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What are stem cells?

There are 2 types of stem cells: Embryonic and Somatic.

 close up of cells

For discussion, embryonic stem cells are from embryonic tissue grown in culture originating from donated or harvested eggs that were grown in tissue culture in a laboratory.  Our clinic does not use embryonic stem cells.

Somatic stem cells are present in each of us and have the potential to become any form of differentiated tissue. Differentiated tissue means end organ tissue like skin, cartilage, kidney, bone and others. That is how we heal.

Again, it is because of stem cells that we are able to heal after an injury.  There are many types of Somatic stem cells. Three examples are neural, hemapoietic and mesenchymal.

Neural stem cells have the potential to differentiate into differentiated nerve tissue.  They are found in the brain, spinal cord and peripheral nerves.

Hemapoietic stem cells are found in the blood.  They form blood cells that carry oxygen, fight infection and form clots.

Mesenchymal stem cells differentiate into bone, cartilage and connective tissue.  They are found in bone marrow and adipose tissue.

This information was summarized from the National Institute of Health and Euro Stem Cell websites both non-commercial sources of credible public information.

How are the stem cells harvested and used?

 Surgeons working together in surgery

Intra-articular joint stem cell injections use your blood and fat to obtain stem cells.  Each is processed in a centrifuge to concentrate the stem cells.

They are harvested in a sterile fashion, the blood from the arm and the fat usually from the abdominal wall or hip region.

The joint is prepared by antiseptic scrub.  Live x-ray, fluoroscopy, is used to guide the injection.  Local anesthesia is used to numb the injection site.  Needle placement is confirmed by x-ray.  The stem cell mixture is then injected.  Patients report a “fullness” and sometimes mild pain that settles over a few days.  After the procedure we ask patients to only partial weight bear on the treated joint for 4 weeks.  Crutches or a walker is ordered for mobility.

In the case of back pain, symptomatic discs are identified by a procedure called a discogram. Stem cells for disc injection, Intra-discal stem cells, are harvested from the bone marrow.  They are injected into the pain generating disc.

Both intra-articular and intradiscal stem cell injections take time to work.  Most patients report some changes in spine related symptoms at 3 month’s time and joint related symptoms at 7 month's time. The healing process can take up to 12 months to complete.

How does Stem Cell Therapy work?

 lab technicians working in a lab

Although not known for certain, there are separate therapeutic effects from stem cell treatment.  Stem cells themselves differentiate into cartilage cells, they exert a paracrine effect on neighboring cells, and they modulate the immune response.

After stem cells are injected, they become native tissue through a process of differentiation.  In discs and joints they become cartilage.  Normal cartilage produces collagen and proteoglycans.  These are structural components of both disc and joint.

The paracrine effect: Most people do not know about the concept of "paracrine effect".  It is a chemical signal made by cells in the body to exert a local effect on other neighboring cells.  Stem cells produce this signal which has a positive effect on the native cells. (The native cells are those already present in the degenerative disc or joint).  This results in improved function of these native cells which stimulates them to produce new collagen and proteoglycans.

The third mechanism is thought to be an anti-inflammatory one.  Immune mediators such as tumor necrosis factor and other cytokines, which are pro-inflammatory, are thought to be suppressed.

References:

Stem Cell Basics. In “Stem Cell Information” [www.stemcells.nih.gov]. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services, 2015 [cited December 13, 2015]

About stem cells” [www.eurostemcell.org] Edinburgh, Scotland: EuroStemCell, 2015 [cited December 13, 2015]

Treating the Pain Generating Disc:
What is the science behind Stem Cell Therapy?

In order to present a fair and accurate answer to this question a review of the medical and scientific literature was performed, and two review articles were found that contain extensive information about the available science. Before a summary of these articles can be discussed groundwork must be presented in order to understand this data:

Disc Anatomy and Physiology

Click image to enlarge.
A motion segment of the spine consists of two facet joints and the disc. It serves to allow bending and twisting motion. The disc height is necessary for proper facet joint spacing and adequate opening for the exiting nerve root.

In order to evaluate and understand stem cell research, you must understand basic anatomy and physiology.

The disc and pair of facet joints together are called a motion segment. The first function of the disc is to allow motion: bending, twisting, turning.

