External mechanical loading overrules cell-cell mechanical communication in sprouting angiogenesis during early bone regeneration.

Sprouting angiogenesis plays a key role during bone regeneration. For example, insufficient early revascularization of the injured site can lead to delayed or non-healing. During sprouting, endothelial cells are known to be mechano-sensitive and respond to local mechanical stimuli. Endothelial cells interact and communicate mechanically with their surroundings, such as outer-vascular stromal cells, through cell-induced traction forces. In addition, external physiological loads act at the healing site, resulting in tissue deformations and impacting cellular arrangements. How these two distinct mechanical cues (cell-induced and external) impact angiogenesis and sprout patterning in early bone healing remains however largely unknown. Therefore, the aim of this study was to investigate the relative role of externally applied and cell-induced mechanical signals in driving sprout patterning at the onset of bone healing. To investigate cellular self-organisation in early bone healing, an in silico model accounting for the mechano-regulation of sprouting angiogenesis and stromal cell organization was developed. Computer model predictions were compared to in vivo experiments of a mouse osteotomy model stabilized with a rigid or a semirigid fixation system. We found that the magnitude and orientation of principal strains within the healing region can explain experimentally observed sprout patterning, under both fixation conditions. Furthermore, upon simulating the selective inhibition of either cell-induced or externally applied mechanical cues, external mechanical signals appear to overrule the mechanical communication acting on a cell-cell interaction level. Such findings illustrate the relevance of external mechanical signals over the local cell-mediated mechanical cues and could be used in the design of fracture treatment strategies for bone regeneration.

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.

Effects of Long-Term Sclerostin Deficiency on Trabecular Bone Mass and Adaption to Limb Loading Differ in Male and Female Mice.

A new therapeutic option to treat osteoporosis is focused on Wnt signaling and its inhibitor sclerostin, a product of the Sost gene. In this work, we study the effect of sclerostin deficiency on trabecular bone formation and resorption in male and female mice and whether it affects mechano-responsiveness. Male and female 10- and 26-week-old Sost knockout (KO) and littermate controls (LCs) were subjected to in vivo mechanical loading of the left tibia for 2 weeks. The right tibia served as internal control. The mice were imaged using in vivo micro-computed tomography at days 0, 5, 10, and 15 and tibiae were collected for histomorphometric analyses after euthanasia. Histomorphometry and micro-CT-based 3D time-lapse morphometry revealed an anabolic and anti-catabolic effect of Sost deficiency although increased trabecular bone resorption accompanied by diminished trabecular bone formation occurred with age. Loading led to diminished resorption in adult female but not in male mice. A net gain in bone volume could be achieved with mechanical loading in Sost KO adult female mice, which occurred through a further reduction in resorbed bone volume. Our data show that sclerostin deficiency has a particularly positive effect in adult female mice. Sclerostin antibodies are approved to treat postmenopausal women with high risk of osteoporotic fractures. Further studies are required to clarify whether both sexes benefit equally from sclerostin inhibition.

Tomography-Based Quantification of Regional Differences in Cortical Bone Surface Remodeling and Mechano-Response.

Bone has an adaptive capacity to maintain structural integrity. However, there seems to be a heterogeneous cortical (re)modeling response to loading at different regions within the same bone, which may lead to inconsistent findings since most studies analyze only one region. It remains unclear if the local mechanical environment is responsible for this heterogeneous response and whether both formation and resorption are affected. Thus, we compared the formation and resorptive response to in vivo loading and the strain environment at two commonly analyzed regions in the mouse tibia, the mid-diaphysis and proximal metaphysis. We quantified cortical surface (re)modeling by tracking changes between geometrically aligned consecutive in vivo micro-tomography images (time lapse 15 days). We investigated the local mechanical strain environment using finite element analyses. The relationship between mechanical stimuli and surface (re)modeling was examined by sub-dividing the mid-diaphysis and proximal metaphysis into 32 sub-regions. In response to loading, metaphyseal cortical bone (re)modeled predominantly at the periosteal surface, whereas diaphyseal (re)modeling was more pronounced at the endocortical surface. Furthermore, different set points and slopes of the relationship between engendered strains and remodeling response were found for the endosteal and periosteal surfaces at the metaphyseal and diaphyseal regions. Resorption was correlated with strain at the endocortical, but not the periosteal surfaces, whereas, formation correlated with strain at all surfaces, except at the metaphyseal periosteal surface. Therefore, besides mechanical stimuli, other non-mechanical factors are likely driving regional differences in adaptation. Studies investigating adaptation to loading or other treatments should consider region-specific (re)modeling differences.

