Cells are compressible and can be regarded as a kind of coated liquid inclusion embedded in a three-dimensional elastic matrix.In the presence of far-field loading,how the coating influences the mechanical response(e....Cells are compressible and can be regarded as a kind of coated liquid inclusion embedded in a three-dimensional elastic matrix.In the presence of far-field loading,how the coating influences the mechanical response(e.g.,volume change)of the liquid inclusion remains elusive,especially when surface tension effects become significant at cell size level.We developed a theoretical model to characterize the mechanical amplification or attenuation role of coating on spherical liquid inclusions,with surface tension and liquid compressibility accounted for.We found that surface tension could increase the volumetric strain of the inclusion through decreasing its effective bulk modulus.We further found that,when there is a monotonic stiffness variation(either decreasing or increasing)from matrix via coating to inclusion,the presence of coating amplified the volumetric strain compared with the case without coating;in the opposite,when there is a non-monotonic stiffness change from matrix via coating to inclusion,the volumetric strain is attenuated by the coating.The results are useful for understanding and exploring the mechanobiological sensation of certain types of cell,e.g.,osteocytes and cancer cells.展开更多
As is well known, hand-arm vibration syndrome (HAVS), or vibration-induced white finger (VWF), which is a secondary form of Raynaud’s syndrome, is an industrial injury triggered by regular use of vibrating hand-held ...As is well known, hand-arm vibration syndrome (HAVS), or vibration-induced white finger (VWF), which is a secondary form of Raynaud’s syndrome, is an industrial injury triggered by regular use of vibrating hand-held tools. According to the related biopsy tests, the main vibration-caused lesion is an increase in the thickness of the artery walls of the small arteries and arterioles resulted from enlarged vascular smooth muscle cells (VSMCs) in the wall layer known as tunica media. The present work develops a mechanobiological picture for the cell enlargement. The work deals with acoustic variables in solid materials, i.e., the non-equilibrium components of mechanical variables in the materials in the case where these components are weakly non-equilibrium. The work derives an explicit expression for the infinite-time cell-volume relative enlargement. This enlargement is directly affected by the acoustic pressure in the soft living tissue (SLT). In order to reduce the enlargement, one can reduce either the ratio of the acoustic pressure in the SLT to the cell bulk modulus or the relaxation time induced by the cell osmosis, or both the characteristics. Also, a mechanoprotective role of the above relaxation time in the cell-volume maintenance is noted. The above mechanobiological picture focuses attention on the pressure in an SLT and, thus, modeling of propagation of acoustic waves caused by the acceleration of a vibrating hand-held tool. The present work analyzes the propagation along the thickness of an infinite planar layer of an SLT. The work considers acoustic modeling. As a general viscoelastic acoustic model, the work suggests linear non-stationary partial integro-differential equation (PIDE) for the weakly non-equilibrium component of the average normal stress (ANS) or, briefly, the acoustic ANS. The PIDE is, in the exponential approximation for the normalized stress-relaxation function (NSRF) reduced to the third-order linear non-stationary partial differential equation (PDE), which is of the Zener type. The unique advantage of the PIDE is that it presents a compact model for the acoustic ANS in an SLT, which explicitly includes the NSRF, thereby enabling a consistent description of the lossy-propagation effects inherent in SLTs. The one-spatial-coordinate version of this PDE in the planar SLT layer with the corresponding boundary conditions is considered. The relevance of these settings is motivated by a conclusion of other authors, which is based on the results of the frequency-domain simulation in three spatial coordinates. The boundary-value problem at arbitrary value of the stress-relaxation time (SRT) and arbitrary but sufficiently regular shape of the external acceleration is analytically solved by means of the Fourier method. The obtained solution is the steady-state acoustic ANS and allows calculation of the corresponding steady-state acoustic pressure as well. The derived analytical representations are computationally implemented. Propagation of the pressure waves in the SLT layer at zero and different nonzero values of the SRT, and the single-pulse external acceleration is presented. They complement the zero-SRT and zero-SRT-asymptote results with the results for various values of the SRT. The obtained pressure values are, at all of the space-time points under consideration, meeting the condition for the adequateness of the linear model. In the case where the SRT is zero, the results well agree with the ones obtained by using the simulation software package LS-DYNA. The dependence of the damping of acoustic variables in an SLT on the SRT in the present third-order case significantly generalizes the one in the second-order linear systems. The related resonance effect in the waves of the acoustic pressure propagating in an SLT is also discussed. The effects of the NSRF-originated memory function provided by the present third-order PDE model are necessary for proper simulation of the pressure, which is of special importance in the aforementioned mechanoboiological picture. The results obtained in the work present a viscoelastic acoustic framework for SLTs. These results open a way to quantitatively specific evaluation of technological strategies for reduction of the vibration-caused injuries or, loosely speaking, achieving “zero’’ injury.展开更多
Nonsegmented negative-sense RNA viruses(nsNSVs)-including highly pathogenic pathogens such as measles virus(MeV),Nipah virus(NiV),Hendra virus(HeV),Ebola virus(EBOV),and others-pose major global health threats,yet mos...Nonsegmented negative-sense RNA viruses(nsNSVs)-including highly pathogenic pathogens such as measles virus(MeV),Nipah virus(NiV),Hendra virus(HeV),Ebola virus(EBOV),and others-pose major global health threats,yet most lack approved antiviral therapeutics.In the recent study,high-resolution cryo-electron microscopy(cryo-EM)revealed previously unrecognized allosteric pockets in the large(L)polymerase proteins of MeV and NiV,spatially distinct from the catalytic nucleotide-binding site.We further demonstrated that the non-nucleoside inhibitor ERDRP-0519 engages these pockets to allosterically‘lock’the polymerase in a mechanically inactive state.These findings reveal an allosteric mechanism of inhibition rooted in the conformational mechanics of the enzyme and highlight opportunities for integrating artificial intelligence(AI)-aided drug discovery(AIDD)into rational drug design.展开更多
Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation,but also by resorbing bone matrix(osteolysis)that releases further stimulatory factors fo...Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation,but also by resorbing bone matrix(osteolysis)that releases further stimulatory factors for tumour growth in a vicious cycle.Changes in the local mechanical environment of bone tissue occur during early metastasis,which might activate mechanobiological responses by resident bone cells(osteocytes)to activate resorption(osteoclasts)and thereby contribute to tumour invasion.The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by(a)implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis(3-weeks after tumour inoculation)and then(b)applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis.We implemented a global resorption rate derived from an experimental model,but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region,the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model.Moreover,the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks.Thus,we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.展开更多
Unlike traditional implants primarily composed of bioinert materials,magnesium(Mg)-a degradable biomaterial-offers significant promise for next-generation bone healing implants,whether utilized as a primary structural...Unlike traditional implants primarily composed of bioinert materials,magnesium(Mg)-a degradable biomaterial-offers significant promise for next-generation bone healing implants,whether utilized as a primary structural component or a supporting material.While most research focuses on Mg's bioactive and osteoimmunological effect,this review highlights its mechanobiological role,summarizing the merits of Mg-containing implants in facilitating mechanotransduction and associated cellular events during the bone healing.Beyond introducing Mg's biomechanical benefits in preventing stress shielding,this review synthesizes its unique attributes:exceptional bone-implant integration and synergistic effects with physical stimuli to amplify new bone formation.Crucially,we also summarize the activation of mechanotransduction signaling pathways,providing a mechanistic basis for Mg's positive mechanobiological influence.Finally,we discuss challenges arising from the interaction between physical loading and Mg degradation,alongside future perspectives and potential solutions to bridge the gap between theory and clinical application,thereby accelerating translation applications of Mg-containing implants.展开更多
