Curvature in Biological Systems: Its Quantification, Emergence, and Implications across the Scales.

Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology is supported by numerous experimental and theoretical investigations in recent years. In this review, first, a brief introduction to the key ideas of surface curvature in the context of biological systems is given and the challenges that arise when measuring surface curvature are discussed. Giving an overview of the emergence of curvature in biological systems, its significance at different length scales becomes apparent. On the other hand, summarizing current findings also shows that both single cells and entire cell sheets, tissues or organisms respond to curvature by modulating their shape and their migration behavior. Finally, the interplay between the distribution of morphogens or micro-organisms and the emergence of curvature across length scales is addressed with examples demonstrating these key mechanistic principles of morphogenesis. Overall, this review highlights that curved interfaces are not merely a passive by-product of the chemical, biological, and mechanical processes but that curvature acts also as a signal that co-determines these processes.

Wall Shear Stress Analysis and Optimization in Tissue Engineering TPMS Scaffolds.

When designing scaffolds for bone tissue engineering (BTE), the wall shear stress (WSS), due to the fluid flow inside the scaffold, is an important factor to consider as it influences the cellular process involved in new tissue formation. The present work analyzed the average WSS in Schwartz diamond (SD) and gyroid (SG) scaffolds with different surface topologies and mesh elements using computational fluid dynamics (CFD) analysis. It was found that scaffold meshes with a smooth surface topology with tetrahedral elements had WSS levels 35% higher than the equivalent scaffold with a non-smooth surface topology with hexahedral elements. The present work also investigated the possibility of implementing the optimization algorithm simulated annealing to aid in the design of BTE scaffolds with a specific average WSS, with the outputs showing that the algorithm was able to reach WSS levels in the vicinity of 5 mPa (physiological range) within the established limit of 100 iterations. This proved the efficacy of combining CFD and optimization methods in the design of BTE scaffolds.

3D Modeling of the Crystalline Lens Complex under Pseudoexfoliation.

Pseudoexfoliation, one of the most frequent crystalline lens complex disorders, is prevalent in up to 30% of individuals older than 60 years old. This disease can lead to severe conditions, such as subluxation or dislocation of the lens, due to the weakening of the zonules. The goal for the present study was to understand the relevant biomechanical features that can lead to the worsening of an individual's visual capacity under pseudoexfoliation. To this end, finite element models based on a 62-year-old lens complex were developed, composed by the capsular bag, cortex, nucleus, anterior, equatorial, and posterior zonular fibers. Healthy and pseudoexfoliative conditions were simulated, varying the location of the zonulopathy (inferior/superior) and the degenerated layer. The accommodative capacity of the models with inferior dialysis of the zonular fibers was, on average, 4.7% greater than for the cases with superior dialysis. If the three sets of zonules were disrupted, this discrepancy increased to 14.9%. The present work provides relevant data to be further analyzed in clinical scenarios, as these models (and their future extension to a wider age range) can help in identifying the most influential regions for the reduction of the visual capacity of the lens.

Modeling the musculoskeletal loading in bone remodeling at the hip of a child.

BACKGROUND AND OBJECTIVES: The mechanical load associated with physical activity affects the bone adaptation process. The bone adaptationeffect varies with age, being more effective during childhood and adolescence, particularly during pre-pubertal years. Bone-strengthening physical activity is recommended for children and adolescents. The number of time periods (bouts) per day of vigorous physical activity seems to be more important than the total cumulative time for optimal bone strength. So, the aim of this study was to evaluate the effects of weight-bearing physical activity on bone mineral density (BMD) of the proximal femur through computational simulation considering the intensity, exposure time (bouts) and regionalization of the results. METHODS: For this purpose, a finite element model of a 7 year-old child femur was developed based on computed tomography images. Musculoskeletal loads were obtained from experimental kinematic data of weight-bearing physical activity performed by children of the same age (standing, walking, running, jumping). The effects of physical activity on BMD of several regions of interest of the femur were analyzed using a bone remodeling model. A daily accumulation of 400 min of physical activity (200 min walking and 200 min standing) was considered as reference, against with which the effects of additional 10 min loading bouts were compared: 10 min bouts of vigorous intensity physical activity vs. 10 min bouts of light to moderate intensity physical activity. RESULTS: The simulations revealed greater increases in BMD associated with higher intensity and longer duration of physical activity. The largest BMD increases occurs during the first 10 min bout compared to longer durations and in less mineralized central regions compared to regions far from the neutral axis of the bone. CONCLUSION: Weight bearing physical activity is more effective in bone remodeling when the musculoskeletal loading is more intense and of short duration and, under these conditions, less mineralized regions are more positively impacted.

