Regenerating the Spine in FOUR Steps
Rehydrating the spine nucleus with stem cells, with or without bone morphogenic proteins, has been bouncing around the periphery of stem cell science for a decade or longer. Degradation of the spine disc from either acute or chronic disc injury and/or degeneration is the basis for most of today’s spinal implant sales. If physicians could rehydrate a degenerated disc reliably it could transform the business of selling spinal fusion implants and instruments.
But the nucleus is not a benign environment. Could, for example, stem cells survive the ph levels, the compressive and stress forces or avascular nature of the nucleus?
About 16 months ago data emerged from a small canine study (n=12) that adipose stem cells in a hyaluronic cocktail could rehydrate the disc to near normal levels. Then later that same year (September 10) a sheep study was presented at the Osteoarthritis Research Society International meeting in Montreal which seemed to show that a single, direct low-dose injection of allogeneic or "off-the-shelf" adult stem cells into the degenerated disc nucleus could rehydrate or regenerate the disc.
Earlier this month, at the BioSpine3 meeting in Amsterdam several researchers presented goat and canine studies that deconstructed the mechanisms of action for disc degeneration and then looked at strategies for rehydrating or regenerating the degenerated disc.
Incidentally, if you missed BioSpine3 you’ll need to wait until 2012-2013 for BioSpine4 and the best overview of European biologics research for the spine.
Is disc rehydration or regeneration a fantasia or a potential reality? Last year’s papers seem to indicate that, yes, cellular therapies COULD rehydrate the degenerated disc. BioSpine3’s first six papers tackled this question head on. Here’s what we learned:. There are four not-so-easy steps to successfully rehydrating the disc.
Step One: Rapidly clear inflammatory and stimulatory factors
Of course, back pain is the whole point. Or back inflammation. Breaking down the components of inflammation or studying the chemical markers that correlate with disc degeneration provides tantalizing clues about what to do when disc degeneration is overwhelming the body’s ability to repair itself.
Laura Creemers, Professor at the University Medical Center Utrecht in the Division of Surgical Specialties, Department of Orthopedics, described the many chemical signals (proteases and messenger RNA) that are correlated with disc degeneration. One very strong correlation she discussed in her presentation was between active MMP-2 and human intervertebral disc degeneration. Other degeneration accelerators Dr. Creemers mentioned were MMP-14 and Interluken 6, 10 or 16. In other words, Dr. Creemers and many other researchers have been rather successful at identifying the chemical signals that support if not contribute to disc degeneration.
These markers are up-regulators of inflammation inside the disc. So, Step One, is to inhibit those chemical signals and other factors that support, if not also stimulate, disc degeneration—and to do so in a sustained manner—perhaps with microbeads or hydrogels, which would elute inhibitor compounds over time.
Easier said than done, of course!. Here is one area where progenitor cells, like mesenchymal cells, may have an impact since they are immune privileged and can down regulate inflammation. But other strategies are also called for and this, it seems to us, represents a major clinical opportunity.
Clearing out the chemical signals that support degeneration of the spinal disc lays the foundation for steps 2, 3 and 4.
Step Two: Reverse the unfavorable biomechanical environment in the disc
There are five grades of disc degeneration—Grade I to Grade V—and where a patient’s degeneration is on this scale determines (or should) what treatment strategies a surgeon might employ. As the cascade of degeneration progresses, the typical disc will move from a wet, spongy, healthy material (Grade 1) to a tough, dry and fibrous (Grade 5) material. The Grade 5 disc space has very different sheer forces, load-bearing tensions and other biomechanical attributes than the healthy, spongy, proteoglycan-rich Grade 1 disc.
What do biomechanics have to do with a healthy disc? A lot, said several of the podium speakers. A biomechanically healthy disc will create and maintain a constant flow of fluid, supporting a better nutrient environment.
Surprisingly (or, I guess, not) several researchers came to the topic of annular repair. A healthy annulus they said is vital to maintaining healthy biomechanics of the spine. "Repair the annulus." I was surprised by how often those words were spoken.
