Regenerative Medicine Therapies for Osteoarthritis and Cartilage

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Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 111 Regenerative Medicine Therapies for Osteoarthritis and Cartilage Majid Alhomrani Department of Clinical Laboratories Science, The Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia Abstract Osteoarthritis (OA) has a high burden and impact on society as it affects the quality of life of both young and older patients. OA is a degenerative joint disease characterized by the degeneration of articular cartilage. This cartilage is an avascular, unique matrix composed of chondrocyte cells, which can resist compression and redistribute loads but have poor self-regenerative capacity. Numerous types of treatment are available, such as non-pharmacology treatments involving diet, physiotherapy, exercise, and pharmacological which include different types of drugs. None of these two types has proven to be the ideal treatment, only symptomatic treatment. Total knee replacement is the final and only treatment available and used only when the other types of treatment fails. The intra-articular injection is an alternative treatment for OA, due to the localized nature of the disease. Various types of blood products are currently used, including platelet-rich plasma and orthokine to alert the inflammation response and enhance the healing process. Recently, regenerative treatments have widely been introduced to overcome the limitations of current treatments. Mesenchymal Stromal Cells (MSCs), which can differentiate into chondrocytes, are used to regenerate articular cartilage. In addition, the improvements in tissue engineering technology such as the use of different types of the scaffold as well as blood product and growth factors with MSC have had a great impact in treating OA and regenerating cartilage. This review will discuss the pathogenesis of OA and describes the current clinical management to treat the OA Keywords: Blood component therapy, Cartilage, Cell therapy, Growth factors, Mesenchymal stromal cell, Osteoarthritis, Synovitis Address for correspondence: Dr. Majid Alhomrani, Department of Clinical Laboratories Science, The Faculty of Applied Medical Sciences, Taif University, Taif, Saudi Arabia. E-mail: sasdaq@gmail.com Received: 22-04-2022 Revised: 18-05-2022 Accepted: 25-05-2022 INTRODUCTION O steoarthritis (OA) is a commonly occurring form of arthritis affecting diarthrodial joints, but most common involved the knee; hip and hand, foot and spinal joints and can cause severe long-term pain, reduced functionality, decreased quality of life and lower life satisfaction [1] It is the most prevalent cause of mobility, disability and chronic musculoskeletal pain in the ageing population affecting millions of people worldwide and causing the World Health Organization to designate the year 2000–2010 the bone and joint decade [2,3] Common OA risk factors include previous joint surgery, joint injury, obesity, occupational bending, and lifting injuries [4] OA has been considered a wear and tear noninflammatory disease leading to the loss of articular cartilage [5] While this condition is considered non-inflammatory, there is still strong evidence supporting the presence of inflammation in the synovium of OA patients leading to synovitis [4,6] In addition, OA is mainly characterized by loss of articular cartilage but also involves the entire joint structure change including the synovial membrane, ligaments, subchondral bone, and calcified cartilage [7,8] Pathological changes occurring with OA include the destruction of cartilage, which is observed at the articular surface in the form of fibrillation. There is also a hypertrophic reaction (sclerosis) in subchondral bone, subchondral bone cysts, newborn formation (osteophyte) at joint margins, synovial membrane alterations, increased synovial fluid volume with decreased viscosity, and degeneration of ligaments. Along with these changes, the knee joint may suffer from menisci destruction [Figure 1] [9] REVIEW AR TICLE

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 112 The articular cartilage is a unique and unusual network composed of a single cell type named chondrocytes, and extracellular matrix (ECM) consist of proteoglycans (aggrecan), collagen type II, and other components which is mainly synthesized by chondrocytes [10-12] The cartilage usually has difficulty in healing or reproducing spontaneously after degeneration or damage. This difficulty is because the cartilage has a unique complex structure resulting from interactions between cells, fluid, framework, and aggrecan and avascular surroundings [13,14] In this review, different aspects of OA therapies were summarized that are available and provide an overview of the regenerative medicine that is currently used OA treatment strategies The current treatment options for OA are aimed to improve health-related quality of life, reduce joint pain, physical disability and handicap, improve and maintain joint mobility, limit the progression of the disorder, and finally educate the patient [15] Non-pharmacological treatment is an important option used for OA. Information and education should be given to all OA patients to unload the damaged joint as well as reduce pain. The patient may benefit from lifestyle changes, weight reduction, and exercises such as aerobics, range of motion exercises, aquatic exercises, walking, and muscle strengthening. It is also important to advise patients about their footwear and the shoe and insoles to benefit the patient. Physical therapy can also be a benefit to patients [15,16] Pharmacological therapies such as the use of acetaminophen (paracetamol) an analgesic that inhibits the cyclooxygenase (COX) enzyme [15] Nonsteroidal anti-inflammatory drugs (NSAIDs), commonly administered to patients who show no benefit with paracetamol, are a method of inhibiting COXs (both COX-1 and COX-2 isoenzymes) [16,17] Both paracetamol and NSAIDs are used to reduce the symptoms of OA without having any effects on cartilage [16] Concomitantly, during the early stage of OA, glucosamine and/or chondroitin sulfate can be used to slow the process of cartilage degeneration or to reverse it. However, evidence is lacking for their therapeutic effects and this has caused the Osteoarthritis Research Society International to recommend discontinuation of these treatments if no response appears in 6 months [15,18,19] On the other hand, The National Institute for Health and Clinical Excellence (NICE) in the UK does not recommend the use of glucosamine or chondroitin products for the treatment of OA [20] Interestingly, the use of injected drugs is increasing due to the monoarticular or oligoarticular nature of OA. These types of treatment avoid the risk of untoward side effects and several types of injected drugs are used. Corticosteroids are anti-inflammatory agents that interrupt the inflammatory and immune cascade at several levels [21] These agents should be considered when the patient does not respond to oral antiinflammatory drugs and has severe pain [15] Hyaluronic acid (HA) is a natural component of cartilage and is essential for joint lubrication, shock absorbency and the formation of the ECM [22] Viscosupplementation is a procedure that involves the injection of HA into the joint space, to restore the viscosity and elasticity of the synovial fluid [22] Viscosupplementation can improve the patient’s condition and has long-term benefits, especially in moderategrade knee OA patients [21,22] However, the NICE does not recommend the use of intra-articular HA injections for the treatment of OA [20] If patients are not benefitting from the use of these pharmacological agents, then the use of weak opioids and narcotic analgesics should be considered. For the management of severe pain, the use of strong opioids can be considered, and non-pharmacological therapies in such patients should be continued [15] When combinations of non-pharmacological and pharmacological therapies do not reduce pain, do not improve functionality and quality of life, and the disease has reached the end stage, then joint replacement surgery should be considered. This is the only treatment that is considered a curative for OA. The surgical treatment for OA is excision and replacement of the entire joint, commonly referred to as a total joint replacement. However, in some patients, the replacement may be partial. In young and physically active patients with symptomatic hip OA, osteotomy and joint preserving surgery should be considered, while a high tibial osteotomy for a young OA patient’s knee could delay the need for knee replacement [15,20,23] It is obvious that the current types of treatments are symptomatic relief for a short period without an improvement in the condition and the only treatment is the total joints replacement. These drawbacks of treatment options increase the demand for the development of new therapeutic options It has been discovered an important role for Rac 1 in OA development. Hence, the inhibition activity of Rac 1 by Figure 1: Comparison between healthy (a) and osteoarthritis (b) joint b a

