text:
the accidental symbol
How Martha Hall Findlay became synonymous with "women in politics" — despite her best efforts
BY Egle Procuta
Photography by Steve Payne
A plane landed at Vancouvers International Airport last September and a tired woman gathered up her bags, her mind preoccupied with the challenges of the next few days. As the longest shot of the long shots hoping to win the top job in the Liberal Party of Canada, Martha Hall Findlay wanted to deliver a dynamite performance at the leadership debate due to take place here. But walking out into the terminal, a news flash derailed her train of thought. Carolyn Bennett, the Toronto MP also in the running, had just announced she was dropping out. Findlay immediately picked up a phone and called up Hedy Fry, the only other woman in the race. She went over to Frys home in Vancouver and the two had a long chat. Findlay spoke passionately about her belief that the leadership campaign needed as many female voices as possible. But just over a week later, Fry also decided to abandon her bid, leaving Findlay on her own to speak out for a cause she had never expected to embrace. A cause that could be mistaken for the name of a university course, or a clich.
Women in politics. It stood against a principle Findlay believed in passionately, back in February of 2006, when she set off on her seemingly quixotic quest for the Liberal leadership. That principle was merit. Here was someone so well-rounded and talented, she wanted no concession for her gender. She had minimal political experience and had never held public office, but Findlay was adamant about being treated as a contender.
Intellectual challenge didnt faze the 47-year-old Toronto lawyerher exceptional IQ allowed her to skip three grades in high school. Physical prowess was a given: she used to be a competitive downhill skier and, without a stitch of previous experience, talked her way into a job on a construction site building houses for most of a year when she was 18. And she had an enviable handle on balancing work and family, writing her bar exams the day before giving birth to the youngest of her three children, who are now in their early to mid-20s. Small wonder Findlay described herself as someone genetically programmed to get things done.
So the perception that she was one of the token women in the racelumped together with Bennett and Fry just because of her genderrankled Findlay. For the first number of months of the campaign, I repeatedly said that I was not running as a woman, she explains. I was saying Im not here to be a woman in politics, Im here to be in politics. But as she toured across Canada on the Big Red Bus that became a symbol of her bare-bones campaign, Findlay had moments of revelation that led to her transformation into an advocate for the cause she initially resisted. A cause that needs all the help it can get.
There is no clear answer for fixing what is undoubtedly a huge flaw in the democratic process in Canada. But there is also no arguing with the numbers. Women make up more than 50 percent of the population of this country, yet our record at electing female politicians ranks us a dismal 48th in the world. The United States and the United Kingdom fare even worse, placing 68th and 53rd respectively. All three countries have a first-past-the-post electoral system, whereas countries with some form of proportional representation consistently elect more women. Thats why those advocating for fairer gender representation in Canadian politics are often strong proponents of electoral reform, as was the late, great feminist Doris Anderson. Does it matter if only 21 percent of the House of Commons and our provincial legislatures are women? Anderson asked in these pages last year. Damn right it does, she said. Women often bring a different viewpoint and have different priorities than men.
But as it stands, the majority of women do not feel engaged in the political process. In fact, theyre actively disillusioned by it. Its easy to understand why. The simple numbers are a turn-off. With women so badly outnumbered in public office, its no wonder that the issues that matter most in their livesthe so-called nurturing issues revolving around family matters or ones relating to social justice (feeding the hungry instead of building the army)are marginalized in policy development.
Canadian politics is in desperate need of renewal. And the new voices and valuable skills that women could bring to the table would do wonders for injecting life into a tired old horse thats been flogged senseless. Research shows that if women had equal political representation, not only would their interest and involvement in the public arena jump significantly, it would outpace that of men.
This is not a womens issue, Findlay insists. This is a societal issue. We need more women in public office. Men need that just as much as women need that.
On a snowy Saturday afternoon in January, in the Beaches neighbourhood of Toronto, Findlay grabs some time out of a hectic schedule for this interview. Then shes off to an event at a supporters home around the corner. It is eight weeks to the day since the Liberal Party crowned Stphane Dion as its great hope to save the country from the clutches of Stephen Harpers right-wing demagoguery. The brunch crowds have long thinned out at the Beacher Caf, but a radiant Findlay fills up the twilight stillness with her enthusiasm. She is not bitter about finishing eighth in a field of eight in the leadership race. She is thrilled to be part of the team of advisors working closely with Dion, behind whom she threw her support at the convention in Montreal when she fell off after the first ballot. She is pumped about running for Parliament in the next election shes been acclaimed as the Liberal candidate in the Willowdale riding of Torontobut in the meantime, she is busy criss-crossing the country, as chair of platform outreach for the party. All in all, Findlay is an overwhelmingly positive person, and a consummate team player. One of the first things I notice about her is how often she uses the pronoun we instead of I.
But she does revert to the first person when describing her new-found calling as a role model for the cause of women in politics. After Carolyn and Hedy pulled out, Findlay says, it was absolutely clear that this was now a responsibility that I hadthat I hadnt asked for but that was so important to so many peopleto stay and to be there in Montreal.
And that inspired her mantra: Ill be damned if in the 21st century the Liberal Party of Canada doesnt have a woman on that stage in Montreal.
A wicked cold front had blown into Montreal in the dying days of November, along with thousands of Liberal delegates, volunteer organizers, party brass, journalists and just plain hangers-on addicted to the adrenaline of the increasingly archaic institution that is a leadership convention. By the Friday morning, the intensity of the freezing rain had gone up a notch, like the rhetoric. But a small meeting room on the upper levels of the Palais des congres felt like a sauna. It was packed, with more people squeezing in every minute. The buzz of excitement in the air exploded into cheers when the kitschy twang of "Man! I Feel Like a Woman" blasted over the loudspeakers. Bopping his head to the Shania Twain tune, Bob Rae strode into the room and clambered onto its small stage.
He was using the last hours before the first ballot to woo female supporters. "Join Bob Rae for Women Mentoring Women" was emblazoned across the top of a flyer that his supporters had been handing out that morning to crowds streaming into the convention centre. "Women must play an equal, meaningful role in shaping the future of Canada," the leaflet read. "Bob Rae is proud to support young women as they grow into the next generation of leaders."
As Rae told heartwarming anecdotes about how he was inspired by his grandmothers, his mother, his wife and his three daughters, a stylish woman turned to me and said, "He's going to make me cry." Rae spoke, with well-deserved pride, about having a cabinet with 40 percent women when he served as NDP premier of Ontario in the 1990s and the difference this made to the kinds of issues that were brought to the table.
A lot of nice things were said in Room 524A that morning, but it is telling that a man did almost all of the talking. The feel-good vibes went on for 35 minutes, evoking an old-fashioned prayer meeting, but it ended abruptly and Rae was gone. A couple of women in the back of the room looked less than impressed as they clutched "We love Martha" signs to their chests. Were they thinking what I was thinking: that it will take a lot more than prayers to reach the goal, as Rae had promised, of having women play "an equal, meaningful role" in Canadian politics?
The barriers keeping women from public office are well documented: lack of money, insufficient party backing and sheer lack of time, when you consider the disproportionate role women play looking after domestic responsibilities. Whats less clear is how to dismantle the barriers in a way that doesnt marginalize women even more. Rightly or wrongly, politics is perceived as a mans game and the rules of the game are ones that put many women off.
Its rare to find an issue on which Olivia Chow, the firebrand NDP MP, agrees with Janet Ecker, a former Progressive Conservative cabinet minister under ber-hard-line Ontario premier Mike Harris. But theyre both trail-blazing female politicians: Chow was the first Asian woman to serve in municipal politics in Toronto; Ecker held three of the top portfolios: finance, education and social services. And both are active supporters of the non-partisan lobby group Equal Voice, which advocates fair representation for Canadian women in elected office.
Differences in gender psychology are a key barrier, Chow says. Women like to get things done, but politicsat least the way its presented in the mediaseems to be one big power game. Who is in the cabinet, who is not. Who has power, who does not. Who has higher polling numbers, who does not. Blah, blah, blah, Chow laughs, her frustration palpable. Its not about the practical things that make peoples lives better.
Politics is perceived as a blood sport, Ecker agrees. Women are put off by the superficiality of some of the political process: the 15-second sound bites, the gotcha mentality that tends to dominate virtually every level of politics.
Its difficult to work cooperatively across party lines, she says. This is a terrible generalization, but women politicians are frequently more ready to work across the aisles. We are not better or worse: were different. But we need to have these voices at the table.
Getting these voices to the table, of course, is easier said than done. Ive asked a lot of women to run in the past, Chow says, and the common thing that I hear back is: Oh, I dont know enough. Im not quite ready. Men seldom say that theyre not ready, that they dont know enough. Most of them should think that, but they dont.
Findlay echoes this sentiment. I cant tell you the number of women who say, I dont know if I have a thick-enough skin, or I dont know if I have what it takes. And I look at them and think: Okay, you told me you have three children. You started your own business. You now employ 73 people. And you tell me you dont have a thick-enough skin and you dont think you have what it takes? Look in a mirror. Why is it that some people who are so capable and so accomplished somehow still dont think they have what it takes?
In a 2006 research paper entitled Called to Speak, the Washington-based Institute for Womens Policy Research took extensive data and boiled them down to six key strategies to boost womens political activism. One example is going out to meet women on their own turf, where they feel safe to try out unfamiliar roles. It might sound simplistic, but it gets to the heart of the matter, the reports author, Amy Caiazza, says. Another simple and profound strategy is providing political role models of women who break the mould. Despite her initial reticence about being labelled as a woman in politics, Findlay is now gratified that this is the legacy of her leadership bid.
It was a pretty risky thing for me to do, she admits, as she orders a coffee refill. She hopes that women who may be thinking about getting into politics will say, Damn it, I can do that, too, after seeing somebody like Findlay take the leap of faith and, not only survive, but come out laughing.
