Regenerative Medicine is the revolution of the future. We are proud to use these technologies with great success in patients with orthopedic needs. Learn more about the science here.
3. The Potential
• 51 y/o female with > 2 yrs of Chronic knee pain s/p
Medial Meniscectomy x’s 2
• Tx: Surgery x’s 2, PT, NSAIDs, Activity
modification, Rest, ice, Eufflexa, Steroid injections,
massage, acupuncture
• PRP: 85% improved at 8 weeks
4. The Potential
• 55 y/o male magician with 3 years of progressive left ankle pain.
• Tx: NSAIDs, Cane, Bracing, Activity Modification, Steroid
injections (2-3 months of relief)
• Opted for BMAC. At 9 months he is 80% improved
5. Goals
• Define Terms
• Briefly review the History and Development of these
technologies
• Engage the Science behind Platelet Rich Plasma and
Stem Cells for Orthopedic uses
• Review patient selection, and both harvesting and
delivery of PRP and Stem Cells
• Results to date in the science and anecdotally (what
to expect)
6. Terms
• Regenerative Medicine
• A branch of translational research in tissue engineering
and molecular biology which deals with the "process of
replacing, engineering or regenerating human cells,
tissues or organs to restore or establish normal
function”
• Broad descriptor
7. Terms
• Orthobiologics:
• Ortho: to make straight or right
• The use of biologic substances to prompt, stimulate or
support a “healing event” within the body
• The use of biologic substances to promote healing or
reduce pain
• The use of platelets and stem cells in treatment and
management of musculoskeletal conditions
8. Terms
• Platelets
• Non-nucleated fragments of cytoplasm derived from
megakaryocytes in the bone marrow
• 20% the diameter of RBC’s
• Rich source of “Growth factors”
• polypeptide signal proteins are instrumental in modulating
cellular functions - including cell proliferation, cell
differentiation, tissue regeneration, and wound healing.
11. Terms
• Platelet Growth Factors
• PDGF: Chemo-attractive to mesenchymal stem cells and
endothelial cells. Promotes differentiation for fibroblasts and
osteoblasts. Up regulate effects of other growth factors on
cells such as macrophages.
• TGF-ß: Promotes cell mitosis and differentiation for
connective tissue and bone. Acts on mesenchymal stem
cells, preosteoblasts and fibroblasts. Inhibits osteoclast
formation.
• VEGF: Stimulates angiogenesis and is chemo-attractive for
osteoblasts
• EGF: Induces epithelial development and promotes
angiogenesis and collagen deposition
12. Terms
• Platelet Rich Plasma:
• A solution of concentrated platelets in a smaller
volume of plasma
• 3-10 x’s concentration of platelets as compared to
whole blood
• Hematocrit: 0-7%
• % of WBC’s variable
• Leukocyte Poor vs Leukocyte Rich
• LP for Joint vs LR for Soft tissue?
15. Terms
• Bone Marrow
• Soft, fatty connective tissue in
the cavities of bone
• Red Marrow: “Young” active,
hematopoetic tissue
• Adult: Skull, Pelvis, Spine, Ribs,
Sternum, Attachment sites etc
• Yellow Marrow: Fat cells,
inactive hematopoetic cells
16. Terms
Stem Cell
• an undifferentiated progenitor/primitive cell
• A: capable of renewing itself through cell division,
sometimes after long periods of inactivity
• B: Under certain physiologic or experimental conditions, it
can be induced to become a tissue- or organ-specific cell
with special functions
http://stemcells.nih.gov/info/basics/pages/basics1.aspx
17. Terms
Stem cellStem cell
typetype DescriptionDescription ExamplesExamples
TotipotentTotipotent
Each cell can developEach cell can develop
into a new individualinto a new individual
Cells from early (1-Cells from early (1-
3 days) embryos3 days) embryos
PluripotentPluripotent
Cells can form any (overCells can form any (over
200) cell types200) cell types
Some cells ofSome cells of
blastocyst (5 to 14blastocyst (5 to 14
days)days)
MultipotentMultipotent
Cells differentiated, butCells differentiated, but
can form a number ofcan form a number of
other tissuesother tissues
Fetal tissue, cordFetal tissue, cord
blood, and adultblood, and adult
stem cellsstem cells
26. PRP Mechanism of Action
