What are the Types of Knee Injections?

By Chris Centeno, MD /

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types of knee injections

There are several types of knee injections. Some your doctor will tell you about and some may not be discussed. My goal here is to cover everything that can be injected into your knee that may help arthritis or pain.

What are the Options?

There are many different options or types of knee injections which include:

  • Steroids (corticosteroids or cortisone)
  • Viscosupplementation (knee gel shots)
  • Prolotherapy
  • Ozone
  • Platelet-Rich Plasma (PRP)
  • Stem Cell Injections (BMC or BMAC)
  • Amniotic or Umbilical Cord Tissue
  • Microfragmented Fat (Lipogems)
  • Cytokine Enriched Plasmas (A2M or IRAP)
  • Exosomes

Regrettably, most physicians will only discuss the first two, because, at this point, that’s what’s covered by insurance, but here you’ll get all the options. Let’s dig in:

Traditional Types of Knee Injections

Steroids

These are powerful anti-inflammatory medications that can reduce swelling, also known as corticosteroids (cortisone). This is by far the most common knee injection performed worldwide to treat knee pain due to arthritis. The problem is that recent high-level research shows that they don’t work as well as we once thought and destroy normal cartilage (1). Hence, we no longer use these shots in our clinic.

Viscosupplementation

This is a fancy word for a knee gel injection. Basically, these products mimic the natural fluid (synovial fluid) that is found in the knee to provide additional cushioning and help cartilage. Different products have different weights of the chemical hyaluronic acid (HA). Brand names include Synvisc, Orthovisc, Euflexxa, and Supartz. The research on whether these injections help is all over the map at this point, meaning some studies say yes and others no (2, 3). However, overall, they seem to work for about 6 months. There is no research that says they hurt cartilage and most studies point in the direction of HA helping arthritis (4).

Newer Types of Knee Injections

Prolotherapy (Prolo)

The “prolo” in prolotherapy is short for “proliferative” which means the injection of a substance which is a chemical irritant which can kick off a healing cycle. The concept is not new but has been revived in the past 10-20 years. The injections are usually of “hypertonic” dextrose which is more concentrated than your body fluids (30).

The research on prolotherapy does show that it works reasonably well, less than PRP, but better than anesthetic or steroid injections (29). The nice thing about “prolo” is that it’s pretty cheap, usually, about half the price of a PRP shot or less. It is not, however, covered by insurance. However, animal studies show that it helps cartilage.

Ozone

Ozone is what it sounds like, the stuff that makes up the ozone layer of the atmosphere. Instead of O2 this is O3, the idea being that it can give off oxygen providing better oxygenation of the area. The machines that make ozone are not FDA approved for human use in the United States, hence this procedure is used more often in Europe than in the US.

The research on knee arthritis treatment does show good results in high-level trials (31), although PRP generally beats these outcomes (34). The treatment is often inexpensive, with a similar cost to prolotherapy. It’s not covered by insurance and we don’t have much research that shows positive effects on cartilage.

Platelet-Rich Plasma (PRP)

PRP is created by concentrating platelets from a blood draw. The platelets then release growth factors that can reduce swelling and help cartilage cells. The research on efficacy for knee arthritis is pretty good with multiple studies showing that PRP beats gel shots (5). However, this is not yet covered by insurance, with costs ranging about $1-2,000 USD per injection. One caveat is that Regenexx has been able to get coverage from large self-insured employers, but not yet major health carriers. A few auto insurances or worker’s comp carriers may also pay for PRP.

For mild knee arthritis, the injections can last about a year, but for more severe arthritis the effect is shorter (6). However, a big plus here is that this is a regenerative injection with some evidence for regenerating or helping cartilage cells (7). In addition, PRP can be used to treat tendons, which are also found around the knee and can be painful.

