Developing 3D Organized Human Cardiac Tissue within a Microfluidic Platform

The leading cause of death worldwide persists as cardiovascular disease (CVD). However, modeling the physiological and biological complexity of the heart ...

Arizona State University

In vitro three-dimensional (3D) microengineered tissue models have been the recent focus of pathophysiological studies, particularly in the field of cardiovascular research. These models, as classified by 3D biomimetic tissues within micrometer-scale platforms, enable precise environmental control on the molecular- and cellular-levels to elucidate biological mechanisms of disease progression and enhance efficacy of therapeutic research. Microengineered models also incorporate directed stem cell differentiation and genome modification techniques that warrant derivation of patient-specific and genetically-edited human cardiac cells for precise recapitulation of diseased tissues. Additionally, integration of added functionalities and/or structures into these models serves to enhance the capability to further extract disease-specific phenotypic, genotypic, and electrophysiological information. This review highlights the recent progress in the development of in vitro 3D microengineered models for study of cardiac-related diseases (denoted as CDs). We will primarily provide a brief overview on currently available 2D assays and animal models for studying of CDs. We will further expand our discussion towards currently available 3D microengineered cardiac tissue models and their implementation for study of specific disease conditions.

Three-dimensional microengineered models of human cardiac diseases.

Background The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell (EC) immune activation and neuroinflammation. We also tested whether monosialoganglioside-containing nanoliposomes could reverse medin's adverse effects. Methods and Results Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors. ECs were exposed to physiologic dose of medin (5 μmol/L), and viability and immune activation (interleukin-8, interleukin-6, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1) were measured without or with monosialoganglioside-containing nanoliposomes (300 μg/mL). Astrocytes were exposed to vehicle, medin, medin-treated ECs, or their conditioned media, and interleukin-8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced EC immune activation (increased interleukin-8, interleukin-6, intercellular adhesion molecule-1, and plasminogen activator inhibitor-1) and reduced EC viability, which were reversed by monosialoganglioside-containing nanoliposomes. Interleukin-8 production was augmented when astrocytes were exposed to medin-treated ECs or their conditioned media. Conclusions Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside-containing nanoliposomes. Medin is a candidate novel risk factor for aging-related cerebrovascular disease and VaD.

Endothelial Immune Activation by Medin: Potential Role in Cerebrovascular Disease and Reversal by Monosialoganglioside-Containing Nanoliposomes.

The tumor microenvironment has been demonstrated to play a crucial role in modulating cancer progression. Amongst various cell types within the tumor microenvironment, cancer associated fibroblasts (CAFs) are in abundance, serving to modulate the biophysical properties of the stromal matrix, through excessive deposition of extracellular matrix (ECM) proteins that leads to enhanced tumor progression. There is still a critical need to develop a fundamental framework on the role of tumor-stromal cell interactions on desmoplasia and tumorigenicity. Herein, we developed a 3D microengineered organotypic tumor-stroma model incorporated with breast cancer cells surrounded by CAF-embedded collagen matrix. We further integrated our platform with atomic force microscopy (AFM) to study the dynamic changes in stromal stiffness during active tumor invasion. Our findings primarily demonstrated enhanced tumor progression in the presence of CAFs. Furthermore, we highlighted the crucial role of crosstalk between tumor cells and CAFs on stromal desmoplasia, where we identified the role of tumor-secreted PDGF-AA/-BB on elevated matrix stiffness. Inhibition of the activity of PDGFRs in CAFs led to attenuation of stromal stiffness. Overall, our work presents a well-controlled tumor microenvironment model capable of dissecting specific biophysical and biochemical signaling cues which lead to stromal desmoplasia and tumor progression.

The role of tumor-stroma interactions on desmoplasia and tumorigenicity within a microengineered 3D platform.

Despite significant efforts in the study of cardiovascular diseases (CVDs), they persist as the leading cause of mortality worldwide. Considerable research into human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) has highlighted their immense potential in the development of in vitro human cardiac tissues for broad mechanistic, therapeutic, and patient-specific disease modeling studies in the pursuit of CVD research. However, the relatively immature state of hPSC-CMs remains an obstacle in enhancing clinical relevance ofengineered cardiac tissue models. In this study, we describe development of a microfluidic platform for 3D modeling of cardiac tissues, derived from both rat cells and hPSC-CMs, to better recapitulate the native myocardium through co-culture with interstitial cells (specifically cardiac fibroblasts), biomimetic collagen hydrogel encapsulation, and induction of highly anisotropic tissue architecture. The presented platform is precisely engineered through incorporation of surface topography in the form of staggered microposts to enable long-term culture and maturation of cardiac cells, resulting in formation of physiologically relevant cardiac tissues with anisotropy that mimics native myocardium. After two weeks of culture, hPSC-derived cardiac tissues exhibited well-defined sarcomeric striations, highly synchronous contractions, and upregulation of several maturation genes, including HCN1, KCNQ1, CAV1.2, CAV3.1, PLN, and RYR2. These findings demonstrate the ability of the proposed engineered platform to mature animal- as well as human stem cell-derived cardiac tissues over an extended period of culture, providing a novel microfluidic chip with the capability for cardiac disease modeling and therapeutic testing.

Engineering anisotropic human stem cell-derived three-dimensional cardiac tissue on-a-chip.

Cardiovascular diseases, including myocardial infarction (MI), persist as the leading cause of mortality and morbidity worldwide. The limited regenerative capacity of the myocardium presents significant challenges specifically for the treatment of MI and, subsequently, heart failure (HF). Traditional therapeutic approaches mainly rely on limiting the induced damage or the stress on the remaining viable myocardium through pharmacological regulation of remodeling mechanisms, rather than replacement or regeneration of the injured tissue. The emerging alternative regenerative medicine-based approaches have focused on restoring the damaged myocardial tissue with newly engineered functional and bioinspired tissue units. Cardiac regenerative medicine approaches can be broadly categorized into three groups: cell-based therapies, scaffold-based cardiac tissue engineering, and scaffold-free cardiac tissue engineering. Despite significant advancements, however, the clinical translation of these approaches has been critically hindered by two key obstacles for successful structural and functional replacement of the damaged myocardium, namely: poor engraftment of engineered tissue into the damaged cardiac muscle and weak electromechanical coupling of transplanted cells with the native tissue. To that end, the integration of micro- and nanoscale technologies along with recent advancements in stem cell technologies have opened new avenues for engineering of structurally mature and highly functional scaffold-based (SB-CMTs) and scaffold-free cardiac microtissues (SF-CMTs) with enhanced cellular organization and electromechanical coupling for the treatment of MI and HF. In this review article, we will present the state-of-the-art approaches and recent advancements in the engineering of SF-CMTs for myocardial repair.

Jaimeson Veldhuizen

School of Biological and Health Systems Engineering

Arizona State University

Developing 3D Organized Human Cardiac Tissue within a Microfluidic Platform

Jaimeson Veldhuizen

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Arizona State University

Developing 3D Organized Human Cardiac Tissue within a Microfluidic Platform

School of Biological and Health Systems Engineering