Publications by authors named "Guy M Genin"

112 Publications

Directed cell migration towards softer environments.

Nat Mater 2022 Jul 11. Epub 2022 Jul 11.

Department of Biomedical Engineering, University of Minnesota, Minneapolis, MN, USA.

How cells sense tissue stiffness to guide cell migration is a fundamental question in development, fibrosis and cancer. Although durotaxis-cell migration towards increasing substrate stiffness-is well established, it remains unknown whether individual cells can migrate towards softer environments. Here, using microfabricated stiffness gradients, we describe the directed migration of U-251MG glioma cells towards less stiff regions. This 'negative durotaxis' does not coincide with changes in canonical mechanosensitive signalling or actomyosin contractility. Instead, as predicted by the motor-clutch-based model, migration occurs towards areas of 'optimal stiffness', where cells can generate maximal traction. In agreement with this model, negative durotaxis is selectively disrupted and even reversed by the partial inhibition of actomyosin contractility. Conversely, positive durotaxis can be switched to negative by lowering the optimal stiffness by the downregulation of talin-a key clutch component. Our results identify the molecular mechanism driving context-dependent positive or negative durotaxis, determined by a cell's contractile and adhesive machinery.
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http://dx.doi.org/10.1038/s41563-022-01294-2DOI Listing
July 2022

Deployable mechanical metamaterials with multistep programmable transformation.

Sci Adv 2022 Jun 8;8(23):eabn5460. Epub 2022 Jun 8.

Department of Engineering Mechanics, CNMM and AML, Tsinghua University, Beijing 100084, PR China.

Transformations in shape are critical to actuation in engineered metamaterials. Existing engineering metamaterials are typically limited to a small number of shape transformations that must be built-in during material synthesis. Here, inspired by the multistability and programmability of kirigami-based self-folding elements, a robust framework is introduced for the construction of sequentially programmable and reprogrammable mechanical metamaterials. The materials can be locked into multiple stable deployed configurations and then, using tunable bistability enabled by temperature-responsive constituent materials, return to their original reference configurations or undergo mode bifurcation. The framework provides a platform to design metamaterials with multiple deployable and reversible configurations in response to external stimuli.
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http://dx.doi.org/10.1126/sciadv.abn5460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9176747PMC
June 2022

Multimodal thrombectomy device for treatment of acute deep venous thrombosis.

Sci Rep 2022 03 28;12(1):5295. Epub 2022 Mar 28.

Caeli Vascular, Inc., St. Louis, USA.

Deep vein thrombosis (DVT) is a potentially deadly medical condition that is costly to treat and impacts thousands of Americans every year. DVT is characterized by the formation of blood clots within the deep venous system of the body. If a DVT dislodges it can lead to venous thromboembolism (VTE) and pulmonary embolism (PE), both of which can lead to significant morbidity or death. Current treatment options for DVT are limited in both effectiveness and safety, in part because the treatment of the DVT cannot be confined to a defined sequestered treatment zone. We therefore developed and tested a novel thrombectomy device that enables the sequesteration of a DVT to a defined treatment zone during fragmentation and evacuation. We observed that, compared to a predicate thrombectomy device, the sequestered approach reduced distal DVT embolization during ex vivo thrombectomy. The sequestered approach also facilitated isovolumetric infusion and suction that enabled clearance of the sequestered treatment zone without significantly impacting vein wall diameter. Results suggest that our novel device using sequestered therapy holds promise for the treatment of high risk large-volume DVTs.
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http://dx.doi.org/10.1038/s41598-022-09001-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964697PMC
March 2022

Nonlinear time-dependent mechanical behavior of mammalian collagen fibrils.

Acta Biomater 2022 Mar 5. Epub 2022 Mar 5.

Aerospace Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address:

The viscoelastic mechanical behavior of collagenous tissues has been studied extensively at the macroscale, yet a thorough quantitative understanding of the time-dependent mechanics of the basic building blocks of tissues, the collagen fibrils, is still missing. In order to address this knowledge gap, stress relaxation and creep tests at various stress (5-35 MPa) and strain (5-20%) levels were performed with individual collagen fibrils (average diameter of fully hydrated fibrils: 253 ± 21 nm) in phosphate buffered saline (PBS). The experimental results showed that the time-dependent mechanical behavior of fully hydrated individual collagen fibrils reconstituted from Type I calf skin collagen, is described by strain-dependent stress relaxation and stress-dependent creep functions in both the heel-toe and the linear regimes of deformation in monotonic stress-strain curves. The adaptive quasilinear viscoelastic (QLV) model, originally developed to capture the nonlinear viscoelastic response of collagenous tissues, provided a very good description of the nonlinear stress relaxation and creep behavior of the collagen fibrils. On the other hand, the nonlinear superposition (NSP) model fitted well the creep but not the stress relaxation data. The time constants and rates extracted from the adaptive QLV and the NSP models, respectively, pointed to a faster rate for stress relaxation than creep. This nonlinear viscoelastic behavior of individual collagen fibrils agrees with prior studies of macroscale collagenous tissues, thus demonstrating consistent time-dependent behavior across length scales and tissue hierarchies. STATEMENT OF SIGNIFICANCE: Pure stress relaxation and creep experiments were conducted for the first time with fully hydrated individual collagen fibrils. It is shown that collagen nanofibrils have a nonlinear time-dependent behavior which agrees with prior studies on macroscale collagenous tissues, thus demonstrating consistent time-dependent behavior across length scales and tissue hierarchies. This new insight into the non-linear viscoelastic behavior of the building blocks of mammalian collagenous tissues may serve as the foundation for improved macroscale tissue models that capture the mechanical behavior across length scales.
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http://dx.doi.org/10.1016/j.actbio.2022.03.005DOI Listing
March 2022

Mechanically Competent Chitosan-Based Bioadhesive for Tendon-to-Bone Repair.

