Preclinical characterization of macrophage-adhering gadolinium micropatches for MRI contrast after traumatic brain injury in pigs

Abstract

The choroid plexus (ChP) of the brain plays a central role in orchestrating the recruitment of peripheral leukocytes into the central nervous system (CNS) through the blood-cerebrospinal fluid (BCSF) barrier in pathological conditions, thus offering a unique niche to diagnose CNS disorders. We explored whether magnetic resonance imaging of the ChP could be optimized for mild traumatic brain injury (mTBI). mTBI induces subtle, yet influential, changes in the brain and is currently severely underdiagnosed. We hypothesized that mTBI induces sufficient alterations in the ChP to cause infiltration of circulating leukocytes through the BCSF barrier and developed macrophage-adhering gadolinium [Gd(III)]–loaded anisotropic micropatches (GLAMs), specifically designed to image infiltrating immune cells. GLAMs are hydrogel-based discoidal microparticles that adhere to macrophages without phagocytosis. We present a fabrication process to prepare GLAMs at scale and demonstrate their loading with Gd(III) at high relaxivities, a key indicator of their effectiveness in enhancing image contrast and clarity in medical imaging. In vitro experiments with primary murine and porcine macrophages demonstrated that GLAMs adhere to macrophages also under shear stress and did not affect macrophage viability or functions. Studies in a porcine mTBI model confirmed that intravenously administered macrophage-adhering GLAMs provide a differential signal in the ChP and lateral ventricles at Gd(III) doses 500- to 1000-fold lower than those used in the current clinical standard Gadavist. Under the same mTBI conditions, Gadavist did not offer a differential signal at clinically used doses. Our results suggest that macrophage-adhering GLAMs could facilitate mTBI diagnosis.

Polymer Micropatches as B-Cell Engagers

“…Previously, we demonstrated the ability of antibody-functionalized polymeric micropatches, a platform termed as Micropatches as Cell Engagers (MACE), to engage multiple cell surface receptors and induce robust signaling via receptor cross-linking . Due to the unique discoidal shape and high aspect ratio, these micropatches can resist cellular internalization and remain attached to the surface of many immune cells, including macrophages, , monocytes, natural killer (NK) cells, and neutrophils . Here, we further develop MACE to induce B-cell signaling via receptor multimerization, resulting in a potent and sustained activation of the cells (Figure ).…”

Dynamic monitoring soft tissue healing via visualized Gd-crosslinked double network MRI microspheres

“…Contrast agents (CAs) are frequently employed to enhance diagnostic accuracy by improving the image signal-to-noise ratio (SNR) [ 17 ]. However, commonly used MRI CAs are low molecular chelates based on Gd (III), present several disadvantages: low tissue specificity, rapid metabolism, high background noise, and a narrow imaging window [ 18 ]. Additionally, their low molecular weight ligands decrease the contrast agent’s relaxation rate, necessitating increased dosage and elevating the risk of long-term toxicity, such as in chronic kidney disease [ 19 ].…”