Ross Hauser, MD

In this article, we will examine the research and the clinical application of stem cell therapy for articular cartilage repair.

Case Histories: Bone marrow stem cell therapy in patients with knee and hip osteoarthritis

Stem cell therapy can be confusing to many patients because there are many services being offered as stem cell therapy. The most common are:

• Bone Marrow derived stem cell therapy
• Adipose (Fat cells) derived stem cell therapy

Both of these treatments are stem cells from you.

There are also stem cell therapies that are not really stem cell therapies. These are:

• Amniotic stem cell therapy, which some are now more appropriately calling: Amniotic Membrane Injections
• Placenta stem cell therapy, which some are now more appropriately calling: Placenta Tissue Injections

Many emails that come into our office ask us to compare the various forms of stem cell therapies. We have a very extensive series of articles discussing the different types of injections for knee pain. You can see that article here: The different types of knee injections. In addition to stem cell therapy, we talk about cortisone, Hyaluronic acid injections, Platelet Rich Plasma Therapy, Botox injections into the knee, and ozone therapy

Young stem cells versus old stem cells

Most of the emails we get are from people who have recently attended a seminar or a webinar in which they were introduced to the idea that a newborn baby was willing to donate his/her amniotic fluid or cord blood or placenta afterbirth material to them to replace the patients own old or weakened stem cells. The use of this donated material is not stem cell therapy as there has not been shown by any credible research that there are actual live stem cells in the treatment. This is discussed further in our article on “amniotic stem cell therapy.” So while these treatments may help some people, and we have seen people who responded positively to these injections, no matter what is in them, we will concentrate this article on bone marrow aspirate concentrate or as we call it bone marrow Prolotherapy. This treatment refers to the use of bone marrow concentrate injections into areas of degenerative joint disease to stop and repair degenerative changes. The use of bone marrow aspirate relies on the action of stem cells to initiate and guide this joint repair.

A December 2020 study published in the journal Knee surgery, sports traumatology, arthroscopy (15) evaluated the effectiveness of intra-articular injections of bone marrow derived mesenchymal stem cells for the treatment of knee osteoarthritis. The study’s authors wrote: “Pre-clinical studies have demonstrated successful, safe and encouraging results for articular cartilage repair and regeneration. . . Subsequently, clinical applications of intra-articular injections of bone marrow derived mesenchymal stem cells (BM-MSCs) are steadily increasing, with most studies demonstrating a decrease in poor cartilage index, improvements in pain, function and Quality of Life; with moderate-to-high level evidence regarding safety for therapeutic administration.”

Mayo Clinic and Yale University studies on your own bone marrow stem cells

Doctors at the Mayo Clinic and Yale University published their research on the benefits of Bone Marrow Aspirate Concentrate for Knee Osteoarthritis in the American Journal of Sports Medicine. (1) Here is the summary of that research:

• Bone marrow aspirate concentrate (BMAC) is increasingly used as a regenerative therapy for musculoskeletal pathological conditions despite limited evidence-based support.
• HYPOTHESIS: Bone marrow aspirate concentrate will prove feasible, safe, and efficacious for the treatment of pain due to mild to moderate degenerative joint disease of the knee.

In their single-blind, placebo-controlled trial, 25 patients with bilateral knee pain from bilateral knee osteoarthritis were randomized to receive Bone marrow aspirate concentrate into one knee and saline placebo into the other.

• Early results show that Bone marrow aspirate concentrate is safe to use and is a reliable and viable (stem cell) cellular product. Study patients experienced a similar relief of pain in both Bone marrow aspirate concentrate- and saline-treated arthritic knees.

“The current literature demonstrates the potential benefits of utilizing concentrated bone marrow aspirate.”

Doctors in New Jersey at the Department of Orthopedic Surgery, Jersey City Medical Center published their findings in support of this research, in the World Journal of Orthopedics,(2) here is what the paper said:

“The current literature demonstrates the potential benefits of utilizing concentrated bone marrow aspirate for the repair of cartilaginous lesions, bony defects, and tendon injuries in the clinical setting.

