Microcontact Printing used to control Cardiomyocyte geometry and cellular architecture.

The Disease Biophysics Group (DBG) at Harvard University is an interdisciplinary team of biologists, physicists, engineers and material scientists actively researching the structure/function relationship in cardiac, neural, and vascular smooth muscle tissue engineering.

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150., Huibin Chang, Jie Xu, Luke A. MacQueen, Zeynep Aytac, Michael M. Peters, John F. Zimmerman, Tao Xu, Philip Demokritou, and Kevin Kit Parker. 6/20/2022. “High-Throughput Coating with Biodegradable Anitmicrobial Pullulan Fibres Extends Shelf Life and Reduces Weight Loss in an Avocado.” Nature Food, 3, Pp. 428-436. Publisher's VersionAbstract

Food waste and food safety motivate the need for improved food packaging solutions. However, current films/coatings addressing these issues are often limited by inefficient release dynamics that require large quantities of active ingredients. Here we developed antimicrobial pullulan fibre (APF)-based packaging that is biodegradable and capable of wrapping food substrates, increasing their longevity and enhancing their safety. APFs were spun using a high-throughput system, termed focused rotary jet spinning, with water as the only solvent, allowing the incorporation of naturally derived antimicrobial agents. Using avocados as a representative example, we demonstrate that APF-coated samples had their shelf life extended by inhibited proliferation of natural microflora, and lost less weight than uncoated control samples. This work offers a promising technique to produce scalable, low-cost and environmentally friendly biodegradable antimicrobial packaging systems.

149., Dilip Thomas, Suji Choi, Christina Alamana, Kevin Kit Parker, and Joseph C. Wu. 6/9/2022. “Cellular and Engineered Organoids for Cardiovascular Models.” Circulation Research, 130, 12, Pp. 1780-1802. Publisher's VersionAbstract

An ensemble of in vitro cardiac tissue models has been developed over the past several decades to aid our understanding of complex cardiovascular disorders using a reductionist approach. These approaches often rely on recapitulating single or multiple clinically relevant end points in a dish indicative of the cardiac pathophysiology. The possibility to generate disease-relevant and patient-specific human induced pluripotent stem cells has further leveraged the utility of the cardiac models as screening tools at a large scale. To elucidate biological mechanisms in the cardiac models, it is critical to integrate physiological cues in form of biochemical, biophysical, and electromechanical stimuli to achieve desired tissue-like maturity for a robust phenotyping. Here, we review the latest advances in the directed stem cell differentiation approaches to derive a wide gamut of cardiovascular cell types, to allow customization in cardiac model systems, and to study diseased states in multiple cell types. We also highlight the recent progress in the development of several cardiovascular models, such as cardiac organoids, microtissues, engineered heart tissues, and microphysiological systems. We further expand our discussion on defining the context of use for the selection of currently available cardiac tissue models. Last, we discuss the limitations and challenges with the current state-of-the-art cardiac models and highlight future directions.

148., Herdeline Ann M. Ardoña, John F. Zimmerman, Kevin Shani, Su Hwan Kim, Feyisayo Eweje, Dimitrios Bitounis, Dorsa Parviz, Evan Casalino, Michael Strano, Philip Demokritou, and Kevin Kit Parker. 4/2022. “Differential Modulation of Endothelial Cytoplasmic Protrusions After Exposure to Graphene-Family Nanomaterials.” NanoImpact, 26. Publisher's VersionAbstract

Engineered nanomaterials offer the benefit of having systematically tunable physicochemical characteristics (e.g., size, dimensionality, and surface chemistry) that highly dictate the biological activity of a material. Among the most promising engineered nanomaterials to date are graphene-family nanomaterials (GFNs), which are 2-D nanomaterials (2DNMs) with unique electrical and mechanical properties. Beyond engineering new nanomaterial properties, employing safety-by-design through considering the consequences of cell-material interactions is essential for exploring their applicability in the biomedical realm. In this study, we asked the effect of GFNs on the endothelial barrier function and cellular architecture of vascular endothelial cells. Using micropatterned cell pairs as a reductionist in vitro model of the endothelium, the progression of cytoskeletal reorganization as a function of GFN surface chemistry and time was quantitatively monitored. Here, we show that the surface oxidation of GFNs (graphene, reduced graphene oxide, partially reduced graphene oxide, and graphene oxide) differentially affect the endothelial barrier at multiple scales; from the biochemical pathways that influence the development of cellular protrusions to endothelial barrier integrity. More oxidized GFNs induce higher endothelial permeability and the increased formation of cytoplasmic protrusions such as filopodia. We found that these changes in cytoskeletal organization, along with barrier function, can be potentiated by the effect of GFNs on the Rho/Rho-associated kinase (ROCK) pathway. Specifically, GFNs with higher surface oxidation elicit stronger ROCK2 inhibitory behavior as compared to pristine graphene sheets. Overall, findings from these studies offer a new perspective towards systematically controlling the surface-dependent effects of GFNs on cytoskeletal organization via ROCK2 inhibition, providing insight for implementing safety-by-design principles in GFN manufacturing towards their targeted biomedical applications.

