Soft Biological Tissues Research Articles

On the fractional transversely isotropic functionally graded nature of soft biological tissues: Application to the meniscal tissue

This paper focuses on the origin of the poroelastic anisotropic behaviour of the meniscal tissue and its spatially varying properties. We present confined compression creep test results on samples extracted from three parts of the tissue (Central body, Anterior horn and Posterior horn) in three orientations (Circumferential, Radial and Vertical). We show that a poroelastic model in which the fluid flow evolution is ruled by non-integer order operators (fractional Darcy’s law) provides accurate agreement with the experimental creep data. The model is validated against two additional sets of experimental data: stress relaxation and fluid loss during the consolidation process measured as weight reduction. Results show that the meniscus can be considered as a transversely isotropic poroelastic material. This behaviour is due to the fluid flow rate being about three times higher in the circumferential direction than in the radial and vertical directions in the body region of the meniscus. The 3D fractional poroelastic model is implemented in the finite element software to estimate the weight loss during the confined compression tests.

Femtosecond laser preparation of resin embedded samples for correlative microscopy workflows in life sciences.

Correlative multimodal imaging is a useful approach to investigate complex structural relations in life sciences across multiple scales. For these experiments, sample preparation workflows that are compatible with multiple imaging techniques must be established. In one such implementation, a fluorescently labeled region of interest in a biological soft tissue sample can be imaged with light microscopy before staining the specimen with heavy metals, enabling follow-up higher resolution structural imaging at the targeted location, bringing context where it is required. Alternatively, or in addition to fluorescence imaging, other microscopy methods, such as synchrotron x-ray computed tomography with propagation-based phase contrast or serial blockface scanning electron microscopy, might also be applied. When combining imaging techniques across scales, it is common that a volumetric region of interest (ROI) needs to be carved from the total sample volume before high resolution imaging with a subsequent technique can be performed. In these situations, the overall success of the correlative workflow depends on the precise targeting of the ROI and the trimming of the sample down to a suitable dimension and geometry for downstream imaging. Here, we showcase the utility of a femtosecond laser (fs laser) device to prepare microscopic samples (1) of an optimized geometry for synchrotron x-ray tomography as well as (2) for volume electron microscopy applications and compatible with correlative multimodal imaging workflows that link both imaging modalities.

The influence of out-of-plane motion on the deformation measurement of planar biaxial tests on biological soft tissue

Planar biaxial testing is a popular technique to characterize a wide range of biological soft tissues. Nevertheless, a lot of variability exists between experimental setups. One particularly important variation relates to the difference in strain measuring techniques to characterize the deformation during the test: digital image correlation using one camera (measuring the out-of-plane motion as false strain), or two cameras (providing a stereo view). This study aimed to compare the two methods and provide practical guidelines for their use. A planar biaxial experiment was performed on ovine arterial samples on which both methods produced similar results in terms of strain measurements and material properties. The two-dimensional approach using a single camera is an appropriate and less time-consuming alternative to measure the deformation of soft biological tissue during planar biaxial loading conditions for similar setups.

Arterial tissues and their inflammatory response to collagen damage: A continuum in silico model coupling nonlinear mechanics, molecular pathways, and cell behavior

