Active viscosupplements for osteoarthritis treatment

Seminars in Arthritis and Rheumatism 49 (2019) 171 183

Contents lists available at ScienceDirect

Seminars in Arthritis and Rheumatism journal homepage: www.elsevier.com/locate/semarthrit

Active viscosupplements for osteoarthritis treatment
ndeza,c, María Rosa Aguilara,c,*, Gloria María Pontes-Queroa,b, Luis García-Ferna a,c b
rez Cano , Blanca Va
zquez-Lasaa,c
n , Juan Pe Julio San Roma a

Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology (ICTP-CSIC), Madrid, Spain Alodia Farmac
eutica SL, Madrid, Spain c Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain b

A R T I C L E

I N F O

Keywords: Hyaluronic acid Synovial fluid Intraarticular administration Viscoelasticity Anti-inflammatory drugs

A B S T R A C T

Objective: Osteoarthritis is a chronic, painful and disabling disease which prevalence is increasing in developing countries. Patients with osteoarthritis present a reduced synovial fluid viscoelasticity due to a reduction in concentration and molecular weight of hyaluronic acid. Currently, the main treatment used to restore the compromised rheological properties of synovial fluid is the viscosupplementation by hyaluronic acid injections that can be combined with oral anti-inflammatory drugs for pain relief. Combination of viscosupplements with chemical agents or drugs is emerging as a new strategy to provide a double action of synovial fluid viscoelasticity recovery and the therapeutic effect of the bioactive principle. Methods: In this review, we present the latest research on the combination of viscosupplements with active molecules. We conducted a literature review of articles published in different web search engines and categorized according to the active molecule introduced into the viscosupplement. Results: Generally, the introduction of anti-inflammatory molecules have shown to improve pain relief although some cytotoxicity has been demonstrated especially for non-steroidal anti-inflammatory drugs. Other molecules such as antioxidant or disease modifying osteoarthritis drugs have been reported to improve viscosupplementation action. Drug delivery systems combined with hyaluronic acid could enhance the activity of the encapsulated molecules and provide better control over the drug release. Finally, biological approaches such as the use of stem cells or platelet-rich plasma seem to be the most promising strategies for cartilage recovery. Conclusions: Combination therapy of viscosupplements with therapeutic agents, drug delivery systems or regenerative therapies can improve viscosupplementation outcome in terms of pain relief and joint functionality. However, further research is needed in order to reach more conclusive results. © 2019 Elsevier Inc. All rights reserved.

Introduction Abbreviations: AD-MSC, adipose-derived mesenchymal stem cell; ADAMTS, A disintegrin and metalloproteinase with thrombospondin motifs; ACR, American College of Rheumatology; BMC, bone marrow concentrate; BM-MSC, bone marrow-derived mesenchymal stem cell; cHA-Dex, crosslinked hyaluronic acid-dexamethasone; Conct, concentration; COX-2, cyclooxygenase-2; DMEM, Dulbecco's Modified Eagle medium; DMOAD, disease modifying drugs for osteoarthritis; DDS, drug delivery system; ECM, extracellular matrix; EDA, ethylenediamine; EULAR, European League Against Rheumatism; EMA, European Medicines Agency; FDA, Food and Drug Administration; GelHA, gelatin methacrylate and hyaluronic acid methacrylate hydrogel; GelMA, gelatin methacrylate; HA, hyaluronic acid; HAMA, hyaluronic acid methacrylate; HA-sCT, HA-salmon calcitonin; IL, interleukin; IA, intraarticular; IOA, ioxaglic acid; KGN, kartogenin; MMP, matrix metalloproteinases; MSC, mesenchymal stem cell; Mw, molecular weight; MP, microparticle; NO, nitric oxide; NSAID, non-steroidal anti-inflammatory drug; OA, osteoarthritis; OARSI, Osteoarthritis Research Society International; PBS, phosphate buffered solution; PRP, platelet-rich plasma; PEG, poly(ethylene glycol); ROS, reactive oxygen species; SC, stem cell; SYSADOA, slow-acting drugs for OA; TA, triamcinolone acetonide; TH, triamcinolone hexacetonide; TNF, tumor necrosis factor. * Corresponding author at: Group of Biomaterials, Department of Polymeric Nanomaterials and Biomaterials, Institute of Polymer Science and Technology, ICTP-CSIC C/ Juan de la Cierva 3 Madrid, Spain. E-mail address: [email protected] (M.R. Aguilar). https://doi.org/10.1016/j.semarthrit.2019.02.008 0049-0172/© 2019 Elsevier Inc. All rights reserved.

Osteoarthritis (OA), the most common form of arthritis, is a chronic, highly prevalent disease and a major contributor to functional disability in older adults. OA can affect any synovial joint, but it occurs most often in knees, hips and hands. According to the World Health Organization in 2016, OA has become the twelfth leading cause of years lived with disability increasing from fourteenth to twelfth within 10 years [1]. The incidence of OA increases with advancing age, affecting 9.6% of men and 18% of women aged over 60 years worldwide [2]. Men are affected more frequently than women among those aged below 45 years, whereas women are more often affected among those aged over 55 years, as a consequence of hormonal changes, primarily estrogen deficiency [3]. Overweight is also a well-recognized risk factor for knee [4,5] and, to a lesser degree, hand [6] and hip OA [7] due to the combination of increased mechanical loads and metabolic factors such as adipokines [8]. There is also evidence that genetic factors play a major role in OA. Genetic polymorphism of genes encoding cartilage matrix proteins or

172

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

proteins involved in the immune cascade can participate on the initiation and development of OA [9,10]. Other risk factors include previous joint injury or mechanical predisposition [11,12]. Population ageing and sedentary lifestyle suggest that the number of people affected by hip or knee OA will increase over the next decades [13]. Synovial joints are formed by two articulating bones covered by cartilage and surrounded by an articular capsule that defines a synovial cavity filled with the synovial fluid (Fig. 1(A)) [14 16]. Lining the inner surface of the joint cavity is the synovial membrane or synovium. Synovial fluid is an ultra-filtrate of blood plasma composed of proteins from the blood plasma, hyaluronan, lubricin and interstitial fluid [17]. It is responsible of providing nutrients and oxygen to the articular cartilage [16]. Normal synovial fluid contains HA, the main contributor to the viscoelastic properties of synovial fluid, in a concentration that ranges between 3 and 4 mg/mL [18]. Viscoelasticity implies that HA acts like a viscous liquid at low shear rates and as an elastic material at high shear rates. This property allows synovial fluid to act as a shock absorber when it is subjected to high loads and as a lubricant during low loads, reducing friction between the articular cartilages [19]. In osteoarthritic joints, there is a progressive cartilage loss, subchondral bone remodeling and inflammation of synovium (see Fig. 1 (B)). Cartilage degradation appears because ECM breakdown exceeds its synthesis. Different cytokines, growth factors and proteases are responsible of this imbalance between synthesis and degradation [20]. OA patients have an increased activity of matrix metalloproteinases (MMP) that have the ability to cleave ECM components like collagen, and A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) involved in aggrecan cleavage, promoting cartilage destruction [21,22]. Furthermore, pro-inflammatory cytokines such as interleukin-1b (IL-1b) and tumor necrosis factor (TNF) have a central role in OA stimulating the production of reactive oxygen species (ROS), nitric oxide (NO), prostaglandin E2 and other pro-inflammatory cytokines that in turn contribute to cartilage inflammation [23 25]. Subchondral bone changes such as decrease in bone remodeling and the formation of osteophytes have also a role in the initiation and progression of OA [26,27]. Inflammation of the synovial membrane, or synovitis, also contributes to the progression of cartilage loss by an increased vascularity, infiltration of mononuclear cells in the synovium and the synthesis of

inflammatory mediators [28,29]. Additionally, patients with OA have a 50% reduction in concentration and molecular weight of HA in synovial fluid as seen in Table 1 [30 32]. Synovial fluid becomes less viscoelastic and its properties as a lubricating, shock-absorbing and filtering agent are diminished [33]. State of the art of osteoarthritis treatments Since OA is a chronic and non-reversible condition, the current management is primarily based on symptomatic treatments, directed to reducing pain and slowing disease progression. This requires a combination of non-pharmacological and pharmacological treatments that will depend on the patient's symptomatology, as presented in Fig. 2. Treatment guidelines for the management of OA have been developed by the European League Against Rheumatism (EULAR), Osteoarthritis Research Society International (OARSI) and the American College of Rheumatology (ACR), based on research evidence. Non-pharmacological therapies are recommended for all patients and include education, self-management, weight loss, aerobic exercise and periarticular muscle strengthening [34 37]. Pharmacological therapies are the most common option for managing OA. Depending on the severity of the disease, physicians can recommend from simple analgesic to surgery. Usually, the treatment at the earliest stages of OA is based on the use of chondroprotective substances or slow-acting drugs for OA (SYSADOA) including glucosamine, chondroitin sulfate and HA (cartilaginous matrix precursors) and diacerin (a cytokine modulator) [38]. SYSADOA provide symptomatic relief by targeting the underlying pathology of OA, but their efficacy in pain reduction is controversial and established as uncertain by the OARSI and ACR [39,40]. However, they are used due to their minor side effects. Patients with low to mild pain use short-term analgesics, i.e., paracetamol or tramadol, although their use is associated with adverse hepatic effects, multi-organ failure in the case of paracetamol [41] or constipation, nausea and dizziness in the case of tramadol [42]. When pain reaches the mild to moderate levels and the analgesic are not sufficient to relieve pain, traditional non-steroidal anti-inflammatory drugs (NSAID) such as ibuprofen or diclofenac are used [43]. The main problem of NSAID for long-term use is the secondary effects

Fig. 1. Comparison of healthy and osteoarthritic synovial joints. (A) Synovial joints are formed by an articular capsule defining the synovial cavity. (B) Osteoarthritic synovial joints are characterized by a progressive cartilage loss, inflammation of synovial membrane and subchondral bone remodeling.

