Dynamic Mechanical Environment Research Articles

Tissue-adhesive, stretchable and compressible physical double-crosslinked microgel-integrated hydrogels for dynamic wound care

Integrated wound care through sequentially promoting hemostasis, sealing, and healing holds great promise in clinical practice. However, it remains challenging for regular bioadhesives to achieve integrated care of dynamic wounds due to the difficulties in adapting to dynamic mechanical and wet wound environments. Herein, we reported a type of dehydrated, physical double crosslinked microgels (DPDMs) which were capable of in situ forming highly stretchable, compressible and tissue-adhesive hydrogels for integrated care of dynamic wounds. The DPDMs were designed by the rational integration of the reversible crosslinks and double crosslinks into micronized gels. The reversible physical crosslinks enabled the DPDMs to integrate together, and the double crosslinked characteristics further strengthen the formed macroscopical networks (DPDM-Gels). We demonstrated that the DPDM-Gels simultaneously possess outstanding tensile (∼940 kJ/m3) and compressive (∼270 kJ/m3) toughness, commercial bioadhesives-comparable tissue-adhesive strength, together with stable performance under hundreds of deformations. In vivo results further revealed that the DPDM-Gels could effectively stop bleeding in various bleeding models, even in an actual dynamic environment, and enable the integrated care of dynamic skin wounds. On the basis of the remarkable mechanical and appropriate adhesive properties, together with impressive integrated care capacities, the DPDM-Gels may provide a new approach for the smart care of dynamic wounds. Statement of significanceIntegrated care of dynamic wounds holds great significance in clinical practice. However, the dynamic and wet wound environments pose great challenges for existing hydrogels to achieve it. This work developed robust adhesive hydrogels for integrated care of dynamic wounds by designing dehydrated, physical double crosslinked microgels (DPDMs). The reversible and double crosslinks enabled DPDMs to integrate into macroscopic hydrogels with high mechanical properties, appropriate adhesive strength and stable performance under hundreds of external deformations. Upon application at the injury site, DPDM-Gels efficiently stopped bleeding, even in an actual dynamic environment and showed effectiveness in integrated care of dynamic wounds. With the fascinating properties, DPDMs may become an effective tool for smart wound care.

Dynamic mechanical mechanism and optimization approach of roadway surrounding coal water infusion for dynamic disaster prevention

Roadway surrounding coal water infusion is a most significant technical means for the dynamic disasters prevention. To evaluate its efficiency in dynamic mechanical environment, the damage distribution and mechanical parameters were analyzed before and after water infusion. And the relationship among damage distribution, dynamic mechanical parameters, and stress wave propagation were established. With the medium of the wave impedance, the stress wave transmission process was characterized, and the dynamic stability criterion was established from the perspectives of energy and stress, respectively. On this basis, the optimization approaches were further proposed and validated in practice. The results demonstrate that water infusion can effectively enlarge the wave impedance difference among each adjacent circumferential coal segment and damage range in the surrounding coal. It will enhances the stress wave attenuation, thereby protecting the roadway from dynamic failure. To better play its role, the optimization approaches should focus on increasing the damage degree and range of the microscopic fracture zone in surrounding coal. These findings provide valuable insights into the design and implementation of surrounding coal water infusion for dynamic disasters prevention.

Microstructure-united heterogeneous sodium alginate doped injectable hydrogel for stable hemostasis in dynamic mechanical environments

Injectable hydrogels that can withstand compressive and tensile forces hold great promise for preventing rebleeding in dynamic mechanical environments after emergency hemostasis of wounds. However, current injectable hydrogels often lack sufficient compressive or tensile performance. Here, a microstructure-united heterogeneous injectable hydrogel (MH) was constructed. The heterogeneous structure endowed MH with a unique “microstructures consecutive transmission” feature, which allowed it to exhibit high compressive and tensile performance simultaneously. In this work, two types of sodium alginate doped hydrogels with different microstructures were physically smashed into microgels, respectively. By mixing the microgels, MH with one micro-pores featured microstructure and another nano-pores featured microstructure can be formed. The obtained MH can withstand both compressive and tensile forces and showed high mechanical performance (compressive modulus: 345.67 ± 10.12 kPa and tensile modulus: 245.19 ± 7.82 kPa). Furtherly, MH was proven to provide stable and sustained hemostasis in the dynamic mechanical environment. Overall, this work provided an effective strategy for constructing injectable hydrogel with high compressive and tensile performance for hemostasis in dynamic mechanical environments.

