ABSTRACT
Autologous cell transplantation holds enormous promise to restore organ and tissue functions in the treatment of various pathologies including endocrine, cardiovascular, and neurological diseases among others. Even though immune rejection is circumvented with autologous transplantation, clinical adoption remains limited due to poor cell retention and survival. Cell transplant success requires homing to vascularized environment, cell engraftment and importantly, maintenance of inherent cell function. To address this need, we developed a three dimensional (3D) printed cell encapsulation device created with polylactic acid (PLA), termed neovascularized implantable cell homing and encapsulation (NICHE). In this paper, we present the development and systematic evaluation of the NICHE in vitro, and the in vivo validation with encapsulated testosterone-secreting Leydig cells in Rag1-/- castrated mice. Enhanced subcutaneous vascularization of NICHE via platelet-rich plasma (PRP) hydrogel coating and filling was demonstrated in vivo via a chorioallantoic membrane (CAM) assay as well as in mice. After establishment of a pre-vascularized bed within the NICHE, transcutaneously transplanted Leydig cells, maintained viability and robust testosterone secretion for the duration of the study. Immunohistochemical analysis revealed extensive Leydig cell colonization in the NICHE. Furthermore, transplanted cells achieved physiologic testosterone levels in castrated mice. The promising results provide a proof of concept for the NICHE as a viable platform technology for autologous cell transplantation for the treatment of a variety of diseases.
Subject(s)
Biocompatible Materials/chemistry , Leydig Cells/transplantation , Polyesters/chemistry , Tissue Scaffolds/chemistry , Animals , Cell Survival , Cells, Cultured , Cells, Immobilized/cytology , Cells, Immobilized/transplantation , Human Umbilical Vein Endothelial Cells , Humans , Hydrogel, Polyethylene Glycol Dimethacrylate/chemistry , Islets of Langerhans/cytology , Leydig Cells/cytology , Male , Mice , Neovascularization, Physiologic , Printing, Three-Dimensional , Tissue EngineeringABSTRACT
In numerous pathologies, implantable drug delivery devices provide advantages over conventional oral or parenteral approaches. Based on the site of implantation and release characteristics, implants can afford either systemic delivery or local administration, whereby the drug is delivered at or near the site of intended action. Unfortunately, current implantable drug delivery systems provide limited options for intervention in the case of an adverse reaction to the drug or the need for dosage adjustment. In the event that drug delivery must be terminated, an urgent surgical retrieval may be the only reliable option. This could be a time sensitive and costly effort, requiring access to trained professionals and emergency medical facilities. To address such limitations, here we demonstrate, in vitro and ex vivo, a novel microsystem for the rapid and effective switch off of drug delivery from an implantable nanofluidic system, by applying a safe external electromagnetic field in the FDA approved dose range. This study represents a proof of concept for a technology with potential for broad applicability to reservoir-based delivery implants for both complete interruption or remote titration of drug administration.
