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David Oxford
member for 8 years, 7 months, 20 days
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I was born and raised in Terre Haute, Indiana, and joined the Air Force at an early age. After two careers (USAF and U.S. Capitol Police), two marriages (death and divorce) and wonderful children AND grandchildren, I completely retired and relocated to North Carolina. I enjoy searching the past..., for myself and others.
I also enjoy being a contributor to this excellent website. When visiting cemeteries for my own purposes or upon request, I will usually photograph and add several other graves from that visit. I feel that they too have a story to tell and will hopefully be found by a loved one. If my entries prove incorrect or incomplete, or you would prefer to replace with your own data, please let me know. I am always willing to make a change for the improvement of a memorial. I will also consider reasonable requests for transfer. Please use the EDIT tab on the applicable memorial(s). PLEASE DO NOT PLACE A DEATH RECORD ON THE MEMORIALS THAT I MANAGE. If you feel that something pertinent is on the record that I have overlooked in the bio, send me an EDIT request.
I do not display a list of Find A Grave Friends..., there are far too many. Rest assured, if you have helped me or I have helped you, then you ARE My Friend.
ADDENDUM: Photographs I have taken at burial locations may be used by others for any legitimate purpose (excluding reposting on other findagrave memorials). Hopefully, I would be given credit for the work. However, personal photographs I have placed on memorials that I created, maintain or posted otherwise, unless specified in that content, remain in my control and are considered copyrighted materials.
But I do hope that you will enjoy viewing the personal photographs I have posted, especially those of my deceased wife
, my
and our extended family, including the
of my second wife and her extended family.
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Sandra Koors
RE: re: Nancy Payton
Stephen Peyton and Nancy Doughty married April 16, 1806,Nicholas,KY... also Nancy Peyton is mentioned in her father's Thomas Doughty Land Division, 1834,Nicholas,KY. The Peyton's came from North Carolina through VA where the Doughty's were. The Ellis,Peyton,Doughty's all came through to Nicholas,KY
Added by
Sandra Koors
on Jul 06, 2015 2:10 PM
RE: re: Walter E. O'Brien, Sr.
So welcome.
Added by
on Jul 03, 2015 8:48 PM
RE: re: Montie Williams McIntosh
Thank you, Mr. Oxford! In research that I did today, my memory was jogged, and I recalled more sisters, and a brother, too. There is actually a book written on those Williamses, and you could also refer to MooreCountyWallaces.com. At any rate, there was Evander, Montie, Mintie (not twins!), Maggie Mae, Fuller, Mary Ella, and a toddler who died at the age of 2. Big family--wow!
Thank you again,
Added by
on Jun 29, 2015 12:52 AM
A Horan
RE: Re: Roman Benavene
You're welcome for the photos, David. Thank you for your kind message!
Added by
A Horan
on Jun 15, 2015 7:01 PM
Ken T
RE: re: E.A. Cornish
You're very welcome.
Added by
Ken T
on Jun 14, 2015 6:57 AM
John William & Cheryl (Colomb) De Ronde
RE: re: My Earlier on B. Moore Photo
NP David. Funny that you relate to my past sort of. I remember vividly spending an evening in a laundromat one night in the early 70's, must have been January or February, feeding dimes in the gas dryer to keep the place warm while my sneakers tumbled around. A buddy of mine and I had decided one day to hitchhike from Des Moines, Iowa to the French lick in Indiana to see a friend of ours. On the way back we got a ride from a man who took us to a McDonalds in Terra Haute and gave us ten bucks to buy us a meal. The next day another ride (still in Indiana) asked I f we minded a fast ride. NP I said as he slammed the pedal to the floor. We were flying!!!!!!!!!!!! We moved to NC about three years ago from Miami. I think we're going back.
Added by
John William & Cheryl (Co...
on Jun 10, 2015 7:10 PM
Bob Wilson
RE: re: Warner Completions
Also, if you would like some help in tracking down other data here in this part of Oregon, I might be able to help -- I'm pretty familiar with the available resources here.
Added by
Bob Wilson
on May 26, 2015 11:23 AM
Bob Wilson
RE: re: Warner Completions
I'm glad I was able to help!
If you figure out hoe Lewis Warner is connected, please let me know. Also, if you locate a burial for Jabez Warner, I'd love to link Elizabeth to him, or that could also be done from the other end.
Have a great week!
Added by
Bob Wilson
on May 26, 2015 11:20 AM
Bob Wilson
RE: re: Warner Requests
I have uploaded photos for those that I had; the other ones that you have requested were not found on my trip to the cemetery in 2012. The fact that Harvey & Wilbur were in the WPA listing indicates that they had gravestones at that time, although the cemetery has been vandalized in addition to being severely neglected -- meaning that their gravestones may no longer even be there.
It would take a crew of a dozen or more working for a couple of weeks to refurbish the cemetery, and there is no way that the rancher would allow that. So for now, "It is what it is. . . ."
Added by
Bob Wilson
on May 26, 2015 1:06 AM
Iriss Hill
John Grossi
Thank you for the nice photo & note you added to his memorial!
Added by
Iriss Hill
on May 25, 2015 7:45 AM
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subset: commoncrawl


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After several top performances from the bench in the league, as well as solid displays when starting in the cups, Sir Alex Ferguson has finally decided to start Anderson in the league.
He came on for the last half an hour against QPR when we were 1-0 down. We were 3-1 up within 15 minutes and Ando even grabbed an assist for himself.
"I thought Ando won the game for us," said Ferguson. "His performance was outstanding. He took the game by the scruff of the neck and he was so positive and determined in his play that he picks himself on Wednesday."
Made in Manchester is available for just £3. Some of the best football writers take a player each, from Sir Bobby Charlton to Ryan Giggs, George Best to David Beckham, Duncan Edwards to Paul Scholes, and many more, with 30 articles in total. All profit goes to Trafford Macmillan so please support this fantastic cause.


text:
A multilayer laminated film useful in chub packaging comprises a core film comprising a biaxially oriented film, and an outer hot blown film bonded to each of the opposing surfaces of the core layer, at least one of the films including a layer of an oxygen barrier polymeric material.
1. A method of making a multilayer laminate useful in chub packaging comprising:
a) melt extruding a first film;
b) biaxially orienting said film;
c) ply separating the first film into two plies, each ply having two outer surfaces;
d) corona treating the two outer surfaces of one of the plies of the first film;
e) melt extruding a second film by a hot blown method;
f) ply separating the second film into two plies, each ply having two outer surfaces;
g) corona treating an outer surface of one of the plies of the second film;
h) melt extruding a third film by a hot blown method;
i) ply separating the third film into two plies, each ply having two outer surfaces;
j) corona treating an outer surface of one of the plies of the third film; and
k) passing the corona treated plies between a pair of nip rolls such that the corona treated ply of the first film is sandwiched between and in communication with corona treated surfaces of the plies of the second and third films respectively to cause bonding thereof.
2. The method according to claim 1 wherein the first film is cross-linked.
3. The method according to claim 2 wherein the cross-linking step is accomplished by pre-blending chemical cross-linking agents into the first and then extruding said film.
4. The method according to claim 2 wherein the cross-linking step is accomplished by irradiation of the first film after extrusion.
This is a divisional application of application Ser. No. 249,631, filed on Sept. 26, 1988 now U.S. Pat. No. 5,037,683.
This invention relates generally to a laminated film suitable for packaging, and more particularly to a laminated film suitable for use in chub packaging and having improved tensile strength and seal strength properties.
Certain foods, and particularly meat products such as ground beef and other comminuted food substances, are commonly packaged in what are called chub packages. These packages are generally produced at central processing plants operated by supermarket chains or meat packing companies. These packages are generally produced using a vertical form fill seal (VFFS) process, in which a tube is formed from a flat sheet of roll stock film. The tube is formed vertically and longitudinally sealed with a vertical sealing bar. The bottom of the tube is then sealed with a clip applied to the bottom of the tube, the meat product such as ground beef is pumped into the open end of the tube, and the top is sealed with a clip to produce the final chub package. In appearance, these chubs resemble semi-rigid tubes with the tubular film forming a skin tight layer around the food product.
Package sizes may range from 1 to 20 pounds, depending on the intended mode of distribution. Pumping equipment typically used to stuff the food product into the tubular film can place great stress on the longitudinal seal of the tube. This longitudinal seal is usually a lap seal.
More recently, crust-frozen items have become more popular, and the hardening of the outer surface of the food product in the tubular casing during the freezing process can produce further stress on the longitudinal seal.
