Rita de Cássia Xavier da Costa, aged 46, for three years has been avoiding leaving her house to go shopping, meeting with friends, or even looking for a job. Her reclusion was only broken at the end of June this year, after undergoing an operation to reconstruct her jaw that gave her back the former shape of her face. “I am a different person after the surgery. I have lost the fear of meeting people, I have started to smile again and to eat solid foods”, says this resident of Petrópolis, in the Rio de Janeiro hills. The raw material used to reconstitute Rita’s jawbone, corroded by a tumor, is a polymer, a material that is similar to plastic, which is based on the castor bean plant, a bush that is widely disseminated in Brazil.
Synthesizing this material, which can be called a biopolymer, because it has a strong capacity for interacting with the cells of the human body and does not cause cases of rejection, like the platinum used up until now in jawbones and in other parts of the body, is the work of Professor Gilberto Orivaldo Chierice, from the São Carlos Chemistry Institute, of the University of São Paulo (USP).
In June this year, Chierice’s invention received the approval of the Food and Drug Administration (FDA), the agency of the American government that is responsible for releasing new foods and drugs. This certificate opens the doors to the biggest market in the world in the area of health, and guarantees scientific and commercial visibility all over the planet. In Brazil, the Ministry of Health had already approved the biomaterial in 1999, eight years after Chierice started his works in this area. In the course of this time, over 2,000 persons victims of accidents with firearms, cars, motorcycles and of tumors were benefited with prostheses to replace bones in the jaw, the skull and the face, or as supports in the backbone, to replace the testicles, in the penis, in the eyeballs and in the gums.
Before granting approval, the FDA carried out chemical and biological tests, like the test for cytotoxicity (to assess whether the product is toxic for the organism), and a series of others that had already been carried out in Brazil. Certification by the American agency does not come cheap. The cost of US$ 400,000 was funded by Doctors Research Groups (DRG), a company from Plymouth, in the state of Connecticut, which is going to distribute the product in the United States and Canada. Their interest in the polymer from the castor bean plant arose when Brazilian physicians were invited to make a presentation in the United States of experimental surgeries with the new material. Representatives of the DRG were at one of these presentations and got in touch with Chierice. In September last year, they went to São Carlos for the first time to get to know the product and, after this, returned another seven times to Brazil, some of them to accompany operations by various groups of doctors.
“They asked a lot of questions and wanted to see everything, but it was worth the trouble, because with the certificate we can export to other countries”, Chierice comments calmly, while he chops up rope tobacco to roll a straw cigarette, a ritual he repeats several times in the course of the day. To market the product, in 1997 the professor created a company he called Poliquil, set up in Araraquara, and he filed the patent for the invention with the National Institute of Industrial Property (INPI) in his own name, in the same year. The company has been run since then by three technicians who used to work with him. According to Chierice’s calculations, the exports of the castor bean polymer to the United States alone should result in earnings of some US$ 500,000 a year for Poliquil.
The polymer, registered in Brazil as ricinus bone compound (RBC), in a reference to the scientific name of the plant (Ricinus communis), was given in the United States the name of RG Kryptonite, a word that recalls the planet of origin of Superman, the famous character of the comic strips and TV and cinema series. Although not confirmed by the company, the name relates the effects of Kryptonite, the metal that takes the strength away from the man of steel, with the biopolymer that should win a market, leaving metal prostheses weaker. The material produced by Poliquil is exported in kit form, with two ampoules, made up of polyol and a prepolymer, extracted from castor seed oil, the products developed by the researchers, plus calcium carbonate, mixed together only the moment that they are to be used.
The biopolymer’s success is explained by the compatibility it has with the human organism. “In the chemical composition of this material, there is a chain of a fatty acids whose molecular structure is present in the fats existing in the human body. That is why the cells do not perceive the castor resin as a foreign body and so do not repel it”, explains Lizeti Toledo Ramalho, a professor from the Araraquara School of Odontology of the São Paulo State University (Unesp). The researches carried out at USP, Unesp and Poliquil have brought about success abroad, even before the approval of the FDA.
“The area in which we most used this new product was in operations on the spine, with over 500 interventions, carried out by six different groups of surgeons”, says Jorge Viscovig, the distributor of the product in Chile and in Argentina, where some 1,700 operations were carried out with the polymer. In one of these interventions, a 60-year-old Argentinean women with fractures in the backbone as a result of osteoporosis, a disease that wears down the bones naturally, freed herself from pain, 40 minutes after being given the castor bean in liquid form.
Injected into the bones with a syringe, using a technique called vertebroplasty, the viscous light yellow colored liquid fills the spaces corroded by the disease and solidifies. This fixes the fractures and the patient feels immediate relief from pain. Chierice stresses the advantage that this material has over acrylic cement, much used in this kind of procedure, is that it contributes towards regenerating the bone, not just immobilizing the fracture.
