Synthetic Coronary Artery Bypass Grafts
( Nov 2015: please note: I wrote this story in February 2008. Much of it describes the efforts of one company, CadioTech, to develop a synthetic coronary graft. About a year or two later CardioTech discontinued this development and changed its name to AdvanSource.) At the bottom of this article are newer developments chronicled as of 2009, 2011, 2012, and 2015. In particular, note the Carmat artificial heart and Heartware LVADs.) (Please excuse the temporary patches and "bypasses" in this article to keep it alive. I'll give it a complete rewrite soon. Meanwhile, here's the original from 2008.)
Arteries clogged by atherosclerosis kill and maim more Americans every year than any other cause.This is the number one cause of death in America.
Heart disease (cause #1) accounted for 650,000 deaths in the USA in 2004. Stroke (#3) accounted for 150,000 in 2004. That's 800,000 deaths total due to vascular disease. Cancer ( #2) caused 550,000 deaths. Even adding Chronic Respiratory Disease (#4) 120,000; Accidents (#5) 110,000; and Diabetes (#6) with 70,000 only leads to a total of 300,000 in 2004 in the USA ( CDC/NCHS ) .
So, atherosclerosis - by far and away, the major cause of vascular disease - is about as lethal as cancer (cause #2) plus causes 4 thru 6 combined.
The coronary arteries are the only blood supply for the heart muscle itself. When a coronary artery becomes suddenly obstructed, it causes a heart attack (myocardial infarction) - death of heart muscle. When a carotid or cerebral artery obstructs blood flow to the brain, it causes a stroke - death of neurons.
There are two principal means of mechanically treating a narrowed coronary artery: opening the narrowed portion by inflating a balloon at the end of a catheter (angioplasty) and leaving a metal stent to keep it open or 2) surgically bypassing the obstructed artery by placing a new conduit between the aorta and the coronary arter y. The surgical option may be chosen if there are three or more arteries that are severely narrowed, if the left main artery is involved, and so on.(Here, since clinical decision making is NOT my emphasis (see disclaimers) I've greatly simplified this discussion.)
About 500,000 coronary bypass graft (CABG) operations are done every year in the United States (466,000 in 2005 per CDC/NCHS ). For a couple of decades, in the nineteen seventies and eighties, most bypasses were done by harvesting saphenous veins from the legs. In addition to the discomfort and morbidity of having long incisions in the legs (beyond the patient's having been sawed through the sternum), many vein grafts would eventually close off. The veins were not evolved to handle the high pressure in the aorta, and vein grafts may reobstruct after a few years. At ten years about half of vein grafts may be obstructed ( Sabik2004 ).
As a result in the past couple of decades, cardiovascular surgeons have tried to use arterial grafts instead of vein grafts where possible ( Rankin2007 ) ( Veeger2008 ). Arterial grafts have a better chance of staying open (90% are open at ten years). The arteries most commonly used are the internal thoracic (internal mammary) arteries, which are already connected to the aorta (via the subclavians), the gastroepiploic artery (stomach), or a radial artery from the wrist. While using an artery is more successful long-term than using a vein, it still involves the morbidity and complexity of harvesting the artery. Furthermore, some patients may have used up all these options, including their saphenous veins, in previous bypass operations.
Every patient must wonder, why not just put in a plastic tube to bypass the obstructed artery? If the drain pipe in the kitchen sink gets plugged and can't be snaked, you go down to Home Depot and buy a new one .
Synthetic Coronary Grafts Are Not Yet Available!!!
How is it possible that in 2008 at the dawning of the Era of Nanotechnology, synthetic coronary grafts are not clinically available? They are being developed by two companies, but the R and D seems amazingly slow, given the need. How can this be?
The shocker for me is this. On the one hand, we've got robotic surgery, 64 slice CT imaging, video pill-cams that can image and biopsy the intestines, and artificial hearts. On the other hand, (seemingly simple) plastic tubes that could prevent thousands of deaths are not available. What's going on?
