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Dr Tom GroganPediatric Orthopedic Surgeon
West Los Angeles
11:00 - 11:55 WS #141: Future Applications of Stem Cell Therapy - An Orthopaedic Perspective
12:05 - 13:00 WS #153: Future Applications of Stem Cell Therapy - An Orthopaedic Perspective
(Repeated)
APPLICATIONS FOR STEM CELL THERAPY
Thomas J. Grogan, MD
June 22, 2019
BACKGROUND
Orthopedic Surgery Residency at UCLA
Fellowships
Adult Reconstruction – NIH
Pediatric Orthopedics – Shriner’s Hospital
Trauma – Munich, Germany
Faculty – UCLA
Assistant Chief – Shriner’s Los Angeles
Currently Private Practice
West Los Angeles, California
Over 40,000 new patients over 22 years
BIOLOGICS IN ORTHOPEDIC SURGERY
Musculoskeletal diseases
Economic impact - $1 Trillion dollars annually
7.4% of GDP
Osteoarthritis leads to chronic pain, disability, difficulty with simple activities of daily living and selfcare
Public awareness may lead to adoption of treatments with little supporting evidence
ARTHRITIS = BIG BUSINESS
43 Million Americans have been told they have “arthritis”
12% of healthcare spending is musculoskeletal
$2.8 Trillion = $336 Billion
20,000 orthopedic surgeons - $16.8 Million each doc
800,000 joint replacements per year
$26,000 per on average
$20.8 Billion dollar industry
STEM CELL PHYSIOLOGY
Stem cells – two common characteristics
Offspring of cell able to reconstitute a functional tissue
Can renew themselves indefinitely
Every second – 15 million blood cells “drop dead”
Bone marrow stem ells keep you alive
MESENCHYMAL STEM CELLS
Adipose Derived Stem Cells (ADSC) versus Stromal Vascular Fraction (SVF)
ADSC – Cultured and expanded in vito
Surface markers – CD73, CD 90, CD 166, CD 105 – but not CD 45 (hematopoetic)
Expanded in 10% Fetal Bovine Serum (FBS)
Fat derived (ADSC) are 500 times more potent than bone marrow derived Stem Cells (BMDSC)
SVF – Fat collected – concentrated to form collection of cells including ADSC
Fat is disrupted / enzymatically broken down
Isolate is centrifuged and washed
Clean room
Can be mechanically isolated
Nano- fat
BIOLOGICS IN ORTHOPEDIC SURGERY
Current cell therapies
Harvest of native tissue – adipose, bone marrow, synovial
Stem cells and progenitor cells – pericytes lining the basement membrane of capillaries
Release by enzymatic digestion - Collagenase
Minimal manipulation
Only 1 in 1,000 to 1 in 1,000,000 cells collected are progenitor or stem cells
Ultimately, expansion in vitro may be key to get enough cells to be maximally effective
STEM CELL HISTORYMESENCHYMAL
2001 – Adipose derived mesenchymal SVF “soup” characterized
Endothelial precursor cells
Macrophages
Smooth muscle cells
Lymphocytes
Periocytes
Source of Adipose Derived Stem Cells
10 – 25 microns in size
Pre-adiposecytes
STEM CELL PHYSIOLOGY
Tissue regeneration – response to an inflammatory process MSC – release
Monocyte chemoattractant protein 1
Growth factors
Cytokines
Paracrine factors
Inflammatory conditions Fracture healing
Ischemia
Myocardial infarction
Arthritis
Lupus
Degenerative disc disease
Diabetes
Pulmonary disease
STEM CELL PHYSIOLOGY
Bone – Organized, highly vascular, dynamic connective tissue
Bone healing –
Inflammatory factors released at fracture site
Signaling molecules, growth factors, pre-inflammatory cytokines, and angiogenic factors
Macrophages – release inflammatory mediators
NK cells – natural killer cells
Stimulates MSC recruitment
Tumor Necrosis Factor (TNF) – promotes cultured BMSC migration via Lucine Rich Alpha Glycoprotein release
STEM CELL PHYSIOLOGY
Humeral factors play a role in healing
Parathyroid hormone – activates MSCs
Circulating hormones –
Low dose BMP-2 and SDF-1
Promote rate of bone healing
Implications for osteoporosis –
Osteoblast versus Osteoclast
BIOLOGICS IN ORTHOPEDIC SURGERY
Platelet Rich Plasma – PRP
Blood = plasma and red blood cells
Centrifugation leads to isolation of various layers – including platelet rich layers with or without leukocytes
Cellular based therapies – SVF, BMD
Mechanical / chemical disruption
Minimally manipulated
Adipose derived, bone marrow, synovial fluid, placenta
ROLE OF PRP IN STEM CELL MEDIATED HEALING
Platelets- when activated initiate cell migration and cell proliferation / differentiation
Exposure to fibrin – platelets become “activated”
Conformational change – release granules containing growth factors and regulatory proteins that stimulate cell growth and repair
Platelet derived growth factors - PDGF
Flash freezing at -70 degrees Celsius – activates platelets
