Platelet Rich Plasma and Knee Arthritis

Knee arthritis is a very common problem for patients worldwide.  With the aging of the population this will become one of the most important medical issues to address with biologic therapies.

Conflicting results have recently been published about the use of platelet rich plasma in the treatment of knee arthritis.  Filardo, Kon et al found no significant differences between PRP and hyaluronic acid injections.  (see full abstract).  Conversely, Cerza et al did find significantly better clinical outcomes when patients were treated with PRP vs hyaluronic acid injections. (see full abstract) The version of PRP used in these two studies were different.  The first study also used three injections and the second four weekly injections.  Clearly, more research is needed to clarify the value of PRP for knee arthritis and determine the optimal formulations and techniques.

AM
TotalTendon

See the video below for a brief description of knee arthritis

Systemic Effects of Platelet Rich Plasma

In a well done study, researchers have shown when athletes are given an intratendinous injection of leukocyte-enriched platelet rich plasma (PRP), they will have elevated levels of growth factors in their blood up to four days after the procedure.  (see abstract below)

Vascular-endothelial growth factor  (VEGF), a molecule known to enhance angiogenesis (new blood vessel formation), was elevated in all 25 patients after injection.  This is very interesting and important data suggesting PRP may trigger a systemic response.  It also helps explain why PRP may be a useful treatment for tendon related injuries and disorders.   Several controlled studies confirm PRP can be an effective treatment for chronic tennis elbow and this study may reveal one of the mechanisms of action.
Tennis Elbow Study 1,  Tennis Elbow Study 2

It would be quite interesting and important to also measure growth factors in athletes who have received a saline injection or dry needling of their tendons to see if the act of introducing a needle into a damaged tendon produces a similar or different systemic response.

AM
TotalTendon.com

Am J Sports Med. 2012 Dec 4.

The Systemic Effects of Platelet-Rich Plasma Injection.

Wasterlain AS, Braun HJ, Harris AH, Kim HJ, Dragoo JL.

Source

Department of Orthopaedic Surgery, Stanford University, Stanford, California.

Abstract

BACKGROUND:Platelet-rich plasma (PRP) is an autologous blood product used to treat acute and chronic tendon, ligament, and muscle injuries in over 86,000 athletes in the United States annually. The World Anti-Doping Agency (WADA) banned intramuscular PRP injections in competitive athletes in 2010 because of concerns that it may increase performance-enhancing growth factors. The ban on PRP was removed in 2011 because of limited evidence for a systemic ergogenic effect of PRP, but the growth factors within PRP remain prohibited. PURPOSE:To quantify the effect of PRP injection on systemic growth factors with performance-enhancing effects and to identify molecular markers to detect treated athletes. STUDY DESIGN:Descriptive laboratory study. METHODS:Six ergogenic growth factors monitored by WADA-human growth hormone (hGH), insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), basic fibroblast growth factor (bFGF or FGF-2), vascular endothelial growth factor (VEGF), and platelet-derived growth factor-BB (PDGF-BB)-were measured in 25 patients before (baseline) and at 0.25, 3, 24, 48, 72, and 96 hours after intratendinous leukocyte-rich PRP injection. Eating and exercise were prohibited for 3 hours before testing. Growth factors were quantified by enzyme-linked immunosorbent assay, and the change relative to each patient's baseline was calculated. RESULTS:Relative to serum, PRP contained significantly more bFGF (226 vs 5 pg/mL), VEGF (1426 vs 236 pg/mL), and PDGF-BB (26,285 vs 392 pg/mL), but IGF-1 and hGH were not elevated. Serum levels increased significantly for IGF-1 at 24 and 48 hours, for bFGF at 72 and 96 hours, and for VEGF at 3, 24, 48, 72, and 96 hours after PRP injection. Additionally, VEGF was increased in all 25 patients after PRP treatment. CONCLUSION:Serum IGF-1, VEGF, and bFGF levels are significantly elevated after PRP injection, supporting a possible ergogenic effect of PRP. An indirect marker for hGH doping, the product of IGFBP-3 × IGF-1, also significantly increased after PRP. Platelet-rich plasma appears to trigger an increase in circulating growth factors through activating biological pathways rather than by serving as a vehicle for the direct delivery of presynthesized growth factors. Elevated VEGF was observed in all patients after PRP, and ≥88% of patients had elevated VEGF at each time point from 3 to 96 hours after PRP, suggesting that VEGF may be a sensitive molecular marker to detect athletes recently treated with PRP. CLINICAL RELEVANCE:This is the first and only adequately powered study of the systemic effects of PRP. We present evidence that PRP contains and may trigger systemic increases in substances currently banned in competitive athletes. Finally, we provide evidence that VEGF could serve as a useful molecular marker to detect athletes treated with PRP.