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

173

Table 1 Properties of healthy and osteoarthritic synovial fluid. Adapted from [30], Copyright 2013, with permission from Elsevier Viscoelastic properties at 2.5 Hz Synovial fluid

HA Molecular weight (kDa)

HA Concentration (mg/mL)

G’(Pa)

G’’ (Pa)

Zero shear viscosity (Pa s)

Healthy Young Osteoarthritic

6300 7600 1600 3480

2.5 4 1 2

23 7

7 5

6 175 0.01 1

related to gastrointestinal, cardiovascular and hepatic problems [44]. Other option is the use of selective cyclooxygenase-2 (COX-2) inhibitors, a subclass of NSAID that directly targets COX-2, an enzyme responsible of inflammation and pain. This selectivity reduces gastrointestinal side effects, but some studies indicate that COX-2 inhibitors are related to increased cardiovascular problems [45,46]. Topical agents can be used as complements or alternatives to oral analgesics, especially for elderly people, due to their safer profile compared to oral NSAID [47]. ACR, OARSI and EULAR guidelines [34 37] recommend the use of capsaicin as a topical analgesic for pain control. In addition, lidocaine patches can be used as topical analgesics although there is small evidence of their efficacy [48,49]. Intraarticular (IA) therapies are commonly used in OA management when patient symptoms are severe, especially for knee OA. Corticosteroids injections are widely used to treat synovium inflammation and pain in osteoarthritic patients. Corticosteroids are antiinflammatory drugs with several mechanisms of action. The most commonly used are crystalline triamcinolone and non-crystalline prednisolone and methylprednisolone. There is evidence that corticosteroids provide short term pain relief but lack long term effects due to their rapid elimination from the synovial cavity [50,51]. Moreover, the formation of crystals due to the crystalline nature of steroids may cause transient inflammation of synovium, and repeated injections can damage the articular cartilage [52]. Another conservative treatment for OA is the IA injection of HA. IA injections of HA were approved by the FDA in 2001, although there are not clear recommendations about its use [35 37]. The rationale behind IA HA injections is the restoration of the viscoelastic properties of synovial fluid, known as viscosupplementation [53]. The newest IA therapies are

based on biological products such as stem cells (SC) or platelet-rich plasma (PRP) in order to favor joint remodelation and healing but there is a lack of consensus about their use and its efficacy [54,55]. Finally, most severe OA cases may require surgical treatments like microfractures, osteotomy, arthroscopy, total joint arthroplasty or transplantation of articular cartilage and autologous chondrocytes in younger patients [56 58]. Methods For this review article, an extensive search was conducted in PubMed, Scopus, web search engines and treatment guidelines using key terms such as: osteoarthritis, hyaluronic acid, viscosupplements, intraarticular, corticosteroids, NSAID, antioxidants, DMOAD, drug delivery systems, liposomes, nanoparticles, stem cells and plateletrich plasma. The search strategy included in vitro, in vivo and clinical studies, systemic reviews and meta-analyses and was limited to publications in English. Articles were classified according to the type of molecule or agent combined with the viscosupplement. Data about properties of both, the viscosupplement and the combined bioactive principle, are provided into summary tables while the results from the articles are discussed in the text. New approaches on combined viscosupplements Several systemic reviews have demonstrated the positive effect of viscosupplementation in alleviating pain [51,59,60], although the efficacy of HA therapies is controversial due to inconsistency within treatment guidelines and the current literature. In vitro and in vivo

Fig. 2. Scheme of current osteoarthritis treatments. The treatment approach depends on the severity of the symptoms and includes non-pharmacological therapies, pharmacological therapies and surgery.

174

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

studies have shown various physiological effects of exogenous HA that may counteract the mechanisms involved in OA pathogenesis [61,62]. Chondroprotection and suppression of aggrecan degradation are the most reported effects. HA injections can also reduce the production of pro-inflammatory mediators and MMP, and reduce nerve impulses and nerve sensitivity associated with OA pain [62]. HA binding to CD44 cell receptors inhibits IL-1b expression and, consequently, the production of MMP, ADAMTS and NO, responsible of cartilage destruction [63,64]. Proteoglycan and glycosaminoglycan synthesis, anti-inflammatory, analgesic and subchondral bone actions are also reported [61]. Viscosupplementation has to be a local therapy since OA is a localized joint disease. For this purpose, its IA administration is the best strategy to achieve the maximum drug concentration in the required tissue [65]. Furthermore, the relief of pain due to the HA action should last as longer as possible, making possible to reduce the number of injections and the patient discomfort. Several clinical trials have demonstrated that viscosupplement injections relief of pain is longer than the relief of pain derived from oral NSAID and corticosteroid injections, lasting up to 6 months [51,66]. Clinically, crosslinked and high molecular weight HA viscosupplements seem to exhibit superior capabilities than linear and low molecular weight HA, which may be due to the greatest difficulty to degrade crosslinked and high molecular weight products [61]. There are different commercial HA formulations for its IA administration that differ in molecular weight, reticulation grade and origin, among other properties [65,67]. Low, moderate and high molecular weight HA formulations include HyalganÒ (500 730 kDa), EuflexxaÒ (2400 3600 kDa) and SynviscÒ (6000 kDa), respectively. Avian-derived products include viscosupplements such as HyalganÒ or SynviscÒ while bacterial products include AdantÒ and MonoviscÒ . However, no product is clearly recommended over others. One of the major problems of IA administration is the fast clearance and short residence time of drugs in the joint, due to the lymphatic system. One approach under research to increase drug residence time is the use of drug delivery systems (DDS) that make possible the sustained release of therapeutic agents [68]. Viscosupplements can be used as drug delivery vehicles for the progressive release of bioactive molecules and, at the same time, restore the viscoelasticity of synovial fluid. Nowadays, several commercial viscosupplements combine HA and other bioactive principles, the most common being different antioxidant molecules such as mannitol and sorbitol (Table 2). Moreover, corticosteroids, DDS and cell-based therapies are also being actively investigated in this application. Corticosteroids are the most common ones since they are widely used in the treatment of OA [69 75]. Introduction of DDS like microparticles and liposomes that could encapsulate drugs in their interior is also under research [76 79]. Moreover, the combination of viscosupplementation and cell-based therapies could favor cartilage and synovial fluid regeneration [80 88]. Viscosupplementation with drugs and bioactive compounds The need for improving the clinical outcome of viscosupplements has led to the association of HA and free drugs. The introduction of drugs in HA networks can avoid some problems presented in IA drug administration, such as drug crystallization and toxicity [53]. Moreover, these combined systems may couple the beneficial effects of both components, maintaining the viscosupplement properties. The inflammatory component of OA has led to the frequent use of antiinflammatory drugs. Corticosteroids are the most investigated agents, since they are commonly used as rapid analgesics for pain management in osteoarthritic patients [69 74]. Other drugs are under research like antioxidant molecules [89 94] and the so called disease modifying drugs for OA (DMOAD) [95 98]. DMOAD include drugs like calcitonin and bisphosphonates that are thought to slow down or

even inhibit the disease progression [99,100]. In Table 3 the latest research on the combination of HA and free bioactive principles for the treatment of OA is found. Anti-inflammatory drugs Through the years, NSAID have been orally administrated for antiinflammatory purposes, but they show several gastrointestinal adverse effects [105] and increase the risk of peptic ulcer disease complications by 3 5-fold [106]. Local administrations of NSAID could drastically reduce or avoid the systemic circulation of the drug [107]. However, induced damage has been observed in some studies when administering NSAID directly into the synovial cavity [108,109]. In a systemic review carried out by Ozkan et al., the IA administration of HA with anti-inflammatories showed greater pain relief than HA alone although a reduction in the expression levels of genes related to cartilage ECM synthesis was observed [102]. Several in vitro and in vivo studies have demonstrated the synergetic effect of viscosupplements with NSAID [101,110,111]. For instance, the effect of carprofen and low molecular weight HA has been studied [101]. Carprofen has a strong anti-inflammatory effect but also presents chondrotoxicity. Despite HA could not reduce the cytotoxicity levels of carprofen in vitro, in explant cultures, the combination of carprofen and HA caused less cartilage loss compared to the control. Moreover, higher levels of type II collagen and aggrecan expression were observed in the combined systems than carprofen alone. Other example is tenoxicam, a NSAID of the oxicam class that has a long half-life, being interesting for long-term pain relief [112]. Usually, tenoxicam is administered after joint surgery as an analgesic. In a recent study, Ozkan et al. showed that the IA injection of tenoxicam in combination with the commercial viscosupplement AdantÒ and vitamin E improved the recovery of OA in a rat model [102]. Clinical studies of viscosupplements combined with NSAID have also been carried out recently. For instance, Palmieri et al. studied the clinical efficacy of diclofenac and sodium clodronate, a bisphosphonate, in combination with a viscosupplement [97]. HA alone or in combination with diclofenac was seen to alleviate pain, although to a lesser degree than the pain relief obtained with the combination of HA with sodium clodronate. IA corticosteroids injections have been used for decades to reduce inflammation and pain in OA patients [113]. Corticosteroids have a dose-dependent effect and provide fast pain relief while viscosupplements seem to exhibit a long lasting relief [114,115]. Low doses of corticosteroids can enhance cartilage recovery from damage while higher doses are associated with chondrotoxicity and further degradation of cartilage [116]. Moreover, the crystalline nature of corticosteroids can derive in the formation of crystals that can produce pain and even crystal-induced arthritis [68]. Therefore, development of combined HA and corticosteroids systems could be a suitable therapy for short and long term results, where HA would act as a local delivery vehicle, at the same time that as a viscosupplement, reducing systemic exposure of cartilage to corticosteroids, as suggested in clinical trials [70,71]. As far as we are concerned, currently there is one commercial formulation of these characteristics called CingalÒ , formed by MonoviscÒ crosslinked HA and triamcinolone hexacetonide. Triamcinolone is one of the most studied corticosteroid for its incorporation in HA hydrogels, that may be because of its highest potency compared to other corticosteroids [116]. Euppayo et al. studied cartilage degradation after the treatment with triamcinolone acetonide in combination with low molecular weight hyaluronan on primary canine chondrocytes and cartilage explants [69]. Chondrocytes cultures showed that triamcinolone reduced cell viability in a concentration-dependent manner. Triamcinolone downregulated the expression of aggrecan while upregulated different cytokines involved in cartilage matrix destruction. In explant cultures, triamcinolone increased cartilage damaged and the combination with HA did not show beneficial effects. Therefore, the authors concluded that the use

