Stimulation of Peri-Implant Vascularization with Bone Marrow-Derived Progenitor Cells: Monitoring byIn VivoEPR Oximetry

Abstract

The poorly vascularized fibrous capsule that develops around implantable biomedical devices (for drug delivery, biosensors, etc.) severely limits their applications. We tested the hypotheses that co-implantation of bone marrow-derived progenitor cells could stimulate the vascularization of implants. To assess the presence of functional peri-implant microvasculature, we developed a novel model of implanted device containing an oxygen (O(2))-sensing spin probe (detectable using electron paramagnetic resonance) placed inside a nanoporous filter-limited capsule. These devices were implanted subcutaneously in C57/Bl6 mice alone, with the addition of a Matrigel plug in front of the filter, or with the addition of Matrigel containing equal proportions of c-kit(+) and stem cell antigen-1(+) bone marrow-derived cells. Implants partial pressure of O(2) (pO(2)) were recorded non-invasively and periodically for up to 10 weeks. Tissue surrounding the implants was collected for immunohistochemistry. Initially, there were no differences in pO(2) between the experimental groups. After 3 weeks, the devices supplied with progenitor cells showed more than twice the O(2) concentrations as controls. This difference remained significant for 4 more weeks and then started to decrease slightly, still being 6 mmHg higher than in the controls at 10 weeks post-implantation. Collagen deposition was detected around the control implants, along with F4/80-positive macrophages and giant cells. In the plugs collected from the cell treatment group, we found an active process of adipogenesis, accompanied by neovascularization, and a highly vascularized adipose layer surrounding the implants. In conclusion, we successfully developed a cell therapy-type strategy to maintain vascularization around implanted devices using co-administration of bone marrow-derived progenitor cells, and we demonstrated a novel O(2)-sensing method to functionally monitor neovascularization in vivo.