The Federal University of São Carlos (UFSCar) has licensed two patents to Vetra, a company formed by former students of the Department of Materials Engineering (DEMa). The first is for a type of glass with a new chemical composition that makes it highly bioactive. It can be used to coat metallic implants and to treat skin lesions, for example. The other is a method to coat medical and dental grafts or ceramics that ensures compatibility with the body, prevents rejection and accelerates integration with bone. Common glass is hard and brittle. By altering its chemical composition with additional quantities of calcium and phosphorus, it becomes bioactive and is called bioglass, featuring antibiotic characteristics and the capability to accelerate bone regeneration and the fusion of prostheses and bone.
The coordinator of the university’s research team, Edgar Dutra Zanotto, professor in the Glass Materials Laboratory (LaMaV) of the DEMa, says that bioglasses have several applications in medicine, dentistry and veterinary medicine. “In powder form, they are able, when dissolved in contact with body fluids, to accelerate the regeneration of damaged human tissue, such as bone fractures, skin wounds, cartilage problems, tooth enamel and dentin, and even nerves,” he explains. According to him, when implanted, these materials trigger a series of reactions that stimulate cell proliferation, contributing to the body’s ability to regenerate complex lesions that would take a long time, or even fail to heal.
Bioglass was first developed in the 1960s. Today’s advances include new chemical formulations and applications. The first bioglass was invented in 1969 by Larry Hench at the University of Florida. Called Bioglass 45S5, this material, still in use, is characterized by its ability to promote a fast, durable chemical bond with bone tissue. But it has limitations, including low mechanical resistance to fracture. In addition, it tends to crystallize, which prevents the manufacture of three-dimensional (3D) pieces, fibers and scaffolds (highly-porous structures that can support bone grafts).
The advance proposed by UFSCar researchers is based on the development of a new formula that prevents crystallization of the material, which can be deposited on the surface of dental or orthopedic implants, and even used to produce components in 3D printers. Additionally, as long fibers, it can be woven to produce bandages for skin wounds and burns, for example. The new bioglass, in addition to calcium and phosphorus, contains silicon, sodium and potassium oxides, plus a few other elements. The work of the UFSCar team was carried out as part of the Center for Research, Teaching and Innovation in Glass (CeRTEV), one of the Research, Innovation and Dissemination Centers (RIDCs) funded by FAPESP.
According to Marina Trevelin Souza, a former PhD student of Zanotto’s and a founding partner of Vetra, the bioactive glass they developed, called F18, similar to other bioglasses, represents a new generation of biomaterials. They are much more effective in regenerating tissues than other products available on the market. “They are osteoinductive, meaning that they stimulate the proliferation of bone cells,” she says. “This stimulation is due to the release of certain types of ions that, when absorbed by bone cells, activate genes related to the cell proliferation process.” Another advantage of the material is the fact that it is totally resorbable. The new formulation also has angiogenic properties, which help in the formation of new blood vessels near the implant or lesion. Souza has two partners at Vetra: Clever Ricardo Chinaglia (former postdoctoral researcher under Zanotto) and Murilo Camuri Crovace, a current postdoctoral researcher in the same department at UFSCar. Souza and Crovace are merely founding partners, and do not participate in company management. Vetra is run by Chinaglia.
The second technology licensed to Vetra is a new process for coating implants with bioglass, which the company’s team calls biofunctionalization. “We use it to coat (metal or ceramic) orthopedic and dental prostheses with a layer of bioactive glass,” explains Souza. “This also accelerates the osseointegration process and prevents infections. Moreover, this coating does not affect the properties of the implant material because it is totally resorbed by the body after a few days.” Souza guarantees that the solubility of Bioglass F18 is greater than that of Bioglass 45S5, sold commercially. It begins to dissolve shortly after the graft is placed in the body and integrates into the bone quickly. According to Crovace, some types of common bioglasses, similar to 45S5, are already being sold commercially abroad, and in clinical use for almost 30 years, but are still not produced in Brazil.
Without a trace
The team performed tests on mice, rabbits and dogs using dental grafts and implants made of biofunctionalized titanium. The most important result was that, after histomorphometric analyses to quantify bone structures, they discovered that the formation of new bone over the grafts coated with bioglass F18 in the first two weeks is twice as fast as for non-biofunctionalized grafts. Moreover, after the osteointegration process, there was no trace found of the bioactive material on the surface of the prostheses.
Founded in 2014, Vetra initially intended to supply the bioactive glass in powder and granular form to companies producing dental, medical and veterinary biomaterials. “In the future, the idea is to produce more complex items, with fibers, woven material and scaffolds,” says Souza. In order to put this plan into practice, “Vetra is seeking to raise funds through investors and establish partnerships with clients interested in innovating and who want to sell advanced, high-performance products.” Many of the company’s technologies are already developed and have had their efficacy proven by clinical trials in humans, such as products with bioglass for hypersensitivity and post-whitening tooth remineralization. “For this reason, we are seeking partners who can introduce these innovative technologies into the market. Potential customers are healthcare companies,” Souza adds.
