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Medicine

Artificial bones

A team from USP is creating innovative solutions for surgical prostheses in bone reconstruction

EESC/USP Polymer trial bodies for a surgical prosthesis, with a structure that is dense on the inside and porous on the outsideEESC/USP

One of the major challenges to the development of artificial bones is to create materials that are as similar as possible to natural bone tissue. Prostheses must be replicas not only in appearance but also in their biological and mechanical properties. This is an important condition for a successful implant not to be rejected by the organism. Therefore, two new materials for making artificial bones that were developed on the campus of the University of São Paulo (USP) in São Carlos, in upstate Sao Paulo, are good news for the bone implant area.

The main difference in these new surgical prostheses is their porous surface structure and the presence of substances in their composition that make them biologically active. According to researchers involved in the discovery these characteristics should lead to the manufacture of more efficient and durable bone implants. The materials, structural ceramics made from alumina and polymeric compounds of polymethyl methacrylate (PMMA), have already been successfully submitted to in vitro tests and trials on live animals. The first surgical operations on human beings are programmed for August.

The two materials being worked upon by the group from USP are already known and certified by the medical authorities for use in implants. They are predictable in relation to their action in the organism and biologically stable. What the researchers did was to modify the properties of alumina and PMMA ceramics. “We created a part that has different levels of density, with a dense nucleus and a porous surface. This porosity is important because it facilitates vascularization and accelerates the adhesion of bone and muscle tissue to the implant”, explains mechanical engineer, Benedito de Moraes Purquerio, coordinator of the biomaterials research group of the Laboratory of Tribology and Composites (LTC) from USP’s School of Engineering in São Carlos. The pores that exist on the surface of the prosthesis allow the bone to grow into the implant and adhere to it.

“We’re satisfied with the results obtained so far and confident in the success of the application of this ceramic and polymer structure in surgical implants and prostheses”, says Purquerio. According to the researcher the new prostheses are likely to be used in reconstructing the mouth, jaw and sides of the face, in plastic surgery of the skull and orthopedic implants in general (knee, thigh, wrist, etc.). Today the most widely used materials in these operations are metallic alloys, especially titanium and stainless steel alloys, ceramic materials, like alumina, zirconium, bioglass, hydroxyapatite and polymer compounds, PMMA, polyurethane and polyethylene. These materials need to be biocompatible, inert and non-toxic and should be of a strength and rigidity that is compatible with our biological system.

EESC/USP Above, samples of ceramic material with pores that are capable of being linked to organic tissueEESC/USP

Ceramic has open and interconnected pores of between 50 to 400 micrometers, which is compatible with the processes of bone repair. The porous part of the implant is very superficial and only 0.5 to 1.0 millimeter thick. “There’s no need for the porosity of the internal layers to be equal to that on the surface because the tissues penetrate up to a certain point. Furthermore, the thicker the external porous layer the less resistant the whole implant may be”, explains materials engineer, Carlos Alberto Fortulan, also from the School of Engineering in São Carlos, who is a member of the team.

The researchers add sucrose during the ceramic agglomerate preparation phase in order to supply the alumina ceramics with porosity. After shaping the part the sucrose is removed by a leaching (washing) process in water. It is then sintered (burned). “Any sucrose particles that may still remain on the implant are decomposed in carbon dioxide during the sintering stage”, says Fortulan.

The conception of porous polymer surface structures is the same as for ceramics, with the difference that in this case the structure that is porous to PMMA is prepared using a polymer derived from pulp, carboxy methyl cellulose (CMC), soaked in water. The part is then ready – whether it is made from ceramics or polymer – and the researchers impregnate the inner surface of the pores with hydroxyapatite and bioglass in a vacuum in order to increase the biological activity of the implant. Hydroxyapatite is the basic bone mineral and helps the organism recognize the implant as a structure that is similar to it.

First surgical operations
“During the bone integration process blood and muscle vessels penetrate the pores of the surgical prosthesis making it possible for the tissue to grow inside the implanted piece. In conventional prostheses of this type made from non-porous materials, or with bioactivity features that come from hydroxyapatite and bioglass, there is no integration between the tissue and the implant”, points out oral and maxillofacial surgeon, Edelto dos Santos Antunes, head of oral and maxillofacial surgical services at the Santa Tereza Hospital in Petrópolis, in Rio de Janeiro State, where the first surgery using the new materials on patients is likely to take place. The operations are going to take place in a partnership between the hospital and the State University of Rio de Janeiro (UERJ).

Another advantage of porosity is that it indirectly provides greater protection against infections to the extent that it causes an integration of the covering tissue with the whole of the porous surface of the implant. The periosteum is a very fine and strong membrane full of blood vessels that completely encloses the outer surface of human bones. During the procedure for inserting the implant the surgeon removes part of the periosteum that covers another bone that is close to the surgical area and encloses the prosthesis. “In doing so any infection is merely localized in its action. Without this enclosing procedure the implanted material is more exposed to possible infections in the future”, says Antunes, who also belongs to the research group. According to Antunes the porous ceramic and PMMA parts that are infiltrated with hydroxyapatite and bioglass more faithfully substitute human bones than other materials currently being used in implants, because their biological and mechanical properties are closer to those of bone.

