Osteopontin Reduces Foreign Body Response in Silicone-Based Implants in Humans and Mice

Subcutaneous implants often elicit an inflammatory foreign body response (FBR) in the shape of a capsule around the implanted material, and it is not yet clear why certain materials such as dermal matrix (ADM), clinically used in breast reconstruction, are more efficient in attenuating this chronic reaction. Here, we investigate the molecular response of human and mouse tissues implanted with silicone treated with ADM by analysing single-cell RNA and proteomics. In patient-derived implanted tissues exposed to ADM, we identify high levels of Osteopontin-1 (SPP1) together with attenuated FBR, in contrast to higher inflammatory response in implanted tissues not exposed to ADM. In a Spp1 knockout mouse model of FBR, we demonstrate that a reduction in SPP1 expression prevents the beneficial effects of ADM in the capsule formation, revealing that the protein is necessary to decrease fibrotic response. In wildtype mice, we demonstrate that a sustained release from a hydrogel of recombinant Spp1 is sufficient to reduce fibrotic encapsulation even in the absence of ADM, suggesting a therapeutic approach for reducing FBR around implants. Overall design: Single cell RNA sequencing of hashed mouse capsule tissue from ADM-coated and non-ADM control implant foreign body response model Single cell RNA sequencing of hashed human capsule tissue from two-stage implant-based breast reconstruction patients. *************************************************************** Submitter states that missing human raw files are due to patient privacy concerns. ***************************************************************