Platelet Rich Plasma useful for Chronic Tennis Elbow

For more than a decade now, platelet rich plasma has been used to treat chronic tennis elbow.   A recently published review article in Hand Clinics reviewed the literature for the use of PRP in the upper extremity.  It was concluded that multiple controlled trials support the use of PRP for tennis elbow.  The literature supporting the its use for rotator cuff tears, however, was not yet conclusive.  (See Abstract Below)

PRP Injection into left elbow

Hand Clin. 2012 Nov;28(4):481-91. doi: 10.1016/j.hcl.2012.08.008.

Platelet-rich plasma and the upper extremity.

Mishra A, Randelli P, Barr C, Talamonti T, Ragone V, Cabitza P.

Source

Department of Orthopaedic Surgery, Menlo Medical Clinic, Stanford University Medical Center, 1300 Crane Street, Menlo Park, CA 94025, USA. 

Abstract

Platelet-rich plasma (PRP) is a fraction of whole blood containing powerful growth factors and cytokines. Preclinical studies suggest PRP may be useful for tendon repair or regeneration. Clinical investigations have focused on the treatment of chronic lateral epicondylar tendinopathy and rotator cuff pathology. Multiple controlled studies support the use of PRP for chronic tennis elbow. Rotator cuff studies, however, have produced conflicting results based on PRP formulation, surgical technique, and size of tendon tear. This article explores the scientific rational for using PRP, its various formulations, and the emerging clinical data. Future potential applications are also explored.

AM

Total Tendon

For more information about Platelet Rich Plasma, visit:  ApexPRP.com

NFL grants $100,000 to study PRP and Stem Cells for Tendon Disorders

The National Football League recently granted $100,000 to the Hospital for Special Surgery to study the effects of platelet rich plasma and stem cells on tendons.  The research will be conducted by Dr. Scott Rodeo, associate team physician for the New York Giants.  The focus will be to better understand the effects of different formulations of PRP in a preclinical model.  Specific evaluations of how PRP influences the tendon structure will be done.

This is important research that should help answer multiple questions.  Clinical studies to date have been variable in their outcomes.  The best available data today supports the use of PRP with white blood cells injected in an unactivated form for chronic tennis elbow.  We need to better understand the mechanisms underlying various forms of PRP in order to best apply it clinically.

We will all be most interested in following the results of their investigations.

See full article about research grant. 

Allan Mishra
TotalTendon
@BloodCure

The Epicenter of Optimism

I am most fortunate to live in the Silicon Valley.  The climate is close to perfect except for the potential for an earthquake.  The United States Geologic Survey is located in the middle of the Valley and tracks seismic activity from all over the world.  (See real time earthquake map)  At some point, this area will have another big one.  Right now, however, hundreds of little quakes are occurring all over the bay area and they don't involve the shifting of tectonic plates.

Silicon Valley

People with indomitable self-confidence in a rainbow of colors populate the valley.  We are united by a goal of "changing the world".  It is not simply a cliche but truly a mantra.  Apple, Google, Twitter, and Intel are just a few of the transformative technology companies that were founded here.  It is important to note that other industries also contribute to the culture.  Genentech, the world's first biotechnology company was founded here over thirty-five years ago by a couple of dreamers that envisioned a world of genetically engineered medicines for challenging diseases such as diabetes.  That was science fiction back then and is reality now.   A new generation of visionaries seek to solve insanely difficult problems such as brain cancer.   (See story about how an eight year old's death continues to inspire Stanford researchers)  Other valley entrepreneurs seek to solve our energy problems via novel approaches to renewable sources or via electric cars such as Tesla.  Many more quixotic ideas will erupt from this fertile ground and inspire other ideas in near and distant lands.

