Tissue Viscosity Research Articles

Visualisation and quantification of subcutaneous injections of different volumes, viscosities and injection rates: An ex-vivo micro-CT study

The effects of subcutaneous (SC) injection parameters such as drug formulation volume, viscosity and injection rate on therapeutic performance and tolerability have not been established for any drug product. In this study four groups of SC injections were performed on fresh ex vivo minipig abdominal tissue samples, varying volume (0.5-1 mL), viscosity (1-11 cP) and rate (0.02-0.1 mL/s). Micro-CT provided high resolution (50 micron) imaging of the SC tissues before and after injection, enabling a detailed 3D visualisation and analysis of how both injection parameters and tissue microstructure influence spatial distribution of injectables. We found that volume was the only significant factor for spatial distribution of injectate within our design space, and there were no significant factors for tissue backpressure. Variability within test groups was typically greater than differences between group means. Accordingly, whilst the higher viscosity formulations consistently exhibited reduced spatial distribution, the sample size was not large enough to establish confidence in this result. Comparing our findings to clinical evidence, we conclude that injection site and depth are more likely to influence PK and bioavailability than volume, viscosity and rate within our experimental space.

Detecting viscosity changes in the limb ischemia-reperfusion in mice with a near-infrared fluorescence probe

BackgroundLimb ischemia-reperfusion is a common phenomenon in clinical surgery, which disrupts the balanced physiological response process and ultimately leads to changes in intracellular viscosity. Intracellular viscosity is an important microenvironmental parameter that affects the normal function of organisms, and its level is closely related to many diseases. In addition, oxidative stress in the lower limbs can impair body function, and changes in pressure can lead to changes in the viscosity of limb tissues. Therefore, it is necessary to develop effective tools to detect changes in intracellular viscosity and visualize the progression of hind limb ischemia-reperfusion injury. ResultsIn order to solve this problem, a near infrared viscometry sensitive fluorescence probe (PH-XQ) with long emission wavelength and stable luminescence performance was designed and synthesized by using oxanthracene derivatives and malononitrile. The fluorescence probe (PH-XQ) has excellent selectivity, high sensitivity, low toxicity, high biocompatibility and excellent detection performance. The fluorescence intensity of the PH-XQ probe at 667 nm is highly sensitive to the change of viscosity. With the increase of viscosity, the fluorescence intensity of probe PH-XQ was significantly enhanced, and the fluorescence enhancement ratio was about 14-fold. In addition, PH-XQ can detect not only changes in viscosity between normal cells and drug-induced inflammatory cells, but also changes in the viscosity of the hind limbs of normal mice and mice after ischemia reperfusion. SignificanceIn particular, we are the first to successfully detect changes in handlimb viscosity after ischemia-reperfusion in mice using a probe. This study clearly elucidates changes in viscosity during ischemia-reperfusion of mouse limbs, providing favorable support for the relationship between viscosity and related diseases, and further providing a potential tool for the diagnosis of viscosity-related diseases.

On the relationship between viscoelasticity and water diffusion in soft biological tissues

