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Adhesive poison

Enzyme replaces traditional sutures with no scarring

MIGUEL BOYAYANFraction of the venom of the jararaca snake has coagulating effectMIGUEL BOYAYAN

From the poison of snakes such as the jararaca pit viper and the cascavel rattlesnake, consisting of a mixture of enzymes, toxins and amino acids with several biological activities, Brazilian researchers have derived a surgical adhesive successfully tested in applications such as attaching skin, nerves and gums, besides being of help in the healing of venous ulcers, among other uses. The adhesive is based on the same natural principle of blood coagulation. “After skin is cut, bleeding stops because fibrinogen, a protein involved in blood coagulation, is broken down into fibrin molecules, which are the chief component of blood clots, forming an adhesive web”, explains Professor Benedito Barraviera, from the Tropical Diseases Department of the Medical School of Paulista State University (Unesp) in Botucatu and director of Cevap, the university’s Center of Study for Poisons and Venomous Animals.

The surgical adhesive developed at Cevap contains both fibrinogen extracted from buffalo blood, that performs better than that of other animals studied, and the thrombin-like enzyme isolated from the cascavel, which fosters blood clotting. There are several commercial products available in the market that mimic human blood coagulation, but they are human fibrinogen and bovine thrombin compounds. “These products are efficient, but as fibrinogen is extracted from human blood it can be contaminated with a range of viruses, such as hepatitis”, says Barravieria. “Because of these risks, the FDA, the American agency that regulates food and drugs, has not approved this surgical glue for use in the United States to this day”, he stresses.

Replacing the bovine thrombin by the cascavel kind has been proven in trials to be a highly effective choice when it comes to tissue healing, given how the molecules of gyroxin, the enzyme from which the thrombin was obtained, join up with animal fibrinogen to form a polymer web with coagulating activity. The possible uses of this adhesive involve primarily solid organs such as the skin, nerves, liver and heart. “In arteries, however, it should be used only with great care, because its components could clog them”, stresses the researcher. The adhesive, which consists of a few drops of snake thrombin and buffalo fibrinogen, can only be prepared at the moment of application. “The two components are put in a syringe with a double opening and only mix at the end”, says Barraviera. If they are mixed before, the adhesive effect goes into action immediately and spoils the product.

Gluing nerves
Since 1989, the Cevap researchers have focused on studying a new fibrin sealant made from the venom of Bothrops genus snakes, which include the jararaca, and from the Crotalus genus, which includes the cascavel. The first person to pore over the development of an adhesive incapable of transmitting infectious diseases was Professor Fausto Vitervo, who was working on a line of research that centered on gluing nerves. At present, the project involves several partners of Unesp itself and institutions such as the Ribeirão Preto Pharmaceutical Sciences School and the Medical School of the University of São Paulo, and the Genetics and Biochemistry Institute of the Federal University of Uberlândia. The trials conducted so far show that using snake venom adhesive, for which a patent request has been deposited, results in perfect healing that is esthetically superior to that produced by conventional suture.

“In the case of skin grafts following cancer removal, there was no vestige of a scar”, Barraviera tells us. He is referring to research that involved 25 patients, conducted by Professor Hamilton Ometo Stolf, from the Dermatology Department of Unesp’s Medical School in Botucatu, who studied the removal of skin tumors near the nose with subsequent skin grafts for his PhD, defended in 1999. A piece of skin from the nasolabial fold (the area beneath the tip of the nose and the top of the mouth) was grafted there. In another study, conducted by the nurse Márcia Gatti as part of her PhD thesis submitted this year to the Tropical Diseases Program at the Botucatu Medical School, under the guidance of Professor Silvia Regina Sartori Barraviera, 22 patients were evaluated who had  venous ulcers, which are due to circulation problems in the lower limbs. Half of them were given the conventional treatment, namely, a zinc oxide impregnated bandage (called Unna’s boot) that is applied to the leg for protection. The other half received, first, an application of fibrin adhesive from snake venom on the wounds, followed by the same protective bandage. “Healing among the patients treated with the adhesive and the boot was far faster”, said Barraviera.

The excellent results achieved in these cases and in gum surgery led other research groups to develop an interest in the new surgical adhesive for as yet untested applications, such as using it with trunk cells and in neurosurgery. However, to be able to supply these groups, it is necessary, first, to set up a semi-industrial lab to produce a larger amount of snake thrombin and fibrinogen for research purposes. The large-scale synthesizing of the venom molecule, sufficient for commercial use, demands complementary studies of its molecular structure. This is one of the stages the researchers are focusing on, while they also study the venom of several different snakes, to find other enzymes that might have a better yield than what has been obtained so far. “Perhaps some other poison has a higher percentage of thrombin-like enzyme than those studied and tested to date”, says the researcher. He recalls that besides functioning as a biological solder, the fraction must not be toxic. The plans consist of going through all the stages required to get to the manufacturing and marketing of the Brazilian surgical adhesive, with the aid of a foundation, along the lines of Fiocruz (the Oswaldo Cruz Foundation), for instance.

The Project
Isolation of coagulating serine-proteases from the venoms of Bothrops neuwiedi pauloensis and Crotalus durissus terrificus: functional and structural characterization (nº 07/05159-7)Type Regular Research Awards; Coordinator Benedito Barraviera – Unesp; Investment R$ 173.168,94 (FAPESP)

Scientific articles
THOMAZINI-SANTOS, I. A. et al. Surgical adhesivesJournal of Venomous Animals and Toxins. v. 7, n. 2, p.159-171, 2001.
BARBOSA, M.D. et al. Fibrin adhesive derived from snake venom in periodontal surgery. Journal of Periodontology. v. 78, n. 10, p. 2.026-2.031, Oct. 2007.