Long-term Animal Studies Research Articles

Nanoporous Immunoprotective Device for Stem-Cell-Derived β-Cell Replacement Therapy.

Encapsulation of human embryonic stem-cell-differentiated beta cell clusters (hES-βC) holds great promise for cell replacement therapy for the treatment of diabetics without the need for chronic systemic immune suppression. Here, we demonstrate a nanoporous immunoprotective polymer thin film cell encapsulation device that can exclude immune molecules while allowing exchange of oxygen and nutrients necessary for in vitro and in vivo stem cell viability and function. Biocompatibility studies show the device promotes neovascular formation with limited foreign body response in vivo. The device also successfully prevented teratoma escape into the peritoneal cavity of mice. Long-term animal studies demonstrate evidence of engraftment, viability, and function of cells encapsulated in the device after 6 months. Finally, in vivo study confirms that the device was able to effectively immuno-isolate cells from the host immune system.

Endodontic microleakage studies: correlation among different methods, clinical relevance, and potential laboratory errors.

Creation of a tight seal in endodontically treated root canals is of utmost importance. Clinical and laboratory studies have a great role in the assessment of the sealing ability of endodontic materials. The present review was undertaken to evaluate correlation between different techniques used in microleakage studies in endodontics and the potential laboratory errors. A systematic search was run using Medline, Biosis, Cochrane Database, Embase, Google Scholar, and Web of Science databases. Furthermore, the reference lists of the articles published on the subject were thoroughly searched. There was no language restriction in the search. Two reviewers separately evaluated the titles and abstracts. All the methods used might have proved useful if the study could have been carried out with a larger sample size, with carefully designed control groups. Furthermore, extra evaluations are recommended on the reliability of the method used. Examinations like glucose reactivity test, assessment of antimicrobial activity of the tested materials and in situ FISH examination for the reliability of bacterial leakage model have been recommended. It has been recommended that two or more methods be considered for each material in the same study. On the other hand, long-term animal studies can be useful with histological and radiographic evaluations for meticulous assessment of leakage. Furthermore, long-term clinical trials on humans might be helpful on the condition that confounding factors are controlled. Studies on microleakage should be focused on animal studies, clinical trials or laboratory tests. On the basis of available evidence, it appears that despite potential errors on microleakage studies they are very valuable.

Human health assessment for long-term oral ingestion of diethylene glycol

Diethylene glycol (DEG) is an organic chemical that is used mostly as a chemical intermediate and has minor uses as a solvent or antifreeze in consumer products; these minor uses could result in potential human exposure. Potential short and long-term human exposures also occur from misuses. The considerable reporting of DEG misuses as a substitute for other solvents in drug manufacturing and summaries of important events in the history of DEG poisonings are reviewed. Given the potential for human exposure, the disposition and toxicity of DEG were examined, and a health assessment was performed. Toxicokinetics and metabolism studies are evaluated, along with a discussion on the renal toxicity mode of action in the rat. Additionally, in-depth assessments of the key animal research studies on the toxic effects of DEG from oral ingestion for various exposure time periods are presented with determination of NOAELs and LOAELs from the long-term exposure animal studies. These are applied in the derivation of a reference dose for a non-cancer endpoint from chronic exposure, resulting in a value of 0.3 mg DEG/kg bw.

Phosphatase POPX2 Exhibits Dual Regulatory Functions in Cancer Metastasis.

Cancer metastasis is a complex mechanism involving multiple processes. Previously, our integrative proteome, transcriptome, and phosphoproteome study reported that the levels of serine/threonine phosphatase POPX2 were positively correlated with cancer cell motility through modulating MAPK signaling. Surprisingly, here we found that POPX2 knockdown cells induced more numerous and larger tumor nodules in lungs in longer term animal studies. Interestingly, our analysis of DNA microarray data from cancer patient samples that are available in public databases shows that low POPX2 expression is linked to distant metastasis and poor survival rate. These observations suggest that lower levels of POPX2 may favor tumor progression in later stages of metastasis. We hypothesize that POPX2 may do so by modulation of angiogenesis. Secretome analysis of POPX2-knockdown MDA-MB-231 cells using LC-MS/MS-based SILAC quantitative proteomics and cytokine array show that silencing of POPX2 leads to increased secretion of exosomes, which may, in turn, induce multiple pro-angiogenic cytokines. This study, combined with our previous findings, suggests that a single ubiquitously expressed phosphatase POPX2 influences cancer metastasis via modulating multiple biological processes including MAPK signaling and exosome cytokine secretion.