Stem Cell Injections

Stem cell injections are usually performed for more severe knee arthritis. There are many types, with the only US legal version being bone marrow concentrate (aka BMC or BMAC). In this procedure, the doctor takes a bone marrow aspirate from the back of the hip (PSIS area) and then concentrates the stem cell fraction of the bone marrow in a centrifuge. The research is still in it’s early stages, but our group has published the largest randomized controlled trial to date (Regenexx procedure) showing good results (8). However, another smaller RCT using a very different technique didn’t show positive outcomes (14). Other lower levels studies show positive results (18, 26, 27).  Like PRP, these procedures are not covered by insurance and tend to run 2-3 times as much as that procedure. Unlike PRP, they tend to work well for more severe arthritis patients (9). Like PRP the benefit is that research has shown that the mesenchymal stem cells in bone marrow can help cartilage repair (13). The Regenexx procedure has been able to get coverage from select employers. In addition, some worker’s comp (WC) or auto insurance carriers (auto) may provide coverage.

 Amniotic or Umbilical Cord Tissue

These therapies are all derived from birth tissues that are normally considered medical waste. The amniotic sac surrounds the baby and yields amniotic membrane/fluid and the umbilical cord connects the baby to the mother and yields umbilical cord blood and Wharton’s Jelly. These products are sold to doctors either dehydrated or frozen.

Many providers claim that these are “stem cell” therapies, but while fresh birth tissues can yield stem cells, once sourced, transported, processed, frozen, and shock thawed no MSCs survive (10-12). They do contain growth factors, but even these levels are oftentimes lower than those found in PRP. However, they may also contain unique growth factors that could help cartilage.

Right now, we have little research that these vastly different products help knee arthritis. However, some research does exist. For example, a high-level trial of ReNu (amniotic membrane) showed good short term 6-month results in knee arthritis. These procedures are not covered by insurance and are expensive. However, there is basic science data that the base materials used in some of these products may help cartilage.

Microfragmented Fat

Microfragment fat (Mfat) is what it sounds like. Doctors take fat via a mini-liposuction procedure and use a lab to process it or use a kit called Lipogems (15). This is different than a fat stem cell procedure known as SVF (Stromal Vascular Fraction) where the fat is digested, which is not legal in the US at this point, although some doctors are floating that risk (16). The early research on Mfat looks promising with some reports of improved cartilage on MRI in small studies (17). Head to head research that compares Mfat to BMC demonstrated that they both helped knee OA to the same degree (18). Like PRP, this isn’t covered by insurance and costs about the same as a BMC procedure. Also like PRP and BMC, limited insurance coverage may be available through Regenexx or WC/auto.

Cytokine Enriched Plasmas

Some of the newest orthobiologics (a term that encompasses all of these natural therapies derived from the body) are focused on concentrating natural chemicals in the blood (cytokines) that may help reduce cartilage breakdown. These include treatments like the Cytonics A2M procedure and the Orthokine or Regenokine procedure (IRAP). A2M is a natural cytokine found in your blood that has been shown in animal models to inhibit cartilage breakdown (19). IRAP (or IL-1ra) is also a cytokine that is produced by white blood cells which blocks other inflammatory chemicals in the knee (IL-1b) (21). The research on A2M is in its infancy, with no clinical trials to date, but promising animal models (20). The research on IRAP is more mature and one study showed reasonable efficacy (22). These procedures are not covered by insurance and generally run somewhere between the cost of a PRP and a bone marrow stem cell injection, but like PRP tend to work better in less severe knee arthritis.

Exosomes

One of the newest treatment options being offered to treat knee arthritis is a product called “exosomes”. These are small packets of information and cytokines released by stem cells as they grow (23). While there is some interesting lab and animal data on the concept, none of that data was collected on the actual products being sold and used in patients (24). In addition, there is no clinical data showing that this works in actual patients with knee arthritis. Finally, these procedures aren’t covered by insurance and can be very expensive, often costing as much as a bone marrow stem cell procedure.

You Need Imaging Guidance to Inject a Knee!

Do not allow a physician or other provider to inject your knee without either ultrasound or x-ray guidance, as blind injections have a significant miss rate. This means that the doctor won’t actually get the substance in your knee joint. In order to see how difficult it can be to inject a knee properly using ultrasound, see a course I taught physicians below:

What is the Best Knee Injection?

types of knee injectionsAs you can see, there are many types of knee injections and they all have pros and cons. To the right I have compared them all on typical out of pocket cost, whether there is insurance coverage, and how much research there is at this point supporting that the procedure is effective. That indicator on the dial is placed to the right for lots of research and to the left for fewer or lower quality studies.

