Over the past 25 years, many laboratory based bioreactors have been used to study the cellular response to hemodynamic forces. The vast majority of these studies have focused on the effect of a single isolated hemodynamic force, generally consisting of a wall shear stress (WSS) or a tensile hoop strain (THS). However, investigating the cellular response to a single isolated force does not accurately represent the true in vivo situation, where a number of forces are acting simultaneously. This study used a novel bioreactor to investigate the cellular response of human umbilical vein endothelial cells (HUVECs) exposed to a combination of steady WSS and a range of cyclic THS. HUVECs exposed to a range of cyclic THS (0-12%), over a 12 h testing period, expressed an upregulation of both ICAM-1 and VCAM-1. HUVECs exposed to a steady WSS (0 dynes/cm2 and 25 dynes/cm2), over a 12 h testing period, also exhibited an ICAM-1 upregulation but a VCAM-1 downregulation, where the greatest level of WSS stimulus resulted in the largest upregulation and downregulation of ICAM-1 and VCAM-1, respectively. A number of HUVEC samples were exposed to a high steady WSS (25 dynes/cm2) combined with a range of cyclic THS (0-4%, 0-8%, and 0-12%) for a 12 h testing period. The initial ICAM-1 upregulation, due to the WSS alone, was downregulated with the addition of a cyclic THS. It was observed that the largest THS (0-12%) had the greatest reducing effect on the ICAM-1 upregulation. Similarly, the initial VCAM-1 downregulation, due to the high steady WSS alone, was further downregulated with the addition of a cyclic THS. A similar outcome was observed when HUVEC samples were exposed to a low steady WSS combined with a range of cyclic THS. However, the addition of a THS to the low WSS did not result in an expected ICAM-1 downregulation. In fact, it resulted in a trend of unexpected ICAM-1 upregulation. The unexpected cellular response to the combination of a steady WSS and a cyclic THS demonstrates that such a response could not be determined by simply superimposing the cellular responses exhibited by ECs exposed to a steady WSS and a cyclic THS that were applied in isolation.

Previous mechano-transduction studies have investigated the endothelial cell (EC) morphological response to mechanical stimuli; generally consisting of a wall shear stress (WSS) and a cyclic tensile hoop strain (THS). More recent studies have investigated the EC biochemical response (intercellular adhesion molecule, ICAM-1, and vascular cellular adhesion molecule, VCAM-1, expression) to idealized mechanical stimuli. However, current literature is lacking in the area of EC biochemical response to combinations of physiological WSS and THS mechanical stimuli. The objective of this study is to investigate the EC response to physiological WSS and THS stimuli and to compare this response to that of ECs exposed to idealized steady WSS and cyclic THS of the same magnitudes. This study also investigated the EC response to a nicotine chemical stimulus combined with a suspected athero-prone physiological mechanical stimulus. A bioreactor was designed to apply a range of combinations of physiological WSS and THS waveforms. The bioreactor was calibrated and validated using computational fluid dynamics and video extensometry techniques. The bioreactor was used to investigated the biochemical response exhibited by human umbilical vein endothelial cells (HUVECs) exposed to physiological athero-protective (first bioreactor test case, pulsatile WSS combined with pulsatile THS) and athero-prone (second bioreactor test case, oscillating WSS combined with pulsatile THS) mechanical environments. The final testing environment (third bioreactor test case) combined a nicotine chemical stimulus with the mechanical stimuli of the second bioreactor test case. In first and second bioreactor test cases, the addition of a pulsatile THS to the WSS resulted in opposite trends of ICAM-1 down-regulation and up-regulation, respectively. This outcome suggests that the effect of the additional pulsatile THS depends on the state of the applied WSS waveform. Similarly, in first and second bioreactor test cases, the addition of a pulsatile THS to the WSS resulted in a VCAM-1 up-regulation. However, it has been previously shown that the addition of a cyclic THS to a high- or low-steady WSS resulted in a VCAM-1 down-regulation, indicating that the EC response to idealized mechanical stimuli (steady WSS and cyclic THS) is not comparable to physiological mechanical stimuli (unsteady WSS and pulsatile THS), even though in both situations the average magnitude of WSS and THS applied were similar. In third bioreactor test case, a nicotine chemical stimulus induced a substantial VCAM-1 up-regulation and a moderate ICAM-1 up-regulation. The addition of the mechanical stimuli of the second bioreactors test case resulted in a greater VCAM-1 up-regulation than what was expected, considering the observations of the previous second bioreactor test case alone. This study found that the EC biochemical response to physiological mechanical stimuli is not comparable to the previously observed EC response to idealized mechanical stimuli, even though in both environments th...

To date many bioreactor experiments have investigated the cellular response to isolated in vitro forces. However, in vivo, wall shear stress ͑WSS͒ and tensile hoop strain ͑THS͒ coexist. This article describes the techniques used to build and validate a novel vascular tissue bioreactor, which is capable of applying simultaneous wall shear stress and tensile stretch to multiple cellular substrates. The bioreactor design presented here combines a cone and plate rheometer with flexible substrates. Using such a combination, the bioreactor is capable of applying a large range of pulsatile wall shear stress ͑−30 to + 30 dyn/ cm 2 ͒ and tensile hoop strain ͑0%-12%͒. The WSS and THS applied to the cellular substrates were validated and calibrated. In particular, curves were produced that related the desired WSS to the bioreactor control parameters. The bioreactor was shown to be biocompatible and noncytotoxic and suitable for cellular mechanical loading studies in physiological condition, i.e., under simultaneous WSS and THS conditions.

Atherosclerosis is a disease that causes obstructions to develop within the arterial system; these obstructions can result in an acute vascular event such as a heart attack or stroke, and potentially death. In the majority of cases a standard angioplasty balloon is sufficient to dilate the site of an obstruction; however difficult obstructions, such as heavily calcified lesions require specialist dilation solutions. One such example of a device is Boston Scientific's cutting balloon. An analysis of the Food and Drug Administration's (FDA) Manufacturer and User Facility Device Experience (MAUDE) database demonstrates that the original cutting balloon has a number of distinct adverse events associated with it. In this study we describe the design, manufacturing, and testing of a new force focused angioplasty balloon that has the potential to reduce or eliminate the adverse events associated with the Boston Scientific cutting balloon. This design incorporates two elastomeric materials to aid recoiling of the device namely: nitinol and a silicone elastomer. New methods of manufacturing are described in this study, that ensure that precision molding and assembly can occur. To determine the effectiveness of our device, we simulated concentric calcified lesions with a surrogate chalk model. These results demonstrate that our device has a significantly lower lesion burst pressure in comparison to a standard angioplasty balloon, 174 atm versus 12.48 atm. To determine if our device reduced potential snagging, and thus reduced the risk of withdrawal resistance being encountered, we performed a withdrawal resistance test. A noticeably lower withdrawal force is associated with our device, the high peaks on the Boston Scientific device indicate that there may be wings forming on the balloon and these are catching on the tip of the introducer sheath. Finally, we demonstrated in vivo efficacy of our device in a porcine model. By the use of elastomeric recoiling features in a new cutting balloon design we have been able to overcome the three main reported adverse events associated with the Boston Scientific cutting balloon. Subsequently we experimentally demonstrated this improved efficacy for one particular peripheral balloon size (e.g., 5 mm diameter).

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