Polymer proves a potent mix for the old bung knee

Autologous chondrocyte implantation, or ACI, is a tissue engineering-based therapy developed to repair degraded cartilage in knees. It involves a two-pronged approach for orthopaedic surgeons: open surgery to clean out damaged tissue and a biopsy to extract tissue from healthy cartilage in the joint, and then further surgery a month later to implant cells expanded in the laboratory from this tissue.

While this process has very good outcomes for some types of cartilage damage, it can still prove a tedious and time-consuming affair for surgeons and an extended hospital length of stay for patients.

Now, CSIRO is using its biomaterial expertise to improve the regeneration of cartilage tissue, reduce the need for open surgery and take cartilage repair into the domain of keyhole surgery.

A team from CSIRO Molecular and Health Technologies and PolyNovo Biomaterials in Melbourne is looking at a whole new approach to the therapy by growing extracted chondrocytes on biodegradable matrix beads, and then mixing these expanded cells with a new biodegradable polymer. The cells and polymer are then implanted in the defect, where they are glued in place. Not only will the technique provide a better scaffold for the regeneration of new cartilage tissue but one of the most tedious aspects of the surgery itself will be eliminated.

CSIRO cell biologist and immunologist Dr Jerome Werkmeister said the current ACI technique involved taking a small biopsy of tissue from a normal, healthy piece of articular cartilage. In the lab the chondrocytes are teased out of the tissue, purified and amplified in a medium. Four weeks later, they are re-implanted in the damaged area.

"While these current cellular procedures are much better than others, they aren't producing the best repair," Werkmeister said. "When you start amplifying cells in vitro you can encounter a lot of problems. It's not just about amplifying the cells but making sure those cells don't change in the process. The cells aren't optimal because they have been expanding in a laboratory for a month, which is a long time in standard procedures."

Creation of periosteal flaps

The ACI procedure, while better than most, also means a time-consuming operation in which the surgeon must displace the kneecap to gain access to the articular cartilage defect. The damaged tissue is cleaned out and a small piece of good tissue is excised and sent to the lab for cell extraction and expansion.

At the second stage of surgery, the surgeon must also create a flap from the periosteum, a tissue that covers the tibia and femur. This periosteal flap is sutured to the remaining articular cartilage around the defect site, a meticulous and difficult procedure that has been likened to sewing tissue paper to a hard-boiled egg. A small area is left unsutured for insertion of the expanded cells.

"It is a very tedious process and the surgeons complain about it a lot," Werkmeister said. "You also have to use a fibrin glue around the flap and the cells are just in medium, so when you put them back in they can slop around and sometimes there is leakage."

The CSIRO team's innovation is to mix the chondrocytes with a biodegradable polymer to create a sound scaffold that will eventually disappear and be replaced by natural regenerated tissue. The polymer mix also allows the lab to better control the density and distribution of cells.

"The polymer has been engineered so it can support the cells," Werkmeister said. "We put them on beads - a sort of matrix that the cell likes - and then you can deliver these into the polymer gel and make that polymer set in place, in the defect. When it sets it glues itself to the adjacent tissue and stays in place.

"We can also get high cell densities very rapidly so we don't necessarily have to wait four weeks - we can cut that back to two weeks if we want to."

The gluing or binding element of the new polymer means periosteal flaps are no longer required and nor is an arthrotomy. The expanded cells and polymer can simply be injected into the damaged area by keyhole surgery, or arthroscopy, and, in time, new regenerated cartilage tissue will form.

"The polymer we are using is designed to support the cells and to glue in place," he said. "These new polymers are non-toxic and are biocompatible in the laboratory and in animals. The polymer biodegrades within the joint - you can tailor-make this to degrade by changing the chemistry of the urethane when you want."

Biodegradable polymers

The new biodegradable polymer was developed by CSIRO's leading polymer chemist Dr Thilak Gunatillake, now seconded to PolyNovo Biomaterials, who had also developed a suite of biostable polyurethane products several years ago.

Those biostable polyurethanes are being marketed by Australian company AorTech for use in heart valves, stents, pacemakers and breast implants. PolyNovo Biomaterials, another CSIRO spin-off, uses biodegradable polyurethanes in bone fusion and biomedical stents. Werkmeister's group saw the potential for these polymers in cartilage repair and is now looking to commercialise the technology.

At the moment the team is targeting articular cartilage but Werkmeister said there was no reason why meniscus cartilage could not be repaired in the same way, with further potential in hips and even spinal tissue.

"Trauma from sports injuries is what we are mainly looking at and then primary osteoarthritis," he said. "There is a huge market out there. The spine is an interesting area because there are cells in there that are very similar to chondrocytes."

The team has done preliminary trials and is now ready to move on to functional animal trials and regulatory studies for Therapeutic Goods Administration (TGA) assessment. CSIRO's commercialisation manager, Dr Sureka Goringe, said the organisation was looking for partners to invest around $6 million to take the technology through the trial phases and then to market.

"One of the problems is that the regulatory compliance issues around therapies like this are fairly novel and ground-breaking," Goringe said. "The rules haven't really been developed yet, so the TGA is still working through what sort of compliance it requires from us."

TGA approval is only half the battle, however. Bringing the surgeons along for the ride is a major issue, Werkmeister said.

"When you are introducing a new therapy on the market you have to make sure that the surgeon is used to this sort of therapy. (ACI) is already well known for articular cartilage - the surgeon already knows that it is a two-stage procedure. Science is great but you've got to have the doctors involved."

In terms of commercialisation, Goringe said she expected CSIRO to spin off a company as a joint venture with PolyNovo and CSIRO. The company that markets the ACI technology, Mercy Tissue Engineering, is also keen to have the opportunity to market the keyhole version, she said.

"The Australian market for the treatment is estimated at 18,000 per year," she said. "This includes sports injuries as well as an ageing population looking for greater activity in old age."

The worldwide potential, on the other hand, is enormous. As Goringe said, there are lots of wealthy Americans out there with bung knees.

As with all new therapies, however, it will take some time to get to market, she said. "There aren't that many of these products out there and this is very cutting-edge technology. It will be probably be three years before the fat lady sings on this one."