Table 2 Characteristics of commercial combined viscosupplements. HA

Bioactive principle Structural formula

Number/volume (mL) of injections

Mw (kDa)

Conct. (mg/mL)

Type

Conct. (mg/mL)

CingalÒ

1900

22

Triamcinolone acetonide (Corticosteroid)

4.5

1/4

Arthrum HCSÒ

2800

20

20

1 3/2

Synovium surgicalÒ

2800

20

Chondroitin sulfate (Polymer) Chondroitin sulfate

20

1/3

Ostenil plusÒ HappyviscÒ HappycrossÒ

1500 1500 1500

20 15.5 16

Mannitol (Antioxidant) Mannitol Mannitol

5 35 35

1/2 3/2 1/2.2

Synolis V-AÒ

2000

20

Sorbitol (Antioxidant)

40

1 3/2

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

Commercial name

175

176

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

Table 3 Experimental viscosupplements combined with bioactive principles for OA treatment developed in the past five years Viscosupplement

Bioactive principle a

Type

Mw (kDa)

Conct. (units )

Name

Type

Conct. (unitsa)

Ref.

HA solution

500 730

2.5 mg/mL

Carprofen

NSAID

[101]

AdantÒ VariofillÒ

600 1200 N/A

10 mg/mL 33 mg/mL

HA solution

500 700

2.5 mg/mL

Tenoxicam Diclofenac Sodium clodronate Triamcinolone acetonide

NSAID NSAID Bisphosphonate (DMOAD) Corticosteroid

VariofillÒ HydrosÒ and HydrosÒ -TA (HA based hydrogels suspended in HA solution) Hylan GF-20Ò HA solution

N/A N/A

33 mg/mL N/A

Triamcinolone acetonide Triamcinolone acetonide

Corticosteroid Corticosteroid

12.5 mg/mL 25 mg/mL 10 mg/mL 10 mg/mL 10 mg/mL 1.25 mg/mL 2.5 mg/mL 5 mg/mL 10 mg/mL 10 mg/6mL

N/A 500 730

N/A 2.5 mg/mL

Triamcinolone acetonide Dexamethasone

Corticosteroid Corticosteroid

[71] [73]

Prednisolone

Corticosteroid

20 mg/mL 0.5 mg/mL 1 mg/mL 2 mg/mL 3.13 mg/mL 6.25 mg/mL 12.5 mg/mL 0.2 mg/mL 0.5 mg/mL 35 mg/mL 3.5% 3.5%

HA hydrogel

N/A

N/A

Dexamethasone

Corticosteroid

HA solution Hanox-M-XLÒ Go-onÒ Hanox-MÒ Hyal G-FÒ Hanox-M-XLÒ Synolis V-AÒ HA-4AR conjugates OstenilÒ

800 N/A 800 1000 1000 1000 N/A 2200 1000 2000

8 mg/mL 16 mg/mL 10 mg/mL 15.5 mg/mL 8 mg/mL 15.5 mg/mL 20 mg/mL 2.7% 0.1%

Mannitol Mannitol Mannitol

Antioxidant Antioxidant Antioxidant

Sorbitol 4-aminoresorcinol L-glutathione

Antioxidant Antioxidant Antioxidant

HA-sCT conjugates HA-ADAMTS inhibitor conjugates HA hydrogel HanoxÒ

200 N/A

24 mg/3.75 mL HA-aldehyde: HA-adipic dihydrazide 1:1 v/v 10 mg/mL 16 mg/mL

Salmon calcitonin ADAMTS-5 inhibitor Doxycycline Cortivazol Triamcinolone hexacetonide Lidocain clorhydrate Ioxaglic acid

60 120 1500

Hanox-M-XLÒ a

Combined with mannitol (3.5%).

[102] [97] [69]

[103] [72]

[74] [89] [93] [91]

[92] [90, 94] [104]

DMOAD DMOAD

40 mg/mL N/A 0.5% 10% 20% 1.5 mg/mL N/A

DMOAD Corticosteroid Corticosteroid Local anesthesic Contrast agent

87.5 mg/mL 2.5 mg/mL 20 mg/mL 10 mg/mL 320 mg Iode/mL

[98] [75]

[96] [95]

Units as represented in the paper.

of triamcinolone alone or with HA should be of concern. Petrella et al. also evaluated the effect of this corticosteroid in the viscosupplement VariofillÒ in a rabbit model, obtaining an improvement of cartilage degeneration in both, the viscosupplement alone or with triamcinolone acetonide, but with no differences between them [103].They also studied the safety and performance of two HA formulations called HydrosÒ and Hydros-TA in patients with knee OA [72]. HydrosÒ is a hyaluronan-based hydrogel suspended in hyaluronan solution, while Hydros-TA has the HydrosÒ formulation plus triamcinolone. All the treatments were well tolerated by the patients with similar adverse effects in all groups and results indicated a greater reduction in pain in patients treated with Hydros-TA. Other clinical study supports these results [71] demonstrating an increased reduction in pain at the short term adding triamcinolone to a viscosupplement. Other corticosteroids have been also studied. Siengdee et al. used porcine explants to test the effects of dexamethasone and prednisolone with and without HA [73]. Regarding the glycosaminoglycan release, results demonstrated that the presence of HA reduced the cytotoxicity of prednisolone. Controversely, the authors observed a reduced cytotoxicity in the case of dexamethasone alone compared to dexamethasone with HA. Moreover, dexamethasone seemed to be more effective for cartilage recovery than prednisolone. Other study that obtained promising results for the use of HA with dexamethasone was the one carried out by Zhang et al. [74], who prepared injectable crosslinked hyaluronic acid-dexamethasone (cHA-Dex)

hydrogels. Cytotoxicity tests revealed that the hydrogels loaded with dexamethasone presented lower cytotoxicity with respect to dexamethasone alone. Histological examination revealed less cartilage damage in the cHA-Dex hydrogel compared to the hydrogel alone. Moreover, cHA-Dex injections increased type II collagen while reduced type X collagen and MMP-13. As a conclusion, bibliography has demonstrated a further improvement of short term pain relief when adding anti-inflammatory drugs to viscosupplements. However, the cytotoxicity of these drugs, especially for NSAID, must be considered, since most of the studies noticed this behavior. Other Oxidative stress, ROS and reactive nitrogen species (RNS) are related to OA progression. During OA, chondrocytes release higher levels of ROS in response to partial oxygen pressure fluctuations, mechanical stress and inflammatory mediators. The increased number of ROS enhances cartilage destruction by interfering in matrix synthesis and inducing cell apoptosis [117,118]. To overcome these drawbacks, some viscosupplements containing antioxidants have been commercialized (Table 3) and molecules like mannitol [89,91,93] and sorbitol [92] are being further studied to add an antioxidant character to HA. Other type of antioxidant HA formulations are under research. Kaderli et al. prepared antioxidant conjugated HA formulations to retard HA degradation and tested in vitro the resistance of the

