Mobile Game Development is one of the most booming industrial sectors in the recent times. The Smartphone sector has grown at a rapid rate and in turn has given gamers with an ultimate gaming experience. The mobile game technology is providing a gaming experience with more technical definitions and it is proving as an emerging technology.
Computer games and game consoles have definitely grabbed the game development market since ages, but with the Smartphones making new entry into the market mobile games have reached new levels. Due to the handy nature of the mobile phones, mobile games have an increased demand. Moreover, the future of game technology is dependent on mobile gaming as more people are inclined towards mobile gaming sector.
Mobile Game Development is classified into various genres and trends and some of the most popular upcoming trends include - Massive Multiplayer Mobile Game Development, Advertising/Promotions through Mobile Game, and Mobile Game promotions for Movies, Products Promotion, and 3D gaming.
Massive Multi-player Mobile Game Development - Online multi-player gaming is highly apprehended by game lovers. The players can choose any opponent from any endeavor of the earth. This has been a trend as well always loved trend by the game buffs.
Interactive or Reciprocal Server Games: All mutual computer games run on a GPRS relation to join with a central server. Most of the game companies work on these new online games strategy, as they gain great profit and popularity in the gaming market.
Business through Mobile Games - Mobile Game Development obtain a great metamorphose when they act as a tool for promoting thoughts or ideas, especially for costumer supported enterprises. Various advertising companies also promote their client's product through these mobile games. It is one of the best cost-efficient methods to promote a business.
Promoting movies via Mobile Games - Here's a new trend how moviemakers grab some audience. Moviemakers and producers promote their upcoming movies through a specific game version. This method suddenly publicizes the movie name and in turn, attracts more gamers as well as viewers.
Advertising/Promotions through Mobile Game - Mobile gaming has been considered as an effective advertising method for any product. The product will be campaigned inside a game for gaining public attention and popularity. The three dimension or 3D game developments have brought a new level to the gaming arena, and it provides the gamers with a real life like experience. This trend of 3D is hugely influencing viewers and brings profit to the gaming sector as well.
Michael writes for Zco Corporation, one of the largest developers of mobile applications, 3D content and custom software in the world.


I just wanted to come up for air and say, hello! I'm still here, and pretty much just working, living, and loving.
I haven't posted in about a month! Mainly, I've been seriously busy working a part-time job and another full-time-ish one as a freelance writer. Partly, however, I must admit that I simply haven't wanted to engage in what feels like alcoholic behavior: identifying AS my problem and relating things that are happening now to my past–in a circular way that doesn't feel like it serves me anymore. One of my tricks to getting out of my bad moods is to ACT and not think. YES, it's important to recognize when a thought is worth addressing and when it's simply just a thought pattern that isn't. I know that most of the time, the mood dips can be SOLVED, and don't have to be embraced, analyzed, or even accepted.
I have a lot of work to do, so I'm going to just sign off. I know there is a huge post coming about what MUST be said: I'm coming to no longer identify with "being" an "alcoholic." AND, the hard part, I'm finding: extracting myself from this mental situation. Yes, I had a problem and yes, I still have no desire to drink the way I drank and to be the way I was. That is a given. However, can I not hold that close and, simultaneously, not get agitated every time I try to approach it? I'm not sure.
Happy holidays week, all! I've missed you, I have to say! Time to start working through some of this weirdness.


the Church has in all ages made a selection from them."
The creation of the universe and the nature of humanity as taught by the Ancient Wisdom.
Clairvoyant observations plus historical records enabled Charles W. Leadbeater to author this absorbing, in-depth study of the mystery schools.
In this volume, the fundamental teachings of Theosophy are explained in simple and clear terms for a beginner so that he may add more details by further study and research.
In print since 1927, this study of our subtle body is based on the works of Theosophical authors and noted clairvoyants, including H. P. Blavatsky, C. W. Leadbeater, and Annie Besant.


Often the line between 'good debt' and 'bad debt' is clear. Good debt will see the money yo borrow be returned to you plus more, so using credit to buy a house or start up a business are both examples. Bad debt on the other hand generally involves spending borrowed money on things you don't need- or like it's money you have already earned. Splashing out on new clothes, holidays and eating out on credit are all examples. However sometimes it can be a little more blurred, and buying a car can sometimes be a tricky one. One one hand, if you already have a perfectly good vehicle but simply want to upgrade then this can be a bad move if you have a habit of getting into debt (or are already in debt). However, it can sometimes be an incredibly wise purchase and change your life for the better. It could mean you can look for jobs that are a little further out, improving your career prospects. It could save you money on expensive public transport, and generally make your life much easier- especially if you have kids and other commitments.
If you don't already own a car, or need to replace a car that's broken down then taking out used car finance can be seen as 'good debt' if you need the vehicle to be able to work and live. With this being said, here are some of the other costs you will need to bear in mind.
If this will be your first car you might be surprised at just how high insurance costs are. Often it's not the price of the car thats the most expensive thing, but the cost to insure it. If you're replacing a car that's no longer usable but have insurance on the vehicle, be sure to check how much it will cost to change the policy over to the car you plan on buying. Even a similar size, model and year can cost significantly more so it's something you need to be aware of before signing on the dotted line.
Depending on where you live, you may have to pay road tax for your vehicle. This is usually based on the levels of emissions your car produces, older cars will emit more and therefore be more expensive. Newer models will usually be very cheap with hybrids and electric cars having zero road tax. You can check how much you will need to pay online, in some cases it could be worth spending a little more on a newer or more eco friendly car to get this cost down.
This is an obvious one but something many drivers overlook. When cars break down they dont tend to be cheap, so it can be well worth having some savings put aside just in case this happens. Even a few hundred dollars can lessen the blow and get you back on the roads as quickly as possible if the worst were to happen.


The estimated worth of 03design.ru is $ 54.61. This is among other things based on 27 pageviews per day which we estimate to turn into a advertisment revenue of $ 2.84 a month. The website is hosted in POKROVKA, RUSSIAN FEDERATION and has a Google Pagerank of 4. This information is last updated on September 02, 2014 at 19:42 CET.


"This is among the most technically advanced and competitive manufacturing sites in Singapore and the Asia Pacific region."
SINGAPORE--(BUSINESS WIRE)--ExxonMobil has commenced startup operations at one of the world's largest ethylene steam crackers, the centerpiece of the company's multi-billion dollar expansion project at its Singapore petrochemical complex.
The expansion, powered by a new 220-megawatt cogeneration plant, adds 2.6 million tonnes per year of new finished product capacity. It includes two new polyethylene plants, a polypropylene plant, a metallocene elastomers unit, an oxo-alcohol unit and an aromatics expansion, all of which are completed and beginning operation. Ethylene production is expected to start in the next few months.
The new cogeneration plant allows for the efficient generation of electricity to run pumps, compressors and other equipment, while at the same time producing additional steam needed in the production processes. Cogeneration is significantly more efficient than traditional methods of producing steam and power separately, resulting in lower operating costs and reduced greenhouse gas emissions.
The petrochemical expansion is significant to ExxonMobil. It makes the Singapore facility ExxonMobil's largest refining and petrochemical complex. It also marks the first production by ExxonMobil of its proprietary specialty elastomers and metallocene-based polyethylene in the Asia Pacific region.
The expansion will increase the chemical plant workforce by 50 percent, bringing total employment at ExxonMobil's Singapore integrated refining and chemical complex to 1,800. During peak construction, the project employed on site 22,000 workers who achieved more than 80 million work hours with no lost-time injuries in construction activities.
ExxonMobil has operated in Singapore for more than 100 years and is one of Singapore's largest foreign manufacturing investors. The company has expanded refining and petrochemical production in Singapore to meet expected demand for transportation fuels and the chemicals used for plastics and other manufacturing across the Asia Pacific region.
ExxonMobil Chemical Company is one of the world's premier petrochemical companies with manufacturing, technology, and marketing operations around the world. The company delivers a broad portfolio of products and solutions efficiently and responsibly, with a commitment to create outstanding customer and shareholder value. ExxonMobil Chemical Company endorses the principles of sustainable development, including the need to balance economic growth, social development and environmental considerations. To learn more, visit www.exxonmobilchemical.com.