To describe running for the Liberal leadership as a pretty risky thing is an understatement, of course. As Findlay got set to announce her candidacy, even some of her closest friends tried to talk her out of it. Almost everybody I knowand certainly everybody I dont knowthought, Oh my god, what is she doing? This is a disaster. Shes going to fall flat on her face. Nobody knows who she is. Shes not going to be able to raise any money. She doesnt have the machine. Is she nuts?
Nuts, no. Determined, definitely.
Her first-ever foray into politics, in the federal election of June 2004, was an impressive debut. Running against then-Conservative star candidate Belinda Stronach in the Ontario riding of Newmarket-Aurora, Findlay unexpectedly came within fewer than 700 votes of beating her big-name rival. This augured well for up-till-then unknown Findlay, so she took the big financial and personal risks of moving from Collingwood, Ontario, to Newmarket, with the perfectly reasonable expectation that she would tackle the riding again in the next election.
Everything was falling into place for Findlay, until the bombshell day in May 2005 when Stronach crossed the floor. Her political reincarnation was a stay-of-execution for Paul Martin. And politics being rife with favouritism, Liberal apparatchiks decreed it was Stronach who would carry the party banner in Newmarketleaving Findlay out in the cold. Findlay took the decision like a trooper, despite her anger and wounded pride, but she also made a personal pledge to show the Liberal Party what it was missing by shunting her aside.
Martins announcement the night of the disastrous 2006 election that he would be stepping down as leader gave Findlay what she describes as a window of opportunity. When Findlay first entered the leadership race, the overwhelming reaction was Martha who? But as the 11-month campaign gathered steam, both those inside and outside the party began to take notice. Short on cash but long on enthusiasm, Findlay crossed the country in the Big Red Busactually a Damon DayBreak motor homethat quickly became her calling card. Most nights on the road, she and her campaign workers would sleep in the RV. Everybody took turns hooking up water and power on arrival in campgrounds, although Findlay does good-naturedly admit that she got a bit more time in the shower to tame the beast of bad-hair days.
She didnt espouse particularly groundbreaking policies. Some of themlike advocating a mix of private and public health-carewouldnt fall on the progressive side of the political spectrum, but Findlay did stand out as a beacon of civility, with a knack for consensus-building.
Despite all the positive feedback Findlay was getting, the Liberals cumbersome process of delegate selection was stacked against her. It was members of local riding associations that elected who got to go to Montreal, and their ranks were very heavily tilted toward candidates at the front of the pack. After the so-called Super Weekend of delegate selection in September, Findlay finished last with only 46 votes, less than one percent of committed supporters. But that didnt mean results of the first ballot of the leadership were a foregone conclusion.
Also due to vote in Montreal were close to 1,000 ex-officio delegatesMPs, senators, defeated Liberal candidates and other party officialswho didnt have to declare who they were supporting. These free agents, then, were an obvious focus of the lastminute wooing going on at the convention.
We had a small but very, very keen team in Montreal, really working the ex-officios, Findlay explains. Their efforts began to bear fruit. Toronto MP Judy Sgro made a public declaration that she would vote for Findlay on the first ballot, and she challenged other ex-officios to do the same. I think as Liberals we need to come out and give her full credit and kudos for her courage and commitment, Sgro said. The only way we can do that is to put an X beside her name.
Findlays supporters were the smallest group at the convention, of course, but, in some way, they seemed to be having the most fun. There were no laggers, no killjoys; everybody in that parade was going for broke. They snaked their way through the throngs, straining their vocal cords, chanting, Martha, Martha, Martha. Then one of the other camps started to shout Martha, Martha, too. And then another camp did the same. Recalling this moment, two months later, Findlay is still incredulous. It was so fantastic ... it just indicated that regardless of the competitive thing, we had somehow resonated.
Findlay received only 130 votes on the first ballot, and was dropped from the race (her next-closest rival, Joe Volpe, had 156 votes). She threw her support behind Dion, who shared her keen intellect and commitment to party renewal, but many of her supporters were crushed that Findlays run for the Liberal crown had ended this way. Its a dark day for Liberals, said Janet Maxwell, a high school special education teacher, and long-time party loyalist. She was particularly disillusioned that more people had voted for Volpe, whose campaign had been marked by a fundraising scandal and who, Maxwell felt, made a rather tasteless reference to Findlay in his speech the night before by boasting about how he toured Canada in his little red Ferrari.
Findlay, on the other hand, put a positive spin on the outcome. We had worked so hard and put so much heart into it that, yeah, it was tough. On the other hand, we did increase our vote. She had arrived with 40 committed delegates and finished with 130 votes.
And she was moved by the tremendous amount of affection she gotfrom family, friends and strangers for having stayed the course to ensure at least one woman in the race. People still come up to me, Findlay says, and give me a hug and say thank you. And so much of that is tied to the fact that we dont have enough women up there doing this.
Just as most parties say they want to take care of the environment, they also say they want more women to run for them. The key is how they will deliver the goods. The NDP has had a policy in place since 1993 that wont allow a nomination process to close until the riding association can prove its taken credible measures to find a candidate who is either female or from a minority group. The Progressive Conservative Party in Ontario has a special fund called Women in Nomination to give women seed capital in this crucial phase of the election process. Stphane Dion declared, shortly after taking over the Liberal helm, that he was committed to fielding at least 103 women, out of 308 ridings, in the next vote. But hes already run into trouble about how to actually make that happen. Dions solutionthat he would simply disallow men from seeking nominations in certain ridingshas resulted in an angry backlash over reverse discrimination.
And even once women actually get elected, there is virulent disagreement about how to treat them. Last fall, when Foreign Affairs Minister Peter MacKay allegedly referred to former girlfriend Belinda Stronach as a dog during a parliamentary debate, many observersboth male and female were vehement in defending Stronach. Others said she deserved the comment, especially since she had broken MacKays heart when she joined the Liberals.
Findlay insists that both sides should just get over it. Ive worked on Bay Street and we get called bitch all the time. Men get called awful things too. People insult each other. Its an unpleasant side of human nature. Politics is no different. My preference is to dismiss those kinds of comments, rather than give them weight.
Findlays personal mission now is to encourage women to work on becoming more comfortable in the public eye, a strategy the U.S. Institute of Womens Policy Research has seen is profoundly effective in such success stories as mentoring at the Georgia Citizens Coalition on Hunger. Many of the staff there are former welfare recipients who are initially reticent to speak out publicly. But the encouragement of colleagues who have embraced political activism helps melt the trepidation. One worker describes how scared she was when sent to the state capital to talk about hunger. When I got up there I was just shaking. And all of a sudden something came over me, and I began to calm down I said what I had to say.
Parties need to do a better job teaching women the nuts and bolts of running for office, Findlay says, Because, unless youve been working the backrooms for a long time, it frankly is intimidating. And a lot of women just simply dont know how to go about it. Equal Voice has an excellent non-partisan solution with a free online course for women interested in running for office.
As Findlay has proven, the crucial thing is having the faith to take the first step, no matter how frightening it may seem. If I have a job over the next little while, she says, a huge part is to encourage women to look in the mirror and realize just how capable they really are.


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Dallas Cowboys and the NFL
Latest news on the Cowboys
Yearly Archive for 2009
Third-down meltdown in Green Bay
IRVING – The Cowboys entered Sunday's game against Green Bay ranked sixth in the league and fifth in the NFC in third-down defense, but you'd never know it by the way they played against the Packers. Green Bay converted 7 of 15 chances (47 percent) againt a defense that had been allowing opponents to convert […] [Read More]
Has Scandrick lost his swagger?
IRVING – Second-year CB Orlando Scandrick was loaded with confidence coming out of training camp, but lately he looks like he's lost his swagger completely. Scandrick had one of his worst games as a pro in Green Bay, committing two penalties (illegal use of hands, pass interference) in a 16-second span during the Packers' meticulous […] [Read More]
Poll: Players favor Cowboys
IRVING – NFL players would rather play for the Cowboys than any other team, according to a Sports Illustrated poll. SI posed this question to 296 players: "Which team would you most like to play for?" The survey revealed the 11.1 percent chose the Cowboys. Other teams in the top five were the Chargers (8.5 […] [Read More]
Colombo has surgery; Hamlin could be out for a month
IRVING – The Cowboys will be without two starters when they host the Redskins next Sunday. RT Marc Colombo could be out for the rest of the season after undergoing surgery Monday to repair torn ligaments in his left ankle. Colombo also broke his left leg in Sunday's 17-7 loss to Green Bay, but only […] [Read More]
Where was Garrett?
IRVING – A tip of the hat to WR Roy Williams for answering questions in the locker room after his mistake-laden performance Sunday at Lambeau. It was real stand up. The same, though, can't be said of Jason Garrett's post-game actions. The Cowboys playcaller dodged reporters eager to ask him why he abandoned the running […] [Read More]
Woodson's wonderful day
IRVING – Hands down, the MVP of the Packers' season-saving win was CB Charles Woodson. In one of the best defensive performances ever against the Cowboys, Woodson had a team-high eight sackles, one sacks, two tackles for loss, one interception and two forced fumbles. He saved a possible touchdown by stripping the ball from Roy […] [Read More]
Spencer provides silver lining
IRVING – If there was a silver lining in the Cowboys' horrendous performance in Green Bay yesterday, it was the play of OLB Anthony Spencer. In his best game of the season, Spencer had eight tackles, two tackles for loss and one quarterback hit. He still doesn't have a sack, but he provided consistent pressure […] [Read More]
Cowboys' home run hitters striking out
MILWAUKEE, Wis. – The Cowboys have two dynamic players in WR Miles Austin and RB/KR Felix Jones. In Sunday's 17-7 loss to the Packers, neither made an impact. Austin, the driving force behind the four-game winning streak that was snapped yesterday, didn't make his first catch until there was 9:13 left and finished with four […] [Read More]
Packers take 10-0 lead
GREEN BAY, Wis. – Aaron Rodgers' 1-yard sneak has the Packers leading 10-0 early in the first quarter. The 15-play, 80-yard drive lasted 8:36 and was Green Bay's longest drive of the season. [Read More]
Hamlin injured
GREEN BAY, Wis. – Cowboys S Ken Hamlin is out of the game after apparently re-aggravating the groin injury that forced him to miss last Wednesday's practice. His return is uncertain. Pat Watkins has replaced him. (UPDATE: Hamlin is being treated for an ankle injury, the Cowboys announced). [Read More]
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subset: commoncrawl


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It has been unveiled by a report lately that some error has been found in network of the popularly known phone operator GiffGaff.
