Ph.D Thesis


Ph.D StudentAmit Goren
SubjectDevelopment and Optimization of Cell Encapsulation System
towards Host Immune Tolerance and Tumor Therapy
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Full Professors Machluf Marcelle
Full Thesis textFull thesis text - English Version
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Abstract

Cell microencapsulation is a promising strategy for cell based therapy and drug delivery. The technology is based on the entrapment of cells within a polymeric matrix surrounded by a semi-permeable membrane. The polymeric microcapsule enables the release of therapeutic agents produced by the cells, while preventing contact between the foreign cells and the body, thus minimizing the response of the immune system. Cell microencapsulation is investigated for the treatment of various diseases such as diabetes type I, CNS degenerative diseases and cancer. Still, the field of cell microencapsulation is away from achieving clinical application. This is mainly due to the lack of biocompatibility of the microcapsule system.

The present work focuses on the development and optimization of polymeric microencapsulation systems towards host immune tolerance and therapeutic applications such as cancer therapy. For this purpose two cell types were studied: suspended T cells and mesenchymal stem cells (MSCs). Suspended cells engulf several cell properties including high cell mass and genetic engineering potential which makes them attractive assets for cell encapsulation. The encapsulated T cells proliferated for more than 28 days. More than 75% of these microcapsules were mechanically stable for more than four months. Moreover, we have encapsulated soluble Fas ligand (sFasL) secreting T cells for cancer therapy. In vivo, encapsulated T-sFasL cells caused to a significant reduction in tumor volume by 95% on day 26 post tumor inoculation.    

Another cell type that was studied for cell encapsulation is mesenchymal stem cells (MSCs). MSCs can serve as a promising platform for cell microencapsulation, as they are characterized by low immunogenicity and can be genetically modified. Encapsulated human MSCs (hMSCs) showed high viability, expressed typical surface markers and differentiated into the mesoderm lineages. In vivo immunogenicity studies revealed that, encapsulated hMSCs were significantly more biocompatible when compared to a commonly used cell lines. To demonstrate their use for therapeutic utility, the hMSCs were genetically modified to express the Hemopexin like protein (PEX), an inhibitor of angiogenesis. In vivo, a single injection of encapsulated hMSCs-PEX, led to an 83% reduction of glioma tumor growth.

To conclude, the suspended cell encapsulation system showed improved functionality compared to tested cell lines. Encapsulated hMSCs were shown to be favorable in their functionality, hypo-immunogenicity and as candidates for cell based therapy. Therefore, it is clear that hMSCs are the cell of choice for microencapsulation cell based therapy thus, bringing this technology closer to clinical application.