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 113 controlled release of Rac 1 inhibitor therapy may consider a good OA treatment strategy [24] BLOOD COMPONENTS-BASED THERAPY In OA patients, both chondrocytes and synovial cells produce high levels of pro-inflammatory cytokine interleukin-1 (IL-1) and tumor necrosis factor α (TNF α ) which destroy articular cartilage through reduced collagen synthesis and increased catabolic activity. IL-1 has two isoforms, α and β , β is the major isoform produced in human tissue. IL-1 can activate the cell through two receptors: cell-surface receptors type I (IL-1 RI) and type II (IL-1 RII). Chondrocytes and synovial fibroblasts are very sensitive to IL-1 due to the high number of IL-1 RI on them. In addition, IL-1 β and TNF α cause chondrocytes to be active and secrete matrix metalloproteinases (MMPs) which can destroy cartilage. Furthermore, a high number of anti-inflammatory cytokines are found in high levels in OA synovial fluid such as upregulation of IL-I receptor antagonists (IL-1 Ra) which inhibit the IL-1 R and have the ability to block several catabolic pathways involved in OA but the IL-1 Ra cannot compete with the high level of IL-1 β [7,25,26] Hence, there is a great interest in using IL-1 Ra as a therapeutic option as this treatment aims to inhibit IL-1 action. Since the early 1980 s, there were several trials through different methods [27-35] leading to the development of Autologous Conditioned Serum (ACS) marketed as Orthokine which is a syringe, that contains ACS rich with anti-inflammatory factors produced by a physicochemical treatment of the whole blood [36] Orthokine causes an increase in many anti-inflammatory agents such as IL-1 Ra, which increased 140-fold, IL-4, and IL-10 with no increase in pro-inflammatory cytokines [36,37] However, other studies have shown an increase in pro-inflammatory cytokines such as IL-1 β and TNF α [37] The injection of Orthokine has excellent benefits on the patient including safety profile, reducing pain, and increasing their functionality [38] The mechanisms of ACS are still not completely understood, and more research needs to be done to determine its effects whether on symptoms or regeneration of cartilage Platelet-rich plasma (PRP) is another blood product. Platelets are non-nucleated small bodies in the blood that contain cytokines, bioactive factors, and proteins and play a major role in hemostasis. Plasma is the liquid component of blood and contains proteins, ions, and clotting factors [39] Autologous PRP therapy has been attracting worldwide attention because it is simple to isolate and prepare, inexpensive, lacks an immune reaction or disease transmission. Natural concentrations of autologous growth factors (GFs) are obtained by minimally invasive methods and the platelets have a physiological role in the natural healing process [40,41] This therapy has been widely experimented with in the field of medicine including wound healing, plastic surgery, cartilage degeneration, and tendon injuries with the hope of enhancing the healing process by increased differentiation, recruitment, and proliferation of cells involved in tissue regeneration [39,42] This enhancement results from the high fold reservoir of important GFs, cytokines, and other bioactive molecules associated with PRP and platelets α and dense granules [Table 1] [43-46] Furthermore, GFs are released by platelet activation. They include insulin-like growth factor (IGF), transforming growth factor β (TGF- β ), platelet-derived growth factor, vascular endothelial growth factor, fibroblast growth factor (FGF), hepatocyte growth factor, platelet factor 4, and epithelial growth factor. These may play a major role in cellular processes including chemotaxis, cell proliferation and differentiation, mitogenesis, angiogenesis, and metabolism [39,43] Preparation of PRP begins with the collection of autologous whole blood from the patient with the addition of an anticoagulant to prevent the activation of the coagulation cascade and clot formation. The citrate anticoagulant is usually used. It is available in various forms including calcium citrate, acid citrate dextrose, and sodium citrate. These bind to the calcium and prevent the clot from occurring. This is followed by the centrifugation steps, which distribute, isolate, and concentrate various blood components. Two different preparation systems exist; they differ based on centrifugation spin parameters. The first is a buffy-coat-based system that requires high and long spins to isolate platelets’ poor plasma and a buffy coat, which has both white and red blood cells. The second is the plasma-based system which requires slow and short spins to isolate the platelets and plasma only without other blood cells [39,47-49] Then the PRP is activated to allow the α -granules to release the GF, in a process known as degranulation. Platelets can be activated endogenously through the collagen tissue or exogenously by thrombin or calcium chloride. Activation causes the release of stored GFs. Approximately 70–90% are released in the first 10 min and the remaining is released in the first hour. However, many human protocols activate PRP endogenously [49] DeLong et al. [48] proposed a classification system to distinguish between PRP products based on three categories: The absolute number of platelets, platelets activation, and WBC counts Several clinical trials evaluate the benefits of using PRP as an alternative treatment for OA. Napolitano et al . treated 27 patients between 18 and 81 years of age and divided them into two groups: A knee arthritis group and a degenerative knee cartilage disease group. Both groups received 3 weekly interval injections of PRP. The assessments parameters Numerical Rating Scale and Western Ontario and McMaster University Osteoarthritis Index (WOMAC) showed dramatic improvement in both groups. The highest improvement was in the 6 th month of the assessment [50] Kon et al . reported that 91 patients diagnosed with chronic degenerative knee and different grades of OA were treated with three PRP injections. The clinical assessment was based on International Knee Documentation Committee (IKDC) and visual analog scale EQ (VAS) score at 6 and 12 months follow-up. The greatest score was at the 6-month