Magnetic resonance elastography (MRE) and diffusion-weighted imaging (DWI) are complementary imaging techniques that detect disease based on viscoelasticity and water mobility, respectively. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering the clinical translation of combined DWI-MRE markers.We used DWI-MRE to study 129 biomaterial samples including native and cross-linked collagen, glycosaminoglycans (GAGs) with different sulfation levels, and decellularized specimens of pancreas and liver, all with different proportions of solid tissue, or solid fractions. We developed a theoretical framework of the relationship between mechanical loss and tissue-water mobility based on two parameters, solid and fluid viscosity. These parameters revealed distinct DWI-MRE property clusters characterizing weak, moderate, and strong water-network interactions. Sparse networks interacting weakly with water, such as collagen or diluted decellularized tissue, resulted in marginal changes in water diffusion over increasing solid viscosity. In contrast, dense networks with larger solid fractions exhibited both free and hindered water diffusion depending on the polarity of the solid components. For example, polar and highly sulfated GAGs as well as native soft tissues hindered water diffusion despite relatively low solid viscosity.Our results suggest that two fundamental properties of tissue networks, solid fraction and network polarity, critically influence solid and fluid viscosity in biological tissues. Since clinical DWI and MRE are sensitive to these viscosity parameters, the framework we present here can be used to detect tissue remodeling and architectural changes in the setting of diagnostic imaging. Statement of significanceThe viscoelastic properties of biological tissues provide a wealth of information on the vital state of cells and host matrix. Combined measurement of viscoelasticity and water diffusion by medical imaging is sensitive to tissue microarchitecture. However, the relationship between viscoelasticity and water diffusion is still poorly understood, hindering full exploitation of these properties as a combined clinical biomarker. Therefore, we analyzed the parameter space accessible by diffusion-weighted imaging (DWI) and magnetic resonance elastography (MRE) and developed a theoretical framework for the relationship between water mobility and mechanical parameters in biomaterials. Our theory of solid material properties related to particle motion can be translated to clinical radiology using clinically established MRE and DWI.

Viscoelasticity quantification of cancerous tongue using intraoral optical coherence elastography: a preliminary study

Quantifying the biomechanical properties of the tongue is significant for early diagnosis of tongue carcinoma. Therefore, an intraoral optical coherence elastography system based on a miniature probe was proposed here to evaluate the viscoelasticity of in vivo tongue for the first time. Results of experiments with Sprague-Dawley rats indicate that considerable elasticity diversity occurred between cancerous and normal tongues, and the corresponding ratio of their Young’s modulus was evaluated to be 3.74. It is also found that, viscosity in diseased tissue is smaller than that in normal tissue. Additionally, healthy, transitional and cancerous regions in the cancerous tongue can be distinguished easily by calculating viscoelasticity characteristics. Based on this preliminary attempt, our method with advantages of noninvasive, high-resolution, high-sensitivity and real-time detection and convenient operation may have good potential to become a useful tool for tongue carcinoma assessment after further optimization.

Cavitation-induced pressure saturation: a mechanism governing bubble nucleation density in histotripsy

Objective. Histotripsy is a noninvasive focused ultrasound therapy that mechanically disintegrates tissue by acoustic cavitation clouds. In this study, we investigate a mechanism limiting the density of bubbles that can nucleate during a histotripsy pulse. In this mechanism, the pressure generated by the initial bubble expansion effectively negates the incident pressure in the vicinity of the bubble. From this effect, the immediately adjacent tissue is prevented from experiencing the transient tension to nucleate bubbles. Approach. A Keller–Miksis-type single-bubble model was employed to evaluate the dependency of this effect on ultrasound pressure amplitude and frequency, viscoelastic medium properties, bubble nucleus size, and transducer geometric focusing. This model was further combined with a spatial propagation model to predict the peak negative pressure field as a function of position from a cavitating bubble. Main results. The single-bubble model showed the peak negative pressure near the bubble surface is limited to the inertial cavitation threshold. The predicted bubble density increased with increasing frequency, tissue viscosity, and transducer focusing angle. The simulated results were consistent with the trends observed experimentally in prior studies, including changes in density with ultrasound frequency and transducer F-number. Significance. The efficacy of the therapy is dependent on several factors, including the density of bubbles nucleated within the cavitation cloud formed at the focus. These results provide insight into controlling the density of nucleated bubbles during histotripsy and the therapeutic efficacy.

