Mechanical Properties Of Biological Tissues Research Articles

Sensitivity of magnetic resonance elastography to extracellular matrix and cell motility in human prostate cancer cell line-derived xenograft models

Prostate cancer (PCa) is a significant health problem in the male population of the Western world. Magnetic resonance elastography (MRE), an emerging medical imaging technique sensitive to mechanical properties of biological tissues, detects PCa based on abnormally high stiffness and viscosity values. Yet, the origin of these changes in tissue properties and how they correlate with histopathological markers and tumor aggressiveness are largely unknown, hindering the use of tumor biomechanical properties for establishing a noninvasive PCa staging system.To infer the contributions of extracellular matrix (ECM) components and cell motility, we investigated fresh tissue specimens from two PCa xenograft mouse models, PC3 and LNCaP, using magnetic resonance elastography (MRE), diffusion-weighted imaging (DWI), quantitative histology, and nuclear shape analysis. Increased tumor stiffness and impaired water diffusion were observed to be associated with collagen and elastin accumulation and decreased cell motility. Overall, LNCaP, while more representative of clinical PCa than PC3, accumulated fewer ECM components, induced less restriction of water diffusion, and exhibited increased cell motility, resulting in overall softer and less viscous properties. Taken together, our results suggest that prostate tumor stiffness increases with ECM accumulation and cell adhesion - characteristics that influence critical biological processes of cancer development.MRE paired with DWI provides a powerful set of imaging markers that can potentially predict prostate tumor development from benign masses to aggressive malignancies in patients. Statement of significanceXenograft models of human prostate tumor cell lines, allowing correlation of microstructure-sensitive biophysical imaging parameters with quantitative histological methods, can be investigated to identify hallmarks of cancer.

Flexible capacitive pressure sensors and their applications in human-machine interactions

Flexible pressure sensors offer more significant advantages than rigid sensors in various applications, including human-computer interaction, medical health, and robot touch. However, this also places more stringent demands on the materials used. For example, the materials must be thin and soft enough to fit onto the surface of the human skin or be implanted into the body while also exhibiting good biocompatibility and matching the mechanical properties of biological tissues. Regarding device performance, flexible pressure sensor design primarily focuses on enhancing sensitivity, response time, detection limit, and stability. Researchers have recently been expanding these sensors' pressure response range, pressure resolution, spatial resolution, and tensile performance, which will further broaden their potential applications. This review provides an overview of the recent classification of flexible pressure sensors, covering their sensing principle, sensing performance, and future application prospects.

Quantifying local stiffness and forces in soft biological tissues using droplet optical microcavities

Mechanical properties of biological tissues fundamentally underlie various biological processes and noncontact, local, and microscopic methods can provide fundamental insights. Here, we present an approach for quantifying the local mechanical properties of biological materials at the microscale, based on measuring the spectral shifts of the optical resonances in droplet microcavities. Specifically, the developed method allows for measurements of deformations in dye-doped oil droplets embedded in soft materials or biological tissues with an error of only 1 nm, which in turn enables measurements of anisotropic stress inside tissues as small as a few pN/μm2. Furthermore, by applying an external strain, Young's modulus can be measured in the range from 1 Pa to 35 kPa, which covers most human soft tissues. Using multiple droplet microcavities, our approach could enable mapping of stiffness and forces in inhomogeneous soft tissues and could also be applied to in vivo and single-cell experiments. The developed method can potentially lead to insights into the mechanics of biological tissues.

