1. A Patient Guide to Stem Cell Therapy Phil Davidson, MD Park City, UT

2. Stem Cell Therapy is NOT done in isolation Best when given by a clinic or specialist that offers a wide array of treatment options including non surgical and surgical There is an ever increasing spectrum of treatments for knees and shoulders, only when ALL these are available can the best choice be made ……“If you walk around with a hammer, everything looks like a nail”

3. Non-Operative Management of Arthritis Oral Anti-inflammatories Dietary supplements and modification Physical Therapy Weight loss Bracing Prolotherapy Accupuncture Injection Therapy – Corticosteroids “cortisone” – Viscosupplementation (Synvisc) – PRP – Autologous Stem Cells (from one’s own self), Commonly know as “BMA” bone marrow aspirate – Amniotic Tissue Graft-Allograft Stem Cells PLUS

4. Legacy Injection Therapies Corticosteroids-good and bad…. Viscosupplementation (Hyaluronic acid; aka Synvisc, Orthovisc, Supatz, Euflexa, etc) – Unpredictable, often ineffective, only potential to address aching, no reparative capacity, many insurances are not authorizing

5. CORTICOSTEROID BENEFITS Rapidly reduce pain due to inflammation Last for several weeks to months Can safely be done about twice per year

6. CORTICOSTEROID POTENTIAL SIDE EFFECTS Atrophy Depigmentation Hyperglycemia Infection Post injection flare Tissue structure weakening, tendon ruptures

7. PRP in Cartilage Repair PRP (platelet rich plasma) is a concentrate of a patient’s platelets Platelets are the circulating cells that promote healing and give off growth factors They represent ONE important aspect of healing This is not as bioactive as Stem Cell therapy PRP preps highly variable Can be know as “ACP” which is one variant

8. BIOLOGICS to treat Osteoarthritis Biologic treatment is interactive KEY ELEMENTS ALL REQUIRED: 1.Cells (MSC mesenchymal stem cells) 2.Growth Factors 3.Scaffold 4.Mechanically favorable environment Potential sources of this bioactive complex: – Bone Marrow Aspirate (from one’s own self) – Amniotic Fluid/Tissue (from tissue bank)

9. MSC’s (stem cells) in Orthopedics MSC’s are undifferentiated cells: – Capacity for prolonged self-renewal – Ability to differentiate into specialized cell types – By definition they are NOT immunogenic ( no rejection) Have shown enhanced cartilage, tendon and meniscus healing These results have increased patient awareness and demand High-profile professional athletes are getting these cell-based therapies, increasing awareness

10. Stem Cells in Orthopedics Regeneration technology rather than replacement Harness your own body’s ability to heal Not taking drugs You are using your own cells to heal your tissues Stem cells have the potential to reverse the trend of degeneration, not just hiding it

11. Stem Cells in Orthopedics Stem cells can potentially recreate and grow tissue Modify the environment to enhance healing Patients feel better-anti-inflammatory effect May potentially reverse Osteoarthritis We don’t know the ideal type or number of stem cells in specific indications

12. Stem Cells: Reparative Promise in Worn Knees Meniscal Regeneration: – Increased meniscal volume in post-menisectomy patients who received adult MSC (stem cells) injections into the knee Restore Cartilage: – MSC injected for knee OA showed improved activity levels and cartilage regeneration – MSC surgical treatment for large full thickness chondral defects showed improvement and significant cartilage fill

13. Mesenchymal Stem Cells (MSCs) Reparative Promise in Knees Current MSC treatments for OA include BMA derived autogenous stem cells that are immediately injected into the knee Andrews Institute believes it controls swelling and inflammation and eases pain in knee OA Results in a pilot study of 31 NFL players, at 10 months, showed efficacy Reported decreased pain up to 45% Knee scores improved by 50% from baseline at 6 months

14. Amniotic Membrane and Fluid Allograft So why use Allograft Stem Cells if BMA works? Growth factors, scaffolding, and MSCs – Amniotic stem cells have a delayed/more robust differentiation compared to bone marrow derived MSC in recent studies – Higher concentration, number of cells – Amniotic stem cells not exposed to toxins, younger, no senescence