Adv Healthc Mater 2022 05 22;11(10):e2102344. Epub 2022 Jan 22.

Department of Orthopedic Surgery, Columbia University, New York, NY, 10032, USA.

Current suture-based surgical techniques used to repair torn rotator cuff tendons do not result in mechanically competent tendon-to-bone attachments, leading to high postoperative failure rates. Although adhesives have been proposed to protect against sutures tearing through tendon during healing, no currently available adhesive meets the clinical needs of adhesive strength, biocompatibility, and promotion of healing. Here, a biocompatible, graded, 3,4-dihydroxy phenyl chitosan (BGC) bioadhesive designed to meet these needs is presented. Although 3,4-dihydroxy phenyl chitosan (DP-chitosan) bioadhesives are biocompatible, their adhesion strength is low; soluble oxidants or cross-linking agents can be added for higher bonding strength, but this sacrifices biocompatibility. These challenges are overcome by developing a periodate-modified ion exchange resin-bead filtration system that oxidizes catechol moieties to quinones and filters off the activating agent and resin. The resulting BGC bioadhesive exhibited sixfold higher strength compared to commercially available tissue adhesives, with strength in the range necessary to improve tendon-to-bone repair (≈1MPa, ≈20% of current suture repair strength). The bioadhesive is biocompatible and promoted tenogenesis; cells exposed to the bioadhesive demonstrated enhanced expression of collagen I and the tenogenic marker Scx. Results demonstrated that the bioadhesive has the potential to improve the strength of a tendon-to-bone repair and promote healing.
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http://dx.doi.org/10.1002/adhm.202102344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9117437PMC
May 2022

Enthesis strength, toughness and stiffness: an image-based model comparing tendon insertions with varying bony attachment geometries.

J R Soc Interface 2021 12 22;18(185):20210421. Epub 2021 Dec 22.

Washington University, Jubel Hall, Room 103F, 1 Brookings Drive, St Louis, MO 63130, USA.

Tendons of the body differ dramatically in their function, mechanics and range of motion, but all connect to bone via an enthesis. Effective force transfer at the enthesis enables joint stability and mobility, with strength and stiffness arising from a fibrous architecture. However, how enthesis toughness arises across tendons with diverse loading orientations remains unclear. To study this, we performed simultaneous imaging of the bone and tendon in entheses that represent the range of tendon-to-bone insertions and extended a mathematical model to account for variations in insertion and bone geometry. We tested the hypothesis that toughness, across a range of tendon entheses, could be explained by differences observed in interactions between fibre architecture and bone architecture. In the model, toughness arose from fibre reorientation, recruitment and rupture, mediated by interactions between fibres at the enthesis and the bony ridge abutting it. When applied to tendons sometimes characterized as either energy-storing or positional, the model predicted that entheses of the former prioritize toughness over strength, while those of the latter prioritize consistent stiffness across loading directions. Results provide insight into techniques for surgical repair of tendon-to-bone attachments, and more broadly into mechanisms for the attachment of highly dissimilar materials.
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http://dx.doi.org/10.1098/rsif.2021.0421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8692040PMC
December 2021

A 3D, Magnetically Actuated, Aligned Collagen Fiber Hydrogel Platform Recapitulates Physical Microenvironment of Myoblasts for Enhancing Myogenesis.

Small Methods 2021 06 13;5(6):e2100276. Epub 2021 May 13.

Bioinspired Engineering and Biomechanics Center (BEBC), The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710049, China.

Many cell responses that underlie the development, maturation, and function of tissues are guided by the architecture and mechanical loading of the extracellular matrix (ECM). Because mechanical stimulation must be transmitted through the ECM architecture, the synergy between these two factors is important. However, recapitulating the synergy of these physical microenvironmental cues in vitro remains challenging. To address this, a 3D magnetically actuated collagen hydrogel platform is developed that enables combined control of ECM architecture and mechanical stimulation. With this platform, it is demonstrated how these factors synergistically promote cell alignment of C2C12 myoblasts and enhance myogenesis. This promotion is driven in part by the dynamics of Yes-associated protein and structure of cellular microtubule networks. This facile platform holds great promises for regulating cell behavior and fate, generating a broad range of engineered physiologically representative microtissues in vitro, and quantifying the mechanobiology underlying their functions.
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http://dx.doi.org/10.1002/smtd.202100276DOI Listing
June 2021

Mechanosensation triggers enhanced heavy metal ion uptake by non-glandular trichomes.

J Hazard Mater 2022 03 3;426:127983. Epub 2021 Dec 3.

