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US 7776021 B2 Resumen Methods and materials for making an apparatus which duplicates the functionality of a physiological system id provided.
Reclamaciones(6) 1. An apparatus for the filtration of small molecules, comprising
a) first polymer substrate, wherein the first polymer substrate comprises a microvascular network for circulation of fluid longitudinally through the first polymer substrate, the microvascular network comprised of acellular microchannels that are about 5 μm to about 100 μm in height, and that begin at one or more inlets, serially branch into a large array of microchannels, and then converge back into one or more microchannels at one or more outlets;
b) a second polymer substrate, wherein the second polymer substrate comprises acellular fluidic chambers; and
c) a semi-permeable membrane disposed between the first and second polymer substrates;
wherein the first and second polymer substrates are fastened together about the semi-permeable membrane, and,
wherein small molecules are filtered from fluid in the microvascular network of the first polymer substrate through the semi-permeable membrane to the acellular fluidic chambers of the second polymer substrate.
2. The apparatus of
3. The apparatus of
4. The apparatus of
5. The apparatus of
6. An apparatus for the filtration of small molecules, comprising 8 to about 2,000 apparatuses as defined by
Descripción Reference is made to U.S. application Ser. No. 10/038,891, filed Jan. 2, 2002, which claims priority to U.S. Appln. Ser. No. 60/259,283, filed Jan. 2, 2001. Reference is made to U.S. application Ser. No. 09/560,480, filed Apr. 28, 2000, which claims priority to U.S. Appln. Ser. No. 60/131,930 filed Apr. 30, 1999, and U.S. Appln. Ser. No. 60/165,329, filed Nov. 12, 1999. The contents of each of these applications are incorporated by reference herein in their entireties. The United States government has certain rights in this invention by virtue of grant number DAMD-17-02-2-0006 from the Department of the Army. Each of the foregoing applications-and patents and articles, and each document cited or referenced in each of the foregoing applications and patents and articles, including during the prosecution of each of the foregoing applications and patents ("application and article cited documents"), and any manufacturer's instructions or catalogues for any products cited or mentioned in each of the foregoing applications and patents and articles and in any of the application and article cited documents, are hereby incorporated herein by reference. Furthermore, all documents cited in this text, and all documents cited or referenced in documents cited in this text, and any manufacturer's instructions or catalogues for any products cited or mentioned in this text or in any document hereby incorporated into this text, are hereby incorporated herein by reference. Documents incorporated by reference into this text or any teachings therein can be used in the practice of this invention. Documents incorporated by reference into this text are not admitted to be prior art. Furthermore, authors or inventors on documents incorporated by reference into this text are not to be considered to be "another" or "others" as to the present inventive entity and vice versa, especially where one or more authors or inventors on documents incorporated by reference into this text are an inventor or inventors named in the present inventive entity. 1. Field of the Invention The present invention generally relates to the fields of organ transplantation and reconstructive surgery, and to the new field of tissue engineering. More specifically, the present invention defines a new method and materials for providing a compact microfluidic system capable of filtering impurities and waste products from the blood stream to treat patients suffering from damaged, malfunctioning or failing vital organs, such as the kidney and liver. 2. Description of the Related Art There are two principal therapeutic avenues for patients suffering from diseased, malfunctioning or failing vital organs responsible for blood filtration. One of these avenues involves organ assistance devices, such as the use of hemodialysis circuits in the renal unit of hospitals, or bridge therapy for liver failure such as the ELAD (Liver Assist Device). In the case of kidney dialysis, patients typically undergo 3 4-hour hemodialysis treatments per week in the clinic, each involving a trip to the clinic and a process in which the patient is connected to a large piece of equipment which filters waste products such as urea and creatinine from the blood stream while maintaining electrolyte, glucose and protein balances. These treatments, while effective at sustaining life for ESRD (End-Stage Renal Disease) patients, are highly invasive, and are limited in effectiveness due to the non-physiological concentration profile of waste and impurities in the bloodstream. Namely, the concentration of urea, for example, becomes elevated well beyond levels in healthy patients for the 2-3 days between treatments, and is then lowered very rapidly during dialysis. These drastic excursions in concentration lead to complications and distress in dialysis patients, and the psychological impact of dialysis is associated with a sharp increase in suicide rates among the patient population. Most significantly, the long-term prognosis for ESRD patients on dialysis is poor, with 5-year survival rates of less than 20%. The cost of these treatments is staggering, totaling approximately $12 Billion per year for the roughly 300,000 ESRD patients, or $40,000 per year per patient. For patients with liver failure, liver assist devices provide only bridge therapy, perhaps a few weeks at best, until a replacement liver is available. The second avenue of treatment for patients with failing organs such as liver and kidney is transplantation, in which a donor organ is implanted into the patient from a variety of sources. These sources include cadaveric organs, which are in extremely limited supply, and therefore the number of patients on the waiting list for a vital organ is approaching 100,000 in the United States. Organ rejection by the recipient's immune system represents a huge challenge for the field of transplant medicine, because it severely limits the potential donor pool. Even when the donor is a match, recipients are consigned to a lifetime of immunosuppressive drugs, which are extremely expensive and are associated with a host of severe side effects. Other sources for donor tissue and organs are living donor transplants, which in the case of the kidney involve one organ from a donor with two healthy kidneys, or split liver transplants in which part of the liver of a healthy patient is transplanted into the recipient. Often involving family members, these transplants are typically safe for the donor but have led to well-documented cases in which previously healthy donors suffered lethal complications following transplant surgery. Avenues beyond these two involve experimental procedures not yet ready for wide clinical practice. These include the use of artificial mechanical organs, such as the artificial fully implantable heart, biohybrid organs involving combinations of mechanical/artificial materials and devices and living cells and tissues, and fully natural tissue engineered organs which replace function. The principal disadvantages of the two general approaches described above relate to the insufficient replacement of physiological organ function without serious limitations or complications. In the case of renal assist devices, specifically, the invasive, complex and discontinuous nature of the treatments limit their therapeutic value, because they do not provide patients with benefits concomitant with a healthy pair of kidneys. These disadvantages can be understood as being associated with limitations in the technology which insufficiently reproduce organ function, and limitations associated with cost, complexity and accessibility. The former set of challenges can be addressed by advances in dialysis involving either acellular processes (superior filtration, hemocompatibility, etc.) or cell-based processes (improvements in the resorption circuit which returns desired blood components to the body following ultrafiltration). The latter set of challenges relates to the fact that dialysis treatments are costly and labor-intensive, require frequent visits to the clinic and large, complex machines, and are not continuous because of the need for centralized dialysis clinics often distant from their patients. Compact organ assist devices with continuous filtration that is physiologic in nature would provide enormous patient benefit. Moreover, a wearable, continuous device will reduce costs and labor associated with treatment, and will eliminate most visits to the clinic except for maintenance and monitoring. Accordingly, there is a need for improved systems. The present invention provides the design, materials, fabrication and assembly processes to construct and implement a vital organ assist or even replacement device that overcomes the problems discussed above as well as other obstacles known in the art. In particular, the present invention provides the design, materials, fabrication and assembly processes to construct and implement a microfabricated system to replace the blood filtering function of a vital organ such as the liver or kidney. In one embodiment, the present invention provides an apparatus which duplicates the functionality of a physiological system, which includes first and second layers, each defining upper and lower surfaces. In specific embodiments, each layer can comprise a mold. A semi-permeable membrane can be secured to the first and second molds such that the upper surface of the membrane is secured adjacent to the lower surface of the first mold and the lower surface of the membrane is secured adjacent to the upper surface of the second mold. In another embodiment, the apparatus is organized into a three-dimensional structure comprised of multiple two-dimensional layers, arranged in a repeating fashion, and stacked vertically in a total stack of at least 8 layers (e.g., stacks of bi-layers, each bi-layer consisting of an upper and lower surface). The present invention can comprise between about 50 and 2000 layers, more preferably between about 100 and 1000 layers and most preferably about 500 layers. In yet another embodiment, the first and/or second molds can optionally include flow control patterns, such as interconnected microchannels cut into the mold, or disposed on a surface thereof. As used herein, the term "flow control pattern" refers to any feature capable of affecting flow, e.g., limiting or directing fluid flow, ranging from two-dimensional surface patterns to three-dimensional features such as posts, walls, channels or other raised structures. The flow control pattern can enhance diffusion and convection, among other things. The patterns in the first mold can be identical or non-identical to the pattern in the second mold. The pattern in the upper surface of the molds can be identical or non-identical to the pattern in the lower surface. The apparatus can further comprise nutrient supply and excretion removal lines in fluid communication with the apparatus, pumping means for circulating fluid through the apparatus. In a specific embodiment, the present invention provides an apparatus which duplicates the functionality of a physiological system comprising a first mold, a semi-permeable membrane, a second mold and a pumping means, wherein the first mold is fastened to the second mold and the semi-permeable membrane is disposed between the first and second molds, and wherein the first and/or second molds have means defining flow control patterns, and a pumping means for circulating fluid through the device. In another specific embodiment, the flow control patterns