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Immune cells encounter tissues with vastly different biochemical and physical characteristics. Much of the research emphasis has focused on the role of cytokines and chemokines in regulating immune cell function, but the role of the physical microenvironment has received considerably less attention. The tissue mechanics, or stiffness, of healthy tissues varies dramatically from soft adipose tissue and brain to stiff cartilage and bone. Tissue mechanics also change due to fibrosis and with diseases such as atherosclerosis or cancer. The process by which cells sense and respond to their physical microenvironment is called mechanotransduction. Here we review mechanotransduction in immunologically important diseases and how physical characteristics of tissues regulate immune cell function, with a specific emphasis on mechanoregulation of macrophages and TLR signaling.

It is well established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether bone mechano-regulation is controlled by mechanical signals in the local in vivo environment and dependent on loading frequency. Specifically, by combining in vivo micro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanical in vivo environment (strain energy density (SED) and SED gradient) of mouse caudal vertebrae over 4 weeks of either cyclic loading at varying frequencies of 2Hz, 5Hz, or 10Hz, respectively or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of bone formation and a decreased probability of bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net remodeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2Hz, 5Hz and 10Hz (+15%, +21% and +24%, p2=0.74). In conclusion, these results suggest that bone adaptation is regulated by mechanical signals in the local in vivo environment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights towards a better understanding of the mechanical signals influencing bone formation and resorption in the local in vivo environment.

It is widely accepted that bones have the ability to adapt to new biomechanical environment by changing their material properties, geometry and inner architecture. Bones have also an exceptional ability to self-repair, to remove microcracks and to prevent the bone damage caused by the fatigue failure. These abilities are enabled through coupled processes of bone resorption and bone formation, the processes collectively referred to as bone remodeling. Numerous studies have shown that bone remodeling is governed by combination of mechanical stimulus (strains) and its frequency, both sensed by sensor cells (osteocytes). Through mechanotransduction, the stimulus is transmitted to actor cells (osteoclasts, osteoblasts) that actually do the bone resorption or formation. Several theories have been proposed to predict bone remodeling and several finite-element-based algorithms have been introduced. The vast majority of them uses strain energy density as the mechanical stimulus. The purpose of this paper is to investigate and discuss the applicability of also other strain-based representations of the mechanical stimulus in simulations of remodeling of bone with an initial microcrack. The need for developing more reliable models is essential for both clinicians and engineers who are interested, for instance, in prediction of bone performance when various implants are involved.

YAP/TAZ activity is regulated by a complex network of signals that include the Hippo pathway, cell polarity complexes, and signaling receptors of the RTK, GPCR, and WNT pathways and by a seamlessly expanding number of intracellular cues including energy and mevalonate metabolism. Among these inputs, we here concentrate on mechanical cues embedded in the extracellular matrix (ECM) microenvironment, which are key regulators of YAP/TAZ activity. We review the techniques that have been used to study mechano-regulation of YAP/TAZ, including conceptual and practical considerations on how these experiments should be designed and controlled. Finally, we briefly review the most appropriate techniques to monitor YAP/TAZ activity in these experiments and their significance to study the mechanisms linking YAP/TAZ to mechanical cues.

Migration through constrictions can clearly rupture nuclei and mis-localize nuclear proteins but damage to DNA remains uncertain as does any effect on cell cycle. Here, myosin-II inhibition rescues rupture and partially rescues the DNA damage marker γH2AX, but an apparent delay in cell cycle is unaffected. Co-overexpression of multiple DNA repair factors and antioxidant inhibition of break formation also have partial effects, independent of rupture. Complete rescue of both DNA damage and cell cycle delay by myosin inhibition plus antioxidant reveals a bimodal dependence of cell cycle on DNA damage. Migration through custom-etched pores yields the same bimodal, with ~4-um pores causing intermediate levels of damage and cell cycle delay. Micronuclei (generated in faulty division) of the smallest diameter appear similar to ruptured nuclei, with high DNA damage and entry of chromatin-binding cGAS (cyclic-GMP-AMP-synthase) from cytoplasm but low repair factor levels. Increased genomic variation after constricted migration is quantified in expanding clones and is consistent with (mis)repair of excess DNA damage and subsequent proliferation.

A new class of supramolecular hydrogels, cross-linked by host-guest interactions between β-cyclodextrin (βCD) and adamantane, were designed for the dynamic regulation of cell-substrate interactions. The initial substrate elasticity can be optimized by selecting the molar fraction of host- and guest monomers for the target cells. Moreover, owing to the reversible nature of host-guest interactions, the magnitude of softening and stiffening of the substrate can be modulated by varying the concentrations of free, competing host molecules (βCD) in solutions. By changing the substrate elasticity at a desired time point, it is possible to switch the micromechanical environments of cells. We demonstrated that the Young's modulus of our "host-guest gels", 4-11 kPa, lies in an optimal range not only for static (ex situ) but also for dynamic (in situ) regulation of cell morphology and cytoskeletal ordering of myoblasts. Compared to other stimulus-responsive materials that can either change the elasticity only in one direction or rely on less biocompatible stimuli such as UV light and temperature change, our supramolecular hydrogel enables to reversibly apply mechanical cues to various cell types in vitro without interfering cell viability.

