Publications by authors named "Guy M Genin"

100 Publications

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

Biophys J 2021 Jul 16. Epub 2021 Jul 16.

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; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, 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 effects 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 (TGF-β1). The model, as verified by experimental data from the literature, predicted that both electrotonic coupling and TGF-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 extrapolation the results of animal models to the predict 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
July 2021

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

ACS Biomater Sci Eng 2021 Jul 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 Jun 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
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

A preliminary study of the local biomechanical environment of liver tumors in vivo.

Med Phys 2019 Apr 28;46(4):1728-1739. Epub 2019 Feb 28.

Institute for Medical Imaging Technology, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, 200030, China.

Purpose: Biomechanical properties can be used as biomarkers to diagnose tumors, monitor tumor development, and evaluate treatment efficacy. The purpose of this preliminary study is to characterize the biomechanical environment of two typical liver tumors, hemangiomas (HEMs) and hepatocellular carcinomas (HCCs), and to investigate the potential of using strain metrics as biomarkers for tumor diagnosis, based on a limited clinical dataset.

Methods: Magnetic resonance (MR) tagging was used to quantify the motion and deformation of the two types of liver tumors. Displacements of the tumors arising from a heartbeat were measured over one cardiac cycle. Local biomechanical conditions of the tumors were characterized by estimating two principal strains (ε and ε ) and an octahedral shear strain (ε ) of the tumor and its peripheral region. Biomechanical conditions of the tumors were compared with those of the arbitrarily selected regions from healthy volunteers.

Results: We observed that the HCCs had significantly smaller strain values compared to their peripheral tissues. However, the HEMs did not have significantly different strains from those of the peripheral tissues, and were similar to healthy liver regions. The sensitivity of using ε , ε , and ε to diagnose HCC were all 1, while the sensitivity of using ε , ε , and ε to diagnose HEM were 0.67, 0.17, and 0.67, respectively.

Conclusions: Lagrangian strain metrics provide insight into the biomechanical conditions of certain liver tumors in the human body and may provide another perspective for tumor characterization and diagnosis.
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http://dx.doi.org/10.1002/mp.13434DOI Listing
April 2019

The multiscale structural and mechanical effects of mouse supraspinatus muscle unloading on the mature enthesis.

Acta Biomater 2019 01 17;83:302-313. Epub 2018 Oct 17.

Department of Orthopedic Surgery, Columbia University, New York, NY, USA; Department of Biomedical Engineering, Columbia University, New York, NY, USA. Electronic address:

The musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although structural and mechanical changes to tendon and bone following paralysis and disuse are well understood, there is a pressing need to understand how this unloading affects the bone-tendon interface (enthesis); the location most prone to tears and injury. We therefore elucidated these effects of unloading in the entheses of adult mice shoulders that were paralyzed for 21 days by treatment with botulinum toxin A. Unloading significantly increased the extent of mechanical failure and was associated with structural changes across hierarchical scales. At the millimeter scale, unloading caused bone loss. At the micrometer scale, unloading decreased bioapatite crystal size and crystallographic alignment in the enthesis. At the nanometer scale, unloading induced compositional changes that stiffened the bioapatite/collagen composite tissue. Mathematical modeling and mechanical testing indicated that these factors combined to increase local elevations of stress while decreasing the ability of the tissue to absorb energy prior to failure, thereby increasing injury risk. These first observations of the multiscale effects of unloading on the adult enthesis provide new insight into the hierarchical features of structure and composition that endow the enthesis with increased resistance to failure. STATEMENT OF SIGNIFICANCE: The musculoskeletal system is sensitive to its loading environment; this is of particular concern under conditions such as disuse, paralysis, and extended-duration space flight. Although changes to tendon and bone following paralysis are understood, there is a pressing need to clarify how unloading affects the bone-tendon interface (enthesis), which is the location most prone to tears and injury. We elucidated the effects of enthesis unloading in adult mice shoulders showing, for the first time, that unloading significantly increased the risk and extent of mechanical failure and was associated with structural changes across hierarchical scales. These observations provide new insight into the hierarchical features of structure and composition that endow the enthesis with resilience. This knowledge can be used to develop more targeted treatments to improve mobility and function.
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http://dx.doi.org/10.1016/j.actbio.2018.10.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343501PMC
January 2019

Regularization-Free Strain Mapping in Three Dimensions, With Application to Cardiac Ultrasound.