Successful films for use in such applications include the HS660 and HS2000 films produced commercially by the Cryovac Division of W. R. Grace & Co. The films are composed of lay-flat tubular film. Prior to collapse, the HS660 film includes an inner layer of ethylene vinyl acetate copolymer (EVA) and an outer layer of polyethylene (PE). The two core layers comprise nylon, with an intermediate layer between each nylon layer and respective outer layer and inner layers comprising ionomer resins. In case of HS2000, an ethylene vinyl alcohol copolymer replaces the nylon layer closest to the inside of the structure.
While such materials have been very useful in producing chub packaging, it is an object of the present invention to further improve the performance of chub packaging materials, especially under conditions where improved seal strength and lower transverse elongation are desirable.
In one aspect of the invention, a multilayer laminated film useful in chub packaging comprises a core film comprising a biaxially oriented film, and an outer film bonded to each of the opposing surfaces of the core film, and comprising a hot blown film, wherein at least one of the films include a layer of an oxygen barrier polymeric material.
In another aspect of the present invention, a method of making a multilayer laminated film useful in chub packaging comprises melt extruding a first film having a layer of ethylene alpha-olefin copolymer and a layer of ethylene vinyl acetate copolymer; biaxially orienting said film; melt extruding two multilayer films by the hot blown method; and adhering each of the two hot blown films, at their bonding layers, to opposing surfaces of the first film; at least one of the films including a layer of an oxygen barrier polymeric material.
The invention may be further understood by reference to the attached drawings wherein:
FIG. 1 is a schematic cross-sectional view of one embodiment of the present invention; and
FIG. 2 is a schematic diagram of a method of making the laminated film of FIG. 1.
Referring to FIG. 1, a multilayer laminated film 10 includes a core film 12 comprising a biaxially oriented film.
In one embodiment, core film 12 has a central layer 18 made up of ethylene vinyl acetate copolymer, and outer layers 20a and 20b of linear low density polyethylene.
In another embodiment, core film 12 has a central layer 18 of ethylene vinyl acetate copolymer, two intermediate layers of linear low density polyethylene, and an additional layer of ethylene vinyl acetate copolymer on each surface to make up a five-layer film. This latter film is commercially available as SSD 310 film manufactured by W. R. Grace & Co.-Conn. through its Cryovac Division.
An alternative material for layers bearing the linear low density polyethylene is very low or ultra low density polyethylene.
Film 12 is preferably cross-linked. This may be done by pre-blending, prior to extrusion, a chemical cross-linking agent into one or more of the resins making up the oriented film.
Another, more preferred method is irradiation.
Irradiation may be accomplished by the use of high energy electrons, ultra violet radiation, X-rays, gamma rays, beta particles, etc. Preferably, electrons are employed up to about 20 megarads (MR) dosage level. The irradiation source can be any electron beam generator operating in a range of about 150 kilovolts to about 6 megavolts with a power output capable of supplying the desired dosage. The voltage can be adjusted to appropriate levels which may be for example 1,000,000 or 2,000,000 or 3,000,000 or 6,000,000 or higher or lower. Many apparatus for irradiating films are known to those of skill in the art. The irradiation is usually carried out at a dosage up to about 20 MR, typically between about 1 MR and about 20 MR, with a preferred dosage range of about 2 MR to about 12 MR. Irradiation can be carried out conveniently at room temperature, although higher and lower temperatures, for example, 0� C. to 60� C. may be employed.
On each side or surface of the core film, hot blown barrier films 14a and 14b are respectively bonded. Film 14a has a central layer 22a of ethylene vinyl alcohol copolymer, an outer heat sealable layer 24a, and an inner bonding layer 26a of ethylene vinyl acetate copolymer.
Film 14b, on the opposing surface of core film 12, has a structure identical to film 14a. Thus, layer 22b will have the same composition as 22a, and layers 26b and 24b will have the same composition as layers 26a and 24a respectively.
In the most preferred embodiment, the outer heat sealable materials making up layers 24a and 24b are a blend of 90% linear low density polyethylene or ethylene vinyl acetate copolymer and about 10% of an antiblock material.
Also in the preferred embodiment, a polymeric adhesive material, such as a graft copolymer or other modified copolymer of ethylene vinyl acetate copolymer is located on either surface of the ethylene vinyl alcohol copolymer. Although EVA-based polymeric adhesives with an anhydride functionality are preferred, other polymeric adhesives with various polyolefinic bases will also be useful to some extent in providing interlaminar adhesion.
Finally, a layer of linear low density polyethylene is disposed between the heat sealable outer layer and one of the polymeric adhesive layers, and between the inner bonding layer and the other of the polymeric adhesive layers.
Thus, in the most preferred embodiment, hot blown film 14a and 14b is a seven layer structure in which the ethylene vinyl alcohol copolymer forms a central layer, and in which two discrete layers of linear low density polyethylene are present.
It has been found that several advantages are obtained from the present invention.
The biaxially oriented, cross-linked core film contributes to reduced elongation of the final laminate. This has an advantage in certain chub packaging applications where high elongation properties of the chub packaging material can detrimentally affect the dimensional stability of the filled package.
At the same time, it is believed that the blown films 14a and 14b provide the necessary oxygen barrier characteristics, and also resistance to shrink during sealing resulting in stronger longitudinal seals. Stronger seals are especially desirable to reduce the possibility of rupture of the filled package and loss of the package contents.
Where as in this case the elongation properties of the laminate are reduced, it is of greater importance to insure adequate seal strength. This is because the stresses put on the package either externally or by reason of the contained food product cannot be as easily accommodated by elongation of the film.
In the preferred embodiment, the biaxially oriented core film is irradiated to a dosage of about 9 MR. A preferable range of irradiation dosage is between about 4 MR and 12 MR.
Cross-linking may also be accomplished by the addition of chemical cross-linking agents to one or more of the components of the core film prior to extrusion.
FIG. 2 shows a method of making the multilayer laminated film of the present invention. Referring to FIG. 2, a double wound half mil blown film is ply separated and one layer 14b is unwound 360� from roll 1 to place the inside of the previous double wound film on the outside. This exposes bonding layer 26b where it can be exposed to corona discharge treatment at station 3. This station is indicated to the left of upper roll 1 in FIG. 2.
The ply separated blown film is drawn over rollers past corona discharge stations 3.
At the same time, a double wound 0.60 mil stretch/shrink film is ply separated at roller 2 and drawn past other corona discharge stations 3 as depicted in the central portion of FIG. 2. At pinch roll 6, the single wound corona treated blown films from rollers 1 sandwich the single wound stretch/shrink film from roller 2 to create the multilayer laminated film of the present invention. This film is taken up on finished rolls 7. It is clear from the schematic drawing of FIG. 2 that this results in two simultaneous finished rolls 7 of film having the same construction.
The present invention may be further understood by reference to the following examples of laminated film constructions made in accordance with the present invention.
A three layer thermoplastic film was coextruded from a first melt stream of linear low density polyethylene (Dowlex 2045) and a second split melt stream of ethylene vinyl acetate copolymer (PE 204 CS95 available from El Paso) having a vinyl acetate content of about 3.6% by weight of the total resin. The coextrudate was irradiated to a dosage of 9 megarads and biaxially oriented by the blown bubble technique.
The linear low density polyethylene layers were extruded from separate extruders.
A second multilayer film was hot blown by standard coextrusion techniques, and having the following composition:
EVA=Exxon 32.89 (vinyl acetate content of about 4.5% by weight)
LLDPE=Dowlex 2045 (0.920 grams/cc density)
Tie=Plexar 169 (EVA based polymeric adhesive)
EVOH=Soarnol DT
Ten percent of an antiblocking agent was preblended with the EVA prior to extrusion. This agent includes 90% low density polyethylene blended with 10% of a colloidal silica master batch.
The hot blown film was unirradiated.
The surface of the hot blown film which had only EVA was corona treated, as were both surfaces of the biaxially oriented stretch/shrink film. A second hot blown film identical to the first film was corona treated at its EVA surface and adhered to the opposite surface of the stretch/shrink film to form a 3-film laminate.
A multilayer laminate like that of Example 1 was produced, with the difference that in place of the outer layer having a blend of 90% EVA and 10% antiblock, a blend of 90% LLDPE (Dowlex 2035) having a density of 0.920 grams/cc was blended with 10% antiblock.
This laminated film had the same gauges as in Example 1, i.e. two outer hot blown films having a thickness of 50 gauge each, and a central stretch/shrink film, biaxially oriented, having a final thickness of 60 gauge.
A laminated film like that of Example 1 was produced, but with the outer hot blown films having a thickness of 75 gauge instead of 50 gauge.
Gauge variation was obtained by decreasing the deflate speed of the hot blown tubular material.
A laminated film like that of Example 3 was produced, with the exception that in place of the 60 gauge stretch/shrink film for the core film of the laminate, a 100 gauge biaxially oriented film having the composition LLDPE/EVA/LLDPE was utilized.