Engineering tools for quantifying and manipulating forces in epithelia.

The integrity of epithelia is maintained within dynamic mechanical environments during tissue development and homeostasis. Understanding how epithelial cells mechanosignal and respond collectively or individually is critical to providing insight into developmental and (patho)physiological processes. Yet, inferring or mimicking mechanical forces and downstream mechanical signaling as they occur in epithelia presents unique challenges. A variety of in vitro approaches have been used to dissect the role of mechanics in regulating epithelia organization. Here, we review approaches and results from research into how epithelial cells communicate through mechanical cues to maintain tissue organization and integrity. We summarize the unique advantages and disadvantages of various reduced-order model systems to guide researchers in choosing appropriate experimental systems. These model systems include 3D, 2D, and 1D micromanipulation methods, single cell studies, and noninvasive force inference and measurement techniques. We also highlight a number of in silico biophysical models that are informed by in vitro and in vivo observations. Together, a combination of theoretical and experimental models will aid future experiment designs and provide predictive insight into mechanically driven behaviors of epithelial dynamics.

Mechanically activated mesenchymal-derived bone cells drive vessel formation via an extracellular vesicle mediated mechanism

Blood vessel formation is an important initial step for bone formation during development as well as during remodelling and repair in the adult skeleton. This results in a heavily vascularized tissue where endothelial cells and skeletal cells are constantly in crosstalk to facilitate homeostasis, a process that is mediated by numerous environmental signals, including mechanical loading. Breakdown in this communication can lead to disease and/or poor fracture repair. Therefore, this study aimed to determine the role of mature bone cells in regulating angiogenesis, how this is influenced by a dynamic mechanical environment, and understand the mechanism by which this could occur. Herein, we demonstrate that both osteoblasts and osteocytes coordinate endothelial cell proliferation, migration, and blood vessel formation via a mechanically dependent paracrine mechanism. Moreover, we identified that this process is mediated via the secretion of extracellular vesicles (EVs), as isolated EVs from mechanically stimulated bone cells elicited the same response as seen with the full secretome, while the EV-depleted secretome did not elicit any effect. Despite mechanically activated bone cell-derived EVs (MA-EVs) driving a similar response to VEGF treatment, MA-EVs contain minimal quantities of this angiogenic factor. Lastly, a miRNA screen identified mechanoresponsive miRNAs packaged within MA-EVs which are linked with angiogenesis. Taken together, this study has highlighted an important mechanism in osteogenic-angiogenic coupling in bone and has identified the mechanically activated bone cell-derived EVs as a therapeutic to promote angiogenesis and potentially bone repair.

Highly stretchable, injectable hydrogels with cyclic endurance and shape-stability in dynamic mechanical environments, by microunit reformation.

Traditional injectable hydrogels have so far found it difficult to accommodate resistance to large deformation and shape-stability under cyclic deformation. Polyampholyte (PA) hydrogels exhibit resistance to large deformation, good fatigue-resistance and rapid self-healing under dynamic forces. The limitations of the preparation process result in non-injectability of polyampholyte (PA) hydrogels. Electrostatic interactions as a medium for resistance to large deformation and shape-stability after cyclic deformation in reformed injectable hydrogels has been explored in this study. The prepared hydrogels (as-prepared PA-N) were dried and smashed into microunits and then mixed with 0.9% NaCl solution to transform them into reformed hydrogels (as-reformed PA-N) via a needle to achieve injectability. The as-reformed PA-N could exhibit 913.6% elongation at break and showed shape-stability under cyclic deformation due to the efficient self-healing abilities of the microunits and the inherited structure of the prepared hydrogels, which are superior to those of current tough injectable hydrogels. Potential applications in elbow cyclic bending and frequent movement of mobile wounds have been proved in this study. Overall, the results showed that the as-reformed PA-N achieved convenient injectability with resistance to large deformation and shape-stability under cyclic deformation at the same time.