The studies have demonstrated using concentrated bone marrow aspirate as an adjunctive procedure can result in cartilage healing similar to that of native hyaline tissue, faster time to bony union, and a lower rate of tendon re-rupture.”

In a 2015 study, (3) which is heavily cited by other research papers, doctors announced their findings in patients who received bone marrow stem cell therapy in the hip, knee, and ankle for treatments of osteoarthritis. All seventeen patients in the study exhibited therapeutic benefits such as increased walking distance, increased function, and reduced pain.”

Doctors publishing in the Journal of Clinical Orthopaedics and Trauma (4) cited this research among others in saying

• “The versatility of mesenchymal stem cells (MSCs) as a treatment modality has landed it another repair target: osteoarthritis, a crippling cartilage disease that frequently afflicts the aged population. Through many studies, this newly discovered method has been shown to significantly alleviate the pain experienced by osteoarthritic patients. “

Doctors at Georgia Regents University wrote in the Clinical and Translational Medicine (5) in support of the above research:

• “Current pharmacological treatment strategies are ineffective to prevent the osteoarthritis progression; however, cellular therapies have the potential to regenerate the lost cartilage, combat cartilage degeneration, provide pain relief, and improve patient mobility. One of the most promising sources of cellular regenerative medicine is from mesenchymal stem cells.”

What are Bone marrow concentrate injections?

Using stem cells taken from a patient’s bone marrow is becoming a therapy of interest due to the potential of these mesenchymal stem cells to differentiate into other types of cells such as bone and cartilage.

Bone Marrow is the liquid spongy-type tissue found in the hallow (interior) of bones. It is primarily a fatty tissue that houses stem cells that are responsible for the formation of other cells. These mesenchymal stem cells (MSC), also called marrow stromal cells, can differentiate (change) into a variety of cell types including osteoblasts (bone cells), chondrocytes (cartilage cells), myocytes (muscle cells), adipocytes (fat), fibroblasts (ligament and tendon) and others when reintroduced into the body by injection. Bone marrow also contains hematopoietic stem cells that give rise to the white and red blood cells and platelets.

Stem cell therapy is a controversial treatment. In some instances, unrealistic expectations and claims may be made in how beneficial this treatment can be. Stem cell therapy does help many people. It does not help everyone. Please see our articles:

• Do stem cell therapy for knee meniscus tears and post-meniscectomy work?
• When stem cell therapy works and does not work for your knee pain

In our office, we focus on bone marrow aspirate or “bone marrow stem cell therapy.” This is will be discussed below.

I am “bone on bone.” “My mom is bone on bone.” “My dad is bone on bone.”

The predominant number of emails we get are from someone who has bone on bone knee or bone on bone hip, or, their aging parents are in a lot of pain and they do not want them to go through the joint replacement surgery. The obvious goal of the treatment that these people or the adult children of aging parents is the avoidance of a knee replacement or hip replacement by growing back the “missing” cartilage.

These are the questions we get:

My 78-year-old mother

• My mother is 78 years old. She has bone on bone in both knees and has been told for years that she needs both knees replaced. She still does not want the surgery. Can stem cells help her?

In these types of questions, we do an initial screening to make a realistic assessment of who stem cell therapy can and cannot help. Stem Cell therapy can help someone who has some normal range of motion in their knee or hip or shoulder.

What are we seeing in this image?

At our center, we use different types of regenerative medicine injections to help restore and repair damaged joints. Not everyone is a good candidate for treatment and in these cases, they would be advised to continue with the possibility of joint replacement. In other cases, because of pre-existing medical conditions or other factors that make surgery impossible, we tell the patients of the realistic expectation of how much these treatments can help.

While this article focuses on stem cell therapy we use the same guidelines in discussing the realistic expectation that Prolotherapy injections with simple dextrose will help as stem cell therapy or Platelet Rich Plasma injections.

