A Soft-Tissue Driven Bone Remodeling Algorithm for Mandibular Residual Ridge Resorption Based on Patient CT Image Data.

The role of the biomechanical stimulation generated from soft tissue has not been well quantified or separated from the self-regulated hard tissue remodeling governed by Wolff's Law. Prosthodontic overdentures, commonly used to restore masticatory functions, can cause localized ischemia and inflammation as they often compress patients' oral mucosa and impede local circulation. This biomechanical stimulus in mucosa is found to accelerate the self-regulated residual ridge resorption (RRR), posing ongoing clinical challenges. Based on the dedicated long-term clinical datasets, we developed an in-silico framework with a combination of techniques, including advanced image post-processing, patient-specific finite element models and unsupervised machine learning Self-Organizing map algorithm, to identify the soft tissue induced residual ridge resorption and quantitatively elucidate the governing relationship between the RRR and hydrostatic pressure in mucosa. The proposed governing equation has not only enabled a predictive simulation for RRR as showcased in this study, providing a biomechanical basis for optimizing prosthodontic treatments, but also extended our understanding of the mechanobiological responses in the soft-hard tissue interfaces and the role in bone remodeling. This article is protected by copyright. All rights reserved.

Mechanical insights into jawbone characteristics under chronic kidney disease: A comprehensive nanoindentation approach.

The mechanical properties of the jawbone play a critical role in determining the successful integration of dental prostheses. Chronic kidney disease (CKD) has been identified to abnormally accelerate bone turnover rates. However, the impact of CKD on the mechanical characteristics of the jawbone has not been extensively studied. This study sought to evaluate the time-dependent viscoelastic behaviors of rat jawbones, particularly in the scenarios both with and without CKD. We hypothesized that CKD might compromise the bone's innate toughening mechanisms, potentially owing to the time-dependent viscoelasticity of the bone matrix proteins. The maxillary and mandibular bones of Wistar rats were subjected to nanoindentation and Raman micro-spectroscopy. Load-hold-displacement curves from the cortical regions were obtained via nanoindentation and were mathematically characterized using a suitable viscoelastic constitutive model. Raman micro-spectroscopy was employed to identify nuanced vibrational changes in local molecular structures induced by CKD. The time course of indenter penetration onto cortical bones during the holding stage (creep behavior) can be mathematically represented by a series arrangement of the Kelvin-Voigt bodies. This configuration dictates the overall viscoelastic response observed during nanoindentation tests. The CKD model exhibited a reduced extent of viscoelastic contributions, especially during the initial ramp loading phase in both the maxillary and mandibular cortical bones. The generalized Kelvin-Voigt model comprises 2 K-Voigt elements that signify an immediate short retardation time (τ1) and a subsequent prolonged retardation time (τ2), respectively. Notably, the mandibular CKD model led to an increase in the delayed τ2 alongside an increase in non-enzymatic collagen cross-linking. These suggest that, over time, CKD diminishes the bone's capability for supplementary energy absorption and dimensional recovery, thus heightening their susceptibility to fractures.

Deciphering load attenuation mechanisms of the dentin-enamel junction: Insights from a viscoelastic constitutive model.

