This article is more than 5 years old. Information may no longer be current.
Research into growth factors, scaffolds may lead to better cartilage repair
Although results were promising in a rabbit model, optimizing delivery of BMP-2 will be imperative for development of a clinical therapeutic.
Click Here to Manage Email Alerts
In Summary
|
More than 13% of this country’s population is affected by arthritis, making it the most widespread debilitating disease. The impairment of knee and hip function that often accompanies arthritis accounts for the implantation of more than 50% of joint replacement devices.
Given those numbers, it is clear that developing biologics such as growth factors and scaffolds could have the biggest impact in cartilage repair.
“We have to be careful when we talk about growth factors. We have to be aware that there are multiple effects and some of them are unknown effects and unknown interactions. Nevertheless, I am excited about using growth factors as a possible modality for cartilage defects,” said Kyriacos Athanasiou, PhD.
Athanasiou, a professor of bioengineering at Rice University and president of the Biomedical Engineering Society, said there are three possible methods to consider for the delivery of growth factors. One would be direct injection into the joint, another would be genetically modifying chondrocytes to produce their own factors, and the third would be the continuous release of factors by delivering them on a carrier.
Chondrocyte implants
|
One method of cartilage repair that has been in use for years is autologous chondrocyte implantation (ACI). Results of its use in the knee were first published in 1994, and the technique has yielded good results.
For the ACI, or Carticel (Genzyme Biosurgery; Cambridge, Mass.) procedure, articular cartilage cells are harvested from the knee and expanded ex vivo in culture. The cells are then reimplanted in the knee via an open arthrotomy. A periosteal graft from the tibia is then sutured over the defect to contain the cells.
At five years postoperatively, 79% of the first 100 patients participating in a prospective 38-center U.S. study showed improvement. But while results have been good, the indications for ACI are narrow and the technique requires several steps and is fairly intricate. In addition, the cost of culturing the chondrocytes alone is about $11,000.
Growth factors
|
As an alternative, researchers began studying the use of growth factors several years ago. In a groundbreaking study published in 2000, bone morphogenetic protein-2 (BMP-2) was used to treat full-thickness focal cartilage defects in New Zealand White rabbits.
Researchers led by Elisabeth A. Morris, DVM, found that at one year follow-up, there was no evidence of cartilage degradation between months six and 12, a period when such degradation typically occurs as repair tissue is exposed to increasing mechanical forces.
The BMP-2-treated defects improved in several categories, including integration at the margin, cellular morphology, architecture within the defect and formation of a new tidemark. Discontinuities and gaps in the integration margins were seen in 22% of the treated defects compared to 75% in the untreated defects. However, although the cartilage repair in the BMP-2-treated defects was generally superior, it was only 70% as thick as normal cartilage.
While the study produced a good deal of interest and excitement, later research uncovered obstacles still to be surmounted, said Morris, of Wyeth Pharmaceutical’s osteoarthritis and cartilage repair program in Cambridge, Mass.
“It definitely works beautifully in the rabbit, but when we moved into higher species, namely sheep, goats and nonhuman primates, we found that the residence time of the proteins had to be significantly longer than in rodents and rabbits,” she said.
“There are some studies that are underway and some that have been completed, and we’re back to bench-top work on delivery systems. … The delivery systems weren’t doing what we wanted them to do.” Morris said that timelines for cartilage repair using BMP-2 have “elongated,” but she was confident that this would be an excellent therapeutic option in the future.
Researchers at the Tulane University School of Medicine have also conducted studies using BMP-7, also known as Osteogenic Protein-1 (OP-1), in a dog model. At one year, repair tissue in OP-1-treated defects was continuous with the adjacent intact cartilage and appeared translucent. Histologically, maturing cartilage similar in appearance to the intact articular cartilage was present in the OP-1-treated defects, but numbers were too small to demonstrate significant differences.
Cartilage-like tissue
In a Japanese study, cartilage defects in 36 knees in 34 human subjects were treated with transplantation of cartilage-like tissue made by cultivating autologous chondrocytes embedded in Atellocollagen Gel. The gel is CE marked and has been used for 15 years in Japan and Europe for facial wrinkles.
At six, 12 and 24 months after implantation, the knees were evaluated using arthroscopic, biomechanical and MRI examinations that showed that knee locking was eliminated and pain and swelling were reduced in all patients. The mean Lysholm score improved from 72.4 points to 96.3 points. According to MRIs, the signal intensity of the graft had become similar to that of normal cartilage in 26 knees (72%) at 24 months’ follow-up.
In a study at the University of Virginia School of Medicine, researchers delivered transforming growth factor beta (TGF-beta) in calcium alginate beads to treat osteochondral defects in the trochlear grooves of 32 New Zealand White rabbits.
The results indicated a significant improvement in the quality of the repair tissue at six and 12 weeks with TGF-beta. In addition, researchers concluded that the use of alginate allowed for the selective, controlled delivery of TGF-beta to the site of the injury, something that could help prevent systemic side effects.
|
