Regenerative Therapy in Pain

Nwadi Igwe; Neil Patel; Tabish Aijaz

Regenerative Therapy in Pain

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Free Review Questions

Continuing Education Activity

Regenerative medicine involves delivering cells or cell products to tissues or organs that are diseased to restore tissue or organ function. Regenerative therapy in pain medicine involves various methods, such as viscosupplementation, stem cells, platelet-rich plasma, and prolotherapy, in the treatment and management of chronic pain. This activity describes and reviews the role of the interprofessional team in Improving care for chronic pain patients who undergo regenerative therapy.

Objectives:

Identify the indications for regenerative pain medicine therapies.
Describe the technique of regenerative pain medicine therapies.
Explain the most common therapy-specific complications and adverse effects associated with regenerative pain medicine.
Outline the clinical significance of regenerative pain medicine.

Introduction

Regenerative medicine has been in existence for many decades, and many therapies have received Food and Drug Administration [FDA] approval for wound healing and orthopedic applications. Regenerative medicine is a field that applies biological science principles to promote regeneration by delivering or replacing organs, cells, or tissues in an attempt to restore diseased and damaged tissues and whole organs.[1] There are four main avenues of therapies in regenerative medicine: viscosupplementation, platelet-rich plasma, stem cells, and prolotherapy.

Viscosupplementation: Injection of hyaluronic acid (HA) into intra-articular space can restore viscosity and elasticity of osteoarthritic synovial fluid.[2][3] HA plays an essential role in shock absorption, lubrication, and the visco-elastic nature of the synovial fluid.

Prolotherapy: Prolotherapy is the injection of a solution to rehabilitate an incompetent structure and promote sclerosis at the injection site.[4][5] Prolotherapy differs from other regenerative medicine techniques because the injectate lacks a biological component. The most commonly used injectate for prolotherapy is hypertonic dextrose which causes a stimulation of the body’s inflammatory cascade.[6][5]

Platelet-rich plasma: Platelet-rich plasma [PRP] releases bioactive proteins which stimulate the body’s ability to heal due to its regenerative, analgesic, and anti-inflammatory properties.

Mesenchymal Stem Cell

According to the International Society for Cellular Therapy, the criteria for cells to be considered Mesenchymal Stem Cell [MSC] include:

Plastic adherence when maintained under standard culture
Expression of CD73, CD 90, and CD 105 and not the expression of CD11b, CD14, CD19, CD34, CD45, or HLA-DR
Ability to differentiate into osteoblasts, chondroblasts, and adipocytes in-vitro[7]

Indications

Viscosupplementation: Viscosupplementation is currently FDA-approved for the treatment of knee OA. It is indicated for patients in whom conservative therapies such as physical therapy, NSAIDs, corticosteroid injections, and aspiration fail. Elderly patients with any stage of OA are good candidates for viscosupplementation. Younger patients with mild to moderate knee OA who have clinical symptoms but are not ready for invasive surgical intervention are also good candidates. Viscosupplementation is also useful in patients with Kellgren-Lawrence stage 1 to 3. Patients with stage 4 OA who want to delay total knee replacement are ideal for viscosupplementation. It can also be used as first-line therapy in patients with multiple comorbidities who are on multiple medications to avoid the side effects of anti-arthritic drugs. It can be considered in patients who cannot take NSAIDs due to gastrointestinal or renal disease or unstable hypertension.

