Review Article

Device-Based In Vitro Techniques for Mechanical Stimulation of Vascular Cells: A Review

[+] Author and Article Information
Caleb A. Davis

Department of Biomedical Engineering,
Texas A&M University,
College Station, TX 77843-3120
e-mail: calebadavis@tamu.edu

Steve Zambrano

Department of Biomedical Engineering,
Texas A&M University,
College Station, TX 77843-3120
e-mail: s1234@tamu.edu

Pratima Anumolu

Department of Biomedical Engineering,
Texas A&M University,
College Station, TX 77843-3120
e-mail: anumolupratima@gmail.com

Alicia C. B. Allen

Department of Biomedical Engineering,
The University of Texas at Austin,
Austin, TX 78712-1801
e-mail: alicia.allen@utexas.edu

Leonardo Sonoqui

Department of Biomedical Engineering,
Texas A&M University,
College Station, TX 77843-3120
e-mail: lsonoqui@tamu.edu

Michael R. Moreno

Department of Mechanical Engineering,
Department of Biomedical Engineering,
Texas A&M University,
College Station, TX 77843-3123
e-mail: michael.moreno@tamu.edu

1Corresponding author.

Manuscript received October 28, 2013; final manuscript received July 25, 2014; published online February 5, 2015. Assoc. Editor: Carlijn V. C. Bouten.

J Biomech Eng 137(4), 040801 (Apr 01, 2015) (22 pages) Paper No: BIO-13-1508; doi: 10.1115/1.4029016 History: Received October 28, 2013; Revised July 25, 2014; Online February 05, 2015

The most common cause of death in the developed world is cardiovascular disease. For decades, this has provided a powerful motivation to study the effects of mechanical forces on vascular cells in a controlled setting, since these cells have been implicated in the development of disease. Early efforts in the 1970 s included the first use of a parallel-plate flow system to apply shear stress to endothelial cells (ECs) and the development of uniaxial substrate stretching techniques (Krueger et al., 1971, “An in Vitro Study of Flow Response by Cells,” J. Biomech., 4(1), pp. 31–36 and Meikle et al., 1979, “Rabbit Cranial Sutures in Vitro: A New Experimental Model for Studying the Response of Fibrous Joints to Mechanical Stress,” Calcif. Tissue Int., 28(2), pp. 13–144). Since then, a multitude of in vitro devices have been designed and developed for mechanical stimulation of vascular cells and tissues in an effort to better understand their response to in vivo physiologic mechanical conditions. This article reviews the functional attributes of mechanical bioreactors developed in the 21st century, including their major advantages and disadvantages. Each of these systems has been categorized in terms of their primary loading modality: fluid shear stress (FSS), substrate distention, combined distention and fluid shear, or other applied forces. The goal of this article is to provide researchers with a survey of useful methodologies that can be adapted to studies in this area, and to clarify future possibilities for improved research methods.

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Grahic Jump Location
Fig. 1

ECs on the inner lumen of an artery experience cyclic circumferential stretching (white arrows on cutout) due to pulsatile pressure as well as FSS (black arrows on cutout) caused by the blood flow

Grahic Jump Location
Fig. 2

Three common methods for applying FSS to cultured cells. The cone and plate system provides Couette flow caused by the spinning of the cone. In an orbital shaker, rotational inertia causes fluid flow over the cultured cells. In a parallel-plate system, the flow over the cells is pressure-driven.

Grahic Jump Location
Fig. 3

Modified POC mini-chamber first described by Yalcin et al. [24] and adapted by Mengistu et al. [12] for shear stress experiments with ECs

Grahic Jump Location
Fig. 4

T-shaped flow chamber used by Sakamoto et al. [30]. The design simulates a vessel bifurcation and creates shear stress gradients on the cultured cells.

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Fig. 7

The device adapted by Huang et al. [95] for uniaxial or equiaxial distension of cultured cells. They also demonstrated its utility for live-cell imaging. (a) Front view of the cell stretcher. (b) Cross-sectional view of the membrane holder ring and indenter ring; the elastic membrane is secured in the circular groove at the bottom. (c) Modular indenter designs allow for application of different strain profiles, e.g., equiaxial and uniaxial.

Grahic Jump Location
Fig. 6

In each of the strain modalities shown in this figure, cells are cultured on a flexible membrane in a circular well. Platen driven strain: The substrate is cyclically stretched by moving a stiff platen vertically with respect to the membrane. The platen may be a cylindrical post (left) or a hollow cylinder (right). Vacuum driven strain: The membrane is cyclically stretched by applying a vacuum in the chamber underneath the cell substrate. To maintain in-plane distension, the cell culture area may be positioned atop a stationary central post (right). Prong driven strain: The membrane is cyclically stretched by moving a stiff rounded prong vertically with respect to the membrane (left). Modifications can allow the prong to move back and forth or in a circular pattern in the horizontal plane as well (right).

Grahic Jump Location
Fig. 5

Illustration of four types of strain which can be applied to cells cultured on a flexible membrane. Uniaxial tests may be unconstrained (top left) or constrained (top right) in the axis perpendicular to stretch; constraining this axis essentially applies a force to counteract the Poisson effect. By definition, we consider a “biaxial” test to be one in which force is applied in two perpendicular axes (bottom left), while an “equiaxial” test applies stretch equally in all directions (bottom right).

Grahic Jump Location
Fig. 8

The Flexcell Flexflow device [120,121], which allows for simultaneous application of FSS and cyclic stretching of cultured cells. The device is also designed to permit live-cell imaging.

Grahic Jump Location
Fig. 10

Device developed by Moreno et al. to apply cyclic substrate stretching and FSS to cultured vascular cells simultaneously [174] (left). This device allows researchers to arbitrarily set the stress angle between shear stress and stretch, from perpendicular to parallel. Idealized computational fluid dynamics of the flow chamber (right).

Grahic Jump Location
Fig. 9

At vessel bifurcations such as the carotid, fluid flow may change from straight laminar flow to something resembling a helical pattern (see also Ref. [173]). In the straight vessel (bottom), FSS (black arrows) usually acts perpendicular to the circumferential stretching (white arrows). At the bifurcation (top), the relative angle of the FSS and CS is not perpendicular, and the forces may actually be parallel to one another. Atherosclerosis tends to develop at curvatures and bifurcations more often than in straight vessels.




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