Based on the recent research showing that steroid shots breakdown cartilage and don’t work as well as we once thought, they should be avoided. A hyaluronic acid is a reasonable option as it’s covered by insurance and doesn’t harm cartilage. PRP works better than HA in multiple studies, so if you have mild knee OA and don’t mind spending out of pocket, it’s a good bet. Knee stem cell procedures based on bone marrow seem to work better in patients with more severe arthritis and may push the need for knee replacement down the road. Finally, newer options like A2M or IRAP may also be options for less severe arthritis, but are more expensive than PRP and likely work about as well. Finally, there no data on exosomes, so I wouldn’t waste your money at this point.

The upshot? There are lots of different types of knee injections, everything from the stuff insurance covers to other things that aren’t covered. These days orthobiologics are the new kids on the block that you should consider.

______________________________________

References:

(1) McAlindon TE, LaValley MP, Harvey WF, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA.2017;317(19):1967–1975. doi: 10.1001/jama.2017.5283

(2) Rutjes AW, Jüni P, da Costa BR, et al. Viscosupplementation for Osteoarthritis of the KneeA Systematic Review and Meta-analysis. Ann Intern Med. 2012;157:180–191. doi: 10.7326/0003-4819-157-3-201208070-00473

(3) Strand V, McIntyre LF, Beach WR, Miller LE, Block JE. Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015;8:217–228. Published 2015 May 7. doi:10.2147/JPR.S83076

(4) Altman RD, Dasa V, Takeuchi J. Review of the Mechanism of Action for Supartz FX in Knee Osteoarthritis. Cartilage. 2018;9(1):11–20. doi:10.1177/1947603516684588

(5) Xing D, Wang B, Zhang W, Yang Z, Hou Y1,2, Chen Y, Lin J. Intra-articular platelet-rich plasma injections for knee osteoarthritis: An overview of systematic reviews and risk of bias considerations. Int J Rheum Dis. 2017 Nov;20(11):1612-1630. doi: 10.1111/1756-185X.13233.

(6) Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, Fornasari PM, Giannini S, Marcacci M. Platelet-rich plasma intra-articular knee injections for the treatment of degenerative cartilage lesions and osteoarthritis. Knee Surg Sports Traumatol Arthrosc. 2011 Apr;19(4):528-35. doi: 10.1007/s00167-010-1238-6.

(7) Southworth TM, Naveen NB, Tauro TM, Leong NL, Cole BJ. The Use of Platelet-Rich Plasma in Symptomatic Knee Osteoarthritis. J Knee Surg. 2019 Jan;32(1):37-45. doi: 10.1055/s-0038-1675170.

(8) Centeno C, Sheinkop M, Dodson E, et al. A specific protocol of autologous bone marrow concentrate and platelet products versus exercise therapy for symptomatic knee osteoarthritis: a randomized controlled trial with 2 year follow-up. J Transl Med. 2018;16(1):355. Published 2018 Dec 13. doi:10.1186/s12967-018-1736-8

(9) Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res Int. 2014;2014:370621. doi:10.1155/2014/370621

(10) Berger D, Lyons N, Steinmetz, N. In Vitro Evaluation of Injectable, Placental Tissue-Derived Products for Interventional Orthopedics. Interventional Orthopedics Foundation Annual Meeting. Denver, 2015. https://interventionalorthopedics.org/wp-content/uploads/2017/08/AmnioProducts-Poster.pdf

(11) Becktell L, Matuska A, Hon S, Delco M, Cole B, Fortier L. Proteomic analysis and cell viability of nine amnion-derived biologics. Orthopedic Research Society Annual Meeting, New Orleans, 2018. https://app.box.com/s/vcx7uw17gupg9ki06i57lno1tbjmzwaf