can form fluidic chambers, supported by posts or walls. The fluidic chambers can be modeled after blood vessels, and can be from about 5 μm (small blood vessel dimension) in width and height to about 100 to 900 μm in width and height. In yet another specific embodiment, the flow control patterns can form microchannels. Microchannels of the invention can be various sizes, for example, ranging from about 5 μm to about 5 mm in width and height, and extend longitudinally or latitudinally through the mold. The patterning of the microchannels can be controlled to form a microvascular network. The microchannels can be connected beginning from one or more inlets, expanding into more channels, and then converging back into one or more outlets. In yet another specific embodiment, the first mold can comprise a microvascular network layer and the second mold can comprise a parenchymal layer having parenchymal cells. "Parenchymal cells" include the functional elements of an organ, as distinguished from the framework or stroma. Parenchymal cells can include but are not limited to smooth or skeletal muscle cells, myocytes, fibroblasts, chondrocytes, adipocytes, fibromyoblasts, ectodermal cells, including ductile and skin cells, hepatocytes, kidney cells, liver cells, cardiac cells, pancreatic islet cells, cells present in the intestine, and other parenchymal cells, osteoblasts and other cells forming bone or cartilage, and hematopoietic cells. In yet another specific embodiment, the present invention provides an apparatus for the filtration of small molecules, comprising a first mold, a semi-permeable membrane, a second mold and a pumping means, wherein the first mold comprises a microvascular network, the second mold comprises parenchymal cells and the pumping means circulates fluid through the apparatus such that small molecules are removed from the microvascular network and passed to the parenchymal cells. In other embodiments, the apparatus is acellular. In one embodiment, where the apparatus is acellular, the supply lines can be connected to a rehydration system. The rehydration system can comprise proximal tubule reabsorptive units of the kidney. Renal filtration involves diffusion and convection processes which result in the removal of important physiologic electrolytes (e.g., calcium, potassium and sodium), and proteins (e.g., the "middle molecules"), in addition to quantities of waste products (e.g., urea and creatinine) and water. Therefore, blood exiting the filtration portion of the kidney contains sub-optimal concentrations of these critical biomolecules. In this embodiment, the microfabricated filtration unit described herein is serially connected to a cell-based reabsorption unit which performs the physiologic function of restoring the concentration of electrolytes and other important biomolecules to desired levels once the blood has passed through the filtration device of the present invention. An engineered reabsorptive unit connected with a system constructed in accordance with the present invention can utilize cell function (i.e., proximal tubule cells of the kidney) or other known means to restore biomolecule concentrations to physiologic levels. The surfaces of the molds are biocompatible can include a coating on the microchannels that promotes cell adhesion to the apparatus. The surfaces are preferably hemocompatible, or treated to promote hemocompatibility by, for example, the application of a hemocompatible film thereto or endothelialization of the surfaces. Blood clot-preventing compounds such as heparin can also be used to further facilitate the uninhibited flow of blood and long-term operation of the device, among other things. In one embodiment, the membrane is made of a hemocompatible material. Furthermore, the molds or membrane can include at least one growth factor covalently linked thereto at least one of the molds. The membrane can be biodegradable and have pores of between about 0.01 and about 20 μm. The molds can include through-holes, and may be fastened to the membrane or each other by a spin-glue process or a plasma bonding process, among other things. The present invention is also directed to a method of fastening a semi-permeable membrane having an upper and an lower surface to a polymeric mold. The steps of such a method in accordance with the present invention can include: exposing the membrane and a polymeric film to oxygen plasma to attach the membrane and film to each other; separating the polymeric film from the membrane; and exposing the membrane and the mold to oxygen plasma to attach the surface of the mold. This method may also include the step of exposing the membrane and a second mold to oxygen plasma to attach the surface of the mold. The present invention is also directed to a method of fastening a semi-permeable membrane having an upper and a lower surface to a polymeric mold that includes the steps of: exposing the surface of the polymeric mold to the liquid state of the polymer used to form the polymeric mold; spinning the polymeric mold with the polymer liquid thereon; bringing the membrane in contact with the surface of the polymeric mold; and allowing the polymeric liquid in contact with the mold and membrane to set. In the aforementioned method, the step of allowing the polymeric liquid in contact with the mold and membrane to set can further include elevating the surrounding temperature. The systems and methods of the invention can be implanted into a subject to supplement or replace the biological function of a tissue or organ. Alternatively, the systems and methods can remain ex vivo, serving as extracorporeal devices to supplement or replace biological function. Examples of tissues and organs which can be fabricated using these methods include, but are not restricted to, organs currently transplanted such as heart, liver, pancreas, lung, kidney and intestine. Other tissues such as muscle, bone, breast, reproductive and neural tissue could also be engineered. These and other embodiments are disclosed or are obvious from and encompassed by, the following detailed description taken in conjunction with the figures as described below. The following detailed description, given by way of example, but not intended to limit the invention to specific embodiments described, may be understood in conjunction with the accompanying Figures, incorporated herein by reference, in which: These and other features of the present invention will become more readily apparent to those having ordinary skill in the art from the following description of the preferred embodiments. In the following detailed description of the present invention, references are made to the accompanying drawings which form a part hereof, and in which is shown by way of simplified schematic illustrations specific embodiments in which the invention may be practiced. These drawings are not necessarily intended to accurately portray the entire system of the present invention, nor are they necessarily intended to be accurate portrayals of the size or shape of the elements of a system constructed in accordance with the present invention. However, one skilled in the art will readily appreciate that these figures along with the description herein are sufficient to enable those skilled in the art to practice the present invention. Devices constructed in accordance with the present invention are designed to mimic proper anatomical and physiological conditions, and preferably provide even flow distribution, minimized flow resistance and a maximized surface area for transfer of oxygen nutrients and waste. Thus, devices constructed in accordance with this invention anticipate, and/or compensate therefore, non-Newtonian blood rheology and its multiphase nature, capillary occlusions causing local pressure drops, uneven velocity profiles and hematocrit distributions, among other things. Devices of the invention can optionally include flow control patterns to enhance diffusion and convection, among other things. Flow control patterns are known in the art, and described in U.S. Pat. Nos. 6,811,752, 6,810,713, 6,808,522, 6,808,075 and 6,802,342; as well as in Khademhosseini A, et al. (2004) Analytical Chemistry 76 (13): 3675-3681; Wang H Z, et al. (2003) J. Micromechanics and Microengineering 13 (6): 801-808; Kuksenok O, (2002) Physical Reviews E 65 (3): Art. No. 031502 Part 1; Delamarche E, et al. (1997) Science 276 (5313): 779-781; Stroock A D, Accounts of Chemical Research 36 (8): 597-604; Ng J M K, et al. (2002) Electrophoresis 23 (20): 3461-3473; and Stroock A D, (2002) Analytical Chemistry (20): 5306-5312, the contents each of which are incorporated herein by reference. Furthermore, the present invention utilizes microfabrication techniques to construct a system which, in addition to possessing the necessary features (e.g., capillary beds, nephrons, tissue, cultured cells, etc.) to duplicate the functionality of a specified physiological system, is also on a size scale similar to that physiological system. The present disclosure provides the design, materials, fabrication and assembly processes to construct and implement a microfabricated system to replace the blood filtering function of a vital organ, such as the liver or kidney. The device can contain cells of the organ and a vascular network, with or without cells, or can be acellular. It should be understood that the present disclosure provides exemplary and preferred embodiments and uses of the present invention, and should not be limited thereto. Extracorporeal and Implantable Devices Devices constructed in accordance with the present invention can be implanted into a subject to supplement or replace the biological function of a tissue or organ. Alternatively, the invention can be adapted to comprise devices for uses in addition to the formation of implantable tissue. The devices can remain ex vivo, serving as extracorporeal devices to supplement or replace biological function. As used herein, the term "biological function" refers to the structural, mechanical or metabolic activity of a tissue or organ. Extracorporeal devices of the present invention can comprise hybrid devices suitable for both ex vivo and in vivo use. Any of the devices constructed in accordance with the present invention may provide partial support function, may extend the time between hospital treatments for patients on chronic organ support therapies, and can improve the quality of life between hospital treatments. Commercially available extracorporeal devices do not incorporate the precise microfabrication capabilities offered by MEMS technology, and therefore function is limited by the resolution limits of current hollow fiber and membrane fabrication methods. Insertion of MEMS technology into this domain will provide major benefits for hemofiltering, dialysis and other applications. For example, the designs can be adapted to produce an extracorporeal renal dialysis device, an extracorporeal liver device, or an extracorporeal artificial lung device. Such devices may or may not be supported with living cells loaded or seeded into the device. Referring now to the drawings wherein like reference numerals identify similar structural features of the invention, there is illustrated in Microfluidic device 10 includes an inlet 12 and an outlet 14 in fluid communication with a support body 16. Support body 16 substantially supports, and preferably encapsulates, a microfluidic network that enables device 10 to provide organ assist capabilities and is discussed in further detail herein below. Active devices that can provide flow and filtration control and optimization, such as pumps, valves, electric fields, transport devices, etc., can also be employed with microfluidic device 10. Standard procedures may be employed to attach tubing connections for inlet 12 and outlet 14 to device 10 and external locations. Preferably, the process involves the bonding of tubing sections using either polymer glue