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Certified Organic and Fair Trade. This is one of those lesser known coffees that often surprises with its wonderful aroma and rich taste. In the highlands of Nicaragua, the fertile rich soils and temperate climates are ideal for producing high quality gourmet coffee. The coffee is grown at approx. 1200 to 1400 meters above sea level in the Matagalpa region. The coffee trees are mostly of the older Bourbon variety with some Caturra and a small amount of Catuai. The coffee is certified organic, shade grown by OCIA Iinternational (The Organic Crop Improvement Association). The complex aroma, medium body, slight wineyness and clean finish are unique characteristics that only a great Nicaraguan coffee can offer. Recommended roast: medium to Full City or French.
Related Products
FreshRoast Plus Home Coffee Roaster -
Nesco Smokeless Home Coffee Roaster -
Other Items from Nicaragua Matagalpa (Fair Trade)
Nicaragua Matagalpa Green Coffee Beans, 2 Lb. Bag -
Nicaragua Matagalpa Green Coffee Beans, 5 Lb. Bag -
Nicaragua Matagalpa Green Coffee Beans, 1 Lb. Bag -


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- Willamette
- Atkinson Graduate School of Management
- Full-Time MBA Formats
- Formats
- Bachelor of Arts/MBA
Bachelor of Arts/MBA
Willamette's Bachelor of Arts/MBA program combines the powerful learning experiences of Willamette University's College of Liberal Arts and Atkinson Graduate School of Management.
As a national leader in early career MBA education, the Willamette MBA emphasizes experiential learning and is specifically designed to help early career students build the knowledge, work experience and career management tools they need to prepare for rewarding careers in entrepreneurial, business, consulting, government and not-for-profit enterprises. Students develop:
- effective communication, analytical and problem-solving skills
- an understanding of the principles of management every manager should know
- in-depth knowledge in one or more career areas of interest
- a resume of real professional experience
- the tools of leadership, team work, networking and professional behavior
BA/MBA Curriculum
BA/MBA students participate in an MBA curriculum comprised of a strategic combination of required and elective course work. Students will participate in all of the following required courses.
- GSM 5103 – Data Analysis, Modeling and Decision Making
- GSM 5104 – Managing Individuals, Teams and Organizations
- GSM 5105 – Accounting for Managers
- GSM 5107 – Marketing: Creating Satisfied Customers
- GSM 5108 – PACE I : Consulting for Not-for-Profit and Government Organizations
- GSM 5109 – PACE II: Developing an Entrepreneurial Venture
- GSM 5110 – Economics, Finance and Markets
- GSM 5114 – Operations and Systems Management
- GSM 6121 – Politics and Public Policy for Managers
- GSM 6122 – Leading Ethical, Socially Responsible and Sustainable Organizations
- GSM 6123 – Strategic Management
- GSM 6___ – MBA Experiential Elective
- GSM 7251 – Internships for Management
In addition to the required courses, BA/MBA students will complete an additional 21 credits of MBA elective course work. Students utilize their elective courses to pursue one or more of their individual career areas of interest in:
|Operations, Analysis and Systems
|Organizational Analysis
|Global Management
|Public and Not-for-Profit Management
|Human Resources
|Sustainability Management
Curricular Path for BA/MBA Students
Students admitted to the BA/MBA program begin MBA studies fall semester of their senior year.
BA/MBA students may begin the MBA program with zero, one or two required CLA courses remaining to be completed during the first year of the MBA program. Students who complete one or two CLA courses during the first year of the MBA program (senior year), will postpone one or two first-year MBA courses to the fifth year of study.
At the end of the senior year, BA/MBA students who have successfully completed all College of Liberal Arts graduation requirements (including successful completion of MBA credits
required for completion of the BA degree) are awarded the Bachelor of Arts degree.
During the fifth year of study, BA/MBA students complete the second year MBA curriculum and any remaining MBA courses that were postponed during their first year of the MBA program.
At the end of the fifth year, BA/MBA students who have completed all BA and MBA graduation requirements are awarded the MBA degree.
Click to see the two year curricular path for BA/MBA students needing zero CLA courses, one CLA course, and two CLA courses when they begin the BA/MBA program.
Advice for Students Considering the BA/MBA
- Start the planning process early!
- Contact your CLA academic advisor and plan your courses to meet the BA/MBA credit and course requirements of your major.
- Contact the Willamette MBA Admission office with your questions.
- It will be helpful to have completed at least one course in mathematics, one course in economics, and a course in psychology or sociology.
- Build a background of leadership and experience in organizations through internships, campus/community activities, athletics, part-time work, etc.
- Recognize the BA/MBA is an experiential, challenging and demanding program designed for highly motivated and mature students who have career interests in management.
The BA/MBA program is a great investment in your future. Completing the BA/MBA program accelerates your career entry into professional positions, provides increased salary opportunities earlier in your career, and saves a year of educational and living expenses because you complete your BA and MBA degrees in just five years of education rather than six.
Download PDF-Format
Early Career/Career Change
MBA Brochure
BA/MBA Fast Facts
- Jump start your career - start your MBA your senior year
- Use any WU major to prepare for your MBA
- Develop your knowledge and build your professional experience
- Prepare for careers in business, government or not-for-profit enterprises
- Complete your BA and MBA in just 5 years
BA/MBA Return on Investment
The BA/MBA program is a great investment in your future. Completing the BA/MBA program accelerates your career entry into professional positions, provides increased salary opportunities earlier in your career, and saves a year of educational and living expenses because you complete your BA and MBA degrees in just five years of education rather than six.
Learn More About the BA/MBA
Application Process for the BA/MBA
Tuition, Scholarships and Loans for the BA/MBA
BA/MBA Advisor Guide for CLA Faculty and Staff
The BA/MBA Advisor Guide provides helpful program information for CLA faculty and staff who advise Willamette undergraduate students interested in the BA/MBA program.
Contact Us with Your Questions
We are available to help you explore Willamette University's BA/MBA program and answer your questions. Email firstname.lastname@example.com, call 503-370-6167 (toll free in the U.S. 866-MBA-AGSM), participate in our online chats, and visit us on campus.

subset: commoncrawl


text: Smoked Cocoa #4 is a bluish black, so it looks almost gray at times, but it is still quite a dark shade. It looked really deep in the pan, but this did not translate in application as the pigmentation was very, very weak. The texture is dry, stiff, and a total pain in the behind to use. It didn't want to apply smoothly, and blending this shade out took far more patience than I had. It looked noticeably faded after six hours of wear. There was a very fine hint of navy micro-shimmer in the shade that I didn't really catch in my permanent pan of Nehru, so while I think they are certainly similar (especially when applied–those micro-shimmers never show up!), they may not be the same shade. MAC Fashion Legend is darker, less blue. LORAC Black is darker. MAC Typographic is grayer, matte. bareMinerals Amnesia is darker. See comparison swatches.


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Trusted Expert Free Valuation: Get started with
free research and validation
Inside heritage
in our May 15 American Indian Art , Pre-Columbian & Tribal Art Auction
Petrified Wood, one of nature's oldest, most beautiful, and rarest creations, is one of those phenomena that takes a little more than a few hours spent outside to understand.
Heritage Events Calendar
DoubleTree San Antonio Airport
37 NE Loop 410 | San Antonio, TX 78216y
Friday, July 17: | 9:00 AM - 4:00 PM
Saturday, July 18: | 9:00 AM - 4:00 PM
Sunday, July 19: | 10:00 AM - 2:00 PM
The National Sports Collectors Convention - Chicago
The White Plains East Coast National
Long Beach Coin, Stamp and Collectibles Expo
Beverly Hills Appraisal Day
September 18 - 19: 9:00 AM - 4:00 PM
September 20: 10:00 AM - 2:00 PM
We are proud to offer our Heritage Live!® software on all auctions marked as:
This software allows you to participate in a live Heritage auction from the comfort of your home or office over the Internet. You will be able to browse and BID LIVE during the auction event against other Internet bidders and floor bidders. Plus, Signature auctions also include live streaming video and audio.
Video Series


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The gates opened at 6 p.m. Tuesday, Oct. 9, and the fair continues through Saturday. Ticket prices remain the same as last year with adult admission $5, students ages 6-18 pay $4, and children under 6 are admitted free. Every night is Family Night, and the price of an armband allows the wearer to ride all they want until the gates close.
The Jones County Lions Club has a Facebook page, and daily fair updates will be posted including any price changes and weather updates.
The fair is held at the Lions Club fairgrounds located on Highway 18 East, about a mile from downtown Gray. The Lions Club has been in existence since 1968 and has been bringing the fair to the community each year for 43 years. The midway is once again provided by Dixieland Carnival.
A big draw for the Lions Club Fair is the safe atmosphere compared to similar events in nearby counties. People travel to Jones County so they can relax in a family environment while their children enjoy the rides and games.
For the full story, pick up a copy of this week's newspaper or subscribe to our e-Edition at http://ee.jcnews.com.


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The gaming industry, and gaming media, is wrong to label upset consumers as 'entitled' or ignore the investment of fans beyond simply spending their hard-earned cash.
Colin Moriarty has a peculiar video up at IGN. In it he talks about the 'mass hysteria' following the release of Mass Effect 3.
