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Find us on:
The National Highway Traffic Safety Administration (NHTSA) was established in 1966. Its highest priority is to reduce deaths, injuries and economic losses resulting from motor vehicle crashes, improve highway safety by promoting both safer vehicles and safer driving practices, sets and enforces Federal safety standards for all new motor vehicles, investigates alleged safety defects and orders recalls where necessary, and conducts extensive research on improving vehicle safety. The NHTSA provides financial and technical assistance to State and local governments, awards grants to states for highway safety and to help combat drunk driving, works closely with private organizations to promote a broad range of driver and traffic safety programs, including programs to combat drunk driving, encourages use of safety belts and child safety seats, improve emergency medical services, driver licensing, traffic recordkeeping and traffic law enforcement, investigates odometer fraud, sets bumper, fuel economy and vehicle theft standards and develops crashworthiness of new cars. The NHTSA maintains a toll-free hotline for consumer complaints on auto safety, reporting alleged defects, requests for auto safety recall information, and consumer publications on traffic and highway safety.
Review Date: Wednesday, July 29, 2015
List reviewed web resources
The U.S. Consumer Product Safety Commission (CPSC) is an independent federal regulatory agency that was created in 1972 by Congress in the Consumer Product Safety Act. CPSC has jurisdiction over about 15,000 types of consumer products, from automatic-drip coffee makers to toys to lawn mowers. Some types of products, however, are covered by other federal agencies. For example, cars, trucks and motorcycles are covered by the Department of Transportation; drugs and cosmetics are covered by the Food and Drug Administration; alcohol, tobacco and firearms are covered by the Department of the Treasury. CPSC works to reduce the risk of injuries and deaths from consumer products by: developing voluntary standards with industry; issuing and enforcing mandatory standards: banning consumer products if no feasible standard would adequately protect the public; obtaining the recall of products or arranging for their repair; conducting research on potential product hazards; informing and educating consumers through the media, state and local governments, private organizations, and by responding to consumer inquiries.
Review Date: Friday, February 20, 2009
The Federal Motor Carrier Safety Administration (FMCSA) was established as a separate administration within the U.S. Department of Transportation on January 1, 2000, pursuant to the Motor Carrier Safety Improvement Act of 1999. The primary mission of the FMCSA is to reduce crashes, injuries and fatalities involving large trucks and buses.
Review Date: Wednesday, October 28, 2009
The Insurance Institute for Highway Safety (IIHS) is an independent, nonprofit, scientific, and educational organization dedicated to reducing deaths, injuries, and property damage that result from crashes on the nation's roads. The IIHS's research focuses on three main areas: human factors, or preventing crashes by changing driver behavior; vehicle factors, or reducing deaths and injuries by improving vehicle design; and environmental factors, or changing roadway design, signs, and signals to reduce crashes.
The Highway Loss Data Institute (HLDI) shares and supports this mission through scientific studies of insurance data representing the human and economic losses resulting from the ownership and operation of different types of vehicles and by publishing insurance loss results by vehicle make and model.
Review Date: Thursday, January 19, 2012
The New York State Governor's Traffic Safety Committee (GTSC) coordinates traffic safety activities in the state. Through the website, the GTSC seeks to share timely, accurate and useful news, information and other resources about traffic safety and the state's highway safety grant program. The GTSC works closely with this network of state and local agencies, non-profit organizations and private-sector partners to deliver quality traffic safety projects, services, and information across the state.
Review Date: Monday, July 14, 2014
Founded in 1981 as Students Against Driving Drunk, SADD's focus initially was to combat teen deaths due to drinking and driving. SADD has expanded its mission and name and now sponsors chapters called Student Against Destructive Decisions. SADD now focuses on prevention of all destructive behaviors and attitudes that are harmful to young people, including underage drinking, substance abuse, violence, reckless driving, depression and suicide. SADD's unique approach involves young people delivering education and prevention programming to their peers through school- and community-wide activities and campaigns responsive to the needs of their particular locations. Projects may include peer-led classes and theme-focused forums; teen workshops; conferences and rallies; prevention education and leadership training; awareness-raising activities; studen/parent programming and legislative work. Since its formation, SADD has spread to all 50 states, Canada, New Zealand and many other international locations.
Review Date: Thursday, June 10, 2010
Safe Kids Worldwide (formerly the National SAFE KIDS Campaign) is the first and only national nonprofit organization dedicated solely to the prevention of unintentional childhood injury--the number one killer of children ages 14 and under. We offer many educational materials for caregivers and children, including brochures, videos and posters, in both English and Spanish. Our complete resource catalog is available online at www.safekids.org or by calling (800) 289-0117.
Review Date: Wednesday, August 04, 2010
The mission of the Department of Transportation (DOT) is to serve the United States by ensuring a fast, safe, efficient, accessible and convenient transportation system that meets our vital national interests and enhances the quality of life of the American people, today and into the future. DOT consists of the Office of the Secretary and eleven individual Operating Administrations: the Federal Aviation Administration, the Federal Highway Administration, the Federal Motor Carrier Safety Administration, the Federal Railroad Administration, the Federal Transit Administration, the Maritime Administration, the National Highway Traffic Safety Administration, the Pipeline and Hazardous Materials Safety Administration, the Research and Innovative Technology Administration, the Saint Lawrence Seaway Development Corporation, and the Surface Transportation Board. The Homeland Security Act of 2002 authorized the establishment of the Department of Homeland Security, which, on March 1, 2003, assumed management of the United States Coast Guard and the Transportation Security Administration, formerly DOT Operating Administrations.
Review Date: Wednesday, September 07, 2011
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Ct100 needed a new wordpress theme design and created a contest on 99designs.
A winner was selected from 19 designs submitted by 4 freelance designers.
Trevino Injury Law
Personal Injury law firm representing injured individuals/members of the community against large corporations and insurance companies. Great trial results in the past few years. Practicing for 7 years. Dedicated to serving the community and providing uncommon customer service for a law firm. Committed to fighting for those who cant fight for themselves, with integrity. Not an ambulance chaser.
Members of the San Antonio, Texas community seriously injured by the negligence of another. Looking for a web site that sets the firm apart from all others. Something memorable. Something that represents trust and security. Something symbolic of dedication. Target audience will be looking for help in a troubled time. Site should reflect a legal theme.
Site must reflect a custom legal theme. Would like to see designer creativity. Visuals are great. No clip art. Would like to see logo incorporated into page design. Attached is a mockup layout I would like followed. I would like the logo colors used for the site. Detail specific.
Here's a link to the website mockup to be referenced:
I would like the site to have a modern feel, I would like the buttons and widgets frames to have shading similar to that of the logo, for examples of the modern feel I am looking for see http://www.tristatelaw.com/ and http://www.webdesignerdepot.com/200 specifically site #14 1nd #16

subset: commoncrawl


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ELON � Shaylen Burnett scored 25 points and Hollie Boggs added 17 as visiting Southern Alamance topped Western Alamance 89-42 in non-conference girls� basketball Tuesday night.
The outcome spoiled the Western Alamance coaching debut of Sean Quinn, who�s a former Southern Alamance coach and athletics director.
The Patriots (2-0) led 50-27 at halftime. Burnett had six steals.
Kierra James scored 23 points for Western Alamance.
-- EASTERN ALAMANCE 52, GRAHAM 39: At Mebane, Deja Dunn led 11 different players to score for Eastern Alamance in a season-opening victory. Dunn scored 12 points and was part of a second unit that drew praise from Eagles coach Tim Krotish.
�I thought we got a lot out of the backups (Tuesday night),� Krotish said. �Every kid that came off the bench got in there and made a contribution, either on the offensive end or the defensive end.�
Terri Rogers scored 10 points for Eastern Alamance.
It was a sour first taste for new Graham coach Melinda Goodson. The Red Devils were led by Kay Kay Wilson�s 16 points, while Deja Cousin added 10.
�We�ve got a ways to go,� Goodson said. �It�s called growth. I saw some good things though � we�re going to take those and run with it.�
-- HIGHPOINT CHRISTIAN 45, BURLINGTON CHRISTIAN ACADEMY 43: At High Point, Hailey Riffe scored 15 points as High Point Christian (1-1) slipped past BCA in a non-conference game.
Brittany Barrett paced the Royals (0-2) with 16 points and nine rebounds. Haley Stokes contributed 14 points, four assists, four steals and two blocked shots while Elizabeth Kukeilka pulled down eight rebounds for BCA.
Boys� basketball
At Sanford, Josiah White had 23 points and Tim Clay added 16 to lead visiting Alamance Christian School past Lee Christian School 69-29 in a non-conference game.
Caleb Pendergraph finished with 10 points and led ACS with 10 rebounds while Chase Johnson handed out a team high six assists for the Warriors.
Kevin Kemp led Lee Christian (0-2) with 12 points.
-- HIGH POINT CHRISTIAN 97, BURLINGTON CHRISTIAN ACADEMY 51: At High Point, Mike Kobani poured in 21 points, Isiah Gill added 19, Jackson Kent had 17 and Diante Baldwin chipped in 13 as High Point Christian rolled past visiting Burlington Christian Academy in a non-league game.
High Point Christian poured it on in the third quarter, outscoring the Royals 33-9 to take control of the game.
Tyree Gattis, Jamison Jeffers and Josh Stewart scored nine points apiece to lead BCA (1-2).