The present laminated film is characterized by relatively low transverse elongation, (see Tables 1 & 2). This property ensures better dimensional stability of the filled tubular film during the filling step of a VFFS process. However, it also puts greater stress on the longitudinal seal of the packaging, since less of the force exerted on the chub package during filling can be accommodated by transverse elongation of the tubular package.
For this reason, improved sealing characteristics are an important attribute of this film. In Tables 3 & 4, seal data is presented which demonstrates the improved seal strength of films of the present invention.
In Table 1, Examples 1 and 2 correspond to Examples 1 and 2 as described above. Comparative Example 1 refers to the HS660 film, and comparative Example 2 refers to the HS2000 film.
In Table 2, Examples 3 and 4 correspond to examples 3 and 4 as described above. Comparative Example 1 refers to the HS660 film, and comparative Example 2 refers to the HS2000 film.
In Table 3, Examples 1 and 2 correspond to the same examples as described above. Comparative Example 2 refers to the HS2000 film.
In Table 4, Examples 3 and 4 correspond to the same examples as described above. Comparative Example 2 refers to the HS2000 film.
Seals were applied with a Sentinel Sealer, equipped with a 1/8 inch seal bar at 40 psi seal pressure. Seal temperatures of 250� F. and 275� F. were used. Seal strength was determined using a CRE1000 Scott Tester. The seals were pulled in the conventional manner (designated "peel strength" in Tables 3 and 4) and also sheared.
As Tables 3 and 4 indicate, peel and shear strength at both 250� F. and 275� F. were improved, in some cases greatly improved, for the four examples of the present invention in comparison with comparative Example 2, with the exception of a weaker peel strength at the lower temperature for Example 2.
TABLE 1______________________________________Elongation1 (%) at 73� F. at Break Example Example Comparative Comparative 1 2 Example 1 Example 2______________________________________Longitudinal 185.7 211.8 521.6 337.8 (1.78) (1.71) (2.08) (2.18)Transverse 199.6 232.6 624.5 592.0 (1.79) (1.78) (2.03) (2.10)______________________________________ 1 ASTM D88281 20 inches/minute draw rate; 2 inches initial length. All values are averages obtained from four (4) replicate measurements. Film gauges are indicated in parenthesis.
TABLE 2______________________________________ Example Example Comparative Comparative 3 4 Example 1 Example 2______________________________________Longitudinal 193.6 199.8 521.6 337.8 (2.12) (2.61) (2.08) (2.18)Transverse 142.7 173.4 624.5 592.0 (2.00) (2.67) (2.03) (2.10)______________________________________
TABLE 3______________________________________SEAL STRENGTH DATA Comparative Example 1 Example 2 Example 2______________________________________Peel Strength 4.23 0.57 1.22(at 250� F.) �0.61 �0.67 �0.16Peel Strength 5.07 3.03 1.26(at 275� F.) �0.47 �0.59 �0.26Shear Strength 10.98 9.42 6.37(at 250� F.) �1.92 �1.15 �0.21Shear Strength 9.81 8.37 6.71(at 275� F.) �1.14 �0.64 �0.39______________________________________
TABLE 4______________________________________Seal Strength Data Comparative Example 3 Example 4 Example 2______________________________________Peel Strength 3.54 4.27 1.22(at 250� F.) �0.93 �1.29 �0.16Peel Strength 6.62 5.85 1.26(at 275� F.) �0.90 �1.52 �0.26Shear Strength 13.82 13.83 6.37(at 250� F.) �1.67 �1.83 �0.21Shear Strength 11.43 17.73 6.71(at 275� F.) �1.63 �2.65 �0.39______________________________________
A five layer thermoplastic film is coextruded from a first and fourth melt stream of a blend of linear low density polyethylene, linear medium density polyethylene, and ethylene vinyl acetate copolymer. A second melt stream of ethylene vinyl alcohol copolymer, and a split melt stream of a polymeric adhesive are also coextruded with the blend, to produce a five layer film having the construction:
This biaxially oriented film is bonded on each of its major surfaces to a hot blown film having the construction of the hot blown film of any of the previous examples, but without the presence of EVOH.
The hot blown films are adhered to each of the major surfaces of the core layer of biaxially oriented film by means of corona bonding.
A laminated film like that of Example 1 is produced, with the difference that in place of the EVOH, a vinylidene chloride copolymer having a methyl acrylate comonomer is used. This material is commonly known as Saran.
A laminated film like that of Example 5 is produced, but having in the biaxially oriented film, in place of the EVOH, a vinylidene chloride copolymer with a methyl acrylate comonomer.
A laminated film like that of Example 6 is made, with the difference that in place of the vinylidene chloride methyl acrylate copolymer, vinylidene chloride vinyl chloride copolymer is used.
A laminated film like that of Example 7 is made, with the difference that in place of the vinylidene chloride methyl acrylate copolymer, a vinylidene chloride vinyl chloride copolymer is used.
While the present invention has been described with respect to preferred embodiments and specific examples, it will be understood by those skilled in the art that modifications may be made after review of the description of the invention without departing from the spirit and scope of the claims that follow.
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'40' - a Kate Moss Retrospective
17 Jan 2014 – 15 Feb 2014
Event times
Gallery open 10am-6pm
Cost of entry
- 27a Devonshire Street
- Marylebone
- London
- United Kingdom
- www.imitatemodern.com
Travel Information
- Short walk from Baker Street or Regent's Street.
AboutWe are hugely excited to present this incredible exhibition celebrating one of the most photographed icons of our times. Beautiful Crime and Imitate Modern present â40â³; a retrospective of Kate Moss by artist Russell Marshall, to coincide with her 40th birthday. Featuring ten photographs spanning her career, we are reminded of Kate Moss newly emerging into the fashion industry to her present day career heights. Marshall has taken these photographs and created ten canvases, in ten different colour combinations, to give a stunning visual tour through Kate Moss's career as a model. Each image is available in the ten colour combinations, producing 100 unique screen-printed images, original, stamped and signed by the artist.
Art form
Have you been to this event? What do you think? Join the discussion here!
Remember, you can include links to your instagram pictures and to videos.


text: File photo [ Veterans Drive To Close Again Thursday Night By Lee Voss April 27, 2011 The Stearns County Engineer's Office says Veterans Drive will be closed again Thursday night into Friday morning. Veterans Drive will be closed from 7:00 p.m. Thursday until 7:00 a.m. Friday for sewer and water crossings Read More|Comment Category: St. Cloud News Tags: road closure, sauk river, stearns county engineer's office, veterans drive, west metro corridor project Send to a friend! Share on Facebook Share on Twitter Pin it! Reddit This! Share on Tumblr!


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Is Rio's Tough Love Strategy Against Violence Working?
December 13, 2011 // 9:00am — 11:30am
A conference to examine the effects of the Rio de Janeiro Pacifying Police Units (UPPs).
The Impact of the Israeli/Palestinian Conflict on the Arab and Jewish Diasporas in Latin America
December 09, 2011 // 9:00am — 10:30am
Kaufman's study builds on previously explored interactions among the homeland, diasporas, and the host country by highlighting the actual and potential links among both Arab and Jewish communities specifically in Latin America and their relation to the Israeli-Palestinian conflict.
The Americas and the World: Public Opinion and Foreign Policy in Brazil, Colombia, Ecuador, Mexico, And Peru
November 29, 2011 // 2:30pm — 5:00pm
CIDE University in Mexico City, the Woodrow Wilson Center's Latin American Program, the Inter-American Dialogue, the Latin American Initiative at the Brookings Institution, and the CSIS America's Program were pleased to host the launch of the report on public opinion in the Americas.
The Unconquered: In Search of the Amazon's Last Uncontacted Tribes
November 21, 2011 // 3:00pm — 5:00pm
Former Public Policy Scholar and author Scott Wallace presented his new book, The Unconquered: In Search of the Amazon's Last Uncontacted Tribes.
Addressing Gender-Based Violence Across Humanitarian Development in Haiti
November 15, 2011 // 12:00pm — 2:00pm
The earthquake in Haiti hit the most vulnerable -- particularly women and girls -- the hardest. Within the first week, reports of sexual violence emerged, as did stories of women and girls struggling to access assistance and living in crowded and unsafe camps. Now, almost one year later, hear from the organizations that remain in place and are gauging their success while also offering innovative solutions.
Following the Money Trail in Central America: Money Laundering and Implications in Regional Security
November 09, 2011 // 12:30pm — 2:30pm
The Red Centroamericana de Pensamientos e Incidencia discussed their recently published paper, "Following the Money Trail in Central America: Money Laundering and Implications for Regional Security."
