PM&R News   •   May 2020

Lumbago, or lower back pain, is a chronic pain condition thought to effect up to 80% of adults older than 18 according to certain observational studies. One systematic review of prospective cohort studies revealed a lifetime prevalence of more than 70% for lower back pain. One of the prominent etiologies contributing to lumbago is degenerative disc disease. Contributions to spine and disc degeneration can be multivariable and include age related changes, trauma, nutrition, and hereditary components. When comparing prevalence in spine degeneration with age in asymptomatic patients aged 30-80 disc degeneration was found in 52% vs 96% respectively. The lumbar discs are, statistically, the most likely to undergo degenerative changes. The lumbar disc is comprised of three main components: the nucleus pulposus, annulus fibrosis, and the cartilaginous endplates. The discs, in particular in the lumbar region, undergo significant loading and tensile forces during physical activity. As these forces are distributed via the annulus and endplates, it is no surprise that, over time, these are the most likely places to undergo force related pathology such as annular tears and micro-fractures in the cartilaginous endplates. There is an acute pain phase resulting from the release of arachidonic acid and its subsequent conversion into inflammatory mediators and prostaglandins. Yet, beyond the acute phase are the chronic disc changes resulting in continued stimulation of the nociceptive receptors located in the annulus. Additionally, degeneration of the discs has thought to be nutrition-related. Aging results in a decrease of nutritional permeability gradient at the end plates along with decreases in the blood supply and consequent disc dessication. Considering that the intervertebral discs are neurologically innervated anteriorly and laterally from the gray ramus commnicans and posteriorly from the sinuvertebral nerve, it becomes clear that these pathological disruptions in the tissue can be significant sources of lower back related pain. One must also consider the fact that degeneration of the discs has been thought to be the catalyst leading to secondary degeneration of the surrounding spinal elements leading to a larger number of potential pain generators in those with lower back pain.

The diagnostic imaging of choice in evaluating discogenic pathology is a non-contrast magnetic resonance imaging. This is preferable due to the more detailed visualization of soft tissue elements that comprise the disc components. Procedures can be implemented in order to discern whether pain is discogenic-related such as discography or discogram. This is a procedure in which contrast medium is injected into the nucleus pulposus. A normal disc can receive between 1 and 1.5 mL of contrast. If greater than 2 mL of contrast is injected, then degenerative disc disease is likely. Additionally, during the provocative injection procedure, localization of pathologic disc degeneration (i.e., nucleus or annulus tears, fissures, or disc protrusion) can be confirmed if pain is reproduced.

Studies have shown approximately 90% of people who develop acute LBP experience a resolution of the symptoms within 6 weeks. For the patients whose pain continues well beyond this window and is refractory to more conservative measures (such NSAIDs, physical therapy, dry needling) intra-disc injections of autologous, minimally manipulated mesenchymal stem cells are being investigated as a viable option for pain relief and disc repair due to their regenerative and restorative properties. Historically, other intra-disc interventions have been implemented with varying degrees of success in differing populations. Some examples of these are intradiscal oxygen-ozone (O ₂ -O ₃ ) chemonucleolysis (used specifically for neural compressions secondary to bulging or herniated disc and intra-discal steroid injections (whose use is debated due to risk of discitis development). The versatility of their application and potential use in degenerative processes, as well as their level of safety has resulted in MSCs being a subject of intense interest, research, and interventional application in the last few decades. The International Society for Cellular Therapy defines MSCs as 1) adhering to plastic in standard culture; 2) phenotypically expressing CD105, CD73, and CD90, and lacking expression of CD45, CD34, CD14 or CD11b, CD79-alpha or CD19, and human leukocyte antigen DR surface molecules; and 3) being capable of differentiating into osteoblasts, adipocytes, and chondroblasts in vivo. In the office-based clinical setting, MSCs are prepared following tissue harvest via centrifugation and separation of MSC-dense fluid that is subsequently injected into the autologous therapeutic target, including but not limited to joint, tendon, cartilage, or intervertebral discs. Multiple studies have shown the efficacy of MSC therapy in treating disk degeneration. The main action of this treatment is to focus on repopulating the IVD (intra-vertebral disc) with cells that have the capability of reproducing the extracellular matrix in the nucleus pulposus and restoring tissue that had been damaged. While a myriad of studies exist that strongly   demonstrate that transplantation of culture-expanded autologous MSCs into the nucleus of degenerated discs slowed the degenerative process and improved annular integrity, they are mostly in animal models. There is less current evidence demonstrating efficacious effect in humans with randomized controlled trials. While the evidence is not robust in volume, there are quality studies that exists and offer auspicious promise.