The organization has recently updated its community pages with the statement that the network has gone down. Also, it has asked its customers not to complain regarding network issue as engineers have already been working to fix the same.
As per the company's report, GiffGaffers might also face some other problems such as balance or goodybags might appear as 'n/a' in the account or some messages might not be delivered until the problem is solved.
It is being believed by the company that the problem is most possibly the consequence of a power problem being solved by one of the suppliers of GiffGaff. Also, the same has probably been identified as a burst water mains pipe causing H2O destruction together with some kit, the report reveals.
Another post on the forum reveals, "This is a serious issue and as a company we are taking this very seriously. We are in constant communication with those fixing the problem and are making sure our supplier is dealing with this as a matter of urgency".
Product Launch
- Samsung signs deal with Amazon.in to sell Galaxy K Zoom handset in India
- GE unveils smart LED light bulb – 'Link'
- Report: iPhone 6 likely to be launched one month earlier than expected
- Huawei officially unveils its new high-end Ascend P7 smartphone
- Samsung launches its 'Galaxy K zoom' camera specialized-smartphone


text:
The present invention provides a method for surface modifying a substrate, such as an implant, to provide the substrate with anticoagulant activity and resistance to the deposition of plasma proteins; and the resulting substrate. The surface of the substrate is modified by first depositing a film of a plasma polymer such as plasma polymerized N-vinyl-2-pyrrolidone or allyl alochol on the surface of the substrate. Optionally, a neutral hydrophilic spacer molecule is attached to the plasma polymer. An anticoagulant, such as heparin, is attatched either directly to the substrate or indirectly to the substrate via attatchment to the spacer molecule, when such spacer molecule is present.
1. A method for reducing the thrombogenicity of a substrate, comprising the steps of:
a. plasma polymerizing polar organic monomers onto the surface of the substrate to provide a plasma polymer film on the surface of the substrate;
b. attaching an a anticoagulant, so that it is bound, directly or indirectly, to the plasma polymer film to provide a substrate having reduced thrombogenicity.
2. The invention of claim 1, wherein the plasma polymer film is comprised of polymerized N-vinyl-2-pyrrolidone.
3. The invention of claim 1, wherein the plasma polymer film is comprised of polymerized allyl alcohol.
4. The invention of claim 1, wherein the anticoagulant is heparin.
5. The invention of claim 1, wherein the anticoagulant is heparin, and plasma polymer film is comprised of polymerized N-vinyl-2-pyrrolidione.
6. The invention of claim 1, wherein the anticoagulant is heparin, and the plasma polymer film is comprised of polymerized allyl alcohol.
7. The invention of claim 1, further comprising the step of attaching a spacer molecule to the plasma polymer film before the step of attaching the anticoagulant.
8. The invention of claim 7, wherein the spacer molecule is 3-aminopropyltriethoxysilane.
9. The invention of claim 7, wherein the spacer molecule is amino-terminated poly(ethyleneoxide).
10. The invention of claim 1, wherein the substrate is nonpolymeric, further comprising the step of first applying a plasma polyhexamethyldisilasane film to the substrate before the step of plasma polymermerizing the organic polar monomers onto the surface of the substrate to provide the plasma polymer film on the polyhexamethyldisilasane film.
This application is a continuation-in-part of Ser. No. 557,740, filed Jul. 26, 1990, now U.S. Pat. No. 5,112,457, issued May 12, 1992.
The use of synthetic biomaterials to sustain, augment or completely replace diseased human organs has increased tremendously over the past thirty years. Synthetic implants have cardiovascular applications such as vascular grafts, heart valves, and ventricular assist devices; extracorporeal systems; and a wide range of invasive treatment and diagnostic systems. Unfortunately, existing biomaterials suffer from problems associated with surface-induced thrombosis, or clot formation, such as thrombotic occlusion and thromboemboli, and infection. Synthetic vascular grafts having a diameter less than 6 mm are currently impracticable, because of potential thrombotic occlusion, and clinical experience with the artificial heart has been plagued with problems of thromboemboli and infection. Advances in the development of artificial organs and artificial vascular grafts have resulted in the need for nonthrombogenic materials.
Thrombosis is initiated by the deposition of a plasma protein layer on the surface of the implanted biomaterial. Thereafter, platelets, fibrin, and possibly leukocytes, adhere to the deposited protein. The interactions between the plasma proteins and the surface of the implant determine the adhesion, activation and spreading of platelets, the activation of coagulation, cell attachment and protein deposition.
There have been several attempts to create nonthrombogenic surfaces on polymer implants thereby increasing the blood-biocompatibility of implants.
Early attempts included precoating the implants with proteins not involved in thrombosis, such as albumin, to mask the thrombogenic surface of the implant. However, such implants loose their nonthrombogenic properties within a short time. Attempts have been made to mask the thrombogenic surface by coating gelatin onto implants such as ventricular assist devices. While the gelatin coating reduced the thrombi, it did not prevent thromboemboli and infection.
Attempts have been made to render implants nonthrombogenic by coating the surface of the implant with polyethylene oxide to mask the thrombogenic surface of the implant. While this reduced thrombogenisis, the coupling of polyethylene oxide to the surface of the implant involves very complex procedures.
There have also been attempts to prepare nonthombogenic surfaces by attaching heparin to biomaterials; heparin was selected because of heparin's potent anticoagulant properties. Such attempts required that the surface of the implant be first modified by the attachment of a coupling molecule before heparin can be attached. For example, the positively charged coupling agent tridodecylmethylammonium chloride, is coated onto an implant, which provides a positively charged surface and allows heparin, which has a high negative charge density, to be attached. However, the heparin slowly dissociates from the surface, to expose the positively charged, TDMAC surface which is particularly thrombogenic. The TDMAC attracts platelets and other cells; cells surfaces have a high negative charge density. Thus the TDMAC heparin coated implant is successful only for short term implants such as catheters.
Implants coated with heparin coupled to coupling molecules typically have limited anti-thrombogenic effectiveness because commercial heparin preparations contain many heparin molecules which having no anticoagulant activity. Moreover, the surfaces soon become covered by adsorbing protein on exposure to blood, thus neutralizing the anticoagulant activity of the active heparin molecule.
It is desirable to have implants which resist plasma protein deposition and which demonstrate anticoagulant activity. Nonthrombogenic implants would reduce the need for aggressive anticoagulant therapy, improve the performance of implants, particularly cardiovascular prosthetic devices, and encourage the development of devices not currently feasible.
The present invention provides a method for surface modifying a substrate, such as an implant, to provide the substrate with anticoagulant activity and resistance to the deposition of plasma proteins, thereby reducing the thrombogenicity of the implant. The invention also relates to the resulting structure. The surface of the substrate is modified by first depositing a film of a plasma generated polymer on the surface of the substrate. Optionally, a neutral hydrophilic spacer molecule is attached to the plasma polymer. An anticoagulant, such as heparin, is attatched either directly to the substrate or indirectly to the substrate via attachment to the spacer molecule, when such spacer molecule is present.
FIG. 1. ATR-FTIR spectra, 1900-1000 cm-1 region, of: (A) PPNVP on PE; (B) PPNVP on PE, where the contribution from PE was removed by digital subtraction; and (C) PPNVP on germanium.
FIG. 2. ATR-FTIR spectra, 1900-1000 cm-1 region, of: (A) PPAA on PE; (B) PPAA on PE, where the contribution from PE was removed by digital subtraction; and (C) PPAA on germaniume
FIG. 3. ATR-FTIR spectra, 1900-1000 cm-1 region, of: (A) PPNVP on PE; (B) PPNVP on PE reduced by aqueous sodium borohydride; and (C) amine terminated polyethylene oxide (PEO-N) coupled to reduced PPNVP on PE.
FIG. 4. ATR-FTIR spectra 1900-900 cm-1 spectral region, of: (A) PPAA on PE; (B) PPAA on PE reduced by aqueous sodium borohydride; (C) amine terminated polyethylene oxide (PEO-N) coupled to reduced PPAA on PE; and (D) 3-aminopropyltriethoxysilane (APTS) coupled to reduced PPAA on PE.
FIG. 5. Affinity chromatography separation of heparin polysaccharides on antithrombin III agrose column. Approximate positions of the non-adsorbed fraction (NA), low affinity fraction (LA) and high affinity fraction (HA) are indicated.
FIG. 6. Molecular weight distribution of high affinity heparin on Sephadex G-75 column by measuring uronic acid content.
FIG. 7. SEM images (4,000×) of HA-heparin on PE which has been surface-modified by PPNVP-PEO, after labeling by an immunogold assay.
FIG. 8. SEM image (4000×) of untreated PE control.
According to the present invention, biomaterials which resist protein deposition, and have anticoagulant activity, and a method for making such biomaterials, are provided. The surface of the substrate, such as polyethylene, is modified by plasma polymerizing polar organic monomers onto the surface of the substrate to provide a film of a plasma generated polymer on the surface. Preferably, a neutral hydrophilic spacer molecule is attached to the plasma polymer. An anticoagulant is ether directly attached to the plasma polymer film, or, preferably, is indirectly attached via the spacer molecule, when such spacer molecule is present, to the plasma polymer film. The anticoagulant, such as, for example, heparin, preferably a polysaccharide or oligosaccharide of heparin, preferably having a high affinity for antithrombin III. (As used herein, the term polysaccharide encompasses oligosaccharide.) The method is surface specific and enhances the biocompatibility of biomedical substrates without adversely affecting the desirable bulk properties of the biomaterial.