Colin is perplexed by the angry reaction of fans over what they perceive as a terrible, horrible, no good, very bad ending. Worse, he says, fans want BioWare to change that ending.
The horror.
A DLC that 'fixed' the ending would not be unprecedented. Bethesda did something similar with Fallout 3.
To be fair, I do worry that an alternative-ending-DLC that was not free might be perceived by some as the plan all along – a deliberately unsatisfying (and possibly unreal) ending followed by the "real" ending a few months later for another $10. Maybe not a horrible idea on its face, but with the rest of the tumult and controversy surrounding the game – probably a pretty terrible idea.
But I digress.
Colin also glosses over entirely the fact that players had been led to believe that the choices they made in all three games would affect the outcome of the final chapter. The one resounding complaint over Mass Effect 3 is that gamers feel as though their choices made no difference. That unique Commander Shepard was not so unique after all.
Veering quickly away from Mass Effect altogether, Colin drums up the notion of gamer "entitlement." Games are cheaper now than ever before, he argues – which, when you adjust for inflation, is pretty much true.
But many gamers would also point out that many titles are shorter.
And why shouldn't games be cheaper now? Lots of our technology has gotten cheaper as increased competition and efficiency (including outsourcing) has brought costs down. We buy more technology than ever before, including more games.
The video game industry has also grown enormously. Estimates have the game industry passing $70 billion by 2015.
How games are sold has also changed. Now gamers have many different options, including monthly subscriptions and free-to-play games with paid extra content. It's difficult to gauge the actual cost of games once all the DLC and various subscription costs are taken into account.
But the notion that angry or disappointed fans are displaying a sense of "entitlement" is deeply misguided, and perhaps unique to the gaming industry – a myth perpetuated by the industry and, apparently, by many journalists who cover the industry. Consumers who purchase your goods or services are not acting like they're "entitled" to something that they have no right to. This implies that they did nothing to deserve their frustration and have no right to complain. It's a term that in this usage is interchangeable with "spoiled."
It's also completely wrong-headed.
Colin says that there's a "proper" way to complain, but he never really says what that is beyond not buying games or DLC that you don't like. That's fine advice, as far as it goes, but I'm not sure why it's "proper" whereas asking for a new ending is the act of a bunch of selfish children stomping their feet.
What Colin is really saying is that gamers have no investment in the games they play and love (or hate.) It's the same attitude you hear in politics when someone says "If you don't love America, why don't you go somewhere else?"
But gamers really do have investment in their games – often more than in television, a medium where you hear plenty of discontent from fans (yet no television reviewers, to my knowledge, calling the fans "entitled.") Gamers are often involved in modding games after release, often with the blessing of the developers. New texture packs, characters, or maps are common in games like Skyrim or Valve's catalogue.
The relationship between gamer and developer, and across the entire community, is a social and participatory relationship. Gamers may not work on the actual development of a title like Mass Effect 3, but they've invested their time and money and support into that franchise and there is no one "proper" way to complain about the ending. Nor are angry fans merely "entitled" or "spoiled" simply for angrily voicing their concerns or asking for a new ending.
Follow me on Twitter or Facebook. Read my Forbes blog here.


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|Renaissance Hotels Pittsburgh properties are listed below. Search for cheap and discount Renaissance Hotels hotel rates in Pittsburgh, PA for your business gathering or personal travels. We list the best Renaissance Hotels Pittsburgh hotels & lodging so you can review the Pittsburgh Renaissance Hotels hotel list below to find the perfect place.
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USDA Announces National Dairy Board Appointments
AMS No. 223-12
Sam Jones-Ellard (202) 660-2268
WASHINGTON, Oct. 10, 2012 Agriculture Secretary Tom Vilsack has announced the appointment of 12 members to the National Dairy Promotion and Research Board. All appointees terms will begin Nov. 1 and end Oct. 31, 2015.
"These appointees represent a cross section of the dairy industry and I am confident that the industry will be well served by them," said Vilsack.
Newly appointed members are: Lawrence A. Hancock, Texas; Lanette M. Harsdorf, Wisconsin; Edward J. Jasurda, Wisconsin; David Veenhouwer, Idaho; and Marilyn K. Hershey, Pennsylvania.
Reappointed to serve second terms were: George Marsh, Oregon; Ray S. Prock, Jr., California; Arlene J. Vander Eyk, California; Paul A. Fritsche, Minnesota; Mark E. Erdman, Illinois; Susan D.K. Troyer, Indiana; and Ronald R. McCormick, New York.
The board was established under the Dairy Production Stabilization Act of 1983, as amended, to develop and administer a coordinated program of promotion, research and nutrition education. The 38-member board is authorized to design programs that strengthen the dairy industrys position in the marketplace.
The Secretary selected the appointees from nominations submitted by eligible producer organizations, general farm organizations, and qualified dairy products promotion, research or nutrition education programs.
Research and promotion programs are industry-funded, authorized by Congress, and date back to 1966, when Congress passed the Cotton Research and Promotion Act. Since then, Congress has authorized the establishment of 20 research and promotion boards. They empower farmers and ranchers to leverage their own resources to develop new markets, strengthen existing markets, and conduct important research and promotion activities. AMS provides oversight, paid for by industry assessments, which ensures fiscal responsibility, program efficiency and fair treatment of participating stakeholders.
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Chattanooga Lady Mocs Basketball Postgame Quotes
Chattanooga at Davidson
John M. Belk Arena - Davidson, N.C.
Friday - Jan. 18, 2013
Head Coach Wes Moore:
Thoughts on the game:
"We did a good job defensively. They are a very good team and you hold them to 56 points, you can't argue with that."
On Kylie Lambert's three at the end of the first half:
"They both went with Kayla Christopher off that double-pick and that left Kylie wide open. We were fortunate that happened. Kylie was 5-7 from the field, 2-3 from 3-pt. line. Alex Black hit a couple of big threes for us too in the first half when we were struggling. Kylie - 12 points, five boards - I know she was in some pain with shin-splints...late in the half we took her out. She was struggling, but she is a warrior. She hung in there and battled when we needed her."
General comments on the win:
"It was a good team win. There were a lot of people that came in and did some good things. Meghan Downes hit a big jump shot when we were struggling a little bit. Taylor Hall went and got seven boards and led us in rebounding. Alex got six defensive boards at the point guard position. A lot of little things...and that is what you have to do to win a game like this."
On the play of freshman Alicia Payne:
"I left Alex out there a little too long and the assistants said we needed to give her a blow and get Red back in there. Red did a solid job. They were pressing and she ended up with no turnovers."


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This wasn't exactly the way Erica Keats planned her career.
While earning a master's degree in audiology from the University of Virginia and a doctor of audiology degree from the University of Florida, she had worked in that field since 2001.
But a little more than a year ago, Keats, 30, was laid off from her position as an audiologist at A&A Hearing Group in Frederick.
In searching for work in her field, she discovered another opportunity dear to her heart: owning a Kidville franchise. The indoor enrichment facility allows newborns to 6-year-old children a chance to tumble on mats, jump on a trampoline, climb on a rock wall, go down a zipline, dance, sing, listen to a band and take classes.
When the Kidville facility in Rockville's Fallsgrove Village Center has a pre-opening band performance on April 26 and grand opening May 4, Keats will go from an environment where she helped people regain their hearing to one where some might lose hearing ability.
"Perhaps I will still have some use for my audiology education here," she smiled. "But it's not really that loud — at least not as loud as a Chuck E. Cheese."
Making such a career change after a layoff is not uncommon these days, especially coming off the worst recession since the 1920s Great Depression. The average person born between 1957 and 1964 changed jobs 11 times from age 18 to age 46, though not all of those were career changes, according to federal labor figures.
The number of workers laid off declined by 8 percent nationally last year from 2011, but 1.7 million employees still lost their jobs in 2012, according to federal labor figures. That figure was down 40 percent from the peak of 2.8 million layoffs in 2009.
Keats said several people she knew are in the midst of career changes, including some opening Kidville franchises in other states. She also has a friend in Mount Airy changing careers to open a Goddard School preschool program later this year.
"It's not unusual these days," she said.
Keats, who has a 2-year-old and a 4-year-old, had taken her children to a Kidville in Bethesda. The drive was a distance from their home in Urbana, but as she said, "My son really loved the music class."
So she discussed opening a Kidville closer to home with her husband, Matthew Keats, a veterinarian who works in Gaithersburg. He was supportive, and she ran with the idea.
Kidville, which started in New York about a decade ago, has more than 30 franchises nationally and a few in other countries. The Fallsgrove one is the second in Montgomery County.
The costs of opening a franchise, including fees, equipment, marketing materials, training and computer software, is more than $230,000, according to the company website.
Besides a gym, the facility has a music and enrichment class room, a dance and art studio, and retail space. There is a kitchen for employees and to accommodate birthday parties that can be for children as old as 9. Some franchises have hair-cutting salons.
"It's a one-stop shop for kids and family entertainment," Keats said.
The 4,700-square-foot space in the corner of the Fallsgrove shopping center — which used to be a salon — is near Wing Stop and a FedEx office.
Keats spent several months in the corporate office in New York being trained and is hiring about 20 employees, including professional musicians to perform in the Rockin' Railroad Band.
"It's a huge learning experience," said the first-time business owner.