Smaller clinical studies like Pettine et al (2015), Mochida et al (2015), and Gou et al (2014) involving human patients that came to show favorable results and good safety of intra-discal MSC injections. One large case series (Centeno et all, 2017) examined the efficacy of an injection of autologous culture-expanded MSCs into the intervertebral disc and annulus of DDD patients with radicular symptoms and a posterior disc bulge. There were no serious adverse events (i.e. death, infection, or tumor) associated with the procedure. Numeric pain score change scores relative to baseline were significant at 3, 36, 48, 60, and 72 months post-treatment. The average modified SANE ratings showed a mean improvement of 60% at 3 years post-treatment. Functional rating index post-treatment change score averages exceeded the minimal clinically important difference at all time points except 12 months. Twenty of the patients treated underwent post-treatment MRI and 85% had a reduction in disc bulge size, with an average reduction size of 23% post-treatment

In another extended study by Elabd et al (2016), 5 patients that were diagnosed with degenerative disc disease and underwent intradiscal injectins of autologous, hypoxic cultured, BMDA MSCs in a previous study were re-consented and followed up 4-6 years after their treatment. They were physically examined, imaged with lumbar MRI, and responded to a quality of life questionnaire. The patients’ lower back MRI showed absence of neoplasms or abnormalities surrounding the treated region. Based on the physical examination and the quality of life questionnaire, no adverse events were reported due to the procedure or to the stem cell treatment 4–6 years post autologous, hypoxic cultured mesenchymal stem cell infusion. All patients self-reported overall improvement, as well as improvement in strength, post stem cell treatment, and four out of five patients reported improvement in mobility.

One study incorporating intra-discal injection of bone marrow aspirate derived mesenchymal stem cells (Pettine 2015) included 26 patients and used BMAC (bone marrow aspirate concentrate) alone; average counts were delineated into colony-forming unit fibroblasts and colony-forming unit and utilized fluoroscopic guidance [42]. The average age of patients (range) with symptomatic moderate to severe discogenic low back pain was 38 (18– 61) years. The outcome was measured by the Oswestry Disability Index (ODI) and VAS. A significant percent improvement in clinical scores was seen (VAS decreased 64.6%, 64.2%, and 58.0% at three, six, and 12 months, respectively; P<0.001; and ODI decreased 58.1%, 55.5%, and 56.8% at three, six, and 12months, respectively; P<0.001). In total, 21/26 patients had significant clinical improvement by ODI and VAS, and additionally eight of 20 patients demonstrated rehydration of their discs by MRI. The average improvement in MRI scoring (Pfirrmann score) per disc injected was 0.27; however, this did not reach statistical significance.

Additionally, systematic review from Wei et al provided a comprehensive outlook of recent advances in stem cell therapy that are directed toward treating disk degeneration that suggests that mesenchymal stem cells (MSCs) are effective in vitro for the treatment of disk degeneration as well as promoting cell survival following transplantation. There are many more animal and in vivo studies showing great promise for this type of therapy. However, overall I have noted that relatively few studies have been published regarding the efficacy of stem cells as a regenerative therapy in patients subjected to disk degeneration. I was not able to locate any randomized control trials that compare stem cell therapy with other treatments such as surgical intervention for IDD. Yet, as noted above, I was able to review studies that analyzed the regeneration of the IVD in comparison with neutral controls.

The horizon is, ostensibly, wide open with regards to future management of DDD using autologous mesenchymal stem cells. While DDD-related lower back pain has traditionally been treated with conservative measures, as well as surgical intervention, these stem cell intra-discal injections are considered an emerging option. They have certainly been proven very safe and effective in the current studies. The advancement of this treatment will be dependent on more studies with larger population size, in particular randomized control trials comparing efficacy to other interventional and surgical approaches.  

Contributing Author:  Thomas Fincke, MD

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