Prolotherapy: Indications for Prolotherapy include OA and degenerative syndromes, myofascial pain syndrome, spine, and pelvic pain, refractory tendinopathies, plantar fasciitis.[6][4][5] Some studies have shown that hypertonic dextrose promotes direct intracellular expression of growth factors in tenocytes and fibroblasts.[8]

The goal for prolotherapy is the stimulation of the body's healing process in the joint to facilitate improvement in the tensile strength of the joint stabilizing structures. Hypertonic dextrose acts by dehydrating the cells at the site of injections that causes local tissue trauma, which attracts granulocytes and macrophages to promote healing. Studies on human fibroblasts and chondrocytes have shown that extracellular dextrose concentrations result in the proliferation and production of essential growth factors for tissue repair. These growth factors promote the expression of type 1 and type 3 collagen in tenocytes which is essential for the growth of tendons, ligaments, and cartilage.[6][8]

Plasma-rich platelets (PRP): Platelet-rich plasma is currently used to treat OA, ligament injury, meniscus injury, muscle injury, tendinopathy, and spine disorders. There are numerous methods of preparing PRP. Due to variability in methods of PRP preparations, there is no universal classification system. However, PRP is mainly categorized into two classifications: leukocyte-rich PRP (LR-PRP) and leukocyte-poor PRP (LP-PRP). LR-PRP has neutrophil counts above baseline and thus is associated with pro-inflammatory effects.[9] Data suggests that LR-PRP is superior for tendinopathy, and LP-PRP is more effective for OA.[10][11]

PRP has piqued the scientific community's interest due to its various properties such as regenerative, analgesic, anti-microbial, and anti-inflammatory.[12] Platelets are nuclear, cytoplasmic fragments of megakaryocytes. The initial steps in the process of wound healing involve platelet activation, adhesion, and aggregation. After the activation phase, alpha granules in the platelets degranulate and release multiple growth factors and cytokines. PRP contains more than 300 growth factors and cytokines which are involved in cell proliferation, tissue remodeling, enhancement of mitogenesis, extracellular matrix synthesis, mesenchymal differentiation, and suppressing inflammation which play an important role in wound healing.[13]

Some of the growth factors and cytokines include PGDF-AA, TGF-B1, IGF-1, VEGF, EGF, IL-1, and many more. PRP delivers supraphysiologic concentrations of these molecules to an injury site to promote tissue remodeling, repair, and regeneration.[14]

Mesenchymal stem cells (MSCs): The indications for MSCs vary depending on the harvest site. Sources of MSCs include bone marrow, adipose tissue, umbilical cord, skeletal, muscle, peripheral blood, and amniotic fluid.[15] Specific indications for bone marrow-derived MSCs include treatment of osteonecrosis of the femoral head and OA of the shoulder. It can also be used for rotator cuff and patellar tendinopathy. Adipose-derived MSCs can be used for lateral epicondylitis and Achilles tendinopathy. Amniotic-derived MSCs can be used for plantar fasciitis.

Contraindications

Contraindications differ depending on the method of regenerative medicine that is employed. General contraindications include active infection, either systemic or at the injection site, and coagulopathy.[16] Therapy-specific contraindications include venous stasis, Hylan allergy, and allergy to eggs for viscosupplementation, as some of the products are derived from rooster combs.[17] Stem cell therapy should be avoided in patients with bone marrow-derived cancers or immunocompromised states.[18]

Absolute contraindications of PRP administrations are critical thrombocytopenia, platelet dysfunction syndrome, and hemodynamic instability. Relative contraindications include bone or blood cancer, anemia, regular NSAID use within 48 hours of the procedure, corticosteroid injection of the knee within one month, or systemic steroid use within two weeks.[19] Absolute contraindications for prolotherapy include active rheumatological disorders, corn allergy, or immunosuppressive therapy.[5]

Technique or Treatment

Viscosupplementation: HA injection can be done in the office and is usually a quick procedure typically performed under Local anesthesia. Usually, 2 to 4 ml of HA should be injected directly into the joint capsule to be effective. Patients are advised to avoid excessive weight-bearing in the first 48 hours after the injections. Physical therapy is recommended afterward to improve functioning and range of motion.

Prolotherapy: The most commonly used agent for prolotherapy is dextrose; concentrations greater than 10% are considered inflammatory, while those lower than 10% are considered noninflammatory.[6] Dextrose proliferates are approved by the FDA for injections but not for prolotherapy. Its current use for prolotherapy is off-label.