EESC/usp Electronic microscopy: alongside, details of the porous surface of the polymer…EESC/usp

“These parts give more predictability and stability to the results of the implants. This material is capable of resisting the mechanical demands the bone is subject to, without interfering so drastically in the physiology of the tissue surrounding it”, says Antunes. “The surgical technique has also undergone adjustments. It’s of fundamental importance that the covering tissues reestablish the anatomy in such  a way that they become well defined and are sufficient to minimize the possibility of exposure and contamination of the porous surface of the surgical prosthesis.”

The special surface structures of alumina and PMMA ceramics underwent cytotoxicity and bone integration studies during the live in vitro tests carried out in São Carlos. The trials with rats and rabbits took place between the end of 2007 and the beginning of this year. “The implants were inserted into the tibia of animals and we saw perfect bone integration with tissue growth inside the pores”, says Carlos Fortulan.

“Operations on human beings are going to begin with implants on smaller cranial defects of up to 10 sq centimeters and then start more complete cranial reconstructions. At a third stage we shall move on to jaw reconstruction in which there are defects that compromise only bone segments. After, it will be the turn of those cases that involve bone and joint segments, where we’ll start using implants of PMMA compounds reinforced with carbon fibers”, says surgeon Edelto Antunes.

Full surgical prostheses of the jaw, for use in more complex surgical operations, will be made from alumina and PMMA, with the ceramic structure limited to the joint component, where it joins the face bone. The rest of the part will be made from polymer and reinforced internally with a carbon fiber tube. By the beginning of next year the researchers intend to start studies with the aim of developing femoral prostheses. “We’re going to begin the work by implanting PMMA splints reinforced with carbon fibers into the tibia of goats. The idea is that these new materials will be used in the future in any type of orthopedic surgery”, says Antunes.

EESC/usp …the remains of the implant and bone growth inside the poresEESC/usp

The research into the development of porous surface structures of alumina and PMMA ceramics, which started at the end of 2004, received funding of R$250,000 from the National Council for Scientific and Technological Development (CNPq), from the Ministry of Science and Technology and the Ministry of Health (Health Sector Fund Project 2004), coordinated by Professor Purquerio. The work has already led to the deposit of three patents, one of them specific to the creation of a bioactive porous ceramic matrix. The scientific production also includes four Masters dissertations, five PhD theses and 39 pieces of academic work. The group presented the alumina ceramic structures at the 8th World Congress of Biomaterials in Amsterdam in the Netherlands in June this year and is going to show the results involving PMMA in two international events over the next few months: the autumn symposium of the Society for Biomaterials, in Atlanta, in the United States in September and the International Bone-Tissue-Engineering Congress (Bone-Tec 2008), in Hanover, in Germany in November.

Protein for bone fractures in the form of medication

An injectable medication for the treatment of fractures should soon be a new ally of patients and doctors. Researchers from the Institute of Chemistry of the University of Sao Paulo (USP) have developed a protein that is capable of increasing and improving bone recuperation. Called bone morphogenetic protein (BMP) it belongs to the class of cell growth factors and encourages the proliferation of stem cells close to the fracture site, thereby promoting its differentiation in bone cells that have an accumulation of calcium. “At this stage we already have a rigid mineralized structure that goes to make up the bone. This protein is applied locally and is recommended for fractures in those cases in which there is no union in the long bones, for example in the femur and the spinal column, a difficult place for bone recovery”, says bio-doctor Erik Halcsik, who was a member of the team with PhD student, Juan Carlos Bustos-Valenzuela. Patients who suffer from osteoporosis who have had dental implants will also benefit from the medication.

BMPs are already produced naturally by the human organism throughout the development of the embryo and when fractures occur, but in very small quantities. The protein produced by USP would be a supplement so that these cells develop more quickly and guarantee the formation of bone tissue. The creation of protein began from human DNA sequences that correspond to the BMP genes. They were transferred to a vector, which are DNA sequences that help in the insertion and maintenance of the introduced gene, and then transferred to special cell strains for producing proteins. The researchers finally selected a large number of the cells that produce type 2 and 7 BMPs which are linked to bone growth.

According to Professor Mari Cleide Sogayar, coordinator of the research and from USP’s Nucleus of Cell and Molecular Therapy (Nucel), the DNA sequences that codify these two proteins were identified from the DNA banks (or complementary DNA) of FAPESP’s Cancer Genome Transcriptome Project, known as the Transcript Finishing Initiative. “It took almost six years of research and development to arrive at these two recombining proteins”, says Mari Sogayar.

At least three North American companies already manufacture similar drugs on the same platform used at USP, which is produced from mammal cells. But very little is known about the production process of this protein, because the companies which have the know-how are keeping it a secret or it is protected by patents. “That’s why we had to develop our own production platform from the DNA of human cells”, says Halcsik. The three companies produce the protein at a price of between US$ 3,500 and US$ 4,500 a dose. “Our product should cost less than foreign company products but its final cost will depend on the scale of industrial production”, says Halcsik. The group’s forecast is that the drug will be on the market within three to five years. Studies are being carried out in partnership with a company that is likely to produce the medication. Because of the contract the researchers cannot reveal the company’s name.

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