A considerable material discontinuity between the enamel and dentin might jeopardize the tooth's mechanical durability over time without the attenuation of the dentin-enamel junction (DEJ). However, the critical loading transmission mechanism at the DEJ remains understudied. This study aimed to define the extent and effective width of the DEJ, along with its mechanical competence. The presence of DEJ interphase layer was identified using a motif analysis based on the ion beam-transmission electron microscopy coupled with nanoindentation modulus mapping. For each region, nanoindentation load-displacement curves were recorded and mathematically analyzed using an appropriate viscoelastic constitutive model. The time-course of indenter penetration (creep) behavior of the tooth tissues can be mathematically approximated by the Kelvin-Voigt model in series, which determined the visco-contribution to the overall mechanical responses. Therefore, the elastic-plastic contribution can be distinguished from the overall mechanical responses of the tooth after subtracting the visco-contributions. During the loading period, the enamel behavior was dominated by elastic-plastic responses, while both the dentin and DEJ showed pronounced viscoelastic responses. The instantaneous modulus of the DEJ, which was measured by eliminating viscoelastic behavior from the raw load-displacement curve, was almost double that of the dentin. The DEJ was stiffer than the dentin, but it exhibited large viscoelastic motion even at the initial loading stage. This study revealed that the load attenuation competence of the DEJ, which involves extra energy expenditure, is mainly associated with its viscoelasticity. The mathematical analysis proposed here, performed on the nanoindentation creep behavior, could potentially augment the existing knowledge on hard-tissue biomechanics. STATEMENT OF SIGNIFICANCE: In this study, we undertake a rigorous mechanical characterization of the dentin-enamel junction (DEJ) using an advanced nanoindentation technique coupled with a pertinent viscoelastic constitutive model. Our approach unveils the substantial viscoelastic contribution of the DEJ during the initial indentation loading phase and offers an elaborate delineation of the DEJ interphase layer through sophisticated image analysis. These insights significantly augment our understanding of tooth durability. Importantly, our innovative mathematical analysis of creep behavior introduces a novel approach with profound implications for future research in the expansive field of hard-tissue biomechanics. The pioneering methodologies and findings presented in this work hold substantial potential to invigorate progress in biomaterials research and fuel further explorations into the functionality of biological tissues.

Functional non-uniformity of periodontal ligaments tunes mechanobiological stimuli across soft- and hard-tissue interfaces.

The bone-periodontal ligament-tooth (BPT) complex is a unique mechanosensing soft-/hard-tissue interface, which governs the most rapid bony homeostasis in the body responding to external loadings. While the correlation between such loading and alveolar bone remodelling has been widely recognised, it has remained challenging to investigate the transmitted mechanobiological stimuli across such embedded soft-/hard-tissue interfaces of the BPT complex. Here, we propose a framework combining three distinct bioengineering techniques (i, ii, and iii below) to elucidate the innate functional non-uniformity of the PDL in tuning mechanical stimuli to the surrounding alveolar bone. The biphasic PDL mechanical properties measured via nanoindentation, namely the elastic moduli of fibres and ground substance at the sub-tissue level (i), were used as the input parameters in an image-based constitutive modelling framework for finite element simulation (ii). In tandem with U-net deep learning, the Gaussian mixture method enabled the comparison of 5195 possible pseudo-microstructures versus the innate non-uniformity of the PDL (iii). We found that the balance between hydrostatic pressure in PDL and the strain energy in the alveolar bone was maintained within a specific physiological range. The innate PDL microstructure ensures the transduction of favourable mechanobiological stimuli, thereby governing alveolar bone homeostasis. Our outcomes expand current knowledge of the PDL's mechanobiological roles and the proposed framework can be adopted to a broad range of similar soft-/hard- tissue interfaces, which may impact future tissue engineering, regenerative medicine, and evaluating therapeutic strategies. STATEMENT OF SIGNIFICANCE: A combination of cutting-edge technologies, including dynamic nanomechanical testing, high-resolution image-based modelling and machine learning facilitated computing, was used to elucidate the association between the microstructural non-uniformity and biomechanical competence of periodontal ligaments (PDLs). The innate PDL fibre network regulates mechanobiological stimuli, which govern alveolar bone remodelling, in different tissues across the bone-PDL-tooth (BPT) interfaces. These mechanobiological stimuli within the BPT are tuned within a physiological range by the non-uniform microstructure of PDLs, ensuring functional tissue homeostasis. The proposed framework in this study is also applicable for investigating the structure-function relationship in broader types of fibrous soft-/hard- tissue interfaces.

An experimental and numerical study of the microstructural and biomechanical properties of human peripheral nerve endoneurium for the design of tissue scaffolds.