text:
EPSRC Reference: EP/R02605X/1
Title: Targeting Molecular Magnetic Hysteresis at Liquid Nitrogen Temperatures
Principal Investigator: Mills, Professor DP
Chilton, Professor NF
Department: Chemistry
Organisation: University of Manchester, The
Scheme: Standard Research
Starts: 01 July 2018 Ends: 31 December 2021 Value (£): 437,939
Co-ordination Chemistry
No relevance to Underpinning Sectors
Panel Date Panel Name Outcome
24 Jan 2018 EPSRC Physical Sciences - January 2018 Announced
For over fifty years economic factors have driven a steady trend of making electronic devices smaller. However, the rate of progress in miniaturisation has started to stall, and it has been predicted that a plateau may be reached within ten years. As such, "bottom-up" alternatives are sought to rival the current "top-down" approach to ensure continued technological advancement. One promising solution for high-density data storage is to use Single Molecule Magnets (SMMs). These are molecules that can store magnetic information, and could therefore give the smallest possible devices.
Lanthanide (Ln) SMMs have emerged as leading candidates due to their favourable magnetic properties, but at present these only function with expensive liquid helium cooling. The highest temperature at which Ln SMMs retain magnetic information is dictated by the choice of Ln, the atoms bonded to the Ln and the resultant molecular geometry, and the competition of magnetic relaxation pathways. These factors can all potentially be controlled but at present the relaxation mechanisms are still poorly understood. Efficient relaxation processes can significantly lower the temperature at which magnetic information is retained, based on what would be predicted solely from consideration of an isolated Ln SMM, and thus these must be investigated to make progress.
We have recently found that Ln cations bonded only to two five-membered carbon atom rings in an axial arrangement give a SMM for which the highest temperatures at which magnetic hysteresis, a memory effect that is essential for data storage, has ever been observed. As such, we target the syntheses of more complex Ln SMM structures based upon this motif to provide even higher hysteresis temperatures. These systems could operate above liquid nitrogen temperatures, at which point they would become technologically viable. The magnetic relaxation pathways of these systems can be studied in depth over a large temperature range. This will allow us to deepen our understanding of the factors governing relaxation mechanisms, so that in future we can design Ln SMMs that disfavour such processes and can store magnetic information at even higher temperatures.
In recent work (Nature, 2017, 548, 439), we have used our Ln SMM design criteria to report by far the largest molecular hysteresis temperature reported to date (60 K). This is the single biggest leap in nearly 25 years (the previous record, 14 K, was set in 2011; 4 K was the initial achievement in 1993) and is now only 17 K away from operation under an economically viable liquid nitrogen regime. We have made theoretical predictions for improvements to the design of this system to raise the hysteresis temperature even further by modifying the carbon atom rings, and have set out synthetic routes to achieve this goal in this proposal. More ambitiously, we target the synthesis of "triple decker" compounds that contain two dysprosium cations and three small carbon atom rings in an approximately cylindrical arrangement. Ln ions prefer high coordination numbers, hence the synthesis of triple decker complexes containing only five-membered carbon atom rings would be a remarkable synthetic achievement.
All synthetic studies in this proposal will be complemented by high level physical analysis of magnetic and electronic properties, including computational modelling. This will provide essential information to guide our pioneering studies of magnetic relaxation pathways and their relationship to the geometry and electronic structure of Ln SMMs. Ideally we may synthesise a Ln SMM that can operate at liquid nitrogen temperatures.
Organisation Website: http://www.man.ac.uk

redpajama_set_name: RedPajamaCommonCrawl


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All of the Ashkenazi Jews alive today can trace their roots to a group of about 330 people who lived 600 to 800 years ago.
So says a new study in the journal Nature Communications. An international team of scientists sequenced the complete genomes of 128 healthy Ashkenazi Jews and compared each of those sequences with the others, as well as with with the DNA of 26 Flemish people from Belgium. Their analysis allowed them to trace the genetic roots of this population to a founding group in the Middle Ages.
"Ashkenaz" in Hebrew refers to Germany, and Ashkenazi Jews are those who originated in Eastern Europe. (Sephardic Jews, by contrast, are from the areas around the Mediterranean Sea, including Portugal, Spain, the Middle East and Northern Africa.) About 80% of modern Jews have Ashkenazi ancestry, according to the Hebrew University of Jerusalem. Albert Einstein was an Ashkenazi Jew, as were Gertrude Stein and Carl Sagan. Steven Spielberg and Scarlett Johansson are also Ashkenazi Jews, along with three current members of the U.S. Supreme Court (Ruth Bader Ginsburg, Stephen Breyer and Elena Kagan).
Despite their close ties with Europe, no more than half of their DNA comes from ancient Europeans, the researchers found. Only 46% to 50% of the DNA in the 128 samples originated with the group of people who were also the ancestors of the Flemish people in the study. Those ancient people split off from the ancestors of today's Middle Easterners more than 20,000 years ago, with a founding group of about 3,500 to 3,900 people, according to the study.
The rest of the Ashkenazi genome comes from the Middle East, the researchers reported. This founding group "fused" with the European founding group to create a population of 250 to 420 individuals. These people lived 25 to 32 generations ago, and their descendants grew at a rate of 16% to 53% per generation, the researchers calculated.
Today there are more than 10 million Ashkenazi Jews around the world, including 2.8 million in Israel, according to the Hebrew University of Jerusalem.
The authors of the new study come from nearly two dozen research groups in New York City, Belgium and Israel. Many of the co-authors are not Jewish, but they are interested in studying this group because it is genetically isolated (since Jews have historically married within their faith, their gene pool is closed). That makes it easier to identify genes linked to specific diseases, like Parkinson's and cancer, links that could well apply to non-Jews as well.
The study was funded by the National Institutes of Health and the National Science Foundation, along with several private foundations.
Fascinated by genetics? Follow me on Twitter @LATkarenkaplan and "like" Los Angeles Times Science & Health on Facebook.