Numerical-experimental analysis of the permeability-porosity relationship in triply periodic minimal surfaces scaffolds.

Bone Tissue Engineering has been focusing on improving the current methods for bone repair, being the use of scaffolds presented as an upgrade to traditional surgery techniques. Scaffolds are artificially porous matrices, meant to promote cell seeding and proliferation, being these properties influenced by the permeability of the structure. This work employed experimental pressure drop tests and Computational Fluid Dynamics models to assess permeability (and fluid streamlines) within different triply periodic minimal surfaces scaffold geometries (Schwarz D, Gyroid and Schwarz P). The pressure outputs from the computational analysis presented a good correlation with the experimental results, with R2 equal to 0.903; they have also shown that a lower porosity may not mean a lower permeability if the geometry is altered, such as the difference between 60% porous Gyroid scaffolds (8.1*10-9 mm2) and 70% porous Schwarz D scaffolds (7.1*10-9 mm2). Fluid streamlines revealed how the Gyroid geometries are the most appropriate design for most bone tissue engineering applications, due to their consistent fluid permeation, followed by Schwarz D. The Schwarz P geometries have shown flat streamlines and significant variation of the permeability with the porosity (an increase of 10% in their porosity lead to an increase in the permeability from 5.1*10-9 mm2 to 11.7*10-9 mm2), which would imply a poor environment for cell seeding and proliferation.

New methodology to assess in-vivo quality of motion in cervical spine.

BACKGROUND: Understanding the kinematics of the spine in the interaction with an implanted device is of utmost importance from a clinical point of view. The characterization of the biomechanical movement of the spine occurring at each functional unit is a difficult task as it involves the measurement of complex patterns of motion while identifying more delicate abnormalities that could result in longer-term disease complications. Center of rotation is a biomechanical parameter that represents the ratio between rotation and translation. It has been recognized as a valid and reliable parameter to identify any delicate abnormal movement of the spine as opposed to the range of motion. However, center of rotation is still not widely used in clinical practice. METHODS: In this study, an algorithm intended to easily identify an imbalanced spine through the center of rotation calculation and a new parameter called distance to the ellipse is presented. In this new approach the distance to the ellipse is a key parameter which represents the distance of the center of rotation lying outside the ellipse that represents the asymptomatic group, from the ellipse itself. FINDINGS: The presented algorithm allows the comparison of pre-op and post-op outcomes, and the rapid identification of cases needing more attention. INTERPRETATION: When a comprehensive analysis is required, a dashboard is provided with detailed information for each functional spine unit at each follow-up appointment. It is found that the new approach has the potential to become a new methodology in clinical practice. LEVEL OF EVIDENCE: Biomechanical Study.

On the permeability of TPMS scaffolds.

This study presents an experimental evaluation of permeability of triply periodic minimal surfaces (TPMS). Permeability is widely used to characterize scaffolds for Tissue Engineering (TE) applications as it gives information about the structure porosity, pore size, tortuosity and pore interconnectivity which have an important impact in cell seeding and proliferation. Three different TPMS structures were used: Schwartz Diamond (SD), Gyroid (SG) and Schwartz Primitive (SP), in four different porosity levels (50, 60, 70 and 80%). Overall, the SG scaffold type was determined to be the most permeable one while the SD was the least permeable. Furthermore, the presence of microscopic inertial pressure losses was verified and the Forchheimer's law proved to be a good mathematical tool as a Darcy's law expansion for the calculation of the structure's permeability while the weak-inertia regime was hard to detect or quantify.