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 114 follow up and the score started to decrease following the 6-month assessment and at the 12-month follow-up, the score was worse but still higher than basal levels [51] At the 24-month follow-up, the results had continuously decreased and showed a worse score compared to the 12-month follow-up but were still higher than basal levels and the greatest results were obtained from younger patients with low-grade cartilage damage. This study concluded that the PRP showed an effective result in increasing the function and quality of life and reducing pain in the short term [44] These studies did not have a control group for comparison of results and improvement. An interesting comparison study had 150 patients between the age of 26–81 years divided into three groups. The first group received three PRPs, the second received high molecular weight HA and the third received low molecular weight HA. The clinical evaluation was based on IKDA and EQ-VAS scores at 2- and Table 1: Different types of molecules found in platelets Molecule Biological activity α ‑Granules Growth factor IGF Cell maturation, proliferation and bone matrix synthesis TGF‑ β Promotes matrix synthesis PDGF Cell proliferation, Chemoattraction ECGF Endothelial cell proliferation and angiogenesis FGF Fibroblast proliferation mediates angiogenesis VEGF Angiogenesis EGF Cell proliferation Fibrinolytic factors Plasminogen Plasmin production α ‑2 antiplasmin Inactivation of plasmin Plasminogen activator inhibitor Regulation of Plasmin production Basic protein Endostatins Inhibit endothelial cell migration and angiogenesis Platelet factor 4 Inhibits angiogenesis β ‑Thromboglobulin Platelets activation and inhibits angiogenesis Adhesive proteins Thrombospondin‑I Inhibits angiogenesis Fibronectin Bind to the cell surface Vitronectin Cell adhesion, chemotaxis Fibrinogen Format fibrin during clotting cascade Proteases and antiproteases MMP‑4 Matrix degradation α Antitrypsin Inhibit proteases and enzymes TIMP‑4 Regulation MMP and matrix degeneration Dense Granules Histamine Attracts and activates macrophages, pro‑and anti‑inflammatory Effects ATP Participates in platelet response to collagen ADP Promotes platelet aggregation Catecholamines Hormones released by the adrenal gland in response to stress Ca++ Platelet aggregation and fibrin formation Dopamine Regulate blood pressure and heart rate, Neurotransmitter Serotonin Increased capillary permeability, macrophage attraction and Vasoconstriction IGF: Insulin‑like growth factor, TGF‑ β : Transforming growth factor β , PDGF: Platelet‑derived growth factor, VEDF: Vascular endothelial growth factor, FGF: Fibroblast growth factor, EGF: Epithelial growth factor, ECgF: Endothelial cell growth factor, MMP‑4: Metalloproteinase 4, TIMP‑4: Metalloproteinase inhibitor 4, ATP: Adenosine triphosphate, ADP: Adenosine diphosphate, Ca: Calcium

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 115 6-month follow-ups. The results showed similar improvements in both PRP and low molecular weight HA but at the 6-month follow-up, only an improvement was found in the PRP group. This indicates that PRP has a lasting improvement in the quality of life and decreases symptoms and pain compared to HA. In addition, the best results were among active younger patients while the worst were among the older patients [40] Patel et al . reported 78 patients with bilateral OA who were divided into three groups. The first group received a single WMC filtrated PRP injection, the second group received two injections and the last group received a single normal saline injection. The clinical evaluation was based on the WOMAC score and showed no improvement in the normal saline group compared to dramatic improvements in the other two groups at 6-week, 3-month, and 6-month follow-up examinations. The best results were obtained again from younger patients with low-grade cartilage degeneration [52] Filardo et al. compared two types of PRP in terms of safety and efficacy using 144 patients suffering from cartilage degeneration lesions and OA and divided them into two groups. The first group received three injections of a single-spin plasma rich in growth factors (PRGF) while the other group received three injections of a double-spin PRP. The outcome evaluation was based on EQ-VAS, IKDC and Tegner scores, which showed high clinical improvements in both groups, and again. The best results were among younger patients with low-grade cartilage degenerative lesions. PRP injections also showed increased swelling and pain reactions compared to PRGF [53] Despite the improvements in patients treated with PRP, reducing pain and increasing the function of life, the mechanisms of PRP are still not clear. Could PRP act as an anti-inflammatory mediator or downregulate cytokines or is its effect on synovial fluid or chondrocytes? Further research needs to address the PRP mechanism Different methods of centrifugation, activation, the concentration of platelets, preparation, and presence or absence of other blood cells lead to an increased demand for the optimal formulation of PRP with high benefits in cartilage degeneration and OA. More research needs to identify the optimal number of injections the patient needs to the disease situation, the patient’s age, activity, and sex CELL-BASED THERAPY The main characterization of OA is the degeneration of articular cartilage, which is a connective tissue consisting of a single type of cell named chondrocytes; their major function is to allow the skeletal structure to have load distribution and shock absorption [12] The self-repairing ability of articular cartilage is restricted due to low cell metabolism and a vascularity which will reduce the ability of healing [12] Different surgical repair techniques have been used that aim to increase the self-healing process, such as abrasion arthroplasty, microfracture, drilling, and Autologous Chondrocyte Implantation (ACI); however, these techniques have their limitations, which include cell to tissue availability and the formation of unwanted fibrocartilage [54] To the best of our knowledge, there are no therapeutic options that can slow the progress of OA and cure it, except treatment to reduce pain and surgical options such as total joint replacement, which has a high percentage for failure and is not satisfying for younger patient [55] However, in recent years, stem cells have raised hope as an alternative source of therapy for regeneration and tissue repair, due to the easy process of preparation, delivery, and large availability [56] CHONDROGENIC DIFFERENTIATION OF MSCS MSCs have the potential to differentiate into chondrocytes. MSCs are fibroblast-like morphologies that change into large, round, shapes during chondrogenic differentiation. The differentiation of MSCs to chondrocytes requires a pellet culture system that culture MSCs as aggregates, first described by Johnstone et al . in 1998. This culture system allows the cell to cell interactions and the synthesis of ECMs which is the main characteristic of cartilage, which contains a network of highly organized collagen, mainly type 2 collagen (col 2), proteoglycans, and glycosaminoglycans that can be detected by Alcian blue [57-59] During the chondrogenesis steps, various transcription factors are involved. The early and necessary transcription factor is protein SRY-related high-mobility group box 9 (Sox 9), which is a member of the Sox family and controls the expression of the genes aggrecan, col 2, col 9, col 10, col 11, and the cartilage link protein. However, the mechanism by which Sox 9 regulates cartilage-specific transcription is still not completely understood [60] Another important transcription factor in chondrogenesis is BapxI, which induces chondrogenic differentiation in sclerotome by mediating Sonic Hedgehog (Shh) signaling that target Pax I and Pax 9 which, in turn, activate BapxI in sclerotome [61,62] Furthermore, the transcription factors of the Twist subfamily act as repressors or transcriptional enhancers and include Twist, DermoI, Paraxis, HAND 2, and Scleraxis. Scleraxis expresses itself during embryogenesis in developing chondrogenic cell lineages and can transactivate the expression of aggrecan. In the region of the somites, the expression of Paraxis precedes the Scleraxis to form the axial skeleton and tendons [63] In addition to the close cell to cell contact achieved by micromass or pellet cultures, the in vitro chondrogenic differentiation of MSCs require the addition of chondrogenic bioactive factors such as TGF- β , bone morphogenetic protein (BMP), dexamethasone, ascorbic acid, IGF, and FGF which enhances chondrogenic differentiation The TGF- β family members TGF- β 1, TGF- β 2, and TGF- β 3 are multifunctional peptides that play important roles in maintaining and including in-vitro chondrogenic differentiation of MSCs. Both TGF- β and dexamethasone represent essential factors for the differentiation of MSC into chondrocytes. TGF- β 1 stimulates the chondrogenesis process in MSCs through

