Home Blog Bone Marrow Stem Cell Dose Matters in Knee Osteoarthritis

If theres one overarching theme in orthobiologics that I have been discussing for almost two decades, its that measuring and delivering higher doses are critical for success. Despite this, 99% of physicians who offer these procedures dont know what dose theyre delivering and use bedside kits that can only achieve low doses. Today well go into our most recent publication that shows that the stem cell dose in bone marrow concentrate is directly tied to clinical outcomes in knee arthritis patients. Lets dig in.

Our study looked at the number of colony-forming mesenchymal stem cells (CFU-fs) in bone marrow concentrate (BMC) in knee arthritis patients and then the clinical outcome of the procedure (1). We found that those patients who had more stem cells in their BMC reported better outcomes. That fits with data published by others on BMC treatments in bone disease and low back degenerative disc disease (2,3).

While this may seem like a mundane finding, its the first of its kind in BMC used for knee osteoarthritis treatment. More importantly, it highlights how important dose is in these treatments and how many BMC treatments being delivered are likely under-dosing patients. Lets dive deeper into that concept.

77 clinic locations offering non-surgical Regenexx solutions for musculoskeletal pain.

77 clinic locations offering non-surgical Regenexx solutions for musculoskeletal pain.

Youre a doctor who just started dipping his toe into the waters of this new field called orthobiologics. You buy a simple bedside kit to produce PRP because its super easy without much commitment. You then at some point add in bone marrow concentrate through the same system with a different kit. Your world is easy and simple, as all your staff needs to know is where to put the kit in the machine and where the On button is located.

However, what you begin to realize after a few years is that all of this simplicity comes at a steep price. For example, you have no idea of the dose of orthobiologic youre delivering. At its most basic, everything else in medicine is tied to a dose, so this seems wrong. In addition, independent research shows that the dose that your simple machine is capable of delivering is low and that higher doses are tied to better outcomes. Hence, at some point, it hits you like one of those clown pies in the face, youve traded simplicity for your staff for poorer patient outcomes.

PRP (Platelet-Rich Plasma) and BMC (Bone Marrow Concentrate) are autologous procedures where the dose of platelets or cells varies widely from patient to patient. This is based on many factors including:

There are other factors that also influence outcomes like where this stuff is injected and how, but today well focus only on how the dose of whats injected can dramatically change how the patient responds.

The machine the doctor buys to produce PRP and BMC matters. The problem is that this decision is often based on a relationship with a sales rep and not the concept of dose as were discussing here. Lets dig in.

Ive blogged a few times on researchers who recently published big and well-done studies, but that used commercial kits that claim to produce PRP, but instead only produce plasma which has fewer than 2 times concentrated platelets (the minimum needed to call the product PRP). These kits are are Arthrex ACP and RegenLab (7). Hence, if you were a doctor who happened to purchase one of these systems and are using this stuff, you think youre delivering PRP, but youre not.

The vast majority of machines produce low-dose PRP at a 3-5X concentration. The good news is that if youre treating young patients this is fine, but as our long-standing research on mesenchymal stem cells in culture and published work on tenocyte healing shows, for older patients this concentration represents a severe under-dose (8). Meaning that if youre middle-aged or older, the higher the dose the better, because your older cells (unlike young ones) will respond to the extra platelets. Given that this is a direct dose-response relationship in these patients, your dose cant be too high in this age group.

High-dose PRP is 7-14X with most older patients needing 10-14X or higher. Few machines can achieve this and all have trade-offs. Take the Arthrex Angel device, which can produce high-dose PRP, but at a price. Rather than producing the more commonly used leukocyte-poor PRP (LP), this machine concentrates white blood cells with platelets, so instead you get bloody and leukocyte-rich PRP (LR). Or other machines that use an off-label double spin technique where the doctor uses the same kit twice. These machines like Emcyte can get to higher concentrations, but as we have seen testing this machine in our lab, the double spin can cause the platelets to clump, distributing them unevenly in the PRP. In addition, no research or FDA clearance is available on using the kit twice, so the reliability of that double spin product is unknown.

Weve never used any of these machines because we can produce any concentration of PRP in the lab that the doctor requires and make it leukocyte poor or rich. We can also produce it from peripheral blood or a bone marrow draw if thats already being done. Whats the downside? This approach takes a bigger commitment from the practice, meaning they have to be all in on orthobiologics.

For BMC, we have seen similar issues with bedside machines. Meaning as we have tested these machines in our lab, their ability to concentrate and get the most stem cells in the smallest volume is limited. The biggest issue is the simple lack of flexibility of the input volume and a higher output volume. What does that mean?

