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Purpose
Coronary angioplasty is a commonly used procedure to reduce the symptoms of coronary artery disease. A persistent complication has been the occurrence of coronary restenosis and the need for repeated revascularizations. The recent introduction of coronary stents has greatly improved the safety of angioplasty and has reduced but not eliminate the problem of restenosis. There is accumulating and compelling evidence that specific drug eluting stents may greatly reduce the magnitude of this problem, although the exact clinical benefit in routine practice has not been fully defined.
A catheter-based procedure is a minimally invasive and relatively inexpensive alternative for surgery. In this procedure, a thin tube is put into one of the blood vessels of the body through a slit, usually in the region of the groin or the upper thigh, and is led to the target area (in this case, the heart). The doctor is able to watch the catheter in the patient’s body through a fluoroscope, which displays the patient’s blood vessels on a screen. The two major kinds of catheter-based procedures dealing with the heart are: (1) balloon angioplasty and (2) atherectomy. In balloon angioplasty, the catheter has an inflatable balloon at its tip. When the tube is brought into the concerned blood vessel, it is inflated and the pressure pushes back the plaque accumulated, thereby opening the vessel. Atherectomy is a procedure in which abrasive materials at the top of the catheter are used to drill away highly calcified plaques. In both these procedures, a stent, a small expandable wire mesh tube is placed in the particular region of the blood vessel to prevent closure after completion of the procedure. |
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Approach and Design
In April of 2003, Johnson & Johnson (J&J) launched the first ever drug-eluting stent in the USA. By studying the current material composition of their stents, the concepts and material behavior will be mimicked with different materials. After analyzing the chemical properties, physical properties, thermodynamics and fluid dynamics needed from the already successful stent, different materials will be observed for their similarities in behavior to J&J’s.
After the materials have been selected they will
be tested against a buffer solution with the chemical properties of
blood. The behavior of the materials will be analyzed and interpreted
leading us to the design of a new prototype drug-delivery system for
stents.
In the efforts to manufacture the best possible
materials to use in an endovascular stent, a compromise must be reached
amongst the materials, stent and body. Some properties the materials
need to exhibit are the desired structural support, mechanical and
physical attributes, biocompatibility, biointegration and hemodynamics.
The biodegradable drug delivery system design must utilize the polymer
in such a way to manipulate its distinct levels
Figure 2: In-Stent Restenosis
Sirolimus is categorized as a cytostatic drug, drugs that inhibit cell division by blocking cell-cycle progression and is usually used to prevent rejection in organ transplants. Sirolumus is encased within a polymer coating. With careful design, polymer stents hold great promise and may introduce new medical methods for the future. (1) Similar to the CYPHERTM stent, a drug-eluting stent will be designed such that the drug chosen (i.e. rapamycin) from Table 1 (p. 13) will be encased in a polymer coating. (2) The polymer coating will sense the protein to be inhibited (i.e. mTOR for rapamycin) by the drug. (3) Upon this sensing the polymer coating will release the drug attach to the protein and inhibit it. The polymer’s ability to sense the protein is key because it is the polymer’s time-release measurement.
Complications:
A large number of complications arise after placement of a stent in a blood vessel. In the past, the blood vessels have been known to close in a very short period after the placement of the stent. This re-closure of blood vessels is called restenosis. The two major causes of restenosis are: (1) neointimal hyperplasmia and (2) sub-acute thrombosis. Neointimal hyperplasmia is a condition in which blood vessel cells, in the region where the stent has been placed, begin to proliferate rapidly, ultimately blocking the vessel (restenosis). When the stent is placed in the blood vessel, lesions or scars are created, which induce the formation of clots (sub-acute thrombosis) and cause blockage of the vessel. Stents should therefore be designed to reduce these conditions, which in turn would lead to a reduction in the rate of restenosis.