• 1st
Mechanism
• Delivery of Growth Factors
27. PRP Mechanism of Action
• 2nd
Mechanism
• “Up regulation” of local GF in
tendons
• TGF-Beta1 for 1st
week post prp,
• Increased IGF-1 for 4 weeks tenocytes
post prp
28. PRP Mechanism of Action
• 3rd
Mechanism
• PRP Stimulates HA Release
• PRGF significantly enhanced HA
secretion compared with platelet-poor
preparations, (P < 0.05)
Anitua, et al. Rheumatology 2007 46(12):1769-1772
29. PRP Mechanism of Action
• 4th
Mechanism
• Chemo-attractant for Stem Cells
• Prompt Migration and Proliferation
http://www.tandfonline.com/doi/abs/10.1080/09537100310001643999
31. PRP and Achilles Tendinopathy
• Platelet Rich Plasma Treatment for Chronic Achilles Tendinosis
Monto, R. Foot & Ankle International May 2012 vol. 33 no. 5 379-
385
• 30 patients with chronic Tendinopathy who failed 6 months of conservative care
• Methods:
• Single PRP injection under US guidance, AOFAS scores at 0,1,2,3,6,12 and 24
months follow up
• MRI at treatment, and 6 months
• Outcomes:
• AOFAS score improved from 34 to 92
• On MRI/US 27 of 29 tendinopathy was resolved
• Clinical success in 28 of 30
32. PRP and Plantar Fasciitis
• PRP injections for chronic plantar fasciitis Martinelli et al.
International Orthopecics May 2013: 37(5) 839-842
• Methods: 14 pts with PF given 3 PRP injections assessed at 12
months
• Results: Excellent in nine (64.3 %), good in two (14.3 %), acceptable
in two (14.3 %) and poor in one (7.1 %) patient.
• VAS for pain was significantly decreased from 7.1±1.1 before
treatment to 1.9±1.5 at the last follow-up ( p<0.01)
• Conclusions: PRP is safe and has the potential to reduce pain in PF.
33. PRP vs Shockwave in Patellar Tendonitis
• Platelet-Rich Plasma Versus Focused Shock Waves in the
Treatment of Jumper’s Knee in Athletes Vatrano et al 2013
AJSM
• Randomized controlled, level 1
• 46 athletes with jumpers knee
• 2 PRP over 2 weeks vs 3 sessions of ESWT
• VISA-P, VAS before, 2, 6 and 12 months post
• No difference at 2 months, PRP better at 6 and 12 months
34. PRP vs Steroid in Lateral Epicondylosis
• Ongoing Positive Effect of Platelet-Rich Plasma Versus
Corticosteroid Injection in Lateral Epicondylitis A
Double-Blind Randomized Controlled Trial With 2-year
Follow-up Gosens et al. AJSM 2011
• 100 patients with chronic lateral epicondylosis received
Single CSI vs PRP
• Results- at 2 yrs f/u
• PRP 68% improvement
• CSI control experienced 15% improvement
35. PRP and Lateral Epicondylosis
• Efficacy of Platelet-Rich Plasma for Chronic Tennis
ElbowA Double-Blind, Prospective, Multicenter,
Randomized Controlled Trial of 230 Patients Mishra et
al 2013 AJSM
• 3 months of symptoms recalcitrant to conservative care
• PNT vs PNT with PRP
• No difference at 12 weeks, PRP superior at 24 wks
• 83% vs 68% had Success (> 25% reduction in VAS)
36. PRP vs Debridement in Lateral
Epicondylosis
• A Retrospective Comparison of the Management
of Recalcitrant Lateral Elbow Tendinosis: Platelet-
Rich Plasma Injections versus Surgery Ford et al
2014 Hand Journal
• 28-PRP vs 50 Surgery
• Followed 48 wks PRP vs 52 weeks Surgery
• Pain Relief 89% PRP vs 84% Surgery
37. PRP and UCL Tears
• Treatment of Partial Ulnar Collateral Ligament
Tears in the Elbow With Platelet-Rich Plasma
Podesta et al 2013 AJSM
• 34 athletes with > 2 months of symptoms and failure
to RTP despite rest, rehab
• 1 PRP injection followed by 12 weeks of rehab
• 88% RTP at same level with no complaints of pain
and a decrease in valgus gapping under US testing
38. PRP and Tendon Review
• Outcomes after Ultrasound guided PRP Injections for Chronic
Tendinopathy Mauntner et al. PMR 2013
• Retrospective Review: 180 M/W 18-75
• Patients: Av. Age 48, Av 18 months prior to treatment
• Sites: Lateral Epicondyle, Achilles, Patellar Tendon, RTC,
Hamstring, Gluteus Medius
• Outcomes: 82% reported moderate to complete improvement
(>50% improvement). 60% received 1 injection, 30% 2 and 10% 3
injections. Patient’s perceived reduction in pain was 75%. 95% pain
free at rest, 68% no pain with activity. 85% reported satisfaction
with the procedure.
