# Mesenchymal Stem Cell Applications in Spine Disorders: A Comprehensive Review
### Clinical Outcomes  
Eleven original studies on the intradiscal injection of MSCs are currently available: two randomized control trials (RCTs), eight prospective studies, and one retrospective study. One study was conducted on patients who previously underwent disectomy at the treated level [17]. All other investigations only included patients with a history of chronic lower back pain and clinical findings consistent with discogenic origin of the symptoms, with failed conservative therapy and no previous surgeries at the level of the treated disc [18; 19; 20; 21; 22; 23; 24; 25]. A summary of the included articles is presented in Table 1.  
In 2006, [PERSON] and [PERSON] [17] published the first prospective study on 10 patients (5 males and 5 females, aged 32-74 years) who underwent intradiscal injections of hematopoietic stem cells (HSCs) for discogenic back pain. All of the included patients had previously undergone endoscopic discectomy. The HSCs were obtained from the iliac crest (bone marrow aspirate), and 1 mL of HSCs was injected into the problematic disc. The treatment was followed by 2 weeks of hyperbaric oxygen therapy to improve the oxygen content of the disc space, which is known to be a district with limited blood flow. At a 12-month follow-up, none of the patients experienced an improvement of pain measured with the visual analogic scale (VAS), and 90% of the subjects proceeded with surgical treatment. The negative outcomes obtained by [PERSON] and [PERSON] potentially resided in the patient selection; all of the treated individuals underwent discectomy prior to treatment, which may have impaired the results. In fact, MSCs are not capable of recreating the nucleus pulposus once this has been extruded (e.g., due to herniation) or surgically removed, as was the case in the presented cohort [9]. Recently a retrospective study by [PERSON] et al. was published [18], reporting the results of intradiscal bone marrow-derived MSC transplantation in 33 patients (19 men, 14 women, mean age of 45 years) suffering from lower back pain. At a 52-week follow-up, positive outcomes in terms of pain and disability were observed; 39% of the patients had an improvement in the VAS of at least 50%, and 31% reported an improvement of at least 50% in the Oswestry Disability Index (ODI). The results of seven prospective studies have been analyzed in a recent meta-analysis [9]. The study included one RCT [23] and six prospective studies [20; 21; 22; 24; 25; 26]. The meta-analysis investigated data obtained from 98 patients with a mean age of 44 years. The MSCs were obtained from bone marrow aspirate in most studies, while [PERSON] et al. [20] performed transplantation from adipose derived stem cells. [PERSON] et al. performed transplantation of centrifuged bone marrow aspirate [26], while all other authors performed a culture of the harvested cells before reinjection. Overall, significant improvements in both disability and pain scores were observed at a 1-year follow-up, with the ODI improving by 21% and the VAS by 30%. [PERSON] et al. [19] successively published the 3-year follow-up of the cohort presented in 2015. At this time point, the authors observed a significant improvement in the ODI and VAS scores compared with the baseline. Six out of 26 patients underwent surgery, but only one of them reported an improvement in the clinical and functional situation in comparison with the baseline at the beginning of the study. Recently, [PERSON] et al. published the results of an RCT comparing the outcomes of the injection of different amounts of allogenic, in vitro expanded MSCs (6 and 18 million) with hyaluronic acid (HA), with the outcomes obtained with HA alone or a saline solution [11]. Of the 100 involved subjects, those in the saline solution arm presented a higher rate of necessity for post-treatment intervention than patients in the 18 million MSCs group.