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

formulations in an oxidative environment mimicking OA [94]. One of the conjugated systems, HA-4-aminoresocinol (HA-4AR), showed an increased viscosity under oxidative stress in a process called oxidoviscosification. This process could lead to a lower degradation rate of the HA conjugate, extending its therapeutic effect. The conjugate was also shown to be biocompatible in vitro and in vivo. In a subsequent study, this group compared the IA administration of HA-4AR to the IA injection of the commercial viscosupplement OstenilÒ in rabbits, demonstrating that the formulation was able to decrease synovial membrane hypertrophy occurring in OA [90]. In order to improve HA action, Yang et al. used L-glutathione, an antioxidant molecule that protects cells from ROS and RNS [104]. HA was supplemented with different concentrations of L-glutathione and were tested in vitro on human FLS. Cell morphology and glycosaminoglycan production were unchanged under all the treatments although cytotoxicity increased in the formulation with the higher concentration of antioxidant. The antioxidant capacity of synoviocytes was restored when treated with HA and L-glutathione after its inhibition by IL-1b stimulation and ROS/RNS levels were decreased. Different inflammatory molecules were downregulated in the cell cultures when treated with HA alone or supplemented with L-glutathione. Therefore, the addition of the antioxidant to HA could enhance an antioxidant activity by modulating inflammatory cytokines in synoviocytes, although higher concentrations of L-glutathione were cytotoxic. Drugs currently used to treat OA are not able to modify the disease progression but are mainly used to treat its symptoms. There is an increasing interest in the use of disease modifying OA drugs (DMOAD) that could retard and inhibit OA progression. Among them, MMP, aggrecanase and cathepsin K inhibitors, calcitonin and bisphosphonates are under investigation [99,100]. Although DMOAD have not been licensed by the Food and Drug Administration (FDA) or the European Medicines Agency (EMA), they are promising future approaches for OA treatment. Calcitonin has been used for decades to treat osteoporosis and can help cartilage recovery by inhibiting MMP and collagen breakdown [119]. However, its rapid elimination from the body presents limitations for its administration. In order to prevent the joint clearance of calcitonin, Mero et al. prepared HA-salmon calcitonin (HA-sCT) covalent conjugates using an aldehyde derivative of HA for N-terminal site-selective coupling of calcitonin [96]. Calcitonin activity was maintained after its coupling to HA in vitro and in vivo and HA-sCT conjugates did not trigger any systemic effect as calcitonin did. Macro and microscopic assessments proved the chondroprotective effect of HA-sCT in a rabbit model. Doxycycline is also a MMP inhibitor and a suppressor of inflammatory cytokine production [99]. Lu et al. prepared injectable HA hydrogels with doxycycline that presented higher chondroprotective effects than HA hydrogels alone in a rabbit model [98]. Besides, macroscopic examination indicated a smoother cartilage surface, smaller osteophytes and fewer fissures compared to HA or doxycycline alone. Aggrecan degradation by ADAMTS plays a key role in cartilage destruction and OA progression, being ADAMTS-5 one of the main catabolic contributors. An in situ cross-linkable hydrogel based on aldehyde HA and adipic dihydrazide HA was developed and conjugated with ADAMTS-5 inhibitor 114,810, to test the synergistic effects of both [95]. Although results showed a poor drug-release behavior, human and rat models revealed the protective effect of the hydrogel with the inhibitor on articular cartilage, promoting the repair of articular osteochondral defects and slowing the progression of surgicallyinduced OA. The rheological behavior of viscosupplements is crucial to restore the lubricating and shock-absorbing properties of synovial fluid. With the aim of investigating the impact of different products in the rheological properties of HA, Conrozier et al. performed a rheological study associating two corticosteroids (triamcinolone and cortivazol), a local anesthetics (lidocaine chlorhydrate) and a contrast agent

177

Fig. 3. Flow curve of linear (A) and cross-linked (B) hyaluronic acid mixed with different products (ratio 1:1). Adapted from [75], Copyright 2016, with permission from Springer.

(ioxaglic acid) with two types of HA, linear and crosslinked [75]. Previously, linear and crosslinked HA were diluted decreasing the viscosity of HA solutions. In brief, the addition of any product to HA can greatly modify the rheological behavior of viscosupplements and, in this case, all the products decreased HA viscosity for linear and crosslinked HA as it can be seen in Fig. 3. Bioactive compounds encapsulated in drug delivery systems into viscosupplements In order to increase drug bioavailability and reduce the systemic effects, different DDS are under study for the treatment of OA, such as liposomes, microparticles (MP) and micelles for their local IA delivery into the affected joint [120,121]. DDS allow a controlled release of therapeutic agents, extend drug residence time and avoid crystalinduced arthritis of crystalline compounds such as corticosteroids, due to their encapsulation and the use of minimal doses [68,122]. The progressive nature of OA makes the maintenance of an effective drug action in the critical joint and, therefore, the use of DDS is a promising solution to extend their action. The addition of particulate vehicles to viscosupplements provides an additional control over the drug release. Drug release from the drug-loaded delivery system would occur by diffusion through the system into the HA hydrogel and then, diffusion from the hydrogel matrix to the joint cavity. Consequently, a dual controlled diffusion mechanism can be achieved. Table 4 summarizes the last research on DDS encapsulating bioactive principles in viscosupplements. It is interesting to notice that the bioactive principles encapsulated inside the delivery vehicles are of different natures. We found a selective NSAID, which is a common drug used to treat OA symptoms, but drugs with specific biological functionalities such as anti-angiogenic or promoters of stem cell differentiation are being encapsulated as well, opening new strategies for the treatment of this disease. Liposomes, artificial lipid vesicles widely used as carriers of drugs and biologically active molecules, are already approved to be used clinically in humans [123]. Liposomes consist of spherical vesicles composed of a phospholipid bilayer that resembles the cell

178

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

Table 4 Experimental bioactive compounds encapsulated in DDS combined with viscosupplements for OA treatment developed in the past five years Viscosupplement

DDS

Bioactive principle

Type

Mw (kDa)

Conct. (units )

Type

Size

Name

Type

Conct. (unitsa)

Ref.

HA solution Photo crosslinked HAMA hydrogel Photo crosslinked GelHA hydrogel HA/PEG/KGN hydrogel

2500 350 N/A 1000

20 mg/mL 2% HAMA 2% HAMA 2%

Liposome Chitosan MP Chitosan MP PEG-KGN micelle

4.98 mm 100 mm 40 100 mm 424.7 nm

Celecoxib Cordycepin Crizotinib Kartogenin

NSAID Derivative of adenosine Anti-angiogenic drug Differentiator promoter

0.5 mg/mL N/A N/A 2%

[78] [79] [76] [77]

a

a

Units as represented in the paper.

membrane with the capacity to encapsulate hydrophilic and hydrophobic drugs and prolong their time of action [124]. Dong et al. studied the effect of celecoxib-loaded liposomes in combination with a gel of HA for IA injection [78]. Celecoxib is a COX-2 inhibitor that reduces inflammation and pain in osteoarthritic patients. Liposomes, fabricated from the film technique, had encapsulation efficacies over 99% due to the poor solubility and high lipophilicity of celecoxib. The in vitro release showed a retarded release of celecoxib when combining the liposomes with the HA gel since celecoxib is first released from the liposomes and then diffused through the HA network to the medium. In this study, rabbits were treated with the combined system, presenting better results than the controls in the histological analysis and demonstrating the protective effect of the system. Other particulate carriers developed to prolong the retention time of drugs in the joints are based on biodegradable MP and microspheres (spherical MP). MP include particles with sizes between 0.1 and 100 mm and have a much higher surface-to-volume ratio than macroparticles [125]. They can be manufactured from different natural and synthetic materials. Poly(lactic-co-glycolic acid) or PLGA is a widely used biodegradable polymer for preparation of drug-loaded microspheres [126]. In 2017, an extended-release formulation of triamcinolone acetonide in PLGA microspheres (FX006) was approved by the FDA for the management of knee OA, after their promising clinical results [127,128]. Single IA injection of the formulations showed a greater pain relief from five to ten weeks after treatment compared to triamcinolone acetonide injections, and from the first to the eleventh week after the treatment compared to placebo. Chitosan has been studied for its application in articular treatments due to its low toxicity, bioactivity and mechanical properties [129,130]. For example, there are commercially available chitosan scaffolds for its use with microfracture procedures to reinforce the technique [131]. Moreover, chitosan MP have shown to be suitable DDS [132,133]. The introduction of cordycepin-loaded chitosan MP in a photo-crosslinked hydrogel of HA methacrylate (HAMA) was recently studied for OA [79]. The authors found that cordycepin, an adenosine derivative, mitigated cartilage destruction by inducing autophagy, an adaptative response that could protect cells during OA progression, using ex vivo and in vivo models. Cordycepin was seen to regulate autophagy by decreasing MMP-13 and ADAMTS-5 expression. However, chitosan MP were only able to sustain the release of cordycepin for 3 days and the release rate of the drug was not different between the cordycepin loaded MP in the presence or absence of the hydrogel. Angiogenesis seems to be increased in articular cartilage, synovium and menisci in OA patients and contributes to osteophyte formation [134]. Following the strategy mentioned above, Chen et al. encapsulated crizotinib in the chitosan MP and introduced them in a photo-crosslinked hydrogel of gelatin MA (GelMA) and HAMA (GelHA) [76]. Crizotinib is a drug that might reduce OA symptoms, as it possesses an antiangiogenic effect. In vitro and ex vivo cultures showed that crizotinib downregulated protein levels of vascular endothelial growth factor proving that its therapeutic effect is related to angiogenesis inhibition. Furthermore, crizotinib downregulated MMP-13 and ADAMTS-5 mRNA expressions and the in vivo studies showed the lowest cartilage structural changes in mice treated with the hydrogels and the encapsulated drug.

