11/21/2017

1

The Future of PRP and Stem Cells in Sports Medicine

Drew A. Lansdown, MD

Assistant Professor

Sports Medicine & Shoulder Surgery

University of California, San Francisco

2

11/21/2017

2

11/21/20173

Outline

Platelet-Rich Plasma

• Composition and preparation

• Clinical evidence to support or not support its use

Bone marrow aspirate and adipose-derived stem cells

• Preparation and differences

• Clinical evidence to support/not support its use

Discuss how to talk about these treatments with patients

11/21/2017

3

What Is Platelet-Rich Plasma?

Volume of plasma with platelet count above baseline of whole blood

Various growth factors are present in alpha granules of platelets

Concentration of these growth factors may be a powerful directed biologic treatment

Role of Various Growth Factors

11/21/2017

4

Not All PRP Is The Same! Type of Platelet Rich Plasma Presence of

Leukocytes?

Fibrin

Architecture

Pure platelet-rich plasma

(P-PRP)

No Low-density

Leukocyte- and platelet-rich

plasms (L-PRP)

Yes Low-density

Pure platelet-rich fibrin

(P-PRF)

No High-density

Leukocyte- and platelet-rich

plasma (L-PRF)

Yes High-density

Caption™ Smith & Nephew

Cascade™ MTFSymphony II™ DePuy

Magellan™ Medtronic GPS®III Biomet

Arthrex ACP™

Patient Factors Contribute To PRP Composition

High-fat meal increases peripheral platelet counts in healthy volunteers compared to fasting (ref 14)

Platelet aggregation in the morning is higher than later in the day (ref 15)

Platelet concentrations increase in the afternoon and activation decreases from noon to midnight (ref 16)

11/21/2017

5

Preparing PRP

Peripheral Blood Draw• Use at least 21 gauge needle• Performed slowly to prevent

premature activation• Use polypropylene tubes

Platelets Separated by Centrifugation

• Initial spin at 1200-1500 RPM• Separates platelets, WBC, RBCs• Second optional spin at

4000-7000 RPM to further concentrate platelets into same layer as WBCs

#1 #2

Final PRP is Ready for Injection

#3

Activating PRP

Advantage of exogenous activation – growth factors are immediately available (ref 36)

• Clot can then be implanted directly at desired location

• Useful in the surgical application of PRP

• Can use bovine thrombin (ref 37) or autologous thrombin (38)

• Calcium chloride can be exogenous activator (ref 8, 41) but has low pH so may be more painful (ref 8)

• Activation gives immediate release, while endogenous activation has release over longer period of time

No additives

• pH-based variation in platelet function

• Ref 46 – platelet function is effected by incubation with lidocaine, bupivicaine, and tocainide

• Recommend injecting without local anesthetic

11/21/2017

6

Frequency of Injection

Variable literature on multiple vs single injection

Most studies lack a comparison of multi vs single injections so hard to isolate this as a variable

Platelet-Rich Plasma:Usage in Practice

Zhang, et al. OJSM, 2016.

Usage of PRP is increasing in clinical setting

Per-patient average charges reported at $1755 (Zhang)

Cost for patient ranges from $500-$1500 per injection (Samuelson, Arthroscopy, 2016)

11/21/2017

7

What Are The Results For PRP In Practice?

Tendinopathies

• Lateral epicondylitis

• Patellar tendinitis

• Achilles tendinitis

• Rotator cuff tendinopathy/partial rotator cuff tears

Ligament injuries

Muscle injuries

Osteoarthritis

PRP For Tendinopathy

11/21/2017

8

20 patients with elbow tendinosis, failed prior treatment:

• 15 patients treated with LR-PRP

• 5 control patients received bupivicaine injection

Symptom duration

• 15 months in PRP group

• 11 months in control group

RCT of LR-PRP vs corticosteroid for chronic lateral epicondylitis

• 51 patients in LR-PRP group

• 49 patients in corticosteroid group

Persistent symptom relief and improved function in PRP group out to 2 years

11/21/2017

9

RCT for chronic lateral epicondylitis with symptoms for at least 3 months:

• 116 in PRP, leukocyte-enriched

• 114 in active control

12-week no difference

24-week significant improvement in pain and reduced tenderness

11/21/201718

Conclusions:“Platelet-rich plasma is a safe and promising therapy in the treatment of recalcitrant PT. However, its superiority over other treatments such as physical therapy remains unproven.”

