3/27/2017 Regenerative Medicine for Tendon and Ligament … · 2017. 4. 3. · 3/27/2017 6 —Graph...

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Regenerative Medicine for Tendon and Ligament Disorders

Joanne Borg Stein, MDAssociate Professor of PM&R

Associate Chair of Sports and Musculoskeletal RehabilitationHarvard Medical School

Spaulding Rehabilitation Hospital

The Advanced Musculoskeletal Ultrasound Skills Course

April 28‐29, 2017

NO DISCLOSURESNO DISCLOSURES

Joanne Borg-Stein, MDHarvard Medical School, Department of PM&R

Goals of the Presentation

• Regenerative Injection treatment of tendinopathy and ligament disorders–ProlotherapyProlotherapy–PRP–Needle tenotomy–Stem cells?

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Goals of the Presentation

• Basic overview of the evolution of the current available techniques

G l i i l i• General principles in selecting amongst these treatments

• Patient Selection for regenerative treatments

• Where is the field headed?

What is regenerative sports medicine?

• Regenerative biomedicine is emerging at the forefront of medicine

• As it relates to musculoskeletal and sports medicine, thisand sports medicine, this includes–– ProlotherapyProlotherapy and sclerosing

agents– Extracorporeal shock wave

therapy–– Platelet rich plasmaPlatelet rich plasma– Nitric oxide– Matrix metalloproteinase–– MesenchymalMesenchymal stem cellsstem cells

The Athlete's PainAs Sports Medicine Surges, Hope

and Hype Outpace Proven

Health

NY Times 2011

a d ype Outpace o eTreatments

Published: September 5, 2011

By: GINA KOLATA

IOC consensus paper on the use of platelet rich plasma in sports

medicine

• “….proceed with caution in the use of PRP in athletic sporting injuries. We believe more work on the basic

Br J Sports Med 2010:44:1072‐1081

science needs to be undertaken….”

• WADA: – Intramuscular injections prohibited until 2011, when approved– All other routes of administration, such as intra-articular, intra-or

peritendinous are permitted and require a declaration of use.

– Isolated growth factors are prohibited: IGF-1, VEGF, PDGF

PROLOTHERAPY in the News

Scar Away Your Pain? Some Docs Back Prolotherapy

Patients, Doctors Say Treatment Works; Some Remain Skeptical

By RADHA CHITALEABC News Medical Unit

Feb. 4, 2008—

In college Barry Taft could bench‐press a maximum of 225 pounds. But over time the strain of weight lifting led Taft to severely injure the rotator cuff in his left shoulder. "Boy, it just really hurt after that," Taft said. "For weeks and weeks it would not get any better." Taft could no longer take the 45‐pound bar off the rack, let alone bench‐press it with weights attached. Eventually he opted for a little‐known treatment that involved four sets of injections over the course fof a year.

Taft says his muscles are now better than ever.

"I wouldn't be skiing now if it weren't for prolotherapy."

‐Bode Miller

February 2006 ESPN interviewA Pinch of Sugar for Pain”Wall Street JournalOct 18, 2010

Definition of Prolotherapy

• Prolotherapy = “Proliferativetherapy”

– “Method of injection treatment using irritant solutions designed g gto stimulate healing and pain relief.

– Targets: Joint space, ligament, tendon insertion

Distel and Best: PMR. Biologics supplement. 2011; 3 S78‐S81

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Solutions Used in Prolotherapy and their proposed mechanisms of action

Injected Solution Mechanism of Action

Hyperosmolar dextrose Creates hypertonic atmosphere, which leads to cell ruptureUpregulates expression of platelet derived growth factors

Morrhuate Sodium Attracts inflammatory mediatorsVascular sclerosant

Phenol – glycerine ‐ glucose Cellular irritant * no longer used

Distel and Best: PMR. Biologics supplement. 2011; 3 S78‐S81

Proposed Mechanisms of Prolotherapy

– Non inflammatory• 10% dextrose– Repair of tissue damage– Stimulation of growth factors

• platelet derived growth factor

• Inflammatory prolotherapy– 12.5-25% dextrose, phenol,

sodium morrhuate– Causes inflammatory activation

to produce growth factors

N l i ff• epidermal growth factor• fibroblast and connective

tissue growth factors• Neural therapy

– Local anesthetic has affect on the autonomic nervous system

• Tissue damage– Chemotactics: sodium

morrhuate

• Neurolytic effects– Lysis or damage to c-fibers via

hypertonic dextrose

Reeves KD and Hassanein. Randomized prospective placebo controlled double blind study of dextrose prolotherapy for osteoarthritic thumbs and finger: evidence of clincal efficacy. Jnl Alt Compl med. 2000. 6(4):311‐20.