I was only able to find two companies working on synthetic coronary grafts: Cardiotech and Kensey Nash. Cardiotech's graft appears to have been under development for fifteen years and is described below. Although Kensey Nash (Nasdaq: KNSY) is a larger company, their device is relatively new and is still in the animal testing (preclinical) phase. Interestingly, it is made from a material similar to Cardiotech's: a microporous polycarbonate polyurethane. Scant information is available about it on the internet; so, the rest of this report focuses on Cardiotech's Cardiopass Graft.
Cardiotech's Cardiopass Synthetic Graft
Cardiotech , is a Massachusetts company (Amex: CTE) that has been developing a synthetic coronary graft for over a decade. Their former CEO, Michael Szycher, PhD, wrote an excellent piece on their Cardiopass Graft for their website. It summarizes the difficulties that have stumped researchers as they have tried in vain to develop what he calls the holy grail - a synthetic coronary graft. In brief: here are the problems. (Please note: as of March 2012 a detailed paper he wrote is, unfortunately, no longer on the web, and this effort has been discontinued. Cardiotech changed its name to AdvanSource .)
1) Although Dacron and PTFE grafts work well for arteries bigger than about 12 millimeters (in the aorta, the iliacs, and the legs), they do not work as coronaries. The internal diameter of the coronaries is only about 4 or 5mm proximally (where they emerge from the aorta)and they taper down to about 2 mm at the point where the bypass would connect (the distal end). So, the coronaries are narrow to begin with and flow is even more sluggish where they are narrowed downstream (distally) by atherosclerosis. As a result of the narrow diameter and low flow, blood clots on Dacron and PTFE .
2) Dacron, PTFE, and other polymeric plastics fail due to mechanical stress, cracking, and biodegradation. Sharing a downfailing with the saphenous veins so often used for CABG, Dacron and most other polymers cannot withstand high, continuous, pulsatile arterial pressure. Small diameter grafts develop microfractures and the roughened surface promotes enyzmatic degradation.
3) The grafts never completely heal. Ideally, you'd like a graft that promotes the growth of an endothelium similar to the inner lining of an artery. That endothelium would retard immune attack and blood clot formation.
4) The connections (anastomoses) between the graft and the aorta and the native coronary arteries are points of failure.The aorta and coronaries pulse with each heart beat and most biomaterials are stiff. This compliance mismatch prevents healing of the junctions and also leads to narrowing due to tissue overgrowth and turbulent flow. Furthermore, surgeons need material they can sew. Each anastomosis (at each end of the graft) requires 20 sutures each of which uses nylon that is 40 microns in diameter. A human hair is about 80 microns in diameter.
Cardiotech was founded in 1993 as a subsidiary of PolyMedica Industries and was spun off in 1996. Since its inception, the company has been researching synthetic coronary grafts. As of 1996 they had created a poly-carbonate based polyurethane that appears to overcome the problems listed above. They call their patented polyurethane ChronoFlex and the synthetic coronary graft made from it is called Cardiopass.
By 2002 the company had performed animal tests of their ChronoFlex grafts. Specifically, the grafts were implanted for three years. The results were encouraging: no stress cracking or degradation and a pseudointimal lining had formed inside the tubes. No clotting. So far, so good.
Cardiotech conducted a limited clinical evaluation of the graft during a few CABG procedures in Brazil. These patients were all patients, whose saphenous veins were unsuitable for grafting. When last reported in 2004, these patients were alive and the grafts were presumably open.
On the strength of this evidence, the company began a trial in Europe in 2007 to obtain the CE Mark, which would enable it to market Cardiopass in many countries (but not in the USA or Japan).
I listened to the company's conference call on February 12, 2008. To the surprise of the securities analysts on the call, the company had not yet been able to recruit the ten patients required by the trial. In fact, the company declined to state how many patients had actually been recruited. The company would only state that they were adding a second recruitment site (presumably a second European medical center) and that they had decided to make available a smaller size (4mm) graft. Furthermore, Cardiotech emphasized that they were being quite selective about which patients were included in the trial.
Agonizingly Slow: If I hadn't followed other medical device companies, I would be astounded at the glacial pace of this clinical trial. However, they are recruiting no option patients; they want to assure that patients and grafts do well; and this microcap company has a limited budget for conducting clinical trials. (In comparison total costs to bring a drug to market may be several hundred million to a billion dollars.)
