The Short Form Health Survey (SF-36) is a questionnaire for the detection of changes in the quality of life in patients. The SF-36 is composed of eight subscales: physical functioning, physical role, bodily pain, general health perceptions, vitality, emotional role functioning, social role functioning, and mental health. These subscales can be divided into two groups, the physical component score and the mental component score. However, this questionnaire is known to be less sensitive than WOMAC essentially because in several studies SF-36 scores were not significantly modified in either control or treated osteoarthritis patients [19, 65, 116].
The Visual Analog Scale (VAS) is a psychometric response scale on which patients specify their level of pain intensity. In this subjective assessment higher score indicate more severe pain [65, 70, 116, 119].
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) is the most used questionnaire in patients with osteoarthritis of the knee or hip. This questionnaire is composed with 24 questions that allows the quantification of pain, stiffness and physical function. Thus, the WOMAC have three categories of questions: 5 for pain, 2 for stiffness and 17 for activities of daily living. The global score has a range of 0 to 96 and higher scores in WOMAC means increased pain and stiffness as well as diminution of function [13, 65, 70, 103, 116, 119].
The Foot and Ankle Outcome Score (FAOS) is a questionnaire which have five components: pain, activities of daily living (ADL), function in sport (sport) and recreation (rec) and foot and ankle-related quality of life. This questionnaire, when answered, takes into consideration only the last week. FAOS have a standardized answer options and each question assigns a score from 0 to 4. The global score has a range from 0-100 and when patients have higher scores means improvement of symptoms [13].
The Harris Hip Score (HHS) is a questionnaire which was developed for the evaluation of patients following a hip surgery but now it is used for the evaluation of many hip disabilities and methods of treatment. The HHS is composed of 4 subscales: pain (44points), function (47 points), deformity (4 points), and range of motion (5 points). The global score has a range of 0 to 100 with higher scores representing less dysfunction and better outcomes, i.e., when HHS total score is smaller than 70 is considered poor, from 70 to 80 is fair, from 80 to 90 is good and scores between 90 and 100 are considered excellent [13].
The International Knee Documentation Committee (IKDC) is a subjective questionnaire for the detection of changes in symptoms, joint function and sport activities. This questionnaire is composed by 18 questions and the total score has a range of 0 to 100. Higher scores of IKDC means that the patient has a better condition [63].
The Numeric Pain Scale (NPS) is a one-item questionnaire for pain severity in the affected area. The NPS has eleven scoring levels of pain ranging from 0 to 10. Thus, in this questionnaire the patient has to choose one of these eleven levels of pain. Marking 0 indicated that the patient had no pain and marking 10 indicated that the patient had the worst possible pain [60, 63, 120].
The Lower Extremity Functional scale (LEFS) is a questionnaire containing 20 questions about activities of daily living and function. In this questionnaire, patients have to select the levels of difficulty for each activity listed. LEFS have 5 possible answers: no difficulty (4 points), a little bit of difficulty (3 points), moderate difficulty (2 points), quite a bit of difficulty (1 point), and finally, extreme difficulty or inability to perform activity (0 point). The global score is the sum of points for the twenty different everyday activities and ranges from 0 to 80. The maximum possible score indicates that the patient has a very high function whereas the minimum possible score indicates that the patient has the lowest functional activity [60, 63].
The Lysholm knee scale is a questionnaire that evaluate 8 domains: limp, support, joint locking, instability, pain, swelling, stair climbing and squatting. Higher score means that the patient has better condition [36, 65, 100, 117, 121, 122].
The Knee Injury and Osteoarthritis Outcome Score (KOOS) is a questionnaire on which patients specify their opinions about their knee and associated problems. This questionnaire is applicable to patients with OA or injuries of the knee that can lead to post-traumatic OA, i.e., anterior cruciate ligament, the meniscus and the articular cartilage. KOOS is intended to be used to monitor and evaluate patients’ response to medicines, physical therapy and surgical intervention. This psychometric test is composed by 42 questions divided into 5 categories: pain, other symptoms (symptoms and stiffness), ADL, sport and recreation (sport/Rec), and quality of life. The number of questions in each category are: 9 questions for pain, 7 questions for other symptoms, 17 questions for ADL, 5 questions for sport and recreation and finally, 4 questions for the quality of life. Each question is assigned a score from 0 to 4 and the value (0 indicating no symptoms and 100 indicating extreme symptoms) of each category are independent. An advantage of KOOS over other surveys is the inclusion of two different categories of physical function relating to activities of daily living and sport and recreation [34, 61, 65, 111].
The Oxford Hip Scale (OHS) is another questionnaire which is intended specifically for the hip joint and usually used for the evaluation of patients undergoing total hip replacement. This questionnaire consists of 12 questions about pain and disability experienced over the past four weeks and each item has standardized answer options. The global score has a range of 0 to 48 and when the score of OHS is higher that means that the patient has a maximum function. In the scale for being considered an improvement, the minimal difference of 4.9 points is necessary [120].