The tilted implant with immediate function is increasingly used in clinical dental therapy for edentulous and partially edentulous patients with excessive bone resorption and the anatomic limitations in the alveolar r...The tilted implant with immediate function is increasingly used in clinical dental therapy for edentulous and partially edentulous patients with excessive bone resorption and the anatomic limitations in the alveolar ridge.However,peri-implant cervical bone loss can be caused by the stress shielding effect.Herein,inspired by the concept of“materiobiology”,the mechanical characteristics of materials were considered along with bone biology for tilted implant design.In this study,a novel Ti-35Nb-2Ta-3Zr alloy(TNTZ)implant with low elastic modulus,high strength and favorable biocompatibility was developed.Then the human alveolar bone environment was mimicked in goat and finite element(FE)models to investigate the mechanical property and the related peri-implant bone remodeling of TNTZ compared to commonly used Ti-6Al-4V(TC4)in tilted implantation under loading condition.Next,a layer-by-layer quantitative correlation of the FE and X-ray Microscopy(XRM)analysis suggested that the TNTZ implant present better mechanobiological characteristics including improved load transduction and increased bone area in the tilted implantation model compared to TC4 implant,especially in the upper 1/3 region of peri-implant bone that is“lower stress”.Finally,combining the static and dynamic parameters of bone,it was further verified that TNTZ enhanced bone remodeling in“lower stress”upper 1/3 region.This study demonstrates that TNTZ is a mechanobiological optimized tilted implant material that enhances load transduction and bone remodeling.展开更多
Vascular smooth muscle cells (VSMCs) in the arterial walls play important roles in regulating vascular contraction and dilation. VSMCs actively remodel the arterial walls and dedifferentiate from the contractile to th...Vascular smooth muscle cells (VSMCs) in the arterial walls play important roles in regulating vascular contraction and dilation. VSMCs actively remodel the arterial walls and dedifferentiate from the contractile to the synthetic phenotype under pathological conditions. The mechanism underlying phenotypic transition of VSMCs is important for understanding its role in the pathophysiology of disease. Although numerous studies have reported various biochemical pathways that stimulate the phenotypic transition of VSMCs, very little is known about relation between their phenotypic transition and cellular traction force, which affects many cellular functions. In this study, we induced the differentiation of cultured VSMCs from the synthetic to the contractile phenotype by a low-serum cultivation and investigated changes in the cell traction forces using traction force microscopy technique. The expression of α-SMA, a contractile phenotype marker protein, was significantly upregulated with maturation of actin stress fibers in the low-serum culture, indicating VSMC differentiation was promoted in our experiments. The cells changed their morphology to an elongated bipolar shape, and the direction of the cell traction forces tended to align in the direction of the cell’s major axis. Despite the promotion of contractile differentiation in VSMCs, the overall cell traction forces were significantly reduced, indicating that excessive cell mechanical tension, which might induce cell proliferation and migration, was suppressed during contractile differentiation. These results suggest that suppression of cell traction force and enhanced force polarity might be key factors in VSMC differentiation induced by low serum culture.展开更多
Nuclear DNA, which is essential for the transmission of genetic information, is constantly damaged by external stresses and is subsequently repaired by the removal of the damaged region, followed by resynthesis of the...Nuclear DNA, which is essential for the transmission of genetic information, is constantly damaged by external stresses and is subsequently repaired by the removal of the damaged region, followed by resynthesis of the excised region. Accumulation of DNA damage with failure of repair processes leads to fatal diseases such as cancer. Recent studies have suggested that intra- and extra-nuclear environments play essential roles in DNA damage. However, numerous questions regarding the role of the nuclear mechanical environment in DNA damage remain unanswered. In this study, we investigated the effects of cell confluency (cell crowding) on the morphology of cell nuclei, and cytoskeletal structures, and DNA damage in NIH3T3 skin fibroblasts and HeLa cervical cancer cells. Although nuclear downsizing was observed in both NIH3T3 and HeLa cells with cell crowding, intracellular mechanical changes in the two cell types displayed opposite tendencies. Cell crowding in NIH3T3 cells induced reinforcement of actin filament structures, cell stiffening, and nuclear downsizing, resulting in a significant decrease in endogenous DNA damage, whereas cell crowding in HeLa cells caused partial depolymerization of actin filaments and cell softening, inducing endogenous DNA damage. Ultraviolet (UV) radiation significantly increased DNA damage in NIH3T3;however, this response did not change with cell crowding. In contrast, UV radiation did not cause DNA damage in HeLa cells under either sparse or confluent conditions. These results suggested that cell crowding significantly influenced endogenous DNA damage in cells and was quite different in NIH3T3 and HeLa cells. However, cell crowding did not affect the UV-induced DNA damage in either cell type.展开更多
Corneal collagen crosslinking(CXL)has revolutionized the treatment of keratoconus in the past decade.In order to evaluate the 3-month effects of CXL on corneal fibroblasts,a longitudinal study at the tissue and cellul...Corneal collagen crosslinking(CXL)has revolutionized the treatment of keratoconus in the past decade.In order to evaluate the 3-month effects of CXL on corneal fibroblasts,a longitudinal study at the tissue and cellular level was carried out with a total of 16 rabbits that underwent CXL,deepithelialization(DEP),or non-treatment(control)and kept for 1 to 3 months.The duration of corneal stromal remodeling after CXL was determined by examining the differentiation,apoptosis,and number changes of keratocytes in tissue sections from animals 1,2,or 3 months post-treatment.Upon the finish of tissue remodeling,separate rabbits were used to extract keratocytes and set up cell culture for vimentin immunofluorescence staining.The same cell culture was used for(1)migration measurement through the wound-healing assay;(2)elastic modulus measurement by atomic force microscope(AFM);(3)the proliferation,apoptosis,cytoskeleton andα-SMA expression tests through EdU(5-ethynyl-2’-deoxyuridine)assay,TUNEL(TdT-mediated dUTP Nick-End Labeling)assay,phalloidin andα-SMA(alpha-smooth muscle actin)immunofluorescence analysis,respectively.Results showed that the migratory activity,elastic modulus,andα-SMA expression of the corneal fibroblasts increased after CXL treatment,while apoptosis,proliferation,and morphology of F-actin cytoskeleton of the fibroblasts had no significant change after 3 months.In contrast,measured cellular parameters(migratory,elastic moduli,α-SMA expression,apoptosis,proliferation,and morphology of F-actin cytoskeleton of fibroblasts)did not change significantly after DEP.In conclusion,the dynamic changes of keratocytes were nearly stable 3 months after CXL treatment.CXL has an impact on corneal fibroblasts,including migration,elastic modulus andα-SMA expression,while epithelialization may not alter the biological behavior of cells significantly.展开更多
The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanic...The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanical environment very close to cells–the cell microenvironment–plays the most important role in determining what a cell feels and how it responds to tissue-level stimuli. To complicate matters further, cells can actively manipulate their microenvironments through pathways of recursive mechanobiological feedback. Harnessing this recursive behavior to understand and control cell physiology and pathophysiology is a critical frontier in the field of mechanobiology. Recent results suggest that the key to opening this scientific frontier to investigation and engineering application is understanding a different frontier: the physical frontier that cells face when probing their mechanical microenvironments.展开更多
Due to the increasing burden on healthcare budgets of musculoskeletal system disease and injury, there is a growing need for safe, effective and simple therapies. Conditions such as osteoporosis severely impact onqual...Due to the increasing burden on healthcare budgets of musculoskeletal system disease and injury, there is a growing need for safe, effective and simple therapies. Conditions such as osteoporosis severely impact onquality of life and result in hundreds of hours of hospital time and resources. There is growing interest in the use of low magnitude, high frequency vibration(LMHFV) to improve bone structure and muscle performance in a variety of different patient groups. The technique has shown promise in a number of different diseases, but is poorly understood in terms of the mechanism of action. Scientific papers concerning both the in vivo and in vitro use of LMHFV are growing fast, but they cover a wide range of study types, outcomes measured and regimens tested. This paper aims to provide an overview of some effects of LMHFV found during in vivo studies. Furthermore we will review research concerning the effects of vibration on the cellular responses, in particular for cells within the musculoskeletal system. This includes both osteogenesis and adipogenesis, as well as the interaction between MSCs and other cell types within bone tissue.展开更多
Mechanics plays a crucial role in a diversity of biological processes at different length(from molecules,cells,tissues,organs to organisms)and time scales.As a rapidly growing field across the interfaces of mechanics,...Mechanics plays a crucial role in a diversity of biological processes at different length(from molecules,cells,tissues,organs to organisms)and time scales.As a rapidly growing field across the interfaces of mechanics,biology,and medical engineering,mechanobiology aims to identify the mechanical and biological responses of cells and tissues of展开更多