Signal detrending in elastographic wave data with large motion artifacts through a 2D Whittaker smoother

A variety of advanced shear wave elastography techniques require the measurement of frequency-resolved phase velocity to properly characterize wave signals where factors such as tissue viscosity or guided wave effects are present. However, when applying these techniques in a dynamic environment where extrinsic motion cannot be limited, nonlinear and nonstationary trends can be expected in the motion signal used for phase velocity estimation. Because such extrinsic motion signals can contaminate a broad range of frequencies, they can produce significant errors in the phase velocity estimates. In this study, we propose a spatiotemporal detrending approach for elastography wave motion signals built from a 2D Whittaker smoother. This smoother has its origins in nonparametric regression and is well suited for fitting nonlinear curves of arbitrary shape. The resulting detrending filter was applied to Lamb wave signals from clinical ultrasound bladder vibrometry measurements. We found that the proposed detrending filter allowed for phase velocity estimates to be made in acquisitions that are otherwise be too corrupted by large motion. This works was supported by a grant from the NIH (DK131685)

Dissecting lysosomal viscosity fluctuations in live cells and liver tissues with an ingenious NIR fluorescent probe

Viscosity is a pivotal component in the cell microenvironment, while lysosomal viscosity fluctuation is associated with various human diseases, such as tumors and liver diseases. Herein, a near-infrared fluorescent probe (BIMM) based on merocyanine dyes was designed and synthesized for detecting lysosomal viscosity in live cells and liver tissue. The increase in viscosity restricts the free rotation of single bonds, leading to enhanced fluorescence intensity. BIMM exhibits high sensitivity and good selectivity, and is applicable to a wide pH range. BIMM has near-infrared emission, and the fluorescent intensity shows an excellent linear relationship with viscosity. Furthermore, BIMM possessing excellent lysosomes-targeting ability, and can monitor viscosity changes in live cells stimulated by dexamethasone, lipopolysaccharide (LPS), and nigericin, and differentiate between cancer cells and normal cells. Noticeably, BIMM can accurately analyze viscosity changes in various liver disease models with HepG2 cells, and is successfully utilized to visualize variations in viscosity on APAP-induced liver injury. All the results demonstrated that BIMM is a powerful wash-free tool to monitor the viscosity fluctuations in living systems.

Lipolytic agents for submental fat reduction: Review.

The review delves into the realm of reducing submental fat, presenting a comprehensive analysis of various lipolytic agents used in plastic surgery and dermatology. The introduction establishes the context by defining the key indicators of a youthful neck and emphasizing the significant influence of fat in the aging process, particularly in the submental area. The usage of aminophylline involves subcutaneous injections, facilitating fat breakdown by increasing cyclic adenosine monophosphate and inhibiting adenosine receptors. Hypotonic pharmacologic lipo-dissolution induces fat dissolution via injected compounds under pressure, while lipolytic lymphatic drainage employs hyaluronidase to reduce tissue viscosity, aiding fat circulation. Glycerophosphorylcholine containing choline alfoscerate claims to activate fat metabolism, whereas the utilization of phosphatidylcholine combined with deoxycholate lacks cosmetic approval due to safety concerns. Deoxycholic acid has FDA approval for submental fat reduction, yet its mechanisms remain incompletely understood. Understanding the complex anatomy and mechanisms of lipolytic agents is essential for safe and effective submental fat reduction, despite evolving practices and off-label utilization. Clinical guidelines and references support this discussion, offering insights for safer applications.

Role of the microtubule network in the passive anisotropic viscoelasticity of right ventricle with pulmonary hypertension progression

