Caring Medical - Where the world comes for ProlotherapyWhy stem cell therapy did not or will not work for your knee pain – an update

Ross Hauser, MD, Caring Medical Regenerative Medicine Clinics, Fort Myers, Florida
David N. Woznica, MD, Caring Medical Regenerative Medicine Clinics, Oak Park, Illinois
Danielle R. Steilen-Matias, MMS, PA-C, Caring Medical Regenerative Medicine Clinics, Oak Park, Illinois

Why stem cell therapy did not or will not work for your knee pain

When opting for regenerative medicine injections, providers and the patients have to have a realistic idea of just how effective or non-effective these treatments can be. For some patients stem cell injections can be of great benefit in helping prevent or delay the need, long-term, for knee replacement surgery. For others, stem cell therapy results will be disappointing and non-effective.

If you are reading this article it is very likely that you are exploring stem cell therapy for your degenerative knee condition or for a loved one. You may have come across a lot of articles, even attended a seminar where a lot of information was presented, some sounding “too good to be true.”

In our clinics, while we do offer stem cell therapy, it is rare that we will use it. We feel based on nearly 27 years experience that we can achieve similar if not better and more stabile results using Prolotherapy and varying strength Platelet Rich Plasma injections.

Before we continue on with this article, we would like to refer to our published research over the years:

When we use bone marrow derived stem cells and Prolotherapy together:

Our 2014 study in the  The Open Arthritis Journal (1) we examined 24 adult patients who had a diagnosis of radiographic osteoarthritis (this was degenerative knee diseases which was seen and documented on an MRI) and had visited our chronic pain clinic in 2009 for Prolotherapy treatment to relieve their chronic pain. The results of our study have shown that a combined bone marrow stem cell Prolotherapy treatment regimen of injections to painful sites in and around the knee provided pain relief and improved joint function. The complete study and results can be read here:  Treating Osteoarthritic Joints Using Dextrose Prolotherapy and Direct Bone Marrow Aspirate Injection Therapy.

Our other published research includes:

These studies represent a small portion of our decades of experience in helping people with chronic knee pain. We believe it gives us a good standing and insight into understanding when stem cells have a very good chance of working and when stem cells may not benefit the patient more so than simple dextrose Prolotherapy injections.

Video: What type of treatment do I need?

In this video Danielle R. Steilen-Matias, MMS, PA-C, offers a brief introduction to treatments. Explanatory and summary notes are below:

Prolotherapy? Platelet Rich Plasma Therapy? Stem Cell Therapy? This is among the most common questions that we get.

A major factor in determining which treatment to get is the extent of your injury and whether this is a recent injury or a problem with degenerative joint disease or degenerative arthritis.

  • General patient type 1: Younger patient, athlete, active, or with a physically demanding job. Recent injury, such as a sprain that has not healed all the way.
    • Injury is still causing pain and discomfort.
    • This is the type of injury that does very well with dextrose Prolotherapy injections.
    • Dextrose is a sugar water that when injected into the injured joint attracts you own healing repair cells into the area to fix damaged soft tissue such as ligaments and tendons.
  • General patient type 2: Chronic problems from an “old” injury, such as a sprain that happened a few years ago,
    • Injury “never really healed,” has progressively worsened. Causing pain, discomfort.
    • Injury has not responded long-term to more conservative care options such as NSAIDS, medications, cortisone, physical therapy
    • Soft tissue damage continues, joint instability has become more permanent.
    • In this patient, it may not be enough to attract your own cells to this damaged area with Prolotherapy, in this type case we may have to put cells there by injection. Our first options would be Platelet Rich Plasma Therapy (PRP). This would put the healing factors found in your blood platelets into the damaged joint.
    • WE DO NOT offer PRP as a stand alone treatment or injection. While PRP brings healing cells into the joint, it acts to repair degenerative damage. In our experience, while PRP addresses damage deep in the joint, we must still address the joint instability problem created around the joint. We do this with Prolotherapy. Here damaged or weakened ligaments that are simply “stretched,” can be strengthened with treatment to help restore and maintain normal joint mobility.
    • Simple PRP on the inside, Prolotherapy on the outside of the joint.
  • General patient type 3: Chronic long-term degenerative problems. Possibly in need of a joint replacement
    • This is a patient who may have had degenerative joint disease for many years even decades. These are the “bone on bone people.” They have exhausted all means of conservative care, they may have had short-term success with PRP treatments, hyaluronic acid treatments, cortisone injections, but none of these are helpful anymore.
    • It is import to realize and it will be explained in this article, that it is rare that we would need to go to stem cell therapy in many of these patients. When we do recommend stem cells it would be from your own stem cell sources and mostly taken from bone marrow. We do not offer “stem cell therapy,” from donated source material.

