Fibrin is the main component of blood clots. The mechanical properties of fibrin are therefore of critical importance in successful hemostasis. One of the divalent cations released by platelets during hemostasis is Zn2+; however, its effect on the network structure of fibrin gels and on the resultant mechanical properties remains poorly understood. Here, by combining mechanical measurements with three-dimensional confocal microscopy imaging, we show that Zn2+can tune the fibrin network structure and alter its mechanical properties. In the presence of Zn2+, fibrin protofibrils form large bundles that cause a coarsening of the fibrin network due to an increase in fiber diameter and reduction of the total fiber length. We further show that the protofibrils in these bundles are loosely coupled to one another, which results in a decrease of the elastic modulus with increasing Zn2+concentrations. We explore the elastic properties of these networks at both low and high stress: At low stress, the elasticity originates from pulling the thermal slack out of the network, and this is consistent with the thermal bending of the fibers. By contrast, at high stress, the elasticity exhibits a common master curve consistent with the stretching of individual protofibrils. These results show that the mechanics of a fibrin network are closely correlated with its microscopic structure and inform our understanding of the structure and physical mechanisms leading to defective or excessive clot stiffness.
Laser coagulation and hemostasis of large diameter blood vessels: effect of shear stress and flow velocity
Abstract Photocoagulation of blood vessels offers unambiguous advantages to current radiofrequency approaches considering the high specificity of blood absorption at available laser wavelengths (e.g., 532 nm and 1.064 µm). Successful treatment of pediatric vascular lesions, such as port-wine stains requiring microvascular hemostasis, has been documented. Although laser treatments have been successful in smaller diameter blood vessels, photocoagulation of larger sized vessels is less effective. The hypothesis for this study is that a primary limitation in laser coagulation of large diameter blood vessels (500–1000 µm) originates from shear stress gradients associated with higher flow velocities along with temperature-dependent viscosity changes. Laser (1.07 µm) coagulation of blood vessels was tested in the chicken chorio-allantoic membrane (CAM). A finite element model is developed that includes hypothetical limitations in laser coagulation during irradiation. A protocol to specify laser dosimetry is derived from OCT imaging and angiography observations as well as finite element model results. Laser dosimetry is applied in the CAM model to test the experimental hypothesis that blood shear stress and flow velocity are important parameters for laser coagulation and hemostasis of large diameter blood vessels (500–1000 µm). Our experimental results suggest that shear stress and flow velocity are fundamental in the coagulation of large diameter blood vessels (500–1000 µm). Laser dosimetry is proposed and demonstrated for successful coagulation and hemostasis of large diameter CAM blood vessels.
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- Award ID(s):
- 1757885
- NSF-PAR ID:
- 10347918
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 12
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Introduction: The mechanical stability of an atheroma fibrous cap (FC) is a crucial factor for the risk of heart attack or stroke in asymptomatic vulnerable plaques. Common determinants of plaque vulnerability are the cap thickness and the presence of micro-calcifications (µCalcs). Higher local stresses have been linked to thin caps(<65µm) and, more recently, our lab demonstrated how µCalcs can potentially initiate cap rupture [1-3]. When combined, these two factors can compromise to a greater extent the stability of the plaque. On this basis, we quantitatively analyzed both individual and combined effects of key determinants of plaque rupture using a tissue damage model on idealized atherosclerotic arteries. Our results were then tested against a diseased human coronary sample. Methods: We performed 28 finite element simulations on three-dimensional idealized atherosclerotic arteries and a human coronary sample. The idealized models present 10% lumen narrowing and 1.25 remodeling index (RI)(Fig.1A). The FC thickness values that we considered were of 50, 100, 150 and 200µm. The human coronary presents a RI=1.31, with 31% lumen occlusion and a 140µm-thick cap(Fig.1B). The human model is based on 6.7μm high-resolution microcomputed tomography (HR-μCT) images. The µCalc has a diameter of 15µm and each artery was expanded up to a systolic pressure of 120mmHg. Layer-specific material properties were de-fined by the HGO model coupled with the hyperelastic failure description proposed by Volokh et al. [4] to repli-cate the rupture of the FC. We considered a max. princi-pal stress for rupture of 545kPa[5]. The lipid core and the µCalc were considered as elastic materials (Ecore = 5kPa, νcore = 0.49; EµCalc= 18,000 kPa, νµCalc=0.3). To obtain a detailed analysis of the cap stresses and rupture progres-sion, a sub-modeling approach was implemented using ABAQUS (Dassault Systemes, v.2019) (Fig. 1). Results: We investigated the quantitative effect of cap thickness and µCalc by simulating tissue failure and de-riving a vulnerability index (VI) for each risk factor. The VI coefficient was defined as the peak cap stress (PCS) normalized by the threshold stress for rupture (545kPa). The relationship between the risk factors and VI was de-termined by deriving the Pearson’s correlation coefficient (PCC) followed by one-tailed t-test (SPSS, IBM, v.25). The null hypothesis was rejected if p<0.05. The presence of the µCalc is the factor that manifests the greater impact on cap stability, leading to at least a 2.5-fold increase in VI and tissue rupture regardless of cap thickness (Fig.2A,B). One µCalc in the cap is the first predictor of vulnerability, with PCCµCalc=0.59 and pµCalc=0.001. Our results also confirm the substantial in-fluence of cap thickness, with an exponential increase in stresses as the cap becomes thinner. The 50µm cap is the only phenotype that ruptures without µCalc (Fig2A). The human sample exhibits PCS levels that are close to the idealized case with 150µm cap and it doesn’t rupture in the absence of the µCalc (PCShuman=233kPa, PCSideal= 252kPa). Conversely, the phenotypes with the µCalc showed an increase in VI of about 2.5 and reached rup-ture under the same blood pressure regime. Conclusions: Our results clearly show the multifactorial nature of plaque vulnerability and the significance of micro-calcifications on the cap mechanical stability. The presence of a μCalc strongly amplifies the stresses in the surrounding tissue, and it can provoke tissue failure even in thick caps that would otherwise be classified as stable. Clearly, plaque phenotypes with a thin cap and μCalcs in the tissue represent the most vulnerable condition. Finally, these observations are well validated by the case of the human atherosclerotic segment, which closely compares to its corresponding idealized model. The novel imple-mentation of the tissue damage description and the defi-nition of a vulnerability index allow one to quantitatively analyze the individual and combined contribution of key determinants of cap rupture, which precedes the for-mation of a thrombus and myocardial infarction.more » « less
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Abstract Spiral/helical forms of blood flow have been observed in large arteries of the cardiovascular system, but their benefits remain underappreciated. Spiral flow has been postulated to improve near‐wall washout, promoting anti‐atherothrombotic conditions. This research aims to study the washout characteristics of spiral flow, specifically, its ability to increase velocity and wall shear stress (WSS) in atherothrombotic‐prone regions. Using 1.2 cm diameter angled test‐conduits (45°, 90°, 135°) with known recirculation/stasis regions at the bend corners, spiral flow washout potential was evaluated in terms of low velocity and low WSS. Two sub‐studies were conducted: the first utilized a spiral flow‐inducing device to enable qualitative analysis of washout‐potential in both computational fluid dynamic (CFD) simulations and benchtop ultrasound visualization; the second used CFD to study the impact of several induced helical wavelengths on the conduit‐dependent recirculation/stasis zones. Physical models of the angled conduits and spiral flow‐inducer were 3D‐printed to facilitate ultrasound visualization. Compared to straight flow, spiral flow generated by the flow‐inducer significantly cleared the recirculation/stasis zones at the corners of the angled conduits. CFD simulations demonstrated that past a geometry‐dependent threshold, increased helical content improved washout, denoted by decreased regions of low velocity and low WSS. Overall, spiral flow markedly improved washout in difficult to reach areas in the angled conduits. This has several important clinical implications: spiral flow shows great promise in reducing blood‐transport‐related complications and can be used to enhance the performance of future medical devices (eg grafts, mechanical circulatory support devices, hemodialysis access ports).
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We employ numerically implicit subgrid-scale modeling provided by the well-known streamlined upwind/Petrov–Galerkin stabilization for the finite element discretization of advection–diffusion problems in a Large Eddy Simulation (LES) approach. Whereas its original purpose was to provide sufficient algorithmic dissipation for a stable and convergent numerical method, more recently, it has been utilized as a subgrid-scale (SGS) model to account for the effect of small scales, unresolvable by the discretization. The freestream Mach number is 2.5, and direct comparison with a DNS database from our research group, as well as with experiments from the literature of adiabatic supersonic spatially turbulent boundary layers, is performed. Turbulent inflow conditions are generated via our dynamic rescaling–recycling approach, recently extended to high-speed flows. Focus is given to the assessment of the resolved Reynolds stresses. In addition, flow visualization is performed to obtain a much better insight into the physics of the flow. A weak compressibility effect is observed on thermal turbulent structures based on two-point correlations (IC vs. supersonic). The Reynolds analogy (u′ vs. t′) approximately holds for the supersonic regime, but to a lesser extent than previously observed in incompressible (IC) turbulent boundary layers, where temperature was assumed as a passive scalar. A much longer power law behavior of the mean streamwise velocity is computed in the outer region when compared to the log law at Mach 2.5. Implicit LES has shown very good performance in Mach 2.5 adiabatic flat plates in terms of the mean flow (i.e., Cf and UVD+). iLES significantly overpredicts the peak values of u′, and consequently Reynolds shear stress peaks, in the buffer layer. However, excellent agreement between the turbulence intensities and Reynolds shear stresses is accomplished in the outer region by the present iLES with respect to the external DNS database at similar Reynolds numbers.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41598-022-12128-1