Damage in soft biological tissues causes an inflammatory reaction that initiates a chain of events to repair the tissue. This work presents a continuum model and its in silico implementation that describe the cascade of mechanisms leading to tissue healing, coupling mechanical as well as chemo-biological processes. The mechanics is described by means of a Lagrangian nonlinear continuum mechanics framework and follows the homogenized constrained mixtures theory. Plastic-like damage, growth and remodeling as well as homeostasis are taken into account. The chemo-biological pathways account for two molecular and four cellular species, and are activated by damage of collagen molecules in fibers. To consider proliferation, differentiation, diffusion and chemotaxis of species, diffusion–advection–reaction equations are employed. To the best of authors’ knowledge, the proposed model combines for the first time such high number of chemo-mechano-biological mechanisms in a consistent continuum biomechanical framework. The resulting set of coupled differential equations describe balance of linear momentum, evolution of kinematic variables as well as mass balance equations. They are discretized in time according to a backward Euler finite difference scheme, and in space through a finite element Galerkin discretization. The features of the model are firstly demonstrated presenting the species dynamics and highlighting the influence of damage intensities on the growth outcome. In terms of a biaxial test, the chemo-mechano-biological coupling and the model’s applicability to reproduce normal as well as pathological healing are shown. A last numerical example underlines the model’s applicability to complex loading scenarios and inhomogeneous damage distributions. Concluding, the present work contributes towards comprehensive in silico models in biomechanics and mechanobiology.

High-resolution phase-contrast X-ray imaging for biological soft tissue

Minimizing the distance between sample and detector achieves high spatial resolution while maintaining high contrast of biological tissue.

Adaptation of the virtual fields method for the identification of biphasic hyperelastic model parameters in soft biological tissues with osmotic swelling

AbstractBiphasic hyperelastic models have become popular for soft hydrated tissues, and there is a pressing need for appropriate identification methods using full‐field measurement techniques such as digital volume correlation. This paper proposes to address this need with the virtual fields method (VFM). The main asset of the proposed approach is that it avoids the repeated resolution of complex nonlinear finite element models. By choosing special virtual fields, the VFM approach can extract hyperelastic parameters of the solid part of the biphasic medium without resorting to identifying the model parameters driving the osmotic effects in the interstitial fluid. The proposed approach is verified and validated through three different examples: the first and second using simulated data and then the third using experimental data obtained from porcine descending thoracic aortas samples in osmotically active solution.

Super-resolution imaging with modulation of point spread function

The spatial resolution of an imaging system using waves is limited by the spatial bandwidth of the point spread function (PSF) of the system, which is related to the wavelength. However, when the PSF is modulated either in amplitude or phase or in both, the resulting spatial bandwidth of the PSF is increased. In this study, the PSF-modulation method is used to obtain super-resolution imaging of objects and to distinguish wave sources that are closely located in space and are not normally separable due to diffraction limit. In imaging using waves, such as ultrasound, acoustics, optics, electromagnetics, radar, and sonar, the PSF can be modulated in their respective fields. For example, in ultrasound, shear wave in biological soft tissues has a low wave speed and thus has a small wavelength. A ring-shaped shear wave can be generated locally (remotely) deep in the tissue by the radiation force of a focused Bessel beam, X wave, or other limited-diffraction beam at their focuses [Lu, 2021 IEEE IUS, 2021 ASA POMA] to produce a sharp peak at the center of the ring (due to shear wave focusing with a small wavelength). This sharp peak of the shear wave modulates the center of a conventional focused beam transmitted after the shear wave ring is produced. The modulated focused beam is then used to scan through an object to obtain a super-resolution image after removing the contribution of the original beam. In this talk, the theory, computer simulation, and experiment results of the super-resolution method will be presented.

Bilayer Stiffness Identification of Soft Tissues by Suction

In vivo mechanical characterisation of biological soft tissue is challenging, even under moderate quasi-static loading. Clinical application of suction-based methods is hindered by usual assumptions of tissues homogeneity and/or time-consuming acquisitions/postprocessing Provide practical and unexpensive suction-based mechanical characterisation of soft tissues considered as bilayered structures. Inverse identification of the bilayers’ Young’s moduli should be performed in almost real-time. An original suction system is proposed based on volume measurements. Cyclic partial vacuum is applied under small deformation using suction cups of aperture diameters ranging from 4 to 30 mm. An inverse methodology provides both bilayer elastic stiffnesses, and optionally the upper layer thickness, based on the interpolation of an off-line finite element database. The setup is validated on silicone bilayer phantoms, then tested in vivo on the abdomen skin of one healthy volunteer. On bilayer silicone phantoms, Young’s moduli identified by suction or uniaxial tension presented a relative difference lower than 10 % (upper layer thickness of 3 mm). Preliminary tests on in vivo abdomen tissue provided skin and underlying adipose tissue Young’s Moduli at 54 kPa and 4.8 kPa respectively. Inverse identification process was performed in less than one minute. This approach is promising to evaluate elastic moduli in vivo at small strain of bilayered tissues.

