Radiopaque alginate microcapsules for X-ray visualization and immunoprotection of cellular therapeutics.

Alginate-poly-L-lysine-alginate (APA) microcapsules have been explored as vehicles for therapeutic drug and cell delivery. The permselectivity of these capsules provides a unique means of controlled drug release and immunoisolation of encapsulated cells. Immunoisolation is especially attractive as it abrogates the need for chronic immunosuppressive therapy and opens up the possibility for the delivery of numerous cell sources including xenogeneic grafts. APA microcapsules containing cellular therapeutics have proven effective in the short-term treatment of a wide range of diseases requiring enzyme or endocrine replacement therapy, including type I diabetes. If these microcapsules could be noninvasively monitored with X-ray imaging modalities (i.e., fluoroscopy, CT, and digital subtraction angiography), questions such as the ideal transplantation site, the best means of delivery, and the long-term survival of grafts could be better addressed. We have developed two novel alginate-based radiopaque microcapsule formulations containing either barium sulfate (Ba X-Caps) or bismuth sulfate (Bi X-Caps). As compared to conventional, nonradiopaque APA capsules, Ba X-Caps and Bi X-Caps containing human cadaveric islets resulted in a decrease in cellular viability of less than 5% up to 14 days after encapsulation. Both radiopaque capsules were found to be permeable to lectins < or =75 kDa, but were impermeable to lectins > or =120 kDa, thus ensuring the blockage of the penetration of antibodies while allowing free diffusion of insulin and nutrients. The glucose-responsive insulin secretion of the radiopaque encapsulated human islets was found to be unaltered compared to that of unlabeled controls, with human C-peptide levels ranging from 3.21 to 2.87 (Ba X-Caps) and 3.23 to 2.87 (Bi X-Caps) ng/islet at 7 and 14 days postencapsulation, respectively. Using fluoroscopy, both Ba X-Caps and Bi X-Caps could be readily visualized as single radiopaque entities in vitro. Furthermore, following transplantation in vivo in mice and rabbits, single capsules could be identified with no significant change in contrast for at least 2 weeks. This study represents the first attempt at making radiopaque microcapsules for X-ray guided delivery and imaging of cellular therapeutics. While human cadaveric islets were used as a proof-of-principle, these radiopaque capsules may have wide ranging therapeutic applications for a variety of cell types.

Response of balloon-expandable endoprosthetic metallic stents subjected to over-expansion in vitro.

We attempted to evaluate the in vitro behavior and performance of balloon-expandable endoprosthetic metallic stents subjected to over-expansion (OE). Seventy-two balloon-expandable endoprosthetic stents, representing 22 models from six manufacturers, were overexpanded in vitro. Stents were initially expanded to their maximum manufacturer- recommended diameter and then over-expanded incrementally to their endpoints. Endpoints for OE were either stent disarticulation or an inability to undergo further expansion despite balloon insufflation to maximum burst pressure. Measurements of stent dimensions were recorded at each overexpanded diameter and comparisons were made to manufacturer's specifications. A total of 288 balloon-driven expansions were performed on 72 stents. Sixteen stents were expanded to large diameters (> or = 16 mm), 20 stents underwent OE of 50% or greater. One model tended to disarticulate after OE greater than 50%. There were five models that had a tendency to disarticulate after minimal OE. Five models were resistant to OE (25% or less OE) but did not disarticulate. Nearly all stents showed some degree of foreshortening with OE, while 36 stents underwent foreshortening of 30% or more. Models that are not recommended for OE include Intrastent, Intrastent DoubleStrut, NIR Royale and Omniflex. Good candidates for OE include Intrastent DoubleStrut LD, Palmaz large, Medtronic Extra Support Biliary Plus and Medtronic Flexible Biliary. Palmaz XL remains the only model available for expansion from 20 to 28 mm in diameter. For the remaining stents, OE is possible, however, caution should be used.

Safety of conscious sedation in interventional radiology.

PURPOSE: To identify rates of adverse events associated with the use of conscious sedation in interventional radiology. METHODS: In a 5-month period, prospective data were collected on patients undergoing conscious sedation for interventional radiology procedures (n = 594). Adverse events were categorized as respiratory, sedative, or major adverse events. Respiratory adverse events were those that required oral airway placement, ambu bag, or jaw thrust. Sedation adverse events were unresponsiveness, oxygen saturation less than 90%, use of flumazenil/naloxone, or agitation. Major adverse events were hypotension, intubation, CPR, or cardiac arrest. The frequency of adverse events for the five most common radiology procedures were determined. RESULTS: The five most common procedures (total n = 541) were biliary tube placement/exchange (n = 182), tunneled catheter placement (n = 135), diagnostic arteriography (n = 125), vascular interventions (n = 52), and other catheter insertions (n = 46). Rates for respiratory, sedation, and major adverse events were 4.7%, 4.2%, and 2.0%, respectively. The most frequent major adverse event was hypotension (2.0%). Biliary procedures had the highest rate of total adverse events (p < .05) and respiratory adverse events (p < .05). CONCLUSION: The frequency of adverse events is low with the use of conscious sedation during interventional procedures. The highest rates occurred during biliary interventions.