Clinical trials are being carried out by several research groups in Brazil. “We created a network called the Biomaterials Research and Technology Network [Bionetec] with more than 64 researchers from different universities carrying out in vitro tests [in biological tissues in the laboratory], in vivo tests [in animals] and clinical trials [in humans] of our materials. Researchers from many different institutions have carried out innumerable tests. These institutions include the Medical Schools of the University of Campinas (Unicamp) and the University of São Paulo (USP) in Bauru, the UFSCar Center for Biological and Health Sciences, the USP Ribeirão Preto School of Dentistry, São Paulo State University, Araraquara, and the School of Biosciences of the Federal University of São Paulo (Unifesp),” says Souza.
Camila Tirapelli, professor at the USP Ribeirão Preto Dental School, and a specialist in dental prostheses, was one of the researchers who conducted tests on a material known as Biosilicate, a precursor of F18, produced by the UFSCar group. “We did clinical trials, employing the bioglass to provide relief from dental hypersensitivity caused by periodontal treatment, ablation and gingival recession in about 180 patients,” says Tirapelli. The study was published in the scientific journal entitled Journal of Oral Rehabilitation. “We also employed the new material to treat dental sensitivity due to whitening. The study, which included a total of 200 patients, was published in Journal of Dentistry. The results were positive.” Now, Tirapelli’s group is performing tests of the bioglass in humans as a coating for teeth with dental caries.
“In Brazil, there are still no bioactive glasses like those developed by Zanotto’s team on the market, at least within my field,” says Tirapelli, who has been carrying out clinical trials in dentistry with biomaterials developed by DEMa at UFSCar. “Worldwide, there are few companies that I am aware of that do the same thing. These products are very expensive in Brazil.” According to her, this biomaterial is still of limited use, even in developed countries. “In Brazil, it is restricted to the academic arena.” The next step towards commercial use is to register the product with the National Health Surveillance Agency (ANVISA).
Vetra is entering a market characterized by accelerated growth. “The biomaterials market is one of the fastest growing in the world, increasing at a rate surpassing 15% annually,” says Zanotto. According to a study by the Indian market research firm MarketsandMarkets (M&M), the global forecast for the biomaterials sector, including types of materials (metals, ceramics and polymers) and applications (cardiovascular, orthopedic, dental, etc.) is that it will reach $130.5 billion in 2020. In 2015, total sales in the sector reached $62 billion.
According to materials engineer Cecilia Amelia de Carvalho Zavaglia, professor in the Department of Manufacturing and Materials Engineering in the School of Mechanical Engineering at Unicamp, the bioglass developed by Zanotto’s team, licensed to Vetra is promising. “People are developing bioglasses all over the world,” she says. “The material created at UFSCar is innovative, not just a copy of what has been done abroad. The difference is the composition.” Now, it needs to be better promoted among health professionals and made available on the market, after approval by ANVISA”
1. CeRTEV – Center for Teaching, Research and Innovation in Glass (nº 2013/07793-6); Grant Mechanism: Research, Innovation and Dissemination Center (RIDC); Principal investigator: Edgar Dutra Zanotto (UFSCar); Investment: R$22,174,519.45 (over five years for CeRTEV as a whole).
2. Development and characterization of highly bioactive flexible vitreous meshes (nº 2011/22937-9); Grant Mechanism: Scholarships in Brazil – Regular – Doctorate; Principal investigator: Edgar Dutra Zanotto (UFSCar); Grant recipient: Marina Trevelin Souza (UFSCar); Investment: R$127,215.87.
3. Bioactive glass-ceramic scaffolds applicable to orthopedics and dentistry obtained by three-dimensional technologies (nº 2013/07059-0); Grant Mechanism: Scholarships in Brazil – Regular – Postdoctorate; Principal investigator: Edgar Dutra Zanotto (UFSCar); Grant recipient: Murilo Camuri Crovace (UFSCar); Investment: R$252,448.23.
4. Development of titanium surfaces with antibacterial activity using bioactive glass coatings (nº 2013/05856-9); Grant Mechanism: Scholarships in Brazil – Regular – Postdoctorate; Principal Investigator: Edgar Dutra Zanotto (UFSCar); Grant Recipient: Clever Ricardo Chinaglia (UFSCar); Investment: R$166,051.07.
TIRAPELLI, C. et al. The effect of a novel crystallized bioactive glass-ceramic powder on dentine hypersensitivity: a long-term clinical study. Journal of Oral Rehabilitation. V. 38, No. 4, p. 253-62. April 2011.
PINTADO-PALOMINO, K. et al. A clinical, randomized, controlled study on the use of desensitizing agents during tooth bleaching. Journal of Dentistry. V. 43, No. 9, p. 1099-105. on-line. July 6, 2015.
GABBAI-ARMELIN, P. R. et al. Effect of a new bioactive fibrous glassy scaffold on bone repair. Journal of Materials Science: Materials in Medicine. V. 26, No. 177, p. 1-13. 2015.
CROVACE, M. C. et al. Biosilicate®—A multipurpose, highly bioactive glass-ceramic. In vitro, in vivo and clinical trials. Journal of Non-Crystalline Solids. V. 432, p. 90-110. Jan. 2016.