Robert P. Liddell

Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging

PURPOSE To develop novel immunoprotective alginate microcapsule formulations containing perfluorocarbons (PFCs) that may increase cell function, provide immunoprotection for xenografted cells, and simultaneously enable multimodality imaging. MATERIALS AND METHODS All animal experiments were approved by an Institutional Animal Care and Use Committee. Cadaveric human islet cells were encapsulated with alginate, poly-l-lysine, and perfluorooctyl bromide (PFOB) or perfluoropolyether (PFPE). In vitro viability and the glucose-stimulation index for insulin were determined over the course of 2 weeks and analyzed by using a cross-sectional time series regression model. The sensitivity of multimodality (computed tomography [CT], ultrasonography [US], and fluorine 19 [(19)F] magnetic resonance [MR] imaging) detection was determined for fluorocapsules embedded in gel phantoms. C57BL/6 mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) islet-containing fluorocapsules and control mice intraperitoneally receiving 6000 PFOB-labeled (n = 6) or 6000 PFPE-labeled (n = 6) fluorocapsules without islets were monitored for human C-peptide (insulin) secretion during a period of 55 days. Mice underwent (19)F MR imaging at 9.4 T and micro-CT. Swine (n = 2) receiving 9000 PFOB capsules through renal artery catheterization were imaged with a clinical multidetector CT scanner. Signal intensity was evaluated by using a paired t test. RESULTS Compared with nonfluorinated alginate microcapsules, PFOB fluorocapsules increased insulin secretion of encapsulated human islets, with values up to 18.5% (3.78 vs 3.19) at 8-mmol/L glucose concentration after 7 days in culture (P < .001). After placement of the immunoprotected encapsulated cells into mice, a sustained insulin release was achieved with human C-peptide levels of 19.1 pmol/L ± 0.9 (standard deviation) and 33.0 pmol/L ± 1.0 for PFPE and PFOB capsules, respectively. Fluorocapsules were readily visualized with (19)F MR imaging, US imaging, and CT with research- and clinical-grade imagers for all modalities. CONCLUSION Fluorocapsules enhance glucose responsiveness and insulin secretion in vitro, enable long-term insulin secretion by xenografted islet cells in vivo, and represent a novel contrast agent platform for multimodality imaging.

In vivo intravascular MR imaging: transvenous technique for arterial wall imaging.

PURPOSE To determine, in vivo, the potential for transvenous magnetic resonance (MR) imaging of the arterial wall and to assess appropriate MR pulse sequences for this method. MATERIALS AND METHODS MR imaging was performed on 19 vessels (right renal artery, N = 9; left renal artery N = 2; external iliac artery, N = 4; abdominal aorta, N = 4) in nine swine. The animals were either low-density lipoprotein receptor knockout (N = 5) or Yucatan mini-pigs fed an atherogenic diet for 6 to 11 weeks (N = 4). The intravascular MR coil/guide wire (IVMRG) (Surgi-Vision, Gaithersburg, MD) was introduced via the external iliac vein into the inferior vena cava (IVC). The following electrocardiograph-gated MR pulse sequences were obtained: T1-weighted precontrast with and without fat saturation and T1-weighted postcontrast with fat saturation. Two observers scored wall signal and conspicuity and classified the vessel as normal, abnormal, or stented. Images were compared with histopathologic findings. RESULTS The T1-weighted precontrast without fat saturation, T1-weighted precontrast with fat saturation, and T1-weighted postcontrast images correlated with histopathologic findings in 12 of 15 vessels, eight of 10 vessels, and 14 of 16 vessels, respectively. Abnormal histopathologic findings included: arterial wall thickening (N = 3), arterial dissection (N = 2), focal fibrous plaque (N = 2), adherent thrombus (N = 1). The T1-weighted postcontrast images were not compromised by artifacts and had the highest score for vessel wall signal and conspicuity. T1-weighted precontrast images were compromised by chemical shift artifact and poor blood suppression. Negligible artifacts were created by the platinum stent. CONCLUSION The T1-weighted fat saturated postcontrast pulse sequence was superior to other sequences for transvenous MR imaging of the arterial wall.