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 116 the transition from an initial N-cadherin-contributing state to a subsequent fibronectin-contributing stage [64] During the adult and embryonic growth and development period, TGF- β 2 participates to enhance in-vitro proliferation and redifferentiation of chondrocytes [65] There are different opinions regarding the specific TGF- β subtypes used in chondrogenesis differentiation of MSCs; some state that any subtypes of the TGF- β can activate chondrogenic factors equally and the difference seems to be in the lot rather than the subtype [66] Still, others conclude that TGF- β 2 and TGF- β 3 are more effective in promoting col 2 and glycosaminoglycans [60] BMP plays a crucial role during skeletal development, including mesenchymal cell condensation, regulation of chondrocyte maturation, and proliferation and joint formation [67,68] The family member of BMP, [69,70] including BMP-2, BMP-4, BMP-6, and BMP-7, enhances the ECM deposition by acting synergistically to TGF- β , but cannot act with dexamethasone in classical pellet cultures to differentiate MSC to chondrocytes [60] Ascorbic acid is used in culture media in combination with dexamethasone to enhance the production of ECM and col 2, and increase the proliferation of chondrocytes [71] The chondrogenesis differentiation potential of bone marrow MSC (BM-MSCs) is achieved by the use of a conditioned medium containing both dexamethasone and TGF- β , while the chondrogenesis differentiation potential of adipose tissue (AD-MSCs) requires the addition of BMP-6 [66] Garza-Veloz et al. concludes that the ability of AD-MSCs to differentiate into chondrocytes can be enhanced using a combination of IGF-1/ FGF-2 [72] The chondrogenic differentiation of MSCs usually requires serum-free media, which reduces the cellular apoptosis induced by the serum [60,73] Mishra et al . demonstrate that the use of media with PRP will significantly increase the mRNA levels of RUNX 2, sox-9, aggrecan, and cellular proliferation, as well as enhance the chondrogenic differentiation of MSCs that indicate that PRP seems to be a promising supplement agent [74] At present, different commercial chondrogenic differentiation media for MSCs are available [60] CLINICAL STUDIES ON MSCS TRANSPLANTATION FOR CARTILAGE REPAIR Several kinds of literature have shown the potential of using MSCs to repair cartilage in vivo using animal models; [75-80] this review will only focus on the benefit of using MSCs in treating humans [ Table 2]. There are two methods of implantation of MSCs, direct surgical implantation and intra-articular injection. The implantation of MSCs could be done alone or applied in combination with a scaffold [81] The scaffold aims to build cartilage that can recapitulate the original mechanical function of native cartilage by allowing high cell suspension and cell to cell contact [56,82] MSC, together with scaffold and bioactive molecular are the basic components of tissue engineering that will allow the regeneration and enhancement of cartilage formation [83] Different types of scaffolds are available, such as hyaluronan gel, collagen preparation, fibrin mixed with synthesis polymers, platelet-rich fibrin glue, and PRP [82,84] SURGICAL IMPLANTATION OF MSCS For cartilage repair, there are many clinical case reports of surgical implantation of MSCs. Gobbi et al. report that 15 patients between 30 and 60 years of age were diagnosed with a grade IV cartilage lesion of the knee. All patients were treated surgically with activated Bone Marrow Aspiration Concentration and covered with collagen-based membrane scaffolds. The clinical assessment was based on X-rays and magnetic resonance imaging (MRIs) at 12 and 24 months and Knee injury and osteoarthritis outcome (KOOS). IKDC, VAS, Marx, Lysholm, SF-36 (physical/mental), and Tegner scores at 6, 12, and 24 months were done to follow-up. The outcome results indicated a significant improvement of all scores and the MRI showed hyaline-like tissues in all patients [85] Wakitani et al. treated 24 OA knee patients ages 49–70 at the time of High Tibial Osteotomy. The patients were divided into two groups: 12 patients received passage (P 2) autologous BM-MSC cultures using Fetal Calf Serum (FCS), embedded in collagen gel sheets and applied to the cartilage defects, and covered with autologous periosteum. The other 12 patients received the same procedure without BM-MSC. 42 weeks following the operations the patients who received BM-MSCs showed white soft and hyaline-like cartilage tissue covering the defected areas. The arthroscopic and histological grading score was better in patients who received MSC compared to the control groups, although no significant clinical improvements were demonstrated [86] A young judo player of 31 years of age suffers from full-thickness cartilage, defect grade IV. The patient was treated with BM-MSC P 2 culture in autologous serum (AS), embedded in collagen gel and covered by an autologous periosteal flap. After a year, the arthroscopy and histology showed that the defect was completely covered by a smooth tissue of hyaline-like cartilage and there was a dramatic improvement in clinical symptoms [87] Wakitani et al. treated nine full-thickness patellofemoral cartilage defects in three patients ages 31, 44, and 45. Collagen gel sheets were embedded with P 1 BM-MSCs culture in AS implantation and covered with autologous periosteum. The clinical symptoms improved 27 months after the procedure. One patient showed fibrocartilage tissue covering the defect by histology and another patient’s MRI results indicated a complete cover of the defect, both after 12 months [88] In another study, two other patients with patella cartilage defects received BM-MSCs embedded in collagen gel and surgical implantations, then covered with autologous periosteum showed a significant improvement in clinical symptoms (movement abilities) which remained for 4 years or more [89] In addition, Wakitani et al . followed up with 41 patients who received 45 transplantation BM-MSCs between 1988 to 2008. The results indicated the safety of transplantation of autologous BM-MSCs due to the