Poly(ethylene glycol) (PEG) is one of the most used synthetic polymers for the elaboration of hydrogels and it has been extensively used to increase the solubility and lower the toxicity of different molecules [135]. Kang et al. prepared HA hydrogels containing covalently bonded PEG-kartogenin (PEG-KGN) micelles that provided better chondroprotection and cartilage regeneration than HA hydrogels in an OA rabbit model [77]. KGN was used as an activator of multipotent mesenchymal stem cells (MSC) differentiation into chondrocytes, in order to favor cartilage repair. Before cross-linking HA and PEG-KGN micelles, HA was reacted with ethylenediamine, which reduced HA degradation and facilitated integration of HA and the micelles. Covalent integration of the micelles into HA hydrogels (HA/PEG/KGN) reduced drug release rates providing a sustained release over 5 days in vitro. Moreover, enzymatic degradation was reduced in the HA/ PEG/KGN systems compared to PEG-KGN formulations and aggrecan and type II collagen expressions were enhanced in the hydrogels. Regenerative therapies in viscosupplements Stem cells and platelet-rich plasma injections, chondrocyte transplantation or surgical procedures such as microfracture and mosaicoplasty are the most used reparative methods to treat cartilage defects [136,137]. Tissue-engineering and regenerative strategies based on biomaterials, cells and other bioactive molecules have emerged as a possibility to repair osteoarthritic cartilage. This regenerative approach tries to stimulate the regeneration of articular cartilage improving the joint function and reducing pain. The combination of HA injections and tissue engineering therapies can consequently couple synovial fluid viscoelasticity restoration and cartilage repair and is one of the most promising strategies in cartilage repair as reported recently in bibliography [82,87,138]. Table 5 summarizes the last research on this approach. PRP treatment has gained attention as an IA therapy for OA due to its anti-inflammatory and anabolic properties. PRP is a concentrate of platelet-rich plasma derived from autologous blood samples and obtained by a two-step centrifugation [139]. This plasma concentrates platelets approximately fourfold to eightfold as compared to untreated blood [140]. Platelets are a potential source of growth factors and other bioactive molecules able to stimulate cellular recruitment, cell proliferation and modulate inflammation events [139,141]. The activation of PRP via the addition of calcium chloride or thrombin, among other, induces the degranulation of platelets and the release of different growth factors entrapped in the platelet granules including platelet-derived growth factor, epidermal growth factor, insulin like growth factor and vascular endothelial growth factor [142,143]. These growth factors have the ability to modulate tissue healing and matrix synthesis and therefore, cartilage repair, making PRP IA injections a suitable choice for OA treatment [144,145]. In fact, PRP administration from the patient blood is a therapy currently applied in clinical practice. Depending on the leukocyte content PRP can be classified into two categories: leukocyte-rich PRP (LR-PRP), with leukocyte content above baseline; and leukocyte-poor PRP (LP-PRP), having a leukocyte concentration below baseline [143,146]. The effect of white blood cells concentration in the PRP effect is unclear [142,143,147].

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

179

Table 5 Research on the combination of regenerative therapies and HA for the treatment of OA developed in the past five years Viscosupplement

Biological component

Type

Mw (kDa)

Conct. (units )

Type

Conct. (unitsa)

Ref.

HA solution HyalubrixÒ Euflexxa-FerringÒ HA solution HYADDÒ 4-G

1550 N/A 2400 3600 50 120 500 730

PRP PRP PRP PRP PRP

PRP:HA 2:2 v/v PRP:HA 5:2 v/v PRP:HA 5:2 v/v N/A PRP/HA 5:15 v/v

[82] [88] [84] [86] [87]

SinovialÒ Sinovial ForteÒ SinovialÒ HyalubrixÒ HA solution HA solution

800 1200 200 1200 1100 1400 1500 2000 500 730 600 1500

20 mg/mL 30 mg/2mL 10 mg/mL N/A 8 mg/mL 15 mg/mL 0.8% 1.6% 3.2% 1.5% 5 mg/mL 25 mg/mL

PRP

PRP/HA 1:1 v/v

[83]

MSC and BMC AD-MSC

[85] [81]

HA solution

N/A

10 mg/mL

BM-MSC

2 £ 106 cells/0.3 mL HA 1 £ 107 cells/2.5 mL HA (low) 5 £ 107 cells/2.5 mL HA (high) 106 cells/0.4 mL HA

a

a

[80]

Units as represented in the paper.

Supporters of LR-PRP formulations consider that the immune regulatory function of leukocytes can improve PRP wound healing activity [148] while others postulate that it can result in an antagonist effect due to the release of inflammatory molecules and catabolic cytokines such as MMP, IL-1b and TNF-a [149 151]. Nonetheless, recent clinical studies support the use of LP-PRP for the treatment of knee OA [148,152]. Regarding the PRP volume, there is not a fixed quantity to be injected although most of the commercial PRP kits [146,147] and clinical trials [153,154] use 3 5 ml PRP. There are several clinical studies comparing the effects of intraarticular PRP injections alone or in combination with viscosupplements [82,84,88, 155 157]. For example, in a systemic review, Kurapati et al. concluded that promising results have been obtained regarding functional improvement and pain relief up to a year after the treatment with PRP and HA [155]. Abate et al. saw that the combined treatment of PRP and HA was effective regarding pain relief and knee function in patients with mild to moderate knee OA, with no difference compared to the treatment with PRP alone [82]. The same conclusion was driven by Dallari et al. that could observe an improvement in hip OA patients when administering PRP alone or in combination with HA but with no difference between the treatments [88]. On the contrary, Lana et al. obtained better functional clinical outcomes when HA and PRP were associated [84]. In vitro and in vivo studies of PRP combined with HA are also being conducted. Chen et al. studied the therapeutic activity of viscosupplements and PRP for tissue regeneration using a 3dimensional neo-cartilage and a mice model [86]. The results demonstrated that the combination of HA and PRP considerably recovered the expression of chondrogenic genes diminished by IL-1b and TNF-a, while decreased chemokine and cytokine expression (Fig. 4). Moreover, intra-articular HA and PRP injection significantly enhanced cartilage recovery in mice. On the contrary, the group of Duan et al. saw no improvements when injecting the viscosupplement HYADDÒ 4-G with PRP in a mice model in which joint injury was induced by axial tibial loading [87]. They concluded that HA and PRP alone or in combination did not exert any therapeutic effect regarding cartilage and subchondral bone in mice. With the aim of studying the influence of PRP introduction in the viscoelastic and biological properties of commercial viscosupplements, Russo et al. prepared mixtures containing both components [83]. Results showed a decrease in viscosity and viscous moduli of about one order of magnitude after PRP addition, reaching values significantly lower than those of viscosupplements. On the other hand, chondrocyte viability and proliferation and glycosaminoglycan production was higher in the mixtures compared to HA alone. Therefore, they concluded that the combination of PRP and viscosupplements

displayed better biological behavior than viscosupplements alone although their rheological properties should be adjusted. SC are of great interest in tissue engineering due to their ability to differentiate in different cell types and modulate the immune response [158]. In osteoarthritic patients, before performing an arthroplasty, other surgical procedures such as autologous SC implantation can be used in order to treat focal defects and generalized cartilage degradation [159]. Moreover, different scaffolds mimicking cartilage ECM are available for cartilage tissue engineering [160]. MSC are the most commonly used SC for cartilage regeneration, since they are multipotent stromal cells able to differentiate into osteoblast, chondrocytes, myocytes and adipocytes [161 163]. Systemic reviews of clinical trials with MSC have demonstrated their safety and efficacy in IA injections [160,162,164]. However, its use presents some limitations such as massive cell death, formation of fibrocartilage instead of hyaline cartilage or an inadequate cell migration outside the joint cavity [159,165]. One major challenge when applying cellular therapies is to induce damage site targeting by the SC. Desando et al. used a rabbit OA model to study the possible effect of HA in the modulation of cell migration and cartilage degradation [85]. Due to the phenotypic changes that SC can suffer when cultured, the whole bone marrow niche can be used, known as bone marrow concentrate (BMC). In this way, the authors prepared solutions of MSC and BMC in PBS or aqueous HA solutions. Cell nuclear staining revealed that MSC preferentially migrate to synovium while BMC prefer to migrate toward cartilage. MMP-1 immunohistochemistry showed the lowest protein expression for BMC-HA formulation while type II collagen increased slightly in all the treatments. The authors observed migration of cells to cartilage when using HA as a cell carrier, especially for BMC-HA preparations, promoting cartilage and joint recovery. In other study, researchers used magnetic resonance imaging and micro-computed tomography to test the efficacy of allogenic adiposederived MSC (AD-MSC) combined with HA to block OA progression in sheeps [81]. Results showed a cartilage layer almost identical to healthy cartilage in animals treated with AD-MSC+HA. Feng et al. reported that secretion of chondrogenesis agonists was higher in animals treated with MSC-HA, suggesting that a possible mechanism of action of cells for cartilage repair could be the secretion of chondrogenic factors. In addition, TNF-a, IL-1b and IL-6 levels were considerably lower in these animals, proving the downregulation of inflammatory factors. Similar results were obtained by Chiang et al. [80]. These authors could observed the recovery of cartilage in the lateral and medial compartments of the knee joint at 6 and 12 weeks after injection of bone marrow-derived MSC (BM-MSC) combined with HA in rabbits (Fig. 5). They also evidenced less surface abrasion and cartilage degradation and better histological scores compared to animals treated only with HA.

180

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

Fig. 4. In order to study the effect of HA and PRP on chondrogenic differentiation and inhibition of inflammation in vitro, chondrocytes RNA was extracted for a genetic analysis using semi-quantitative RT-PCR. HA+PRP (A) enhanced the expression chondrogenic genes (SOX9, COL II and AGN) while (B) inhibited inflammatory genes (IL-1b, COX2 MMP-1 and MMP-3). The results were normalized to GAPDH mRNA levels *p<0.05, **p<0.01 and ***p<0.001 compared with the value in cells cultured in IL-1b and TNF-a using t-test. The results are shown as mean §S.D. for 3 replicates. Adapted from [86], Copyright 2014, with permission from Elsevier.

Fig. 5. Histological analysis of femur condyles of animals at 6 and 12 weeks post-treatment assessed by Safranin-O staining. Adapted from [80] under the CC BY 4.0 license.