Hebei Key Laboratory of Plant Physiology and Molecular Pathology, College of Life Sciences, Hebei Agricultural University, Baoding 071001, Hebei, China; State Key Laboratory of North China Crop Improvement and Regulation, Hebei Agricultural University, Baoding 071001, Hebei, China. Electronic address:

The trichomes of Arabidopsis thaliana serve as accumulation sites for heavy metals such as Cd, and thereby both help plants cope with heavy metal stress and detoxify the soil. These trichomes are also believed to prime plant defenses against insect herbivores in response to mechanical stimulation. Because Cd in such trichomes may be beneficial for plant defenses, we hypothesized that mechanical stimulation would enhance sequestration of Cd in trichomes. We quantified the distribution and concentration of Cd in leaves of A. thaliana, of the glabrous mutant gl1-1 of A. thaliana, and Brassica rapa L. subsp. pekinensis (Lour.) Hanelt (Chinese cabbage) and examined how these changed following mechanical stimulation of the trichomes or leaves. Light brushing or exposure to caterpillars of Spodoptera exigua led trichomes of both A. thaliana and Chinese cabbage to accumulate Cd complexes more rapidly and to a higher concentration than trichomes in unstimulated controls. Comparison to responses in leaves of gl1-1 mutants suggested that this acceleration and enhancement of Cd storage requires signaling through trichomes. In wild type A. thaliana, Cd was found exclusively in trichomes, whereas in gl1-1 mutants, Cd was found mainly in the - mesophyll cells. Results suggest a mechanobiological pathway for improving heavy metal detoxification of soils through the action of hyperaccumulator plant leaves containing non-glandular trichomes.
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http://dx.doi.org/10.1016/j.jhazmat.2021.127983DOI Listing
March 2022

Toughening mechanisms for the attachment of architectured materials: The mechanics of the tendon enthesis.

Sci Adv 2021 Nov 26;7(48):eabi5584. Epub 2021 Nov 26.

Department of Orthopedic Surgery, Columbia University, New York, NY 10032, USA.

Architectured materials offer tailored mechanical properties but are limited in engineering applications due to challenges in maintaining toughness across their attachments. The enthesis connects tendon and bone, two vastly different architectured materials, and exhibits toughness across a wide range of loadings. Understanding the mechanisms by which this is achieved could inform the development of engineered attachments. Integrating experiments, simulations, and previously unexplored imaging that enabled simultaneous observation of mineralized and unmineralized tissues, we identified putative mechanisms of enthesis toughening in a mouse model and then manipulated these mechanisms via in vivo control of mineralization and architecture. Imaging uncovered a fibrous architecture within the enthesis that controls trade-offs between strength and toughness. In vivo models of pathology revealed architectural adaptations that optimize these trade-offs through cross-scale mechanisms including nanoscale protein denaturation, milliscale load-sharing, and macroscale energy absorption. Results suggest strategies for optimizing architecture for tough bimaterial attachments in medicine and engineering.
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http://dx.doi.org/10.1126/sciadv.abi5584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8626067PMC
November 2021

Three-Dimensional Visualization of the Podocyte Actin Network Using Integrated Membrane Extraction, Electron Microscopy, and Machine Learning.

J Am Soc Nephrol 2022 01 10;33(1):155-173. Epub 2021 Nov 10.

Division of Nephrology, Washington University School of Medicine, St. Louis, Missouri

Background: Actin stress fibers are abundant in cultured cells, but little is known about them . In podocytes, much evidence suggests that mechanobiologic mechanisms underlie podocyte shape and adhesion in health and in injury, with structural changes to actin stress fibers potentially responsible for pathologic changes to cell morphology. However, this hypothesis is difficult to rigorously test due to challenges with visualization. A technology to image the actin cytoskeleton at high resolution is needed to better understand the role of structures such as actin stress fibers in podocytes.

Methods: We developed the first visualization technique capable of resolving the three-dimensional cytoskeletal network in mouse podocytes in detail, while definitively identifying the proteins that comprise this network. This technique integrates membrane extraction, focused ion-beam scanning electron microscopy, and machine learning image segmentation.

Results: Using isolated mouse glomeruli from healthy animals, we observed actin cables and intermediate filaments linking the interdigitated podocyte foot processes to newly described contractile actin structures, located at the periphery of the podocyte cell body. Actin cables within foot processes formed a continuous, mesh-like, electron-dense sheet that incorporated the slit diaphragms.

Conclusions: Our new technique revealed, for the first time, the detailed three-dimensional organization of actin networks in healthy podocytes. In addition to being consistent with the gel compression hypothesis, which posits that foot processes connected by slit diaphragms act together to counterbalance the hydrodynamic forces across the glomerular filtration barrier, our data provide insight into how podocytes respond to mechanical cues from their surrounding environment.
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http://dx.doi.org/10.1681/ASN.2021020182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8763187PMC
January 2022

Mechanics-driven nuclear localization of YAP can be reversed by N-cadherin ligation in mesenchymal stem cells.

Nat Commun 2021 10 28;12(1):6229. Epub 2021 Oct 28.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, People's Republic of China.

Mesenchymal stem cells adopt differentiation pathways based upon cumulative effects of mechanosensing. A cell's mechanical microenvironment changes substantially over the course of development, beginning from the early stages in which cells are typically surrounded by other cells and continuing through later stages in which cells are typically surrounded by extracellular matrix. How cells erase the memory of some of these mechanical microenvironments while locking in memory of others is unknown. Here, we develop a material and culture system for modifying and measuring the degree to which cells retain cumulative effects of mechanosensing. Using this system, we discover that effects of the RGD adhesive motif of fibronectin (representative of extracellular matrix), known to impart what is often termed "mechanical memory" in mesenchymal stem cells via nuclear YAP localization, are erased by the HAVDI adhesive motif of the N-cadherin (representative of cell-cell contacts). These effects can be explained by a motor clutch model that relates cellular traction force, nuclear deformation, and resulting nuclear YAP re-localization. Results demonstrate that controlled storage and removal of proteins associated with mechanical memory in mesenchymal stem cells is possible through defined and programmable material systems.
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http://dx.doi.org/10.1038/s41467-021-26454-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8553821PMC
October 2021

A Biosynthetic Hybrid Spidroin-Amyloid-Mussel Foot Protein for Underwater Adhesion on Diverse Surfaces.