In this image, we see a poor candidate’s hip. What makes them a poor candidate? They have severe degeneration of the right hip. They have lost all the joint space and have developed bone spurs throughout the hip. This patient had severely limited range of motion and was unable to flex or bend the hip to 90 degrees or internally rotate it at all. Due to these factors, this patient was rated as a poor candidate for injection treatment.

What are we seeing in this image?

On the scale of poor-fair-good-excellent candidates for treatment, this knee was assessed as a fair candidate for treatment. The reason is that this person had lost nearly all her cartilage at the outer edge of the knee. She also had a limited range of motion on physical examination. She did however have a successful treatment that helped improve her quality of life. This is not the case for all fair candidates but successful treatment is usually for typical treatment that fails.

What are we seeing in this image?

On the scale of poor-fair-good-excellent candidates for treatment, this shoulder was assessed as a good candidate for treatment. The reason is that this shoulder has maintained a good overall architecture. Simple this means that this shoulder still looks like a shoulder. Degenerative shoulder disease and bone spurs have not altered the shoulder’s natural appearance or function, yet. Most importantly, even with pain, the patient had a full range of motion in their shoulder.

Does stem cell therapy regrow cartilage?

So let’s now return to the original question. Does stem cell therapy regrow cartilage? The answer is yes, but we must have a realistic expectation of how much, how fast, and how effective this can be. The treatment will not work for everyone with poor candidates having a less than likely successful outcome.

How does stem cell therapy regrow cartilage? Researchers are not sure.

In early 2017, doctors writing in the medical journal Stem Cells International (6) wrote that “Although the role of stem cells in cartilage regeneration is certain, the mechanism underlying this process in cartilage repair is not yet clear. The full range of limitations and possibilities, with respect to clinical application of various stem cells, remains to be established, but the advantages of stem cells seem obvious.”

What does all this mean? 

• Stem cells in cartilage regeneration are certain – it has been proven to work.
• Not all applications of stem cells work, please see Ross Hauser’s, MD article – Why didn’t stem cell therapy work for my knee pain?

July 2020 (7) built on this research to suggest: “Full-thickness cartilage defects if left alone would increase the risk of osteoarthritis with severe associated pain and functional disability.  . . The capability of the mesenchymal stem cells to repair and regenerate cartilage has been widely investigated. . .Several studies have demonstrated promising results in the clinical application for repair of chondral defects as an adjuvant (during surgery in some cases) or independent procedure. Intra-articular (mesenchymal stem cells (MSCs)  provide improvements in pain and function in knee osteoarthritis at short-term follow-up in many studies.

The Conclusion of this paper: “Some efficacy has been shown of mesenchymal stem cells (MSCs) for cartilage repair in osteoarthritis; however, the evidence of the efficacy of intra-articular MSCs on both clinical outcomes and cartilage repair remains limited. Despite the high quality of evidence to support, MSC therapy has emerged but further refinement of methodology will be necessary to support its routine clinical use.”

In other words: It works for many people, not all, there needs to be a refinement in the treatment’s application to make it more successful for more people.

The “certain” ability of stem cell therapy to regenerate articular cartilage has been documented by a series of landmark studies published over the more than last two decades.

In a 1994 landmark study (8) from the Department of Orthopaedics, Case Western Reserve University School of Medicine, University Hospitals of Cleveland, doctors found that osteochondral progenitor cells (in simple terms stem cells that accelerate and enhance bone and articular cartilage repair) could be used to repair large, full-thickness defects of the articular cartilage that had been created in the knees of rabbits.

Of note:

• As early as two weeks after the initial treatment, the autologous (cells used were from the same animal) osteochondral progenitor cells had uniformly differentiated (remodeled themselves) into chondrocytes (cartilage cells) throughout the defects.
• At twenty-four weeks after treatment, the subchondral bone was completely repaired, without loss of overlying articular cartilage.