Retinal Response of Low Myopes during Orthokeratology Treatment.

The aim of this study was to evaluate the changes in retinal activity during orthokeratology (OK) treatment in 20 myopic eyes. Pattern electroretinography (PERG) and visual evoked potential (VEP) were assessed with the RETI-port/scan21 (Roland Consult, Wiesbaden, Germany). Measurements were taken at baseline (BL) and 1 night (1N), 15 nights (15N), 30 nights (30N), and 60 nights (60N) of OK lens wear. Repeated measures analysis of variance (ANOVA) and the Friedman test were used. Twenty eyes (23.20 ± 3.46 years, 70% female) with visual acuity ≤ 0.00 logMAR in post-treatment showed that despite a slight increase in retinal and cortical response amplitude, observed with both PERG and VEP, respectively, immediately after the initial treatment, these differences found were not statistically significant during the 60 days of OK treatment, despite a statistically significant increase in N95 response with PERG. This shows that retinal and cortical visual-related electrical activity is maintained or slightly increased during OK treatment.

Impact of contact lens materials on the mfERG response of the human retina.

PURPOSE: To investigate the effect of different hydrophilic and rigid gas-permeable contact lens (CL) materials on multifocal electroretinography (mfERG). METHODS: The mfERG was recorded in 18 healthy subjects with RETI-port/scan21™: 11 subjects underwent mfERG recording wearing two different hydrophilic CLs with different water contents in a randomized order (1 silicone hydrogel-Comfilcon A, 48%EWC, and 1 hydrogel-Omafilcon A, 62% EWC) and 7 other subjects wore a hydrophobic rigid gas-permeable scleral lens (SL)-Hexafocon A. Control measures were recorded without CL in both groups. mfERG recordings were performed with a stimulus array pattern of 103-scaled hexagons displayed on a 19-inch RGB monitor at 28 cm distance at a frame rate of 60 Hz. The amplitude (nV), implicit time and response density (nV/deg2) of the first-order kernel components N1, P1 and N2 were evaluated for the total mfERG response and for the response averages of 4 quadrants and of 6 successive concentric rings. Subjects were optically corrected for the working distance of ERG display. RESULTS: Hydrophobic material significantly decreased the P1 amplitude of the total mfERG response, at Rings 3, 4 and 6 and Quadrant 4 (> 53.77 ± 43.2 nV; P ≤ 0.050), as well as the total (- 71.59 ± 50.68 nV) and Ring 6 (- 104.76 ± 79.88 nV) N2 amplitude (P ≤ 0.043). N1, P1 and N2 peak times suffered significant changes with both hydrophilic CL (P ≤ 0.050). Omafilcon A significantly increased P1 amplitude of Ring 5 and N2 amplitude of Ring 4, when compared to baseline (52.40 ± 71.87 nV; P = 0.036) and to Comfilcon A (39.51 ± 48.63 nV; P = 0.023), respectively. CONCLUSIONS: Hydrophobic CL slightly attenuated the strength of the mfERG signal, especially at the middle to peripheral retinal areas, while hydrophilic CL slightly changed the implicit time of the response. Different hydrophilic CL materials might affect the mfERG response differently. When considering the measurement of mfERG obtained with a CL in place, researchers should bear in mind that some changes can be related to CL material.

Automated femoral landmark extraction for optimal prosthesis placement in total hip arthroplasty.