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Impact of land-use on savanna vegetation and populations of non-timber forest product-providing tree species in West Africa
Savannas are the most important timber and non-timber forest products (NTFPs) providing ecosystems in West Africa. They have been shaped by traditional human land-use (i.e. agriculture, grazing, and harvesting) for thous
Savannas are the most important timber and non-timber forest products (NTFPs) providing ecosystems in West Africa. They have been shaped by traditional human land-use (i.e. agriculture, grazing, and harvesting) for thousands of years. In the last decades, land-use has drastically changed due to the rapid population growth and the growing production of cash-crop in West Africa and this process is still continuing. The percentage of land intensively used for agriculture has increased, while the length of fallow periods has decreased. Such changes have enormous ecological, economic, and social consequences. In the context of land-use changes, there is an urgent need to better understand and evaluate the impact of land-use on savannas. Such an understanding provides insights on appropriate management activities that ensure the maintenance of savannas and guarantee the availability of savanna products for subsistence and commercial use of rural West African people. The major objective of the present thesis was to study the impact of land-use on savanna vegetation and diversity as well as on populations of two important NTFP-providing tree species in a semi-arid area in West Africa. The study area was located in the south-eastern part of Burkina Faso and comprised the protected W National Park and its adjacent communal area. In the first study (chapter 2), I investigated in cooperation with a colleague from Burkina Faso (Blandine Nacoulma) the impact of land-use on the savanna vegetation. We analyzed which environmental factors determine the occurrence of the vegetation types and investigated the effect of land-use on vegetation structure and the occurrence of life forms and highly valued tree species. Furthermore, we tested whether land-use has an impact on plant diversity pattern and if this impact differed between the vegetation types and layers (woody and herb layer). Vegetation relevés were performed and the vegetation and plant diversity of the protected W National Park were compared with those of its surrounding communal area. Our results reveal five vegetation types occurring in both areas. Elevation and physical soil characteristics and thus soil water availability for plants played the most important role for the occurrence of the vegetation types. The influence of land-use on plant diversity differed between the five vegetation types and the two layers. The impact was highest on the vegetation types with the most favorable soil conditions for cultivation and lowest on rocky habitats with poor soils. While the diversity of the woody layer was increased under human land-use, the diversity of the herb layer was diminished. Overall, as land-use effects were not only negative, our findings suggest that land-use does not automatically lead to a loss of plant species and to a degradation of savanna habitats. We conclude that both protected and communal areas are of great importance for the conservation of savanna vegetation and diversity. Our study highlights furthermore the importance of different management strategies for each vegetation type. In the following two studies (chapter 3 and 4), the impact of land-use - and in particular of harvesting - on populations of Adansonia digitata L., the baobab tree, and Anogeissus leiocarpa (DC.) Guill. & Perr. was examined. These two tree species were chosen as they provide several NTFPs for the local population and as they show different levels of human protection and opposed life histories. Thus, they may react differently to land-use. Stands of the protected W National Park were compared with those of its surrounding communal area (in fallows, croplands, and villages). I applied dendrometric methods to study the population structures and combined it with rates and patterns of NTFP-harvesting (debarking and chopping/pruning). Furthermore, the impact of land-use and harvesting on the fruit production of A. digitata and on the sprouting ability of A. leiocarpa were studied. The inverse J-shaped size class distribution curve indicates that the stands of A. digitata were in a healthy state in the park, while the low number of smaller size classes in fallows, croplands, and villages may give evidence of an ageing population. However, a high number of seedlings were recorded in villages. The stands of A. leiocarpa were also in healthy states in the park and likewise in fallows. In contrast, the absence of saplings gives evidence of a declining population in croplands. Both species were strongly harvested by local people and harvesting was tree size-specific. Pruning in interaction with tree-size had a significant impact on fruit production of A. digitata. While smaller trees were more vulnerable to pruning, bigger trees benefited from slight-pruning. A. leiocarpa had a great ability to respond to chopping by sprouting. The sprouting ability increased even with higher chopping intensity. Results suggest that despite the intense harvesting and the land-use impact, populations of both species are still well preserved. While A. digitata can withstand the harvesting and land-use pressure by its longevity, extremely low adult mortality rates, and particularly due to positive human influences, A. leiocarpa is able to withstand the use pressure by its fast growing, high recruitment, and high sprouting ability. I conclude that a none protected tree species (A. leiocarpa) might not necessarily be at higher risk to the harvesting and land-use impact than a protected tree species (A. digitata) as the adverse impact of harvesting and land-use can be compensated by its specific life history. Important additional information to such ecological findings can be provided by local people. Learning from traditional knowledge and management systems of local people will help to produce culturally and ecologically reasonable conservation and management strategies. Thus, I investigated local uses and management strategies of A. digitata and A. leiocarpa in the last two studies (chapter 5 and 6). Quantitative ethnobotanical surveys among the Gulimanceba people were conducted in the communal area in order to document uses of the different plant parts, harvesting modes, perceptions about the population status, and conservation status of both species. Hereby, differences in knowledge between gender, generations, and people from different villages were tested. Interviews reveal that both species are harvested for multipurpose and emphasize the high importance of both species for local people. Especially the leaves and fruits of A. digitata add valuable minerals and vitamins to the otherwise micronutrient-"poor" staple crops of the Gulimanceba people. In comparison with other studies in West Africa, it has turned out that people in this area could benefit even more from A. leiocarpa, e.g. for dyeing of clothes, for treatment of malaria and skin problems. Local knowledge did not differ between genders and generations, while it slightly differed between people from different villages. The lack of age differences suggests that the traditional knowledge about these two species is passed on from one generation to another. Differences between people from different villages might be explained by influences from the neighboring countries Niger and Benin. Current local harvesting modes and management strategies of both species resulted in sustainable use. However, ongoing land-use intensifications require adapted harvesting and management techniques to guarantee the persistence of these economically important species. These results provide, in combination with the ecological findings (chapter 3 and 4), appropriate management recommendations for A. digitata and A. leiocarpa that are reliable under currently practiced management strategies.…
|Katharina Schumann
|Rüdiger Wittig, Georg Ziska
|Document Type:
|Doctoral Thesis
|Date of Publication (online):
|Year of first Publication:
|Publishing Institution:
|Univ.-Bibliothek Frankfurt am Main
|Granting Institution:
|Johann Wolfgang Goethe-Univ.
|Date of final exam:
|Release Date:
|HeBIS PPN:
|Institut für Ökologie, Evolution und Diversität
|Dewey Decimal Classification:
|580 Pflanzen (Botanik)
|Biologische Hochschulschriften (Goethe-Universität)
|Licence (German):
|Veröffentlichungsvertrag für Publikationen


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Devices are provided for the controlled exposure or release of contents stored in hermetically sealed reservoirs. The devices comprise a primary substrate having a front side and a back side, and including one or more hermetic sealing materials; a plurality of reservoirs in the primary substrate positioned between the front side and the back side; reservoir contents, which comprise chemical molecules (such as drugs) or a secondary device (such as a glucose sensor), located inside the reservoirs; a hermetic sealing substrate having a surface composed of one or more hermetic sealing materials; and a hermetic seal formed between and joining the primary substrate and the hermetic sealing substrate, wherein the hermetic seal independently seals the reservoirs.
1. An implantable medical device comprising:
a primary substrate having a front side and a back side, and including one or more hermetic sealing materials;
a plurality of reservoirs in the primary substrate positioned between the front side and the back side;
a plurality of biosensors disposed in the reservoirs;
a plurality of discrete reservoir caps sealing the reservoirs at the front side of the primary substrate;
a hermetic sealing substrate having a surface composed of one or more hermetic sealing materials;
a plurality of hermetic seals formed between and joining the primary substrate and the hermetic sealing substrate, wherein each of the hermetic seals individually seals one of the reservoirs at the back side of the primary substrate; and
means for selectively disintegrating the reservoir caps to expose the biosensors to the environment outside of the reservoirs.
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32. An implantable medical device comprising:
a primary substrate having a front side and a back side, and including one or more hermetic sealing materials;
a plurality of reservoirs in the primary substrate positioned between the front side and the back side;
a plurality of biosensors disposed in the reservoirs;
a plurality of discrete reservoir caps sealing the reservoirs at the front side of the primary substrate;
a hermetic sealing substrate having a surface composed of one or more hermetic sealing materials;
a plurality of hermetic seals formed between and joining the primary substrate and the hermetic sealing substrate, wherein each of the hermetic seals, at the back side of the primary substrate, isolates a first at least one of the discrete reservoirs from a second at least one of the discrete reservoirs; and
control circuitry and a power source for selectively disintegrating the reservoir caps to expose the biosensors to the environment outside of the reservoirs.
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This application is a divisional of U.S. application Ser. No. 10/184,259, filed Jun. 28, 2002, now U.S. Pat. No. 6,827,250 which claims benefit of U.S. Provisional Application No. 60/301,686, filed Jun. 28, 2001. These applications are incorporated herein by reference.
This invention is generally in the field of implantable miniaturized devices that provide controlled delivery or exposure of molecules or smaller devices. More specifically, the invention relates to implantable microchip devices.
U.S. Pat. No. 5,797,898 to Santini, et al. describes active or passive microchips for the delivery, i.e. release, of molecules such as drugs. These microchip devices contain reservoirs filled with the molecules to be released. In some embodiments, the reservoir openings must be sealed after they are filled to prevent leakage from or between any of the reservoirs.