Criminal Organizations and Illicit Trafficking within Guatemala's Border Communities
November 03, 2011 // 8:30am — 11:30am
The authors of a new CNA study on the effects of criminal organizations and illicit trafficking on Guatemala's border communities discussed theirs findings together with others.
Argentina's Presidential Elections: A Post-Elections Assessment
October 28, 2011 // 9:00am — 11:00am
A distinguished panel of experts discussed the election results and what they tell us about Argentina's current realities and prospects for the future.
Fixing Haiti: MINUSTAH and Beyond
October 19, 2011 // 8:30am — 11:00am
Panelists will discuss Haiti's decades of complex political crises and severe social problems, as well as the current government's plans for the future.
Peru under Humala: Perspectives for Change?
October 14, 2011 // 9:00am — 11:30am
In October, two months after Ollanta Humala took office as president of Peru, a panel of experts will join us to examine policy initiatives emanating from the new administration in the light of long-standing issues and challenges.


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Goo Goo Dolls
Love this picture!!
Is this a remix? I like it. It has more of a chance on the radio.
LOVE this song <3
Easily my go-to CD since the day it came out. I've had to purchase it at least three times due to wearing it out and taking it everywhere with me LOVE.
I agree....John needs his hair back.


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Jeremy Renner was presenting an award at the Golden Globes with Jennifer Lopez when he decided to comment on the pop star's low-cut dress and cleavage.
Kevin Spacey was being interviewed before the Golden Globes with Kate Mara. A reporter asked him to do his Frances Underwood impression, but he says, "No baby."


text: Best Music Of 2008 Top 10 Great Unknowns, From Second Stage January 1, 2009 It was an unusually strong year for great unknown artists. While bigger, more established bands continued to attract the most attention, smaller, lesser-known acts made the most memorable music of 2008. All of the great unknown artists featured here made music that was inspired, original and heartfelt. Listen Loading… Playlist Download Embed Embed Close embed modal <iframe src="http://www.npr.org/player/embed/98206712/98932091" width="100%" height="290" frameborder="0" scrolling="no">


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Culture and community groups awarded more than £30,000 by Hampshire County Council
Thursday, 03 July 2014
From street entertainers to symphony orchestras and joyful jams in older people's homes, the groups who help keep Hampshire's arts and culture open to all are to share in £32,795 grants from Hampshire County Council.
The grants were awarded by Councillor Keith Chapman, Hampshire County Council's Executive Member for Culture, Recreation and Countryside, at his decision day on Thursday 3 July.
The money was distributed from the Culture and Community Activities Grants. These grants provide general support, up to a maximum of £5,000, to groups and organisations which encourage and provide opportunities for individuals and communities to participate in community focussed, cultural and recreational activities.
Cllr Chapman said: "These groups provide opportunities for people to participate and enjoy a range of community focused, cultural and recreational activities. This complements our work in many ways and the investment we make supports the wider economic, cultural and social wellbeing for Hampshire residents and all the benefits that brings."
The Eastleigh Mela is in its ninth year and is a free festival to promote community learning about cultures and people, while celebrating the diverse range of cultures that already make up the local community.
Romsey's Beggars Fair has been running since 1993 and aims to showcase local talent in a friendly environment.
Most Read
- Work complete at Hartford Bridge Flats
- Forces grants benefit Totton, Waterside and South Wonston communities
- Celebrating National Care Home Open Day 19 June 2015 - come and join in the fun
- Countdown to the reopening of the Meon Valley Trail
- North Hampshire to benefit from £20 million schools investment


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When it comes to the topic of foreplay, most articles out there are on foreplay tips for the benefit of women. However, you should know that if you treat your boyfriend/husband/lover to some great foreplay tricks of your own, you'll be a sex goddess in his eyes because his orgasm will be extremely more powerful than before!
So, the next time you guys have a romp, don't be one of the women out there who 'nag' they don't get enough foreplay. Instead, surprise him with pre-play moves that will make him treat you like a sex queen.
Men are such visual creatures. Show them a nude photo, and blood gushes to their member. Hmmm, so what about presenting him with not just a nude photo of yourself but simply you, 100% nude.
How best to do it: Let us count the ways… try any of the tips below.
For the last tip be sure he gets to see everything but won't be able to touch. Feed his eyes and maybe even his sense of smell… but don't let him touch you. At least, not until he begs for it.
I bet you didn't know how sexy and arousing your very own steamy breath on his exposed skin can be. The reason behind this is that your warm breathe will cause a temperature change on his skin, which in turn increases sexual arousal.
How best to do it: Engage in foreplay. When he's already warm and aroused, go down and position your slightly parted lips to a sensitive area of his body such as his inner thighs, belly button, or the side of his neck, and then exhale your warm breathe on that spot.
You can also try the link-and-breathe approach. For example, lick the side of his neck and then exhale lightly on it. (Personally, my boyfriend loves it when I lick his lips and then exhale on it.) Another thing to try this trick on: lick his nipples and blow on it!
Now, go down and with his erect manhood standing mighty proud in front of your face, blow a steady jet of warm breath on his penis from top to bottom. Mind-blowing!
Ok, so by now you know that both men and women will benefit greatly with a lot of foreplay. However, there is a difference; while women tend to go for slow seduction foreplay techniques; men tend to want more vigorous pre-play sessions.
I guess this is because most men tend to look at women as the 'shy' or 'less animalistic' one in bed. As such, if you unleash a more 'raw' you in bed, your man will be turned on all the more by this new, slightly more sexually aggressive you. You see, men take female aggressiveness in bed as assign of pure lust, which further fuels their desire. Besides, it's A LOT of fun to be the one in control in bed every now and then, right?
How best to do it: Tonight, don't be the timid one. Be the one to approach him and initiate sex. Be the one to kiss him roughly. And last, but definitely not the least, be the one to command what sexual positions you guys should engage in.
For example, if he's angling to go down on you, change positions and go down on him instead! OR maneuver in bed in such a way that he doesn't go down on you but you sit on his face instead. Further, if he's angling for the missionary, go ahead and beat him to it by going woman-on-top. And don't just do the usual woman-on-top (where you face him), do reverse cow-girl where you face his feet.
I guarantee he won't know what hit him in bed… but he'll like it!
True, all men desire to have your lovely hands on their members but your lover can also receive a few other types of touches not just down there but all over his body. You see, men require a lot of hands-on stimulation and it should not necessarily all be focused on his penis.
How best to do it: Tonight, mix up your touchy feely moves. Flatten your palms and grope him all over. The warmth of your palms should make him feel warm all over too. Feel free to grab him too. For instance, run your palms all over his chest, reach down, reach back, and then grab a handful of his buttocks!
When he's already undressed, run your palms slightly roughly across his chest and then very gently caress his erect nipples with your flat palms. The rough and then gentle approach will surely drive him wild!
You can also opt to need his back with long hand strokes or graze his sides gently with your fingernails. Mix up the sensations and he'll be sexually dazzled he won't know what to expect.
Nothing can be more sexually mind-blowing than ALMOST reaching a climax, ebbing, and then being brought up to that 'almost there' high again. Yes, tease your man tonight until he literally begs you for release.
How best to do it: Show him how romantic you are by drawing an imaginary heart shape over his groin with your lips! Trace the outline of his groin slowly by planting kisses and/or using your tongue. This will make him focus and pay sole attention to his groin. Now, perform fellatio. Just when you sense he's nearing his release… let go of his member and go back to your lazy heart shape drawing again!
To up the ante, ride him for all you're worth. And just when he - or you! - are about to come, let go and engage in some hot, passionate kissing. Then go back up on that horse again for the next round!
Following is a list of unusual sexual stimulants that you may want to try too to add more fun to your foreplay.
Snapshots. Let him play with is camera and snap a picture of you… naked… while on top of him.
Wigs. Walk into the bedroom with nothing on but a completely different wig. He'll think you're somebody else… and you get to be somebody else in bed too.
Stockings. Bondage sounds such a harsh word. Tonight, wear a sheer body suit and as he peels it off your body, whisper something like "honey, why don't you tie my hands and show me who's my daddy?".
RED, very red lipstick. I know what you're thinking, draw lazy circles and cute heart shapes all over his body, right? You can do that… OR write down dirty words all over his body. I bet your man prefers the latter!
Take just a minute to check out 'Blow His Mind Tonight': "What Your Man Secretly Wishes You Knew About Oral Sex… But Will Never, Ever Tell You To Your Face!"
Related articles:


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- Canada
Member Since:
September 9th, 2011
About J McCombie
WELCOME! ... to each and every one of you.
