Introduction: Cell therapy has become increasingly studied for therapeutic use in drug delivery and regenerative medicine. Immunoisolating devices intended for implantation of cells require construction of membranes that can safely contain transplanted cells, provide a barrier to the host immune system, and induce close vessel formation. Sheep make an excellent model for translational research because of their nearly comparable size, physiology, and disease profile with humans, as well as their docility, capacity for repeated blood draws, ability to tolerate numerous implants during a single operation, and affordability. In this study, sheep were implanted with devices containing allogeneic primary fetal sheep or xenogeneic Rat-2 fibroblasts, to determine cell survival in immunoisolating devices and immune response.

Methods: Primary fetal sheep fibroblasts were isolated from a healthy fetus and cultured in RPMI. Rat-2 fibroblasts (ATCC) were cultured in DMEM. On the day of transplant, cells were aliquoted and loaded into devices at different densities. Sheep underwent allogeneic or xenogeneic transplantation with cell-loaded devices, as well as empty control and perforated devices. Devices were implanted subcutaneously through small incisions along the flank within individual pockets made by blunt dissection. Devices remained in vivo until explant at days 3, 7, 21 and 38 to evaluate host responses, vascularization, and cell survival. Explanted devices were fixed, embedded, and sectioned for histological evaluation.

Results: Primary fetal sheep cells survived at different densities as assessed by histology, confirming alloprotection with good vascularization and absence of a major foreign body response or extensive inflammation around the device host interface. Devices at the highest densities were overloaded and exhibited some host immune responses.
Perforated devices exhibited a greater immune response that infiltrated the device. A robust inflammatory response was seen around devices loaded with xenogeneic Rat-2 fibroblasts with no encapsulated cells surviving.

Conclusion: Sheep make a valuable large animal model in cell therapy research. The results of this study concluded alloprotection in immunoisolating devices, allorejection in purposely perforated devices, as well as host immune response to xenogeneic transplantation, representing a feasible model for translational development of cell therapies. Future work with this accessible and relevant platform will include not only allogeneic studies but also avoiding xenogeneic rejection by incorporating immunomodulatory technologies using genetically edited cells or factors.