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We pull up at the Melbourne zoo and as we are walking in Tannah points at the sign and says
"That says ZOO! Just like on the Australia Zoo magazine and on the TV when we watch The Zoo"
I tell her that it does indeed say zoo. She continues to find the word around the zoo on our day out.
Tannah is playing her DSi. It's a Littlest Pet Shop game. She calls me.
"Muuuum! I need help. I want to name this pet Sequin can you tell me the letters?"
I say the letters out loud and she is finding them with no help-except for the Q.
She asks for the set of first readers I bought her so she can read the story to her baby sister. I watch her from a distance as she "reads" the book using the pictures as a guide.
Tannah calls me in to the kitchen to show me this
It's so exciting watching her literacy skills grow! I won't be long before I will have to find another option for spelling out things I would rather she didn't overhear like "Luke when the kids are in bed can you get me some i.c.e.c.r.e.a.m."
I'm joining in with Owlet for Unschool Monday. Her post today about rhythm and routine is great!


text: PROBLEM: Christopher Ranch, a garlic farm in the Santa Clara Valley of California, noticed extreme rusting on the steel columns, beams and purlins of their interior processing facility. At the farm, previously applied epoxy coating systems were not holding up under regular washings. As a result, the facility experienced aggressive rusting. A Rust-Oleum representative visited the ranch to inspect the processing facility and understand their needs. SOLUTION: To combat the aggressive rusting, Noxyde along with Industrial Choice 5200 System DTM Acrylic were selected as a trustworthy combination for the facility. Noxyde, a heavy duty, water based elastomeric acrylic, provides long term corrosion protection with an easy spray application. After two coats of Noxyde, the area was top coated with Industrial Choice 5200 System DTM Acrylic. The 5200 System is a low VOC, low odor coating. After almost one year, the facility has not had any problems with rusting and the coating system is adhering well and is easy to maintain.


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Lawsuit targets last scraps of Net-obscenity law
By Sam Costello (IDG News)
CNN, December 20, 2001
The National Coalition for Sexual Freedom (NCSF) and artist Barbara Nitke have filed a lawsuit challenging the remaining provisions of the Communications Decency Act, much of which was struck down by the U.S. Supreme Court in 1997.
The act, or CDA, was passed in 1996 and was the first U.S. law designed to allow the regulation of Internet content. The remaining provision of the law bars the publication of material online that is deemed obscene under "contemporary community standards." The lawsuit, filed last week in Federal District Court in New York, challenges that aspect of the law saying it is so broad and vague that it violates the First Amendment freedom of speech protection and could prohibit frank sexual discussion among adults on the Internet.
Under the law, obscenity is determined using local community standards. But applying that standard to the Internet means asking the question whether the local community is the one where the Web site is hosted or the one where it is viewed, said Susan Wright, spokesperson for the NCSF.
This existing CDA provision balances on the narrow difference in the legal definitions of the terms "obscenity" and "indecency." In its CDA ruling, the Supreme Court allowed that the government could investigate and prosecute obscene speech, that is, speech with no redeeming merit.
Those obscenity provisions are too broad and vague in the view of the NCSF.
"What is the local community standard," Wright asked. "Is it where you live? Where the Web site is? Is it the most restrictive community in America? The least?"
The rest of the CDA should be overturned, she said, as it isn't right for members of a small, rural town to be able to determine the community standards of cities like New York or San Francisco.
The NCSF filed the suit because "the CDA could have a dangerous effect on the Internet in the hands of an overzealous administration and this attorney general," Wright said.
Attorney General John Ashcroft indicated a willingness to pursue CDA prosecutions when he met with a number of conservative groups earlier this year, Wright said, noting that the NCSF had obtained copies of information those groups had sent to their members after the meetings.
Ashcroft has come under fire from some groups for his expansion of government surveillance powers after the September 11 terrorist attacks. Ashcroft has responded to those criticisms by charging that his critics are aiding terrorists by raising such concerns.
Wright dismissed notions that Ashcroft is too occupied by antiterrorism efforts to worry about Internet indecency. He made moves in early November that effectively blocked a voter-approved assisted suicide law in Oregon, a measure unrelated to terrorism, she noted.
"He's demonstrated he has the time and resources for other battles (than terrorism)," she said.


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As Fitness Month continues here at Windows Phone Central and all of the Mobile Nations sites, we turn our sites on apps to help with our diet. While exercise is a key element of staying fit, so is what we consume during the day. You defeat the purpose of exercise with poor eating habits.
This week's Fitness App Roundup will concentrate on a collection of top rated Windows Phone apps designed to help you count your calories and monitor what foods you take in during the week. There's also an app that will find you recipes based on the ingredients you prefer while avoiding those you are allergic to.
We'll close things out with a Reader's Poll to let you decide which of these diet apps are tops. If we've missed your favorite app, feel free to sound off below in the comments.
Full story from the WPCentral blog...


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text: Took a break from frame quilting this weekend and made this little cutie. The pattern is called Don't Touch Me, designed by AMANDA, heres a link to her blog http://fabricengineer.blogspot.com/ . So I decided to call my version Don't touch the Daisies. You can find the pattern at http://www.craftsy.com/user/pattern/store/594563 . It was such a fun and quick pattern to put together. Her instructions were very well written. You know how sometimes you get a pattern or a quilt book you have to go on a wild search of information to find out what in the world they are talking about. Not with this pattern, she explains everything, which I need sometimes...LOL! When choosing the fabric for this I was in the mood for girly fun! And what are a bunch of girls but LOUD! And this little quilt is loud....I love it!


text: Avoderm Natural Original Formula contains high levels of mega 6 and 3 fatty acids for a healthy skin and coat. Many of the nutrients your dog needs for a healthy skin and coat can be found in the remarkable fruit known as the avocado. Nutrient rich avocados contain vitamins A, E and C in abundance. They're also an excellent source of balanced nutritional essentials for your dog's skin and coat health-and good health in general. Avocados are high in folate, potassium, niacin, essential fatty acids, and many other nutrients. They have no cholesterol, very little sodium, and are high in monosaturated fats. Ounce for ounce, the avocado is simply one of the most nutritious fruits there is.


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Ferguson schools to double counseling staff
Public schools in Ferguson, Mo., are reinforcing their counseling services for the first day of school Monday in anticipation of students' anxieties after two weeks of protests in their community.
Ferguson-Florissant School District is doubling the number of counselors Monday, and it's training school staff to identify "signs of distress," said Jana Shortt, spokeswoman for the school district.
School was supposed to begin Aug. 14, but the first day was pushed back because of demonstrations after the shooting death of Michael Brown, an unarmed black 18-year-old, by a police officer.
The school district, which has 11,000 students, has one counselor for each of its 24 schools. It's adding 25 more counselors from Great Circle, a St. Louis-based behavioral health organization.
Great Circle is in discussions with the district about a long-term counseling plan, said Angela Bratcher, a clinical director at Great Circle.
"A lot of times with crisis situations, you don't see the response right away. It comes later," she said.
Nearly 2,200 Ferguson-Florrisant school staff — including teachers, bus drivers and custodians — are getting crisis training today, Shortt said.
"While we couldn't have predicted any of this, we hope to make it a learning opportunity for our children," Shortt said.
'Caught in a whirlwind'
Younger children may not be able to verbalize how they feel, and anxiety can reveal itself in headaches, stomachaches or other physical complaints, said Steven Bruce, director of the Center for Trauma Recovery at the University of Missouri-St. Louis.
Traumatic events have a much more "pervasive" impact on children than on adults, said Ken Oliver, associate professor of counseling at Quincy University in Illinois.
Children may think a situation represents how things are supposed to be. In the case of Ferguson, "they will assume all white police officers are mean to black people or black children," Oliver said.
Some early research shows "racial identity development happens early on in child development," Oliver said.
Teens in the community have described the past two weeks as surreal, said Gail Babcock, a program director at Ferguson Youth Initiative, a non-profit group.
"It feels like they're caught in a whirlwind, that they feel trapped," Babcock said. "It's scary, devastating, stressful. Some say they want to hide."
Some teens say they have nightmares and trouble sleeping, Babcock said.
"They need school to start because that's where they feel they can do the healing," she said.
Follow @JolieLeeDC on Twitter.
Read more stories on Ferguson:


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Quantico Postmortem: Boss on Liam's Cohort, That "Very Sad" Death and Alex's Next Mission
May 15, 2016 11:00 PM EDT
[WARNING: The following story contains spoilers about Sunday's season finale of Quantico. Read at your own risk.] As Quantico creator Josh Safran promised, there was no other red herring in Sunday's Season 1 finale: Liam (Josh Hopkins) was in fact th… Read more