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As they say, art is a form of personal expression. This website is able to offer you several options on what background material and size you would like the artist's work to be printed. However here, I am also offering you the opportunity to personalize even further the artwork you choose by providing the option of formats the artwork could take. What you see here doesn't necessarily mean it's what you have to get.
For example … you might wish one of my "Colourful Individuals" photographs as: "Black and White" (plain, textured or embossed); "Sepia" (plain or embossed); "Painted" (with or without texture) or just have the original "Embossed"; or you could go even further and have one made into something more digitally manipulated as in my "Individuals of Different Shapes" Gallery … or even more abstract as in my "Colour Composition of Nature" Gallery. You might favour one of my mixed media "Portraits" in a different colour. Perhaps you would like to select several items to be made into a collage or have a collage broken down into individual pieces. You may wish an item to be flipped horizontally or vertically or the name of your final decision to be printed on it. I have tried to design the Galleries so they can all be mixed and matched for any particular artistic statement you might wish to make. So, this website is about you and what you like … I'm just providing pieces and abilities I have to help you do that.
If you see an item in any one of my Galleries and would like to see it in the format of another, or even a format I haven't tried yet … don't hesitate to drop me a line. I would be more than happy to help make the artwork you choose fit YOUR personal expression!
I hope you've enjoyed what you've seen. May whatever you purchase be a good representation of you! And if your artistic expression changes, please allow me to help you convey it with another piece at that time. Thanks again for your visits and your purchases! ...J. McCombie
I know ... I'm supposed to have a biography in this space - so, here's a little about me ...
DRAWING: A friend drew a portrait for me in the late 1970's ... so I thought I would give it a try and have been drawing pencil portraits since for myself, family and friends. Some have been submitted to magazines. April 2012 marked my first attempts drawing animals with colour pencil; June 2013 was my first attempt with cars in black and white pencil; September 2013, flowers; and October 2014 my first attempt with soft pastels.
PHOTOGRAPHY: I began just a few years ago to take photographs of the beauty in my own backyard.
PAINTINGS, DIGITAL ART and MIXED MEDIA: Since I began uploading those photographs and drawings to sell here, I've begun to mess around with them on the computer ... just for something different.
THE FUTURE: I'm hoping to expand my artistic ability to more genres as time passes. For the present, all skills which have brought me to this point pertaining to what you see on this website are still evolving ... because they are all self-taught.
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Respond to Review of Kadena's
by andreafbe
Review: We were only in Missoula for the day. I don't know the town well at all. I used Happy Cow for an idea of places to eat and was concerned that there weren't many places that were reviewed. We chose Kadena's b/c it sounded like it had a lot of choices for vegans. The food was not very good at all. As for the salads, they only have one type of dressing and it is a creamy parmesan - that's it, nothing else. Obviously salads are not an option. I ordered a pasta dish and my husband ordered a sandwich. All in all, it was not worthwhile. Clearly I would not go here again. I'd try any of the other places listed on Happy Cow in Missoula before coming here.
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A device useful for localized delivery of a therapeutic agent is provided. The device includes a structure including a porous polymeric material and an elutable therapeutic agent in the form of a solid, gel, or neat liquid, which is dispersed in at least a portion of the porous polymeric material. Methods for making a medical device having a blood-contacting surface is also provided. One method involves: providing a structure comprising a porous material; contacting the structure comprising a porous material with a concentrating agent to disperse the concentrating agent throughout at least a portion of the porous material; contacting the structure comprising a porous material and the concentrating agent with a solution of a therapeutic agent; and removing the therapeutic agent from solution within the porous material at the locations of the concentrating agent. Another method involves multiple immersion steps without the use of a concentrating agent.
1. A stent delivery system for delivering and deploying a stent within a body lumen, comprising:
a catheter having a dilatation balloon disposed on a distal end thereof; and
a stent disposed on the dilatation balloon, wherein the stent includes a porous material disposed on an outer surface thereof having a precipitating agent and a therapeutic agent therein, wherein the precipitating agent is comprised of a material different from that of the therapeutic agent and has an affinity for the therapeutic agent.
2. The stent delivery system of
3. The stent delivery system of
4. The stent delivery system of
5. The stent delivery system of
6. The stent delivery system of
7. The stent delivery system of
8. The stent delivery system of
The present application is a continuation of U.S. Ser. No. 09/070,192, filed Apr. 30, 1998, abandoned, which is a continuation-in-part application of U.S. Ser. No. 08/728,541, filed Oct. 9, 1996, U.S. Pat. No. 5,776,184, which is a division of U.S. Ser. No. 08/482,346, filed on Jun. 7, 1995, U.S. Pat. No. 5,679,400, which is a continuation-in-part of 08/052,878, filed on Apr. 26, 1993, U.S. Pat. No. 5,464,650.
This invention relates to a medical device employing a therapeutic agent as a component thereof. For example, in an arterial site treated with percutaneous transluminal coronary angioplasty therapy for obstructive coronary artery disease a therapeutic antithrombogenic substance such as heparin may be included with a device and delivered locally in the coronary artery. Also provided is a method for making a medical device capable of localized application of therapeutic agents.
Medical devices which serve as substitute blood vessels, synthetic and intraocular lenses, electrodes, catheters, and the like, in and on the body, or as extracorporeal devices intended to be connected to the body to assist in surgery or dialysis are well known. For example, intravascular procedures can bring medical devices into contact with the patient's vasculature. In treating a narrowing or constriction of a duct or canal percutaneous transluminal coronary angioplasty (PTCA) is often used with the insertion and inflation of a balloon catheter into a stenotic vessel. Other intravascular invasive therapies include atherectomy (mechanical systems to remove plaque residing inside an artery), laser ablative therapy, and the like. However, this use of mechanical repairs can have adverse consequences for the patient. For example, restenosis at the site of a prior invasive coronary artery disease therapy can occur. Restenosis, defined angiographically, is the recurrence of a 50% or greater narrowing of a luminal diameter at the site of a prior coronary artery disease therapy, such as a balloon dilatation in the case of PTCA therapy. In particular, an intra-luminal component of restenosis develops near the end of the healing process initiated by vascular injury, which then contributes to the narrowing of the luminal diameter. This phenomenon is sometimes referred to as "intimal hyperplasia." It is believed that a variety of biologic factors are involved in restenosis, such as the extent of the injury, platelets, inflammatory cells, growth factors, cytokines, endothelial cells, smooth muscle cells, and extracellular matrix production, to name a few.
Attempts to inhibit or diminish restenosis often include additional interventions such as the use of intravascular stents and the intravascular administration of pharmacological therapeutic agents. Examples of stents which have been successfully applied over a PTCA balloon and radially expanded at the same time as the balloon expansion of an affected artery include the stents disclosed in U.S. Pat. No. 4,733,665 (Palmaz), U.S. Pat. No. 4,800,882 (Gianturco), and U.S. Pat. No. 4,886,062 (Wiktor).
Also, such stents employing therapeutic agents such as glucocorticoids (e.g. dexamethasone, beclamethasone), heparin, hirudin, tocopherol, angiopeptin, aspirin, ACE inhibitors, growth factors, oligonucleotides, and, more generally, antiplatelet agents, anticoagulant agents, antimitotic agents, antioxidants, antimetabolite agents, and anti-inflammatory agents have been considered for their potential to solve the problem of restenosis. Such substances have been incorporated into (or onto) stents by a variety of mechanisms. These mechanisms involve incorporating the therapeutic agents into polymeric coatings and films, including hydrogels, as well as covalently binding the therapeutic agents to the surface of the stent.
For example, therapeutic agents have been dissolved or dispersed in a solution of polymer in an organic solvent. This is then sprayed onto the stent and allowed to dry. Alternatively, therapeutic agents have been incorporated into a solid composite with a polymer in an adherent layer on a stent body with fibrin in a separate adherent layer on the composite to form a two layer system. The fibrin is optionally incorporated into a porous polymer layer in this two layer system. The therapeutic agent, however, is incorporated into the underlying solid polymer. The overlying porous polymer layer provides a porous barrier through which the therapeutic agent is transferred.
Conventional methods of loading the therapeutic agent into a polymer, such as spray coating, do not provide high concentrations of therapeutic agents. Typically, upon spray coating a therapeutic agent onto a stent body, only about 2 percent of the spray is captured by the stent. This can be prohibitively expensive for therapeutic agents that are extremely costly and scarce, such as peptidic drugs.
Thus, what is needed is a medical device, preferably, a stent, having a porous polymeric material, typically a polymer layer in the form of a coating or film, with a therapeutic agent incorporated therein at sufficiently high concentrations that the therapeutic agent can be delivered over an extended period of time. Improved methods by which the therapeutic agent can be incorporated into the porous polymeric material with lower levels of waste are also needed.
