Nicholas Stowe

Quantification of in vivo doxorubicin transport from PLGA millirods in thermoablated rat livers.

The objective of this research was to quantify the key parameters governing the drug transport processes in radiofrequency (RF) thermoablated and non-ablated liver tissues. Experimentally, doxorubicin-containing polymer millirods were implanted in the ablated rat livers and spatial distribution of doxorubicin was measured by fluorescence imaging from 1 to 96 h after millirod implantation. At all time points, doxorubicin had significantly higher tissue penetration and retention in ablated tissues than in non-ablated tissues. A mathematical model was developed to quantitatively describe the transport processes in ablated and non-ablated rat livers. Based on the experimental data and mathematical models, the optimal estimates of apparent drug diffusivities in ablated and non-ablated tissues were 1.1 x 10(-7) and 6.7 x 10(-7) cm(2) s(-1), respectively, and the apparent drug elimination rate coefficient was 9.6 x 10(-4) s(-1) in non-ablated tissues. Results from this study contribute to the fundamental understanding of in vivo drug transport in liver tissues and provide the quantitative parameters for the rational design of polymer millirods for liver cancer treatment.

Pneumoperitoneum upregulates preproendothelin-1 messenger RNA

BackgroundLaparoscopic pneumoperitoneum has been shown to decrease glomerular filtration rate (GFR) and urine volume (UV). Endothelin-1 (ET-1), a potent renal vasoconstrictor, has been implicated. The purpose of this study was to determine renal function, ET-1 gene expression, and peptide localization in kidneys subjected to CO2 pneumoperitoneum.MethodsExperiments were performed in three groups of anesthetized Sprague-Dawley rats in which GFR and UV were measured before, during, and after insufflation. In the first group (n=8), pneumoperitoneum (10 mmHg) was established for 30 min. The second group (n=4) underwent a sham operation without pneumoperitoneum. In the final group (p=4), kidneys were obtained from normal control animals without any prior surgical instrumentation. PreproET-1 (ppET-1) mRNA levels were measured by reverse transcription-polymerase chain reaction (RT-PCR). The ET-1 peptide was localized within kidneys by immunohistochemistry (IHC).ResultsPneumoperitoneum caused a significant (p<0.05) 87% decrease in GFR and a 79% decrease in UV from baseline, with a return to baseline values after desufflation. RT-PCR showed a significant (p<0.05) increase in expression of ppET-1 mRNA in the laparoscopic group; it was 3.52±0.33 densitometric units (DU), as compared to 0.35±0.06 DU and 0.57±0.12 DU in the control and sham groups, respectively. IHC showed enhanced expression of the ET-1 peptide in the vascular endothelium and proximal tubular cells of the laparoscopic group compared to the control and sham groups.ConclusionPneumoperitoneum induces ET-1 gene and peptide upregulation in the kidney. Expression of ET-1 is increased in the renal vasculature and proximal tubular cells. The elevation of ET-1 and its localization may account for some of the renal dysfunction observed during pneumoperitoneum. This suggests that antagonism of ET-1 may be beneficial in patients with renal impairment undergoing prolonged laparoscopic procedures or in protecting allograft function during and after living donor nephrectomy.

Comparison of Doxorubicin Concentration Profiles in Radiofrequency-Ablated Rat Livers from Sustained- and Dual-Release PLGA Millirods

