Andrew J.M. Gregory, M.D., F.A.A.P., F.A.C.S.M. SEACSM 2018 - Chattanooga Stem Cells Review & EBM Andrew J.M. Gregory, M.D., F.A.A.P., F.A.C.S.M. Vanderbilt University Medical Center, Nashville, TN

Disclosures In the past 12 months, I have no relevant financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity. I do intend to discuss unapproved/investigative use of a commercial products/devices in my presentation. 0:30 + 0:10

Learning Objective(s): Upon completion of this session, you (the learner) should be able to: Understands the basics of stem cells (NIH, ISSCR) Know what conditions there is evidence for their use 11/10/2018 Footer

Gregory Regenerative Medicine Center – Nashville, TN We use stem cells to treat: Osteoarthritis Degenerative joint disease Knee pain including knee osteoarthritis, degenerative joint disease, meniscal tears and ACL/PCL tears.  Research studies have shown cartilage growth and repair after just one stem cell injection. Shoulder pain including rotator cuff injuries, arthritis etc. Hip pain Chronic pain disorders including chronic lower back and neck pain. 11/10/2018 Footer

When to be cautious… Claims based on patient testimonials. Multiple diseases treated with the same cells. The source of the cells or how the treatment will be done is not clearly documented. Claims there is no risk. High cost of treatment or hidden costs. http://www.closerlookatstemcells.org/ 11/10/2018 Footer

Stem Cells Unspecialized cells with the remarkable potential to develop into many different cell types in the body during early life and growth capable of renewing themselves through cell division, sometimes after long periods of inactivity can be induced to become tissue- or organ-specific cells with special functions https://stemcells.nih.gov/info/basics/1.htm 11/10/2018 Footer

Stem Cell Types Embryonic (ESCs) Somatic or Adult Mouse 1981, Human 1988 Somatic or Adult Bone Marrow Derived (hMSCs) Hematopoietic (HSCs) Neural (NSCs) Induced Pluripotent (iPSCs) 11/10/2018 Footer

Embryonic Stem Cells (ESCs) derived from embryos eggs that have been fertilized in vitro Cell culture - cells transferred from a preimplantation-stage embryo into a plastic laboratory culture dish and grown cells that have proliferated in cell culture for 6 months without differentiating are pluripotent Differentiation spontaneous if allowed to clump Directed (induced) 11/10/2018 Footer

Adult Stem Cells undifferentiated cell, found among differentiated cells in a tissue or organ can renew itself and can differentiate to yield some or all of the major specialized cell types of the tissue or organ identified in brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovary and testis 11/10/2018 Footer

Potential uses of human stem cells Cancer and birth defects Testing new drugs Cell-based regenerative therapy macular degeneration, hearing loss, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis, and rheumatoid arthritis. 11/10/2018 Footer

Placenta Placenta has a long history of use for treating burns and wounds It is a rich source of collagen and other extracellular matrix proteins, tissue reparative growth factors, and stem cells, including mesenchymal stem cells (MSCs) 11/10/2018 Footer

McIntyre et al. The Placenta: Applications in Orthopedic Sports Medicine. AJSM. 2018 Jan;46(1):234-247 High degree of variability in placental cell types, placental tissue preparation, routes of administration, and treatment regimens, which prohibits making any definitive conclusions Current clinical use of placenta limited to only commercial placental tissue allografts there are no placenta-derived biological drugs approved for the treatment of orthopedic conditions in the US The application of placental cells or tissue appears to be safe and has potential to improve outcomes for orthopedic indications 11/10/2018 Footer

Bone Marrow Derived Stem Cells Mesenchymal stem cells (MSCs) - multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes and adipocytes Osteogenic Chondrogenic Adipogenic 11/10/2018 Footer

Injectable Stem Cell Sources Marrow Fat Synovium Blood Amniotic Fluid – Tissue Bank Cord Blood – Tissue Bank 11/10/2018 Footer

Protocol Collection – Bone marrow aspiration (0.001% of nucleated cells are MSCs) Concentration - Density-gradient centrifugation (fake) Culture in lab (real) Injection/ Scaffold Not standardized 11/10/2018 Footer

Potential MSK Uses Tendinopathy Osteoarthritis Articular Cartilage Defect Osteochondritis Dessicans Meniscal Tear Fractures 11/10/2018 Footer

Gianakos et al. Clinical application of concentrated bone marrow aspirate in orthopaedics: A systematic review. World J Orthop. 2017 Jun 18;8(6):491-506. 36 studies were included 31/ 36 (86%) reported the method of centrifugation and preparation 15 (42%) reported a cell concentration Variation of cBMA application was seen 21/ 36 (58%) LOE IV, 12/36 (33%) LOE III, 3/36 (8%) LOE II Studies on full thickness chondral lesions (7), osteochondral lesions (10), osteoarthritis (5), nonunion or fracture (9), or tendon injuries (5) Significant clinical improvement, presence of hyaline-like values and less fibrocartilage on T2 mapping in patients treated for cartilaginous lesions. Bone consolidation and time to bone union was improved in fracture treatment Enhanced healing rates, improved quality of the repair on US and MRI and a decreased risk of re-rupture in patients adjunctively treated with tendon repair 11/10/2018 Footer