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Open Friday to Wednesday 11am - 5pm & Thursday 1pm - 8pm.
Reserve this exceptional home, plot 128 at Greenhall Village with Help to Buy available and free flooring included.
To the front of the property there is an open plan designer kitchen and dining area. Beyond is a light and spacious living area extending, through bi-fold doors, into the rear garden. In addition, you'll also find a WC and under-stairs storage cupboard.
Upstairs, is a large master bedroom with storage cupboard, a second double bedroom and a generous single. There's also a family bathroom, with full-height tiling, contemporary sanitaryware and heated towel rail. Heating controlled by Hive wireless thermostat.
Enquire today.
Hamilton Road, Blantyre, South Lanarkshire, G72 9UD
Why rent when you can buy a new home like no other, thanks to the Government-backed Help to Buy (Scotland) Scheme:
Contact us today to find out how Help to Buy (Scotland) can make things possible.
^Help to Buy (Scotland) is available on selected plots only. Eligible applicants will be offered an equity loan by the government of up to a maximum of 15% of the purchase price (based on open market value). Applicants are required to fund at least 85% of the purchase price by means of a conventional mortgage, savings and any deposit where required. Terms and conditions apply and full details will be provided on request. This offer is only available on selected developments and properties in Scotland up to £200,000. It is not offered with any other promotion. Applicants will need to use a Mortgage Broker from Avant Homes panel who will act solely for the applicant. Please speak with your Sales Advisor for full terms and conditions across all schemes. YOUR HOME IS AT RISK IF YOU DO NOT KEEP UP REPAYMENTS ON YOUR MORTGAGE
Please note that we have endeavoured to portray a reasonable account of the properties we are planning to build. Circumstances may force us to change certain issues and therefore we would advise you to carefully discuss all issues with your Sales Advisor at each stage of the process. All facts and photographs used in our marketing literature are intended to reasonably convey the lifestyle offered by an Avant Homes property. Each home may differ in external finish and appearance and elevational issues may differ from those photographed or illustrated. Floor plans are as accurate as we can be but please be aware that individual construction may result in a slight variance. Please also note that the interior design, furnishings and some fittings and finishings that make up our showhome are not part of our standard specification. These particulars do not form part of a contract or a warranty.
• Bi-folding doors
• Choice of stylish internal doors with chrome-finished door handles
• Ceilings & walls finished in off-white emulsion throughout
• Gas central heating with radiators throughout
• Loft and exterior wall insulation
• Heat, smoke and CO2 detectors
• Fully fitted handleless designer kitchen in a range of colours and styles
• Stainless steel fan oven, hob splashback, built-in microwave oven with grill and 60cm gas hob
• Integrated extractor hood
• Fridge/freezer
• Stainless steel splashback behind hob
• Single bowl stainless steel sink and drainer
• Choice of designer chrome mixer taps
• White finish sockets above worktops
• USB charging point
• Downlights underneath wall units
• White contemporary sanitaryware
• Shower over bath, with glass and chrome bath screen and a choice of complementary bath panels
• Range of tiling in a selection of colours
• Quality designer taps & fittings
• Chrome heated towel rail
• Shaver socket
• Chrome low voltage downlighters in ceiling
• Front entrance light
• White UPVC fascia & soffit
• White UPVC double glazed windows with locking system
• Front GRP doors with multi-point locking system
• Driveway*
• Garage including power and light^
• Allocated parking*
• Outside tap
• Turf to rear garden with patio/decking area†
*Allocated Parking or Driveway for these house types is Plot Specific. Speak to your Sales Advisor for more details. ^Dependent on location of the garage (where applicable). † Speak to your Sales Advisor for regional variations.


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About kyra
Actually, I recently upgraded my AT&T phone, and kept my grandfathered unlimited plan. They even switched me from the 3G unlimited to their 4g lte one. They also let me downgrade my contract and drop and block texting.
I'm not really happy w/ them, but they are the only nationwide carrier to service most of my famil's rural farm land.
After having an iphone for years, I stopped using most apps after only 2 weeks. Currently the most used apps on my phone are Soduko, Redbox, Pandora, and TWC.
I'm very happy to keep my Iphone on the 3.0 version of the OS, not only do I get to keep my $30 unlimited plan, but due to a simple hack I get to use tethering without jailbreaking it.
Will you also be sharing the results of who chooses you or the hoodie and how those lunches go? I'm thinking of getting the music just so I can have lunch with you now!
I love you guys, I just had to go with the books. I'm interested in seeing what your t-shirt design is though.