materials, tight-fit connections, plasma bonding, or other means known in the art. With particular regard to plasma bonding, support body 16 preferably includes a protective capsule. This can be an additional or optional step, which can provide further structural rigidity, as well as a more implantation-friendly shape for a device constructed in accordance with the present invention for such purpose, among other things. In such an embodiment, the material forming the capsule should be the same as the material from which the actual device is formed. This allows the two to unite into a single, continuous material when the capsule polymer has completely cured. The shape of the capsule is conferred by the mold from which it is created. Preferably, it is of a generally ovoid shape with connector tubes for inlet 12 and outlet 14 emerging from the tip of one of the long ends. The mold can be either rigid or conformal, and either single or multi-usage (i.e., the mold can be discarded after one molding process or it can be used multiple times to form several bodies of like shape). Alternatively, balloons can be used as single-usage, conforming molds. The opening of a balloon is placed around the opening of a filtration flask, and the balloon is allowed to hang in the flask. Vacuum is drawn from a secondary inlet to the flask, causing the balloon to inflate. When the desired size is reached, the vacuum is maintained at its current pressure. Liquid polymer is poured to cover the remaining space and the top of the balloon is closed by means such as a string or similar closure. The polymer is allowed to cure and the balloon is then cut open to release the encased microfluidic network. Another way to produce the capsule is to use a rigid, multi-usage mold with the desired shape. In one embodiment, the mold is constructed from two parts. A small hole is formed on the first or upper part of the mold to allow for polymer to be poured therein. One of the two longer sides should carry a small outlet hole for the connecting tubing. A thin layer of polymer is poured into the lower part of the mold and it is allowed to cure. The device is then positioned on a layer of polymer, and the connecting tubing is threaded through the appropriate hole of the upper part of the mold. The two parts are secured together by known means and the encasing is filled with liquid polymer through the hole at the top of the upper part of the mold. In addition, the encasing mold can be a rigid, single-usage container such as a beaker or similar piece of glassware. The process is similar to the multi-usage mold described above. However, the mold can be sacrificed to release the device, which can prove to be an easier task to accomplish than preserving and reconditioning a multi-usage mold. Materials and Methods A two-dimensional (x, y) mold can be fabricated from a substrate material using high-resolution molding processes, such as micromachined wafer technology, thick photoresist processes, or other techniques, optionally micromachined, small dimensioned channels ("microchannels") can be patterned on the surface of the mold and connected for the circulation of fluid through a microfluidic network. Microchannels can comprise, for example, open-faced channels defined by walls extending from a tissue-defining surface of the substrate. Materials suitable for forming the device and microfluidic network within support body 16 in accordance with the present invention preferably meet several criteria. First, such materials are preferably amenable to the microfabrication and assembly techniques such as those described herein below, including replica molding and bonding processes. These materials are preferably biocompatible, and not prone to fouling by such things as biofilms, proteins or other biological materials during use. Additionally, such materials preferably do not invoke an inflammatory or an immune system response. Materials suitable for use as the substrate for the mold fabrication include, but are not limited to, poly-dimethyl-siloxane (PDMS), poly-glycerol-sebacate (PGS), polylactic acid (PLA), poly-L-lactic acid (PLLA), poly-D-lactic acid (PDLA), polyglycolide, polyglycolic acid (PGA), polylactide-co-glycolide (PLGA), polydioxanone, polygluconate, polylactic acid-polyethylene oxide copolymers, modified cellulose, collagen, polyhydroxybutyrate, polyhydroxpriopionic acid, pglyphosphoester, poly(alpha-hydroxy acid), polycaprolactone, polycarbonates, polyamides, polyanhydrides, polyamino acids, polyorthoesters, polyacetals, polycyanoacrylates, degradable urethanes, aliphatic polyesterspolyacrylates, polymethacrylate, acyl substituted cellulose acetates, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl flouride, polyvinyl imidazole, chlorosulphonated polyolifins, polyethylene oxide, polyvinyl alcohol, teflon RTM, nylon silicon, and shape memory materials, such as poly(styrene-block-butadiene), polynorbomene, hydrogels, metallic alloys, and oligo(c-caprolactone)diol as switching segment/oligo(p-dioxyanone)diol as physical crosslink. Other suitable polymers can be obtained by reference to The Polymer Handbook, 3rd edition (Wiley, N.Y., 1989). Combinations of these polymers may also be used. In a preferred embodiment, polymers are selected based on the ability of the polymer to elicit the appropriate biological response from cells, for example, attachment, migration, proliferation and gene expression. Solvents for most of the thermoplastic polymers disclosed herein are known, for example, methylene chloride or other organic solvents. Organic and aqueous solvents for protein and polysaccharide polymers are also known. The binder can be the same material as is used in conventional powder processing methods or can be designed to ultimately yield the same binder through chemical or physical changes that occur as a result of heating, photopolymerization, or catalysis. Properties of the mold and/or polymer surface can be controlled and changed to impart desirable properties through the inclusion of materials on the mold or in polymer surface which alter cell attachment (e.g., by altering the surface charge or structure), porosity, flexibility or rigidity (which may be desirable to facilitate removal of tissue constructs). Moreover, advances in polymer chemistry can aid in the mechanical tasks of lifting and folding as well as the biologic tasks of adhesion and gene expression. The preferred material for microfluidic devices of this embodiment is PDMS, which is a silicone rubber material which is moderately biocompatible and highly amenable to microfabrication and assembly. This material is not known for hemocompatibility, and therefore it is typically coated with materials such as collagen, Matrigel®, Vitrogen, or other substances which enhance biocompatibility. In order to reduce clotting, the coated PDMS can be endothelialized to impart the microfluidic network with the same anti-thrombotic qualities as those provided to blood vessels by the presence of the endothelium. Further steps may be taken by pre-filtering of the blood at the front end of the device, either by removing blood components such as thrombocytes or by injecting compounds such as heparin to reduce clotting. Alternative materials to PDMS for the structural component (e.g., channels for vascular and dialysate compartments of a renal dialysis device) can include polymethylmethacrylate (PMMA), polyethylene, or even biodegradable materials such as polyLactic (co-glycolic) acid (PLGA) or polyglycerol sebacate (PGS), among other things. Some of these materials, particularly PMMA and PGS, are known to be highly biocompatible, as well as hemocompatible. The biodegradable properties of PLGA and PGS, for instance, will limit the useful life of the device, but may be acceptable for systems in which the device is replaced on a regular basis (e.g., monthly) for maintenance purposes. The filtration membrane material is preferably selected with care because of the significant and direct contact of blood with the membrane during the filtering process. Initial work in hemodialysis, for instance, employed the use of cellulose fibers, but these materials showed a propensity for clotting in dialysis systems. More recently, materials such as PMMA, polysulfone (PS) and polyethersulfone (PES) have been used for the hemodialysis membrane, with generally far superior results. Accordingly, the membrane can be made of a biologically compatible, nondegradable material such as cellulose, PolyDiMethylSiloxane (PDMS), PolyMethylMethacrylate (PMMA), PolyEtherSulfone (PES), PolySulfone (PS), PolyCarbonate (PC), or from a degradable material such as PLGA, PolyCaproLactone (PCL) or Biorubber, but the invention is not so limited. Some exemplary devices constructed in accordance with the subject invention have used PDMS as the structural material of the microfluidic device while the membranes have been either polycarbonate (PC) or PES. The PC membrane has been used however it is not believed to have enhanced biocompatibility or hemocompatibility. For a presently preferred embodiment, the structural material is selected from endothelialized PDMS, PGS or PMMA, or a combination thereof, with the membrane being either PES or PMMA, or a combination thereof. Some exemplary, non-limiting fabrication methods for manufacturing microfluidic networks for use with a device in accordance with the present invention are discussed below. In particular, polymer substrates having microfluidic networks thereon have been constructed using double-sided molding techniques. In conventional soft photolithography, a silicon wafer is first processed with traditional micromachining techniques to carry a certain pattern. The wafer is placed in a petri dish with the pattern facing upwards and the polymer in its liquid, non-crosslinked form is poured over the silicon mold. The polymer conforms to the shape of the mold and, with the help of heat or light, is converted to its solid, cross-linked state. The double-sided molding technique uses two silicon molds and sandwiches the polymer in between the two. Materials other than silicon may also be used, however, one other consideration in this embodiment is that typical 500 μm thick silicon wafers may not provide sufficient mechanical strength for all applications and embodiments in accordance with the present invention. This is because, after the polymer has set, it becomes difficult to separate the wafer-polymer-wafer sandwich without breaking the silicon molds. Therefore the use of thicker silicon wafers is preferred, such as, for example, 700 μm, 1 mm, 1.5 mm, or even thick glass wafers may be used to ensure safe separation of the molds from the cured polymer. The two mold wafers may be fabricated using either conventional bulk silicon processing, such as described in the related, commonly assigned application, U.S. patent application Ser. No. 10/187,247. Alternatively, an epoxy resin process, which is also described in the aforementioned Application, can be used in which a thick photoresist directly serves as the mold and silicon micromachining is not involved. The aforementioned patent application is incorporated herein by reference. The molds can carry the same or different patterns. Each mold is placed on a small pedestal, which sits in a large petri dish. The radius of the petri dish should be greater than the radius of the silicon mold to collect excess of polymer dripping from the sides of the mold. The pedestal can range from a small petri dish to a metallic stand. The key feature is that the radius of the pedestal should be sufficiently smaller than the radius of the silicon wafer, and the pedestal must be tall enough to allow for polymer poured in excess of the capacity of the mold surface to flow freely off the surface without trapping the mold in the petri dish after it has cured. Spacers may be applied to one of the two molds. The spacers are thin, uniformly flat objects that will keep the two molds