147 -, K. Y. Lee, S.-J. Park, D. G. Matthews, S. L. Kim, C. A. Marquez, J. F. Zimmerman, H. A. Ardoña, A. G. Kleber, G. Lauder, and K. K. Parker. 2/10/2022. “An autonomously swimming biohybrid fish designed with human cardiac biophysics.” Science, 375, 6581, Pp. 639–647. Publisher's VersionAbstract
Biohybrid systems have been developed to better understand the design principles and coordination mechanisms of biological systems. We consider whether two functional regulatory features of the heart—mechanoelectrical signaling and automaticity—could be transferred to a synthetic analog of another fluid transport system: a swimming fish. By leveraging cardiac mechanoelectrical signaling, we recreated reciprocal contraction and relaxation in a muscular bilayer construct where each contraction occurs automatically as a response to the stretching of an antagonistic muscle pair. Further, to entrain this closed-loop actuation cycle, we engineered an electrically autonomous pacing node, which enhanced spontaneous contraction. The biohybrid fish equipped with intrinsic control strategies demonstrated self-sustained body–caudal fin swimming, highlighting the role of feedback mechanisms in muscular pumps such as the heart and muscles.
146 -, Lee KY, Nguyen HT, Setiawati A, Nam S-J, Kim M, Ko I-G, Jung WH, Parker KK, Kim C-J, and Shin KW. 2/2022. “An Extracellular Matrix-Liposome Composite, a Novel Extracellular Matrix Delivery System for Accelerated Tissue Regeneration.” Advanced Healthcare Materials. Publisher's VersionAbstract
The unfolded states of fibronectin (FN) subsequently induce the formation of an extracellular matrix (ECM) fibrillar network, which is necessary to generate new substitutive tissues. Here, the authors demonstrate that negatively charged small unilamellar vesicles (SUVs) qualify as candidates for FN delivery due to their remarkable effects on the autonomous binding and unfolding of FN, which leads to increased tissue regeneration. In vitro experiments revealed that the FN-SUV complex remarkably increased the attachment, differentiation, and migration of fibroblasts. The potential utilization of this complex in vivo to treat inflammatory colon diseases is also described based on results obtained for ameliorated conditions in rats with ulcerative colitis (UC) that had been treated with the FN-SUV complex. Their findings provide a new ECM-delivery platform for ECM-based therapeutic applications and suggest that properly designed SUVs may be an unprecedented FN-delivery system that is highly effective in treating UC and inflammatory bowel diseases.
145 -, Ziad AT, Zimmerman JF, Rao J, Sieiro D, McNamara HM, Cherrier T, Rodriguez-delaRosa A, Hick-Colin A, Bousson F, Fugier-Schmucker C, Marchianoi F, Habermanni B, Chala J, Nesmith AP, Gapon, Svetlana, Wagner E, Gupta VA, Bassel-Dubyk R, Olsonk EN, Cohen AE, and Parker KK. 7/2021. “Prednisolone Rescues Duchenne Muscular Dystrophy Phenotypes in Human Pluripotent Stem Cell–Derived Skeletal Muscle in Vitro.” Proceedings of the National Academy of Sciences of the United States of America, 118, 28, Pp. 1-12. Publisher's VersionAbstract
Duchenne muscular dystrophy (DMD) is a devastating genetic disease leading to degeneration of skeletal muscles and premature death. How dystrophin absence leads to muscle wasting remains unclear. Here, we describe an optimized protocol to differentiate human induced pluripotent stem cells (iPSC) to a late myogenic stage. This allows us to recapitulate classical DMD phenotypes (mislocalization of proteins of the dystrophin-associated glycoprotein complex, increased fusion, myofiber branching, force contraction defects, and calcium hyperactivation) in isogenic DMD-mutant iPSC lines in vitro. Treatment of the myogenic cultures with prednisolone (the standard of care for DMD) can dramatically rescue force contraction, fusion, and branching defects in DMD iPSC lines. This argues that prednisolone acts directly on myofibers, challenging the largely prevalent view that its beneficial effects are caused by antiinflammatory properties. Our work introduces a human in vitro model to study the onset of DMD pathology and test novel therapeutic approaches.
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