This invention relates generally to drug-releasing coatings for medical devices which are inserted or implanted into the body. More particularly, the invention is directed to medical devices having a drug-releasing coating comprising at least two layers: a reservoir layer and an outer layer comprising an ionic surfactant complexed to a biologically active material. Furthermore, the invention is directed to methods of stabilizing ionically complexed drug coatings.
Exposure to a medical device which is implanted or inserted into the body of a patient can cause the body tissue to exhibit adverse physiological reactions. For instance, the insertion or implantation of certain catheters or stents can lead to the formation of emboli or clots in blood vessels. Similarly, the implantation of urinary catheters can cause infections, particularly in the urinary tract. Other adverse reactions to medical devices include cell proliferation which can lead to hyperplasia, occlusion of blood vessels, platelet aggregation, rejection of artificial organs, and calcification.
To reduce such adverse effects, pharmaceuticals, such as anticoagulants and antibiotics, have been administered in or on medical devices. A number of methods for delivering the drug(s) through implantation or insertion of the medical device involve covalently bonding the drug to the medical device, i.e, substrate. For example, U.S. Patent No. 4,613,665 to Larm describes the coupling of heparin with reactive aldehyde groups to an animated surface by reductive amination.
Also, U.S. Patent Nos. 5,112,457 and 5,455,040 to Marchant disclose the use of a similar approach to end-bind heparin on modified substrates. The substrate modification consists of depositing a film of plasma polymerized N-vinyl-2-pyrrolidone and attaching a spacer (e.g. PEG) on the film. The end group of the spacer is a primary amine, which can be bonded to aldehyde-ended heparin through reductive amination.
However, the covalent bonding approaches are limited. Only the surfaces of covalently bound coatings provide pharmaceutical activity, resulting in insufficient pharmaceutical activity at the treatment site. Furthermore, the drug loading of the medical device is limited by its surface area since the drug must be attached to the surface of the coating.
Pharmaceuticals have also been applied to medical devices by covering the surface with a coating containing them. A number of these coatings involve the ionic binding of the drug to the substrate. These approaches generally comprise the deposition of water-insoluble complexes of drugs and ionic surfactants on the surfaces of medical devices.
Illustrative of such approaches is the use of tridodecylmethylammonium chloride (TDMAC) or benzalkonium chloride, positively charged or cationic surfactants which are ionically complexed to negatively charged molecules of pharmaceuticals. Typical examples include tridodecylmethylammonium (TDMA)-heparin and TDMA-antibiotics. The former complex has been widely used as coatings on catheters, shunts and other blood contacting devices. The TDMA-heparin treatment can be applied to numerous biomedical materials including polyurethane, silicone, polypropylene, polycarbonate, PVC, metals and glass. TDMA-antibiotics have been used to reduce infections related to implants, urinary catheters and the like.
Although these ionic complex approaches allow numerous biomaterials to be coated with drugs without elaborate surface modification, they suffer from certain disadvantages. Notably, the ionically complexed drug tends to be quickly released from the medical device upon contact with body fluids so that its activity at the point of implantation or insertion diminishes rapidly. Attempts have been made to stabilize these coatings by crosslinking the ionically complexed drugs with glutaraldehyde or other bifunctional reagents. Recently, U.S. Patent No. 5,441,759 to Crouther et al. discloses that exposure to gamma radiation and post-exposure heat treatment can strengthen the complex of TDMA-heparin to PVC surfaces. However, these attempts have demonstrated limited improvement. Specifically, such exposure to gamma radiation has been demonstrated in certain cases to have adverse effects upon the device. For instance, certain polymers degrade, crosslink, or change color upon exposure to gamma radiation, which may result in a loss of mechanical properties.
Also, attempts have been made to prolong the activity of ionically complexed drugs by mixing polymers with the drug-surfactant complexes to form coating compositions. See e.g. U.S. Patent No. 5,525,348 to Whitbourne et al., U.S. Patent No. 5,061,738 to Solomon et al., and U.S. Patent No. 4,670,975 to McGary et al. However, inclusion of a polymer has not shown significant increase in prolonging activity. Moreover by employing drugs which are ionically complexed to surfactant, the amount of drug that can be loaded into the coating is limited since in general the drug constitutes only 20-50% of the complex. Thus the incorporation of the surfactant restricts the amount of drug that can be placed into the coatings of the medical device.
wherein the reservoir layer comprises a polymer incorporating the biologically active material which is substantially free of any ionic surfactant such that the biologically active material of the reservoir layer can migrate outwardly from the reservoir layer.
Hence, there is a need for stable coatings for medical devices which permit sufficient release of drugs at a certain rate or over a desired period of time into body fluid while maintaining high pharmaceutical activity on the surface. Therefore it is an object of the invention to provide such a coating for timed release of the incorporated drugs.
It is also an object of this invention to provide a drug-containing medical device which allows sustained delivery of the pharmaceutical or sufficient pharmaceutical activity at or near the coated surfaces of the devices.
Also, it is an object of the invention to provide medical devices with stabilized ionically complexed drug coatings and methods for making such devices.
Additionally, it is an object of the invention to provide a drug-releasing coating which adequately adheres to a medical device to allow the timed or prolonged application of the drug to body tissue.
It is a further object of the invention to provide methods for making a drug-releasing medical device which permit timed-delivery or long-term delivery of the drug.
These and other objects are accomplished by the present invention. To achieve these objectives, we have developed a coating which permits timed or prolonged pharmacological activity on the surface of medical devices through a reservoir concept. Specifically, the coating comprises at least two layers: an outer layer containing at least one drug-ionic surfactant complex overlying a reservoir layer or tie layer containing a polymer and the drug which is substantially free of an ionic surfactant. Upon exposure to body tissue of a medical device covered with such coating, the ionically complexed drug in the outer layer is released into body fluid or tissue. Following release of such complexed drug, the ionic surfactant complex sites in the outer layer are left vacant. To maintain the pharmacological activity after delivery of the ionically complexed drug, additional amounts of the drug are embedded or incorporated in the reservoir layer in a manner which allows the drug, which is substantially free of ionic surfactants, to form a complex with the vacant complex sites of the ionic surfactant of the outer layer. As a result, the surface of the medical device is enriched with the drug to provide sustained pharmacological activity to prevent the adverse reaction due to the presence of the medical device. In use, some of the drug which is embedded or incorporated in the reservoir layer can complex to vacant complex sites in the outer layer, while some of the drug, which is embedded or incorporated in the reservoir layer can freely elute into the body fluid.
The coatings of the invention can be used for a variety of medical devices such as catheters, shunts, stents, (e.g. self expandable or balloon expandable vascular or non-vascular stents) heart valves, grafts, and artificial organs or prostheses. The coatings may be used with polymeric, metallic or ceramic surfaces.
The polymers suitable for use in the invention, such as in forming the reservoir layer, should be ones that are biocompatible and avoid irritation of body tissue. Preferably for medical devices which undergo mechanical challenges, elastomeric polymers such as silicones, polyurethanes, thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDM rubbers may be used. For medical devices which do not undergo mechanical challenge, bioabsorbable polymers may be used. Such bioabsorbable polymers included polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose and the like.
The biologically active material suitable for the invention can be in a particulate form. Average particle size can be 1 to 100 microns. The biologically active materials useful for the invention include glucocorticoids, heparin, hirudin, angiopeptin, aspirin, growth factors, oligonucleotides, antiplatelet agents, anti-coagulant agents, antimitotic agents, antioxidants, antimetabolite agents, anti-inflammatory agents, anti-hypertensives, and antibiotics such as penicillin. The reservoir layer can contain 0.1 to 90 weight % of the biologically active material, preferably 10-45 weight %, and can have a thickness ranging from about 5 to about 1000 microns. Preferably, the reservoir layer ranges from about 15 to about 50 or 200 microns thick.
For the outer layer, suitable ionic surfactants comprise tridodecylammonium chloride, or benzalkonium chloride. The outer layer can have a thickness ranging from about 0.1 to about 10 microns; preferably, the outer layer is about 1 to about 5 microns thick.
In accordance with the present invention, negatively charged drugs contact positively charged surfactants to form a complex. Once the complex is formed, the solubility of the drug in body fluid is significantly reduced. Thus, the release rate of the drug in the body fluid is decreased. Similarly, positively charged drugs can form complexes with negatively charged surfactants to achieve similar results.
The complexes formed according to the present invention will result primarily from ionic interactions between negatively charged drugs and positively charged surfactants or positively charged drugs and negatively charged surfactants. However, certain secondary forces may also exist to contribute to the formation or maintenance of the complexes, such as hydrogen bonding, dipole-dipole interaction, charge-dipole interaction, and the complexes of the initial outer layer may be identical or similar to the complexes subsequently formed by the biologically active material of the reservoir. However, the complexes may differ. For instance an initial complex may have a higher density of charge-charge interaction between a pharmaceutical agent and a surfactant as compared to subsequent complexes formed by biologically active material of the reservoir and the surfactant.
To prepare the reservoir coatings of the present invention, the reservoir layer is first formed on the medical device. The drug is incorporated by dissolving or suspending it in a polymer and solvent composition. A crosslinking agent can optionally be added to the solution or suspension. The reservoir layer composition is then applied to a surface of the medical device by methods such as, but not limited to, spraying or dipping. The reservoir layer can then be optionally heat cured. The outer layer is prepared by dissolving a drug-ionic surfactant complex in a solvent or a mixture of solvents which are swellable to the polymer(s) in the reservoir layer. The outer layer composition is applied over the reservoir layer to form the outer layer. Some of the complex will penetrate into the polymeric reservoir coat.
FIGURE 1 is a plot showing the release rate of heparin for stents with the coatings made according to Example 1.
The medical devices suitable for the present invention include but are not limited to catheters, implantable vascular access ports, blood storage bags, vascular stents, blood tubing, central venous catheters, arterial catheters, vascular grafts, intraaortic balloon pumps, heart valves, cardiovascular sutures, total artificial heart and ventricular assist pump, extracorporeal devices such as blood oxygenators, blood filters, hemodialysis units, hemoperfusion units, plasmapheresis units, hybrid artificial organs such as pancreas or liver and artificial lungs.
Devices which are particularly suitable include vascular stents such as self-expanding stents and balloon expandable stents. Examples of self-expanding stents useful in the present invention are illustrated in U.S. Patent Nos. 4,655,771 and 4,954,126 issued to Wallsten and 5,061,275 issued to Wallsten et al. Examples of appropriate balloon-expandable stents are shown in U.S. Patent No. 4,733,665 issued to Palmaz, U.S. Patent No. 4,800,882 issued to Gianturco and U.S. Patent No. 4,886,062 issued to Wiktor. Similarly, urinary implants such as drainage catheters are also particularly appropriate for the invention.
The surfaces of the medical devices may be formed from polymeric, metallic and/or ceramic materials. Suitable polymeric materials include without limitation polyurethane and its copolymers, silicone and its copolymers, ethylene vinyl-acetate, thermoplastic elastomers, polyvinyl chloride, polyolefins, cellulosics, polyamides, polyesters, polysulfones, polytetrafluorethylenes, polycarbonates, acrylonitrile butadiene styrene copolymers, acrylics, polylactic acid, polyglycolic acid, polycaprolactone, polylactic acid-polyethylene oxide copolymers, cellulose, collagens, and chitins.
Metallic materials include metals and alloys based on titanium (such as nitinol, nickel titanium alloys, thermomemory alloy materials), stainless steel, tantalum, nickel-chrome, or cobalt-chromium (such as Elgiloy® and Phynox®). Metallic materials also include clad composite filaments, such as those disclosed in WO 94/16646. Examples of ceramic materials include ceramics of alumina and glass-ceramics such as Macor®.
As described above, the reservoir layer composition comprises a polymer and a biologically active material. Optionally a cross-linking agent may be included. The following is a more detailed description of suitable materials or agents and methods useful in producing the reservoir layer of the coatings of the invention.
The polymer(s) useful for forming the reservoir layer should be ones that are biocompatible and avoids irritation to body tissue. Preferably the polymers are biostable ones, such as polyurethanes, silicones, and polyesters. Other polymers which can be used include ones that can be dissolved and cured or polymerized on the medical device or polymers having relatively low melting points that can be blended with therapeutic agents. Suitable polymers include polyolefins, polyisobutylene, ethylene-alphaolefin copolymers, acrylic polymers and copolymers, vinyl halide polymers and copolymers such as polyvinyl chloride, polyvinyl ethers such as polyvinyl methyl ether, polyvinylidene halides such as polyvinylidene fluoride and polyvinylidene chloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics such as polystyrene, polyvinyl esters such as polyvinyl acetate; copolymers of vinyl monomers, copolymers of vinyl monomers and olefins such as ethylene-methyl methacrylate copolymers, acrylonitrile-styrene copolymers, ABS resins, ethylene-vinyl acetate copolymers, polyamides such as Nylon 66 and polycaprolactone, alkyd resins, polycarbonates, polyoxymethylenes, polyimides, polyethers, epoxy resins, polyurethanes, rayon-triacetate, cellulose, cellulose acetate, cellulose butyrate, cellulose acetate butyrate, cellophane, cellulose nitrate, cellulose propionate, cellulose ethers, carboxymethyl cellulose, collagens, chitins, polylactic acid, polyglycolic acid, and polylactic acid-polyethylene oxide copolymers.