apart from each other and allow a polymer layer of uniform thickness to go between them. They control the thickness of the resulting polymer layer. A preferred embodiment utilizes four washers (e.g., Rockford 508 washers) with a measured thickness of 1.2 mm+/−0.015 mm. Alternatively, one may deploy small silicon wafer pieces, bringing the thickness of the mold layer down to 500 μm. It is preferably that the spacers does not prevent the polymer from flowing radially away from the mold as the two molds are brought together. It is also preferably that the spacer is placed on mold "dead-space", which bears no raised features. Washers may be used to ensure uniform separation between the two molds across the entire area of the silicon wafer. In the next step, the polymer is poured over the mold. Roughly 15-20 mL of polymer is sufficient to completely cover the mold. After letting the molds settle for a sufficient period to ensure complete coverage, both are placed in a vacuum chamber. A vacuum is then drawn, and the molds degas for about one hour. This removes all the microbubbles from the polymer, which may have either originated from mixing the polymer with the curing agent, or were trapped in the features of the mold when pouring the polymer over them. After some time has passed, (e.g., about one hour) the molds are taken out of the vacuum. The mold is then lifted without the spacers, and quickly flipped so that its features and the polymer face downwards. It can be positioned over the mold with the washers. The molds are then placed proximate to one another, in that the end of the upper mold is situated next the respective end of the lower mold so that the silicon surface makes contact with the washer. The upper mold is then slowly lowered so that the two polymer layers come in complete contact with each other. A gentle force is applied to push the excess polymer out and complete the sandwich. The large petri dish carrying the pedestal, mold and polymer mold layer is placed in an oven at a temperature of about 65° C. for about 20 minutes. Because of the minute thickness of the polymer compared to the surface area of the silicon wafer this time is sufficient for complete curing. The petri dish is then taken out of the oven and allowed to cool. The next step is to detach the two molds from the polymer mold layer. A very thin, blunt object, such as flat spatula, is used as a wedge in the plane between the silicon and the polymer across the whole circumference of the mold, on both molds. The spatula can be inserted just a few millimeters to sufficiently ensure release. It is critical to completely separate the washers from the molds on both sides because that is where the highest stress concentration takes place, and where the mold layer is most likely to tear upon release. Insertion of the spatula between the top mold and the washer along with a gentle, constant force for a few seconds, is the preferred method for accomplishing this task. This same process is then repeated on all spacers up until the top mold has lifted off from the polymer. The same process is then repeated for the lower mold. Note that the order of starting with the top mold and following with the lower one is important to ensure separation without breaking the molds or tearing the mold layer. An example of a polymer mold layer 18 having pluralities of microvascular networks 20 formed thereon by the microfabrication techniques of the present invention described herein is shown in Membrane A filtration membrane can be used to separate the first mold from the second mold of the present invention. Preferably, the membrane is semi-permeable and the pore size of the membrane is smaller than the cell diameters, thus, cells will not be able to pass through (i.e., a low permeability for animal cells), while low molecular weight nutrients and fluids can pass through (i.e., a high permeability for nutrients), thereby providing adequate cell-to-cell signaling. Cell sizes vary but in general, they are in the range of microns. For example, a red blood cell has a diameter of 8 μm. Preferably, the average membrane pore size is on a submicron-scale to ensure effective screening of the cells. Semi-permeable membranes of the present invention comprise a wide array of different membrane types and morphologies, which can be classified as follows:
Track-etch type membranes are preferred, as they limit the fluid motion in one direction. Preferably, fluid motion is in the vertical direction. Fibrous membranes permit fluid motion both laterally and vertically. In the exemplary embodiment discussed herein, once mold layers 18 have been fabricated, they are attached to a porous filtration membrane 22, an example of which is shown in The first step is to expose the membrane and a blank piece of PDMS to oxygen plasma. Next, the membrane is attached to the blank piece of PDMS. Once the two surfaces have been attached together, the membrane is peeled from the blank PDMS. The membrane is then exposed to oxygen plasma again, along with a layer of PDMS with microchannels, and these two pieces are attached together. Finally, the membrane/microchannel sandwich and the opposing microchannel layer are exposed to oxygen plasma and then attached together, forming the mold layer with the semipermeable membrane. The spin-glue process is a viable alternative to the plasma bonding technique and achieves polymer-to-membrane bonding. In this process, a polymer mold layer 18 (or single layer) is positioned with the side holding the design of interest upwards. A small portion (about 1-2 ml) of the liquid state of the same polymer the mold layer 18 is made of is poured onto the mold layer 18. This is counterintuitive since the architectural features of interest (e.g., microfluidic channels) are buried under the liquid polymer "glue". The mold layer 18 is then positioned on a spinner chuck and spun for 1 minute at a set speed in the range of about 2000 rpm to about 3500 rpm. Spinning provides a conformal coating over the entire top surface of the mold layer 18, while exposing all the channels previously buried under the glue. The spin speed defines the thickness of the glue. A spin curve (i.e., what spin speed corresponds to what thickness) can be readily established. Mold layer 18 is taken out of the spinner and put on a flat surface covered with laboratory wipes. Membrane 22 (or another layer) is slowly brought in proximity with mold layer 18. One can either make contact by hand, or gently release membrane 22 in very close proximity to mold layer 18. With pressure from the center of mold layer 18 to the periphery, membrane 22 is gently contacted to ensure it contacts everywhere with the polymer. Care should be taken not to apply too much force, which would cause membrane 22 to touch down at the bottom of the channels, pick up glue and potentially occlude. The polymer glue needs to set, and thus, the device can be left at room temperature for approximately two hours or put in an oven at about 65° C. for about five minutes, among other things. However, in using the latter technique, buckling of the device may be observed. This is because the polymer expands more than membrane 22 when heated. This can be advantageous, as a method of quality control, that is, if buckling is observed then the polymer and membrane 22 have been successfully bonded to each other. Buckling helps relax the stress produced by the differential expansion of the two materials upon heating only if the two materials are tightly bonded to each other. The same process may be used as many times as necessary to bond all mold layers 18 to membranes 22 and to each other, thus creating a multilayer device. Preferably, mold layer 18 on which glue has been spun on needs to remain with the glue facing upwards, and the layer/membrane without the glue is preferably facing downward. The first step in this modeling method is to create a hypothetical "mesh" depicting the device. Once the mesh is constructed, time-varying behavior is modeled in a series of discrete timesteps. At each timestep, three sets of calculations are made. First, the boundary conditions and concentration distribution are used to calculate solvent velocities throughout the device. Second, the solvent velocities are used to determine the solute fluxes. Third, the solute fluxes are used to update the concentration distribution. The next timestep is then started by calculating the solvent velocities from the boundary conditions and the modified concentration distribution. An orthogonal mesh is created, filling the space of the device. The mesh consists of a set of nodes, each specifying an (x,y,z) location, and a set of vessels. Each vessel connects two nodes and is specified by those two nodes. The mesh spacing is uniform. Inlets and outlets to the device are included by defining appropriate nodes as inlet and outlet nodes, and their associated vessels as inlet and outlet vessels. Inlets have specified solvent flow rates and outlets allow solvent and solutes to flow out of the device. Each vessel is assigned a set of conductances L1, L2, L3, and L4 representing the mass transport properties of the device in the region of that vessel. These conductances will be discussed further in the following sections. An initial concentration distribution is specified by assigning an initial concentration value at each node. Calculation of Solvent Fluxes The solvent velocity between any two points can be calculated knowing the pressures and concentrations at those two points, and the conductances between the points. Solvent flow has two components, convection and osmosis. Convection contributes a flux
The osmotic contribution to the flux is The total volumetric flux of the solvent is the sum of the convective and osmotic components,
This equation cannot be used to directly calculate the fluxes since the pressures are unknown. The flux must be converted to flow rate q by multiplying by an area,
Solute flux is the sum of convective and diffusive terms. The convective flux of solvent j is
The diffuse flux is given by Fick's Law,
Total volumetric solute flux is a sum of the convective and difflusive terms,
Update of Concentrations Concentration of solvent j at any node changes in time as described by Iteration Once the concentration has been updated, the simulation returns to the first step. The vector [L2ΔCAc] is modified by using the updated concentrations, and all three stages are repeated. The three stages taken together represent one time step. Initial Results The above methods have been implemented in Matlab and run in test cases up to 200 nodes on a mesh representing a mold layer design with inlet and outlet on each layer. The method is convergent in various combinations of convection, osmosis, diffusion, and forced flows. Results obtained on single bilayer devices tested for ultrafiltration of urea and creatinine are described in the following discussion. Single bilayer devices were constructed using some or all of the techniques described in the above fabrication section. A device 110 of the present invention is shown schematically in In a specific embodiment, the microvascular network is comprised of small and/or midsized vessels and connecting the vessels within one layer to at least one additional layer with vertical links, as described by PCT/US03/29880, filed on Sep. 23, 2003, the contents of which are incorporated herein by reference. In this embodiment, channels carrying blood (e.g., a vascular network) would be arranged proximally to channels containing dialysate in the same layer, such that impurities in the bloodstream would be filtered laterally across an intervening membrane into the dialysate channel network, rather than vertically. Mass transport of the filtered blood products would occur through a set of "vertical pores" rather than through a horizontally positioned semipermeable membrane. The geometries of the vertical pores can be controlled to enable efficient