Plasma-rich platelets: PRP is obtained from the patient’s blood using the two-step centrifugation method. The first step separates whole blood into platelet and cell fractions. The second centrifugation step is performed at a higher speed. It further separates platelet growth factors. The final concentration range for the PRP product is 1.5 to 8 times the whole blood. It is usually activated by calcium chloride, bovine thrombin, or autologous thrombin.

Mesenchymal stem cells: About 60 ml of bone marrow aspirate is collected and centrifuged to produce about 6 ml of bone marrow aspirate concentrate. MSCs are multipotent and can be harvested from several tissues, e.g., bone marrow, adipocytes, and amniotic tissue. The usual location for bone marrow aspiration is the iliac crest under anesthesia due to the associated pain and discomfort with the harvest.[18]

Complications

Regenerative therapy is generally well tolerated. The most common side effects are injection site swelling, pain or soreness, or stiffness.[20][21] Therapy-specific complications include hemarthrosis, septic arthritis, seizures, pulmonary embolism, anaphylactic reaction. However, these more severe side effects are extremely rare. Stem cell therapy is very well tolerated, with most patients reporting satisfaction with the procedure. Other reported side effects include low-grade fevers.[22][23]

Complications of PRP injections are extremely rare. Since PRP is an autologous product, the chance of having an allergic or immune reaction is non-existent. The most common side effect includes local site infection and pain at the injection site. Historically, bovine thrombin serves as an activator in some commercially available PRP kits. It carries a potential risk of coagulopathy. When bovine thrombin is used as an activator, patients develop antibodies to bovine factor V and bovine thrombin itself. When factor V level decreases below 30%, the risk of hemorrhage increases in patients; for this reason, autologous thrombin or recombinant human thrombin is available as an activator.[24][25]

Rare adverse effects of prolotherapy reported include sleep disturbance, radicular pain, irregular menstruation, lumbar puncture headache. Other even rarer effects reported include meningitis, adhesive arachnoiditis, and encephalomyelitis.[26][27]

Clinical Significance

Multiple systemic reviews and meta-analyses have shown that intra-articular knee HA injections are safe, decrease pain and improve function in patients.[28][29][30][31] A Cochrane database review of 76 trials concluded that HA is a safe and efficacious option for knee OA.[32] It showed improved pain and functional status for up to 26 weeks.

Prolotherapy offers a cost-effective and conservative approach to the treatment of chronic pain. Several studies have shown the efficacy of prolotherapy for treating pain and dysfunction associated with various chronic musculoskeletal conditions, especially tendinopathies and OA. Further studies are needed to determine a standard protocol for prolotherapy injections.

PRP is currently used as a treatment modality for OA, ligament injury, meniscus injury, muscle injury, tendinopathy, and spine disorders. Multiple randomized control trials, systemic reviews, and meta-analyses have supported the use of PRP in the management of chronic tendinopathy. However, variation in PRP preparation methods, post-intervention rehabilitation protocol, and different anatomic sites translate into variation in outcomes of the studies.[33][34][35]

LP-PRP has improved pain and functional status for knee OA patients. Some studies have shown symptom relief of up to 1 year after PRP injection for knee OA. Patients in earlier stages of knee OA may benefit more from PRP than HA injections. Studies have not shown any significant benefits of PRP in treating hip OA.[36][37]

Many studies have examined the efficacy of PRP for the treatment of ligament injuries. There is promising evidence that PRP can improve anterior cruciate ligament (ACL) reconstruction outcomes.[38] Even though PRP has been used in clinical practice as a non-operative treatment for ligament injuries, a higher level of literature is scarce to prove any benefit or safety profile of PRP for ligament injuries.[39]

