SMALL BUSINESS INNOVATIVE RESEARCH (PIPE)

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Now made in Brazil

First stent produced Brazil to correct narrowed arteries has a market

YURI VASCONCELOS | ED. 173 | JULY 2010

 

Stent being molded by laser at Innovatech

Some 800 Brazilians already have in their chests the first stent fully designed and manufactured in the country. The metal device, used for treating cardiac patients with narrowing of the heart arteries, was developed by Innovatech Medical, housed at the Center for Innovation, Entrepreneurship and Technology (Cietec), in São Paulo. Stents are tiny mesh cylinders, accompanied by a balloon, that are placed in the heart’s arteries or the peripheral blood vessels in other parts the body that have been partially blocked by fatty or calcium-containing plaque. On inflating the balloon, the stent expands, causing the blood to flow normally again, thus avoiding heart attacks or major surgery such as heart bypass grafts.

To put the product on the market, Innovatech signed a partnership agreement with Scitech Medical, from Goiânia (GO), a specialist in the manufacture and distribution of invasive medical devices in the areas of cardiology, radiology, neurology, oncology and endoscopy. “We make the metal platform of the stent and Scitech does the final assembly on a balloon catheter, a device that will be used to place the product in the patient’s artery,” says Spero Morato, managing partner of Innovatech, which started research with the stent in 2003 (see Pesquisa FAPESP nº 110). The catheter comprises a transparent tube (145 centimeters long and 6 mm in diameter), with a balloon at its tip; the metal stent is placed on this balloon. The end product has the brand name Cronus.

By means of a procedure called angioplasty, which unblocks the artery, the device is generally introduced via an incision in the patient’s groin to the place where the lesion is and where the stent will be implanted. A 35mm thick guide wire is used to guide the balloon. When it reaches the lesion, the balloon is inflated, crushing the plaque that caused the blockage and expanding the stent, which sticks to the artery’s inner wall, keeping it from closing. Then the balloon is deflated and removed from the patient?s body along with the catheter and guide wire. This procedure is performed some 100,000 times a year in Brazil. Until the end of 2009, when Cronus came onto the market, all devices used were imported, because neither the technology nor a manufacturer existed in the country. The company needed six years to research, develop and start producing on an industrial scale. In addition to supplying the domestic market, there are plans to export the product. “We’ve already received orders from Spanish and Italian companies that distribute medical supplies to hospitals,” says the physicist, Spero Morato, managing partner of Innovatech.

Pharmacological version
Cronus is made from fine chrome and cobalt tubes, a metal alloy considered ideal for producing the device because it has greater mechanical strength, making it possible to make finer rods than those of stainless steel stents. Innovatech offers doctors a family of stents in six lengths (9 mm, 13 mm, 16 mm, 19 mm, 23 mm and 26 mm) and three different diameters (2.5 mm, 3 mm and 3.5 mm). Cronus stent consists of conjoined rings, with rods that are 75 microns thick. “Its structural characteristics, with fine rods and single geometry, seem to be very suitable for use as a platform in pharmacological stents,” emphasized the cardiologists Daniel Chamié and Alexandre Abizaid, in the article “Stent Cronus: chegou o momento de adotarmos um stent nacional?” [Cronus stent: has the moment arrived to use a Brazilian stent?], published in the July 2009 issue of Revista Brasileira de Cardiologia Invasiva [Brazilian Journal of Invasive Cardiology], the official publication of the Brazilian Society of Hemodynamics and Interventionist Cardiology. Pharmacological stents are covered with drugs that prevent the proliferation of scar tissue on the artery wall where it is implanted, which would cause a new obstruction of the vessel. “[Cronus] has the potential for causing a low amount of injury to the vessel wall and allowing the homogenous distribution of the drug. Proof of the flexibility and navigability of this device is that it can also be used in vessels with a more complex anatomy,” wrote the experts, who practice at the Dante Pazzanese Institute of Cardiology in São Paulo.

“The pharmacological stent is in the clinical trials stage at the Heart Institute of the Clínicas hospital at the Medical School of the University of São Paulo (InCor) and has already been experimentally implanted in 40 patients,” says Melchiades Cunha Neto, owner of Scitech and a partner of Morato’s in Innovatech – each has a 50% share of the company. “We expect, by the end of this year, to get authorization from Anvisa [the Brazilian Health Inspection Regulatory Agency] to start marketing it.”  In addition to carrying out the final assembly of the device and making it ready for use, Scitech, winner of the 2008 Finep Prize for National Innovation in the medium-sized company category, is also responsible for the polymer coating for impregnating the Innovatech stent with anti-restinosis drugs, which prevent an artery narrowing again.