Biomimetic design of scaffold architectures represents a promising strategy to enable the repair of tissue defects. Natural endoneurium extracellular matrix (eECM) exhibits a sophisticated microstructure and remarkable microenvironments conducive for guiding neurite regeneration. Therefore, the analysis of eECM is helpful to the design of bionic scaffold. Unfortunately, a fundamental lack of understanding of the microstructural characteristics and biomechanical properties of the human peripheral nerve eECM exists. In this study, we used microscopic computed tomography (micro-CT) to reconstruct a three-dimensional (3D) eECM model sourced from mixed nerves. The tensile strength and effective modulus of human fresh nerve fascicles were characterized experimentally. Permeability was calculated from a computational fluid dynamic (CFD) simulation of the 3D eECM model. Fluid flow of acellular nerve fascicles was tested experimentally to validate the permeability results obtained from CFD simulations. The key microstructural parameters, such as porosity is 35.5 ± 1.7%, tortuosity in endoneurium (X axis is 1.26 ± 0.028, Y axis is 1.26 ± 0.020 and Z axis is 1.17 ± 0.03, respectively), tortuosity in pore (X axis is 1.50 ± 0.09, Y axis is 1.44 ± 0.06 and Z axis is 1.13 ± 0.04, respectively), surface area-to-volume ratio (SAVR) is 0.165 ± 0.007 µm-1 and pore size is 11.8 ± 2.8 µm, respectively. These were characterized from the 3D eECM model and may exert different effects on the stiffness and permeability. The 3D microstructure of natural peripheral nerve eECM exhibits relatively lower permeability (3.10 m2 × 10-12 m2) than other soft tissues. These key microstructural and biomechanical parameters may play an important role in the design and fabrication of intraluminal guidance scaffolds to replace natural eECM. Our findings can aid the development of regenerative therapies and help improve scaffold design.

The structural motifs of mineralized hard tissues from nano- to mesoscale: A future perspective for material science.

Biological tissues have developed structures that fulfil their various specific requirements. Mineralized tissues, such as tooth and bone, are often of mechanical competence for load bearing. Tooth enamel is the hardest and toughest mineralized tissue. Despite a few millimeters thick and with minimal regenerative capacity, human tooth enamel maintains its functions throughout a lifetime. Bone provides skeletal support and essential metabolism to our body. Degenerative diseases and ageing induce the loss of mechanical integrity of the bone, increasing the susceptibility to fractures. Tooth and bone share certain commonalities in chemical components and material characteristics, both consisting of nanocrystalline apatite and matrix proteins as their basic foundational structural units. Although the mechanical properties of such mineralized hard tissues remain unclear, it is plausible that they have an inherent toughening mechanism. Nanoindentation is able to characterize the mechanical properties of tooth enamel and bone at multiscale levels, and the results suggest that such toughening mechanisms of enamel and bone may be mainly associated with the smallest-scale structure-function relationships. These findings will benefit the development of advanced biomaterials in the field of material science and will further our understanding of degenerative bone disease in the clinical community.

The biomechanics of metaphyseal cone augmentation in revision knee replacement.

The demand for revision knee replacement (RKR) has increased dramatically with rising patient life expectancy and younger recipients for primary TKR. However, significant challenges to RKR arise from osseous defects, reduced bone quality, potential bone volume loss from implant removal and the need to achieve implant stability. This study utilizes the outcomes of an ongoing RKR clinical trial using porous metaphyseal cones 3D-printed of titanium, to investigate 1) bone mineral density (BMD) changes in three fixation zones (epiphysis, metaphysis, and diaphysis) over a year and 2) the biomechanical effects of the cones at 6 months post-surgery. It combines dual-energy x-ray absorptiometry (DXA), computed tomography (CT) with patient-specific based finite element (FE) modelling. Bone loss (-0.086 ± 0.05 g/cm2) was found in most patients over the first year. The biomechanical assessment considered four different loading scenarios from standing, walking on a flat surface, and walking downstairs, to a simulated impact of the knee. The patient-specific FE models showed that the cones marginally improved the strain distribution in the bone and shared the induced load but played a limited role in reducing the risks of bone fracture or cement debonding. This technique of obtaining real live data from a randomized clinical trial and inserting it into an in-silico FE model is unique and innovative in RKR research. The tibia RKR biomechanics examined open up further possibilities, allowing the in-silico testing of prototypes and implant combinations without putting patients at risk as per the recommended IDEAL framework standards. This process with further improvements could allow rapid innovation, optimization of implant design, and improve surgical planning.