Sometimes a patient will reach out to us and suggest, “I had one PRP injection it did not work, I definitely need stem cells.” That is not always the case. One injection of anything Prolotherapy, PRP, or stem cells, while possibly providing relief in many patients short-term, is typically not a long-term answer. This is explained below.

When someone sends us an email or comes into our office seeking answers as to why previous stem cell therapy treatments did not work for their knee pain, they want to know if joint replacement is now their only option.

These emails will typically begin with:

  • I used my own stem cells, my chiropractor told me they were too old and that is why my treatment did not work. I should have used “birth baby stem cells,” (placenta, umbilical cord blood or amniotic tissue).
  • Some realized that placenta, umbilical or amniotic tissue “stem cell therapy,” was not stem cell therapy at all and want to start all over again.
  • Some thought that one injection of stem cells provided the answer to reversing their joint erosion. That stem cell therapy is a single shot treatment like cortisone or a one time injection given as a series as in Hyaluronic acid injections. 
  • I was reading that fat stem cells were better to use and I got something else.
  • I got the fat stem cells, the procedure was so painful I had to stop treatment before I had enough treatments to fix my knee

Another answer is that for some people, knee degeneration is so far gone, is so beyond repair, that knee replacement may be the only option. In our clinics we find this type of person to be the exception and not the rule.

Degenerative knee disease does not happen overnight. Healing degenerative knee disease with stem cell therapy cannot be expected to repair decades of wear and tear as a one-time injection treatment. Failure is an over expectation of treatment.

When you have knee joint erosion and advancing knee osteoarthritis, these conditions did not happen overnight. They took a long time to develop. When your doctor shows you your knee MRI and he/she shows you no joint space, bone spurs, degenerative soft tissue damage, these things developed over time. To have someone tell you that one injection of anything, more or less randomly given somewhere in the knee, will reverse all this damage, is an extraordinary claim that requires extraordinary evidence. That evidence is not there.

Slow degenerative disease requires slow, deliberate treatment to repair. Stem cell therapy is one treatment option. Knee replacement is another. Knee replacement too is a slow methodical repair of the function of your knee requiring lengthy rehab.

If you put a patch on the hole, the patch will eventually wear away too

Stem cell therapy will often fail because stem cell clinicians think that if you injected the stem cells into the holes of the cartilage, they will instantly patch up the knee and the bone on bone situation will be gone. Maybe that will work in the short term but you still have a problem that the patch is going to be subjected to the same type of degenerative problems that caused your knee to go bone on bone in the first place. Single injection, one-time stem cell therapy only tries to patch a hole in the cartilage. The comprehensive stem cell treatment people should have explored seeks to patch a hole in cartilage and prevent it from returning by stabilizes the knee’s ligament and tendon support structure. That is done with Prolotherapy injections which we will discuss later in this article. Prolotherapy stops joint erosion.

The cartilage would have a chance to repair if the destructive motion of the knee that created the hole and the bone-on-bone situation was fixed too. That is ligament repair with Prolotherapy.

Before we get further into this discussion, people need to know that despite the best intention of a surgeon, many joint replacements do not work. Despite the best intention of conservative care, hyaluronic acid, cortisone injections, anti-inflammatory medications, and physical therapy do not always work.

  • Despite the best intention of a doctor knowledgeable in stem cell injection therapy, stem cell treatment does not always work. Nothing in medicine is 100%. This article will discuss what we believe can be done to give stem cell therapy for knee osteoarthritis the best chance of working.

A toxic knee environment kills stem cells – you must change the environment to heal

A healthy knee is surrounded by a healthy soup of nutrients and synovial fluid. The synovial fluid is a thick gel-like liquid that helps cushion the knee and acts to absorb the daily impact of walking, running and stair climbing our knees are subjected to. 

As we get older or suffer from repetitive injury or overuse syndrome, the healthy protective synovial fluid and the nutrient soup becomes poisoned with the toxins of inflammation. Why is the inflammation there? To protect against knee erosion. The obvious signs of the body’s attempt to stop the erosion and stabilize the knee and stop the damage is SWELLING. 

Inflammation is a state of emergency reacting to destructive knee joint motion

Nature created a powerful inflammatory system in all of us to act quickly, decisively and aggressively to repel disease and heal injury. You need inflammation to get over the flu, you need inflammation to heal a wound, you need inflammation to fix a damaged joint.

Inflammation is filled with oxidants and chemical stimulants that take control of the injury site and puts the area into a “state of emergency.”

As with all “States of Emergency,” the inflammation authorities take over communication, the highways and shut down secondary vital services. These are necessary actions inflammation must take to stop destructive joint motion and to reroute energy into healing (inflammation). The longer the state of emergency, (the inflammation) exists, the longer the knee swims in a toxic soup of oxidants and toxic chemicals.