J Biomech Eng 2019 01;141(1)

Fellow ASME Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130; NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, Green Hall, CB 1099, 1 Brookings Drive, St. Louis, MO 63130 e-mail: .

Quantifying dynamic strain fields from time-resolved volumetric medical imaging and microscopy stacks is a pressing need for radiology and mechanobiology. A critical limitation of all existing techniques is regularization: because these volumetric images are inherently noisy, the current strain mapping techniques must impose either displacement regularization and smoothing that sacrifices spatial resolution, or material property assumptions that presuppose a material model, as in hyperelastic warping. Here, we present, validate, and apply the first three-dimensional (3D) method for estimating mechanical strain directly from raw 3D image stacks without either regularization or assumptions about material behavior. We apply the method to high-frequency ultrasound images of mouse hearts to diagnose myocardial infarction. We also apply the method to present the first ever in vivo quantification of elevated strain fields in the heart wall associated with the insertion of the chordae tendinae. The method shows promise for broad application to dynamic medical imaging modalities, including high-frequency ultrasound, tagged magnetic resonance imaging, and confocal fluorescence microscopy.
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http://dx.doi.org/10.1115/1.4041576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298532PMC
January 2019

Energy dissipation in mammalian collagen fibrils: Cyclic strain-induced damping, toughening, and strengthening.

Acta Biomater 2018 10 19;80:217-227. Epub 2018 Sep 19.

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

As the fundamental structural protein in mammals, collagen transmits cyclic forces that are necessary for the mechanical function of tissues, such as bone and tendon. Although the tissue-level mechanical behavior of collagenous tissues is well understood, the response of collagen at the nanometer length scales to cyclical loading remains elusive. To address this major gap, we cyclically stretched individual reconstituted collagen fibrils, with average diameter of 145 ± 42 nm, to small and large strains in the partially hydrated conditions of 60% relative humidity. It is shown that cyclical loading results in large steady-state hysteresis that is reached immediately after the first loading cycle, followed thereafter by limited accumulation of inelastic strain and constant initial elastic modulus. Cyclic loading above 20% strain resulted in 70% increase in tensile strength, from 638 ± 98 MPa to 1091 ± 110 MPa, and 70% increase in toughness, while maintaining the ultimate tensile strain of collagen fibrils not subjected to cyclic loading. Throughout cyclic stretching, the fibrils maintained a steady-state hysteresis, yielding loss coefficients that are 5-10 times larger than those of known homogeneous materials in their modulus range, thus establishing damping of nanoscale collagen fibrils as a major component of damping in tissues. STATEMENT OF SIGNIFICANCE: It is shown that steady-state energy dissipation occurs in individual collagen fibrils that are the building blocks of hard and soft tissues. To date, it has been assumed that energy dissipation in tissues takes place mainly at the higher length scales of the tissue hierarchy due to interactions between collagen fibrils and fibers, and in limited extent inside collagen fibrils. It is shown that individual collagen fibrils need only a single loading cycle to assume a highly dissipative, steady-state, cyclic mechanical response. Mechanical cycling at large strains leads to 70% increase in mechanical strength and values exceeding those of engineering steels. The same cyclic loading conditions also lead to 70% increase in toughness and loss properties that are 5-10 times higher than those of engineering materials with comparable stiffness.
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http://dx.doi.org/10.1016/j.actbio.2018.09.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510236PMC
October 2018

The relationship between thiol-acrylate photopolymerization kinetics and hydrogel mechanics: An improved model incorporating photobleaching and thiol-Michael addition.

