Publication of the Month | August 2008

Simon MA, Watson J, Baldwin JT, Wagner WR, and Borovetz HS

Current and Future Considerations in the Use of Mechanical Circulatory Support Devices

Heart failure (HF) is a major public health problem in the United States, and its prevalence is likely to increase with the aging U.S. population. Mechanical circulatory support (MCS) utilizing bladder-based blood pumps generating pulsatile flow has been reserved for patients with severe HF failing medical therapy. As MCS technology has advanced to include rotary blood pumps, so has our understanding of the biological and clinical responses to MCS, which in turn has altered the risk/benefit profile of this therapy. This may lead to paradigm shifts in device usage from support of end-stage HF to temporary support for recovery of cardiac function and earlier usage, to, ultimately, prevention of disease progression. This review serves to explore the current state and future opportunities of MCS within our larger understanding of the epidemiology, pathophysiology, and treatment options for HF.

Annu Rev Biomed Eng. 2008 Aug 15;10:59-84

2008

July

Velliste, M, Perel S, Spalding MC, Whitford AS, Schwartz AB

Cortical control of a prosthetic arm for self-feeding

Arm movement is well represented in populations of neurons recorded from the motor cortex. Cortical activity patterns have been used in the new field of brain-machine interfaces to show how cursors on computer displays can be moved in two- and three-dimensional space. Although the ability to move a cursor can be useful in its own right, this technology could be applied to restore arm and hand function for amputees and paralysed persons. However, the use of cortical signals to control a multi-jointed prosthetic device for direct real-time interaction with the physical environment ('embodiment') has not been demonstrated. Here we describe a system that permits embodied prosthetic control; we show how monkeys (Macaca mulatta) use their motor cortical activity to control a mechanized arm replica in a self-feeding task. In addition to the three dimensions of movement, the subjects' cortical signals also proportionally controlled a gripper on the end of the arm. Owing to the physical interaction between the monkey, the robotic arm and objects in the workspace, this new task presented a higher level of difficulty than previous virtual (cursor-control) experiments. Apart from an example of simple one-dimensional control, previous experiments have lacked physical interaction even in cases where a robotic arm or hand was included in the control loop, because the subjects did not use it to interact with physical objects-an interaction that cannot be fully simulated. This demonstration of multi-degree-of-freedom embodied prosthetic control paves the way towards the development of dexterous prosthetic devices that could ultimately achieve arm and hand function at a near-natural level.

Nature. 2008 Jun 19;453(7198):1098-101. Epub2008 May 28.

June

Adipose tissue has been shown to contain adult mesenchymal stem cells that have therapeutic applications in regenerative medicine. There is evidence that the ability of adipose precursor cells to grow and differentiate varies among fat depots and changes with age. Defining these variations in cell function and molecular mechanisms of adipogenesis will facilitate the development of cell-based therapies. We compared cells harvested from 5 different subcutaneous (SC) adipose depots in 12 female patients classified into 3 age ranges (25-30, 40-45, and 55-60 years old). Capacity for differentiation of isolated adipose-derived stem cells (ASCs) with and without ciglitazone, a strong peroxisome proliferator activated receptors (PPAR)-gamma agonist, was assessed in vitro. ASCs were also characterized by lipolytic function, proliferation, and sensitivity to apoptosis. Additionally, PPAR-gamma-2 protein expression was determined. We observed a difference in the apoptotic susceptibility of ASCs from various SC depots, with the superficial abdominal depot (above Scarpas layer) significantly more resistant to apoptosis when compared with the 4 other depots. We have also demonstrated that a PPAR-gamma agonist aids in the induction of differentiation in cells from all depots and ages. Although sensitivity to apoptosis was linked to anatomic depot, differences in cell proliferation were related primarily to age. Stimulated free glycerol release has been shown to be highest in the arm depot. The arm depot has also consistently shown expression of PPAR-gamma-2 with and without a PPAR-gamma agonist. Younger patients have increased PPAR-gamma-2 expression in all depots, whereas the older patients have consistent elevated expression only in the arm and thigh depots. We have shown there is variability in function of ASCs that have been harvested from different SC depots. Additionally, we have shown age-related changes in function. These data will help select patients and cell harvest sites most suitable for tissue engineering therapies.

May

Inflammation is a complex, multi-scale biologic response to stress that is also required for repair and regeneration after injury. Despite the repository of detailed data about the cellular and molecular processes involved in inflammation, including some understanding of its pathophysiology, little progress has been made in treating the severe inflammatory syndrome of sepsis. To address the gap between basic science knowledge and therapy for sepsis, a community of biologists and physicians is using systems biology approaches in hopes of yielding basic insights into the biology of inflammation.
‘‘Systems biology’’ is a discipline that combines experimental discovery with mathematical modeling to aid in the understanding of the dynamic global organization and function of a biologic system (cell to organ to organism). We propose the term translational systems biology for the application of similar tools and engineering principles to biologic systems with the primary goal of optimizing clinical practice. We describe the efforts to use translational systems biology to develop an integrated framework to gain insight into the problem of acute inflammation. Progress in understanding inflammation using translational systems biology tools highlights the promise of this multidisciplinary field. Future advances in understanding complex medical problems are highly dependent on methodological advances and integration of the computational systems biology community with biologists and clinicians.

April

Tissue engineered heart valves (TEHV) have been observed to respond to mechanical conditioning in vitro by expression of activated myofibroblast phenotypes followed by improvements in tissue maturation. In separate studies, cyclic flexure, stretch, and flow (FSF) have been demonstrated to exhibit both independent and coupled stimulatory effects. Synthesis of these observations into a rational framework for TEHV mechanical conditioning has been limited, however, due to the functional complexity of tri-leaflet valves and the inherent differences of separate bioreactor systems. Toward quantifying the effects of individual mechanical stimuli similar to those that occur during normal valve function, a novel bioreactor was developed in which FSF mechanical stimuli can be applied to engineered heart valve tissues independently or in combination.

The FSF bioreactor consists of two identically equipped chambers, each having the capacity to hold up to 12 rectangular tissue specimens (25 x 7.5 x 1 mm) via a novel "spiral-bound" technique. Specimens can be subjected to changes-in-curvature up to 50 mm(-1) and uniaxial tensile strains up to 75%. Steady laminar flow can be applied by a magnetically coupled paddlewheel system. Computational fluid dynamic (CFD) simulations were conducted and experimentally validated by particle image velocimetry (PIV). Tissue specimen wall shear stress profiles were predicted as a function of paddlewheel speed, culture medium viscosity, and the quasi-static state of specimen deformation (i.e., either undeformed or completely flexed). Velocity profiles predicted by 2D CFD simulations of the paddlewheel mechanism compared well with PIV measurements, and were used to determine boundary conditions in localized 3D simulations.

March

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