text:
Implantable, tissue conforming drug delivery device
A drug delivery device for implantation into a patient is provided that includes at least one device element which comprises a substrate having a plurality of discrete reservoirs disposed therein, said reservoirs containing drug molecules and a degradable matrix material which controls in vivo release of the drug molecules from the reservoirs, wherein the drug delivery device is adapted to conform to a curved bone tissue surface. In one embodiment, the substrate is flexible and conforms to a bone tissue surface. In another embodiment, the device has two or more device elements attached to or integral with a flexible supporting layer.
This is a continuation of U.S. patent application Ser. No. 10/042,996, filed Jan. 9, 2002, which claims benefit under 35 U.S.C. §119 of U.S. Provisional Application No. 60/260,725, filed Jan. 9, 2001. These applications are incorporated herein by reference.
The present invention is generally in the field of implantable microchip devices and methods for use thereof, particularly in ophthalmic and other medical applications.
The relatively small size, rounded shape, and location of the eye have made the development of new methods and devices for drug delivery to the eye difficult. The most common method of drug delivery to the eye is by liquid eye drops. This method of drug delivery is limited to those drugs that can diffuse through the eye tissue (i.e. typically low molecular weight drugs) and those drugs that can be formulated as a liquid or gel.
Alternative delivery methods include the implantation of drug delivery devices inside of the eye. For example, U.S. Pat. No. 6,063,116 to Kelleher discloses an intraocular polymeric implant for sustained release of a cell proliferation-modulating agent. As another example, Ambati, et al, "Transscleral Delivery of Antibodies to the Posterior Segment" Investigative Ophthalm. & Visual Sci., 40(4): 457-B417 (Mar. 15, 1999) discloses implanting osmotic pumps containing FITC-IgG on the scleral surface or beneath a lamellar scleral flap for targeted delivery to the choroid and retina.
These implants may allow larger molecular weight drugs to be delivered (depending on the presence of diffusion limitations based on the depth of the target tissue layer), but they typically only have the ability to passively release a single drug.
PCT WO 00/40089 discloses a method for delivering a therapeutic or diagnostic agent to the retina and choroid by contacting the sclera with the agent and using an implant device for enhancing transport of the agent through the sclera. The reference mentions that the implant can be a microchip comprising reservoirs containing the desired agent. It would be advantageous to develop new and improved systems using microchip devices, as described in U.S. Pat. No. 5,797,898, U.S. Pat. No. 6,123,861, PCT WO 01/64344, PCT WO 01/35928, and PCT WO 01/12157, for the controlled delivery of drugs and the controlled exposure of sensors in ophthalmic and other medical applications wherein implantation presents challenges such as described above for the eye. It also would be desirable to provide devices and methods of use thereof for delivery and sensing at locations in patients where implantation is desirable in small spaces, particularly those involving curved or rounded tissue surfaces.
Microchip device arrays that can conform to a curved surface are provided for the controlled release or exposure of reservoir contents. The arrays comprise two or more microchip device elements, each of which includes a plurality of reservoirs that contain molecules for controlled release or components for selective exposure, and a means for flexibly connecting the device elements.
Preferably, the means for flexibly connecting comprises a flexible supporting layer attached to a surface of the device elements. The flexible supporting layer can, for example, comprise a polymer, such as a polyimide, polyester, parylene, or hydrogel. The flexible supporting layer typically is attached the microchip device elements on the side distal the release/exposure opening of the reservoirs (i.e. the release side). Additionally or alternatively, the flexible supporting layer can be secured to the release side if the flexible supporting layer is provided with one or more apertures aligned the reservoir openings or if the flexible supporting layer is porous or permeable to (i) molecules releasable from the reservoirs or (ii) environmental molecules of interest that would need to contact the reservoir contents). Alternatively, the microchip device elements could be effectively imbedded within the flexible supporting layer.
In other embodiments, the means for flexibly connecting comprises one or more hinges or flexible tethers connecting two or more of the device elements.
In preferred embodiments, the microchip device array is suitable for implantation onto or into a patient, wherein the array can conform to the curvature of a tissue surface. In one embodiment, the array is implanted into or onto the eye of the patient, wherein the tissue surface comprises ophthalmic tissue.
In several embodiments, the reservoirs of the device elements contain drug molecules for release. In other embodiments, the reservoirs contain one or more secondary devices, such as a sensor, for exposure. A single array or a single device element can include both drugs for release and sensors. Such an array could be automated to release a particular dosage of drug in response to a condition or change measured by the sensors. The reservoirs also can contain diagnostic reagents, catalysts, combinatorial chemistry precursors, and fragrance molecules.
The microchip device array may comprise reservoir caps over the reservoirs, and optionally can include means for a user to wirelessly communicate with the microchip device elements. Such communicating means can comprise a photocell to receive incident light energy, such as from a laser source.
Microchip device array having active microchip device elements can comprise an energy storage means, such as a capacitor, a battery, or both. Optionally, the array includes electrical connections between two or more of the microchip device elements, such that the microchip device elements can be powered or controlled by a common energy source or control source, respectively.
Methods are provided for delivering drug molecules to a patient comprising implanting into or onto a tissue surface of the patient the microchip device array which contains drug, and selectively releasing from one or more of the reservoirs an effective amount of the drug molecules. In one embodiment, the microchip device array is implanted onto or into the sclera or another surface of the eye of the patient. The release of drug can be activated wirelessly, such as by application of light to the microchip device array. For example, an ophthalmic laser could be used. The laser light could, in one method, remove or permeate one or more reservoir caps which cover the reservoirs. Other suitable tissue surfaces include, but are not limited to, the stratum corneum or other skin tissues, mucosal membranes, blood vessels, bone, brain, and bladder.
In another method, molecules or a physical property is sensed at a site, wherein the method comprises implanting at a site the microchip device array which contains sensors, and selectively exposing at least one sensor of the sensors to molecules or a property at said site, thereby permitting said at least one sensor to sense said molecules or property. The sensor, for example, could comprise a pressure sensor or a chemical sensor.
More general methods are also provided for ophthalmic sensing.
Microchip devices have the advantage of small size, variable shape, and the ability to actively or passively control release or exposure of the contents of its reservoirs. The microchip devices can contain multiple drugs or chemicals, can contain sensors or diagnostic reagents, and can be controlled using microprocessors, remote control (i.e. telemetry), or biosensors. Additionally, the microchip devices for chemical delivery and selective exposure can be used with known ophthalmic technology (such as ophthalmic light sources, such as lasers or other focused light) to provide a source of power or data transmission, or as a means for opening reservoirs in the microchip devices, for example by triggering reservoir cap disintegration. The microchips can provide accurate and controlled local delivery of drugs, advantageously reducing or avoiding systemic release.
FIGS. 1A-C illustrate how an array of flat, rigid microchips are incorporated onto a flexible supporting layer containing electronic connections and shared power and control sources.
The eye is a relatively small organ. Both the inside and outside surfaces of the eye are curved, so the size, shape, and rigidity of any device used to deliver drugs to the eye or used as a sensor in the eye is therefore important. Microchip devices can be made large or small, depending on the specific requirements of the particular application. The substrates for these microchips can be composed of semiconductors or other material that protects the contents of the reservoirs until it is desired to release them or expose them to the surrounding environment. For small devices, the shape and rigidity of the substrate material is not as important as it is for larger devices. Some typically rigid substrate materials (e.g., silicon) can be made flexible, for example, if they are made thin enough. However, as a flat, rigid microchip is enlarged or made thicker, it is less able to conform to the curvature of the eye. This can be a problem if it is necessary for the entire surface of the device to contact the surface of the eye, another curved tissue surface, or any other curved surface for that matter.
Therefore, microchip device arrays which can conform to curved surfaces, that is, flexible microchip devices, have been developed. In a preferred embodiment, this is accomplished with a microchip device that is made up of an array of several small microchip device elements that are attached to a flexible supporting layer. Each microchip on the supporting layer may be independently controlled (i.e. individual power and control sources) or the array of microchips may be controlled as one unit (i.e. shared power and control sources) through electrical connections built into the flexible supporting layer (see
In preferred embodiments, the devices are adapted for use in delivering drugs or other chemicals to the eye, sensing changes in the eye or conducting other diagnostic tests, and combinations thereof, using, for example, a device array composed of rigid microchips which conforms to a curved surface of either the interior or exterior of the eye. Certain eye conditions, notably macular degeneration and diabetic retinopathy, can be treated with periodic administration of medication delivered to the eye; however, the means for doing so, such as injections, are difficult. An implanted microchip device, such as described herein, should provide an improved means for delivering doses of one or more types of medication to the eye on a periodic basis for an extended period of time. The microchips can provide accurate and controlled local delivery of drugs, advantageously reducing or avoiding systemic release.
The Devices
In preferred embodiments, the device comprises microchip device elements that are attached to or integral with a flexible supporting layer. Preferably, an array of at least two (e.g., at least four, at least five, at least twelve, etc.), microchip device elements forms a single, larger flexible device that can conform to the curvature of tissue surfaces, such as on surfaces of the eye, as detailed below.
In other embodiments, flexible microchip devices are provided in the form of a single microchip device element, or an array of two or more microchip device elements, having a flexible substrate. Such embodiments could be provided, for example, by molding or otherwise forming appropriate polymeric substrates, and would be particularly suitable for passive release designs.
The Microchip Device Elements
The microchip device (i.e. the microchip device elements) is described in U.S. Pat. No. 5,797,898 and No. 6,123,861, both to Santini, et al., and PCT WO 01/64344, WO 01/41736, WO 01/35928, and WO 01/12157, which are hereby incorporated by reference in their entirety. Each microchip device includes a substrate having a plurality of reservoirs containing reservoir contents for release or exposure.
The molecules to be delivered may be inserted into the reservoirs in their pure form, as a liquid solution or gel, or they may be encapsulated within or by a release system. As used herein, "release system" includes both the situation where the molecules are in pure form, as either a solid or liquid, or are in a matrix formed of degradable material or a material which releases incorporated molecules by diffusion out of or disintegration of the matrix. The molecules can be sometimes contained in a release system because the degradation, dissolution or diffusion properties of the release system provide a method for controlling the release rate of the molecules. The molecules can be homogeneously or heterogeneously distributed within the release system. Selection of the release system is dependent on the desired rate of release of the molecules. Both non-degradable and degradable release systems can be used for delivery of molecules. Suitable release systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents such as, but not limited to, calcium carbonate and sugar. Release systems may be natural or synthetic, although synthetic release systems are preferred due to the better characterization of release profiles. The release system is selected based on the period over which release is desired, generally in the range of at least three to twelve months for in vivo applications. In contrast, release times as short as a few seconds may be desirable for some in vitro applications. In some cases, continuous (constant) release from a reservoir may be most useful. In other cases, a pulse (bulk) release from a reservoir may provide more effective results. A single pulse from one reservoir can be transformed into pulsatile release by using multiple reservoirs. It is also possible to incorporate several layers of a release system and other materials into a single reservoir to achieve pulsatile delivery from a single reservoir. Continuous release can be achieved by incorporating a release system that degrades, dissolves, or allows diffusion of molecules through it over an extended period of time. In addition, continuous release can be simulated by releasing several pulses of molecules in quick succession.
The release system material can be selected so that molecules of various molecular weights are released from a reservoir by diffusion out or through the material or degradation of the material. Biodegradable polymers, bioerodible hydrogels, and protein delivery systems are preferred for release of molecules by diffusion, degradation, or dissolution. In general, these materials degrade or dissolve either by enzymatic hydrolysis or exposure to water in vivo or in vitro, or by surface or bulk erosion. Representative synthetic, biodegradable polymers include: poly(amides) such as poly(amino acids) and poly(peptides); poly(esters) such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and poly(caprolactone); poly(anhydrides); poly(orthoesters); poly(carbonates); and chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof. Representative synthetic, non-degradable polymers include: poly(ethers) such as poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide); vinyl polymers—poly(acrylates) and poly(methacrylates) such as methyl, ethyl, other alkyl, hydroxyethyl methacrylate, acrylic and methacrylic acids, and others such as poly(vinyl alcohol), poly(vinyl pyrolidone), and poly(vinyl acetate); poly(urethanes); cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; poly(siloxanes); and any chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), copolymers and mixtures thereof.
Each reservoir can contain a different molecule and dosage. Similarly, the release kinetics of the molecule in each reservoir can be varied by the choice of the release system and cap materials. In addition, the mixing or layering of release system and cap materials in each reservoir can be used to tailor the release kinetics to the needs of a particular application.
The distribution over the microchip of reservoirs filled with the release system containing the molecules to be delivered can vary depending on the medical needs of the patient or other requirements of the system. For applications in drug delivery, for example, the drugs in each of the rows can differ from each other. One row may contain a hormone and another row may contain a metabolite. In addition, the release system can differ within each row to release a drug at a high rate from one reservoir and a slow rate from another reservoir.
In a preferred embodiment, each reservoir has a reservoir cap positioned on the reservoir over the reservoir contents, wherein release or exposure of the reservoir contents is controlled by diffusion through or disintegration of the reservoir cap.
The reservoir cap can be an anode, such that upon application of an electric potential between a cathode and the anode the reservoir cap is oxidized to facilitate its disintegration, thereby exposing the reservoir contents to a surrounding fluid. In another embodiment, the reservoir cap includes an electrically- or thermally-responsive polymer whose integrity or porosity can be modulated (i.e. increased or decreased) upon application of electrical energy to the reservoir cap (e.g., for the electrically responsive polymer) or to a nearby resistor or resistive heater (e.g., for the thermally responsive polymer). Similarly, the reservoir cap can include or be formed of a polymer having a porosity that can be modulated by application of electromagnetic energy, acoustic energy, or a particular chemical species (e.g., for chemical actuation) provided by the microchip device or other source.
In the passive timed release drug delivery devices, the reservoir caps are formed from a material that degrades or dissolves over time, or does not degrade or dissolve but is permeable to the molecules to be delivered. These materials are preferably polymeric materials. Materials can be selected for use as reservoir caps to give a variety of degradation rates or dissolution rates or permeabilities to enable the release of molecules from different reservoirs at different times and, in some cases, different rates. To obtain different release times (amounts of release time delay), caps can be formed of different polymers, the same polymer with different degrees of crosslinking, or a UV polymerizable polymer. In the latter case, varying the exposure of this polymer to UV light results in varying degrees of crosslinking and gives the cap material different diffusion properties or degradation or dissolution rates. Another way to obtain different release times is by using one polymer, but varying the thickness of that polymer. Thicker films of some polymers result in delayed release time. Any combination of polymer, degree of crosslinking, or polymer thickness can be modified to obtain a specific release time or rate. In one embodiment, the release system containing the molecules to be delivered is covered by a degradable cap material which is nearly impermeable to the molecules. The time of release of the molecules from the reservoir will be limited by the time necessary for the cap material to degrade or dissolve. In another embodiment, the cap material is non-degradable and is permeable to the molecules to be delivered. The physical properties of the material used, its degree of crosslinking, and its thickness will determine the time necessary for the molecules to diffuse through the cap material. If diffusion out of the release system is limiting, the cap material delays the onset of release. If diffusion through the cap material is limiting, the cap material determines the release rate of the molecules in addition to delaying the onset of release.
The microchip devices can be made and assembled using microfabrication methods known in the art, particularly those methods described and referenced in U.S. Pat. No. 5,797,898 and No. 6,123,861, both to Santini, et al., and in PCT WO 01/64344, WO 01/41736, WO 01/35928, and WO 01/12157. These publications are hereby incorporated by reference.
The device is preferably constructed of, and/or coated with, materials known in the art to be physiologically acceptable for long-term implantation or contact with the ocular tissues.
Means for Flexibly Connecting
Preferably, the means for flexibly connecting comprises a flexible supporting layer secured to at least one surface of each of the device elements.
The flexible supporting layer typically is attached the microchip device elements on the side distal the release/exposure opening of the reservoirs (i.e. the release side). Additionally or alternatively, the flexible supporting layer can be secured to the release side if the flexible supporting layer is provided with one or more apertures aligned the reservoir openings or if the flexible supporting layer is porous or permeable to (i) molecules releasable from the reservoirs or (ii) environmental molecules of interest that would need to contact the reservoir contents). Alternatively, the microchip device elements effectively could be imbedded within the flexible supporting layer.
The flexible supporting layer can be made of essentially any flexible material, but preferably comprises a polymer. Representative examples of suitable polymers include polyimide, polyester, parylene, and hydrogels. Other flexible materials that are especially biocompatible include polyethylene, polypropylene and silicone.
The flexible supporting layer also could be a laminate structure. For example, it could be comprised of an inner flexible material containing electrical conductors that is coated with one or more biocompatible materials.
The microchip device elements, as well as other components, can be surface mounted onto or imbedded into the flexible supporting layer. For example, the microchip device elements and other components can be surface mounted using conductive adhesives, non-conducting adhesives (e.g., an epoxy), soldering, or wirebonding. Alternatively, the microchip elements could be mechanically attached, for example by screws or clips.
The flexible layer also may consist of or comprise a mesh material, which would generally be easier to suture to tissue. Such a mesh material could be biodegradable or non-biodegradable, depending upon the application.
In one embodiment, electrical connections or traces are built into the means for flexibly connecting the device elements. For example, the incorporation of electrical connections into flexible polymer films is well known by those skilled in the art of microelectronics packaging. Typical approaches include single and multiple layer flexible printed circuits, and Multichip Modules-Deposited (MCM-D) using organic (usually polyimide) dielectric layers. For example, in the 37 chips first" style of MCM-D, thinned chips are placed on a bottom dielectric layer and then interconnected layers are built up over them, thereby embedding the chips. Other chips, e.g., the microchip device elements can then be surface mounted. Flexible circuit and MCM-D fabrication techniques are described, for example, in Coombs, Printed Circuits Handbook, 4th ed. (McGraw-Hill 1996) and Harper, Electronic Packaging and Interconnection Handbook, 3rd ed. (McGraw-Hill 2000).
It is also understood that small, rigid, passive-release microchips also can be incorporated onto a supporting layer so that they can better conform to the curvature of the eye. Unlike the active microchips, the passive microchips do not require any power or control sources or electrical connections in the flexible substrate. In this case, the flexible substrate serves only to hold the passive microchip device elements in place.
In other embodiments, the means for flexibly connecting comprises one or more hinges or flexible tethers connecting two or more of the device elements, so that the array can conform to the curved surface. For example, each of the four edges of a square microchip device element could be connected by one or more hinges or flexible tethers to the edge of an adjacent microchip device element. The hinges or tethers could be connected at the corners or along the edges of the device elements. A flexible supporting layer could be used to form such tethers or hinges, or to complement them.
Contents of the Microchip Reservoirs
The microchip reservoir contents can be essentially any chemical or a secondary device, or portion thereof, that can be contained in a reservoir of the microchip device. The term "secondary device" typically refers to structures and does not include drugs or other chemical molecules that are intended to be released from the reservoirs. The microchip devices can contain multiple drugs or chemicals in a variety of forms (e.g., solid, liquid, or gel) and can contain sensors or diagnostic reagents.
In a preferred embodiment, the chemical is a therapeutic, prophylactic, or diagnostic agent. The term "drug" refers to any of these agents, unless a particular one is explicitly indicated. Representative types of suitable drugs include proteins, purified polypeptides and nucleic acid molecules, as well as synthetic and natural organic molecules.
Representative examples of suitable therapeutic or prophylactic molecules include antibiotics (e.g., tetracycline, chlortetracycline, bacitracin, neomycin, gentamicin, erythromycin, and penicillin); antibacterials such as sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole and sulfisoxazole, nitrofurazone and sodium propionate; antivirals (e.g., idoxuridine, trifluorothymidine, acyclovir, gancyclovir and interferon); other anti-microbial drugs such as iodine-based preparation (e.g., triclosan, chlorhexidine); anti-allergenics (e.g., sodium cromoglycate, antazoline, methapyriline, chlorpheniramine); anti-inflammatories (e.g., hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluorocinolone, medrysone, prednisolone acetate, fluoromethalone, betamethasone, and non-steroidal agents such as indomethacin, diclofenac, flurbiprofen, ibuprofen and acetylsalicylic acid); mydriatics (e.g., atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine, and hydroxyamphetamine); sympathomimetics such as epinephrine; immunological drugs such as vaccines and immune stimulants; beta adrenergic blockers such as timolol maleate, levobunclol HCl and betaxolol HCI; growth factors such as epidermal growth factor and fibronectin; carbonic anhydrase inhibitors such as dichlorphenamide, acetazolamide and methazolamide and other drugs such as prostaglandins, antiprostaglandins, and prostaglandin precursors; angiogenesis inhibitors such as steroids, angiostatin, antiproliferative agents such as flurouracil and mitomycin; anti-angiogenic factors; immunomodulatory agents; vectors for gene transfer (e.g, DNA plasmids, viral vectors); cytotoxic agents, and chemotherapy medications.
Examples of diagnostic agents include imaging agents, such as contrast agents. The reservoir contents also can be selected from catalysts (e.g., zeolites, enzymes), non-therapeutic reagents, precursors for combinatorial chemistry, or combinations thereof, for example for use in diagnostic sensing and analytical biochemistry. The reservoir contents also could be non-biomedical molecules, such as fragrance molecules.
The reservoir contents also can include a secondary device, such as a sensor and sensing component. In a particularly preferred embodiment, the reservoirs contain pressure sensors, for example to measure intraocular pressure. The reservoir contents may either be released from or remain immobilized in the reservoir, depending on the particular application.
Types of sensors that can be contained within or provided near a reservoir include biosensors, chemical sensors, physical sensors, or optical sensors. Preferred sensors measure properties such as biological activity, chemical activity, pH, temperature, pressure, optical properties, radioactivity, and electrical conductivity. These may be discrete sensors (e.g., "off-the-shelf" sensors) or sensors integrated into the substrate. Biosensors typically include a recognition element such as an enzyme or antibody. The transducer used to convert the interaction between the analyte and recognition element into an electronic signal may be, for example, electrochemical, optical, piezoelectric, or thermal in nature. Representative examples of biosensors constructed using microfabrication methods are described in U.S. Pat. No. 5,200,051, No. 5,466,575, No. 5,837,446, and No. 5,466,575.
There are several different options for receiving and analyzing data obtained with the secondary devices located in the microchip devices. First, the output signal from the device can be recorded and stored in writeable computer memory chips. Second, the output signal from the device can be directed to a microprocessor for immediate analysis and processing. Third, the signal can be sent to a remote location away from the microchip. For example, a microchip can be integrated with a radio transmitter in order to transmit a signal (e.g., data) from the microchip to a computer or other remote receiver source. The microchip can also be controlled using the same transmission mechanism. Power can be supplied to the microchip locally by a microbattery or remotely by wireless transmission. Ophthalmic lasers can be used to wirelessly transmit power and data, as described in detail below.
Individual reservoirs may contain multiple types of chemicals, multiple types of devices, or combinations of devices and chemicals. In various embodiments, the microchip devices may include one or more drugs, one or more sensors, or combinations thereof.
Interface with the Eye or Other Implantation Sites
The microchip devices described herein are useful at a variety of site in which a single, larger, rigid microchip device may not be preferred. Examples of such sites include, but are not limited to, implantation sites in humans and other mammals. As used herein, "implantation" and "implanting" typically refer to securely positioning a microchip device onto a tissue surface. For example, the microchip devices described herein can be attached to an outer surface of the eye or implanted within the eye using or adapting known medical and surgical techniques.
Alternatively, the device is designed to conform to another curved tissue surface, such as the skin, mucosal tissue surfaces, blood vessel walls (interior or exterior side), the stratum corneum or other skin tissues, mucosal membranes, blood vessels, bone (e.g., the skull, the femur), brain, and other organs tissue surfaces, such as the bladder. Such devices can be used for drug delivery and sensing applications. The flexible devices also may serve to reposition the contacted tissue for therapeutic purposes, such as to mechanically maintain the patency of a tissue lumen, for example, while releasing anti-coagulants or anti-atherosclerotic agents. In the bladder, the flexible device could be used, for example, to deliver bacillus Calmette-Guerin (BCG) to the interior surface for the treatment of superficial bladder cancer.
Power and Data Transmission
The active microchip devices require power to initiate release of molecules from the reservoirs or exposure of reservoir contents. There are two primary methods of supplying power to initiate release or exposure from active microchip devices. These include the use of pre-charged power sources and the use of on-demand power sources. Pre-charged power sources (e.g., pre-charged micro-batteries) can be integrated with the microchip and its associated electronics. Such a pre-charged micro-battery can be, for example, a thin film battery fabricated on the microchip itself, or it can exist as a separate component that is connected to the microchip through interconnects and packaging. In the case of pre-charged power sources, the power source must store all the power required during the operating lifetime of the microchip. If it cannot store all of the required power, then a new battery at some point must replace the old battery during the life of the microchip.
On-demand power sources (e.g., wireless transmission and reception of power) do not require a power storage unit to be physically connected to or included with the microchip, because the necessary power can be transmitted to the microchip at any time. Unlike pre-charged power sources, microchip systems with the capability to receive power by wireless methods do not need to store all of the power required for the operating life of the microchip. Instead, power can be applied to the microchip on demand (i.e. when needed). However, microchips relying on on-demand power sources can include a "re-chargeable" power storage unit (i.e. capacitor, re-chargeable micro-battery), if it is desired to store small amounts of power on or near the microchip. The distinction is that pre-charged power sources must contain all the required power or be replaced, and on-demand power sources do not have to contain all the required power because they can receive power or be re-charged at any time. On-demand power by wireless transmission is known, and is described for example in U.S. Pat. No. 6,047,214 to Mueller, et al.; U.S. Pat. No. 5,841,122 to Kirchhoff; and U.S. Pat. No. 5,807,397 to Barreras. The basic elements of a system for the wireless transmission of power to a microchip for chemical release or selective exposure of reservoir contents include a transmitter to deliver power by means of electromagnetic waves (i.e. radio frequency signal generator or RF), light (e.g., ophthalmic laser) or ultrasound, and a receiver. Additional components may include a means of power conversion such as a rectifier, a transducer, a power storage unit such as a battery or capacitor, and an electric potential/current controller (i.e. potentiostat/galvanostat).
Each of these units (except for the external energy transmission source) may be fabricated on the microchip ("on-chip" components) using MEMS fabrication techniques as described, for example, in Madou, Fundamental of Microfabrication (CRC Press, 1997) or using standard microelectronics processing techniques as described, for example, in Wolf & Tauber, Silicon Processing for the VLSI Era (Lattice Press, 1986). In addition, each of these units (except the external energy transmission source) may exist as "off the shelf" microelectronic components that can be connected to the microchips using hybrid electronic packaging or multi-chip modules (MCMs). An active microchip with the capability of receiving power through wireless means also can be composed of a combination of "on-chip" components and "off the shelf" components. Methods for sending and receiving data using wireless technology are very similar to those used for the wireless transmission of power. Therefore, the design and fabrication of such wireless power and data transmission systems are known or can be made using no more than routine experimentation by those skilled in the art.
Ophthalmic Embodiments
In one embodiment, the ophthalmic microchip device is in the form of an array of small, rigid, drug-containing microchips that are attached to a flexible supporting layer so that the entire array can conform to the outer surface of the back of the eye. The microchips are connected to each other by flexible electrical connections incorporated into the supporting layer. In this embodiment, the array of microchips is controlled by a single microprocessor and power is supplied by a small battery. The array is attached to the back surface of the eye and is held in place by several small sutures through the supporting layer and into the outer tissue of the eye. The microprocessor is preprogrammed to release drug from specific reservoirs by directing power from the battery to specific reservoir caps through multiplexing circuitry. In a specific embodiment, the caps are made of gold and they disintegrate in biological solutions when electric potentials of approximately 1 volt (vs. SCE) are applied to them. Once the drug is released from a reservoir, it is in contact with the surface of the eye and diffuses into the eye. This process can be repeated numerous times with several different drugs being released from a single microchip or array of microchips. The type and configuration of device components and the number of microchips in the array can be varied as needed for particular applications.
This embodiment is illustrated in FIGS. 1A-C.
Methods of Using the Devices
The microchip device elements can be used and operated generally as described in U.S. Pat. No. 5,797,898, U.S. Pat. No. 6,123,861, PCT WO 01/64344, PCT WO 01/35928, and PCT WO 01/121517, and as described herein.
As described herein, reservoir activation can be conducted wirelessly. Generally, this refers to telemetry (i.e. the transmitting and receiving) accomplished using a first coil to inductively couple electromagnetic energy to a matching/corresponding second coil. The means of doing this are well established, with various modulation schemes such as amplitude or frequency modulation used to transmit the data on a carrier frequency. The choice of the carrier frequency and modulation scheme will depend on the location of the device and the bandwidth required, among other factors. Other data telemetry means also may be used. Examples include optical communication, where the receiver is in the form of a photocell, photodiode, and/or phototransistor, and where the transmitter a light-emitting diode (LED) or laser.
Light Actuation of Microchip Devices
The power requirements for electrochemically actuated silicon microchip devices with thin film gold reservoir caps are sufficiently small that this power can be supplied optically. An ophthalmic laser can be used to both supply the power and communicate instructions to the device, as is done in many wireless systems where the signal carrying power is modulated to contain information to be communicated to the device. Alternatively, focused light from a non-laser source can be sufficient to operate the device.
In a preferred embodiment, focused light, such as from a laser source, is used to activate or actuate the reservoirs of microchip devices following implantation of the device. For example, lasers are used routinely in eye surgeries and other eye procedures for the treatment of conditions such as diabetic retinopathy, retinal detachments, and age-related macular degeneration. Many of these procedures are simple, outpatient procedures carried out in an ophthalmologist's office. The microchip devices can be implanted into the eye and then activated using such lasers to transmit power, data or both for powering and controlling the device. An ophthalmologist can initiate drug release and communication with eye-implanted microchips by directing an ophthalmic laser toward the appropriate portion of the microchip in (or on) the patient's eye for those locations (i.e. implantation sites) where the microchip device is readily accessible. Many ophthalmologists are already skilled in the use of such lasers.
In a preferred embodiment, the implanted wireless ocular delivery system includes the drug-containing microchip, controller, external interface(s), power conversion electronics, and actuation electronics. The external interface and power conversion electronics typically consists of a photocell to receive the incident light (e.g., laser) energy, circuitry to generate the needed voltage(s), storage means such as a capacitor or battery, and circuitry to decode information transmitted by modulating the laser input. The controller typically is a microprocessor, memory, clock, though a dedicated integrated circuit may be useful for some applications.
Electronics required to actuate electrochemical microchips includes means for controlling the electrode potential, such as a potentiostat/galvanostat, and a demultiplexer to direct the potential to the desired reservoir(s). If desired, the system can provide feedback, for example, to confirm the successful delivery of a dose. This information can be transmitted back to the operator or to a computer monitoring system optically using a light-emitting diode (LED) or by other modes of wireless transmission (e.g., RF).
Wireless Reservoir Activation
Ophthalmic lasers also can be used to open the reservoirs of microchip devices implanted inside the eye or attached to the outside of the eye. The physician can direct the laser to one or more reservoir caps, causing the cap material to disintegrate or become permeable, thereby releasing the drugs or chemicals contained in the reservoir or exposing other reservoir contents (e.g., sensors) of the reservoir to the surrounding environment. For example, the reservoir cap is made of a low melting temperature polymer and the reservoir is opened when the laser softens or melts the reservoir cap.
In one embodiment, a microchip device having polymeric reservoir caps is implanted into the interior of the eye and held in place with sutures. The polymer caps do not dissolve or allow the drug to be released into the eye without the application of an external stimulus. In this embodiment, an ophthalmic laser is directed at one or more polymeric reservoir caps when release is desired from the corresponding reservoirs. The ophthalmic laser creates a local increase in temperature that causes the polymeric reservoir cap to soften and melt. The drug inside that reservoir then diffuses out of the reservoir and into the intraocular fluid. This implanted device can be used, for example, to deliver drug as needed over an extended period of time. For example, the patient can visit the physician periodically, e.g., every two to four weeks, and the physician uses an ophthalmic laser to open one reservoir (or several of them) of the implanted microchip device to release drugs into the patient's eye.
In a similar embodiment, the physician uses the ophthalmic laser to open a reservoir that contains one or more sensors, which can be exposed by the physician when desired. Representative sensors included pressure sensors, chemical sensors, and immunological sensors. A chemical sensor, such as an oxygen electrode, is one example of a useful sensor. Another example is a pressure sensor, which can be used to help monitor the progression of some eye diseases, such as glaucoma, by measuring and recording pressure changes in the eye. The pressure sensing function can be related to the release of drug from another reservoir, so that, for example, upon detection of an abnormally high intraocular pressure, the microchip device signals the release of a pressure reducing drug from another microchip reservoir, which can be in the same device or in separately fabricated device that is in communication with the pressure sensing microchip device.
An implantable wireless ocular delivery system would typically include (1) the microchip device (containing one or more drugs and/or sensors) with its local controller, external interfaces, power conversion electronics, and actuation electronics; and (2) the focused light source. The external interface and power conversion electronics typically would include a photocell to receive the incident light energy, circuitry to generate the needed voltage, storage means such as a capacitor or battery, and circuitry to decode information transmitted by modulating the laser input. The controller typically would be a microprocessor with associated support circuitry such as a memory and a clock, although a dedicated integrated circuit may work for some embodiments. Electronics required to actuate electrochemical microchips typically would include means for controlling the electrode potential, such as a potentiostat or galvanostat, and a demultiplexer to direct the potential to the desired reservoir. If desired, the system would provide feedback, for example, to confirm the successful delivery of a dose. This information could be transmitted back to the operator or to a computer monitoring system, either optically by using a light-emitting diode (LED) or by other modes of wireless transmission, such as RF.
An ophthalmologist could initiate drug release and communication with eye-implanted microchip device by directing an ophthalmic laser toward the appropriate portion of the implanted microchip in the patient's eye. See
Applications of the Ophthalmic Microchip Devices
The microchip devices and methods of use can be used for a variety of therapeutic, prophylactic, and diagnostic ophthalmic applications, as well as other (non-ophthalmic) medical implant application.
In a preferred embodiment, the devices are used in the treatment of retinal or choroidal diseases, such as macular degeneration, glaucoma, diabetic retinopathy, retinitis pigmentosa, retinal vein occlusions, sickle cell retinopathy, choroidal neovascularization, retinal neovascularization, retinal edema or ischemia.
In some applications, the devices are used in the control of inappropriate proliferation of cells on or within the eye. The specific type and location of the cells depends upon the particular disease or disorder. Examples of types of inappropriate cell proliferation include cancerous malignancies, wherein the cell is a cancer cell, scarring, wherein the cell is a normal fibroblast, and diseases wherein the proliferating cell is an epithelial cell, such as a lens epithelial cell, which can impair vision. One specific application is the inhibition of wound healing at the site of implantation of a filtering bleb or fistula to create a drainage channel for aqueous humor outflow to lower elevated intraocular pressure, which is associated with glaucoma.
Other Applications of the Microchip Device Arrays
The devices described herein have a wide variety of both medical and non-medical uses. For example, other medical applications for the microchip devices include drug delivery and sensing at sites such as the wall (interior or exterior side) of a blood vessel and on or within other organs such as the bladder. Other tissue surfaces (i.e. implantation sites) include skin (e.g., the stratum comeum, for example, where the microchip device could be used for transderrnal drug delivery) and mucosal tissue surfaces (e.g., for vaginal or buccal drug delivery), blood vessel walls (interior or exterior side), and other organs, such as the bladder.
Representative non-medical uses include industrial diagnostics, chemical research, consumer products (e.g., fragrance release), etc. Modifications and variations of the methods and devices described herein will be obvious to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to come within the scope of the appended claims.
1. A drug delivery device for implantation into a patient comprising:
- at least one device element which comprises a substrate having a plurality of discrete reservoirs disposed therein, said reservoirs containing drug molecules and a degradable matrix material which controls in vivo release of the drug molecules from the reservoirs,
- wherein the drug delivery device is adapted to conform to a curved bone tissue surface.
2. The device of claim 1, wherein the substrate is flexible and can conform to a bone tissue surface.
3. The device of claim 1, having two or more device elements attached to or integral with a flexible supporting layer.
4. The device of claim 3, wherein the flexible supporting layer comprises a biocompatible polymer.
5. The device of claim 4, wherein the biocompatible polymer comprises a polyimide, polyester, parylene, hydrogel, polyethylene, polypropylene or silicone.
6. The device of claim 3, wherein the supporting layer comprises tethers or hinges connecting the two or more device elements.
7. The device of claim 3, wherein the supporting layer is porous or provided with apertures therethrough.
8. The device of claim 1, wherein the drug molecules are dispersed in a polymeric matrix material.
9. The device of claim 8, wherein the polymeric matrix material comprises a synthetic biodegradable polymer.
10. The device of claim 8, wherein the polymeric matrix material comprises a poly(lactic acid), a poly(glycolic acid), a poly(lactic-co-glycolic acid), a poly(caprolactone), or a poly(anhydride).
11. The device of claim 1, further comprising a plurality of discrete reservoir caps covering openings in the reservoirs, wherein release of the drug molecules from the reservoir is further controlled by disintegration of the reservoir cap.
12. The device of claim 11, wherein the reservoir caps comprise a polymer which degrades in vivo to release the drug molecules.
13. The device of claim 11, wherein disintegration of the reservoir caps is actively controlled.
14. The device of claim 13, wherein the reservoir caps comprise a metal film and the device further comprises a power source and active electronics.
15. The device of claim 1, wherein the drug molecules comprise a therapeutic or prophylactic molecules.
16. The device of claim 15, wherein the therapeutic or prophylactic molecules comprise an antibiotic agent.
17. The device of claim 15, wherein the therapeutic or prophylactic molecules comprise a growth factor.
18. The device of claim 15, wherein the therapeutic or prophylactic molecules comprise fibronectin.
19. The device of claim 15, wherein the therapeutic or prophylactic molecules comprise a chemotherapeutic agent.
20. A drug delivery device for implantation into a patient comprising:
- two or more device elements which each comprise a substrate having a plurality of discrete reservoirs disposed therein, said reservoirs containing therapeutic or prophylactic molecules and a degradable matrix material which controls in vivo release of the therapeutic or prophylactic molecules from the reservoirs,
- wherein the two or more device elements are flexibly connected together by tethers or hinges.
21. The device of claim 20, which is adapted to conform to a bone tissue surface.
22. The device of claim 20, wherein the therapeutic or prophylactic molecules comprise an antibiotic agent or growth factor.
Patent History
Type: Application
Filed: Dec 1, 2005
Publication Date: Aug 10, 2006
Patent Grant number: 7582080
Inventors: John Santini (Belmont, MA), Michael Cima (Winchester, MA), Norman Sheppard (Bedford, MA), Stephen Herman (Andover, MA)
Application Number: 11/291,973
International Classification: A61K 9/22 (20060101); A61M 31/00 (20060101);