There is a lack of effective tissue repair and regeneration strategies in current clinical practices.Numerous studies have suggested that smart or responsive biomaterials possessing the ability to respond to endogenou...There is a lack of effective tissue repair and regeneration strategies in current clinical practices.Numerous studies have suggested that smart or responsive biomaterials possessing the ability to respond to endogenous stimuli in vivo may positively mediate the tissue micro-environment towards a tissue repair or regeneration.Mechanical stimuli,which constantly exist in a wide range of biological systems and are involved in almost all the physiological processes,belong to such stimuli to which responsive biomaterials can respond.In recent studies,a new type of smart biomaterials,which can dynamically adapt to the mechanical stimuli in vivo and thus has specific functionality consistently mediated by such mechanical stimuli,has emerged.In contrast to common biomaterials that passively react to the mechanical environment of an implantation site,such mechano-active biomaterials have enabled various active or automatic strategies for tissue repair or regeneration,such as providing precise spatial-temporal controls on delivery of drugs or cells in the organs of the musculoskeletal and the circulatory systems;in situ reconstructing the original or a favorable mechanical environment at a lesion site;and accelerating the tissue remodeling or healing process via a mechanobiological effect.This article elucidates a perspective of perfecting tissue repair or regeneration using mechano-active biomaterials,especially highlighting the rationale behind the concept of mechano-active biomaterials and their potential in the repair or regeneration of musculoskeletal and cardiovascular tissues.Albeit outstanding challenges and unknowns,the emergence of mechano-active biomaterials has become a new avenue for tissue engineering and regenerative medicine.展开更多
Both biological and engineering approaches have contributed significantly to the recent advance in the field of mechanobiology.Collaborating with biologists,bio-engineers and materials scientists have employed the tec...Both biological and engineering approaches have contributed significantly to the recent advance in the field of mechanobiology.Collaborating with biologists,bio-engineers and materials scientists have employed the techniques stemming from the conventional semiconductor industry to rebuild cellular milieus that mimic critical aspects of in vivo conditions and elicit cell/tissue responses in vitro.Such reductionist approaches have help to unveil important mechanosensing mechanism in both cellular and tissue level,including stem cell differentiation and proliferation,tissue expansion,wound healing,and cancer metastasis.In this mini-review,we discuss various microfabrication methods that have been applied to generate specific properties and functions of designer substrates/devices,which disclose cell-microenvironment interactions and the underlying biological mechanisms.In brief,we emphasize on the studies of cell/tissue mechanical responses to substrate adhesiveness,stiffness,topography,and shear flow.Moreover,we comment on the new concepts of measurement and paradigms for investigations of biological mechanotransductions that are yet to emerge due to on-going interdisciplinary efforts in the fields of mechanobiology and microengineering.展开更多
Cell adhesion and migration are basic physiolog- ical processes in living organisms. Cells can actively probe their mechanical micro-environment and respond to the ex- ternal stimuli through cell adhesion. Cells need ...Cell adhesion and migration are basic physiolog- ical processes in living organisms. Cells can actively probe their mechanical micro-environment and respond to the ex- ternal stimuli through cell adhesion. Cells need to move to the targeting place to perform function via cell migration. For adherent cells, cell migration is mediated by cell-matrix adhesion and cell-cell adhesion. Experimental approaches, especially at early stage of investigation, are indispensable to studies of cell mechanics when even qualitative behaviors of cell as well as fundamental factors in cell behaviors are unclear. Currently, there is increasingly accumulation of ex- perimental data of measurement, thus a quantitative formula- tion of cell behaviors and the relationship among these fun- damental factors are highly needed. This quantitative under- standing should be crucial to tissue engineering and biomed- ical engineering when people want to accurately regulate or control cell behaviors from single cell level to tissue level. In this review, we will elaborate recent advances in the ex- perimental and theoretical studies on cell adhesion and mi- gration, with particular focuses laid on recent advances in experimental techniques and theoretical modeling, through which challenging problems in the cell mechanics are sug- gested.展开更多
It is known that mechanical forces play critical roles in physiology and diseases but the underlying mechanisms remain largely unknown[1].Most studies on the role of forces focus on cell surface molecules and cytoplas...It is known that mechanical forces play critical roles in physiology and diseases but the underlying mechanisms remain largely unknown[1].Most studies on the role of forces focus on cell surface molecules and cytoplasmic proteins.However,increasing evidence suggests that nuclear mechanotransduction impacts nuclear activities and functions.Recently we have revealed that transgene dihydrofolate reductase(DHFR)gene expression is directly upregulated via cell surface forceinduced stretching of chromatin [2].Here we show that endogenous genes are also upregulated directly by force via integrins.We present evidence on an underlying mechanism of how gene transcription is regulated by force.We have developed a technique of elastic round microgels to quantify 3D tractions in vitro and in vivo[3].We report a synthetic small molecule(which has been stiffened structurally)that inhibits malignant tumor repopulating cell growth in a low-stiffness(force)microenvironment and cancer metastasis in mouse models without detectable toxicity[4].These findings suggest that direct nuclear mechanotransduction impacts mechanobiology and mechanomedicine at cellular and molecular levels.展开更多
Mechanobiology is the study of how stress and strain are generated by cells and how these mechanical factors regulate cell morphology and function.The vascular system is subject to tensile and compressive stress and s...Mechanobiology is the study of how stress and strain are generated by cells and how these mechanical factors regulate cell morphology and function.The vascular system is subject to tensile and compressive stress and strain in the blood vessel wal that are generated by blood pressure and play a pivotal role in regulating vascular cell activities including proliferation,differentiation,apoptosis,and migration.These cellular processes are essential to vascular development,performance,and pathogenic alterations.Dr.Y.C.Fung has made significant contributions to vascular mechanobiology—establishing the uniform stress theory,addressing the generation and significance of uniform stress and strain across the blood vessel wall,and proposing the stress-growth theory,addressing the role of mechanical stress in regulating cell proliferative ac-tivities(Fung 1984,Fung 1990).These theories have exerted a profound impact on the development of Biomechanics and Mechanobiology in the vascular as well as other systems.展开更多
Bone is able to adapt its composition and structure in order to suit its mechanical environment.Osteocytes,bone cells embedded in the calcified matrix,are believed to be the mechanosensors and responsible for orchestr...Bone is able to adapt its composition and structure in order to suit its mechanical environment.Osteocytes,bone cells embedded in the calcified matrix,are believed to be the mechanosensors and responsible for orchestrating the bone remodeling process[1].However,detailed cellular and molecular mechanism underlying osteocyte mechanobiology is not well understood.Further,how osteocytes communicate with other cell populations under mechanical loading is unclear.Recently,we developed several microfluidic platforms to address these questions.In this talk,osteocyte intracellular response under mechanical loading in the microfluidic environment will first be presented.Next,inter cell-population communications under mechanical loading and its implication in bone disorder management such as bone metastasis prevention will be discussed.1.Study osteocyte response to mechanical loading in a microfluidic environment Current research has focused on observing bone cell mechanotransduction under different simulated physiological conditions(e.g.,shear stress,strain,pressure,etc.)using macro-scale devices.However,these devices often require large sample volumes,low through-put,extensive setup protocol,as well as very limited designs only suitable for general cell culture[2].On the other hand,in vitro microfluidic devices provide an optimal tool to better understand this biological process with its flexible design,physiologically-relevant dimensions,and high-throughput capabilities.Recent work on co-culture platform has demonstrated the feasibility of building more complex microfluidic devices for osteocyte mechanotransduction studies,while maintaining its biological relevance[3].However,there lacks a robust system where multi-physiological flow conditions are applied to bone cells to study their intercellular communication.We aim to fulfill this gap by designing and fabricating a multi-shear stress,co-culture platform to study interaction between osteocytes and other bone cells when exposed to an array of physical cues.The project will rely on standard microfluidic principles in designing devices that utilize changing geometric parameters to induce different flow rates that are directly proportional to the levels of shear stress.All channels within the same device will share a common inlet,while