Combined Autologous Bone Marrow Concentrate Intraosseous and Intra-articular Injection

Mar 24, 2021
Clinical Outcomes and Safety of a Combined Autologous Bone Marrow Concentrate Intraosseous and Intra-articular Injection for
We have been using cellular therapeutics for orthopedic diseases like knee arthritis since 2006 and were among the first orthopedic surgery groups in the United States to advance the field...

Clinical Outcomes and Safety of a Combined Autologous Bone Marrow Concentrate Intraosseous and Intra-articular Injection for Knee Arthritis at 12 months

Analysis of the study by M Sheinkop et al. Journal of Regenerative Medicine 2020 

We have been using cellular therapeutics for orthopedic diseases like knee arthritis since 2006 and were among the first orthopedic surgery groups in the United States to advance the field after the work of Phillippe Hernigou MD in France and the late Dan Eglington MD in the US.

Many studies have confirmed the value of cellular therapeutics, often referred to as ‘stem cell treatments’. This paper similarly reports on the safety and efficacy of cellular therapies to treat the clinical pain syndrome associated with knee arthritis. Other very important studies by Dr. Hernigou have found improvements both clinically and on imaging studies where subchondral bone recovery and cartilage growth have been serially confirmed. (Hernigou, International Orthopedics, April 2020). The very vast majority of publications concerning treatment of OA report an intra-articular cell therapy technique. Similarly the vast majority of clinics operating under the headline of regenerative medicine do not offer subchondral bone injection or real orthopedic surgical intervention. 

Recently Chris Centeno MD, owner of the highly-publicized Regenexx® regenerative medicine clinic franchise focused on the fact that injecting the bone is the ‘new standard’ for knee arthritis stem cell therapy. We agree and have been injecting the subchondral bone since 2016. In fact, we have elaborated an entire patented treatment algorithm around our subchondral bone injection procedure. This procedure involves nanoplasty of the subchondral bone using our seventh generation technique and a mechanical axis deviation protocol, known as NAMAD® for short. 

Knee joint arthritis must be considered a whole-joint disease and is primarily a disease of the subchondral bone beneath the cartilage. Arthritis does not progress until the subchondral bone stiffens and loses its impact elasticity. This loss of elastic bony integrity progresses in a stepwise fashion beginning on the concave side of the joint, progressing to the convex side of the joint and ultimately impacts the articular cartilage.

 The authors use the Celling Biosciences ARTII Plus processor, which we also have used since 2006. While we continue to experiment with other vendors, we have consistently obtained our best cell counts with the ART II Plus. Other features including the built in backside nanofilter that allows for a custom engineered cell scaffolding are also appealing.

The ART II Plus processor is unique in that it has a built-in backside nanofilter that eliminates small molecular weight (>60kD) pro-inflammatory mediators while conserving larger, high molecular weight anti-inflammatory molecules in the platelet poor plasma (PPP) component after the isopycnic separation on the centrifuge (the spin). Platelet poor plasma contains critical anabolic and anti-infalmmatory cytokines and protein molecules that drive cellular metabolism. The processor gives the surgeon the ability to concentrate PPP to a very viscous consistency by eliminating water and unwanted pro-inflammatory molecules by size exclusion. After concentration, this scaffolding can even hold a suture in the setting of rotator cuff or other soft tissue surgical repair. Calcium chloride is often added to the mix in order to form a platelet lysate via growth factor dense granule lysis and activation of the clotting cascade. We also use the Arthrex® thrombinator when engineering our cellular scaffold to lend additional structure to the cell therapy product. This allows the subchondral injectate to remain secure in the trabecular bone of the tibial plateau following re-insertion of the obturator and removal of the Jamshidi. 

This study sets out to determine the safety and therapeutic benefit of a cell therapy technique that uses a combined intraosseous and intra articular injection strategy to combat the clinical symptoms associated with knee osteoarthritis. This study was interesting to us because it uses a similar technique to the one we have described in the past. The authors describe a dual intraosseous and intraarticular bone marrow concentrate injection which we agree with.

Arthritis begins with stiffening of the subcondral bone and loss of Young’s modulus of elasticity. Initially, the load that is typically absorbed in the subchondral bone exceeds the loading capacity of the protein cadherin and integrin networks connecting cells and matrix. Particularly in the growth plate, these signals are amplified, prompting the immune system to generate an osteoclastic resorption front to the subchondral bone. Osteoblasts follow and lay down additional bone and matrix, fully remodeling the subchondral bone to be able to withstand the loads at impact.

