Platelet Rich Plasma (PRP) / Platelet Rich Fibrin Matrix (PRFM)

PRP/PRFM are injections of a concentration of a patient’s own platelets to assist with the healing of injured tendons, ligaments, muscles, and joints. PRP/PRFM injections are prepared by taking anywhere from one to a few tubes of your own blood and running it through a centrifuge to concentrate the platelets. These activated platelets are then injected directly into your injured or diseased body tissue. This releases growth factors that stimulate and increase the number of reparative cells your body produces.

Owing to the high concentrations of growth factors, this product has been extensively used in musculoskeletal disorders to modulate progression of the inflammatory process and promote healing.

Osteoarthritis is a main cause of musculoskeletal disabilities – Platelet-rich plasma could offer a more practical and accessible option of biological therapy for osteoarthritis compared to other biological therapies. Furthermore, PRFM has been shown to be even more efficacious than PRP for joint repair.

References:

https://www.sciencedirect.com/science/article/pii/S0737080619305696

AOD 9604 + HA

AOD9604 is a GH fragment which comprises the last 16 amino acids of the larger growth hormone molecule. Although originally studied for fat loss, further studies have transitioned its application for regenerative medicine. In combination with hyaluronic acid (HA), it is now being used to help regenerate hyaline cartilage and is showing strong efficacy in the treatment of osteoarthritis. 

The combination acts to enhance the differentiation of adipose mesenchymal stem cells into bone, promote proteoglycan and collagen production in chondrocytes, and promote differentiation of myoblasts into C2C12 cells; all of which are essential for bone, cartilage, and muscle repair. These studies indicate that it has stronger therapeutic benefits compared to Bone Marrow Aspirate Concentrate (BMAC) and Platelet Rich Plasma (PRP) therapy, which have also been emerging as candidates for osteoarthritis medications. AOD9604 + HA has proceeded to human WOMAC trials which allow the combination to be investigated for on an osteoarthritis index which considers pain, stiffness, and functionality on a variety of scores.

References

Summer 2015;45(4):426-32 Effect of Intra-articular Injection of AOD9604 with or without Hyaluronic Acid in Rabbit Osteoarthritis Model Dong Rak Kwon, Gi Young Park 

Alpha-2-Macroglobulin (A2M)

Alpha-2-Macroglobulin, more commonly referred to as A2M, is a master protease inhibitor that already exists in your blood and acts as a powerful inhibitor of cartilage breakdown. It is our body’s own defense mechanism.  This special molecule works by binding to proteases that degrade the cartilage cells and tissue. However, it is too big and complex to enter the joint or disc space in large enough quantities. As a result, it is necessary to inject additional concentrated A2M into the affected area to restore balance and relieve pain. A patented and proprietary filtration process has been developed that can concentrate the naturally occurring A2M molecule from a patient’s own blood. This process allows therapeutic injections in concentrated dosages that:

• Boost natural healing by reducing the additional deterioration of cartilage and inflammation
• Support tissue growth with naturally occurring compounds from your own blood

PENTOSAN POLYSULFATE

Australian researcher and physician, Dr. Peter Ghosh from the University of Sydney has brought an old drug back into the light for arthritis sufferers. The drug is called pentosan polysulfate sodium (known in medical circles as PPS). To date, trials of the drug involving human patients have been proven highly successful. As PPS eliminates pain associated with arthritic disease by acting on bone marrow lesions that cause pain and cartilage degeneration. By controlling these lesions there is a reduction in symptoms and pain.

PPS is a very safe drug and has been successfully used for 70 years to treat urinary infections in women and is FDA-approved and used for the treatment of interstitial cystitis (or painful bladder syndrome) and deep vein thrombosis. The drug is neither an anabolic steroid nor an opioid-based pain reliever so is not considered to enhance performance.

How does Pentosan work?

In osteoarthritis, pentosan reduces the destruction of cartilage by affecting inflammatory mediators. It also increases the number of proteoglycans into the extracellular matrix. Proteoglycans are important because they allow tissues like collagen to withstand compression and swelling forces. Joint cartilage also contains Proteoglycans.

In the synovium, the part that surrounds the inner lining of your joint, pentosan increases both the production and the molecular weight of hyaluronan. Hyaluran or Hyaluronic acid is a compound that occurs naturally in your body, and it is responsible for attracting and retaining moisture. Pentosan also has another anti-inflammatory function due to its fibrinolytic activity. This activity improves the blood flow not only in the synovium but also in the subchondral bone.

Recently, Paradigm Pharmaceuticals, an Australian biotech company doing studies on Pentosan had reported greater than 50% reduction in chronic knee pain by a group of osteoarthritis patients being treated with its injectable Pentosan Polysulfate Sodium drug. Researchers hope that it may work as well in relieving pain in other parts of the body.

Paradigm Biopharmaceuticals also concluded a phase 2A clinical trials of Pentosan Polysulfate to treat viral arthritis caused by mosquito-borne alphavirus infections, including the debilitating Ross River virus (RRV) and chikungunya virus (CHIKV).  The clinical trials passed both safety and efficacy measures amongst participants with chronic RRV-induced arthralgia who were treated with the injectable pentosan polysulfate sodium (PPS). At their three-month follow-up, 72.7% of the study participants treated with PPS showed near remission of symptoms in contrast to those participants who were administered with a placebo (14.3%). 