One approach for sealing small reservoirs is to use a waterproof epoxy or other material impervious to any fluids surrounding the device. It is generally important, however, to avoid contacting the reservoir contents, particularly drug molecules, with chemical adhesives. The use of a chemical adhesive sealant may necessitate additional testing to determine the presence and nature of any interactions between the chemical adhesive and each drug or other chemical to be contained in and released from the reservoirs. The use of chemical adhesives also may require long times, high temperatures, and/or exposure to ultraviolet light in order to cure completely, processes that may degrade sensitive drug or chemical molecules in the reservoirs.
It is known that such adhesives and polymers generally cannot function as true hermetic seals over extended periods of time. Hermeticity, however, would be highly advantageous for microchip reservoirs to provide a controlled environment until the reservoirs are activated (i.e. opened). In fact, hermeticity likely is essential for most long term in vivo applications of such microchip devices. It would therefore be beneficial to provide methods of hermetically sealing a microchip device, including any control electronics and power source packaged with the device.
While hermetic sealing techniques are commonly found in implantable devices, such as pacemakers and cochlear implants, new or improved hermetic sealing methods are required for hermetically bonding a microchip reservoir device to an outer enclosure/packaging structure, which serves to protect the internal device components while also allowing a portion of the microchip reservoir device to contact/interface with the environment.
It would be desirable for seals incorporated within a microchip device for in vivo applications to prevent communication of drug, body fluids, or other substances between reservoirs or from the reservoirs into other portions of the microchip device. In addition, the seal desirably should withstand mechanical forces and chemical attack over time, and should not interfere with the process of opening reservoir caps and other aspects of the release processes. The materials forming the seals desirably are biocompatible, biostable, have very low or no permeability to water vapor and other materials, and should not react with the drug or other reservoir contents. Furthermore, the process of sealing should not degrade the reservoir contents, for example due to high temperatures, excessive vibratory forces, or exposure to incompatible chemicals or materials. It therefore would be advantageous to provide devices and methods for sealing the reservoirs of microchip devices for the controlled release of drugs and other molecules, which satisfy these several sealing parameters.
Methods are provided for hermetically sealing the reservoirs of microchip devices and for hermetically sealing the substrate assemblies in a hermetic packaging structure. In one embodiment, the method comprises (1) providing a primary substrate having a front side and a back side, the substrate comprising a plurality of reservoirs positioned between the front side and the back side, each reservoir being loaded with molecules or a secondary device for controlled release or exposure, the reservoirs having at least one opening in need of sealing, the primary substrate including one or more hermetic sealing materials; (2) providing a hermetic sealing substrate having a surface composed of one or more hermetic sealing materials; (3) positioning the hermetic sealing substrate over the reservoir openings and contacting said hermetic sealing materials of the primary substrate with said hermetic sealing materials of the hermetic sealing substrate; and (4) applying energy or a mechanical force to the contacted sealing materials effective to form a hermetic seal between the hermetic sealing substrate and the primary substrate to hermetically seal the reservoir openings.
In one embodiment, the energy can be applied through a welding process, such as one that comprises ultrasonic welding or laser welding. In another embodiment, the energy can be applied by heating to cause a reaction between the hermetic sealing materials of the primary substrate and the hermetic sealing materials of the hermetic sealing substrate. Preferably, the reaction is a eutectic reaction, for example, to form a eutectic bond comprising a eutectic composition selected from gold/silicon, gold/germanium, gold/tin, gold/indium, lead/tin, lead/indium, and platinum/silicon. The heating could comprise, for example, localized resistive heating using a patterned resistor, or could be provided by a laser.
In still other embodiments, the hermetic sealing material of the hermetic sealing substrate can comprise a metal gasket and a compressive force could be applied in an amount effective to deform the metal gasket around each reservoir opening. Tapered structures extending from the primary substrate surface could be used to concentrate the compressive forces at areas around the reservoir opening.
The hermetic sealing substrate preferably comprises or consists of a metal film or metal foil. In other embodiments, the hermetic sealing materials of the primary substrate, of the sealing substrate, or both, can comprise, for example, a silicate glass and/or a metal selected from gold, platinum, titanium, palladium, tantalum, aluminum, and stainless steel. Preferably, the primary substrate comprises a hermetic material selected from the group consisting of ceramics, metals, silicon, or glasses.
In some embodiments, the hermetic sealing substrate is a reservoir cap which can selectively be disintegrated to release or expose the molecules or secondary device. In a preferred embodiment, the molecules are drug molecules. In one method to form reservoir caps, the front side of the substrate comprises metal traces and the hermetic sealing substrate is welded onto the metal traces. In other embodiments of the sealing method, the reservoir end distal the opening in need of sealing comprises the reservoir caps.
In one embodiment, the method includes the optional step of applying a protective coating material, such as a polymer, over the hermetic sealing substrate, on a surface distal the surface that contacts the hermetic sealing materials of the primary substrate, before or after the reservoirs are hermetically sealed.
In another embodiment, the hermetic sealing substrate is a multi-layered structure comprising a glass layer which is anodically bonded to the primary substrate, wherein the glass layer has apertures in communication with the reservoirs. The multi-layered structure can further include a patterned metal layer which is anodically or eutectically bonded to the glass layer on the side distal the primary substrate, wherein the patterned metal layer has apertures in communication with the reservoirs and with the apertures in the glass layer. The multi-layered structure can further comprise a metal foil which is laser welded to the patterned metal layer on the side distal the glass layer, to hermetically seal the space defined by the reservoirs and apertures.
In one aspect, a method is provided for packaging an active-release microchip device which comprises: (1) providing a microchip device having a substrate, a plurality of reservoirs containing contents for release or exposure, and reservoir caps over the reservoir contents; (2) providing a hermetic packaging structure; and (3) forming a hermetic seal between the substrate of the microchip device and one or more surfaces of the packaging structure, effective to encase the microchip device yet leave the reservoir caps exposed and operational. The forming step can, for example, comprise laser welding, ultrasonic welding, or both. Alternatively, the forming step can include electroplating a metal across an interface between a surface of the substrate and a surface of the packaging structure. In another embodiment, the hermetic seal can include a eutectic bond. The packaging structure can further comprise power sources, control electronics, or a combination thereof, for powering disintegration of the reservoir caps, controlling the activation time of for disintegration of the reservoir caps, or both.
In one embodiment, the packaging structure comprises two metal pieces which are laser welded together after encasing the substrate between portions of the two pieces. In another embodiment, the packaging structure is a single piece.
Improved methods and devices have been developed to hermetically seal microchip reservoir devices. As used herein, the term "hermetic" refers to preventing undesirable ingress or egress of chemicals into or from one or more compartments of the device, particularly the device reservoirs, over the useful life of the device, using a seal is composed of materials, such as ceramics, glasses, and metals, which are essentially impermeable to chemicals and biological fluids, including such as water, air, and carbon dioxide. The seal is formed to prohibit permeation of chemicals through the sealing interface by positioning the opposing sealing materials' surfaces in intimate contact and applying thermal, mechanical, and/or chemical energy to produce a hermetic seal.
The microchip devices incorporating one or more of these hermetic seals include a substrate having a plurality of reservoirs that contain reservoir contents. The reservoirs can be individually filled and addressed, enabling the time and rate of release or exposure of multiple contents to be controlled. The reservoirs are closed at a first surface of the substrate by a reservoir cap. Controlled release or exposure of reservoir contents is via a reservoir opening through this first surface following opening of the reservoir cap. For those embodiments where the reservoir initially extends all the way through the substrate, the reservoirs also are closed at a second surface of the substrate distal the first surface. In either embodiment, the reservoir is sealed following filling of the reservoir with the reservoir contents, so that the reservoir contents are protected from the environment until exposure to the environment is desired. The microchip devices can further include a packaging structure hermetically bonded to a surface of the device substrate in order to protect the electronic systems (which control the release mechanisms) of the device from the environment, especially for implantation for use in in vivo applications. As used herein, the "environment" refers to the environment external the reservoirs, including, but not limited to, biological fluids and tissues at a site of implantation, air, fluids, and particulates present during storage or in vitro use of the microchip devices.
The hermetically sealed microchip device includes a substrate having reservoirs, which are covered by reservoir caps and which contain reservoir contents (e.g., a drug, a sensor), and means for selectively opening the reservoir caps to release or expose the reservoir contents. The substrate, reservoirs, reservoir caps, reservoir contents, as well as control circuitry and power sources for actively controlling the cap opening, are described below and in U.S. Pat. Nos. 5,797,898 and 6,123,861, as well as PCT WO 02/30401, WO 02/30264, WO 01/91902, WO 01/64344, WO 01/41736, WO 01/35928, and WO 01/12157. The microchip devices further include one or more hermetic sealing elements, which hermetically seal the reservoirs, device electronics, or both.
The substrate (also call the "primary substrate") contains the reservoirs and serves as the support for the microchip. Any material which can serve as a support, which is suitable for etching or machining or which can be cast or molded, and which is impermeable (during the time scale of the microchip's use) to the contents of the reservoir and to the surrounding environment may be used as a substrate. Suitable materials include metals, semiconductors, and ceramic materials. An example of a suitable semiconductor material includes silicon. Representative examples of ceramic materials include alumina (aluminum oxide), aluminum nitride, silicon dioxide, silicon nitride, and other various nitrides and oxides. The substrate can be formed of only one material or can be a composite or multi-laminate material.