Elastographic measurements on soft biological tissues using holographic imaging by Rayleigh wave tracing

Tissue elasticity is one of the significant diagnostic parameters to study disease progression in biological tissues. Elastography measurements hold strong potential for determining the mechanical properties of malignant tissues in clinical practice. Optical methods for quantifying the elastic properties have received the attention of both research and medical community. In the current work, we calculate the elastic modulus of tissue-mimicking phantoms and ex-vivo biological tissue using holographic imaging by tracing Rayleigh wave propagation on the tissue surface. Rayleigh waves produced by the electromechanical actuator over a set of excitation frequencies are imaged by an ultrafast camera. The phase map reconstruction of the Rayleigh wave is carried out using a phase-shifting algorithm and the distance-time slope method is analyzed to compute Rayleigh wave velocities. The elastic modulus calculated by holographic imaging is validated against the gold standard mechanical compressional testing data. The quantitative results obtained from this current optical system combining holographic imaging and Rayleigh wave tracing are highly effective in ex-vivo and in-vivo tissue characterization and carry high potential as a promising tool in clinical translations and commercial adaptations.

Extreme Bottom-up Gold Filling of High Aspect Ratio Features.

ConspectusWhere copper interconnects fabricated using superconformal electrodeposition processes have enabled dramatic advances in microelectronics over the past quarter century, gold filled gratings fabricated using superconformal Bi3+-mediated bottom-up filling electrodeposition processes promise to enable a new generation of X-ray imaging and microsystem technologies. Indeed, bottom-up Au-filled gratings have demonstrated excellent performance in X-ray phase contrast imaging of biological soft tissue and other low Z element samples even as studies using gratings with inferior Au fill have captured the potential for broader biomedical application. Four years ago, the Bi-stimulated bottom-up Au electrodeposition process was a scientific novelty where gold deposition was localized entirely on the bottoms of metallized trenches 3-μm-deep and 2-μm-wide, an aspect ratio of only 1.5, on centimeter scale fragments of patterned silicon wafers. Today the room-temperature processes routinely yield uniformly void-free filling of metallized trenches 60-μm-deep and 1-μm-wide, an aspect ratio 60, in gratings patterned across 100 mm Si wafers. Four distinctive characteristics of the evolution of void-free filling in the Bi3+-containing electrolyte are seen in experimental Au filling of fully metallized recessed features such as trenches and vias: (1) an "incubation period" of conformal deposition, (2) subsequent Bi-activated deposition localized on the bottom surface of features, (3) sustained bottom-up deposition that yields void-free filling, and (4) self-passivation of the active growth front at a distance from the feature opening defined by operating conditions. A recent model captures and explains all four features. The electrolyte solutions are simple and nontoxic, being near-neutral pH and composed of Na3Au(SO3)2 + Na2SO3 containing micromolar concentrations of Bi3+ additive, the latter generally introduced through electrodissolution from the metal. The influences of additive concentration, metal ion concentration, electrolyte pH, convection, and applied potential have been examined in some depth using both electroanalytical measurements on planar rotating disk electrodes and studies of feature filling, thereby defining and elucidating relatively wide processing windows for defect-free filling. The process control for bottom-up Au filling processes is observed to be quite flexible, with online changes of potential as well as concentration and pH adjustments during the course of filling compatible with processing. Furthermore, monitoring has enabled optimization of the filling evolution, including to shorten the incubation period for accelerated filling and to fill features of ever higher aspect ratio. The results to date indicate that the demonstrated filling of trenches with an aspect ratio of 60 represents a lower bound, a value determined only by the features presently available.