More preferably for medical devices which undergo mechanical challenges, e.g. expansion and contraction, the polymers are selected from elastomeric polymers such as silicones (e.g. polysiloxanes and substituted polysiloxanes), polyurethanes, thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDM rubbers. Because of the elastic nature of these polymers, the coating better adheres to the surface of the medical device when the device is subjected to forces or stress.
Furthermore, although the invention can-be practiced by using a single type of polymer to form the reservoir layer, various combinations of polymers can be employed. The appropriate mixture of polymers can be coordinated with biologically active materials of interest to produce desired effects when coated on a medical device in accordance with the invention.
The drugs or biologically active materials which can be used in the invention can be any therapeutic substances such as those which reduce or prevent adverse physiological reactions from exposing body tissue to the medical device. The drugs incorporated into the reservoir layer should be substantially free of ionic surfactants. The drugs can be of various physical states, e.g., molecular distribution, crystal forms or cluster forms. A combination of suitable pharmaceuticals can be incorporated into the reservoir layer.
Suitable therapeutic substances include glucocorticoids (e.g. dexamethasone, betamethasone), heparin, hirudin, angiopeptin, aspirin, growth factors, oligonucleotides, and, more generally, antiplatelet agents, anti-coagulant agents, antimitotic agents, antioxidants, antimetabolite agents, and anti-inflammatory agents could be used. Antiplatelet agents can include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory and antiplatelet drug. Dipyridamole is a drug similar to aspirin in that it has anti-platelet characteristics. Dipyridamole is also classified as a coronary vasodilator. Anticoagulant agents can include drugs such as heparin, protamine, hirudin and tick anticoagulant protein. Antimitotic agents and antimetabolite agents can include drugs such as methotrexate, azathioprine, vincristine, vinblastine, 5-fluorouracil, adriamycin and mutamycin. Antibiotic agents can include penicillin, cefoxitin, oxacillin, tobramycin, and gentamycin.
The biologically active agents can be incorporated by dissolving or suspending them in the polymer and solvent of the reservoir layer composition. If the drugs are suspended in the solution, they should be dispersed as fine particles ranging from 1-100 microns in average particle size. Alternatively, if a polymer having a relatively low melting point is used, the polymer and biologically active agent can be blended in the molten stage (such as by casting or coextrusion) if the biologically active agent does not degrade at the molten temperature. The ratio of reservoir layer thickness to average particle diameter is preferably greater than about 3, and more preferably greater than about 5.
The concentration or loading of the biologically active material in the reservoir layer may be varied according to the therapeutic effects desired. Also, the loading, in terms of the ratio of pharmaceutical to polymer in the reservoir layer, will depend upon the efficacy of the polymer in securing the pharmaceutical onto the medical device and the rate at which the coating is to release the pharmaceutical to the body tissue. Generally, the reservoir layer may contain 0.1-90% by weight or preferably 10-45% by weight of the biologically active material. Most preferably, 25-40% by weight of the drug should be incorporated in the reservoir layer.
The reservoir layer will generally be prepared to be substantially free of any ionic surfactant. However, small amounts may become present, especially at an interface between an outer layer and a reservoir layer. For instance, small amounts of ionic surfactant may become present as a result of penetration during an outer layer spraying process or due to migration from the outer layer during shelf storage. The reservoir layer, apart from the interface with the outer layer, will preferably have less than 0.5 weight percent complex, more preferably less than 0.4 weight percent complex.
Solvents suitable for forming the reservoir layer composition are ones which can dissolve the polymer into solution and do not alter or adversely impact the therapeutic properties of the biologically active material employed. Examples of useful solvents for silicone include tetrahydrofuran (THF), chloroform and dichloromethane.
To enhance the stability of the reservoir layer and the timed or long-term release of the pharmaceuticals, crosslinkers may be incorporated into the reservoir layer. For instance, hydridosilane may be used as a crosslinking agent for silicone.
The reservoir layer composition is generally prepared by adding micronized drug particles into a selected amount of polymer. Solvent and optional crosslinking agent are then added to this mixture which is then stirred until it is homogeneous. Depending on the nature of the biologically active material and the solvent and polymers used, the mixture need not be a solution. The drug particles need not be dissolved into the mixture but may be suspended therein.
The mixture is then applied to a surface of the medical device. The reservoir layer composition may be applied by dipping the medical device into the composition or by spraying the composition onto the device. The thickness of the reservoir layer formed may range from about 5 microns to about 100 microns and preferably from about 15 microns to about 50 microns.
Since different coating thicknesses can be readily achieved by adjusting the number of spray cycles, spray coating the medical device with the reservoir layer is preferred. Typically, an airbrush such as a Badger Model 150 (supplied with a source of pressurized air) can be used to coat the device. If a significant amount of surface area is to be coated, it may be preferable to place the device in a rotating fixture to facilitate the coverage of the device's surface. For example, to coat the entire surface of a vascular stent, the ends of the device are fastened to a rotating fixture by resilient retainers, such as alligator clips. The stent is rotated in a substantially horizontal plane around its axis. The spray nozzle of the airbrush is typically placed 2-4 inches from the device.
The thickness of the reservoir coat can be adjusted by the speed of rotation and the flow rate of the spray nozzle. The speed of rotation is usually adjusted at about 30-50 rpm, typically at about 40 rpm. The flow rate of the spray nozzle, which can range from 4-10 ml coating per minute may also be adjusted. Usually, a number of spraycoats will be required to achieve the desired thickness of a reservoir layer. If a non-spray process is utilized, such as dip coating, casting or coextrusion, then one coat may be sufficient.
Moreover, several reservoir layers of different compositions may be used so that more than one drug and/or polymer may be incorporated into the underlying coat. The placement of the different layers may be determined by the diffusion or elution rates of the drugs involved as well as the desired rate of delivering the drug to the body tissue.
After application of the reservoir layer, the polymer can be cured to produce a polymer matrix containing the biologically active material and the solvent evaporated. Certain polymers, such as silicone, can be cured at relatively low temperatures, (e.g. room temperature) in what is known as a room temperature vulcanization (RTV) process. More typically, the curing/evaporation process involves higher temperatures so that the coated device is heated in a oven. Typically, the heating occurs at approximately 90°C or higher for approximately 1 to 16 hours when silicone is used. For certain coatings such as ones containing dexamethasone, the heating may occur at temperatures as high as 150°C. The time and temperature of heating will of course vary with the particular polymer, drugs, solvents and/or crosslinkers used. One of skill in the art is aware of the necessary adjustments to these parameters. Also, the devices may be cured after the outer layer has been applied.
The outer layer containing the ionic surfactant-drug complex is preferably prepared by dissolving the complex in a solvent or a mixture of solvents, however, it can also be prepared by blending the ionic surfactant drug complex with polymer(s) or polymer(s)/solvent mixtures. Suitable drugs have been described above. Appropriate ionic surfactants include quaternary ammonium compounds such as one of the following: benzalkonium chloride, tridodecylmethylammonium chloride (TDMAC), cetylpyridinium chloride, benzyldimethylstearylammonium chloride, benzylcetyl dimethyl ammonium chloride. An additional example of an appropriate ionic surfactant includes a polymeric surfactant, such as a quaternary ammonium salt of acrylate polymer including 2-(trimethyl amine)-ethyl methacrylate bromide, or a quaternary ammonium salt of cellulose such as JR400 and QUATRISOFT manufactured by Union Carbide. Preferably, the ionic surfactant comprises TDMA.
The surfactant-drug complex can either be purchased on the open market or made in the laboratory. For instance, benzalkonium chloride is made and sold by ALDRICH. TDMA-heparin is made and sold by STS POLYMERS. The skilled artisan is aware of methods for making surfactant-drug complexes.
The concentration or loading of biologically active material in the outer layer may be varied according to the therapeutic effects desired. Generally, the outer layer may contain 10-100% by weight or preferably 30-100% by weight of the complex of the biologically active material. Most preferably, 45-100% by weight of the drug complex should be incorporated in the outer layer.
The solvent(s) used to dissolve the complex should be swellable to the reservoir layer polymers. In other words, the solvent(s) should allow the outer layer composition to somewhat mix with the reservoir layer at the interface of the two layers. Hence, if possible, the solvent used to prepare the outer layer should preferably be the same as that used to make the reservoir layer.
The outer layer composition is then applied to the medical device. The composition can be applied by such methods as dipping, casting, extruding or spray coating to form a layer in which some of the drug-surfactant complex will penetrate into the very top of matrix polymer of the reservoir layer. As with the reservoir layer, spray coating the outer layer onto the medical device is preferred since it permits the thickness of the coating to be readily adjusted. The thickness of the outer layer can range from about 0.1 to about 10 microns. Preferably, this layer is about 1 to about 5 microns thick. When spray coating, 1-2 spray cycles is preferred, however additional cycles may be applied depending upon the coating thickness desired.
The coating thickness ratio of the outer layer to the reservoir layer may vary from about 1:2 to 1:100 and is preferably in the range of from about 1:10 to 1:25.
The release rate and release profile of the device can be affected by the thickness of the outer layer as well as the concentration of the ionically bound pharmaceutical in that layer. If a greater amount of the biologically active material is to be delivered initially, thinner outer layers should be used.
Following stabilization, the ionic surfactant drug complex of the outer layer will generally be molecularly distributed or in particle form.
A reservoir layer composition of heparin, silicone, and THF was prepared by the following method. An amount of a silicone-xylene mixture (∼35% solid weight from Applied Silicone Corporation) was weighed. The solid silicone content was determined according to the vendor's analysis. Precalculated and weighed amounts of finely micronized heparin (2-6 microns) were added into the silicone to make a final coating of 37.5% by weight heparin. Then tetrahydrofuran (THF) HPLC grade (from Aldrich or EM Science) was added to the silicone and heparin in the amount of VTHF = 25Wsilicone solid. Finally, a silane was added as a crosslinking agent. The solution was stirred with a stirring rod or magnet until the suspension was homogeneous.
Three Wallstent® self-expanding vascular stents were then spraycoated with the suspension. By adjusting the number of spray cycles, different coating thicknesses were placed upon the stents as shown in Table 1a. The coating thicknesses were measured using optical microscopy. After allowing the stents to rest at room temperature for about 30 minutes, the coated stents were moved to a convection oven and heated at 90°C for 16 hours. Argon gas plasma treatment was applied to further cure the coating after the heat cure cycle. Each coated stent was thus cut in half to provide a total of six stent segments.
10mg/ml of TDMA-heparin/THF solution was prepared by dissolving a weighed amount of the TDMA-heparin powder into a beaker and adding THF solvent. The powder fully dissolved in the solvent in about 15 minutes. The outer layer composition was spray coated onto three of the stent segments, namely ND 815-1, 5, & 9 at, to produce outer layers of approximately 2 µm thick. The coated stents were air-dried. The remaining three stent segments, namely ND 815 - 1, 5, & 9 a, were not covered with an outer layer, and served as comparative examples.
To determine the heparin release profile of the coated stents, azure A assays were performed. About 2 cm of each coated stent was cut and placed into 100ml of phosphate buffered saline and incubated in a shaker at 37°C. Periodic samplings of the solution were processed by complexing Azure A dye with the heparin to determine the amount of heparin released from the coatings into the sample solutions. At the time of sampling, the buffer was replaced with fresh saline.
Specifically 250 µl of each sample solution was diluted and pipetted into the wells of the 96-well microplate. 100 µl of Azure A dye solution of concentration 100 µg/ml (from Aldrich Chem. Co.) was pipetted into each sample well. The whole plate was then shaken and incubated at room temperature for exactly one hour. Absorbance of the solutions was then read at 505 nm using a micro plate reader. The concentrations of the samples were then determined by interpolation from a standard curve of solutions of known concentrations from 0 to 6.0 µg/ml in the increment of 0.6 µg/ml.
Table 1b summarizes the release rates of the stents at various times during an eight day period. This data has been compiled to generate the release profile of Figure 1.
To measure the concentration of heparin at the surface of the stents, a semi-quantitative toluidine blue assay was performed. About 1.5 cm of the stents were prepared and placed in small test tubes. 2 ml of the 100 µg/ml toluidine blue dye solution (from Aldrich) was added into the tubes. The test tubes were shaken gently and left under room conditions for exactly 30 minutes. The stents were then taken out of the dye and washed exhaustively with cold water. The surface of the stents were dried gently with paper towel. The stent samples were then transferred to another set of test tubes containing 2.00 ml of 1% sodium dodecyl sulfate solution and left under room conditions for 10 minutes, prior to reading the absorbance of the solution at 640 nm in a UV spectrometer.