J Mech Behav Biomed Mater 2018 12 24;88:160-169. Epub 2018 Aug 24.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an 710049, PR China; Bioinspired Engineering & Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an 710049, PR China. Electronic address:

Biocompatible hydrogels with defined mechanical properties are critical to tissue engineering and regenerative medicine. Thiol-acrylate photopolymerized hydrogels have attracted special interest for their degradability and cytocompatibility, and for their tunable mechanical properties through controlling factors that affect reaction kinetics (e.g., photopolymerization, stoichiometry, temperature, and solvent choice). In this study, we hypothesized that the mechanical property of these hydrogels can be tuned by photoinitiators via photobleaching and by thiol-Michael addition reactions. To test this hypothesis, a multiscale mathematical model incorporating both photobleaching and thiol-Michael addition reactions was developed and validated. After validating the model, the effects of thiol concentration, light intensity, and pH values on hydrogel mechanics were investigated. Results revealed that hydrogel stiffness (i) was maximized at a light intensity-specific optimal concentration of thiol groups; (ii) increased with decreasing pH when synthesis occurred at low light intensity; and (iii) increased with decreasing light intensity when synthesis occurred at fixed precursor composition. The multiscale model revealed that the latter was due to higher initiation efficiency at lower light intensity. More broadly, the model provides a framework for predicting mechanical properties of hydrogels based upon the controllable kinetics of thiol-acrylate photopolymerization.
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http://dx.doi.org/10.1016/j.jmbbm.2018.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6392438PMC
December 2018

Energy dissipation in quasi-linear viscoelastic tissues, cells, and extracellular matrix.

J Mech Behav Biomed Mater 2018 08 26;84:198-207. Epub 2018 May 26.

NSF Science and Technology Center for Engineering Mechanobiology, Washington University in St. Louis, St. Louis, MO, USA. Electronic address:

Characterizing how a tissue's constituents give rise to its viscoelasticity is important for uncovering how hidden timescales underlie multiscale biomechanics. These constituents are viscoelastic in nature, and their mechanics must typically be assessed from the uniaxial behavior of a tissue. Confounding the challenge is that tissue viscoelasticity is typically associated with nonlinear elastic responses. Here, we experimentally assessed how fibroblasts and extracellular matrix (ECM) within engineered tissue constructs give rise to the nonlinear viscoelastic responses of a tissue. We applied a constant strain rate, "triangular-wave" loading and interpreted responses using the Fung quasi-linear viscoelastic (QLV) material model. Although the Fung QLV model has several well-known weaknesses, it was well suited to the behaviors of the tissue constructs, cells, and ECM tested. Cells showed relatively high damping over certain loading frequency ranges. Analysis revealed that, even in cases where the Fung QLV model provided an excellent fit to data, the the time constant derived from the model was not in general a material parameter. Results have implications for design of protocols for the mechanical characterization of biological materials, and for the mechanobiology of cells within viscoelastic tissues.
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http://dx.doi.org/10.1016/j.jmbbm.2018.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995675PMC
August 2018

Enhanced tendon-to-bone repair through adhesive films.

Acta Biomater 2018 04 8;70:165-176. Epub 2018 Feb 8.

Department of Orthopedic Surgery, Columbia University, New York, NY 10032, United States; Department of Biomedical Engineering, Columbia University, New York, NY 10027, United States. Electronic address:

Tendon-to-bone surgical repairs have unacceptably high failure rates, possibly due to their inability to recreate the load transfer mechanisms of the native enthesis. Instead of distributing load across a wide attachment footprint area, surgical repairs concentrate shear stress on a small number of suture anchor points. This motivates development of technologies that distribute shear stresses away from suture anchors and across the enthesis footprint. Here, we present predictions and proof-of-concept experiments showing that mechanically-optimized adhesive films can mimic the natural load transfer mechanisms of the healthy attachment and increase the load tolerance of a repair. Mechanical optimization, based upon a shear lag model corroborated by a finite element analysis, revealed that adhesives with relatively high strength and low stiffness can, theoretically, strengthen tendon-to-bone repairs by over 10-fold. Lap shear testing using tendon and bone planks validated the mechanical models for a range of adhesive stiffnesses and strengths. Ex vivo human supraspinatus repairs of cadaveric tissues using multipartite adhesives showed substantial increase in strength. Results suggest that adhesive-enhanced repair can improve repair strength, and motivate a search for optimal adhesives.

Statement Of Significance: Current surgical techniques for tendon-to-bone repair have unacceptably high failure rates, indicating that the initial repair strength is insufficient to prevent gapping or rupture. In the rotator cuff, repair techniques apply compression over the repair interface to achieve contact healing between tendon and bone, but transfer almost all force in shear across only a few points where sutures puncture the tendon. Therefore, we evaluated the ability of an adhesive film, implanted between tendon and bone, to enhance repair strength and minimize the likelihood of rupture. Mechanical models demonstrated that optimally designed adhesives would improve repair strength by over 10-fold. Experiments using idealized and clinically-relevant repairs validated these models. This work demonstrates an opportunity to dramatically improve tendon-to-bone repair strength using adhesive films with appropriate material properties.
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http://dx.doi.org/10.1016/j.actbio.2018.01.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871607PMC
April 2018

Melting Away Pain: Decay of Thermal Nociceptor Transduction during Heat-Induced Irreversible Desensitization of Ion Channels.

ACS Biomater Sci Eng 2017 Nov 24;3(11):3029-3035. Epub 2017 Feb 24.

Department of Acupuncture, Shaanxi Hospital of Traditional Chinese Medicine, Xi'an 710003, PR China.

Thermal transient receptor potential channels play a key role in thermal sensation. Although predictive models exist for temperature-dependent transduction through these channels and for the associated sensations of pain, the ability to predict irreversible desensitization has been lacking. We explored the role of irreversible ion channel desensitization in pain sensation and hypothesized that desensitization of ion channels would follow the kinetics similar to the denaturation of catalytic enzymes. We therefore proposed a three-state model to simulate the kinetic of temperature-sensitive ion channels from the closed state through opening and irreversible thermal desensitization. We tested the model against data obtained in vivo from a feline model. The theoretical model predicts all experimental data with reasonable accuracy, and represents an important step toward the ability for understanding of the molecular basis of nociceptor signaling providing the possibility to design local anesthesia regimens and to the prediction of postoperative pain.
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http://dx.doi.org/10.1021/acsbiomaterials.6b00789DOI Listing
November 2017

Integrated Multiscale Biomaterials Experiment and Modeling.

ACS Biomater Sci Eng 2017 Nov;3(11):2628-2632

Department of Civil and Environmental Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

The integration of modeling and experimentation is an integral component of all engineering design. Developing the technologies to achieve this represents a critical challenge in biomaterials because of the hierarchical structures that comprise them and the spectra of timescales upon which they operate. Progress in integrating modeling and experiment in biomaterials represents progress towards harnessing them for engineering application. We present here a summary of the state of the art, and outlooks for the field as a whole.
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http://dx.doi.org/10.1021/acsbiomaterials.7b00821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544164PMC
November 2017

Fibroblasts Slow Conduction Velocity in a Reconstituted Tissue Model of Fibrotic Cardiomyopathy.

ACS Biomater Sci Eng 2017 Nov 18;3(11):3022-3028. Epub 2016 Oct 18.

Department of Mechanical Engineering and Materials Science, 1 Brookings Drive, Washington University in St. Louis, St. Louis, MO 63130 USA.

