(WHS-O.03) MECHANO-IMMUNO-FIBROTIC WOUND HEALING PATHWAYS REGULATE THE CELLULAR AND MOLECULAR ECOLOGY OF FOREIGN BODY RESPONSE
Thursday, May 16, 2024
6:00 PM – 6:30 PM East Coast USA Time
Background: Implantable biomedical devices have revolutionized medicine, with >70 million device implantations annually that benefit millions of patients. ~30% of devices will undergo premature failure during their lifetime, primarily due to an immune-mediated physiologic reaction known as the foreign body response (FBR). Biophysiochemical incompatibilities between host tissues and device biomaterials, regulated through immune signaling, activates the wound healing pathway resulting in fibrosis and collagenous tissue encapsulation of the device. Herein, we characterized the cellular and molecular ecology of human FBR capsule tissue.
Methods: Breast implant FBR tissue was collected with an IRB protocol from patients (n=14) undergoing standard of care surgical explanation of biomedical devices. Baker capsular contracture grading (B1: n=5; B2: n=3, B3: n=2, B4: n=4) was evaluated. Histological staining and analysis using hematoxylin and eosin (H&E), Masson’s trichrome, and picrosirius red was performed to assess tissue morphology, collagen deposition, and collagen architecture. Immunofluorescent staining and analysis was performed using CD68 (macrophage marker), aSMA (myofibroblast marker), and FAK (mechanical signaling marker).
Results: Severe FBR, Baker grades 3 & 4 (B3/B4), demonstrated significantly increased capsule thickness on H&E staining compared to mild FBR B1/B2 (p=0.0006). Analyzing collagen architecture with software algorithms CT-FIRE and CurveAlign, we found severe FBR significantly increased collagen fiber length compared to mild FBR (p=0.0408), while also creating a trend of increased collagen fiber angle and density (p=0.1920 and p=0.1774) and decreased mean distance (p=0.1093). Severe FBR caused an increase in CD68+ (macrophage) and aSMA (myofibroblast) layering within the FBR capsule, shown by significantly increased co-localized expression of CD68 and aSMA (p < 0.01) and co-localized CD68 and FAK (p=0.0465). More severe FBR also increased aSMA and immune cell numbers (p < 0.009).
Conclusions: We uncovered that increased immune-mediate crosstalk between macrophages and myofibroblasts within the FBR capsule correlated with higher degree Baker capsules, characterized by elevated fibrosis and collagen deposition. Interestingly, more severe FBR in humans also caused more colocalized macrophage-myofibroblast cellular layering, as well as elevated mechanoresponsive myeloid cells. Since myeloid cells circulate through the blood stream and home to sites of wound injury, targeting these myeloid cells could lead to new therapies to prevent FBR.