The Substrate
The substrate is any material demonstrating suitable biocompatability, such as, for example polyethylene. Other suitable materials include, for example: polyesters, for example: Dacron®, carbon into pyrolytic carbon; polycarbonate; polymer membranes, for example, cellulose acetate, polyacrylonitrile; fluorocarbon polymers, for example Teflon®, Impra® and Gortex®; polysulfones; polyvinly chloride; silicone rubber for example, Silastic® from Dow Corning; silicone polymers; polypropylene; polyurethanes; nonpolymeric materials such as metals, for example, titanium, silicone, glass; and, mixtures or composites thereof. The selection of the substrate material depends upon the mechanical and functional properties required for the implant.
The Plasma Polymerized Film
Monomers which may be plasma polymerized so as to provide a plasma polymer film that is covalently bound to the substrate, and which will provide a plasma polymer film which will bind to either the anticoagulant or to a spacer molecule that binds the anticoagulant, are suitable. As used herein, "plasma polymer film" means a plasma generated polymer film, which provides functional groups for the attachment of the anticoagulant or the spacer molecule. Suitable monomers include N-vinyl-2-pyrrolidone (NVP) available from Aldrich Chemical Company, Milwaukee, Wis., and allyl alcohol from Aldrich Chemical Company, both of which produced polymer films that adhere to the substrate. The formation of the plasma polymer film is generally independent of the substrate material and is surface specific, so that the methodology described herein could be adapted to modify the surfaces of substrates composed other biomaterials, in addition to PE, regardless of composition. The plasma polymerization enhances the biocompatibility of the substrate without adversely affecting the desirable bulk properties of the substrate. Where the substrate is nonpolymeric, it is preferred that a base layer of polyhexamethyldisilazane film be first applied to the substrate and then the plasma generated polymer film be applied to the polyhexamethyldisilazane, to provide the plasma polymer film with better adhesion to the substrate. While the polyhexamethyldisilazane is applied to the substrate by plasma polymerization the term "plasma polymer film" does not include the polyhexamethyldisilazane film.
The Spacer Molecule
The spacer molecule serves not only to promote the binding of the anticoagulant to the plasma polymer, but also to provide a solvated surface for the implant and lifts the attached anticoagulant off the surface of the substrate. However, depending on the anticoagulant, the surface may be suitably solvated so as not to require a spacer molecule. Suitable spacer molecules include, for example, 3-aminopropyltriethoxysilane ("APTS") and amino-terminated poly(ethyleneoxide) ("N-PEO").
The Anticoagulant
The anticoagulant is a molecule which possess some anticoagulant activity. Suitable anticoagulants include, for example, heparin, preferably polysaccharides of heparin.
Radiofrequency (RF) plasma synthesis (glow discharge) was used to generate thin, less than 100 nm, plasma polymerized films on the NHLBI Primary Reference low density polyethylene, (PE), according to the methods contained in U.S. Pat. No. 5,112,457 which is incorporated by reference herein. The PE is ethylene oxide sterilized, 8.25 cm×2.7 cm×0.28 mm sheets, from Abiomed Inc, Danvers, MA. The RF plasma system is composed of a cylindrical flow-through Pyrex reaction chamber having a wavelength of 55 cm, and an internal diameter of 7.5 cm, which is inductively coupled to 13.56M Hz RF power source from RF Plasma Products; a monomer/gas inlet system; and a vacuum system, to provide a vacuum during the entire plasma polymerization reaction.
The argon and monomer were introduced into the reaction chamber by a stainless steel monomer inlet system. The reaction pressure was continuously monitored and maintained throughout the period of plasma reaction. The reaction chamber was coupled to the radio frequency supply by an induction coil with seven turns and about 10 mm between each turn. Fine metering valves from Nupro Company and a mass flow meter from Unit Instruments were used to control and measure the argon flow rate. Monomer flow rates were controlled by fine metering valves and measured from the pressure change during specific time period with valve to vacuum pump closed. This system is also described in Marchant, R. E., et. al., "Preparation and characterization of plasma polymerized N-vinyl-2-pyrrolidone films," J. Polym. Sci., Polym. Chem., 27, 881-895 (1989) and Yu D., et al., "Formation of hydroxyl groups in plasma polymerized N-vinyl-2-pyrrolidone by reduction with sodium borohydride," Macromolecules, 22, 2957-2961 (1989). The PE sheets were sonicated in methanol for 15 minutes, air-dried in a class 100 clean hood and then placed into the reaction chamber along with a germanium internal reflection element which was subsequently used for infrared analysis. The sample substrates were supported in the reaction chamber by cleaned glass slides mounted on a glass rod tray. Ultra high purity grade argon, from Air Products, Inc., was used for purging the reactor, and for a plasma pretreatment consisting of a 5 minutes argon glow discharge carried out at 60 watts net input power, 0.03 torr pressure and gas flow rate of 3.0 cm3 (STP)/minute. The plasma polymerization reactions were performed for 5 minutes at 25 watts net input power, a reaction pressure of 0.03 torr, an inlet monomer flow rate of 0.22 cm3 (STP)/minute. These deposition conditions yielded 80-100 nm thick films of PPNVP determined by ellipsometry measurements of films deposited on silicone After polymer film deposition, the chamber was evacuated to a pressure of 3×10-3 torr, typically for one hour, to remove possible residues. Then the chamber was purged with argon and then raised to atmospheric pressure with argon.
Both the plasma polymerized NVP (PPNVP) and the plasma polymerized allyl alcohol (PPAA) films contain hydroxyl groups, about 1-2 mmol/g, and carbonyl groups. The carbonyl groups were converted to hydroxyl groups by interfacial reduction using aqueous an 0.26M NaBH4, according to methods of D. Yu, et al., described in "Formation of hydroxyl groups in plasma polymerized N-vinyl-2-pyrrolidone by reduction with sodium borohydride," Macromolecules, 22, 2957-2961 (1989). The plasma polymer film was placed onto a glass slide for support then placed in water. The reducing agent NaBH4 was added under an argon purge to a concentration of 0.26M and stirred for 24 hours. The film was removed and rinsed with acetone. The hydroxylated plasma polymers on PE were washed three times with distilled water, left stirring in distilled water for 10 hours, then air-dried in a class 100 clean hood and stored in a desiccator.
To couple the spacer molecule amino-terminated poly(ethylene oxide) (N-PEO) on to the PPNVP, the hydroxylated samples were first washed with distilled water, and then with acetone:water (30:70, v/v), and acetone:water (60:40, v/v) solutions. The samples were then transferred to a stirred, ice-cold, acetone:water (60:40, v/v) solution, and then 0.5 ml of freshly prepared 1-cyano-4-dimethlaminopryidinium tetrafluoroborate (CDAP) in acetonitrile having a concentration of 0.1 g/ml, was added. The CDAP activates the hydroxyl groups on the PPNVP so that the N-PEO may be coupled to the hydroxyl groups on other PPNVP. After 1 minute, about 0.3-0.5 ml of a catalyst, in 0.2M triethylamine solution, was added over 1-2 minute period, which was followed by the addition 120 ml of ice-cold 0.05N HCl. The solution was allowed to stand for 15 minutes, after which, the polymer samples were retrieved and washed briefly with cold distilled water, and 20 mM phosphate buffer saline (PBS) solution having a pH of 7.0. The activated samples were placed immediately in small bottles containing 0.2 g/ml N-PEO, having a molecular weight of about 2000 from Sp2 Scientific Polymer Products, Ontario, N.Y., in PBS. The coupling reaction of the NPEO to the PPNVP was carried out by rocking the bottles on an aliquot mixer for 24 hours at 4° C. to provide PPNVP-NPEO The samples were washed repeatedly with distilled water and then air dried in a clean hood and stored in a desiccator.
For coupling the PPNVP-PE samples to the APTS spacer molecule, the hydroxylated samples were prepared as in Example 1, then immersed for 2 hours in an anhydrous solution of 0.15 ml/ml APTS, from Aldrich Chemical Company, in benzene. The samples were then washed repeatedly with acetone and with distilled water, air dried in a clean hood and stored in a desiccator.
Plasma polymerized films of allyl alcohol on polyethylene were prepared as in Example 1, except that allyl alcohol was used instead of the NVP, and the inlet monomer flow rate was 0.5 cm3 (STP)/minute. The PPAA films were about 120-140 nm thick. The resulting product in which the P-NEO spacer molecule is attached to the PPAA is designated PPAA-PNEO and was prepared as in Example 1.
Plasma polymerized films of allyl alcohol on polyethylene were prepared as in Example 3. The APTS was coupled to the PPAA by immersing the hydroxylated samples in an anhydrous solution of 0.15 ml/ml APTS in benzene, to provide PPAA-APTS. The samples were then repeatedly washed with acetone and distilled water, air dried in a clean hood and stored in a desiccator.
A plasma generated polymer film of hexamethyldisilazane was generated on nonpolymeric substrates, such as glass and germanium crystals, to provide a base layer and promote the adhesion of the PPNVP polymer film, according to the plasma polymerization method in example 1. However, liquid nitrogen, rather than dry ice and acetone, was used to degass the monomers before the initial argon treatment. The plasma polymerization for the hexamethyldisilazane lasted about 12 to 15 seconds, to provide a 3-5 nm thick film.