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Legion - A House Divided part 4
Walkthrough - Legion - A House Divided part 4
There's not much to say as far as specifics are concerned here, though the upcoming fight is going to take some time to navigate and survive. Basically, using that computer you just accessed has informed a whole group of Geth as to your presence, and they'll storm your position in some four or five separate waves. The waves of enemies will eventually climb up to your location, where you'll need to deal with them in close proximity via the two conduits they can use to get there (one on either side of the terminal). You may be able to sway things in your favor by remotely hacking the turrets down where the enemies spawn, as well as the ones around you. You can also snipe away at them when they're running around below, thinning their ranks. But a majority of the damage will be dealt here in close-quarters, which can make things difficult. Seek cover and take your time -- waves will never come on top of one another, so you'll have to clear one wave before the next wave's entrance is catalyzed. The waves get harder and harder, with more Hunters and rocket-toting enemies showing up, but you should be able to survive if you're smart and patient. Don't hesitate to use your best weapons and Medi-Gel here, if necessary, because this fight is no joke.
Following the successful survival of the horrendous Geth onslaught you just had to go through, another cutscene will take place. Now that all is temporarily quiet, Shepard has found the time to ask Legion just what he intends to do. Now that they have complete access to the virus the heretics were using, Legion can either reprogram it to make the Geth see their way, or outright kill the heretics, eliminating their "thought processes" from the picture all-together. Because Legion and his friends can't reach a decisive consensus, he leaves the choice up to Shepard (not surprisingly). Paragons will want to reprogram the Geth heretics in lieu of destroying them, while Renegades will want to make the opposite decision. Either way, this mission's endgame will begin in earnest as soon as a decision is made.
At the last minute, when Legion transmits the virus (or does whatever it is you decide you wanted to have done), he'll let you know that the resulting pulse will kill unshielded organic entities, which would include Shepard and your third current party member. Thus, you'll be given three minutes to get off of the ship in one piece. Doing so is fairly easy, though you're going to hit a couple of roadblocks en route. Thankfully, the door adjacent to you is now unsealed and open, and you can head on through this linear corridor to escape. Run down this corridor and take cover when some Geth arrive on-scene. Make quick work of them, and then veer leftward down the next branch. More Geth will show up here, and you can eliminate them easily as well. However, when you turn the corner once more, a gigantic Geth enemy, Geth Prime, will arrive. You've fought these guys before, but they are a true nuisance. Thin out any lesser accompanying enemies that are with Prime, and then focus solely on him. Though time is of the essence, don't push things here. Whittle down Prime's shield and barrier, and then lay the killing blows, but don't do it all at once, or he'll cut you down rapidly, and with little remorse. Once he's fallen, you should then have a clear shot at the escape hatch. You'll then witness the Normandy making its grand escape, with all crew members alive and well, and with the renegade Geth dealt with, one way or another.
When you return to the ship, however, you're going to have to deal with an automatic cutscene before the events of the previous mission have truly concluded. Shepard will be informed that Tali and Legion are currently having a fray somewhere on the ship. Shepard runs off to investigate. It seems that Legion was uploading information on the Quarian flotilla from Tali's datapad back to the Geth, and now Tali is holding Legion up at gunpoint. You'll have to navigate this simple quarrel however you'd like. There are neutral options, as well as Paragon and Renegade options. As Paragons, we were able to talk Tali down and convince her that Legion is acting in his peoples' best interest. Renegades and neutral players will have a different outcome, no doubt. Keep in mind that this friction happens automatically, whether or not you brought Tali along with you on Legion's quest or not.
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"it takes immigration of millions to hold us back"
People fear the unknown. And that fear is often exploited by those in power. An active imagination and a good speech writer can also turn our hesitations into hatred. Thus rulers enforce racially based edicts and governments justify wars - all based on drawing out what is familiar and suppressing what is different.
M.I.A. (Maya Arulpragasam) is an artist that embraces difference as a tool for spreading knowledge. Everything from the clothes she wears to the literal sound of her music is engineered to stand out amongst an increasingly cookie-cut crowd. Her purpose is not merely to be a unique artist, but she is unique precisely because her artistry seems to have purpose. With the video for "Bird Flu," a new song from her upcoming sophomore album, she has a number of things of social and political consequence on her mind.
Bird Flu is a vein of the influenza virus that has been around for centuries, but has recently re-emerged as a global threat in a few countries around the world. The exact origins of this particular strain are not necessarily known but the possibility of outbreak in South East Asia is higher than in most places. But the real reason for this has little to do with biology or geography.
Not only are there large populations of poultry on farms in the area (bird droppings are a source of infection), but the conditions and safety precautions of these countries are thought to be less than desirable - which has much to do with poverty and unstable government. M.I.A. sings/raps, "bird flu gonna get you/made it in my stable/from the crap you drop/on my crop when they pay you." Which reminds us that very few problems in the world are completely independent phenomenon, and that those in luxurious power are complicit in the death of those who are simply fighting to get by.
So M.I.A., looking absolutely radiant, decides to film her entire video among the villagers and birds that we fear as possibly diseased. She embraces goats, chickens and random children while jubilantly dancing through the town. She puts her t-shirts on the people, choreographs large-scale movements, and throws one huge party in the streets. Yet from a seamstress closing up shop to some boat hands heading off to work, M.I.A. doesn't shy from celebrating the mundane, realistic and foreign (to most viewers) aspects of these people's daily lives. In interweaving these two themes she emphasizes the common underbelly of human expression that is often obscured by our focus on difference. So while the quick pace of the editing and bright colors of the shots can be hard to follow, the pure energy of the dance sequences and watching the child M.I.A. imitators is something anyone can see and understand.
As an artist she consistently looks to contradict and challenge our heavily invested assumptions about her, where she is from and all outcast groups of people in general. In the video she dons both the bandannas traditionally associated with criminals and the police officer hats (with feathers) which tend to represent justice. Here is a singer who actually believes in the power of her work to affect real change - especially on the younger generations. She speaks of one day raising legitimate leaders, rather than the unreliable men who seem to run things nowadays. In one particularly telling shot a boy holds his mother's hand while listening to a Walkmen. They may still use cassette players in this village, but they understand great music just the same. The kids that permeate this video represent the hope that M.I.A. spreads through her work.
Throughout the song she alludes to her status of being on the brink of super-stardom, as if she is hoarding rations for that leap to the next level. And while she rebukes the idea of simply becoming a "rocawear model," she doesn't deny wanting to jump to a global stage. Instead she suggests that every time someone attempts to hold her back or literally "drops" on her ability, they are simply planting the seeds for her infectious rebuttals.
By the same token the hard-looking kids on rooftops imply that cycles of violence and hatred breed entire communities of soldiers ready to fight. The ignorance and prejudice of certain people among powerful nations will eventually have its consequences. Contemporary society seems to be asking for a type of "bird flu" by continuing to demonize and ostracize those whom they don't understand. But thankfully M.I.A.'s movement is one virus we don't have to fear. She harnesses the rebellious spirit of the forgotten streets and channels it into music that burns with passion. The knowledge and self-confidence that she brings to her brand of fun, danceable music & video is something her more popular contemporaries could use a heavy dose of.


