Survival of encapsulated islets:More than a membrane story

At present, proven clinical treatments but no cures are available for diabetes, a global epidemic with a huge economic burden. Transplantation of islets of Langerhans by their infusion into vascularized organs is an experimental clinical protocol, the first approach to attain cure. However, it is associated with lifelong use of immunosuppressants. To overcome the need for immunosuppression, islets are encapsulated and separated from the host immune system by a permselective membrane. The lead material for this application is alginate which was tested in many animal models and a few clinical trials. This review discusses all aspects related to the function of transplanted encapsulated islets such as the basic requirements from a permselective membrane (e.g., allowable hydrodynamic radii, implications of the thickness of the membrane and relative electrical charge). Another aspect involves adequate oxygen supply, which is essential for survival/performance of transplanted islets, especially when using large retrievable macro-capsules implanted in poorly oxygenated sites like the subcutis. Notably, islets can survive under low oxygen tension and are physiologically active at > 40 Torr. Surprisingly, when densely crowded, islets are fully functional under hyperoxic pressure of up to 500 Torr (> 300% of atmospheric oxygen tension). The review also addresses an additional category of requirements for optimal performance of transplanted islets, named auxiliary technologies. These include control of inflammation, apoptosis, angiogenesis, and the intra-capsular environment. The review highlights that curing diabetes with a functional bio-artificial pancreas requires optimizing all of these aspects, and that significant advances have already been made in many of them

The Photosynthetic Pancreas: From Fantasy to Reality

Islets of Langerhans implantation is a viable method to treat type I diabetes. Unfortunately, during islets isolation their vascular system is disrupted, and they need external supply of oxygen and other nutrients. A photosynthetic bioartificial device was constructed to support the oxygen consumption of the islets and to treat type I diabetes. The bioartificial device is built in layers where the core is an illumination module composed of a LED array and a light guide. The next layer is immobilized photosynthetic organism (Synechococcus lividus). An oxygen-permeable silicon/Teflon membrane separates the photosynthetic layer from the islets of Langerhans layer. This layer is protected from the immune system of the body by a porous Teflon membrane. The device is powered by batteries that supply electricity to a LED array. The oxygen produced by S. lividus is consumed by implanted islets of Langerhans that produce insulin and allow the reversal of diabetes in the patient. In this chapter, we demonstrate the ability of S. lividus to produce oxygen after being implanted for prolonged periods and eventually the ability of the device containing S. lividus and the islets of Langerhans to reverse diabetes for 10 days. To achieve this task, we developed improved media to grow cyanobacteria and, inter alia, developed a method to disperse light uniformly and in very short distances

Long-term viability and function of transplanted islets macroencapsulated at high density are achieved by enhanced oxygen supply

Transplantation of encapsulated islets can cure diabetes without immunosuppression, but oxygen supply limitations can cause failure. We investigated a retrievable macroencapsulation device wherein islets are encapsulated in a planar alginate slab and supplied with exogenous oxygen from a replenishable gas chamber. Translation to clinically-useful devices entails reduction of device size by increasing islet surface density, which requires increased gas chamber pO Here we show that islet surface density can be substantially increased safely by increasing gas chamber pO to a supraphysiological level that maintains all islets viable and functional. These levels were determined from measurements of pO profiles in islet-alginate slabs. Encapsulated islets implanted with surface density as high as 4,800 islet equivalents/cm in diabetic rats maintained normoglycemia for more than 7 months and provided near-normal intravenous glucose tolerance tests. Nearly 90% of the original viable tissue was recovered after device explantation. Damaged islets failed after progressively shorter times. The required values of gas chamber pO were predictable from a mathematical model of oxygen consumption and diffusion in the device. These results demonstrate feasibility of developing retrievable macroencapsulated devices small enough for clinical use and provide a firm basis for design of devices for testing in large animals and humans

Multiple clock and voltage domains for chip multi processors

Power and thermal are major constraints for delivering compute performance in high-end CPU and are expected to be so in the future. CMP is becoming important by delivering more compute performance within the power constraints. Dynamic Voltage and Frequency Scaling (DVFS) has been studied in past work as a mean to increase save power and improving the overall processor’s performance while meeting the total power and/or thermal constraints. For such systems, power delivery limitations are becoming a significant practical design consideration, unfortunately this aspect of the design was almost ignored by many research works. This paper explores the various possible topologies to build a high end multi-core CPU and the available policies that maximize performance within the set of physical limitations. It evaluates single and multiple voltage and frequency domains and introduces a new clustered topology, grouping several cores together. A hybrid model, using measurements of a real CPU, cycle accurate simulator and an analytical model is introduced. The results presented indicate that considering power delivery limitations diverts the conclusions when such limitations are ignored. This paper shows that a single power domain topology performs up to 30 % better than multiple power domains on light-threaded workload. In the fully threaded application the results divert. Clustered topology performs well for any number of 1 threads