Cardiomyocytes are viscoelastic and contribute significantly to right ventricle (RV) mechanics. Microtubule, a cytoskeletal protein, has been shown to regulate cardiomyocyte viscoelasticity. Additionally, hypertrophied cardiomyocytes from failing myocardium have increased microtubules and cell stiffness. How the microtubules contribute to the tissue-level viscoelastic behavior in RV failure remains unknown. Our aim was to investigate the role of the microtubules in the passive anisotropic viscoelasticity of the RV free wall (RVFW) during pulmonary hypertension (PH) progression. Equibiaxial stress relaxation tests were conducted in the RVFW from healthy and PH rats under early (6%) and end (15%) diastolic strains, and at sub- (1Hz) and physiological (5Hz) stretch-rates. The RVFW viscoelasticity was also measured before and after the depolymerization of microtubules at 5Hz. In intact tissues, PH increased RV viscosity and elasticity at both stretch rates and strain levels, and the increase was stronger in the circumferential than longitudinal direction. At 6% of strain, the removal of microtubules reduced elasticity, viscosity, and the ratio of viscosity to elasticity in both directions and for both healthy and diseased RVs. However, at 15% of strain, the effect of microtubules was different between groups – both viscosity and elasticity were reduced in healthy RVs, but in the diseased RVs only the circumferential viscosity and the ratio of viscosity to elasticity were reduced. These data suggest that, at a large strain with collagen recruitment, microtubules play more significant roles in healthy RV tissue elasticity and diseased RV tissue viscosity. Our findings suggest cardiomyocyte cytoskeletons are critical to RV passive viscoelasticity under pressure overload. Statement of SignificanceThis study investigated the impact of microtubules on the passive anisotropic viscoelasticity of the right ventricular (RV) free wall at healthy and pressure-overloaded states. We originally found that the microtubules contribute significantly to healthy and diseased RV viscoelasticity in both (longitudinal and circumferential) directions at early diastolic strains. At end diastolic strains (with the engagement of collagen fibers), microtubules contribute more to the tissue elasticity of healthy RVs and tissue viscosity of diseased RVs. Our findings reveal the critical role of microtubules in the anisotropic viscoelasticity of the RV tissue, and the altered contribution from healthy to diseased state suggests that therapies targeting microtubules may have potentials for RV failure patients.

Free volume theory explains the unusual behavior of viscosity in a non-confluent tissue during morphogenesis.

A recent experiment on zebrafish blastoderm morphogenesis showed that the viscosity (η) of a non-confluent embryonic tissue grows sharply until a critical cell packing fraction (ϕS). The increase in η up to ϕS is similar to the behavior observed in several glass-forming materials, which suggests that the cell dynamics is sluggish or glass-like. Surprisingly, η is a constant above ϕS. To determine the mechanism of this unusual dependence of η on ϕ, we performed extensive simulations using an agent-based model of a dense non-confluent two-dimensional tissue. We show that polydispersity in the cell size, and the propensity of the cells to deform, results in the saturation of the available free area per cell beyond a critical packing fraction. Saturation in the free space not only explains the viscosity plateau above ϕS but also provides a relationship between equilibrium geometrical packing to the dramatic increase in the relaxation dynamics.

Free volume theory explains the unusual behavior of viscosity in a non-confluent tissue during morphogenesis

A recent experiment on zebrafish blastoderm morphogenesis showed that the viscosity (η) of a non-confluent embryonic tissue grows sharply until a critical cell packing fraction (ϕS). The increase in η up to ϕS is similar to the behavior observed in several glass-forming materials, which suggests that the cell dynamics is sluggish or glass-like. Surprisingly, η is a constant above ϕS. To determine the mechanism of this unusual dependence of η on ϕ, we performed extensive simulations using an agent-based model of a dense non-confluent two-dimensional tissue. We show that polydispersity in the cell size, and the propensity of the cells to deform, results in the saturation of the available free area per cell beyond a critical packing fraction. Saturation in the free space not only explains the viscosity plateau above ϕS but also provides a relationship between equilibrium geometrical packing to the dramatic increase in the relaxation dynamics.

Comparison of breast skin resistance against protease digestion between young and elderly individual based on attenuation-of-sound values