From a broader standpoint, however, and the one perspective that matters most - the patients' - the health care system is letting us down. OK, Cardiotech is undercapitalized for clinical testing of its coronary graft. The consequence is that the research and development of this crucial device is frustratingly slow and some patients are left with no options.
To me this is a first world situation that invites comparison to the situation of orphan drugs and diseases in the third world. While many millions more people are affected by malaria, tuberculosis, and AIDS in the third world, patients had been left to die before the intervention of the Gates Foundation. It appears that a similar financial savior is needed for the development of synthetic coronary grafts. (Hopefully, in the future some large medical device company will play this role. Why they haven't done so, thus far, remains a mystery. Cardiotech's officials stated in the call that they will be looking to sell their technology to a larger player in exchange for royalty payments.)
A second point that motivated this article was the notion, widely purveyed in some circles, that the Age of Nanotech Health Care is just around the corner. Some enthusiasts might have us believe that progress in health care will track Moore's Law, doubling every couple of years. The Golden Age of Bioengineering and Engineered Negligible Senescence may happen but R D in health care, unlike electronics, will always be slowed down by the need for prolonged and expensive clinical trials, unexpected disappointments, government regulations, litigation and intellectual property constraints, and financial constraints. While many aspects of medical research have been accelerated by the information technology explosion, human clinical trials are intrinsically slow. Therefore, the rollout of new medical treatments, while accelerating, can be agonizingly slow and, unfortunately, less predictable than Moore's Law. Addendum: April 26, 2009 * * * * *
I can find no evidence on-line that Kensey Nash is continuing its efforts to develop a synthetic coronary graft. It appears to've had a product recall of another of its products a couple of years ago and is now refocused on its biomaterials business. Likewise, Cardiotech does not appear to have progressed in its development of a synthetic coronary graft. The company was renamed AdvanSource, which signals that it too (like Kensey Nash), has refocused on its biomaterials business. There have been no further announcements of progress in its European clinical trial of Cardiopass. The implication is that patient recruitment has stalled. These developments are a great disappointment for those of us who follow this field. But, to end on a more optimistic note here are three (among many) developments to give hope to patients needing coronary revascularization. First is TECAB Surgery. This is Totally Endoscopic Coronary Artery Bypass Robotic Surgery. This is done using the da Vinci robot. Watch the master of this operation, Dr. Srivastava of University of Chicago, in action in this video from inside the OR: live TECAB .
Second is the Cardica systems for proximal and distal anastomoses: shown at Cardica's website . Third is developments in tissue engineering. One can't help but be impressed by the tremendous effort now going into stem cells and regenerative medicine. The most tangible evidence is the construction of new university facilities throughout California that will house research efforts in this field. An early example of work in this field is that of Cytograft Tissue Engineering , which constructs living vascular grafts from patient's own cells. Addendum: February 2011 * * * * *
A brief update today, catalyzed by the recent founding of Humacyte, a new private start-up, dedicated to developing off-the-shelf biosynthetic vein grafts. Humacyte just announced the successful development of biosynthetic veins for potential use in CABG and dialysis. These are 3 to 6mm vein grafts that can be stored for a year and are now in animal studies.
Also, a British team at University College London (UCL) is developing synthetic arteries made from nanomaterials that attract stem cells from circulating blood. These cells then spontaneously convert to intimal cells, which prevent thrombosis.
Finally, although this article is not intended to cover the huge field of coronary stents, one new stent has my attention: the Abbott ABSORB, drug eluting bioresorbable scaffold. Abbot expects the stent to be widely available in Europe in two years. ABSORB has the tauted advantage of treating the target lesion and then dissolving within a few months.Addendum: September 2012 * * * * *
Abbott has just announced that its ABSORB bioresorbable (dissolving) coronary scaffold has been approved for sale in Europe and other CE Mark countries. Next the company will take steps leading to FDA approval in the USA, which may take a couple of years.
Addendum: January 2015 ******
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