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 117 Table 2: Summary table showing the human studies included in MSCs First author and Year of publication Original stem cell Patients number Disorder Methods Gobbi et al . 2011 BMAC 15 Grade IV cartilage lesion Surgical implantation of activated BMAC and cover with collagen‑based membrane scaffold Wakitani et al . 2002 BM‑MSC 24 Knee OA Surgical implantation of P 2 BM‑MSC culture in FCS using collagen gel sheet and cover with autologous periosteum Kuroda et al . 2007 BM‑MSC 1 Grade IV cartilage defect Surgical implantation of P 2 BM‑MSC culture in AS embedded in collagen sheet and cover with autologous periosteum Wakitani et al . 2007 BM‑MSC 3 Cartilage defect in patellae Surgical implantation of P 1 BM‑MSC culture in AS using collagen gel sheet and cover with autologous periosteum Wakitani et al . 2004 BM‑MSC 2 Cartilage defect in patellae Surgical implantation of collagen gel sheet containing BM‑MSC and cover with autologous periosteum Haleem et al . 2010 BM‑MSC 5 Chondral defect femoral condyle Surgical implantation of P 2 BM‑MSC embedding in PR‑FG scaffold and cover with autologous periosteum Giannini et al . 2009/2013 BM‑MSC 48 Talar osteochondral lesion One‑step arthroscopic implantation of BM‑MSC with collagen powder and platelet gel or HA with platelet gel scaffold Nejadnik et al . 2010 BM‑MSC/ACI 72 (2 groups 35 each) Several lesion BM‑MSC and chondrocyte harvest and culture in FBS until cell sheet P 1 then implantation Giannin et al . 2010 BMDC/ACI 81 10 surgical ACI 46 arthroscopic ACI 25 arthroscopic MBDC Talar osteochondral Surgical groups received ACI with collagen gel scaffold and both arthroscopic groups received cells with HA membrane Teo et al . 2012 BM‑MSC/ACI 23 3 BM‑MSC 20 ACI OLD Both cells culture in FBS until preparation of cell sheet P 1 then surgical implantation Lee et al . 2012 BM‑MSC 70 35 surgical 35 IA injection of BM‑MSC with HA Cartilage defect First groups received BM‑MSC cell sheet culture in FBC surgically Second groups arthroscopic microfraction then P 1 BM‑MSC culture in FBS injected IA followed by HA Centeno et al . 2008 BM‑MSC 1 Knee‑OA IA injection of P 5 BM‑MSC culture using PL Centeno et al . 2010/2011 BM‑MSC 430 Various orthopedic condition IA injection of BM‑MSC culture using PL ( Contd..)