The automated extraction of anatomical reference landmarks in the femoral volume may improve speed, precision, and accuracy of surgical procedures, such as total hip arthroplasty. These landmarks are often hard to achieve, even via surgical incision. In addition, it provides a presurgical guidance for prosthesis sizing and placement. This study presents an automated workflow for femoral orientation and landmark extraction from a 3D surface mesh. The extraction of parameters such as the femoral neck axis, the femoral middle diaphysis axis, both trochanters and the center of the femoral head will allow the surgeon to establish the correct position of bony cuts to restore leg length and femoral offset. The definition of the medullary canal endosteal wall is used to position the prosthesis' stem. Furthermore, prosthesis alignment and sizing methods were implemented to provide the surgeon with presurgical information about performance of each of the patient-specific femur-implant couplings. The workflow considers different commercially available hip stems and has the potential to help the preoperative planning of a total hip arthroplasty in an accurate, repeatable, and reliable way. The positional and orientation errors are significantly reduced, and therefore, the risk of implant failure and subsequent revision surgery are also reduced.

Computational design and fabrication of a novel bioresorbable cage for tibial tuberosity advancement application.

Tibial tuberosity advancement (TTA) is a promising method for the treatment of cruciate ligament rupture in dogs that usually implies the implantation of a titanium cage as bone implant. This cage is non-biodegradable and fails in providing adequate implant-bone tissue integration. The objective of this work is to propose a new process chain for designing and manufacturing an alternative biodegradable cage that can fulfill specific patient requirements. A three-dimensional finite element model (3D FEM) of the TTA system was first created to evaluate the mechanical environment at cage domain during different stages of the dog walk. The cage microstructure was then optimized using a topology optimization tool, which addresses the accessed local mechanical requirements, and at same time ensures the maximum permeability to allow nutrient and oxygen supply to the implant core. The designed cage was then biofabricated by a 3D powder printing of tricalcium phosphate cement. This work demonstrates that the combination of a 3D FEM with a topology optimization approach enabled the design of a novel cage for TTA application with tailored permeability and mechanical properties, that can be successfully 3D printed in a biodegradable bioceramic material. These results support the potential of the design optimization strategy and fabrication method to the development of customized and bioresorbable implants for bone repair.

Fully automatic segmentation of femurs with medullary canal definition in high and in low resolution CT scans.

Femur segmentation can be an important tool in orthopedic surgical planning. However, in order to overcome the need of an experienced user with extensive knowledge on the techniques, segmentation should be fully automatic. In this paper a new fully automatic femur segmentation method for CT images is presented. This method is also able to define automatically the medullary canal and performs well even in low resolution CT scans. Fully automatic femoral segmentation was performed adapting a template mesh of the femoral volume to medical images. In order to achieve this, an adaptation of the active shape model (ASM) technique based on the statistical shape model (SSM) and local appearance model (LAM) of the femur with a novel initialization method was used, to drive the template mesh deformation in order to fit the in-image femoral shape in a time effective approach. With the proposed method a 98% convergence rate was achieved. For high resolution CT images group the average error is less than 1mm. For the low resolution image group the results are also accurate and the average error is less than 1.5mm. The proposed segmentation pipeline is accurate, robust and completely user free. The method is robust to patient orientation, image artifacts and poorly defined edges. The results excelled even in CT images with a significant slice thickness, i.e., above 5mm. Medullary canal segmentation increases the geometric information that can be used in orthopedic surgical planning or in finite element analysis.

In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2.

The healing of bone defects is a challenge for both tissue engineering and modern orthopaedics. This problem has been addressed through the study of scaffold constructs combined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing process, bone morphogenetic protein-2 (BMP-2) has been identified as one of the most powerful osteoinductive proteins. The aim of this work is to develop and validate a mechano-chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature concerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differentiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone defects under the following conditions: natural healing, an empty hydrogel implanted in the defect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies.

Bioresorbable scaffolds for bone tissue engineering: optimal design, fabrication, mechanical testing and scale-size effects analysis.