Summary TCRs recognize cognate pMHCs to initiate T cell signaling and adaptive immunity. Mechanical force strengthens TCR-pMHC interactions to elicit agonist-specific catch bonds to trigger TCR signaling, but the underlying dynamic structural mechanism is unclear. We combined steered molecular dynamics (SMD) simulation, single-molecule biophysical approaches, and functional assays to collectively demonstrate that mechanical force induces conformational changes in pMHCs to enhance pre-existing contacts and activates new interactions at the TCR-pMHC binding interface to resist bond dissociation under force, resulting in TCR-pMHC catch bonds and T cell activation. Intriguingly, cancer-associated somatic mutations in HLA-A2 that may restrict these conformational changes suppressed TCR-pMHC catch bonds. Structural analysis also indicated that HLA polymorphism might alter the equilibrium of these conformational changes. Our findings not only reveal critical roles of force-induced conformational changes in pMHCs for activating TCR-pMHC catch bonds but also have implications for T cell-based immunotherapy.

This paper describes the bone healing process of fractured long bones such as a tibia applied by composite IM rods using finite element analysis. To simulated tissue differentiation process mechano-regulation theory with a deviatoric strain was implemented and a user’s subroutine programmed by a Python code for an iterative calculation was used. To broadly find the appropriate rod modulus for healing bone fractures, composite IM rods were analyzed considering the stacking sequence. To compare mechanical stimulation at fracture gap, two kinds of initial loading conditions were applied. As a result, it was found that the initial loading condition was the most sensitive factor for the healing performance. In case a composite IM rod made of a plain weave carbon fiber/epoxy (WSN3k) had a stacking sequence of [±45] nT , the healing efficiency was the most effective under a initial load of 10%BW. 초 록 본 논문에서는 복합재료 IM rod가 적용된 골절부의 세포 분화과정을 모사하기 위해 유한요소해석을 실시하였다. 세포의 골화 과정을 해석하기 위해 편향 변형률을 이용한 메카노 규제 이론을 사용하였으며, 반복 계산을 위해 Python 코드를 이용하여 서브루틴을 구현하였다. 치료에 가장 적절한 복합재료 IM rod의 강성을 찾기 위해 직물 탄소섬유/에폭시 복합재료 (WSN3k)의 적층 각도를 바꾸어 해석을 실시하였다. 골절부에 가해지는 기계적 자극에 따른 치료효율을 비교하기 위해 두 가지 초기 하중 조건을 적용하였다. 그 결과 치료효율은 강성의 차이보다 하중에 의해 큰 영향을 받았으며, 초기 하중이 몸무게의 10%이고, 적층순서가 [±45]

The endochondral ossification process of fractured long bones was simulated using a three-dimensional finite element model when various composite bone plates were applied to the fracture site. To simulate time-varying cell phenotypes and the corresponding deviatoric strains in the calluses, a user’s subroutine was programmed for iterative calculations. Three representative initial loading conditions were investigated to find a relationship between the initial loading condition and tissue differentiation. Through finite element analysis, the trends in tissue differentiation and healing efficiency in the calluses were evaluated according to the plate modulus and loading conditions; further, the most appropriate plate modulus under each initial loading condition was suggested.

In this work, a bone adaptation law based on fully coupled stimulus function taking into account strain–damage effects and spatial function influence based on ruptured osteocytes processes concept have been developed and implemented into Abaqus code. Contrary to previous works where the spatial function was considered without damage influence, in the present model, we propose a novel idea to describe osteocytes ruptured processes using damaged spatial function. Also, the stimulus reference value for bone resorption threshold is considered cycles depending variable and an experimental fitted relation between the strain reference value and the cycle’s number was proposed. In order to reduce the computation time, the integration of the damage growth rate is based on the cycle blocks approach. The idea is that the real cycles number are reduced (divided) into equivalent cycles blocks. Damage accumulation is computed over the cycles blocks and extrapolated over the real correspond cycles. To illustrate the capabilities of the remodeling algorithm, four mechano-regulation laws have been implemented and tested corresponding to four stimuli functions: (i) strain based stimulus without damage influence, (ii) fully coupled strain–damage without spatial function influence, (iii) fully coupled strain–damage with non damaged spatial function influence and (iv) fully coupled strain–damage with damaged spatial function influence.