How to implement constrained mixture growth and remodeling algorithms for soft biological tissues

Biological soft tissues are constantly adapting to their mechanical environment and remodel to restore certain mechanobiological homeostatic conditions. These effects can be modeled using the constrained mixture theory, that assumes degradation of material over time and the gradual replacement of extant material by newly deposited material. While this theory presents an elegant way to grasp phenomena of growth and remodeling in soft biological tissues, implementation difficulties may arise. Therefore, we give a detailed overview of the mathematical description of the constrained mixture theory and its homogenized equivalent, and present practical suggestions to numerically implement the theories. These implementations are thoroughly tested with multiple example growth and remodeling models. Results show a good correspondence between both theories, with the homogenized theory favored in terms of time efficiency. Results of a step time convergence study show the importance of choosing a small enough time step, especially when using the classical theory.

Metal-Coordinated Dynamics and Viscoelastic Properties of Double-Network Hydrogels

Biological soft tissues are intrinsically viscoelastic materials which play a significant role in affecting the activity of cells. As potential artificial alternatives, double-network (DN) gels, however, are pure elastic and mechanically time independent. The viscoelasticization of DN gels is an urgent challenge in enabling DN gels to be used for advanced development of biomaterial applications. Herein, we demonstrate a simple approach to regulate the viscoelasticity of tough double-network (DN) hydrogels by forming sulfonate-metal coordination. Owing to the dynamic nature of the coordination bonds, the resultant hydrogels possess highly viscoelastic, mechanical time-dependent, and self-recovery properties. Rheological measurements are performed to investigate the linear dynamic mechanical behavior at small strains. The tensile tests and cyclic tensile tests are also systematically performed to evaluate the rate-dependent large deformation mechanical behaviors and energy dissipation behaviors of various ion-loaded DN hydrogels. It has been revealed based on the systematic analysis that robust strong sulfonate-Zr4+ coordination interactions not only serve as dynamic crosslinks imparting viscoelastic rate-dependent mechanical performances, but also strongly affect the relative strength of the first PAMPS network, thereby increasing the yielding stress σy and the fracture stress at break σb and reducing the stretch ratio at break λb. It is envisioned that the viscoelasticization of DN gels enables versatile applications in the biomedical and engineering fields.

A variational RVE-based multiscale poromechanical formulation applied to soft biological tissues under large deformations

Investigations on micromechanics of soft biological tissues may lead to significant contributions within the fields of mechanobiology and tissue engineering. Multiscale models can be interesting numerical tools, since they may provide important insights on the micromechanics of these tissues. Due to the several multiphysics phenomena observed in soft biological tissues, the coupling between the fluid transport throughout the solid phases is one of major interest. In this regard, poromechanical models are widely used to represent the fluid diffusion through a deformable porous media. Motivated by these facts, this work presents an extension of the variational single-field multiscale formulation considering poromechanical phases at finite strain aiming at applications to soft biological tissues. To verify the suitability of the proposed formulation, numerical examples are compared with direct numerical simulations. In this case, two states are considered: an undrained and a drained condition. The results point out that the minimally constrained boundary condition for the fluid flow seems to properly represent only an undrained condition. However, for the drained one, proper multiscale boundary conditions must be developed.