GPIIb-IIIa receptor inhibitors: what the interventional radiologist needs to know.

The glycoprotein IIb-IIIa (GPIIb-IIIa) receptor inhibitors have established themselves as first line therapy in the treatment of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI). The benefit of these agents rests in their ability to attenuate the deleterious effects of platelet activation, both at the site of an inflamed vessel wall (due to a ruptured plaque or PCI) and in the microcirculation as a result of embolization. Based on these results, interventional radiologists are beginning to explore the potential of using GPIIb-IIIa inhibitors during interventions in the peripheral circulation. This paper reviews the molecular biology of the GPIIb-IIIa receptor, the pharmacology of the GPIIb-IIIa receptor inhibitors, the current coronary and peripheral vascular literature as it pertains to the GPIIb-IIIa receptor inhibitors, and potential future applications of the GPIIb-IIIa receptor inhibitors in the peripheral circulation.

Chemoembolization of liver tumor in a rabbit model: assessment of tumor cell death with diffusion-weighted MR imaging and histologic analysis.

PURPOSE: To assess the efficacy of chemoembolization of liver tumors by determining the fraction of viable tumor cells remaining after treatment with use of diffusion magnetic resonance (MR) imaging and histologic analysis. MATERIALS AND METHODS: VX2 tumor was grown in the livers of 12 rabbits. Animals were divided into a chemoembolization group and an untreated group. Conventional, perfusion, and diffusion MR imaging was performed on all rabbits. Histopathologic analysis of explanted livers was performed to document tumor cell death and measure Bcl-2 levels (inhibitor of apoptosis). RESULTS: Diffusion-weighted MR imaging delineated zones of tumor cell death as regions of lower signal intensity in both groups. Apparent diffusion coefficients were significantly greater in the area of tumor necrosis than in the area of viable tumor. Histologic analysis demonstrated a significantly lower percentage of viable cells in the treated group (<1%) than in the control group (55%). Bcl-2 expression detected within the viable areas of the tumor was greater in the treated group than in the control group. CONCLUSIONS: Chemoembolization causes extensive tumor cell destruction. Diffusion MR imaging can detect tumor cell death and can be used to assess the efficacy of chemoembolization. Bcl-2 was expressed in the treated group, suggesting an apoptotic pathway of cell death.

An in-depth examination of the excretion of albumin and other sensitive markers of renal damage in mild hypertension.

In an in-depth examination to better define the renal effects of mild hypertension, we used urinary proteins to indicate damage to the glomerulus (albumin), tubular reabsorption capability (retinol-binding protein), and turnover of tubular tissue (alanine aminopeptidase and N-acetyl-beta-D-glucosaminidase) in a group of 18 people with mild hypertension not associated with diabetes and a control group (n = 12). The participants' activity was controlled on a high normal salt diet for 3 days followed by a low salt diet for 4 days. Two distinct patterns of albumin excretion were evident in the hypertensive group: 22% had elevated, highly variable excretion patterns, and the rest had tightly grouped values below 16 mg/g creatinine, 16 micrograms/min, or 16 mg/L, with the lowest within-person biological variability given by albumin calculated as a ratio to creatinine. Albumin and NAG excretion primarily correlated with systolic blood pressure and the best correlations were given by ratios to creatinine. A marked decrease in salt excretion of 71% (to 50.8 mEq/day) resulted in significant (P < .0005) decreases in systolic (13.9 mm Hg), diastolic (6.4 mm Hg), and mean arterial pressures (8.9 mm Hg) only in the group with mild hypertension. However, albumin excretion did not decrease when dietary salt content was lowered. The group with hypertension also had higher urinary excretion of lysosomal N-acetyl-beta-D-glucosaminidase (P < .01), and whites in the group had a higher excretion of retinol-binding protein than did whites in the control group (P < .02). Retinol-binding protein values, however, were within the normal range, indicating that the elevated albumin values were the result of changes in selectivity of the glomerulus.