This invention relates to a medical device having a porous polymeric material with a therapeutic agent therein. Preferably, the device according to the invention is capable of applying a highly localized therapeutic agent into a body lumen to treat or prevent injury. The term "injury" means a trauma, that may be incidental to surgery or other treatment methods including deployment of a stent, or a biologic disease, such as an immune response or cell proliferation caused by the administration of growth factors. In addition, the methods of the invention may be performed in anticipation of "injury" as a prophylactic. A prophylactic treatment is one that is provided in advance of any symptom of injury in order to prevent injury, prevent progression of injury or attenuate any subsequent onset of a symptom of such injury.
In accordance with the invention, a device for delivery of localized therapeutic agent includes a structure including a porous material and an elutable (i.e., capable of being dissolved under physiological conditions) therapeutic agent in the form of a solid, gel, or neat liquid, which is dispersed throughout at least a portion, and preferably a substantial portion, of the porous material. Preferably, the device is capable of being implanted in a body so that the localized therapeutic agent can be delivered in vivo, typically at a site of vascular injury or trauma. Preferably, the porous material is biocompatible, sufficiently tear-resistant, and non-thrombogenic.
The porous material may be a layer (e.g., a film, i.e., a sheet material or a coating) on at least a portion of the structure. Alternatively, the porous material may be an integral portion of the structure. Preferably, the porous material is a polymeric material selected from the group of a natural hydrogel, a synthetic hydrogel, silicone, polyurethane, polysulfone, cellulose, polyethylene, polypropylene, polyamide, polyester, polytetrafluoroethylene, and a combination of two or more of these materials. Examples of natural hydrogels include fibrin, collagen, elastin, and the like. More preferably, the porous polymeric material is a nonswelling biostable polymer selected from the group of silicone, polyurethane, polysulfone, cellulose, polyethylene, polypropylene, polyamide, polyester, polytetrafluoroethylene, and a combination of two or more of these materials.
The therapeutic agent can be one or more of a wide variety of therapeutic agents, including peptidic drugs. Preferably, the therapeutic agent includes an antithrombotic material. More preferably, the antithrombotic material is a heparin or heparin derivative or analog. Such therapeutic agents are soluble in water such that they elute from the porous polymeric material.
The structure of the device can be adapted for its intended extracorporeal or intravascular purpose in an internal human body site, such as an artery, vein, urethra, other body lumens, cavities, and the like or in an extracorporeal blood pump, blood filter, blood oxygenator or tubing. In one aspect of the invention, the shape is preferably generally cylindrical, and more preferably, the shape is that of a catheter, a stent, or a guide wire. In particularly preferred embodiments, the medical device is an intralumenal stent.
The invention also provides methods for making a medical device which includes therapeutic agents. In one embodiment, a method of the invention includes: providing a structure comprising a porous material; contacting the structure comprising a porous material with a concentrating agent to disperse the concentrating agent throughout at least a portion of the porous material; contacting the structure comprising a porous material and the concentrating agent with a solution of a therapeutic agent; and removing the therapeutic agent from solution within the porous material at the locations of the concentrating agent.
The present invention also provides a method for making a medical device that includes: providing a structure comprising a porous material; immersing the structure comprising a porous material in a saturated solution of a therapeutic agent for a sufficient period of time to allow the solution to fill the porous material; removing the medical device from the solution; drying the medical device; and repeating the steps of immersing, removing, and drying to provide a therapeutic agent dispersed within the porous material. Preferably, the method further includes a step of removing air bubbles from the porous material while being immersed in the solution of the therapeutic agent. The step of removing air bubbles from the porous material can include applying ultrasonics, reduced pressure, elevated pressure, or a combination thereof, to the solution. Preferably, the method involves loading a stent having a porous polymeric film thereon, and subsequently applying an overlayer of a polymer.
A therapeutic agent may be loaded onto a structure including a porous material at any number of points between, and including, the point of manufacture and the point of use. For example, the device can be stored and transported prior to incorporation of the therapeutic agent. Thus, the end user can select the therapeutic agent to be used from a wider range of therapeutic agents.
One of the more preferred configurations for a device according to the invention is a stent for use in artery/vascular therapies. The term "stent" refers to any device capable of being delivered by a catheter and which, when placed into contact with a portion of a wall of a lumen to be treated, will also deliver localized therapeutic agent at a luminal or blood-contacting portion of the device. A stent typically includes a lumen wall-contacting surface and a lumen-exposed surface. Where the stent is shaped generally cylindrical or tube-like, including a discontinuous tube or ring-like structure, the lumen-wall contacting surface is the surface in close proximity to the lumen wall whereas the lumen-exposed surface is the inner surface of the cylindrical stent. The stent can include polymeric or metallic elements, or combinations thereof, onto which a porous material is applied. For example, a deformable metal wire stent is useful as a stent framework of this invention, such as that described in U.S. Pat. No. 4,886,062 (Wiktor), which discloses preferred methods for making a wire stent. Other metallic stents useful in this invention include those of U.S. Pat. No. 4,733,655 (Palmaz) and U.S. Pat. No. 4,800,882 (Gianturco).
Other medical devices, such as heart valves, vascular grafts, pacing leads, etc., can also include the embodiments of the present invention. As used herein, medical device refers to a device that has surfaces that contact tissue, blood, or other bodily fluids in the course of their operation, which fluids are subsequently used in patients. This can include, for example, extracorporeal devices for use in surgery such as blood oxygenators, blood pumps, blood sensors, tubing used to carry blood and the like which contact blood which is then returned to the patient. This can also include endoprostheses implanted in blood contact in a human or animal body such as vascular grafts, stents, pacemaker leads, heart valves, and the like that are implanted in blood vessels or in the heart. This can also include devices for temporary intravascular use such as catheters, guide wires, and the like which are placed into the blood vessels or the heart for purposes of monitoring or repair.
Referring now to
Polymeric stents can also be used in this invention. The polymers can be nonbioabsorbable or bioabsorbable in part, or total. Stents of this invention can be completely nonbioabsorbable, totally bioabsorbable or a composite of bioabsorbable polymer and nonabsorbable metal or polymer. For example, another stent suitable for this invention includes the self-expanding stent of resilient polymeric material as disclosed in International Publication No. WO 91/12779 (Medtronic, Inc.).
Nonbioabsorbable polymers can be used as alternatives to metallic stents. The stents of this invention should not substantially induce inflammatory and neointimal responses. Examples of biostable nonabsorbable polymers that have been used for stent construction with or without metallic elements include polyethylene terephthalate (PET), polyurethane urea, and silicone. Although the porous material is shown as a coating 24, it is to be understood that, for the purposes of this invention, the porous material can be incorporated into the material of the stent.
Referring to
Porous Material
As mentioned above, the device according to the invention is generally a structure including a porous material. In one embodiment, the porous material includes a polymeric film or coating on at least a portion of the structure. In another embodiment, the porous material is an integral portion of the structure. Preferably, the porous material is a biocompatible polymer and is sufficiently tear-resistant and nonthrombogenic. Examples of suitable polymers are disclosed in U.S. Pat. No. 5,679,400 (Tuch). More preferably, the porous material is selected from the group of a natural hydrogel, a synthetic hydrogel, silicone, polyurethane, polysulfone, cellulose, polyethylene, polypropylene, polyamide, polyester, polytetrafluoroethylene, and a combination of two or more of these materials. Examples of natural hydrogels include fibrin, collagen, elastin, and the like. In materials which do not include pores in their usual structural configurations, pores of about 10 micrometers in diameter or as large as 1000 micrometers in diameter can be introduced by conventional means such as by introducing a solvent soluble particulate material into the desired structure and dissolving the particulate material with a solvent.
Typically, and preferably, the porous material is in the form of a sheet material or coating of a nonswelling biostable polymer. As used herein, a "nonswelling biostable" or "nonswellable biostable" polymer is one that does not absorb a significant amount of water (i.e., it absorbs less than about 10 weight percent water) and it is not readily degraded in the body. Such nonswelling biostable polymers include, for example, silicone, polyurethane, polysulfone, cellulose, polyethylene, polypropylene, polyamide, polyester, polytetrafluoroethylene, and combinations thereof. If the polymer is biodegradable, the rate at which it degrades is slower than the rate at which the therapeutic agent elutes.
If the porous material is in the form of a porous sheet (i.e., film) or coating, it can be made by a variety of methods. These methods can include, for example, using a solid particulate material (also referred to herein as pore-forming material) that can be substantially removed after the film or coating is formed, thereby forming pores. By using a solid particulate material during film or coating formation, the size of the pores can, to some extent, be controlled by the size of the solid particulate material being used. The particulate material can range from less than about 1 micrometer in diameter to about 1000 micrometers, preferably about 1 micrometer to about 100 micrometers, more preferably about 5 micrometers to about 50 micrometers. For uniformity of pores, the particulate material can be screened through successively finer mesh sieves, e.g., through 100, 170, 270, 325, 400, and 500 mesh analytical grade stainless steel mesh sieves, to produce a desired range of particle sizes.