Benefits of Pentosan

• Treats bone marrow edema lesions (BMLs)
• Limiting cartilage deterioration;
• Promoting new cartilage formation;
• Thickening the joint fluid – thus acting as a better lubricant;
• Improving blood supply to the joint, in turn helping it heal;
• By virtue of these actions, it provides pain relief for a much longer period of time
• Treats all joints of the body at the same time
• Inhibits in vitro replication of HIV and other enveloped viruses

References

Kenji Kumagai, Susumu Shirabe, Noriaki Miyata, Masakazu Murata, Atsushi Yamauchi, Yasuhumi Kataoka and Masami Niwa. Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis – An open clinical trial. BMC Clin Pharmacol. 2010; 10:7. Published online 2010 Mar 28. doi: 10.1186/1472-6904-10-7. PMCID: PMC2873929. PMID: 20346179

Ghosh P, Edelman J, March L, Smith M. Effects of pentosan polysulfate in osteoarthritis of the knee: A randomized, double-blind, placebo-controlled pilot study. Current Therapeutic Research. 2005;66:552–571. doi: 10.1016/j.curtheres.2005.12.012.

Ghosh P. The pathobiology of osteoarthritis and the rationale for the use of pentosan polysulfate for its treatment. Semin Arthritis Rheum. 1999 Feb;28(4):211-67.

Takizawa M, Yatabe T, Okada A, Chijiwa M, Mochizuki S, Ghosh P, Okada Y. Calcium pentosan polysulphate directly inhibits enzymatic activity of ADAMTS4 (aggrecanase-1) in osteoarthritic chondrocytes. FEBS Letters. 2008;582:2945–2949. doi: 10.1016/j.febslet.2008.07.036.

Troeberg L, Fushimi K, Khokha R, Emonard H, Ghosh P, Nagase H. Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. FASEB J. 2008;22:3515–3524. doi: 10.1096/fj.08-112680. 

Munteanu SE1, Ilic MZ, Handley CJ. Calcium pentosan polysulfate inhibits the catabolism of aggrecan in articular cartilage explant cultures. Arthritis Rheum. 2000 Oct;43(10):2211-8.

Guangyong Ma, Jun-ichirou Yasunaga, Koichi Ohshima, Tadashi Matsumoto, Masao Matsuoka. Pentosan Polysulfate Demonstrates Anti-human T-Cell Leukemia Virus Type 1 Activities In Vitro and In Vivo. Journal of Virology Jul 2019, 93 (16) e00413-19; DOI: 10.1128/JVI.00413-19 

Lara J. Herrero, Suan-Sin Foo, Kuo-Ching Sheng, Weiqiang Chen, Mark R. Forwood, RichardBucala, Suresh Mahalingam. Pentosan Polysulfate: a Novel Glycosaminoglycan-Like Molecule for Effective Treatment of Alphavirus-Induced Cartilage Destruction and Inflammatory Disease. Journal of Virology Jul 2015, 89 (15) 8063-8076; DOI: 10.1128/JVI.00224-15

Extracellular Vesicles

Extracellular vesicles are produced by virtually every cell type as a means of intercellular communication. They contain proteins (growth factors), mRNA (blueprint for protein production) and microRNA (on-off switch for specific protein production), all contained within a membrane similar to their parent cells that protects proteins and RNA from degradation until they are delivered to the target cell. The physiologic effects of the growth factors can be used to stimulate the healing of acute and chronic wounds, regenerate collagen in aging and damaged skin, and reduce inflammation.  

Treatments using extracellular vesicles have been shown to help with optimal cartilage healing and have beneficial anti-inflammatory effects. 

References 

Ahmed N et al (2007) Soluble signalling factors derived from differentiated cartilage tissue affect chondrogenic differentiation of rat adult marrow stromal cells. Cell Physiol Biochem 20(5):665–678

Asik M et al (2008) The microfracture technique for the treatment of full-thickness articular cartilage lesions of the knee: midterm results. Arthroscopy 24(11):1214–1220

Bang OY, Kim EH (2019) Mesenchymal stem cell-derived extracellular vesicle therapy for stroke: challenges and progress. Front Neurol 10:211

Becerra J et al (2011) The stem cell niche should be a key issue for cell therapy in regenerative medicine. Stem Cell Rev Rep 7(2):248–255

Bexkens R et al (2017) Clinical outcome after arthroscopic debridement and microfracture for osteochondritis dissecans of the capitellum. Am J 

Sports Med 45(10):2312–2318

Int J Biol Sci 2020; 16(11):1811-1820. doi:10.7150/ijbs.41637 Review

Hear What We Had to Say to Jeff

Meet Jeff, in his 40s with chronic pain.

Jeff was injured ten years ago and has suffered from chronic pain ever since.  He misses biking with his buddies and is in a never ending circle of not being able to heal because he can’t exercise to get stronger.

Listen in as Dr. Yurth suggests areas that Jeff, a healthy male in his 40s,  should keep on his radar.

Hear What We Had to Say to Katie

Meet Katie, 25, with an acute injury.

Katie was having a great day skiing the bumps, and the next thing she knew, she was being brought down the mountain in a sled.

Accidents happen, but what can Katie do to make sure she not only heals quickly, but prevents re-injury and avoids chronic pain later in life?

The key to healing long term is how you deal with inflammation, blood flow, and scar tissue.  Listen in for suggestions Dr. Yurth would give Katie, or any healthy person in the age range of 20-35.