61. Acellular Dermal Matrix Modulates Monocyte Transcriptome In Mice And Humans To Attenuate Foreign Body Response

Introduction: Implant-based breast reconstruction is limited by a foreign body response wherein the breast implant invokes an inflammatory fibrotic reaction characterized by chronic inflammation and eventual fibrotic encapsulation of the material. Clinically referred to as capsular contracture, this is a common surgical complication among implant-based breast reconstruction, often resulting in pain, aesthetic changes, and device failure. Acellular dermal matrix (ADM) is thought to decrease the incidence of capsular contracture through downregulating inflammation. We sought to identify the mechanism of action through which ADM modifies the peri-prosthetic foreign body response. Methods: Two-stage breast reconstruction was performed, with incomplete ADM coverage of the tissue-expander (TE) at the index operation and peri-prosthetic capsule harvested at implant exchange. ADM-adjacent capsule ("ADM capsule") and TE-adjacent capsule ("native capsule") biopsies were sent for histology and single-cell RNA-sequencing (scRNA-seq). A mouse model of capsule formation with and without ADM was developed to compare response across species. To further explore potential mechanisms underlying observations seen in human specimens, silicone implants with and without ADM ("mADM capsule" and "mNative capsule," respectively) were placed subcutaneously in the dorsi of C57BL/6 mice. Peri-implant tissue was then harvested at post-operative day 28 for histology, scRNA-seq and CODEX spatial analysis. Results: Paired capsule specimens were obtained from 13 patients, with a mean age of 51 years and time to implant exchange of 7 months. Hematoxylin and eosin staining demonstrated thinner, more porous capsules in ADM specimens, and thicker, denser capsules in native specimens. There was also increased collagen density by Masson's trichrome (MT) staining in native vs. ADM capsules (*P < 0.05). These data were mirrored in the mouse FBR model, with increased collagen density by MT staining in mNative versus mADM capsules (*P < 0.0001). scRNA-seq analysis revealed notable heterogeneity across all cells, conserved between human and mouse data. Interestingly, monocyte subset analysis demonstrated similar expression of regenerative genes by human cluster 0 and mouse cluster 4 in ADM and mADM capsules relative to native and mNative capsules, respectively. CODEX spatial protein analysis confirmed similiar monocyte subpopulation distributions in human ADM and Native capsules. In addition, ADM capsules showed significantly greater regenerative cell-cell spatial interactions vs Native capsules (*P < 0.001). Conclusion: ADM application is associated with decreased fibrosis of the peri-prosthetic capsule in breast reconstruction and a decrease in the incidence of capsular contracture. scRNA-seq analysis and CODEX spatial analysis revealed that ADM alters gene expression in monocytes, modulates the peri-prosthetic microenvironment, and attenuates the foreign body response.