Conclusion Viscosupplementation is one of the first line osteoarthritis treatments for the recovery of the synovial fluid viscoelasticity. However, new approaches are emerging combining hyaluronic acid with drugs or bioactive principles in a single injection, in order to provide an additional benefit to the viscosupplementation. Drugs such as antiinflammatories or antioxidant molecules are being incorporated in

viscosupplements freely or covalently conjugated. Injections of hyaluronic acid with anti-inflammatory drugs seem to improve short-term pain relief although these formulations can introduce some cytotoxicity as reported in vitro and in vivo. Antioxidant molecules inside hyaluronic acid formulation have shown to provide and enhanced its antioxidant capacity, avoiding HA degradation or reducing synovial membrane inflammation. In order to enhance the beneficial effect of the bioactive principle at the site of the injured cartilage, they are being encapsulated in drug delivery systems and introduced in hyaluronic acid. This strategy achieves a dual mechanism of drug release increasing the retention time locally, and hence, the efficiency of the principle. Other approach that is emerging and being studied nowadays is to join together viscosupplements with regenerative therapies. The combination of hyaluronic acid and platelet-rich plasma is one of the most promising approaches due to the ability of platelets to stimulate intrinsic cartilage repair by the release of molecules like growth factors, which have a critical role in tissue healing. Injection of viscosupplements charged with stem cells is other hopeful approach to promote cartilage regeneration, although more research is needed to achieve and draw safer and more reproducible clinical conclusive results. Overall, advances in active viscosupplements are expected to provide new solutions to osteoarthritis by improving pain relief or articular functionality and, ultimately, improving patient's quality of life. Acknowledgment This work was developed as part of the project IND2017/IND7614, supported financially by the Comunidad de Madrid (Spain) and Alo
utica SL. dia Farmace

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

Supplementary materials Supplementary material associated with this article can be found in the online version at doi:10.1016/j.semarthrit.2019.02.008. References [1] Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390:1211–59. [2] Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ 2003;81:646–56.
n M, Castan ~ eda S. Estrogens, osteoarthritis and inflammation. Joint [3] Martín-Milla Bone Spine 2013;80:368–73. [4] Jiang L, Tian W, Wang Y, Rong J, Bao C, Liu Y, et al. Body mass index and susceptibility to knee osteoarthritis: a systematic review and meta-analysis. Joint Bone Spine 2012;79:291–7. [5] Silverwood V, Blagojevic-Bucknall M, Jinks C, Jordan JL, Protheroe J, Jordan KP. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthr Cartil 2015;23:507–15. [6] Yusuf E, Nelissen RG, Ioan-Facsinay A, Stojanovic-Susulic V, DeGroot J, Van Osch G, Middeldorp S, Huizinga TWJ, Kloppenburg M. Association between weight or body mass index and hand osteoarthritis: a systematic review. Ann Rheum Dis 2010;69:761–5. [7] Jiang L, Rong J, Wang Y, Hu F, Bao C, Li X, Zhao Y. The relationship between body mass index and hip osteoarthritis: a systematic review and meta-analysis. Joint Bone Spine 2011;78:150–5. [8] Castrillo PD, Olmos D, Amador DR. Real dispersion of isolated fumed silica nanoparticles in highly filled PMMA prepared by high energy ball milling, 308 (2007) 318 324. [9] Sandell LJ. Etiology of osteoarthritis: genetics and synovial joint development. Nat Rev Rheumatol 2012;8:77–89. [10] van Meurs JBJ. Osteoarthritis year in review 2016: genetics, genomics and epigenetics. Osteoarthr Cartil 2017;25:181–9. [11] Guilak F. Biomechanical factors in osteoarthritis. Best Pract Res Clin Rheumatol 2011;25:815–23. [12] Buckwalter JA, Martin JA. Osteoarthritis. Adv Drug Deliv Rev 2006;58:150–67. [13] Salmon JH, Rat AC, Sellam J, Michel M, Eschard JP, Guillemin F, Jolly D, Fautrel B. Economic impact of lower-limb osteoarthritis worldwide: a systematic review of cost-of-illness studies. Osteoarthr Cartil 2016;24:1500–8. [14] Poole AR, Kojima T, Yasuda T, Mwale F, Kobayashi M, Laverty S. Composition and structure of articular cartilage: a template for tissue repair. Clin Orthop Relat Res 2001;1:S26–33. [15] Dudhia J. Aggrecan, aging and assembly in articular cartilage. Cell Mol Life Sci 2005;62:2241–56. [16] Tamer TM. Hyaluronan and synovial joint: function, distribution and healing. Interdiscip Toxicol 2013;6:111–25. [17] Blewis ME, Nugent-Derfus GE, Schmidt TA, Schumacher BL, Sah RL. A model of synovial fluid lubricant composition in normal and injured joints. Eur Cell Mater 2007;13:26–39. [18] Temple-Wong MM, Ren S, Quach P, Hansen BC, Chen AC, Hasegawa A, et al. Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration. Arthritis Rese Ther 2016;18 18. [19] Barbucci R, Lamponi S, Borzacchiello A, Ambrosio L, Fini M, Torricelli P, et al. Hyaluronic acid hydrogel in the treatment of osteoarthritis. Biomaterials 2002;23:4503–13. [20] Cawston TE, Wilson AJ. Understanding the role of tissue degrading enzymes and their inhibitors in development and disease. Best Pract Res Clin Rheumatol 2006;20:983–1002. [21] Kapoor M, Martel-Pelletier J, Lajeunesse D, Pelletier JP, Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 2011;7:33–42. [22] Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007;213:626–34. [23] Goldring SR, Goldring MB. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop Relat Res 2004(427 Suppl):27–36. [24] Sandell LJ, Aigner T. Articular cartilage and changes in arthritis an introduction: cell biology of osteoarthritis. Arthritis Res 2001;3:107–13. [25] Fernandes JC, Martel-Pelletier J, Pelletier JP. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002;39:237–46. [26] Burr DB, Gallant MA. Bone remodelling in osteoarthritis. Nat Rev Rheumatol 2012;8:665–73. [27] Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum 2004;50:1193–206. [28] Mathiessen A, Conaghan PG. Synovitis in osteoarthritis: current understanding with therapeutic implications. Arthritis Res Ther 2017;19:1–9. [29] Scanzello CR, Goldring SR. The role of synovitis in osteoarthritis pathogenesis. Bone 2012;51:249–57. [30] Fakhari A, Berkland C. Applications and emerging trends of hyaluronic acid in tissue engineering, as a dermal filler and in osteoarthritis treatment. Acta Biomater 2013;9:7081–92. [31] Krause WE, Bellomo EG, Colby RH. Rheology of sodium hyaluronate under physiological conditions. Biomacromolecules 2001;2:65–9.