Despite the recent economic difficulties, young, middle age and older people in this valley continue to search for and even demand dramatically better solutions to the most challenging problems of our time.  They embrace Les Brown's suggestion:  "Shoot for the moon.  Even if you miss, you'll land among the stars".  The valley is about 25 miles long and only three miles wide but truly is the epicenter of optimism.

Allan Mishra
@BloodCure

Steroid Injections may Deplete Tendon Stem Cell Pools

Steroid injections are commonly used for a number of musculoskeletal conditions.  There is increasing evidence to suggest this is not a good idea especially for tendon related problems such as tennis elbow or rotator cuff tendinopathy.  Clinical studies only confirm short term pain relief for cortisone injections.  Basic science studies are now revealing that such injections may deplete tendon stems cells pools or increase the risk of tendon rupture.  (See Abstract Below)

Platelet rich plasma has been shown to be superior to cortisone injection in a double blind randomized trial at least for tennis elbow.  When discussing the value of evolving biologic therapies it is crucial to compare them to commonly used treatments.  In the case of cortisone for tendon related injuries and disorders at least for now PRP is the superior choice based on basic science and clinical publications for tennis elbow.  (Gosens et al Study)

Allan Mishra, MD

@Bloodcure
TotalTendon

J Orthop Res. 2012 Aug 8. 

The effects of dexamethasone on human patellar tendon stem cells: Implications for dexamethasone treatment of tendon injury.

Zhang J, Keenan C, Wang JH.

Source

Abstract

Injection of Dexamethasone (Dex) is commonly used in clinics to treat tendon injury such as tendinopathy because of its anti-inflammatory capabilities. However, serious adverse effects have been reported as a result of Dex treatment, such as impaired tendon healing and tendon rupture...... Dex treatment depletes the stem cell pool and leads to the formation of non-tendinous tissues (e.g., fatty and cartilage-like tissues), which make tendon susceptible to rupture. 

© 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 

Copyright © 2012 Orthopaedic Research Society.

See Full Abstract

Orthopedic Innovation

Innovation within medicine more often arises via persistence and determination than from dramatic breakthroughs.  In fact, many paradigm shifting advancements are not initially embraced by the medical establishment.  In orthopedics, total joint replacement and arthroscopy are two excellent examples.  Sir John Charnley deserves much of the credit for the modern development of hip replacement surgery.  His initial designs used Teflon and those implants typically failed early.  He redesigned his implant to use a novel liner that significantly improved  its longevity.  Use of other materials and techniques over several decades via the hard work of many have led us to the point where we complain when a total hip lasts less than 10 or even 15 years.  (Read more)

Arthroscopy, one of the first minimally invasive types of surgery, at its beginning took longer and was more complicated than open surgery.  The first examination of joint via a "scope" was close to 100 years ago.    Over the last 30 years, it has become the standard of care for evaluating and treating many joint injuries such as ACL reconstruction and Rotator Cuff Repair.  This innovation is the result of contributions of thousands of researchers, surgeons and their patients.  It is also led to less invasive surgery for spine disorders.  (See Spine Surgery Video) (Read more/source)

We are now about a decade into "Biologic Orthopedics".  Therapies such as Platelet Rich Plasma, Stem Cells, Genetic Engineering, and Genome Sequencing are revolutionizing how we evaluate and treat patients.  As we surf the choppy waters of innovation, however, we will not always embrace ideal ideas.  Some "innovations" will fade as fads but others will emerge as commonplace treatments that significant improve the lives of millions of patients.  We need to balance our approach to novel methods of helping our patients.  We must seek their safety and benefit first.   In doing so, we are obligated to consider emerging biologic treatment options because they may be the best and most appropriate.

Allan Mishra, MD
@BloodCure

Medicare (CMS) Announces Payment Coverage for Platelet Rich Plasma For Wound Healing

Platelet Rich Plasma has been used for years to treat chronic wounds.  In a landmark decision, the Centers for Medicare and Medicaid Services (CMS) announced coverage for PRP that is being used in clinical trials for wound healing.  This is a crucial first step for a broad range of biologic therapies.  If government payers are willing to support these types of treatments when they are backed up with appropriate data, more innovative treatments will arise.  This is good news for patients and the providers who are developing novel options for difficult problems.

