Soft Biological Tissues Research Articles

Hydrogel-based Soft Robotics for Surgical Machinery

Hydrogel-based soft robotics represent a transformative approach in surgical machinery, offering unparalleled adaptability, biocompatibility, and precision for minimally invasive procedures. Hydrogels, with their high water content and tunable mechanical properties, mimic soft biological tissues, making them ideal for applications in delicate surgical environments. This research explores the integration of hydrogel materials into soft robotic systems, focusing on their fabrication, actuation mechanisms, and performance in surgical applications. Key advancements include the development of stimuli-responsive hydrogels that enable precise control of movement and force, enhancing the capability to navigate complex anatomical structures. The study also examines computational models for simulating hydrogel behavior and optimizing robotic designs. While the potential benefits of hydrogel-based soft robotics in improving patient outcomes are significant, challenges remain in ensuring durability, scalability, and reliable control systems. This research aims to address these limitations by integrating advanced materials science with robotic engineering. By doing so, it contributes to the evolution of surgical technologies, paving the way for safer and more effective procedures.

Temperature and state-dependent electrical conductivity of soft biological tissue at hyperthermic temperatures

Objective: We present a physics-based, temperature and state-dependent electrical conductivity model for soft biological tissue under thermal therapies with a quantified damage parameter that represents the state of soft biological tissue (degree of denaturation). Most existing models consider electrical conductivity to be only temperature-dependent and evaluate tissue damage during post-processing after temperature calculation. Our model allows tissue damage to be coupled into the thermal model for a more accurate description of both RF ablation and electrosurgery. Methods: We model the denaturation process with an Arrhenius-type differential equation for chemical kinetics and a modified Stogryn equation for electrical conductivity under state transition. We present experimental data from two types of heating procedures at 128 kHz to validate and showcase the capability of our model. Results: Our model is able to capture the change in electrical conductivity during heating, cooling, and reheating procedures, which distinguishes different states and shows the irreversibility of denaturation. The model also accurately captures tissue change during slow cooking at a constant temperature, highlighting a state dependence. Conclusion: By incorporating state dependence into the model for electrical properties, we are able to capture the denaturation process more accurately and distinguish different degrees of damage. Our model allows the modeling of procedures involving repeated heating or cooling, which is impossible for models without a state dependence. While being able to adapt to patient-specific needs, the model can be used to improve planning and control in future robot-assisted surgeries to reduce unnecessary damage.

Tailoring the mechanical properties of macro-porous PVA hydrogels for biomedical applications

Polyvinyl alcohol (PVA) is a biocompatible biopolymer with superior dimensional and mechanical stability when compared to naturally available biomaterials such as collagen and gelatin. Furthermore, PVA in hydrogel form behaves non-linearly during mechanical loading, generating a response like soft biological tissues. Generally, PVA hydrogels are fabricated using freeze-thaw cycles (FTCs) and changing the number of FTCs gives control over its mechanical properties. Porosity of the hydrogel is another important factor which determines its mechanical properties and is also evident in biological soft tissues. Incorporating macro-pores in PVA hydrogels substantially reduces the stiffness of the material and can mimic some porous tissues such as lung, liver, bone marrow, kidneys, urethra and penile tissues (corpus cavernosa). Within this study, we developed macro-porous PVA hydrogels using the freeze-thaw process followed by particulate leaching of sacrificial 3D-printed and milled PVA (m-PVA) filler particles. This fabrication method enables control over the porosity in macro-porous PVA hydrogels, which is crucial not only for tuning mechanical properties but also for mimicking the structure of spongy tissues, such as liver tissue and corpus cavernosum in the penile tissue, for example. We investigated the level of porosity in the specimen using optical microscopy to understand the distribution of the pores and the pore size. The tunability of the mechanical properties of PVA hydrogels is, a key finding of this study and is achieved using three factors: (i) weight percentage of sacrificial fillers, (ii) number of FTCs and (iii) concentration of PVA. These macro-porous PVA specimens have wide ranging biomedical applications as biological soft tissue analogues, or tissue engineering scaffolds, where the PVA hydrogel can be tuned to match the mechanical properties of these soft biological tissues.