Multiscale elasticity mapping of biological samples in 3D at optical resolution

The mechanical properties of biological tissues have emerged as an integral determinant of tissue function in health and disease. Nonetheless, characterizing the elasticity of biological samples in 3D and at high resolution remains challenging. Here, we present a µElastography platform: a scalable elastography system that maps the elastic properties of tissues from cellular to organ scales. The platform leverages the use of a biocompatible, thermo-responsive hydrogel to deliver compressive stress to a biological sample and track its resulting deformation. By surrounding the specimen with a reference hydrogel of known Young's modulus, we are able to map the absolute values of elastic properties in biological samples. We validate the experimental and computational components of the platform using a hydrogel phantom and verify the system's ability to detect internal mechanical heterogeneities. We then apply the platform to map the elasticity of multicellular spheroids and the murine lymph node. With these applications, we demonstrate the platform's ability to map tissue elasticity at internal planes of interest, as well as capture mechanical heterogeneities neglected by most macroscale characterization techniques. The µElastography platform, designed to be implementable in any biology lab with access to 3D microscopy (e.g., confocal, multiphoton, or optical coherence microscopy), will provide the capability to characterize the mechanical properties of biological samples to labs across the large community of biological sciences by eliminating the need of specialized instruments such as atomic force microscopy. Statement of significanceUnderstanding the elasticity of biological tissues is of great importance, but characterizing these properties typically requires highly specialized equipment. Utilizing stimulus-responsive hydrogels, we present a scalable, hydrogel-based elastography method that uses readily available reagents and imaging modalities to generate resolved maps of internal elasticity within biomaterials and biological samples at optical resolution. This new approach is capable of detecting internal stiffness heterogeneities within the 3D bulk of samples and is highly scalable across both imaging modalities and biological length scales. Thus, it will have significant impact on the measurement capabilities of labs studying engineered biomaterials, mechanobiology, disease progression, and tissue engineering and development.

In-Plane Wave Propagation Analysis of Human Breast Lesions Using a Higher-Order Nonlocal Model and Deep Learning

The wave propagation characteristics of biological tissues are of high importance in improving healthcare technologies and can be used as an early clinical indicator of many diseases. However, the current mathematical models that describe the mechanical properties of biological tissues do not account for the difference in softening and hardening observed at different scales and this limits their utility in biomedical imaging. In this paper, a higher-order nonlocal model is developed to study in-plane wave propagation in healthy, benign, and cancerous breast tissues. To verify the mathematical approach, finite element simulations are conducted. Furthermore, a sequential deep neural network model of feedforward type with multiple hidden layers is developed to understand the intrinsic in-plane wave characteristics of breast tissues. The deep learning algorithm shows potential in accurately extracting the frequencies and phase velocities of breast lesions under in-plane waves even when there is a limited number of clinical samples. Using the higher-order nonlocal model, significant differences between healthy fibroglandular tissue and early breast cancer in the form of ductal carcinoma in situ have been found. The combination of nonlocal and strain gradient parameters allows for the concurrent incorporation of stiffness hardening and softening, solving the rigid-tumour–soft-cell paradox of cancer biomechanics.

Quantifying the Impact of Cancer on the Viscoelastic Properties of the Prostate Gland using a Quasi-Linear Viscoelastic Model

Pathological disorders can alter the mechanical properties of biological tissues, and studying such changes can help to better understand the disease progression. The prostate gland is no exception, as previous studies have shown that cancer can affect its mechanical properties. However, most of these studies have focused on the elastic properties of the tissue and have overlooked the impact of cancer on its viscous response. To address this gap, we used a quasi-linear viscoelastic model to investigate the impact of cancer on both the elastic and viscous characteristics of the prostate gland. By comparing the viscoelastic properties of segments influenced by cancer and those unaffected by cancer in 49 fresh prostates, removed within two hours after prostatectomy surgery, we were able to determine the influence of cancer grade and tumor volume on the tissue. Our findings suggest that tumor volume significantly affects both the elastic modulus and viscosity of the prostate (p-value less than 2%). Specifically, we showed that cancer increases Young's modulus and shear relaxation modulus by 20%. These results have implications for using mechanical properties of the prostate as a potential biomarker for cancer. However, developing an in vivo apparatus to measure these properties remains a challenge that needs to be addressed in future research. Statement of significanceThis study is the first to explore how cancer impacts the mechanical properties of prostate tissues using a quasi-linear viscoelastic model. We examined 49 fresh prostate samples collected immediately after surgery and correlated their properties with cancer presence identified in pathology reports. Our results demonstrate a 20% change in the viscoelastic properties of the prostate due to cancer. We initially validated our approach using tissue-mimicking phantoms and then applied it to differentiate between cancerous and normal prostate tissues. These findings offer potential for early cancer detection by assessing these properties. However, conducting these tests in vivo remains a challenge for future research.

