flap.

Titanium patient-specific (CAD/CAM) plates are frequently used in mandibular reconstruction. However, titanium is a very stiff, non-degradable material which also induces artifacts in the imaging. Although magnesium has been proposed as a potential material alternative, the biomechanical conditions in the reconstructed mandible under magnesium CAD/CAM plate fixation are unknown. This study aimed to evaluate the primary fixation stability and potential of magnesium CAD/CAM miniplates. The biomechanical environment in a one segmental mandibular reconstruction with fibula free flap induced by a combination of a short posterior titanium CAD/CAM reconstruction plate and two anterior CAD/CAM miniplates of titanium and/or magnesium was evaluated, using computer modeling approaches. Output parameters were the strains in the healing regions and the stresses in the plates. Mechanical strains increased locally under magnesium fixation. Two plate-protective constellations for magnesium plates were identified: (1) pairing one magnesium miniplate with a parallel titanium miniplate and (2) pairing anterior magnesium miniplates with a posterior titanium reconstruction plate. Due to their degradability and reduced stiffness in comparison to titanium, magnesium plates could be beneficial for bone healing. Magnesium miniplates can be paired with titanium plates to ensure a non-occurrence of plate failure.

Reduced Bone Regeneration in Rats With Type 2 Diabetes Mellitus as a Result of Impaired Stromal Cell and Osteoblast Function-A Computer Modeling Study.

Bone has the fascinating ability to self-regenerate. However, under certain conditions, such as type 2 diabetes mellitus (T2DM), this ability is impaired. T2DM is a chronic metabolic disease known by the presence of elevated blood glucose levels that is associated with reduced bone regeneration capability, high fracture risk, and eventual non-union risk after a fracture. Several mechanical and biological factors relevant to bone regeneration have been shown to be affected in a diabetic environment. However, whether impaired bone regeneration in T2DM can be explained due to mechanical or biological alterations remains unknown. To elucidate the relevance of either one, the aim of this study was to investigate the relative contribution of T2DM-related alterations on either cellular activity or mechanical stimuli driving bone regeneration. A previously validated in silico computer modeling approach that was capable of explaining bone regeneration in uneventful conditions of healing was further developed to investigate bone regeneration in T2DM. Aspects analyzed included the presence of mesenchymal stromal cells (MSCs), cellular migration, proliferation, differentiation, apoptosis, and cellular mechanosensitivity. To further verify the computer model findings against in vivo data, an experimental setup was replicated, in which regeneration was compared in healthy and diabetic after a rat femur bone osteotomy stabilized with plate fixation. We found that mechanical alterations had little effect on the reduced bone regeneration in T2DM and that alterations in MSC proliferation, MSC migration, and osteoblast differentiation had the highest effect. In silico predictions of regenerated bone in T2DM matched qualitatively and quantitatively those from ex vivo µCT at 12 weeks post-surgery when reduced cellular activities reported in previous in vitro and in vivo studies were included in the model. The presented findings here could have clinical implications in the treatment of bone fractures in patients with T2DM. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Patients ' perspectives on bone replacement materials in a German university hospital setting.

BACKGROUND: The challenges in developing new bone replacement materials and procedures reside not solely in technological innovation and advancement, but also in a broader patient therapy acceptance. Therefore, there is a need to assess patients' perspectives on the materials and approaches in use as well as the ones being developed to better steer future progress in the field. METHODS: A self-initiating cross-sectional questionnaire aimed at people seeking treatment at the university hospital environment of Charité Berlin was formulated. The survey contained 15 close-ended questions directed toward the participant's epidemiological profile, willingness, acceptance, and agreement to receive different bone replacement materials, as well as, worries about the post-surgical consequences that can arise post bone replacement surgery. Descriptive and categorical analysis was performed to compare the observed number of subjects, their profile and each related response (Pearson's chi-square test or Fischer's test, p < 0.05). RESULTS: A total of 198 people engaged with the questionnaire, most of them Millennials. Overall patients trusted scientifically developed biomaterials designed for bone replacement, as demonstrated by their willingness to participate in a clinical trial, their acceptance of alloplastic materials, and the none/few worries about the presence of permanent implants. The data revealed the preferences of patients towards autologous sources of cells and blood to be used with a biomaterial. The data have also shown that both generation and education influenced willingness to participate in a clinical trial and acceptance of alloplastic materials, as well as, worries about the presence of permanent implants and agreement to receive a material with pooled blood and cells. CONCLUSION: Patients were open to the implantation of biomaterials for bone replacement, with a preference toward autologous sources of blood and/or tissue. Moreover, patients are concerned about strategies based on permanent implants, which indicates a need for resorbable materials. The knowledge gained in this study supports the development of new bone biomaterials.