Extended Microbiological Characterization of Göttingen Minipigs in the Context of Xenotransplantation: Detection and Vertical Transmission of Hepatitis E Virus

Xenotransplantation has been proposed as a solution to the shortage of suitable human donors. Pigs are currently favoured as donor animals for xenotransplantation of cells, including islet cells, or organs. To reduce the xenotransplantation-associated risk of infection of the recipient the pig donor should be carefully characterised. Göttingen minipigs from Ellegaard are often used for biomedical research and are regularly tested by their vendor for the presence of numerous bacteria, fungi, viruses and parasites. However, screening for some pathogens transmittable to humans had not been performed.The presence of microorganisms was examined in Göttingen Minipigs by PCR methods. Since zoonotic transmission of porcine hepatitis E virus HEV to humans has been demonstrated, extended search for HEV was considered as a priority. RNA from sera, islet and other cells from 40 minipigs were examined for HEV using different real-time reverse transcription (RT)-PCRs, among them two newly established. In addition, sera were examined by Western blot analysis using two recombinant capsid proteins of HEV as antigens. HEV RNA was not detected in pigs older than one year including gilts, but it was detected in the sera of three of ten animals younger than 1 year. Furthermore, HEV was also detected in the sera of three sows six days after delivery and their offspring, indicating vertical transmission of the virus. PCR amplicons were cloned, sequenced and the viruses were found to belong to the HEV genotype (gt) 3/4. Anti-HEV immunoglobulins G were detected in one sow and maternal antibodies in her six day old piglet. Since Göttingen minipigs were negative for many xenotransplantation-relevant microorganisms, they can now be classified as safe. HEV may be eliminated from the Ellegaard herd by selection of negative animals and/or by treatment of the animals

A comprehensive evaluation of power delivery schemes for modern microprocessors

The continuous quest for energy-efficient computing has led towards the adoption of fine-grained controls in processor sub-systems, of which power delivery network is the most prominent one. Recent industry trends reflect a shift towards on-chip, integrated voltage regulator (IVRs) to that effect. We undertake a thorough and quantitative evaluation of different power delivery networks for modern microprocessors. In contrast to the current trend, we conclude that IVR schemes perform worse compared to the conventional off-chip voltage regulator scheme. Further, we present studies on diverse workloads and Thermal Design Points (TDPs) to highlight the importance of workload-specific power delivery scheme. To the best of our knowledge, this is the first comprehensive study across processors' TDPs and workloads.Accepted versio

Transplantation of bovine adrenocortical cells encapsulated in alginate.

Current treatment options for adrenal insufficiency are limited to corticosteroid replacement therapies. However, hormone therapy does not replicate circadian rhythms and has unpleasant side effects especially due to the failure to restore normal function of the hypothalamic–pituitary–adrenal (HPA) axis. Adrenal cell transplantation and the restoration of HPA axis function would be a feasible and useful therapeutic strategy for patients with adrenal insufficiency. We created a bioartificial adrenal with 3D cell culture conditions by encapsulation of bovine adrenocortical cells (BACs) in alginate (enBACs). We found that, compared with BACs in monolayer culture, encapsulation in alginate significantly increased the life span of BACs. Encapsulation also improved significantly both the capacity of adrenal cells for stable, long-term basal hormone release as well as the response to pituitary adrenocorticotropic hormone (ACTH) and hypothalamic luteinizing hormone-releasing hormone (LHRH) agonist, [D-Trp6]LHRH. The enBACs were transplanted into adrenalectomized, immunodeficient, and immunocompetent rats. Animals received enBACs intraperitoneally, under the kidney capsule (free cells or cells encapsulated in alginate slabs) or s.c. enclosed in oxygenating and immunoisolating βAir devices. Graft function was confirmed by the presence of cortisol in the plasma of rats. Both types of grafted encapsulated cells, explanted after 21–25 d, preserved their morphology and functional response to ACTH stimulation. In conclusion, transplantation of a bioartificial adrenal with xenogeneic cells may be a treatment option for patients with adrenocortical insufficiency and other stress-related disorders. Furthermore, this model provides a microenvironment that ensures 3D cell–cell interactions as a unique tool to investigate new insights into cell biology, differentiation, tissue organization, and homeostasis