Infared Analysis
The surface-modification of the PE by the deposition of the plasma polymer film was characterized by fourier transform infrared spectroscopy using the attenuated total reflectance (FTIR-ATR) technique. Infrared analysis of untreated PE, plasma polymer modified PE, and of plasma polymer films deposited directly on germanium, were carried out using a Digilab FTS-40 FTIR spectrometer equipped with an ATR accessory from Wilkes Scientific, and a liquid nitrogen cooled MCT detector. A germanium internal reflection element with dimensions of 50×20×2 mm and nominal incidence angle of 45° was used with the ATR accessory. Spectra were obtained by co-adding 1024 interferogram scans obtained at a resolution of 8 cm-1. Absorbance spectra were obtained by ratioing the single beam spectra with the single beam spectra of the cleaned germanium crystal. To obtain absorbance spectra of plasma polymerized films on PE, spectral subtraction techniques were used to eliminate the contribution of the PE, after the spectra were normalized to the (C--H) peak at 1466 cm-1 in untreated PE.
The infrared analysis confirmed the formation of plasma polymer films on the PE; the completion of the derivatization reaction; and the coupling of the spacer molecule to the plasma polymer films. The treatment of PE with argon glow-discharge plasma leads to electron impact dissociation of surface hydrogens, which in turn generates free radical sites in the plasma polymer surface as well as the formation of unsaturated carbon-carbon bonds. The latter result is seen in the IR spectra of FIGS. 1-4 as an out-of-plane bending vibration, (C--H), in trans vinyl, located at 960 cm-1. The monomers, NVP and allyl alcohol, also undergo electron impact dissociation in the non-equilibrium plasma environment generating free radicals. The dissociated monomer diffuses to the surface of the PE and combines with surface free radicals to provide a covalently-bound polar polymer film.
FIG. 1 shows three ATR-FTIR spectra (1800-900 cm-1 region) of: spectra (a) PPNVP on PE; spectra (b) PPNVP on PE after digital subtraction of the untreated PE; and, spectra (c) PPNVP on germanium. The close similarity between spectra B and C demonstrates that the spectral subtraction emphasizes the thin film, 80-100 nm, PPNVP component of the surface region. There are only minor differences between spectra of the plasma polymerized films deposited directly on germanium as compared to the films deposited on PE. However, since untreated PE was used as the reference for digital subtraction, the analysis did not take into account the contribution of the argon treatment. The effect was observed in subtracted spectra by the presence of the trans vinyl absorption band at 960 cm-1.
A possible effect of the electron impact dissociation on the monomer structure is the loss of desired functional groups during the polymerization. Such effect may depend upon the functional group, the monomer structure and RF plasma deposition conditions. Under the discharge conditions employed, a significant loss of hydroxyl groups was observed for the PPAA compared to the monomer allyl alcohol. Spectra of PPAA on PE, PPAA on PE after digital subtraction, and PE on germanium, are shown in FIG. 2. The carbonyl groups that are formed in the PPAA films and in the PPNVP films, were subsequently reduced by chemical derivatization to obtain the desired hydroxyl groups, which are apparent at about 1080 cm-1, v(C--O(H).
FIG. 3 is an IR spectra of PPNVP on PE, the product of interfacial reduction following conversion of carbonyl to hydroxyl groups, and the subsequent coupling reaction to N-PEO. Hydroxyl groups were identified in the reduced PPNVP by in relative increase of v(C--O--)H, in hydroxyl at 1150-980 cm-1, and a relative decrease in the intensity and band width of v(C═O) at 1670 cm-1. FIG. 3, spectra c, confirmed the presence of PEO on the surface of PE as indicated by a shift in the band position of the v(CO); evidence for the presence of the amine comes from the v(C--N) at 1250 cm-1 and δ(N--H) at 1550 cm-1.
FIG. 4 shows the same group of spectra as FIG. 3 but for PPAAon PE, and has a spectra for PPAA-PE with APTS. The spectral changes were comparable with those for PPNVP. However, there was a marked spectral shift in the carbonyl peak after reduction. This difference may be attributed to the presence of reducible carbonyl groups, possibly keto or aldehyde groups, in the PPAA, which were not present in significant concentrations in PPNVP. Spectra D in FIG. 4, is of the reduced PPAA-APTS film. Spectra D has two strong overlapping peaks at 1100 cm-1 and 1070 cm-1, which are attributed to v(C--O) and v(Si--O) in the APTS; such peaks are not present in Spectra B of FIG. 4.
ESCA Analysis
Surface analysis of the reduced PPAA was performed using a Perkin Elmer PHI-5400 ESCA system with a 400 W magnesium X-ray source at 44.74 pass energy and 45° take off angle. The ESCA result confirmed the presence of 2.9 atomic percent silicon after coupling APTS to the reduced PPAA.
Heparin is a structurally heterogeneous, highly sulfated glycosaminoglycan, consisting of an alternating glycine-serine protein core t with polysaccharide side chains composed of alternating 1→4 linked residues of uronic acid (L-glucuronic and D-glucuronic acids) and glucoasamine attached to the serine residues by a tetrasaccharide linkage region. The anticoagulant activity of heparin is due to its ability to greatly accelerate, by 2-3 orders of magnitude, the rate at which antithrombin III (ATIII) inactivates serine proteases of the coagulation system, including thrombin and factor Xa. Heparin dissociates after the ATIII-protease complex has formed, so that the catalytic action of a single heparin molecule is capable of accelerating the formation of multiple ATIII-protease complexes. A unique pentasaccharide sequence, containing 3-0 and a 6-0 sulfated glucosamine residues, is essential for the binding-induced conformational change in ATIII.
The protein core of heparin was removed because it has no anticoagulant activity and its presence on the surface of the substrate would reduce entropic repulsive force and increase the adsorption of plasma proteins.
First, an aqueous solution of crude heparin having an average MW 5,000-25,000, derived from porcine intestinal mucosa, was obtained from Sigma Chemical Co. St Louis, Mo. The crude heparin and 10.0 mg/ml sodium salt solution was passed through a 3×8 cm cation exchange column containing 200-400 mesh Dowex 50W-X8 H+resin and washed with about 100 ml water. The pH was monitored during the ion exchange. The elutate was then mixed with 250 ml ethylene glycol dimethyl ether and cooled to -10° C. using an ice-salt bath. Partial deaminative cleavage of crude heparin was carried out by the addition of 10 ml isopentyl-nitrite. The reaction was quenched after 40 minutes by adjusting the pH to 8.0 with 2.0M Tris buffer. The mixture was concentrated by vacuum distillation at 37° C., and desalted by passage through an Amicon 8400 ultrafiltration membrane having a 500 molecular weight cutoff, from Diaflo Ultrafilters Company. Next, 5 ml saturated aqueous sodium acetate solution was added to 20 ml of the mixture and poured immediately into 2 liters of stirred cold 95% ethanol. The heparin polysaccharide precipitated and was collected on a glass filter having a pore size 0.45 μm and washed with 95% ethanol. The resulting heparin polysaccharide was a mixture of polysaccharides having varying affinities for ATIII (hereinafter referred to as "mixed affinity heparin"). This mixed affinity heparin possesses a terminal aldehyde group on the terminal 2-5 anhydromanose unit.
High affinity heparin, that is heparin polysaccharides having a high affinity for ATIII, was prepared as above, but before reductive amination, 170 ml of the cleaved heparin was dissolved in 10 ml of aqueous buffer containing 50 mMNaCl and 50 mM Tris-HCl at pH of 7.4. The cleaved heparin solution was applied to an 3×37 cm affinity column containing antithrombin III-agarose, fro Sigma Chemical Company. The column was equilibrated with the same buffer. The heparin solution was washed through the column with the buffer, and the non-adsorbed heparin fraction was eluted. A 3 m NaCl linear salt gradient elution of increasing ionic strength was then used to obtain the polysaccharide fractions with increasing affinity for ATIII. The concentration of polysaccharide in elutant fractions was analyzed for uronic acid by the carbazole reaction, standardized with known amount of 2-glucuronolactone and using a 33% uronic acid content in the polysaccharides according to Bitter, T. et. al., "A Modified Uronic Acid Carbazole Reaction", Anal. Biochem., 4, 330-334 (1962). The collected fractions were pooled to provide three different fractions: non-adsorbed heparin (NA-heparin), low affinity heparin (LA-heparin) and high-affinity heparin (HA-heparin). The fractions were then concentrated and desalted on an Amico 8400 ultrafiltration membrane system having a 1000 molecular weight cut-off. The heparin polysaccharide was then desalted and lyophilized.
Anticoagulant Activity and Binding of the Anticoagulant
The anticoagulant activities of the crude heparin and the affinity separated polysaccharide heparin fractions were measured by commercial chromogenic assays for the inhibition of factor Xa and thrombin, enzymes necessary for the coagulation of blood. The commercial assays are available from Kabi Vitrum in Columbus, Ohio. The heparin was analyzed as a complex consisting of the heparin sample and added purified ATIII. The crude heparin and the polysaccharide heparin samples were incubated with an excess of bovine factor Xa, which was neutralized in proportion to the concentration of active heparin-ATIII complex present. The remaining factor Xa then catalysed the cleavage of p-nitroaniline (pNA) from the commercial chromogenic substrate S-2222. The amount of pNA that was released was measured photometrically at 405 nm after quenching the reaction with 20% acetic acid. The correlation between the absorbance and the heparin concentration was linear between the range of 0.1-0.7 IU/mL, and this assay was used to estimate the anticoagulant activity of the HA-heparin attached to the substrate. Untreated polyethylene samples were used as reference blanks for the assay. A similar procedure using a commercial assay from Kabi Vitrum containing the chromogenic substrate S2238 was used for the determination of thrombin inhibition for solution samples.
The anti-factor Xa activity, thrombin activity, uronic acid content, and percent recovery for the pooled fractions are shown in Table I.