Full Story Link

Allan Mishra, MD

@BloodCure

TotalTendon.com

Can Platelet Rich Plasma Heal Difficult Meniscus Tears?

Meniscus tears are very common and come in a variety of types and occur in different zones of the knee.  The peripheral part of the meniscus is known as the red-red zone because it has the best blood supply.  The central portion is known as the red-white zone becuase of its moderate blood supply and the white-white zone has a poor blood supply.  Typically, tears in this white-white zone are surgical resected because of their poor healing capacity.  Newer mechanical techniques are being developed to suture these tears together.  And, now biologic enhancement with platelet-rich plasma has been formally proposed as a way to improve the chances of such a tear healing.  Data will need to be developed but it is clear we will need both better devices to suture the meniscus AND biologic stimulation in order for white-white tears to heal.

See video below about meniscus tears and the abstract of an article proposing PRP to help heal meniscus tears. 


AM
TotalTendon.com


A novel hypothesis: The application of platelet-rich plasma can promote the clinical healing of white-white meniscal tears.

Wei LC, Gao SG, Xu M, Jiang W, Tian J, Lei GH.
Med Sci Monit. 2012 Aug 1;18(8):HY47-50.


The white-white tears (meniscus lesion completely in the avascular zone) are without blood supply and theoretically cannot heal. Basal research has demonstrated that menisci are unquestionably important in load bearing, load redistribution, shock absorption, joint lubrication and the stabilization of the knee joint. It has been proven that partial or all-meniscusectomy results in an accelerated degeneration of cartilage and an increased rate of early osteoarthritis. Knee surgeons must face the difficult decision of removing or, if possible, retaining the meniscus; if it is possible to retain the meniscus, surgeons must address the difficulties of meniscal healing. Some preliminary approaches have progressed to improve meniscal healing. However, the problem of promoting meniscal healing in the avascular area has not yet been resolved. The demanding nature of the approach as well as its low utility and efficacy has impeded the progress of these enhancement techniques. Platelet-rich plasma (PRP) is a platelet concentration derived from autologous blood. In recent years, PRP has been used widely in preclinical and clinical applications for bone regeneration and wound healing. Therefore, we hypothesize that the application of platelet-rich plasma for white-white meniscal tears will be a simple and novel technique of high utility in knee surgery. 

SourceDepartment of Orthopaedics, Xiangya Hospital, Central South University, ChangSha, Hunan, China and Department of Orthopaedics, First People's Hospital of ShaoYang City, ShaoYang, Hunan, China.

Epigenetic Marker for Osteoarthritis Discovered

Epigenetics refers to chemical modifications surrounding DNA that result in alterations of how that DNA is expressed.  In English, changes in epigenetics can affect how much of a protein is produced by the underlying DNA.  In a newly published study, from Newcastle in the United Kingdom, researchers discovered less methylation (an epigenetic chemical modification) at a specific spot along the DNA led to increased production of the destructive enzyme MMP-13.  This all sounds very complicated and it is but this discovery may lead to a new class of drugs to treat osteoarthritis.  Interesting and potentially very exciting news for millions of arthritis patients.

Allan Mishra, MD

"Scientists discover an epigenetic cause of osteoarthritis"


"New research in the FASEB Journal suggests that DNA methylation is responsible for switching on and off a gene that produces the MMP13 enzyme that is known to be important in the destruction of cartilage

Bethesda, MD—In what could be a breakthrough in the practical application of epigenetic science, U.K. scientists used human tissue samples to discover that those with osteoarthritis have a signature epigenetic change (DNA methylation) responsible for switching on and off a gene that produces a destructive enzyme called MMP13. This enzyme is known to play a role in the destruction of joint cartilage, making MMP13 and the epigenetic changes that lead to its increased levels, prime targets for osteoarthritis drug development. In addition to offering a new epigenetic path toward a cure for osteoarthritis, this research also helps show how epigenetic changes play a role in diseases outside of cancer. This finding was recently published online in the FASEB Journal."