For in vivo applications, the substrate generally is formed of or coated with a biocompatible material. Non-biocompatible materials may be encapsulated or contained in a biocompatible material, such as parylene, poly(ethylene glycol), polytetrafluoroethylene-like materials, or titanium, before use. For in vitro applications, such as in medical diagnostics, the substrate can be constructed of biocompatible or non-biocompatible materials.
Molecules and Secondary Devices (Reservoir Contents)
The reservoirs contain molecules, secondary devices, or combinations thereof, that need to be protected from surrounding environmental components until their release or exposure is desired. Proper functioning of certain reservoir contents, such as a catalyst or sensor, generally does not require their release from the reservoir; rather their intended function, e.g., catalysis or sensing, occurs upon exposure of the reservoir contents to the environment outside of the reservoir after opening of the reservoir cap. Thus, the catalyst molecules or sensing component can be released or can remain immobilized within the open reservoir.
The reservoir contents can include essentially any natural or synthetic, organic or inorganic molecule or mixture thereof, for release (i.e., delivery) or retained and exposed. The molecules (i.e., chemicals) may be in pure solid, liquid, or gel form, or mixed with other materials that affect the release rate and/or time. Chemicals may be in the form of solid mixtures including, but not limited to, amorphous and crystalline mixed powders, monolithic solid mixtures, lyophilized powders, and solid interpenetrating networks; in the form of liquid mixtures including, but not limited to, solutions, emulsions, colloidal suspensions, and slurries; and in the form of gel mixtures including, but not limited to, hydrogels.
For in vivo applications, the chemical preferably is a therapeutic, prophylactic, or diagnostic agent. In one embodiment, the microchip device is used to deliver drugs systemically to a patient in need thereof. In another embodiment, the construction and placement of the microchip in a patient enables the local or regional release of drugs that may be too potent for systemic delivery of an effective dose. As used herein, "drugs" include any therapeutic, prophylactic or diagnostic agent, including organic or inorganic molecules, proteins, nucleic acids, polysaccharides and synthetic organic molecules, having a bioactive effect. Representative examples include analgesics, steroids, cytokines, psychotropic agents, chemotherapeutic agents, hormones, anesthetics, vaccines, metabolites, sugars, immunomodulators, antioxidants, ion channel regulators, and antibiotics. An example of a diagnostic agent is an imaging agent such as a contrast agent. The drugs can be in the form of a single drug or drug mixtures and can include pharmaceutically acceptable carriers.
For in vitro applications, the molecules can be any of a wide range of molecules where the controlled release of a small (milligram to nanogram) amount of one or more molecules is required, for example, in the fields of analytic chemistry or medical diagnostics. Molecules can be effective as pH buffering agents, diagnostic reagents, and reagents in complex reactions such as the polymerase chain reaction or other nucleic acid amplification procedures. In other embodiments, the molecules to be released are perfumes, fragrances, dyes, coloring agents, sweeteners, or a variety of other compounds, which for example, may be useful to release as a function of temperature change. In yet other embodiments, the reservoirs contain immobilized molecules. Examples include any chemical species which can be involved in a reaction, including, but not limited to, reagents; catalysts, including enzymes, metals, and zeolites; proteins; nucleic acids; polysaccharides; polymers; cells, as well as organic or inorganic molecules, including diagnostic agents.
The molecules can be provided as part of a release system. As used herein, "release system" includes the situation where the molecules are in pure form, as either a solid or liquid, or are in a matrix formed of biodegradable material or a material which releases incorporated molecules by diffusion or disintegration of the matrix. The degradation, dissolution, or diffusion properties of the release system can 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, polymeric matrices, non-polymeric matrices, and inorganic and organic excipients and diluents. Examples of such excipients and diluents include 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 one 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, pulsed (variable) release from a reservoir may provide results that are more effective.
Pulsatile release can be achieved from an individual reservoir, from a plurality of reservoirs, or a combination thereof. For example, where each reservoir provides only a single pulse, multiple pulses (i.e., pulsatile release) are achieved by temporally staggering the single pulse release from each of several reservoirs. Alternatively, multiple pulses can be achieved from a single reservoir by incorporating several layers of a release system and other materials into 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. In addition, continuous release can be approximated by releasing several pulses of molecules in rapid succession ("digital" release, analogous to the digital storage and reproduction of music). Active and passive release systems can be combined. For example, a metal film or membrane reservoir cap, which is removed actively, can cover a passive release system that only begins its passive release after the metal film has been actively removed. Alternatively, a given substrate can include both passive and active release reservoirs.
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 polyamides such as poly(amino acids) and polypeptides; polyesters such as poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid), and polycaprolactone; polyanhydrides; polyorthoesters; polycarbonates; 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 polyethers such as poly(ethylene oxide), poly(ethylene glycol), and poly(tetramethylene oxide); vinyl polymers—polyacrylates and polymethacrylates 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); polyurethanes; cellulose and its derivatives such as alkyl, hydroxyalkyl, ethers, esters, nitrocellulose, and various cellulose acetates; polysiloxanes; 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.
The release system may include a pharmaceutical excipient. Suitable pharmaceutically acceptable excipients include most carriers approved for parenteral administration, including water, saline, Ringer's solution, Hank's solution, and solutions of glucose, lactose, dextrose, ethanol, glycerol, albumin, and the like. The release system may optionally include stabilizers, antioxidants, antimicrobials, preservatives, buffering agents, surfactants, and other additives useful for storing and releasing molecules from the reservoirs in vivo.
Secondary Devices
As used herein, unless explicitly indicated otherwise, the term "secondary device" includes, but is not limited to, any device and component thereof which can be located in or designed to operably communicate with one or more reservoirs in a microchip device. In a preferred embodiment, the secondary device is a sensor or sensing component. As used herein, a "sensing component" includes, but is not limited to, a component utilized in measuring or analyzing the presence, absence, or change in a chemical or ionic species, energy, or one or more physical properties (e.g., pH, pressure) at a site. Types of sensors include biosensors, chemical sensors, physical sensors, or optical sensors. Secondary devices are further described in PCT WO 01/64344.
Examples of sensing components include components utilized in measuring or analyzing the presence, absence, or change in a drug, chemical, or ionic species, energy (or light), or one or more physical properties (e.g., pH, pressure) at a site. In a preferred embodiment, the microchip device is implantable in a patient (e.g., a human or other mammal) and includes sensors for monitoring the levels of glucose or urea in blood and other body fluids.
There are several different options for receiving and analyzing data obtained with devices located in the microchip devices. Typically, the operation of the microchip system will be controlled by an on-board (i.e., within the package) microprocessor. The output signal from the device, after conditioning by suitable circuitry if needed, will be acquired by the microprocessor. After analysis and processing, the output signal can be stored in a writeable computer memory chip, and/or can be sent (e.g., wirelessly) to a remote location away from the microchip. Power can be supplied to the microchip system locally by a microbattery or remotely by wireless transmission.
In one embodiment, the microchip device includes both drug and a sensor or sensing component. For example, the sensor or sensing component can be located in a reservoir or can be attached to the device substrate. The sensor can operably communicate with the device, e.g., through a microprocessor, to control or modify the drug release variables, including dosage amount and frequency, time of release, effective rate of release, selection of drug or drug combination, and the like. The "sensing component" includes, but is not limited to, a component utilized in measuring or analyzing the presence, absence, or change in a chemical or ionic species, energy, or one or more physical properties (e.g., pH, pressure). Types of sensors include biosensors, chemical sensors, physical sensors, or optical sensors. Such sensors and sensor components are further described in PCT WO 01/64344. The sensor or sensing component detects (or not) the species or property at the site of in vivo implantation (e.g., in a bodily fluid or tissue), and further may relay a signal to the microprocessor used for controlling release from the microchip device, as detailed below. Such a signal could provide feedback on and/or finely control the release of parathyroid hormone. There are several different options for receiving and analyzing data obtained with devices located in the microchip devices. Active microchip devices may be controlled by local microprocessors or remote control. Biosensor information may provide input to the controller to determine the time and type of activation automatically, with human intervention, or a combination thereof.
In one embodiment, the microchip device includes one or more biosensors (which may be sealed in reservoirs until needed for use) that are capable of detecting and/or measuring signals within the body of a patient. As used herein, the term "biosensor" includes, but is not limited to, sensing devices that transduce the chemical potential of an analyte of interest into an electrical signal, as well as electrodes that measure electrical signals directly or indirectly (e.g., by converting a mechanical or thermal energy into an electrical signal). For example, the biosensor may measure intrinsic electrical signals (EKG, EEG, or other neural signals), pressure, temperature, pH, or loads on tissue structures at various in vivo locations. The electrical signal from the biosensor can then be measured, for example by a microprocessor/controller, which then can transmit the information to a remote controller, another local controller, or both. For example, the system can be used to relay or record information on the patient's vital signs or the implant environment, such as drug concentration.