Bone remodeling following mandibular reconstruction using fibula free flap.

To investigate bone remodelling responses to mandibulectomy, a joint external and internal remodelling algorithm is developed here by incorporating patient-specific longitudinal data. The primary aim of this study is to simulate bone remodelling activity in the conjunction region with a fibula free flap (FFF) reconstruction by correlating with a 28-month clinical follow-up. The secondary goal of this study is to compare the long-term outcomes of different designs of fixation plate with specific screw positioning. The results indicated that the overall bone density decreased over time, except for the Docking Site (namely DS1, a region of interest in mandibular symphysis with the conjunction of the bone union), in which the decrease of bone density ceased later and was followed by bone apposition. A negligible influence on bone remodeling outcome was found for different screw positioning. This study is believed to be the first of its kind for computationally simulating the bone turn-over process after FFF maxillofacial reconstruction by correlating with patient-specific follow-up.

Microstructural heterogeneity of the collagenous network in the loaded and unloaded periodontal ligament and its biomechanical implications.

The periodontal ligament (PDL) is a highly heterogeneous fibrous connective tissue and plays a critical role in distributing occlusal forces and regulating tissue remodeling. Its mechanical properties are largely determined by the extracellular matrix, comprising a collagenous fiber network interacting with the capillary system as well as interstitial fluid containing proteoglycans. While the phase-contrast micro-CT technique has portrayed the 3D microscopic heterogeneity of PDL, the topological parameters of its network, which is crucial to understanding the multiscale constitutive behavior of this tissue, has not been characterized quantitatively. This study aimed to provide new understanding of such microscopic heterogeneity of the PDL with quantifications at both tissue and collagen network levels in a spatial manner, by combining phase-contrast micro-CT imaging and a purpose-built image processing algorithm for fiber analysis. Both variations within a PDL and among the PDL with different shapes, i.e. round-shaped and kidney-shaped PDLs, are described in terms of tissue thickness, fiber distribution, local fiber densities, and fiber orientation (namely azimuthal and elevation angles). Furthermore, the tissue and collagen fiber network responses to mechanical loading were evaluated in a similar manner. A 3D helical alignment pattern was observed in the fiber network, which appears to regulate and adapt a screw-like tooth motion under occlusion. The microstructural heterogeneity quantified here allows development of sample-specific constitutive models to characterize the PDL's functional and pathological loading responses, thereby providing a new multiscale framework for advancing our knowledge of this complex limited mobility soft-hard tissue interface.

Interfacial Curvature in Confined Coculture Directs Stromal Cell Activity with Spatial Corralling of Pancreatic Cancer Cells.

Interfacial cues in the tumor microenvironment direct the activity and assembly of multiple cell types. Pancreatic cancer, along with breast and prostate cancers, is enriched with cancer-associated fibroblasts (CAFs) that activate to coordinate the deposition of the extracellular matrix, which can comprise over 90% of the tumor mass. While it is clear that matrix underlies the severity of the disease, the relationship between stromal-tumor cell assembly and cell-matrix dynamics remains elusive. Micropatterned hydrogels deconstruct the interplay between matrix stiffness and geometric confinement, guiding heterotypic cell populations and matrix assembly in pancreatic cancer. Interfacial cues at the perimeter of microislands guide CAF migration and direct cancer cell assembly. Computational modeling shows curvature-stress dependent cellular localization for cancer and CAFs in coculture. Regions of convex curvature enhance edge stress that activates a myofibroblast phenotype in the CAFs with migration and increased collagen I deposition, ultimately leading to a central "corralling" of cancer cells. Inhibiting mechanotransduction pathways decreases CAF activation and the associated corralling phenotype. Together, this work reveals how interfacial biophysical cues underpin aspects of stromal desmoplasia, a hallmark of disease severity and chemoresistance in the pancreatic, breast, and prostate cancers, thereby providing a tool to expand stroma-targeting therapeutic strategies.