The skin is a gateway through which bacteria can establish infection. Evidence has shown that the components of the skin change with age, with elderly individuals exhibiting fewer epidermal rete ridges, dermal collagen, and elastic fibers. In the present study, paraffin sections of breast skin were digested with proteolytic enzymes of bacterial origin, after which skin fragility was assessed by observing attenuation-of-sound (AOS) images over time. Accordingly, studies have shown that AOS values are correlated with tissue viscosity and can serve as a numerical indicator of protein density. Breast skin sections were digested using two types of collagenases and actinase E, a broader peptidase. Notably, our results showed that skin sections from young and elderly patients showed resistance to digestion with the two types of collagenases. However, the epidermis and dermis were successfully digested using actinase over time. All layers of the epidermis, except for the keratin layer, were digested, whereas collagen and elastic fibers in the dermis were broken down, along with a decrease in AOS levels. Although actinase affected both young and aged skin, elderly skin showed much lower AOS values given its naturally reduced thickness and density due to aging. This finding suggests that older patients experience greater damage from proteolytic enzymes. AOS is an excellent approach to visualizing the process of protease digestion over time and statistically comparing proteolytic damage.The skin is a gateway through which bacteria can establish infection. Evidence has shown that the components of the skin change with age, with elderly individuals exhibiting fewer epidermal rete ridges, dermal collagen, and elastic fibers. In the present study, paraffin sections of breast skin were digested with proteolytic enzymes of bacterial origin, after which skin fragility was assessed by observing attenuation-of-sound (AOS) images over time. Accordingly, studies have shown that AOS values are correlated with tissue viscosity and can serve as a numerical indicator of protein density. Breast skin sections were digested using two types of collagenases and actinase E, a broader peptidase. Notably, our results showed that skin sections from young and elderly patients showed resistance to digestion with the two types of collagenases. However, the epidermis and dermis were successfully digested using actinase over time. All layers of the epidermis, except for the keratin layer, were digested, whereas collagen and elastic fibers in the dermis were broken down, along with a decrease in AOS levels. Although actinase affected both young and aged skin, elderly skin showed much lower AOS values given its naturally reduced thickness and density due to aging. This finding suggests that older patients experience greater damage from proteolytic enzymes. AOS is an excellent approach to visualizing the process of protease digestion over time and statistically comparing proteolytic damage.

Keratoconus: Ocular surface considerations, from bench to bedside

Aims/Purpose: This comprehensive systematic narrative study is aimed to describe the close interactions between the ocular surface and keratoconus with its vast spectrum of diagnostic and treatment techniques, both basic and clinical.Methods: This investigation searched PubMed, Scopus, Cochrane, Embase, and Web of Science for relevant papers published up to January 2023. The systematic review used MeSH and non‐MeSH terms. Unrestricted language and publishing schedule. After a comprehensive search, all of the search results were imported into Endnote software after a thorough search. Duplicate and less relevant citations have been eliminated in Endnote. In addition to the databases indicated, we searched Google Scholar for “Ocular surface” AND ((keratoconus) OR (“pellucid marginal degeneration”) OR (“corneal ectasia”) OR (“iatrogenic ectasia”)).Results: Treating dry eye, MGD, and blepharitis may slow KC progression and relieve symptoms. Eye rubbing and mechanical injury could spread bacteria to the eyelids, causing blepharitis. Tarsorrhaphy is the most powerful manoeuvre to help heal epithelial defects, especially in moderate and severe forms of DED. Use high‐quality eyedrops, especially preservative‐free ones, to increase tissue viscosity on the ocular surface and protect tear film to reduce epithelium injury before and after surgery. Finally, Vitamins, minerals, metal ions, and antioxidants may prevent dry eye and KC. In addition, improper air quality, wind, pollution, low humidity, watching TV, reading, and surgical procedures can cause dry eye illness, increase MMP‐9 and IL‐6 and decrease EGF during exacerbation.Conclusions: This is the first systematic narrative review to explore the mutual interaction between the ocular surface and KC and the wide spectrum of diagnostic and therapeutic options. Dry eye and tear film instability have been documented as a non‐ectatic differential diagnosis for KC and ectatic disorders. Nonetheless, KC and DED are both common topics. Future research should look into the effect of pre‐treating ocular surface health on postoperative outcome and the efficacy of the therapeutic strategy in reversing KC ocular surface changes.

The Effect of Mechanical Stress on Hyaluronan Fragments' Inflammatory Cascade: Clinical Implications.