39.
40. PRP and Osteoarthritis
• Platelet-rich plasma intra-articular knee injections for the
treatment of degenerative cartilage lesions and osteoarthritis Knee
Surgery, Sports Traumatology, ArthroscopyApril 2011, Volume 19,
Issue 4, pp 528-535
• Single PRP injection
• 2 year follow up
• Improved function, pain scores, quality of life
41. PRP and Knee OA
• Intra-articular Autologous Conditioned Plasma
Injections Provide Safe and Efficacious Treatment
for Knee OsteoarthritisAn FDA-Sanctioned,
Randomized, Double-blind, Placebo-controlled
Clinical Trial AJSM 2016
• Patients with mild-moderate knee OA
• 3 weekly injections of ACP vs Saline
• 78% improvement in WOMAC scores vs 7%
42. PRP superior to HA for Knee OA
• Cerza F, Carni S, Carcangiu A, et al. Comparison Between Hyaluronic Acid and Platelet-Rich
Plasma, Intra-articular Infiltration in the Treatment of Gonarthrosis. The American journal of
sports medicine. Dec 2012;40(12):2822-2827.
• Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular injection versus
hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early
degeneration to osteoarthritis. Arthroscopy : the journal of arthroscopic & related surgery :
official publication of the Arthroscopy Association of North America and the International
Arthroscopy Association. Nov 2011;27(11):1490-1501.
• Sanchez M, Fiz N, Azofra J, et al. A randomized clinical trial evaluating plasma rich in growth
factors (PRGF-Endoret) versus hyaluronic acid in the short- term treatment of symptomatic knee
osteoarthritis. Arthroscopy : the journal of arthroscopic & related surgery : official publication of
the Arthroscopy Association of North America and the International Arthroscopy Association.
Aug 2012;28(8):1070-1078.
• Spakova T, Rosocha J, Lacko M, Harvanova D, Gharaibeh A. Treatment of knee joint
osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. American
journal of physical medicine & rehabilitation / Association of Academic Physiatrists. May
2012;91(5):411-41
43. PRP and Hip OA
• Ultrasound-guided platelet-rich plasma injections
for the treatment of osteoarthritis of the hip
Sanchez et al. Rheumatology 2011
• 40 pts with severe hip OA
• 1 injection of PRP weekly for 3 weeks
• 57% had significant reduction in pain (30-70%)
• Followed up to 6 months with persistent gains
44. PRP in OA
• Platelet-rich plasma: why intra-articular? A systematic
review of preclinical studies and clinical evidence on PRP
for joint degeneration Knee Surgery, Sports Traumatology,
Arthroscopy 2013
• “the preclinical literature shows an overall support toward this
PRP application. An intra-articular injection does not just
target cartilage; instead, PRP might influence the entire joint
environment, leading to a short-term clinical improvement.”