Relationship between nanoscale mineral properties and calcein labeling in mineralizing bone surfaces.

Bone's mineral properties, such as particle thickness and degree of alignment have been associated with bone quality. Bone formation, remodeling, aging of the tissue and mineral homeostasis influence mineral particle properties leading to specific patterns across bone. Scanning small angle X-ray scattering (sSAXS) with synchrotron radiation is a powerful tool, which allows us to study bone's nanoscale mineral properties in a position-resolved way. We used sSAXS, fluorescence light microscopy and backscattered electron (BSE) imaging to study bone's mineral properties at the tibial midshaft of in vivo-loaded mice. By combining these techniques, we could detect local changes in mineral properties. Regions labeled with calcein fluorochrome have lower mean mineral thickness and degree of mineral alignment. We also observed thinner and less aligned mineral particles near blood vessels. We conclude that mineral properties (i) are altered by fluorochrome labeling and (ii) depend on the proximity to blood vessels.

Spatial variations in the osteocyte lacuno-canalicular network density and analysis of the connectomic parameters.

Osteocyte lacuno-canalicular network (LCN) is comprised of micrometre-sized pores and submicrometric wide channels in bone. Accumulating evidence suggests multiple functions of this network in material transportation, mechanobiological signalling, mineral homeostasis and bone remodelling. Combining rhodamine staining and confocal laser scanning microscopy, the longitudinal cross-sections of six mouse tibiae were imaged, and the connectome of the network was quantified with a focus on the spatial heterogeneities of network density, connectivity and length of canaliculi. In-vivo loading and double calcein labelling on these tibiae allowed differentiating the newly formed bone from the pre-existing regions. The canalicular density of the murine cortical bone varied between 0.174 and 0.243 µm/µm3, and therefore is three times larger than the corresponding value for human femoral midshaft osteons. The spatial heterogeneity of the network was found distinctly more pronounced across the cortex than along the cortex. We found that in regions with a dense network, the LCN conserves its largely tree-like character, but increases the density by including shorter canaliculi. The current study on healthy mice should serve as a motivating starting point to study the connectome of genetically modified mice, including models of bone diseases and of reduced mechanoresponse.

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.

Computational design and evaluation of the mechanical and electrical behavior of a piezoelectric scaffold: a preclinical study.

Piezoelectric scaffolds have been recently developed to explore their potential to enhance the bone regeneration process using the concept of piezoelectricity, which also inherently occurs in bone. In addition to providing mechanical support during bone healing, with a suitable design, they are supposed to produce electrical signals that ought to favor the cell responses. In this study, using finite element analysis (FEA), a piezoelectric scaffold was designed with the aim of providing favorable ranges of mechanical and electrical signals when implanted in a large bone defect in a large animal model, so that it could inform future pre-clinical studies. A parametric analysis was then performed to evaluate the effect of the scaffold design parameters with regard to the piezoelectric behavior of the scaffold. The designed scaffold consisted of a porous strut-like structure with piezoelectric patches covering its free surfaces within the scaffold pores. The results showed that titanium or PCL for the scaffold and barium titanate (BT) for the piezoelectric patches are a promising material combination to generate favorable ranges of voltage, as reported in experimental studies. Furthermore, the analysis of variance showed the thickness of the piezoelectric patches to be the most influential geometrical parameter on the generation of electrical signals in the scaffold. This study shows the potential of computer tools for the optimization of scaffold designs and suggests that patches of piezoelectric material, attached to the scaffold surfaces, can deliver favorable ranges of electrical stimuli to the cells that might promote bone regeneration.

The decisive early phase of bone regeneration.