Readily prepared and processed multifunctional MXene nanocomposite hydrogels for smart electronics

AbstractBooming sophisticated robotics and prosthetics put forward high requirements on soft conductive materials that can bridge electronics and biology, those soft conductive materials should imitate the mechanical properties of biological tissues and build information transmission networks. Until now, it remains a great challenge to handle the trade‐off among ease of preparation, high conductivity, processability, mechanical adaptability, and external stimuli responsiveness. Herein, a kind of readily prepared and processed multifunctional MXene nanocomposite hydrogel is reported, which is prepared via the fast gelation of cationic monomer initiated by delaminated MXene sheets. The gelation time can be adjusted (several seconds to minutes) based on the MXene loadings. By adjusting the MXene ratio, the resulting nanocomposites are ultrastretchable (>5000%), three‐dimensional (3D) printable, and show outstanding mechanical and electrical self‐healing. As expected, the integration of multifunctional systems onto various substrates (e.g., gloves and masks) is further demonstrated via 3D printing and could achieve diverse sensory capabilities toward strain, pressure, and temperature, showing great prospects as smart flexible electronics.

Non-destructive Characterization of Skeletal Muscle Extracellular Matrix Morphology by Combining Optical Coherence Tomography (OCT) Imaging with Tissue Clearing.

Histology is an essential step to visualize and analyze the microstructure of any biological tissue; however, histological processing is often irreversible, and histological samples are unable to be imaged or tested further. In this work, a novel non-destructive protocol is proposed for morphological analysis of skeletal muscles, combining Optical Coherence Tomography (OCT) imaging with Tissue Clearing. Imaging combining OCT and Propylene Glycol (PG) as a tissue-clearing agent, was performed on rat tail and extensor digitorum longus (EDL) muscle. The results show that the extracellular matrix morphology of skeletal muscles, including muscular fibers and the whole microstructure architecture were clearly identified. PG improved OCT imaging as measured by image quality metric Contrast Per Pixel CPP (increases by 3.9%), Naturalness Image Quality Evaluator NIQE (decreases by 23%), and Volume of Interest VOI size (higher for CPP and lower for NIQE values). The tendon microstructure was observed with less precision, as collagen fibers could not be clearly detected. The reversibility of the optical effects of the PG on the immersed tissue (in a Phosphate-Buffered Saline solution) was studied comparing native and rehydrated OCT image acquisition from a single EDL sample. Optical properties and microstructure visibility (CPP and NIQE) have been recovered to 99% of the native sample values. Moreover, clearing process caused shrinkage of the tissue recovered to 86% of the original width. Future work will aim to employ the proposed experimental protocol to identify the local mechanical properties of biological tissues.

From dynamic to passive elastography, what technique used?

Elastography is a method that allows to quantify mechanical properties of biological tissues. In medical imaging, this last technique has been developed mainly in ultrasound (US) and in magnetic resonance imaging (MRI). Both imaging techniques have advantages and drawbacks depending on the organs and pathologies investigated. In this presentation we focused on two organs, where each technique has its advantage to investigate mechanical properties: brain and muscle. In brain, the preferred technique is MRI since US propagation is very complicated through the skull bone. Taking advantage of 3D acquisition, we investigated brain tumors with a new elastography approach: passive elastography. From the natural vibration, such as cardiac beating or respiration, we locally recover the natural shear wavelength that propagates giving access a stiffness mapping of the brain. Results are compared with US acquire during neurosurgery, showing a good accordance between both techniques. In muscles, US are used to recover not only stiffness but also others mechanical parameters such as viscoelastic anisotropy or shear non-linearity. Special US sequences were developed to quantify these two parameters in different physiological conditions that change in real-time. This presentation shows that depending on the investigated organ, physicists and physicians need to adapt the imaging strategy to better characterize tissues.

Effects of different preservation on the mechanical properties of cortical bone under quasi-static and dynamic compression.