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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 118 absence of infection and tumors in the patients during longterm follow-up [90] Haleem et al. reported that five young patients diagnosed with full-thickness cartilage defects of femoral condyles were treated with autologous BM-MSCs which culture using fetal bovine serum (FBS) for two passages and then was placed on platelet-rich fibrin glue (PR-FG) scaffolds implanted surgically and then covered with autologous periosteum. The clinical evaluation based on Lysholm and revised Hospital for Special Surgery Knee scores, X-Ray, and MRI at the 6 and 12 months follow-ups. The results showed improvement in all patient symptoms; three patients showed complete coverage of the defected surface with native cartilage, while two patients showed incomplete coverage by MRI [91] Giannin et al. treated 48 patients diagnosed with talar osteochondral lesions ages 14–50-years-old. The patients received BM-MSCs with either scaffold of collagen powder with platelet gel, or HA with platelet gel, which is done by one step arthroscopic transplantation technique. The clinical evaluation was based on the American Orthopaedic Foot and Ankle Society (AOFAS), MRI, and histology for 4 years. The histology results showed regenerative tissue progression. The clinical scores lowered between 24 and 36 months significantly and were negatively affected by the time between trauma and surgery, but the AOFAS score improved at the 24 month follow-up. MRI T 2- mapping analysis showed regenerated tissue similar to hyaline cartilage and its quality correlated with clinical results directly [92,93] An interesting comparison study by Nejadnik et al . comparing ACI and BM-MSCs outcomes in 72 matched patients divided them into two groups, with 36 patients in each group. The clinical assessments were based on IKDC, ICRS, Tegner activity level scale, and Lysholm Knee Scale at 3, 6, 9, 12, 18, and 24 months after implantation. Both chondrocytes and BM-MSCs were harvested and cultured in FBS until the preparation of cell sheets P 1 and then implanted. Both groups showed great improvements in quality of life, with better physical role function in BM-MSCs groups compared to the ACI groups; in terms of clinical outcomes, there were no differences. Nejadnik et al . concluded that both groups had similar effects; however, BM-MSC required only one-step surgery, lower cost, and donor-site morbidity [94] Giannin et al. evaluated the treatment of cartilage defects by presenting the results and comparing three types of techniques for treating talar osteochondral, including open ACI surgery, arthroscopic ACI, and arthroscopic bone marrow-derived cells (BMDC) in 3 patients, were 10, 25, and 46, respectively. In open ACI surgery, the collagen gel was used, while the HA membrane was used in arthroscopic ACI. The clinical evaluation was based on X-ray, MRI, and AOFAS scores. All three groups showed an improvement in AOFAS scores; however, the BMDC reduced the morbidity and cost [95] Teo et al. reported the treatment of 23 young patients diagnosed with patellar Osteochondritis dissecans (OLD). The patients’ ages were between 12 and 21-years-old; twenty of them received ACI and three received BM-MSCs. Both chondrocyte and stem cell culture were used FBS until the preparation of the cell sheet P 1. The clinical assessment was based on IKDC subjective, Tenger-Lysholm scales and Lysholm-Gillquist scores at 6, 12, and 24 months follow-up. All three groups showed improvement in assessments except for two patients who showed hypertrophy [96] Lee et al. investigated the clinical outcome and safety of injected BM-MSCs and HA after arthroscopic microfracture and compared it with (control) surgical implantation of BM-MSCs cell sheets. Seventy matched patients with symptoms of cartilage defect were divided into two groups, each with 35 patients. The first group received intra-articular injections of P 1 BM-MSC culture Table 2: (Continued) First author and Year of publication Original stem cell Patients number Disorder Methods Davatchi et al . 2011 BM‑MSC 4 Knee OA IA injection of BM‑MSC culture in FBS Emadedin et al . 2012 BM‑MSC 6 Knee OA IA injection of P 2 BM‑MSC culture using HBS Kon et al . 2013 Infrapatellar fat MSC 18 Knee OA IA injection of non‑expanded MSC with PRP Pak 2011 SVF 2 Knee OA IA injection of SVF+HA+PRP+Calcium chloride+dexamethasone Pak et al . 2013 SVF 3 Chondromalacia patellae IA injection of SVF+AH+activated PRP+calcium chloride Hauser and Orlofsky 2013 Unfractionated WBM 7 Hip, ankle, or knee Osteoarthritis Unfractionated whole bone marrow injection into osteoarthritic joints BMAC: Activated bone marrow aspiration concentration, BM‑MSC: Bone marrow mesenchymal stromal cell, OA: Osteoarthritis, AS: Autologous serum, P: Passage, PR‑FG: Platelet‑rich fibrin glue, ACI: Autologous chondrocyte implantation, BMDC: Bone marrow‑derived cells, OCD: Osteochondral defect, FBS: fetal bovine serum, FCS: Fetal calf serum, PL: Platelet lysate, IA: Intra‑articular injection, HBS: Hyclone bovine serum, HA: Hyaluronic acid, SVF: Stromal vascular fraction, WBM: Whole bone marrow

[Find the meaning and references behind the names: Curtin, Man, Pfleger, Four, Less, Dis, Care, Gene, Engl, Coleman, Ann, Peat, Topic, Safe, Six, Woolf, Organ, Future, Price, Ther, Koh, Post, Female, Barry, Med, Serious, Croft, Murphy, Positive, Pre, Hum]

Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 119 in FBS, followed by HA injections after the arthroscopic microfracture. The other group received surgically implanted BM-MSC after culturing them in FBS until cell sheet. The evaluation is based on using ICRS Cartilage Injury Evaluation Package, IKDC subjective, the Tegner activity scale and the Lysholm scale. Both groups showed similar improvements in the short term and intra-articular injections are safe and minimally invasive [97] INTRAARTICULAR INJECTION OF MSCS The intra-articular injection technique is considered the easiest method due to its potential advantage as a less invasive method, its minimal recovery time and its cheap price [98] Centeno et al. treated a 36-year-old man diagnosed with knee OA by culture BM-MSCs in platelet lysate (PL) until P 5 and then giving an intra-articular injection. The post-injection 3 months later showed improvement and a decrease in the VAS score; the MRI analysis before and after the procedure demonstrated an increase in meniscus [99] The same author reported that in 2010, 227 patients were diagnosed with various orthopedic conditions between 2005 and 2009 and treated with P 5 BM-MSC cultures in PL. Then in 2011 updated paper with the addition of 113 patients were treated. The follow-up indicated no tumor formations and less morbidity detected based on HHS criteria, compared with surgical procedure [100,101] Davatchi et al. treated four patients with knee OA by P 1 BM-MSCs cultures in FBS. After intra-articular injections of BM-MSC, the patients improved in walking time and stair climbing at the in follow-up evaluation [102] Emadedin et al. noted the improvement in six patients of quality of life 6 months post intra-articular injections of P 2 BM-MSCs cultures in Hyclone Bovine Serum (HBS). The patients diagnosed with knee OA showed evidence of increased thickness of cartilage during an MRI, but after the first 6 months, the pain started to appear [103] Koh et al. evaluated the results of intra-articular injections of non-expanded MSCs isolated from intrapatellar fat pads with PRP; the clinical results were based on Lysholm scores, VAS, Western Ontario and McMaster University OA Index and MRI pre and post operations. The results indicated an improvement in MRI scores, reduced pain, and improved knee function [104] Pak treated two old female patients diagnosed with knee OA using adipose tissue MSC. The patients received intraarticular injections of Stromal Vascular Fraction (SVF), along with HA, PRP calcium chloride, and dexamethasone. There were significant improvements in patient quality of life with positive MRI results [105] Furthermore, another study done by the same author where he treated three patients with intraarticular injections of SVF for chondromalacia patellae, found similar results. SVF is mixed with calcium chloride, activated PRP, and HA. The patients’ outcome evaluations were based on MRI, VAS, Function rating index, and physical therapy assessments pre and post-treatments. Significant improvement in terms of pain at the 1 year follow-up was concluded, no serious side effects and MRI results showed improvements in the damaged tissue [106] However, more clinical trials are required to address the ability of MSC to regenerate cartilage and its anti-inflammatory effect, especially in OA patients since the synovial fluid in OA patients prevent the ability of MSC to differentiate into chondrocytes [107,108] CONCLUSIONS Cell-based therapies represent promising and effective methods for cartilage regeneration. The development in cell-based therapy has been massive, starting from two-step surgery in ACI, to one-step surgery in BM-MSC, and now the intra-articular injection of SVF. MSCs are alternative sources of cells that could differentiate into chondrocytes, are easy to isolate and culture, and have an anti-inflammatory ability compared with chondrocytes. Furthermore, some animal and human experiments using MSCs in treating cartilage defects gave encouraging results, making MSCs the future hope for the regeneration of cartilage. In addition, more research is needed to analyze the MSC profile and the mechanism, which will address the specific need of other GFs, autologous products (serums, PRPs), and scaffolds to allow the regeneration of cartilage Significance statement OA is one of the most commonly occurring degenerative joint problems, affecting more than one-quarter of the population over the age of 18 years. It impairs the quality of life to a great extent. Unfortunately, the precise molecular pathways behind OA onset and progression are still unknown, and the therapeutic regimen for its management is not well established. Hence, based on recently released scientific findings, it is worthwhile to present the existing knowledge on the progression and management of OA. This review examines the many therapeutic options available and discusses their benefits and drawbacks, with a particular focus on cell-based therapies. These therapies represent potential and successful cartilage regeneration strategies. This review will serve as a comprehensive source of knowledge for scientists and researchers working on the topic of OA REFERENCES 1. Coleman CM, Curtin C, Barry FP, O’Flatharta C, Murphy JM. Mesenchymal stem cells and osteoarthritis: Remedy or accomplice? Hum Gene Ther 2010;21:1239-50 2. Peat G, McCarney R, Croft P. Knee pain and osteoarthritis in older adults: A review of community burden and current use of primary health care. Ann Rheum Dis 2001;60:91-7 3. Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646-56 4. Felson DT. Osteoarthritis of the knee. N Engl J Med 2006;354:841-8.

