If you were in the orthopedics business from the late 1990’s through just recently, you saw the rise and fall of Bone Morphogenetic Proteins (BMP’s) on the commercial market. Their story differs somewhat depending on the specific products: those based on BMP-2 and those based on BMP-7 (aka OP-1). BMP-2 fared better than its close relative, but like any commercial product it’s always bigger than just the laboratory epic. Operations factor into it. So does clinical performance, and for one of these products both fell flat. For the other one, the sales soared to heights of over a million dollars per day at its peak.
Like anything, however, the longer you use it, the more pronounced its drawbacks become. Call it age. Call it statistics. It happens. For both of these BMP’s, there was one insurmountable fact: they grow bone everywhere, even where bone does not normally grow. “Ectopic bone formation” is the name of this phenomenon, when bone grows outside of a usually bony area, like under the skin or into the spinal canal. Designing a product to retain as much of the BMP in place as possible helps, but does not make it foolproof.
What if this one issue could be mitigated? What if there was a way to chemically activate bone growth in a biological setting, but only where you want it to happen? This will likely be the reality of a new orthopedic product awaiting FDA approval called “P-15″. Amino acids are the building blocks of proteins, much like nucleotides are the building blocks of DNA and RNA. All proteins are made from chains of amino acids, even BMP’s. In this case, there are 15 amino acids in the chain. Hence the name “P-15″. Though the name seems innocuous, the science behind it is not. This specific chain mimics part of a longer chain of amino acids known as collagen. Collagen is the most abundant kind of protein in the body and there are at least 28 types of it. P-15 mimics a piece of collagen Type I, which is most prevalent in bone.
Now let’s stop here and clear something up. Growth factors like BMP are proteins. Collagen is also a protein. However, collagen is not a growth factor. Not all proteins are growth factors. The term “growth factor” usually implies that it is secreted by a cell to affect other cells. The other cells have receptors that pick up the growth factor which causes changes inside the cells, usually large changes in how those cells express their characteristics. By contrast, proteins like collagens just sit there. Most of the time they do not travel around affecting cells. They do however have ways of attracting cells to them and along them. Like the case with growth factors, cells have receptors on their surface that can bind to these proteins and cause changes within the cell.
So why is the concept of something like P-15 potentially better for the purposes of clinical bone repair? There are a couple of reasons:
Since it is not a growth factor, P-15 is not likely to cause ectopic bone formation.
In fact, it has been used for a while now in dental applications and is being worked on by Cerapedics for release in treating the spine without such occurrence. The product supports cells needed for bone formation like osteoblasts and the attachment of fibroblasts by mimicking the site where cells normally attach to collagen through their integrin receptors. Integrin receptors are a family of cell binding sites that are majorly responsible for how cells attach to surfaces. Like anything in biology, there are many sub-types. In this case, P-15 copies the way collagen binds to the “α2β1” integrin receptor. This receptor ticks off changes inside the cell that cause it to release growth factors, proliferate, and differentiate to be more “osteoblast-like”. In English, this means that if the cells in the area are already thinking about doing the work of bone cells, this protein will push that along. If they are not, then it probably won’t. That is in contrast to something like BMP-2 which will push all the cells in the area towards bone cell characteristics whether they like it or not, especially if they are stem cells.
P-15 makes more sense physiologically.
Most growth factor products on the market come in milligram quantities. In tissues, they exist in nanogram and picogram quantities. That’s thousands to millions of times smaller than the commercial products. To get a result clinically, it seems we must flood the patient with supra-physiological quantities of growth factor because 99.99999999…..% of what we put in probably gets washed away before it affects anything, and whatever is left over is still higher in quantity than exists in nature. That can cause side effects and antibody formation. With something like P-15, we are acting further up the chain of events. The P-15 just enhances what the cells in the area are naturally expressing. If they don’t normally express a growth factor in the area, they are not likely to with P-15, but if they do; they will. Also, since collagen is so abundant, adding milligram quantities of P-15 is not going to really change the amount of P-15 sequence found in the tissues overall.
There are also some handling characteristics and operational things that work out for the better, but I will not get into that here. Overall, this is one for the product watchers to check out. P-15 has spent quite a while in the orthopedic test bed we call Dentistry, and it may soon be ready and coming to an OR supply closet near you.