Fall 2007
In this Issue:
Focus On Biomaterials
A Materials Answer to Deadly Blood Clots
Penn State professor and researcher Chris Siedlecki works at the interface where the surface of devices meets the human body, and in particular where artificial materials contact the blood supply. In two carefully isolated laboratories at the Penn State Milton S. Hershey School of Medicine, one lab for materials fabrication and characterization, and the other a biology lab devoted primarily to blood studies, he pursues the understanding of the cascade of events that occur when proteins in the blood meet a foreign object, such as a vascular stent or heart assist device, in the circulatory system.
The numbers of blood contacting devices inserted into the body each year can be staggering, including almost a million vascular stents alone. And the results of the failure to control the formation of clots can be devastating, leading to death or stroke. As Siedlecki remarks, “There is very little that can be put into the body without having to take drugs to keep you from clotting.”
Blood thinning drugs used to control clotting, such as heparin and warfarin, carry their own risks. It is hard to control the amount of drug that will keep a patient from clotting without making the blood too thin. Too much of the drug can cause bleeding in places you wouldn’t like to see bleed, the brain, for instance. Bleeding complications are found in as many as 20 percent to 50 percent of patients receiving some forms of blood contacting devices, such as artificial hearts.
A recent approach to the problem of clotting has been to keep blood proteins that initiate the clotting process from ever attaching to the foreign material. When blood comes into contact with a foreign device, often a synthetic material, proteins in the blood adsorb to the material and attract platelets that are then activated to help form fibrous materials that turn into clots. The same complex mechanism that keeps us from losing all our blood supply when a blood vessel is damaged also can clog the vascular device or cause a clot to break loose and block a distant blood vessel. Chemical or biologically active coatings that repel the proteins or platelets before they can take hold have been used for several years, with some successes and many remaining problems.
Siedlecki had spent a good deal of time on one of these approaches, developing polymer materials with chemical properties that kept proteins from attaching to the device, but the results were never as satisfactory as he would have liked. “We decided to accept the fact that the proteins are going to stick to our material and instead look at ways to minimize the binding force that holds the platelets in place. What we came up with is the idea that we could minimize the contact area between the platelets and the material by constructing a surface with little pillars sticking up – call it a bed of nails – which limits the contact area between platelets and the material to only about 25 to 30 percent of what it would be in a smooth material.”
Blood platelets attached to 700 nm diameter pillars
have less surface adhesion and are swept off
by blood flow before forming clots.
In blood there is always a moving fluid applying a shear stress. If the binding force of the platelets to the device is less than the shear stress, the platelets will be swept away before they can initiate the cascade that helps clots to form. If modifying the surface of devices can keep clots from forming, there is no need for drugs or chemicals, less of the prolonged and expensive monitoring involved with drug regimens, or the risk of coatings failure. It was an approach that seemed ideal for the kind of devices that remained in contact with blood for long periods, such as the artificial hearts and ventricular assist devices for which Hershey Medical Center is renowned.
At the Penn State Nanofab
A shuttle runs between the Penn State School of Medicine in Hershey and University Park several times a day, carrying students and faculty back and forth between the two campuses that are situated almost two hours apart. Siedlecki and his students make the trip frequently to utilize the specialized instruments located in the Materials Research Institute’s nanofabrication facility, commonly known as the Nanofab. With the Nanofab’s lithography instruments, Siedlecki’s postdoctoral researcher Keith Milner, who was trained on site, would attempt to create the surface structures that would defeat clotting.
Milner, using a two-stage soft lithography replication molding technique, first created patterns of pillars roughly 1/2 to 1/4 the size of the platelets, in a layer of photoresist on a silicone wafer. Using the Nanofab’s 248-nm 5:1 Reduction Stepper, he exposed and developed the photoresist, creating a pattern of pillars 700 nm wide and 700 nm apart on the first wafer, and 400 nm wide and 400 nm apart on the second. The photoresist was then covered by a layer of PDMS, a silicone material. After it cured, the silicone layer was pulled off, creating a negative mold with holes where each of the pillars had been. Filling the negative mold with polymer created a positive surface with pillars in the exact spacing of the original photoresist.
“We take the negative mold and we can put on any polymer we want, at least none of the ones that we’ve tried so far have failed,” Siedlecki comments. “The main one we’re interested in is a polyurethane material that is used in the Penn State artificial heart and ventricular assist device. They are also used in vascular grafts, so they’re pretty common in a lot of blood contacting applications.”
Back in their own labs at Hershey, the team, which also includes Alan J. Snyder, professor of surgery and bioengineering, tested the molds in a machine simulating the flow of blood through medical devices. Using a rotating disk system, a smooth surface polymer-coated disk was compared with the bed of nails disk at various shear rates in samples of bovine platelets.
The 700-nm spacing in particular showed a significant decrease in adhesion of platelets at low shear. With further refinements of the material, platelet adhesion was reduced by almost 10-fold, equivalent to the best results that can be achieved chemically. “
The nice thing about this process is that the silicone negative that we make in the first repetition step we can use over and over. We’ve done this in wafers that are 6 inches in diameter. A wafer that size is big enough to start making devices out of. It’s big enough to make parts to an artificial heart or vascular graft, or anything similar, from the original wafer. We’re working now to develop techniques to take what are two-dimensional lithography techniques and create three-dimensional structures. We’ve been successful in making tubes that could be used as either vascular grafts or conduits into other medical devices, like artificial hearts or blood pumps. We’ve succeeded at that. Now we can coat the whole inside of a tube with the textures. We have done some preliminary bench-top testing of those tubes and find that the results we saw for decreased platelet adhesion seems to hold in the tubes also,” says Siedlecki.
Penn State has filed a U.S. patent application on the sub-micron texturing technique. Some companies have already shown interest, Siedlecki says. For the significant number of people who cannot tolerate the anticoagulant drug regimen required for current device implants, a materials solution to blood clotting will come as an important development.
Contacts:
- Christopher A. Siedlecki, associate professor of surgery and bioengineering: Validate to view contact info
- Alan J. Snyder, professor of surgery and bioengineering, and associate dean for technology development: Validate to view contact info