The Lequesne index is one of the most used questionnaires in patients with osteoarthritis of the knee or hip. This questionnaire was initially designed to aid the orthopaedic surgeon to know when indicating surgery. Lequesne index is composed by 10 questions that allow the quantification of pain, stiffness and function. The global score has a range of 0 to 100 [19, 40, 116].
The Functional Rating Index (FRI) is another subjective questionnaire, which was developed by combining Oswestry and Neck Disability Index. This questionnaire is intended to measure changes in function and pain. The 10 items of FRI used are: pain intensity, pain frequency, sleeping, work, personal care, travel, recreation, lifting, walking and standing. The total score has a range from 0 to 100 and higher scores means that the patient has a severe disability and pain [123].
The Tegner activity scale is a questionnaire focus on sports activities and work that can be used for the evaluation of knee, hip and ankle. This questionnaire was developed to complement the Lysholm knee scale. The score varies from 0 to 10 and each score indicates the ability to perform specific activities, for example a score of 0 is assigned when a person is on sick leave or receiving a disability pension, whereas a score of 10 corresponds to participation in competitive sports [124, 125].
The Health Assessment Questionnaire (HAQ) is a questionnaire containing 20 questions about the difficulty in performing activities of daily living. These 20 items, specific functions, are divided into 8 categories: dressing and grooming, arising, eating, walking, personal hygiene, reaching, gripping and other activities. Patients have to select the levels of difficulty for each listed activity. HAQ have 4 possible answers: no difficulty (0 point), some difficulty (1 point), much difficulty (2 points) and unable to do (3 points). Of note, if the patient is depending on physical assistance or equipment, the category score is 2 [126].
X-rays remains the most accessible tool and can be used to evaluate the overall state of the jointosteoarthritis [42, 110].
The main advantages of ultrasound are the ability to imagine dynamic structure in real-time, to visualize various tissues involved in OA without using contrast enhancement, the lack of ionizing radiation, multiplanar image acquisition and the utility in interventional procedures. Ultrasonography has been used successfully in the evaluation of soft tissues, muscles, tendons, ligaments, meniscal tears and articular cartilage abnormalities. In addition, it is more cost-effective than MRI for some soft tissue structures [110, 111].
The greatest benefits of Magnetic Resonance Imaging (MRI) as a method for cartilage imaging are its non-invasiveness, reproducibility and accuracy [112]. This method is commonly used not only to see if the therapy promotes the cartilage repair but also as a surveillance procedure, i.e., to see if the therapy promotes tumor formation or ectopic tissue formation [13, 113-115].
The Magnetic Resonance Imaging (MRI) quantitative T2-mapping is used to evaluate cartilage quality and its biggest advantage is giving consistent outcome measures without being an invasive method as arthroscopy or biopsy. This method is sensitive to changes in the chemical composition and structure of cartilage. For instance, T2 relaxation time is shorter in hyaline cartilage versus inflammatory tissue, increases in OA and decreases in healing areas. For the quantitative analysis, the articular cartilage is segmented in 88 well-defined regions of interest (ROIs) and the mean T2 relaxations are computed. The Poor Cartilage Index (PCI) is estimated as the percentage of sample points with a T2 relaxation values >50 milliseconds (ms). The worst possible value of PCI is 100 whereas a value near 5 is considered healthy [18, 19, 40, 116].
The whole-organ Magnetic Resonance Imaging score allows the evaluation of whole-organ knee joint. Thus, in this semi-quantitative method, images from the conventional MRI are analyzed by musculoskeletal radiologists and scored with respect to 14 independent articular features: cartilage signal and morphology, subarticular bone marrow abnormality, subarticular bone attrition, subarticular cysts, marginal osteophytes, medial and lateral meniscal integrity, medial and lateral collateral ligament integrity, anterior and posterior cruciate ligament integrity, synovitis, loose bodies and periarticular cysts or bursae. The final WORMS scores is tabulated as follows: (a) independent values for each feature in each of the three compartments of the knee (patellofemoral joint, PFJ; medial femorotibial joint, MFTJ; and lateral femorotibial joint, LFTJ), (b) cumulative surface feature (cartilage, marrow abnormality, subarticular cysts, bone attrition, osteophytes) scores of each compartment, (c) cumulative scores for each feature throughout the knee, and finally, (d) a total combined score for the entire knee [117].
Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores is a scoring systems that evaluates the quality of repair tissue. The description of the morphology and signal intensity of the repair tissue is compared to the adjacent native cartilage by using nine parameters. The parameters used for the evaluation are: the degree of defect filling, the integration to the border zone, signal intensity, quality of the structure and surface, the status of subchondral bone and subchondral lamina, and records presence or absence of synovitis and adhesions. If the repaired cartilage appears as thick as the adjacent native cartilage with complete integration into margins, and a smooth articular surface which reproduces the original articular contour with no adhesions and an intact subchondral bone plate and marrow, the repair is considered complete [112, 118].
Arthroscopy allows to evaluate the healing status of degenerative cartilage. This healing status can be classified as very positive (cartilage formation with good integration and normal gross appearance), positive (partial cartilage regeneration), neutral (an uncertain change when compared to the preoperative status) or negative (progression of degenerative cartilage). Even though arthroscopy, as histological analysis of a biopsy, is the golden standard to evaluate the cartilage regeneration, this method is invasive for patients [83, 100].