Low back pain is very prevalent among US adults and is one of the most common debilitating outpatient complaints.[40] Many researchers have focused on PRP as a treatment modality for low back pain associated with disc degeneration and facet joint osteoarthritis. Recent in vitro studies have shown PRP to stimulate proliferation and matrix synthesis in annulus fibrosus and nucleus pulposus. It exhibits anti-inflammatory effects on nucleus pulposus cells as well.[41][42][43]

Despite promising in-vitro results, very few high-quality clinical studies have been done to evaluate the role of PRP in the treatment of low back pain.[44][45] Multiple small-scale studies have shown PRP to be safe and beneficial in treating discogenic and facet joint-related back pain. Still, more high-quality studies are needed to prove the efficacy of PRP for spine disorders.[46][47][48]

A review of various studies involving the use of BMC in treating musculoskeletal disorders of the knee has shown level II evidence in the treatment of knee OA.[49]

Enhancing Healthcare Team Outcomes

All the regenerative therapies discussed are best administered by an interprofessional healthcare team, sharing information, keeping each other informed regarding patient status changes post-procedure, and empowered to offer their view on the case without fear of reprisal. This interprofessional approach will create the environment for optimal patient outcomes with the fewest adverse events [Level 5]

Details

References

[1]

Mao AS, Mooney DJ. Regenerative medicine: Current therapies and future directions. Proceedings of the National Academy of Sciences of the United States of America. 2015 Nov 24:112(47):14452-9. doi: 10.1073/pnas.1508520112. Epub [PubMed PMID: 26598661]

Level 3 (low-level) evidence

[2]

Henrotin Y, Raman R, Richette P, Bard H, Jerosch J, Conrozier T, Chevalier X, Migliore A. Consensus statement on viscosupplementation with hyaluronic acid for the management of osteoarthritis. Seminars in arthritis and rheumatism. 2015 Oct:45(2):140-9. doi: 10.1016/j.semarthrit.2015.04.011. Epub 2015 Apr 30 [PubMed PMID: 26094903]

Level 3 (low-level) evidence

[3]

Balazs EA, Denlinger JL. Viscosupplementation: a new concept in the treatment of osteoarthritis. The Journal of rheumatology. Supplement. 1993 Aug:39():3-9 [PubMed PMID: 8410881]

[4]

Dagenais S, Yelland MJ, Del Mar C, Schoene ML. Prolotherapy injections for chronic low-back pain. The Cochrane database of systematic reviews. 2007 Apr 18:2007(2):CD004059 [PubMed PMID: 17443537]

Level 1 (high-level) evidence

[5]

Siadat AH, Isseroff RR. Prolotherapy: Potential for the Treatment of Chronic Wounds? Advances in wound care. 2019 Apr 1:8(4):160-167. doi: 10.1089/wound.2018.0866. Epub 2019 Apr 3 [PubMed PMID: 31646060]

Level 3 (low-level) evidence

[6]

Hauser RA, Lackner JB, Steilen-Matias D, Harris DK. A Systematic Review of Dextrose Prolotherapy for Chronic Musculoskeletal Pain. Clinical medicine insights. Arthritis and musculoskeletal disorders. 2016:9():139-59. doi: 10.4137/CMAMD.S39160. Epub 2016 Jul 7 [PubMed PMID: 27429562]

Level 1 (high-level) evidence

[7]

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006:8(4):315-7 [PubMed PMID: 16923606]

[8]

Vora A, Borg-Stein J, Nguyen RT. Regenerative injection therapy for osteoarthritis: fundamental concepts and evidence-based review. PM & R : the journal of injury, function, and rehabilitation. 2012 May:4(5 Suppl):S104-9. doi: 10.1016/j.pmrj.2012.02.005. Epub [PubMed PMID: 22632688]

[9]

Dragoo JL, Braun HJ, Durham JL, Ridley BA, Odegaard JI, Luong R, Arnoczky SP. Comparison of the acute inflammatory response of two commercial platelet-rich plasma systems in healthy rabbit tendons. The American journal of sports medicine. 2012 Jun:40(6):1274-81. doi: 10.1177/0363546512442334. Epub 2012 Apr 10 [PubMed PMID: 22495144]