"We've already seen how epigenetics has advanced our approach to cancer. Now we're seeing it with other diseases and even exercise." said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "This study not only lays the groundwork for a new understanding of osteoarthritis, but also shows that the old 'either/or' nature v. nurture argument is outdated: epigenetics teaches us that nature (the daily wear and tear of joints) regulates nurture (the genes in our cartilage) to cause arthritis."

See Full Press Release

Platelet Rich Plasma Eyedrops for Chemical Eye Injuries

In the study outlined below, platelet rich plasma eyedrops were used to augment standard treatment of chemical injuries to the eye.  The researchers found PRP to be "safe and effective, and it promotes rapid reepithelialization of ocular surface"

Novel and interesting application of PRP.

Allan Mishra

TotalTendon

Topical Autologous Platelet-Rich Plasma Eyedrops for Acute Corneal Chemical Injury.

Panda A, Jain M, Vanathi M, Velpandian T, Khokhar S, Dada T.

Source

Cornea. 2012 Jul 2. 

Abstract

PURPOSE:

Evaluation of efficacy of autologous platelet-rich plasma eyedrops as an adjunct to standard medical treatment as compared with standard medical treatment with artificial tears in acute ocular chemical injury.

METHODS:

Twenty eyes with grade III to grade V chemical injury were randomly assigned to 2 groups. Group I (10 eyes) received autologous platelet-rich plasma eyedrops along with standard medical treatment, and group II (10 eyes) received standard medical treatment alone. Follow-up was on days 3, 7, 14, 21, 30, 60, and 90. Chi-square test for categorical variables and Mann-Whitney test for quantitative variables were applied for statistical analysis.

RESULTS:

The mean time between exposure and presentation was 2.15 ± 0.93 days (group I, 2.2 ± 0.73 days; group II, 2.1 ± 0.98 days; P = 0.81). Complete epithelialization was achieved in all the eyes. The mean ± SD and median (range) time to complete epithelialization were 40 ± 31.57 days and 25.5 (7-90) days in group I and 47 ± 26.15 days and 30.0 (21-90) days in group II (P = 0.29). For grade III injuries, mean ± SD and median (range) time to complete epithelialization were 14 ± 7 days and 14 (7-21) days in group I and 28.5 ± 3.67 days and 28.5 (21-30) days in group II (P = 0.006) [Wilcoxon rank sum (Mann-Whitney) test]. At 3 months, corneal clarity showed significant improvement in grade I compared with grade II (P = 0.048). Similarly, the percentage improvement in best-corrected visual acuity was 63.64 ± 55.75 and 37.74 ± 9.66 for grades I and II, respectively (P = 0.082).

CONCLUSIONS:

Topical autologous platelet-rich plasma therapy is safe and effective, and it promotes rapid reepithelialization of ocular surface and can be administered along with standard medical therapy.

Platelet Rich Plasma effective in treating Chronic Achilles Tendonitis

In the study outlined below, patients with chronic achilles tendinosis (also known as achilles tendonitis) severe enough to consider surgery were treated with platelet rich plasma.  Clinical success was found in 93% of patients treated with PRP (28/30).  This is an uncontrolled study but did show efficacy in a very difficult group of patients.  

Allan Mishra (@bloodcure)

TotalTendon

Foot Ankle Int. 2012 May;33(5):379-85.

Platelet rich plasma treatment for chronic achilles tendinosis.

Monto RR.

Source

Abstract

BACKGROUND:

Chronic Achilles tendinosis is a relatively common but difficult orthopedic condition to treat. In this study, autologous platelet rich plasma (PRP), a concentrated bioactive blood component rich in cytokines and growth factors, was evaluated to determine its potential long-term efficacy in treating chronic cases of Achilles tendinosis resistant to traditional nonoperative management.

METHODS:

Thirty patients with chronic Achilles tendinosis who did not respond to a minimum of 6 months of traditional nonoperative treatment modalities were treated with a single ultrasound guided injection of PRP. AOFAS scoring was completed for all patients pretreatment and at 0, 1, 2, 3, 6, 12, and 24 months post-treatment. MRI and/or ultrasound studies were completed for all patients pre-treatment and at 6 months post-treatment. Prior to the PRP treatment all of the patients in this study were considering surgical Achilles repair for their severe symptoms.