(12) Panero, A, Hirahara, A., Andersen, W, Rothenberg J, Fierro, F. Are Amniotic Fluid Products Stem Cell Therapies? A Study of Amniotic Fluid Preparations for Mesenchymal Stem Cells With Bone Marrow Comparison. The American Journal of Sports Medicine, 2019 47(5), 1230–1235. https://doi.org/10.1177/0363546519829034

(13) Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008 May-Jun;11(3):343-53. https://www.ncbi.nlm.nih.gov/pubmed/18523506

(14) Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O’Connor MI. A Prospective, Single-Blind, Placebo-Controlled Trial of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis. Am J Sports Med. 2017 Jan;45(1):82-90. doi: 10.1177/0363546516662455.

(15) Tremolada C, Colombo V, Ventura C. Adipose Tissue and Mesenchymal Stem Cells: State of the Art and Lipogems® Technology Development. Curr Stem Cell Rep. 2016;2(3):304–312. doi:10.1007/s40778-016-0053-5

(16) USFDA. Federal court issues decision holding that US Stem Cell clinics and owner adulterated and misbranded stem cell products in violation of the law. https://www.fda.gov/news-events/press-announcements/federal-court-issues-decision-holding-us-stem-cell-clinics-and-owner-adulterated-and-misbranded-stem. Last updated 06/04/2019. Accessed 9/19/19.

(17) Hudetz D, Borić I, Rod E, et al. The Effect of Intra-articular Injection of Autologous Microfragmented Fat Tissue on Proteoglycan Synthesis in Patients with Knee Osteoarthritis. Genes (Basel). 2017;8(10):270. Published 2017 Oct 13. doi:10.3390/genes8100270

(18) Mautner K, Bowers R, Easley K, Fausel Z, Robinson R. Functional Outcomes Following Microfragmented Adipose Tissue Versus Bone Marrow Aspirate Concentrate Injections for Symptomatic Knee Osteoarthritis. Stem Cells Transl Med. 2019 Jul 21. doi: 10.1002/sctm.18-0285.

(19) Rehman AA, Ahsan H, Khan FH. α-2-Macroglobulin: a physiological guardian. J Cell Physiol. 2013 Aug;228(8):1665-75. doi: 10.1002/jcp.24266.

(20) Wang S, Wei X, Zhou J, et al. Identification of α2-macroglobulin as a master inhibitor of cartilage-degrading factors that attenuates the progression of posttraumatic osteoarthritis. Arthritis Rheumatol. 2014;66(7):1843–1853. doi:10.1002/art.38576

(21) Akash MS, Rehman K, Chen S. IL-1Ra and its delivery strategies: inserting the association in perspective. Pharm Res. 2013 Nov;30(11):2951-66. doi: 10.1007/s11095-013-1118-0.

(22) Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage. 2009 Feb;17(2):152-60. doi: 10.1016/j.joca.2008.06.014.

(23) H Rashed M, Bayraktar E, K Helal G, et al. Exosomes: From Garbage Bins to Promising Therapeutic Targets. Int J Mol Sci. 2017;18(3):538. Published 2017 Mar 2. doi:10.3390/ijms18030538

(24) Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther. 2017;8(1):189. Published 2017 Aug 14. doi:10.1186/s13287-017-0632-0

(25) Kia C, Baldino J, Bell R, Ramji A, Uyeki C, Mazzocca A. Platelet-Rich Plasma: Review of Current Literature on its Use for Tendon and Ligament Pathology. Curr Rev Musculoskelet Med. 2018;11(4):566–572. doi:10.1007/s12178-018-9515-y

(26) Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res Int. 2014;2014:370621. doi:10.1155/2014/370621

(27) Centeno CJ, Al-Sayegh H, Bashir J, Goodyear S, Freeman MD. A dose response analysis of a specific bone marrow concentrate treatment protocol for knee osteoarthritis. BMC Musculoskelet Disord. 2015;16:258. Published 2015 Sep 18. doi:10.1186/s12891-015-0714-z

(28) Wu T, Dong Y, Song Hx, Fu Y, Li JH. Ultrasound-guided versus landmark in knee arthrocentesis: A systematic review. Semin Arthritis Rheum. 2016 Apr;45(5):627-32. doi: 10.1016/j.semarthrit.2015.