Effects of buccal thickness augmentation on bone remodeling after maxillary anterior implantation.

The biomechanics associated with buccal bone thickness (BBT) augmentation remains poorly understood, as there is no consistent agreement in the adequate BBT to avoid over-loading resorption or over-augmenting surgical difficulty. This study utilizes longitudinal clinical image data to establish a self-validating time-dependent finite element (FE)-based remodeling procedure to explore the effects of different buccal bone thicknesses on long-term bone remodeling outcomes in silico. Based upon the clinical computed tomography (CT) scans, a patient-specific heterogeneous FE model was constructed to enable virtual BBT augmentation at four different levels (0.5, 1.0, 1.5, and 2.0 mm), followed by investigation into the bone remodeling behavior of the different case scenarios. The findings indicated that although peri-implant bone resorption decreased with increasing initial BBT from 0.5 to 2 mm, different levels of the reduction in bone loss were associated with the amount of bone augmentation. In the case of 0.5 mm BBT, overloading resorption was triggered during the first 18 months, but such bone resorption was delayed when the BBT increased to 1.5 mm. It was found that when the BBT reached a threshold thickness of 1.5 mm, the bone volume can be better preserved. This finding agrees with the consensus in dental clinic, in which 1.5 mm BBT is considered clinically justifiable for surgical requirement of bone graft. In conclusion, this study introduced a self-validating bone remodeling algorithm in silico, and it divulged that the initial BBT affects the bone remodeling outcome significantly, and a sufficient initial BBT is considered essential to assure long-term stability and success of implant treatment.

Effect of different implant configurations on biomechanical behavior of full-arch implant-supported mandibular monolithic zirconia fixed prostheses.

Mechanical failure of zirconia-based full-arch implant-supported fixed dental prostheses (FAFDPs) remains a critical issue in prosthetic dentistry. The option of full-arch implant treatment and the biomechanical behaviour within a sophisticated screw-retained prosthetic structure have stimulated considerable interest in fundamental and clinical research. This study aimed to analyse the biomechanical responses of zirconia-based FAFDPs with different implant configurations (numbers and distributions), thereby predicting the possible failure sites and the optimum configuration from biomechanical aspect by using finite element method (FEM). Five 3D finite element (FE) models were constructed with patient-specific heterogeneous material properties of mandibular bone. The results were reported using volume-averaged von-Mises stresses (σVMVA) to eliminate numerical singularities. It was found that wider placement of multi-unit copings was preferred as it reduces the cantilever effect on denture. Within the limited areas of implant insertion, the adoption of angled multi-unit abutments allowed the insertion of oblique implants in the bone and wider distribution of the multi-unit copings in the prosthesis, leading to lower stress concentration on both mandibular bone and prosthetic components. Increasing the number of supporting implants in a FAFDPs reduced loading on each implant, although it may not necessarily reduce the stress concentration in the most posterior locations significantly. Overall, the 6-implant configuration was a preferable configuration as it provided the most balanced mechanical performance in this patient-specific case.

Three-dimensional reconstruction of internal fascicles and microvascular structures of human peripheral nerves.

