Tissue-organization of Oscillating Cardiomyocytes via Matrix-mediated Biomechanical Signals

by Florian Spreckelsen
Doctoral thesis
Date of Examination:2019-12-06
Date of issue:2020-02-04
Advisor:Prof. Dr. Ulrich Parlitz
Referee:Prof. Dr. Stefan Klumpp
Referee:Prof. Dr. Ulrich Parlitz
Persistent Address: http://dx.doi.org/10.53846/goediss-7826

 

 

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Abstract

English

Tissue engineering, specifically engineered human myocardium (EHM), offers a promising therapeutic perspective for patients suffering from heart failure and also might improve drug development and testing. We therefore want to understand the interaction of heart muscle cells -- cardiomyocytes (CM) -- in the very early stages of tissue generation. Deeper understanding may not only lead to improved fabrication but also will give insights into tissue organization in mammalian hearts in general. Therefore a mathematical model of mechanically coupled cardiomyocytes is devised in this thesis. Detailed numerical simulations are performed to investigate the conditions under which they synchronize. Synchronization is deemed necessary for the successful growth of engineered tissue. Mechanical coupling in the early stages of EHM growth happens via the extracellular matrix (ECM), i.e., the collagen hydrogel (with or without fibroblasts) surrounding the cells. The mechanical properties of these hydrogels with and without fibroblasts and CM were investigated in rheological experiments. In the numerical simulations of viscoelastically coupled CM, various forms of n:m synchronization -- including n=m=1 -- of the cells are observed if the coupling matrix is sufficiently stiff. This matches qualitatively the regime of viscoelastic parameters into which the ECM is observed to develop in the rheological experiments. In those, the presence of fibroblasts is found to further stiffen the ECM compared to pure collagen or collagen with CM only. Fibroblasts thus improve the conditions for synchronization of CM coupled by the ECM. The special case of purely elastic coupling, though being unphysiological in the context of tissue engineering, shows interesting antiphase Synchronization and chimera behavior in the numerical simulations.
Keywords: PhD Thesis; Physics; Synchronization; Nonlinear Oscillators; Cardiomyocytes; Fibroblasts; Collagen; Tissue Engineering; Viscoelastic Coupling; Extracellular Matrix
 
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