The dye uptaking results from the toluidine blue assay are presented in Table 1a. They show that the estimated concentrations of heparin present at the surfaces of the coated stents tended to be greater for the stents covered with the coatings of this invention as compared to stents covered only by a reservoir layer.
To determine the pharmaceutical activity of the coated stent as well as the surface concentration of heparin a Factor Xa Assay was performed. About 0.5 cm of each stent sample was prepared and placed in a small test tube. 20 µl of antithrombin III at 1 IU/ml (from Helena Lab.) and 180 µl of 0.5 mol/l of tris buffer are added into the test tubes. The contents was shaken and incubated at 37°C for about 10 minutes. Then 200 µl of Factor Xa, 71 nkat reagent (from Helena Lab.) was added into the test tubes. After about 1 minute, 200 µl of chromogenic substrate S 2765 1 mg/ml (Coatest, 82-14 13-39/5) was added into the tubes. The test tubes were vortexed and incubated at 37°C for exactly 5 minutes. 300 µl of a 20% acetic acid solution was added to stop the reaction. Absorbance of the chromophoric group was measured at 405 nm.
The antithrombin activity of the samples were calculated based on the standard curve of standard solutions of 0.1, 0.3, 0.5 and 0.7 IU/ml in heparin. It should be noted that the volumes of the reagents used for the test can be changed such that the ratio of the reagents are unchanged in order to obtain the absorbance of the testing solution within the range of the standard curve.
The results for the samples are presented in Table la. They show that the stents of the invention demonstrated significantly greater heparin or antithrombin activity and heparin surface concentrations than the stents which did not include a TDMA-heparin outer layer.
A mixture of heparin, silicone and THF was prepared by the following method. A silicone-xylene mixture (35% solid weight from Applied Silicone Corporation) was weighed. The solid silicone content was determined according to the vendor's analysis. Precalculated and weighed amounts of finely micronized heparin (2-6 microns) were added into the silicone to make a final coating of 37.5% heparin. Tetrahydrofuran (THF) HPLC grade (Aldrich or EM Science) was added until the solid content of silicone was 3.5%. Finally, crosslinking agent from the manufacturer was added into the suspension. The solution was stirred with a stirring rod or magnet until the suspension was homogeneous.
Wallstent® endoprostheses were then spraycoated with the suspension to achieve the reservoir coating thicknesses shown in Table 2a. Three coating series (e.g. A, B and C) were prepared as follows. After resting at room temperature for 30min., the coated stents designated as series A and C were moved to a convection oven and heated at 90°C for 16 hours.
An outer layer composition was prepared by dissolving a weighed amount of TDMA-heparin powder into a beaker and adding THF to form a 10mg/ml TDMA-heparin/THF solution. The powdered complex was fully dissolved in the solvent in about 15 minutes. Stent series A and B were spraycoated with this solution to form outer layers of the same thickness and allowed to air dry. The series B stents were heat cured at 90°C for 16 hours.
The series C stents were then dip coated with the TDMA-heparin solution. The thickness of these outer layers is the same as that of the series A and B stents. Finally, argon gas plasma treatment was applied to further cure the coatings for all the series.
1) spraycoated with a 37.5% heparin reservoir composition, 2) heat cured at 90°C for 16 hours, 3) spraycoated with TDMA-heparin outer layer composition, and 4) exposed to argon gas plasma treatment.
1) spraycoated with a 37.5% heparin reservoir composition, 2) spraycoated with TDMA-heparin outer layer composition, 3) heat cured at 90°C for 16 hours, and 4) exposed to argon gas plasma treatment.
1) spraycoated with a 37.5% heparin reservoir composition, 2) heat cured at 90°C for 16 hours, 3) dip-coated with TDMA-heparin outer layer composition, and 4) exposed to argon gas plasma treatment.
The three assays described in Example 1 were performed for the stents. The results which are presented in Tables 2a and 2b show that the order of curing and means of applying the outer layer to the stent did not have significant effect on the activity or concentration of the heparin at the surface of the stent. However it should be noted that the stents of coating series B, in which the outer layer was exposed to heat curing showed improved surface morphology.
Wallstent® endoprostheses were spraycoated with the reservoir composition of Example 2 to achieve the coating thicknesses shown in Table 3a. An outer layer composition was prepared by weighing TDMA-heparin powder, placing it in a beaker, and adding THF to make the solution containing 10 mg/ml of TDMA-heparin in THF. The powder fully dissolved in the solvent in about 15 minutes. Four of the six sample stents were spraycoated with the TDMA-heparin solution to form outer layers of about 2 microns in thickness. All the samples were subjected to the toluidine blue assay and Azure A assay described above. Tables 3a and 3b detail the experimental results.
As shown in Table 3a, stents coated according to the invention (e.g. Sample TD1) exhibited greater heparin surface concentrations than stents having equal or thicker coatings comprised only of a reservoir layer (e.g. sample TD5).
To form the first layer of the coating, a silicone-xylene mixture (35% solid weight from Applied Silicone Corporation) was weighed and added to tetrahydrofuran (THF) HPLC grade (from Aldrich or EM Science). A crosslinking agent was added into the solution. The homogeneous solution was sprayed onto stents to form layers having thicknesses of 5 µm or less. The stents coated with the first layer of silicone were cured at 150°C for 30 minutes. The stents were then treated with argon plasma for further curing.
Top layer compositions of silicone, THF and TDMA-heparin were prepared by dissolving the TDMA-heparin in the THF. The silicone-xylene mixture was added to the solution so that the solid silicone content was 3.5%. A crosslinking reagent was added to the solutions. The content of TDMA-heparin in the final solutions were 20% and 60% of the solid silicone.
The top layer compositions were sprayed onto the silicone coated stents. The thicknesses of the top layers of the samples as well as the amount of TDMA-heparin on the samples are given in Table 5a. The stents were then cured at 90°C for 16 hours and then treated with argon plasma.
After the coated stents were cut into 2 cm pieces, four pieces of each sample were placed into 100 mL of phosphate buffer solution (PBS). The buffer solution was changed daily and azure A assays were performed on the solution to determine the released heparin concentrations for the samples. The results are present in Table 5b.
The first layer of the coating was prepared and applied as in Example 5. In experiment series A, the coated stents were heat cured at 90°C for 16 hours. In experiment series B, no heat treatment was applied.
A 10 mg/mL TDMA-heparin/THF top layer solution was prepared by dissolving the TDMA-heparin in the THF. The stents were sprayed coated with top layer solution and then air dried. The amount of TDMA-heparin applied to each sample stent is provided in Table 6a. The coated stents of series B were then heat treated in a convection oven at 90°C for 16 hours. Both series of stents were treated with argon plasma.
1) spraycoated with silicone first layer solution, 2) heat cured, 3) spraycoated with TDMA-heparin top layer composition, and 4) argon plasma treated.
1) spraycoated with silicone first layer solution, 2) spraycoated with TDMA-heparin top layer composition, 3) heat cured and 4) argon plasma treated.
Four 2 cm pieces of coated stents from each sample of each series were placed into 100 mL of phosphate buffer solution (PBS) having a pH of 7.4. Another 4 pieces from each series were placed into 100 mL of polyethylene glycol (PEG)/water solution (40/60 v/v, MW of PEG=400). The stent pieces were incubated at 37°C in a shaker. The buffer and PEG solution were changed daily and azure A assays were performed on the solution to determine the released heparin concentrations. The results are present in Table 6b.
On the third, sixth and eleventh days, a piece from each sample was used for toluidine blue dye uptaking assay (See Table 5a for results). FXa assay was performed on the last piece of each sample to determine the heparin activity. It was found that the heparin activity was too high to be quantified by a FXa assay.
To examine the effect of the curing order and the argon plasma treatment on the binding effect of TDMA-heparin on silicone surfaces, the following samples were prepared. 5.0 mm Elgiloy stents were coated with silicone having a coating weight of 13.5 mg/cm2. A top layer solution of 10 mg/ml of TDMA-heparin/THF was sprayed onto the stents. The coating weight of the top layer was about 0.4 mg/cm2. The heating and argon plasma treatment steps were applied to the stents as described below. The stents were heat cured at 90°C for 16 hours.
1) spraycoated with silicone solution, 2) heat cured, 3) spraycoated with TDMA-heparin top layer solution, and 4) argon plasma treated.
1) spraycoated with silicone solution, 2) heat cured and 3) spraycoated with TDMA-heparin top layer solution.
1) spraycoated with silicone solution, 2) spraycoated with TDMA-heparin top layer solution 3) heat cured and 4) argon plasma treated.
1) spraycoated with silicone solution, 2) spraycoated with TDMA-heparin top layer solution and 3) heat cured.
To further compare the binding efficacy of coatings exposed to both heat and plasma treatment and that of coatings which are only heat treated, the following samples were prepared. The thicknesses of both the silicone layer and top layer were kept constant at 3 mg/cm2 and 0.5 mg/cm2, respectively.
4) heat cured at 90°C for 16 hours.
same as ND-1 but further treated with argon plasma.
3) heat cured at 90°C for 16 hours.
same as ND-2 but further treated with argon plasma.
3) spraycoated with TDMA-heparin top layer solution.
same as ND-3 but further treated with argon plasma.
wherein the reservoir layer comprises a polymer incorporating the biologically active material which is substantially free of any ionic surfactant such that the biologically active material of the reservoir layer can migrate outwardly from the reservoir layer, and at least some of the biologically active material of the reservoir can complex with the ionic surfactant in the outer layer as the biologically active material releases from the outer layer.
The device of claim 1 wherein the device is an expandable stent.
The device of claim 2 wherein the device is a self-expanding stent.
The device of claim 1 wherein the polymer of the reservoir layer is an elastomeric material.
The device of claim 4 wherein the polymer of the reservoir layer is selected from the group consisting of silicones, polyurethanes, thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers, and EPDM rubbers.
The device of claim 5 wherein the polymer of the reservoir layer is silicone.
The device of claim 1 wherein the biologically active material of the reservoir layer is in a particulate form having an average particle size of 1 to 100 microns.
The device of claim 7 wherein the ratio of reservoir layer thickness to average particle diameter is greater than 3.
The device of claim 7 wherein the ratio of reservoir layer thickness to average particle diameter is greater than 5.
The device of claim 1 wherein the biologically active material is selected from the group consisting of glucocorticoids, heparin, hirudin, angiopeptin, aspirin, ACE inhibitors, growth factors, oligonucleotides, antiplatelet agents, anti-hypertensives, anti-coagulant agents; antimitotic agents, antioxidants, antimetabolite agents, anti-inflammatory agents and antibiotics.
The device of claim 10 wherein the biologically active material is heparin.
The device of claim 1 wherein the reservoir layer comprises 0.1 to 90 weight % of the biologically active material.
The device of claim 12 wherein the reservoir layer comprises 10 to 45 weight % of the biologically active material.
The device of claim 1 wherein the reservoir layer is 5 to 200 microns thick.
The device of claim 14 wherein the reservoir layer is 15 to 50 microns thick.
The device of claim 1 wherein the ionic surfactant of the outer layer is a quaternary ammonium complex.
The device of claim 16 wherein the ionic surfactant comprises a tridodecylammonium ion.
The device of claim 1 wherein the outer layer is 0.1 to 10 microns thick.
The device of claim 1 wherein the coating is constructed to maintain biologically active material on the surface of the device for long periods of time.
b) forming an outer layer over the reservoir layer by applying an outer layer composition comprising an ionic surfactant complexed to the biologically active material.
The method of claim 20 wherein the reservoir layer is formulated in a solvent.
The method of claim 21 wherein the method further comprises allowing the solvent of the reservoir layer composition to evaporate.
The method of claim 20 wherein formulation of the reservoir layer includes combining the biologically active material with a molten polymer.
The method of claim 20 wherein the reservoir layer composition and the outer layer composition are applied by spray coating.
The method of claim 20 wherein the polymer of the reservoir layer is an elastomeric material.
The method of claim 25 wherein the polymer of the reservoir layer is selected from the group consisting of silicones, polyurethanes, thermoplastic elastomers, ethylene vinyl acetate copolymers, polyolefin elastomers and EPDM rubbers.
The method of claim 20 wherein the biologically active material of the reservoir layer is in a particulate form having an average particle size of 1 to 100 microns.
The method of claim 27 wherein the ratio of reservoir layer thickness to average particle diameter is greater than 3.
The method of claim 27 wherein the ratio of reservoir layer thickness to average particle diameter is greater than 5.
The method of claim 20 wherein the biologically active material is selected from the group consisting of glucocorticoids, heparin, hirudin, angiopeptin, aspirin, growth factors, oligonucleotides, antiplatelet agents, anti-hypertensives, anti-coagulant agents, antimitotic agents, antioxidants, antimetabolite agents, anti-inflammatory agents and antibiotics.
The method of claim 30 wherein the biologically active material is heparin.
The method of claim 20 wherein the reservoir layer is 5 to 200 microns thick.
The method of claim 32 wherein the reservoir layer is 15 to 50 microns thick.
The method of claim 20 wherein the ionic surfactant of the outer layer is a quaternary ammonium compound.
The method of claim 34 wherein the ionic surfactant comprises a tridodecylammonium ion.
The method of claim 20 wherein the outer layer is 0.1 to 10 microns thick.
The method of claim 20 which further comprises heat curing the reservoir layer composition after it is applied to the surface.
The method of claim 37 which further comprises treating the reservoir layer with a low energy, relatively non-penetrating energy source.
The method of claim 20 which further comprises treating the coating with a low energy, relatively non-penetrating energy source after the forming of the outer layer.
The method of claim 39 which further comprises heat curing that coating before the coating is treated with the energy source.
The method of claim 20 wherein the coating is constructed for maintaining the biologically active material on the surface of the device for long periods of time.


