A comprehensive review on modeling aspects of infusion-based drug delivery in the brain

Brain disorders represent an ever-increasing health challenge worldwide. While conventional drug therapies are less effective due to the presence of the blood-brain barrier, infusion-based methods of drug delivery to the brain represent a promising option. Since these methods are mechanically controlled and involve multiple physical phases ranging from the neural and molecular scales to the brain scale, highly efficient and precise delivery procedures can significantly benefit from a comprehensive understanding of drug-brain and device-brain interactions. Behind these interactions are principles of biophysics and biomechanics that can be described and captured using mathematical models. Although biomechanics and biophysics have received considerable attention, a comprehensive mechanistic model for modeling infusion-based drug delivery in the brain has yet to be developed. Therefore, this article reviews the state-of-the-art mechanistic studies that can support the development of next-generation models for infusion-based brain drug delivery from the perspective of fluid mechanics, solid mechanics, and mathematical modeling. The supporting techniques and database are also summarized to provide further insights. Finally, the challenges are highlighted and perspectives on future research directions are provided. Statement of significance: Despite the immense potential of infusion-based drug delivery methods for bypassing the blood-brain barrier and efficiently delivering drugs to the brain, achieving optimal drug distribution remains a significant challenge. This is primarily due to our limited understanding of the complex interactions between drugs and the brain that are governed by principles of biophysics and biomechanics, and can be described using mathematical models. This article provides a comprehensive review of state-of-the-art mechanistic studies that can help to unravel the mechanism of drug transport in the brain across the scales, which underpins the development of next-generation models for infusion-based brain drug delivery. More broadly, this review will serve as a starting point for developing more effective treatments for brain diseases and mechanistic models that can be used to study other soft tissue and biomaterials.