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Introduction 2 1.1.1.

Introduction 2 1.1.1. Major aspects of Tissue Engineering The main concept of Tissue Engineering (TE) is the application of multipotent progenitor cells on biomimetic scaffolds in combination with growth factors or differentiation cytokines in order to grow an organ-like precursor construct and replant it into the side of the defect which should be healed 10 . This complex network of different variables makes an interdisciplinary collaboration of medical doctors, biologists, engineers, physicists and scientists from many other research fields necessary. In reference to bone defects, TE requires functional active osteogenic progenitor cells, osteoconductive matrices, osteoinductive growth factors and a sufficient oxygen and nutrient supply within the construct 11,12 . For this reason, it is essential that cells’ to be transplanted adhere to the osteoconductive matrices, which must ensure the mechanical stability of the defect until a complete in vivo remodelling by scaffold adsorption is completed 13 . Recent studies imply the use of rapid prototyping and ceramics such as hydroxyapatite reveal a major advantage for TE of bone. These scaffolds can be produced completely interconnected and designed individually from threedimensional patient data sets (e.g. computer tomography - CT, magnetic resonance imaging – MRI) which then perfectly fits into the defect side 14 . Due to the fact, that most bioengineering challenges, like scaffold design or material composition made sophisticated improvements, concentrated effort is put into biological mechanisms. In addition to osteoblasts, MSCs, which are the precursor cells for adult mesenchymal tissue, play a pivotal clinical role due to their multilineage potential. Until now little is understood of the pathways regulating the differentiation, factors influencing cell survival and quiescence and furthermore the influence of physiological oxygen concentrations. Especially the differences between standard cell culture conditions of hMSCs and the original stem cell niche are not got fully explored and understood. 1.1.2. Mesenchymal stem cells Since the first discovery of multipotent cells from mesenchymal tissue more than 40 years ago by Friedenstein et. al. 15 , great effort was put into this field of research. They initial reported plastic adherence, fibroblast-like phenotype and colony forming potential along with an osteogenic potential for these bone marrow derived cells. Over the following years, a broad variety of surface markers on these pluripotent cells of mesenchymal origin (bone marrow, fat, muscles, tendons or cartilage) was

Introduction 3 identified, such as CD90, CD105, CD44, CD29, CD133, p75 or ALCAM, whereas hematopoietic markers like CD34, CD45 or CD14 were continuously negativ 16 . Additionally, hMSCs can be differentiated in vitro into various lineages, i.e. osteogenic (osteblasts), chondrogenic (chondrocytes), adipogenic (adipocytes), myogenic (myocytes), neurogenic (neurons) and other tissues of the mesenchymal lineage 17,18 . Dominici and colleagues defined in 2007 the minimum criteria for hMSCs 19 . Thus, hMSCs must be plastic adherent and can be differentiated into the osteogenic, adipogenic and chondrogenic lineage. Furthermore, they must express CD73, CD90 and CD105, while being negative for the hematopoetic markers CD14, CD19, CD34, CD45 and HLA-DR. Caplan A.I. summarized the current knowledge of the multilineage potential (fig. 1) 20 . Fig. 1: Schematic overview of the multilineage potential of human mesenchymal stem cells 21 . This capability of differentiation in diverse lineages is responsible for the great potential of hMSCs for the clinical use of Tissue Engineering. Several positive results in animal studies bore the first artificial organs for humans, such as skin or trachea transplants. Furthermore, numerous in vivo studies showed the regenerative efficiency for bone defects in small, as well in big animal models (reviewed by Cancedda

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