Biodegradation of Pure Magnesium and Bone Tissue Reaction in Rabbit Femur 1 Year Results of 3D Micro-CT Monitoring and Histological Observation

Pure magnesium and its alloys are biocompatible and biodegradable. In cardiovascular surgery, they have been experimentally applied for short-term use as tiny devices. Many studies have been performed on rats and mice using X-ray imaging and CT scanning. However, these small animals have a low radiation resistance and the lethal exposure dosage is small. In orthopedic surgery, fracture fixation using magnesium materials has high potential applicability. Although long-term stable fixation is required, few long-term animal studies have been performed. Therefore, many unclear issues still remain. Accordingly a long-term animal study was performed on Dutch rabbits to investigate the biodegradation of pure magnesium. Specimens implanted into rabbit femurs showed a volume reduction of 40–50% at 52 weeks. Bone resorption was observed in cancellous bone, and new bone formation and direct contact were partially observed. No magnesium hydroxide was observed in the surrounding area.

Development of novel implants with self-antibacterial performance through in-situ growth of 1D ZnO nanowire

To prevent the attachment of bacteria to implant surfaces, the 1D zinc oxide nanowire-coating has been successfully developed on material surfaces by using a custom-made hydrothermal approach. The chemical nature, surface topography and wettability of spike-like 1D ZnO nanowire-coating are comprehensively investigated. The anti-adhesive and antimicrobial properties of 1D nanowire-coating are tested against Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli by using in vitro live/dead staining and scanning electron microscopy. We find that the adhesion of bacteria can be reduced via the special spike-like topography and that the release of Zn2+ ions can help suppress the growth of attached bacteria. Furthermore, the antimicrobial effect is also evaluated under in vivo conditions by using a rat model infected with bioluminescent S. aureus. The amount of live bacteria in the rat implanted with a nanowire-coated sample is less than that of the control at various time points. Hence, it is believed that the nanowire-coated material is promising for application in orthopaedic implantation after the long-term animal studies have been completed.

Development of an Experimental Drug Eluting Suprachoroidal Microstent as Glaucoma Drainage Device.

A novel glaucoma drainage device (GDD) with local drug delivery (LDD) system was created and characterized for safety and effectiveness after implantation into the suprachoroidal space (SCS) of rabbit eyes. Thin films of two different polymers, Poly(3-hydroxybutyrate) (P(3HB)) and Poly(4-hydroxybutyrate) (P(4HB)), containing the drugs mitomycin C (MitC) or paclitaxel (PTX) were attached to silicone-tubes to create LDD devices. The release kinetics of these drugs were explored in vitro using high performance liquid chromatography (HPLC). Twenty-four New Zealand white rabbits, randomly divided into eight groups, were implanted with different kinds of microstents into SCS. The intraocular pressure (IOP) was monitored noninvasively. After 6 weeks, rabbits were sacrificed and enucleated eyes were used for anterior segment optical coherence tomography (OCT), micro magnetic resonance imaging (MRI), and histology. In vitro, faster drug release from both polymers was observed for MitC compared to PTX. Comparing polymers, the release from P(3HB) matrix was slower for both drugs. MRI and OCT showed all implants maintained a proper location. An effective IOP reduction was observed for up to 6 weeks in eyes with microstents combined with a drug-releasing LDD system. Overall, the surrounding tissue revealed mild-to-moderate inflammation. No pronounced fibrosis was observed in any of the groups. However, both drugs caused damage to the neighboring retina. The suprachoroidal microstent reduced IOP with mild inflammation in rabbit eyes. To avoid negative effects on the retina, it is necessary to identify novel drugs with less cytotoxicity. Future studies are needed to explore the fibrotic process over the long-term. The presented data serve as a proof of principle study for the concept of a suprachoroidal drug eluting microstent. Future device improvements will be focused on the design of LDD systems and the use of specific anti-inflammatory or antifibrotic agents with less cytotoxicity compared to MitC or PTX. Long-term animal studies using a reliable glaucoma model will be a further step towards clinical application and improvement of surgical glaucoma therapy.