Solutions:
A large number of biomedical companies are trying to minimize the aforesaid problems created by stent implantation. Many have invented new stents that yield very low rates of restenosis. One successful prototype invented by a company called Medinol Inc. is described below. This stainless steel stent coated with the polymer (pLA/pCL) and with 200 micrograms of the drug paclitaxel, prevented restenosis of the blood vessel for over six months. Paclitaxel inhibited human arterial cell migration when it was present in the artery at a concentration of 0.01 to 10mmol/L. Paclitaxel interferes with cellular migration and proliferation, primarily, by stabilizing microtubules. It interferes with cells’ capacities to maintain shape, move, transmit intracellular signals and effect intracellular transport. In addition, paclitaxel may alter inflammatory cell activity, which is directly linked to the genesis of stent-induced neointima (cell proliferation), by enhancing macrophage production, production of nitric oxide, prostaglandins or other cytokines. It was shown through experiments that while the level of macrophages, which inhibited stent induced proliferation, dropped within two months when bare stents were used, this level remained very high even after 6 months, when stents coated with the drug paclitaxel were used. Even though paclitaxel coated stent prevented cell proliferation, it allowed for the normal re-growth of the endothelial layer of the arterial wall, thereby making it better than, radiation emitting stents. Besides, this polymer-coated stent did not instigate cell proliferation as other polymer stents did. It was found that though the release of paclitaxel by the coated stent stopped within the two months, the drug prevented cell proliferation and restenosis for six months. This indicated that the drug persisted in the blood vessel and continued to have effect. Studies have also shown that since restenosis was inhibited by paclitaxel for six months, it was unlikely for the process of cell proliferation and restenosis to begin after the drug had stopped taking effect.
Final Design |
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Stent Types:
Pressure cleaning of the stent and better methods of implanting the stent do not get eliminate all the factors that lead to restenosis. In order to deal with these factors more effectively, modifications have to be made in the material of the stent. As seen from the facts stated above, bare metal stents stimulate the neointimal (cell proliferative) response to coronary injury. Therefore, different kinds of stents such as fibrin film stents, autologous graft stents, drug-coated polymer stents and radioactive stents have been designed. All these stents have a metal base. All of them, (with the exception of radioactive stents), differ only in their coating. Fibrin film stents or fibrin-coated stents are more advantageous to use than bare metal stents because they cover a greater arterial area and are in fact are able to cover the area with lesions very effectively. This prevents the blood flowing in the vessel from coming into contact with the lesions and thus prevents clotting. Since these stents provide a more uniform coverage, they can also be used to provide uniform local drug delivery. The drugs being delivered at that location can be aimed at reducing cell proliferation. Hence, fibrin film stents can play an effective role in inhibiting both neointimal hyperplasmia and subacute thrombosis. Furthermore, there is no exaggerated foreign body reaction to the fibrin stent, and local vascular integrity is maintained. Autologous vein graft stents also seem to be an attractive option because they are combinations of the metal stent and vascular tissue. They create a barrier between the metal stent and coronary blood flow. This barrier consists of immediately viable endothelium, which reduces the potential for thrombus formation and subsequent neointimal proliferation. The third kind of stent that has been investigated is the polymeric stent. In order for the polymeric stent to be active it has to incorporate sufficient mechanical support to maintain lumen gain and keep the vessel open. It has to allow endothelialization (normal re-growth of the endothelial cell layer) of the diseased arterial segment after the procedure. In addition, the stent has to be biocompatible and must not initiate local thrombus formation or foreign body reaction. Polymeric stents can also act as a vehicle for local drug delivery during the period associated with neointimal thickening.
Apart from trying to reduce the rates of restenosis with the use of coated stents, radiationtherapy has also been attempted. In this process a stent, which emits beta particles, is placed in the subject. The release of radioactive particles inhibits neointimal proliferation. However, many complications arise when dealing with radioactive particles. The first major complication deals with the length of the half-life of these radioactive particles and the amount of time for which they emit radiation. The second major complication that arises, which is peculiar to the use of radiation therapy to reduce restenosis, is the inhibition of the normal re-growth of the endothelial layer. If the endothelial layer does not grow back over the lesions created by the removal of the plaque, (by atherectomy), or the placement of the stent, thrombosis will occur and a clot will form in the blood vessel. Radiation prevents cell proliferation (which is good) but it also prevents prevents the normal endothelialization. |
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