Introduction: Mechanical properties of biological tissue are important for numerical simulations. Preservative treatments are necessary for disinfection and long-term storage when conducting biomechanical experimentation on materials. However, few studies have been focused on the effect of preservation on the mechanical properties of bone in a wide strain rate. The purpose of this study was to evaluate the influence of formalin and dehydration on the intrinsic mechanical properties of cortical bone from quasi-static to dynamic compression. Methods: Cube specimens were prepared from pig femur and divided into three groups (fresh, formalin, and dehydration). All samples underwent static and dynamic compression at a strain rate from 10-3s-1 to 103s-1. The ultimate stress, ultimate strain, elastic modulus, and strain-rate sensitivity exponent were calculated. A one-way ANOVA test was performed to determine if the preservation method showed significant differences in mechanical properties under at different strain rates. The morphology of the macroscopic and microscopic structure of bones was observed. Results: The results show that ultimate stress and ultimate strain increased as the strain rate increased, while the elastic modulus decreased. Formalin fixation and dehydration did not affect elastic modulus significantly whereas significantly increased the ultimate strain and ultimate stress. The strain-rate sensitivity exponent was the highest in the fresh group, followed by the formalin group and dehydration group. Different fracture mechanisms were observed on the fractured surface, with fresh and preserved bone tending to fracture along the oblique direction, and dried bone tending to fracture along the axial direction. Discussion: In conclusion, preservation with both formalin and dehydration showed an influence on mechanical properties. The influence of the preservation method on material properties should be fully considered in developing a numerical simulation model, especially for high strain rate simulation.

Light-driven biological actuators to probe the rheology of 3D microtissues

The mechanical properties of biological tissues are key to their physical integrity and function. Although external loading or biochemical treatments allow the estimation of these properties globally, it remains difficult to assess how such external stimuli compare with cell-generated contractions. Here we engineer microtissues composed of optogenetically-modified fibroblasts encapsulated within collagen. Using light to control the activity of RhoA, a major regulator of cellular contractility, we induce local contractions within microtissues, while monitoring microtissue stress and strain. We investigate the regulation of these local contractions and their spatio-temporal distribution. We demonstrate the potential of our technique for quantifying tissue elasticity and strain propagation, before examining the possibility of using light to create and map local anisotropies in mechanically heterogeneous microtissues. Altogether, our results open an avenue to guide the formation of tissues while non-destructively charting their rheology in real time, using their own constituting cells as internal actuators.

Atomic Force Microscopy Micro-Indentation Methods for Determining the Elastic Modulus of Murine Articular Cartilage.

The mechanical properties of biological tissues influence their function and can predict degenerative conditions before gross histological or physiological changes are detectable. This is especially true for structural tissues such as articular cartilage, which has a primarily mechanical function that declines after injury and in the early stages of osteoarthritis. While atomic force microscopy (AFM) has been used to test the elastic modulus of articular cartilage before, there is no agreement or consistency in methodologies reported. For murine articular cartilage, methods differ in two major ways: experimental parameter selection and sample preparation. Experimental parameters that affect AFM results include indentation force and cantilever stiffness; these are dependent on the tip, sample, and instrument used. The aim of this project was to optimize these experimental parameters to measure murine articular cartilage elastic modulus by AFM micro-indentation. We first investigated the effects of experimental parameters on a control material, polydimethylsiloxane gel (PDMS), which has an elastic modulus on the same order of magnitude as articular cartilage. Experimental parameters were narrowed on this control material, and then finalized on wildtype C57BL/6J murine articular cartilage samples that were prepared with a novel technique that allows for cryosectioning of epiphyseal segments of articular cartilage and long bones without decalcification. This technique facilitates precise localization of AFM measurements on the murine articular cartilage matrix and eliminates the need to separate cartilage from underlying bone tissues, which can be challenging in murine bones because of their small size. Together, the new sample preparation method and optimized experimental parameters provide a reliable standard operating procedure to measure microscale variations in the elastic modulus of murine articular cartilage.

3D Printing of Self-Assembling Nanofibrous Multidomain Peptide Hydrogels.

3D printing has become one of the primary fabrication strategies used in biomedical research. Recent efforts have focused on the 3D printing of hydrogels to create structures that better replicate the mechanical properties of biological tissues. These pose a unique challenge, as soft materials are difficult to pattern in three dimensions with high fidelity. Currently, a small number of biologically derived polymers that form hydrogels are frequently reused for 3D printing applications. Thus, there exists a need for novel hydrogels with desirable biological properties that can be used as 3D printable inks. In this work, the printability of multidomain peptides (MDPs), a class of self-assembling peptides that form a nanofibrous hydrogel at low concentrations, is established. MDPs with different charge functionalities are optimized as distinct inks and are used to create complex 3D structures, including multi-MDP prints. Additionally, printed MDP constructs are used to demonstrate charge-dependent differences in cellular behavior in vitro. This work presents the first time that self-assembling peptides have been used to print layered structures with overhangs and internal porosity. Overall, MDPs are a promising new class of 3D printable inks that are uniquely peptide-based and rely solely on supramolecular mechanisms for assembly.