The current production capacity is 600 Cronus stents a month, but the goal is to reach 15,000 units a year and thus gain a 15% share of the Brazilian market. This objective will be reached by expanding Innovatech’s production capacity, with the acquisition of new equipment. To assemble the current structure, the partners invested US$ 200,000 from their own pockets to buy imported equipment, including a laser cutting machine. They also managed to get funding for two projects from FAPESP’s Innovative Research in Small Companies (Pipe) system, in the amount of R$ 610,000, and from an Economic Subvention Project from Finep, of the Ministry of Science and Technology, in the amount of about R$ 530,000. As a result of the space limitations at the Innovatech facilities in Cietec –  it is housed in an area of just 50 m2 –  Morato and Cunha are planning to transfer the company to Goiânia next year. “In this way we’ll be closer to the production line of our partner, Scitech, which should reduce production costs,”  says Morato. “We’ll leave just a research and development unit at Cietec, for testing new designs, sizes and metal alloys.”

The Cronus price is comparable with that of the imported stents in the Brazilian market. Scitech sells the product to the SUS – Sistema Único de Saúde [Single Health System] for R$ 2,034.00 each. According to Morato, the price has fallen a lot over the last five years due to increased competition from stents from China, India and other countries. Previously, the market was dominated by American products. These stents are still more widely used but have lost the big leadership margin they used to have.

Tiny production
The Cronus production process is careful and divided into various stages. It all begins when the metal tube made from the chrome and cobalt alloy is cut with a laser to form the stent’s characteristic mesh. This tube, 1.6 mm or 1.8 mm in diameter, then goes through a mechanically-controlled laser beam that employs a technique known as Computerized Numeric Command (CNC), which machines the metal part in a controlled manner, according to a digital mold. This machine produces a circular and translation movement in the tube, thus giving the stent its final shape, which is similar to a spring. When it leaves the apparatus, the piece, already with its final appearance, has its surface cleaned to remove any oxidation that may have occurred during the laser-cutting process. The surface is cleaned in an acid bath. The stent then undergoes high vacuum thermal treatment to relieve stress and adjust the size of the alloy grain. As a result, it acquires the right mechanical characteristics, such as flexibility and expandability. The effectiveness of the thermal treatment is checked using an electronic microscope, which enables one to analyze the stent’s morphology and structure.

The subsequent stage consists of electrical or electrochemical polishing, to adjust the dimensions of the rods that form the stent’s mesh and leave the surface polished. Rigorous inspection is carried out at the end of each stage, as well as at the end of the process. With the help of a device that amplifies the size of the stent dozens of times,  the Innovatech technicians assess the dimensions of each item, thus certifying that it is of the right size. Finally, the stent is sterilized and sent to Scitech, in Goiânia, for final assembly of the catheter-balloon. It is then ready for implanting or for being covered with a layer of the anti-restenosis drug.

To begin with, the Cronus development was the responsibility of LaserTools, a company set up in 1998, which also belongs to Morato and another partner, and specializes in the laser-processing of materials. To carry the stent project forward, they created Innovatech in 2004 in a partnership with InCor. Researchers from the institution were responsible for carrying out animal trials (on rabbits and pigs) and for clinical trials on humans to confirm the device’s safety and effectiveness. First, the stents were implanted in rabbit arteries, of a similar size to a human coronary, and removed after 30 days for evaluation. The next step was to place them in pigs, which remained with the implant for six months. “Comparative studies carried out by the InCor team using Cronus stents and imported models showed that ours were more effective,” says Morato.

The device was also the subject of an international clinical trial, with the participation of Cimeq, the Center for Medical and Surgical Investigations of Havana, in Cuba, and InCor. Between February 2007 and December 2008, 53 patients were treated with 69 stents, with evidence of the successful use of the device in 98.5% of the cases. The study was detailed in the article “Resultados clínicos iniciais do primeiro stent de cromo-cobalto concebido no Brasil” [Initial clinical results of the first cobalt-chromium stent designed in Brazil], published last year in the Revista Brasileira de Cardiologia Invasiva, in which its 11 authors state that “the Cronus stent was considered safe, showing a satisfactory rate of adverse cardiac events.” It concludes: “The importance of this device lies in the fact that its engineering, its pre-clinical development and its clinical evaluation were conducted in Brazil, with findings similar to those of international studies,  in effect a pioneering analysis in this sense.”

The Projects
1. Biocompatible metal implants (nº 02/02134-0); Type Innovative Research in Small Companies (Pipe); Coordinator Spero Penha Morato- LaserTools/Innovatech; Investment R$ 150,080.00 and US$ 133,510.00 (FAPESP)
2. Development of laser-processed vascular endoprostheses (stents) (nº 07/55757-8); Type Innovative Research in Small Companies (Pipe); Coordinator Spero Penha Morato – LaserTools/Innovatech; Investment R$ 102.947.82 and US$ 74,066.00 (FAPESP)


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