Freeze 15 minutes – thaw to 37 degrees
Leukocytes in PRP release growth factors involving the NF-LoB pathway
STEM CELL RESEARCH
Currently –
385 ongoing mesenchymal stem cell trials
Over 4,000 studies have been published
STEM CELL DATASTROMAL VASCULAR FRACTION
Chinese J. of Trauma 12:92 (2009)
27 NZW rabbits
ADSC + calcium alginate gel
Calcium alginate gel only
Controls
Group 1 – sig improved healing
Chinese J. of Trauma 14:6 (2011)
20 NZW rabbits – tenotomy healing
Placebo vs. SVF
Superior rate of healing, neo-tendon formation, collagen deposition in SVF group
STEM CELL DATASTROMAL VASCULAR FRACTION
Journal of Medical Case Reports 5:296 (2011)
Anecdotal evidence of healing
Osteonecrosis hips , Osteoarthritis knees
SVF, PRP, HA, Calcium Alginate
Journal of Medical Engineering (2013)
Mouse Model – articular injury created with needle, sacrifice at 45 days
SVF group – 62% surface healing – 35% new cartilage
Control group – 53% surface healing – 15% new cartilage
STEM CELL DATASTROMAL VASCULAR FRACTION
Clinical Journal of Sports Medicine - Feb 2013
Use of PRP (alone)in DJD
6 ml. PRP – 1 year follow-up (including MRI)
Pain down 41.7% @ 6m, 55.9% @ I year
AAOS Poster – Chicago 2013 – SVF + PRP
Yun-Jin Choi, MD Seoul, Korea
30 Patients – OA knee – 24 month follow-up
25 women, 5 men – average age 70.2
45 Million cells on average injected via arthroscopy
Results: Significant improvement in Lysolm joint score and decrease in VAS scores (P<.001)
BONE MARROW DERIVED MCSS MRI FOLLOW-UP
Shin et al. – KSSR 2018 Sept. 30(3)
Meta analysis – 8 studies with follow up MRI
Pain and functional outcomes significantly improved at final follow up in all studies
VAS, WOMAC, HSS Knee, Lysholm score
MRI taken at final follow up – no significant difference compared to baseline
PRELIMINARY EXPERIENCE
Safety
Efficacy
Appropriateness Criteria
PRELIMINARY EXPERIENCE
Efficacy
Joints followed every 3 months with weight bearing x-rays
Follow pain med usage
PROSPECTIVE STUDY
IRB approved study – 2,586 patients
All treated with mini-liposuction extraction under sub-dermal anesthesia
Point of care centrifugation and cell separation utilizing GMP coagulase
Further centrifugation, filtration, and deployment
82% of all patients – improved results up to 5 years of follow-up
VAS scale 0 to 10
Rest standing walking running
All BMIs showed improvement, although higher BMI – less
No difference to SVF alone or SVF + PRP (total injected)
3159 SVF to 1459 SVF + PRP
RELEASE OF SAFETY PAPER – 2,586 PATIENTS
Prospective Study of Adipose Derived Stromal Vascular Fraction Containing Stem Cells for the Treatment of Knee Osteoarthritis
Mark Berman, MD, Elliot Lander, MD, Thomas Grogan, MD, Walter O’Brien, MD, and Jonathan Braslow, MD
INTERESTING RESULTS
Patients in general very satisfied – especially as we refine the selection criteria
No injected patient has gone on to joint replacement
Knees improve the fastest, shoulders 6 – 8 months
IV SVF seems very helpful
Sometimes nice surprises
Does no harm
APPROPRIATENESS CRITERIA
What does not work
Bone on bone osteoarthritis
Osteochondral defects
Chondrolysis
Infection
BONE MARROW STEM CELLSEXPANDED
Deployment options
Scaffolding material
Hydroxyapetite
Fibrin glue
Collagen
Collagen membrane
Nejadnik (2010) – BMSC periosteal flap vs. Autologous Chondrocyte Implantation (ACI)
72 patients 24 month follow-up
Both improved quality of life
Men did better than women
Under 45 better than over 45 in the BMSC group
ACI - cost $35-40,000
STEM CELL – NEXT ACT
Will replace Iliac Crest Bone Graft
Aspiration from Iliac crest is problematic
Need to aspirate from multiple injection sites to yield 30 ml
Bleeding dilution caused by aspiration is major issue
Spinal fusions / arthrodesis prime indications
Osteonecrosis – cell instillation following core decompression
Tissue engineering
Manipulating cells towards specific tissue types
Chondrogenesis – need truly hyaline cartilage versus fibrocartilage
STEM CELL – NEXT ACT
Future directions
Modulate / facilitate fracture healing
Delayed unions / non-unions
Facilitate spinal fusions
Osteoporosis treatment
Adjunct to or even replace biphosphanate therapies
Improve ligament healing
Aseptic necrosis – Avascular necrosis treatment
Limb ischemia
Spur vascular neogenesis
CONCLUSIONS
Procedure is safe
Effectiveness on a patient to patient basis
Response is probably dose dependent
PRP is probably a useful adjunct to cell based therapy
CONCLUSIONS
Data will drive the future
THANK YOU!