(29) Arias-Vázquez PI, Tovilla-Zárate CA, Legorreta-Ramírez BG, Burad Fonz W, Magaña-Ricardez D, González-Castro TB, Juárez-Rojop IE, López-Narváez ML. Prolotherapy for knee osteoarthritis using hypertonic dextrose vs other interventional treatments: systematic review of clinical trials. Adv Rheumatol. 2019 Aug 19;59(1):39. doi: 10.1186/s42358-019-0083-7.

(30) Reeves KD, Sit RW, Rabago DP. Dextrose Prolotherapy: A Narrative Review of Basic Science, Clinical Research, and Best Treatment Recommendations. Phys Med Rehabil Clin N Am. 2016 Nov;27(4):783-823. doi: 10.1016/j.pmr.2016.06.001.

(31) Lopes de Jesus CC, Dos Santos FC, de Jesus LMOB, Monteiro I, Sant’Ana MSSC, Trevisani VFM. Comparison between intra-articular ozone and placebo in the treatment of knee osteoarthritis: A randomized, double-blinded, placebo-controlled study. PLoS One. 2017;12(7):e0179185. Published 2017 Jul 24. doi:10.1371/journal.pone.0179185

(32) Farr J1, Gomoll AH, Yanke AB, Strauss EJ, Mowry KC; ASA Study Group. A Randomized Controlled Single-Blind Study Demonstrating Superiority of Amniotic Suspension Allograft Injection Over Hyaluronic Acid and Saline Control for Modification of Knee Osteoarthritis Symptoms. J Knee Surg. 2019 Sep 18. doi: 10.1055/s-0039-1696672.

(33) Marino-Martínez IA, Martínez-Castro AG, Peña-Martínez VM, et al. Human amniotic membrane intra-articular injection prevents cartilage damage in an osteoarthritis model. Exp Ther Med. 2019;17(1):11–16. doi:10.3892/etm.2018.6924

(33) Raines AL, Shih MS, Chua L, Su CW, Tseng SC, O’Connell J. Efficacy of Particulate Amniotic Membrane and Umbilical Cord Tissues in Attenuating Cartilage Destruction in an Osteoarthritis Model. Tissue Eng Part A. 2017 Jan;23(1-2):12-19. doi: 10.1089/ten.TEA.2016.0088.

(34) Shen L, Yuan T, Chen S, Xie X, Zhang C. The temporal effect of platelet-rich plasma on pain and physical function in the treatment of knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials. J Orthop Surg Res. 2017;12(1):16. Published 2017 Jan 23. doi:10.1186/s13018-017-0521-3

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6 thoughts on “What are the Types of Knee Injections?

  1. V

    Dr Centeno,
    Are the results roughly the same for shoulder treatments in relation to knee injections? Would you consider stem cell treatment more of a permanent procedure or a longer lasting results procedure in relation to healing both tissue and pain for both knee and shoulder? Thanks

    1. Chris Centeno, MD Post author

      Shoulder treatments tend to outperform the average knee treatment based on our registry data.

  2. Cindy Hellstern

    Please can you help me. I was treated in CO at your home clinic in 2013, and last week a friend from church referred me to his chiropractor for umbilical stem cell injections. After a 10 minute telephone consult he charged my cc $6k 9.18.19, for an appt for a PA to blind inject on 9.25.19 i calked this am and made appt to ask questions. At appointment, I did not like answers and asked to cancel, and he is refusing to refund. I need guidance. I am in Dallas.

  3. Richard McKay

    Is the combination of prolotherapy, stem cells, and prp a good protocol for knee injury with arthritis??

    1. Regenexx Team

      Hi Richard,
      Yes, in that order. But what’s being injected, by whom, where, when and how are also crucial. Please see: https://regenexx.com/blog/how-to-choose-the-right-stem-cell-clinic-who-what-where-when-and-how/

Chris Centeno, MD

Regenexx Founder

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications.
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