TABLE I______________________________________Properties of Crude Heparin and HeparinPolysaccharide Fractions Factor Xa Factor IIa Uronic Acid Yield Inhibition Inhibition Content (% (% recoveryHeparin (IU/mg) (IU/mg) dry weight) from crude)______________________________________Crude 138 ± 20 111 ± 7 30.3 --HeparinNon- 93 ± 15 36 ± 1 25.2* 61.6AdsorbedLow 64 ± 36 16 ± 10 29.2 24.1AffinityHigh 592 ± 120 182 ± 34 32.3 14.3Affinity______________________________________ n = 3, ± standard deviation. Estimated errors for the uronic acid content = ±1%. *Protein content in the nonadsorbed fraction was estimated to be 9.45 .+- 1%, as measured by Pierce micro BCA assay. -- no data available IUinternational units
The HA-heparin showed an approximately 5 fold increase in anti-factor Xa activity, as compared to the crude heparin. However, the HA-heparin showed only a marginal increase in thrombin inhibition. Significant inhibition of thrombin requires a minimum polysaccharide molecular weight of approximately 5400 Daltons, equivalent to 18 monosaccharide units. The high affinity heparin fraction included polysaccharides of heparin that have a molecular weight below 5400. These polysaccharides demonstrate a high anti-factor Xa activity, but low anti-thrombin activity, thereby lowering the average antithrombin activity of the fraction. The difference in the functional properties among the three fractions results from distinct structural differences of the heparin polysaccharide molecules. The non-adsorbed heparin fraction, which has an anti-factor Xa activity of 93 IU/mg consists of: a protein core (-Gly-Ser-)n; a linkage region containing D-glucuronic acid, two D-galactose and D-xylose residues; and some short sequences of oligosaccharides that may be retained on this linkage region. Some of the molecules contain the unique pentasaccharide sequence for binding ATIII. However, the structural feature of heparin required for the heparin to bind to ATIII and to exhibit anticoagulant activity is a unique pentasaccharide sequence. The pentasaccharide sequence is present on the heparin molecules in the HA-heparin fraction. The HA-heparin fraction had an anti-factor Xa activity of 592 IU/mg.
Molecular Weight of the HA-Heparin
The molecular weight distribution of the HA-heparin fraction was estimated by gel chromatography using a 2.5×92 cm Sephadex G-75 column, and an elution solvent containing 20 mM Tris, 50 mM NaCl, having a pH 7.0. at a flow rate of 2.0 m/minute Linear dextrans having molecular weights of: 39,100; 19,600; 11,000; 8,000 and 5,000 from Sigma Chemical Company, were used as reference molecular weight standards, with analysis of the uronic acid content as determined by the carbazole reaction. Bitter, T. et. al., "A Modified Uronic Acid Carbazole Reaction" Anal. Biochem., 4, 330-334 (1962). A calibration curve of KaV values against log molecular weight was calculated for the standards, which was then used to estimate the molecular weight of the HA-heparin.
Based on the calibration curve derived from dextran standards, the average molecular weight of the HA-heparin is about 17,500. The molecular weight distribution of HA-heparin, as determined by uronic acid content, is shown in FIG. 6. Molecular weights and calculated Kav values for the eluted HA-heparin fractions are listed in Table II.
TABLE II______________________________________Molecular Weights of Polysaccharide Fractionsin HA-heparina Molecular WeightcSample Kav b (Weight average)______________________________________Dextran Standards1 0.00 39,1002 0.288 19,6003 0.582 11,0004 0.673 8,0005 1.00 5,000HA-heparin FractionsA 0.00 >39,100B 0.063 33,400C 0.38 16,200D 0.54 11,300E,F <5,000______________________________________ a :Molecular weights determined on Sephadex G75 column b :KaV is defined as (Ve - Vo)/(Vt - Vo), where Ve = elution volume, Vo = void volume, Vt = column volume. c :Molecular weights were determined by comparing the KaV values wit those of dextran standards of known molecular weight.
Attachment of HA-Heparin Polysaccharides to the substrate
The plasma polymer modified PE and the untreated PE were cut into 5 mm diameter disks using a biopsy punch and then washed with distilled water. Six polymer disks were prepared from each of the plasma polymer modified PE samples from Examples 1-4 and untreated PE samples. Each disk was immersed in an aqueous solution containing 0.2-0.4 mg/ml HA-heparin, to which 0.40.6 mg/ml sodium cyanoborohydride was added for a final concentration of sodium cyanoborohydride of 1.9 mg/ml. The vials were then placed on a rocker for 24 hours, after which, the disks were washed repeatedly with PBS buffer having a pH 7.0 and distilled water, and stored under distilled water. It is believed that the aldehyde on the reducing terminal 2-5 anhydromannose unit of the HA-heparin was reductively aminated with the terminal amino group on either the NPEO or the APTS which were coupled to the plasma polymer modified PE.
For control experiments, the HA-heparin was adsorbed from the aqueous solution onto untreated PE and onto PE samples surfacemodified by plasma polymerization. The samples were then washed by the same procedure employed for immobilized samples.
Analysis of HA-heparin Bound to the Substrate
The anticoagulant activities of the HA-heparin bound to plasma polymer modified PE were measured by the chromogenic assay for the inhibition of factor Xa. Based on this measurement, the anticoagulant activity for the bound heparin was estimated to be 30-70 mIU/cm2, with binding estimated to be 56-119 ng/cm2, as shown in Table III.
Sulfur content on the surface of samples was measured by ESCA using a Perkin Elmer PHI5400 ESCA system with a magnesium x-ray source. Surface sulfur was determined using a take-off angle of 45°, and binding energies were referenced to the hydrocarbon C1s core level peak centered at 285.0 eV. The results are shown in Table III.
TABLE III______________________________________Activity and Sulfur Content ofHA-Heparin on Bound to the Substrate Factor Xa Inhibition SulfurSubstrate (mIU/cm2) (ng/cm2) (atomic %)______________________________________PE-PPNVP-PEO-HA 68 ± 3 114.8 ± 0.1 1.1 ± 0.3HeparinPE-PPAA-PEO-HA 38 ± 5 64.8 ± 0.1 --HeparinPE-PPAA-APTS-HA 45 ± 2 76.2 ± 0.1 1.3 ± 0.1Heparin______________________________________ n = 3, ± standard deviation surface sulfur content was measured by ESCA. -- data not available
Control samples of untreated PE exhibited negligible anti-factor Xa activity, and no surface sulfur was detected by ESCA analysis The highest anticoagulant activity, 68 mlU/cm2, for bound HA-heparin was obtained with the HA-heparin bound to PPNVP-PE with a PEO spacer molecule. The next highest anticoagulant activity was obtained for PPAA film on PE with APTS spacer molecule. The sulfur content, as determined by ESCA analysis, did not significantly differ between the HA-heparin samples.
Confirmation of the presence of, HA-heparin on the plasma polymer modified PE was also obtained using a gold bead-labeled double antibody method as described by Panktowski et al. "Morphologic characteristics of adsorbed human plasma proteins on vascular grafts and biomaterials," J. Vasc. Surg., 11, 599-606 (1990). Silver enhanced gold beads, having a diameter of about 200 nm, were attached to a secondary antibody, which is directed to a primary antibody (anti-antithrombin III). The anti-antithrombin III is directed against antithrombin III. The HA-heparin plasma polymer modified PE was exposed to antithrombin III and rinsed. The heparin molecules having the pentasaccharide sequence bind the antithrombin III to form a heparin antithrombin III complex. When the complex was exposed to the beads which the anti-antithrombin III was attached, the anti-antithrombin bound to the complex. The presence of the beads was determined using scanning electron microscopy.
FIG. 7 is an SEM image for HA-heparin bound to a PEO-PPNVP modified PE. From the SEM images it was determined that approximately 15% of the surface area was covered by beads, at a density of about 40×107 beads/cm2, in an even distribution. In comparison, FIG. 8 shows sparse bead distribution, that is 2×107 beads/cm2, which is less than 10% coverage on the the untreated PE control.
Similarly, the SEM image shown in FIG. 9 shows HA-heparin bound to PPAA-APTS modified PE having a bead densisty of 31×107 beads/cm2, while the results for HA-heparin attached to the PPAA-PEO modified PE was lower at 10×107 beads/cm2.
The results of the anticoagulant activity assay, that is, the Factor Xa inhibition assay, and antibody-binding assay indicated that HAheparin polysaccharides did bind to the two types of plasma polymerized PE. Some differences were observed between the PPNVP and the PPAA films as well as between the two types of spacer molecules, the APTS and the P-NEO on PPAA film. Factors that influence the coupling efficiency of the heparin polysaccharide include the concentration of hydroxyl groups in the respective plasma polymers, the degree of interfacial solvation of the plasma films by the media used during the coupling reaction, which affects functional group mobility, and the molecular weight of the heparin polysaccharide molecule to be bound.
However, the infrared results did not suggest significant differences in hydroxyl concentration for PPAA film as compared to the PPNVP film. The apparent differences in the coupling of HAheparin to the PPAA film and to the PPNVP film with the PEO spacer molecule are believed to be due to the extent of interfacial solvation which affected the PEO coupling to the PPAA. This is supported by the fact that the PPAA film exhibits a higher water contact angle, 52°±2 than the PPNVP film 35°±2, as well as lower contact angle hysteresis. The observed differences in the amount of the HA-heparin bound to the two spacer molecules on the PPAA film, probably reflects a higher binding efficiency for the small APTS spacer molecule compared with the higher molecular weight PEO spacer molecule.
The use of the HA-heparin results in the binding of relatively small molecule with high anticoagulant activity, and increases the surface density of the anticoagulant on the substrate. Polysaccharides have greater stability in vivo compared with proteins, and the anticoagulant action of heparin is catalytic, so a heparin polysaccharide-ATIII-protease complex should dissociate. In addition, bound anticoagulants are likely to provide an interface with blood that resists non-specific protein adsorption, because the polysaccharide anticoagulants are highly solvated in aqueous media such as blood.
The heparin polysaccharides in combination with RF plasma polymerization offers a methodology for coupling such biomolecules to existing clinically used substrates to provide non-thrombogenic surfaces.
