Profile: tending the tendons by tissue repair

Ailments that affect the musculoskeletal system loom large in human health, with damaged tendons and ligaments ranking second only to back pain in specialist referrals. In the US, for instance, there are approximately 250,000 shoulder tendon surgeries performed and almost two million referrals to clinicians.

In Australia alone there are about 14,000 surgeries for damaged shoulder tendons and about 6000 operations for tendons of the ankle each year.

What’s more, patients must commit to a prolonged convalescence, there are no drug therapies available to specifically treat damaged tendons and ligaments, and many surgical repairs fail within a year.

Such injuries are not only painful, but they also come with a high economic cost, since they severely curtail the sufferer’s day-to-day activities and ability to work.

“It’s a pretty large market that ranges across sportspeople and weekend warriors, as well as the general wear and tear and degeneration that takes place over the years,” says Paul Anderson, managing director of Perth-based biotherapeutic company Orthocell.

Orthocell is pioneering a groundbreaking approach to combating these complaints. The company’s solution, called autologous tenocyte therapy (ATT), harvests some of the patient’s healthy tissue and then regenerates the damaged tendons and ligaments.

“What we’re looking to do is to regenerate the damaged tendon and return it to a functional, pre-injury state, where the patient is able to return to their normal activities of daily living,” Anderson says. “We’re hoping to use the building blocks – the cells themselves – to regenerate the tissue, as opposed to just dealing with the symptoms.”

The process itself is very straightforward: the patient undergoes a small biopsy, which is done under local anaesthetic. The harvested cells are then taken to Orthocell’s laboratory where they are put into the tissue culturing process, which takes approximately four to five weeks.

The cells are cultivated to what Anderson describes as a clinically significant level and then they are returned back to the damaged tendon in the hope that those cells – the building blocks of the tendon – will regenerate effective tissue and return the tendon to structural integrity.

---PB--- Tenocyte therapy

Orthocell’s treatments take two forms. The first, called autologous tenocyte implantation (ATI), involves only the tendon cells on their own. Designed to be percutaneously inserted, ATI is aimed at patients who are in the early- to mid-stages of tendon breakdown, where the tendon still has structural capacity but is still on a degenerative pathway.

The second solution, matrix-assisted tenocyte therapy (MATT), employs a collagen-based scaffold that Orthocell is developing, known as CellGro, as a delivery mechanism to provide mechanical strength to the tendon, as well as providing the delivery of regenerated cells to the tendon.

MATT is used for more severe cases, particularly in shoulder injuries, where the rotator cuff often requires biomechanical support as well as the regenerative assistance of the tenocyte cells.

“Currently there’s a large unmet clinical need within the tendon market,” Anderson says. “At the moment, tendons are treated via a mechanical stabilisation process, and [tenocyte therapy] offers the first opportunity for the tissue to actually be regenerated as opposed to just mechanically repaired or stabilised using the tendon you currently have.”

Orthocell’s regenerative solution offers an alternative way to repair damaged tendons and ligaments that is less invasive and has fewer side effects than the current treatments, he says.

“If you have tennis elbow, or something similar, the current treatment regimen is conservative exercise, physiotherapy and rehabilitation – but also corticosteroid injections.

“Corticosteroids are often referred to as a ‘three strikes and you’re out’ solution because they have been reported in scientific journals to have a potentially deleterious affect on the tendon. It’s not even used in the Achilles tendon because it’s been known to rupture tendons. So there’s some reluctance in the clinical community to use corticosteroids but they currently don’t have any other option.”

---PB--- WA’s biotech hub

Orthocell was formed in 2006 by Anderson and Professor Ming Hao Zheng, who invented Orthocell’s intellectual property while working in the department of orthopaedic surgery at the University of Western Australia. Zheng is a fellow of the Royal College of Pathologists and has been working in the area of cell therapies research for the last 12 years.

Zheng and Anderson have been working together for about eight years. Previously, the pair worked together at a company called Verigen, which developed autologous chondrocyte implantation (ACI) for the regeneration of articular cartilage of the knee joint.

“Following that experience, we saw the opportunity to develop a similar approach to the regeneration of other tissue types, particularly soft tissue injuries,” Anderson says.