[10]

Fitzpatrick J, Bulsara M, Zheng MH. The Effectiveness of Platelet-Rich Plasma in the Treatment of Tendinopathy: A Meta-analysis of Randomized Controlled Clinical Trials. The American journal of sports medicine. 2017 Jan:45(1):226-233. doi: 10.1177/0363546516643716. Epub 2016 Jul 21 [PubMed PMID: 27268111]

Level 1 (high-level) evidence

[11]

Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. The American journal of sports medicine. 2014 May:42(5):1204-10. doi: 10.1177/0363546514525593. Epub 2014 Mar 14 [PubMed PMID: 24634448]

[12]

Harrison P, Cramer EM. Platelet alpha-granules. Blood reviews. 1993 Mar:7(1):52-62 [PubMed PMID: 8467233]

[13]

Coppinger JA, Cagney G, Toomey S, Kislinger T, Belton O, McRedmond JP, Cahill DJ, Emili A, Fitzgerald DJ, Maguire PB. Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood. 2004 Mar 15:103(6):2096-104 [PubMed PMID: 14630798]

[14]

El-Sharkawy H, Kantarci A, Deady J, Hasturk H, Liu H, Alshahat M, Van Dyke TE. Platelet-rich plasma: growth factors and pro- and anti-inflammatory properties. Journal of periodontology. 2007 Apr:78(4):661-9 [PubMed PMID: 17397313]

[15]

Veronesi F, Giavaresi G, Tschon M, Borsari V, Nicoli Aldini N, Fini M. Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem cells and development. 2013 Jan 15:22(2):181-92. doi: 10.1089/scd.2012.0373. Epub 2012 Nov 16 [PubMed PMID: 23030230]

[16]

Medical Advisory Secretariat. Intra-articular viscosupplementation with hylan g-f 20 to treat osteoarthritis of the knee: an evidence-based analysis. Ontario health technology assessment series. 2005:5(10):1-66 [PubMed PMID: 23074461]

[17]

Axe JM, Snyder-Mackler L, Axe MJ. The role of viscosupplementation. Sports medicine and arthroscopy review. 2013 Mar:21(1):18-22. doi: 10.1097/JSA.0b013e3182673241. Epub [PubMed PMID: 23314264]

[18]

Chahla J, Mannava S, Cinque ME, Geeslin AG, Codina D, LaPrade RF. Bone Marrow Aspirate Concentrate Harvesting and Processing Technique. Arthroscopy techniques. 2017 Apr:6(2):e441-e445. doi: 10.1016/j.eats.2016.10.024. Epub 2017 Apr 10 [PubMed PMID: 28580265]

[19]

Jain NK, Gulati M. Platelet-rich plasma: a healing virtuoso. Blood research. 2016 Mar:51(1):3-5. doi: 10.5045/br.2016.51.1.3. Epub 2016 Mar 25 [PubMed PMID: 27104183]

[20]

Dechow E, Davies RK, Carr AJ, Thompson PW. A randomized, double-blind, placebo-controlled trial of sclerosing injections in patients with chronic low back pain. Rheumatology (Oxford, England). 1999 Dec:38(12):1255-9 [PubMed PMID: 10587555]

Level 1 (high-level) evidence

[21]

Buchanan BK, DeLuca JP, Lammlein KP. Technical Innovation Case Report: Ultrasound-Guided Prolotherapy Injection for Insertional Achilles Calcific Tendinosis. Case reports in orthopedics. 2016:2016():1560161 [PubMed PMID: 27974984]

Level 3 (low-level) evidence

[22]

Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. The Journal of bone and joint surgery. American volume. 2014 Jan 15:96(2):90-8. doi: 10.2106/JBJS.M.00058. Epub [PubMed PMID: 24430407]

