ABSTRACT
Standard treatment for glioblastoma is noncurative and only partially effective. Convection-enhanced delivery (CED) was developed as an alternative approach for effective loco-regional delivery of drugs via a small catheter inserted into the diseased brain. However, previous CED clinical trials revealed the need for improved catheters for controlled and satisfactory distribution of therapeutics. In this study, the arborizing catheter, consisting of six infusion ports, was compared to a reflux-preventing single-port catheter. Infusions of iohexol at a flow rate of 1 µL/min/microneedle were performed, using the arborizing catheter on one hemisphere and a single-port catheter on the contralateral hemisphere of excised pig brains. The volume dispersed (Vd) of the contrast agent was quantified for each catheter. Vd for the arborizing catheter was significantly higher than for the single-port catheter, 2235.8 ± 569.7 mm3 and 382.2 ± 243.0 mm3, respectively (n = 7). Minimal reflux was observed; however, high Vd values were achieved with the arborizing catheter. With simultaneous infusion using multiple ports of the arborizing catheter, high Vd was achieved at a low infusion rate. Thus, the arborizing catheter promises a highly desirable large volume of distribution of drugs delivered to the brain for the purpose of treating brain tumors.
ABSTRACT
Convection-enhanced delivery (CED) is an investigational therapy developed to circumvent the limitations of drug delivery to the brain. Catheters are used in CED to locally infuse therapeutic agents into brain tissue. CED has demonstrated clinical utility for treatment of malignant brain tumors; however, CED has been limited by lack of CED-specific catheters. Therefore, we developed a multiport, arborizing catheter to maximize drug distribution for CED. Using a multiphasic finite element (FE) framework, we parametrically determined the influence of design variables of the catheter on the dispersal volume of the infusion. We predicted dispersal volume of a solute infused in a permeable hyperelastic solid matrix, as a function of separation distance (ranging from 0.5 to 2.0 cm) of imbedded infusion cavities that represented individual ports in a multiport catheter. To validate the model, we compared FE solutions of pressure-controlled infusions to experimental data of indigo carmine dye infused in agarose tissue phantoms. The Tc50, defined as the infusion time required for the normalized solute concentration between two sources to equal 50% of the prescribed concentration, was determined for simulations with infusion pressures ranging from 1 to 4 kPa. In our validated model, we demonstrate that multiple ports increase dispersal volume with increasing port distance but are associated with a significant increase in infusion time. Tc50 increases approximately tenfold when doubling the port distance. Increasing the infusion flow rate (from 0.7 µL/min to 8.48 µL/min) can mitigate the increased infusion time. In conclusion, a compromise of port distance and flow rate could improve infusion duration and dispersal volume.
ABSTRACT
Foot ulcers are a severe complication of diabetic patients resulting from nerve and tendon pathologic alterations. In diabetic patients the tendons are thicker, shorter and have increased stiffness. We examined C57BL/KsJ (BKS.Cg-Dock7(m) +/+ Lepr (db) /J) (db/db) mice tendons to determine whether they are an animal model for human diabetic tendon changes. We hypothesized that the Achilles tendons of db/db diabetic mice would be thicker, stiffer, fail at lower loads and stresses, and have degenerative changes compared to control mice. Biomechanical and histologic analyses of the Achilles tendons of 16 week old db/db and control male mice were performed. There was a significant increase in tendon diameter and significant decreases in maximum load, tensile stress, stiffness and elastic modulus in tendons from diabetic mice compared to controls. Mild degenerative and neutrophil infiltration was observed near the tendon insertions on the calcaneous in 25% of db/db mice. In summary, hyper-glycemia and obesity lead to severe changes in db/db mice will be a useful model to examine mechanisms for tendon alterations.
ABSTRACT
BACKGROUND: Allograft safety is contingent on effective sterilization. However, current sterilization methods have been associated with decreased biomechanical strength and higher failure rates of soft-tissue allografts. In this study, electron beam (e-beam) sterilization was explored as an alternative sterilization method to preserve biomechanical integrity. We hypothesized that e-beam sterilization would not significantly alter the biomechanical properties of tendon allograft compared with aseptic, nonsterilized controls and gamma-irradiated grafts. METHODS: Separate sets of forty fresh-frozen tibialis tendon allografts (four from each of ten donors) and forty bisected bone-patellar tendon-bone (BTB) allografts (four from each of ten donors) were randomly assigned to four study groups. One group received a 17.1 to 21.0-kGy gamma radiation dose; two other groups were sterilized with an e-beam at either a high (17.1 to 21.0-kGy) or low (9.2 to 12.2-kGy) dose. A fourth group served as nonsterilized controls. Each graft was cyclically loaded to 200 N of tension for 2000 cycles at a frequency of 2 Hz, allowed to relax for five minutes, and then tested in tension until failure at a 100%/sec strain rate. One-way analysis of variance testing was used to identify significant differences. RESULTS: Tibialis tendons sterilized with both e-beam treatments and with gamma irradiation exhibited values for cyclic tendon elongation, maximum load, maximum displacement, stiffness, maximum stress, maximum strain, and elastic modulus that were not significantly different from those of nonsterilized controls. BTB allografts sterilized with the high e-beam dose and with gamma irradiation were not significantly different in cyclic tendon elongation, maximum load, maximum displacement, stiffness, maximum stress, maximum strain, and elastic modulus from nonsterilized controls. BTB allografts sterilized with the e-beam at the lower dose were significantly less stiff than nonsterilized controls (p = 0.014) but did not differ from controls in any other properties. The difference in stiffness likely resulted from variations in tendon size rather than the treatments, as the elastic moduli of the groups were similar. CONCLUSIONS: The biomechanical properties of tibialis and BTB allografts sterilized with use of an e-beam at a dose range of 17.1 to 21.0 kGy were not different from those of aseptic, nonsterilized controls or gamma-irradiated allografts. CLINICAL RELEVANCE: E-beam sterilization can be a viable method to produce safe and biomechanically uncompromised soft-tissue allografts.