adjusting the resistance of each individual channel will result in a different flow rate.Devices are fabricated using PDMS,and bonded to glass slides of equal sizes.MLO-Y4 osteocyte like cells seeded in the device are stimulated with oscillatory fluid flow with a custom in-house pump.Significant differences in RANKL levels are observed between channels,demonstrating that proper cellular response to flow can be elicit from each distinct shear stress channels as designed.Furthermore,we aim to pair these multi-shear stress channels with corresponding culturing chambers connected through perfusion pores.Through perfusion between the multi-shear stress channels and culturing chambers,different cell population can communicate to each other as they are stimulated by varying levels of shear stress.Using this platform,we will be able to mimic the interaction between osteocytes and other bone cells in vitro.Due to the advantage of using microfluidic devices,various analytical methods can be used on-chip to determine cellular response,such as staining for biomarkers and differentiation factors.2.Microfluidic platform for investigation of mechanoregulation of breast cancer bone metastasis Approximately 70%of advanced breast cancer patients experience bone metastasis.Breast cancer cells(BCC)that extravasate across the endothelium to the bone reduce bone quality by disrupting the healthy bone remodeling balance.Exercise,a common cancer intervention strategy,can regulate bone remodeling,thus potentially affect BCC metastasis to bone through signals released by mechanical loaded osteocytes.Our recent in vitro studies showed that mechanically stimulatedosteocytes can regulate BCC migration via endothelial cells[5].However,a more physiologically relevant platform is needed to better investigate the mechanisms leading to interactions between BCC and bone microenvironment under mechanical loading.We present here a novel in vitro microfluidic tri-culture lumen system for studying mechanical regulation of breast cancer metastasis in bone.In this study,highly metastatic MDA-MB-231 human BCCs were cultured inside a cylindrical lumen lined with human umbilical vein endothelial cells(HUVECs),which is adjacent to a population of either static or mechanically-stimulated osteocyte-like MLO-Y4 cells.Physiologically relevant oscillatory fluid flow(OFF)(1 Pa,1 Hz)was produced by a custom pump to mechanically load the MLO-Y4 cells.Soluble factors were diffused through hydrogel-filled side channels to enable inter-cell population communication between MLO-Y4 cells and BCCs over 3 days.BCC extravasation distance and percentage were measured and normalized to the acellular control with MLO-Y4 media only.Paired t-tests(n=5)were used for statistical analysis and the Holm-Bonferroni method was applied for multiple comparison analysis.Statistical significance was taken at P<0.05.Photolithography and soft lithography were used to fabricate silicon SU-8 master and PDMS replicates,respectively.A HUVEC lumen was successfully cultured in the PDMS microfluidic device.Extravasation distance was significantly decreased in the flowed osteocytes(33.6%of control)compared to static osteocytes(108.0%of control),while the extravasation percentage showed a non-significant decreasing trend between the flow(58%of control)and static(106.3%of control)osteocytes.In summary,we developed the first microfluidic platform allowing the integration of physiologically relevant bone fluid stimulation and real-time intercellular signaling between different cell populations in vitro.Using this platform,the significantly reduced extravasation distance was found in the group where conditioned medium from osteocytes exposed to flow.We speculate this could be due to regulation of matrix metallopeptidase 9(MMP-9)used by cancer cells to degrade the surrounding matrix during extravasation.Future work with this platform will determine the key mechanisms involved in osteocyte regulation of BCC metastasis.展开更多
As a frontier of biology,mechanobiology plays an important role in tissue and biomedical engineering.It is a common sense that mechanical cues under extracellular microenvironment affect a lot in regulating the behavi...As a frontier of biology,mechanobiology plays an important role in tissue and biomedical engineering.It is a common sense that mechanical cues under extracellular microenvironment affect a lot in regulating the behaviors of cells such as proliferation and gene expression,etc.In such an interdisciplinary field,engineering methods like the pneumatic and motor-driven devices have been employed for years.Nevertheless,such techniques usually rely on complex structures,which cost much but not so easy to control.Dielectric elastomer actuators(DEAs)are well known as a kind of soft actuation technology,and their research prospect in biomechanical field is gradually concerned due to their properties just like large deformation(>100%)and fast response(<1 ms).In addition,DEAs are usually optically transparent and can be fabricated into small volume,which make them easy to cooperate with regular microscope to realize real-time dynamic imaging of cells.This paper first reviews the basic components,principle,and evaluation of DEAs and then overview some corresponding applications of DEAs for cellular mechanobiology research.We also provide a comparison between DEA-based bioreactors and current custom-built devices and share some opinions about their potential applications in the future according to widely reported results via other methods.展开更多
Osteoporosis and osteopenia are major health issues that mainly affect elderly people,women after menopause and immobilized patients.Our previous studies have proved that sclerostin antibody(Scl-Ab)can dramatically en...Osteoporosis and osteopenia are major health issues that mainly affect elderly people,women after menopause and immobilized patients.Our previous studies have proved that sclerostin antibody(Scl-Ab)can dramatically enhance bone formation and reduce bone resorption in a severe osteoporosis rat model with the combination of ovariectomy(OVX)and hindlimb immobilization(HLS).However,the mechanism in the cellular level is unclear.The objective of this study is to assess the effect of Scl-Ab on osteocytic morphology change in a combined OVX and HLS rat model via quantification of long-and short-axis and the ratio and osteocyte volume in midshaft cortical bone.Four-month-old virgin female SD rats were divided into 7 groups(n=11 per group):Sham+Veh,Sham+HLS+Veh,Sham+HLS+Scl-Ab,OVX+Veh,OVX+Scl-Ab,OVX+HLS+Veh,OVX+HLS+Scl-Ab.HLS was performed 2 weeks after sham or OVX surgery;and treatment was initiated at the time of HLS.Scl-Ab(25 mg/kg)or vehicle was subcutaneously injected twice per week for 5 weeks.Femurs were harvested at the end of study and embedded in PMMA and polished for SEM imaging.Cortical bone mid shaft osteocyte number per bone area was quantified under 1K magnification;the ratios between long axis and short axis of osteocytes were quantified under 2K magnification;osteocyte dendrite number and surface area were quantified under 5K magnification.Osteocyte dendrites width was quantified using 10K magnification.All the quantification was done by ImageJ.We have reported that multiple morphological and structural changes in osteocytes,including a decreased osteocyte density and reduced osteocyte dendrite number in HLS,OVX or the combination group and Scl-Ab’s ability to abolish these unfavorable alterations.We continued our SEM analysis on osteocytes and discovered that the oval shape of osteocyte under HLS,OVX or HLS+OVX has been distorted toward a spindle-like shape,with relatively longer long axis and shorter short axis,assuming osteocyte has a perfect spheroid shape.The ratio between long-and short-axis showed an increased trend in OVX and HLS condition,but Scl-Ab inhibited these increases(P<0.001,P<0.01,respectively).The volume decreased in HLS,OVX group,but Scl-Ab maintained osteocytes’volume in HLS condition(P<0.001).It indicates that cortical bone responds to HLS and/or OVX and Scl-Ab treatment via multiple cellular mechanisms,including density of osteocyte,dendrite number and osteocyte shape.The change of osteocyte shape may imply an altered cytoskeleton system within osteocyte and a subsequent disruption of mechanosensing ability for osteocyte,which lead to bone loss macroscopically.These data suggest Scl-Ab’s therapeutic potential could be related with its ability to maintain osteocyte’s morphologic and structural changes induced by OVX,HLS or both.展开更多
基金supported by the National Natural Science Foundation of China(Grants 12032010,11532009,and 11902155)the Natural Science Foundation of Jiangsu Province(Grant BK20190382)the foundation of“Jiangsu Provincial Key Laboratory of Bionic Functional Materials”,the Foundation for the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘Cells are compressible and can be regarded as a kind of coated liquid inclusion embedded in a three-dimensional elastic matrix.In the presence of far-field loading,how the coating influences the mechanical response(e.g.,volume change)of the liquid inclusion remains elusive,especially when surface tension effects become significant at cell size level.We developed a theoretical model to characterize the mechanical amplification or attenuation role of coating on spherical liquid inclusions,with surface tension and liquid compressibility accounted for.We found that surface tension could increase the volumetric strain of the inclusion through decreasing its effective bulk modulus.We further found that,when there is a monotonic stiffness variation(either decreasing or increasing)from matrix via coating to inclusion,the presence of coating amplified the volumetric strain compared with the case without coating;in the opposite,when there is a non-monotonic stiffness change from matrix via coating to inclusion,the volumetric strain is attenuated by the coating.The results are useful for understanding and exploring the mechanobiological sensation of certain types of cell,e.g.,osteocytes and cancer cells.