Dechow et.al. A randomized, double blind, placebo‐contolled trial of sclerosing injections in patients with chronic lbp. Rheumatology. 1999; 38:1255‐9

Reeves KD. Prolotherapy: Basic science, clinical studies, and technique. In Lennard TA (ed): Pain procedures in clinical practice. Hanley and Belfus. 2000172‐190.

Growth factors the Dextrose Elevates (non inflammatory effect)

• Ligament/tendon healing: – PDGF, TGFb, EGF, bFGF, CTGF

• Cartilage Healingg g

– PDGF, TGFb, IGF,

Murphy M, Godson C. et al. J Biol Chem 1999;274(9): 5830‐5834

Dextrose Levels > 10% Stimulate the Inflammatory Cascade

• Osmotic effect – cell shrink – stress – leakage of glipids – temporary inflammation

Wheaton et al. Journal of Prolotherapy. 2011

The Needle Itself Stimulates Repair

• Cell membrane disruption

• Small blood vessel disruption

www.drreeves.com

p

• Bleeding with platelet and blood effects

• Challenge to do injection control studies.

The use of prolotherapy in the sacro‐iliac jointManuel Cusi, Jeni Saunders, Barbara Hungerford, et al.Br J Sports Med published online April 9, 2008 doi: 10.1136/bjsm.2007.042044

Treatment Paradigm for Prolotherapy

• Technique: important concepts – “ABC’s”:– Anatomy: entheses, vasculature, nerves

– Bony endpoint: always touch bone with needle tip before injecting

– Compression of superficial tissues while injecting to maximize accuracy

Reeves KD. Prolotherapy: Basic science, clinical studies, and technique. In Lennard TA (ed): Pain procedures in clinical practice. Hanley and Belfus. 2000: 172‐190

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Scientific evidence for treatment oftendinopathy

• Clinical series

• Double blind controlled studies

Best practice recommendations for dextrose prolotherapy : 2017

• TMJ with painful laxity– No specific recommendation

• Achilles tendonopathy*– The combination of DPT and ELE may be utilized as potentially superior to y p y p

either treatment alone

• Lateral Epicondylosis*– DPT may improve pain and function in those who failed other treatments

• Plantar fasciosis– DPT may improve functional status

• Rotator cuff tendonopathy*– DPT in combination with PT if no sustained response to PT

Adapted with permission from Dr. Dean Reeves

Prolotherapy and Tendinopathies

• Studies in chronic tendinopathies– Lateral epicondylosis

• Scarpone, et al• Carayonopoulos, et al

– Achilles tendinopathy• Yelland et alYelland et al• Maxwell et al• Ryan et al

– Plantar fasciopathy• Ryan et al

– Patella tendinopathy• Ryan et al

– Hip adductor tendinopathy• Topol and Reeves

– Osgood Schlatter’s• Topol, Podesta, Reeves, et al.

– Rotator cuff tendonopathy• Bertrand, Reeves, et. Al.

TREATMENT: PROLOTHERAPY

• Lateral epicondylosis (Scarpone2008, Clin J Sport Med):

– Pilot studyy

– RCT: prolotherapy (dextrose-sodium morrhuate) (n=10) vs saline (n=10) with refractory lateral epicondylosis

– Clinical and MRI confirmed diagnosis.

– Injections at 0, 4 and 8 week intervals

– Statistically significant improvement of prolotherapy group over control group in pain and function out to 1 year post-injection.

Prolotherapy vs. corticosteroid therapy for treatment of lateral epicondylitis.

• Patients with chronic lateral epicondylitis (>3mos) recruited to a non-inferiority trial.

