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There is critical need for a predictive model of human cardiac physiology in the drug development process for assessment of compound toxicology and pharmacology. In vitro two-dimensional monolayer culture of cardiomyocytes provides biochemical and cellular readouts, and in vivo small and large animal models provide information on systemic cardiovascular response. However, there remains a significant gap in these models due to an incomplete recapitulation of adult human cardiovascular physiology, which results in more difficult safety interpretations. Recent efforts in developing in vitro models from engineered heart tissues have demonstrated potential for bridging this gap using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) in a three-dimensional tissue structure. Here we advance this paradigm by implementing FRESH™ 3D bioprinting to build human cardiac tissues in a medium throughput, well-plate format with controlled tissue architecture, tailored cellular composition, and native-like physiological function, specifically in its adrenergic agonist drug response. To do this, we combined hiPSC-CMs, endothelial cells and fibroblasts in a cellular bioink and FRESH™ 3D bioprinted this mixture in the format of a thin tissue strip stabilized on a tissue fixture. Our results confirmed that FRESH™ 3D bioprinted cardiac tissues could be fabricated directly in a 24-well plate format, were composed of dense and highly aligned hiPSC-CMs at >600 million cells/mL, and within 14 days demonstrated reproducible calcium transients and fast conduction velocity of ∼25 cm/s. Interrogation of these cardiac tissues with the ß-adrenergic receptor agonist isoproterenol showed native-like positive chronotropic and inotropic responses, a combination of responses that is not typically observed in 2D monolayer models or standard 3D engineered heart tissue approaches. These results confirm that FRESH™ 3D bioprinted cardiac tissues represents a novel in vitro platform that enables early in vitro pharmacology and toxicology screening.

Here we report the 3D bioprinting of a simplified model of the heart, similar to that observed in embryonic development, where the heart is a linear tube that pumps blood and nutrients to the growing embryo. To this end, we engineered a bioinspired model of the human heart tube using freeform reversible of embedding of suspended hydrogels 3D bioprinting. The 3D bioprinted heart tubes were cellularized using human stem cell-derived cardiomyocytes and cardiac fibroblasts and formed patent, perfusable constructs. Synchronous contractions were achieved ∼3–4 days after fabrication and were maintained for up to a month. Immunofluorescent staining confirmed large, interconnected networks of sarcomeric alpha actinin-positive cardiomyocytes. Electrophysiology was assessed using calcium imaging and demonstrated anisotropic calcium wave propagation along the heart tube with a conduction velocity of ∼5 cm s−1. Contractility and function was demonstrated by tracking the movement of fluorescent beads within the lumen to estimate fluid displacement and bead velocity. These results establish the feasibility of creating a 3D bioprinted human heart tube and serve as an initial step towards engineering more complex heart muscle structures.

Current breast cancer care involves a multidisciplinary clinical approach for diagnosis and treatment including input from radiology, surgery, pathology, radiation, and medical oncology. Radiation is an integral part of the treatment for locoregionally confined breast cancer, and has well-recognized long-term risks of secondary malignancies, such as angiosarcomas. Basal cell carcinoma (BCC), a common skin malignancy, is not typically considered a radiation-induced carcinoma following breast cancer treatment. Our recent experience with 4 patients with vastly different presentations of BCC in previous radiation fields prompts the current report in order to alert clinicians to this entity.

Sickle cell disease (SCD) is a genetic red blood cell disorder characterized by increased reactive oxygen species (ROS) and a concordant reduction in antioxidant capacity in the endothelium. Superoxide dismutase 2 (SOD2) is a mitochondrial-localized enzyme that catalyzes the dismutation of superoxide to hydrogen peroxide. Decreased peripheral blood expression of SOD2 is correlated with increased hemolysis and cardiomyopathy in SCD. Here, we report for the first time that endothelial cells exhibit reduced SOD2 protein expression in the pulmonary endothelium of SCD patients. To investigate the impact of decreased SOD2 expression in the endothelium, SOD2 was knocked down in human pulmonary microvascular endothelial cells (hPMVECs). We found that SOD2 deficiency in hPMVECs results in endothelial cell dysfunction, including reduced cellular adhesion, diminished migration, integrin protein dysregulation, and disruption of permeability. Furthermore, we uncover that SOD2 mediates changes in endothelial cell function via processing of fibronectin through its inability to facilitate dimerization. These results demonstrate that endothelial cells are deficient in SOD2 expression in SCD patients and suggest a novel pathway for SOD2 in regulating fibronectin processing.