ACS Appl Mater Interfaces 2021 Oct 11;13(41):48457-48468. Epub 2021 Oct 11.

Department of Energy, Environmental & Chemical Engineering, Washington University in St. Louis, One Brookings Drive, Saint Louis, Missouri 63130, United States.

Strong underwater adhesives are attractive materials for biomedical healing and underwater repair, but their success in applications has been limited, owing to challenges with underwater setting and with balancing surface adhesion and cohesion. Here, we applied synthetic biology approaches to overcome these challenges through design and synthesis of a novel hybrid protein consisting of the zipper-forming domains of an amyloid protein, flexible spider silk sequences, and a dihydroxyphenylalanine (DOPA)-containing mussel foot protein (Mfp). This partially structured, hybrid protein can self-assemble into a semi-crystalline hydrogel that exhibits high strength and toughness as well as strong underwater adhesion to a variety of surfaces, including difficult-to-adhere plastics, tendon, and skin. The hydrogel allows selective debonding by oxidation or iron-chelating treatments. Both the material design and the biosynthetic approach explored in this study will inspire future work for a wide range of hybrid protein-based materials with tunable properties and broad applications.
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http://dx.doi.org/10.1021/acsami.1c14182DOI Listing
October 2021

A new model of myofibroblast-cardiomyocyte interactions and their differences across species.

Biophys J 2021 09 17;120(17):3764-3775. Epub 2021 Jul 17.

Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an, P.R. China; Bioinspired Engineering and Biomechanics Center, Xi'an Jiaotong University, Xi'an, P.R. China. Electronic address:

Although coupling between cardiomyocytes and myofibroblasts is well known to affect the physiology and pathophysiology of cardiac tissues across species, relating these observations to humans is challenging because the effect of this coupling varies across species and because the sources of these effects are not known. To identify the sources of cross-species variation, we built upon previous mathematical models of myofibroblast electrophysiology and developed a mechanoelectrical model of cardiomyocyte-myofibroblast interactions as mediated by electrotonic coupling and transforming growth factor-β1. The model, as verified by experimental data from the literature, predicted that both electrotonic coupling and transforming growth factor-β1 interaction between myocytes and myofibroblast prolonged action potential in rat myocytes but shortened action potential in human myocytes. This variance could be explained by differences in the transient outward K current associated with differential Kv4.2 gene expression across species. Results are useful for efforts to extrapolate the results of animal models to the predicted effects in humans and point to potential therapeutic targets for fibrotic cardiomyopathy.
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http://dx.doi.org/10.1016/j.bpj.2021.06.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456177PMC
September 2021

Elastomer-Grafted iPSC-Derived Micro Heart Muscles to Investigate Effects of Mechanical Loading on Physiology.

ACS Biomater Sci Eng 2021 07 21;7(7):2973-2989. Epub 2020 Oct 21.

Department of Biomedical Engineering, Washington University in Saint Louis, University City, St. Louis, Missouri 63130, United States.

Mechanical loading plays a critical role in cardiac pathophysiology. Engineered heart tissues derived from human induced pluripotent stem cells (iPSCs) allow rigorous investigations of the molecular and pathophysiological consequences of mechanical cues. However, many engineered heart muscle models have complex fabrication processes and require large cell numbers, making it difficult to use them together with iPSC-derived cardiomyocytes to study the influence of mechanical loading on pharmacology and genotype-phenotype relationships. To address this challenge, simple and scalable iPSC-derived micro-heart-muscle arrays (μHM) have been developed. "Dog-bone-shaped" molds define the boundary conditions for tissue formation. Here, we extend the μHM model by forming these tissues on elastomeric substrates with stiffnesses spanning from 5 to 30 kPa. Tissue assembly was achieved by covalently grafting fibronectin to the substrate. Compared to μHM formed on plastic, elastomer-grafted μHM exhibited a similar gross morphology, sarcomere assembly, and tissue alignment. When these tissues were formed on substrates with different elasticity, we observed marked shifts in contractility. Increased contractility was correlated with increases in calcium flux and a slight increase in cell size. This afterload-enhanced μHM system enables mechanical control of μHM and real-time tissue traction force microscopy for cardiac physiology measurements, providing a dynamic tool for studying pathophysiology and pharmacology.
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http://dx.doi.org/10.1021/acsbiomaterials.0c00318DOI Listing
July 2021

Tailoring of arteriovenous graft-to-vein anastomosis angle to attenuate pathological flow fields.

Sci Rep 2021 06 9;11(1):12153. Epub 2021 Jun 9.

Vascular Surgery Biomedical Research Laboratory, Washington University School of Medicine, Saint Louis, MO, 60613, USA.