hemofiltration. In this system, countercurrent flows of blood and dialysate streams into and out of device 110 are illustrated by arrows 124 and 126, respectively. Ultrafilitration flow through microporous membrane 122 within device 110, from first mold layer 118 a to second mold layer 118 b, is illustrated by arrows 128. To study the ultrafiltration capabilities of a device having a microvascular mold layer and a parenchymal layer, the clearances of urea and creatinine from the vascular/"blood" stream 124 into the parenchymal/"dialysate" stream 126 were examined at varying flow rates under single-pass countercurrent conditions. For the purposes of this exercise, the parenchymal layer as well as the microvascular mold layer was empty, i.e., acellular. Microvasculature 120 a refers to a microfluidic network modeled after a vascular network in order to mimic the capillary networks developed for vascularized tissues as the flow patter for the blood, among other things. The vascular fluid in flow stream 124 consisted of ultra-pure water containing dissolved urea and creatinine at concentrations of 400 and 200 mg/dl respectively, while the parenchymal fluid of stream 126 consisted of only ultra-pure water. The urea and creatinine solutions were pumped through the vascular layer 118 a containing the microvasculature 120 a and the ultra-pure water/"dialysate" was pumped through the parenchymal layer 118 b. The flow-rate ratios of vascular flow (QB), parenchymal flow (QD) and individual flow rates used for each solute were approximately at a 2:1 ratio (QB:QD) at 0.9 and 2.0 ml/hr respectively, 1:1 (QB:QD) at 1.0 ml/hr, and 1:1 (QB:QD) at 2.0 ml/hr. In an incubator at 37° C., a syringe pump was used to administer each fluid into its respective layer, under conditions of countercurrent, single-pass flow. As the fluids moved through their respective layers, samples from each flow stream were taken at various time points, up to five hours, and analyzed for final concentration levels. The temporal distribution of urea and creatinine concentration in the vascular and dialysate flows (see The results of the ultrafiltration experiments illustrated promising results with regard to the clearance of uremic solutes (i.e., urea and creatinine) from a vascular stream into a dialysate stream in these micro-fabricated devices, especially when compared to conventional hemodialysis clearances. When the data is normalized and compared to conventional hemodialysis parameters, including total surface area for filtration, total internal volume, and total flow rate through the system, these bilayer devices, such as that depicted in The concentration versus time data for urea and creatinine show slightly different trends with respect to the dialysate-side clearances. However, both sets of data, suggest that an approximate 2:1 vascular: parenchymal flow rate ratio, where QB=0.9 ml/hr and QD=2.0 ml/hr, is the optimal ratio for the clearance of both solutes, which is the ratio used in conventional hemodialysis. This can be attributed to the establishment of a higher concentration gradient of solute between the vascular and parenchymal networks when the vascular fluid is allowed to remain in device 110 longer, relative to the parenchymal fluid. The normalized data for both urea and creatinine clearance show that these bilayer devices are significantly to moderately more efficient at clearing uremic solutes from an incoming vascular stream than conventional hemodialysis membranes, with urea clearance at a 2:1 flow rate ratio showing the most drastic improvement. As shown in Blood flow 224 enters device 210 and contacts mold layer 218 a. Ultrafiltrate blood flow 234, and ultrafilitration 228 through membrane 222 a, are directed to chamber 230 where exposure to proximal tubule cells occurs. Reabsorption flow 236 from chamber 230 is drawn through membrane 222 b to mold layer 218 b, while treated blood (i.e., ultrafiltrate and reabsorption) flow 238 and filtered blood/dialysate flow 226 exit device 210. Having thus described in detail preferred embodiments of the present invention, it is to be understood that the invention defined by the appended claims is not to be limited to particular details set forth in the above description, as many apparent variations thereof are possible without departing from the spirit or scope of the present invention. For example, devices with greater amounts of layers, such as between about 50 and 2000 layers, more preferably between about 100 and 1000 layers and most preferably about 500 layers stacked together, can be constructed in accordance with the present invention and using the process techniques described above. Also, alternate methods for fabricating a device in accordance with the present invention include the use of the assembly processes described herein with rolling or folding schemes, rather than stacking methods, to provide high-throughput systems capable of reproducing organ function. Other alternatives include the use of laser machining, roll machining, injection molding and other techniques for machining of polymers or other suitable materials to generate layers for these filtration devices. Another set of alternative methods for generating blood filtering devices in accordance with the present invention involve the use of monolithic structures rather than stacked sandwich structures with membranes and fluidic layers, as is described in International PCT Application US04/16059, filed on May 21, 2004, and incorporated herein by reference. In such devices individual layers of the comprise channels having multiple cell types (e.g., organ-specific cells and a vascular supply) divided by membrane. Each layer comprises channels divided longitudinally into two compartments by a centrally positioned membrane, with each compartment containing a different cell type. In another embodiment, the device of the invention are augmented by the addition of active microdevices, such as pumps, valves and sensors, to monitor the performance and to actively contribute to the filtration process by altering the flows, pressures, distribution of blood components, and other critical parameters to enhance filtration. For example, micropumps, microvalves and microsensors have been developed using MEMS processes for a wide range of medical and non-medical applications, including drug delivery, bioanalysis, drug discovery and clinical diagnostics. Pumps, valves and sensors are well known in the art for use in in vivo applications in which both biocompatibility and hemocompatibility are factors, and therefore are suitable for integration with devices of the present invention. In one embodiment, devices of the invention can modulate the filtration process to preferentially filter certain classes of blood components over other components. For example, a renal assist device of the invention can preferentially filter urea and creatinine while maintaining a physiological concentration of electrolytes in the vascular network. This can be accomplished, for example, coupling the renal assist device with a pump which filters charged electrolytes differently than urea and creatinine. Further modifications and variations of the methods and devices described herein, other than, and including those described above, will be obvious to those skilled in the art, and are intended to be encompassed by the following claims. Citas de patentes
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- Robert F. Bennett U.S. Senator [R] Utah
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MTG Slumps as Nordea Sees Burdened TV Margins: Stockholm Mover
June 24 (Bloomberg) -- Modern Times Group AB fell the most in eight months in Stockholm trading after Nordea Bank AB said margins at the company's Pay TV operations will continue to be burdened and downgraded its rating on the stock.
MTG lost as much as 12.5 kronor, or 4.6 percent, to 261 kronor, its steepest intraday drop since Oct. 18. It traded 2.1 percent lower at 267.7 kronor at 9:36 a.m. local time, giving MTG a market value of 18.3 billion kronor ($2.7 billion).
Nordea cut its rating on MTG shares to hold from buy with a price estimate of 300 kronor "after a 21 percent share uptick" this year, according to a note to clients from analyst Johan Grabe today. It also reduced its earnings per share estimates in 2013 to 2015 by 2 percent to 3 percent.
"We expect MTG to post stable progress for its Nordic Free TV business, while the second-quarter Pay TV margins will remain burdened at around 11 percent due to cost hikes," Grabe said. "We expect continued margin pressure debate to hold back the valuation."
To contact the reporter on this story: Niklas Magnusson in Stockholm at firstname.lastname@example.com
To contact the editor responsible for this story: Tasneem Brogger at firstname.lastname@example.com


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Tour Scotland Home Page
Click Here For Small Group Tours of Scotland Click For Scottish Gifts USA or Scottish Gifts UK Scottish Books, Cooking, Music, iTunes, DVDs Best Scottish Tours or Rent a Cottage in Scotland Ancestry Tours Of Scotland or Best Travel Bargains
Pipe Major Angus MacDonald World's Greatest Pipers
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Bagpipe Music
Bagpipe Jokes
Bagpipes are thought to have been used in ancient Egypt.
The bagpipe was the instrument of the Roman infantry while the trumpet was used by the cavalry.
Bagpipes existed in many forms in many places around the world. In each country the basic instrument was the same, a bag with a chanter and one or more drones. Some of these were mouth blown while others used a bellows attachment to supply the air. The bag provided a sustained tone while the musician took a breath and allowed several tones to be played at once.
The origins of the pipes in Scotland is uncertain. Some say it was a Roman import. Others believe that the instrument came from Ireland as the result of colonization. Another theory is that they were developed there independently. Historians can only speculate on the origins of the Scottish clans' piob mhor, or great Highland bagpipe, but the Highlanders were the ones to develop the instrument to its fullest extent and make it, both in peace and war, their national instrument.
The original pipes in Scotland probably had, at the most, a single drone. The second drone was added to the pipes in the mid to late 1500s. The first written mention of the "Great Pipes" was in 1623 when a piper from Perth was prosecuted for playing on the Sabbath. The third drone, or the great drone, came into use early in the 1700s.
In the Lowlands of Scotland, pipers occupied well-defined positions as town pipers, performers for weddings, feasts and fairs. There was no recorded "master piper" nor were there any pipe schools. Lowland pipers played songs and dance music, as was expected by their audience. Over the mountains and glens, however, Highland pipers were strongly influenced by their background of the Celtic legends and the wild nature of the Highlands. The Highland piper occupied a high and honored position within the Clan system. To be a piper was sufficient and, if he could play well, nothing else would be asked of him.
As bagpipe use faded throughout most of Europe, a new form of music was starting in the Highlands. Beginning with Iain Odhar, who lived in the mid-1500s, the MacCrimmon family was responsible for elevating Highland pipe music to a new level, according to historians. This music is called piobaireachd (pronounced piobroch). This classical music is an art form which can compare to the music of any other country and most of it was composed 100 years before the piano and without written notation.
Clan pipers titles were mostly hereditary and held in much esteem. The best known were the MacCrimmons, pipers to MacLeod of Dunvegan; the MacAuthurs, pipers to MacDonald of the Isles; the MacKays, pipers to the MacKenzie; the Rankins, pipers to MacLearn of Duart.
