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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158., Michael M. Peters, Jackson K. Brister, Edward M. Tang, Felita W. Zhang, Veronica M. Lucian, Paul D. Trackey, Zachary Bone, John F. Zimmerman, Qianru Jin, F. John Burpo, and Kevin Kit Parker. 12/1/2023. “Self-organizing behaviors of cardiovascular cells on synthetic nanofiber scaffolds.” APL Bioengineering, 7, 4. Publisher's VersionAbstract
In tissues and organs, the extracellular matrix (ECM) helps maintain inter- and intracellular architectures that sustain the structure–function relationships defining physiological homeostasis. Combining fiber scaffolds and cells to form engineered tissues is a means of replicating these relationships. Engineered tissues' fiber scaffolds are designed to mimic the topology and chemical composition of the ECM network. Here, we asked how cells found in the heart compare in their propensity to align their cytoskeleton and self-organize in response to topological cues in fibrous scaffolds. We studied cardiomyocytes, valvular interstitial cells, and vascular endothelial cells as they adapted their inter- and intracellular architectures to the extracellular space. We used focused rotary jet spinning to manufacture aligned fibrous scaffolds to mimic the length scale and three-dimensional (3D) nature of the native ECM in the muscular, valvular, and vascular tissues of the heart. The representative cardiovascular cell types were seeded onto fiber scaffolds and infiltrated the fibrous network. We measured different cell types' propensity for cytoskeletal alignment in response to fiber scaffolds with differing levels of anisotropy. The results indicated that valvular interstitial cells on moderately anisotropic substrates have a higher propensity for cytoskeletal alignment than cardiomyocytes and vascular endothelial cells. However, all cell types displayed similar levels of alignment on more extreme (isotropic and highly anisotropic) fiber scaffold organizations. These data suggest that in the hierarchy of signals that dictate the spatiotemporal organization of a tissue, geometric cues within the ECM and cellular networks may homogenize behaviors across cell populations and demographics.
157., M. Rodriguez-Millan, I. Rubio, F.J. Burpo, A. Olmedo, J.A. Loya, K. K. Parker, and M.H Miguélez. 11/2023. “Impact response of advance combat helmet pad systems.” International Journal of Impact Engineering, 181. Publisher's VersionAbstract
Combat helmets are designed to protect against ballistic threats and fragments of explosive devices. There are numerous types of helmet comfort foams available. However, pad systems have not been evaluated in combat helmets to understand to what extent they mitigate head accelerations. In this work, different pad systems are studied to analyze the ballistic performance of combat helmets using a Hybrid III dummy equipped with longitudinal accelerometers at the head and a neck simulator. The tests are conducted with 9 mm Full Metal Jacket (FMJ) projectiles according to the performance requirements III-A of the NIJ 0106.01 standard. This experimental methodology allows the evaluation of brain and neck injuries. The thicker bicomponent polyurethane foams and the honeycomb configuration provided the best results in terms of mitigating brain damage due to accelerations applying different criteria (PLA, WSTC, HIC). However, it was concluded that there is no cervical injury or cranial fracture risk for any of the cases studied.
155., Sean L. Kim, Michael A. Trembley, Keel Yong Lee, Suji Choi, Luke A. MacQueen, John F. Zimmerman, Lousanne H.C. de Wit, Kevin Shani, Douglas E. Henze, Daniel J. Drennan, Shaila A. Saifee, Li Jun Loh, Xujie Liu, Kevin Kit Parker, and William T. Pu. 8/17/2023. “Spatiotemporal cell junction assembly in human iPSC-CM models of arrhythmogenic cardiomyopathy.” Stem Cell Reports, 18, Pp. 1-16. Publisher's VersionAbstract
Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disorder that causes life-threatening arrhythmias and myocardial dysfunction. Pathogenic variants in Plakophilin-2 (PKP2), a desmosome component within specialized cardiac cell junctions, cause the majority of ACM cases. However, the molecular mechanisms by which PKP2 variants induce disease phenotypes remain unclear. Here we built bioengineered platforms using genetically modified human induced pluripotent stem cell-derived cardiomyocytes to model the early spatiotemporal process of cardiomyocyte junction assembly in vitro. Heterozygosity for truncating variant PKP2R413X reduced Wnt/β-catenin signaling, impaired myofibrillogenesis, delayed mechanical coupling, and reduced calcium wave velocity in engineered tissues. These abnormalities were ameliorated by SB216763, which activated Wnt/β-catenin signaling, improved cytoskeletal organization, restored cell junction integrity in cell pairs, and improved calcium wave velocity in engineered tissues. Together, these findings highlight the therapeutic potential of modulating Wnt/β-catenin signaling in a human model of ACM.