Power-Law Modeling for Swift Viscoelastic Assessment in Biological Soft Tissues

In addressing the viscoelastic behavior of biological soft tissues, the precise and expeditious measurement methodologies hold paramount significance, given the intrinsic softness and heightened aqueous content of such substrates. We have introduced an expeditious modality for the characterization of viscoelasticity in biological soft tissues, hinged upon a power-law model. This method has been rigorously validated through ramp–hold tests conducted on mechanically stable hydrogels. Notably, during the Ramp phase, the viscoelastic parameters of the material can be readily extracted. Furthermore, we applied unconfined compression stress-relaxation/creep tests with three different ramp–strain rates, namely [Formula: see text], on both white and gray matter to enable rapid quantification. The results indicate that the predicted curves during the Hold phase exhibit notable consistency with experimental data. Moreover, under quasi-static loading conditions, an increase in strain rate significantly enhances the predictive adaptability. Nonetheless, it is crucial to be mindful of the sensitivity to initial stress conditions. This study offers a promising avenue for the expeditious characterization of soft tissue viscoelasticity. It underscores the feasibility of mechanical characterization metrics from a phenomenological model for the assessment of physiological variations and pathological mechanisms in tissue states.

Three-dimensional anisotropic unified continuum model for simulating the healing of damaged soft biological tissues.

The soft biological tissues have the ability to heal and self-repair after damage or injury. During the healing process, damaged tissues are replaced by newly produced undamaged tissue to restore homeostasis. Computational modeling serves as an effective tool for simulating the healing process and understanding the underlying mechanisms. In previous work, we developed the first unified continuum damage model for the healing of soft biological tissues. However, the initial theory lacked generalizability to more realistic scenarios and applicability to biomechanical problems due to the simplicity of the isotropic constitutive model and two-dimensional simulations. Therefore, we further improve our approach by developing a three-dimensional anisotropic unified healing model to address more realistic challenges. By using the Holzapfel-Gasser-Ogden model as the hyperelastic term, the influence of the collagen fibers is considered and the reorientation of fibers in healing is simulated. Three numerical examples related to hypertension, aneurysm, and restenosis of the atherosclerotic artery after balloon angioplasty are presented to demonstrate the effectiveness of the proposed model. By comparing numerical solutions and reference solutions, we demonstrate the ability of the proposed model in simulating long-term tissue healing process and analyze the impact of anisotropic terms.

Multiscale homogenized constrained mixture model of the bio-chemo-mechanics of soft tissue growth and remodeling.

Constrained mixture models have successfully simulated many cases of growth and remodeling in soft biological tissues. So far, extensions of these models have been proposed to include either intracellular signaling or chemo-mechanical coupling on the organ-scale. However, no version of constrained mixture models currently exists that includes both aspects. Here, we propose such a version that resolves cellular signal processing by a set of logic-gated ordinary differential equations and captures chemo-mechanical interactions between cells by coupling a reaction-diffusion equation with the equations of nonlinear continuum mechanics. To demonstrate the potential of the model, we present 2 case studies within vascular solid mechanics: (i) the influence of angiotensin II on aortic growth and remodeling and (ii) the effect of communication between endothelial and intramural arterial cells via nitric oxide and endothelin-1.

Synchrotron X-ray imaging of soft biological tissues - principles, applications and future prospects.

Synchrotron-based tomographic phase-contrast X-ray imaging (SRµCT or SRnCT) is a versatile isotropic three-dimensional imaging technique that can be used to study biological samples spanning from single cells to human-sized specimens. SRµCT and SRnCT take advantage of the highly brilliant and coherent X-rays produced by a synchrotron light source. This enables fast data acquisition and enhanced image contrast for soft biological samples owing to the exploitation of phase contrast. In this Review, we provide an overview of the basics behind the technique, discuss its applications for biologists and provide an outlook on the future of this emerging technique for biology. We introduce the latest advances in the field, such as whole human organs imaged with micron resolution, using X-rays as a tool for virtual histology and resolving neuronal connections in the brain.

Enhancing the Biomimetic Mechanics of Bottlebrush Graft-Copolymers through Selective Solvent Annealing.