• Double blinded study comparing – P2G/sodium morrhuate

**DASH stands for "Disabilities of the Arm, Shoulder and Hand."

– Vs depomedrol (40mg) plus procaine• Primary outcome measures

– VAS– QVAS– DASH**

• Secondary outcome measures– Grip strength

• 3 office visits and 1 phone f/u at 6mos.

Carayannopoulos, Borg‐Stein et al, PMR 2011

Prolotherapy vs. corticosteroid therapy for treatment of lateral epicondylitis

• Results:– 24 patients recruited– 17 completed study– Paired T-test analysis between the two

i l i dtreatment groups inconclusive due to small sample size.

– Unpaired t-test analyses within each treatment group demonstrated a change

• Conclusion:– A benefit for prolotherapy in the treatment

of lateral epicondylitis appears to exist. Similar randomized controlled trials using larger sample sizes is warranted

Carayannopoulos et al, PMR 2011

Figure 2. Surface anatomy of injection sites. (A) Commonextensor tendon. (B) Radial collateral ligament. (C) Annular ligament

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Prolotherapy injections and eccentrialloading exercises for painful achillestendinosis: a randomized trial

• Single blind randomized clinical trial• Setting: 5 Australian primary care centers• Participants: 43 patients with painful mid-portion achilles tendinosis

with pain at least 6 weeks• Interventions: participants randomized• Interventions: participants randomized

– 12 week program of eccentric loading– Prolotherapy: hypertonic glucose and lidocaine– Combined

• Oucome measures– VISA-A, – Pain– Stiffness and limitation of activity scores– Treatment costs

Yelland et al Br J Sports Med 2011

• Eccentric loading exercises

– Twice daily in 3 sets of 15 repititions with the knee straight

– Twice daily in 3 sets of 15 repetitions with the knee bent

– Not to exceed pain intensity of 4/10

– As pain eases, weights added to backpack

• Prolotherapy injections• Prolotherapy injections– Tender points in the subcutaneous tissues adjacent to the affected

tendon with 20% glucose solution for 4‐12 treatments, using the technique described by Lyftogt

– At each point .5‐1.0 cc of solution used.

– Treated until pain free


Conclusions

– In painful achilles tendinosis prolotherapy and ELEs combined with prolotherapy injections


give more rapid improvement in symptoms than ELEs alone, but long‐term VISA‐A scores are similar

Sonographically Guided intratendinous injection of hyperosmolar dextrose to treat chronic tendinosis of the achilles tendon: a pilot study

• Subjects and methods– 36 consecutive patients– Symptoms > 3mos– Sonographically guided

intratendinous injections of j25% dextrose every 6 weeks until symptoms resolved or no improvement shown

• VAS 1 (rest pain), VAS 2 (ADL pain) , VAS 3 (sports)

• Sonographic parameters– Tendon thickness– Echogencity– neovascularity

Maxwell , Ryan et al AJRonline 2007

Maxwell , Ryan et al AJR 2007

• Results

– Statistically significant reductions in pain scores at 6 weeks

– Decreased neovascularity by 55%

A

B55%

– No significant change in hypoechoic areas

– *excluded patients without improvement in their data analysis. No control group.

– Referred one patient for surgery

Fig. 3—49‐year‐old man with insertional Achillestendinosis.A, Sonographic image shows typical appearance ofinsertional tendinosis.B and C, Sonographic images obtained after singlehyperosmolar dextrose injection into distal thickenedportion of tendon show large bursal‐surface partialthicknesstear that has opened up. This patient waswithdrawn from study and referred for surgical consultations

C

Favorable outcome after sonographically guided intratendinous injection of hyperosmolar dextrose for chronic insertional and midportion achilles tendinosis

• Objective– Short term and 2 year follow up for us guided prolotherapy injections

• Subjects and methods– 108 tendons: 86 midportion; 22 insertional

P i > 6– Pain > 6 mos

– 25% dextrose intratendinous

• Results– Mean of 5 injections 6 weeks apart

– Significant improvement in pain scores for both groups

– Reductions in the size and severity of hypoechoic regions, intratendious tears and neovascularity

Ryan et al. Am J Roentgenol 2010

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—Graph shows overview of change from baseline to 28 weeks posttest and subsequent 28‐month follow‐upfor visual analog scale (VAS) item scores for pain at rest, during activities of daily living (ADL), and during or

immediately after sports participation (Sport) after individuals received injections of hyperosmolar dextrose for chronic Achilles midportion tendinosis.