Arteriovenous grafts are routinely placed to facilitate hemodialysis in patients with end stage renal disease. These grafts are conduits between higher pressure arteries and lower pressure veins. The connection on the vein end of the graft, known as the graft-to-vein anastomosis, fails frequently and chronically due to high rates of stenosis and thrombosis. These failures are widely believed to be associated with pathologically high and low flow shear strain rates at the graft-to-vein anastomosis. We hypothesized that consistent with pipe flow dynamics and prior work exploring vein-to-artery anastomosis angles in arteriovenous fistulas, altering the graft-to-vein anastomosis angle can reduce the incidence of pathological shear rate fields. We tested this via computational fluid dynamic simulations of idealized arteriovenous grafts, using the Bird-Carreau constitutive law for blood. We observed that low graft-to-vein anastomosis angles ([Formula: see text]) led to increased incidence of pathologically low shear rates, and that high graft-to-vein anastomosis angles ([Formula: see text]) led to increased incidence of pathologically high shear rates. Optimizations predicted that an intermediate  ([Formula: see text]) graft-to-anastomosis angle was optimal. Our study demonstrates that graft-to-vein anastomosis angles can significantly impact pathological flow fields, and can be optimized to substantially improve arteriovenous graft patency rates.
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http://dx.doi.org/10.1038/s41598-021-90813-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190231PMC
June 2021

Anomalous Loss of Stiffness with Increasing Reinforcement in a Photo-Activated Nanocomposite.

Macromol Rapid Commun 2021 Jul 29;42(14):e2100147. Epub 2021 May 29.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, P. R. China.

Hydrogels are commonly doped with stiff nanoscale fillers to endow them with the strength and stiffness needed for engineering applications. Although structure-property relations for many polymer matrix nanocomposites are well established, modeling the new generation of hydrogel nanocomposites requires the study of processing-structure-property relationships because subtle differences in chemical kinetics during their synthesis can cause nearly identical hydrogels to have dramatically different mechanical properties. The authors therefore assembled a framework to relate synthesis conditions (including hydrogel and nanofiller mechanical properties and light absorbance) to gelation kinetics and mechanical properties. They validated the model against experiments on a graphene oxide (GO) doped oligo (ethylene glycol) diacrylate (OEGDA), a system in which, in apparent violation of laws from continuum mechanics, doping can reduce rather than increase the stiffness of the resulting hydrogel nanocomposites. Both model and experiment showed a key role light absorbance-dominated gelation kinetics in determining nanocomposite mechanical properties in conjunction with nanofiller reinforcement, with the nanofiller's attenuation of chemical kinetics sometimes outweighing stiffening effects to explain the observed, anomalous loss of stiffness. By bridging the chemical kinetics and mechanics of nanocomposite hydrogels, the authors' modeling framework shows promise for broad applicability to design of hydrogel nanocomposites.
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http://dx.doi.org/10.1002/marc.202100147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298289PMC
July 2021

Quantification of the flexural rigidity of peripheral arterial endovascular catheters and sheaths.

J Mech Behav Biomed Mater 2021 07 30;119:104459. Epub 2021 Mar 30.

Center for Innovation in Neuroscience and Technology, Washington University in St. Louis, Missouri, USA; McKelvey School of Engineering, Washington University in St. Louis, St. Louis, Missouri, USA; Section of Vascular Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA. Electronic address:

Endovascular catheter-based technologies have revolutionized the treatment of complex vascular pathology. Catheters and endovascular devices that can be maneuvered through tortuous arterial anatomy have enabled minimally invasive treatment in the peripheral arterial system. Although mechanical factors drive an interventionalist's choice of catheters and sheaths, these decisions are mostly made qualitative and based on personal experience and procedural pattern recognition. However, a definitive quantitative characterization of endovascular tools that are best suited for specific peripheral arterial beds is currently lacking. To establish a foundation for quantitative tool selection in the neurovascular and lower extremity peripheral arterial beds, we developed a nonlinear beam theory method to quantify catheter and sheath flexural rigidity. We applied this assessment to a sampling of commonly utilized commercially available peripheral arterial catheters and sheaths. Our results demonstrated that catheters and sheaths adopted for existing practice patterns to treat peripheral arterial disease in the lower extremities and neurovascular system have different but overlapping ranges of flexural rigidities that were not sensitive to luminal diameters within each procedure type. Our approach provides an accurate and effective method for characterization of flexural rigidity properties of catheters and sheaths, and a foundation for developing future technologies tailored for specific peripheral arterial systems.
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http://dx.doi.org/10.1016/j.jmbbm.2021.104459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802324PMC
July 2021

Characterizing poroelasticity of biological tissues by spherical indentation: an improved theory for large relaxation.

J Mech Phys Solids 2020 May 3;138. Epub 2020 Mar 3.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Shaanxi, 710049, P.R. China.

Flow of fluids within biological tissues often meets with resistance that causes a rate- and size-dependent material behavior known as poroelasticity. Characterizing poroelasticity can provide insight into a broad range of physiological functions, and is done qualitatively in the clinic by palpation. Indentation has been widely used for characterizing poroelasticity of soft materials, where quantitative interpretation of indentation requires a model of the underlying physics, and such existing models are well established for cases of small strain and modest force relaxation. We showed here that existing models are inadequate for large relaxation, where the force on the indenter at a prescribed depth at long-time scale drops to below half of the initially peak force (, (0)/() > 2). We developed an indentation theory for such cases of large relaxation, based on Biot theory and a generalized Hertz contact model. We demonstrated that our proposed theory is suitable for biological tissues (, spleen, kidney, skin and human cirrhosis liver) with both small and large relaxations. The proposed method would be a powerful tool to characterize poroelastic properties of biological materials for various applications such as pathological study and disease diagnosis.
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http://dx.doi.org/10.1016/j.jmps.2020.103920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595329PMC
May 2020

Spatiotemporally Controlled Photoresponsive Hydrogels: Design and Predictive Modeling from Processing through Application.