Self-assembled networks of bottlebrush copolymers are promising materials for biomedical applications due to a unique combination of ultra-softness and strain-adaptive stiffening, characteristic of soft biological tissues. Transitioning from ABA linear-brush-linear triblock copolymers to A-g-B bottlebrush graft copolymer architectures allows significant increasing the mechanical strength of thermoplastic elastomers. Using real-time synchrotron small-angle X-ray scattering, it is shown that annealing of A-g-B elastomers in a selective solvent for the linear A blocks allows for substantial network reconfiguration, resulting in an increase of both the A domain size and the distance between the domains. The corresponding increases in the aggregation number and extension of bottlebrush strands lead to a significant increase of the strain-stiffening parameter up to 0.7, approaching values characteristic of the brain and skin tissues. Network reconfiguration without disassembly is an efficient approach to adjusting the mechanical performance of tissue-mimetic materials to meet the needs of diverse biomedical applications.

Development of a nanometre scale X-ray speckle-based CT technique through the 3-D histological assessment of an acute respiratory distress syndrome model

The study of biological soft tissue structures at the micron scale details the function of healthy and pathological tissues, which is vital in the diagnosis and treatment of diseases. Speckle based X-ray phase contrast tomographic scans at a nanometer scale have the potential to thoroughly analyse such tissues in a quantitative and qualitative manner. Diamond light source, the UKs national synchrotron facility developed and refined a 1-D X-ray speckle-based imaging technique, referred to as Fly scan mode. This novel image acquisition technique was used to perform a rapid structural composition scan of rodent lung histology samples. The rodent samples were taken from healthy and Staphylococcus aureus induced acute respiratory distress syndrome models. The analysis and cross comparison of the fly scan method, absorption-based tomography and conventional histopathology H&E staining microscopy are discussed in this paper. This analysis and cross comparison outline the ways the speckle-based technique can be of benefit. These advantages include improved soft tissue contrast, 3-D volumetric rendering, segmentation of specific gross tissue structures, quantitative analysis of gross tissue volume. A further advantage is the analysis of cellular distribution throughout the volumetric rendering of the tissue sample. The study also details the current limitations of this technique and points to ways in which future work on this imaging modality may progress.

Existence of solutions to k‐Wave models of nonlinear ultrasound propagation in biological tissue

AbstractWe investigate models for nonlinear ultrasound propagation in soft biological tissue based on the one that serves as the core for the software package k‐Wave. The systems are solved for the acoustic particle velocity, mass density, and acoustic pressure and involve a fractional absorption operator. We first consider a system that incorporates additional viscosity in the equation for momentum conservation. By constructing a Galerkin approximation procedure, we prove the local existence of its solutions. In view of inverse problems arising from imaging tasks, the theory allows for the variable background mass density, speed of sound, and the nonlinearity parameter in the systems. Second, under stronger conditions on the data, we take the vanishing viscosity limit of the problem, thereby rigorously establishing the existence of solutions for the limiting system as well.

Assessing Transducer Parameters for Accurate Medium Sound Speed Estimation and Image Reconstruction.

The influence of the transducer lens on image reconstruction is often overlooked. Lenses usually exhibit a lower sound speed than soft biological tissues. In academic research, the exact lens sound speed and thickness are typically unknown. Here, we present a simple and nondestructive method to characterize the lens sound speed and thickness as well as the time to peak of the round-trip ultrasound waveform, another key parameter for optimal image reconstruction. We applied our method to three transducers with center frequencies of 2.5, 7.5, and 15 MHz. We estimated the three parameters with an element-by-element transmission sequence that records internal reflections within the lens. We validated the retrieved parameters using an autofocusing approach that estimates sound speed in water. We show that the combination of our parameters estimation method with two-layer ray tracing outperforms standard image reconstruction. For all transducers, we successfully improved the accuracy of medium sound speed estimation, spatial resolution, and contrast. The proposed method is simple and robust and provides an accurate estimation of the transducer lens parameters and the time to peak of the ultrasound waveform, which leads to improved ultrasound image quality.