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Sunday Sweets: You're The Top!
Hello and welcome to The Wedding Cake Topper Emporium! Thank you for choosing us for all your wedding cake topper needs! From the improper to the show-stopper, we've got every type of topper! That's our slogan. I made it up myself. Here, let me show you around...
I can see that you're a special couple, and not just any old cake topper will do, no. You need to tell the story of your love through fondant and frosting! For instance, did you meet on a boat? Get engaged in a canoe? Reeeeeally like the movie Titanic?
Submitted by Nikki and made by Torten-Lotta
Near, far, wherever you are, here is the topper for you!
No, wait, don't tell me. You're a professor at the local university. She's the campus librarian who caught your eye. Each week you headed to the library to check out The Princess Bride, hoping that she would finally notice you and strike up a conversation about Buttercup and Westley...
Submitted by Vivienne V-L. and made by Peachy Juban
...wherein, beguiled by your wit and grace, she asked to meet you for coffee later, to which you replied with a breathy "As you wish." Your eyes locked, and at that moment you fell truly, madly, and deeply, and now you crazy kids want to commemorate it all on your wedding cake topper!
(Which even comes in a handy fun-size to send home with your guests!)
But maybe I'm being a bit too specific.
Perhaps a simple set of lovebirds would do the trick?
Submitted by Emma F. and made by Flickr user sugar_rush_confections
So strikingly sophisticated!
Or perhaps you had your first date in a park? Carved your initials in a tree? (So cute!) And there happened to be a lot of sheep around?
Submitted by Angie I. and made by Jagode & Dinozavri
Ha ha, what fun! We've got the topper for you!
Or were you childhood sweethearts? (Ahh, schoolyard romance...)
Submitted by Emily B. and made by All About Cake
Why not display your devotion with our patented 'Charmingly-Childlike Doodle Topper?' It's like a chalkboard drawing come to life!
Oh, I am growing rather fond of you two. You're such a couple of characters!
By Erin Salerno
Or should I say caricatures?
If you're finding it hard to make a decision, how about a compromise? It's the secret to successful marriages, I hear! So why not let the bride choose the cake, and the groom choose the topper?
Made by Laura A.
Or maybe in this instance it was the other way around. Either way, everybody wins!
Our Serengeti Sunsets line is also quite popular, representing solidarity, security and sensuality!
Submitted by Keeley S. and made by Bubolinkata
May your marriage be blessed with all three! And may you also be blessed with a honeymoon in the Serengeti, because wow, even in cake form it's gorgeous!
Ahhh, now here is one of my favorite toppers. Remember when your man went all Edward Cullen on you, and composed you your very own song? This beautiful topper can be an ode to your love, and an ode to your ode! (Does that make sense? It made sense in my brain. You know, before I said it out loud).
Submitted by Kristy L., and made by The Cupcake Gallery
Look at the bride's delicate little curl of hair! So demure and delightful, I think I'm getting weepy.
And finally, if you're looking for something over-the-top, sometimes it helps to look at the very bottom.
The bottom of the sea, that is!
Submitted by Kate O. and made by deviantART user ~The-EvIl-Plankton
"Darling it's better, down where it's wetter, under the sea!"
You can't see it, but the octopus is actually shaking eight tiny maracas*.
*Ok, not really. But wouldn't that be awesome?
Well, thanks so much for visiting The Wedding Cake Topper Emporium. Remember, we're your one-stop-cake-topper-shop! Shop till you drop at our topper shop! 'Cuz we don't sell no slop! At the hop! Pop pop, don't stop!
Yes, I'm done.
Have a Sweet to nominate? Then send it Sunday Sweets [at] Cake Wrecks [dot] com.