The tibial side of the knee joint is the concave side. The femoral side is the convex side. The convex side of the femur drives into the concave tibia and the process of tibial subchondral stiffening begins. What happens next may surprise you because it doesn’t seem intuitive until you think back to your college physics days when you learned about elastic forces and how they apply to billiard balls. When the convex side of the joint drives into the stiffening tibia, once the load can no longer be absorbed because the elasticity is gone, it is reflected back to the femoral subchondral bone where the same process occurs. Arthritis progresses in this same fashion each time. 

Once the bone is no longer able to absorb loads at impact, the loads are transferred directly to the cartilage matrix and cells, which are mechanically shortly thereafter enzymatically degraded by inflammatory cells and processes that are a function of knee lining cells. Approximately 15-20% of knee lining cells are inflammatory. These inflammatory mediators accelerate cartilage matrix degeneration. Cartilage matrix is made by the cells to provide cushion and as it wears away, the cartilage cells become exposed. Because they are weak in shear, they are ultimately denuded down to cortical bone. The end result is unopposed catabolism in the knee that is regulated by inflammatory mediators that cause knee pain. That’s why so many labs are working on drugs and smart molecules that target these cytokines and proteins.

While the authors do not state it in their study, let’s assume that their surgical targets are appropriate for the reasons we have long laid out. That means that it’s important to not just target the joint, but to also target the subchondral bone where arthritis comes from. See above to see how osteoarthritis develops. It would make sense then to target these bone lesions and to replace the catabolic, inflammatory cytokine storm that is brewing in the knee joint. We think that’s just what they have done based on the same trajectory we follow. What’s different about our approach is the product we engineer and our perioperative/postoperative approach. In addition to a specific unloading and physical therapy algorithm, we think there is a potential for dietary supplementation and low intensity pulsed ultrasound in this setting. Sermorelin has become of great interest lately and may play a role in augmenting anabolic treatments like knee cell therapy. 

The authors of the study used knee society score (KSS), lower extremity functional score (LEFS) and visual analog scoring. A visual analog is a fancy name for marking somewhere 0-10 along a line. It’s simple but it works. Visual analog scores have been validated and are accurate. We also include a visual analog scale for perceived procedure value at 1, 2 and 5 years. The authors compared patient demographics, pretreatment clinical values and bone marrow concentrate to cell composition to their results at 1 year. Outcomes for the VAS, LEFS, KSS all showed statistically meaningful improvement from pre-treatment values to 52 weeks.

There were no adverse events in the 12 months of follow up in this study. Based on the research instruments, there was meaningful improvement in mean clinical outcome from baseline to 52 weeks in all scoring systems. These improvements exceeded acceptable values for minimum clinically important difference (MCID). In the setting of higher cell counts, the KSS and the LEFS were influenced by a 10-fold increase in total nucleated cell concentration. 


This is a case series study that used validated and accurate outcomes analyses to determine the safety and efficacy at 12 months for a dual intraosseous/intraarticular autologous concentrated bone marrow cell therapy procedure in the setting of kellgren-lawrence stage 2-3 (moderate) osteoarthritis of the knee. Introsseous and intraarticular cell therapy injections appear to be a safe procedure without durable complications. Marked improvement was noted by 6 weeks and continued to the end point of the study of at least 52 weeks.

The study found improvements in the outcomes measures used and there were no adverse events reported in this small number of patients. Only total nucleated cell count (TNC) of bone marrow concentrate and pre-treatment values of the clinical outcomes of the patient-related factors assessed showed a significant correlation to the change in clinical outcome values at one year. A substantial positive increase in the KSS and decrease the visual analog score for pain correlated with a 10 fold increase in TNC. Using the numbers present it is not possible to conclude that higher cell concentrations lead to greater clinical improvement in patients. In fact it is perhaps of greatest interest that just two of the four clinical outcomes were associated with with total nucleated cell concentration in the BMC and none with the total number of cells. Participant factors showed no correlation with 52 week changes. Higher pre-treatment values on outcomes analysis led to lower outcomes scores, perhaps underscoring the need for earlier intervention.


Limitations of this study are considerable from a scientific standpoint as very few patients were included in the study and no power analysis was done to determine how many patients would be necessary to actually demonstrate statistically significant improvements in symptoms, although the authors do use general MCID to justify their conclusions that improvments were indeed clinically meaningful. Perhaps most importantly, the follow up time is too short to draw many meaningful conclusions in recommending treatment to patients, particularly because these are expensive procedures with high out of pocket costs and as with any surgery, no guarantee of success.

Treatment was not uniform in that some patients were treated for clinically diagnosed synovitis and given supplemental injections of hyaluronic acid “if they requested it”.

The authors did not make any attempt to classify subchondral bone lesions as to size or location on the tibial and or femoral side or how that related to patient based outcomes analysis. Additional study of larger patient popuations with rigorously designed scientific studies is warranted as this may represent a novel first line approach to patients being evaluated for total knee replacement indications.