• Clinical studies demonstrate most benefit in younger(<65) and
less severely affected (mild-moderate) individuals
45. PRP and Discogenic Back Pain
• Lumbar Intradiskal Platelet-Rich Plasma (PRP)
Injections: A Prospective, Double-Blind, Randomized
Controlled Study Tuakli-Worsono et al. PMR 2016
• 47 patients with > 6 months of refractory discogenic low
back pain
• Over 8 weeks of follow-up, there were statistically significant
improvements in participants who received intradiskal PRP
with regards to pain (NRS Best Pain) (P = .02), function (FRI)
(P = .03), and patient satisfaction (NASS Outcome Questionnaire)
(P = .01) compared with controls. No adverse events of disk space
infection, neurologic injury, or progressive herniation were reported
following the injection of PRP.
46. PRP Wrap Up
• Great potential
• Mild-moderate OA
• Various Tendinopathies: Limitations in science
• Lasts 6 months-Lifetime
• Uses appear varied but not a panacea
• < 65, < severe disease = better candidates
49. Safety
• Safety of autologous bone marrow-derived mesenchymal
stem cell transplantation for cartilage repair in 41 patients
with 45 joints followed for up to 11 years and 5 months
Wakitani et al. Journal of Tissue Engineering and
Regenerative Medicine Volume 5, Issue 2, pages 146–150,
February 2011
• Excellent Safety
• No Cancer, no Infections
50. Homing and Growth
• Homing and reparative effect of intra-articular injection
of autologus mesenchymal stem cells in osteoarthritic
animal model. Mokbel et al BMC Musculoskelet Disord. 2011 Nov 15;12:259.
• Methods: 27 donkeys (induced arthritis with Amphotericin B)
• MSC harvested and tagged with fluorescent proteins
• Control was HA injection vs HA with MSC’s
• Outcomes: Synovial fluid, histopathologically; articular cartilage structural changes, reduction of
articular cartilage matrix staining, osteophyte formation, and subchondral bone plate thickening were
graded
• The reparative effect of MSCs was significant both clinically and
radiologically in all treated groups (P < 0.05) compared to the control
groups. Tagged cells were found integrated within the cartilage surface
• CONCLUSIONS: Homing was confirmed by the incorporation of injected GFP-labeled MSCs
within the repaired newly formed cartilage. Significant recovery proves that the use of IA injection of
autologous MSCs is a viable and a practical option for treating different degrees of osteoarthritis.
51. Reparative Effects of Stem Cell
• Cartilage regeneration by selected chondrogenic clonal
mesenchymal stem cells in the collagenase-induced monkey
osteoarthritis model. Jiang et al J Tissue Eng Regen Med.
2014 Nov;8(11):896-905
• Methods: Intra-articular cartilage lesions induced by
collagenase injections in monkeys were treated with normal
saline (NS) or stem cells
• Outcomes: Functional parameters, radiographic images,
histological and immunohistochemical examinations at weeks
8, 16 and 24 post-treatment demonstrated that the abrasions of
articular cartilage were significantly improved and repaired
by MSC-based treatment
53. Stem Cells in Shoulder
• A prospective multi-site registry study of a specific protocol of
autologous bone marrow concentrate for the treatment of shoulder
rotator cuff tears and osteoarthritis. Centeno et al. J Pain Res. 2015
Jun 5;8:269-76.
• 115 shoulders in 102 patients
• Dash Score improves 36.1-17.1 , average subjective improvement of
48.8%
54. • Mesenchymal Stem Cell Implantation in Knee
Osteoarthritis: An Assessment of the Factors
Influencing Clinical Outcomes. Kim et al Am J Sports
Med. 2015 Jun 25
• Methods: Retrospective follow up of 49 pts s/p MSC
injection for knee OA
• Inclusion: Isolated full-thickness cartilage lesion and
Kellgren-Lawrence OA grade 1 or 2
• Outcomes: Excellent (43.6%), 17 as good (30.9%), 11 as fair
(20.0%), and 3 as poor (5.5%)
• Poor Predictive factors: Age > 60 and lesion size > 6cm
squared
Stem Cell in Knee OA
55. A Case Review
• 77 y/p female with Left Knee Pain and Xray with moderate
knee OA
• Tx: NSAIDs, Ice, rest, activity modification, Multiple IA
steroid injections, Eufflexa, Medial mensicectomy in 2014
• Opted for BMAC: At 8 weeks 0% improved
57. BMAC Injection vs ACI
• Autologous bone marrow-derived mesenchymal
stem cells versus autologous chondrocyte
implantation: An observational cohort study. Am J
Sports Med 38:1110–1116 Nejadnik et al 2010
• 72 matched patients followed for 3, 6, 9, 12, 18, 24
months
• Functional outcomes were equal at 2 years' follow-up,
with less cost and donor site morbidity noted in the
BMAC group
58. • Long-Term Follow-up of Intra-articular Injection of
Autologous Mesenchymal Stem Cells in Patients with Knee,
Ankle, or Hip Osteoarthritis. Emadedin et al. Arch Iran
Med. 2015 Jun;18(6):336-44.