文摘As is well known, hand-arm vibration syndrome (HAVS), or vibration-induced white finger (VWF), which is a secondary form of Raynaud’s syndrome, is an industrial injury triggered by regular use of vibrating hand-held tools. According to the related biopsy tests, the main vibration-caused lesion is an increase in the thickness of the artery walls of the small arteries and arterioles resulted from enlarged vascular smooth muscle cells (VSMCs) in the wall layer known as tunica media. The present work develops a mechanobiological picture for the cell enlargement. The work deals with acoustic variables in solid materials, i.e., the non-equilibrium components of mechanical variables in the materials in the case where these components are weakly non-equilibrium. The work derives an explicit expression for the infinite-time cell-volume relative enlargement. This enlargement is directly affected by the acoustic pressure in the soft living tissue (SLT). In order to reduce the enlargement, one can reduce either the ratio of the acoustic pressure in the SLT to the cell bulk modulus or the relaxation time induced by the cell osmosis, or both the characteristics. Also, a mechanoprotective role of the above relaxation time in the cell-volume maintenance is noted. The above mechanobiological picture focuses attention on the pressure in an SLT and, thus, modeling of propagation of acoustic waves caused by the acceleration of a vibrating hand-held tool. The present work analyzes the propagation along the thickness of an infinite planar layer of an SLT. The work considers acoustic modeling. As a general viscoelastic acoustic model, the work suggests linear non-stationary partial integro-differential equation (PIDE) for the weakly non-equilibrium component of the average normal stress (ANS) or, briefly, the acoustic ANS. The PIDE is, in the exponential approximation for the normalized stress-relaxation function (NSRF) reduced to the third-order linear non-stationary partial differential equation (PDE), which is of the Zener type. The unique advantage of the PIDE is that it presents a compact model for the acoustic ANS in an SLT, which explicitly includes the NSRF, thereby enabling a consistent description of the lossy-propagation effects inherent in SLTs. The one-spatial-coordinate version of this PDE in the planar SLT layer with the corresponding boundary conditions is considered. The relevance of these settings is motivated by a conclusion of other authors, which is based on the results of the frequency-domain simulation in three spatial coordinates. The boundary-value problem at arbitrary value of the stress-relaxation time (SRT) and arbitrary but sufficiently regular shape of the external acceleration is analytically solved by means of the Fourier method. The obtained solution is the steady-state acoustic ANS and allows calculation of the corresponding steady-state acoustic pressure as well. The derived analytical representations are computationally implemented. Propagation of the pressure waves in the SLT layer at zero and different nonzero values of the SRT, and the single-pulse external acceleration is presented. They complement the zero-SRT and zero-SRT-asymptote results with the results for various values of the SRT. The obtained pressure values are, at all of the space-time points under consideration, meeting the condition for the adequateness of the linear model. In the case where the SRT is zero, the results well agree with the ones obtained by using the simulation software package LS-DYNA. The dependence of the damping of acoustic variables in an SLT on the SRT in the present third-order case significantly generalizes the one in the second-order linear systems. The related resonance effect in the waves of the acoustic pressure propagating in an SLT is also discussed. The effects of the NSRF-originated memory function provided by the present third-order PDE model are necessary for proper simulation of the pressure, which is of special importance in the aforementioned mechanoboiological picture. The results obtained in the work present a viscoelastic acoustic framework for SLTs. These results open a way to quantitatively specific evaluation of technological strategies for reduction of the vibration-caused injuries or, loosely speaking, achieving “zero’’ injury.
基金supported by a grant from ShanghaiTech University to H.Z.,and a grant from the Shanxi Key Laboratory of Protein Structure Determination(202104010910006)to H.Z.
文摘Nonsegmented negative-sense RNA viruses(nsNSVs)-including highly pathogenic pathogens such as measles virus(MeV),Nipah virus(NiV),Hendra virus(HeV),Ebola virus(EBOV),and others-pose major global health threats,yet most lack approved antiviral therapeutics.In the recent study,high-resolution cryo-electron microscopy(cryo-EM)revealed previously unrecognized allosteric pockets in the large(L)polymerase proteins of MeV and NiV,spatially distinct from the catalytic nucleotide-binding site.We further demonstrated that the non-nucleoside inhibitor ERDRP-0519 engages these pockets to allosterically‘lock’the polymerase in a mechanically inactive state.These findings reveal an allosteric mechanism of inhibition rooted in the conformational mechanics of the enzyme and highlight opportunities for integrating artificial intelligence(AI)-aided drug discovery(AIDD)into rational drug design.
基金support of the Irish Research Council Laureate Award Programme 2017/18(MEMETic,IRCLA/2017/217)the Hardiman Postgraduate Research Scholarship,provided by the University of Galway(UG)in Ireland,and Science Foundation Ireland under Grant number(18/SPP/3522)as part of Precision Oncology Ireland,with co-funding from the National Breast Cancer Research Institute.
文摘Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation,but also by resorbing bone matrix(osteolysis)that releases further stimulatory factors for tumour growth in a vicious cycle.Changes in the local mechanical environment of bone tissue occur during early metastasis,which might activate mechanobiological responses by resident bone cells(osteocytes)to activate resorption(osteoclasts)and thereby contribute to tumour invasion.The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by(a)implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis(3-weeks after tumour inoculation)and then(b)applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis.We implemented a global resorption rate derived from an experimental model,but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region,the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model.Moreover,the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks.Thus,we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.
基金supported by Health and Medical Research Fund(18190481)Areas of Excellence(AoE/M-402/20)+6 种基金General Research Fund(14120924)Research Impact Fund(R4034-23F)Cofunding Mechanism on Joint Laboratories with the CAS(JLFS/M-401/24)Passion for Perfection Scheme(PFP202307012)the National Natural Science Foundation of China(32171332)the Knowledge Transfer Project Fund(KPF24GWP05)the IdeaBooster Fund(IDBF25MED07).
文摘Unlike traditional implants primarily composed of bioinert materials,magnesium(Mg)-a degradable biomaterial-offers significant promise for next-generation bone healing implants,whether utilized as a primary structural component or a supporting material.While most research focuses on Mg's bioactive and osteoimmunological effect,this review highlights its mechanobiological role,summarizing the merits of Mg-containing implants in facilitating mechanotransduction and associated cellular events during the bone healing.Beyond introducing Mg's biomechanical benefits in preventing stress shielding,this review synthesizes its unique attributes:exceptional bone-implant integration and synergistic effects with physical stimuli to amplify new bone formation.Crucially,we also summarize the activation of mechanotransduction signaling pathways,providing a mechanistic basis for Mg's positive mechanobiological influence.Finally,we discuss challenges arising from the interaction between physical loading and Mg degradation,alongside future perspectives and potential solutions to bridge the gap between theory and clinical application,thereby accelerating translation applications of Mg-containing implants.
