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Research Papers

Tissue-Engineering for the Study of Cardiac Biomechanics

[+] Author and Article Information
Stephen P. Ma

Department of Biomedical Engineering,
Columbia University,
622 West 168th Street,
VC12-234,
New York, NY 10032
e-mail: spm2145@columbia.edu

Gordana Vunjak-Novakovic

Department of Biomedical Engineering
and Department of Medicine,
Columbia University,
622 West 168th Street,
VC12-234,
New York, NY 10032
e-mail: gv2131@columbia.edu

1Corresponding author.

Manuscript received November 11, 2015; final manuscript received December 15, 2015; published online January 27, 2016. Editor: Victor H. Barocas.

J Biomech Eng 138(2), 021010 (Jan 27, 2016) (14 pages) Paper No: BIO-15-1576; doi: 10.1115/1.4032355 History: Received November 11, 2015

The notion that both adaptive and maladaptive cardiac remodeling occurs in response to mechanical loading has informed recent progress in cardiac tissue engineering. Today, human cardiac tissues engineered in vitro offer complementary knowledge to that currently provided by animal models, with profound implications to personalized medicine. We review here recent advances in the understanding of the roles of mechanical signals in normal and pathological cardiac function, and their application in clinical translation of tissue engineering strategies to regenerative medicine and in vitro study of disease.

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Figures

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Fig. 1

Mechanical function of the heart. (a) The heart consists of four chambers that circulate blood through the systemic and venous circulations. (b) Blood flow through the heart is controlled by the four valves as depicted pictorially in the diagrams. The opening and closing of the valves is controlled by the relative pressures between the various compartments. The contours of the left ventricular PV loop for each contractile cycle are partially determined by the intrinsic properties of the heart (EDPVR and ESPVR). (c) Changes in mechanical stiffness change the EDPVR. (d) Changes in ionotropy change the ESPVR. (Images in (a) and (b) were modified from work done by Eric Pierce, available under a GNU Free Documentation License or a Creative Commons Attribution-ShareAlike License.)

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Fig. 2

Normal and pathological conditions of preload and afterload in the heart. The contours of the left ventricular PV loop are further modified by mechanical loading, which depend on (a) the volume of blood in the ventricle prior to the stroke and (b) the pressure against which the ventricle contracts. (c) Chronic increases in these loads can lead to pathological changes in the heart. (Images in C were reproduced from Servier Medical Art library of images.)

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Fig. 3

Mechanical and electrical stimulation strategies for the maturation of cardiac tissue constructs. (a) Brightfield and α-actinin staining depict cardiac response to static, isometric stretch in a biaxial arrangement (reproduced with permission from [167]). (b) Auxotonic stretch is more biomimetic, and allows for the tuning of tissue properties by adjusting the spring constant of the resisting material [168]. The sequence of brightfield images shows shrinkage of the gel and alignment of the tissue over seven days. The bar graphs depict changes in cross-sectional area and force generation as a function of the pillar spring constant and collagen concentration (reproduced with permission from [168]). (c) Cyclic stretch substitutes active dynamic loading [169] for the passive loads described in (a) and (b) (reproduced with permission from [169]). (d) Electrical stimulation of tissue constructs subjected to auxotonic stretch (spring device on the left) is commonly achieved through the use of bioreactors with carbon rod electrodes (black rectangular blocks on the right), and have produced aligned tissues with electrophysiological maturity (reproduced with permission from [71]).

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Fig. 4

In vitro methods for studying preload and afterload. (a) Increased preload is commonly modeled by stretching cardiomyocytes grown on 2D membranes (reproduced with permission from [75]). (b) Increased afterload can be modeled by actively changing the spring constant of the resisting material after tissues have been formed (reproduced with permission from [36]).

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Fig. 6

The application of optogenetics in cardiology. (a) Light-induced multisite pacing of a Lagendorff-perfused heart was demonstrated through the use of AAV-9 as a vector for ChR2 delivery, recapitulating the benefits of multisite electrode pacing (reproduced with permission from [158]). (b) Optogenetics is also being used as a basic science tool in vivo to probe the mechanisms that underlie spiral wave arrhythmias and their termination, such as an increased first half winding distance (1/2 W.D.) (reproduced with permission from [159]).

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Fig. 5

The use of engineered human cardiac tissues to model cardiac disease. (a) Titin mutations are a common cause of dilated cardiomyopathy. The structure of the cardiac sarcomere is depicted on the left, with TTN, thick filaments (rods with globular heads), and thin filaments (coiled ovals). TTN protein segments (Z disk, I band, A band, M band) are shown below, along with the locations of patient-derived (p) and CRISPR-induced (c) mutations. hiPS-CMs carrying these mutations were used to create microtissues (center, brightfield and immunofluorescence of phalloidin staining). These in vitro models recapitulated a number of relevant parameters including the change incontractile force [120] in mutated lines as shown on the right (reproduced with permission from [120]). (b) The development of organ-on-a-chip models using hiPS-derived cells has advanced to the point where multi-organ integration is a possibility. One avenue of exploration is to combine heart, liver, and vasculature for the purpose of drug testing [126]. The CAD drawings on the left depict a modular platform with different compartments specifically designed for the culture of heart and liver tissues. The bottom photos on the left show cardiac microtissues. The middle column of images from top to bottom depict (1) the scale of the individual modules, (2) dissolvable sugar lattices for the introduction of vasculature, (3) a cardiac microtissue, and (4) the even propagation of electrical signals through cardiac tissue. The images on the right depict angiogenic sprouting from the initial channels created through the use of sacrificial sugar filaments coated by human endothelial stem cells (reproduced with permission from [126]).

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