Clinical and Technical Validation of Novel Bite Force Measuring Device for Functional Analysis after Mandibular Reconstruction.

Bite force measuring devices that are generally suitable for edentulous patients or patients undergoing mandibular reconstruction are missing. This study assesses the validity of a new bite force measuring device (prototype of loadpad®, novel GmbH) and evaluates its feasibility in patients after segmental mandibular resection. Accuracy and reproducibility were analyzed with two different protocols using a universal testing machine (Z010 AllroundLine, Zwick/Roell, Ulm, Germany). Four groups were tested to evaluate the impact of silicone layers around the sensor: no silicone ("pure"), 2.0 mm soft silicone ("2-soft"), 7.0 mm soft silicone ("7-soft") and 2.0 mm hard silicone ("2-hard"). Thereafter, the device was tested in 10 patients prospectively who underwent mandibular reconstruction using a fibula free flap. Average relative deviations of the measured force in relation to the applied load reached 0.77% ("7-soft") to 5.28% ("2-hard"). Repeated measurements in "2-soft" revealed a mean relative deviation of 2.5% until an applied load of 600 N. Maximum bite force decreased postoperatively by 51.8% to a maximum mean bite force of 131.5 N. The novel device guarantees a high accuracy and degree of reproducibility. Furthermore, it offers new opportunities to quantify perioperative oral function after reconstructive surgery of the mandible also in edentulous patients.

On the role of mechanical signals on sprouting angiogenesis through computer modeling approaches.

Sprouting 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.

Computer-assisted preoperative planning of bone fracture fixation surgery: A state-of-the-art review.

Background: Bone fracture fixation surgery is one of the most commonly performed surgical procedures in the orthopedic field. However, fracture healing complications occur frequently, and the choice of the most optimal surgical approach often remains challenging. In the last years, computational tools have been developed with the aim to assist preoperative planning procedures of bone fracture fixation surgery. Objectives: The aims of this review are 1) to provide a comprehensive overview of the state-of-the-art in computer-assisted preoperative planning of bone fracture fixation surgery, 2) to assess the clinical feasibility of the existing virtual planning approaches, and 3) to assess their clinical efficacy in terms of clinical outcomes as compared to conventional planning methods. Methods: A literature search was performed in the MEDLINE-PubMed, Ovid-EMBASE, Ovid-EMCARE, Web of Science, and Cochrane libraries to identify articles reporting on the clinical use of computer-assisted preoperative planning of bone fracture fixation. Results: 79 articles were included to provide an overview of the state-of-the art in virtual planning. While patient-specific geometrical model construction, virtual bone fracture reduction, and virtual fixation planning are routinely applied in virtual planning, biomechanical analysis is rarely included in the planning framework. 21 of the included studies were used to assess the feasibility and efficacy of computer-assisted planning methods. The reported total mean planning duration ranged from 22 to 258 min in different studies. Computer-assisted planning resulted in reduced operation time (Standardized Mean Difference (SMD): -2.19; 95% Confidence Interval (CI): -2.87, -1.50), less blood loss (SMD: -1.99; 95% CI: -2.75, -1.24), decreased frequency of fluoroscopy (SMD: -2.18; 95% CI: -2.74, -1.61), shortened fracture healing times (SMD: -0.51; 95% CI: -0.97, -0.05) and less postoperative complications (Risk Ratio (RR): 0.64, 95% CI: 0.46, 0.90). No significant differences were found in hospitalization duration. Some studies reported improvements in reduction quality and functional outcomes but these results were not pooled for meta-analysis, since the reported outcome measures were too heterogeneous. Conclusion: Current computer-assisted planning approaches are feasible to be used in clinical practice and have been shown to improve clinical outcomes. Including biomechanical analysis into the framework has the potential to further improve clinical outcome.

A mechanobiological computer optimization framework to design scaffolds to enhance bone regeneration.

The treatment of large bone defects is a clinical challenge. 3D printed scaffolds are a promising treatment option for such critical-size defects. However, the design of scaffolds to treat such defects is challenging due to the large number of variables impacting bone regeneration; material stiffness, architecture or equivalent scaffold stiffness-due it specific architecture-have all been demonstrated to impact cell behavior and regeneration outcome. Computer design optimization is a powerful tool to find optimal design solutions within a large parameter space for given anatomical constraints. Following this approach, scaffold structures have been optimized to avoid mechanical failure while providing beneficial mechanical stimulation for bone formation within the scaffold pores immediately after implantation. However, due to the dynamics of the bone regeneration process, the mechanical conditions do change from immediately after surgery throughout healing, thus influencing the regeneration process. Therefore, we propose a computer framework to optimize scaffold designs that allows to promote the final bone regeneration outcome. The framework combines a previously developed and validated mechanobiological bone regeneration computer model, a surrogate model for bone healing outcome and an optimization algorithm to optimize scaffold design based on the level of regenerated bone volume. The capability of the framework is verified by optimization of a cylindrical scaffold for the treatment of a critical-size tibia defect, using a clinically relevant large animal model. The combined framework allowed to predict the long-term healing outcome. Such novel approach opens up new opportunities for sustainable strategies in scaffold designs of bone regeneration.