As a musical instrument of war, the Great Pipes of the Highlands were without equal, according to historians. The shrill and penetrating notes worked well in the roar and din of battle and pipes could be heard at distances up to 10 miles. Because of the importance of the bagpipes to any Highland army, they were classified as an instrument of war by the Loyalist government during the Highland uprising in the 1700s. After the defeat of Bonnie Prince Charlie in 1745, kilts and bagpipes were outlawed, the pipes being classified as instruments of war.
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2014 Annual Security and Fire Safety Report
Fire Safety & Education
2014 Fire & Safety Report
2014 Campus Safety and Security Survey
The Director of Public Safety, Director of Housing and Student Life and Residence Director life meet with each resident in every residence hall at a mandatory meeting on the first evening at the start of each Semester to pass important safety information.
Fire Safety, Housekeeping and Evacuation Procedures are discussed. Fire drills are conducted each semester to ensure all students are aware of their evacuation routes and are out of the buildings within three minutes. Unannounced drills are repeated until all facets of evacuation have been met. False fire alarms are not counted as part of these drills. All resident halls are patrolled throughout the day, evening and night. These patrols are designed to notice conditions that need to be corrected such as fire exits blocked or lights extinguished.
Housekeeping and policies such as trash removal and banned items (candles, incense or any electrical hazards) are reported to the Facilities Department immediately through repairs request written as Conditions Observed. A follow-up report is sent to Public Safety when these discrepancies have been repaired or corrected.
Fire Safety Tips
- Please familiarize yourself with fire extinguisher locations, exits, and building fire alarms pull stations in the event of a fire.
- Smoke is the greatest danger in a fire.
- As you evacuate, or if you are trapped, always stay near the floor where the air is less toxic.
- Activate the closest building fire alarm for emergency response.
- When the building fire alarm is sounded, always assume an emergency exists.
- If a fire appears controllable, discharge a fire extinguisher toward the base of the flame.
- Assist persons with disabilities to exit.
- Close doors to confine fire.
- Do not use elevators.
- Should your clothing catch on fire-STOP DROP and ROLL to smother the flame.
- If trapped shout at regular intervals to alert emergency crews of your location.
- Find a window and place an article of clothing outside of it to use as a marker for rescue crews.
Important Phone Numbers
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dial 911 |
Ambulance* |
dial 911 |
Poison Center |
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Public Safety |
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ROME, Ga. — For the second day in a row, Newt Gingrich amped up his rhetoric about the Obama administration's relationship with the Islamic world.
"There's something sick about an administration which is so pro-Islamic that it can't even tell the truth about the people who are trying to kill us," Mr. Gingrich said to applause from a crowd in a small airport hangar here. Mr. Gingrich accused the White House of being unwilling to discuss threats from some Muslims. And he slammed President Barack Obama for mounting a "war" on the Catholic Church over contraception but apologize to Afghan President Hamid Karzai over the burning of Qurans.
Turning to Mr. Obama's apology and the rising violence against American soldiers in Afghanistan, he said, "I think we can look into the mind of a president in the speed and thoroughness with which they have disowned their own people."
Mr. Gingrich made headlines Monday when he said it was "not possible" to "fix" Afghanistan and suggested its citizens should be told to, "figure out how to live your own miserable life."
On Tuesday, he also included Pakistan. "I would say to the Pakistanis and I would say to the Afghans – you don't want us to be there, we sure don't need to be there," he said. " You don't want our money, we sure don't need to send it."
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Two successful curative operations using stomach-preserving distal pancreatectomy with celiac axis resection for the treatment of locally advanced pancreatic body cancer. | |
MedLine Citation:
PMID: 19224117 Owner: NLM Status: MEDLINE |
Large vessel invasion is a serious factor determining whether an operation for pancreatic body cancer is feasible. The Appleby operation is a radical operation for the treatment of pancreatic body cancer that has infiltrated the celiac axis. Since this procedure includes a total gastrectomy, the operation is associated with a high morbidity, mortality, and deteriorating postoperative quality of life (QOL). We experienced two cases in which radical operations consisting of a stomach-preserving distal pancreatectomy with en bloc resection of the celiac, common hepatic, and left gastric artery were performed. The use of adjuvant chemotherapy in these cases led to a good postoperative QOL. |
Satoshi Mizutani; Takeshi Shioya; Kentaro Maejima; Osamu Komine; Masanori Yoshino; Arichika Hoshino; Masao Ogata; Masanori Watanabe; Kunio Yanagimoto; Tetsuo Shibuya; Akira Tokunaga; Takashi Tajiri |
Related Documents
15567757 - Pancreatoduodenectomy with vascular reconstruction in treating carcinoma of the pancrea... 1279997 - Characteristics of cystic neoplasms of the pancreas and results of aggressive surgical ... 17629037 - Laparoscopic distal pancreatectomy for solid pseudopapillary neoplasm of the pancreas-r... 16837797 - Cystadenomas with ovarian stroma in liver and pancreas: an evolving concept. 17216827 - Hypocalcemia after neck exploration for untreated primary hyperparathyroidism. 22415437 - Anesthetic concerns for robotic-assisted laparoscopic radical prostatectomy. |
Publication Detail:
Type: Case Reports; Journal Article Date: 2009-02-18 |
Journal Detail:
Title: Journal of hepato-biliary-pancreatic surgery Volume: 16 ISSN: 1436-0691 ISO Abbreviation: J Hepatobiliary Pancreat Surg Publication Date: 2009 |
Date Detail:
Created Date: 2009-03-24 Completed Date: 2009-07-22 Revised Date: - |
Medline Journal Info:
Nlm Unique ID: 9431940 Medline TA: J Hepatobiliary Pancreat Surg Country: Japan |
Other Details:
Languages: eng Pagination: 229-33 Citation Subset: IM |
Institute of Gastroentorology, Nippon Medical School Musashikosugi Hospital, Nakahara, Kawasaki, Japan. email@example.com |
Export Citation:
APA/MLA Format Download EndNote Download BibTex |
MeSH Terms | |
Aged Celiac Artery / pathology, surgery* Cholangiopancreatography, Endoscopic Retrograde Cholangiopancreatography, Magnetic Resonance Female Humans Male Pancreatectomy / methods* Pancreatic Neoplasms / diagnosis, pathology, surgery* Stomach / surgery Tomography, X-Ray Computed |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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I finally decided to do it. My first AR. An LWRC M6A2. Put on a Wilson Combat TTU. Then bought the ACOG. First time out "what a blast". Few more goodies on it now. The grip pod is really nice for those long shots.
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Pics or It didn't happen.
Nice. I have an older LWRC that I have enjoyed.
The bitterness of poor quality Lingers long after The sweetness of low price is forgotten. -John Ruskin
Thanks. She is last years model. But she was new in the box and gotta great deal on her.


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Vatican St Peter, BIG APARTMENT up to 8 people, WIFI, SAT TV, air conditioning, garage
From $146 / night
Hide Property Details
Description from the owner
- 4 bedrooms
- 3 bathrooms
- Sleeps 8
- Apartment
Bedrooms: 4
Bathrooms: 3
Sleeps: 8
Type: Apt. / Condo
Vatican St Peter, BIG APARTMENT up to 8 people, WIFI, SAT TV, air conditioning, garageDescription from the owner
SILVER APARTMENT at the Residenza Piccolomini.
The apartment is very big, so it's perfect for FAMILIES, GROUPS OF FRIENDS, COUPLES.....UP TO 8 PEOPLE.
BABIES UNDER 3 YEARS OLD ARE FREE and we provide: BABY COT, HIGH CHAIR and BABY BATHTUBE.
OUR RATES ARE ALL-INCLUSIVE: cleaning services, linen, towels, utilities, full Air Conditioning, Satellite TV with international channels and Internet WIFI are included in the rent price !
IN THE HEART OF ROME, VATICAN ST PETER, a very good and charming place to stay !
The house is elegantly decorated, finely renovated with hardwood floors, and it's equipped with every comfort. Located at the 2nd floor of ...Read more
About the owner
About the owner
Residenza Piccolomini
Residenza Piccolomini
Response rate 95%
Response time Within a day
Calendar updated today
Overall rating4.5 / 5.0 based on 8 reviews and 3 properties
Vatican St Peter, BIG APARTMENT up to 8 people, WIFI, SAT TV, air conditioning, garage
Rome, Lazio, Italy
Additional Location Information
THE VATICAN AREA: the apartment is located in a quiet small building of VIA NICOLO' PICCOLOMINI, a side street close to the main street called Via Gregorio VII.
The location is perfect if you want to be in the heart of Rome, but in the same time you wish a quiet side street where you can sleep without noises.
From the apartment you'll be able to reach St Peter Square just walking in a few minutes, and also a short walk away there's Villa Pamphili, the biggest Park of Rome.
The bus stops are in front of the building and it takes just 10 minutes to reach historic centre as Navona square, Campo dè fiori, Trastevere, Spanish steps, etc...
The metro station 'Ottaviano St Peter' is 10 minutes by bus.
In the area (300/500 meters from the apartment) there're shops, restaurants, groceries, bakeries, pharmacies, supermarkets, etc..
The view of St. Peter's Dome from via Piccolomini is a truly wonderful experience !!!
Everyone know that Rome is a fascinating city. Even more so on certain days, at certain times, but above all, in certain places. Via Nicolò Piccolomini is a small residential street in the heart of the city. One of those fascinating points, where you can enjoy a splendid view of the Eternal City.
The feature that makes this place a real gem, is that from via Piccolomini you see the Dome of St. Peter like you've never seen before.