The researchers concluded: The current modalities (in 1994 knee cartilage surgery and conservative care, medications, and painkillers) for the repair of defects of the articular cartilage have many disadvantages. The transplantation of progenitor (stem) cells that will form cartilage and bone offers a possible alternative to these methods.

In 2014, Dr. Shinya Yamasaki who lead the above-cited 1994 study twenty years earlier, lead another study, (9) this time from the Department of Orthopaedic Surgery, Sinshu University School of Medicine, Japan.

In this study again, the doctors found that there is no widely accepted method to repair articular cartilage defects. Bone marrow mesenchymal cells have the potential to differentiate into bone, cartilage, fat, and muscle. Bone marrow mesenchymal cell transplantation is easy to use clinically because cells can be easily obtained and can be multiplied without losing their capacity of differentiation. The objective of this study was to apply these cell transplantations to repair human articular cartilage defects in osteoarthritic knee joints.

In a heavily cited 2003 study (10) from Osiris Therapeutics in Baltimore, doctors reported significant improvement in the medial meniscus and cartilage regeneration with autologous stem cell therapy in an animal model. Not only was there evidence of marked regeneration of meniscal tissue, but the usual progressive destruction of articular cartilage, osteophytic remodeling, and subchondral sclerosis (hardening of the bone beneath the cartilage) commonly seen in the osteoarthritic disease was reduced in MSC-treated joints compared with controls.

Part of the excitement was the discovery that stem cells could control various healing mechanisms that enabled articular cartilage repair. This includes the capability to inhibit T cell growth, thus showing that they have the ability to down-regulate the natural inflammatory response in osteoarthritis.

In addition to stem cells’ capacity to both differentiate into new cartilage cells as well as suppress inflammation, recent studies have found that stem cells can also combat osteoarthritis through paracrine mechanisms. They release important cytokines such as epidermal growth factor (EGF), transforming growth factor-beta (TGFB), vascular endothelial growth factor (VEGF), as well as other cytokines and new cartilage proteins that are essential in combating osteoarthritis and degenerative processes. It has also been suggested that stem cells could release cytokines and proteins that could help combat neurogenic pain, which would have numerous benefits in treating osteoarthritis pain.

Our Research: Caring Medical published studies

Regenerative Injection Therapy with Whole Bone Marrow Aspirate for Degenerative Joint Disease: A Case Series

In this study, we suggested that to make stem cell therapy’s ability to regrow cartilage more effective, a supportive treatment, Prolotherapy, injections of simple dextrose, should be considered. This is explained further below and demonstrated in the videos of this article. In our paper we noted:

• An alternative approach to regenerative therapy is the injection of substances or cells that may support chondrogenesis (regrowth of cartilage) by enhancing the availability of
  pro-chondrogenic microenvironmental factors. One such therapy is prolotherapy, in which the joint is injected with an irritant substance such as hyperosmolar dextrose or sodium morrhuate that may act as a proliferant via the induction of local inflammatory and wound healing cascades.
  • What we are suggesting is that the cartilage repair of stem cell therapy would be enhanced if we could strengthen and repair the ligaments and soft tissue of the joint that allowed the degenerative process to begin in the first place. Prolotherapy has decades of documented research in this matter. Please see our Prolotherapy research article.

This was a case history study. These are the cases we presented:

Right ankle pain – Stem Cell Treatment alone

Case 1: A 59-year-old female with a history of three years of right ankle pain. The patient was unable to walk more than 30 feet without severe ankle pain and had to stop all weight-bearing recreational activities. Cortisone therapy had been unsuccessful and ankle fusion had been recommended. Based on X-ray and MRI findings, the patient was diagnosed with osteoarthritis, avascular necrosis of the talus, and synovitis.