Increased rate of pseudarthrosis in the anterior intersegmental gap after mandibular reconstruction with fibula free flaps: a volumetric analysis.

OBJECTIVES: Pseudarthrosis after mandibular reconstruction leads to chronic overload of the osteosynthesis and impedes dental rehabilitation. This study evaluates the impact of gap site on osseous union in mandible reconstruction using a new volumetric analysis method with repeated cone-beam computed tomography (CBCT). METHODS: The degree of bone regeneration was evaluated in 16 patients after mandible reconstruction with a fibula free flap and patient-specific reconstruction plates. Percentual bone volume and width changes in intersegmental gaps were retrospectively analyzed using a baseline CBCT in comparison to a follow-up CBCT. Patients' characteristics, plate-related complications, and gap sites (anterior/posterior) were analyzed. Detailed assessments of both gap sites (buccal/lingual/superior/inferior) were additionally performed. RESULTS: Intersegmental gap width (p = 0.002) and site (p < 0.001) significantly influence bone volume change over two consecutive CBCTs. An initial larger gap width resulted in a lower bone volume change. In addition, anterior gaps showed significantly less bone volume changes. Initial gap width was larger at posterior segmental gaps (2.97 vs 1.65 mm, p = 0.017). CONCLUSIONS: A methodology framework has been developed that allows to quantify pseuarthrosis in reconstructed mandibles using CBCT imaging. The study identifies the anterior segmental gap as a further risk factor for pseudarthrosis in reconstructions with CAD/CAM reconstruction plates. Future research should evaluate whether this outcome is related to the biomechanics induced at this site.

Initial mechanical conditions within an optimized bone scaffold do not ensure bone regeneration - an in silico analysis.

Large bone defects remain a clinical challenge because they do not heal spontaneously. 3-D printed scaffolds are a promising treatment option for such critical defects. Recent scaffold design strategies have made use of computer modelling techniques to optimize scaffold design. In particular, scaffold geometries have been optimized to avoid mechanical failure and recently also to provide a distinct mechanical stimulation to cells within the scaffold pores. This way, mechanical strain levels are optimized to favour the bone tissue formation. However, bone regeneration is a highly dynamic process where the mechanical conditions immediately after surgery might not ensure optimal regeneration throughout healing. Here, we investigated in silico whether scaffolds presenting optimal mechanical conditions for bone regeneration immediately after surgery also present an optimal design for the full regeneration process. A computer framework, combining an automatic parametric scaffold design generation with a mechano-biological bone regeneration model, was developed to predict the level of regenerated bone volume for a large range of scaffold designs and to compare it with the scaffold pore volume fraction under favourable mechanical stimuli immediately after surgery. We found that many scaffold designs could be considered as highly beneficial for bone healing immediately after surgery; however, most of them did not show optimal bone formation in later regenerative phases. This study allowed to gain a more thorough understanding of the effect of scaffold geometry changes on bone regeneration and how to maximize regenerated bone volume in the long term.

Bone morphogenetic protein 2-induced cellular chemotaxis drives tissue patterning during critical-sized bone defect healing: an in silico study.

Critical-sized bone defects are critical healing conditions that, if left untreated, often lead to non-unions. To reduce the risk, critical-sized bone defects are often treated with recombinant human BMP-2. Although enhanced bone tissue formation is observed when BMP-2 is administered locally to the defect, spatial and temporal distribution of callus tissue often differs from that found during regular bone healing or in defects treated differently. How this altered tissue patterning due to BMP-2 treatment is linked to mechano-biological principles at the cellular scale remains largely unknown. In this study, the mechano-biological regulation of BMP-2-treated critical-sized bone defect healing was investigated using a multiphysics multiscale in silico approach. Finite element and agent-based modeling techniques were combined to simulate healing within a critical-sized bone defect (5 mm) in a rat femur. Computer model predictions were compared to in vivo microCT data outcome of bone tissue patterning at 2, 4, and 6 weeks postoperation. In vivo, BMP-2 treatment led to complete healing through periosteal bone bridging already after 2 weeks postoperation. Computer model simulations showed that the BMP-2 specific tissue patterning can be explained by the migration of mesenchymal stromal cells to regions with a specific concentration of BMP-2 (chemotaxis). This study shows how computational modeling can help us to further understand the mechanisms behind treatment effects on compromised healing conditions as well as to optimize future treatment strategies.

