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 SIGNIFICANCE: The 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.

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 SIGNIFICANCE: Xenograft 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.

Solid fraction determines stiffness and viscosity in decellularized pancreatic tissues.

The role of extracellular matrix (ECM) composition and turnover in mechano-signaling and the metamorphic fate of cells seeded into decellularized tissue can be elucidated by recent developments in non-invasive imaging and biotechnological analysis methods. Because these methods allow accurate quantification of the composition and structural integrity of the ECM, they can be critical in establishing standardized decellularization protocols. This study proposes quantification of the solid fraction, the single-component fraction and the viscoelasticity of decellularized pancreatic tissues using compact multifrequency magnetic resonance elastography (MRE) to assess the efficiency and quality of decellularization protocols. MRE of native and decellularized pancreatic tissues showed that viscoelasticity parameters depend according to a power law on the solid fraction of the decellularized matrix. The parameters can thus be used as highly sensitive markers of the mechanical integrity of soft tissues. Compact MRE allows consistent and noninvasive quantification of the viscoelastic properties of decellularized tissue. Such a method is urgently needed for the standardized monitoring of decellularization processes, evaluation of mechanical ECM properties, and quantification of the integrity of solid structural elements remaining in the decellularized tissue matrix.

In Vivo Quantification of Water Diffusion, Stiffness, and Tissue Fluidity in Benign Prostatic Hyperplasia and Prostate Cancer.

OBJECTIVES: Water diffusion, tissue stiffness, and viscosity characterize the biophysical behavior of tumors. However, little is known about how these parameters correlate in prostate cancer (PCa). Therefore, we paired tomoelastography of the prostate with diffusion-sensitive magnetic resonance imaging for the quantitative mapping of biophysical parameters in benign prostatic hyperplasia (BPH) and PCa. MATERIALS AND METHODS: Multifrequency magnetic resonance imaging elastography with tomoelastography processing was performed at 60, 70, and 80 Hz using externally placed compressed-air drivers. Shear-wave speed (SWS) and loss angle (φ) were analyzed as surrogate markers of stiffness and viscosity-related fluidity in the normal peripheral zone (PZ), hyperplastic transition zone (TZ), which is consistent with BPH, and PCa lesions. The SWS and φ were correlated with the normalized apparent diffusion coefficient (nADC). RESULTS: Thirty-nine men (median age/range, 67/49-88 years), 25 with BPH and 14 with biopsy-proven PCa, were prospectively enrolled in this institutional review board-approved study. The SWS in PCa (3.1 ± 0.6 m/s) was higher than in TZ (2.8 ± 0.3 m/s, P = 0.004) or tended to be higher than in PZ (2.8 ± 0.4 m/s, P = 0.025). Similarly, φ in PCa (1.1 ± 0.1 rad) was higher than in TZ (0.9 ± 0.2 m/s, P < 0.001) and PZ (0.9 ± 0.1 rad, P < 0.001), whereas nADC in PCa (1.3 ± 0.3) was lower than in TZ (2.2 ± 0.4, P < 0.001) and PZ (3.1 ± 0.7, P < 0.001). Pooled nADC was inversely correlated with φ (R = -0.6, P < 0.001) but not with SWS. TZ and PZ only differed in nADC (P < 0.001) but not in viscoelastic properties. Diagnostic differentiation of PCa from normal prostate tissues, as assessed by area under the curve greater than 0.9, was feasible using nADC and φ but not SWS. CONCLUSIONS: Tomoelastography provides quantitative maps of tissue mechanical parameters of the prostate. Prostate cancer is characterized by stiff tissue properties and reduced water diffusion, whereas, at the same time, tissue fluidity is increased, suggesting greater mechanical friction inside the lesion. This biophysical signature correlates with known histopathological features including increased cell density and fibrous protein accumulation.