Ryan M et al. AJR 2010;194:1047‐1053©2010 by American Roentgen Ray Society

—Graph shows overview of change from baseline to 28 weeks posttest and subsequent 28‐month follow‐up for visual analog scale (VAS) item scores for pain at rest, during activities of daily living (ADL), and during

or immediately after sports participation (Sport) after individuals received injections of hyperosmolar dextrose for chronic Achilles insertional tendinosis.

Ryan M et al. AJR 2010;194:1047‐1053©2010 by American Roentgen Ray Society

Efficacy of Dextrose Prolotherapy in Elite Male Kicking-Sport Athletes with Chronic Groin pain

• Participants– 22 rugby and 2 soccer players with chronic groin

pain that prevented full sport participation and who were non-responsive both to therapy and to graded re-introduction onto sports activity

• Intervention– Monthly injection of 12.5% dextrose and 0.5%

lidocaine

– Injected sites

• Adductor origins

• Suprapubic abdominal insertions

• Symphysis pubis

» **injections were given until complete resolution of pain or lack of improvement for 2 consecutive treatments. Average of 2.8 treatments

Topol GA, Reeves DK et al: Arch Phys Med Rehab, 86(697‐701) Apr 2005

Efficacy of Dextrose Prolotherapy in Elite Male Kicking-SportAthletes With Chronic Groin PainGastrin Andres Topol, MD, K. Dean Reeves, MD, Khatab Mohammed Hassanein, PhDArch Phys Med Rehabil 2005;86: 697-702.

Prolotherapy in Athletes with Chronic Groin Pain (cont.)

• Results– 20 of 24 patients had no

pain and 22 of 24 were unrestricted with sports at final data collection an average of 17.2 mos after gtreatment

• Conclusion– Dextrose prolotherapy

showed marked efficacy for chronic groin pain in this group of elite rugby and soccer athletes


• Objective– Multisport and long term

data on prolotherapy on career-threatened athletes

• Design– Monthly injections of 12.5%

dextrose abdominal and adductor attachments

Topol GA, Reeves DK. Am J Phys Med Rehabil

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• Results– 75 athletes enrolled

– 72 completed treatment

– Average # treatments: 3

– 66 returned to unrestricted sportp

– Return to sport occurred in average of 3 mos.

– VAS sport and Nirschl measured at 0 and avg 26 mos after treatment

• Avg VAS: 82% improved

• Avg Nirschl: 78% improved

Topol GA, Reeves DK. Am J Phys Med Rehabil 2008

Sonographically guided intratendinous injections of hyperosmolar dextrose/lidocaine: a pilot study for the

treatment of chronic plantar fasciitis

• Case series

• 20 patientsAverage age: 51

Ryan, Wong et al. Br J Sports Med 2009

– Average age: 51

– 3 men; 17 women

• Interventions– 27g needle

– 25% dextrose under US guidance

– 6 week intervals for 3 visits Wong SM, Ann Rheum Dis 2001;60:639

• Outcome measures– VAS 1: pain level at rest– VAS 2: pain level with ADL– VAS 3: during or after physical activity

P d 11 8 f/ b h

Ryan, Wong et al. Br J Sports Med 2009

– Pre-test, post-test and 11.8 mo. f/u by phone• Results

– 16 patients: good – excellent outcome– 4: unchanged

• Conclusion: – Good clinical response in patients with chronic plantar fasciitis during

rest and activity– Further studies needed: control group

Ultrasound guided injections of hyperosmolar dextrose for overuse patellar tendinopathy: a pilot study

• Methods

– 47 consecutive referrals

– Patients failed conservative treatment

Ryan, Wong, Rabago, Lee and Taunton. Br J Sports Med. 2011

– US Guided 25% dextrose with lido into the area of tendinopathy until they were satisfied with treatment

– primary outcome measure: 3 part VAS

– Secondary outcome measure: US appearance of tendon

• Results

– Mean of 4 injections

– 45 week follow up

• Improvement in pain and hypoechogenecity

• Conclusion

– “There was a reduction in pain and an improvement in ultrasound appearance following US guided dextrose injections

– Improved hypoechoic appearance of the tendon was

Ryan, Wong, Rabago, Lee and Taunton. Br J Sports Med. 2011

p yp ppassociated with decreased pain scores

– Suggestion that dextrose injections may modify patella tendinopathy at the tissue level

Hyperosmolar Dextrose injection for recalcitrant osgood-schlatter diseasePediatrics, 2011, Topol et al.

