By: 13 February 2015
Regenerative medicine: chasing the phantom?

Adam Gale ponders whether regenerative medicine and cell therapies will enable the human body to use its own latent powers to heal itself

If there’s one word in biomedical research that can be guaranteed to excite the public, it’s ‘regenerative’. Articles about stem cells and regenerative medicine abound in the popular press, and it’s not hard to see why.

Instead of merely playing catch up with degeneration and disease, cell therapies offer the hope of harnessing the body’s own latent powers to restore itself. But is this a realistic hope for orthopaedics, or will it remain a distant dream?

Regenerative medicine is attracting a lot of attention in the second decade of the 21st century, and a lot of hard cash. In 2012, and with a combined investment to date of £115 million, the British government set up the UK Regenerative Medicine Platform (UKRMP) and the Cell Therapy Catapult to help better co-ordinate research into regenerative technologies and translate research into clinical outcomes, respectively.

Much of their attention, including over half of the UKRMP’s projects, has been focused on the musculoskeletal system.

“Orthopaedics is a particularly appropriate discipline in which to exploit cell therapy, because the musculoskeletal system is naturally adaptive and its tissues have an inherent regenerative capacity,” says Allen Goodship, Professor of Orthopaedic Sciences at UCL.

The mood of the academic community remains more cautious than that of the wider public, however, and Goodship warns not to get carried away. It’s a sentiment his colleague Dr Helen Birch echoes: “it is unlikely that stem cells will prove to be a magic bullet and their potential is probably overstated.”

Although stem cells have the capability to express a specific phenotype and turn into a needed cell, Birch says, the necessary stimuli and architecture are unlikely to be found in an injury site. Furthermore, simply expressing the appropriate proteins doesn’t mean that they’ll be arranged correctly in the extracellular matrix. The cells might grow, but they won’t necessarily grow in the right place.

As a result, Birch argues, we shouldn’t get our hopes up too far. “The idea that stem cells can regenerate whole limbs or structures as opposed to tissue in clinical practice remains a distant hope.”

So just what should our hopes be, and just how is regenerative medicine actually changing orthopaedics?

The beginnings of clinical change

At present, acknowledges Mr Mustafa Rashid, Specialist Registrar at Barts and the London NHS Trust, the main clinical role of regenerative technology is to improve the outcomes of certain surgeries, rather than to replace them altogether.

“In non-unions of fractures,” Mr Rashid says, “we used to do an operation to freshen up the bone ends to stimulate them to heal, but now there’s a push to find synthetic grafts to put into the fracture site at the time of the operation to stimulate healing.”

These grafts are engineered out of ‘smart’ biomaterials that provide a suitable microenvironment and delivery mechanism for growth factors such as stem cells or protein rich plasma. Such tissue engineering approaches currently offer the best outcomes for orthopaedic regenerative medicine, because they can fulfil both biological and mechanical roles.

“There’s a lot of work being done on rotator cuff patches, that add mechanical support but can also be a stimulant for growth factors that will help the tendon integrate onto the bone,” points out Rashid.

In different parts of the body, this combination of tissue engineering and cell therapies is beginning to have another significant impact – allowing new early-stage interventions that can delay the need for joint replacements.

Decellularised cartilage, implanted into the knee, acts a matrix to attract stem cells and facilitate the regeneration of torn menisci, a condition which tends to lead to arthritis.

“While it may not cure osteoarthritis,” says Dr Joanne Tipper, a researcher at the University of Leeds, where decellularised cartilage was developed, “it has the ability to regenerate the joint to a certain extent. It may be only five to ten years before there’s a pressing need for a joint replacement, but at least we’ll be able to give that patient an improved quality of life for five to ten years.”

Research challenges

Despite these areas of promise, regenerative technologies have had a limited overall impact on clinical applications so far. For them to develop further, says Allen Goodship, it is imperative that we better understand how exactly stem cells regenerate tissues.

“Cells are multipotent or pluripotent and can go into a lot of different lineages,” he says, “but they can also be like the conductor of an orchestra that modulates the inflammatory process and pushes it into a regenerative process using cells already in the body.”

It cannot, therefore, be just about injecting stem cells into the site and expecting results. In his own research using stem cells to regenerate horse tendons – now translating into human clinical trials – Goodship and his team looked at various fluids in which to suspend the cells.

They settled on marrow supernatant because it was shown to stimulate the protein COMP, which is made by fibroblasts in tendons subjected to loading. “Chemistry, physical topography and the proteins in the environment where you put the stem cell all influence whether that cell will go into a particular lineage,” says Goodship.

The potential of cell therapies to treat musculoskeletal diseases will therefore be fundamentally limited by our knowledge of the exact environments into which the cells will be placed.

Helen Birch, whose research at UCL focuses on tendons, says that understanding regenerative technology requires an understanding of the complex interactions between cell behaviour and the extra-cellular matrix, and the matrix structure and skeletal mechanical function: “Developing cell therapies further requires a recognition that mechanical stimuli are important as well as biological signalling molecules.”

Essentially, understanding the body’s functions and diseases must come before cell therapies can be expected to do anything about them. Indeed, says Goodship, recent discoveries in pathology are changing how regenerative therapies would be approached. “We’re now looking at osteoarthritis and we’re finding there are actually changes in the bone that precede changes in the cartilage, and therefore the strategy for preventing degeneration there may have to change.”

Getting there?

Regenerative technology has a long way to go before it can be hailed as the panacea of orthopaedic medicine. In some patients, such as those urgently requiring total joint replacements, it is highly unlikely ever to be an alternative to implants.

But it is emerging as a promising tool in the treatment of smaller scale and degenerative conditions, and more and more research is being done all the time. According to the Cell Therapy Catapult, there were 86 UK clinical and preclinical projects underway in April 2014, up from 70 one year previously (a 23% increase). To learn about Adderall and how it works please visit this Adderall online website for buying
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While the Catapult aims to get more research into its final stages, the UKRMP is simultaneously focusing on weaving together the different and often disparate strands of research into a coherent whole. “While all these advances have been going on, they weren’t put together in a strategic manner,” Says Dr David Pan, UKRMP Programme Director. “The Platform identifies different areas where we can make significant advances to the translational problems that are out there.”

Pan says it is critical to solve problems such as the mass production, in vivo tracking and delivery of cells, and hopes the UKRMP’s research hubs will help provide researchers everywhere with the general tools and techniques to solve specific challenges.

Predicting the future of regenerative medicine is ultimately impossible, and it is too early to tell how quickly the major research and translational problems are being overcome, or even whether they will be. But, as Goodship puts it, everything’s moving in the right direction: “It’s an exciting time scientifically, it’s exciting for clinicians and it’s potentially exciting for a healthier economy.”