A knee cannot continuously maintain a state of emergency.

What happens to the knee if it tries to continuously maintain a state of emergency and sits long-term in a toxic soup of oxidants and chemicals?

  • First, the swelling creates pressure, stiffness, and pain in the joint. This is necessary to immobilize the knee to stop the destructive forces.
  • The knee ligaments are inadvertently bathed in corrosive chemicals, they get fewer nutrients. With the swelling holding the knee together the ligaments are left unprotected and underfed, innocent casualties of inflammation war.
  • The knee’s nerves fall to the same fate unprotected and underfed, innocent casualties of inflammation war, when you feel knee pain, this is your nerves crying out.
  • The bone of the knee suffers from erosion, bone spurs begin to form to fuse or lock the knee to protect it from further bone damage.
  • The last of the great impacts is the chemical dissolving the protective articular cartilage and meniscus.

Stem cells do have the ability to change this degenerative toxic environment into a regenerative healing environment, but sometimes they can’t do it themselves

  • When stem cells are injected into this diseased joint in a state of emergency they start talking to the repair cells, the blood cells, the inflammatory cells, and the native stem cells in a “reboot” command to restart the natural healing of the joint. This comes under the phenomena of “cell signaling.” The stem cells are trying to communicate in the toxic soup.

However, the stem cells can be bogged down and the messages blurred by the toxic soup, so repair can take longer and be more challenging, if at all.

In a 2017 study, Dr. Ming Pei of West Virginia University  publishing in the medical journal Biomaterials suggests that while adult stem cells are a promising cell source for cartilage regeneration, increasing evidence indicates that environmental preconditioning is a powerful approach in promoting stem cells’ ability to resist a harsh environment such as hypoxia (the lack of oxygen) and inflammation, even that following surgery.(1)

What are examples of “environmental preconditioning?” 

  • One way is to provide more nutrients into the knee with Prolotherapy.

Paving the way for stem cell therapy success with Prolotherapy treatments

In the simplest terms, Prolotherapy is the injection of sugar water into a damaged joint. Prolotherapy injections work to heal damaged joints by stimulating nature’s healing and regenerative processes through inflammation. Prolotherapy does so by causing a controlled, specifically targeted inflammation that helps grow new ligament and tendon tissue.

Stem cell therapy is an injection of your own harvested stem cells. Stem cell therapy is typically utilized when we need to “patch” holes in cartilage and stimulate bone. We explore this option in patients when there is a more advanced osteoarthritis and a recommendation to a joint replacement has been made or suggested.

In our published research, cited earlier in this article, Ross Hauser MD, along with co-author Amos Orlofsky, Ph.D. of Albert Einstein College of Medicine were able to demonstrate and document clinical results in patients receiving bone marrow-derived stem cells and dextrose Prolotherapy.(2)

In the study above the idea is to get the stem cells ready to more efficiently heal by changing their conditioning and the joint environment by removing oxidative stress in the joint. You start this by rebooting the repair process. You fight inflammation with inflammation. Prolotherapy injections can provide that inflammation that reboots the chronic inflammation into acute inflammation. Acute inflammation is short-term.

Prolotherapy in the toxic knee environment – Prolotherapy brings oxygen and glucose that makes stem cells work

One important published paper on stem cell research from Purdue University confirmed this notion that dextrose, especially hypertonic (extra) dextrose is a significant factor in the ability of mesenchymal stem cells from bone marrow to proliferate.(3) How?

  • The cells of the body obtain their energy via aerobic metabolism. In other words, cells need to “breathe” to make their energy.
  • Stem cells cannot make energy in a toxic knee environment. They need oxygen and food.
  • The dextrose in the Prolotherapy provides both.

Now let’s talk about the ligaments

Doctors in Iran are among the leading researchers when it comes to the problems of the knee and their regenerative medicine solutions. Listen to this research from doctors at Tabriz University of Medical Sciences, publishing in the prestigious international journal Therapeutic advances in musculoskeletal disease, published in London.

In this research, doctors explored the use of simple dextrose Prolotherapy for problems of knee osteoarthritis. Here 24 female patients were followed after treatment. The results:

Prolotherapy with three intra-articular injections of hypertonic dextrose given four weeks apart for selected patients with knee osteoarthritis, resulted in significant improvement of validated pain, range-of-motion, and WOMAC-(post-treatment questionnaire based function scores), when baseline levels were compared at 24 weeks.

