Heart disease is at the top of the list of the world’s most serious health problems, as the number of deaths from heart failure is rising and is expected to balloon as the population ages. Currently, most treatments only slow down the progression of the disorder, creating a great need for the development of novel preventative and regenerative therapies. Doing this successfully requires more insight into the molecular and genetic nature of the underlying diseases, which cannot be acquired without human heart disease models.

Pioneering

Animal and cell models have so far failed to capture human heart disease effectively and have poor predictive value for drug responses. Furthermore, primary human heart cells are difficult to obtain and can only be maintained in culture for a short time and is not suitable as a robust testing model. hDMT is therefore pioneering modeling of the heart on (microfluidic) chips based on induced Pluripotent Stem cells (iPSC). The resulting devices can be used for heart disease research, cardiotoxicity screening, drug target discovery and drug efficacy testing.

Program coordinators

Chair
Robert Passier
University Twente

Vice-chair
Jolanda van der Velden
Amsterdam UMC

Upcoming meeting

  • 22 March (10-16h, UMCU)
  • 20 September (10-16h, UTwente)

Previous meetings

  • 22 September 2023 (LUMC)
  • 31 March 2023 (Amsterdam UMC)
  • 14 September 2022, Enschede (UTwente)
  • 10 February 2022 (from 1-4pm)
  • 15 September 2021, Online (10-13h)
  • 14 april 2021, Online (10-13h)
  • 14 September 2020, Online
  • 5 November 2019, Delft (TU Delft)
  • 8 May 2019, Exploratory Skeletal Muscle-on-Chip group meeting (host LUMC)
  • 5 March 2019, Rotterdam (host Erasmus MC)

 

Interdisciplinary research

Heart on Chip is an interdisciplinary program to which each partner contributes based on its own ongoing research and clinical interest. Collaboration between partners who complement and reinforce each other in joint projects will create synergy, resulting in innovative ideas and solutions.

Turn into iPS cells

Leiden University Medical Center provides (anonymized) patient samples and corresponding medical histories and turns the patient’s cells into iPS cells, which can be stimulated to form any cell-type of the human body, including heart cells. Using mRNA sequencing technology at the Hubrecht Institute it is possible to analyze molecular profiles at the single cell level, which is important is important to identify pathways and molecular markers that are changed in diseased cells. Pluriomics, a biotech spin-off company of LUMC, is responsible for quality-controlled production of cardiac cells in large quantities and also develops assays for toxicity screening. Through the participation of Galapagos (specialized in drug discovery & development) hDMT stays in contact with the needs of the pharmaceutical industry.

True-to nature

TU Delft, TUe and Philips have expertise on fabricating a true-to-nature physical micro-environment for the heart cells, allowing for mechanical forces such as stretching and electrical stimulation, as well as on advanced sensor technology. The Leiden Academic  Centre for Drug Research contributes expertise in metabolomics and mass spectrometry for studying the energy metabolism of the heart muscle cells, in order to gain more insight into cardiac development and the role of metabolic disorders in heart disease.

Twente University contributes expertise on microfluidics and nanotechnology facilitating development of “heart-on-chip” devices. Furthermore, micro-droplet technology enables studying the interaction between two single cells. In collaboration with the Organ-on-a-chip company Mimetas, hDMT can utilize the high throughput microfluidic platform OrganoPlate for the further development of 3D models for study cardiac disease and toxicity.

Toxicity screening

As a pilot project within the Heart-on-Chip program hDMT is working on the so-called Cytostretch device, which is capable of mechanically stimulating heart muscle cells (cardiomyocytes). It will be used for screening new drugs at an early stage of their development for possible side-effects that cause lethal arrhythmias. Unexpected cardiotoxicity is one of the major reasons why new drugs are withdrawn from the market, as currently available in vitro model systems and animal models fail to reliably predict the effects in the human body.

