Elsevier

Cytotherapy

Volume 21, Issue 1, January 2019, Pages 54-63
Cytotherapy

Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: a pilot study

https://doi.org/10.1016/j.jcyt.2018.11.003Get rights and content

Abstract

Objective

Knee osteoarthritis (OA) is a common skeletal impairment that can cause many limitations in normal life activities. Stem cell therapy has been studied for decades for its regenerative potency in various diseases. We investigated the safety and efficacy of intra-articular injection of placental mesenchymal stem cells (MSCs) in knee OA healing.

Methods

In this double-blind, placebo-controlled clinical trial, 20 patients with symptomatic knee OA were randomly divided into two groups to receive intra-articular injection of either 0.5–0.6 × 108 allogenic placenta-derived MSCs or normal saline. The visual analogue scale, Knee OA Outcome Score (KOOS) questionnaire, knee flexion range of motion (ROM) and magnetic resonance arthrography were evaluated for 24 weeks post-treatment. Blood laboratory tests were performed before and 2 weeks after treatment.

Results

Four patients in the MSC group showed mild effusion and increased local pain, which resolved safely within 48–72 h. In 2 weeks post-injection there was no serious adverse effect and all of the laboratory test results were unchanged. Early after treatment, there was a significant knee ROM improvement and pain reduction (effect size, 1.4). Significant improvements were seen in quality of life, activity of daily living, sport/recreational activity and decreased OA symptoms in the MSC-injected group until 8 weeks (P < 0.05). These clinical improvements were also noted in 24 weeks post-treatment but were not statistically significant. Chondral thickness was improved in about 10% of the total knee joint area in the intervention group in 24 weeks (effect size, 0.3). There was no significant healing in the medial/lateral meniscus or anterior cruciate ligament. There was no internal organ impairment at 24 weeks follow-up.

Conclusion

Single intra-articular allogenic placental MSC injection in knee OA is safe and can result in clinical improvements in 24 weeks follow-up. Trial registration number: IRCT2015101823298N.

Introduction

As life expectancy increases, age-related diseases will become a serious concern. According to the World Health Organization (WHO) report 2002, osteoarthritis (OA) is the fourth leading cause of disability worldwide with a burden mostly attributed to arthritis of hips and knees [1]. According to multiple resources including the Framingham Osteoarthritis Study, National Health and Nutrition Examination Survey (NHANES) III and the Johnston County Osteoarthritis Project, 26.9 million people aged >25 years in the United States have experienced at least one form of OA up until 2005 [2]. Knee pain has a high prevalence in the Asian region [3] and is the most common musculoskeletal symptom in Iran [4], [5].

OA is a progressive joint degenerative disorder that involves all structures of a joint, such as hyaline cartilage, subchondral bone and synovium, and can results in subchondral sclerosis, cyst or osteophyte formation and synovitis. All joints of the human body, especially the weight-bearing joints, can be affected in a multifactorial background, including genetics and environmental factors [6].

Recommended OA treatments based on American College of Rheumatology guidelines include both non-pharmacological (activity modification, patient education, physical therapy modalities, exercises, assistive devices, weight loss, splints) and pharmacological modalities (acetaminophen, oral and topical nonsteroidal anti-inflammatory drugs, tramadol, intra-articular corticosteroid injections) [7]. Despite the substantial prevalence of OA, a 2-year follow-up in comparison with placebo reported no approved medical treatments such as glucosamine, chondroitin sulphate, combinations thereof and celecoxib for reversing cartilage degeneration [8]. The conventional treatment is considered mainly to impede the disease process and minimize disability and pain, but not to regenerate the joint structures. Unsuccessful medical treatment may lead to surgical interventions as standard final approaches with considerable side effects, such as mortality [9], persistent postsurgical pain [10] and patient dissatisfaction [11]. Moreover, arthroscopic surgery for moderate to severe knee OA provides no additional benefit to optimized physical and medical therapies [12].

Cell therapy for treating OA has been studied for about two decades. Although the efficacy of autologous chondrocyte transplantation in cartilage defect reconstruction has been proven, efficacies remain questionable due to reported donor site morbidity, downregulation of chondrocytes with fibrocartilage formation and not being fully evaluated in end-stage OA [13]. The important practical considerations for clinical application of mesenchymal stem cells (MSCs) that may alter their regenerative potential are as follows: (i) cell source (autologous/allogenic), (ii) dose (from thousands to millions of MSCs), (iii) delivery system (arthroscopic or surgical MSC scaffold transplantation/intra-articular MSC injection), (iv) number of injections and (v) MSC combined injection with co-stimulators (platelet-rich plasma [PRP], hyaluronic acid [HA] or growth factors) [13], [14].

MSCs can be harvested from different tissues of the human body (e.g., bone marrow [BM], adipose tissue [AT] and placental/umbilical cord tissue). Safe clinical applications of MSCs have been reported in non-hematologic [15], and hematologic disorders [16]. MSCs have remarkable potential for differentiating into chondral, osseous and AT [17] and have been widely studied for treating degenerative joint diseases [14]. Given the comparable regenerative potential and hypo-immunogenicity of placental/umbilical cord blood MSCs as compared with BM- or AT-derived MSCs, placental/umbilical cord blood MSCs stand to become more accessible and noninvasive MSC sources [13], [18], [19], [20], [21].

Many published or ongoing studies on the safety and efficacy of AT- or BM-derived stem cells for treating mild to severe OA [14] report their safety [22], [23] and variable promising therapeutic potential in knee OA [24], [25]. The present study is one of the first reports of placenta-derived MSCs (PLMSCs) as an allogeneic source for treating knee OA. We designed this pilot study to assess the safety of single intra-articular injection of allogeneic PLMSCs and to obtain preliminary data of their therapeutic value in 10 patients with grade 2–4 Kellgren–Lawrence (KL) knee OA.

Section snippets

Patients

Twenty patients with knee OA (grades 2–4 based on the KL criteria in knee standing anteroposterior and lateral radiographs were enrolled from November 2015 to December 2016. The study was registered in the Iranian registry of clinical trials (http://www.irct.ir) after being approved by the Ethics Committee of the Iran University of Medical Sciences. All participants signed an informed consent form before participation. Patients in both groups were allowed to use acetaminophen to alleviate pain

Patients

Based on Kellgren-Lawrence (KL) criteria, 18 patients had grade 2 and 3 and two patients had grade 4 knee OA. There were no significant differences between the two groups regarding age (P = 0.730), gender (P = 0.736), BMI (P = 0.716) and knee OA grading (P = 0.752). Supplementary Table 1 presents the results of the investigations of the variables and demographic characteristics.

Safety

Four patients in the MSC group had increased local pain and mild effusion. Their symptoms were mild and self-limited

Discussion

To date, most of the published clinical trials have reported that autologous MSC therapy is a safe and promisingly effective method for treating OA [24]. In this clinical trial, we evaluated the clinical and para-clinical safety and efficacy of allogenic PLMSC intra-articular injection in 10 patients with mild to advanced knee OA as compared with 10 control patients. The allogenic PLMSC significantly improved the clinical measures of pain, symptoms, ADL, QOL, S/R factors and knee ROM.

Acknowledgments

This study was supported by grant number 943798 of the National Institute For Medical Research Development (NIMAD) granted to M. Vasei. The authors thank the Babak Radiology Center team for their cooperation in performing the MRAs.

Disclosure of interests: There is no relevant financial or nonfinancial conflict of interests in this article.

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