• Methods: 18 patients followed with clinical examinations,
MRI and laboratory tests at 2, 6, 12, and 30 months post-
transplantation
• Outcomes: All patients exhibited therapeutic benefit
including increased walking distance, decreased visual
analog scale (VAS), and total Western Ontario and McMaster
Universities OA Index (WOMAC) scores and MRI findings.
Longevity
59. Longevity
• Mesenchymal stem cell therapy for knee osteoarthritis:
5 years follow-up of three patients. Davatchi et al. Int J
Rheum Dis. 2015 May 20
• Outcomes: All parameters improved in transplant knees
at 6 months (walking time, stair climbing, patella
crepitus, flexion contracture and the visual analogue
score on pain).
• Gradually deteriorated, but at 5 years they were still better than at
baseline. PGA (Patient Global Assessment) improved from baseline to
5 years. The better knee at baseline (no MSC), continued its progression
toward aggravation and at 5 years became the worse knee.
60. • Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow
Mesenchymal Stem Cells: A Randomized Controlled Trial. Vega
et al Transplantation. 2015 Mar 27.
• Methods: 30 patients with knee OA , non responsive to
“conservative measures.”
• Bone Marrow derived MSC injection vs HA (single injection)
• Outcomes:
• The MSC-treated patients displayed significant improvement in
algofunctional indices versus the active controls treated with
hyaluronic acid. Quantification of cartilage quality by T2
relaxation measurements showed a significant decrease in poor
cartilage areas, with cartilage quality improvements in MSC-
treated patients.
Stem Cell Compared to HA
63. Contraindications to PRP
• Platelet count (<1000/uL), Low hemoglobin (<10.9g/dL)
• Hemodynamic instability (low BP etc)
• Known dysfunctional platelets or clotting disorder
• Eg: Giant Platelet Disorder, ITP, hemophilia
• Active use of pharmacologic blood thinners ( eg: Coumadin, Xarelto )
• NSAIDs in the last week
• Corticosteroid injection at treatment site within 6 weeks of PRP procedure
• Corticosteroid by mouth or i.v. within 6 weeks of PRP
• Active signs of systemic infection
• Fever, chills, Nausea, vomiting, advancing rash
• Active cancer – especially hematopoetic or bone
• Rash or unclear skin changes at injection site
• Pregnancy
64. Contraindications to BMAC
• Platelet count (<1000/uL), Low hemoglobin (<10.9g/dL)
• Hemodynamic instability (low BP etc)
• Known dysfunctional platelets or clotting disorder
• Eg: Giant Platelet Disorder, ITP, hemophilia
• Active use of pharmacologic blood thinners ( eg: Coumadin, Xarelto )
• NSAIDs in the last week
• Corticosteroid injection at treatment site within 6 weeks of BMAC procedure
• Corticosteroid by mouth or i.v. within 6 weeks of BMAC
• Active signs of systemic infection
• Fever, chills, Nausea, vomiting, advancing rash, “Colds”, Sniffles, Sore throat
• Active cancer – especially hematopoetic or bone
• Rash or unclear skin changes at injection sit or over harvest site
• Pregnancy
66. PRP Procedure
• Consider CBC and same day
Platelet smear if possible
• Draw peripheral blood volume
according to recommendations
of the centrifuge company
• Inject to machine and
concentrate the platelets
accordingly (10-35 min)
• Goal is 4-10 x’s concentration
from baseline
• Usual volume of PRP is 2-6cc
67. Pre-BMAC Procedure
• Labs: Consider CBC, TSH, Vitamin D, Other?