It is a common experience, reported by patients who have undergone manual therapy that uses deep friction, to perceive soreness in treatment areas; however, it is still not clear what causes it and if it is therapeutically useful or a simple side effect. The purpose of this narrative review is to determine whether manual and physical therapies can catalyze an inflammatory process driven by HA fragments. The literature supports the hypothesis that mechanical stress can depolymerize into small pieces at low molecular weight and have a high inflammatory capacity. Many of these pieces are then further degraded into small oligosaccharides. Recently, it has been demonstrated that oligosaccharides are able to stop this inflammatory process. These data support the hypothesis that manual therapy that uses deep friction could metabolize self-aggregated HA chains responsible for increasing loose connective tissue viscosity, catalyzing a local HA fragment cascade that will generate soreness but, at the same time, facilitate the reconstitution of the physiological loose connective tissue properties. This information can help to explain the meaning of the inflammatory process as well as the requirement for it for the long-lasting resolution of these alterations.

Significance of Shear Wave Dispersion Slope Values Before Versus After Biliary Drainage in Patients With Obstructive Jaundice: A Single-Center Prospective Observational Cohort Study.

The shear wave dispersion (SWD) slope has become available in the clinical practice and is related to tissue viscosity. However, clinical evaluation using SWD was not yet performed for obstructive jaundice. We aimed to evaluate the change of SWD values between before and after biliary drainage in patients with obstructive jaundice. This prospective observational cohort study evaluated 20 patients with obstructive jaundice who underwent biliary drainage. The SWD and liver elasticity values were measured before versus after biliary drainage, comparing between days -5 and 0 (day 0), days 1 and 3 (day 2), and days 6 and 8 (day 7). The mean ± SD values of SWD measured at day 0, day 2, and day 7 were 15.3 ± 2.7, 14.2 ± 3.3, and 13.3 ± 2.4 m/s/kHz, respectively. Dispersion slope values were decreased significantly from day 0 to day 2, from day 2 to day 7, and from day 0 to day 7 (P < 0.05). Liver elasticity levels and serum hepatobiliary enzymes were additionally decreased significantly over time after biliary drainage. The correlations between SWD and liver elasticity values were strong (r = 0.91, P < 0.01). In conclusion, the SWD values decreased significantly over time after biliary drainage concomitant with liver elasticity.

"Dual-Key-and-Lock" NIR-II NSCyanines Enable High-Contrast Activatable Phototheranostics in Extrahepatic Diseases.

Conventional cyanine dyes with a symmetric structure are "always-on", which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR-II non-symmetric cyanine (NSCyanine) dyes by harnessing a non-symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a "dual-key-and-lock" strategy. These NSCyanine dyes with a low pKa (<4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target-to-liver ratios up to 19.5/1. Notably, high-contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis-imaging, acute gastritis-imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.

“Dual‐Key‐and‐Lock” NIR‐II NSCyanines Enable High‐Contrast Activatable Phototheranostics in Extrahepatic Diseases

AbstractConventional cyanine dyes with a symmetric structure are “always‐on”, which can easily accumulate in the liver and display high liver background fluorescence, inevitably interfering the accurate diagnosis and therapy in extrahepatic diseases. We herein report a platform of NIR‐II non‐symmetric cyanine (NSCyanine) dyes by harnessing a non‐symmetric strategy, which are extremely sensitive to pH/viscosity and can be activated via a “dual‐key‐and‐lock” strategy. These NSCyanine dyes with a low pKa (&lt;4.0) only show weak fluorescence at lysosome pH (key1), however, the fluorescence can be completely switched on and significantly enhanced by intracellular viscosity (key2) in disease tissues, exhibiting high target‐to‐liver ratios up to 19.5/1. Notably, high‐contrast phototheranostics in extrahepatic diseases are achieved, including intestinal metastasis‐imaging, acute gastritis‐imaging, bacteria infected wound healing, and tumor ablation via targeted combined photothermal therapy and chemotherapy.

Clinical applications of shear wave dispersion imaging for breast lesions: a pictorial essay.