Walking along the street, observing the Dome, something strange happens: the closer you approach it, the further the Dome moves away. If you walk backwards, the Dome looks bigger and closer. A game of perspectives that makes the view even more fascinating and the visual effect even more strange. Getting closer to a point in space and watching it move further way is not something that happens every day. Especially if the point is the Dome of St. Peter.
It is a curious optical effect due to the arrangement of buildings and from the point of observation.
This is why via Piccolomini is a special place. The ideal location to beautifully end your evenings in the downtown area, or to start a romantic stroll.
More About This Location
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go ahead... be a heretic | |
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Re^2: Problem with wxperl/constructors.pmby bedohave9 (Acolyte) |
on Aug 30, 2012 at 18:35 UTC ( #990819=note: print w/ replies, xml ) | Need Help?? |
I have changed it to use wxPerl::Constructors; in the script, but still getting the same error as shown below.
In Section
Seekers of Perl Wisdom


text:
Review: The Closer - The Life (winter premiere)
(S05E13) "What does L.A. have in store for us today?" -- Brenda
Major crimes was back on the job with a case that was gruesome and grim at the same time. How Brenda managed to face the morning crime scene without blanching is proof that she's as tough as nails beneath that smiling, sweet Southern facade. Brenda needed to be when dealing with a triple homicide, gang rape and possible gang war. Welcome to L.A. More on the case and the kitty situation, after the jump.
Jericho: Heart of Winter
(S01E14) I got a lot of heat because of my review of last week's show and usually I ignore all criticism because I'm so brilliant. However, when 99% of the comments are negative, I'm forced to take another look at my reviews. So, as I watched Jericho this week, I vowed to pay close attention so as not to miss any pertinent information and it totally paid off. During the opening, the Morse code message clearly said, "Don't bother watching. This episode is kind of lame."
To be honest, I couldn't really concentrate on everything that happened because of the scene early on where Gerald McRaney & Pamela Reed decided to get boozed up. It may me wonder: Why aren't more people getting drunk in the middle of the day? I mean, it's not like anyone has a job to go to and shouldn't a small town like Jericho have at least one town drunk anyway?
The Olympics: Day 15
Actual competition continues on NBC in the form of speed skating, a six-mile marathon race that features American Chad Hedrick. Also, the women compete in the alpine giant slalom and four men climb into a bobsled and race down an icy track at break-neck speeds. Plus, more curling!
Check it out:
The Olympics: Day 14
Also tonight, to fill the time between figure skating competitors, the women snowboarders compete in the parallel giant slalom. Curling, hockey, bobsledding and marathon speed skating are also on the schedule:
The Olympics: Day 13
No figure skating tonight but the ladies will be back Thursday to determine the gold.
Here's the schedule:
The Olympics: Day 12
Also on the ice tonight, speed skaters Chad Hedrick, Shani Davis, Joey Cheek and Derek Parra race each other in the 1500m. Hedrick, Davis, and Cheek have all won gold medals so far in these games.
Here's the schedule on all of NBC's networks:
The Olympics: Day 10
Also tonight, the women's freestyle aerials competition, and the two-man bobsled. Here is the schedule for all of NBC's stations:
The Olympics: Day 6
There are some Americans to watch, too. Apolo Anton Ohno races in the 1000m speed skate and hopefully he'll be able to stay on his feet for this one. Also, gorgeous Jeremy Bloom (seriously, girls, look at him) competes in the moguls.
Here's tonight's line-up on all of NBC's stations:
The Olympics: Day 4
Here's tonight's schedule on all of NBC's networks:
The Olympics: Day 3
Here's today's Olympic schedule:
Brian Williams ruined Opening Ceremonies
He joined Bob Costas as the commentator for the Opening Ceremonies of the Turino, Italy Olympic games last night. And I almost
His comments were unfair to the athletes of those nations. The news and controversy surrounding certain nations lately are not representative of the athletes who are competing.
**Apparently, the Daily Nightly commenters agree.
The Olympics: what's happening today
Here's the schedule:
NBC milking the Olympics through the fall
The list of candidates is after the jump:
TV Squad Hot Topics
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Sonya J. Merriman, MD is certified by the American Board of Plastic Surgery and specializes in cosmetic surgery of the face, breast, and body.
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Mesembryanthemum | |
Mesembryanthemum crystallinum | |
Scientific classification | |
Kingdom: | Plantae |
(unranked): | Angiosperms |
(unranked): | Eudicots |
(unranked): | Core eudicots |
Order: | Caryophyllales |
Family: | Aizoaceae |
Subfamily: | Mesembryanthemoideae |
Genus: | Mesembryanthemum L. |
Species | |
Several, see text. |
Synonyms | |
Mesembrianthemum (lapsus) |
Mesembryanthemum (meaning "midday flowering") is a genus of flowering plants native to southern Africa. Many species formerly placed herein, such as Dorotheanthus bellidiformis, Carpobrotus and Sceletium have since been moved into other genera.
Fig marigold or Icicle plant is a name for any of several South African taxa of Mesembryanthemum which are cultivated as ornamental plants for their showy pink or white flowers. "Pebble plant" or "Ice plant" are other but rather ambiguous common names, usually referring to other Aizoaceae.
Mesembryanthemum is a member of the family Aizoaceae; like many members of this family, it is characterized by long-lasting flower heads. Flowers of Mesembryanthemum protect their gametes from night-time dews or frosts but open in sunlight. There is an obvious evolutionary advantage to doing this; where sun, dew, frost, wind or predators are likely to damage exposed reproductive organs, closing may be advantageous during times when flowers are unlikely to attract pollinators.
Ornamental Mesembryanthemum may escape into the wild and consequently has become widely naturalized outside their native range. They are considered an invasive weed in certain places. Some species are thought to be hallucinogenic plants like related Aizoaceae[1] and as such may be subject to legal restrictions (e.g. Louisiana State Act 159).
Jacob Breyne coined the name of the flower in 1684, using the spelling Mesembrianthemum, from the Greek roots μεσημβρία, meaning "noon", and ἄνθεμον, meaning "flower", because the species known at his time flowered at midday. In 1719, on the discovery that some species flowered at night, Johann Jacob Dillenius changed the spelling to "Mesembryanthemum", rederiving the first part of the word from Greek μεσος ("middle") and ἔμβρυον ("rudimentary fruit" or "embryo").[2]
Selected species[edit]
- Mesembryanthemum cordifolium
- Mesembryanthemum crystallinum
- Mesembryanthemum nodiflorum
- Mesembryanthemum salmii
See also[edit]
Notes and references[edit]
- ^ Watt, John Mitchell; Breyer-Brandwijk, Maria Gerdina: The Medicinal and Poisonous Plants of Southern and Eastern Africa 2nd ed Pub. E & S Livingstone 1962
- ^ Oxford English Dictionary Online, s.v. "Mesembryanthemum, n." (accessed June 24, 2008).
- Pink, A. (2004). Gardening for the Million. Project Gutenberg Literary Archive Foundation.
- Webster's Revised Unabridged Dictionary (1913)
External links[edit]
Wikimedia Commons has media related to Mesembryanthemum. |


text:
Registration Policies
Students must complete the published registration procedures each semester, including payment of all tuition and fees, to gain admission to classes. No student can be registered until all registration procedures have been completed. Class sizes are limited; early registration is advised. Registration priority in all sections is given to matriculated students. Students receive academic advising services from the Director of Continuing Education. A continuing education student may request an advising appointment by calling 617-994-4233.
Students wishing to cancel their registration or withdraw from a course must notify the Continuing Education division of the School of Art & Design in writing either by certified mail, fax, email, or in person. To cancel registration, this must be done prior to the start of the class(es) for which they have registered. Cancellation or withdrawal will be dated from the day such notice is postmarked, faxed, emailed, or submitted in person. Students who cancel their registration at any time prior to the start of classes will receive a full refund of tuition paid, less the $25 registration fee and any other applicable fees.
Students enrolling in Continuing Education division courses must be 18 years or older and be high school graduates or possess the equivalent of a high school education (i.e. GED). The school reserves the right to ensure international students have demonstrated proficiency in the English language in order to enroll in Continuing Education courses. Exceptions to these rules may be made at the discretion of the Director of Continuing Education and Preparatory Programs for applicants of unusual motivation or ability. Students intending to apply continuing education division courses toward BFA or certificate requirements must consult the general catalog and complete an application and change of status procedure.
Visa Policy & English Proficiency Requirement
United States immigration policy no longer permits students on B-1 (business) or B-2 (tourist) visas to enroll in courses at any college or university. If you are in the United States on a B-type visa, you will not be allowed to enroll in courses at the School of Art & Design at Suffolk University.
All non-native English speakers must demonstrate proficiency in the English language. Upon registering for courses, students may be required to have their English language skills evaluated.
Health Insurance
Massachusetts state law requires that all students taking nine or more credits in a term have adequate health coverage. Suffolk University will provide any student registered for nine or more credits per term with health insurance for a fee. If you already have health insurance and are registering for nine or more credits as a continuing education student, you will need to formally waive the University's health insurance to avoid being charged. International students, regardless of their credit load, will be automatically enrolled in Suffolk University's student health insurance plan. Waivers are granted at the discretion of the Office of Health & Wellness Services. Please visit www.suffolk.edu/health for up-to-date information.
Disability Services
Disability Services functions as the ADA compliance office and coordinates services for students with disabilities at Suffolk. In all cases, appropriate diagnostic documentation is required to receive disability services at Suffolk.
