An arborizing, multiport catheter for maximizing drug distribution in the brain via convection enhanced delivery
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Glioblastoma (GBM) is a high-grade malignant glioma with a mortality rate that exceeds 95% despite over eight decades of medical research dedicated to improve outcomes. GBM is extremely difficult to treat and practically incurable with standard treatment involving surgical resection, radiation, concomitant and/or adjuvant chemotherapy. Therefore, convection enhanced delivery (CED) was developed to improve therapeutic outcomes. CED involves intraparenchymal delivery of drugs into diseased tissue via a small catheter. CED has proven to bypass the blood brain barrier and achieve better drug distribution than diffusion-based therapies. Nevertheless, the large volumes necessary to target entire tumors and peritumor volumes have been previously unachievable with currently-available catheters. This dissertation describes the development of a multiport, arborizing catheter designed specifically for improving drug distribution in the brain. The performance of early-stage arborizing catheter prototypes was compared to single-port catheters in infusion studies using agarose brain phantoms. Volume dispersed (V [subscript d]) and mean distribution ratios (V [subscript d] :V [subscript i]) were quantified and compared between the two catheters. The arborizing catheter produced higher V [subscript d] values; however, it did not exhibit the greatest V [subscript d] :V [subscript i], likely due to overlapping distribution volumes from the multiple individual ports. Following infusion in brain phantoms, a biotransport study of the arborizing catheter was conducted using a multiphasic finite element framework. The model was used to predict dispersion volume of a solute in a permeable hyperelastic solid matrix as a function of separation distance between adjacent ports. Results show that increasing port distance can increase V [subscript d]; however, infusion time also increases significantly with greater port distance. One way to mitigate increased infusion times is to employ higher infusion flow rates. Finally, the performance of improved arborizing catheters was compared to reflux-preventing single-port catheters in excised pig brains. CT scans were used to quantify V [subscript d] and V [subscript d] :V [subscript i] of infused iohexol (contrast-enhancing agent). The average volume dispersed for the arborizing catheter was 5.8 times greater than the single-port catheter. Mean distribution ratios for both catheters were similar. Using the multiple ports of the arborizing catheter, high V [subscript d] was achieved at a low infusion rate with negligible reflux. Given that previous attempts of CED reported poor drug distribution, the arborizing catheter may help overcome the limitations of CED.