Rechargeable neurostimulator with H‐shaped fractal slots in PCB copper layers

Rechargeable neurostimulators make it possible to research and treat brain disorders for a long period of time. However, metal objects such as device cases and inner copper layers of the printed circuit board (PCB) lower the energy transfer efficiency and can even present safety risks due to the eddy currents in these metals. The use of a fractal pattern slot in the metal to suppress the eddy currents is proposed and a rechargeable neurostimulator with deformed H-shape fractal slots in the PCB inner copper layers is described. The results show that the use of an H-shaped fractal pattern slot is effective over a relatively wide frequency range and the maximum temperature of the neurostimulator is in the range of 34.5–39.5°C, which indicates that the device can be used safely for long-term animal studies and even in the clinical treatment of brain disorders.

Using Online Tool (iPrior) for Modeling ToxCast™ Assays Towards Prioritization of Animal Toxicity Testing.

The use of long-term animal studies for human and environmental toxicity estimation is more discouraged than ever before. Alternative models for toxicity prediction, including QSAR studies, are gaining more ground. A recent approach is to combine in vitro chemical profiling and in silico chemical descriptors with the knowledge about toxicity pathways to derive a unique signature for toxicity endpoints. In this study we investigate the ToxCast™ Phase I data regarding their ability to predict long-term animal toxicity. We investigated thousands of models constructed in an effort to predict 61 toxicity endpoints using multiple descriptor packages and hundreds of in vitro assays. We investigated the use of in vitro assays and biochemical pathways on model performance. We identified 10 toxicity endpoints where biologically derived descriptors from in vitro assays or pathway perturbations improved the model prediction ability. In vivo toxicity endpoints proved generally challenging to model. Few models were possible to readily model with a balanced accuracy (BA) above 0.7. We also constructed in silico models to predict the outcome of 144 in vitro assays. This showed better statistical metrics with 79 out of 144 assays having median balanced accuracy above 0.7. This suggests that the in vitro datasets have a better modelability than in vivo animal toxicities for the given datasets. Moreover, we published an online platform (http://iprior.ochem.eu) that automates large-scale model building and analysis.

Influence of the respirator on volatile organic compounds: an animal study in rats over 24 hours

Long-term animal studies are needed to accomplish measurements of volatile organic compounds (VOCs) for medical diagnostics. In order to analyze the time course of VOCs, it is necessary to ventilate these animals. Therefore, a total of 10 male Sprague–Dawley rats were anaesthetized and ventilated with synthetic air via tracheotomy for 24 h. An ion mobility spectrometry coupled to multi-capillary columns (MCC–IMS) was used to analyze the expired air. To identify background contaminations produced by the respirator itself, six comparative measurements were conducted with ventilators only. Overall, a number of 37 peaks could be detected within the positive mode. According to the ratio peak intensity rat/ peak intensity ventilator blank, 22 peaks with a ratio >1.5 were defined as expired VOCs, 12 peaks with a ratio between 0.5 and 1.5 as unaffected VOCs, and three peaks with a ratio <0.5 as resorbed VOCs. The peak intensity of 12 expired VOCs changed significantly during the 24 h measurement. These results represent the basis for future intervention studies. Notably, online VOC analysis with MCC–IMS is possible over 24 h in ventilated rats and allows different experimental approaches.

Long-term taurine supplementation leads to enhanced hepatic steatosis, renal dysfunction and hyperglycemia in mice fed on a high-fat diet.

There is growing interest in the nutraceutical applications of taurine (TAU) for the prevention and treatment of obesity, diabetes and cardiovascular diseases. The lack of long-term clinical and animal studies available makes it difficult to address the safety of supraphysiological TAU exposure over prolonged periods. Here, we assessed growth parameters, renal function and glucose homeostasis in mice fed on a high-fat diet (HFD) and supplemented with 5 % TAU for 12 months. Body weight and fat depots were increased by the HFD and unaltered by TAU supplementation. TAU enhanced diet-induced hepatomegaly and liver steatosis. TAU-supplemented mice developed renal dysfunction as judged by increased urinary proteins and albumin, kidney weight and accumulation of lipid vacuoles in renal tubule. Long-term TAU enhanced the deleterious effects of the HFD upon glucose control, as indicated by fasting hyperglycemia, insulin hypersecretion, lower hepatic Akt activation and peripheral insulin resistance. In conclusion, long-term TAU supplementation enhanced the HFD-induced ectopic lipid accumulation in the liver and kidney and disrupted body glucose control and renal function. TAU-based interventions for obese and diabetic subjects should be carefully planned to avoid extended treatments over prolonged periods.