Reservoir Caps
As used herein, the term "reservoir cap" includes a membrane or other structure suitable for separating the contents of a reservoir from the environment outside of the reservoir. It generally is self-supporting across the reservoir opening, although supports could be built into the cap. Selectively removing the reservoir cap or making it permeable will then "expose" the contents of the reservoir to the environment (or selected components thereof) surrounding the reservoir. In preferred embodiments, the barrier layer can be selectively disintegrated, e.g., on demand. As used herein, the terms "disintegrate," "disintegration," and "disintegrating" in reference to reservoir caps include any mechanism of loss of structural integrity and thus loss of barrier to the environment outside of the reservoir, including, but not limited to, oxidation, mechanical rupture, degradation or dissolving, unless otherwise indicated. The "mechanical rupture" typically does not include puncturing the reservoir cap from the outside, such as with a needle. In one embodiment, the reservoir cap is composed of a metal, such as copper, gold, and silver, which is disintegrated by electrochemical dissolution via the application of electrical potential, as described in U.S. Pat. No. 5,797,898 to Santini.
In active devices, the reservoir cap includes any material that can be disintegrated or permeabilized in response to an applied stimulus (e.g., electric field or current, magnetic field, change in pH, or by thermal, chemical, electrochemical, or mechanical means). In one embodiment, the reservoir cap is a thin metal membrane and is impermeable to the surrounding environment (e.g., body fluids or another chloride containing solution). Based on the type of metal and the surrounding environment, a particular electric potential is applied to the metal reservoir cap, which is then oxidized and disintegrated by an electrochemical reaction, to expose the contents of the reservoir to the surrounding environment. Examples of suitable reservoir cap materials include gold, silver, copper, and zinc. Any combination of passive or active barrier layers can be present in a single microchip device.
Means for Controlling Release or Exposure
Typically, the operation of the microchip system will be controlled by an on-board (i.e., within the package) microprocessor. The output signal from the device, after conditioning by suitable circuitry if needed, will be acquired by the microprocessor. After analysis and processing, the output signal can be stored in a writeable computer memory chip, and/or can be sent (e.g., wirelessly) to a remote location away from the microchip. Power can be supplied to the microchip system locally by a microbattery or remotely by wireless transmission.
Means for controllably releasing the molecules from active devices require actuation, which typically is done under the control of a microprocessor. For example, in one embodiment, the microchip device includes a substrate having a two-dimensional array of reservoirs arranged therein, a release system comprising drug molecules contained in the reservoirs, anode reservoir caps covering each of the reservoirs, cathodes positioned on the substrate near the anodes, and means for actively controlling disintegration of the reservoir caps. Preferably, such means includes an input source, a microprocessor, a timer, a demultiplexer, and a power source. The power source provides energy to drive the reaction between selected anodes and cathodes. Upon application of a small potential between the electrodes, electrons pass from the anode to the cathode through the external circuit causing the anode material to oxidize and dissolve into the surrounding fluids, exposing the release system containing the molecules for delivery to the surrounding fluids, e.g., in vivo. The microprocessor directs power to specific electrode pairs through a demultiplexer as directed, for example, by a PROM, remote control, or biosensor.
The microprocessor is programmed to initiate the disintegration or permeabilization of the reservoir cap in response at a pre-selected time or in response to one or more of signals or measured parameters, including receipt of a signal from another device (for example by remote control or wireless methods) or detection of a particular condition using a sensor such as a biosensor.
The control circuitry typically includes a microprocessor, a timer, a demultiplexer, and an input source (for example, a memory source, a signal receiver, or a biosensor), and a power source. The timer and demultiplexer circuitry can be designed and incorporated directly onto the surface of the microchip during electrode fabrication. The criteria for selection of a microprocessor are small size, low power requirement, and the ability to translate the output from memory sources, signal receivers, or biosensors into an address for the direction of power through the demultiplexer to a specific reservoir on the microchip device (see, e.g., Ji, et al., IEEE J. Solid-State Circuits 27:433-43 (1992)). Selection of a source of input to the microprocessor such as memory sources, signal receivers, or biosensors depends on the microchip device's particular application and whether device operation is preprogrammed, controlled by remote means, or controlled by feedback from its environment (i.e., biofeedback).
The criteria for selection of a power source are small size, sufficient power capacity, the ability to be integrated with the control circuitry, the ability to be recharged, and the length of time before recharging is necessary. Batteries can be separately manufactured (i.e., off-the-shelf) or can be integrated with the microchip itself. Several lithium-based, rechargeable microbatteries are described in Jones & Akridge, "Development and performance of a rechargeable thin-film solid-state microbattery", J. Power Sources, 54:63-67 (1995); and Bates et al., "New amorphous thin-film lithium electrolyte and rechargeable microbattery", IEEE 35th International Power Sources Symposium, pp. 337-39 (1992). These batteries are typically only ten microns thick and occupy 1 cm2 of area. One or more of these batteries can be incorporated directly onto the microchip device. Binyamin, et al., J. Electrochem. Soc., 147:2780-83 (2000) describes work directed toward development of biofuel cells, which if developed, may provide a low power source suitable for the operation of the present microchip devices and other microelectronic devices in vivo.
A microprocessor is used in conjunction with a source of memory such as programmable read only memory (PROM), a timer, a demultiplexer, and a power source such as a microbattery or a biofuel cell. A programmed sequence of events including the time a reservoir is to be opened and the location or address of the reservoir is stored into the PROM by the user. When the time for exposure or release has been reached as indicated by the timer, the microprocessor sends a signal corresponding to the address (location) of a particular reservoir to the demultiplexer. The demultiplexer routes an input, such as an electric potential or current, to the reservoir addressed by the microprocessor.
The manufacture, size, and location of the power source, microprocessor, PROM, timer, demultiplexer, and other components are dependent upon the requirements of a particular application. In one embodiment, the memory, timer, microprocessor, and demultiplexer circuitry is integrated directly onto the surface of the microchip. The microbattery is attached to the other side of the microchip and is connected to the device circuitry by vias or thin wires. However, in some cases, it is possible to use separate, prefabricated, component chips for memory, timing, processing, and demultiplexing. In one embodiment, these components are attached to the back side of the microchip device with the battery. In another embodiment, the component chips and battery are placed on the front of or next to the microchip device, for example similar to how it is done in multi-chip modules (MCMs) and hybrid circuit packages. The size and type of prefabricated chips used depends on the overall dimensions of the microchip device and the number of reservoirs, and the complexity of the control required for the application.
Welding and Sealing Materials
A variety of metals, glasses, ceramics, and combinations thereof can be used to form the hermetic seals. The sealing material can be provided in the form of a thin foil that is welded or chemically bonded to one or more surfaces of the device, or alternatively, the sealing material can be provided in the form of a deposited film on another material or structure. For example, two substrates could be bonded together, with one surface of one substrate providing the sealing material for the other. In any event, effective bonding depends on the surface chemistry at the interface of the sealing material and the substrate. The sealing material is bonded to the substrate along the sealing surfaces on the back side of the substrate between the reservoirs, thereby isolating each reservoir.
In a preferred embodiment, particularly for ultrasonic welding, the sealing material is a metal foil, preferably having a thickness between about 1 and 50 μm. A defect-free gold foil is preferred, although other biocompatible, weldable metals are suitable. Examples of other suitable metals include platinum and titanium, as well as various alloys such as stainless steels and low melting temperature alloys.
The term "layer" as used herein in reference to metals generally refers to thin metal structures made by a deposition technique, such as e-beam or sputtering. The term "foil" as used herein generally refers to thicker metal structures made by rolling or shaping molten material. The term "layer" can however include foils, unless otherwise indicated.
In another similar embodiment, the sealing material is a reservoir cap material, which is welded to the front side of the substrate over the reservoir opening. In this embodiment, the reservoir cap preferably is a metal foil. The reservoir cap should be thick enough to be weldable, yet thin enough to be degradable.
The sealing material also may be or include silicon or glass. Glass, like metal, can provide a hermetic seal. In one embodiment, a hermetic seal is formed using a glass substrate having a metallic surface that will react, i.e. form a eutectic, with one or more surfaces of the substrate, e.g., the outer surfaces of the substrate between the reservoirs (i.e., the reservoir "streets") upon application of laser energy. Examples of the eutectic compositions include, but are not limited to Au/Si, Au/Ge, Au/Sn, Pb/Sn, Pb/In, Pt/Si, Ag/In, Al/Cu. (The lead and silver containing compositions typically would be used only for in vitro applications.)
The sealing can also be formed by directly using laser welding techniques to directly melt and bond two glass surfaces. One skilled in the art can select the proper glass chemistry and wavelength of light that will result in melting and mixing of these glass materials at the seal interface. Other laser welding examples rely on the formation of metallic bonds that can be formed using pure metallic species as well as various alloys. Representative examples of laser weldable metallics include titanium, stainless steels, platinum, palladium, and gold.
Other materials which could be suitable for welding include titanium, aluminum, gold/silicon, and nickel-titanium alloys (e.g., Ninitol, which exhibits super-elastic and shape-memory effects).
The sealing material optionally is provided, after welding, with an overcoat layer to increase the mechanical strength of the seal, to enhance the biocompatibility of the device, to serve as a secondary (i.e., back up) sealing mechanism, or to provide a combination of these functions. In one embodiment, the overcoat layer is a coating of biocompatible polymeric materials, such as poly(hydroxy acid) or poly(lactic acid), an epoxy, a polyurethane, a latex, a silicone, or a parylene.