Compliance-tunable thermal interface materials based on vertically oriented carbon fiber arrays for high-performance thermal management

With the ever-shrinking characteristic dimension of chips and the increasing of packaging density, heat dissipation has become the most critical technology challenge for electronic devices. The development of high-performance thermal interface materials (TIMs) for enhancing thermal coupling and minimizing thermal resistance between heterogeneous components is the key to achieving efficient thermal management of electronic devices. Herein, we report a high-performance carbon fiber/polydimethylsiloxane (CF/PDMS) TIM based on the construction of vertically oriented carbon fiber arrays and the modulation of PDMS's crosslinking density. The resulting CF/PDMS TIM exhibits highly desirable characteristics of through-plane thermal conductivity up to 43.47 W/m∙K (only 20 vol% loading), outstanding elastic compliance similar to soft biological tissues (stress ∼ 35 kPa at 35% compressive strain), and excellent resilience performance (resilience rate of 85% after compression cycles). In addition, the heat dissipation capability of CF/PDMS TIM is improved further by forming interconnected heat-conducting structures on the CF/PDMS TIM's surface. The optimal CF/PDMS TIM in microprocessor cooling application exhibits superior heat dissipation capability and stability during 1000 power cycles, resulting in a 68 °C reduction in the chip temperature compared with the state-of-the-art commercial TIM. This work opens up a new avenue for fabricating high-performance TIMs that meet the heat dissipation requirements of high-performance computing.

Engineering Tridimensional Hydrogel Tissue and Organ Phantoms with Tunable Springiness

AbstractBiomimicking organ phantoms with vivid biological structures and soft and slippery features are essential for in vitro biomedical applications yet remain hither to unmet challenges in their fabrication such as balancing between spatial structural complexity and matchable mechanical properties. Herein, 3D printable tissue‐mimicking elastomeric double network hydrogels with tailorable stiffness are evolved to idiosyncratically match diverse biological soft tissues by regulating the compositions of hydrogel matrix and the density of metal coordination bonds. Relying on digital light processing 3D printing, various mechanically tunable biomimetic volumetric hydrogel organ constructs with structural complexity and fidelity, including kidney, brain, heart, liver, stomach, lung, trachea, intestine, and even the intricate vascularized tissues, are fabricated faultlessly. Proof‐of‐concept 3D printed hydrogel heart and liver phantoms provide sophisticated internal channels and cavity structures and external realistic anatomical architectures that more closely mimic native organs. For the in vitro application demonstration, a 3D printed hydrogel brain phantom with tortuous cerebral arteries and slippery characters serves as an effective neurosurgical training platform for realistic simulation of endovascular interventions. This platform offers a means to construct mechanically precisely tunable hydrogel‐based biomimetic organ phantoms that are expected to be used in surgical training, medical device testing, and organs‐on‐chips.

Crack‐tip blunting and its implications on fracture of soft materials

AbstractFracture of compliant materials is preceded by large deformations that reshape initially sharp cracks into rounded defects. This phenomenon, known as elastic crack blunting, is peculiar of rubber‐like polymers and soft biological tissues, such as skin, vessel walls, and tendons. With this work, we aim to provide a discussion on crack‐tip blunting and its implications in terms of tearing resistance and flaw tolerance of soft elastic materials. The characteristic features of the crack‐tip zone in the framework of nonlinear elasticity are reviewed analytically and with the help of finite element analyses on pure shear cracked geometries. Specifically, the strain‐hardening behavior typical of soft biological tissues is addressed, and we illustrate its effect on crack‐tip blunting, in terms of a local radius of curvature at the crack tip. A simplified geometrically nonlinear model, proposed to describe the progressive blunting at the crack tip and its effect on flaw tolerance, is validated through finite element analyses and experimental tests on silicone samples. We show how this can lead to a simplified criterion to define the fracture condition in nonlinear soft materials.

Evolving microstructures in relaxed continuum damage mechanics for the modeling of strain softening