Simulating irregular symmetry breaking in gut cross sections using a novel energy-optimization approach in growth-elasticity

Growth-elasticity (also known as morphoelasticity) is a powerful model framework for understanding complex shape development in soft biological tissues. At each instant, by mapping how continuum building blocks have grown geometrically and how they respond elastically to the push-and-pull from their neighbors, the shape of the growing structure is determined from a state of mechanical equilibrium. As mechanical loads continue to be added to the system through growth, many interesting shapes, such as smooth wavy wrinkles, sharp creases, and deep folds, can form on the tissue surface from a relatively flatter geometry.Previous numerical simulations of growth-elasticity have reproduced many interesting shapes resembling those observed in reality, such as the foldings on mammalian brains and guts. In the case of mammalian guts, it has been shown that wavy wrinkles, deep folds, and sharp creases on the interior organ surface can be simulated even under a simple assumption of isotropic uniform growth in the interior layer of the organ. Interestingly, the simulated patterns are all regular along the tube’s circumference, with either all smooth or all sharp indentations, whereas some undulation patterns in reality exhibit irregular patterns and a mixture of sharp creases and smooth indentations along the circumference. Can we simulate irregular indentation patterns without further complicating the growth patterning?In this paper, we have discovered abundant shape solutions with irregular indentation patterns by developing a Rayleigh–Ritz finite-element method (FEM). In contrast to previous Galerkin FEMs, which solve the weak formulation of the mechanical-equilibrium equations, the new method formulates an optimization problem for the discretized energy functional, whose critical points are equivalent to solutions obtained by solving the mechanical-equilibrium equations. This new method is more robust than previous methods. Specifically, it does not require the initial guess to be near a solution to achieve convergence, and it allows control over the direction of numerical iterates across the energy landscape. This approach enables the capture of more solutions that cannot be easily reached by previous methods. In addition to the previously found regular smooth and non-smooth configurations, we have identified a new transitional irregular smooth shape, new shapes with a mixture of smooth and non-smooth surface indentations, and a variety of irregular patterns with different numbers of creases. Our numerical results demonstrate that growth-elasticity modeling can match more shape patterns observed in reality than previously thought.

On the experimental identification of equilibrium relations and the separation of inelastic effects in soft biological tissues

The mechanical characterization of vascular tissues has been mainly focused on the measurement of elastic properties, while the investigation of inelastic effects has received comparatively little attention. Even the relatively simple, purely elastic description of the material behavior requires an appropriate set of experimental data that cannot be easily isolated using standard testing procedures. The presence of viscous and damage-related phenomena poses some challenges in the definition of appropriate testing protocols capable of identifying an equilibrium response, which in general does not solely represent the elastic material behavior. The primary goal of the present study is therefore to devise an experimental procedure that can distinguish and evaluate the different constitutive phenomena separately. To this end, we apply methodologies widely used in the mechanical testing of rubber-like materials and transfer them to the field of biomechanics. We performed two types of experiments in equibiaxial extension on porcine thoracic aorta: a continuous cyclic test followed by a single-step relaxation test and a cyclic multi-step relaxation test, each at varying stretch rates. We demonstrate that the approximation of quasi-stationarity through continuous testing at slow rates is inadequate for the identification of an equilibrium relation. Alternatively, a step-wise protocol allows for the separation of equilibrium and viscous effects. This motivates a thermodynamic discussion of the experimental results in terms of energy dissipation and a closer look at the interplay of inelastic phenomena.

A Deep Recurrent Neural Network for Predicting Subject-specific Facial Soft Tissue Interaction

Predicting biological soft tissue interaction is of great interest for developing computer-aided decision systems. This study aims to develop and evaluate a novel deep-learning approach based on the recurrent neural network for predicting facial soft tissue impact with a rubber ball. A computational workflow was established including a subject-specific finite element model of the facial soft tissue under interaction with the rubber ball. A series of simulations under different ball velocities was performed to build the learning database. We implemented a long-short-term memory (LSTM) model and then evaluated its performance using root mean square error (RMSE) and regression coefficient metrics. The obtained results showed a RMSE of 3.13 mm and a Pearson correlation coefficient of 0.98 for soft tissue displacement prediction. A RMSE of 0.001 MPa and a Pearson correlation coefficient of 0.94 was also obtained for soft tissue von Mises stress prediction. The present study showed the robustness and accuracy of the recurrent neural network for predicting complex soft tissue interaction behaviours. Our findings open new avenues for deploying novel deep learning workflow for human-facial softtissue interaction. As perspective, this workflow will be integrated into our interactive facial analysis and rehabilitation system.

Universal phase-field mixture representation of thermodynamics and shock-wave mechanics in porous soft biologic continua.

