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In the present study we assessed the potential of human outgrowth endothelial cells (OEC), a subpopulation within endothelial progenitor cell cultures, to support the vascularization of a complex tissue engineered construct for bone. OEC cultured on starch polycaprolactone fiber meshes (SPCL) in monoculture retained their endothelial functionality and responded to angiogenic stimulation by VEGF (vascular endothelial growth factor) in fibrin gel-assays in vitro. Co-culture of OEC with human primary osteoblasts (pOB) on SPCL, induced an angiogenic activation of OEC towards microvessel-like structures achieved without additional supplementation with angiogenic growth factors. Effects of co-cultures with pOB on the vascularization process by OEC in vivo were tested by subcutaneous implantation of Matrigel plugs containing both, OEC and pOB, and resulted in OEC-derived blood vessels integrated into the host tissue and anastomosed to the vascular supply. In addition, morphometric analysis of the vascularization process by OEC indicated a better performance of OEC in the co-cultures with primary osteoblasts compared to monocultures of OEC. The contribution of OEC to vascular structures and the beneficial effect of the co-culture with primary human osteoblasts on the vascularization in vivo was additionally proven by subcutaneous implantation of pre-cellularized and pre-cultured SPCL constructs. OEC contributed to the vascular structures, by generating autogenic vessels or by incorporation into chimeric vessels consisting of both, human and mouse endothelial cells. The current data highlight the vasculogenic potential of OEC for bone tissue engineering applications and indicate a beneficial influence of constructs including both osteoblasts and endothelial cells for vascularization strategies.

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The increasing prevalence of fragility fractures of the sacrum (FFS) occurring predominantly in osteoporotic individuals poses a diagnostic and therapeutic challenge. The clinical presentation varies from longstanding low back pain without the patient remembering a traumatic event to immobilized patients after suffering a low-energy trauma. FFS are often combined with a fracture of the anterior pelvic ring; hence they are classified as a part of fragility fractures of the pelvis (FFP). If not displaced, the patients are treated with weight bearing as tolerated and analgesics; however, we advocate to treat displaced fractures surgically according to the fracture personality and the patient’s comorbidities. Surgical options include minimal invasive sacro-iliac screws, trans-sacral bar osteosynthesis, open reduction and internal fixation, or spinopelvic stabilization. In the light of the high complication rate associated with immobilized patients, an operative approach often is indicated to accelerate the patient’s mobility.

Tissue regeneration involves complex processes in the interaction between different cell types that control the process of neo-vascularization. In bone, osteoblasts and bone marrow stem cells provide cue elements for the proliferation of endothelial cells, differentiation of endothelial precursors, and the maturation of a vascular network. In this study, we investigated outgrowth endothelial cells (OECs), a potential source of autologous endothelial cells derived from human peripheral blood, in direct 2-dimensional (2-D) and 3-D co-culture systems with cells relevant for the regeneration of bone tissue, such as osteoblasts. In the co-cultures, OECs were evaluated in terms of their stability as an endothelial population at the single cell level using flow cytometry and their ability to establish a pre-vascular network at the light-microscopical and ultra-structural level. In co-cultures with the osteoblast cell line MG63 and with human primary osteoblasts (pOBs), OECs, in contrast to human umbilical vein endothelial cells, formed highly organized microvessel-like structures. These microvessel-like structures included the formation of a vascular lumen with tight junctional complexes at intercellular contacts of endothelial cells. In the co-culture, the formation of this vascular network was achieved in the standard growth medium for OECs. Furthermore, using a rotating culture vessel system, 3-D co-cultures consisting of OECs and pOBs were generated. Based on these observations, we conclude that OECs could provide a valuable source of autologous endothelial cells for the generation of complex tissue-engineered tissues.