• The patient received four bone marrow stem cell treatments over a period of eight months.
  • At the second treatment, the patient reported the ability to stand for long periods and walk for half a mile without pain.
  • A third treatment, she reported improved range of motion, less frequent pain, and ability to take two-mile walks on hilly, uneven ground, although steep
    climbs still induced pain.
  • These gains were maintained throughout the treatment period.

Pain in Both Knees – Stem Cell Treatment alone

Case 2: A 69-year-old male with pain in both knees. In his left knee, he reported pain of 4/10 and a 30% frequency of what that pain occurred. His right knee was worse. He reported a 7/10 pain scale and a 90% frequency. The pain almost all the time.

• The patient was diagnosed with osteoarthritis and received five bone marrow stem cell treatments in both knees at two-month intervals.
  • In an interview conducted two months after the final treatment, the patient reported that he was completely free of pain or stiffness in both knees, had regained full range of motion, no longer suffered sleep interruption, and was no longer limited in exercise or daily life activities.

Pain in Both Hips – Stem Cell Treatment alone

Case 3: A 76-year-old woman with pain in both hips. Worse on the left side. She was unable to walk more than a mile without significant pain. The patient had received a recommendation for hip replacement.

• X-rays revealed moderate to severe bilateral degenerative changes in the hips, including osteophyte formation, subchondral sclerosis, and joint space narrowing, with the left side more
  affected than the right. Degenerative changes of the lower lumbar spine were also noted. At the first visit, pain intensity was 6/10 and pain frequency 60%.
  • The patient received seven bone marrow stem cell treatments in both hips.
  • Over a period of 12 months and adhere to a program of daily bicycle exercise. She reported incremental improvements in pain and function at each visit.
  • At the final visit the patient reported pain intensity of 4/10 and pain frequency of 20%, and described significant gains since the onset of treatment with respect to a range of motion, resumption of exercise, reduced crepitus, and reduction of pain medication use by two thirds. She reported her overall improvement as 90%.

Pain in Both Knees and Right Hip – Stem Cell Treatment alone

Case 4: A 56-year-old female had pain in both knees and right hip. The pain was severe in the right knee, with frequent crepitus (cracking, crunching) and instability, and had forced the patient to discontinue running.

• MRI with a previous physician had shown cartilage degeneration. The hip pain prevented sleep on the affected side, she stopped bicycle exercise and walking exercise was limited to three miles. MRI with a previous physician showed a labral tear. The patient was diagnosed with hip osteoarthritis and labral tear, and bilateral knee osteoarthritis.
  • The patient received treatments at 8–10 week intervals.
    • At visits 1 and 2, the right knee and right hip were treated with bone marrow stem cell treatments.
    • At visits 3 and 4, both knees and right hip were treated with bone marrow stem cell treatments. The patient reported modest (20%–35%) overall improvement following these treatments.
    • At the final two visits, bilateral knees and right hip were treated with bone marrow stem cell treatments. During the treatment period, the left hip was also treated for pain resulting from a flexor injury incurred following visit 1.
    • Two months after visit 6, the patient reported 65%–95% overall improvement for the three joints. She is able to walk for two hours, no longer has disturbed sleep, and
      has been able to resume bicycle exercise with minimal discomfort. The patient still experiences intermittent soreness in a small region in the medial aspect of the
      right patella.

Case presentations: Stem Cell Therapy and Prolotherapy combined

Case 5: A 56-year-old man with bilateral knee pain. The patient is a former competitive weightlifter who continues to do strength training exercises. He complained of instability in both knees during exercise, as well as sleep interruption.

• The patient received 29 bilateral dextrose prolotherapy treatments over five years. At the final prolotherapy visit, sleep interruption was still present, pain intensity was 4/10, and pain frequency was 100%. Four months later, the patient was treated with platelet-rich plasma. Three months after plasma treatment, the patient began a series of three bone marrow stem cell injection treatments (without dextrose prolotherapy) at 2–3 month intervals. A
• At the time of the second bone marrow stem cell treatment, stability was improved.
• At the time of the third treatment, pain intensity was 2/10, and pain frequency was 30%. Sleep was no longer affected.
  These gains were maintained for nine months.