[Find the meaning and references behind the names: Van Den Berg, De Lange, Van Dijk, Van Osch, Zhang, Liu, Gerwin, Muir, Madry, Mol, Bruckner, Royal, Mckenna, Fitzgerald, Leung, Aigner, Lucke, Pandita, Arden, Chevalier, Strauss, Wang, Joslin, Clin, Kiefer, Massoni, Jelic, Adv, Pegg, Sci, Welch, Fernandes, Dupuis, Doherty, Pandit, Veale, Rosen, Abramson, Berg, Rest, Part, Cochrane, Masiero, Giraudeau, Tardif, Oliva, Zhu, Hart, Moskowitz, Ioan, Smith, Evans, Gulin, Rep, Janson, Beta, Georgescu, Martel, Liddle, Caron, Altman, Mao, Jama, Robbins, Centre, Uthman, Benito, Coman, Miller, Shea, Pelletier, Maxwell, Chen, Meta, Jones, Jovanovic, Baltimore, Lange, Moldovan, Giannotti, Lin, Dijk, Arend]

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Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol (Baltimore, Md. 1950) 1985;134:3868-75 28. Arend WP, Smith MF Jr., Janson RW, Joslin FG. IL-1 receptor antagonist and IL-1 beta production in human monocytes are regulated differently. J Immunol 1991;147:1530-6 29. Arend WP, Leung DY. IgG induction of IL-1 receptor antagonist production by human monocytes. Immunol Rev 1994;139:71-8 30. Pelletier JP, Caron JP, Evans C, Robbins PD, Georgescu HI, Jovanovic D, et al . In vivo suppression of early experimental osteoarthritis by interleukin-1 receptor antagonist using gene therapy. Arthritis Rheum 1997;40:1012-9 31. Frisbie DD, Ghivizzani SC, Robbins PD, Evans CH, McIlwraith CW. Treatment of experimental equine osteoarthritis by in vivo delivery of the equine interleukin-1 receptor antagonist gene. Gene Ther 2002;9:12-20 32. Frisbie DD, McIlwraith CW. 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[Find the meaning and references behind the names: Di Martino, De Girolamo, De Boer, Eng, Gomes, Jorgensen, Caplan, Pharm, Reinecke, Marwaha, Song, Aggarwal, Steinert, Bossio, Smyth, Pearl, Zeng, Choi, Araujo, Fortier, Mazzocca, Fox, Kwon, Buda, Puskas, Foster, Vater, Djouad, Kasten, Gerhardt, Mano, Murawski, Goldberg, Manas, Stephens, Vieira, Kennedy, Matera, Matteucci, Jain, Woodall, Pereira, Banfi, Boer, Harmon, Tholen, Vaccaro, Jansen, Mendes, Paw, Bendinelli, Yoon, Dhillon, Reis, Costabile, Maroni, Steffen, Imai, Seo, Chemical, Moser, Pearls, Ruiz, Cole, Yoo, Dev, Becker, Metcalf, Russell, Middleton, Stoop, Corsi, Girolamo, Bank, Hill, Hering, Martino, Meijer, Chick, Rodrigo, Santo]

Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 121 J Rheumatol 2005;32:1317-23 36. Meijer H, Reinecke J, Becker C, Tholen G, Wehling P. The production of anti-inflammatory cytokines in whole blood by physico-chemical induction. Inflamm Res 2003;52:404-7 37. Fox BA, Stephens MM. Treatment of knee osteoarthritis with Orthokine®-derived autologous conditioned serum. Expert Rev Clin Immunol 2010;6:335-45 38. Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis Cartilage 2009;17:152-60 39. Foster TE, Puskas BL, Mandelbaum BR, Gerhardt MB, Rodeo SA. Platelet-rich plasma: From basic science to clinical applications. Am J Sports Med 2009;37:2259-72 40. Kon E, Mandelbaum B, Buda R, Filardo G, Delcogliano M, Timoncini A, et al . Platelet-rich plasma intra-articular injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: From early degeneration to osteoarthritis. Arthroscopy 2011;27:1490-501 41. Smyth NA, Murawski CD, Fortier LA, Cole BJ, Kennedy JG. Platelet-rich plasma in the pathologic processes of cartilage: Review of basic science evidence. Arthroscopy 2013;29:1399-409 42. Bendinelli P, Matteucci E, Dogliotti G, Corsi MM, Banfi G, Maroni P, et al . Molecular basis of anti‐ inflammatory action of platelet‐rich plasma on human chondrocytes: Mechanisms of NF‐ κ B inhibition via HGF. J Cell Physiol 2010;225:757-66 43. Steinert AF, Middleton KK, Araujo PH, Fu FH. Plateletrich plasma in orthopaedic surgery and sports medicine: Pearls, pitfalls, and new trends in research. Oper Tech Orthop 2012;22:91-103 44. Filardo G, Kon E, Buda R, Timoncini A, Di Martino A, Cenacchi A, et al . 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[Find the meaning and references behind the names: Top, Art, Martini, Inoue, Carrier, Diaz, Dong, Nakamura, Scimeca, King, Lyons, Sadick, Mazzucco, Cremers, Rodriguez, Chung, Mizuno, Hunziker, Fang, Piccirilli, Cavallo, Fink, Gonzalez, Int, Hui, Woo, Marino, Orlandi, Tse, Sung, Jin, Yeh, Drive, Pogue, Aldini, Saito, Kuo, Chin, Richter, Hung, Mauriello, Sun, Situ, Martinez, Iida, Baldi, Koyama, Veronesi, Yamamoto, Murata, Fierro, Yamada, Matsumoto, Plate, Mater, Bonanno, Kraus, Lett, Kim, Hormann, Fini, Kai, Chang, Roberts, Romero, Ishida, Scotti, Mahajan, Bari, Prabhakaran, Yasuda, Maglio, Ramakrishna, Liao]

Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 122 during chondrogenic differentiation of MSC induced by TGF-beta(1). Chin J Traumatol 2005;8:349-51 65. Goessler UR, Bugert P, Bieback K, Deml M, Sadick H, Hormann K, et al . In-vitro analysis of the expression of TGFbeta-superfamily-members during chondrogenic differentiation of mesenchymal stem cells and chondrocytes during dedifferentiation in cell culture. Cell Mol Biol Lett 2005;10:345-62 66. Richter W. Mesenchymal stem cells and cartilage in situ regeneration. J Intern Med 2009;266:390-405 67. Pogue R, Lyons K. BMP signaling in the cartilage growth plate. Curr Top Dev Biol 2006;76:1-48 68. Scimeca M, Bonanno E, Piccirilli E, Baldi J, Mauriello A, Orlandi A, et al . Satellite cells CD 44 positive drive muscle regeneration in osteoarthritis patients. Stem Cells Int 2015;2015:469459 69. Abula K, Muneta T, Miyatake K, Yamada J, Matsukura Y, Inoue M, et al . 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Alhomrani: Osteoarthritis and regenerative therapies Asian Journal of Pharmaceutic s • Apr-Jun 2022 • 16 (2) | 123 91. Haleem AM, Singergy AA, Sabry D, Atta HM, Rashed LA, Chu CR, et al . The clinical use of human culture-expanded autologous bone marrow mesenchymal stem cells transplanted on platelet-rich fibrin glue in the treatment of articular cartilage defects: A pilot study and preliminary results. Cartilage 2010;1:253-61 92. Giannini S, Buda R, Vannini F, Cavallo M, Grigolo B. One-step bone marrow-derived cell transplantation in talar osteochondral lesions. Clin Orthop Relat Res 2009;467:3307-20 93. Giannini S, Buda R, Battaglia M, Cavallo M, Ruffilli A, Ramponi L, et al . One-step repair in talar osteochondral lesions: 4-year clinical results and t 2-mapping capability in outcome prediction. Am J Sports Med 2013;41:511-8 94. Nejadnik H, Hui JH, Feng Choong EP, Tai BC, Lee EH. Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: An observational cohort study. Am J Sports Med 2010;38:1110-6 95. Giannini S, Buda R, Cavallo M, Ruffilli A, Cenacchi A, Cavallo C, et al . Cartilage repair evolution in posttraumatic osteochondral lesions of the talus: From open field autologous chondrocyte to bone-marrow-derived cells transplantation. Injury 2010;41:1196-203 96. Teo BJ, Buhary K, Tai BC, Hui JH. Cell-based therapy improves function in adolescents and young adults with patellar osteochondritis dissecans. Clin Orthop Relat Res 2013;471:1152-8 97. Lee KB, Wang VT, Chan YH, Hui JH. A novel, minimally-invasive technique of cartilage repair in the human knee using arthroscopic microfracture and injections of mesenchymal stem cells and hyaluronic acid-a prospective comparative study on safety and shortterm efficacy. Ann Acad Med Singap 2012;41:511-7 98. Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I. Mesenchymal stem cell-based therapy for cartilage repair: A review. Knee Surg Sports Traumatol Arthrosc 2009;17:1289-97 99. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses 2008;71:900-8 100. Centeno CJ, Schultz JR, Cheever M, Robinson B, Freeman M, Marasco W. Safety and complications reporting on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 2010;5:81-93 101. Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, et al . Safety and complications reporting update on the re-implantation of cultureexpanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 2011;6:368-78 102. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis 2011;14:211-5 103. Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, et al . Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med 2012;15:422-8 104. Koh YG, Jo SB, Kwon OR, Suh DS, Lee SW, Park SH, et al . Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy 2013;29:748-55 105. Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: A case series. J Med Case Rep 2011;5:296 106. Pak J, Lee JH, Lee SH. A novel biological approach to treat chondromalacia patellae. PLoS One 2013;8:e 64569 107. Hauser RA, Orlofsky A. Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: A case series. Clin Med Insights Arthritis Musculoskelet Disord 2013;6:65-72 108. Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek E, van den Berg WB, et al . Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A 2012;18:45-54 Source of Support: Nil. Conflicts of Interest: None declared.

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