The blood-brain barrier (BBB) presents a formidable obstacle to the effective delivery of systemically administered pharmacological agents to the brain, with ~5% of candidate drugs capable of effectively penetrating the BBB. A variety of biomaterials and therapeutic delivery devices have recently been developed that facilitate drug delivery to the brain. These technologies have addressed many of the limitations imposed by the BBB by: (1) designing or modifying the physiochemical properties of therapeutic compounds to allow for transport across the BBB; (2) bypassing the BBB by administration of drugs via alternative routes; and (3) transiently disrupting the BBB (BBBD) using biophysical therapies. Here we specifically review colloidal drug carrier delivery systems, intranasal, intrathecal, and direct interstitial drug delivery methods, focused ultrasound BBBD, and pulsed electrical field induced BBBD, as well as the key features of BBB structure and function that are the mechanistic targets of these approaches. Each of these drug delivery technologies are illustrated in the context of their potential clinical applications and limitations in companion animals with naturally occurring intracranial diseases.
Introduction: Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we explore the use of constant pressure infusions in addition to controlled catheter movement as a means to increase volume dispersed (Vd) in an agarose gel brain tissue phantom. Methods: Constant flow rate and constant pressure infusions were conducted with a stationary catheter, a catheter retracting at a rate of 0.25 mm/min, and a catheter retracting at a rate of 0.5 mm/min. Results: The 0.25 mm/min and 0.5 mm/min retracting constant pressure catheters resulted in significantly larger Vd compared to any other group, with a 105% increase and a 155% increase compared to the stationary constant flow rate catheter, respectively. These same constant pressure retracting infusions resulted in a 42% and 45% increase in Vd compared to their constant flow rate counterparts. Conclusions: Using constant pressure infusions coupled with controlled catheter movement appears to have a beneficial effect on Vd in agarose gel.
Convection-enhanced delivery (CED) is a drug delivery technique used to deliver therapeutics directly to the brain and is a continually evolving technique to treat glioblastoma. Early versions of CED have proven to result in inadequate drug volume dispersed (Vd), increasing the likelihood of tumor recurrence. Fiber optic microneedle devices (FMDs) with the ability to deliver fluid and thermal energy simultaneously have shown an ability to increase Vd, but FMDs have historically had low light transmission efficiency. In this study, we present a new fabrication method, solid fiber inside capillary (SFIC) FMD, and a modified fusion splicing (FS) method with the goal of increasing light delivery efficiency. The modified FS FMD resulted in an increase in light transmission efficiency between 49% and 173% compared to previous prototypes. However, the FS FMD resulted in significantly lower transmission efficiencies compared to the SFIC FMD (p = 0.04) and FS FMDs perform much worse when light-absorptive materials, like black dye, are placed in the bore. The light absorption of a candidate cytotoxic agent, QUAD-CTX, appear to be similar to water, and light delivery through FS FMDs filled with QUAD-CTX achieves a transmission efficiency of 85.6 ± 5.4%. The fabrication process of the SFIC FMDs results in extremely fragile FMDs. Therefore, the use of a modified FS FMD fabrication process appears to be better suited for balancing the desire to increase light transmission efficiency while retaining a sturdy FMD construction.
Convection-enhanced delivery (CED) is an experimental method of localized treatment to release high concentrations of the drug into a target area. An implementation of CED by our lab is the convection-enhanced thermo-therapy catheter system (CETCS). The device is a collection of arborizing microneedles used to affect a broader coverage of a dispersed volume in the regions of interest. We suspect the coverage of the dispersal volume depends on the material properties of the brain the infusate is being administered. In this study, we create a computational model to evaluate how two adjacent materials with varying permeability (4.45 mm4 N-1 s-1 with 13.35 or 35.6 mm4 N-1 s-1) will disperse into a 0.6% (w/w) agarose gel. Transient state analysis was conducted using the FEBio Software Suite. As expected, results show a much larger dispersal volume in the material with the higher permeability and along the border of the two materials.
The Convection-Enhanced Thermo-Therapy Catheter System (CETCS) was developed by our group at The University of Texas at Austin for the treatment of glioblastoma. This arborizing catheter is remotely operated and provides the ability to position and infuse in regions of the tumor and tumor margins to increase the dispersal volume coverage capability. The next step in developing this device is the further characterization of the materials being used in this design. Device characterization included evaluating the behavior of the microneedles under compression while they were in contact with several types of durometers (50A, 80A, 90A, and 95A). This test method was used to determine if the microneedles would experience breakage at the tip or along the microneedle. After the compression-durometer testing, it was determined the tips of the microneedles were more likely to puncture the durometer prior to experiencing any breakage. The device’s microneedles are not expected to come into contact with materials that have a higher durometer rating of 50A and will be acceptable in the current CETCS design meant for the treatment of glioblastomas.
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