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Le billet électronique  (aussi appelé e-ticket de l'anglais electronic ticket) est un billet dématérialisé qui remplace un support d'information matériel par des informations numériques.

Les billets électroniques sont principalement utilisés comme titre de transport, notamment par les compagnies aériennes ainsi que dans les transports en commun terrestres (train, bus, tramway…) et maritimes. Il est également employé pour l'achat d'une place de spectacle ou comme ticket de cinéma.

Dans les transports aériens

Aux États-Unis, le billet électronique a été inventé en 1994 avec le dépôt d'un brevet, mais ce système de réservation et d'achat des billets d'avion s'est surtout généralisé dans le secteur aérien depuis fin 2008 après que l'Association internationale du transport aérien (IATA) l'a rendu obligatoire pour ses membres. Aujourd'hui, les billets d'avion sont complètement dématérialisés et ont rapidement remplacé les anciens billets papier qui, lorsqu'ils existent encore, font parfois l'objet d'une surcharge de prix par certaines compagnies.

Fonctionnement

L'achat d'un billet électronique se fait habituellement par internet ou par téléphone, directement par le voyageur ou bien par l'intermédiaire d'une agence de voyage. Lorsque la réservation est faite, le billet électronique n'existe que comme enregistrement sur les serveurs informatiques des compagnies aériennes. Le passager reçoit une confirmation par courrier électronique puis, selon les pays et les compagnies aériennes, il peut soit imprimer son billet, soit le retirer sur une borne ou un guichet à l'aéroport.

Détenir un billet électronique permet à tout passager aérien d'éviter le passage aux comptoirs d'enregistrement et de se rendre directement à la sécurité s'il n'a pas de bagage à enregistrer.

Avantages et inconvénients
Les tickets électroniques permettent de réduire les coûts et facilitent l'organisation pour les compagnies aériennes en suivant la tendance de la dématérialisation. Côté voyageur, la perte du ticket devient moins préjudiciable étant donné qu'il est plus facile d'éditer à nouveau le ticket.

Certains voyageurs préfèrent toujours utiliser le billet papier historique, considérant qu'il est plus enclin à prouver la réalité de la réservation. Dans certaines situations, telles que les pannes matérielles, les clients détenteurs de billets papier peuvent être avantagés pour être redirigés vers d'autres compagnies ce qui n'est pas le cas avec les tickets électroniques qui ne constituent pas un élément de facturation.

Dans les transports en commun terrestres
Dans les bus, trains, métros et tramways, la tendance actuelle est à la généralisation des billets électroniques dans la plupart des pays développés. Aux États-Unis, la société de transport Amtrak a commencé à offrir des billets électroniques sur toutes ses lignes de train depuis le 30 juillet 2012. Plusieurs opérateurs ferroviaires ou de transports routiers européens proposent également des billets électroniques. La dématérialisation des titres de transports se développe et repose sur des technologies diverses.

Les solutions conventionnelles, encore répandues, sont de recourir à des tickets en carton (généralement munis d'une bande magnétique) ou des cartes d'abonnement. Source de pollution et de contraintes (oubli, perte, dégradation), ils sont en voie de remplacement par des solutions utilisant les smartphones ou les cartes bancaires sans contact pour les opérateurs les plus modernes, ou pour les moins avancés proposent des cartes à puces sans contact.

