title: A novel miniaturized multimodal bioreactor for continuous in situ assessment of bioartificial cardiac tissue during stimulation and maturation.
abstract: Stem cell-based cardiac tissue engineering is a promising approach for regenerative therapy of the injured heart. At present, the small number of stem cell-derived cardiomyocytes that can be obtained using current culture and enrichment techniques represents one of the key limitations for the development of functional bioartificial cardiac tissue (BCT). We have addressed this problem by construction of a novel bioreactor with functional features of larger systems that enables the generation and in situ monitoring of miniaturized BCTs. BCTs were generated from rat cardiomyocytes to demonstrate advantages and usefulness of the bioreactor. Tissues showed spontaneous, synchronized contractions with cell orientation along the axis of strain. Cyclic stretch induced cardiomyocyte hypertrophy, demonstrated by a shift of myosin heavy chain expression from the alpha to beta isoform, together with elevated levels of atrial natriuretic factor. Stretch led to a moderate increase in systolic force (1.42 ± 0.09 mN vs. 0.96 ± 0.09 mN in controls), with significantly higher forces observed after β-adrenergic stimulation with noradrenalin (2.54 ± 0.11 mN). Combined mechanical and β-adrenergic stimulation had no synergistic effect. This study demonstrates for the first time that mechanical stimulation and direct real-time contraction force measurement can be combined into a single multimodal bioreactor system, including electrical stimulation of excitable tissue, perfusion of the culture chamber, and the possibility of (fluorescence) microscopic assessment during continuous cultivation. Thus, this bioreactor represents a valuable tool for monitoring tissue development and, ultimately, the optimization of stem cell-based tissue replacement strategies in regenerative medicine.
authors.affiliation: Leibniz Research Laboratories for Biotechnology and Artificial Organs, Department of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: George
authors.initials: G
authors.lastname: Kensah
authors.forename: Ina
authors.initials: I
authors.lastname: Gruh
authors.forename: Jörg
authors.initials: J
authors.lastname: Viering
authors.forename: Henning
authors.initials: H
authors.lastname: Schumann
authors.forename: Julia
authors.initials: J
authors.lastname: Dahlmann
authors.forename: Heiko
authors.initials: H
authors.lastname: Meyer
authors.forename: David
authors.initials: D
authors.lastname: Skvorc
authors.forename: Antonia
authors.initials: A
authors.lastname: Bär
authors.forename: Payam
authors.initials: P
authors.lastname: Akhyari
authors.forename: Alexander
authors.initials: A
authors.lastname: Heisterkamp
authors.forename: Axel
authors.initials: A
authors.lastname: Haverich
authors.forename: Ulrich
authors.initials: U
authors.lastname: Martin
mesh_terms: D000818:Animals; D001187:Artificial Organs; D015415:Biomarkers / Q000378:metabolism; D019149:Bioreactors; D002470:Cell Survival; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D055595:Mechanical Phenomena; D008856:Microscopy, Fluorescence; D008904:Miniaturization / Q000295:instrumentation*; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology; D009928:Organ Specificity / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering / Q000295:instrumentation* / Q000379:methods*
chemical_list: D015415:Biomarkers