Shear wave dispersion (SWD) imaging is a newly developed ultrasound technology designed to evaluate the dispersion slope of shear waves, which is related to tissue viscosity. This advanced imaging technique holds potential for distinguishing malignant lesions from benign lesions and normal breast tissue. The SWD slope, as determined by shear wave elastography (SWE), could offer crucial insights into the characterization of breast lesions. This article presents SWE and SWD images of both malignant and benign breast lesions, in addition to normal breast tissue.

Abstract P2038: Role Of The Microtubule Network In Right Ventricle Passive Viscoelasticity With Pulmonary Hypertension Development

Microtubule (MT) polymerization is a key contributor to myocardium viscoelasticity, which describes elastic and viscous resistance under stress and impacts the contractile function. MT de- or hyper-polymerization has been shown to decrease or increase healthy cardiomyocyte viscoelasticity, but the responses of hypertrophied cells to these modifications are unknown. Moreover, the ventricular free wall is a complex tissue composed of myofibers, collagen and vasculature, and it exhibits anisotropic mechanical behavior. To fully understand the role of MT in the tissue-level anisotropic viscoelasticity of myocardium, we investigated the responses of healthy and failing rat right ventricles (RV) to alterations in MT network. All procedures were approved by Colorado State University IACUC. Adult male rats were treated with monocrotaline to induce pulmonary hypertension and RV failure. After euthanasia, the RV free wall underwent equibiaxial stress relaxation in intact state (baseline) and under the treatment of colchicine and deuterium oxide (D 2 O) to remove and enhance MT network, respectively. Viscoelastic parameters were quantified as previously described. As expected, the diseased RV had greater viscoelasticity than the healthy RV. Depolymerization of MT in healthy RVs reduced tissue viscosity (relaxation rate) and elasticity (relaxation modulus), and the changes were more significant in the longitudinal (outflow tract) direction. MT hyper-polymerization increased tissue elasticity and decreased viscosity, with the changes stronger in the circumferential direction. In diseased RVs, MT depolymerization reduced viscosity in both directions and elasticity only in the circumferential direction. However, MT hyper-polymerization unexpectedly decreased tissue elasticity and tended to decrease viscosity, as well. The altered MT polymerization dynamics after D 2 O treatment in a fibrotic environment may explain these heterogeneous responses This is the first report of distinct impacts of MT polymerization on the tissue mechanical behavior between the hypertrophied and healthy myocardium. The exact molecular mechanisms involving MT polymerization dynamics and the interactions with collagen await further investigation.

New Metric to Evaluate Cardiac Anisotropic Mechanics by Directional High-Frequency Ultrasound-Based Transverse Wave Elastography

The evaluation of cardiac anisotropic mechanics is important in the diagnosis of heart disease. However, other representative ultrasound imaging-based metrics, which are capable of quantitatively evaluating anisotropic cardiac mechanics, are insufficient for accurately diagnosing heart disease due to the influence of viscosity and geometry of cardiac tissues. In this study, we propose a new ultrasound imaging-based metric, maximum cosine similarity, for quantifying anisotropic mechanics of cardiac tissues by evaluating the periodicity of the transverse wave speeds depending on the measurement directions using ultrasound imaging. We developed a high-frequency ultrasound-based directional transverse wave imaging system to measure the transverse wave speed in multiple directions. The ultrasound imaging-based metric was validated by performing experiments on forty rats randomly assigned to four groups; three doxorubicin treatment groups received 10 mg/kg, 15 mg/kg, or 20 mg/kg doxorubicin, while the control group received 0.2 ml/kg saline. In each heart sample, the developed ultrasound imaging system allowed measuring transverse wave speeds in multiple directions, and the new metric was then calculated from 3D ultrasound transverse wave images to evaluate the degree of anisotropic mechanics of the heart sample. The results of the metric were compared with histopathological changes for validation. A decrease in the maximum cosine similarity value was observed in the doxorubicin treatment groups, with the degree of decrease depending on the dose. These results are consistent with the histopathological features, suggesting that our ultrasound imaging-based metric can quantify the anisotropic mechanics of cardiac tissues and potentially be used for the early diagnosis of heart disease.