Bone has a remarkable endogenous regenerative capacity that enables scarless healing and restoration of its prior mechanical function, even under challenging conditions such as advanced age and metabolic or immunological degenerative diseases. However - despite much progress - a high number of bone injuries still heal with unsatisfactory outcomes. The mechanisms leading to impaired healing are heterogeneous, and involve exuberant and non-resolving immune reactions or overstrained mechanical conditions that affect the delicate regulation of the early initiation of scar-free healing. Every healing process begins phylogenetically with an inflammatory reaction, but its spatial and temporal intensity must be tightly controlled. Dysregulation of this inflammatory cascade directly affects the subsequent healing phases and hinders the healing progression. This Review discusses the complex processes underlying bone regeneration, focusing on the early healing phase and its highly dynamic environment, where vibrant changes in cellular and tissue composition alter the mechanical environment and thus affect the signalling pathways that orchestrate the healing process. Essential to scar-free healing is the interplay of various dynamic cascades that control timely resolution of local inflammation and tissue self-organization, while also providing sufficient local stability to initiate endogenous restoration. Various immunotherapy and mechanobiology-based therapy options are under investigation for promoting bone regeneration.

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.

In vivo tracking of segmental bone defect healing reveals that callus patterning is related to early mechanical stimuli.

This study addresses the hypothesis that callus formation, patterning, and mineralisation are impaired during the early phase of critical sized bone defect healing, and may relate to inter-fragmentary tissue strains within the bone defect area. Twenty four 12 week old Sprague Dawley rats were used for this study. They were divided into two groups defined by the femur bone defect size: (i) 1 mm resulting in normal healing (NH), and (ii) a large sized 5 mm defect resulting in critical healing (CH). Callus formation, patterning, and mineralisation kinetics in both groups were examined in the periosteal and osteotomy gap regions using a novel longitudinal study setup. Finite element analyses on µCT generated tomograms were used to determine inter-fragmentary tissue strain patterns and compared to callus formation and patterning over the course of time. Using a novel longitudinal study technique with µCT, in vivo tracking and computer simulation approaches, this study demonstrates that: (i) periosteal bone formation and patterning are significantly influenced by bone defect size as early as 2 weeks; (ii) osteotomy gap callus formation and patterning are influenced by bone defect size, and adapt towards a non-union in critical cases by deviating into a medullary formation route as early as 2 weeks after osteotomy; (iii) the new bone formation in the osteotomy gap enclosing the medullary cavity in the CH group is highly mineralised; (iv) inter-fragmentary strain patterns predicted during the very early soft callus tissue phase (less than 2 weeks) are concurrent with callus formation and patterning at later stages. In conclusion, bone defect size influences early onset of critical healing patterns.

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.

A 3D in Silico Multi-Tissue Evolution Model Highlights the Relevance of Local Strain Accumulation in Bone Fracture Remodeling.

Since 5-10% of all bone fractures result in non-healing situations, a thorough understanding of the various bone fracture healing phases is necessary to propose adequate therapeutic strategies. In silico models have greatly contributed to the understanding of the influence of mechanics on tissue formation and resorption during the soft and hard callus phases. However, the late-stage remodeling phase has not been investigated from a mechanobiological viewpoint so far. Here, we propose an in silico multi-tissue evolution model based on mechanical strain accumulation to investigate the mechanobiological regulation of bone remodeling during the late phase of healing. Computer model predictions are compared to histological data of two different pre-clinical studies of bone healing. The model predicted the bone marrow cavity re-opening and the resorption of the external callus. Our results suggest that the local strain accumulation can explain the fracture remodeling process and that this mechanobiological response is conserved among different mammal species. Our study paves the way for further understanding of non-healing situations that could help adapting therapeutic strategies to foster bone healing.

The Degradation of Synthetic Polymeric Scaffolds With Strut-like Architecture Influences the Mechanics-dependent Repair Process of an Osteochondral Defect in Silico.