A Flexible Magnetic Soft Continuum Robot for Manipulation and Measurement at Microscale

Magnetic soft continuum robots have received interest in diverse fields, because of their active steering and remote control capabilities. However, a more challenging task is the development of magnetic soft continuum robots for analyzing the mechanical properties of biological tissue during intravascular treatments. Here, we present a force-controlled soft continuum robot with a magnetic end-effector for measurement of biological mechanical properties. The magnetically driven system contains a set of Helmholtz coils and a permanent magnet. The Helmholtz coils produce an oscillating magnetic field for overcoming friction. The permanent magnet is responsible for steering and providing traction for forward motion. The force on the magnetic tip was calibrated with a soft rod with a known elasticity coefficient. Experimental results indicated that the magnetic soft continuum robot successfully achieved manipulation and stiffness measurement of biological embryos. This strategy for mechanical property analysis of biological tissue expands the opportunities for use of soft continuum robots and broadens the field of functionalization for continuum microrobots.

Formation and informative content of photoplethysmographic signal under the conditions of controllable external compression

The physical nature and quantitative characteristics of the photoplethysmographic (PPG) signal under conditions of external compression of the studied tissue area are theoretically investigated. Dependences of the constant and variable components of the PPG signal on the applied pressure are revealed, which have maxima at certain compression values. The physical model of the PPG signal formation process takes into account the optical and mechanical properties of biological tissues. The model is based on the consideration of the diffuse propagation of light in a two-component scattering medium (blood + surrounding tissues) and employs the Kubelka – Munk two-stream theory; in this case, the amount of blood in the tissues is determined by the conditions of mechanical equilibrium and the laws of tissue deformation.
 It is shown that the developed model correctly describes the observed qualitative features of the PPG signal, and the condition for the best agreement between theoretical and experimental curves allows real-time determination of the peripheral microcirculation quantitative characteristics (mean value and amplitude of the blood pressure fluctuations in precapillaries, erythrocyte concentration, average degree of blood oxygenation, the vessel walls elasticity, etc.). The developed methods for determining the blood circulation parameters can be used as the basis for inexpensive and effective express methods of research and medical diagnostics, which are especially useful in mass surveys or in environmental monitoring.

Investigation of the relationship between tensile viscoelasticity and unloaded ultrasound shear wave measurements in ex vivo tendon

Mechanical properties of biological tissues are of key importance for proper function and in situ methods for mechanical characterization are sought after in the context of both medical diagnosis as well as understanding of pathophysiological processes. Shear wave elastography (SWE) and accompanying physical modelling methods provide valid estimates of stiffness in quasi-linear viscoelastic, isotropic tissue but suffer from limitations in assessing non-linear viscoelastic or anisotropic material, such as tendon. Indeed, mathematical modelling predicts the longitudinal shear wave velocity to be unaffected by the tensile but rather the shear viscoelasticity. Here, we employ a heuristic experimental testing approach to the problem to assess the most important potential confounders, namely tendon mass density and diameter, and to investigate associations between tendon tensile viscoelasticity with shear wave descriptors. Small oscillatory testing of animal flexor tendons at two baseline stress levels over a large frequency range comprehensively characterized tensile viscoelastic behavior. A broad set of shear wave descriptors was retrieved on the unloaded tendon based on high frame-rate plane wave ultrasound after applying an acoustic deformation impulse. Tensile modulus and strain energy dissipation increased logarithmically and linearly, respectively, with the frequency of the applied strain. Shear wave descriptors were mostly unaffected by tendon diameter but were highly sensitive to tendon mass density. Shear wave group and phase velocity showed no association with tensile elasticity or strain rate-stiffening but did show an association with tensile strain energy dissipation.The longitudinal shear wave velocity may not characterize tensile elasticity but rather tensile viscous properties of transversely isotropic collagenous tissues.

