Abstract Body: Ischemic strokes often disrupt white matter (WM) microstructure, particularly affecting the corticospinal tract (CST) in the internal capsule (IC), leading to significant motor deficits. While evidence shows that axon sprouting occurs post-stroke, it often follows erratic paths, limiting functional recovery. Recent advances in 3D-printed hydrogel scaffolds have shown promise in guiding axon regeneration in spinal cord injury models. We hypothesize that implanting these scaffolds at white matter sites affected by stroke, aligned with CST fibers, will enhance functional axonal regeneration and motor recovery. Our aim is to develop and validate a precise and clinically applicable scaffold delivery system for future human studies.
We have developed a novel, minimally invasive stereotaxic method for the precise deployment of 1.3 mm diameter scaffolds within the IC of non-human primates (NHPs). Our approach utilizes a clinically available stereotactic robot (ROSA, ZimmerBiomet) combined with a linear cannula system (AlphaOmega) to plan scaffold placement. Then, we attempted to deploy scaffolds devices into thermally coagulated lesions in NHPs (n=2) and simulated lesions within hydrogel phantoms (n=2). Post-implant MRI, co-registered with high-resolution diffusion tensor imaging were applied to check for scaffold placement accuracy (n=4). We further complement the scaffold placement method by using a novel neurosurgical microrobot (Robeauté) designed for navigation along 3D nonlinear curves, with accuracy confirmed by CBCT imaging in phantom tests.
Our implantation methods accurately placed scaffolds in the intended locations and orientations, aligning with CST fibers in both phantom models and NHP brains. The deviation angle between the scaffold and CST fibers was 17.83° (SD 6.71°, n=3). The scaffolds were precisely positioned within the IC, validating our approach. Our robot-guided method accurately steered them to their intended position, demonstrating minimal errors in targeted white matter regions.
The methods described are poised for clinical translation, potentially extending the applicability of scaffold technology for improving motor function post-stroke. We are preparing NHPs for behavioral and upper limb motor assessments to evaluate the impact of scaffold implantation on axon regeneration, recovery, and performance. This research aims to enhance our understanding of ischemic stroke and develop innovative therapies to restore motor function in patients.