Age-Related Changes in the Mechanical Regulation of Bone Healing Are Explained by Altered Cellular Mechanoresponse.

Increasing age is associated with a reduced bone regeneration potential and increased risk of morbidities and mortality. A reduced bone formation response to mechanical loading has been shown with aging, and it remains unknown if the interplay between aging and mechanical stimuli during regeneration is similar to adaptation. We used a combined in vivo/in silico approach to investigate age-related alterations in the mechanical regulation of bone healing and identified the relative impact of altered cellular function on tissue patterns during the regenerative cascade. To modulate the mechanical environment, femoral osteotomies in adult and elderly mice were stabilized using either a rigid or a semirigid external fixator, and the course of healing was evaluated using histomorphometric and micro-CT analyses at 7, 14, and 21 days post-surgery. Computer models were developed to investigate the influence of the local mechanical environment within the callus on tissue formation patterns. The models aimed to identify the key processes at the cellular level that alter the mechanical regulation of healing with aging. Fifteen age-related biological alterations were investigated on two levels (adult and elderly) with a design of experiments setup. We show a reduced response to changes in fixation stability with age, which could be explained by reduced cellular mechanoresponse, simulated as alteration of the ranges of mechanical stimuli driving mesenchymal stem cell differentiation. Cellular mechanoresponse has been so far widely ignored as a therapeutic target in aged patients. Our data hint to mechanotherapeutics as a potential treatment to enhance bone healing in the elderly. © 2019 American Society for Bone and Mineral Research.

Computational Modeling to Quantify the Contributions of VEGFR1, VEGFR2, and Lateral Inhibition in Sprouting Angiogenesis.

Sprouting 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.

The emergence of extracellular matrix mechanics and cell traction forces as important regulators of cellular self-organization.

Physical cues play a fundamental role in a wide range of biological processes, such as embryogenesis, wound healing, tumour invasion and connective tissue morphogenesis. Although it is well known that during these processes, cells continuously interact with the local extracellular matrix (ECM) through cell traction forces, the role of these mechanical interactions on large scale cellular and matrix organization remains largely unknown. In this study, we use a simple theoretical model to investigate cellular and matrix organization as a result of mechanical feedback signals between cells and the surrounding ECM. The model includes bi-directional coupling through cellular traction forces to deform the ECM and through matrix deformation to trigger cellular migration. In addition, we incorporate the mechanical contribution of matrix fibres and their reorganization by the cells. We show that a group of contractile cells will self-polarize at a large scale, even in homogeneous environments. In addition, our simulations mimic the experimentally observed alignment of cells in the direction of maximum stiffness and the building up of tension as a consequence of cell and fibre reorganization. Moreover, we demonstrate that cellular organization is tightly linked to the mechanical feedback loop between cells and matrix. Cells with a preference for stiff environments have a tendency to form chains, while cells with a tendency for soft environments tend to form clusters. The model presented here illustrates the potential of simple physical cues and their impact on cellular self-organization. It can be used in applications where cell-matrix interactions play a key role, such as in the design of tissue engineering scaffolds and to gain a basic understanding of pattern formation in organogenesis or tissue regeneration.

Simulation of angiogenesis and cell differentiation in a CaP scaffold subjected to compressive strains using a lattice modeling approach.

Mechanical 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.

Corroboration of mechanobiological simulations of tissue differentiation in an in vivo bone chamber using a lattice-modeling approach.

It is well established that the mechanical environment modulates tissue differentiation, and a number of mechanoregulatory theories for describing the process have been proposed. In this study, simulations of an in vivo bone chamber experiment were performed that allowed direct comparison with experimental data. A mechanoregulation theory for mesenchymal stem cell differentiation based on a combination of fluid flow and shear strain (computed using finite element analysis) was implemented to predict tissue differentiation inside mechanically controlled bone chambers inserted into rat tibae. To simulate cell activity, a lattice approach with stochastic cell migration, proliferation, and selected differentiation was adopted; because of its stochastic nature, each run of the simulation gave a somewhat different result. Simulations predicted the load-dependency of the tissue differentiation inside the chamber and a qualitative agreement with histological data; however, the full variability found between specimens in the experiment could not be predicted by the mechanoregulation algorithm. This result raises the question whether tissue differentiation predictions can be linked to genetic variability in animal populations.