Project description: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.
Project description:Silicone-based medical devices are widely used in chronic implants and are generally perceived to be safe. However, immune-related complications including malignancies have recently been linked to textured breast implants. Here, we examine the influence of clinically approved breast implants surface features on host immune responses. Prosthetics with surface roughness of 0, 4, and 90 (Ra) were implanted in mammary fat pads of mice for 2 weeks and cells adjacent to the resulting tissue capsules were evaluated for foreign body immune responses using single-cell RNA-seq. Our findings identify a unique and finely tuned surface topography that is capable of modulating implant immunity to suppress foreign body response.
Project description:Foreign body reaction (FBR), initiated by adherence of macrophages to biomaterials, is associated with several complications. Searching for mechanisms potentially useful to overcome these complications, we have established the signaling role of macrophages in the development of FBR. This study profiles gene expression of in vitro fibrinogen activated macrophages as well as that of freshly isolated macrophages from 3-days implants, against a background of unactivated macrophages/monocytes.
Project description:Polymeric elastomers are extensively employed to fabricate implants intended for prolonged implantation. However, implantation of the elastomers can induce strong immune rejection reaction known as foreign body response (FBR), resulting in the rejection of foreign implants and thereby diminishing their in vivo efficacy. Herein, we present a group of immunocompatible elastomers, termed easy-to-synthesize vinyl-based anti-FBR dense elastomers (EVADE), synthesized via a straightforward and scalable method. In contrast to the pronounced immune reaction triggered by the commonly used implantable elastomers, EVADE materials effectively suppress the inflammation and long-term capsule formation in subcutaneous models of rodents and non-human primates for at least one year and two months, respectively. Implantation of EVADE materials significantly reduces the expression of inflammation-related proteins S100A8/A9 in adjacent tissues compared to polydimethylsiloxane (PDMS). We also show that inhibition or knockout of S100A8/A9 leads to substantial attenuation of fibrosis in mice, suggesting a target for fibrosis inhibition. Continuous subcutaneous insulin infusion (CSII) catheters constructed from EVADE elastomers demonstrate significantly improved longevity and performance compared to commercial catheters. The EVADE materials reported here may enhance and extend function in various medical devices by resisting local immune responses to implanted biomaterials.
Project description:Polymeric elastomers are extensively employed to fabricate implants intended for prolonged implantation. However, implantation of the elastomers can induce strong immune rejection reaction known as foreign body response (FBR), resulting in the rejection of foreign implants and thereby diminishing their in vivo efficacy. Herein, we present a group of immunocompatible elastomers, termed easy-to-synthesize vinyl-based anti-FBR dense elastomers (EVADE), synthesized via a straightforward and scalable method. In contrast to the pronounced immune reaction triggered by the commonly used implantable elastomers, EVADE materials effectively suppress the inflammation and long-term capsule formation in subcutaneous models of rodents and non-human primates for at least one year and two months, respectively. Implantation of EVADE materials significantly reduces the expression of inflammation-related proteins S100A8/A9 in adjacent tissues compared to polydimethylsiloxane (PDMS). We also show that inhibition or knockout of S100A8/A9 leads to substantial attenuation of fibrosis in mice, suggesting a target for fibrosis inhibition. Continuous subcutaneous insulin infusion (CSII) catheters constructed from EVADE elastomers demonstrate significantly improved longevity and performance compared to commercial catheters. The EVADE materials reported here may enhance and extend function in various medical devices by resisting local immune responses to implanted biomaterials.
Project description:Foreign body reaction (FBR), initiated by adherence of macrophages to biomaterials, is associated with several complications. Searching for mechanisms potentially useful to overcome these complications, we have established the signaling role of macrophages in the development of FBR. This study profiles gene expression of in vitro fibrinogen activated macrophages as well as that of freshly isolated macrophages from 3-days implants, against a background of unactivated macrophages/monocytes. Total RNA was isolated from fibrinogen activated macrophages, FBR macrophages and macrophages from blood (control). Samples were processed in triplicate on Rat Genome 230 2.0 Array GeneChips, adding up to 9 arrays in total. Microarray processing was performed at DNAVision (Charleroi, Belgium). The RMA comparisons between macrophases are linked below.
Project description:This study dermined the temporal gene expression profile of myeloid subpopulations recruited to the peritoneal cavity to encapsulate implanted foreign material. Sterile foreign objects were inserted into the peritoneal cavities of MacGreen mice (in which the Csf1r promoter directs myeloid-specific EGFP expression). At various time-points post-surgery (days 2, 4, 7, 14), mice were euthanased, and peritoneal exudate cells removed by lavage. Peritoneal exudate cells from MacGreen mice that had not received implants were used as controls (day 0; 'unstimulated'). Free-floating objects encapsulated with tissue were removed from the peritoneal cavities of different mice at days 7, 14, 21, 28 days, and single cell suspensions obtained by collagenase digestion. Single-cell suspensions from peritoneal exudate or tissue capsules were separated on the basis of size/granularity and EGFP fluorescence using FacsVantage SE Diva. Total RNA was extracted from FACS-sorted EGFP-hi cells.