基金supported by the National Natural Science Foundation of China[grant number 52171075,51831011,U2032124]the Medical Engineering Cross Key Research Foundation of the Shanghai Jiao Tong University[grant number YG2017ZD06]+1 种基金the Science and Technology Commission of Shanghai Municipality[grant number 201409006300]the Opening Project of Shanghai Key Laboratory of Orthopaedic Implant[grant number KFKT2021001].
文摘The tilted implant with immediate function is increasingly used in clinical dental therapy for edentulous and partially edentulous patients with excessive bone resorption and the anatomic limitations in the alveolar ridge.However,peri-implant cervical bone loss can be caused by the stress shielding effect.Herein,inspired by the concept of“materiobiology”,the mechanical characteristics of materials were considered along with bone biology for tilted implant design.In this study,a novel Ti-35Nb-2Ta-3Zr alloy(TNTZ)implant with low elastic modulus,high strength and favorable biocompatibility was developed.Then the human alveolar bone environment was mimicked in goat and finite element(FE)models to investigate the mechanical property and the related peri-implant bone remodeling of TNTZ compared to commonly used Ti-6Al-4V(TC4)in tilted implantation under loading condition.Next,a layer-by-layer quantitative correlation of the FE and X-ray Microscopy(XRM)analysis suggested that the TNTZ implant present better mechanobiological characteristics including improved load transduction and increased bone area in the tilted implantation model compared to TC4 implant,especially in the upper 1/3 region of peri-implant bone that is“lower stress”.Finally,combining the static and dynamic parameters of bone,it was further verified that TNTZ enhanced bone remodeling in“lower stress”upper 1/3 region.This study demonstrates that TNTZ is a mechanobiological optimized tilted implant material that enhances load transduction and bone remodeling.
文摘Vascular smooth muscle cells (VSMCs) in the arterial walls play important roles in regulating vascular contraction and dilation. VSMCs actively remodel the arterial walls and dedifferentiate from the contractile to the synthetic phenotype under pathological conditions. The mechanism underlying phenotypic transition of VSMCs is important for understanding its role in the pathophysiology of disease. Although numerous studies have reported various biochemical pathways that stimulate the phenotypic transition of VSMCs, very little is known about relation between their phenotypic transition and cellular traction force, which affects many cellular functions. In this study, we induced the differentiation of cultured VSMCs from the synthetic to the contractile phenotype by a low-serum cultivation and investigated changes in the cell traction forces using traction force microscopy technique. The expression of α-SMA, a contractile phenotype marker protein, was significantly upregulated with maturation of actin stress fibers in the low-serum culture, indicating VSMC differentiation was promoted in our experiments. The cells changed their morphology to an elongated bipolar shape, and the direction of the cell traction forces tended to align in the direction of the cell’s major axis. Despite the promotion of contractile differentiation in VSMCs, the overall cell traction forces were significantly reduced, indicating that excessive cell mechanical tension, which might induce cell proliferation and migration, was suppressed during contractile differentiation. These results suggest that suppression of cell traction force and enhanced force polarity might be key factors in VSMC differentiation induced by low serum culture.
文摘Nuclear DNA, which is essential for the transmission of genetic information, is constantly damaged by external stresses and is subsequently repaired by the removal of the damaged region, followed by resynthesis of the excised region. Accumulation of DNA damage with failure of repair processes leads to fatal diseases such as cancer. Recent studies have suggested that intra- and extra-nuclear environments play essential roles in DNA damage. However, numerous questions regarding the role of the nuclear mechanical environment in DNA damage remain unanswered. In this study, we investigated the effects of cell confluency (cell crowding) on the morphology of cell nuclei, and cytoskeletal structures, and DNA damage in NIH3T3 skin fibroblasts and HeLa cervical cancer cells. Although nuclear downsizing was observed in both NIH3T3 and HeLa cells with cell crowding, intracellular mechanical changes in the two cell types displayed opposite tendencies. Cell crowding in NIH3T3 cells induced reinforcement of actin filament structures, cell stiffening, and nuclear downsizing, resulting in a significant decrease in endogenous DNA damage, whereas cell crowding in HeLa cells caused partial depolymerization of actin filaments and cell softening, inducing endogenous DNA damage. Ultraviolet (UV) radiation significantly increased DNA damage in NIH3T3;however, this response did not change with cell crowding. In contrast, UV radiation did not cause DNA damage in HeLa cells under either sparse or confluent conditions. These results suggested that cell crowding significantly influenced endogenous DNA damage in cells and was quite different in NIH3T3 and HeLa cells. However, cell crowding did not affect the UV-induced DNA damage in either cell type.
基金supported by the National natural science foundation of China(Nos.31370952,31470914).
文摘Corneal collagen crosslinking(CXL)has revolutionized the treatment of keratoconus in the past decade.In order to evaluate the 3-month effects of CXL on corneal fibroblasts,a longitudinal study at the tissue and cellular level was carried out with a total of 16 rabbits that underwent CXL,deepithelialization(DEP),or non-treatment(control)and kept for 1 to 3 months.The duration of corneal stromal remodeling after CXL was determined by examining the differentiation,apoptosis,and number changes of keratocytes in tissue sections from animals 1,2,or 3 months post-treatment.Upon the finish of tissue remodeling,separate rabbits were used to extract keratocytes and set up cell culture for vimentin immunofluorescence staining.The same cell culture was used for(1)migration measurement through the wound-healing assay;(2)elastic modulus measurement by atomic force microscope(AFM);(3)the proliferation,apoptosis,cytoskeleton andα-SMA expression tests through EdU(5-ethynyl-2’-deoxyuridine)assay,TUNEL(TdT-mediated dUTP Nick-End Labeling)assay,phalloidin andα-SMA(alpha-smooth muscle actin)immunofluorescence analysis,respectively.Results showed that the migratory activity,elastic modulus,andα-SMA expression of the corneal fibroblasts increased after CXL treatment,while apoptosis,proliferation,and morphology of F-actin cytoskeleton of the fibroblasts had no significant change after 3 months.In contrast,measured cellular parameters(migratory,elastic moduli,α-SMA expression,apoptosis,proliferation,and morphology of F-actin cytoskeleton of fibroblasts)did not change significantly after DEP.In conclusion,the dynamic changes of keratocytes were nearly stable 3 months after CXL treatment.CXL has an impact on corneal fibroblasts,including migration,elastic modulus andα-SMA expression,while epithelialization may not alter the biological behavior of cells significantly.
文摘The fields of biomechanics and mechanobiology have long been predicated on the premise that mechanics governs cell behavior. However, over the past few years, a growing body of evidence has suggested that the mechanical environment very close to cells–the cell microenvironment–plays the most important role in determining what a cell feels and how it responds to tissue-level stimuli. To complicate matters further, cells can actively manipulate their microenvironments through pathways of recursive mechanobiological feedback. Harnessing this recursive behavior to understand and control cell physiology and pathophysiology is a critical frontier in the field of mechanobiology. Recent results suggest that the key to opening this scientific frontier to investigation and engineering application is understanding a different frontier: the physical frontier that cells face when probing their mechanical microenvironments.
基金Engineering and Physical Sciences Research Council
文摘Due to the increasing burden on healthcare budgets of musculoskeletal system disease and injury, there is a growing need for safe, effective and simple therapies. Conditions such as osteoporosis severely impact onquality of life and result in hundreds of hours of hospital time and resources. There is growing interest in the use of low magnitude, high frequency vibration(LMHFV) to improve bone structure and muscle performance in a variety of different patient groups. The technique has shown promise in a number of different diseases, but is poorly understood in terms of the mechanism of action. Scientific papers concerning both the in vivo and in vitro use of LMHFV are growing fast, but they cover a wide range of study types, outcomes measured and regimens tested. This paper aims to provide an overview of some effects of LMHFV found during in vivo studies. Furthermore we will review research concerning the effects of vibration on the cellular responses, in particular for cells within the musculoskeletal system. This includes both osteogenesis and adipogenesis, as well as the interaction between MSCs and other cell types within bone tissue.