Case 6: A 69-year-old female came into our office with pain in both knees.

She had been previously diagnosed with osteoarthritis, had arthroscopic surgery to both knees eight years earlier, and medial meniscus repair in both knees 15 years earlier.

The patient reported pain occurred climbing or descending stairs and with standing or walking for two hours. Pain interrupted sleep and limited participation in racquet sports and golf.

The patient received six treatments in both knees with dextrose prolotherapy over a ten-month period.

• After the first month of this period, the patient reported uninterrupted sleep, pain intensity of 2/10, resumption of limited golf, and an overall improvement of 50%–55%.

One year after the final prolotherapy, pain intensity had returned to 4/10 with a frequency of 20%, and sleep interruption had resumed. At this time, the patient received the first of two bone marrow stem cell injection/dextrose treatments, five months apart.

• At the time of the second treatment, pain intensity was 1/10 with a frequency of 20%, sleep interruption was reduced by half, and patient-reported overall improvement was 90%.
• Eight months following the final bone marrow stem cell injection/dextrose treatment, the patient reported being free of pain and able to resume full participation in all of her usual athletic activities.

Case 7: A 63-year-old male came into our office with pain in both hips.

The patient received five treatments with dextrose prolotherapy in both hips over a period of 5 months. During this period, the patient reported an overall improvement of 50%; however, this reduced to 30%–40% at the conclusion of the treatment period, at which time pain intensity was 6/10 increased but with less frequency.

Crepitus, previously absent, was now marked. At this point, the patient began a series of two bone marrow stem cell injection/dextrose treatments two months apart.

At the time of the second treatment, pain intensity reduced. Crepitus was reduced. Specific pain manifestations previously noted, including ischial tuberosity pain and lateral hip pain, had abated, and the patient reported being able to walk without a cane for the first time in years.

Two months after the second bone marrow stem cell injection/dextrose treatments, pain intensity was 1/10 with a frequency of 10%. The patient reported walking without a limp and no longer needing a cane.

More research: Treating Osteoarthritic Joints Using Dextrose Prolotherapy and Direct Bone Marrow Aspirate Injection Therapy

Dextrose and stem cells

Hauser R, Eteshola E. Rationale for using direct bone marrow aspirate as a proliferant for regenerative injection therapy (prolotherapy). The Open Stem Cell Journal. 2013;4:7-14. (14)

In this research Ross Hauser MD found: Initial observations using whole bone marrow injections in conjunction with dextrose prolotherapy for treatment of osteoarthritic joints suggest that the procedure is safe and effective. Treatment courses of less than 12 months are associated with substantial gains in pain relief and functionality. Read Full Article

Highlights of this study:

• The major goal of stem cell therapy is the stimulation of regenerative processes in the joint that will facilitate the restoration of degenerated cartilage to a healthy state.
• One approach to regenerative therapy is to supply affected joints with either autologous chondrocytes (cartilage building cells from you – cartilage transplant) or chondrogenic bone marrow-derived mesenchymal stem cells (also from you from your bone marrow).

We are going to bring in research and an important published paper from Purdue University to help understand and confirm the notion that dextrose, especially hypertonic (extra) dextrose is a significant factor in the ability of mesenchymal stem cells from bone marrow to proliferate. (15)

Simply, the researchers took stem cells and glucose and put them in an experimental situation. The experiment was to see how varying levels of glucose affected stem cell numbers (proliferation).  What the experiment found was that mesenchymal stem cell consumption of glucose increased proportionally with the glucose concentration in the medium. The more glucose, the more the stem cells ate, the more the stem cells multiplied.

In summary, hypertonic dextrose in published studies helps stem cell proliferation in vitro (in cultures.)  While this is important, more important is what it does in the human body.  We have written numerous studies on hypertonic dextrose Prolotherapy and stem cells and feel the results speak for themselves.

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