Micropatterns 

The cardiomyocytes are cultured in a nutritious solution on top of a thin stretchable silicon membrane containing stretchable electrodes for measuring and applying electrical signals. By designing micropatterns on the surface of the membrane it is possible to align the cells in a specific direction. The electrodes are able to register the electrical activity and contraction of the heart cells while being subjected to a compound. By stretching the membrane it is possible to simulate strenuous physical activity, which often is the cause of arrhythmia, thus creating an accurate model of the human heart under exercise conditions. The Cytostretch can be used for high throughput compound library screening. In addition, other complementary 3D models are being developed.

Future outlook

Within ten years’ time it will be our goal to generate heart models that mimic the human heart and reliably predict the patient’s response to new drugs. In addition, we expect to generate robust, highly defined functional multi-cellular heart tissues, which can be coupled to mimics of other organs. The new heart model systems will enable, for example, the study of the effects of the liver’s metabolic products on the heart or of the interaction between the immune system and the heart. With our advanced sensor technology we will be able to easily pick up biomarkers, increasing our understanding of the underlying mechanisms of heart failure and facilitating drug target discovery and safety pharmacology.

Genetic subpopulations

The hearts-on-chip that are based on iPS cells from cardiac patients will also result in more accurate risk assessment of new drugs, as it becomes possible to match patients from genetic subpopulations to specific drugs, by using companion diagnostics. It is even conceivable that drugs that have been withdrawn from the market because of adverse side effects, are reintroduced, because the iPS based models can accurately predict which patients will benefit from it and which will not.

Tailor-made piece 

In the distant future hDMT’s technology may also be useful for regenerative medicine, when it becomes possible to print a tailor-made piece of three-dimensional multi-cellular heart tissue, extracellular matrix included, in order to replace the part of the heart muscle that got damaged during a myocardial infarction.

Disease modeling

The use of human iPS cells from cardiac patients in hDMT’s heart disease models offers unprecedented opportunities for mimicking genetic diseases in vitro, since the genome of the patient is captured in the derivative heart cells in culture. This allows one to determine whether the patients’ cells show any abnormal electrical or metabolic activity compared to heart cells of healthy people, and to study how patients with specific gene mutations that trigger an inherited heart disease, respond to different drugs.

Risk 

An important research question is how to differentiate iPS cells into heart muscle cells that are developmentally more mature. As many heart diseases take years to manifest in patients, there is a risk that they do not appear in the relatively immature heart cells that have been generated so far.

3D co-culture

More complex heart-on-chip disease models are needed when the dysfunction results from a complicated interaction of various cell types. One of the objectives in the Heart-on-Chip program is to mimic this interaction by realizing 3D co-culture of all cell types that make up the heart (including the fibroblasts that synthesize the extracellular matrix) and to get a deeper understanding of this interaction. This is made possible by hDMT’s expertise in stem cell biology, biomaterials, microfluidics, nanotechnology, mechanics, electronics,  single-cell technologies and metabolomics, combined with a number of advanced readout technologies.

To maintain heart tissue for a longer period of time it has to be continuously perfused by nutrients, which calls for the integration of the “heart-on-a-chip”  into a vessels-on-chip microfluidic device (creating an interface with the Vessels-on-Chip program). The resulting (low throughput) heart disease mimics can be used for drug target discovery and for ‘clinical trial on a chip’ testing. 

News

Milica Dostanic continues Heart-on-Chip research as postdoc in Leiden

Recruited from TU Delft as joint postdoc with Leiden on the Netherlands Organ-on-Chip Initiative (NOCI) program Milica Dostanic continues her research on miniaturised Engineered Heart Tissues (EHTs). In the group of Christine Mummery (LUMC) she will focus on optimizing cell ratios for the heart (cardiomyocytes, fibroblasts), optimizing pillar flexibility and...

