Efficacy and safety of culture-expanded, mesenchymal stem/stromal cells for the treatment of knee osteoarthritis: a systematic review protocol

Osteoarthritis (OA) is a progressive condition affecting the articular cartilage and underlying subchondral bone, leading to significant pain and limitations in movement [1]. Knee OA is the most prevalent form of arthritis worldwide and is one of the leading causes of disease and disability amongst aging populations [2]. Recommended treatments for Knee OA can improve symptoms in many patients [3] but do not modify the underlying degeneration of the articular cartilage and alterations in architecture of the surrounding tissue. Emerging treatments derived from cellular products including platelet-rich plasma, bone marrow aspirate and mesenchymal stem/stromal cells (MSCs) have been proposed as minimally invasive alternatives to conventional therapies [4]. In particular, MSCs have been indicated as a promising treatment for degenerative musculoskeletal conditions given their anti-inflammatory properties and capacity to differentiate into osteochondral tissues [4‐7].

MSCs can be obtained from the stroma of various tissues, including bone marrow, umbilical cord blood, adipose tissue, peripheral blood and synovium, and expanded in culture to increase yield and enhance desired functional properties [8]. The optimal choice of tissue source is based on considerations of patient safety, ease of access, yield and indications of functional improvements in preclinical and early clinical studies [7]. Evidence obtained in vitro and in animal models indicates that MSCs from different tissue sources differ regarding their cell surface protein expression and capacity to differentiate into specific cell types [9‐13]. Thus, it is not currently clear whether the source of cells has a substantial impact on functional or structural outcomes following injection into osteoarthritic knees.

There are a large number of preclinical studies reporting a beneficial effect of MSCs on cartilage degeneration and injury, ranging from mouse [14, 15], rabbit [16‐18], guinea pig [19], horse [20], goat [21], to pig models of OA [22, 23]. However, the degree of methodological heterogeneity and limitations in translational relevance for particular animal models of arthritis have complicated interpretations of results [24‐26]. Nonetheless, a growing number of clinical studies indicate that mesenchymal stromal cells have the potential to reduce pain; increase joint mobility, walking ability and cartilage/meniscus growth and repair tissue extension over the subchondral bone [5, 27]. In addition, a number of studies have reported no serious adverse events as a result of MSC treatment [5, 28]. However, it is not clear whether these outcomes have been examined consistently across studies.

Considering the aforementioned lack of clarity regarding cell source, methodological factors, clinical translation and outcome measurement, a systematic review is required to synthesize and evaluate the quality of the available evidence regarding the safety and efficacy of mesenchymal stem/stromal cells for knee OA. The primary objective of this review is to establish in patients or animal models of knee osteoarthritis treated with culture-expanded mesenchymal stem/stromal cells from adipose tissue, bone marrow or synovium, with or without adjunct nonoperative therapies, the clinical, structural and functional outcomes of treatment, as well as the incidence and severity of adverse events. The secondary objective of this review is to identify study, measurement and other methodological characteristics associated with treatment outcomes.

The protocol was registered on the PROSPERO international prospective register of systematic reviews, registration number CRD42018091763. The systematic review follows the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement [29] and protocol (PRISMA-P) guidelines [30].

For preclinical studies, outcomes considered will include clinically relevant outcomes such as mortality, morbidity and adverse events. Structural outcomes considered include results of histological analyses, including grading of pathology according to the Osteoarthritis Research Society International (OARSI) histopathology initiative guidelines for specific animal models [33‐37], and other commonly used measures such as the Grading of Recommendations Assessment, Development and Evaluation (HHGS)/Mankin score and its modifications, the O’Driscoll and Pineda scores [38]. Outcomes of noninvasive imaging including cartilage thickness [39], presence of osteosclerotic lesions or intraosseous cysts [40] visible on MRI will also be included for analysis. Functional outcomes considered for analysis will include behavioural and mechanical measures of nociception and gait analysis such as hind paw weight as appropriate to specific species [25].

For clinical studies, outcomes considered for analysis will include clinically relevant outcomes, such as mortality, morbidity and adverse events, classified as per the US Department of Health and Human Services Common Terminology Criteria for Adverse Events [41]. Structural outcomes will include results of arthroscopic evaluation, specifically ratings of severity such as the International Cartilage Repair Society (ICRS) clinical cartilage injury classification system [42, 43], and Oswestry Arthroscopic Score (OAS) [44]. Also considered will be the results of medical imaging, including ratings of x-rays such as the Kellgren-Lawrence (KL) Classification of Osteoarthritis [45] and ratings of pathology via magnetic resonance imaging such as the OMERACT Knee Inflammation MRI Scoring System (KIMRISS) [46], the Boston Leeds Osteoarthritis Knee Score (BLOKS) [47], the MRI Osteoarthritis Knee Score (MOAKS) [48] and the Whole-Organ Magnetic Resonance Imaging Score (WORMS) [49]. Results of histological analyses considered for analysis include grading systems such as the HHGS [50] and the OARSI Cartilage Histopathology Assessment System [51]. Patient-reported outcomes considered for review include validated measures of treatment response [52, 53], including measures of knee function, pain, quality of life and patient satisfaction, such as the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) [54], the Knee injury and Osteoarthritis Outcome Score (KOOS) [55], Knee Pain Scale (KPS) [56] and visual analogue scales (VAS). Objective functional outcomes including strength, range of motion, locomotion, gait and proprioception will also be examined if reported in included studies.

The results of this review will be published in relevant scientific journals or presented at national or international conferences (‘publications’) by the Investigators.