A continuum mixture theory is formulated for large deformations, thermal effects, phase interactions, and degradation of soft biologic tissues suitable at high pressures and low to very high strain rates. Tissues consist of one or more solid and fluid phases and can demonstrate nonlinear anisotropic elastic, viscoelastic, thermoelastic, and poroelastic physics. Under extreme deformations or shock loading, tissues may fracture, tear, or rupture. Existing models do not account for all physics simultaneously, and most poromechanics and soft-tissue models assume incompressibility of some or all constituents, generally inappropriate for modeling shock waves or extreme compressions. Motivated by these prior limitations, a thermodynamically consistent formulation that combines a continuum theory of mixtures, compressible nonlinear anisotropic thermoelasticity, viscoelasticity, and phase-field mechanics of fracture is constructed to resolve the pertinent physics. A metric tensor of generalized Finsler space supplies geometric insight on effects of rearrangements of microstructure, for example degradation, growth, and remodeling. Shocks are modeled as singular surfaces. Hugoniot states and shock decay are analyzed: Solutions account for concurrent viscoelasticity, fracture, and interphase momentum and energy exchange not all contained in previous analyses. Suitability of the framework for representing blood, skeletal muscle, and liver is demonstrated by agreement with experimental data and observations across a range of loading rates and pressures. Insight into previously unresolved physics is obtained, for example importance of rate sensitivity of damage and quantification of effects of dissipation from viscoelasticity and phase interactions on shock decay.

A Universal Biocompatible and Multifunctional Solid Electrolyte in p-Type and n-Type Organic Electrochemical Transistors for Complementary Circuits and Bioelectronic Interfaces.

The development of soft and flexible devices for collection of bioelectrical signals is gaining momentum for wearable and implantable applications. Among these devices, organic electrochemical transistors (OECTs) stand out due to their low operating voltage and large signal amplification capable of transducing weak biological signals. While liquid electrolytes have demonstrated efficacy in OECTs, they limit its operating temperature and pose challenges for electronic packaging due to potential leakage. Conversely, solid electrolytes offer advantages such as mechanical flexibility, robustness against environmental factors, and ability to bridge the interface between rigid dry electronics systems and soft wet biological tissues. However, few systems have demonstrated generality and compatibility with a wide range of state-of-the-art organic mixed ionic-electronic conductors (OMIECs). This paper introduces a highly stretchable, flexible, biocompatible, self-healable gelatin-based solid-state electrolyte, compatible with both p- and n-type OMIEC channels while maintaining high performance and excellent stability. Furthermore, this nonvolatile electrolyte is stable up to 120°C and exhibits high ionic conductivity even in dry environment. Additionally, an OECT-based complementary inverter with a record-high normalized-gain of 228 V-1 and a corresponding ultralow static power consumption of 1 nW is demonstrated. These advancements pave the way for versatile applications ranging from bioelectronics to power-efficient implants.

Design and FEA verification of high dimensional and multi-field smart soft material

Abstract We designed a sophisticated smart soft tissue material that simulates the properties of biological soft tissue and detects three-dimensional force. Inspired by electronic skin, this material uses capacitive pressure sensors and multi-layer sensor packaging. Finite element analysis and multi-field simulation were employed for structural design and verification. The study evaluated the theory and practicality of a flexible capacitive 3D force sensor for detecting pressure and shear force. Mechanical and electrical properties were confirmed through force and electric field simulations. The 3D force detection method proved feasible, achieving sensitivity levels of 10−4 kPa −1 in the X and Y directions, and 10−3 kPa −1 in the Z direction, demonstrating the effectiveness of our design.

How well do 3D-printed tissue mimics represent the complex mechanics of biological soft tissues? An example study with Stratasys' cardiovascular TissueMatrix materials.