The second function of the disc is to provide a gap or space between the bony portions of the spine, the vertebral bodies. The discs of the spine function as spacers for the facet joints.  Without this spacing, motion at the facet joint would be restricted and result in facet joint arthritic changes. In fact, facet joint arthritis is a major generator of spine related pain and disability. In addition, spacing is important for the foraminal aperture necessary for the unrestricted exiting of the spinal nerves. It is this restriction that is one cause of sciatica.

 

Click image to enlarge. 
The disc has two parts: A soft, gelatinous center called "nuclear pulposus" and a tough outer shell called "annulus fibrosus."

Discs also function as shock absorbers.  They consist of two parts: The fibrous annulus surrounding the softer and deformable nucleus pulposus. The nucleus pulposus functions in a way similar to the Nike air bladder in the tennis shoe.

Discs are made up of cells and matrix.  The matrix is both structural, collagen, and viscous, proteoglycans.  Proteoglycans serve to hold water and maintain elasticity and deformability.

 

 

Click image to enlarge.
MRI findings showing normal and degenerative lumbar spine discs. Degenerative discs look black, demonstrating loss of water content. High Intensity Zone (HIZ) identifies annular disc tear. Disc shows loss of normal height.

As discs degenerate through aging or trauma they begin to lose water content.  This can be seen on an MRI scan.  They lose height and structural integrity.  This combination of factors diminish both the disc's and the motion segment's ability to perform their three functions: motion, spacing and shock absorption.

Discs contain no vascular structures and cells there depend upon diffusion for nutrition, oxygenation and elimination of waste products. This is a harsh environment for living cells. The circular faces of the vertebral bodies, the end plates, are the interface for this diffusion process. Over time the endplate can change and become fatty. This "Modic" change interferes with this diffusion process and bodes poorly for stem cell outcome. Earlier treatment before the appearance of Modic change yields best treatment results.

 


Literature Review

 lab technicians working in lab

Pettine, 2015 conducted a prospective study of 26 patients suffering lumbar degenerative disc disease treated with bone marrow derived stem cells. These patients, 11 male and 15 female ranging in age from 18 to 61 years, were followed for 24 months.  Their pre-procedure baseline and post-procedure pain level and functional status was measured using the visual analogue scale (VAS) and the Oswestry Disability Index (ODI). The results demonstrated a 72% reduction in pain and a 67% improvement in functional status. These improvements were present at the 3 month follow-up and persisted through the 24 month study period.

None of the subjects suffered a complication related to the procedure. Pain and disability were not worsened as a result of the procedure.

The authors report that five of the study participants went on to undergo surgical fusion during the 24 month study period. Of these 5 only 1 showed an improvement in pain (VAS) or function (ODI) after the surgery.

Oehme’s review article 2015 discusses Stem cell Intra-discal treatment in both animal and human studies.

In this article there were 14 separate animal studies reviewed.  In these studies, there were differences in species used, method of disc lesion generation and type of stem cells utilized.  Outcomes were measured by studying treated discs microscopically and radiographically. 

In 12 of 14 studies, (92%)  “Degeneration was slowed or reversed” by microscopic analysis.  Increased cellular matrix (proteoglycan or collagen) was demonstrated when compared to untreated controls.  Radiographic analysis demonstrated positive response in 7/14 (50%) of the studies.  Findings in these favorable studies demonstrated preservation of disc height or increased disc water content on MRI evaluation.

Oehme cites four clinical studies utilizing stem cells to treat humans.  Three of four studies (75%) cited positive results.  Positive outcomes were significant reduction in both back and radicular (sciatic or leg) symptoms.  One of the cited studies by Orozco, et al found a 90% improvement in pain reduction, resulting in decreased disability and improved quality of life.

A second review by Wang, et al 2015 published in Gene, reviewed 22 animal studies of Intervertebral Disc Degeneration treated with stem cells.  This was a meta-analysis of 642 studies that were pared down to include only those meeting strict criteria for credibility and exclusion of bias.

A meta-analysis uses statistical analysis to combine the results from multiple studies to increase the ability to draw a conclusion and to resolve uncertainty.

Of the studies included, 13 were identified to provide information on the change in disc height after treatment with stem cells. Greater disc height indicates a healthier disc.  In those studies, the disc height index was significantly better than the controls (p<.001).

Fourteen of these studies were able to be analyzed with regard to radiographic evidence of disc improvement.  Brighter signal indicates greater water content and healthier disc. MRI signal (T2 weighted images) were significantly improved in the stem cell implantation group compared to control (p <.001).