Although it is beyond doubt that mechanical stimulation is crucial to maintain bone mass, its role in preserving bone architecture is much less clear. Commonly, it is assumed that mechanics helps to conserve the trabecular network since an “accidental” thinning of a trabecula due to a resorption event would result in a local increase of load, thereby activating bone deposition there. However, considering that the thin trabecula is part of a network, it is not evident that load concentration happens locally on the weakened trabecula. The aim of this work was to clarify whether mechanical load has a protective role for preserving the trabecular network during remodeling. Trabecular bone is made dynamic by a remodeling algorithm, which results in a thickening/thinning of trabeculae with high/low strain energy density. Our simulations show that larger deviations from a regular cubic lattice result in a greater loss of trabeculae. Around lost trabeculae, the remaining trabeculae are on average thinner. More generally, thin trabeculae are more likely to have thin trabeculae in their neighborhood. The plausible consideration that a thin trabecula concentrates a higher amount of strain energy within itself is therefore only true when considering a single isolated trabecula. Mechano-regulated remodeling within a network-like architecture leads to local concentrations of thin trabeculae., Biomechanics and Modeling in Mechanobiology, 14 (4), ISSN:1617-7959, ISSN:1617-7940

Lumbar interbody fusion cages are commonly used to treat painful spinal degeneration and instability by achieving bony fusion. Many different cage designs exist, however the effect of cage morphology and material properties on the fusion process remains largely unknown. This finite element model study aims to investigate the influence of different cage designs on bone fusion using two mechano-regulation algorithms of tissue formation. It could be observed that different cages play a distinct key role in the mechanical conditions within the fusion region and therefore regulate the time course of the fusion process.

Minimally invasive percutaneous fixation techniques play a role of crucial relevance in the clinical practice. In spite of their consolidated use, little is reported in the literature to provide a mechanobiological explanation on how design of fixation devices can affect the healing process within fractured vertebrae.

Angiogenesis, the formation of new capillaries from pre-existing vessels, plays a critical role during bone regeneration and repair. In addition to an appropriate mechanical environment, sufficient supply of oxygen and nutrients is critical for bone formation.

Tissue differentiation can be regulated by mechanical loading. A bone chamber experiment has been conducted in order to investigate the effect of loading on tissue differentiation in vivo. In this study a computational model of the experiment was developed in which a mechano-regulation algorithm for stem cell differentiation in response to mechanical stimulus was combined with algorithms for cell migration, proliferation and apoptosis. The results show that the simulation is feasible to forecast the tissue differentiation process inside a bone chamber.

It is well established that cyclic, but not static, mechanical loading has anabolic effects on bone. However, the function describing the relationship between the loading frequency and the amount of bone adaptation remains unclear. Using a combined experimental and computational approach, this study aimed to investigate whether trabecular bone mechano-regulation is controlled by mechanical signals in the local in vivo environment and dependent on loading frequency. Specifically, by combining in vivo micro-computed tomography (micro-CT) imaging with micro-finite element (micro-FE) analysis, we monitored the changes in microstructural as well as the mechanical in vivo environment (strain energy density (SED) and SED gradient) of mouse caudal vertebrae over four weeks of either cyclic loading at varying frequencies of 2Hz, 5Hz, or 10Hz, respectively or static loading. Higher values of SED and SED gradient on the local tissue level led to an increased probability of trabecular bone formation and a decreased probability of trabecular bone resorption. In all loading groups, the SED gradient was superior in the determination of local bone formation and resorption events as compared to SED. Cyclic loading induced positive net (re)modeling rates when compared to sham and static loading, mainly due to an increase in mineralizing surface and a decrease in eroded surface. Consequently, bone volume fraction increased over time in 2Hz, 5Hz and 10Hz (+15%, +21% and +24%, p≤0.0001), while static loading led to a decrease in bone volume fraction (-9%, p≤0.001). Furthermore, regression analysis revealed a logarithmic relationship between loading frequency and the net change in bone volume fraction over the four week observation period (R2=0.74). In conclusion, these results suggest that trabecular bone adaptation is regulated by mechanical signals in the local in vivo environment and furthermore, that mechano-regulation is logarithmically dependent on loading frequency with frequencies below a certain threshold having catabolic effects, and those above anabolic effects. This study thereby provides valuable insights towards a better understanding of the mechanical signals influencing trabecular bone formation and resorption in the local in vivo environment.

Cardiovascular tissue engineering (CVTE) aims to create living tissues, with the ability to grow and remodel, as replacements for diseased blood vessels and heart valves. Despite promising results, the (long-term) functionality of these engineered tissues still needs improvement to reach broad clinical application. The functionality of native tissues is ensured by their specific mechanical properties directly arising from tissue organization. We therefore hypothesize that establishing a native-like tissue organization is vital to overcome the limitations of current CVTE approaches. To achieve this aim, a better understanding of the growth and remodeling (G&R) mechanisms of cardiovascular tissues is necessary. Cells are the main mediators of tissue G&R, and their behavior is strongly influenced by both mechanical stimuli and cell–cell signaling. An increasing number of signaling pathways has also been identified as mechanosensitive. As such, they may have a key underlying role in regulating the G&R of tissues in response to mechanical stimuli. A more detailed understanding of mechano-regulated cell–cell signaling may thus be crucial to advance CVTE, as it could inspire new methods to control tissue G&R and improve the organization and functionality of engineered tissues, thereby accelerating clinical translation. In this review, we discuss the organization and biomechanics of native cardiovascular tissues; recent CVTE studies emphasizing the obtained engineered tissue organization; and the interplay between mechanical stimuli, cell behavior, and cell–cell signaling. In addition, we review past contributions of computational models in understanding and predicting mechano-regulated tissue G&R and cell–cell signaling to highlight their potential role in future CVTE strategies.