Safety and efficacy of allogenic placental mesenchymal stem cells for treating knee osteoarthritis: a pilot study
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.
References (55)
- et al.
Persistent pain after joint replacement: prevalence, sensory qualities, and postoperative determinants
PAIN®
(2011) - et al.
Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: analysis of engraftment and acute graft-versus-host disease
Blood
(1996) - et al.
Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells
Cell Bio Int
(2006) - et al.
Safety of intra-articular cell-therapy with culture-expanded stem cells in humans: a systematic literature review
Osteoarth & Cartil
(2013) - et al.
The MSC: an injury drugstore
Cell Stem Cell
(2011) - et al.
Knee MR-arthrography in assessment of meniscal and chondral lesions
Ortho & Trau: Surg & Res
(2009) - et al.
Safety, tolerability, clinical, and joint structural outcomes of a single intra-articular injection of allogeneic mesenchymal precursor cells in patients following anterior cruciate ligament reconstruction: a controlled double-blind randomised trial
Arthrit Res & Ther
(2017) - et al.
Regeneration of meniscus tissue using adipose mesenchymal stem cells-chondrocytes co-culture on a hybrid scaffold: in vivo study
Biomaterials
(2017) - et al.
Human placenta-derived cells (PDA-001) for the treatment of adults with multiple sclerosis: a randomized, placebo-controlled, multiple-dose study
Mult Scler Relat Disord
(2014) - et al.
HLA expression and immunologic propertiesof differentiated and undifferentiated mesenchymal stem cells
Exp Hematol
(2003)
Donor sex and age influence the chondrogenic potential of human femoral bone marrow stem cells
Osteoarthritis cartilage
The burden of osteoarthritis: clinical and quality-of-life issues
Am J Manag Care
The epidemiology of osteoarthritis in Asia
Int J Rheum Dis
Prevalence of musculoskeletal disorders in southeastern Iran: a WHO‐ILAR COPCORD study (stage 1, urban study)
Int J Rheum Dis
Rheumatology in Iran
International journal of rheumatic diseases
Clinical aspects, pathology and pathophysiology of osteoarthritis
J Musculoskelet Neuronal Interact
American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee
Arth Care & Res
Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from GAIT
Ann of the Rheum Dis
Early postoperative mortality following joint arthroplasty: a systematic review
J Rheum
Patient satisfaction after total knee arthroplasty: who is satisfied and who is not?
Clinical Orthop and Related Res
A randomized trial of arthroscopic surgery for osteoarthritis of the knee
New Engl J of Med
Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy–a review
BMC Musculoskel Diso
Current perspectives in mesenchymal stem cell therapies for osteoarthritis
Stem Cells Int
Umbilical cord blood stem cells: clinical trials in non-hematological disorders
Brit Med Bul
Chondrogenesis of adult stem cells from adipose tissue and bone marrow: induction by growth factors and cartilage-derived matrix
Tissue Eng Part A
Human placenta‐derived cells have mesenchymal stem/progenitor cell potential
Stem Cells
Cited by (81)
Harnessing knee joint resident mesenchymal stem cells in cartilage tissue engineering
2023, Acta BiomaterialiaPlacenta-Derived Products Demonstrate Good Safety Profile and Overall Satisfactory Outcomes for Treating Knee Osteoarthritis: A Systematic Review of Clinical Evidence
2023, Arthroscopy - Journal of Arthroscopic and Related SurgeryTherapies related to mesenchymal stem cells for cartilage, joint, and bone diseases
2023, Joint and Bone: From Bench to BedsideMesenchymal stem cells in osteoarthritis: The need for translation into clinical therapy
2023, Progress in Molecular Biology and Translational ScienceImmunity-and-matrix-regulatory cells enhance cartilage regeneration for meniscus injuries: a phase I dose-escalation trial
2023, Signal Transduction and Targeted Therapy