• Objective– dextrose vs lidocaine vs supervised usual care in adolescent athletes

with Osgood-Schlatter

• Patients and methods– Randomly assigned to either therapist-supervised usual care or y g p p

double blind injection of 1% lidocaine with/without 12.5% dextrose – Monthly injections x 3 mos.– measured: unaltered sport (Nirschl pain score <4) and

asymptomatic sport (Nirschl pain score = 0) at 1 year

• Results/Conclusions– Significant symptom reduction efficacy of injection therapy over

usual care. A significant component of the effect seems to be associated with the dextrose component.

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Anteroposteror photograph of knee showing injection points starting over the most distal area of pain on the tibial tuberosity and moving proximally in

1-cm increments to the most proximal painful point with pressure.

Topol G A et al. Pediatrics 2011;128:e1121-e1128

©2011 by American Academy of Pediatrics

No significant change in US appearance of the tendons

Summary: Where does prolotherapy fit in the treatment of tendinopathy?

Injectate Pros Cons

Steroid Short term relief Avoid intra‐tendinousAvoid weight bearing tendons

l h i h d dProlotherapy Less expensiveTreat region, not pointIncreased volumeEvidence suggests applicable to tendon / enthesis

More research neededNeedling effect may be primary

Platelet Rich Plasma More data for intra and peri‐tendinousapplication

Small volumeExpensiveTenotomy may be primary

Prolotherapy and Recalcitrant Tendinopathy: Clinical Recommendations 2017

• “The current, most promising indication for the use of prolotherapy appears to be the treatment of tendinopathies” (Distel and Best 2011)

• Relatively safe. Few adverse effects

• Growing evidence to support use in refractory tendinopathiesGrowing evidence to support use in refractory tendinopathies– Lateral epicondylopathy

– Achilles tendinopathy

• Treatment paradigm to consider– Peritendinous / intratendinous with US guidance

– Enthesis

– Treat region, not point.

• Further research needed

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The optimal techniques for application need to be determined

• Frequency-weekly vs. 3-6 weeks

• Concentration of solutions-10-15-25%solutions-10-15-25%

• Optimal solutions –dextrose only vs. with phenol, sodium morhuate, pumice, platelet rich plasma

• Placement and volume of injections.

PRP and Tendon

Just prior to the kickoff of superbowl XLIII, on field reporters from NBC credited Hines Ward's rapid recovery with a knee sprain (MCL) to Platelet Rich Plasma therapy.

PRP in the Sports News

Takashi Saito, a star pitcher for the LA dodgers suffered a tear of his ulnar collateral ligament.

IOC consensus paper on the use of platelet rich plasma in sports medicine

• WADA: – Intramuscular injections prohibited until 2011, then

Br J Sports Med 2010:44:1072-1081

approved

– All other routes of administration, such as intra-articular, intra-or peritendinous are permitted and require a declaration of use.

– Isolated growth factors are prohibited: IGF-1, VEGF, PDGF

Platelets: Not just for clotting

• Platelets are the first cells to arrive at the site of injury

• Responsible for initiation of healing cascade

• α-granules and dense granules

Courtesy of Dr. Ken Mautner

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Aim: IRB approved prospective pilot study to evaluate the efficacy of using PRP as a potential treatment for chronic severe epicondylar tendinosis.