Histologic evidence (evaluation of the tissue microscopically) of disc degeneration was evaluated in 11 of these studies.  Microscopic examination of treated discs compared to control yielded significant improvement (p<.001).

Lastly, collagen expression was increased in treated discs in the 9 studies which were analyzed compared to controls (p <.001).

References:

Pettine, K., Suzki, R., Sand, T., Murphy, M., 2015. Treatment of discogenic back pain with autologous bone marrow concentrate injection with minimum two year follow-up. International Orthopaedics 2015: DOI 10.1007/s00264-015-2886-4

Oehme, D., Goldschlager, T, Ghosh, P., Rosenfeld, J., Jenkin, G., 2015.  Cell-based Therapies used to treat Lumbar Degenerative Disc disease: A systematic review of animal studies and human clinical trials.  Stem Cells Int.  2015: 946031

Wang, E., Carman, P., Smith, J., Mauck, W., Shelerud, R., Mans, T., Yang, T., Murad, M., Goy, S., Terry, M., Danttenbach, J., Pingvee, M., Eldridge, J., Nohammed, K., Benkhadra, K., Van Wijen, A., Qu, W., 2015. Efficacy of Intervertebral Disc Regeneration with Stem Cells- A systematic review and meta-analysis of animal controlled trials. Gene 564 (2015)1-8

Treating the Pain Generating Joint:
What is the science behind Stem Cell Therapy?

 therapist lifting leg of patient

Sampson 2010 studied platelet rich plasma injections in humans. Platelet rich plasma is a component of the blood containing growth factors, and anti-inflammatory cytokines that have paracrine activity in the joint environment. Growth factors stimulate stem cell attraction and activation. Although platelet rich plasma is not “stem cell”,  it works in a complementary and parallel fashion.

This study enrolled 14 patients with knee osteoarthritis. The progress was measured by evaluating pretreatment baseline and then after three platelet rich plasma injections at two, five, 11, 18, and 52 week intervals.

Outcomes were measured with the 0-10 pain scale (visual analog scale) while walking, resting, and bending the knee. Additionally, the Knee Injury and Osteoarthritis Outcome Score (KOOS) was also used to measure pain but also function and quality of life. Ultrasound was used to measure the change in cartilage thickness.

Both the symptom relief and pain relief timeline showed about 50% improvement attributable to therapy 10 to 12 weeks post platelet rich plasma injection and 100% improvement attributable to therapy at 52 weeks.

Both function and pain were both reduced about 50 percent over baseline at 52 weeks. Quality of life scales demonstrated significant improvement as well.

Ultrasound cartilage measurement at three sites within the knee demonstrated either some or no improvement in cartilage thickness but no further decrease of cartilage thickness from baseline over the 52 weeks of follow-up.

Mazor 2014 published a review article studying stem cells in cartilage repair.

Several case reports in human subjects demonstrated improved walking and reduced pain in stem cell treated knee joints. Improvements were seen in cartilage with microscopic analysis and arthroscopy.

Grassel 2014 published a review article studying the use of mesenchymal stem cells to repair chondral and osteochondral tissue.

Animal studies in pigs (3 studies), sheep (5 studies), and horses (2 studies) were reviewed. All studies demonstrated positive results and repair of cartilage defects and microscopic demonstration of repair and increased collagen production. All large animal studies reported improvement after bone marrow derived stem cell joint treatment.

Review of five human studies in subjects suffering osteoarthritis included 124 subjects yielded improvements in function, decreased pain, improved quality of life, improvements in imaging and cartilage thickness and resolution of focal cartilage defects.

Methodology varied between each study as did the type of stem cell used, the method of introducing the stem cell into the joint, and outcome measurement parameters. Overall the results indicated treatment efficacy in spite of this variability.

References:

Sampson, S., Reed, M., Silvers, H., Meng, M., Mandelbaum, B. 2010. Injection of Platelet Rich Plasma in Patients with Primary and Secondary Knee Osteoarthritis. American Journal of Physical Medicine & Rehabilitation 89:961-969

Mazor, M., Lespessailles, E., Coursier, R., Best, T., Toumi, H. 2014. Mesenchymal stem-cell potential in cartilage repair: an update. Journal of cellular and molecular medicine 18 (12) 2340-2350

Grassel, S., Lorenz, J. 2014. Tissue-engineering strategies to repair chondral and osteochondral tissue in osteoarthritis: use of mesenchymal stem cells. Current Rheumatology Reports 16 (10): 452