In trying to maximize the number of stem cells in a BMC sample, you first need to be able to increase the volume of high-quality marrow aspirate taken from the patient. That starts with taking a small volume of marrow aspirate from many sites, which maximizes the number of stem cells in the sample (2-4). Regrettably, we still see physicians short-changing patients by taking one large marrow pull from the patient, which dramatically reduces the number of stem cells taken from the patient.

Next, you need the flexibility to increase the marrow aspirate volume based on the age of the patient and the number of areas treated. For example, in an older patient who may have fewer stem cells per ml of BMA, just take more BMA to compensate. This really cant happen with bedside centrifuge kits, as they have a fixed input volume. That means that you only get one option on how much marrow can be processed. Compare that to a flexible lab-based system where you easily increase the volume processed to compensate for the clinical scenario.

Finally, the output volume is critical as well. Meaning, that if you take more BMA to get more stem cells, thats useless if your system gives you a single large volume of BMC to inject. Instead, you need the highest concentration possible from your large volume and that means that the system youre using puts all of those cells in the smallest possible volume. As an example, using a lab-based system, we often take 120 ml of BMA and get that down to 3-5 ml of BMC.

Once you leave the orthobiologic training wheels behind and get a significant number of treated patients completed, whats next? Based on the existing and emerging research, thats making sure that you can deliver the highestPRP and BMC dose possible. That means leaving the bedside kit world and transitioning to a lab. No company on earth has more experience than Regenexx helping providers graduate to a flexible lab platform safely and efficiently with strict SOPs and controls.

The upshot? Dose matters. The research continues to show that the providers who can maximize the dose of platelets and stem cells are likely getting better results than those who have maximized their convenience by using limited bedside kits. Is your practice ready for an upgrade? Is it time to leave the orthobiologic training wheels behind? If so, we got you covered.

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References:

(1) Centeno CJ, Berger DR, Money BT, Dodson E, Urbanek CW, Steinmetz NJ. Percutaneous autologous bone marrow concentrate for knee osteoarthritis: patient-reported outcomes and progenitor cell content. Int Orthop. 2022 Aug 6. doi: 10.1007/s00264-022-05524-9. Epub ahead of print. PMID: 35932306.

(2)Pettine KA, Murphy MB, Suzuki RK, Sand TT. Percutaneous injection of autologous bone marrow concentrate cells significantly reduces lumbar discogenic pain through 12 months. Stem Cells. 2015 Jan;33(1):146-56. doi: 10.1002/stem.1845. PMID: 25187512.

(3) Hernigou P, Beaujean F. Treatment of osteonecrosis with autologous bone marrow grafting. Clin Orthop Relat Res. 2002 Dec;(405):14-23. doi: 10.1097/00003086-200212000-00003. PMID: 12461352.

(4) Batini D, Marusi M, Pavleti Z, Bogdani V, Uzarevi B, Nemet D, Labar B. Relationship between differing volumes of bone marrow aspirates and their cellular composition. Bone Marrow Transplant. 1990 Aug;6(2):103-7. PMID: 2207448.

(5) Muschler GF, Boehm C, Easley K. Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. J Bone Joint Surg Am. 1997 Nov;79(11):1699-709. doi: 10.2106/00004623-199711000-00012. Erratum in: J Bone Joint Surg Am 1998 Feb;80(2):302. PMID: 9384430.

(6) Fennema EM, Renard AJ, Leusink A, van Blitterswijk CA, de Boer J. The effect of bone marrow aspiration strategy on the yield and quality of human mesenchymal stem cells. Acta Orthop. 2009 Oct;80(5):618-21. doi: 10.3109/17453670903278241. PMID: 19916699; PMCID: PMC2823327.

(7) Magalon J, Bausset O, Serratrice N, Giraudo L, Aboudou H, Veran J, Magalon G, Dignat-Georges F, Sabatier F. Characterization and comparison of 5 platelet-rich plasma preparations in a single-donor model. Arthroscopy. 2014 May;30(5):629-38. doi: 10.1016/j.arthro.2014.02.020. PMID: 24725317.

(8) Berger DR, Centeno CJ, Steinmetz NJ. Platelet lysates from aged donors promote human tenocyte proliferation and migration in a concentration-dependent manner. Bone Joint Res. 2019 Feb 2;8(1):32-40. doi: 10.1302/2046-3758.81.BJR-2018-0164.R1. PMID: 30800297; PMCID: PMC6359887.

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NOTE: This blog post provides general information to help the reader better understand regenerative medicine, musculoskeletal health, and related subjects. All content provided in this blog, website, or any linked materials, including text, graphics, images, patient profiles, outcomes, and information, are not intended and should not be considered or used as a substitute for medical advice, diagnosis, or treatment. Please always consult with a professional and certified healthcare provider to discuss if a treatment is right for you.

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Bone Marrow Stem Cell Dose Matters in Knee Osteoarthritis

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