154., Suji Choi, Keel Yong Lee, Sean L. Kim, Luke A. MacQueen, Huibin Chang, John F. Zimmerman, Qianru Jin, Michael M. Peters, Herdeline Ann M. Ardoña, Xujie Liu, Ann-Caroline Heiler, Rudy Gabardi, Collin Richardson, William T. Pu, Andreas R. Bausch, and Kevin Kit Parker. 7/27/2023. “Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3-D printed ventricles.” Nature Materials, 22, Pp. 1039 – 1046. Publisher's VersionAbstract
Hydrogels are attractive materials for tissue engineering, but efforts to date have shown limited ability to produce the microstructural features necessary to promote cellular self-organization into hierarchical three-dimensional (3D) organ models. Here we develop a hydrogel ink containing prefabricated gelatin fibres to print 3D organ-level scaffolds that recapitulate the intra- and intercellular organization of the heart. The addition of prefabricated gelatin fibres to hydrogels enables the tailoring of the ink rheology, allowing for a controlled sol–gel transition to achieve precise printing of free-standing 3D structures without additional supporting materials. Shear-induced alignment of fibres during ink extrusion provides microscale geometric cues that promote the self-organization of cultured human cardiomyocytes into anisotropic muscular tissues in vitro. The resulting 3D-printed ventricle in vitro model exhibited biomimetic anisotropic electrophysiological and contractile properties.
156., M. Rodriguez-Millan, I. Rubio, F.J. Burpo, K.M. Tse, A. Olmedo, J.A. Loya, K. K. Parker, and M.H. Migu´elez. 9/2023. “Experimental and Numerical Analyses of Ballistic Resistance Evaluation of Combat Helmet using Hybrid III Headform.” International Journal of Impact Engineering, 179. Publisher's VersionAbstract
Combat helmets are the primary system for protecting the head against ballistic impacts. Generally, combat helmets have been evaluated using a ballistic plasticine head surrogate based on international standards. More realistic human head models have recently been introduced to assess combat helmet performance considering biomechanical requirements. In this work, the Hybrid III dummy head and neck has been introduced to evaluate the performance of the combat helmet against the ballistic impact of live ammunition at different impact locations, considering two different thicknesses of the padding system. A numerical model including a helmet and a Hybrid III head and neck, is developed and validated with our experimental data. The results reveal the influence of the location, where the rear impact leads to the highest risk of brain damage. The effect of pad thickness is closely related to the energy absorbed by the helmet, the backface deformation (BFD), the contact force and the acceleration measured on the head.
152., V. Vurro, K. Shani, H. A. M. Ardona, J. F. Zimmerman, V. Sesti, K. Y. Lee, Q. Jin, C. Bertarelli, K. K. Parker, and G. Lanzani. 5/23/2023. “Light-triggered Cardiac Microphysiological Model.” APL Bioengineering , 7, 2.Abstract
Light is recognized as an accurate and noninvasive tool for stimulating excitable cells. Here, we report on a non-genetic approach based on
organic molecular phototransducers that allows wiring- and electrode-free tissue modulation. As a proof of concept, we show photostimulation
of an in vitro cardiac microphysiological model mediated by an amphiphilic azobenzene compound that preferentially dwells in the cell membrane.
Exploiting this optical based stimulation technology could be a disruptive approach for highly resolved cardiac tissue stimulation.
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