Researchers seek safe, effective injectable bone substitutes

Microparticulate systems may offer ‘very interesting prospects’ as options to autografts and other allograft products.

Issue: October 2005

Injectable materials that harden in situ are very promising for bone regeneration and may serve as viable alternatives to some of the current allograft products and autografts.

Mário A. Barbosa, PhD, scientific coordinator of the Instituto de Engenharia Biomédica Laboratorio de Biomaterials in Porto, Portugal, said recent advances in injectable materials are inspiring as surgeons seek better materials to repair bone fractures.

Nevertheless, “The idea of having injectable bone substitutes is not new,” Barbosa said, noting such injectables were first used over 100 years ago.

Those precursors were calcium sulphates, but their rate of degradation was too fast.

“It’s only recently that these drugs have started to gain momentum,” Barbosa said. “Bone repair and regeneration require an adequate support for tissue growth, particularly in cases where significant bone loss has occurred. Common examples are the filling of cavities resulting from resection of bone tumors and accidents.

“The use of autologous bone grafts is the gold standard method, but it has severe limitations associated with morbidity of the donor site and diminished ability of self-regeneration in older patients, particularly when large masses are involved,” he added.

Disease transmission

Given the threat of the transmission of diseases such as hepatitis and HIV, Barbosa cautioned against the use of cadaveric or bovine bone. “For [those] reasons, [we have] increasingly advocated the use of synthetic bone grafts,” he said.

Barbosa also said microparticulate systems “open very interesting prospects, particularly when present in injectable forms capable of locally delivering biologically active agents, such as growth factors, enzymes, proteins and genes.

“In terms of microparticles, their shape, size and distribution is very important for two reasons: first, in order to possibly facilitate an injection, and second, to improve in vitro behavior of the material,” Barbosa said.

Gel injections

Barbosa reported that other investigators, including Stevens (Biomaterials, 2004), found that cartilage formed after six weeks with injection of alginate gel.

“When you use perioteum, you actually find that after six weeks you have good signs and evidence for the formation of cartilage,” he said. “The gellation time is quite low.”

Barbosa added: “The main conclusions that can be taken from the work conducted by the group … is essentially that the material is non-toxic, and sterilization by steam only causes a slight decrease in viscosity, whereas gamma radiation was inconvenient because the gel lost consistently.

“The other problem is a question: Is there degradation of the primary material or is it carried away in the blood stream? This is something that hasn’t been investigated,” he said.

Avoid small particles

Barbosa said injectable materials that are 10 µm or smaller should not be used.

“Very small particles — that is, particles below 10 µm — should be avoided because they have a negative effect on osteoblast viability,” he noted. “Very fine particles do not leave enough free space to allow cell migration and are more susceptible to rapid degradation, while large particles hamper injectability.

“Furthermore, if the particles present sharp edges, the probability of producing small fragments increases. It is estimated that the ideal dimension of injectable particles should range from 0.3 to 0.6 mm.”

Barbosa said a uniform size distribution is critical in order to ensure that new bone and blood vessels are formed.

“Colonization of the construct can proceed in vitro or in vivo. In the former case, cell expansion is conducted until a certain cell density is obtained, which is then followed by implantation in the patient,” he said.

Strict criteria

Orthopedic biomaterial must display a variety of properties and characteristics to aid in bone formation, he said. The engineered tissue must not elicit an inflammatory response or demonstrate immunogenicity or cytotoxicity. Along with those requirements, the injectable material must resorb or degrade at a controlled rate without releasing inflammatory byproducts.

“We thought that microspheres with a narrow size distribution would help us in several respects because we could have more predictable flowing properties,” Barbosa said.

For more information:
Barbosa M. Injectable materials for bone regeneration in orthopaedic surgery. Presented at the 7th European Federation of National Associations of Orthopaedics and Traumatology Congress. June 4-7, 2005. Lisbon, Portugal.