Location: 73 Tremont St, 7th Floor
Website: www.suffolk.edu/disability
Phone: 617-994-6820 -
Academic Credit Policies
In the case of studio courses, a credit is defined as a total of 30 hours of class time. Most School of Art & Design courses are studio courses (indicated by the letter S preceding the course number). In the case of academic courses, the University defines a credit as a total of 15 hours of class time. For more information on credit hours, please refer to Suffolk University's credit hour definition.
Courses taken by Continuing Education students may later be applied toward BFA or Graphic Design certificate requirements, provided the student has applied to and been accepted into the designated program. A maximum of 30 credits can be applied toward the BFA programs and a maximum of nine credits for the Graphic Design certificate. In both cases, a tuition differential will be applied. Only credit-bearing courses in which a grade of C or better has been earned may be applied; credits awarded will be considered transfer credits.
Please note: While individuals may elect to take additional courses as Continuing Education students, credits earned beyond the above stated transfer maximums cannot be applied toward certificate or degree requirements.
Courses taken as a Continuing Education student earn undergraduate credit only and are therefore not directly applicable to graduate programs. However, undergraduate credits earned as a Continuing Education student can later be used to waive the undergraduate-equivalent preparatory coursework required in the MA programs. Please note: Students planning on matriculating into the Master's of Interior Architecture program should not take Construction Documents (ADI-S372) nor Interior Marketing and Contracts (ADI-384) as CE students.
Please note: Under no circumstances may credits taken by Continuing Education students be applied toward the course requirements (30 credits at the 700-level or above) of our master's programs.
Administrative Policies
This website does not constitute a contractual agreement. The school reserves the right to change programs, courses, policies, fees, or faculty described on this site at its discretion.
Plagiarism, cheating, and stealing will be considered grounds for dismissal. In addition, the school reserves the right to withdraw the privileges of enrollment from any student whose activities or behavior are disruptive to the ongoing educational and professional life of the school, or from any student who fails to meet his or her financial obligations to the school in a timely manner.
The university does not discriminate on the basis of race, color, national origin, religion, sex, age, disability, sexual orientation, or Vietnam-era or disabled veteran status in its employment or admissions policies, or in the administration of, operation of, or access to its academic or non-academic programs and policies. It does not discriminate on the basis of disability in violation of Section 504 of the Rehabilitation Act of 1973. College of Arts & Sciences student and applicant inquiries regarding disabilities and Section 504 of the Rehabilitation Act of 1973 may be directed to the dean of students, 73 Tremont Street, 12th floor, tel: 617-573-8239.
In keeping with the provisions of the Family Educational Rights and Privacy Act of 1974 (P.L. 93-380) as amended (P.L. 93-568), also known as the Buckley Amendment, the university will provide eligible students or their parents the opportunity to review the student's educational records, to seek corrections of information contained in those records, and to limit disclosure of information contained in those records. The university is required to give students or their parents annual written notice of these rights and the right to file complaints with the Department of HEW concerning alleged failures by the institution to comply with the requirements of the act. A written policy governing institutional record-keeping is on file at the registrar's office. Americans with Disabilities Act The Americans with Disabilities Act (ADA) prohibits discrimination against persons with disabilities. This law assures that persons with disabilities have access to employment, public accommodation, public service, transportation and telecommunications programs, and services.
According to university policy, no official transcripts or diplomas will be made available until all financial obligations to the University have been met. In addition, those with outstanding balances will not be allowed to register with the Continuing Education Office until their accounts are clear. Reasonable collection costs, including attorney fees, will be added to delinquent accounts.
Refund Policies
Students wishing to cancel their registration or withdraw from a course must notify the School of Art & Design in writing either by certified mail, fax, email, or in person. To cancel registration, this must be done prior to the start of the class(es) for which they have registered. Cancellation or withdrawal will be dated from the day such notice is postmarked, faxed, emailed, or submitted in person. Students who cancel their registration at any time prior to the start of classes will receive a full refund of tuition paid, less the $25 registration fee and any other applicable fees. Students who withdraw from a course after the first class should refer to the following refund policy:
Continuing education students withdrawing from a course will receive refunds on tuition, less the $25 registration fee and any other applicable fees, according to the following schedule within 30 days of the receipt of the written notice of withdrawal. Refunds for withdrawing students are calculated from the start date of each course until the date written notice of withdrawal is post-marked, faxed, emailed, or submitted in person. The refund is based on the number of classes which have been held, not the number of classes the student attended. There is no refund for workshops.
Please note: the Gateway Program, Accelerated Graphic Design Program, and workshops have separate refund policies.
The percentages indicated below are percentages of total term tuition due.
• Withdrawal after the 1st class: 90% refund
• Withdrawal after the 2nd class: 70% refund
• Withdrawal after the 3rd class: 50% refund
• Withdrawal after the 4th class: no refund -
Tuition Differential Policy
Continuing Education students who took courses which are applicable to BFA or certificate program requirements must pay the tuition differential for those courses upon matriculating into a formal program of study. The student is responsible for paying the tuition differential for each course which he/she wishes to upgrade from continuing education to BFA or certificate credit. This differential calculation is based on the tuition rates for the semester(s) during which the student completed applicable courses.
For example, a student took 2-Dimensional Design for continuing education credit in spring 2012 and paid $1,450. In the spring of 2012, BFA credit for this course was $2,350. Upon changing their status from continuing education to BFA, the student is responsible for paying the difference of $900 to apply the course toward their BFA requirements.
Grades are issued by the university registrar at the end of each semester. All students will receive a grade report unless financial obligations to the university have not been met.
Grades are as follows: A (Outstanding), B (Above Average), C (Average), D (Poor), F (Failure), I (Incomplete), L (Lost), W (Withdrew). Letter grades of A, B, C, D, and F carry numerical values of 4, 3, 2, 1, and 0, respectively. A (+) notation will add 0.3 to the numerical value of a letter grade (e.g. B+ equals 3.3) and a (-) notation will similarly subtract 0.3 (e.g. B- equals 2.7).
A grade of I (Incomplete) indicates a student has done passing work in a course but has not yet submitted all the work required for a formal evaluation. The I is awarded at the instructor's discretion only if the student has completed at least half of the course requirements satisfactorily at the end of the semester, and there is a reasonable expectation that all course requirements can be completed in one academic year. Unless an I is formally reevaluated by the instructor within one academic year, it automatically converts to an F.
A grade of L (Lost) is awarded when a student's name appears on a roster, but the student never appears in class or disappears before being formally evaluated by the instructor.
A grade of W signifies official withdrawal from a course and is assigned administratively if a student drops a course between the end of the drop/add period and the semester's withdrawal deadline, or when a student drops or withdraws from the school after the semester's deadline with approval from the director of continuing education and preparatory programs. Permission is given only for valid cause, such as debilitating illness, relocation, serious family crisis, or other circumstances beyond a student's control.
Student Artwork Policies
Statement of Use
Suffolk University reserves the right to retain artwork produced by students for exhibition and reproduction as part of their program of study while enrolled at the University, and has a non- exclusive, royalty-free, worldwide license to photograph, tape, reproduce, or otherwise use or display student work for marketing, promotional, archival, reference, research, classroom, educational, and other purposes. Students will be credited for the use of such reproductions at the discretion of the University. Reproductions of student artwork may be edited at the University's discretion, but in doing so, the University will make a good faith effort to act respectfully and responsibly so as not to unduly compromise the integrity of the original artwork.Abandoned Student Artwork
Student artwork left on Suffolk University's premises must be picked up within one week of the end of each academic semester because of limited space on campus. Any property remaining after that date shall be considered abandoned and it will become the property of Suffolk University, unless a formal arrangement has been made with a faculty member or administrator to retain the work beyond this deadline. The University will not be responsible for the location and/or condition of abandoned student artwork. -
Cancellation Policies
Suffolk University reserves the right, in the case of insufficient enrollment, to cancel any course and can exercise that right at any time prior to the first scheduled class meeting. If this occurs, students will be notified and may select a substitute course or receive a full refund. Classes will not be held on national or state holidays, and these particular days are listed on the term calendar. In case of cancellations due to instructor illness, we will attempt to notify students as far in advance as possible.
When weather or other emergency conditions warrant the closing or delayed opening of the university, announcements will be made between the hours of 6 a.m. and 9 a.m. If the storm occurs late in the day, evening cancellations may be announced from 3 p.m. - 5 p.m. Cancellation announcements will be made on the Suffolk University website home page, via the University Switchboard at 617-573-8000, and on the following radio and television stations:
• WBZ-TV Channel 4
• WCVB-TV Channel 5
• WHDH-TV Channel 7


text:
Ticket #10305 (new defect)
Opened 3 years ago
OVA/OVF import ignores virtual machine name
Reported by: | diegows | Owned by: | |
Priority: | minor | Component: | OVF |
Version: | VirtualBox 4.1.8 | Keywords: | |
Cc: | Guest type: | other | |
Host type: | other |
I've created an OVA/OVF file using Vmware Workstation and I found that VirtualBox is ignoring the virtual machine name when I import it. Virtualbox is using the "ovf:id" attribute of the "VirtualSystem" tag instead of the "Name" element inside the "VirtualSystem" section.
I'm setting "ovf:id" with the "Name" element value as workaround, but I think that VirtualBox should use the "Name" element if it exists.
Vmware Player/Workstation imports the name correctly.
Note: See
TracTickets for help on using