基金Supports from the National Natural Science Foundation of China (Grants 11432008 and 11620101001) are acknowledged
文摘Mechanics plays a crucial role in a diversity of biological processes at different length(from molecules,cells,tissues,organs to organisms)and time scales.As a rapidly growing field across the interfaces of mechanics,biology,and medical engineering,mechanobiology aims to identify the mechanical and biological responses of cells and tissues of
基金sponsored by the National Natural Science Foundation of China(Nos.81622032,31801585,81930070and 51672184)Suzhou Science and Technology Project(No.SYS2019022)+3 种基金Natural Science Foundation of Jiangsu Province(Nos.BK20180837 and BK20181045)Postdoctoral Science Foundation(No.2018T110546)Natural Science Research of Jiangsu Higher Education Institutions(No.17KJA180011)the Priority Aca-demic Program Development of Jiangsu High Education Institutions(PAPD)。
文摘There is a lack of effective tissue repair and regeneration strategies in current clinical practices.Numerous studies have suggested that smart or responsive biomaterials possessing the ability to respond to endogenous stimuli in vivo may positively mediate the tissue micro-environment towards a tissue repair or regeneration.Mechanical stimuli,which constantly exist in a wide range of biological systems and are involved in almost all the physiological processes,belong to such stimuli to which responsive biomaterials can respond.In recent studies,a new type of smart biomaterials,which can dynamically adapt to the mechanical stimuli in vivo and thus has specific functionality consistently mediated by such mechanical stimuli,has emerged.In contrast to common biomaterials that passively react to the mechanical environment of an implantation site,such mechano-active biomaterials have enabled various active or automatic strategies for tissue repair or regeneration,such as providing precise spatial-temporal controls on delivery of drugs or cells in the organs of the musculoskeletal and the circulatory systems;in situ reconstructing the original or a favorable mechanical environment at a lesion site;and accelerating the tissue remodeling or healing process via a mechanobiological effect.This article elucidates a perspective of perfecting tissue repair or regeneration using mechano-active biomaterials,especially highlighting the rationale behind the concept of mechano-active biomaterials and their potential in the repair or regeneration of musculoskeletal and cardiovascular tissues.Albeit outstanding challenges and unknowns,the emergence of mechano-active biomaterials has become a new avenue for tissue engineering and regenerative medicine.
文摘Both biological and engineering approaches have contributed significantly to the recent advance in the field of mechanobiology.Collaborating with biologists,bio-engineers and materials scientists have employed the techniques stemming from the conventional semiconductor industry to rebuild cellular milieus that mimic critical aspects of in vivo conditions and elicit cell/tissue responses in vitro.Such reductionist approaches have help to unveil important mechanosensing mechanism in both cellular and tissue level,including stem cell differentiation and proliferation,tissue expansion,wound healing,and cancer metastasis.In this mini-review,we discuss various microfabrication methods that have been applied to generate specific properties and functions of designer substrates/devices,which disclose cell-microenvironment interactions and the underlying biological mechanisms.In brief,we emphasize on the studies of cell/tissue mechanical responses to substrate adhesiveness,stiffness,topography,and shear flow.Moreover,we comment on the new concepts of measurement and paradigms for investigations of biological mechanotransductions that are yet to emerge due to on-going interdisciplinary efforts in the fields of mechanobiology and microengineering.
基金supported by the National Natural Science Foundation of China(11221202and11025208)the State Key Laboratory of Explosive Science and Technology of Beijing Institute of Technology(YBKT12-05)
文摘Cell adhesion and migration are basic physiolog- ical processes in living organisms. Cells can actively probe their mechanical micro-environment and respond to the ex- ternal stimuli through cell adhesion. Cells need to move to the targeting place to perform function via cell migration. For adherent cells, cell migration is mediated by cell-matrix adhesion and cell-cell adhesion. Experimental approaches, especially at early stage of investigation, are indispensable to studies of cell mechanics when even qualitative behaviors of cell as well as fundamental factors in cell behaviors are unclear. Currently, there is increasingly accumulation of ex- perimental data of measurement, thus a quantitative formula- tion of cell behaviors and the relationship among these fun- damental factors are highly needed. This quantitative under- standing should be crucial to tissue engineering and biomed- ical engineering when people want to accurately regulate or control cell behaviors from single cell level to tissue level. In this review, we will elaborate recent advances in the ex- perimental and theoretical studies on cell adhesion and mi- gration, with particular focuses laid on recent advances in experimental techniques and theoretical modeling, through which challenging problems in the cell mechanics are sug- gested.
基金supported by funds from National Institutes of Health,USA and Huazhong University of Science and Technology,Wuhan,Chinathe support from Hoeft Professorship at University of Illinois at Urbana-Champaign
文摘It is known that mechanical forces play critical roles in physiology and diseases but the underlying mechanisms remain largely unknown[1].Most studies on the role of forces focus on cell surface molecules and cytoplasmic proteins.However,increasing evidence suggests that nuclear mechanotransduction impacts nuclear activities and functions.Recently we have revealed that transgene dihydrofolate reductase(DHFR)gene expression is directly upregulated via cell surface forceinduced stretching of chromatin [2].Here we show that endogenous genes are also upregulated directly by force via integrins.We present evidence on an underlying mechanism of how gene transcription is regulated by force.We have developed a technique of elastic round microgels to quantify 3D tractions in vitro and in vivo[3].We report a synthetic small molecule(which has been stiffened structurally)that inhibits malignant tumor repopulating cell growth in a low-stiffness(force)microenvironment and cancer metastasis in mouse models without detectable toxicity[4].These findings suggest that direct nuclear mechanotransduction impacts mechanobiology and mechanomedicine at cellular and molecular levels.
文摘Mechanobiology is the study of how stress and strain are generated by cells and how these mechanical factors regulate cell morphology and function.The vascular system is subject to tensile and compressive stress and strain in the blood vessel wal that are generated by blood pressure and play a pivotal role in regulating vascular cell activities including proliferation,differentiation,apoptosis,and migration.These cellular processes are essential to vascular development,performance,and pathogenic alterations.Dr.Y.C.Fung has made significant contributions to vascular mechanobiology—establishing the uniform stress theory,addressing the generation and significance of uniform stress and strain across the blood vessel wall,and proposing the stress-growth theory,addressing the role of mechanical stress in regulating cell proliferative ac-tivities(Fung 1984,Fung 1990).These theories have exerted a profound impact on the development of Biomechanics and Mechanobiology in the vascular as well as other systems.