Adv Funct Mater 2020 Aug 18;30(32):2000639. Epub 2020 Jun 18.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education School of Life Science and Technology Xi'an Jiaotong University Xi'an 710049 P. R. China.

Photoresponsive hydrogels (PRHs) are soft materials whose mechanical and chemical properties can be tuned spatially and temporally with relative ease. Both photo-crosslinkable and photodegradable hydrogels find utility in a range of biomedical applications that require tissue-like properties or programmable responses. Progress in engineering with PRHs is facilitated by the development of theoretical tools that enable optimization of their photochemistry, polymer matrices, nanofillers, and architecture. This review brings together models and design principles that enable key applications of PRHs in tissue engineering, drug delivery, and soft robotics, and highlights ongoing challenges in both modeling and application.
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http://dx.doi.org/10.1002/adfm.202000639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418561PMC
August 2020

Fluorescence Correlation Spectroscopy and Photon Counting Histograms in Finite, Bounded Domains.

Biophys J 2020 07 10;119(2):265-273. Epub 2020 Jun 10.

Department of Biochemistry and Molecular Biophysics, School of Medicine, Washington University in St. Louis, St. Louis, Missouri. Electronic address:

Analysis of fluctuations arising as fluorescent particles pass through a focused laser beam has enabled quantitative characterization of a broad range of molecular kinetic processes. Two key mathematical frameworks that have enabled these quantifications are fluorescence correlation spectroscopy (FCS) and photon counting histogram (PCH) analysis. Although these frameworks are effective and accurate when the focused laser beam is well approximated by an infinite Gaussian beam with a waist that is small compared to the size of the region over which the fluorescent particles can diffuse, they cannot be applied to situations in which this region is bounded at the nanoscale. We therefore derived general forms of the FCS and PCH frameworks for bounded systems. The finite-domain form of FCS differs from the classical form in its boundary and initial conditions and requires development of a new Fourier space solution for fitting data. Our finite-domain FCS predicts simulated data accurately and reduces to a previous model for the special case when the system is much larger than the Gaussian beam and can be considered to be infinite. We also derived the PCH form for the bounded systems. Our approach enables estimation of the concentration of diffusing fluorophores within a finite domain for the first time, to our knowledge. The method opens the possibility of quantification of kinetics in several systems for which this has never been possible.
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http://dx.doi.org/10.1016/j.bpj.2020.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376089PMC
July 2020

The acoustic radiation force of a focused ultrasound beam on a suspended eukaryotic cell.

Ultrasonics 2020 Dec 18;108:106205. Epub 2020 Jun 18.

State Key Laboratory of Mechanics and Control of Mechanical Structures, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China; Nanjing Center for Multifunctional Lightweight Materials and Structures (MLMS), Nanjing University of Aeronautics and Astronautics, Nanjing 210016, PR China. Electronic address:

Although ultrasound tools for manipulating and permeabilizing suspended cells have been available for nearly a century, accurate prediction of the distribution of acoustic radiation force (ARF) continues to be a challenge. We therefore developed an analytical model of the acoustic radiation force (ARF) generated by a focused Gaussian ultrasound beam incident on a eukaryotic cell immersed in an ideal fluid. The model had three layers corresponding to the nucleus, cytoplasm, and membrane, of a eukaryotic cell. We derived an exact expression for the ARF in relation to the geometrical and acoustic parameters of the model cell components. The mechanics of the cell membrane and nucleus, the relative width of the Gaussian beam, the size, position and aspect ratio of the cell had significant influence on the ARF. The model provides a theoretical basis for improved acoustic control of cell trapping, cell sorting, cell assembly, and drug delivery.
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http://dx.doi.org/10.1016/j.ultras.2020.106205DOI Listing
December 2020

The Balance between Actomyosin Contractility and Microtubule Polymerization Regulates Hierarchical Protrusions That Govern Efficient Fibroblast-Collagen Interactions.

ACS Nano 2020 07 20;14(7):7868-7879. Epub 2020 Apr 20.

NSF Science and Technology Center for Engineering Mechanobiology and Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, Missouri 63130 United States.

Fibroblasts undergo a critical transformation from an initially inactive state to a morphologically different and contractile state after several hours of being embedded within a physiologically relevant three-dimensional (3D) fibrous collagen-based extracellular matrix (ECM). However, little is known about the critical mechanisms by which fibroblasts adapt themselves and their microenvironment in the earliest stage of cell-matrix interaction. Here, we identified the mechanisms by which fibroblasts interact with their 3D collagen fibrous matrices in the early stages of cell-matrix interaction and showed that fibroblasts use energetically efficient hierarchical micro/nano-scaled protrusions in these stages as the primary means for the transformation and adaptation. We found that actomyosin contractility in these protrusions in the early stages of cell-matrix interaction restricts the growth of microtubules by applying compressive forces on them. Our results show that actomyosin contractility and microtubules work in concert in the early stages of cell-matrix interaction to adapt fibroblasts and their microenvironment to one another. These early stage interactions result in responses to disruption of the microtubule network and/or actomyosin contractility that are opposite to well-known responses to late-stage disruption and reveal insight into the ways that cells adapt themselves and their ECM recursively.
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http://dx.doi.org/10.1021/acsnano.9b09941DOI Listing
July 2020

Correction of bias in the estimation of cell volume fraction from histology sections.