Impact of different pan-frying conditions on the formation of heterocyclic aromatic amines and sensory quality in fried bacon

Heterocyclic aromatic amines (HAAs) are formed in the crust of cooked meat products. Most HAAs are carcinogenic in long-term animal studies. Besides precursors in raw materials, important factors are temperature and heating time. Bacon slices were investigated for concentrations of HAAs after pan-frying under different monitored heating conditions. Two HAAs, MeIQx (2-amino-3,8-dimethylimidazo [4,5-f]quinoxaline) (1.5–5.6ng/g) and PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) (0.1–2.6ng/g), were found in pan-fried bacon slices. The bacon clearly contained higher concentrations of HAAs both with longer frying times and at temperatures of 200–220°C rather than 150–170°C, respectively. A similar continuous increase of the concentrations was observed for norharman (5.0–19.9ng/g) and harman (0.3–1.7ng/g). The sensory evaluation, using a hedonic test design for colour and flavour, of the pan-fried bacon slices resulted in a preferred frying time of 5min at 150–170°C. However, some testers clearly preferred crispy and darker bacon slices containing higher HAA concentrations.

Evidence for Obesogens: Interpretations and Next Steps

Traditionally toxicologists have embraced the presumption that “Alle Ding' sind Gift, und nichts ohn' Gift; allein die Dosis macht, das ein Ding kein Gift ist” or “All things are poison, and nothing [is] without poison; only the dose makes a thing not be poison”, as first proposed by Paracelsus in 1538, but hypothesized non-monotonic, low dose adverse effects of some substances challenge this premise. Three perspectives on environmental chemicals as ‘obesogens’ are presented in this issue. Schug and Heindel suggest there is compelling evidence demonstrating many industrial and agricultural chemicals act as obesogens and provide hypotheses on how endocrine disruption, particularly during early development, could lead to obesity later in life. On the other hand, Sharpe and Drake are skeptical of the current evidence linking environmental chemicals to obesity, emphasizing two primary criticisms: 1) Animal model studies have largely relied on high dose levels that do not reflect routes and magnitudes of exposures experienced by humans and 2) Epidemiological studies linking chemicals to obesity are likely confounded by high fat diets, since fat in the diet is the primary route of exposure for many of the lipophilic environmental chemicals considered obesogens, as well as total food intake which will increase obesity. Unwilling to draw conclusions on the current evidence, Legler stresses the need for further research and introduces the OBELIX (“OBesogenic Endocrine disrupting chemicals: LInking prenatal eXposure to the development of obesity later in life”) project, which is examining endocrine disrupters in the diet through a prospective birth cohort in four European countries and long-term animal studies using exposures that are comparable to those experienced in human populations.

Anti-proliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor‑positive clinical breast cancer

Selective estrogen receptor modulators and a combination of mechanistically distinct chemotherapeutic agents represent conventional therapeutic interventions for estrogen receptor-positive (ER+) clinical breast cancer. Long-term treatment with these agents is associated with acquired tumor resistance and other adverse side effects that impact on patient compliance. Herbal medicines are being widely used in complementary and alternative medicine. However, long-term safety and efficacy of the use of herbal medicines, as well as their interaction with conventional endocrine and chemotherapeutic drug regimens remain largely unknown. The present study utilized a human cell culture model for ER+ clinical breast cancer to examine the potential therapeutic efficacy of an aqueous extract prepared from the fruit of popular Chinese herb Cornus officinalis (CO), also known as Fructus cornii. The human mammary carcinoma-derived MCF-7 cell line represented the model. Status of anchorage-independent growth and cellular metabolism of 17β-estradiol (E₂) represented the quantitative end-point biomarkers for efficacy. MCF-7 cells adapted for growth in serum-depleted medium (0.7% serum, <1 nM E₂) retained their endocrine responsiveness as evidenced by growth promotion by physiological levels of E₂, and growth inhibition by the selective ER modulator tamoxifen at the clinically achievable concentrations. Treatment of MCF-7 cells with CO resulted in inhibition of E₂-stimulated growth in a dose-dependent manner. Similarly, CO treatment also produced a dose-dependent progressive reduction in the number of anchorage-independent colonies, indicating effective reduction of the carcinogenic risk. Treatment of MCF-7 cells with CO at a maximally effective cytostatic concentration resulted in a 5.1-fold increase in the formation of the anti-prolifertive E₂ metabolite 2-hydoxyestrone (2-OHE₁), a 63.6% decrease in the formation of the pro-mitogenic metabolite 16α-hydroxestrone (16-αOHE₁) and a 9.1% decrease in the formation of mitogenically inert metabolite estrone (E₃). These alterations led to a 14.5-fold increase in the 2-OHE₁:16α-OHE₁, and a 3.3-fold increase in the E₃:16α-OHE1 ratios. These data validate a rapid cell culture-based mechanistic approach to prioritize efficacious herbal medicinal products for long-term animal studies and future clinical trials on ER+ clinical breast cancer.