AbstractPurpose. To evaluate and compare the local pharmacokinetics of doxorubicin in radiofrequency (rf)-ablated rat livers after interstitial delivery from sustained- and dual-release poly(D,L-lactide-co-glyco- lide) (PLGA) millirods. Methods. PLGA millirods with sustained- and dual-release kinetics (burst followed by sustained release) of doxorubicin were implanted in rf-ablated rat livers. Doxorubicin release kinetics in vivo were measured from explanted millirods by UV-Vis spectrophotometer over 8 days. Spatial distribution of doxorubicin in liver tissues was measured by fluorescence imaging. Results. In the initial 24 h after millirod implantation, dual-release millirods released significantly more doxorubicin into liver tissues than the sustained millirods. Subsequently, both types of millirods provided comparable sustained-release kinetics over 8 days. With dual-release millirods, doxorubicin concentration and penetration distance in liver tissue increased more rapidly. To reach 30 μg/g doxo- rubicin concentration at the ablation boundary (targeted site of action), the time required was 6 days and 1.5 days for sustained- and dual-release millirods, respectively. Conclusions. Compared with sustained-release millirods, dual-release millirods provide a quick concentration elevation and sustaining of the drug concentration at the ablation boundary. Additionally, the steady-state drug concentration agrees well with model predictions based on previously determined transport parameters, which demonstrates the feasibility of rational design of drug formulations in polymer millirods.

Noninvasive monitoring of local drug release in a rabbit radiofrequency (RF) ablation model using X-ray computed tomography

In this study, X-ray computed tomography (CT) was utilized as a noninvasive method to directly examine local drug release kinetics in livers before and following radiofrequency thermal ablation. Iohexol, a CT contrast agent, was used as a drug-mimicking molecule. Release of iohexol in healthy and ablated rabbit livers over 48 h was quantified and correlated with the release profiles from phosphate-buffered saline (PBS) in vitro. The results show that iohexol release in ablated livers is significantly slower than both release in normal livers and in vitro. The time at which 50% of the drug was released (t(1/2)) into ablated liver (20.6+/-5.9 h) was 1.7 times longer than in normal liver (12.1+/-5.4 h) and approximately two times longer than that in PBS (10.1+/-1.2 h). The slower release in ablated livers is a result of severe tissue damage inflicted by thermal ablation, as supported by histological examination. This data suggests that a noninvasive imaging method provides a superior measurement over in vitro release studies in accurately quantifying the local release kinetics of an agent in an altered physiological system in vivo. Because the development of a successful local drug therapy is dependent on the understanding of the agent release kinetics at the implantation site, the noninvasive data may be indispensable in effectively predicting the implant behavior in a physiological system.

Design optimization of a stiffened flexible panel under turbulent boundary layer excitation

The vibration and noise generated from turbulent boundary layer (TBL) flow are main design considerations in the Automotive, Aerospace, Shipbuilding industries, as well as many others. Simulation has been widely applied to help reduce TBL-induced vibration and noise; however, a fully coupled CFD + FEA analysis is still a computational challenge for high-fidelity models. On the other hand, when the block pressure assumption is applicable, a general approach applies the fluctuating pressure underneath the TBL as excitation to the structure to predict its vibratory response and noise. This paper first uses the general approach to predict the vibration and noise of a stiffened flat panel subjected to TBL excitation. The various methods, both empirical and numerical, that are used to estimate the TBL wall spectrum are outlined. Structural transfer functions from Energy Finite Element Analysis (N. Vlahopoulos, K. Wu, MAST Americas 2010) are calculated for the panel. The calculated TBL excitation (M. Goody, AIAA...

High‐intensity focused ultrasound for liver biopsy hemostasis

In vivo experiments were conducted to demonstrate the feasibility of HIFU application to control postliver biopsy hemorrhage. Yorkshire pigs were anesthetized and their livers were surgically exposed. Core biopsies (n=74) were performed on the exposed hepatic parenchyma with 14‐gauge (n=41) and 18‐gauge (n=33) core biopsy needles that were inserted 1.5–2 cm deep into the liver. Hemorrhage was determined from the weight of the blood collected from each biopsy puncture site using surgical sponges immediately after biopsy needle retraction. To stop hemorrhage, immediate HIFU was applied to the needle entry site (n=44) after needle retraction. HIFU was generated using a piezoelectric (PZT) transducer (diameter=42 mm, F number=1.2) at 4.23 MHz. Whole‐blood clotting times were measured at various times throughout the experiments. Mean blood loss from control biopsy sites using a 14‐gauge needle (n=18) was 1.78 g, while mean blood loss using an 18‐gauge needle (n=10) was 1.22 g (two 14‐gauge‐needle control biops...