Contributions to Science
1. Biologically Inspired Materials/Devices and Organs-on-Chips.
I have been interested in innovating biomedical devices and engineered biomaterials through the use of multi-scale biofabrication techniques, including micro/nano-fabrication, microfluidics, and 3D bioprinting. My laboratory has made important contributions to developing bioinspired and biomimetic micro/nano-structures, their integration in functional devices, and their translational applications. By more closely mimicking the in vivo microenvironment of specific tissues, in terms of ECM composition, rigidity, and topography, we have generated a combinatorial set of synthetic material cues better suited to promoting structural and functional maturation of cultured human stem cells, which in turn can be employed for more predictive studies of human tissue responses to chemical, mechanical, or pathological challenge. My lab also developed various types of human heart-on-a-chip assays for predictive assessment of drug-induced cardiotoxicity. Recently, we created a new class of decellularized ECM (dECM)-graphene composite bioink library with tunable electrical conductivity and stiffness for excitable tissue engineering applications. My laboratory has also developed thermoresponsive nanofabricated substrates (TNFS) to generate scaffold-free 3D cell-dense tissue constructs with controllable architectures for studying the structure-function relationships in complex 3D tissues in healthy and diseased states.
a. Tunable electroconductive decellularized extracellular matrix hydrogels for engineering human cardiac microphysiological systems. Tsui JH, Leonard A, Camp ND, Long JT, Nawas ZY, Chavanachat R, Smith AST, Choi JS, Dong Z, Ahn EH, Wolf-Yadlin A, Murry CE, Sniadecki NJ, Kim DH. Biomaterials, 2021; 272:120764. PMCID: PMC8074529
b. NanoMEA: a tool for high-throughput, electrophysiological phenotyping of patterned excitable cells. Smith AST, Choi E, Gray K, Macadangdang J, Ahn EH, Clark EC, Laflamme MA, Wu JC, Murry CE, Tung L, Kim DH. Nano Letters, 2020;20(3), 1561-1570. PMID: 31845810
c. Multiscale cues drive collective cell migration. Nam KH, Kim P, Wood DK, Kwon S, Provenzano PP, Kim DH. Scientific Reports. 2016;6:29749. PMCID: PMC4962098
d. A thermoresponsive nanofabricated substratum for the engineering of three-dimensional tissues with layerby-layer architectural control. Jiao A, Trosper NE, Yang HS, Kim J, Tsui JH, Frankel SD, Murry CE, Kim DH. ACS Nano, 2014 8:4430-4439. PMID: 24628277
2. Mechanobiology of Cell-Matrix Interactions.
My laboratory has been focused on investigating the role of mechano-biological processes associated with cell-matrix interactions (e.g. topography, rigidity, dimensionality, etc.) in the regulation of cell/tissue function and fate decisions that are essential for tumor progression and metastasis, tissue repair and regeneration following injury, and various developmental events. Recently, my laboratory developed a high-throughput screening assay to investigate the interaction of stem cells with their microenvironmental cues in a combinatorial manner. We have also used similar tools to explore the potential role of mechanical guidance in the regulation of tumor progression and invasion under the presence/absence of growth factor-induced signals. By experimenting with the nanotopographically-defined cell culture substrates (i.e. quasi 3D cell culture system) and tissue specific dECM bioinks, we are also investigating the role of ECM composition, structure, and mechanics on directed differentiation and functional maturation of cardiomyocytes from human pluripotent stem cells, and the biophysical and signaling mechanisms that underpin these processes. We utilize FRET biosensors, along with systems biology analysis techniques (e.g. mass spectrometry–based proteomics), to study the signaling mechanisms that translate exogenous mechanical cues to changes in gene and protein expression. Using this multifaceted approach, we aim to gain a greater understanding of the mechanisms that regulate complex interactions between stem cells and their local microenvironment (or niche), and how manipulation of these pathways can enable the functional maturation of human pluripotent stem cell-derived tissues. These works will provide insight into stem cell and developmental biology and the role of the cardiac microenvironment in controlling cardiac development and maturation in vitro.
