An aging global population and an increase in the prevalence of obesity are increasing demand for orthopedic interventions to repair or replace damaged bones and joints. Although the orthopedics market is mature, it is an area of constant innovation. Central to this innovation are advances in biomaterials and their application to orthopedic procedures. The choice of biomaterial in a bone graft, implant, or replacement is critical to the success of the implant, affecting aspects such as biocompatibility, rate of healing, and the extent to which permanent implants suffer from long-term wear and tear. A clear development in this sector is for new products either to resemble the body's own materials and structures more closely or to have bioactive properties so that they are able to direct the body's own cells to initiate healing and repair from within.
Titanium-Foam Implant Mimics Bone Structure
The structure of load-bearing titanium-based implants looks set to change following research led by scientists working at the Fraunhofer Institute for Manufacturing Technology and Advanced Materials Research (IFAM) in Dresden, Germany. The researchers have created a titanium foam for use in implants into which bone cells and blood vessels could grow, enabling better integration of implants into the skeleton. Another advantage of titanium foam is that it has mechanical properties that are more similar to those of bone than to those of solid metal alloys. Traditional implants are stiffer than bone, which means that they tend to carry a greater load than the surrounding natural bone tissue carries. This load imbalance may lead, in some cases, to the deterioration of the surrounding bone and the implant's working itself loose. Titanium foam, in contrast, has minimal rigidity, but it maintains the strength and durability of solid metal alloys. The German research team created the titanium foam using a powder-metallurgy-molding process. They saturated polyurethane foam with a solution containing titanium powder and binding agents. They vaporized the polyurethane and binding agents before stabilizing the titanium-foam structure by sintering. InnoTerre, a partner on the IFAM TiFoam project, is now working to develop titanium-foam implants for market. The company was founded in 2004 and is also based in Dresden, Germany.
Laser Shaping Technique Creates Custom-Fit, Degradable Implants
In a separate Fraunhofer Institutes development, scientists from the Institute for Laser Technology (ILT; Aachen, Germany) have announced that they are now able to manufacture custom-fit, degradable implants suitable for facial, maxillary, and cranial bone replacement. Because the implants contain β-tricalciumphosphate (β-TCP), they are also osteoinductive and encourage the growth of new bone to repair the break before the implant itself degrades. The scientists created the implants using a laser-shaping technique that enables them to build tiny interconnecting pores into the structure. Importantly, these pores encourage the growth of blood vessels and connective tissue into the implant, essential for the successful breakdown of the implant later. Simon Höges, project manager at the Fraunhofer ILT, says, "Creating this sponge-like lattice structure was the biggest challenge of process development.... Previous types of implant could only be penetrated by native cells to a limited extent. The new technique enables us to generate porous channels with a diameter of 500 to 1000 µm to an accuracy of 100 µm." Such degradable implants could be particularly useful in a pediatric context in which permanent implants are problematic because they soon become too small for the growing child.
Use of the laser-shaping technique also enables the scientists to control precisely the macrostructure of the implant. Such control has the advantage of cutting down on the time patients spend in surgery, because clinicians have no need to cut TCP cubes or the patient's own harvested bone material to size in order to cover the damaged area. Manufacturing starts with a CT scan of the existing bone structure. Software modeling then creates a precise template of both the micro- and the macrostructure of the implant. The laser-shaping technique builds the implant up, layer by layer, from a powder mixture containing polyactide and β-TCP. Not only is this method precise, but also it can be relatively rapid—producing a 5-centimeter section of cranium overnight. This work proceeded under the Resobone project with funding from the German Federal Ministry of Education and Research.
Biological Joint Replacement Is a Step Closer
Scientists have used for the first time endogenous stem cells to regenerate a missing joint in animals, suggesting that biological joint replacement in humans may be a realistic goal. Publishing their findings in The Lancet, scientists from Columbia University (New York, New York), the University of Missouri College of Veterinary Medicine and School of Medicine (Columbia, Missouri), and Clemson University (South Carolina) reported that rabbits—from which they had removed a hip joint and replaced it with a growth-factor-infused scaffold—were able to regenerate a functional joint within four weeks. Jeremy Mao from Columbia University Medical Center, who led the study, said, "In patients who need the knee, shoulder, hip or finger joints regenerated, the rabbit model provides a proof of principle."
The research team developed its joint-replacement technique using a collagen hydrogel infused with transforming growth factor β 3 (TGFβ3), which attracted the rabbit's own stem cells to an anatomically accurate scaffold comprising a composite of poly-ε-caprolactone and hydroxyapatite. Upon reaching the scaffold, the stem cells differentiated into cartilage and bone, forming separate layers. Within four weeks of surgery, rabbits that had received the TGFβ3-infused scaffold were able to place weight on their new joint and use it to move around. Stress tests after four months suggested that the new articular cartilage performed almost identically to native cartilage.