A new relaxation approach is proposed which allows for the description of stress- and strain-softening at finite strains. The model is based on the construction of a convex hull replacing the originally non-convex incremental stress potential which in turn represents damage in terms of the classical (1−D) approach. This convex hull is given as the linear convex combination of weakly and strongly damaged phases and thus, it represents the homogenization of a microstructure bifurcated in the two phases. As a result thereof, damage evolves in the convexified regime mainly by an increasing volume fraction of the strongly damaged phase. In contrast to previous relaxed incremental formulations in Gürses and Miehe (2011) and Balzani and Ortiz (2012), where the convex hull has been kept fixated after construction, here, the strongly damaged phase is allowed to elastically unload upon further loading. At the same time, its volume fraction increases nonlinearly within the convexified regime. Thus, strain-softening in the sense of a decreasing stress with increasing strain can be modeled. The major advantage of the proposed approach is that it ensures mesh-independent structural simulations without the requirement of additional length-scale related parameters or nonlocal quantities, which simplifies an implementation using classical material subroutine interfaces. In this paper, focus is on the relaxation of one-dimensional models for fiber damage which are combined with a microsphere approach to allow for the description of three-dimensional fiber dispersions appearing in fibrous materials such as soft biological tissues. Several numerical examples are analyzed to show the overall response of the model and the mesh-independence of resulting structural calculations.

A magnetically actuated, optically sensed tensile testing method for mechanical characterization of soft biological tissues.

Mechanical properties of soft biological tissues play a critical role in physiology and disease, affecting cell behavior and fate decisions and contributing to tissue development, maintenance, and repair. Limitations of existing tools prevent a comprehensive characterization of soft tissue biomechanics, hindering our understanding of these fundamental processes. Here, we develop an instrument for high-fidelity uniaxial tensile testing of soft biological tissues in controlled environmental conditions, which is based on the closed-loop interaction between an electromagnetic actuator and an optical strain sensor. We first validate the instrument using synthetic elastomers characterized via conventional methods; then, we leverage the proposed device to investigate the mechanical properties of murine esophageal tissue and, individually, of each of its constitutive layers, namely, the epithelial, connective, and muscle tissues. The enhanced reliability of this instrument makes it an ideal platform for future wide-ranging studies of the mechanics of soft biological tissues.

Tough, Transparent, and Slippery PVA Hydrogel Led by Syneresis.

Slippery and transparent polyvinyl alcohol (PVA) hydrogels with mechanical robustness exhibit broad applications in artificial biological soft tissues, flexible wearable electronics, and implantable biomedical devices. Most of the current PVA hydrogels, however, are unable to integrate these features, which compromises its performance in biological and engineering applications. To achieve such purpose, herein, a novel tactic is proposed, salting-out-after-syneresis of PVA, to realize a mechanically robust and highly transparent slippery PVA hydrogel. The syneresis of PVA sol is first conducted to form highly dense and transparent PVA polymer networks, then the salting-out effect tunes the aggregation of the polymer chains to rapidly induce the phase separation and crystallization. The resultant hydrogels show the transparency up to 98% in the visible region, the tribological coefficient down to 0.0081, and the excellent mechanical properties with strength, modulus, and toughness of 26.72±1.05, 6.66±0.29MPa, and 55.21±1.62MJm-3 , respectively. To reveal the potentials, PVA contact lens that combine remarkable lubrication, anti-protein adhesion, biocompatibility, and drug-loading functions are demonstrated. This strategy provides a simple and new avenue for developing the mechanically robust, transparent, and hydrated hydrogels, showing the potential in biomedicine and wearable devices.

A Flexible Organic Electrochemical Synaptic Transistor With Dopamine-Mediated Plasticity

Artificial synapses relying on electrical and optical stimuli to implement neuromorphic tasks have been intensively developed, but very few of them can directly respond to real biological neurotransmitter stimulus, thus limiting the seamless integration of bio-electronic interfaces. In this letter, we report a flexible organic electrochemical transistor-based synaptic device, which demonstrates not only short-term synaptic behaviors dominated by the kinetics of ions but also long-term synaptic behaviors derived from the redox reaction of dopamine neurotransmitters. More importantly, we systematically studied the dopamine-mediated synaptic plasticity under both flat and bending states, which shows reliable synaptic response and excellent mechanical flexibility. These results reveal that our device providing a promising way for direct biohybrid integration with soft biological tissues.