Scott R. Wilson

Improved distribution of small molecules and viral vectors in the murine brain using a hollow fiber catheter

OBJECT A hollow fiber catheter was developed to improve the distribution of drugs administered via direct infusion into the central nervous system (CNS). It is a porous catheter that significantly increases the surface area of brain tissue into which a drug is infused. METHODS Dye was infused into the mouse brain through convection-enhanced delivery (CED) using a 28-gauge needle compared with a 3-mm-long hollow fiber catheter. To determine whether a hollow fiber catheter could increase the distribution of gene therapy vectors, a recombinant adenovirus expressing the firefly luciferase reporter was injected into the mouse striatum. Gene expression was monitored using in vivo bioluminescent imaging. To assess the distribution of gene transfer, an adenovirus expressing green fluorescent protein was injected into the striatum using a hollow fiber catheter or a needle. RESULTS Hollow fiber catheter-mediated infusion increased the volume of brain tissue labeled with dye by 2.7 times relative to needle-mediated infusion. In vivo imaging revealed that catheter-mediated infusion of adenovirus resulted in gene expression that was 10-times greater than that mediated by a needle. The catheter appreciably increased the area of brain transduced with adenovirus relative to a needle, affecting a significant portion of the injected hemisphere. CONCLUSIONS The miniature hollow fiber catheter used in this study significantly increased the distribution of dye and adenoviral-mediated gene transfer in the mouse brain compared with the levels reached using a 28-gauge needle. Compared with standard single-port clinical catheters, the hollow fiber catheter has the advantage of millions of nanoscale pores to increase surface area and bulk flow in the CNS. Extending the scale of the hollow fiber catheter for the large mammalian brain shows promise in increasing the distribution and efficacy of gene therapy and drug therapy using CED.

Large-Volume Infusions into the Brain: A Comparative Study of Catheter Designs

Background/Aims: “Whole-brain” infusions have emerged as a potential need with the promise of disease-modifying therapies for neurodegenerative diseases. In addition, several current clinical trials in brain cancer utilize direct delivery of drugs that are required to fill large volumes. Such requirements may not be well served by conventional single port catheters with their “point source” of delivery. Our aim is to examine infusions into large volumes of heterogeneous tissue, aiming for uniformity of distribution. Methods: A porous catheter (porous brain infusion catheter, PBIC), designed by Twin Star TDS LLC, for brain infusions was developed for this study and compared with another convection-enhanced delivery catheter (SmartFlowTM NGS-NC-03 from MRI Interventions, a step end-port catheter, SEPC) in current use in clinical trials. The studies were in vivo in porcine brain. A total of 8 pigs were used: the size of the pig brain limited the porous length to 15 mm. The placements of the tips of the two catheters were chosen to be the same (at the respective brain hemispheres). Results: The PBIC and SEPC both performed comparably and well, with the PBIC having some advantage in effecting larger distributions: p ∼ 0.045, with 5 infusions from each. Conclusions: Given the performance of the PBIC, it would be highly appropriate to use the device for therapeutic infusions in human clinical trials to assess its capability for large-volume infusions.

A pilot study in intraparenchymal therapy delivery in the prostate: a comparison of delivery with a porous needle vs standard needle

BackgroundNew biologic therapies directly injected into the prostate are in clinical trials for prostatic diseases. There is a need to understand distribution of injected therapies as a function of prostatic anatomy, physiology, and device design.MethodsA needle with a porous length of customizable-length was tested and its performance compared with a standard needle. Injections of magnetic resonance contrast reagent were placed into ex-vivo human prostates after surgical excision in standard of care therapy for invasive bladder cancer patients. Magnetic resonance images were acquired using sequences to quantify volume delivered, distributed, and backflow.ResultsMagnetic resonance images analysis revealed heterogeneity distribution with injection into the specimens. There was low resistance to flow along ductal pathways and high resistance to flow into glandular nodules and smooth muscle/fibrous parenchyma. Data confirm previous studies showing injection loss via urethra backflow, urethra, and prostatic ducts. Tissue fraction of dose was significantly higher with porous needle compared with standard needle (p = .03). We found that a greater volume of distribution divided by the amount infused (Vd/Vi) increased by 80% with the porous needle, though no statistically significant association due to small sample size.ConclusionsThis study demonstrated that prostatic tissue is anatomically heterogenic and limits distribution of needle injection. There is greater distribution in the ex-vivo prostate using a porous needle. The complexity of intra prostatic flow pathways suggests preoperative imaging and pre-treatment planning will enhance therapy.

MP52-16 INTRAPARENCHYMAL THERAPY DELIVERY IN THE PROSTATE: THE ROLE OF IMAGING AND DEVICE DESIGN

Cook (4.15mg) and lowest with Bard Max-Core (2.60mg, p<0.0001). Needle tip deflection varied by needle and by medium (p<0.0001 for all media; Figure 1). Deflection in all 4 media was lowest with BioPince and highest with TSK. The noise level ranged from 100.62dB for Bard MaxCore to 107.24dB for TSK (p<0.0001)a sound pressure difference of approximately 2.2 times. No difference in ultrasound visibility was detected. Of note, in the present study, the BioPince needle did not exhibit “zero biopsy”, as reported by patient studies. CONCLUSIONS: Six core biopsy needles demonstrate significant differences in quantitative measures of overall sample quality, needle tip deflection, and noise level. These can be used for needle selection in the clinical setting.