11/21/2017

10

11/21/201719

83 patientsProspective study6 month follow up

No ruptures, 10% failure rate requiring repeat injectionConcluded single LR PRP injection safe and effective

11/21/201720

placebo.

PRP injection did not result in an improved VISA-A score over a 3-month period in patients with chronic AT compared with placebo.

Randomized control trial with 24 total patients

• 12 in PRP group

• 12 in saline group

13 patients discontinued study after 3 months due to unsatisfactory results

• 9/12 in PRP group, 4/12 in saline group

11/21/2017

11

11/21/201721

Randomized Controlled Trials—Achilles Tendinopathy

Authors Year Journal N Findings

De Vos 2010 JAMA 54 No difference in saline vs PRP when added to eccentric exercises

De Jonge 2011 AJSM 54 No difference in outcomes between placebo and PRP injection

Kearney 2013 BJR 20 No difference in outcomes between placebo and PRP injection when added to eccentric exercises

TAKEAWAY POINT: PRP not harmful in the treatment of Achilles tendinopathyMinimal clinical benefit proven at this point in time.

What about PRP for tendinopathy/PTRCT?

Randomized patients with partial tears to steroid vs PRP injection

Both groups got betterPRP slightly better than steroid at 12 weeksNo difference at 6 monthsNo difference in MRI findings at 6 months

11/21/2017

12

wA

Slight improvement with PRPAt 3 months, no difference at 6 months

What about PRP for tendinopathy/PTRCT?

ANo difference between exerciseAnd PRP injections at 1 year

What about PRP for tendinopathy/PTRCT?

11/21/2017

13

18 studies including 1066 patients with tennis elbow, rotator cuff tendinitis, and Achilles tendinopathy

Greatest effect seen with leukocyte-rich PRP

Standardized mean differences in pain scores:

• LR-PRP: 36.38

• LP-PRP: 26.77

• Controls: 14.6-25.2

PRP For Muscle Injuries

11/21/2017

14

Meta-analysis of 5 level 1 or 2 comparative studies

Grade 1 or 2 muscle strains (primarily hamstring)

Heterogeneous with regards to PRP formulation and dosing regimens

Re-injury rate of 14.3% (PRP) vs 17.1% (control)

PRP For Ligament Injuries

11/21/2017

15

Ulnar Collateral Ligament Injuries

34 high-level throwing athletes with partial UCL tears

Single type 1A PRP injection under ultrasound

88% returned to same level of play

Average return to play was 12 weeks

One subject underwent UCL reconstruction

High-Ankle Sprains 16 athletes randomized to two injections of LP-PRP activated with calcium chloride

Control group received rehab program

11/21/2017

16

PRP For Osteoarthritis

11/21/201732

AJSM 2017

11/21/2017

17

11/21/201733

AJSM 2017

W

L

Worked better for mild OA, lower BMI

Lowers pro-inflammatory cytokines.

Conclusion: “significant improvements were seen in other patient-reported outcome measures, with results favoring PRP over HA.”