Impact of Non-Muscle Cells on Excitation-Contraction Coupling in the Heart and the Importance of In Vitro Models.

Excitation-coupling (ECC) is paramount for coordinated contraction to maintain sufficient cardiac output. The study of ECC regulation has primarily been limited to cardiomyocytes (CMs), which conduct voltage waves via calcium fluxes from one cell to another, eliciting contraction of the atria followed by the ventricles. CMs rapidly transmit ionic flux via gap junction proteins, predominantly connexin 43. While the expression of connexin isoforms has been identified in each of the individual cell populations comprising the heart, the formation of gap junctions with nonmuscle cells (i.e., macrophages and Schwann cells) has gained new attention. Evaluating nonmuscle contributions to ECC in vivo or in situ remains difficult and necessitates the development of simple, yet biomimetic in vitro models to better understand and prevent physiological dysfunction. Standard 2D cell culture often consists of homogenous cell populations and lacks the dynamic mechanical environment of native tissue, confounding the phenotypic and proteomic makeup of these highly mechanosensitive cell populations in prolonged culture conditions. This review will highlight the recent developments and the importance of new microphysiological systems to better understand the complex regulation of ECC in cardiac tissue.

Quantitative Evaluation of Cardiac Cell Interactions and Responses to Cyclic Strain.

The heart has a dynamic mechanical environment contributed by its unique cellular composition and the resultant complex tissue structure. In pathological heart tissue, both the mechanics and cell composition can change and influence each other. As a result, the interplay between the cell phenotype and mechanical stimulation needs to be considered to understand the biophysical cell interactions and organization in healthy and diseased myocardium. In this work, we hypothesized that the overall tissue organization is controlled by varying densities of cardiomyocytes and fibroblasts in the heart. In order to test this hypothesis, we utilized a combination of mechanical strain, co-cultures of different cell types, and inhibitory drugs that block intercellular junction formation. To accomplish this, an image analysis pipeline was developed to automatically measure cell type-specific organization relative to the stretch direction. The results indicated that cardiac cell type-specific densities influence the overall organization of heart tissue such that it is possible to model healthy and fibrotic heart tissue in vitro. This study provides insight into how to mimic the dynamic mechanical environment of the heart in engineered tissue as well as providing valuable information about the process of cardiac remodeling and repair in diseased hearts.

Magnetic nanocomposite hydrogel with tunable stiffness for probing cellular responses to matrix stiffening

As cells have the capacity to respond to their mechanical environment, cellular biological behaviors can be regulated by the stiffness of extracellular matrix. Moreover, biological processes are dynamic and accompanied by matrix stiffening. Herein, we developed a stiffening cell culture platform based on polyacrylamide-Fe3O4 magnetic nanocomposite hydrogel with tunable stiffness under the application of magnetic field. This platform provided a wide range of tunable stiffness (∼0.3–20 kPa) covering most of human tissue elasticity with a high biocompatibility. Overall, the increased magnetic interactions between magnetic nanoparticles reduced the pore size of the hydrogel and enhanced the hydrogel stiffness, thereby facilitating the adhesion and spreading of stem cells, which was attributed to the F-actin assembly and vinculin recruitment. Such stiffening cell culture platform provides dynamic mechanical environments for probing the cellular response to matrix stiffening, and benefits studies of dynamic biological processes. Statement of significanceCellular biological behaviors can be regulated by the stiffness of extracellular matrix. Moreover, biological processes are dynamic and accompanied by matrix stiffening. Herein, we developed a stiffening cell culture platform based on polyacrylamide/Fe3O4 magnetic nanocomposite hydrogels with a wide tunable range of stiffness under the application of magnetic field, without adversely affecting cellular behaviors. Such matrix stiffening caused by enhanced magnetic interaction between magnetic nanoparticles under the application of the magnetic field could induce the morphological variations of stem cells cultured on the hydrogels. Overall, our stiffening cell culture platform can be used not only to probe the cellular response to matrix stiffening but also to benefit various biomedical studies.

Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity.

The understanding of the electrophysiological mechanisms that underlie mechanosensitivity of the sinoatrial node (SAN), the primary pacemaker of the heart, has been evolving over the past century. The heart is constantly exposed to a dynamic mechanical environment; as such, the SAN has numerous canonical and emerging mechanosensitive ion channels and signaling pathways that govern its ability to respond to both fast (within second or on beat-to-beat manner) and slow (minutes) timescales. This review summarizes the effects of mechanical loading on the SAN activity and reviews putative candidates, including fast mechanoactivated channels (Piezo, TREK, and BK) and slow mechanoresponsive ion channels [including volume-regulated chloride channels and transient receptor potential (TRP)], as well as the components of mechanochemical signal transduction, which may contribute to SAN mechanosensitivity. Furthermore, we examine the structural foundation for both mechano-electrical and mechanochemical signal transduction and discuss the role of specialized membrane nanodomains, namely, caveolae, in mechanical regulation of both membrane and calcium clock components of the so-called coupled-clock pacemaker system responsible for SAN automaticity. Finally, we emphasize how these mechanically activated changes contribute to the pathophysiology of SAN dysfunction and discuss controversial areas necessitating future investigations. Though the exact mechanisms of SAN mechanosensitivity are currently unknown, identification of such components, their impact into SAN pacemaking, and pathological remodeling may provide new therapeutic targets for the treatment of SAN dysfunction and associated rhythm abnormalities.

Isometric contraction force measurement of hiPSC-CMs on a movable plate with a feedback-controlled MEMS cantilever probe

We propose a measurement method with a feedback system to evaluate the contraction forces of human iPS cell-derived cardiomyocytes (hiPSC-CMs) in a dynamic mechanical environment. The measurement of the hiPSC-CM contraction forces is important for regenerative medicine; however, conventional methods are not able to evaluate these forces when the cells are subjected to a dynamic load similar to that from the heart. The proposed measurement system is composed of a micromachined piezoresistive cantilever attached to a feedback-controlled piezo stage and a micromachined movable plate where cells are cultured. A high sampling rate (2 kHz) and real-time control of the cell length were realized via the feedback-controlled piezo stage, while the contraction forces were measured by the cantilever. We evaluated the contraction forces of hiPSC-CMs in conditions of isometric and auxotonic contractions. Due to feedback-controlled loading for isometric contraction, the cell shrinkage was controlled to be less than 200 nm. Auxotonic contraction forces of 3.9 μN were measured without feedback control, while the contraction forces of isometric contraction were 6.0 μN with feedback-controlled loading. The results showed that the method leads to a work-loop evaluation of the hiPSC-CM cardiac cycle.

Effects of chondrogenic priming duration on mechanoregulation of engineered cartilage