Bone scaffolds for tissue regeneration require an optimal trade-off between biological and mechanical criteria. Optimal designs may be obtained using topology optimization (homogenization approach) and prototypes produced using additive manufacturing techniques. However, the process from design to manufacture remains a research challenge and will be a requirement of FDA design controls to engineering scaffolds. This work investigates how the design to manufacture chain affects the reproducibility of complex optimized design characteristics in the manufactured product. The design and prototypes are analyzed taking into account the computational assumptions and the final mechanical properties determined through mechanical tests. The scaffold is an assembly of unit-cells, and thus scale size effects on the mechanical response considering finite periodicity are investigated and compared with the predictions from the homogenization method which assumes in the limit infinitely repeated unit cells. Results show that a limited number of unit-cells (3-5 repeated on a side) introduce some scale-effects but the discrepancies are below 10%. Higher discrepancies are found when comparing the experimental data to numerical simulations due to differences between the manufactured and designed scaffold feature shapes and sizes as well as micro-porosities introduced by the manufacturing process. However good regression correlations (R(2) > 0.85) were found between numerical and experimental values, with slopes close to 1 for 2 out of 3 designs.

Peripheral refraction with eye and head rotation with contact lenses.

PURPOSE: To evaluate the impact of eye and head rotation in the measurement of peripheral refraction with an open-field autorefractometer in myopic eyes wearing two different center-distance designs of multifocal contact lenses (MFCLs). METHODS: Nineteen right eyes from 19 myopic patients (average central M ± SD = -2.67 ± 1.66 D) aged 20-27 years (mean ± SD = 23.2 ± 3.3 years) were evaluated using a Grand-Seiko autorefractometer. Patients were fitted with one multifocal aspheric center-distance contact lens (Biofinity Multifocal D(®)) and with one multi-concentric MFCL (Acuvue Oasys for Presbyopia). Axial and peripheral refraction were evaluated by eye rotation and by head rotation under naked eye condition and with each MFCL fitted randomly and in independent sessions. RESULTS: For the naked eye, refractive pattern (M, J0 and J45) across the central 60° of the horizontal visual field values did not show significant changes measured by rotating the eye or rotating the head (p > 0.05). Similar results were obtained wearing the Biofinity D, for both testing methods, no obtaining significant differences to M, J0 and J45 values (p > 0.05). For Acuvue Oasys for presbyopia, also no differences were found when comparing measurements obtained by eye and head rotation (p > 0.05). Multivariate analysis did not showed a significant interaction between testing method and lens type neither with measuring locations (MANOVA, p > 0.05). There were significant differences in M and J0 values between naked eyes and each MFCL. CONCLUSION: Measurements of peripheral refraction by rotating the eye or rotating the head in myopic patients wearing dominant design or multi-concentric multifocal silicone hydrogel contact lens are comparable.

Is the callus shape an optimal response to a mechanobiological stimulus?

After bone trauma, the natural response to restore bone function is the formation of a callus around the fracture. Although several bone healing models have been developed, none have effectively perceived early callus formation and shape as the result of an optimal response to a mechanobiological stimulus. In this paper, we investigate which stimulus regulates early callus formation. An optimal design problem is formulated, and several objective functions are defined, each using a different mechanobiological stimulus. The following stimuli were analysed: the interfragmentary strain, the second invariant of the deviatoric strain tensor and a generic inflammatory factor. Different regions for callus formation were also evaluated, such as the gap region, the periosteum and the periosteum border. Each stimulus was computed using the finite element method, and the callus shape was optimised using the steepest descent method. The results demonstrated that the inflammatory factor approach, the interfragmentary strain and the second invariant of the deviatoric strain tensor over the inner gap provided the best results when compared with histological callus shapes. Therefore, this work suggests that callus growth can be an optimal mechanobiological response to either local mechanical instability and/or local inflammatory reaction.

Oscillatory fluid flow influences primary cilia and microtubule mechanics.

