Surgeon at the cutting edge of the healing process
Renowned surgeon Professor Peter Giannoudis, an expert in trauma and orthopaedic surgery, explains how stem cell therapy has revolutionised treatment of complex, non union limb fractures often seen in medicolegal cases.
One of the most common complications after fracture fixation, the surgical procedure to stabilise and align broken bones, is fracture non-union – where the break fails to heal within the expected timeframe.
Normally, healing is a natural process, and every bone is programmed to heal by default. There are endogenous mechanisms that kickstart the process and, after a series of events, we end up with the union of the fracture where the bone tissue is healed with no scar formation.
If a fracture fails to unite then in order to heal, it needs good stabilisation and mechanical support along with optimum biological conditions for the body to initiate and complete the healing process.
With the biological environment, you need a matrix, a foundation where the progenitor cells that deposit new bone can stay and treat the problem. A signal is also needed for the cells to start doing their job.
Stem cells
In our bodies we have a reservoir of stem cells or progenitor cells, for example in the bone marrow of our pelvis or the ribs or the medullary cavity of long bones like the femur. With the appropriate stimuli, they can convert to a specific type of cell to produce a specific function.
For instance, these progenitor cells can become osteoblasts, the bone-forming cells or chondrocytes, cartilage-forming cells.
So, stem cells and their ability to differentiate to produce a specific tissue represent the hallmark of fracture healing. If they are not present, new bone can’t be deposited so we must deliver them to the local deprived environment and find them a home or matrix in which to reside.
Then they can do two things. One is to multiply, to undergo mitogenesis and create more cells, the daughter cells. When these cells multiply, they can then differentiate to become osteoblasts and start the new bone deposition. This is how fractures heal and how a non-union, with the appropriate treatment, should progress to healing.
Etiopathogenesis of Fracture non-union
Research shows there are 21 factors that have been associated with the development of non-union.
These can be patient-related factors - a lot of patients have diseases or comorbidities which can affect the physiological evolution of events that lead to union.
Then there are injury-related factors. If you have a very severe injury the muscle is contused, the layer that covers the bone, the periosteum, is damaged and the bone edges at the fracture site become avascular. The blood supply to the bone is disrupted and the local processes cannot be kick-started because it's a deprived environment.
The surgeon needs to work out if there are progenitor cells - stem cells - at the site of interest. If not, that is a problem as there is nothing to build new bone. Naturally the bone should have some inherent sources of cells and there is also the capacity to take some progenitor cells from the muscle.
Every muscle for instance has 10 per cent satellite cells which have the progenitor phenotypic characteristics to be differentiated to osteoblasts. So, we've got the muscle, the periosteum, the medullary cavity of the bone and the subcutaneous fat layer acting as reservoir sources of stem cells.
But imagine if you had a bad injury with a severe fracture where the muscle is contused, bruised and damaged, the 10% availability of progenitor cells is not possible any more. Also, with a severe fracture (highly fragmented) or even an open fracture where everything is exposed to the environment, you have degloving of the periosteum and thus another important layer of availability of stem cells is disrupted.
Noteworthy, the periosteum brings blood supply to the bone. If that is not damaged as a result of the injury, extensile surgical approach not respecting the vitality of the soft tissues, can violate the vascularity of the bone and the surgical impact created can lead to the development of fracture non-union. The surgeon therefore has an important role to play to minimise the risk of surgical insult to the local fracture environment. This is even more important if the patient is elderly, with a reduced regenerative capacity.
Bone regeneration
In any kind of bone regeneration treatment, it makes sense to bring stem cells to the local environment to help the host to heal.
We think a lot of these cells will migrate through systemic circulation. But there is a difference of opinion as to whether these stem cells can migrate because of systemic cues from the brain. Even if it indeed is happening, it is at a very small scale. So, putting something that is needed (stem cells) where there is a need only makes sense.
And then the question is, how do we deliver them? You can inject cells, but then you need to contain them in the area of interest, or you will lose them. Or you can have a carrier, like a matrix, a scaffold, to put them in the non-union area. You put that carrier into the non-union and the cells will stay there. Some of them might go to apoptosis and die but by dying, they release cytokines which can be cues for other surrounding cells to come to the area of interest for bone guided regeneration. Either way, it will be a win-win situation.
What we're really trying to do is to produce a normal physiological environment to the non-union site to give it everything that is needed to make the healing process easier.
I have carried out a lot of work in this area and written many publications. What I have come up with is known nowadays as the 'diamond concept' for bone repair.
Basically, within this diamond conceptual framework of fracture healing, there has been this big effort to create a common language amongst the clinicians. The aim is to make them aware that the minimum basic requirements for a successful fracture healing response involve combining mechanical stability with optimum biological conditions (involving stem cells, a matrix/scaffold for cells to reside and a signal (growth factor) for the cells to be primed/activated to undergo the processes of mitogenesis and differentiation to osteoblasts.
Graft materials
Long time ago in my practice I started mixing different graft materials making the so-called 'composite grafts' involving growth factors, cells and scaffolds for the treatment of fracture non-unions and bone defects. This is the reason why my unit has the highest success rate of healing fracture non-unions and bone defects, because of the way we do manage patients in Leeds.
The Diamond Concept, guiding the surgeon what is needed for a successful treatment outcome was published almost 19 years ago. Since then, there have been over 1,400 citations and 50 relevant papers published by other researchers, professors and clinicians. The message is getting through, but it takes time.
The diamond concept not only gives guidance what materials to consider for grafting but also is focused on bridging vascularity/blood supply to the non-union area. If blood supply is not present, then the progenitor cells will die. They need food and oxygen to stay alive and to deposit new bone.
Overall, the diamond concept has been a major contribution to the understanding and treatment of these difficult clinical cases associated with non-union and bone defect treatment.
Peter Giannoudis is Professor of the School of Medicine at the University of Leeds and Honorary Consultant in the Major Trauma Centre at the Leeds General Infirmary. He is also Editor in Chief of the Injury Journal a Fellow of the Royal College of Surgeons (England) among many professional memberships and Chair of the Global Research Commission at the AO Foundation.
He has published 14 textbooks on trauma and orthopaedic surgery and 820 peer reviewed publications. His has an H-index of 135 and his work has been cited 67,500 times. He is also a celebrated keynote lecturer. Prof Giannoudis received an MBE for services to Orthopaedic and Trauma Surgery in the New Years Honours List 2024.