Read more

Publications

van Meer BJ, Krotenberg A, Sala L, Davis RP, Eschenhagen T, Denning C, Tertoolen LGJ, Mummery CL. (2019) Simultaneous measurement of excitation-contraction coupling parameters identifies mechanisms underlying contractile responses of hiPSC-derived cardiomyocytes. Nat Commun. 20;10(1):4325. doi: 10.1038/s41467-019-12354-8.

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2. Eltzschig, H.K. and Eckle,  T.“Ischemia and reperfusion—from mechanism to translation,” Nat Med, vol. 17, no. 11, pp. 1391–1401, Nov. 2011.

3. Elliott, D.A., Braam, S.R., Koutsis, K., Ng, E.S., Jenny, R., Lagerqvist, E.L., Biben, C., Hatzistavrou, T., Hirst, C.E., Yu,  Q.C., Skelton, R.J.P., Ward-van Oostwaard, D., Lim,  S.M., Khammy,  O., Li, X.,  Hawes, S.M., Davis, R.P., Goulburn, A.L., Passier, R., Prall, O.W.J., Haynes, J.M., Pouton, C.W., Kaye, D.M., Mummery, C.L., Elefanty, A.G. and Stanley, E.G. “NKX2-5eGFP/w hESCs for isolation of human cardiac progenitors and cardiomyocytes”,  Nat Methods, vol. 8, no. 12, pp. 1037–1040, Oct. 2011.4.

4. Braam, S.R., Tertoolen, L., van de Stolpe, A., Meyer, T., Passier, R. and Mummery, C.L. “Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes,” Stem Cell Res, vol. 4, no. 2, pp. 107–116, Mar. 2010.

 

5. Braam, S.R., Tertoolen, L., Casini, S., Matsa, E., Lu, H.R., Teisman, A., Passier, R., Denning, C.,  Gallacher, D.J., Towart, R. and  Mummery,  C.L. “Repolarization reserve determines drug responses in human pluripotent stem cell derived cardiomyocytes,” Stem Cell Res, vol. 10, no. 1, pp. 48–56, Jan. 2013.

6. Khoshfetrat Pakazad, S., Savov, A. , van de Stolpe, A. and Dekker, R. “A novel stretchable micro-electrode array (SMEA) design for directional stretching of cells,” J. Micromech. Microeng., vol. 24, 034003, 2014.

7. Trietsch, S.J., Israëls, G.D., Joore, J., Hankemeier, T., Vulto, P. Microfluidic titer plate for stratified 3D cell culture .Lab Chip. 2013 Sep 21;13(18):3548-54.

8. Vulto, P., Podszun, S., Meyer, P., Hermann, C., Manz, A., Urban, G.A. Phaseguides: a paradigm shift in microfluidic priming and emptying .Lab Chip. 2011 May 7;11(9):1596-602.

9. Oedit, A., Vulto, P., Ramautar, R., Lindenburg, P.W., Hankemeier, T. Lab-on-a-Chip hyphenation with mass spectrometry: strategies for bioanalytical applications. Curr Opin Biotechnol. 2014 Sep 15;31C:79-85.

10. Yildirim, E., Trietsch, S.J., Joore, J., van den Berg, A., Hankemeier, T., Vulto, P. Phaseguides as tunable passive microvalves for liquid routing in complex microfluidic networks. Lab Chip. 2014 Sep 7;14(17):3334-40. doi: 10.1039/c4lc00261j.

11. Phurimsak, C., Yildirim, E., Tarn, M.D., Trietsch, S.J., Hankemeier, T., Pamme, N., Vulto, P. Phaseguide assisted liquid lamination for magnetic particle-based assays. Lab Chip. 2014 Jul 7;14(13):2334-43.

12. Junker,J.P., Noël, E.S., Guryev, V., Peterson, K.A., Shah, G., Huisken, J., McMahon, A.P., Berezikov, E., Bakkers, J. and van Oudenaarden, A.. Genome-wide RNA tomography in the zebrafish embryo. Cell, in press (2014).

