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Disclosures:
• Regenexx (RSI)-Employed/Stockholder-Active• Biorestorative Therapies-Stockholder/Royalties-Active• Neostem-Stock options-Not Active
Note to CME provider-will add pictures and formatting at a later date…
Stem Cells for DDD and Discogenic Pain
Christopher J. Centeno, M.D.Centeno-Schultz Clinic
Colorado
What we’ll discuss:
• Basic science of Regen Med for discogenic pain• PRP for discogenic pain• BMC, cultured MSCs (auto and allo) for discogenic
pain/DDD• Cultured MSCs-autologus for DDD with a bulge• The future
Basic Science• What’s in PRP?• Lots of growth factors-TGF-b, IGF, FGF, VEGF, PDGF
• What’s in BMC?Mesenchymal
Stem Cells (MSC)Orchestrate repair of bone, cartilage,
tendon, and ligament.
Hematopoietic Stem Cells (HSC)Create new blood vessels and repair
muscle and nerves.
EndothelialProgenitor Cells
(EPC)Create new blood
vessels.
PericytesCreate new blood
vessels and can become MSCs.
Osteochondroreticular Cells (OCR)
Create cartilage and bone cells.
MUSE CellsStress resistant
cells that can turn into most tissue
types.
MacrophagesClean up cell
debris after injury.Platelets
Release growth factors to assist
repair.
Basic science research that PRP helps discs:• PRP:
• Reduces the negative effects to TNF-alpha on porcine annulus fibrosis (AF) cells and helps proliferation and ECM production of bovine AF cells-Artif Organs. 2015 Jul 6 and Eur Spine J. 2014 Apr;23(4):745-53..
• Helps reduce degeneration in nucleus pulposis (NP) cells and and in animal models-Int Orthop. 2015 May;39(5):927-34.
• Component PDGF reduces NP cell apoptosis. J Orthop Res. 2014 Sep;32(9):1181-8. • Is anti-inflammatory toward NP cells by reducing TNF-alpha and IL-1. J Orthop Res.
2014 Apr;32(4):551-6. • Components PDCF and IGF reduce mechanical stress induced apoptosis of NP cells.
J Orthop Sci. 2014 Mar;19(2):313-22. • Releasate (high doses) reduced stab induced DDD in a rabbit model. Arthritis Res
Ther. 2012 Nov 5;14(6):R241.
BMC versus MSCs-What’s the difference?• BMC contains lost of cells including MSCs• Most of the research to date hasn’t been done
with BMC, but isolated and culture expanded MSCs
Basic science research that BMC helps discs:•Nada…
Basic science research that MSCs helps discs:• MSCs:• Restore disc height and normal MRI T2 NP signal characteristics in rabit DDD
stab model. Biomaterials. 2003 Sep;24(20):3531-41.• Delay canine DDD progression and this is dose dependent (too little cause
slack of cell survival and too many apoptosis). J Orthop Res. 2010 Oct;28(10):1267-75. • That are the TieP+ sub-type are plentiful in young discs and exhausted in DDD.
Nat Commun. 2012;3:1264. • Combined with AF cells restored NP ECM better than MSCs alone. Genet Mol
Res. 2015 Mar 27;14(1):2365-73. • Delay NP cells matrix degradation through upregulation of TGF-beta and
downregulation of the FF-KB pathway. Spine J. 2015 Mar 1;15(3):530-8. This is not an all inclusive list, just the high points…
Moving from pigs, dogs, rabbit and mice to humans…• Huge leap• Some porcine studies show robust healing in saline
controls• Quadrupeds are not bipeds• Stab injury models aren’t the same as true clinical DDD
PRP for Discogenic Pain
• Nothing published•Well done DB RCT at HSS• (Note to CME provider-will add data here that is unpublished
after permission is obtained by lead author)
Cultured MSCs
Haufe, et al. (Stem Cells Dev. 2006 Feb;15(1):136-7.)
• 10 patients with symptomatic DDD (axial LBP)• Autologous bone marrow HSCs• Percutaneous injection with hyperbaric oxygen• No improvement in LBP in any patient, 8/10
underwent surgery by one year
Meisel et al. (Biomol Eng. 2007 Feb;24(1):5-21.• 28 patients undergoing microdiscectomy• Autologous cultured expanded chondrocytes (not MSCs)• Percuteneous injection 12 weeks post microdisc• Cell tx patients had less LVP at 2 years postop• Improved MRI T2 signal of treated and adjacent discs
Orozco et al. (Transplantation. 2011 Oct 15;92(7):822-8. )
• 10 patients with symptomatic DDD (axial LBP and/or leg sx)• Autologous culture expanded MSCs percutaneously implanted• Improved LBP, leg symptoms, and MRI T2 signal, no change in disc
height
Yoshikawa et al. (Spine 2010 May 15;35(11):E475-80.
• 2 patients with LBP and radicular symptoms• Autologous culture expanded bone marrow MSCs• Percutaneous injection with collagen• Increased MRI T2 signal, less instability on stress radiographs, clinical
improvement in both patients
Pettine et al. (Stem Cells. 2015 Jan;33(1):146-56.)• 26 patients with axial LBP• Autologous BMC percutaneous into 1 symptomatic level (n=13) or two levels
(n=13)• Provocative discography not performed on all patients• Patients older than 40 who received fewer MSCs (low CFU count) has minimal
improvement at 12 months• All other patients with a higher MSC content had more robust relief (70%
improvement in ODI and VAS)• 11/26 had less than 50% response• 8/20 had a 1 grade Pfirrmann score improvement (but radiologist not blinded
and this is within reading margin of error for the scale)
Mesoblast Phase I/II FDA Clinical Trials• DB RCT at 13 clinical sites• n=100 patients with moderate-severe LBP with DDD• 60 patients got two doses of allogeneic culture expanded MSCs in
hyaluronic acid for single level DDD• Improvement in both groups over HA and saline, but unimpressive
clinically at 12 months• 3.7-4/10 pain reduction in MSC groups• 2.7/10 pain reduction in the HA only and saline groups!• Hence VAS pain reduction is about 1/10 over baseline• Missed major structural end-point (significant changes in MRI)
The company made a big deal of many other endpoints…• All unimpressive clinically• Will insurers pay big bucks (likely about
10K US a vial give or take) for marginal improvement in pain and function without evidence of significant disc regeneration on MRI?• A script for Percocet filled at Walmart
and medical management for 10 years is a fraction of the cost
Our clinical experience…
• Note to CME provider-will add clinical data from a small case series of non-FDA approved autologous cultured cells with up to 7 year follow-up-data being prepared now
Poking a hole in the disc?
• Some studies show this causes disc injury• Cytotoxic effects of local anesthetics and contrast on IVD cells-(PLoS One.
2014 Mar 18;9(3) and Spine J. 2014 Mar 1;14(3):491-8 and Spine J. 2013 Nov;13(11):1556-62).• Controversial Caragee study-discography accelerates DDD: Spine (Phila
Pa 1976). 2009 Oct 1;34(21):2338-45.
• Take home-don’t poke a hole in the disc unless there’s a good reason:• Few of these regen med studies show that there is dramatic clinical
improvement in most treated discs with PRP and BMC• Reduce contrast use
Future?
• Biorestorative therapies pursuing FDA IND and soon to be in clinical trials for disc protrusion/radiculopathy market using specific protocol of autologous MSCs (CONFLICT ALERT)• Will they fare any better?
•Will notochord or chondrocyte lineage disc studies fare better?• Can we bio-print discs?
Questions?