Examination of the foreign body response to biomaterials by nonlinear intravital microscopy

Abstract

Implanted biomaterials often fail because they elicit a foreign body response (FBR) and concomitant fibrotic encapsulation. To design clinically relevant interference approaches, it is crucial to first examine the FBR mechanisms. Here, we report the development and validation of infrared-excited nonlinear microscopy to resolve the three-dimensional (3D) organization and fate of 3D-electrospun scaffolds implanted deep into the skin of mice, and the following step-wise FBR process. We observed that immigrating myeloid cells (predominantly macrophages of the M1 type) engaged and became immobilized along the scaffold/tissue interface, before forming multinucleated giant cells. Both macrophages and giant cells locally produced vascular endothelial growth factor (VEGF), which initiated and maintained an immature neovessel network, followed by formation of a dense collagen capsule 2–4 weeks post-implantation. Elimination of the macrophage/giant-cell compartment by clodronate and/or neutralization of VEGF by VEGF Trap significantly diminished giant-cell accumulation, neovascularization and fibrosis. Our findings identify macrophages and giant cells as incendiaries of the fibrotic encapsulation of engrafted biomaterials via VEGF release and neovascularization, and therefore as targets for therapy.

Immune-informed mucin hydrogels evade fibrotic foreign body response in vivo

“…We focused our 9 attention on macrophages (CD68 + CD11b + ) and other myeloid cells (CD68 -Gr1 low/-CD11b + ) that were predominant fractions of immune cells sorted by FACS (Figure 4, S-4). Macrophages are especially relevant in this context since they display remarkable functional plasticity and participate in the host defence, immune regulation, and tissue repair, all aspects playing a pivotal role in mediating implant-triggered fibrosis 3,34,35 .…”

Novel ultrafine‐grained β‐type Ti–28Nb–2Zr–8Sn alloy for biomedical applications

“…46 The bone implants often fail in the osteolysis and aseptic loosening induced by prolonged inflammatory response around the implant materials. [48][49][50] The proinflammatory mediators including IL-6 and TNF-α are often found at the implantation site. Macrophages are one of the inflammatory cells accepted as a crucial source of inflammatory signals.…”

“…Macrophages are one of the inflammatory cells accepted as a crucial source of inflammatory signals. [48][49][50] The proinflammatory mediators including IL-6 and TNF-α are often found at the implantation site. 47 A recent study found that titanium with smooth morphology expressed a higher mRNA level of IL-6 and TNF-α compared with the rough surface.…”

An Ectopic Imaging Window for Intravital Imaging of Engineered Bone Tissue

“…Enhanced insight into the processes that contribute to successful repair therefore requires a method for nondestructive, high‐resolution visualization of bone tissue–engineered constructs in vivo. A promising approach for the study of living tissue exists in the combination of intravital microscopy with multiphoton fluorescence excitation, which is increasingly being applied to investigate tumor biology and host reactions on implanted biomaterials …”

“…A promising approach for the study of living tissue exists in the combination of intravital microscopy with multiphoton fluorescence excitation, which is increasingly being applied to investigate tumor biology and host reactions on implanted biomaterials. (5,6) Multiphoton-intravital microscopy (MP-IVM) relies on the nonlinear excitation of fluorophores through absorption of two or more photons at once. (7) This means that near-infrared excitation wavelengths can be used which penetrate deeper into the tissue, result in less off-target phototoxicity, and allow the label-free visualization of collagen fibrils through secondharmonics generation.…”