Although particular embodiments of this invention has been shown and described, various adaptations and modifications can be made without departing from the scope of the invention as defined in the appended claims.
Referenziert von
Juristische Ereignisse


text:
The present invention comprises a device for adjusting the height and supporting internal anatomical organs. The device comprises a chamber having elastic properties, the volume of which varies in accordance with the amount of fluid in the container. To increase or decrease the volume, a capsule connected by a tube to the container is provided which is adapted to be located near the skin of the patient. A hypodermic needle can extract or introduce fluid into the capsule thereby to change the volume of the chamber. A thread is connected to one base of the chamber and the other base is adapted to sit on an anatomical region in the body. The thread is adapted to surround the selected organ whereby changes in the volume of the chamber changes the distance between the bases thereby to move the organ.
1. A device for adjusting the height of internal organs comprising an elastic chamber the volume of which varies in relation to the amount of a fluid received in said container, said chamber being sized to be received within a selected area of the body, at least one thread connected to said container and adapted to be connected with a body part whereby changes in the volume of said chamber causes movement of said thread to affect consequent movement of the body part, a subcutaneous capsule adapted to be located close to the skin of a patient, and a tube connecting said capsule with said chamber, whereby the introduction or removal of a fluid from said capsule causes variations in the volume of said chamber.
2. A device as in claim 1, and a fluid for filling said chamber, said fluid carrying a contrasting component.
3. A device as in claim 2, wherein said fluid is water.
4. A device as in claim 1, wherein said elastic chamber comprises two opposed bases, the first base being adapted to sit on a selected anatomical region, said second base being connected to said thread for suspension of the selected body part.
5. A device as in claim 4, wherein said elastic chamber has unidirectional deformation characteristics.
6. A device as in claim 5, wherein the lateral walls of said elastic chamber are stronger than said base walls to permit unidirectional deformation in the direction of separation of said first and second bases from each other.
7. A device as in claim 4, wherein the elastic chamber is provided with high strength plates on said first and second bases.
8. A device as in claim 7, and a web comprising a grid between said first base and said plate provided thereon.
9. A device as in claim 7, wherein the plate connected to said second base is rigidly connected thereto.
10. A device as in claim 7, wherein said plates are made of titanium.
11. A device as in claim 1, and tubular elements positioned adjacent said chamber and receiving said thread therethrough to prevent damage to the walls of said chamber.
12. A device as in claim 1, wherein said thread comprises high strength, biocompatible synthetic material.
13. A device as in claim 1, and a hypodermic needle for introducing or extracting the liquid from said capsule.
14. A device as in claim 1, wherein the ends of said thread are attached to said elastic chamber.
1. Field of the Invention
The present invention is intended to disclose a device for the height-adjustable fixing and support of internal anatomical organs, by means of which it is possible to effect in a very simple manner the securing of internal anatomical structures and organs when they are positioned in the desired position by the surgeon, additionally having properties of adjustment in height as required.
As is already known, in operating practice there are situations in which the surgeon wishes to position and ensure the securing of internal anatomical organs at a certain height with respect to specific references of the human body, for the purpose of completing the operation carried out and/or in order to perform organic functions, making good certain bodily functions or assisting them.
One of the fields of more specific application of the device which is the subject of the present invention will be that of urinary tract surgery, in particular urinary tract surgery concerned with the correction of urinary incontinence.
2. Description of the Related Art
In particular, the object of the present invention is to ensure a complete cure for severe urinary incontinence in women, which has been repeatedly operated on without success with the conventional surgical techniques, since at present no method has been described which ensures a cure for this.
The problem of urinary incontinence is one of the most widespread nowadays, the attempt to propose effective remedies in order to try to reduce its effects being very costly. For example, in North America, according to CARL G. KLUTKE of the Urology Department of the University of Washington, incontinence affects more than twenty million people and more than half the admissions to chronic centres and an annual expense of a billion dollars for absorbent devices and others are attributed to it.
Moreover, the said problem is increasing with the expectation of greater longevity of the population. Increasing costs are assumed which become insupportable for the various health administrations of each country.
In particular, the treatment of female urinary stress incontinence continues to be a formidable task for the health community, according to what is stated by C. G.KLUTKE in his publication "Female stress incontinence in the 90's". Considerable efforts have been made, but it is necessary to understand the problem better and achieve a more effective treatment. The surgical treatment of this ailment will continue to be an important feature of urology. The enthusiasm for new innovative surgical approaches should be weighed against objective evidence of results and with a clear understanding of the morbidity involved.
Multiple vaginal deliveries, removal of the uterus, and menopausal vaginal changes are factors which contribute to prolapse and to urinary stress incontinence in women.
The involuntary loss of urine may occur by means of two mechanisms which, for the moment, require different surgical techniques for their correction. The most common is the descent or dropping of the neck of the urinary bladder and of the urethra (hypermobile urethra).
The other is due to the fact that the urethra has lost its closure capacity (deficiency of the internal sphincter). In men, incontinence is produced by lesion of the external sphincter in the course of operations on the prostate.
More than a hundred surgical techniques for the correction of incontinence have been described. The large number of procedures proposed demonstrates that the problem persists. The percentage of failures is very high and increases with the passage of time, as attested by the most recent publication of Stefan Conrad of the University of Hamburg (J. Urol. No. 1 32-37, 1998), who presents the long term results (5 years) of the Stamey suspension intervention, which is the treatment of choice for stress incontinence in women, and in which he emphasises that the failure rate is 50% out of a total of 130 patients evaluated.
When the neck of the bladder and the urethra are found to have descended, the object of surgery is to return them to their original anatomical position; in order to achieve this, it is necessary to displace these structures upwards and forwards, and they have to be raised behind the pubis.
The treatment of defective functioning of the sphincter of the urethra causing urinary incontinence is linked to achieving greater urethral resistance, which is obtained either by means of a sling suspending the neck of the bladder, or by the reconstruction of the said neck, or also by means of periurethral injections of polytetrafluorethylene or by means of an artificial urinary sphincter.
The procedure based on the sling suspending the neck of the bladder is relatively simple and offers certain advantages over the remaining procedures. Many procedures based on the technique of the suspension sling are known and have been described since the beginning of this century.
The ALDRIDGE technique is classic and has remained for many years the most frequently employed. Another similar technique was described by MOIR and in 1984 POLLACK and his associates described the use of tendons and aponeurosis as a sling for suspending the neck of the bladder when connecting it with the COOPER ligament.
Another suspension procedure was described by BEYDEREV of the Centre for the Treatment of Incontinence, of Irvine University in California. This consists of a percutaneous procedure which makes it possible to capture with a threaded needle a maximum portion of the mobile part of the pubocervical fascia and of the tissues situated laterally and on both sides of the neck of the bladder and of the urethra, the suspension of the said neck being achieved by means of anchorage of the ends of the aforesaid lateral suspension threads on two points of the pubic bone. These suspension threads are tensioned and fastened in a first intervention to these anchorage points inserted into the bone. But it is clear that the initial tension imparted to the aforesaid suspension threads cannot be adjusted easily nor modified afterwards after time has lapsed since the urological intervention.
The great problem which arises in all the surgical procedures described is to know to what precise degree the neck of the bladder should be raised and positioned or the precise degree of compression of the urethra in order to guarantee the correction of the incontinence and to obtain normal micturition. Because if the surgeon exceeds it by raising the urethro-vesical union a few millimetres more or extensively compresses the urethra, a urinary obstruction will be produced, a frequent complication which renders repeated or permanent explorations necessary. On the other hand, if by default the surgeon falls short in the lifting or compression of the urethra, then the incontinence will soon reappear.
There is no test or proof available which makes it possible to know this, that is to say, there are no parameters for determining the appropriate degree of tension for the fixing of the sling. This crucial moment of fastening the two sutures which support and raise the neck of the bladder and the urethra depends on subjective appraisal or empirical determination on the part of the surgeon; it is more art than science. But even accepting that the appropriate point of elevation of the urethro-vesical union or that of compression of the urethra has been found, and the two objectives have been achieved, that of curing the incontinence and that of restoring normal micturition, it is not known for how long this situation will last or persist, since it is rarely permanent or definitive and this is because the correction mechanisms fail or because the tissues fail through the natural process of involution or ageing. The urethral closure pressure (sphincter) declines markedly with age, or in the course of life an illness may occur (bronchitis, asthma) which entails an increase in the intra-abdominal pressure which strains the containment system created and the incontinence reappears.
More recently, endeavouring to overcome this indeter-minate adjustment of the effect of suspension of the neck of the bladder, various mechanical adjustment procedures have been proposed. But these procedures require the establishment, during the intervention and on the abdomen of the patient, of mechanical adjustment means, either a single one located in the central part and on which the lateral suspension threads are joined, or by means of two lateral adjustment mechanisms generally formed, in both cases, by screw-threaded parts which can be adjusted manually from outside above the abdomen of the patient. These adjustment mechanisms remain on the one hand inside, and on the other hand outside the abdomen of the patient after the urological operation and for several days, with a risk of infection, until the adjustment operations are deemed to have been completed. Then, the said adjustment mechanisms have to be separated from the body and the retaining means or final anchorage of the ends of the said threads arranged, in order, finally, for the said open wounds at the anchorage points to be covered by the corres-ponding adipose tissue and the skin in order to cover up the incisions made, as well as the aforesaid fixed retain-ing means for the ends of the suspension threads.
It will be understood that after all these operations have been carried out, further mechanical adjustments will not be possible except by means of further surgical interventions.
But, in practice, further adjustments of the tension of the sling are always necessary, since the tensioning threads stretch in different proportions after the urological intervention or simply when the tissues suffer certain structural changes after a period of time.
This plethora of procedures described in the medical technical literature confirms the non-existence of ideal methods.
As already stated, the principal reason for the difficulties encountered for the suspension sling procedure is the impossibility of obtaining easy control of the tension of the suspension threads thereof.