Myocardial function deteriorates over the course of fibrotic cardiomyopathy, due to electrophysiological and mechanical effects of myofibroblasts that are not completely understood. Although a range of experimental model systems and associated theoretical treatments exist at the levels of isolated cardiomyocytes and planar co-cultures of myofibroblasts and cardiomyocytes, interactions between these cell types at the tissue level are less clear. We studied these interactions through an engineered heart tissue (EHT) model of fibrotic myocardium and a mathematical model of the effects of cellular composition on EHT impulse conduction velocity. The EHT model allowed for modulation of cardiomyocyte and myofibroblast volume fractions, and observation of cell behavior in a three-dimensional environment that is more similar to native heart tissue than is planar cell culture. The cardiomyocyte and myofibroblast volume fractions determined the retardation of impulse conduction (spread of the action potential) in EHTs as measured by changes of the fluorescence of the Ca probe, Fluo-2. Interpretation through our model showed retardation far in excess of predictions by homogenization theory, with conduction ceasing far below the fibroblast volume fraction associated with steric percolation. Results point to an important multiscale structural role of myofibroblasts in attenuating impulse conduction in fibrotic cardiomyopathy.
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http://dx.doi.org/10.1021/acsbiomaterials.6b00576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527425PMC
November 2017

Arabidopsis Leaf Trichomes as Acoustic Antennae.

Biophys J 2017 Nov;113(9):2068-2076

Biomedical Engineering and Biomechanics Center (BEBC), School of Life Sciences, Xi'an Jiaotong University, Xi'an, China; Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, Missouri; Gladys Levis Allen Laboratory of Plant Sensory Physiology, Biology Department, Washington University in St. Louis, St. Louis, Missouri; NSF Center for Engineering MechanoBiology, Washington University in St. Louis, St. Louis, Missouri. Electronic address:

The much studied plant Arabidopsis thaliana has been reported recently to react to the sounds of caterpillars of Pieris rapae chewing on its leaves by promoting synthesis of toxins that can deter herbivory. Identifying participating receptor cells-potential "ears"-of Arabidopsis is critical to understanding and harnessing this response. Motivated in part by other recent observations that Arabidopsis trichomes (hair cells) respond to mechanical stimuli such as pressing or brushing by initiating potential signaling factors in themselves and in the neighboring skirt of cells, we analyzed the vibrational responses of Arabidopsis trichomes to test the hypothesis that trichomes can respond acoustically to vibrations associated with feeding caterpillars. We found that these trichomes have vibrational modes in the frequency range of the sounds of feeding caterpillars, encouraging further experimentation to determine whether trichomes serve as mechanical antennae.
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http://dx.doi.org/10.1016/j.bpj.2017.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5685652PMC
November 2017

Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment.

Chem Rev 2017 Oct 9;117(20):12764-12850. Epub 2017 Oct 9.

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

The cell microenvironment has emerged as a key determinant of cell behavior and function in development, physiology, and pathophysiology. The extracellular matrix (ECM) within the cell microenvironment serves not only as a structural foundation for cells but also as a source of three-dimensional (3D) biochemical and biophysical cues that trigger and regulate cell behaviors. Increasing evidence suggests that the 3D character of the microenvironment is required for development of many critical cell responses observed in vivo, fueling a surge in the development of functional and biomimetic materials for engineering the 3D cell microenvironment. Progress in the design of such materials has improved control of cell behaviors in 3D and advanced the fields of tissue regeneration, in vitro tissue models, large-scale cell differentiation, immunotherapy, and gene therapy. However, the field is still in its infancy, and discoveries about the nature of cell-microenvironment interactions continue to overturn much early progress in the field. Key challenges continue to be dissecting the roles of chemistry, structure, mechanics, and electrophysiology in the cell microenvironment, and understanding and harnessing the roles of periodicity and drift in these factors. This review encapsulates where recent advances appear to leave the ever-shifting state of the art, and it highlights areas in which substantial potential and uncertainty remain.
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http://dx.doi.org/10.1021/acs.chemrev.7b00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494624PMC
October 2017