Biofabricated nanostructured and microstructured scaffolds have exhibited great potential for nerve tissue regeneration and functional restoration, and prevascularization and biotransportation within 3D fascicle structures are critical. Unfortunately, an ideal internal fascicle and microvascular model of human peripheral nerves is lacking. In this study, we used microcomputed tomography (microCT) to acquire high-resolution images of the human sciatic nerve. We propose a novel deep-learning network technique, called ResNetH3D-Unet, to segment fascicles and microvascular structures. We reconstructed 3D intraneural fascicles and microvascular topography to quantify the fascicle volume ratio (FVR), microvascular volume ratio (MVR), microvascular to fascicle volume ratio (MFVR), fascicle surface area to volume ratio (FSAVR), and microvascular surface area to volume ratio (MSAVR) of human samples. The frequency distributions of the fascicle diameter, microvascular diameter, and fascicle-to-microvasculature distance were analyzed. The obtained microCT analysis and reconstruction provided high-resolution microstructures of human peripheral nerves. Our proposed ResNetH3D-Unet method for fascicle and microvasculature segmentation yielded a mean intersection over union (IOU) of 92.1% (approximately 5% higher than the U-net IOU). The 3D reconstructed model showed that the internal microvasculature runs longitudinally within the internal epineurium and connects to the external vasculature at some points. Analysis of the 3D data indicated a 48.2 ± 3% FVR, 23.7 ± 1.8% MVR, 4.9 ± 0.5% MFVR, 7.26 ± 2.58 mm-1 FSAVR, and 1.52 ± 0.52 mm-1 MSAVR. A fascicle diameter of 0.98 mm, microvascular diameter of 0.125 mm, and microvasculature-to-fascicle distance of 0.196 mm were most frequent. This study provides fundamental data and structural references for designing bionic scaffolding constructs with 3D microvascular and fascicle distributions.

In vivo effects of different orthodontic loading on root resorption and correlation with mechanobiological stimulus in periodontal ligament.

Orthodontic root resorption is a common side effect of orthodontic therapy. It has been shown that high hydrostatic pressure in the periodontal ligament (PDL) generated by orthodontic forces will trigger recruitment of odontoclasts, leaving resorption craters on root surfaces. The patterns of resorption craters are the traces of odontoclast activity. This study aimed to investigate resorptive patterns by: (i) quantifying spatial root resorption under two different levels of in vivo orthodontic loadings using microCT imaging techniques and (ii) correlating the spatial distribution pattern of resorption craters with the induced mechanobiological stimulus field in PDL through nonlinear finite-element analysis (FEA) in silico. Results indicated that the heavy force led to a larger total resorption volume than the light force, mainly by presenting greater individual crater volumes ( p < 0.001) than increasing crater numbers, suggesting that increased mechano-stimulus predominantly boosted cellular resorption activity rather than recruiting more odontoclasts. Furthermore, buccal-cervical and lingual-apical regions in both groups were found to have significantly larger resorption volumes than other regions ( p < 0.005). These clinical observations are complemented by the FEA results, suggesting that root resorption was more likely to occur when the volume average compressive hydrostatic pressure exceeded the capillary blood pressure (4.7 kPa).

Investigation on masticatory muscular functionality following oral reconstruction - An inverse identification approach.

The human masticatory system has received significant attention in the areas of biomechanics due to its sophisticated co-activation of a group of masticatory muscles which contribute to the fundamental oral functions. However, determination of each muscular force remains fairly challenging in vivo; the conventional data available may be inapplicable to patients who experience major oral interventions such as maxillofacial reconstruction, in which the resultant unsymmetrical anatomical structure invokes a more complex stomatognathic functioning system. Therefore, this study aimed to (1) establish an inverse identification procedure by incorporating the sequential Kriging optimization (SKO) algorithm, coupled with the patient-specific finite element analysis (FEA) in silico and occlusal force measurements at different time points over a course of rehabilitation in vivo; and (2) evaluate muscular functionality for a patient with mandibular reconstruction using a fibula free flap (FFF) procedure. The results from this study proved the hypothesis that the proposed method is of certain statistical advantage of utilizing occlusal force measurements, compared to the traditionally adopted optimality criteria approaches that are basically driven by minimizing the energy consumption of muscle systems engaged. Therefore, it is speculated that mastication may not be optimally controlled, in particular for maxillofacially reconstructed patients. For the abnormal muscular system in the patient with orofacial reconstruction, the study shows that in general, the magnitude of muscle forces fluctuates over the 28-month rehabilitation period regardless of the decreasing trend of the maximum muscular capacity. Such finding implies that the reduction of the masticatory muscle activities on the resection side might lead to non-physiological oral biomechanical responses, which can change the muscular activities for stabilizing the reconstructed mandible.