RELOADABLE INTRACEREBRAL IMPLANTS BASED ON BIOLOGICALLY INSPIRED MASS EXCHANGE AND BRAIN COMPATIBLE HYDROGELS

Abstract

Glioblastoma (GBM) is a common and highly aggressive form of malignant brain tumor characterized by poor prognoses and high recurrence rates. Recurrence describes the phenomenon of cancer cells remaining within the resection cavity, following gross tumor mass removal, where those remaining cells subsequently infiltrate surrounding tissue and promote tumor reformation. Currently, the standard of care for GBM recurrence following tumor resection is the Stupp protocol, or adjuvant radiation therapy and oral chemotherapy temozolomide. Further, existing technology promotes a one-dose method of local drug delivery immediately following resection with no intention for further reload administration aside from repeated surgical intervention. Many solutions utilize a degradation mechanism to locally deliver treatment (e.g., chemotherapy or radiation) and do not prioritize mechanical compatibility within brain microenvironment. The resulting mismatch is often associated with numerous adverse reactions. To address those residual cancer cells, the following work describes an implantable, internally perfused device designed to occupy the resection cavity following surgical removal of diseased brain tissue (i.e., hematoma, tumor, or other) and composed of soft, brain mimetic material to promote mechanical advantage within resection space. The system integrates a brain-compatible reservoir, catheter access, and port on the skull surface for cyclic re-loading and drug delivery to immediate implant surroundings, enabling chronic and localized treatment of the peri-implant brain. The proposed soft material implants are 3D printed using an advanced extrusion-based technique (FRESH) designed to support continuous printing of soft, low-viscosity bioinks. In enabling the use of this technique, support bath microspheres were investigated in multiple design of experiments (DOE) and produced small (< 50 μm), circular (index > 0.8) particles intended to optimize print resolution, support bath stiffness under low strain, and yield-stress behavior. The interior designs of the implants were modeled after biologically inspired mass exchange. Print fidelity of prototype halves were established prior to prototype assembly and functionality evaluation methods consisted of reload capabilities and quantification of drug release profile differences between cyclically loaded and not previously loaded prototypes. Two prototypes of distinct internal geometry demonstrated cyclic load capabilities via model drug encapsulation efficiency and resistance to deformation. Model molecule release profiles observed were highly similar between designs and across loading cycles, which may be attributed to limitations of fabrication. These novel prototypes establish the foundation for future work in intracerebral, soft material implants, furthering the advancement of externally reloadable mass exchange at the site of glioblastoma recurrence.