Such advances in stem-cell therapy clearly threaten the long-term dominance of metal implants. One significant advantage of a biological joint replacement is that future surgical intervention would be less likely than with today's artificial joints, which need replacement if they wear out. That surgery can be difficult, particularly if the patient is elderly or if little bone remains to support another implant. However, biological joint replacement may not be feasible in many cases—for example, if patients have a low capacity for regeneration because of age or preexisting conditions or if a long period of immobility may pose significant risks. Even if biological joint replacement were to become a feasible option, opportunities would still exist for biomaterials companies to assist in the manufacture of appropriate scaffolds.
Synthetic-Bone-Graft Market Remains Competitive
The health industry often regards autograft bone—bone from the patient's own skeleton for grafting—as the "gold standard" material for grafting. Cadaver-harvested allograft material has also seen wide use historically, but it carries the risk of virus transmission and rejection. If a synthetic alternative can foster healing in a way that is comparable to that of autograft material, several advantages would occur. In particular, synthetic bone-graft materials should reduce infection risks, decrease time in theater, and reduce patient pain or discomfort and could be available in near limitless supply. Since the last Viewpoints treatment of bone repair and replacement in April 2009, a number of organizations have been developing novel synthetic-bone-graft materials or have brought products to market.
Reporting in the Proceedings of the National Academy of Sciences, a team of scientists from the Netherlands, the United Kingdom, and Australia has shown that porous calcium phosphate particles can find use in large bone grafts, provided that the particles are made with appropriate physiochemical and structural characteristics. The tiny ceramic particles can attract stem cells and growth factors to the site of the damaged bone, but their ability to promote the growth of new bone appears to depend on the particles' microporosity, structure, and degradation according to an as-yet-unknown mechanism. Calcium phosphate–based cements currently find use for repair of small defects in bone structure, but generally they do not induce the stem-cell differentiation necessary for the repair of large bone defects. This new study suggests that this biomaterial could find wider use, especially in grafts following serious injuries, widening the potential market for the product. Joost de Bruijn, professor of biomaterials at Queen Mary University of London, England, led the study and says of the work, "The rate of bone repair we see with these materials rivals that of traditional grafts using a patient's own bone.... What sets it apart from other synthetic graft substitutes is its ability to attract stem cells and the body's natural growth factors, which coincide to form new, strong, natural bone around an artificial graft." de Bruijn is also chief executive officer of Progentix Orthobiology B.V., a spinout company from Twente University (Netherlands) that is developing synthetic calcium phosphate bone substitutes for application in bone-regenerative surgery. The company was established in 2007 and received a $15 million cash injection from NuVasive (San Diego, California) in 2009 in return for access to Progentix's bone substitutes and exclusive worldwide distribution rights.
Clinical trials of HydroxyColl, a synthetic-bone-graft substitute developed by a team of scientists from the Royal College of Surgeons of Ireland (RCSI; Dublin), began in 2010. HydroxyColl is a biodegradable mixture containing both hydroxyapetite and collagen, which according to Dr. John Gleeson, project and business development manager at the RCSI, has shown "phenomenal" results in preclinical trials. HydroxyColl apparently acts as a bioactive scaffold and is able to attract stem cells to encourage new bone growth. Because it is a highly porous material, cells are able to migrate right into the center of the scaffold, promoting vascularization. Dr. Gleeson speculates that HydroxyColl could be an "excellent material for small to medium bone grafts." The RCSI team is currently collaborating with scientists at the School of Dentistry at Trinity College (Dublin, Ireland) to investigate whether HydroxyColl may be a suitable material for dental reconstruction as a bone-void filler or as a coating for implants.
Cerapedics Inc. (Westminster, Colorado) is launching its second bone-graft product, having received the CE mark for i-FACTOR Flex in June 2010. i-FACTOR Flex is a lyophilized version of the company's successful i-FACTOR putty that has seen use in some 2000 spine and trauma surgeries worldwide. Both products combine a bovine-derived organic bone-mineral component with a small peptide, P-15. The P-15 peptide acts as an attachment factor for bone cells, thereby encouraging graft healing following surgery. Clinical trials are under way with a view to securing US Food and Drug Administration (FDA) approval for i-FACTOR.
Orthovita (Malvern, Pennsylvania) is adding VITOMATRIX to its product portfolio in the United States, having gained FDA clearance to market the bone-graft scaffold for dental procedures requiring filling, augmentation, or reconstruction of bones within the oral/maxillofacial region. VITOMATRIX is part of the VITOSS family of products, made from the osteoinductive ceramic β-TCP. Orthovita is seeking a commercial partner to distribute VITOMATRIX or to license the underlying technology. Orthovita is an orthobiologics and biosurgery company that achieved worldwide sales of $92.9 million in 2009.