Bone Marrow Stem Cell Dose Matters in Knee Osteoarthritis

If there’s one overarching theme in orthobiologics that I have been discussing for almost two decades, it’s that measuring and delivering higher doses are critical for success. Despite this, 99% of physicians who offer these procedures don’t know what dose they’re delivering and use bedside kits that can only achieve low doses. Today we’ll 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. Let’s dig in.

What Did We Find?

Our study looked at the number of colony-forming mesenchymal stem cells (CFU-f’s) 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, it’s 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. Let’s dive deeper into that concept.

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The Orthobiologics Dose Dilemma

You’re 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 it’s 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 you’re 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, you’ve traded simplicity for your staff for poorer patient outcomes.

Dose and Orthobiologics

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:

  1. The initial concentration of platelets in the blood or stem cells in the bone marrow
  2. The efficiency of the draw. This becomes a bigger issue in taking bone marrow aspirate, where the technique used by the doctor can vary the stem cell dose as much as 10X higher or lower (4-6).
  3. The handling of the sample. Here, in BMC, which anti-coagulant the doctor uses makes a huge difference in the number of cells isolated. This is based on years of internal Regenexx research.
  4. The machine and process used. Here, a simple bedside machine can produce 10X lower concentrations of platelets or stem cells compared to lab-based methods of concentration.

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

Simple Bedside Machines and Dose

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 we’re discussing here. Let’s dig in.

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Platelet-Rich Plasma

No Dose PRP

I’ve 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 you’re delivering PRP, but you’re not.

Low Dose PRP

The vast majority of machines produce low-dose PRP at a 3-5X concentration. The good news is that if you’re 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 you’re 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 can’t be too high in this age group.

High Dose PRP

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.

Lab PRP

We’ve 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 that’s already being done. What’s the downside? This approach takes a bigger commitment from the practice, meaning they have to be “all in” on orthobiologics.

Bone Marrow Concentrate

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 can’t 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, that’s 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 you’re 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.

How Does the Simple Bedside Kit You Use Dictate the Dose You Can Provide?

Once you leave the orthobiologic training wheels behind and get a significant number of treated patients completed, what’s next? Based on the existing and emerging research, that’s making sure that you can deliver the highest  PRP 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) Batinić D, Marusić M, Pavletić Z, Bogdanić V, Uzarević 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.

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. View Profile

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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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