Level 1 (high-level) evidence

[23]

Poulos J. The limited application of stem cells in medicine: a review. Stem cell research & therapy. 2018 Jan 2:9(1):1. doi: 10.1186/s13287-017-0735-7. Epub 2018 Jan 2 [PubMed PMID: 29291747]

[24]

Zehnder JL, Leung LL. Development of antibodies to thrombin and factor V with recurrent bleeding in a patient exposed to topical bovine thrombin. Blood. 1990 Nov 15:76(10):2011-6 [PubMed PMID: 2242423]

[25]

Landesberg R, Burke A, Pinsky D, Katz R, Vo J, Eisig SB, Lu HH. Activation of platelet-rich plasma using thrombin receptor agonist peptide. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2005 Apr:63(4):529-35 [PubMed PMID: 15789326]

[26]

HUNT WE, BAIRD WC. Complications following injection of sclerosing agent to precipitate fibro-osseous proliferation. Journal of neurosurgery. 1961 Jul:18():461-5 [PubMed PMID: 13716870]

[27]

SCHNEIDER RC, WILLIAMS JJ, LISS L. Fatality after injection of sclerosing agent to precipitate fibro-osseous proliferation. Journal of the American Medical Association. 1959 Aug 8:170(15):1768-72 [PubMed PMID: 13672766]

[28]

Richette P, Chevalier X, Ea HK, Eymard F, Henrotin Y, Ornetti P, Sellam J, Cucherat M, Marty M. Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD open. 2015:1(1):e000071. doi: 10.1136/rmdopen-2015-000071. Epub 2015 May 14 [PubMed PMID: 26509069]

Level 1 (high-level) evidence

[29]

Yu FF, Xia CT, Fang H, Han J, Younus MI, Guo X. Evaluation of the therapeutic effect of treatment with intra-articular hyaluronic acid in knees for Kashin-Beck disease: a meta-analysis. Osteoarthritis and cartilage. 2014 Jun:22(6):718-25. doi: 10.1016/j.joca.2014.04.012. Epub 2014 Apr 30 [PubMed PMID: 24792210]

Level 1 (high-level) evidence

[30]

Miller LE, Block JE. US-Approved Intra-Articular Hyaluronic Acid Injections are Safe and Effective in Patients with Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized, Saline-Controlled Trials. Clinical medicine insights. Arthritis and musculoskeletal disorders. 2013:6():57-63. doi: 10.4137/CMAMD.S12743. Epub 2013 Sep 1 [PubMed PMID: 24027421]

Level 1 (high-level) evidence

[31]

Miller LE, Bhattacharyya S, Parrish WR, Fredericson M, Bisson B, Altman RD. Safety of Intra-Articular Hyaluronic Acid for Knee Osteoarthritis: Systematic Review and Meta-Analysis of Randomized Trials Involving More than 8,000 Patients. Cartilage. 2021 Dec:13(1_suppl):351S-363S. doi: 10.1177/1947603519888783. Epub 2019 Nov 16 [PubMed PMID: 31735075]

Level 1 (high-level) evidence

[32]

Campbell KA, Erickson BJ, Saltzman BM, Mascarenhas R, Bach BR Jr, Cole BJ, Verma NN. Is Local Viscosupplementation Injection Clinically Superior to Other Therapies in the Treatment of Osteoarthritis of the Knee: A Systematic Review of Overlapping Meta-analyses. Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2015 Oct:31(10):2036-45.e14. doi: 10.1016/j.arthro.2015.03.030. Epub 2015 May 19 [PubMed PMID: 25998016]

Level 1 (high-level) evidence

[33]

Peerbooms JC, Sluimer J, Bruijn DJ, Gosens T. Positive effect of an autologous platelet concentrate in lateral epicondylitis in a double-blind randomized controlled trial: platelet-rich plasma versus corticosteroid injection with a 1-year follow-up. The American journal of sports medicine. 2010 Feb:38(2):255-62. doi: 10.1177/0363546509355445. Epub [PubMed PMID: 20448192]