Chondrocyte maturation during cartilage development occurs under diverse and dynamic mechanical environments. Mechanical stimulation through bioreactor culture may mimic these conditions to direct cartilage tissue engineering in vitro. Mechanical cues can promote chondrocyte homeostasis or hypertrophy and mineralization, depending potentially on the timing of load application. Here, we tested the effects of chondrogenic priming duration on the response of engineered human cartilage constructs to dynamic mechanical compression. We cultured human bone marrow stromal cells (hMSCs) in fibrin hydrogels under chondrogenic priming conditions for periods of 0, 2, 4, or 6 weeks prior to two weeks of either static culture or dynamic compression. We measured construct mechanical properties, cartilage matrix composition, and gene expression. Dynamic compression increased the equilibrium and dynamic modulus of the engineered tissue, depending on the duration of chondrogenic priming. For priming times of 2 weeks or greater, dynamic compression enhanced COL2A1 and AGGRECAN mRNA expression at the end of the loading period, but did not alter total collagen or glycosaminoglycan matrix deposition. Load initiation at priming times of 4 weeks or less repressed transient osteogenic signaling (RUNX2, OPN) and expression of CYR61, a YAP/TAZ-TEAD-target gene. No suppression of osteogenic gene expression was observed if loading was initiated after 6 weeks of in vitro priming, when mechanical stimulation was observed to increase the expression of type X collagen. Taken together, these data demonstrate that the duration of in vitro chondrogenic priming regulates the cell response to dynamic mechanical compression and suggests that early loading may preserve chondrocyte homeostasis while delayed loading may support cartilage maturation.

Synthesis of Poly(l-lactide-co-ε-caprolactone) Copolymer: Structure, Toughness, and Elasticity.

Biodegradable and bioabsorbable polymers have drawn considerable attention because of their mechanical properties that mimic human soft tissue. Poly(l-lactide-co-ε-caprolactone) (PLCL), the copolymer of L-lactic (LA) and ε-caprolactone (CL), has been applied in many tissue engineering and regenerative medicine fields. However, both the synthesis of PLCL and the structure-activity relationship of the copolymer need to be further investigated to allow tuning of different mechanical properties. The synthesis conditions of PLCL were optimized to increase the yield and improve the copolymer properties. The synthetic process was evaluated by while varying the molar ratio of the monomers and polymerization time. The mechanical properties of the copolymer were investigated from the macroscopic and microscopic perspectives. Changes in the polymerization time and feed ratio resulted in the difference in the LA and CL content, which, in turn, caused the PLCL to exhibit different properties. The PLCL obtained with a feed ratio of 1:1 (LA:CL) and a polymerization time of 30 h has the best toughness and elasticity. The developed PLCL may have applications in dynamic mechanical environment, such as vascular tissue engineering.

Design of azobenzene-bearing hydrogel with photoswitchable mechanics driven by photo-induced phase transition for in vitro disease modeling

Mechanics of the extracellular matrix (ECM) exhibit changes during many biological events. During disease progression, such as cancer, matrix stiffening or softening occurs due to crosslinking of the collagen matrix or matrix degradation through cell-secreted enzymes. Engineered hydrogels have emerged as a prime in vitro model to mimic such dynamic mechanics during disease progression. Although there have been a variety of engineered hydrogels, few can offer both stiffening and softening properties under the same working principle. In addition, to model individual disease progression, it is desirable to control the kinetics of mechanical changes. To this end, we describe a photoresponsive hydrogel that undergoes stiffness changes by the photo-induced phase transition. The hydrogel was composed of a copolymer of azobenzene acrylate monomer (AzoAA) and N,N-dimethyl acrylamide (DMA). By tuning the amount of azobenzene, the phase transition behavior of this polymer occurs solely by light irradiation, because of the photoisomerization of azobenzene. This phase behavior was confirmed at 37 °C by turbidity measurements. In addition, the crosslinked poly(AzoAA-r-DMA) gel undergoes reversible swelling-deswelling upon photoisomerization by ultraviolet or visible light. Furthermore, the poly(AzoAA-r-DMA) sheet gels exhibited modulus changes at different isomerization states of azobenzene. When MCF-7 cells were cultured on the gels, stiffening at different timepoints induced varied responses in the gene expression levels of E-cadherin. Not only did this suggest an adaptive behavior of the cells against changes in mechanics during disease progression, this also demonstrated our material's potential towards in vitro disease modeling. Statement of significanceDuring disease progression such as cancer, cellular microenvironment called extracellular matrix (ECM) undergoes stiffness changes. Hydrogels, which are swollen network of crosslinked polymers, have been used to model such dynamic mechanical environment of the ECM. However, few could offer both stiffening and softening properties under the same working principle. Herein, we fabricated a novel photoresponsive hydrogel with switchable mechanics, activated by photo-induced structural change of the polymer chains within the hydrogel. When breast cancer cells were cultured on our dynamic hydrogels, gene expression and morphological observation suggested that cells react to changes in stiffness by a transient response, as opposed to a sustained one. The photoresponsive hydrogel offers possibility for use as a patient-specific model of diseases.