The particulate material may include inorganic and organic particulate material, including, for example, sodium chloride, lithium chloride, sucrose, glucose, sorbitol, sodium citrate, sodium ascorbate, urea, citric acid, dextran, poly(ethylene glycol), sodium nitroprusside, mannitol, sodium bicarbonate, ascorbic acid, sodium salicylate, or combinations thereof. It will be understood by one of skill in the art that a mixture of different particulate materials can be used if desired. Also, it will be understood by one of skill in the art that because a portion of the particulate material may remain within the film, it is preferred that the solid particulate material be biocompatible.
Typically, the particulate material chosen is less soluble than the polymer in the chosen solvent (e.g., water or an organic solvent) used to deposit or form the polymer. The particulate material may actually be soluble in the solvent; however, to form pores, it only has to be less soluble than the polymer in the solvent of choice. As the solvent is removed from the solution, the pore-forming material will precipitate out of solution and form particles surrounded by the polymer, which is still in solution. The polymer then will come out of solution as more solvent is removed and the particles will be dispersed within the polymer. After the solvent is removed, the particulate material is removed using a liquid in which the polymer is not soluble, thereby forming pores.
In one method according to the present invention, a porous sheet material (e.g., polyurethane sheet material) can be made by dissolving a polymer (e.g., polyether urethane) in an organic solvent (e.g., 1-methyl-2-pyrrolidone); mixing into the resulting polymer solution a crystalline, particulate material (e.g., sodium chloride, sucrose, etc.) that is not soluble in the solvent; casting the solution with particulate material into a thin film; and then applying a second solvent (e.g., water), to dissolve and remove the particulate material, thereby leaving a porous sheet. Such a method is disclosed in U.S. Pat. No. 5,591,227 (Dinh et al.) and U.S. Pat. No. 5,599,352 (Dinh et al.).
Preferably, a combination of soluble and insoluble particulate material may be used to create a broader range of pore sizes. The use of a soluble particulate material, such as poly(ethylene glycol), may create small (<2 μm diameter) interconnecting pores that create a solvent path for the removal of the larger (e.g., 50 μm) particles, which may not be in particle-to-particle contact.
A suspension of particulate material may be created by first dissolving the particulate in a solvent, then precipitating the mixture in a solution of polymer in a second solvent in which the particulate is insoluble. For example, an 8% solution of sodium nitroprusside in ethanol can be added with rapid stirring to a 2% solution of polyurethane in tetrahydrofuran. The sodium nitroprusside precipitates to form a suspension of less than about 5 μm particles.
The weight ratio of pore-forming material to polymer in a coating composition may range from about 1:3 to about 9:1,preferably, about 2:1 to about 9:1, although this is not necessarily limiting. In theory, the porosity is limited by the toughness of the polymer.
A smooth coating may be obtained by applying an atomized spray to the stent. The spray should be applied at a rate such that evaporation prevents the accumulation of sufficient liquid to form drips along the stent. A macroscopically smooth surface may also be obtained by keeping the particle size less than about � of the coating or film thickness.
Although films (i.e., sheet materials) for medical devices, particularly stent bodies, according to the present invention can be manufactured separately from the support structure of the medical device and attached to the support structure after formation, preferred methods include forming the films directly on the support structure sucl that the support structure is at least partially, preferably completely, encapsulated by the film (i.e., sheet material).
Alternatively, medical devices can include a coating of a porous polymer made by spraying a solution of the polymer and particulate material directly on the support. In this way, the coating does not necessarily form a film that encapsulates the device; rather it forms a coating around the structure (e.g., wire) of the device. The geometry of the porous material (coated wires vs. sheets or films) depends on the coating substrate and is largely independent of the pore forming and application methods used. A film can be made by spraying, dipping, or casting, as long as the mandrel is a rod or a flat sheet. The stent wires can be coated by any of these methods as well, although most preferably, they are coated by spraying to prevent droplet formation.
In one such method, which is disclosed in International Publication No. WO 97/07973 (Medtronic, Inc.), a stent is placed on a mandrel. A particulate material is then applied to the mandrel and stent such that it is lightly adhered to the mandrel. The particulate material should be readily soluble in a solvent which will not also dissolve the polymer chosen for the film. For example, crystalline sodium bicarbonate is a water soluble material that can be used as the particulate material. A nonaqueous liquid, preferably a solvent for the polymer film material, can be applied to the mandrel before applying the particulate material in order to retain more of the particulate material on the mandrel. For example, when a polyurethane is to be used for the film material, the solvent 1-methyl-2-pyrrolidinone (NMP) can be used to wet the surface of the mandrel before the application of particulate material. Preferably, the mandrel is completely dusted with the particulate in the portions of the mandrel to be coated with the polymer film. This can be accomplished by dipping the mandrel in NMP, allowing it to drain vertically for a few seconds and then dusting the sodium bicarbonate onto the mandrel while rotating it horizontally until no further bicarbonate particles adhere. Excess particulate material can be removed by gently tapping the mandrel.
Coating with polymer may proceed immediately following application of the particulate material. A polymer is provided in a dilute solution and is applied to the particle-coated stent and mandrel. For example, polyurethane can be dissolved in NMP to make a 10% solution. Gel particles and particulate impurities can be removed from the solution by use of a clinical centrifuge. The polymer solution can be applied by dipping the mandrel into the solution and letting the solvent evaporate. With the solution of polyurethane and NMP, a single dip in the solution can provide a film of adequate thickness. To assist in the formation of communicating passageways through the polymer between the blood-contacting surface and the lumen-contacting surface, additional sodium bicarbonate particles are preferably dusted onto the polymer solution immediately after the dipping operation and before the polymer solution has dried. Excess particulate material can be removed by gently tapping the mandrel. To precipitate and consolidate the polyurethane film on the stent, it can be dipped briefly (about 5 minutes) in water and then rolled gently against a wetted surface, such as a wet paper towel. The stent assembly can then be placed into one or more water baths over an extended period (e.g., 8 hours) to dissolve and remove the sodium bicarbonate. After drying in air at temperatures from about 20� C. to about 50� C., the film then can be trimmed to match the contour of the wire.
In yet another method, a solvent in which the polymer is soluble that is capable of phase separating from the polymer at a reduced temperature can be used to prepare a porous polymer film. In this method, the stent or other medical device is placed in a cavity of a mold designed for forming a film around the stent, similar to that disclosed in U.S. Pat. No. 5,510,077 (Dinh et al.). A solution of the desired polymer, such as polyurethane, dissolved in a solvent, such as dioxane, is added to the mold. The temperature of the solution is then reduced to a temperature at which the solvent freezes and phase separates from the polymer, thereby forming particulate material (i.e., frozen solvent particles) in situ. Typically, for polyurethane in dioxane, this is a temperature of about −70� C. to about 3� C. The composition is then immersed in an ice cold water bath (at about 3� C.) for a few days to allot the dioxane to dissolve into the ice cold water, thereby forming pores. The number and size of the pores can be controlled by the concentration of the polymer and the freezing temperature. A method similar to this is disclosed in Liu et al., J. Biomed. Mater. Res., 26, 1489 (1992). This method can be improved on by using a two-step freezing process as disclosed in U.S. Pat. No. 6,013,099.
In yet another embodiment, a porous material can be created from a mixture of a low boiling good solvent and a higher boiling poor solvent, in which the polymer is soluble. After application to the target substrate, the lower boiling good solvent evaporates preferentially until a point is reached where the polymer precipitates from the remaining solvent mixture, which is relatively richer in the poor solvent. The polymer precipitates in and around pockets of the poor solvent, creating a porous structure. The number and size of pores can be controlled by the boiling points of the two solvents, the concentration of polymer and the drying rate. An example is a 1% solution of poly(l-lactic acid) (PLLA) in a 60:40 mixture of chloroform:iso-octane. As the chloroform evaporates, the PLLA precipitates from the iso-octane to create an opague PLLA coating containing 2–5 μm pores. This method is further described in U.S. Pat. No. 5,679,400 (Tuch).
