Effects of enzyme-based removal of collagen and elastin constituents on the biaxial mechanical responses of porcine atrioventricular heart valve anterior leaflets.

http://manuscript.elsevier.com/S1742706121006218/pdf/S1742706121006218.pdf

Biaxial mechanics of thermally denaturing skin - Part 1: Experiments

Biaxial mechanics of thermally denaturing skin - Part 1: Experiments.

The mechanics of collageneous soft tissues, such as skin, are sensitive to heat. Thus, quantifying and modeling thermo-mechanical coupling of skin is critical to our understanding of skin9s physiology, pathophysiology, as well as its treatment. However, key gaps persist in our knowledge about skin9s coupled thermo-mechanics. Among them, we haven9t quantified the role of skin9s microstructural organization in its response to superphysiological loading. To fill this gap, we conducted a comprehensive set of experiments in which we combined biaxial mechanical testing with histology and two-photon imaging under liquid heat treatment. Among other observations, we found that unconstrained skin, when exposed to high temperatures, shrinks anisotropically with the principle direction of shrinkage being aligned with collagen9s principle orientation. Additionally, we found that when skin is isometrically constrained, it produces significant forces during denaturing that are also anisotropic. Finally, we found that denaturation significantly alters the mechanical behavior of skin. For short exposure times, this alteration is reflected in a reduction of stiffness at high strains. At long exposure times, the tissue softened to a point where it became untestable. We supplemented our findings with confirmation of collagen denaturation in skin via loss of birefringence and second harmonic generation. Finally, we captured all time-, temperature-, and direction-dependent experimental findings in a hypothetical model. Thus, this work fills a fundamental gap in our current understanding of skin thermo-mechanics and will support future developments in thermal injury prevention, thermal injury management, and thermal therapeutics of skin.

https://www.biorxiv.org/content/biorxiv/early/2021/06/07/2021.06.04.447116.full.pdf

The biaxial mechanics of thermally denaturing skin - Part I: Experiments

Understanding the response of skin to superphysiological temperatures is critical to the diagnosis and prognosis of thermal injuries, and to the development of temperature-based medical therapeutics. Unfortunately, this understanding has been hindered by our incomplete knowledge about the nonlinear coupling between skin temperature and its mechanics. In Part I of this study we experimentally demonstrated a complex interdependence of time, temperature, direction, and load in skin’s response to superphysiological temperatures. In Part II of our study, we test two different models of skin’s thermomechanics to explain our observations. In both models we assume that skin’s response to superphysiological temperatures is governed by the denaturation of its highly collageneous microstructure. Thus, we capture skin’s native mechanics via a microstructurally-motivated strain energy function which includes probability distributions for collagen fiber orientation and waviness. In the first model, we capture skin’s response to superphysiological temperatures as a transition between two states that link the kinetics of collagen fiber denaturation to fiber coiling and to the transformation of each fiber’s constitutive behavior from purely elastic to viscoelastic. In the second model, we capture skin’s response to superphysiological temperatures instead via three states in which a sequence of two reactions link the kinetics of collagen fiber denaturation to fiber coiling, followed by a state of fiber damage. Given the success of both models in qualitatively and quantitatively capturing our observations, we expect that our work will provide guidance for future experiments that could probe each model’s assumptions toward a better understanding of skin’s coupled thermo-mechanics and that our work will be used to guide the engineering design of heat treatment therapies. Statement of significance Quantifying and modeling skin thermo-mechanics is critical to our understanding of skin physiology, pathophysiology, as well as heat-based treatments. This work addresses a lack of theoretical and computational models of the coupled thermo-mechanics of skin. Our model accounts for skin microstructure through modeling the probability of fiber orientation and fiber stress-free states. Denaturing induces changes in the stress-free configuration of collagen, as well as changes in fiber stiffness and viscoelastic properties. We propose two competing models that fit all of our experimental observations. These models will enable future developments of thermal-therapeutics, prevention and management of skin thermal injuries, and set a foundation for improved mechanistic models of skin thermo-mechanics. © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Biaxial mechanics of thermally denaturing skin-Part 2: Modeling

Myxomatous mitral valve degeneration is a common cause of mitral regurgitation and is often associated with mitral valve prolapse. With no known targets to pharmacologically treat mitral valve prolapse, surgery is often the only treatment option. Recently, radiofrequency ablation has been proposed as a percutaneous alternative to surgical resection for the reduction of mitral valve leaflet area. Using an in vitro model of porcine mitral valve anterior leaflet enlargement following enzymatic digestion, we sought to investigate mechanisms by which radiofrequency ablation alters the geometry, microstructural organization, and mechanical properties of healthy and digested leaflets. Paired measurements before and after radiofrequency ablation revealed the impact of ablation on leaflet properties. Multiphoton imaging was used to characterize changes in the structure and organization of the valvular extracellular matrix; planar biaxial mechanical testing and constitutive modeling were used to estimate mechanical properties of healthy and digested leaflets. Enzymatic digestion increased leaflet area and thickness to a similar extent as clinical mitral valve disease. Radiofrequency ablation altered extracellular matrix alignment and reduced the area of digested leaflets to that of control. Additionally, enzymatic digestion resulted in fiber alignment and reorientation toward the radial direction, causing increased forces during ablation and a structural stiffening which was improved by radiofrequency ablation. Radiofrequency ablation induces radial extracellular matrix alignment and effectively reduces the area of enlarged mitral valve leaflets. Hence, this technique may be a therapeutic approach for myxomatous mitral valve disease and is thus an avenue for future study.

Radiofrequency Ablation Alters the Microstructural Organization of Healthy and Enzymatically Digested Porcine Mitral Valves

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Radiofrequency Ablation Alters the Microstructural Organization of Healthy and Enzymatically Digested Porcine Mitral Valves