J Biomech 2020 05 2;104:109705. Epub 2020 Mar 2.

Department of Mechanical Engineering & Materials Science, Washington University in St. Louis, United States; NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, United States; Bioinspired Engineering and Biomechanics Center, School of Life Sciences and Technology, Xi'an Jiaotong University, China. Electronic address:

Accurate determination of the fraction of a tissue's volume occupied by cells is critical for studying tissue development, pathology, and biomechanics. For example, homogenization methods that predict the function and responses of tissues based upon the properties of the tissue's constituents require estimates of cell volume fractions. A common way to estimate cellular volume fraction is to image cells in thin, planar histologic sections, and then invoke either the Delesse or the Glagolev principle to estimate the volume fraction from the measured area fraction. The Delesse principle relies upon the observation that for randomly aligned, identical features, the expected value of the observed area fraction of a phase equals the volume fraction of that phase, and the Glagolev principle relies on a similar observation for random rather than planar sampling. These methods are rigorous for analysis of a polished, opaque rock sections and for histologic sections that are thin compared to the characteristic length scale of the cells. However, when histologic slices cannot be cut sufficiently thin, a bias will be introduced. Although this bias - known as the Holmes effect in petrography - has been resolved for opaque spheres in a transparent matrix, it has not been addressed for histologic sections presenting the opposite problem, namely transparent cells in an opaque matrix. In this note, we present a scheme for correcting the bias in volume fraction estimates for transparent components in a relatively opaque matrix.
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http://dx.doi.org/10.1016/j.jbiomech.2020.109705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594628PMC
May 2020

Nanoscale integrin cluster dynamics controls cellular mechanosensing via FAKY397 phosphorylation.

Sci Adv 2020 03 4;6(10):eaax1909. Epub 2020 Mar 4.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, P.R. China.

Transduction of extracellular matrix mechanics affects cell migration, proliferation, and differentiation. While this mechanotransduction is known to depend on the regulation of focal adhesion kinase phosphorylation on Y397 (FAKpY397), the mechanism remains elusive. To address this, we developed a mathematical model to test the hypothesis that FAKpY397-based mechanosensing arises from the dynamics of nanoscale integrin clustering, stiffness-dependent disassembly of integrin clusters, and FAKY397 phosphorylation within integrin clusters. Modeling results predicted that integrin clustering dynamics governs how cells convert substrate stiffness to FAKpY397, and hence governs how different cell types transduce mechanical signals. Existing experiments on MDCK cells and HT1080 cells, as well as our new experiments on 3T3 fibroblasts, confirmed our predictions and supported our model. Our results suggest a new pathway by which integrin clusters enable cells to calibrate responses to their mechanical microenvironment.
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http://dx.doi.org/10.1126/sciadv.aax1909DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056303PMC
March 2020

Direct Estimation of Surface Strain Fields From a Stereo Vision System.

J Biomech Eng 2020 07;142(7)

Department of Mechanical Engineering and Materials Science, NSF Science and Technology Center for Engineering MechanoBiology, Washington University, St Louis, MO 63130.

Estimating strain on surfaces of deforming three-dimensional (3D) structures is a critical need in experimental mechanics. Although single-camera techniques excel at estimating deformation on a surface parallel to the imaging plane, they are prone to artifact for 3D motion because they cannot distinguish between out-of-plane motion and in-plane dilatation. Multiview (e.g., stereo) camera systems overcome this via a three-step process consisting of: (1) independent surface registration, (2) triangulation to estimate surface displacements, and (3) deformation estimation. However, existing methods are prone to errors associated with numerical differentiation when computing estimating strain fields from displacement fields unless regularization schemes are used. Such regularization schemes can introduce inaccuracy into strain estimation. Inspired by previous work which combined registration and deformation estimation into a single step for 2D images and 3D imaging stacks, we developed a theory for simultaneous image registration, 3D triangulation, and deformation estimation in a multiview system. The deformation estimation does not require numerical differentiation of displacement fields to estimate strain fields. We present here the theoretical foundations and derivation of two related implementations of this approach, and discuss their strengths and weaknesses.
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http://dx.doi.org/10.1115/1.4045813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104767PMC
July 2020

Translation of a Coated Rigid Spherical Inclusion in an Elastic Matrix: Exact Solution, and Implications for Mechanobiology.

J Appl Mech 2019 May 5;86(5):0510021-5100210. Epub 2019 Mar 5.

State Key Laboratory for Strength and Vibration of Mechanical Structures, Xi'an Jiaotong University, Xi'an 710049, China.

