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C In-vivo grafting of large engineered heart tissue patches for cardiac repair
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  1. Richard J Jabbour1,
  2. Thomas J Owen1,
  3. Pragati Pandey1,
  4. Marina Reinsch2,
  5. Godfrey Smith4,
  6. Florian Weinberger2,
  7. Thomas Eschenhagen2,
  8. Sian E Harding1
  1. 1National Heart and Lung Institute, Imperial College London, London, UK
  2. 2Department of Cardiovascular Science, Hamburg University, Germany
  3. 3Institute of Molecular and Translational Therapeutic Strategies, Hannover Medical School, Germany
  4. 4Department of Cardiovascular Science, University of Glasgow, UK
  5. 5Centre of Advanced Biomedical Imaging, University College London, London, UK

Abstract

Introduction Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix may overcome the limitations of intracoronary/myocardial cell delivery routes. EHTs regenerate heart muscle in small animal models but data regarding clinically relevant engineered heart tissue (EHT) patches large enough for first-in-human studies are lacking.

Methods An upscaled EHT patch (approx. 3 cm × 2 cm × 1.5 mm) consisting of 15–20 million human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) embedded in a fibrin based hydrogel was developed. A rabbit myocardial infarction model was then developed to test for feasibility and efficacy of EHT grafting.

Results The patches began to beat spontaneously within 3 days of fabrication and after 28 days of dynamic culture (late EHTs) showed the development of several mature characteristics when compared to early patches (<14 days from fabrication). Late EHTs contained hiPSC-CMs which were more aligned; showed better contraction kinetics, and faster calcium transients.

We then tested the EHT patch in-vivo using a rabbit model. Patches were applied to infarcted hearts (n=14 [n=7 EHT vs n=7 sham]). Sham operations used non-cellular fibrin patches. Blinded echocardiographic analysis revealed a significant improvement in function in infarcted hearts that underwent EHT patch grafting (n=7; absolute difference of 10.04 ± 3.1% over sham group; fractional area change, P<0.01).

In-vivo telemetry recordings (n=5 MI/sham vs n=7 MI/EHT) indicated that no clinically relevant arrhythmia was seen in the MI/EHT group and arrhythmia provocation protocols (ex vivo n=5 MI/sham vs n=6 MI/EHT) confirmed that the patch was not pro-arrhythmic (arrhythmia inducibility score 5.6 ± 1.0 [MI/patch] vs 5.0 ± 0.6 [MI/sham]; p=ns).

Conclusion An upscaled clinically relevant EHT patch was developed and improved function in infarcted hearts without causing arrhythmia. Therefore EHT may have specific advantages over the direct intramyocardial injection of cells.

  • Induced pluripotent stem cell
  • engineered heart tissue
  • heart failure

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