Background: The COVID-19 pandemic presented a unique challenge to our healthcare system and rapidly changed the delivery of cancer care. During the height of the pandemic in New York State, non-emergent surgery, including cancer surgery, was postponed. For patients with hormone receptor positive breast cancer, “bridge” neoadjuvant hormonal therapy was initiated until surgery could be safely performed. Objective: We present our institutional experience with this approach and lessons learned, including oncologic outcomes and factors which may lead to increased medication compliance. Method: This is a single institution, retrospective, observational chart review. Using data from the NYU Perlmutter Cancer Center, we created a database of patients who were diagnosed with ER+ stage 0, I, or II breast cancer and were offered preoperative endocrine therapy (tamoxifen or aromatase inhibitors) between March 12, 2020 and June 1, 2020. Variables collected included demographics, tumor characteristics, as well as the rates of medication uptake and compliance. Patients eligible for review were adult (age>18) males and females who had initial visits at our two cancer centers between March 12, 2020 and June 1, 2020, during the height of the COVID-19 pandemic in New York. Results: Of 192 newly diagnosed breast cancer patients seen at the NYU Perlmutter Cancer Center during the study time period, 136 (71%) patients had early stage ER positive breast cancer. Forty-five patients (23%) had not yet undergone surgery, and were recommended to receive presurgical hormonal therapy as a bridge. Average age: 60.5 +/- 13.8 years old (range 31-89). Thirty-four patients (75.6%) had invasive cancer, 8 had DCIS (17.8%), 3 had DCIS with microinvasion (6.7%). There were 9 patients (20%) who did not take the medication. Thirty-six patients (80%) took medication for an average of 43.6 +/- 27.3 days (range 9-101 days) prior to surgery. Twenty-eight patients (77.8%) took an aromatase inhibitor, and 8 (22.2%) took tamoxifen. Forty-two patients have now undergone surgery (93.3%) – the remaining patients include one who is refusing all treatment, one patient who relocated out of state, and another patient who has not yet scheduled surgery, but is still taking an aromatase inhibitor. Conclusion: Despite traditionally low uptake and adherence to endocrine therapy, acceptance of neo-adjuvant bridge therapy during the COVID-19 pandemic was high (80%). We plan to investigate our patient population further, especially psychosocial and behavioral factors that influence willingness to take endocrine therapy – and apply these lessons to management of early-stage ER positive breast cancer.

Investigating and modulating electrical activity of cardiomyocytes and neurons is essential to understanding their physiology, regeneration of excitable cells/tissues, and treatment of various disorders. Recently, microelectrode arrays (MEAs) have gained tremendous popularity since they enable multi-site recordings at sub-msec temporal resolution, provide two-way interaction with cells i.e. recording and stimulation, and have well-established microfabrication methods. However, currently used planar MEAs are not able to record and stimulate at sub-cellular resolution due to significant increase in electrode impedance which reduces the signal-to-noise ratio (SNR) of recorded signal. Currently there is a need to (i) enable high density electrode arrays, (ii) provide high spatial resolution, and (iii) prevent averaging of signals from multiple cells. To address these needs, we have developed three-dimensional out-of-plane grown fuzzy graphene (3DFG)-based MEA. Out-of-plane growth of single-to-few layers of graphene flakes leverages graphene's outstanding surface-to-volume ratio. The high surface area leads to significant reduction in impedance, thus enabling electrical recordings with high SNR and development of ultra-microelectrode arrays to perform sub-cellular measurements. Furthermore, the high flake density of graphene in 3DFG lead to high photo-absorbance in UV-NIR range. This opens up avenues to enable photo-thermal stimulation of cells with high precision and sub-cellular resolution. Our presented approach would greatly impact our basic understanding of signal transduction in complex cellular assemblies. Furthermore, it would provide a platform for developing and screening of therapeutics, and treatment of various cardiac and neurological diseases.

Understanding cellular electrical communication is of growing interest in stem cell biology. Electrical properties have been linked to specification and differentiation of stem cells into targeted progeny such as neurons and cardiomyocytes. Basic research at the tissue level of the heart and brain electrical activity has led to the development of tools to treat various ailments, such as pacemaker and deep brain stimulation electrodes for the treatment of cardiac arrhythmias and Parkinson’s disease respectively. Currently, there is a critical need and tremendous interest in developing new ways to complement fluorescent indicators such as voltage and Ca2+-sensitive dyes, for direct electrophysiological measurements of cells and tissue. Graphene, a honeycomb sp2 hybridized two-dimensional (2D) carbon lattice is a promising bioelectronic building block due to its outstanding electrical conductivity (charge carrier mobility up-to 200,000 cm2 V-1 s-1), mechanical flexibility, and optical properties (optical transmittance of ~97.7%). Here we report a unique transparent graphene-based electrical platform that enables concurrent electrical and optical investigation of ES-derived cardiomyocytes’ intracellular processes and intercellular communication. The graphene-based bioelectronics platform is also shown to be biocompatible in terms of adhesion, viability and cell stress. Our presented approach will greatly impact our basic understanding of signal transduction in complex cellular assemblies, and create new avenues for bidirectional communication (sensing and stimulation) with electrically active tissues. The developed nanomaterials-based measurement platform will set the ground for further investigations of the relationship between electrical signals and reported diseases such as Alzheimer, Parkinson’s disease and Arrhythmias.