181

[32] Band PA, Heeter J, Wisniewski HG, Liublinska V, Pattanayak CW, Karia RJ, et al. Hyaluronan molecular weight distribution is associated with the risk of knee osteoarthritis progression. Osteoarthr Cartil 2015;23:70–6. [33] Bhuanantanondh P, Grecov D, Kwok E, Guy P. Rheology of osteoarthritic synovial fluid mixed with viscosupplements: a pilot study. Biomed Eng Lett 2011;1:213–9. [34] Fernandes L, Hagen KB, Bijlsma JWJ, Andreassen O, Christensen P, Conaghan PG, et al. EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis. Ann Rheum Dis 2013;72:1125–35. [35] McAlindon TE, Bannuru RR, Sullivan MC, Arden NK, Berenbaum F, Bierma-Zeinstra SM, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthr Cartil 2014;22:363–88. [36] Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, Arden NK, et al. OARSI recommendations for the management of hip and knee osteoarthritis. Part III: changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthr Cartil 2010;18:476–99. [37] Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J, et al. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res 2012;64:465–74.
pez-Pen ~ a M, Mun ~ oz F, Caeiro J-R, Gonza
lez-Cantalapie[38] Permuy M, Guede D, Lo dra A. Comparison of various SYSADOA for the osteoarthritis treatment: an experimental study in rabbits. BMC Musculoskelet Disord 2015;16:120. ~ eda S, Sa
nchez-Pernaute O, Largo R, Herrero-Beaumont G. [39] Roman-Blas JA, Castan Combined treatment with chondroitin sulfate and glucosamine sulfate shows no superiority over placebo for reduction of joint pain and functional impairment in patients with knee osteoarthritis: a six-month multicenter, randomized, double-blind. Placebo-Co, Arthritis Rheumatol 2017;69:77–85. € ller I, Castillo JR, Arden N, Beren[40] Hochberg MC, Martel-Pelletier J, Monfort J, Mo
nech G, Henrotin Y, Pap T, Richette P, baum F, Blanco FJ, Conaghan PG, Dome Sawitzke A, Souich PD, Pelletier JP. Combined chondroitin sulfate and glucosamine for painful knee osteoarthritis: a multicentre, randomised, double-blind, non-inferiority trial versus celecoxib. Ann Rheum Dis 2016;75:37–44. [41] Craig DGN, Bates CM, Davidson JS, Martin KG, Hayes PC, Simpson KJ. Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity. Br J Clin Pharmacol 2012;73:285–94. [42] Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. J Rheumatol 2007;34:543–55. [43] Badri W, Miladi K, Nazari QA, Greige-Gerges H, Fessi H, Elaissari A. Encapsulation of NSAIDs for inflammation management: overview, progress, challenges and prospects. Int J Pharm 2016;515:757–73. [44] Pelletier JP, Martel-Pelletier J, Rannou F, Cooper C. Efficacy and safety of oral NSAIDs and analgesics in the management of osteoarthritis: evidence from reallife setting trials and surveys. Semin Arthritis Rheum 2016;45:S22–7. [45] Laine L, White WB, Rostom A, Hochberg M. COX-2 selective inhibitors in the treatment of osteoarthritis. Semin Arthritis Rheum 2008;38:165–87. [46] Chen LC, Ashcroft DM. Risk of myocardial infarction associated with selective COX-2 inhibitors: meta-analysis of randomised controlled trials. Pharmacoepidemiol Drug Saf 2007;16:762–72. [47] Rannou F, Pelletier JP, Martel-Pelletier J. Efficacy and safety of topical NSAIDs in the management of osteoarthritis: evidence from real-life setting trials and surveys. Semin Arthritis Rheum 2016;45:S18–21. [48] Gammaitoni AR, Galer BS, Onawola R, Jensen MP, Argoff CE. Lidocaine patch 5% and its positive impact on pain qualities in osteoarthritis: results of a pilot 2week, open-label study using the Neuropathic Pain Scale. Curr Med Res Opin 2004;20:S13–9. [49] Burch F, Codding C, Patel N, Sheldon E. Lidocaine patch 5% improves pain, stiffness, and physical function in osteoarthritis pain patients. A prospective, multicenter, open-label effectiveness trial. Osteoarthr Cartil 2004;12:253–5. [50] Juni P, Hari R, Rutjes AW, Fischer R, Silletta MG, Reichenbach S, da Costa BR. Intra-articular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015:CD005328. [51] He WW, Kuang MJ, Zhao J, Sun L, Lu B, Wang Y, et al. Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: a meta-analysis. Int J Surg 2017;39:95–103. [52] Butoescu N, Jordan O, Doelker E. Intra-articular drug delivery systems for the treatment of rheumatic diseases: a review of the factors influencing their performance. Eur J Pharm Biopharm 2009;73:205–18. [53] He Z, Wang B, Hu C, Zhao J. An overview of hydrogel-based intra-articular drug delivery for the treatment of osteoarthritis. Colloids Surf B 2017;154:33–9. [54] Torrero JI, Martinez C. New developments in the treatment of osteoarthritis focus on biologic agents. Open Access Rheumatol 2015;7:33–43. [55] Richards MM, Maxwell JS, Weng L, Angelos MG, Golzarian J. Intra-articular treatment of knee osteoarthritis: from anti-inflammatories to products of regenerative medicine. Phys Sportsmed 2016;44:101–8. [56] Vincent TL, Watt FE. Osteoarthritis. Medicine 2018;42:213–9. [57] Richmond JC. Surgery for osteoarthritis of the knee. Rheum Dis Clin N. Am 2013;39:203–11. [58] de l'Escalopier N, Anract P, Biau D. Surgical treatments for osteoarthritis. Ann Phys Rehabil Med 2016;59:227–33. [59] Altman R, Hackel J, Niazi F, Shaw P, Nicholls M. Efficacy and safety of repeated courses of hyaluronic acid injections for knee osteoarthritis: a systematic review. Semin Arthritis Rheum 2018;48:168–75. [60] Strand V, McIntyre LF, Beach WR, Miller LE, Block JE. Safety and efficacy of USapproved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res 2015;8:217–28.

182

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

[61] Altman RD, Manjoo A, Fierlinger A, Niazi F, Nicholls M. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskelet Disord 2015;16:1–10. [62] Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther 2003;5:54–67. [63] Yatabe T, Mochizuki S, Takizawa M, Chijiiwa M, Okada A, Kimura T, et al. Hyaluronan inhibits expression of ADAMTS4 (aggrecanase-1) in human osteoarthritic chondrocytes. Ann Rheum Dis 2009;68:1051–8. [64] Julovi SM, Ito H, Nishitani K, Jackson CJ, Nakamura T. Hyaluronan inhibits matrix metalloproteinase-13 in human arthritic chondrocytes via CD44 and P38. J Orthop Res 2011;29:258–64.
-boyer V. Viscosupplementation: techniques, indications, results. Orthop[65] Legre aed Traumatol Surg Rese 2015;101:S101–8. [66] Askari A, Gholami T, NaghiZadeh MM, Farjam M, Kouhpayeh SA, Shahabfard Z. Hyaluronic acid compared with corticosteroid injections for the treatment of osteoarthritis of the knee: a randomized control trail. Springerplus 2016;5:442. [67] Shewale AR, Barnes CL, Fischbach LA, Ounpraseuth ST, Painter JT, Martin BC. Comparison of low-, moderate-, and high-molecular-weight hyaluronic acid injections in delaying time to knee surgery. J Arthroplasty 2017;32:2952–7. e2921. [68] Yang X, Du H, Zhai G. Progress in intra-articular drug delivery systems for osteoarthritis. Curr Drug Targets 2014;15:888–900. [69] Euppayo T, Siengdee P, Buddhachat K, Pradit W, Chomdej S, Ongchai S, et al. In vitro effects of triamcinolone acetonide and in combination with hyaluronan on canine normal and spontaneous osteoarthritis articular cartilage. In Vitro Cell Dev Biol Animl 2016;52:723–35. [70] Ozturk C, Atamaz F, Hepguler S, Argin M, Arkun R. The safety and efficacy of intraarticular hyaluronan with/without corticosteroid in knee osteoarthritis: 1-year, single-blind, randomized study. Rheumatol Int 2006;26:314–9. [71] de Campos GC, Rezende MU, Pailo AF, Frucchi R, Camargo OP. Adding triamcinolone improves viscosupplementation: a randomized clinical trial. Clin Orthop Relat Res 2013;471:613–20. [72] Petrella RJ, Emans PJ, Alleyne J, Dellaert F, Gill DP, Maroney M. Safety and performance of hydros and hydros-TA for knee osteoarthritis: a prospective, multicenter, randomized, double-blind feasibility trial. BMC Musculoskelet Disord 2015;16:57. [73] Siengdee P, Radeerom T, Kuanoon S, Euppayo T, Pradit W, Chomdej S, et al. Effects of corticosteroids and their combinations with hyaluronanon on the biochemical properties of porcine cartilage explants. BMC Vet Res 2015;11:298. [74] Zhang Z, Wei X, Gao J, Zhao Y, Zhao Y, Guo L, et al. Intra-articular injection of cross-linked hyaluronic acid-dexamethasone hydrogel attenuates osteoarthritis: an experimental study in a rat model of osteoarthritis. Int J Mol Sci 2016;17:411. [75] Conrozier T, Patarin J, Mathieu P, Rinaudo M. Steroids, lidocain and ioxaglic acid modify the viscosity of hyaluronic acid: in vitro study and clinical implications. Springerplus 2016;5:170. [76] Chen P, Mei S, Xia C, Zhu R, Pang Y, Wang J, et al. The amelioration of cartilage degeneration by photo-crosslinked GelHA hydrogel and crizotinib encapsulated chitosan microspheres. Oncotarget 2017;8:30235–51. [77] Kang ML, Jeong SY, Im GI. Hyaluronic acid hydrogel functionalized with selfassembled micelles of amphiphilic PEGylated kartogenin for the treatment of osteoarthritis. Tissue Eng Part A 2017;23:630–9. [78] Dong J, Jiang D, Wang Z, Wu G, Miao L, Huang L. Intra-articular delivery of liposomal celecoxib-hyaluronate combination for the treatment of osteoarthritis in rabbit model. Int J Pharm 2013;441:285–90. [79] Xia C, Chen P, Mei S, Ning L, Lei C, Wang J, et al. Photo-crosslinked HAMA hydrogel with cordycepin encapsulated chitosan microspheres for osteoarthritis treatment. Oncotarget 2017;8:2835–49. [80] Chiang E-R, Ma H-L, Wang J-P, Liu C-L, Chen T-H, Hung S-C. Allogeneic mesenchymal stem cells in combination with hyaluronic acid for the treatment of osteoarthritis in rabbits. PLoS One 2016;11:e0149835. e0149835. [81] Feng C, Luo X, He N, Xia H, Lv X, Zhang X, et al. Efficacy and persistence of allogeneic adipose-derived mesenchymal stem cells combined with hyaluronic acid in osteoarthritis after intra-articular injection in a sheep model. Tissue Eng Part A 2017;24:3–4. [82] Abate M, Verna S, Schiavone C, Di Gregorio P, Salini V. Efficacy and safety profile of a compound composed of platelet-rich plasma and hyaluronic acid in the treatment for knee osteoarthritis (preliminary results). Eur J Orthop Surg Traumatol 2015;25:1321–6. [83] Russo F, D'Este M, Vadal a G, Cattani C, Papalia R, Alini M, et al. Platelet rich plasma and hyaluronic acid blend for the treatment of osteoarthritis: rheological and biological evaluation. PLoS One 2016;11:1–12. [84] Lana JFSD, Weglein A, Sampson SE, Vicente EF, Huber SC, Souza CV, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med 2016;12:69–78. [85] Desando G, Bartolotti I, Cavallo C, Schiavinato A, Secchieri C, Kon E, et al. ShortTerm Homing of Hyaluronan-Primed Cells: therapeutic implications for osteoarthritis treatment. Tissue Eng Part C: Methods 2018;24:121–33. [86] Chen WH, Lo WC, Hsu WC, Wei HJ, Liu HY, Lee CH, et al. Synergistic anabolic actions of hyaluronic acid and platelet-rich plasma on cartilage regeneration in osteoarthritis therapy. Biomaterials 2014;35:9599–607. [87] Duan X, Sandell LJ, Chinzei N, Holguin N, Silva MJ, Schiavinato A, et al. Therapeutic efficacy of intra-articular hyaluronan derivative and platelet-rich plasma in mice following axial tibial loading. PLoS One 2017;12:e0175682.