Level 1 (high-level) evidence

[34]

Gosens T, Peerbooms JC, van Laar W, den Oudsten BL. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. The American journal of sports medicine. 2011 Jun:39(6):1200-8. doi: 10.1177/0363546510397173. Epub 2011 Mar 21 [PubMed PMID: 21422467]

Level 1 (high-level) evidence

[35]

Krogh TP, Fredberg U, Stengaard-Pedersen K, Christensen R, Jensen P, Ellingsen T. Treatment of lateral epicondylitis with platelet-rich plasma, glucocorticoid, or saline: a randomized, double-blind, placebo-controlled trial. The American journal of sports medicine. 2013 Mar:41(3):625-35. doi: 10.1177/0363546512472975. Epub 2013 Jan 17 [PubMed PMID: 23328738]

Level 1 (high-level) evidence

[36]

Sundman EA, Cole BJ, Karas V, Della Valle C, Tetreault MW, Mohammed HO, Fortier LA. The anti-inflammatory and matrix restorative mechanisms of platelet-rich plasma in osteoarthritis. The American journal of sports medicine. 2014 Jan:42(1):35-41. doi: 10.1177/0363546513507766. Epub 2013 Nov 5 [PubMed PMID: 24192391]

[37]

Riboh JC, Saltzman BM, Yanke AB, Fortier L, Cole BJ. Effect of Leukocyte Concentration on the Efficacy of Platelet-Rich Plasma in the Treatment of Knee Osteoarthritis. The American journal of sports medicine. 2016 Mar:44(3):792-800. doi: 10.1177/0363546515580787. Epub 2015 Apr 29 [PubMed PMID: 25925602]

[38]

Orrego M, Larrain C, Rosales J, Valenzuela L, Matas J, Durruty J, Sudy H, Mardones R. Effects of platelet concentrate and a bone plug on the healing of hamstring tendons in a bone tunnel. Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association. 2008 Dec:24(12):1373-80. doi: 10.1016/j.arthro.2008.07.016. Epub 2008 Sep 30 [PubMed PMID: 19038708]

[39]

Podesta L, Crow SA, Volkmer D, Bert T, Yocum LA. Treatment of partial ulnar collateral ligament tears in the elbow with platelet-rich plasma. The American journal of sports medicine. 2013 Jul:41(7):1689-94. doi: 10.1177/0363546513487979. Epub 2013 May 10 [PubMed PMID: 23666850]

[40]

Dines JS, Williams PN, ElAttrache N, Conte S, Tomczyk T, Osbahr DC, Dines DM, Bradley J, Ahmad CS. Platelet-Rich Plasma Can Be Used to Successfully Treat Elbow Ulnar Collateral Ligament Insufficiency in High-Level Throwers. American journal of orthopedics (Belle Mead, N.J.). 2016 Jul-Aug:45(5):296-300 [PubMed PMID: 27552453]

[41]

Pirvu TN, Schroeder JE, Peroglio M, Verrier S, Kaplan L, Richards RG, Alini M, Grad S. Platelet-rich plasma induces annulus fibrosus cell proliferation and matrix production. European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 2014 Apr:23(4):745-53. doi: 10.1007/s00586-014-3198-x. Epub 2014 Jan 28 [PubMed PMID: 24469887]

[42]

Akeda K, An HS, Pichika R, Attawia M, Thonar EJ, Lenz ME, Uchida A, Masuda K. Platelet-rich plasma (PRP) stimulates the extracellular matrix metabolism of porcine nucleus pulposus and anulus fibrosus cells cultured in alginate beads. Spine. 2006 Apr 20:31(9):959-66 [PubMed PMID: 16641770]

[43]