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This middling horror-genre item from the Matt Damon-Ben Affleck-Chris Moore Project Greenlight folks is set inside the lonely Beer Trap Tavern, which even people in the middle of nowhere would deem remote. "Feast" follows a common horror flick recipe (people under siege from hungry monsters--so much for Greenlight's search for originality), adding a dash of humor to keep things from becoming too much of a checklist.
New characters arrive with a sometimes clever freeze-frame biographical pop-up--including a (not always accurate) life expectancy prediction. The characters fill a standard checklist: a salty bartender (Clu Gulager, father of the first-time director), a seen-it-all/done-it-all old woman (Eileen Ryan), a nefarious boss man (Duane Whitaker), a single-mom waitress who condescends to sex with the boss man because she needs the money (Krista Allen), the son who moves from his mom-assigned hiding spot to give us a fright (Tyler Patrick Jones), a Kewpie-doll waitress called Honey Pie who wants better things (Jenny Wade--promoted from her role as Cupcake in "The Ice Harvest"), annoying business guy/motivational speaker (Henry Rollins), a guy in a wheelchair who develops a clever escape plan (Josh Zuckerman), jerky brother of the wheelchair guy whose jerkiness is forgiven because he loves his brother (Balthazar Getty), a few folks for appetizers and, of course, monsters with a hunger for humans. Check, and double-check.
Now the plot: Shotgun-toting Hero (Eric Danes), carrying a decapitated critter's head, bursts through the door warning of imminent danger. Monsters launch first attack, causing confusion and some friendly-fire casualties along with those chomped by monsters. Hero's wife, Heroine (Navi Rawat), arrives and takes control. Oh no, the phone was destroyed and cells don't work out here! Let's split up, so some can go upstairs to use the shortwave radio, while other head for more ammo in the basement. Splitting up is always a good idea, right?
You get the idea.
When monsters attack, the camera gets all jerky, creating the horror effect known as motion sickness. There's blood--lots of spurting, waitress-dousing blood--so that soon Honey Pie needs to peel down to her skivvies to wash off and arouse the boys. She's real purty. Yup.
Fans of the horror-comedy genre probably will enjoy this movie (which, for the home-entertainment crowd, will be available on DVD Oct. 17), even though chuckles outnumber scares. There are a few near-surprises that are OK. The best news is, there's room for a sequel--and don't run out when the credits begin to roll.