Methods: 140 patients were evaluated for this study

20 patients (15%) met strict inclusion criteria

Chronic Elbow Tendinosis

Mishra, A et al; “Treatment of Chronic Elbow Tendinosis with Buffered Platelet-Rich Plasma”, American Journal of Sports Medicine,, May 30, 2006

p ( )

55 ml of whole blood was processed to produce 5 ml of PRP with a mean increase of 5.4x above baseline

2-3 ml of either PRP or bupivacaine (control) were injected using a 22-g needle into thecommon extensor tendon

Results: Outcome Data

Visual Analog Pain Scores Mean Mayo Elbow Scores

Time PRP Control p value PRP Control p value

Initial 80.3 86 0.259 50.3 49.5 0.838

1 month 43.4 71.0 0.028 71.3 59.5 0.120

2 month 32.0 72 0.001 76.3 56.5 0.008


Mishra, A et al; “Treatment of Chronic Elbow Tendinosis with Buffered Platelet-Rich Plasma”, American Journal of Sports Medicine, Nov. 2006

6 month 15.1 - 86.3 -

24 month 5.7 -

At 6 months, the PRP-treated patient’s

1. Visual analog pain scores improved 81% (p=0.0001) over baseline

2. Mean mayo elbow scores improved 72% (p=0.0001) over baseline

Key Points: PRP treated patients demonstrated significant improvement with a single injection that was sustained over time

There were no reported complications (specifically, no infections, neurovascular changes, or worsening of patient’s

i d l i )


epicondylar pain)

Treatment of patients with chronic elbow tendinosis with buffered PRP significantly reduced pain

PRP may be considered before surgical intervention

Mishra, A et al; “Treatment of Chronic Elbow Tendinosis with Buffered Platelet-Rich Plasma”, American Journal of Sports Medicine,, May 30, 2006

PRP vs Corticosteroid in Lateral Epicondylitis: Netherlands Study. AJSM

Feb 2010

• Purpose: determine effectiveless of PRP vs corticosteroid injection in patients with chronic LE

• Design: randomized controlled trial

• 100 patient100 patient– 51 PRP

– 49 steroid

• Technique: peppering technique plus site of maximal tenderness

• Outcomes: VAS and DASH

• Successful treatment: >25% improvement in VAS or DASH without reintervention after 1 year

Peerbooms et al. AJSM. 2010. 38 (2)

PRP vs Corticosteroid in Lateral Epicondylitis: Netherlands Study.

AJSM Feb 2010

• Results:

– VAS scores: 49% improved in steroid group

VAS 73% i h PRP i d– VAS scores: 73% in the PRP group improved

– DASH: 51% in steroid group improved

– DASH: 73% in the PRP group

– PRP group kept getting better over the next year. • PRP patients: 64% improvement in pain, 84% disability

• Steroid group: 24% improvement in pain, 17% disability

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Comparison of Surgically Repaired

Achilles Tendon using Platelet-Rich Fibrin Matrices

• 12 male athletes with spontaneous complete rupture of Achilles tendon. – 6 received platelet-rich fibrin matricesp– Regained ROM earlier (P=.025)– Less time to take up gentle running (P=.042)– Resumed training activities earlier (P=.004)– Less increase in cross-sectional area (P=.009)

Sanchez et al. Comparison of surgically repaired Achilles tendon tears using platelet rich fibrin matrices. Am J Sports Med 2007;2:245-251

PRP and tendon: AAOS March 19, 2010: Weber et al.

• Blinded, prospective, randomized trial of PRP vs placebo in patients undergoing surgery to repair a torn rotator cuff,

• There was no difference in pain relief or in function between the 2 said Stephen C Weber MD2, said Stephen C. Weber, MD,

• All patients had arthroscopic rotator cuff repair under general anesthesia, and those randomized to PRP received it at the conclusion of the repair.

• However, VAS scores and postoperative narcotic use did not differ between the 2 groups and, at 3 months postop, both groups showed residual defects on magnetic resonance imaging (MRI).

Medscape orthopedics 2010

JAMA. 2010; 303(2): 144149. Jan 13

Monto et al. PRP in chronic achilles tendinopathy

• AAOS annual meeting March 19, 2010• 30 patients with chronic refractory achilles

tendinopathy > 8mos. 1 MSK US id d 4 i j i i b l• 1 MSK US guided 4cc injection into abnormal area

• 48 hrs in CAM walker, then activity as tolerated• AOFAS hindfoot scores improved

– 34 pre– 84 post– 92 at 6 mos follow up

PRP and tendon

• Platelet-rich plasma: New clinical application A pilot study for treatment

f j ’ kof jumper’s knee

–

Elizaveta Kon, Giuseppe Filardo et al. Injury 2009

– 20 male athletes with a mean history of 20.7 months of pain received treatment,

• Baseline injection then 2 additional injections at 15 day intervalsintervals

• PRP activated with Calcium chloride

– Outcomes were prospectively evaluated at 6 months follow-up.

