1. Andrew J.M. Gregory, M.D., F.A.A.P., F.A.C.S.M.
SEACSM 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

2. 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

3. 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
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4. 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.
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5. 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.
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6. 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
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7. 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)
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8. 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)
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9. 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
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10. 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.
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11. 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)
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12. McIntyre et al. The Placenta: Applications in Orthopedic Sports Medicine. AJSM. 2018 Jan;46(1):
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
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13. 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
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14. Injectable Stem Cell Sources
Marrow
Fat
Synovium
Blood
Amniotic Fluid – Tissue Bank
Cord Blood – Tissue Bank
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15. 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
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16. Potential MSK Uses Tendinopathy Osteoarthritis
Articular Cartilage Defect
Osteochondritis Dessicans
Meniscal Tear
Fractures
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17. Gianakos et al. Clinical application of concentrated bone marrow aspirate in orthopaedics: A systematic review. World J Orthop. 2017 Jun 18;8(6):
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
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18. Pas et al. No evidence for the use of stem cell therapy for tendon disorders: a systematic review. BJSM. 2017 Jul;51(13):
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
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19. 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
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20. 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: S (18)
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
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21. Madry et al. Bone Marrow Aspirate Concentrate-Enhanced Marrow Stimulation of Chondral Defects. Stem Cells Int. 2017;2017:
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)
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22. 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:
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"
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23. 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
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24. Riboh et al. Human Amniotic Membrane-Derived Products in Sports Medicine: Basic Science, Early Results, and Potential Clinical Applications. AJSM. 2016 Sep;44(9):
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
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25. Thank You http://www.childrenshospital.vanderbilt.org/sportssafety