Pas et al. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. BJSM. 2017 Jul;51(13):996-1002. 4 published and 3 unpublished/pending trials with a total of 79 patients. No unpublished data were available. 2 trials evaluated bone marrow-derived stem cells in rotator cuff repair surgery and found lower re-tear rates compared with historical controls 1 trial of allogenic adipose-derived stem cells to treat lateral epicondylitis showed improved Mayo Elbow Performance Index, VAS & US findings at 1-year Bone Marrow derived SC’s-treated patellar tendinopathy showed improved IKDC, Knee injury and OA Outcome Score subscales and Tegner scores at 5-years 1 trial reported adverse events and found them to be mild (eg, swelling, effusion) All trials were at high risk of bias and only level 4 evidence was available 11/10/2018 Footer

Xing et al. Mesenchymal stem cells injections for knee osteoarthritis: a systematic overview. Rheumatol Int. 2017 Dec 22. Systematic review of systematic reviews 4 were eligible for inclusion Using the ROBIS tool, 1/4 had a low risk of bias Pas et al. - highest AMSTAR score Evidence synthesis via the CERQual tool, confidence for decision making was either low (self-reported measurement and MRI/histological outcome) or moderate (adverse events) Moderate confidence could be placed in safety of MSCs therapy for knee OA, but with low confidence in efficacy outcomes 11/10/2018 Footer

Xing D. Intra-articular Injection of Mesenchymal Stem Cells in Treating Knee Osteoarthritis: a Systematic Review of Animal Studies. Osteoarthritis Cartilage. 2018 Feb 7. pii: S1063-4584(18)30048-7. 23 KOA animal studies were included Using the SYRCLE's tool, all studies had high risk of bias Between-study heterogeneity was substantial For all outcomes, the evidence quality was low or very low We do not have absolute confidence to recommend use MSCs injection for KOA clinical trials 11/10/2018 Footer

Madry et al. Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects. Stem Cells Int. 2017;2017:1609685. 4 studies Microfracture and drilling used BMA from iliac crest, then concentrated good evidence from translational studies that BMAC-enhanced microfracture results in a significantly increased defect filling, better structural parameters of the repair tissue, and improved integration compared with microfracture alone 2 year significant improvements in clinical scores of patients with relatively large chondral defects (median size: 6.5 cm2) 11/10/2018 Footer

Park et al. Stem Cell Therapy for Articular Cartilage Repair: Review of the Entity of Cell Populations Used and the Result of the Clinical Application of Each Entity. AJSM 2017 Oct 1:363546517729152. 46 clinical studies were identified to focus on cartilage repair with MSCs 20 studies with bone marrow-derived MSCs, 21 studies with adipose tissue-derived MSCs, 3 studies with peripheral blood-derived MSCs, 1 study with synovium-derived MSCs & 1 study with umbilical cord blood-derived MSCs All clinical studies reported that cartilage treated with MSCs showed favorable clinical outcomes in clinical scores or evaluation by MRI. Most studies were limited to case reports and case series 18 studies erroneously referred to adipose tissue-derived stromal vascular fractions as "adipose-derived MSCs”, 2 studies referred to peripheral blood-derived progenitor cells as "peripheral blood-derived MSCs“, 1 study referred to bone marrow aspirate concentrate as "bone marrow-derived MSCs" 11/10/2018 Footer

Chew et al. Mesenchymal stem cells in human meniscal regeneration: A systematic review. Ann Med Surg 2017 Oct 5;24:3-7. 4 were studies included Marked differences in the method of stem cell harvest 3 used injection and 1 used a collagen scaffold MRI analysis, functional scores and safety were assessed and the longest follow-up period was 2 years VAS was most commonly used to assess function and patients generally showed an improvement There were no reported adverse events 11/10/2018 Footer

Riboh et al. Human Amniotic Membrane-Derived Products in Sports Medicine: Basic Science, Early Results, and Potential Clinical Applications. AJSM. 2016 Sep;44(9):2425-34. 25 articles described preclinical and clinical trials of AM-derived products Level of evidence obtained was inadequate for systematic review Amniotic membranes have many promising applications They are a source of pluripotent cells, highly organized collagen, antifibrotic and anti-inflammatory cytokines, immunomodulators, and matrix proteins These properties may make it beneficial when applied as tissue engineering scaffolds, improving tissue organization   The current body of evidence in sports medicine is heavily biased toward in vitro and animal studies, with little to no human clinical data 11/10/2018 Footer

Thank You http://www.childrenshospital.vanderbilt.org/sportssafety www.vanderbiltsportsmedicine.com www.vanderbiltconcussion.com