Convection-enhanced delivery of macromolecules into nervous tissue: Computational modeling, MR imaging, and experiments

Convection-enhanced delivery (CED) is a local drug delivery technique which directly infuses drug into the parenchyma of nervous tissue via a cannula. CED provides a promising drug delivery method for treating diseases of the nervous system such as brain tumors, spinal cord injury, and Parkinson's disease since it circumvents the blood brain barrier, provides more accurate targeting, and reduces the potential of systemic toxicity. CED enhances drug transport into nervous tissue by introducing convectional transport in addition to diffusional transport. This is particularly important for therapy where a large drug distribution volume on the order of centimeters is necessary.;Drugs delivered to undesired regions may cause side effects or damage healthy tissues, especially for tumor therapy where many therapeutic agents are toxic. Therapeutic doses should also be in an appropriate range since high doses may be toxic while low doses may result in ineffectual treatment. Concentration distribution of therapeutic agents after infusion is significantly related to CED protocol such as cannula shape and size, infusion site and rate, and infusate concentration. Thus, the CED protocol needs to be well designed. To improve CED protocol design, previous studies have used mathematical models to investigate the mechanics of infusion. These studies provided limited prediction ability. MR imaging methods have also been used to monitor drug distribution during CED. These imaging studies provided limited quantification capacity. Additional prediction tools and imaging techniques need to be developed for potential application in clinical CED protocol optimization and planning.;The purpose of this dissertation is to provide fundamental methodologies, in computational modeling and MR imaging techniques, for CED to improve the CED technique and application.;First, a biphasic finite element (FE) modeling of CED into nervous tissue was developed. The FE-based model solved for both the fluid flow and macromolecular transport. The model also accounted for deformation-dependent hydraulic permeability, which is difficult to account for using analytical methods. Infusion from a constant pressure source was modeled. In addition, parametric analysis was conducted to determine the sensitivity of macromolecular distribution to changes in tissue properties and infusion parameters. The developed FE model provides a platform upon which anisotropic transport and realistic anatomical boundaries may be modeled in the future.;Second, experimental micro-indentation to measure biphasic properties, i.e., Young's modulus and hydraulic permeability, was investigated. Characterization of these tissue properties is necessary for further development of computational transport models. Previous property measurements using micro-indentation are limited to specific indentation configurations. This dissertation used a biphasic FE model for micro-indentation. Micro-indentation using a spherical impermeable indenter on a thin hydrogel contact lens was conducted. Curve-fitting method based on the biphasic FE simulation and micro-indentation was developed. Systemic analysis to understand how biphasic properties and indenter velocity affect the indentation response and fitting result was also investigated. Such an analysis will aid in the design of a more efficient micro-indentation strategy.;Third, a non-invasive MR imaging method to quantify the concentration distribution during CED was developed. Previous studies have used MR imaging to quantify the distribution volume of MR-visible tracers in tissues. These studies did not quantify local concentration profiles, and used a simple linear relationship between signal intensity and tracer concentration. In this dissertation, a basic relationship between signal intensity and tracer concentration was quantified. An MR imaging scheme and data analysis method was designed. The method maximally utilized the intrinsic material properties (e.g., T1 and R1) to determine the concentration, and reduces the effect of instrumental factors (e.g., magnetic field inhomogeneity) on concentration calculation. Developing such a non-invasive quantification method is important since spatial concentration profiles can provide more information on the dose at different tissue regions. Comparison between computational transport model predictions and measured concentration profiles may also provide important transport parameters of drugs in nervous tissue in the future.;Finally, experiments of CED into spinal cord via the peripheral nerve infusion were conducted. A CED protocol for delivery of compound agents into the rat spinal cord was developed. A real-time in vivo MRI methodology to monitor the agent transport during CED was also developed. Experimental parameters and distribution characteristics of drug transport from the sciatic nerve to the spinal cord was investigated for macromolecular tracers. The developed MR imaging technique and CED protocol provided the infrastructure for further CED studies on rat models. Results of these animal experiments also provided fundamental knowledge of transport pathways from the sciatic nerve to the spinal cord.