Kim HJ, Yeom JS, Koh YG, Yeo JE, Kang KT, Kang YM, Chang BS, Lee CK. Anti-inflammatory effect of platelet-rich plasma on nucleus pulposus cells with response of TNF-α and IL-1. Journal of orthopaedic research : official publication of the Orthopaedic Research Society. 2014 Apr:32(4):551-6. doi: 10.1002/jor.22532. Epub 2013 Dec 11 [PubMed PMID: 24338609]

[44]

Levi D, Horn S, Tyszko S, Levin J, Hecht-Leavitt C, Walko E. Intradiscal Platelet-Rich Plasma Injection for Chronic Discogenic Low Back Pain: Preliminary Results from a Prospective Trial. Pain medicine (Malden, Mass.). 2016 Jun:17(6):1010-22. doi: 10.1093/pm/pnv053. Epub 2015 Dec 26 [PubMed PMID: 26814283]

[45]

Tuakli-Wosornu YA, Terry A, Boachie-Adjei K, Harrison JR, Gribbin CK, LaSalle EE, Nguyen JT, Solomon JL, Lutz GE. Lumbar Intradiskal Platelet-Rich Plasma (PRP) Injections: A Prospective, Double-Blind, Randomized Controlled Study. PM & R : the journal of injury, function, and rehabilitation. 2016 Jan:8(1):1-10; quiz 10. doi: 10.1016/j.pmrj.2015.08.010. Epub 2015 Aug 24 [PubMed PMID: 26314234]

Level 1 (high-level) evidence

[46]

Monfett M, Harrison J, Boachie-Adjei K, Lutz G. Intradiscal platelet-rich plasma (PRP) injections for discogenic low back pain: an update. International orthopaedics. 2016 Jun:40(6):1321-8. doi: 10.1007/s00264-016-3178-3. Epub 2016 Apr 12 [PubMed PMID: 27073034]

[47]

Wu J, Du Z, Lv Y, Zhang J, Xiong W, Wang R, Liu R, Zhang G, Liu Q. A New Technique for the Treatment of Lumbar Facet Joint Syndrome Using Intra-articular Injection with Autologous Platelet Rich Plasma. Pain physician. 2016 Nov-Dec:19(8):617-625 [PubMed PMID: 27906940]

[48]

Wu J, Zhou J, Liu C, Zhang J, Xiong W, Lv Y, Liu R, Wang R, Du Z, Zhang G, Liu Q. A Prospective Study Comparing Platelet-Rich Plasma and Local Anesthetic (LA)/Corticosteroid in Intra-Articular Injection for the Treatment of Lumbar Facet Joint Syndrome. Pain practice : the official journal of World Institute of Pain. 2017 Sep:17(7):914-924. doi: 10.1111/papr.12544. Epub 2017 Feb 22 [PubMed PMID: 27989008]

[49]

Manchikanti L, Centeno CJ, Atluri S, Albers SL, Shapiro S, Malanga GA, Abd-Elsayed A, Jerome M, Hirsch JA, Kaye AD, Aydin SM, Beall D, Buford D, Borg-Stein J, Buenaventura RM, Cabaret JA, Calodney AK, Candido KD, Cartier C, Latchaw R, Diwan S, Dodson E, Fausel Z, Fredericson M, Gharibo CG, Gupta M, Kaye AM, Knezevic NN, Kosanovic R, Lucas M, Manchikanti MV, Mason RA, Mautner K, Murala S, Navani A, Pampati V, Pastoriza S, Pasupuleti R, Philip C, Sanapati MR, Sand T, Shah RV, Soin A, Stemper I, Wargo BW, Hernigou P. Bone Marrow Concentrate (BMC) Therapy in Musculoskeletal Disorders: Evidence-Based Policy Position Statement of American Society of Interventional Pain Physicians (ASIPP). Pain physician. 2020 Mar:23(2):E85-E131 [PubMed PMID: 32214287]