– No severe adverse events were observed,

– Statistically significant improvements in all scores were recorded.

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Fig. 4. Health status evaluated with EQ‐VAS (means and CIs). CI, confidenceinterval; FU, follow‐up.

Fig. 5. Sport activity level evaluated with the Tegner score (means and CIs). CI,confidence interval; FU, follow‐up.

Fig. 6. Percentage of participants resuming sports after treatment, at differentfollow‐up points.

Gaweda K, Tarczynska, M, Krzyzanowski W. Treatment of Achilles Tendinopathy with Platelet-Rich Plasma. Int J Sports Med. 2010 Jun 9

Gaweda K et all . Treatment of Achilles Tendinopathy with Platelet-Rich Plasma

14 patients (15 tendons)

3 cc PRP injected, No mention of platelet concentration

US guidance used

N o mention of buffer

No mention of activator

No mention of lidocaine/ marcaine

Rehab –PWB x 3 days, PROM x 2 wks, then active ROM, stretching from 2-6 wks, then >6wks, full load active exercises (with heel lift)

No mention of eccentrics, no mention of RTP

Used US imaging to document healing of tendon (only study)

Gaweda K, Tarczynska, M, Krzyzanowski W. Treatment of Achilles Tendinopathy with Platelet-Rich Plasma. Int J Sports Med. 2010 Jun 9

• Significant improvement was observed in the clinical and imaging results.

• The AOFAS scale improved from a baseline median of 55 points to 96 points at 18 months (p=0 000655) hile the VISA A scaleto 96 points at 18 months (p=0.000655), while the VISA-A scale improved from a baseline of 24 to 96 (p=0.000655) in the final evaluations.

• During the final evaluation, one subject experienced minor pain following prolonged daily activity, while another subject complained of pain following overloading activity.

• CONCLUSION: Local, accurate PRP administration improved symptoms of non-insertional Achilles tendinopathy.

PRP fails to improve long term outcome after surgical rotator cuff repair

• Randelli et al: JSES, 2010. PRP in arthroscopic rotator cuff repair: A prospective RCT study: 2 years follow upp

• Castricine R: et al; Am J Sports Med 2011. Platelet fibrin matrix augmentation for arthroscopic rotator cuff repair: a randomized controlled trial

– Looked at double row repair in small to medium RTC tears

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PRP for ligament injury

• ACL– No benefit to surgical reconstruction after 24 mos. May accelerate graft

to bone incorporation, improve healing, reduce edema, inflammation• MCL

– One case report– One case report• Ankle sprain

– Double blind RCT comparing PRP to saline placebo: no significant difference at 30 days (Rowden et al. 2015)

– Other study: added US guided PRP injection to rehab of AITFL in elite athletes: accelerated return to play by 3 weeks., improved joint stability and reduced pain (Laver et al. 2015)

• UCL– Case series demostrated favorable outcome for tx of partial UCL tears of

the elbow (Podesta et al, 2013)

Percutaneous tenotomy

• US guided PNT has been used as an independent strategy or in combination with orthobiologics

• PNT: passes a needle through a tendon with the goal of disrupting the chronic degenerative process.

• Minimal research on PNT alone. • Complications are rare• Complications are rare.

Advanced Ultrasound‐Guided Interventions for Tendinopathy

Evan Peck, MD, Elena Jelsing, MD, Kentaro Onishi, DO, 2016

Automated percutaneoustenotomy

• MSK ultrasound guidance• Local anesthetic• Longitudinal vibration energy at a specific frequency debrides and aspirates

the targeted damaged tendon tissue

Advanced Ultrasound‐ Guided Interventions for Tendinopathy

Evan Peck, MD, Elena Jelsing, MD, Kentaro Onishi, DO, 2016

High Volume Injection and Percutaneous Needle Scraping

Peck, et al. PMR clinics 2016

Emerging treatments for chronic tendinopathy

• Stem cell use

• Bioscaffolds

CSU Junior Nordic Ski Team

May 2011

Peyton Manning

Bartolo Colon

Stem cells for rotator cuff(fat and BMSC)