But while the documented success of dextrose Prolotherapy in treating knee osteoarthritis is a great validation for the treatment, the best part of the research was the acknowledgment that these doctors would have had greater success had they treated the whole knee. Listen to this, remember, the results of the study showed benefits of Prolotherapy for knee osteoarthritis:

Studies have reported that the (Prolotherapy) improvements reduce over time and sometimes the symptoms are worse after several months, which indicate the short-term effects of the treatment, similar to the injections of hyaluronic acid agents. Though post-treatment pain is not as severe as their experienced original pretreatment pain, this could suggest that these patients need several injections at intervals to keep the desired results.

Here is the extraordinary part:

“Ignoring the patient’s other pain sources including joint-surrounding tendons and ligaments could be another potential cause in this regard; we did not treat enthesopathies or the ligament fibro-osseous junctions with extra-articular dextrose injections around these elements in our study. So, it appears that ligaments or other structures need to be treated to get the full benefit from Prolotherapy.”(4)

You need to treat the whole knee. The primary reasons why Prolotherapy and stem cell therapy will not achieve the desired results? Single injection treatment plans that DO NOT address the toxic and eroding knee on the whole

This study continues and concludes with this:

“(In this study) extra-articular injection (those to the outer and surrounding ligaments and tendons)  in addition to intra-articular injection (directly into the knee meniscus and cartilage area) was not included in the research protocol.

“In other words, the first priority in our study was a focus on the damaged cartilage and not on external ligaments or tendons. However, this would be a promising method for showing the better efficacy of prolotherapy, especially for young or middle-aged patients with ligament injury, and even for elderly patients with knee osteoarthritis in whom lateral collateral ligament (LCL) damage is not uncommon.”(4)

More validation for treating the whole knee

In this study, from the Journal of pain research, doctors compared results in patients who received Prolotherapy with dextrose periarticular injections around the knee joint with patients who received Prolotherapy intra-articular injections. In other words, one group received injections around the knee joint, another group received injections directly into the knee joint.

  • Both peri- and intra-articular prolotherapy patients showed reduced pain and disability of their knee osteoarthritis after 5 months of follow-up.
  • Interestingly, periarticular prolotherapy group had better effects on pain scores and disability scores in some respects.
    • Periarticular Prolotherapy injections showed superior effects on healing of knee disability and pain score compared with intra-articular injections.
    • Pain score was significantly lower at 1-, 2-, 3-, 4-, and 5-month visits in the periarticular group compared with the intra-articular group.
    • Periarticular injections have been suggested in some recent reports for analgesic effect after total knee replacement
    • Periarticular injections can significantly reduce the requirements for patient-controlled analgesia and can improve patient satisfaction following total knee replacement.
  • Periarticular injection showed adjuvant effects to intra-articular prolotherapy.(5)

Simply, Prolotherapy for knee osteoarthritis is not a single or few injections, it is many injections. For stem cell therapy to achieve its best chance of success you need to treat the whole joint.

The evidence presented

In this article we showed how:

  • It is unrealistic in many cases to expect stem cell therapy to repair a long-damaged knee with a one shot – one time treatment
  • In our clinics, we treat the causes of joint instability (ligament damage) the lead to the knee erosion. The holes in the cartilage that create the bone-on-bone situation
  • Stem cell therapy works best as part of a comprehensive treatment program that includes dextrose Prolotherapy

Finally, most importantly, stem cells and Prolotherapy can help many people. They do not help everyone. A realistic expectation of treatments success should be made during discussions with the providers office prior consultation.

Do you want to ask about your stem cell treatment for your knees? Get help and information from our Caring Medical staff

1. Pei M. Environmental preconditioning rejuvenates adult stem cells’ proliferation and chondrogenic potential. Biomaterials. 2017 Feb;117:10-23. doi: 10.1016/j.biomaterials.2016.11.049. Epub 2016 Nov 25. [Google Scholar.]

2 Hauser RA, Orlofsky A. Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: a case series. Clinical Medicine Insights: Arthritis and Musculoskeletal Disorders. 2013 Jan;6:CMAMD-S10951. [Google Scholar]

3 Deorosan B, Nauman EA. The Role of Glucose, Serum, and Three-Dimensional Cell Culture on the Metabolism of Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cell International. 2011;  Article ID 429187, 12 pages. Doi:10.4061/2011/429187

4 Eslamian F, Amouzandeh B. Therapeutic effects of prolotherapy with intra-articular dextrose injection in patients with moderate knee osteoarthritis: a single-arm study with 6 months follow up. Therapeutic Advances in Musculoskeletal Disease. 2015;7(2):35-44. [Google Scholar]

5 Rezasoltani Z, Taheri M, Mofrad MK, Mohajerani SA. Periarticular dextrose prolotherapy instead of intra-articular injection for pain and functional improvement in knee osteoarthritis. Journal of Pain Research. 2017;10:1179-1187. [Google Scholar]


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