Cartes à puce sans contact

Les cartes à puce sans contact reposent sur une technologie de communication en champ proche (ou NFC, de l'anglais near field communication). Il s'agit donc d'une carte qui contient les informations relatives au billet (durée d'abonnement, type de trajet, identification du passager…) qui peut être validée en la présentant à distance (jusqu'à une dizaine de centimètres) devant un portillon d'accès ou un composteur. Elle est progressivement remplacée par une solution sur smartphone ou carte bancaire sans contact, plus pratqiue et vertueuse pour l'environnement.

Cette solution est utilisée dans plusieurs villes et pays du monde :
 en France : Carte Navigo à Paris, Carte Ginko Mobilités à Besançon, Carte Grand R à Reims, Carte Badgeo à Strasbourg et dans le Bas-Rhin, Suncarte à Nice, e-Técély à Lyon, Carte Pass Pass dans le Nord-Pas-de-Calais, Carte Pastel à Toulouse et en Midi-Pyrénées, Carte OùRA! en Rhône-Alpes, KorriGo en Bretagne, Carte JVmalin en Centre Val de Loire
 dans le monde : MoBIB à Bruxelles en Belgique, Carte OPUS au Québec, Carte Presto dans les régions du Grand Toronto et de Hamilton au Canada, Oyster card à Londres au Royaume-Uni, CharlieCard dans le Massachusetts aux États-Unis, Carte Octopus à Hong Kong en Chine, Carte HOP à Auckland en Nouvelle-Zélande, OV-chipkaart aux Pays-Bas

Cartes enregistreuses

Cette solution est en cours de test en Allemagne : les usagers possèdent une carte à puce avec un écran, une batterie et une antenne. Lorsqu'il entre dans un autobus, le voyage est automatiquement enregistré grâce au système d'antennes radio. Il n'est plus nécessaire d'acheter de tickets à chaque voyage : à la fin du mois, le passager reçoit un compte de tous ses voyages.

Utilisation de la téléphonie

 Téléphones dotés d'un transpondeur NFC : Cette solution est utilisée à Londres depuis les jeux olympiques de 2012, dans le cadre d'un partenariat entre TFL (Transport for London) et Samsung. Le transpondeur NFC qui équipe le téléphone permet en effet de simuler un objet NFC (carte ou tag).

 Téléphones dotés de carte SIM compatible NFC : Cette solution est en cours d'étude à Paris, avec un projet RATP-Bouygues Telecom, et à Caen avec un projet Orange-Ville de Caen. Le but est de pouvoir stocker les données usuellement contenues dans les cartes sans contact directement dans le téléphone portable de l'usager, pour peu que celui-ci soit équipé d'une carte SIM compatible. Ce mode de fonctionnement est très développée au Japon (avec la société DoCoMo).

 Utilisation des fonctionnalités de communications intégrées aux téléphones portables : La majeure partie des téléphones portables et PDA actuellement sur le marché sont équipés du Bluetooth, et de la Wifi. L'idée est d'acheter les tickets (sur le WAP, sur Internet, via un serveur téléphonique ou des bornes spécifiques…), de les stocker directement sur le téléphone portable, et de les valider/contrôler électroniquement en utilisant le Bluetooth ou la Wifi.

Clés usb dotés d'une puce compatible NFC

Cette solution repose sur une puce compatible NFC introduite dans une clé USB, comme la carte SIM compatible NFC dans le téléphone portable. Les avantages et inconvénients sont donc les mêmes en ajoutant l'avantage du coût faible d'une clé usb comparée à un téléphone portable (utile dans le cas d'utilisateurs ne possédant pas de téléphone mobile) mais aussi l'inconvénient de la perte facile de celle-ci.

Envoi de codes à barres 2D par MMS

C'est une solution explorée notamment par la SNCF avec ses projets Mobitick et Tikefone. Celle-ci consiste à envoyer au client un code-barres 2D (plus fiable que les codes à barres 1D actuellement dans nos supermarchés) sous forme de MMS.

Avantages :
 compatible avec la majorité des téléphones du marché (qui sont capables d'afficher des images)
 très souple (code à barre valable pour un trajet, ou pour un abonnement, ou…)

Inconvénients :
 nécessite d'équiper les contrôleurs de lecteurs optiques
 coût de l'envoi du MMS : à la charge du client ou du prestataire de service ?
 inutilisable si le portable n'a plus de batterie
 temps de compostage (environ 40 s *)

Autres utilisations
Le e-billet se démocratise de plus en plus et, avec l'augmentation des smartphones, de nombreuses entreprises encouragent son développement.

Dans le domaine des spectacles (cinémas, spectacles, concerts), une loi française de 2006  autorise la mise en place des billets dématérialisés permettant aux organisateurs de mettre en place la vente directe par Internet. Par exemple, pour les cinémas Gaumont, il est possible de payer sa place sur internet, de recevoir son e-billet sur son téléphone (par mail de manière classique, sans bluetooth…) et ensuite de montrer l'écran de son téléphone à l'entrée, le personnel scanne alors le code-barres.

Les billets électroniques sont aussi utilisés pour des réservations dans des parcs de loisirs.

Par ailleurs, le ticket électronique peut être aussi utilisé comme carte de fidélité, ou comme coupon de réduction. Associé à une géolocalisation du porteur, il peut même servir à obtenir des réductions instantanées.

Notes et références

Annexes

Articles connexes
 Dématérialisation
 Communication en champ proche (NFC)
 Carte Navigo
 Radio-identification
 Bluetooth

Liens externes

Technologie du transport
Transport aérien
Technologie ferroviaire

redpajama_set_name: RedPajamaWikipedia


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"In a world where girl-loves-boy lyrics permeate pop, Sugarbeach is an exciting discovery for the lesbian pop-loving community. Based in Vancouver, Canada, Sugarbeach consists of Marlee Walchuk and Tully Callender, two out artists who bring queer issues into the limelight through ear-catching tracks."
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Her version of Girls Just Want To Have Fun charted in Billboards Hot 100 and topped the overall iTunes charts at #5. All of her LIVE performance recordings made iTunes overall Top 50. Madi definitely made her mark as an artist on the show, singing what she loves, with poise beyond her years...all 16 of them.
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text:
Q: How to compress hdf5 file when resizing? Here is my code:
n = 100000       #This is what makes it tricky - lots of files going into this hdf5 file

with h5py.File('image1.h5','w') as f:
    dset_X = f.create_dataset('X',(1,960,224,224),maxshape=(None,960,224,224),chunks=True,compression='gzip')
    dset_y = f.create_dataset('y',(1,112,224*224),maxshape=(None,112,224*224),chunks=True,compression='gzip')
    n_images = 0
    for fl in files[:n]:
        X_chunk,y_chunk = get_arrays(fl)
        dset_X.resize(n_images+1,axis=0)
        dset_y.resize(n_images+1,axis=0)
        print dset_X.shape,dset_y.shape
        dset_X[n_images:n_images+1,:,:,:]=X_chunk
        dset_y[n_images:n_images+1,:,:]=y_chunk
        n_images+=1

This works fine and dandy. However, with 1 file, the size of the hdf5 is 6.7MB. With 2 files its 37MB ( should be 12 MB right?). With 10 its all the way up to 388MB (should be 67 right?)
So clearly adding the compression flag to the end of the 2nd and third line isn't working as intended. How can I achieve something like this?

A: I ended up doing this successfully using pytables.
def get_arrays(each_file):
    lab = color.rgb2lab(io.imread(each_file))
    X = lab[:,:,:1]
    y = lab[:,:,1:]
    X_rows,X_columns,X_channels=X.shape
    y_rows,y_columns,y_channels=y.shape
    X_channels_first = np.transpose(X,(2,0,1))
    X_sample = np.expand_dims(X_channels_first,axis=0)
    X_3d = np.tile(X_sample,(1,3,1,1))
    X_3d_scaled = X_3d * 255.0/X_3d.max()
    hc = extract_hypercolumn(model,[3,8,15,22],X_3d_scaled)
    hc_scaled = (hc -hc.min())/(hc.max()-hc.min())
    print hc_scaled.max(),hc_scaled.min()
    hc_expand_dims = np.expand_dims(hc_scaled,axis=0)
    y_reshaped = np.reshape(y,(y_rows*y_columns,y_channels))
    classed_pixels_first = KNN.predict_proba(y_reshaped)
    classed_classes_first = np.transpose(classed_pixels_first,(1,0))
    classed_expand_dims = np.expand_dims(classed_classes_first,axis=0)
    print "hypercolumn shape: ",hc_expand_dims.shape,"classified output color shape: ",classed_expand_dims.shape
    return hc_expand_dims,classed_expand_dims

filters = tables.Filters(complevel=5, complib='zlib')

with tables.openFile('raw.h5','w') as f:
#    filters = tables.Filters(complib='blosc', complevel=5)
    dset_X = f.create_earray(f.root, 'X', tables.Atom.from_dtype(np.dtype('Float64')), (0,960,224,224),filters=filters)
    dset_y = f.create_earray(f.root, 'y', tables.Atom.from_dtype(np.dtype('Float64')), (0,112,224*224),filters=filters)
    for fl in files[0:12000]:
        X_chunk,y_chunk=get_arrays(fl)
        dset_X.append(X_chunk)
        dset_y.append(y_chunk)