It really does, the bone regenerates itself. In a biochemical process not yet totally explained, the organism replaces the polymer with bone cells. “It gets dismembered, and bone grows in its place”, says Sérgio Augusto Catanzaro Guimarães, a retired professor from USP’s Bauru School of Odontology and the coordinator of research at the Sacred Heart University, also in Bauru. In his research, he used the resin to recover bone defects in the skull and in the face. The biopolymer’s capacity for regenerating the bone or not is related to the way it is prepared. According to the molecular arrangement of the substances that form the material, it may either be absorbed by the organism or not.
This factor is stressed by the researchers and surgeons who are working with the castor polymer, like Edelto dos Santos Antunes, a doctor from Petrópolis. In August, he reconstructed part of the jawbone of a patient with a polymer in two different textures. “The harder, outside part, will remain forever as a prosthesis. The inner part, which stays in contact with the bone and is porous, is going to be replaced by a bone structure”, reports the specialist in maxillofacial surgery, who has already done 30 castor bean prostheses in the last four years, all of them made by the Single Health System (SUS The public health system in Brazil) at the Saint Theresa Hospital in Petrópolis.
The castor bean resin is also emerging as a good promise in the area of esthetics. One of the more recent lines of research shows that the polymer has great potential, in the form of very fine threads, to alleviate wrinkles and to combat flaccid skin. “These threads have now been implanted in laboratory animals, with excellent results”, says Lizeti, from Unesp. She thinks that the biopolymer thread is a potential candidate for replacing the thread made of polypropylene, a plastic derived from petroleum, developed in Russia in 1999. “The Russian thread is much used by plastic surgeons. After being introduced into the face using a cannula, it remains in the conjunctive tissue of the dermis for an indeterminate time”, he reports. “But the thread of castor bean resin has greater biocompatibility and does not cause rejections or allergies like the ones made of polypropylene”, the researcher points out; in August, he presented the results of his research to plastic surgeons at a workshop in Araraquara.
Wrinkles and jawbones did not pass through Chierice’s head when he started the first studies that resulted in the eclectic polymer. It all started in 1984, when the Research and Development Center at Telebrás, then the public sector telecommunications holding company located in Campinas, was facing problems with an imported resin used to protect the underground and above-ground cables for humidity. As they degraded prematurely, the company turned to USP’s Chemistry Institute to assess the material. “I began to analyze the resin and came to the conclusion that I could do something better”, says Chierice. It was a job forecast to last six months that afterwards extended to athree-year contract with Telebrás. “We made a new polymer for them, derived from the castor bean plant, with fantastic results.”
The research would have probably stopped there, were it not for the interest that the product aroused at the beginning of the 90’s in a doctor from the Amaral de Carvalho Hospital, in Jaú, upstate São Paulo, an institution that is a benchmark in the treatment of cancer. “During a visit to USP in São Carlos, urologist Renato Prado Costa, who at the time was the hospital’s clinical director, became enthusiastic over the novelty, and proposed that we should make some prostheses for testicles, to replace the silicon ones then in use at the hospital”, says Chierice.
The prostheses were made and sent for testing at the hospital of Unesp’s School of Veterinary Medicine in Botucatu. After some time, Prado Costa got in touch with Chierice to say that the material had some unknown properties, which needed to be studied. This was so, as reported by the people in Botucatu, the rabbit that was given the polymer showed no signs of rejection. “Until then, there had been no talk of the biocompatibility of the polymer”, says Chierice. Experiments were carried out on rats, pigs and dogs, and the results confirmed the experience with the rabbit. It was then that the tests on human beings were started.
Prado Costa asked Chierice to make several prostheses of testicles, intended for terminal patients with prostate cancer. The urologist talked to the patients families and they authorized the procedure. When the patients died, the prostheses were removed and the analyses showed perfect compatibility with the organism. Prado Costa decided to widen the researches. “I put in 50 testicle prostheses and 12 penile ones, and there was no report of any rejection”, he says. Almost ten years afterwards, some patients still have the prostheses. Prado Costa says that he has achieved his objective. “I showed that the polymer is biocompatible and lends itself to making prostheses for medical uses”, he reports. “Not to mention that the ones made of polymer costs up to 15% less than the silicon ones.”
Patient recovered
The reports of the successful experiments called the attention of specialists in cancer of the head and neck in Jaú, who also wanted to try the material out. A few modifications in the arrangements of the molecules made the polymer more rigid, making jawbone implants possible, for example. Chierice tells how he was moved when he saw a patient at the Amaral de Carvalho Hospital who had lost half his jawbone due to cancer, bite into a steak, after being given a prosthesis with the polymer. Another similar case is Alexandre do Nascimento, a 30-year old driver who was given the same kind of prosthesis after going through a fair period with swelling and pain caused by a tumor. “I eat bread, meat and don’t feel any difference. When I go to a barbecue, I don’t stand on ceremony”, he reports. “People don’t believe that I have a prosthesis, because I eat well and the scar is a small one.”
The work of reconstructing jawbones and skulls with the polymer is done in conjunction with researchers from the São Carlos School of Mechanical Engineering (EESC), also USP’s. Theirs is the task of designing and calculating each detail of the made-to-measure prothesis, such as the exact place to fit the screw that makes possible the articulation of the jawbone. The first step in this work is to get a tomography of the place where the prosthesis is going to be put.