The displacement of relatively rigid beads within a relatively compliant, elastic matrix can be used to measure the mechanical properties of the matrix. For example, in mechanobiological studies, magnetic or reflective beads can be displaced with a known external force to estimate the matrix modulus. Although such beads are generally rigid compared to the matrix, the material surrounding the beads typically differs from the matrix in one or two ways. The first case, as is common in mechanobiological experimentation, is the situation in which the bead must be coated with materials such as protein ligands that enable adhesion to the matrix. These layers typically differ in stiffness relative to the matrix material. The second case, common for uncoated beads, is the situation in which the beads disrupt the structure of the hydrogel or polymer, leading to a region of enhanced or reduced stiffness in the neighborhood of the bead. To address both cases, we developed the first analytical solution of the problem of translation of a coated, rigid spherical inclusion displaced within an isotropic elastic matrix by a remotely applied force. The solution is applicable to cases of arbitrary coating stiffness and size of the coating. We conclude by discussing applications of the solution to mechanobiology.
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http://dx.doi.org/10.1115/1.4042575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871264PMC
May 2019

Programmable and robust static topological solitons in mechanical metamaterials.

Nat Commun 2019 12 6;10(1):5605. Epub 2019 Dec 6.

Department of Engineering Mechanics, CNMM and AML, Tsinghua University, 100084, Beijing, P.R. China.

Solitary, persistent wave packets called solitons hold potential to transfer information and energy across a wide range of spatial and temporal scales in physical, chemical, and biological systems. Mechanical solitons characteristically emerge either as a single wave packet or uncorrelated propagating topological entities through space and/or time, but these are notoriously difficult to control. Here, we report a theoretical framework for programming static periodic topological solitons into a metamaterial, and demonstrate its implementation in real metamaterials computationally and experimentally. The solitons are excited by deformation localizations under quasi-static compression, and arise from buckling-induced kink-antikink bands that provide domain separation barriers. The soliton number and wavelength demonstrate a previously unreported size-dependence, due to intrinsic length scales. We identify that these unanticipated solitons stem from displacive phase transitions with periodic topological excitations captured by the well-known [Formula: see text] theory. Results reveal pathways for robust regularizations of stochastic responses of metamaterials.
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http://dx.doi.org/10.1038/s41467-019-13546-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6898320PMC
December 2019

Regulation of Cell Behavior by Hydrostatic Pressure.

Appl Mech Rev 2019 Jul 23;71(4):0408031-4080313. Epub 2019 Jul 23.

The Key Laboratory of Biomedical InformationEngineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, China.

Hydrostatic pressure (HP) regulates diverse cell behaviors including differentiation, migration, apoptosis, and proliferation. Abnormal HP is associated with pathologies including glaucoma and hypertensive fibrotic remodeling. In this review, recent advances in quantifying and predicting how cells respond to HP across several tissue systems are presented, including tissues of the brain, eye, vasculature and bladder, as well as articular cartilage. Finally, some promising directions on the study of cell behaviors regulated by HP are proposed.
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http://dx.doi.org/10.1115/1.4043947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808007PMC
July 2019

Cryoprotectant enables structural control of porous scaffolds for exploration of cellular mechano-responsiveness in 3D.

Nat Commun 2019 08 2;10(1):3491. Epub 2019 Aug 2.

Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, 100084, China.

Despite the wide applications, systematic mechanobiological investigation of 3D porous scaffolds has yet to be performed due to the lack of methodologies for decoupling the complex interplay between structural and mechanical properties. Here, we discover the regulatory effect of cryoprotectants on ice crystal growth and use this property to realize separate control of the scaffold pore size and stiffness. Fibroblasts and macrophages are sensitive to both structural and mechanical properties of the gelatin scaffolds, particularly to pore sizes. Interestingly, macrophages within smaller and softer pores exhibit pro-inflammatory phenotype, whereas anti-inflammatory phenotype is induced by larger and stiffer pores. The structure-regulated cellular mechano-responsiveness is attributed to the physical confinement caused by pores or osmotic pressure. Finally, in vivo stimulation of endogenous fibroblasts and macrophages by implanted scaffolds produce mechano-responses similar to the corresponding cells in vitro, indicating that the physical properties of scaffolds can be leveraged to modulate tissue regeneration.
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http://dx.doi.org/10.1038/s41467-019-11397-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677882PMC
August 2019

Adhesive-based tendon-to-bone repair: failure modelling and materials selection.

J R Soc Interface 2019 04;16(153):20180838

6 NSF Science and Technology Center for Engineering Mechanobiology, Department of Mechanical and Aerospace Engineering, Washington University , St Louis, MO 63130 , USA.

Surgical reattachment of tendon to bone is a procedure marked by high failure rates. For example, nearly all rotator cuff repairs performed on elderly patients with massive tears ultimately result in recurrence of tearing. These high failure rates have been attributed to stress concentrations that arise due to the mechanical mismatch between tendon and bone. Although recent studies have identified potential adhesives with mechanical properties tuned to alleviate these stress concentrations, and thereby delay the onset of failure, resistance to the progression of failure has not been studied. Here, we refined the space of adhesive material properties that can improve surgical attachment by considering the fracture process. Using cohesive zone modelling and physiologically relevant values of mode I and mode II adhesive fracture toughnesses, we predicted the maximum displacement and strength at failure of idealized, adhesively bonded tendon-to-bone repairs. Repair failure occurred due to excessive relative displacement of the tendon and bone tissues for strong and compliant adhesives. The failure mechanism shifted to rupture of the entire repair for stiffer adhesives below a critical shear strength. Results identified a narrow range of materials on an Ashby chart that are suitable for adhesive repair of tendon to bone, including a range of elastomers and porous solids.
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http://dx.doi.org/10.1098/rsif.2018.0838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505561PMC
April 2019
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