11/21/201734

Systematic Reviews of Level 1 and Level 2 evidence

Riboh et al AJSM 2015Campbell et al Arthrosc 2015

Khoshbin et al Arthrosc 2013Chang et al APMR 2014

Studies favor PRP with modest effectNo evaluation of alteration of natural history

11/21/2017

18

11/21/201735

PRP and Early OA

Level 1, 2 evidence

Likely beneficial with LP-PRPResults seem to last for ~1 year

No evidence to support structural regenerationNo long term data on natural history

PRP and Early OA

Level 1, 2 evidence

Likely beneficial with LP-PRPResults seem to last for ~1 year

No evidence to support structural regenerationNo long term data on natural history

Stem Cell Injections

11/21/2017

19

Rationale For Stem Cell Treatment

Mesenchymal stem cells (MSCs) have potential to differentiate into cartilage, bone, tendon, and muscle

May allow for targeted regeneration of tissue

MSCs are present in both bone marrow and adipose tissue

Selected Animal Evidence for Stem Cell UseAuthors Journal Year Findings

Harman, et al Frontiers in Veterinary Science

2016 Allogeneic adipose-derived MSCs showed improvement in functional scores and apparent pain in dogs with OA

Latief, et al Cell Biology International

2016 Treatment of arthritic rat knees with differentiated chondrocytes from adipose-derived stem cells showed cartilage regeneration while no changes noted in control group

Moreno, et al Journal of Nuclear Medicine

2016 Mice with OA treated with human adipose-derived stem cells showed decrease in knee inflammation and cartilage degeneration relative to saline control

Fortier, et al JBJS 2010 Treatment of full-thickness chondral defects with BMAC resulted in significantly better healing of defects compared to microfracture control group

11/21/2017

20

Stem Cell SourcesBone Marrow Aspirate Concentrate (BMAC)

Source Commonly iliac crestOther options proximal tibia, calcaneus, other sources

Harvest Method Bone marrow aspiration needle into anterior or posterior iliac crest

Quantity Extracted 60-120 ml

Mesenchymal Stem Cell Yield 0.01-0.001% of cells (ref 42 from Dragoo)

Stem Cell Sources

Adipose-Derived Stem Cells

Source Commonly intra-abdominalPotentially infrapatellar fat pad

Harvest Method 17 gauge needle to inject 120 ml saline/local anesthetic into abdomen

QuantityExtracted

80-120 ml

MesenchymalStem Cell Yield

Up to 10% of cells (ref 4, 52 from Dragoo)

11/21/2017

21

18 patients with knee OA

Treated with low, medium, or high-dose injection of adipose-derived MSCs

Performed knee arthroscopy/lavage followed by injection of AD-MSCs

No adverse events

11/21/2017

22

Limited level 3 and level 4 studies

Treatment appears safe but no data available to recommend dosing, aspirate amount, or efficacy

Limitations of Studies

Many reports have no control group

Inconsistent reporting of exact formulation of biologic

When interpreting these studies, pay attention to:

• Injection protocol

• Presence/absence of leukocytes

• Control group comparison

11/21/2017

23

Discussing These Treatments With Patients

Will PRP/stem cell injections re-grow cartilage?

Will this regenerate my meniscus?

Can this keep me from getting a knee/hip/shoulder replacement?

NO!

Discussing These Treatments With Patients

How does it work then?

• Likely pain relief through anti-inflammatory mediators

• Unlikely to change structure

What about the cost?

• Most treatments are out-of-pocket and expensive

• Limited duration of relief with most treatments

• Consider participating in clinical trials when possible

11/21/2017

24

My Recommendations Recommend LR-PRP for:

• Lateral epicondylitis with >3 months of symptoms

Consider PRP for:

• Elite-level athlete with high-ankle sprain, partial UCL tear, or grade 1-2 muscle strain

• Early osteoarthritis (KL grades 1-2) if non-responsive to cortisone/HA injections

No data to currently support:

• PRP for patellar tendinitis, Achilles tendinitis, and rotator cuff tendinopathy

Need further studies on BMAC/AD-MSC injections

Conclusions

Platelet-rich plasma and stem cell injections hold promise as potential treatment options for various musculoskeletal conditions

Not all formulations are the same

High level, controlled trials are needed before widespread recommendation of these methods

11/21/2017

25

Questions?