This image, worked on a computer, goes to a prototyping machine, where the prosthesis is produced in rigid plastic, for a mold to be made next in silicon, and in the final stage to be made in the polymer. “When the patient goes to the operating table, the prosthesis is already ready, personalized”, says Professor Jonas de Carvalho, from EESC. “The intervention used to last 16 or 17 hours by the traditional method, but with this procedure it takes two hours on average.” By the old process, all the measurements and adjustments of the new prosthesis would be done in the operating theater itself. Not to mention that platinum, the material used in this kind of prosthesis, can be rejected by the organism, but not the castor bean kind.
Modified material
The studies involving the polymer are a chapter apart in this trajectory. According to Chierice’s calculations, there are today over 200 works published and about 40 master’s and doctor’s degrees, in the areas of medicine, dentistry, veterinary medicine and engineering. Part of the professor’s studies was funded by FAPESP through a grant for the research.The profusion of studies about the polymer from the castor bean plant has produced solutions hardly imagined by the researchers linked to the production of prostheses. One of them lies in the bactericidal and fungicidal potential of this biomaterial, revealed by professors Izabel Froner, from USP’s School of Odontology in Ribeirão Preto, and Izabel Yoko Ito, from the School f Pharmaceutical Sciences of the same university. This research resulted in the registration of two new bactericidal products, endoquil, used in the treatment of tooth roots, and perioquil, for application in periodontology (gums).
Cheap insulator
In the sphere of electrical engineering, one more unprecedented use. Mixed with other materials, the biopolymer was approved as an electrical insulator for high voltage networks. “We used the resin to make an insulator and, to improve its mechanical and thermal properties, we put in different additives, like sand and silicon”, says Professor Ruy Alberto Correa Altafim, from EESC. “With these additive, we managed to bring the costs down while maintaining the electrical characteristics of the material”, says Altafim, who has now applied for a patent for the polymeric insulator.
Even with so many encouraging results, no company was willing to invest in the polymer until the mid-90s. Chierice decided then to create the conditions for producing the polymer commercially, albeit on a small scale. At the same time, the mayor of Araraquara was thinking of installing technology-based companies in the municipality. It only took one meeting for Poliquil to take shape. According to Antônio Rossi, one of the partners, today the parts are prepared in accordance with the necessity. “The doctor has the idea, and we design the part.” There are 300 items in the catalog. Another product from the factory in Araraquara is a variety used as an adhesive in filters of an extracorporeal pump, an apparatus that handles the filtering of the blood in surgical operations.
When you listen to Chierice and other researchers talking about the possible uses for the biopolymer, it appears to be a panacea for everything. But actually it is the fruit of academic research that mobilized scholars from several São Paulo universities and is now being transformed into products for society. But the story of this vegetable oil looks like it is not stopping here. Given the interest aroused by the castor bean polymer, the researchers are promising many surprises yet.
Domestic dispersion
Castor oil, also known in Brazil as ricinus oil, has enormous chemical versatility in the industrial sphere. It can be used in the plastics, cosmetics, paints and varnishes and steel industries, besides being indispensable for preventing aircraft fuels and lubricants from freezing at extremely low temperatures. Extracted from the seeds of a herbaceous bush from the euphorbiaceae family, also known as krapata, castor oil was widely used in Brazil as a laxative and a vermifuge.
The existence of a large number of varieties of this plant, found both on the African continent and in Asia, makes impossible any attempt to establish its real origin. Seeds found in tombs show that the castor bean was already used by the Egyptians at least 4,000 years ago. In ancient Greece, some philosophers mentioned in their writings the use of castor oil in Egypt for lighting and in the production of unguents.
“The castor bean is always found where there are agglomerations of humans, and is indicative of domestic dispersion”, says Márcia Barreto de Medeiros Nóbrega, a researcher with the Brazilian Agricultural Research Corporation, at Embrapa Cotton, in Campina Grande (PB), who is working on genetic improvement of oleaginous plants. “From Porto Alegre (RS) to Tabatinga (AM), this is the situation to be seen anywhere I go.” The plant was brought to Brazil by the Portuguese, with the purpose of using its oil for lighting and lubricating the axles of carts.
The tropical climate made it easy to spread.Over the decades, Brazil kept the place of the biggest producer and exporter world-wide of castor oil. But in the last few years it has lost the first place and fell behind India and China, in that order. In the 2001/2002 harvest, Brazil produced 82,200 tons of castor beans (seeds), with an average production of 651 kilos per hectare, according to figures from the National Supply Company (Conab). Bahia produced 75,700 tons of this total.
The Project
Characterizations of Polyurethane Polymers Derived from Castor Oil to be Used in the Medical Area (nº 97/06801-0); Modality Regular research grants line; Coordinator Gilberto Orivaldo Chierice – IQSC-USP; Investment R$ 99,245.00