&amp;#947;-Secretase Inhibitors and Modulators for the Treatment of Alzheimer's Disease: Disappointments and Hopes

According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and non-transgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ secretase shifting its cleavage activity from longer to shorter β-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the cerebrospinal fluid of healthy humans. Unfortunately, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-sparing γ-secretase inhibitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.

Tissue-engineered vascular graft remodeling in a growing lamb model: expression of matrix metalloproteinases

We have previously demonstrated the functionality and growth of autologous, living, tissue-engineered vascular grafts (TEVGs) in long-term animal studies. These grafts showed substantial in vivo tissue remodeling and approximation to native arterial wall characteristics. Based on this, in vitro and in vivo matrix metalloproteinase (MMP) activity of TEVGs is investigated as a key marker of matrix remodeling. TEVGs fabricated from biodegradable scaffolds (polyglycolic-acid/poly-4-hydroxybutyrate, PGA/P4HB) seeded with autologous vascular cells were cultured in static and dynamic in vitro conditions. Thereafter, TEVGs were implanted as pulmonary artery replacements in lambs and followed up for 2 years. Gelatin gel zymography to detect MMP-2 and -9 was performed and collagen content quantified (n=5). Latent (pro) and active MMP-2 and -9 were detected. Comparable levels of active MMP-9 and pro-MMP-2 were detected in static and dynamic culture. Higher levels of active MMP-2 were detected in dynamic cultures. Expression of MMP-2 and -9 was minimal in native grafts but was increased in implanted TEVG. Pro-MMP-9 was expressed 20 weeks post implantation and persisted up to 80 weeks post implantation. Collagen content in vitro was increased in dynamically conditioned TEVG as compared with static constructs and was increased in vivo compared with the corresponding native pulmonary artery. MMPs are up-regulated in vitro by dynamic culture conditions and could contribute to increased matrix remodeling, native analogous tissue formation and functional growth of TEVGs in vivo. Monitoring of MMP activity, for example, by molecular imaging techniques, may enable the non-invasive assessment of functional tissue quality in future clinical tissue-engineering applications.

HETEROCYCLIC AROMATIC AMINES IN MEAT

Heterocyclic aromatic amines (HCAs) are formed during cooking proteinaceous foods such as meat at temperatures above 150C. Epidemiologic studies have shown that all HCAs are mutagenic, and many are carcinogenic. To date, more than 25 HCAs have been identified at ng/g levels in cooked foods. It is therefore recommended minimizing HCAs occurrence in foods consumed by humans. Thus, more information about them is needed. The purpose of this review is to explain chemistry, formation, precursors, mutagenicity and carcinogenicity, and also levels of HCAs in cooked meats. PRACTICAL APPLICATIONS Heterocyclic aromatic amines (HCAs) are formed during cooking of protein-rich foods. They are therefore widely consumed by humans. On the basis of results from long-term animal studies, several HCAs are considered mutagenic and carcinogenic. The competent authorities in most Western countries recommend minimizing HCA occurrence. Thus, it is important to learn more about the formation and inhibition of these compounds in cooked foods. Detailed information about HCAs in cooked meats is briefly presented in this review.