• Confirm no NSAID exposure in last 2 weeks
• Confirm no recent illness
• Be sure the patients understand the procedure, post
procedural reccs etc.
68. BMAC Procedure
• Position patient Prone or Side-Lying
• Use Ultrasound or Fluoroscopy to identify the Posterior
Superior Iliac Spine, mark appropriately
• Prepare all equipment according to BMAC centrifuge
harvesting company (Heparin/ACDA etc)
• Clean skin surface with Chlorhexidine, set up sterile drapes
• Anesthetize the surface and down to the PSIS with a
combination of 5cc of Lidocaine and 5cc of Nl Saline
• Make incision with 11-blade
69. BMAC Procedure
• Insert Trochar through the skin and contact the PSIS
• Press firmly and twist until you feel “pop” and a “give
sensation.”
• Draw out 1st
5cc of bone marrow and discard due to bone
chips and peripheral blood contamination
• Then draw volume indicated by BMAC company
• Centrifuge/purify accordingly
• 1 Joint: 60cc 2 Joints: 90cc
• Final injectate: 2-6cc total
70. BMAC Procedure
• Clean puncture sites
• Dress with pressure dressing and consider K-Tape or
other pressure tape to reduce hematoma formation
71. BMAC Injection
• Using a 25g or 22g needle of appropriate length to reach
the target tissue inject the BMAC under US guidance or
fluoroscopy
• Joints: Directly into joint, target area of injury
• Tendons: Pepper the tendon to spread BMAC and
facilitate additional platelets and growth factors via
percutaneous tenotomy
• Prolotherapy: Consider Dextrose, PPP etc for growth
factor effects (eg: Medial capsule with medial meniscal
extrusion)
74. PRP Knee OA
• 51 y/o female with > 2 yrs of Chronic knee pain s/p
Medial Meniscectomy x’s 2
• Tx: Surgery x’s 2, PT, NSAIDs, Activity modification,
Rest, ice, Eufflexa, Steroid injections, massage, acupuncture
• PRP: 80% improved at 8 weeks
75. PRP and Fat for Tendon
• 45 y/o female avid cross fitter and runner with >3
months of proximal hamstring pain and an MRI proven
partial tear at the insertion.
• Tx: heat, ice, NSAIDs, massage, rest, activity
modification, DC, trochanteric injections
• PRP with Fat: 95% better at 8 weeks
76. BMAC and Hip OA
• 57 y/o female avid
scuba diver with left
hip pain for 6 months
• Tx: Rest, activity
modification,
NSAIDS, IA steroid
Inj (2 months relief)
• Opted for BMAC
• At 8 week follow up
from BMAC she
reported 75%
improvement in
symptoms
77. PRP and Meniscal Tear with OA
• 42 y/o tennis professional with left knee pain and
swelling. MRI proven oblique full thickness
symptomatic meniscal tear
• Tx: rest, ice, NSAIDs
• Tx: Intramensical PRP injection, Dextrose to
medial capsule, serial drainage of parameniscal cyst
with thrombin x’s 1, crutches for 5 days and
progressive gentle rehab
78. PRP and Fat for RTC Tear
• 67 y/o male with 10 months of chronic right
shoulder pain. MRI proven full thickness
supraspinatus tendon tear through 70% of tendon
• Tx: Rest, PT (8 wks), NSAIDs, Steroid injection
• Tx: PRP and Fat graft
79. BMAC and Knee OA
• 58 y/o female avid traveler with bilateral knee pain
and swelling worse with stairs, prolonged walking
• Tx: PT, NSAIDs, Ice, Heat, Rest, IA Steroid
injection, Eufflexa
• Tx: BMAC, now 5 months out 80% better
• KOOS 312-396 and 314-453
81. Take Homes
• Patients with mild-moderate OA and those with
chronic tendinopathies or partial tendon or ligament
tears or injuries are “good” candidates
• The “healthier” the patient is the better the
outcomes
• Insurance will not reimburse at this time: WC
• Results take time: PRP: 6-8 wks, BMAC: up to 8
months