Therapeutic Agent
The therapeutic agent used in the present invention could be virtually any therapeutic agent which possesses desirable therapeutic characteristics and which can be provided in a form that can be solubilized, for example, by water or an organic solvent, and are capable of being eluted from the porous polymeric material in the body of a patient. Preferred therapeutic agents are solids, gels, or neat liquids (i.e., materials not dissolved in a solvent) at room temperature (i.e., about 20–25� C.), and preferably at body temperatures, that are capable of being eluted from the porous polymeric material in the body of a patient. For example, antithrombotics, antiplatelet agents, antimitotic agents, antioxidants, antimetabolite agents, anti-inflammatory agents, enzyme inhibitors, and anti-angiogenic factors as disclosed in U.S. Pat. No. 5,716,981 (Hunter et al.) could be used. Anticoagulant agents, such as heparin, heparin derivatives, and heparin analogs, could also be used to prevent the formation of blood clots on the device.
Methods of Making an Implantable Device
A structure having a porous material, preferably a porous polymeric material, can be loaded with one or more therapeutic agents using a wide variety of methods. For example, the porous material can be immersed in a solution or dispersion of the therapeutic agent in a solvent. The solution (preferably, a supersaturated solution) or dispersion is allowed to fill the pores and the solvent is allowed to evaporate leaving the therapeutic agent dispersed within at least a portion of the pores. The solvent can be water or an organic solvent that does not dissolve the polymer. If the solvent does not dissolve the therapeutic agent, the particles of the therapeutic agent are smaller than the pore openings. Alternatively, in certain embodiments, the solvent can be chosen such that it swells the polymer, thereby achieving a greater level of incorporation of the therapeutic agent.
The following methods for loading one or more therapeutic agents into porous material are improved over prior art methods, such as spray coating methods. Although the same amount of therapeutic agent can be loaded onto a medical device, significantly less (e.g., about 100� less) waste of the therapeutic agent occurs using the following methods. This is particularly important for expensive therapeutic agents, such as peptic drugs.
In one embodiment of the invention, filling of the pores can be enhanced through the use of ultrasonics, vacuum, and/or pressure. While the device is submerged in solution, ultrasonic energy or vacuum can be used to accelerate the removal of air bubbles from the pores allowing the pores to fill with the solution containing the therapeutic agent. Hyperbaric pressure on the solution may cause the air in the pores to be dissolved in the solution, thereby allowing the pores to fill with liquid. Furthermore, the level of incorporation can be increased by using multiple dip-vacuum-dry cycles. If the therapeutic agent saturates, the solution by 10% by volume, for example, when the solvent evaporates the pores will be 10% filled with the agent. Repeating the cycle will fill the remaining 90% void space and fill an additional 9% of the original pore volume. Further cycles continue the trend. For this procedure to be effective, however, the solution is saturated so that the previously deposited agent does not dissolve in subsequent cycles.
Preferably, a method of the invention includes loading a structure comprising a porous material with a concentrating agent, which may be a precipitating agent (e.g., a binding agent, sequestering agent, nucleating agent, etc.), a seed crystal, or the like, dispersed throughout at least a portion, preferably, a substantial portion, of the porous material, and subsequently loading the structure comprising a porous material and the concentrating agent with a solution of a therapeutic agent, wherein the therapeutic agent is removed from solution (e.g., as by crystallization and/or precipitation) within the porous material at the locations of the concentrating agent. This is a significantly improved method in that the concentrating agent provides a driving force for localization of the drug within the pores of the polymer. That is, it is believed that the concentrating agent provides a thermodynamically favorable surface for crystallization or precipitation.
The concentrating agent can be a precipitating agent or a seed crystal, for example, or any substance that can cause the therapeutic agent to fall out of solution. As used herein, a seed crystal is a solid material that is the same as the therapeutic agent being deposited. As used herein, a precipitating agent is a solid material that is different from the therapeutic agent being deposited. It can include, for example, materials that have a particular affinity for the therapeutic agent of interest, such as binding agents, sequestering agents, nucleating agents, and mixtures thereof. Examples of sequestering agents include heparin to sequester heparin binding growth factors such as bFGF and, for example, cyclodextrins to trap appropriately sized therapeutic agents to fit in their ring structures. Examples of binding agents include polycations (e.g., protamine) and polyanions (e.g., heparin sulfate) for binding anionic and cationic therapeutic agents, respectively. The binding agent can also include a counterion of a salt that is insoluble upon complexation with the therapeutic agent in the solvent used in the solution of the therapeutic agent.
The solution containing the therapeutic agent is preferably a supersaturated solution, although this is not a necessary requirement. This can be prepared at elevated temperatures taking into consideration the limits of stability of the therapeutic agents and the porous material. The porous polymeric material with concentrating agent therein can be immersed in a solution of the therapeutic agent in a solvent. The solution is allowed to fill the pores and the therapeutic agent allowed to come out of solution (e.g., as by the formation of crystals). The solvent can be water or an organic solvent that does not dissolve the porous polymer, although it may swell the polymer as described above. The choice of solvent is one that is compatible with the therapeutic agent and porous material of choice. Filling of the pores can be enhanced through the use of ultrasonics, vacuum, and/or pressure, as well as by using multiple dip-vacuum-dry cycles, as described above.
Crystal and/or precipitate formation can be initiated by a variety of mechanisms. They may spontaneously form. Alternatively, the solution of the therapeutic agent within the pores may need to be cooled to initiate crystallization and/or precipitation. It may be possible to initiate crystallization and/or precipitation by changing the pH and/or ionic strength of the solution of the therapeutic agent within the pores.
The initial concentrating agent, which may be a solid, liquid, or a gel, can be placed in the pores of the porous material by a variety of methods. For example, if the concentrating agent is a seed crystal of the therapeutic agent of interest, immersing the porous material in a solution or dispersion of the therapeutic agent in a solvent, allowing it to fill the pores, and allowing the solvent to evaporate, provides the therapeutic agent dispersed within at least a portion of the pores, as described above. Similarly, if the concentrating agent is a precipitating agent, the porous material can be immersed in a solution of this agent.
The methods of the present invention are advantageous in that the structure can be loaded with the therapeutic agent in situ, i.e., at or near the point of therapeutic use, typically before administration, preferably implantation, to a patient. This is particularly useful because the device can be stored and transported prior to incorporation of the therapeutic agent. This feature has several advantages. For example, the relevant consumer can select the therapeutic agent to be used from a wider range of therapeutic agents. Thus, the therapeutic agent selected is not limited to only those supplied with the device but can instead be applied according to the therapy required.
In order to provide additional control over the elution of the therapeutic agent, an overlayer may be applied to the medical device, as is disclosed in U.S. Pat. No. 5,679,400 (Tuch), U.S. Pat. No. 5,624,411 (Tuch), and U.S. Pat. No. 5,624,411 (Tuch). The overlayer, typically in the form of a porous polymer, is in intimate contact with the therapeutic agent and allows it to be retained on the medical device. It also controls the administration of the therapeutic agent following implantation. For a stent, an overlayer is particularly desirable to retain the therapeutic agent on the stent during expansion of the stent.
The following nonlimiting examples will further illustrate the invention. All parts, percentages, ratios, etc. are by weight unless otherwise indicated.
Wiktor stents were coated as follows: 4 grams of a 5 wt % solution of polyurethane as disclosed in U.S. Pat. No. 4,873,308 (Coury et al.) in tetrahydrofuran (THF) and 20 grams of a 5 wt % solution of citric acid in THF were combined and sprayed onto wiktor stents using an air brush, similar to the method disclosed in U.S. Pat. No. 5,679,400 (Tuch). Citric acid was extracted with deionized water for 10 minutes. The stent was then air dried at ambient temperature and weighed. The porous polyurethane coating weights were 0.5–0.7 mg.
Into a microcentrifuge tube was added 0.12 g tissue factor pathway inhibitor (TFPI) and 1.0 ml sterile water. This was agitated to dissolve the TFPI. The polyurethane coated stents were immersed in the TFPI solution, which was subjected to reduced pressure (28 inches of Hg) to evacuate the air from the pores. The stents were air dried and the immersion/vacuum process was repeated twice. After the last immersion process, stents were air dried at ambient temperature for 20 minutes. Each stent was immersed for less than two seconds in deionized water to remove TFPI on the surface of the stents. The stents were then dried in ambient temperature under vacuum for about 12 hours. The stents were weighed to determine the amount of TFPI loaded into the pores, which ranged from 0.15 mg to 0.33 mg.
Half the stents were overcoated with a 2 wt % solution of polyurethane solution in THF using the spray coating method described above, resulting in a coating weight of 0.6 mg. These stents were tested for elution. The stents with the overcoating eluted more slowly than the stents without the overcoating.
The complete disclosures of all patents, patent applications, and publications referenced herein are incorporated herein by reference as if individually incorporated. Various modifications and alterations of this invention will become apparent to those skilled in the art without departing from the scope and spirit of this invention, and it should be understood that this invention is not to be unduly limited to illustrative embodiments set forth herein.
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text:
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