However, it should be emphasized that only 5 out of 19 studies had a control group. In the first study, performed by Lee et al., the authors compared intra-articular injection of autologous expanded BM-MSCs and HA following arthroscopic debridement and microfracture with surgical transplantation of BM-MSCs included in a solid matrix (control group) in patients with knee OA. They concluded that the injective treatment is as good as the surgical procedure, with the advantage of being minimally invasive and requiring only a single operation [131]. In the second study, performed by Wong et al., the authors evaluated the effects of injecting autologous expanded BM-MSCs following knee surgeryies in patients with osteoarthritic knees and genu varum. A total of fifty-six patients, who underwent HTO and microfracture, were randomized into two groups: MSCs and control. The MSCs group received autologous expanded BM-MSCs with HA by intra-articular injection, whereas the control group received intra-articular injection of HA. At the final follow-up, the MSCs group was superior to the control group in MOCART and clinical evaluations. Thus, the injective treatment with MSCs is safe and effective for OA [133]. In the third study, performed by Centeno and Freeman, they compared the intra-articular injection of expanded BM-MSCs with untreated patients (control group). At the end of follow-up, the results obtained were encouraging, however, due to the small number of treated subjects and minimally matched control groups as well as the use of only subjective methods, these results must be interpreted with caution. Therefore, these results suggest that this injective treatment with BM-MSCs is safe, because no adverse events were reported, and effective in osteoarthritic hand disease by improving range of motion and symptoms. However, it is vital to perform more controlled randomized studies with larger groups not only to confirm the results but also to evaluate the cartilage regeneration by structural methods, such as high-field MRI [134]. The fourth study, performed by Vangsness et al., was the first to use allogenic MSCs. A total of fifty-five patients, who underwent a partial medial meniscectomy, were randomized into three groups: Group A, patients received an injection of 50×106 allogeneic BM-MSC in combination with HA; Group B, patients received an injection of 150×106 allogeneic BM-MSC in combination with HA; and Group C, the control group, received an intra-articular injection of HA (this scaffold is an “active†control because it is used for the treatment of pain caused by osteoarthritis ). During the follow-up, they observed no ectopic formation , but some adverse events were reported, most of them being mild, such as joint swelling or pain. Patients who receiveds MSCs experienced a significant pain relief and increased cartilage volume compared with those who received the control vehicle. Yet, it should be noted that group A, who received a lower number of cells, obtainedproduced better results in both cartilage volume increase and pain relief. Also, higher dose of allogeneic MSCs can be safely injected into the knee [115]. Last but not least, the fifth study, performed by Vega et al., also evaluateds the safety and feasibility of using allogenic MSCs to treat knee OA. For this evaluation, the authors compared intra-articular injection of allogeneic BM-MSCs, with intra-articular injection of HA (control group). At the end of follow-up, they concluded that allogeneic MSCs therapy is feasible, safe and effective by reducing pain and disability, improving quality of life as well as promoting cartilage repair [116].
The success of these last two studies indicates that allogenic MSCs could be an alternative source for OA. In fact, the application of allogeneic MSC has been successfully performed in several clinical trials for treating various diseases, as aforementioned. Allogenic MSCs are advantageous over autologous MSCs [116, 152, 153]. For example, the usage of these cells does not require surgery to harvest bone marrow in patients, resulting in less discomfort to the patients, as well as the contiguously beginning of the treatment [6]. Since in the autologous therapy it is necessary to harvest and cultivate MSCs, the beginning of the treatment do not start immediatelyis delayed [6]. Moreover, the cell expansion of autologous MSCs makes the procedure slow and expensive, whereas the allogeneic cells would be cheaper with higher homogeneity [116]. In addition, as a result of MSCs being affected by diseases and age of patients, the allogeneic MSCs have higher quality [57, 86, 152, 153]b. Because the control of donor age and health of the bone marrow donors is performed [57, 153] [57, 86, 152, 153]. One possible disadvantage of using allogeneic cells would be the rejection of these cells by the immune system. However, as already discussed, MSC are immune privileged, immune evasive and inhibit immune responses [86, 116]. On the other hand, it should be noted that in the study performed by Vega et al., the authors compared their results with results achieved by Orozco et al. [19] and Jo et al. [103], who used autologous BM-MSCs and AD-MSCs, respectively. They concluded that the efficacy of allogeneic treatment appears to be somewhat smaller than thatose reported for treatment with autologous MSC. However, direct comparisons are difficult because the other studies were uncontrolled. Therefore, it is important to confirm this observation in future studies designed to directly compare autologous with allogeneic cells in different arms of the same trial [116] .
Alexander Friedenstein and co-workers were the first to describe MSCs in1966 [67, 84]. They characterized these cells as an adherent, fibroblast-like population within the stromal compartment of the bone marrow [71]. In 1970, Caplan and colleagues provided the first evidence of the differentiation potential of MSCs and in 1991 they introduced the term “mesenchymal stem cells†[67] .