13. Grun, D., Kessert, L. and van Oudenaarden, A. Validation of noise models for single-cell transcriptomics. Nature Methods 11, 637 – 640 (2014).

14. Lekkerkerker AN, Aarbiou J, van Es T, Janssen RA.. Cellular players in lung fibrosis Curr Pharm Des. 2012. 18: 4093-102.

15. Michiels, F., van Es, H., van Rompaey, L., Merchiers, P., Francken, B., Pittois, K., van der Schueren, J., Brys, R., Vandersmissen, J., Beirinckx, F., Herman, S., Dokic, K., Klaassen, H., Narinx, E., Hagers, A., Laenen, W., Piest, I., Pavliska, H., Rombout, Y., Langemeijer, E., Ma, L., Schipper, C., Raeymaeker, M.D., Schweicher, S., Jans, M., van Beeck, K., Tsang, I.R., van de Stolpe, O., Tomme, P. Arrayed adenoviral expression libraries for functional screening. Nat Biotechnol 2002. 20: 1154-1157.

16. Appel, W.P.J., Meijer, E.W. & Dankers, P.Y.W. (2011). Enzymatic activity at the surface of biomaterials via supramolecular anchoring of peptides : the effect of material processing. Macromolecular Bioscience, 11(12), 1706-1712.

17. Muntean, S.A., Michels, M.A.J. & Lyulin, A.V. (2014). Myoglobin interactions with polystyrene surfaces of different hydrophobicity. Macromolecular Theory and Simulations, 23(2), 63-75.

18. E.A. Novikova and C. Storm (2013): Contractile fibers and catch-bond clusters: a biological force sensor?, Biophys. J. 105, 1336-1345.

19.  Liu, D., Bastiaansen, C.W.M., Den Toonder, J., Broer, D.J.: (Photo-) Thermally induced Formation of Dynamic Surface Topographies in Polymer Hydrogel Networks. Langmuir, 2013, 29 (18), pp 5622–5629.

20. Liu, D., Bastiaansen, C.W.M., den Toonder,J.M.J. and Broer, D.J.  Photo-Switchable Surface Topologies in Chiral Nematic Coatings. Angew. Chem.I, 123, 2012, DOI: 10.1002/ange.201105101.

21. Spreeuwel, A.C.C. van, Bax, N.A.M., Bastiaens, A.J., Foolen, J., Loerakker, S., Borochin, M.A., Schaft, D.W.J. van der, Chen, C.S., Baaijens, F.P.T. & Bouten, C.V.C. (2014). The influence of matrix (an)isotropy on cardiomyocyte contraction in engineered cardiac microtissues. Integrative Biology, 6(4), 422-429.

22. Dijkman, P.E., Driessen – Mol, A., Frese, L., Hoerstrup, S. & Baaijens, F.P.T. (2012). Decellularized homologous tissue-engineered heart valves as off-the-shelf alternatives to xeno- and homografts. Biomaterials, 33(18), 4545-4554.

23. Bouten, C.V.C., Dankers, P.Y.W., Driessen – Mol, A., Pedron, S., Brizard, A.M. & Baaijens, F.P.T. (2011). Substrates for cardiovascular tissue engineering. Advanced Drug Delivery Reviews, 63(4-5), 221-241.

24  Gaio, N., van Meer, B., Quirós Solano, W., Bergers, L., van de Stolpe, A., Mummery, C., Sarro, P.M., Dekker, R., Cytostretch, an Organ-on-Chip Platform; Micromachines 2016, 7(7), 120; doi:10.3390/mi7070120

25. van Spreeuwel, A.C.C., Bax, N.A.M., Van Nierop, B., Aartsme-Rus, A., Goumans, M.J., Bouten, C.V.C., Mimicking cardiac fibrosis in a dish: fibroblast density rather than collagen density weakens cardiomyocyte function, Journal of Cardiovascular Translational Research (2017) DOI 10.0007/s12265-017-9737-1.