Finally, presenters at BioSpine3 kept returning to a fundamental truism of stem cell therapy. Stem cells (or progenitor cells) respond to the biomechanical environment of the human body as they move to differentiate. Different biomechanical signals prompt stem cells to differentiate into different tissues. So, as one researcher asked, if the biomechanical environment in the disc is not healthy, then why would we expect stem cells to differentiate into healthy disc tissue? Why indeed!
Step Two is essential. If the biomechanics of the disc can be restored, then the disc has a chance to rehydrate or regenerate.
Step Three: Restore the osmotic pressure
Spine discs do not have a direct blood supply. There are no arteries to feed the disc tissues with oxygen or nutrients. Virtually all other tissues in the body rely on blood for oxygen and nutrients. If spine discs don’t, then how do they stay healthy and vital? The answer is that normal, healthy discs are “fed” and oxygenated by the constant recycling of the disc fluid that occurs from everyday walking, stepping and lifting. The natural motion of the spine squeezes and releases the spine disc and creates a constant in and out flow of cerebral fluid, with oxygen and nutrients being added and waste fluids being released.
This process of sponging fluid in and out of the disc creates the healthy environment and reinforces the ability of the disc to maintain disc pressure.
So, after clearing out the chemical signals that support degeneration and then restoring the biomechanics the next logical step to regenerating the disc is to restore osmotic pressure. How to do that? Hydrogels may be one answer. A combination of materials including cells, growth factors along with hydrogels may be another answer.
Restoring osmotic pressure rehabilitates the disc’s ability to rehydrate, maintain disc pressure, absorb shock, access nutrients and release waste materials. Obviously it's a good thing.
Step Four: Identify ideal patient populations
Some patients with clear X-ray evidence of degenerative disc disease feel no pain. Other patients with no X-ray or MRI evidence of disc degeneration feel debilitating pain. According to a recent paper in the New England Journal of Medicine:
“Perhaps 85% of patients with isolated low back pain cannot be given a precise pathoanatomical diagnosis. The association between symptoms and imaging (e.g., MRI, X-ray, CT) results is weak. Thus, nonspecific terms such as strain, sprain, or degenerative processes, are commonly used. Strain and sprain have never been anatomically or histologically characterized and patients given these diagnoses might accurately be said to have idiopathic (source is unknown) low back pain.”
Professor Kenneth M.C. Cheung from the University of Hong Kong, Queen Mary Hospital, presented his research into those markers that appear to predict which patients are likely to feel pain from degenerative disc disease and those who do not. Professor Cheung is the author of the first large-scale population study into whether first-time low back pain correlates with MRI findings. Among his findings is that increased disc degeneration on MRI correlated positively with the level of back pain reported.
Said Dr. Cheung, “We were able to demonstrate that when you have a more severe form of degeneration than expected for your age, you are much more likely to be symptomatic.” Cheung and colleagues created a microsatellite marker analysis of 1, 043 subjects from southern China between the ages of 18 and 55 years who also underwent genetic evaluation for predisposition to back problems. Cheung and his co-investigator Jaro Karpinnen, M.D. of Oulu, Finland, read each subject’s sagittal whole-spine MRI and then used that data to grade the severity of degeneration at the lumbar level.
The researchers then had their subjects complete Oswestry Disability Index (ODI), Visual Analog Scale (VAS), Roland Morris score (RM) and SF-36 low back pain (LBP) questionnaires. Using that data, Dr. Cheung and his colleagues correlated the reported pain with MRI findings.
Dr. Cheung’s data is fascinating.
If it were possible to accurately predict which patients would feel pain, then surgeons could intervene earlier and, for example, inject cells or proteins into a healthier, nutrient rich disc where all the conditions exist to support cellular growth and disc regeneration.
We may have a model emerging for rehydrating the disc—although achieving those four steps is not a simple matter. This model could help improve the treatment of degenerative disease and change the standard of care from a type of salvage operation to a less disruptive preventative operation.
There is no question, if we can more accurately determine which patients are most susceptible to painful DDD, then those four steps to a rehydrated/regenerated spine might move from fantasia to reality after all.