Gradual collagen recruitment has been hypothesized as the underlying mechanism for the mechanical stiffening with increasing stress in arteries. In this work, we investigated this hypothesis in eight rabbit carotid arteries by directly measuring the distribution of collagen recruitment stretch under increasing circumferential loading using a custom uniaxial (UA) extension device combined with a multi-photon microscope (MPM). This approach allowed simultaneous mechanical testing and imaging of collagen fibers without traditional destructive fixation methods. Fiber recruitment was quantified from 3D rendered MPM images, and fiber orientation was measured in projected stacks of images. Collagen recruitment was observed to initiate at a finite strain, corresponding to a sharp increase in the measured mechanical stiffness, confirming the previous hypothesis and motivating the development of a new constitutive model to capture this response. Previous constitutive equations for the arterial wall have modeled the collagen contribution with either abrupt recruitment at zero strain, abrupt recruitment at finite strain or as gradual recruitment beginning at infinitesimal strain. Based our experimental data, a new combined constitutive model was presented in which fiber recruitment begins at a finite strain with activation strain represented by a probability distribution function. By directly including this recruitment data, the collagen contribution could be modeled using a simple Neo-Hookean equation. As a result, only two phenomenological material constants needed to be fit from the stress stretch data. Three other models for the arterial wall were then compared with these results. The approach taken here was successful in combining stress-strain analysis with simultaneous microstructural imaging of collagen recruitment and orientation, providing a new approach by which underlying fiber architecture may be quantified and included in constitutive equations.
Background and Purpose Saccular intracranial aneurysm (sIA) is a common disease that may cause devastating intracranial hemorrhage. Hemodynamics, wall remodeling, and wall inflammation have been associated with sIA rupture. We investigated how sIA hemodynamics associates with wall remodeling and inflammation of the sIA wall. Methods Tissue samples resected during sIA surgery (11 unruptured, 9 ruptured sIAs) were studied with histology and immunohistochemistry. Patient-specific computational models of hemodynamics were created from preoperative CT-angiographies. Results More stable and less complex flows were associated with thick, hyperplastic sIA walls while slower flows with more diffuse inflow were associated with degenerated and decellularized sIA walls. Wall degeneration (p=0.041) and rupture was associated with increased inflammation (CD45+, p=0.031). High wall shear stress (WSS, p=0.018), higher vorticity (VO, p=0.046), higher viscous dissipation (VD, p=0.046), and high shear rate (SR, p=0.046) associated with increased inflammation. Inflammation was also associated with lack of intact endothelium (p=0.034), and presence of organized luminal thrombosis (p=0.018), although overall organized thrombosis was associated with low minimum WSS (p=0.034) and not with the flow conditions that associated with inflammation. Conclusions Flow conditions in the sIA associate with wall remodeling. Inflammation, which is associated with degenerative wall remodeling and rupture, is associated with high flow activity including elevated WSS. Endothelial injury may be a mechanism by which flow induces inflammation in the sIA wall. Hemodynamic simulations might prove to be useful in identifying sIAs at risk of developing inflammation, a potential biomarker for rupture.
OBJECTIVES Patients with bicuspid aortic valve (BAV) are predisposed to developing ascending thoracic aortic aneurysms (TAA) at an earlier age than patients who develop degenerative TAAs and have a tricuspid aortic valve (TAV). The hypothesis tested is that BAV-associated aortopathy is mediated by a mechanism of matrix remodeling that is distinct from that seen in TAAs of TAV patients. METHODS Aortic specimens were collected during ascending aortic replacement, aortic valve replacement and heart transplants from non-aneurysmal (NA) donors and recipients. Matrix architecture of the aortic media was assessed qualitatively using multi-photon microscopy followed by quantification of collagen and elastin fiber orientation. α-elastin was determined and matrix maturity was assessed by quantifying immature and mature collagen and lysyl oxidase (Lox) expression and activity in aortic specimens. Matrix metalloproteinase (MMP)-2/9 activity was quantified in aortic smooth muscle cells. RESULTS Elastin and collagen fibers were more highly aligned in BAV-NA and BAV-TAA patients relative to TAV-TAA patients while TAV-TAA was more disorganized than TAV-NA. α-elastin content was unchanged. Immature collagen was reduced in BAV-NA and BAV-TAA when compared with TAV-NA and TAV-TAA. Mature collagen was elevated in TAV-TAA relative to TAV-NA and BAV-TAA. There was a trend toward elevated Lox gene expression and activity and MMP-2/9 activity for TAV-TAA, BAV-NA and BAV-TAA specimens. CONCLUSIONS The highly aligned matrix architecture in BAV patients indicates that wall remodeling is distinct from TAV-TAA. Altered matrix architecture and reduced collagen maturity suggests that the effector molecules mediating remodeling of TAA are different in BAV and TAV patients.
Intracranial aneurysms are pathological enlargements of brain arteries that are believed to arise from progressive wall degeneration and remodeling. Earlier work using classical histological approaches identified variability in cerebral aneurysm mural content, ranging from layered walls with intact endothelium and aligned smooth muscle cells, to thin, hypocellular walls. Here, we take advantage of recent advances in multiphoton microscopy, to provide novel results for collagen fiber architecture in 15 human aneurysm domes without staining or fixation as well as in 12 control cerebral arteries. For all aneurysm samples, the elastic lamina was absent and the abluminal collagen fibers had similar diameters to control arteries. In contrast, the collagen fibers on the luminal side showed great variability in both diameter and architecture ranging from dense fiber layers to sparse fiber constructs suggestive of ineffective remodeling efforts. The mechanical integrity of eight aneurysm samples was assessed using uniaxial experiments, revealing two sub-classes (i) vulnerable unruptured aneurysms (low failure stress and failure pressure), and (ii) strong unruptured aneurysms (high failure stress and failure pressure). These results suggest a need to refine the end-point of risk assessment studies that currently do not distinguish risk levels among unruptured aneurysms. We propose that a measure of wall integrity that identifies this vulnerable wall subpopulation will be useful for interpreting future biological and structural data.
The objective of this study was to evaluate the long term performance of cell-free vascular grafts made from a fast-degrading elastic polymer. We fabricated small arterial grafts from microporous tubes of poly(glycerol sebacate) (PGS) reinforced with polycaprolactone (PCL) nanofibers on the outer surface. Grafts were interpositioned in rat abdominal aortas and characterized at 1 year post-implant. Grafts remodeled into “neoarteries” (regenerated arteries) with similar gross appearance to native rat aortas. Neoarteries mimic arterial tissue architecture with a confluent endothelium and media and adventita-like layers. Patent vessels (80%) showed no significant stenosis, dilation, or calcification. Neoarteries contain nerves and have the same amount of mature elastin as native arteries. Despite some differences in matrix organization, regenerated arteries had similar dynamic mechanical compliance to native arteries in vivo. Neoarteries responded to vasomotor agents, albeit with different magnitude than native aortas. These data suggest that an elastic vascular graft that resorbs quickly has potential to improve the performance of vascular grafts used in small arteries. This design may also promote constructive remodeling in other soft tissues.
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