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A summary of cell therapies in different cell origins

• Mesenchymal stem cells

• FibroblastsFibroblasts

• Tendon progenitor stem cells

Muscle derived mesenchymal stem cells

• Limited evidence in tendon therapy





Dermal Fibroblasts

• In vitro and animal studies have shown that dermal fibroblasts have potential in tendon engineering and repair

• Connell et al: human study for chronic lateral epicondylosisClini l pil t– Clinical pilot

• 12 patients with refractory lateral epicondylopathy. • 4mm punch biopsy for skin sample

– Fibroblasts expanded in number in the laboratory and collagen producing cells with features similar to tenocytes were identified

– these cells were embedded into the patients own plasma and injected under ultrasound guidance.

– Improved ultrasound appearance, decreased pain and improved function at 6 mos.

Connell et al. Br J sports Med. 2009

Dermal Fibroblasts

• 60 tendons from 46 patients with refractory patella tendinopathy– Randomized controlled trial– 4mm skin biopsy to grow tenocyte-like

collagen producing cells– Randomized

• Cells plus autologous plasma• Autologous plasma alone

– Results: 6 mos. Follow up.• Ultrasound guided injec of

autologous skin-derived tendon-like cells can be safely used in the short term to treat patella tendonopathy

• Faster response and greater improvement in pain and function over plasma alone

Clarke et al. Am J Sports Med. 2011

A

before

After

Figure 9. Histopathologic specimen of cell‐injected tendon at 19 5003 magnification showing almost‐normal‐appearing tendon‐like cells.

Figure 8. A, ultrasound of the right patellar tendon in the longitudinalplane showing patellar tendon before (inset) and aftertreatment with plasma only. The large arrow shows echogenicscarring within the initial hypoechogenic abnormality (smallarrow). B, ultrasound of the left patellar tendon in the longitudinalplane of the other knee of the same patient treated withplasma and cells shows almost complete replacement of theinitial hypoechogenic abnormality (inset; small arrow) with normal‐appearing fibrillar tendon material (large arrow).

Clarke et al. Am J Sports Med. 2011

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Tendon Stem / Progenitor cells

• Multipotent stem cells exist inherently in tendons and ligaments

• Rabbit and porcine research using bioscaffolds seeded with tenocyte or intrasynovial tendon cells suggests better tendon healing (1,2)

• In vitro studies demonstrate that platelet-rich plasma releasatepromotes differentiation of tendon stem cells into active tenocytes (3)

1. Zhang et al. Journal of Rehab Res and Development 46 (4) 20092. Chen et al. Tissue Eng. 20073. Zhang et al. Am J of Sports Med. 38 (12) 2010

Bioscaffolds

• A number of studies demonstrate that seeded constructs have better histological and biomechanical properties that scaffold alone

• St dies• Studies– Synthetic biodegradable polymers

– PLGA (poly-lactide-co-glycolide)

– Acellularized tendon grafts

– Collagen sponge

Treatment selection: soft tissue

Injectate Pros Cons

BMAC Theoretical tissue repair. Few human studies (tendon)

Invasive. ExpensiveFDA non compliant

Prolotherapy Less expensive More research neededTreat region, not pointIncreased volumeTendon / enthesisReduce hypermobility

Needling effect may be primary

Platelet Rich Plasma More data for intra and peri‐tendinousapplicationUCL

Small volumeExpensiveTenotomy may be primary

Adipose graft Filling of tissue defect InvasiveExpensive

Take home points

• Literature provides promising evidence with regard to the application and effectiveness of regenerative injection therapies in tendinopathyregenerative injection therapies in tendinopathy

• The ideal injectate, technique, scaffold and cell source for tissue engineering and tendon repair remains uncertain

• More research needed.

• Regulation must be consideredObaid et al. Cell therapy in tendon disorders: What is the Current evidence? Am J Sports Med. 2010. 38 (10)

THANK YOU

Joanne Borg Stein, [email protected]

3/27/2017 Regenerative Medicine for Tendon and Ligament … · 2017. 4. 3. · 3/27/2017 6 —Graph...

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