Filament evanescence of myosin II and smooth muscle function.

Smooth muscle is an integral part of hollow organs. Many of them are constantly subjected to mechanical forces that alter organ shape and modify the properties of smooth muscle. To understand the molecular mechanisms underlying smooth muscle function in its dynamic mechanical environment, a new paradigm has emerged that depicts evanescence of myosin filaments as a key mechanism for the muscle's adaptation to external forces in order to maintain optimal contractility. Unlike the bipolar myosin filaments of striated muscle, the side-polar filaments of smooth muscle appear to be less stable, capable of changing their lengths through polymerization and depolymerization (i.e., evanescence). In this review, we summarize accumulated knowledge on the structure and mechanism of filament formation of myosin II and on the influence of ionic strength, pH, ATP, myosin regulatory light chain phosphorylation, and mechanical perturbation on myosin filament stability. We discuss the scenario of intracellular pools of monomeric and filamentous myosin, length distribution of myosin filaments, and the regulatory mechanisms of filament lability in contraction and relaxation of smooth muscle. Based on recent findings, we suggest that filament evanescence is one of the fundamental mechanisms underlying smooth muscle's ability to adapt to the external environment and maintain optimal function. Finally, we briefly discuss how increased ROCK protein expression in asthma may lead to altered myosin filament stability, which may explain the lack of deep-inspiration-induced bronchodilation and bronchoprotection in asthma.

Photodegradable Polyacrylamide Gels for Dynamic Control of Cell Functions.

Cross-linked polyacrylamide hydrogels are commonly used in biotechnology and cell culture applications due to advantageous properties, such as the precise control of material stiffness and the attachment of cell adhesive ligands. However, the chemical and physical properties of polyacrylamide gels cannot be altered once fabricated. Here, we develop a photodegradable polyacrylamide gel system that allows for a dynamic control of polyacrylamide gel stiffness with exposure to light. Photodegradable polyacrylamide hydrogel networks are produced by copolymerizing acrylamide and a photocleavable ortho-nitrobenzyl (o-NB) bis-acrylate cross-linker. When the hydrogels are exposed to light, the o-NB cross-links cleave and the stiffness of the photodegradable polyacrylamide gels decreases. Further examination of the effect of dynamic stiffness changes on cell behavior reveals that in situ softening of the culture substrate leads to changes in cell behavior that are not observed when cells are cultured on presoftened gels, indicating that both dynamic and static mechanical environments influence cell fate. Notably, we observe significant changes in nuclear localization of YAP and cytoskeletal organization after in situ softening; these changes further depend on the type and concentration of cell adhesive proteins attached to the gel surface. By incorporating the simplicity and well-established protocols of standard polyacrylamide gel fabrication with the dynamic control of photodegradable systems, we can enhance the capability of polyacrylamide gels, thereby enabling cell biologists and engineers to study more complex cellular behaviors that were previously inaccessible using regular polyacrylamide gels.

Biomimetic strategies for fabricating musculoskeletal tissue scaffolds: a review

The advancements in musculoskeletal tissue engineering have been substantial in recent decades. Fabrication of biomimetic microenvironment closely resembling the native tissues has been widely accepted as the golden rule for tissue engineering. This paper reviews recent progress in fabrication strategy of biomimetic scaffolds for musculoskeletal tissue engineering from three key aspects: bioinspired materials, biomimetic structures, and biofabrication techniques. The emerging hybrid biofabrication technologies that enable rapid manufacturing of 3D composite constructs with complex features will be a promising pathway toward highly efficient bench-to-bedside translation. Future biomimetic scaffolds should possess modulated functions in response to the dynamic physiological and mechanical environments. This is the prerequisite of future development of reliable, flexible, and cost-effective alternatives to achieve long-term regeneration and good clinical outcomes.