Many tissues are sensitive to mechanical stimuli; however, the mechanotransduction mechanism used by cells remains unknown in many cases. The primary cilium is a solitary, immotile microtubule-based extension present on nearly every mammalian cell which extends from the basal body. The cilium is a mechanosensitive organelle and has been shown to transduce fluid flow-induced shear stress in tissues, such as the kidney and bone. The majority of microtubules assemble from the mother centriole (basal body), contributing significantly to the anchoring of the primary cilium. Several studies have attempted to quantify the number of microtubules emanating from the basal body and the results vary depending on the cell type. It has also been shown that cellular response to shear stress depends on microtubular integrity. This study hypothesizes that changing the microtubule attachment of primary cilia in response to a mechanical stimulus could change primary cilia mechanics and, possibly, mechanosensitivity. Oscillatory fluid flow was applied to two different cell types and the microtubule attachment to the ciliary base was quantified. For the first time, an increase in microtubules around primary cilia both with time and shear rate in response to oscillatory fluid flow stimulation was demonstrated. Moreover, it is presented that the primary cilium is required for this loading-induced cellular response. This study has demonstrated a new role for the cilium in regulating alterations in the cytoplasmic microtubule network in response to mechanical stimulation, and therefore provides a new insight into how cilia may regulate its mechanics and thus the cells mechanosensitivity.

Optimization of scaffold design for bone tissue engineering: A computational and experimental study.

In bone tissue engineering, the scaffold has not only to allow the diffusion of cells, nutrients and oxygen but also provide adequate mechanical support. One way to ensure the scaffold has the right properties is to use computational tools to design such a scaffold coupled with additive manufacturing to build the scaffolds to the resulting optimized design specifications. In this study a topology optimization algorithm is proposed as a technique to design scaffolds that meet specific requirements for mass transport and mechanical load bearing. Several micro-structures obtained computationally are presented. Designed scaffolds were then built using selective laser sintering and the actual features of the fabricated scaffolds were measured and compared to the designed values. It was possible to obtain scaffolds with an internal geometry that reasonably matched the computational design (within 14% of porosity target, 40% for strut size and 55% for throat size in the building direction and 15% for strut size and 17% for throat size perpendicular to the building direction). These results support the use of these kind of computational algorithms to design optimized scaffolds with specific target properties and confirm the value of these techniques for bone tissue engineering.

Biomechanical analysis of the tibial tray design in TKA: comparison between modular and offset tibial trays.

PURPOSE: The aim of this work was to develop a computational biomechanical study to compare the performance of tibial trays with different offsets for a total knee arthroplasty. The goal was to investigate whether the offset tibial tray shifts the bone stress distribution, influencing the clinical outcome. METHODS: Three geometric models were developed for the intact tibia bone: one considering a standard tibia case and the other two reproducing tibias with a medial or a lateral offset of the metaphysis. Appropriate prosthetic components were assembled in the bone for the aforementioned cases. The finite element method was used to obtain the mechanical stress distribution for the models, and the stress shielding effect due to the prosthesis was analysed. RESULTS: The obtained results revealed that the offset cases are subjected to higher stresses than the standard case. These values can be two times superior to the ones verified in a standard case. The stress shielding effect was confirmed along all the analysed paths, except near the stem's end in some areas. CONCLUSION: The higher stresses registered can originate lower clinical outcomes in the offset cases. These findings can be an important beginning to understand whether better bone stress distribution could be achieved in deformity correction with associated osteotomies instead of offsetting.

Subject-specific bone remodelling of the scapula.

Finite element analyses, with increasing levels of detail and complexity, are becoming effective tools to evaluate the performance of joint replacement prostheses and to predict the behaviour of bone. As a first step towards the study of the complications of shoulder arthroplasty, the aim of this work was the development and validation of a 3D finite element model of an intact scapula for the prediction of the bone remodelling process based on a previously published model that attempts to follow Wolff's law. The boundary conditions applied include full muscle and joint loads taken from a multibody system of the upper limb based on the same subject whose scapula was here analysed. To validate the bone remodelling simulations, qualitative and quantitative comparisons between the predicted and the specimen's bone density distribution were performed. The results showed that the bone remodelling model was able to successfully reproduce the actual bone density distribution of the analysed scapula.