Optionally, a layer of a barrier material, such as a wax or poly(ethylene oxide), can be included in the reservoir prior to placement and bonding of the sealing material to isolate or insulate the drug or other reservoir contents from the sealing energy.
The basic microchip devices (i.e., substrate, reservoirs, reservoir caps, release system, and control means) can be made using microfabrication methods known in the art, particularly those methods described in U.S. Pat. No. 5,797,898; U.S. Pat. No. 6,123,861; PCT WO 01/41736, and WO 01/91902, which are hereby incorporated by reference in their entirety. These basic structures are then hermetically sealed as described herein.
There are several approaches available for forming the hermetic seal. One sealing technique is laser welding in which the weld materials maybe the same or dissimilar compositions, such as titanium (Ti), tantalum (Ta), palladium (Pd), platinum (Pt), stainless steel or silicate glasses. A second embodiment uses ultrasonic energy, and the sealing material preferably is a thin ductile metal foil, such as gold. A third embodiment uses resistive heating to initiate a reaction between the two mating surfaces. A specific example would be resistive heating of either a silicon (Si) or gold (Au) trace, which is in intimate contact with its counterpart yielding a eutectic Au/Si reaction. A eutectic reaction is useful because it occurs at a temperature that is lower than the melting temperatures of either of the component sealing materials.
As illustrated in
Hermetically Sealing the Reservoirs
Generally, the back side sealing method comprises (i) providing a microchip device substrate having a front side and a back side, wherein the back side has a plurality of reservoir openings in need of sealing; (ii) providing a back side substrate surface that is composed of one or more sealing materials, (iii) providing a thin substrate having at least one surface composed of one or more sealing materials, (iv) positioning the thin substrate over the reservoir openings, and (v) contacting the sealing surfaces together to seal the reservoir openings, wherein the contacting is effective to form a hermetic seal. This contacting step may or may not require chemical interaction or reaction (e.g., welding or bonding).
In forming the hermetic seal of the back side, the reservoirs of the microchip substrate can be sealed using thermal, mechanical, and/or chemical bonding techniques. In various embodiments, a sealing material is welded to the substrate along the sealing surfaces (i.e., the back side of the substrate between the reservoirs), thereby isolating each reservoir.
In an optional embodiment, a polymer coating (not shown) could be applied onto the outer surface of the metal foil following the welding process. Such a coating could provide extra reservoir sealing and/or improved biocompatibility for the device.
In another embodiment, hermetic sealing of the reservoirs is accomplished with the use of a metal gasket. The metal gasket is preferably a thin, ductile metal sheet, such as gold. One example is illustrated in
In preferred embodiments, the welding is achieved using acoustic, more preferably ultrasonic, energy. Ultrasonic welding is advantageous in that it requires no flux or shielding gas, and produces relatively little heat. Excessive heat could degrade a thermally labile chemical or drug in the reservoirs. Examples of ultrasonic welding methods are described in U.S. Pat. No. 5,651,494 to Ogino, et al. (welding different metals), and U.S. Pat. No. 5,785,786 to Suzuki et al (welding metal sheets). Other welding techniques that may be suitable include laser welding, e-beam welding, and RF welding, which are known in the art. Examples of laser welding and e-beam welding methods are described in U.S. Pat. No. 5,574,313 to McKleroy and in U.S. Pat. No. 4,093,843 to Lindstrom et al.
In the case of ultrasonic welding, all of the reservoirs can be sealed simultaneously by a planar welding tip the same size as the microchip substrate, or the reservoirs can be sealed one reservoir or one row at a time by an appropriately shaped ultrasonic horn, whether stationary or mobile. In a typical process, a welding horn is applied to the metal foil or other sheet of sealing material to bond it to the substrate surface, thereby sealing the reservoirs, and the opposing side of the substrate is in contact with the anvil of the acoustic welding machine.
In the case of laser welding and e-beam welding, the weld spot is formed by impinging the seal interface with an intense energy beam of either photons or electrons, effective to cause localized heating to fuse together the two adjacent surfaces. The weld "spot" typically has a diameter between about 10 and 300 μm. The energy beam can be guided along the seal interface such that the welds overlap, ultimately forming a hermetic bond.
In another embodiment, the step of sealing and the step of formation of a reservoir cap over the reservoir opening can be combined. This is particularly useful for devices in which the reservoirs are filed and released from the same side, for example, in embodiments where the reservoirs are formed in a substrate without penetrating through the entire thickness of the substrate. One example of such a process is shown in
Thus, in one embodiment, the microchip device fabrication process includes (i) providing a substrate having a front side and a back side, wherein the front side comprises a plurality of reservoirs; (ii) filling the reservoirs with reservoir contents for release or exposure; and (iii) capping the reservoir openings with a cap material which can be selectively disintegrated to release or expose the reservoir contents, wherein the capping step comprises welding the cap material to the front side of the substrate. The capping step preferably comprises positioning a metal foil (cap material) over the reservoir opening and then ultrasonically welding the cap material onto a metal trace deposited onto the front side of the substrate circumferential to the reservoir opening. In this embodiment, the reservoirs preferably are fabricated into the substrate such that an aperture is not formed; rather, the reservoir has a single opening through which both filling and release occur.
Packaging the Substrate Assembly
The hermetic sealing methods described above can be used in other aspects of the fabrication and assembly of the microchip devices. In particular, an active-release microchip device can be welded to one or more surfaces of a packaging structure. The term "packaging structure" refers to an enclosure, casing, or other containment device for encasing the microchip device, control electronics, and power elements (e.g., microbattery or devices for receiving wireless transmission of power), so as to expose only the front side of the substrate or reservoir caps. The term "microchip device" refers to either packaged or unpackaged devices, unless one or the other is expressly referenced.
In one embodiment, ultrasonic welding techniques are used to hermetically secure a device substrate to a packaging structure for the microchip device. Steps for such a "packaging" type of sealing method can include contacting a metal surface of the substrate with a metal surface of a packaging substrate and then applying ultrasonic energy to the interface so that deformation occurs at the metallic interface to produce a hermetic bond. Two variations of this approach are illustrated in
In a preferred embodiment for the formation of a front side hermetic microchip-to-package seal, the method comprises the steps of (i) providing a microchip device substrate having a front side and a back side, wherein the front side has surface composed of at least one sealing material; (ii) providing a packaging structure surface that is composed of a second at least one sealing material; (iii) aligning the front side of the substrate and the packaging structure surface so that the sealing surfaces mate; and (iv) bringing the first and second sealing materials into intimate contact effective to form a hermetic seal between the front side surface of the microchip and the packaging structure without obstructing the operation of the device.
In an alternative approach, electro-plating is used to form the hermetic bond between the front side surface of the microchip reservoir device and the packaging structure. An example of electroforming hermetic glass to metal seals is described in U.S. Pat. No. 3,932,227 to Rothenberg. In one embodiment of a front side electroformed hermetic seal, the method of fabrication comprises (i) metallizing and bringing into electrical contact the two mating surfaces, i.e. the front side surface of the microchip and a surface of the package; (ii) immersing this electrically conductive interface into an electroplating solution; (iii) and applying an electrical potential to the interface so that a metal layer is electro-deposited forming a hermetic "bridge" across the interface. Gold is a preferred plating material, as it provides a biocompatible surface. Such a technique could be performed prior to filling the reservoirs or subsequent to filling and sealing the reservoirs. A representative example is illustrated in
Another example of a front side sealing technique is based on eutectic bonding. In one embodiment, a hermetic eutectic seal is formed by (i) depositing thin layers of materials in eutectic proportions onto the surfaces to be bonded; (ii) contacting these two mating surfaces, e.g., the front side surface of the microchip and the surface of the enclosure, together; and (iii) heating the interface to a temperature at which the two surfaces undergo the specified eutectic reaction. A specific surface configuration would be surface chemistries capable of forming the Au/Si eutectic composition, typically at a localized temperature of 363� C. A specific surface configuration would be surface chemistries capable of forming the Au/Si eutectic composition. Various applications of eutectic bonding to form hermetic seals are described in U.S. Pat. No. 6,148,673 to Brown (pressure sensor applications) and in U.S. Pat. No. 5,568,585 to Kramer (optical fiber applications). A representative example is illustrated in
Surface Preparation
Sealing surfaces may be prepared to promote an effective seal. Such surfaces include the front side and the back side of the microchip substrate, as well as the side of the sealing material facing the substrate. For example, the silicon of the sealing surface of the substrate may be provided with an attached (mating) material, that is, a layer of material(s) to which the sealing material will bond. For instance, welding of a metal foil may be enhanced by depositing a metal, preferably the same composition as the metal foil, onto the substrate. The deposited mating material is intended to improve the quality of the bond by providing additional bonding sites. The mating material may be attached to the substrate by a variety of techniques. For example, it may be applied using MEMS techniques known in the art, for example, by using a combination of metal deposition and photolithography steps. The material may be deposited, for example, by electronic beam evaporation, sputtering, or plating.
In addition, one or both surfaces (i.e., sealing material and substrate) may be roughened or adhesion features may be micromachined into the surface of the substrate to enhance bonding.