Tissue mimicking materials are designed to represent real tissue in applications such as medical device testing and surgical training. Thanks to progress in 3D-printing technology, tissue mimics can now be easily cast into arbitrary geometries and manufactured with adjustable material properties to mimic a wide variety of tissue types. However, it is unclear how well 3D-printable mimics represent real tissues and their mechanics. The objective of this work is to fill this knowledge gap using the Stratasys Digital Anatomy 3D-Printer as an example. To this end, we created mimics of biological tissues we previously tested in our laboratory: blood clots, myocardium, and tricuspid valve leaflets. We printed each tissue mimic to have the identical geometry to its biological counterpart and tested the samples using identical protocols. In our evaluation, we focused on the stiffness of the tissues and their fracture toughness in the case of blood clots. We found that the mechanical behavior of the tissue mimics often differed substantially from the biological tissues they aim to represent. Qualitatively, tissue mimics failed to replicate the traditional strain-stiffening behavior of soft tissues. Quantitatively, tissue mimics were stiffer than their biological counterparts, especially at small strains, in some cases by orders of magnitude. In those materials in which we tested toughness, we found that tissue mimicking materials were also much tougher than their biological counterparts. Thus, our work highlights limitations of at least one 3D-printing technology in its ability to mimic the mechanical properties of biological tissues. Therefore, care should be taken when using this technology, especially where tissue mimicking materials are expected to represent soft tissue properties quantitatively. Whether other technologies fare better remains to be seen.

Hypostomus plecostomus-inspired soft sucker to adsorb slippery tissues: a stabilizing post-valvular cavity and stiffness gradient materials provide excellent adsorption performance

The hard suckers commonly used in surgical operations often cause adsorption extrusion damage to the biological tissue. To tackle this problem, from the perspective of bionics, through in-depth observation and research on the special sucker adsorption process and adsorption mechanism of hypostomus plecostomus (HP), this paper proposes a bionic soft hypostomus plecostomus sucker (BSHPS) with a variable stiffness gradient structure with a good adsorption performance on soft moist irregular biological tissues. The BSHPS comprises a lip disc, a pre-valvular cavity, and a post-valvular cavity. Through the volume changes of the pre- and post-valvular cavities, a pressure difference is generated between the inside and outside of the sucker, enabling the lip disc to remain sealed. The experiments were carried out by an automatic tensile force measurement system equipped with a vacuum pump, and the results showed that in slippery environment, the adsorption performance of the BSHPS is improved by a maximum of 61.9% compared to that in dry environment. On a biological tissue surface, the adsorption force is as high as 13.7765 N. The most important advantage of the proposed BSHPS is that it can be firmly adsorbed the surface of soft moist irregular biological tissues, effectively slowing down or avoiding adsorption extrusion damage to the biological tissue. Therefore, the BSHPS is expected to have good application prospects in modern surgical medicine.

Phase-contrast visualization of human tissues using superimposed wavefront imaging of diffraction-enhanced x-rays.

Phase-contrast computed tomography (CT) using high-brilliance, synchrotron-generated x-rays enable three-dimensional (3D) visualization of microanatomical structures within biological specimens, offering exceptionally high-contrast images of soft tissues. Traditional methods for phase-contrast CT; however, necessitate a gap between the subject and the x-ray camera, compromising spatial resolution due to penumbral blurring. Our newly developed technique, Superimposed Wavefront Imaging of Diffraction-enhanced x-rays (SWIDeX), leverages a Laue-case Si angle analyzer affixed to a scintillator to convert x-rays to visible light, capturing second-order differential phase contrast images and effectively eliminating the distance to the x-ray camera. This innovation achieves superior spatial resolution over conventional methods. In this paper, the imaging principle and CT reconstruction algorithm based on SWIDeX are presented in detail and compared with conventional analyzer-based imaging (ABI). It also shows the physical setup of SWIDeX that provides the resolution preserving second-order differential images for reconstruction. We compare the spatial resolution and the sensitivity of SWIDeX to conventional ABI. To demonstrate high-spatial resolution achievable by SWIDeX, the internal structures of four human tissues-ductal carcinoma in situ, normal stomach, normal pancreas, and intraductal papillary mucinous neoplasm of the pancreas-were visualized using an imaging system configured at the Photon Factory's BL14B beamline under the High Energy Accelerator Research Organization (KEK). Each tissue was thinly sliced after imaging, stained with hematoxylin and eosin (H&E) for conventional microscope-based pathology. A comparison of SWIDeX-CT and pathological images visually demonstrates the effectiveness of SWIDeX-CT for biological tissue imaging. SWIDeX could generate clearer 3D images than existing analyzer-based phase-contrast methods and accurately delineate tissue structures, as validated against histopathological images. SWIDeX can visualize important 3D structures in biological soft tissue with high spatial resolution and can be an important tool for providing information between the disparate scales of clinical and pathological imaging.