Ensemble Kalman inversion for magnetic resonance elastography

Magnetic resonance elastography (MRE) is an MRI-based diagnostic method for measuring mechanical properties of biological tissues. MRE measurements are processed by an inversion algorithm to produce a map of the biomechanical properties. In this paper a new and powerful method (ensemble Kalman inversion with level sets (EKI)) of MRE inversion is proposed and tested. The method has critical advantages: material property variation at disease boundaries can be accurately identified, and uncertainty of the reconstructed material properties can be evaluated by consequence of the probabilistic nature of the method. EKI is tested in 2D and 3D experiments with synthetic MRE data of the human kidney. It is demonstrated that the proposed inversion method is accurate and fast.

Optical coherence elastography based on inverse compositional Gauss-Newton digital volume correlation with second-order shape function.

A digital volume correlation (DVC)-based optical coherence elastography (OCE) method with inverse compositional Gauss-Newton (IC-GN) algorithm and second-order shape function is presented in this study. The systematic measurement errors of displacement and strain from our OCE method were less than 0.2 voxel and 4 × 10-4, respectively. Second-order shape function could better match complex deformation and decrease speckle rigidity-induced error. Compared to conventional methods, our OCE method could track a larger strain range up to 0.095 and reduce relative error by 30-50%. This OCE method has the potential to become an effective tool in characterising mechanical properties of biological tissue.

Evaluating Tissue Mechanical Properties Using Quantitative Mueller Matrix Polarimetry and Neural Network

Evaluation of the mechanical properties of biological tissues has always been an important issue in the field of biomedicine. The traditional method for mechanical properties measurement is to perform in vitro tissue deformation experiments. With the fast development of optical and image processing techniques, more and more non-invasive and non-contact optical methods have been applied to the analysis of tissue mechanical features. In this study, we use Mueller matrix polarimetry to quantitatively obtain the mechanical properties of bovine tendon tissues. Firstly, to study the structural information and the changes in the optical characteristics of the tendon tissue under different stretching states, 3 × 3 Mueller matrix images of bovine tendon tissue samples are acquired by backscattering measurement setups based on a polarized camera. Then, we extract the frequency distribution histograms (FDHs) of the Mueller matrix elements to reveal the structural changes of the tendon tissue more clearly during the stretching process. Last, we calculate the Mueller matrix transformation (MMT) parameters, the total anisotropy t1 and the anisotropy direction α1 of the tendon tissue samples under different stretching processes to quantitatively characterize their structural changes under different mechanical states. The central moments of the MMT parameters can be used to distinguish the different stretching states of the tendon tissue. For better discrimination based on the MMT parameters, we design a multilayer neural network that takes the first-order moments of the MMT parameters as the input features. After training, a high-precision classification model of the stretching states of tendon tissue samples is finally obtained, and the total classification accuracy achieves 98%. The experimental results show that the Mueller matrix polarimetry can be a potential non-contact tool for tissue mechanical properties evaluation.

Acoustoelastic equations and Lamb waves dispersion characteristics of finitely deformed biological soft tissues with the growth-mechanical coupling

Acoustoelastic equations, especially the incremental constitutive law and the constitutive parameters associated with the growth increment, were presented for biological soft tissues coupling the growth and the mechanical effects. Both the initial growth deformation and the growth increment make biological tissues different from the general soft materials in acoustoelastic equations. Lamb waves dispersion in two finitely deformed biological soft layers was then investigated to explore the wave dispersion in biological tissues. The frequency dispersion equations were derived from which characteristics of wave dispersion of the first two modes were discussed. The influence of the predeformation and the external load on Lamb waves dispersion was quantitatively examined. It is found that some special dispersion phenomena such as the mode vanishment, frequency cut-off, frequency block, frequency pass and frequency gap may come up in Lamb waves dispersion. These dispersion features are dependent on the existence of phase velocity limits, the two-layer structure and the type of predeformation. Moreover, phase velocity limits were analytically deduced from the dispersion equations for the pre-stretched biological soft tissues. The elastic predeformation and the mechanical properties of biological tissues can then be determined from phase velocity limits, which provides a potential method to distinguish the growth deformation.