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Redefine Natural Skin Care With Painted Earth's Blueberry Cranberry Oxygen Scrub
Description: Redefine Natural Skin Care Infused with blueberries and cranberries, this all natural facial scrub exfoliates and restores skin back to its optimal, radiant state. Loading skin with a variety of natural supplements, including anti-oxidants and Vitamin C, this gentle scrub decongests pores, leaving skin smooth and supple after just one use. "This is an amazingly thick scrub that looks good and smells delicious."
Price: $28.00 to $29.00


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Activists + > Music Index
Leona Lewis turns down 1m-pounds to open the Harrods sale in anti-fur protest
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Leona Lewis turns down 1m-pounds to open the Harrods sale in anti-fur protest
By Daily Mail Reporter
Fur concern: Leona Lewis is against animal cruelty
The X Factor winner turned chart-topping recording artist Leona Lewis rejected a 1m-pound offer from Harrods boss Mohammed Fayed to open this year's summer sale because the department store sells fur.
A staunch vegetarian since the age of 12, the Bleeding Love singer stuck to her principles and turned the lucrative offer down, the job going instead to 52-year-old Sex And The City star Kim Cattrall.
Lewis, who was this year voted animal rights campaign Peta's World's Sexiest Vegetarian Celebrity, said: 'I'm totally against animal cruelty.
'I don't have clothes, shoes or bags made from any animal products.'
Harrods, which declined to comment, is the only department store in the UK that continues to sell fur, and is regularly targeted by animal cruelty campaigners.
Its sales are traditionally opened by an A-list female celebrity.
Most of those invited have jumped at the opportunity to parade around Knightsbridge in a horse and carriage before being given a private tour of the discounted goods by Mr Fayed himself.
Last summer, Hollywood actress Sarah Michelle Geller, 31, was given the honour, while singer Lily Allen, 23, opened the winter sale last December.
Other leading ladies who have cut the ribbon include Victoria Beckham, 34, Eva Longoria, 33, Christina Aguilera, 27, and Lucy Liu, 39.
Meanwhile, Lewis is reportedly in talks with Bhs boss Sir Philip Green about creating a range of nonleather bags and shoes for Topshop.
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