文摘Bone is able to adapt its composition and structure in order to suit its mechanical environment.Osteocytes,bone cells embedded in the calcified matrix,are believed to be the mechanosensors and responsible for orchestrating the bone remodeling process[1].However,detailed cellular and molecular mechanism underlying osteocyte mechanobiology is not well understood.Further,how osteocytes communicate with other cell populations under mechanical loading is unclear.Recently,we developed several microfluidic platforms to address these questions.In this talk,osteocyte intracellular response under mechanical loading in the microfluidic environment will first be presented.Next,inter cell-population communications under mechanical loading and its implication in bone disorder management such as bone metastasis prevention will be discussed.1.Study osteocyte response to mechanical loading in a microfluidic environment Current research has focused on observing bone cell mechanotransduction under different simulated physiological conditions(e.g.,shear stress,strain,pressure,etc.)using macro-scale devices.However,these devices often require large sample volumes,low through-put,extensive setup protocol,as well as very limited designs only suitable for general cell culture[2].On the other hand,in vitro microfluidic devices provide an optimal tool to better understand this biological process with its flexible design,physiologically-relevant dimensions,and high-throughput capabilities.Recent work on co-culture platform has demonstrated the feasibility of building more complex microfluidic devices for osteocyte mechanotransduction studies,while maintaining its biological relevance[3].However,there lacks a robust system where multi-physiological flow conditions are applied to bone cells to study their intercellular communication.We aim to fulfill this gap by designing and fabricating a multi-shear stress,co-culture platform to study interaction between osteocytes and other bone cells when exposed to an array of physical cues.The project will rely on standard microfluidic principles in designing devices that utilize changing geometric parameters to induce different flow rates that are directly proportional to the levels of shear stress.All channels within the same device will share a common inlet,while adjusting the resistance of each individual channel will result in a different flow rate.Devices are fabricated using PDMS,and bonded to glass slides of equal sizes.MLO-Y4 osteocyte like cells seeded in the device are stimulated with oscillatory fluid flow with a custom in-house pump.Significant differences in RANKL levels are observed between channels,demonstrating that proper cellular response to flow can be elicit from each distinct shear stress channels as designed.Furthermore,we aim to pair these multi-shear stress channels with corresponding culturing chambers connected through perfusion pores.Through perfusion between the multi-shear stress channels and culturing chambers,different cell population can communicate to each other as they are stimulated by varying levels of shear stress.Using this platform,we will be able to mimic the interaction between osteocytes and other bone cells in vitro.Due to the advantage of using microfluidic devices,various analytical methods can be used on-chip to determine cellular response,such as staining for biomarkers and differentiation factors.2.Microfluidic platform for investigation of mechanoregulation of breast cancer bone metastasis Approximately 70%of advanced breast cancer patients experience bone metastasis.Breast cancer cells(BCC)that extravasate across the endothelium to the bone reduce bone quality by disrupting the healthy bone remodeling balance.Exercise,a common cancer intervention strategy,can regulate bone remodeling,thus potentially affect BCC metastasis to bone through signals released by mechanical loaded osteocytes.Our recent in vitro studies showed that mechanically stimulatedosteocytes can regulate BCC migration via endothelial cells[5].However,a more physiologically relevant platform is needed to better investigate the mechanisms leading to interactions between BCC and bone microenvironment under mechanical loading.We present here a novel in vitro microfluidic tri-culture lumen system for studying mechanical regulation of breast cancer metastasis in bone.In this study,highly metastatic MDA-MB-231 human BCCs were cultured inside a cylindrical lumen lined with human umbilical vein endothelial cells(HUVECs),which is adjacent to a population of either static or mechanically-stimulated osteocyte-like MLO-Y4 cells.Physiologically relevant oscillatory fluid flow(OFF)(1 Pa,1 Hz)was produced by a custom pump to mechanically load the MLO-Y4 cells.Soluble factors were diffused through hydrogel-filled side channels to enable inter-cell population communication between MLO-Y4 cells and BCCs over 3 days.BCC extravasation distance and percentage were measured and normalized to the acellular control with MLO-Y4 media only.Paired t-tests(n=5)were used for statistical analysis and the Holm-Bonferroni method was applied for multiple comparison analysis.Statistical significance was taken at P<0.05.Photolithography and soft lithography were used to fabricate silicon SU-8 master and PDMS replicates,respectively.A HUVEC lumen was successfully cultured in the PDMS microfluidic device.Extravasation distance was significantly decreased in the flowed osteocytes(33.6%of control)compared to static osteocytes(108.0%of control),while the extravasation percentage showed a non-significant decreasing trend between the flow(58%of control)and static(106.3%of control)osteocytes.In summary,we developed the first microfluidic platform allowing the integration of physiologically relevant bone fluid stimulation and real-time intercellular signaling between different cell populations in vitro.Using this platform,the significantly reduced extravasation distance was found in the group where conditioned medium from osteocytes exposed to flow.We speculate this could be due to regulation of matrix metallopeptidase 9(MMP-9)used by cancer cells to degrade the surrounding matrix during extravasation.Future work with this platform will determine the key mechanisms involved in osteocyte regulation of BCC metastasis.
基金the financial support from the National Natural Science Foundation of China(Grant Nos.81822024,11761141006,and 21605102)the National Key Research and Development Program of China(Grant No.2017YFC1200904).
文摘As a frontier of biology,mechanobiology plays an important role in tissue and biomedical engineering.It is a common sense that mechanical cues under extracellular microenvironment affect a lot in regulating the behaviors of cells such as proliferation and gene expression,etc.In such an interdisciplinary field,engineering methods like the pneumatic and motor-driven devices have been employed for years.Nevertheless,such techniques usually rely on complex structures,which cost much but not so easy to control.Dielectric elastomer actuators(DEAs)are well known as a kind of soft actuation technology,and their research prospect in biomechanical field is gradually concerned due to their properties just like large deformation(>100%)and fast response(<1 ms).In addition,DEAs are usually optically transparent and can be fabricated into small volume,which make them easy to cooperate with regular microscope to realize real-time dynamic imaging of cells.This paper first reviews the basic components,principle,and evaluation of DEAs and then overview some corresponding applications of DEAs for cellular mechanobiology research.We also provide a comparison between DEA-based bioreactors and current custom-built devices and share some opinions about their potential applications in the future according to widely reported results via other methods.
文摘Osteoporosis and osteopenia are major health issues that mainly affect elderly people,women after menopause and immobilized patients.Our previous studies have proved that sclerostin antibody(Scl-Ab)can dramatically enhance bone formation and reduce bone resorption in a severe osteoporosis rat model with the combination of ovariectomy(OVX)and hindlimb immobilization(HLS).However,the mechanism in the cellular level is unclear.The objective of this study is to assess the effect of Scl-Ab on osteocytic morphology change in a combined OVX and HLS rat model via quantification of long-and short-axis and the ratio and osteocyte volume in midshaft cortical bone.Four-month-old virgin female SD rats were divided into 7 groups(n=11 per group):Sham+Veh,Sham+HLS+Veh,Sham+HLS+Scl-Ab,OVX+Veh,OVX+Scl-Ab,OVX+HLS+Veh,OVX+HLS+Scl-Ab.HLS was performed 2 weeks after sham or OVX surgery;and treatment was initiated at the time of HLS.Scl-Ab(25 mg/kg)or vehicle was subcutaneously injected twice per week for 5 weeks.Femurs were harvested at the end of study and embedded in PMMA and polished for SEM imaging.Cortical bone mid shaft osteocyte number per bone area was quantified under 1K magnification;the ratios between long axis and short axis of osteocytes were quantified under 2K magnification;osteocyte dendrite number and surface area were quantified under 5K magnification.Osteocyte dendrites width was quantified using 10K magnification.All the quantification was done by ImageJ.We have reported that multiple morphological and structural changes in osteocytes,including a decreased osteocyte density and reduced osteocyte dendrite number in HLS,OVX or the combination group and Scl-Ab’s ability to abolish these unfavorable alterations.We continued our SEM analysis on osteocytes and discovered that the oval shape of osteocyte under HLS,OVX or HLS+OVX has been distorted toward a spindle-like shape,with relatively longer long axis and shorter short axis,assuming osteocyte has a perfect spheroid shape.The ratio between long-and short-axis showed an increased trend in OVX and HLS condition,but Scl-Ab inhibited these increases(P<0.001,P<0.01,respectively).The volume decreased in HLS,OVX group,but Scl-Ab maintained osteocytes’volume in HLS condition(P<0.001).It indicates that cortical bone responds to HLS and/or OVX and Scl-Ab treatment via multiple cellular mechanisms,including density of osteocyte,dendrite number and osteocyte shape.The change of osteocyte shape may imply an altered cytoskeleton system within osteocyte and a subsequent disruption of mechanosensing ability for osteocyte,which lead to bone loss macroscopically.These data suggest Scl-Ab’s therapeutic potential could be related with its ability to maintain osteocyte’s morphologic and structural changes induced by OVX,HLS or both.
