I’m kind of on a roll with infographics lately. In this one I compare the amount of research that led to the FDA approval of Genzyme Carticel versus the amount that currently exists for Regenexx-C, so Carticel research vs. Regneexx-C research. Carticel is an FDA approved product where surgically harvested cartilage samples are taken from an arthritic knee with a hole in the cartilge (OCD). This is then sent to a central lab in California, where the cells are grown to bigger numbers and shipped back to the surgeon. The cartilage cells are then reimplanted in a second procedure.
There’s some recent evidence that the Carticel process really produces mesenchymal stem cells rather than cartilage cells [more on that below, see scientific review]. Carticel was initially approved in 1995 through a simple device registration. However, in 1997 they were informed that they would need a full drug style approval (called a BLA). It was an interesting exercise digging into the BLA approval documents for Carticel to see how much research they submitted to get FDA drug approval. I then compared this to the amount of data we had published on Regenexx-C. Check it out, as basically, we now have more data than Carticel did at the time of it’s approval in 1997. The problem is that the FDA has since dramatically raised that bar, now requiring the same amount of data for an autologous surgical procedure involving stem cells as a mass produced chemical drug. Click here for a bigger version of the infographic…
[Research summary by Centeno et al showing the Carticel process really produces stem cells]
Culturing autologous chondrocytes for surgical re-implantation was first described by Brittberg. In this seminal paper, he describes taking a cartilage biopsy, mincing the cartilage, digesting it with collagenase, plating the cells in monolayer culture supplemented with autologous serum for 11-21 days, and then suspending cells for re-injection in autologous serum into a cartilage defect. This paper was presented as one of the primary pieces of evidence for efficacy and safety at the FDA approval hearing for Carticel. Other than microscopic observation, there was no sophisticated analysis of identity of what was being injected (i.e. flow cytometry). It should be noted that other than cell source (cartilage versus bone marrow), this procedure is identical to the Regenexx procedure. The FDA Approval Summary (BLA Ref. No. 96-0372) states that the approved Carticel procedure is similar to that published by Brittberg et al and references the above paper.
Cartilage Biopsies contain an MSC Population
Dowthwaite et al first described a progenitor cell population on the surface of bovine cartilage. Williams et al obtained human cartilage biopsies from femoral condyles in the same manner as Brittberg. These were digested and plated as in the Carticel procedure. In this study they then used a finbronectin adhesion assay to select adherent cells. They note that it is well documented that full depth chondrocytes in monolayer culture lose their rounded cell configuration and phenotype. In addition, their study demonstrated that this loss of phenotype is associated with an MSC-like progenitor population. Koelling also isolated a similar population of progenitor cells in cartilage. Chang has found that these mesenchymal progenitor cells in cartilage constitute approximately 4-6% of the cells taken from a Carticel type biopsy of adult and elderly knees. Pretzel performed various immunofluorescence tests and found between 11-16% of normal and osteoarthritic cartilage cells were CD105+/CD166+ progenitor cells. Interestingly, the CD166+ cells had many of the same characteristics of MSCs and these were found almost exclusively in the middle and superficial cartilage zone most likely to be biopsied by a surgeon (22-24% concentration). Khan recently noted that the Brittberg ACI procedure predated the discovery of MSCs in cartilage and as a result, his opinion this procedure utilizes MSCs for its effect.
1. Brittberg, M., et al., Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med, 1994. 331(14): p. 889-95.
2. Dowthwaite, G.P., et al., The surface of articular cartilage contains a progenitor cell population. J Cell Sci, 2004. 117(Pt 6): p. 889-97.
3. Williams, R., et al., Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS One, 2010. 5(10): p. e13246.
4. Koelling, S., et al., Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell, 2009. 4(4): p. 324-35.
5. Chang, H.X., et al., Age-related biological characterization of mesenchymal progenitor cells in human articular cartilage. Orthopedics, 2011. 34(8): p. e382-8.
6. Pretzel, D., et al., Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Res Ther, 2011. 13(2): p. R64.
7. Khan, W.S. and U.G. Longo, ACI and MACI procedures for cartilage repair utilise mesenchymal stem cells rather than chondrocytes. Med Hypotheses, 2011.