Development and Non-invasive Quality Assessment of Advanced Therapy Medicinal Products

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Dokumentart: Dissertation
Date: 2021-04-23
Language: English
Faculty: 7 Mathematisch-Naturwissenschaftliche Fakultät
Department: Biologie
Advisor: Schenke-Layland, Katja (Prof. Dr.)
Day of Oral Examination: 2021-03-12
DDC Classifikation: 570 - Life sciences; biology
610 - Medicine and health
Keywords: Fibronectin , Zellen , Elektrospinnen , Epigenetik , Raman-Spektrum , Blutgefäß
Other Keywords:
vascular graft
License: Publishing license including print on demand
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In recent years, a new complex group of medicinal products known as Advanced Therapy Medicinal Products (ATMPs), has attracted increasing attention. Based on genes, cells or tissues, these products offer new treatment options for serious diseases such as hereditary diseases and blood cancers and they can also serve as a tissue replacement. However, due to the high complexity of these products, which affects their development, production, approval and quality control, their translation into clinical practice remains a challenge. This thesis presents solutions for addressing these hurdles. An important element in ensuring the safety and functionality of ATMPs is the non-destructive and non-invasive monitoring of their quality. As part of this thesis, a possibility for a non-invasive quality control of stem cells based on DNA methylation was developed. I successfully demonstrated that Raman microspectroscopy in combination with multivariate data analysis is capable of distinguishing between lower and higher global DNA methylation states indicating the pluripotency of stem cells. In the second part of this thesis, I fabricated an electrospun vascular graft with mechanical properties comparable to those of a native blood vessel. The surface of the graft was biofunctionalized with two different extracellular matrix proteins, decorin and fibronectin, of which the latter promoted the adherence and proliferation of primarily isolated vascular endothelial cells and endothelial progenitor cells in vitro. Due to the characteristics of the graft, it can be considered for future use in in-situ tissue engineering. In this case, a cell-free construct can be implanted, reducing biological complexity and simplifying production and storage, thus saving costs. Finally, I focused on investigating fibronectin adsorption on polyurethane surfaces with different chemical and topographic properties. I successfully demonstrated that surface roughness and chemistry influence the orientation and conformation of the adsorbed protein and thus its bioactivity. Using two different endothelial cell phenotypes, I was able to show that the adsorbed fibronectin on the different surfaces alters the cell response in terms of cell-cell and cell-material interaction. These findings can help to design surfaces that direct cell response by modulating protein adsorption, thereby improving the biocompatibility of biomaterials for the fabrication of ATMPs.

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