According to what was published in the Journal of Urology (Vol. 14, January 1989), some doctors, researchers of the Nagoya University School Department of Urology, state that the tension of the threads of the sling has not been quantified either for the genuine incontinence stress or for the neurogenic bladder.
In spite of the popularity of the system of suspension of the neck of the bladder, no articles have appeared which have mentioned and quantitatively specified the degree of tension which should be imparted to the suspension threads of the sling at the moment when they are tied to a rela-tively fixed retaining part.
The stretching of the threads is generally understood to be between 4 and 8 per cent after a period of 70 days, depending on their initial tension.
The result of this ambiguity is frequently manifested in transitory or definitive retention or difficulty in urinating if the threads have been tied with too much tension at the end of the intervention, or in persistent incontinence if the opposite occurs.
The present invention is intended precisely to remedy the drawbacks previously mentioned, both in the correction of incontinence in cases where the neck of the bladder and the urethra have descended, and in those where the cause is deficiency of the internal sphincter of the urethra, the present invention providing the means for correct anatomical positioning of the organs in a very simple manner, unaggressive from the operating standpoint, and which also has a capacity for adjustment, for life, and without the need to have recourse to a further operation.
In order to achieve its objectives, the device which is the subject of the present invention comprises a unit in the form of an elastic chamber, expansible by the action of a fluid contained within it and which is intended to be surgically incorporated in the most anatomically appropriate place so that use may be made of the said unit for fixing at the desired height the internal anatomical organs which are the subject of the surgical intervention and in such a manner that, given the elastic properties of the said unit, it is possible to act on it, effecting its selective deformation by the action of the fluid contained in the elastic chamber, for the purpose of producing controlled displacement of the anchorage points of the internal means for securing the anatomical organs, principally constituted by fine, strong cables of biologically compatible materials.
In order to obtain greater efficiency in the control of the height of suspension which the device provides, the unit deformable by the action of the fluid will have differentiated characteristics of rigidity in its structure, so that the action of the fluid inside the said unit is basically manifested in a variation in the height of the elastic unit, it thus being possible to exploit to the optimum degree the effect of adjustment on introducing or extracting specific amounts of control liquid. For this purpose, the elastic unit will basically comprise a chamber with a lower wall or base intended to sit in the most suitable place, selected from the anatomical standpoint, and an upper face or upper base carrying the connections to the threads for the suspension and fixing of the anatomical organ, so that the said upper and lower bases can carry in one of the cases, preferably on its upper base, a plate of a high strength material, for example titanium, in order to improve the functioning of the chamber and permit easy and strong fastening of the ends of the threads for the suspension of the anatomical organ or organs.
In order to permit the placing of the elastic unit deformable by means of fluid in the most convenient place from the anatomical standpoint, the present invention provides for the said chamber to communicate, by means of a fine tube of biocompatible synthetic material, with a small capsule which will be coupled in a subcutaneous arrangement, but sufficiently close to the skin of the patient so that from the outside a puncture can be made with a fine hypodermic needle in order to gain access to the said control cell or capsule for the purpose of introducing or extracting liquid in the required manner to adjust the desired fixing height of the anatomical organ.
For the purpose of improving the identification of the liquid and being able to exert greater control, the liquid will preferably carry a marker or contrast of the compatible dye type.
The device of the present invention may be applicable not only as a device for the raising of the neck of the bladder and of the urethra by means of a suitable sling, but also to other operating systems which require adjustable suspension, such as that termed transvaginal colpo-suspension.
For the remainder, owing to its characteristics, the device which is the subject of the invention will be applicable to a wide range of surgical interventions not limited to interventions in women, but also in men for urological or other purposes.
To make it easier to understand, drawings showing a preferred embodiment of the present invention are provided on an explanatory but non-limiting basis.
FIG. 1 shows diagrammatically an illustrative anatomical section of a characteristic form of application of the device which is the subject of the present invention.
FIGS. 2 and 3 are different diagrammatic sections showing the application of the device to the suspension and adjustment in height of the urethral canal.
FIGS. 4 and 5 show different views in lateral elevation and in plan of a device produced in accordance with the present invention, with the chamber unexpanded.
FIG. 6 shows a plan view of an embodiment of the sling used for raising purposes.
FIG. 7 is a simplified side view which shows the position of the expandable chamber, the lower support plate, connection threads and sling.
FIG. 8 is a simplified view showing the introduction of liquid under low pressure by means of an specific capsule, representing the chamber in its expanded form.
FIG. 9 shows a simplified side view corresponding to FIG. 8.
FIG. 10 shows a plan view of the elements of FIG. 8 with the chamber in an expanded situation.
FIGS. 11 and 12 show, respectively, a plan view and a front view of a variant for the fastening of the suspension threads.
As can be observed in the figures, the device of the present invention comprises a unit 1 having elastic properties and preferably deformable in a controlled manner from the directional standpoint, which unit, in the form of a chamber with elastic walls, is incorporated in the appropriate anatomical region in order to obtain sufficient support for its lower face, for example the muscular mass 2, being connected by means of thread-like elements of a strong and biologically compatible material, such as nylon threads 3 and 4, with a sling 5 for raising the urethral canal 6, having a tube 7 communicating with a small capsule 8 located close to the skin 9 of the patient for the purpose of permitting easy access to the said capsule by means of a hypodermic needle. The thread-like elements 3 and 4 may be constituted in a very varied manner, for example, monofilaments, braided threads, micro-chains, etc.
As will be seen in FIGS. 2 and 3 the chamber 1 has a lower base 10 and an upper base 11, joined by the lateral walls 12. It is a characteristic of the device which is the subject of the present invention that the chamber 1 has elastic properties, preferably unidirectional, comprising a fluid, in particular a liquid, inside it in a variable amount, so that the volume of the chamber 1 will increase or decrease as a function of the volume of liquid intro-duced, and making use of the elastic properties of the chamber. For the introduction of the liquid into the inside of the chamber 1, a tube 7 will preferably be provided, connecting the said chamber with a flattened capsule 8 arranged close to the skin of the patient which has been indicated, as in FIG. 1, by the number 9.
In order to obtain the preferably unidirectional effect in the elastic deformation of the chamber 1, the latter will preferably have the two bases 10 and 11 with characteristics of lower strength than the lateral walls 12. In this manner, the increase in volume of the chamber, as shown by way of example in FIG. 3, will preferably be manifested in a difference between the separation of the bases 10 and 11 of the chamber 1, without appreciable lateral deformation. This is intended to permit the greatest possible displacement between the aforesaid bases, that is to say, the greatest effect of height control on the connecting threads 3 and 4 for a specific amount of liquid introduced into or extracted from the chamber 1.
As already indicated, the introduction and extraction of liquid will be effected, for example, by means of a hypodermic needle 15 which will pass through the skin and the capsule 8, making it possible to introduce or extract the liquid.
The liquid used in the device which is the subject of the present invention will preferably be water or some other biocompatible liquid with a radiological contrast having a specific control coloration.
The fastening of the threads 3 and 4 to the chamber 1 in order to enable the deformation of the said chamber to be manifested in an effect of tensioning or slackening of the threads 3 and 4 can be effected in a version similar to that shown in FIG. 3, in which can be seen the fixing of the ends of the threads 3 and 4 above a strong plate 16, associated with the upper base 11 of the chamber 1, by means of bonding or welding points such as 20 and 21, the said plate being able to consist, for example, of a titanium plate which will make it possible to obtain high strength combined with extreme lightness. In order to improve the suspension of the threads 2 and 3, tubular elements may be associated, such as those represented by the numbers 17 and 18, which will allow the threads 3 and 4 to be guided, avoiding lateral chafing on the walls of the chamber 1, which could result in damage or breakage.
As will be understood, by means of the device which is the subject of the present invention, it will be very easy to introduce a liquid into the inside of the elastic chamber 1 for the purpose of increasing the distance which separates the upper and lower bases 10 and 11 of the main chamber of the device or also to extract said liquid in order to reduce the separation between the bases. The said effects will respectively result in tensioning or slackening of the threads 3 and 4. As can be seen in FIGS. 4 and 5, the elastic chamber 1, apart from carrying at the top the plate of titanium or other suitable material 16, may also similarly have at the bottom a second plate 19 intended to improve the characteristics of seating of the device in the part of the anatomy intended to contain it. The base 19 may also be associated to an intermediate grid-like web 22 located between the support plate and the lower base of the expandable chamber 1. Said support plate 19 may be made out of titanium as well.
Although the fastening of the threads 3 and 4 has been represented in the figures preferably my means of fixing knots on the upper base of the expandable chamber, said fastening could also be carried out by means of flat fixing clamp as shown in FIGS. 11 and 12, in which said clamp is comprised of the two parts 23 and 24, between which the threads are clamped. To this end said plates may have small guiding grooves. The fastening is carried out by means of a screw 25 or other similar means.
Although the invention has been defined above with reference to a concrete exemplary embodiment, it may also exhibit numerous alternative forms within the essential concepts claimed. In particular, it should be understood that the precise structure of the chamber may vary widely, assuming different geometric shapes, such as parallele-pipedal, cylindrical, oval, conical or prismatic shapes, etc. Likewise, the number of threads for suspension of the anatomical organs, as well as the precise points of suspension thereof, may vary within wide limits.
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The Retina is the keyword in today's technology world. It started with iPad Retina display. Now other brand tablets too are in the race to offer more resolution than what Apple is offering in its big-sized iPad tablets.
Now, isn't Apple too need to be similarly cautious with its mini iPad?
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NPD DisplaySearch analyst Richard Shim said, "We should see the start of mass production of the panels in June or July."
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Retina iPad Mini to sport 7.9-inch screen providing a resolution of 2048 x 1536 pixels, which will roughly give similar PPI to what we have seen on the iPhone 5 Retina screen. If this is true then it will be the highest densities to date for a tablet.
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