Antihypertensive effect of corn peptides, produced by a continuous production in enzymatic membrane reactor, in spontaneously hypertensive rats

The aim of this study was to produce corn peptides (CP) with potent angiotensin converting enzyme (ACE)-inhibitory activity and to investigate antihypertensive effects in spontaneously hypertensive rats (SHRs). Results showed that the hydrolysate yield and quality were stable during continuous CP production using an enzymatic membrane reactor (EMR). The hydrolysate was then filtered through a 3kDa cut-off membrane and the IC50 value of permeate was decreased fourfold (IC50=0.29mg protein/ml). Gastric-intubation CP (Mw<3kDa) at a dose of 100mg/kgbw revealed the best antihypertensive effects in both acute and long-term animal studies using SHRs’ models, the reductions in maximal systolic blood pressure (SBP) were 26.57mmHg and 34.45mmHg, respectively. Long-term antihypertensive effect of CP administration at a dose of 100mg/kgbw was comparable to Captopril at 2mg/kgbw dose. The CP significantly inhibited the ACE activities in SHRs’ lungs and testes (p<0.01∼p<0.05) suggesting that these were CP’s target sites.

Current Status of the Toxicology of Diesel Engine Exhaust — and the ACES Project

A clear understanding of the health risks of DE has been elusive, because exposures of the workers and general populations studied epidemiologically have not been accurately measured. Experimental exposures of humans and animals can be measured and these have suggested potential health hazards, but results of experimental exposures have been difficult to place in a realistic human exposure context. Experimental human exposures must be of only short duration and relatively high concentrations of DE have been necessary to produce short-term effects. Short-term and long-term animal studies have been conducted and significant progressive health effects have been produced at extreme exposure concentrations, but it is difficult to translate those results into risk factors for humans with acceptable confidence. Diesel technologies have advanced markedly over the past few decades, and emissions have been reduced and altered in composition. No published epidemiological or toxicological study has used exhaust produced by recent diesel technologies. The ACES program in the United States was created to conduct animal studies of the potential health hazards of recent technology diesel exhaust. Rats and mice are exposed to different dilutions of exhaust from a heavy-duty engine meeting the 2007 on-road emission standards and operated on a variable-duty cycle. The study is underway and early results will be available in early 2011. Final results from the long-term study of the hazards of cancer and progressive non-cancer disease will be available in late 2013.

Invited Commentary

The ideal position for the orifice of the inflow cannula of a ventricular assist device (VAD) is in the center of the ventricular cavity, because this position allows unrestricted flow into the VAD. In contrast, if the cannula tip rests on the ventricular septum or papillary muscle, flow restriction to the VAD, ventricular arrhythmias, or both, may result. Therefore, properly positioning the inflow cannula during VAD implantation is important. We have found that placing the inflow cannula through the diaphragmatic region of the left ventricle, rather than more apically, usually results in better positioning of the cannula, keeping it away from the ventricular septum. Transesophageal echocardiography can help confirm that the cannula is in proper alignment. Occasionally, the position of the cannula shifts during the postoperative period as a result of mechanical factors or hypovolemia. If flow to the VAD is severely restricted, reoperation to reposition the cannula may be necessary. Shiose and colleagues [1Shiose A. Kim H.I. Takaseya T. et al.Performance of extracorporeally adjustable ventricular assist inflow cannula.Ann Thorac Surg. 2010; 90: 1682-1687Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar] have designed an inflow cannula that can be adjusted extracorporeally by using cables attached to the cannula. The authors achieved a maximum of ±15-degree mobility in a short-term calf model, and the cannula performed well. Flows could be increased or decreased by changing the position of the cannula. If similar results can be achieved in long-term animal studies, this technology may significantly improve VAD design, assuming that it can be adapted to currently used VADs. One drawback of the current design is the need to have the steering cables exit the skin separately. The more hardware that exits through the skin, the higher the risk of infection. The authors have indicated they are designing detachable cables that could be removed once the optimal cannula position has been achieved. Performance of Extracorporeally Adjustable Ventricular Assist Device Inflow CannulaThe Annals of Thoracic SurgeryVol. 90Issue 5PreviewThis study evaluated the feasibility and efficacy of a newly developed adjustable left ventricular assist device inflow cannula in a short-term calf model. Full-Text PDF