a. Engineering a 3D collective cancer invasion model with control over collagen fiber alignment. Su C-Y, Burchett A, Dunworth M, Choi JS, Ewald AJ, Ahn EH, Kim DH. (2021) Biomaterials. 275: 120922. PMCID: PMC8450056
b. Switch-like enhancement of epithelial-mesenchymal transition by YAP through feedback regulation of WT1 and small Rho-family GTPases. *Park JS, *Kim DH, Shah SR, Kim HN, Kshitiz, Kim P, QuiñonesHinojosa A, Levchenko A. Nature Communications. 2019;10:2797. PMCID: PMC6594963
c. Directed migration of cancer cells by the graded texture of the underlying matrix. Park J, Kim DH, Kim HN, Wang CJ, Kwak MK, Hur E, Suh KY, An SS, Levchenko A. Nature Materials. 2016 15: 792-801. PMID: 26974411
d. Migration phenotype of brain cancer cells predicts patient outcomes. Smith CL, Kilic O, Schiapparelli P, Kim DH, Sedora-Roman N, Guerrero-Cazares H, Gupta S, O’Donnell T, Chaichana K, Rodriguez F, Abbadi S, Quiñones‐Hinojosa A, Levchenko A. Cell Reports. 2016 15: 2616-2624. PMID: 27292647
3. Human Stem Cell and Tissue Engineering.
With advances in nanofabrication and biomaterials, scaffolding materials can be designed to integrate biomimetic structural and mechanical cues present in the in vivo ECM environment. Inspired by ultrastructural analyses of the native heart tissue, my laboratory are using our nanopatterned 3D cell sheet engineering technology to develop biomimetic cardiac tissue models to better understand the structure-function relationships in the 3D human heart. The development of these engineered cardiac tissues is also applicable to stem cell-based therapies for heart regeneration. My research in this area focuses on elucidating the relationships between scaffold-mediated nanostructural cues and tissue engineered cardiac graft contractility and function. In addition, my laboratory is also studying the therapeutic potential of a nanopatterned cardiac stem cell graft in vitro and in vivo (implantation onto the infarcted hearts). Combining our TNFS-based 3D cell sheet engineering technique with a potent angiogenic and myogenic factor, sphigosine 1-phosphate (S1P), my laboratory is also developing 3D vascularized skeletal muscle tissue patches for treatment of myopathic conditions. To better understand the development and functional phenotypes of diseased human tissues, we are also working to develop disease models of various muscular disease states, including Duchenne Muscular Dystrophy and Familial Cardiomyopathy. Through enabling a greater understanding of the development and maturation of diseased tissues, these models will provide valuable information pertaining to new targets for therapeutic treatment.
a. Engineering 3D tubular tissues with flexible thermoresponsive nanopatterned substrates. Williams NP, Rhodehamel M, Yan C, Smith AST, Jiao A, Murry CE, Scatena M, Kim DH. Biomaterials, 2020;240:119856. PMCID: PMC7536133
b. Nanopatterned human iPSC-based model of a dystrophin-null cardiomyopathic phenotype. Macadangdang J, Guan X, Smith AS, Lucero R, Czerniecki S, Childers MK, Mack DL, Kim DH. Cellular and Molecular Bioengineering, 2015. 8:320-332. PMCID: PMC4564135
c. Nanopatterned muscle cell patches for enhanced myogenesis and dystrophin expression in a mouse model of muscular dystrophy. Yang HS, Ieronimakis N, Tsui JH, Kim HN, Suh KY, Reyes M, Kim DH. Biomaterials, 2014 35:1478-1486. PMID: 24290810
d. Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Kim DH, Lipke EA, Kim P, Cheong R, Thompson S, Delannoy M, Suh KY, Tung L, Levchenko A. Proceedings of the National Academy of Sciences USA. 2010 107:565-570. PMCID: PMC2818944