For embodiments in which the reservoirs are filled prior to forming the seal, an insulating material, e.g., boro-silicate glass, is optionally patterned onto the surface of the microchip reservoir substrate between the outer most sealing surface and the sealing material (see
It may be desirable to apply a protective polymer coating (such as photoresist) on the front side of the substrate (e.g., over the reservoir caps) that is not removed until after filling and sealing are complete. This protective coating will support the reservoir caps to withstand the additional mechanical forces that may be introduced during the proceeding filling and sealing processes, such as by ultrasonic welding.
Post-Sealing Processes
The sealed microchip substrates may be further treated to improve the robustness and integrity of the seal. The devices may be inspected by a technique to determine whether the reservoirs have been completely sealed. An overcoat layer can be applied over the sealed substrate, for example with a vapor deposition technique, such as commonly used to apply a parylene coating on electronic devices. Sealing may be further enhanced with a mechanical sealing technique, for example by positioning and compressing the sealed substrate between a gasket material and sealing frame.
Following completion of the sealing process, any protective polymer coating can be removed with a solvent and/or oxygen plasma cleaning step, as known in the art.
Using the Microchip Devices
The hermetically sealed microchip devices described herein can be used in a wide variety of applications. Preferred applications include the controlled delivery of a drug, biosensing, or a combination thereof. For example, the hermetically sealed microchip devices are suitable for implantation into a patient, such as a human or other vertebrate animal, for controlled drug delivery, locally, regionally, or systemically. The microchip device can be implanted in vivo using standard surgical or minimally-invasive implantation techniques, e.g., via a catheter. The microchip devices are especially useful for drug therapies in which one needs to very precisely control the exact amount, rate, and/or time of delivery of the drug. Preferred drug delivery applications include the delivery of potent compounds, including both small and large molecules, such as hormones, steroids, chemotherapy medications, vaccines, gene delivery vectors, and some strong analgesic agents.
The passive or active devices have numerous in vivo, in vitro, and commercial diagnostic applications. The microchips are capable of delivering precisely metered quantities of molecules and thus are useful for in vitro applications, such as analytical chemistry and medical diagnostics, as well as biological applications such as the delivery of factors to cell cultures. In other applications, the devices are used to control release of fragrances, dyes, or other useful chemicals. Other methods of using the microchip devices for controlled release of drug and other molecules, as well as for controlled exposure and release of molecules or secondary devices, are described in U.S. Pat. Nos. 5,797,898 and 6,123,861; and PCT WO 02/30401, WO 02/30264, WO 01/91902, WO 01/64344, WO 01/41736, WO 01/35928, and WO 01/12157.
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.
Patent Citations
Non-Patent Citations
Referenced by
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November 13, 2006
Google Apps Has a Start Page
As reported in September, Google Apps for Your Domain now includes a personalized homepage, "a central place for your users to preview their inboxes and calendars, access your essential content, and search the web". The page is similar to what you see in Google's IG, except that administrators have more control over the page. They can lock down the left column, provide a list of recommended gadgets and change the logos, colors, and fonts.
For more information about the personalized start page, visit the help center.
Google Apps for Your Domain
Homepage 2.0
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The Bachelorette
Michael Stagliano Takes His Girlfriend on Adrenaline-Pumping New Years Date
We all know that New Year's Eve can be incredibly romantic, but when you're dating Michael Stagliano — the New Year's romance doesn't just end there.
The Bachelor nation hottie celebrated the New Year with his girlfriend Emily Tuchscherer, and while we haven't seen any photos of their New Year's Eve festivities, Michael did take to Instagram to share a peek at what the couple was up to on New Year's Day.
On January 1, Michael tweeted this photo of himself, his twin brother, Stephen, and Emily on their way for an action-packed day at the beach.
"She's nervous about surfing. #stayawaysharks! #illprotecther #unlessthereisagoodwave @emilytuch @stephenstag" he wrote.
It sounds like there's never a dull moment for these two. Obviously, Michael's time on both The Bachelorette and Bachelor Pad must have given him plenty of ideas for how to plan a memorable date. There's nothing like a bit of action and excitement to make things memorable!
Also, we're pretty sure that the danger getting bit by an actual shark is quite minimal — but we'd gladly have Michael swoop on over to protect us, either way.
Unless, of course, there was a really good wave. No need to let a silly little thing like a near-death experience make him miss out on that.
Source: Michael Stagliano on Instagram


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Cheap ski holidays in hundreds of ski resorts worldwide.
Nb: infants must be under the age of 2 and
children must be under the age of 12 at the time of
Les Lauzieres is situated on the route du Petit Plan (first left at the entrance to resort). Depending on snow conditions it is virtually ski-in/out using the Petite Aiguille piste (blue) and skiing 200 metres (approx) to the Petite Aiguille chairlift. Alternatively, beginners use the free bus stop opposite the chalet, which currently runs until 20:00hrs. NB The centre of town is a 15 minute walk (approx).Chalet Les Lauzieres has comfortable, modern furnishings in the living and dining room and all bedrooms are en suite. The focal point of the chalet is the open plan living/dining area with a high-beamed ceiling, floor to ceiling windows and a warming fireplace. Chalet Les Lauzieres is a popular chalet thanks to its easy access to the skiing so early booking is recommended.
Lauzieres is a popular chalet thanks to its easy access to the skiing and recent refurbishments so early booking is recommended.Ground Floor:Entrance hall with heated ski and boot roomLarge open-plan living and dining area with open fire placeSeparate WC Ground Floor: (east wing)Rooms 1 & 2 = 2 twins with shower and WCRooms 3 & 4= 2 twins with shower and WC (skylights) Ground Floor: (west wing)Room 5 = twin with bath and WC (skylight)Room 6 = twin with shower and WC (skylight) Room 7 = twin with shower and WC Chalet staff live in.
Iglu acts as a travel agent for disclosed principals/tour operators, further details
of which will be made available at the time of booking. Your holiday contract will
be bound by the tour operators terms and conditions.
Prices are shown for a basic room or unit, can be subject to change and are indicative
until time of booking. Please call on 020 8544 7114 for prices for other travel
and room options for this property.
Prices shown are per person per week based on maximum occupancy. Descriptions and
quality ratings are provided by the Tour Operator (or one of the Tour Operators
where similar holidays are offered by more than one supplier). We reserve the right
to make minor adjustments to the description or rating based on staff and customer
feedback. For payments by credit card, a 2.5% credit card charge (4% for AMEX) will
be added to your invoice. If you pay by a UK issued debit card, there is no charge.
All bookings are subject to a £5 per person Passenger Admin Fee charged by Iglu.com.


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Volvo C70 Model History
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Volvo Prices and Values: A Swedish manufacturer widely known for its high marks in crash testing, Volvo has been recognized for decades as the benchmark in safety and functionality. Volvo is also a popular manufacturer of heavy-duty diesel vehicles worldwide. Since it was founded more than 80 years ago, Volvo has continued to build high-quality, safe vehicles.
Review all model year Volvo C70 prices & values
2013 Volvo C70
Carried over for 2013, the Volvo C70 is a luxury hard-top convertible powered by a 2.5-liter 5-cylinder turbocharged engine that produces 227 hp.
2012 Volvo C70
A luxury hard-top convertible, the 2012 Volvo C70 is a unique blend of safety, luxury, and performance.
2011 Volvo C70
Equipped with a retractable hard-top, the 2011 Volvo C70 is well-equipped for fun in the sun.
2010 Volvo C70
A two-door four-passenger sports car, the 2010 Volvo C70 features a power retractable hardtop and a turbocharged five-cylinder engine.
2009 Volvo C70
A hardtop coupe convertible, the two-door 2009 Volvo C70 proves to be one cool customer.
2008 Volvo C70
The 2008 Volvo C70 is a premium four-passenger two-door with a retractable hardtop for a nice day of top-down motoring and listening to all 227 hp from the fun turbocharged five-cylinder engine.
2007 Volvo C70
The 2007 Volvo C70 is a two-door four-passenger convertible with a retractable hardtop which helps retain its coupe styling when the top is up.
2006 Volvo C70
Totally restyled for the new year, the 2006 Volvo C70 is a two-door premium car that seats four and is fitted with a power-retractable hardtop.
2004 Volvo C70
A two-door convertible with seating for up to four passengers, the 2004 Volvo C70 is well-equipped with standard amenities and safety features.
2003 Volvo C70
A premium two-door, four-passenger convertible, the 2003 Volvo C70 is available with a choice between two five-cylinder turbocharged engines.
2002 Volvo C70
A sporty two-door with seating for four, the 2002 Volvo C70 is available as a well-equipped coupe or convertible featuring such standard features as dual-zone climate control and keyless entry.
2001 Volvo C70
A premium two-door four-passenger car, the 2001 Volvo C70 is available as a coupe or a convertible and is available with an automatic transmission or a manual.
2000 Volvo C70
The 2000 Volvo C70 is a premium two-door sporty car which is available as a coupe or a convertible, and it offers a choice between two turbocharged five-cylinder engines.
1999 Volvo C70
The 1999 Volvo C70 is a brand-new compact premium two-door that seats four passengers and is available as a coupe or convertible.
1998 Volvo C70
The 1998 Volvo C70 is a premium, compact coupe with sporty styling and an exciting turbocharged five-cylinder engine.