redpajama_set_name: RedPajamaStackExchange


text:
The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site
Glavije Amirjamshidi, Enrico Fodde, Dina D'Ayala, Eskandar Mokhtari
Department of Architecture & Civil Engineering
Centre for Innovative Construction Materials (CICM)
Buildings must pass the test of authenticity and integrity to be considered as World Heritage sites. The combination of these attributes can be referred to as the genuineness of the site.
Bam suffered from a devastating earthquake in December 2003, but even after the disaster, the area was acknowledged to have a high degree of authenticity and integrity and was successfully put forward for consideration as a World Heritage site. Apart from the uniqueness of Bam's Citadel as the world's greatest mud brick structure and of a number of buildings in the immediate vicinity of the Citadel, the rationale for its inscription was also influenced by its intangible aspects and cultural landscape. Examples of intangible heritage in Bam include the legend of Haftvad and the Kot-e Kerm and its relation to the Silk Road as well as the beliefs of people of Bam in the rituals linked to the well of the Master of Time (Imam Zaman), and the ritual of Ashura. Until recently, the integrity of a World Heritage site was mostly assessed by studying its tangible heritage. However, in 1982, UNESCO introduced a new mandate for consideration of intangible heritage to emphasise its significance and to strive for protection of traditional culture and folklore. Several regional assessments have since been made on the impacts and recommendations on the protection of traditions, culture and folklore. When protecting a tangible heritage site, the practice is mainly based on pragmatic conservation and restoration. Non-tangible heritage, on the other hand, is more subtle and requires more sophisticated approaches and methods for its preservation.
This paper investigates the intangible heritage associated with the Bam Citadel as part of Bam and its cultural landscape and, where appropriate, highlights the relationship between these assets and the architectural aspects to accentuate the cultural importance of this of World Heritage site.
This paper will discuss the role and function of historical integrity in the conservation of Bam and its cultural landscape by describing the intangible heritage of the site and by comparing it with Central Asian case studies and by suggesting safeguarding guidelines for its conservation.
https://doi.org/10.2495/ST120321
5th International Conference on Sustainable Tourism, ST 2012;A. Coruna; - A Coruna, Spain
Duration: 12 Jun 2012 → 14 Jun 2012
5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;
10.2495/ST120321
http://library.witpress.com/pages/PaperInfo.asp?PaperID=23450
http://dx.doi.org/10.2495/ST120321
Dive into the research topics of 'The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site'. Together they form a unique fingerprint.
Intangible Heritage Arts & Humanities 100%
World Heritage Site Arts & Humanities 99%
Cultural Landscape Arts & Humanities 78%
Citadel Arts & Humanities 70%
Intangibles Arts & Humanities 66%
Integrity Arts & Humanities 63%
Conservation Arts & Humanities 57%
Folklore Arts & Humanities 33%
Amirjamshidi, G., Fodde, E., D'Ayala, D., & Mokhtari, E. (2012). The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site. 393-402. Paper presented at 5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;, A Coruna, Spain. https://doi.org/10.2495/ST120321
The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site. / Amirjamshidi, Glavije; Fodde, Enrico; D'Ayala, Dina et al.
2012. 393-402 Paper presented at 5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;, A Coruna, Spain.
Amirjamshidi, G, Fodde, E, D'Ayala, D & Mokhtari, E 2012, 'The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site', Paper presented at 5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;, A Coruna, Spain, 12/06/12 - 14/06/12 pp. 393-402. https://doi.org/10.2495/ST120321
Amirjamshidi G, Fodde E, D'Ayala D, Mokhtari E. The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site. 2012. Paper presented at 5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;, A Coruna, Spain. doi: 10.2495/ST120321
Amirjamshidi, Glavije ; Fodde, Enrico ; D'Ayala, Dina et al. / The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site. Paper presented at 5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;, A Coruna, Spain.10 p.
@conference{3dc3e0968a8d402ba41706349c1b4ba1,
title = "The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site",
abstract = "Buildings must pass the test of authenticity and integrity to be considered as World Heritage sites. The combination of these attributes can be referred to as the genuineness of the site. Bam suffered from a devastating earthquake in December 2003, but even after the disaster, the area was acknowledged to have a high degree of authenticity and integrity and was successfully put forward for consideration as a World Heritage site. Apart from the uniqueness of Bam's Citadel as the world's greatest mud brick structure and of a number of buildings in the immediate vicinity of the Citadel, the rationale for its inscription was also influenced by its intangible aspects and cultural landscape. Examples of intangible heritage in Bam include the legend of Haftvad and the Kot-e Kerm and its relation to the Silk Road as well as the beliefs of people of Bam in the rituals linked to the well of the Master of Time (Imam Zaman), and the ritual of Ashura. Until recently, the integrity of a World Heritage site was mostly assessed by studying its tangible heritage. However, in 1982, UNESCO introduced a new mandate for consideration of intangible heritage to emphasise its significance and to strive for protection of traditional culture and folklore. Several regional assessments have since been made on the impacts and recommendations on the protection of traditions, culture and folklore. When protecting a tangible heritage site, the practice is mainly based on pragmatic conservation and restoration. Non-tangible heritage, on the other hand, is more subtle and requires more sophisticated approaches and methods for its preservation. This paper investigates the intangible heritage associated with the Bam Citadel as part of Bam and its cultural landscape and, where appropriate, highlights the relationship between these assets and the architectural aspects to accentuate the cultural importance of this of World Heritage site. This paper will discuss the role and function of historical integrity in the conservation of Bam and its cultural landscape by describing the intangible heritage of the site and by comparing it with Central Asian case studies and by suggesting safeguarding guidelines for its conservation.",
author = "Glavije Amirjamshidi and Enrico Fodde and Dina D'Ayala and Eskandar Mokhtari",
doi = "10.2495/ST120321",
note = "5th International Conference on Sustainable Tourism, ST 2012;A. Coruna; ; Conference date: 12-06-2012 Through 14-06-2012",
T1 - The role of intangible assets in the conservation of Bam and its cultural landscape as a World Heritage site
AU - Amirjamshidi, Glavije
AU - Fodde, Enrico
AU - D'Ayala, Dina
AU - Mokhtari, Eskandar
N2 - Buildings must pass the test of authenticity and integrity to be considered as World Heritage sites. The combination of these attributes can be referred to as the genuineness of the site. Bam suffered from a devastating earthquake in December 2003, but even after the disaster, the area was acknowledged to have a high degree of authenticity and integrity and was successfully put forward for consideration as a World Heritage site. Apart from the uniqueness of Bam's Citadel as the world's greatest mud brick structure and of a number of buildings in the immediate vicinity of the Citadel, the rationale for its inscription was also influenced by its intangible aspects and cultural landscape. Examples of intangible heritage in Bam include the legend of Haftvad and the Kot-e Kerm and its relation to the Silk Road as well as the beliefs of people of Bam in the rituals linked to the well of the Master of Time (Imam Zaman), and the ritual of Ashura. Until recently, the integrity of a World Heritage site was mostly assessed by studying its tangible heritage. However, in 1982, UNESCO introduced a new mandate for consideration of intangible heritage to emphasise its significance and to strive for protection of traditional culture and folklore. Several regional assessments have since been made on the impacts and recommendations on the protection of traditions, culture and folklore. When protecting a tangible heritage site, the practice is mainly based on pragmatic conservation and restoration. Non-tangible heritage, on the other hand, is more subtle and requires more sophisticated approaches and methods for its preservation. This paper investigates the intangible heritage associated with the Bam Citadel as part of Bam and its cultural landscape and, where appropriate, highlights the relationship between these assets and the architectural aspects to accentuate the cultural importance of this of World Heritage site. This paper will discuss the role and function of historical integrity in the conservation of Bam and its cultural landscape by describing the intangible heritage of the site and by comparing it with Central Asian case studies and by suggesting safeguarding guidelines for its conservation.
AB - Buildings must pass the test of authenticity and integrity to be considered as World Heritage sites. The combination of these attributes can be referred to as the genuineness of the site. Bam suffered from a devastating earthquake in December 2003, but even after the disaster, the area was acknowledged to have a high degree of authenticity and integrity and was successfully put forward for consideration as a World Heritage site. Apart from the uniqueness of Bam's Citadel as the world's greatest mud brick structure and of a number of buildings in the immediate vicinity of the Citadel, the rationale for its inscription was also influenced by its intangible aspects and cultural landscape. Examples of intangible heritage in Bam include the legend of Haftvad and the Kot-e Kerm and its relation to the Silk Road as well as the beliefs of people of Bam in the rituals linked to the well of the Master of Time (Imam Zaman), and the ritual of Ashura. Until recently, the integrity of a World Heritage site was mostly assessed by studying its tangible heritage. However, in 1982, UNESCO introduced a new mandate for consideration of intangible heritage to emphasise its significance and to strive for protection of traditional culture and folklore. Several regional assessments have since been made on the impacts and recommendations on the protection of traditions, culture and folklore. When protecting a tangible heritage site, the practice is mainly based on pragmatic conservation and restoration. Non-tangible heritage, on the other hand, is more subtle and requires more sophisticated approaches and methods for its preservation. This paper investigates the intangible heritage associated with the Bam Citadel as part of Bam and its cultural landscape and, where appropriate, highlights the relationship between these assets and the architectural aspects to accentuate the cultural importance of this of World Heritage site. This paper will discuss the role and function of historical integrity in the conservation of Bam and its cultural landscape by describing the intangible heritage of the site and by comparing it with Central Asian case studies and by suggesting safeguarding guidelines for its conservation.
UR - http://library.witpress.com/pages/PaperInfo.asp?PaperID=23450
UR - http://dx.doi.org/10.2495/ST120321
U2 - 10.2495/ST120321
DO - 10.2495/ST120321
T2 - 5th International Conference on Sustainable Tourism, ST 2012;A. Coruna;
Y2 - 12 June 2012 through 14 June 2012


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