Endovascular Model of Rabbit Hindlimb Ischemia: A Platform to Evaluate Therapeutic Angiogenesis

PURPOSE Current animal hindlimb ischemia models involve surgical ligation of the femoral artery and delivery of therapeutic angiogenic agents into the adductor compartment. The authors hypothesize that an endovascular model of hindlimb ischemia would be a more appropriate platform, closely resembling atherosclerosis by occluding the vessel from within, causing less inflammation, wound healing and subsequent collateralization. MATERIALS AND METHODS The left superficial femoral artery in 17 rabbits was occluded by endovascular coil embolization (n=9) or surgical ligation (n=8). Animals (n=3; in each group) were sacrificed on day 3 to determine the arteriolar luminal area, number of arterioles, microsphere determined perfusion, and degree of inflammation. On day 28, the remaining animals underwent calf blood pressure measurements and angiography to determine the number of collaterals and diameter of vessels supplying the hindlimb. RESULTS Immediate postprocedure (day 0) and presacrifice (day 3 or 28) occlusion rates were 89% (eight of nine rabbits) and 100% for the endovascular model; 100% and 100% for the surgical model, respectively. Hindlimb paralysis and muscle atrophy was found in one surgical animal. On day 3, there was an increase in hindlimb perfusion (surgery, 0.04+/-0.01; endovascular, 0.02+/-0.01; P=.02), an increase in arteriolar luminal area (surgery, 481 microm+/-240; endovascular, 345 microm+/-151; P=.04), and a trend toward more inflammation (surgery, 5.5+/-3.8; endovascular, 2.5+/-3.0; P=.08) in the surgical group. There was no difference in number of vessels between both groups. On day 28 there was no difference in the calf blood pressure ratios or in the number of collaterals. However, there was enlargement of the distal profunda femoris artery, the vessel closest to the surgical incision, in the surgical group (L/R ratio: immediate post-occlusion, 1.06+/-0.11; day 28, 1.27+/-0.08; P=.02). CONCLUSION The endovascular model was efficacious in providing occlusion of the superficial femoral artery, and induced less of an arteriogenic response compared with the surgical model. The authors believe that this endovascular model is a superior platform for studying therapeutic angiogenic agents.

Transcatheter Coil Embolization of Large Pulmonary Artery Pseudoaneurysms in a Child

The authors report a case of a 5-year-old boy who initially presented with mastoiditis, underwent successful surgical treatment, and during the immediate postoperative period developed multiple, bilateral pulmonary artery pseudoaneurysms. The large size and multiplicity of the pseudoaneurysms precluded the patient from undergoing thoracic surgery. Successful endovascular coil and wire embolization was performed in a staged set of procedures with use of more than 30 m of wire and coils.

Prediction of post-TACE necrosis of hepatocellular carcinoma usingvolumetric enhancement on MRI and volumetric oil deposition on CT, with pathological correlation

ObjectiveTo investigate whether volumetric enhancement on baseline MRI and volumetric oil deposition on unenhanced CT would predict HCC necrosis and response post-TACE.MethodOf 115 retrospective HCC patients (173 lesions) who underwent cTACE, a subset of 53 HCC patients underwent liver transplant (LT). Semiautomatic volumetric segmentation of target lesions was performed on dual imaging to assess the accuracy of predicting tumour necrosis after TACE in the whole cohort and at pathology in the LT group. Predicted percentage tumour necrosis is defined as 100 % - (%baseline MRI enhancement - %CT oil deposition).ResultsMean predicted tumour necrosis by dual imaging modalities was 61.5 % ± 31.6%; mean percentage tumour necrosis on follow-up MRI was 63.8 % ± 31.5 %. In the LT group, mean predicted tumour necrosis by dual imaging modalities was 77.6 % ± 27.2 %; mean percentage necrosis at pathology was 78.7 % ± 31.5 %. There was a strong significant correlation between predicted tumour necrosis and volumetric necrosis on MRI follow-up (r = 0.889, p<0.001) and between predicted tumour necrosis and pathological necrosis (r = 0.871, p<0.001).ConclusionVolumetric pre-TACE enhancement on MRI and post-TACE oil deposition in CT may accurately predict necrosis in treated HCC lesions.Key Points• Imaging-based tumour response can assist in therapeutic decisions.• Lipiodol retention as carrier agent in cTACE is a tumour necrosis biomarker.• Predicting tumour necrosis with dual imaging potentially obviates immediate post-treatment MRI.• Predicting tumour necrosis would facilitate further therapeutic decisions in HCC post-cTACE.• Pre-TACE MRI and post-TACE CT predict necrosis in treated HCC.