RESULTS:

The average AOFAS score increased from 34 (range, 20 to 60) to 92 (range, 87 to 100) by 3 months after PRP treatment and remained elevated at 88 (range, 76 to 100) at 24 months post-treatment. Pretreatment imaging abnormalities present in the Achilles tendon on MRI and ultrasound studies resolved in 27 of 29 patients at 6 months post-treatment. Clinical success was achieved in 28 of 30 patients.

CONCLUSION:

Platelet-rich plasma was used effectively to treat chronic recalcitrant cases of Achilles tendinosis.

Platelet Rich Plasma better than Prolotherapy for Biceps Tendonitis

In an abstract published by the American Journal of Sports Medicine of a Korean language article, platelet rich plasma was found to be more effective than prolotherapy for proximal biceps tendinitis.  In the study 100 patients were studied in a case-control fashion and then followed for 12 months.  No significant differences were noted between the groups in the first months.  However, significant differences were found between the groups at 3, 6 and 12 months in visual analog pain scores, Korean Shoulder Society score, UCLA score and Constant shoulder score (p < 0.05).  The conclusion of the study was "PRP therapy is more effective treatment than prolotherapy"

The details of this study are not known.  It does provide some data to support the use of PRP for this common problem.  If anyone out there can find and translate this article it would be most helpful.  This dramatically speaks to the importance of finding these articles (in any language) and then coordinating the information for patients and providers.


AM
TotalTendon

"Comparative Studies of Platelet-Rich Plasma (PRP) and Prolotherapy for Proximal Biceps Tendintis"
Moon et al
Department of Orthopaedic Surgery; Gwangju, Korea
Journal of the Korean Orthopedic Association
Quoted in Vol. 40:6 June 2012 of the American Journal of Sports Medicine

Regenokine featured on ABC's Nightline

ABC's Nightline newsmagazine, in a story by Ron Claibourne, discussed Regenokine.  This therapy was developed in Germany and focuses on incubating blood in glass beads to concentrate an anti-inflammatory protein known as IL-1 RA.  (Long name:  Interleukin Receptor Antagonist)  It has been used to treat osteoarthritis and back pain.

The story features Tracy McGrady and how it helped him return to an elite level in the NBA after a knee injury.  Kobe Bryant, Alex Rodriguez and Fred Couples are also discussed in the story as successes.  This treatment and technology are promising but more level one evidence is needed to confirm its value.

Blood derived treatments such as this or platelet rich plasma have now been used for more than a decade with superior safety profiles.  Data continues to emerge suggesting these types of treatments have significant clinical value at a reasonable cost.

Allan Mishra, MD
@BloodCure

Shockwave Therapy and Knee Osteoarthritis

Extracorporeal shockwave therapy is the external application of high intensity sound energy.  This type of treatment has been applied to kidney stones, fractures, tendonitis and now osteoarthritis.   Two preclinical studies published today suggest this technique may be promising.

Two different models of knee osteoarthritis were utilized.  One involves cutting the ACL, the other creates a cartilage defect in the knee.  Both of these studies suggest shockwave therapy may have value in the treatment of knee osteoarthritis.  Appropriate human clinical trials still need to be conducted.


AM

Here are the two studies:

Clin Orthop Relat Res. 2012 Jun 6. 

Does Extracorporeal Shock Wave Therapy Enhance Healing of Osteochondritis Dissecans of the Rabbit Knee?: A Pilot Study.

Lyon R, Liu XC, Kubin M, Schwab J.

Conclusions

Shockwave therapy "accelerated the healing rate and improved cartilage and subchondral bone quality in the OCD (osteochondritis dissecans) rabbit model.

Link to full abstract

Journal of Surgical Research

Extracorporeal shockwave therapy shows time-dependent chondroprotective effects in osteoarthritis of the knee in rats

Ching-Jen Wang, MD

, 

Yi-Chih Sun, BS

, 

To Wong, MD

, 

Shan-Ling Hsu, MD

, 

Wen-Yi Chou, MD

, 

Hsueh-Wen Chang, PhD

• Conclusion

  "Extracorporeal shockwave therapy is effective in preventing osteoarthritis of the knee in rats. The beneficial effects of ESWT appear to be time-dependent beginning at 4 weeks after treatment."
  Link to full abstract