Since the intellectual property behind Orthocell’s treatments was created at the University of Western Australia, Zheng and Anderson signed an agreement with the university to licence and then acquire that technology. On the back of that, they were then able to raise seed capital needed to establish and develop Orthocell.

“With that seed capital we were able to leverage it with Commercial Ready grants, as well as some local and state government grants, and this enabled us to develop the infrastructure that’s required to develop prototypes, to deliver clinical trial scenarios and to provide some early commercialization opportunities,” Anderson says.

The funding also enabled Orthocell to develop a state-of-the-art clean room facility, which is based at Murdoch University. Indeed, Murdoch University is turning into a burgeoning commercial and technology hub for biotech companies. Fiona Stanley Hospital, which ranks as Australia’s largest infrastructure investment in a hospital, is being built over the road from Orthocell’s offices at the university, making for easy access to facilities and candidates for clinical trials.

Murdoch University has also signed a deal with Westscheme, WA’s largest public sector superannuation fund, to set up an investment fund to capitalise on intellectual property that comes out of Murdoch nd other sources.

Known as the SRV Murdoch Westscheme Enterprise Partnership (MWEP) the initiative is designed to assist researchers in developing their ideas into commercial opportunities. MWEP was established in January 2005 and invests in projects flowing from the university through a $20 million early stage fund, investing in return for equity in a project.

“As it turned out we were one of their second or third investments,” Anderson says. “We were from the University of Western Australia, but a deal’s a deal.

“We now rent commercial space from the university and obviously we’re able to tap into the infrastructure they provide on campus, so for a start-up company it was an excellent opportunity.”

Anderson says Orthocell’s market development pathway is predominantly focused on Australia and southeast Asia in the short to medium term. “We have the capacity to do some very cost-effective clinical trials via our manufacturing facility here in Perth, which is ideally placed, from a time zone perspective, to deliver products to southeast Asia,” Anderson says.

“We’re in the same time zone as Singapore, Hong Kong and even as far away as Beijing, which is very conducive to doing business with southeast Asia and transporting cells – perhaps even more so than the east coast of Australia, from a manufacturing perspective.”

In keeping with that strategy, Orthocell’s board of directors currently features two significant figures in the medical-scientific field. One is former Australian of the Year Professor Fiona Wood, who has significant experience in the tissue engineering processes with her innovative scar-reducing burns treatment, and who is well known for her work with the Bali bombing victims.

Also on Orthocell’s board of directors is Professor Lars Lidgren, a Swedish orthopaedic professor who has multiple publications and patents to his name. Lidgren is a successful researcher, clinician and entrepreneur, and he has successfully shepherded several other biotechnology companies to the marketplace. He is perhaps best known as the founder of the Bone And Joint Decade, which is a UN-ratified and WHO-supported decade of focus on muscular-skeletal injuries and the cost-economic outcomes of those.

“In our endeavours to make sure we’re not just an Australian-focused company, and that we have a very fierce local-to-global approach, we’ve tried to generate a board which reflects that,” Anderson says. “Professor Lidgren has significant relationships both in Europe and the United States, as well as a lot of experience in this area, and we’re delighted to have him on board as one of our board members.”

---PB--- Clinical trials

Orthocell has completed pre-clinical studies with autologous tenocyte implantation, whereas the CellGro scaffold is still in development and about to move into the prototype stage.

The company also recently received ethics committee approval and now has the go-ahead from the Therapeutic Goods Administration to conduct initial Phase I clinical trials for safety and tolerability of percutaneously inserted ATI. That clinical study will be undertaken at Sir Charles Gairdner Hospital, which is one of the major tertiary teaching institutions in Western Australia.

It will be conducted on 15 patients for upwards of a year to assess safety and tolerability, and to see if there’s any evidence of efficacy. Anderson says the company has started the patient recruitment process and expects to be conducting the first implant about the time this article goes to print.

The CellGro scaffold, on the other hand, has a development pathway that’s slightly longer than the ATI pathway. Currently in the process of creating an initial prototype, Anderson says that the company is developing the collagen scaffold with a view to registering it on the Australian register of therapeutic goods, both for use with the company’s own CellGro technology as well as for other potential forms of soft-tissue regeneration.

“As far as I’m aware we’re going to be first in humans globally for this type of treatment,” Anderson says. “I think that is a significant milestone both for the company and the country.”