Safety and tolerability of intradiscal implantation of combined autologous adipose-derived mesenchymal stem cells and hyaluronic acid in patients with chronic discogenic low back pain: 1-year follow-up of a phase I study

Abstract

Background: Adipose tissue-derived mesenchymal stem cells (AT-MSCs) offer potential as a therapeutic option for chronic discogenic low back pain (LBP) because of their immunomodulatory functions and capacity for cartilage differentiation. The goal of this study was to assess the safety and tolerability of a single intradiscal implantation of combined AT-MSCs and hyaluronic acid (HA) derivative in patients with chronic discogenic LBP.

Methods: We performed a single-arm phase I clinical trial with a 12-month follow-up and enrolled 10 eligible chronic LBP patients. Chronic LBP had lasted for more than 3 months with a minimum intensity of 4/10 on a visual analogue scale (VAS) and disability level ≥ 30% on the Oswestry Disability Index (ODI). The 10 patients underwent a single intradiscal injection of combined HA derivative and AT-MSCs at a dose of 2 × 107 cells/disc (n = 5) or 4 × 107 cells/disc (n = 5). Safety and treatment outcomes were evaluated by assessing VAS, ODI, Short Form-36 (SF-36), and imaging (lumbar spine X-ray imaging and MRI) at regular intervals over 1 year.

Results: No patients were lost at any point during the 1-year clinical study. We observed no procedure or stem cell-related adverse events or serious adverse events during the 1-year follow-up period. VAS, ODI, and SF-36 scores significantly improved in both groups receiving both low (cases 2, 4, and 5) and high (cases 7, 8, and 9) cell doses, and did not differ significantly between the two groups. Among six patients who achieved significant improvement in VAS, ODI, and SF-36, three patients (cases 4, 8, and 9) were determined to have increased water content based on an increased apparent diffusion coefficient on diffusion MRI.

Conclusions: Combined implantation of AT-MSCs and HA derivative in chronic discogenic LBP is safe and tolerable. However, the efficacy of combined AT-MSCs and HA should be investigated in a randomized controlled trial in a larger population.

Trial registration: ClinicalTrials.gov NCT02338271 . Registered 7 January 2015.

Keywords: Adipose-derived mesenchymal stem cells; Cell therapy; Hyaluronic acid; Intervertebral disc degeneration; Nucleus pulposus.

Conflict of interest statement

Authors’ information

HK is basic researcher at Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, South Korea.

D-HH is radiologist at Department of Radiology, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, South Korea.

E-JL is researcher at CHA Biotec®, Seongnam-si, Gyeonggi-do, South Korea.

JHP and JHS are neurosurgeons at Department of Neurosurgery, Shim Jeong Hospital, Seoul, South Korea.

T-KA is orthopedic surgeon at Department of Orthopedic Surgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, South Korea.

K-TK is neurosurgeon at Department of Neurosurgery, Kyungpook National University Hospital, South Korea.

AER is neurosurgeon at Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.

SS and I-BH are neurosurgeons at Department of Neurosurgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, South Korea.

C-HK is plastic surgeon at Department of Plastic and Reconstructive Surgery, CHA University, CHA Bundang Medical Center, Seongnam-si, Gyeonggi-do, South Korea.

DKT is researcher at Anioplex LLC, Campbell, CA, USA.

S-HL is researcher at Department of Biomedical Science, CHA University, Seongnam-si, Gyeonggi-do, South Korea.

Ethics approval and consent to participate

The study protocol was approved by the institutional review boards and ethics committees of CHA Bundang Medical Center (BD2013-158, December 2013). The study was also approved by the Ministry of Food and Drug Safety of South Korea (MFDS, 1403-6583-4849-0120, June 2014). Written informed consent was obtained from all study subjects.

Consent for publication

All of the authors consent to publishing the paper in Stem Cell Research and Therapy.

Competing interests

The authors declare that they have no competing interests.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Measurement of the apparent diffusion coefficient (ADC) in lumbar degenerated discs. Mid-sagittal T2-weighted images were chosen and a region of interest (ROI, 50 mm2) placed in the central half of each disc. Sagittal fast spin echo (FSE) T2-weighted images (a) and diffusion-weighted images (DWI) with b factors of 0 (b) and 500 s/mm2 (c). ROI in the T2-weighted image copied to the ADC map from the DWI at the same level (d)

Fig. 2

Visual analogue scale (a) and Oswestry Disability Index (b). Six patients (cases 2, 4, 5, 7, 8, and 9) presented an effective reduction in pain and ODI (≥50% improvement of VAS and ODI compared with pretreatment) at 12 months

Fig. 3

Assessment of disc degeneration grade using T2-weighted MRI. Sagittal T2-weighted images (a, pre treatment) show increased signal intensity of the L4/5 intervertebral disc from IV to III at 6 months (b) and 12 months (c), suggesting an increase of water content (case 1)

Fig. 4

Possible causes of treatment failures in cases 3 and 6. Lumbar lateral X-ray imaging (a), T2 sagittal MRI (b), and T2 axial MRI (c) of case 3 showing degenerative spondylolisthesis of L4 on L5 (slippage or displacement of L4 vertebra compared to L5 vertebra) and spinal stenosis. T2 sagittal MRI (d) and T2 axial MRI (e) of case 9 revealed left-sided L4–5 herniated NP with decreased disc height