Current clinical treatments of osteochondral defects in articulating joints are frequently not successful in restoring articular surfaces. Novel scaffold-based tissue engineering strategies may help to improve current treatment options and foster a true regeneration of articulating structures. A frequently desired property of scaffolds is their ability to degrade over time and allow a full restoration of tissue and function. However, it remains largely unknown how scaffold degradation influences the mechanical stability of the tissue in a defect region and, in turn, the regenerative process. Such differing goals-supporting regeneration by degrading its own structure-can hardly be analyzed for tissue engineered constructs in clinical trials and in vivo preclinical experiments. Using an in silico analysis, we investigated the degradation-induced modifications in material and architectural properties of a scaffold with strut-like architecture over the healing course and their influence on the mechanics-dependent tissue formation in osteochondral defects. The repair outcome greatly varied depending on the degradation modality, i.e. surface erosion or bulk degradation with and without autocatalysis, and of the degradation speed, i.e. faster, equal or slower than the expected repair time. Bulk degradation with autocatalysis, independently of degradation speed, caused the mechanical failure of the scaffold prior to osteochondral defect repair and was thereby deemed inappropriate for further application. On the other hand, scaffolds with strut-like architecture degrading by both surface erosion and bulk degradation with slow degradation speed resulted in comparably good repair outcomes, thereby indicating such degradation modalities as favorable for the application in osteochondral defects.

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.

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.

PCL strut-like scaffolds appear superior to gyroid in terms of bone regeneration within a long bone large defect: An in silico study.

The treatment of large bone defects represents a major clinical challenge. 3D printed scaffolds appear as a promising strategy to support bone defect regeneration. The 3D design of such scaffolds impacts the healing path and thus defect regeneration potential. Among others, scaffold architecture has been shown to influence the healing outcome. Gyroid architecture, characterized by a zero mean surface curvature, has been discussed as a promising scaffold design for bone regeneration. However, whether gyroid scaffolds are favourable for bone regeneration in large bone defects over traditional strut-like architecture scaffolds remains unknown. Therefore, the aim of this study was to investigate whether gyroid scaffolds present advantages over more traditional strut-like scaffolds in terms of their bone regeneration potential. Validated bone defect regeneration principles were applied in an in silico modeling approach that allows to predict bone formation in defect regeneration. Towards this aim, the mechano-biological bone regeneration principles were adapted to allow simulating bone regeneration within both gyroid and strut-like scaffolds. We found that the large surface curvatures of the gyroid scaffold led to a slower tissue formation dynamic and conclusively reduced bone regeneration. The initial claim, that an overall reduced zero mean surface curvature would enhance bone formation, could not be confirmed. The here presented approach illustrates the potential of in silico tools to evaluate in pre-clinical studies scaffold designs and eventually lead to optimized architectures of 3D printed implants for bone regeneration.

An in silico model predicts the impact of scaffold design in large bone defect regeneration.

Large bone defects represent a clinical challenge for which the implantation of scaffolds appears as a promising strategy. However, their use in clinical routine is limited, in part due to a lack of understanding of how scaffolds should be designed to support regeneration. Here, we use the power of computer modeling to investigate mechano-biological principles behind scaffold-guided bone regeneration and the influence of scaffold design on the regeneration process. Computer model predictions are compared to experimental data of large bone defect regeneration in sheep. We identified two main key players in scaffold-guided regeneration: (1) the scaffold surface guidance of cellular migration and tissue formation processes and (2) the stimulation of progenitor cell activity by the scaffold material composition. In addition, lower scaffold surface-area-to-volume ratio was found to be beneficial for bone regeneration due to enhanced cellular migration. To a lesser extent, a reduced scaffold Young's modulus favored bone formation. STATEMENT OF SIGNIFICANCE: 3D-printed scaffolds offer promising treatment strategies for large bone defects but their broader clinical use requires a more thorough understanding of their interaction with the bone regeneration process. The predictions of our in silico model compared to two experimental set-ups highlighted the importance of (1) the scaffold surface guidance of cellular migration and tissue formation processes and (2) the scaffold material stimulation of progenitor cell activity. In addition, the model was used to investigate the effect on the bone regeneration process of (1) the scaffold surface-area-to-volume ratio, with lower ratios favoring more bone growth, and (2) the scaffold material properties, with stiffer scaffold materials yielding a lower bone growth.

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.