The molecular mechanism of mechanotransduction in vascular homeostasis and disease

Blood vessels are constantly exposed to mechanical stimuli such as shear stress due to flow and pulsatile stretch. The extracellular matrix maintains the structural integrity of the vessel wall and coordinates with a dynamic mechanical environment to provide cues to initiate intracellular signaling pathway(s), thereby changing cellular behaviors and functions. However, the precise role of matrix-cell interactions involved in mechanotransduction during vascular homeostasis and disease development remains to be fully determined. In this review, we introduce hemodynamics forces in blood vessels and the initial sensors of mechanical stimuli, including cell-cell junctional molecules, G-protein-coupled receptors (GPCRs), multiple ion channels, and a variety of small GTPases. We then highlight the molecular mechanotransduction events in the vessel wall triggered by laminar shear stress (LSS) and disturbed shear stress (DSS) on vascular endothelial cells (ECs), and cyclic stretch in ECs and vascular smooth muscle cells (SMCs)-both of which activate several key transcription factors. Finally, we provide a recent overview of matrix-cell interactions and mechanotransduction centered on fibronectin in ECs and thrombospondin-1 in SMCs. The results of this review suggest that abnormal mechanical cues or altered responses to mechanical stimuli in EC and SMCs serve as the molecular basis of vascular diseases such as atherosclerosis, hypertension and aortic aneurysms. Collecting evidence and advancing knowledge on the mechanotransduction in the vessel wall can lead to a new direction of therapeutic interventions for vascular diseases.

Mechanical response of cortical bone in compression and tension at the mineralized fibrillar level in steroid induced osteoporosis

Nanocomposites like bone are used in vivo in a dynamic mechanical environment, and musculoskeletal fracture during traumatic events lead to pain and immobilisation, especially significant in elderly and patients with metabolic bone diseases. To mitigate against these occurrences, it is essential to understand the dynamic mechanical response of bone over short timescales, but the underlying matrix-level mechanisms are not well understood. Here, we studied the mechanical response of cortical bone at nano- and micro-scale in a mouse model with glucocorticoid induced osteoporosis and their wild type littermates using real-time synchrotron small-angle X-ray diffraction (SAXD) combined with in situ compression testing and micro-tensile testing under controlled strain rates. Under compression, the tissue modulus, yield stress, effective fibril modulus and fibrillar reorientation rate in osteoporotic bone is significantly lower than that in healthy bone. Under tension, when going from low to high strain rates, the effective fibril modulus of healthy bone increase by a factor of 4.8, but this tendency is suppressed in osteoporotic bone. Also, bone microstructure in osteoporotic showed large fraction of cavities with disrupted mineralization. Our results demonstrate how the nano- and microscale deformation mechanisms of bone ultrastructure change in osteoporotic bone under compression and tension. Our results suggest that material level changes of bone matrix contributed to the reduced mechanical competence of bone in metabolic bone diseases such as osteoporosis.

In Vitro Models of the Small Intestine: Engineering Challenges and Engineering Solutions.

Pathologies affecting the small intestine contribute significantly to the disease burden of both the developing and the developed world, which has motivated investigation into the disease mechanisms through in vitro models. Although existing in vitro models recapitulate selected features of the intestine, various important aspects have often been isolated or omitted due to the anatomical and physiological complexity. The small intestine's intricate microanatomy, heterogeneous cell populations, steep oxygen gradients, microbiota, and intestinal wall contractions are often not included in in vitro experimental models of the small intestine, despite their importance in both intestinal biology and pathology. Known and unknown interdependencies between various physiological aspects necessitate more complex in vitro models. Microfluidic technology has made it possible to mimic the dynamic mechanical environment, signaling gradients, and other important aspects of small intestinal biology. This review presents an overview of the complexity of small intestinal anatomy and bioengineered models that recapitulate some of these physiological aspects.