15. Journal Transplantation, April 2015 Prospective Randomized Trial for Knee OA Allograft MSC vs Hyaluronic Acid injected in knee One year follow up MSC patients improved clinical outcomes, including pain vs. HA MSC patients showed actual IMPROVEMENT in cartilage quality and quantity on MRI vs. HA

16. Allograft Stem Cell Therapy 900,000 cells/mL 44% MSC’s; remainder-kerintinocytes, fibroblasts, epidermal Collagen Types III, IV, V, VII Amino acid precursors – taurine, glutamine Growth factors: Epidermal growth factor, Transforming growth factor alpha & beta-1, Insulin-like growth factor 1, Granulocyte colony stimulating factor (AmnioTechnology LLC, with permission)

17. PRP 1 Element Tx BMA 2 Element Tx Allograft Stem Cells All Elements Stem cell- amniotic tissue graft

18. Amniotic Membrane Source of stem cells- elective caesarean births, tissue banked rather than discarded

19. Scanning Electron Microscopic image of cryofractured amniotic membrane particles. Membrane particle Amniotic Scaffolding Cryofractured Amnion

20. What makes Allograft Stem Cell therapy (Pallingen) different? Growth factors Scaffolding Cells and lots of them and immature-pluri- potential-900,000 viable cells/ml, 44% are MSCs in one ml BMA has 1,500 CFU-f/ml, another article stating 2,300 CFU-f/ml (donors 60) BMA cells are senile

21. Allograft Stem Cells vs BMA: MSC Comparison Amniotic 440,000 MSC’s/1ml Bone Marrow Aspirate 1,600 MSC’s/1ml Jing Li et al: Chin J Cancer Res 23(1): 43-48, 2011

22. Human MSCs Decline with Age Adopted from: Al Caplan. J Pathol 2009; 217:318-314, 2008 Age (Years) MSCs per Marrow Cells Newborn Teen 305080 _______ 1,000 1 _______ 100,000 1 _______ 250,000 1 _______ 400,000 1 _______ 2,000,000 1 Estimates obtained by CFU- f assay

23. Relative Number of MSC’s by Age Adopted from: Al Caplan. J Pathol 2009; 217:318-314, 2008 Age (Years) MSCs per Marrow Cells Newborn Teen 305080 2000 400250 100 1

24. Amniotic Tissue Allograft Growth Factors/Peptides Cellular Components Extracellular Matrix + +

25. “A multipotent stem cell population that is still of fetal origin and may be superior in proliferation and differentiation to cells deriving from adult tissues” Francesco Alviano et al, BMC Developmental Biology How do the sources compare? Allograft stem cells

26. Why do I offer my patients Allograft Stem Cells ? Patients can benefit from this non surgical treatment Many patients want/need to avoid surgery Large demographic of patients wants to “try everything before considering surgery” This is only modality that has the actual ability heal cartilage and tissues (vs steroid/HA) Easier to administer than PRP/BMA Cost is not out of line with PRP/BMA

27. How do I discuss stem cell therapy? Safe, no rejection, no after-pain New technology without specific indication parameters I discuss the concept of orthobiologic treatment to include the 3 key elements: cells, growth factors and scaffolding I explain that senescent MSC’s (BMA) makes very little sense to me It is not a magic bullet but it does have promise I explain that it is costly, but many patients find it worthwhile

28. My experience with Nanofactor Flow Appx 45 patients thus far Response to treatment is early: 1-4 weeks Average patient now out 15 months Presence of inflammation/effusion seems to enhance the response Aspirate first Ultrasound guidance BMI & level of OA (KL grade) are theoretically negative predictors KL2

29. PEARLS No anti-inflammatories or ASA (6 weeks pre & post) Increased tissue vascularity improves cellular incorporation Full activity (restrictions only if warranted by diagnosis) Not use – systemically, open growth plates, oncologic process, active infection

30. Summary Allograft Stem Cell therapy is a very attractive alternative therapy to treat inflammatory and degenerative musculoskeletal conditions. It makes sense given what we know about orthobiologic principles with MSCs, growth factors and scaffolds Patients are asking for this type of treatment The cost is not prohibitive Early observations very encouraging More data being collected

31. Thank You phildavidsonmd@gmail.com