[88] Dallari D, Stagni C, Rani N, Sabbioni G, Pelotti P, Torricelli P, et al. Ultrasoundguided injection of platelet-rich plasma and hyaluronic acid, separately and in combination, for hip osteoarthritis: a randomized controlled study. Am J Sports Med 2016;44:664–71. [89] Rinaudo M, Lardy B, Grange L, Conrozier T. Effect of mannitol on hyaluronic acid stability in two in vitro models of oxidative stress. Polymers 2014;6:1948–57. [90] Kaderli S, Viguier E, Watrelot-Virieux D, Roger T, Gurny R, Scapozza L, et al. Efficacy study of two novel hyaluronic acid-based formulations for viscosupplementation therapy in an early osteoarthrosic rabbit model. Eur J Pharm Biopharm 2015;96:388–95. [91] Conrozier T, Mathieu P, Rinaudo M. Mannitol preserves the viscoelastic properties of hyaluronic acid in an in vitro model of oxidative stress. Rheumatol Ther 2014;1:45–54. [92] Mongkhon JM, Thach M, Shi Q, Fernandes JC, Fahmi H, Benderdour M. Sorbitolmodified hyaluronic acid reduces oxidative stress, apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes. Inflamm Res 2014;63:691–701. [93] Conrozier T, Bozgan AM, Bossert M, Sondag M, Lohse-Walliser A, Balblanc JC. Standardized follow-up of patients with symptomatic knee osteoarthritis treated with a single intra-articular injection of a combination of cross-linked hyaluronic acid and mannitol. Clin Med Insights Arthritis Musculoskelet Disord 2016;9:175–9. [94] Kaderli S, Boulocher C, Pillet E, Watrelot-Virieux D, Roger T, Viguier E, et al. A novel oxido-viscosifying hyaluronic acid-antioxidant conjugate for osteoarthritis therapy: biocompatibility assessments. Eur J Pharm Biopharm 2015;90:70–9. [95] Chen P, Zhu S, Wang Y, Mu Q, Wu Y, Xia Q, et al. The amelioration of cartilage degeneration by ADAMTS-5 inhibitor delivered in a hyaluronic acid hydrogel. Biomaterials 2014;35:2827–36. [96] Mero A, Campisi M, Favero M, Barbera C, Secchieri C, Dayer JM, et al. A hyaluronic acid-salmon calcitonin conjugate for the local treatment of osteoarthritis: chondro-protective effect in a rabbit model of early OA. J Control Release 2014;187:30–8. [97] Palmieri B, Rottigni V, Iannitti T. Preliminary study of highly cross-linked hyaluronic acid-based combination therapy for management of knee osteoarthritisrelated pain. Drug Des Devel Ther 2013;7:7–12. [98] Lu H-T, Sheu M-T, Lin Y-F, Lan J, Chin Y-P, Hsieh M-S, et al. Injectable hyaluronicacid-doxycycline hydrogel therapy in experimental rabbit osteoarthritis. BMC Vet Res 2013;9:68. [99] Karsdal MA, Michaelis M, Ladel C, Siebuhr AS, Bihlet AR, Andersen JR, et al. Disease-modifying treatments for osteoarthritis (DMOADs) of the knee and hip: lessons learned from failures and opportunities for the future. Osteoarthr Cartil 2016;24:2013–21. [100] Davies PS, Graham SM, MacFarlane RJ, Leonidou A, Mantalaris A, Tsiridis E. Disease-modifying osteoarthritis drugs: in vitro and in vivo data on the development of DMOADs under investigation. Expert Opin Investig Drugs 2013;22:423–41. [101] Euppayo T, Siengdee P, Buddhachat K, Pradit W, Viriyakhasem N, Chomdej S, et al. Effects of low molecular weight hyaluronan combined with carprofen on canine osteoarthritis articular chondrocytes and cartilage explants in vitro. In Vitro Cell Dev Biol Anim 2015;51:857–65. [102] Ozkan FU, Uzer G, Turkmen I, Yildiz Y, Senol S, Ozkan K, et al. Intra-articular hyaluronate, tenoxicam and vitamin e in a rat model of osteoarthritis: evaluation and comparison of chondroprotective efficacy. Int J Clin Exp Med 2015;15:1018–26. [103] Iannitti T, Elhensheri M, Bingol AO, Palmieri B. Preliminary histopathological study of intra-articular injection of a novel highly cross-linked hyaluronic acid in a rabbit model of knee osteoarthritis. J Mol Histol 2013;44:191–201. [104] Yang KC, Wu CC, Chen WY, Sumi S, Huang TL. L-Glutathione enhances antioxidant capacity of hyaluronic acid and modulates expression of pro-inflammatory cytokines in human fibroblast-like synoviocytes. J Biomed Mater Res A 2016;104:2071–9. [105] Graham DY, Opekun AR, Willingham FF, Qureshi WA. Visible small-intestinal mucosal injury in chronic NSAID users. Clin Gastroenterol Hepatol 2005;3:55–9. [106] Frech EJ, Go MF. Treatment and chemoprevention of NSAID-associated gastrointestinal complications. Ther Clin Risk Manag 2009;5:65–73. [107] Heyneman CA, Lawless-Liday C, Wall GC. Oral versus topical NSAIDs in rheumatic diseases: a comparison. Drugs 2000;60:555–74. [108] Orak MM, Ak D, Midi A, Lacin B, Purisa S, Bulut G. Comparison of the effects of chronic intra-articular administration of tenoxicam, diclofenac, and methylprednisolone in healthy rats. Acta Orthop Traumatol Turc 2015;49:438–46. [109] Saricaoglu F, Dal D, Atilla P, Iskit AB, Tarhan O, Asan E, et al. Effect of intraarticular injection of lornoxicam on the articular cartilage & synovium in rat. Indian J Med Res 2008;127:362–5. [110] Mihara M, Higo S, Uchiyama Y, Tanabe K, Saito K. Different effects of high molecular weight sodium hyaluronate and NSAID on the progression of the cartilage degeneration in rabbit OA model. Osteoarthr Cartil 2007;15:543–9. [111] Euppayo T, Punyapornwithaya V, Chomdej S, Ongchai S, Nganvongpanit K. Effects of hyaluronic acid combined with anti-inflammatory drugs compared with hyaluronic acid alone, in clinical trials and experiments in osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord 2017;18:387. [112] Oztuna V, Eskandari M, Bugdayci R, Kuyurtar F. Intra-articular injection of tenoxicam in osteoarthritic knee joints with effusion. Orthopedics 2007;30:1039–42. [113] Klocke R, Levasseur K, Kitas GD, Smith JP, Hirsch G. Cartilage turnover and intraarticular corticosteroid injections in knee osteoarthritis. Rheumatol Int 2018;38:455–9. [114] Wang F, He X. Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: A meta-analysis. Exp Ther Med 2015;9:493–500.

G.M. Pontes-Quero et al. / Seminars in Arthritis and Rheumatism 49 (2019) 171 183

[115] Wehling P, Evans C, Wehling J, Maixner W. Effectiveness of intra-articular therapies in osteoarthritis: a literature review. Ther Adv Musculoskelet Dis 2017;9:183–96. [116] Wernecke C, Braun HJ, Dragoo JL. The effect of intra-articular corticosteroids on articular cartilage: A systematic review. Orthop J Sports Med 2015;3:1–7. [117] Lepetsos P, Papavassiliou AG. ROS/oxidative stress signaling in osteoarthritis. Biochim Biophys Acta 2016;1862:576–91. [118] Gu YT, Chen J, Meng ZL, Ge WY, Bian YY, Cheng SW, et al. Research progress on osteoarthritis treatment mechanisms. Biomed Pharmacother 2017;93:1246–52. [119] Esenyel M, Icagasioglu A, Esenyel CZ. Effects of calcitonin on knee osteoarthritis and quality of life. Rheumatol Int 2013;33:423–7. [120] Kang ML, Im GI. Drug delivery systems for intra-articular treatment of osteoarthritis. Expert Opin Drug Deliv 2014;11:269–82. [121] Rai MF, Pham CT. Intra-articular drug delivery systems for joint diseases. Curr Opin Pharmacol 2018;40:67–73. [122] Zhang Z, Huang G. Micro- and nano-carrier mediated intra-articular drug delivery systems for the treatment of osteoarthritis. J Nanotechnol 2012;2012:1–11. [123] Zylberberg C, Matosevic S. Pharmaceutical liposomal drug delivery: a review of new delivery systems and a look at the regulatory landscape. Drug Deliv 2016;23:3319–29. [124] Vanniasinghe AS, Bender V, Manolios N. The potential of liposomal drug delivery for the treatment of inflammatory arthritis. Semin Arthritis Rheum 2009;39:182–96. [125] Siepmann J, Siepmann F. Microparticles used as drug delivery systems. Berlin Heidelberg: Springer 2006:15–21. [126] Ramazani F, Chen W, van Nostrum CF, Storm G, Kiessling F, Lammers T, et al. Strategies for encapsulation of small hydrophilic and amphiphilic drugs in PLGA microspheres: State-of-the-art and challenges. Int J Pharm 2016;499:358–67. [127] Bodick N, Lufkin J, Willwerth C, Kumar A, Bolognese J, Schoonmaker C, et al. An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. J Bone Joint Surg Am 2015;97:877–88. [128] Conaghan PG, Cohen SB, Berenbaum F, Lufkin J, Johnson JR, Bodick N. Brief Report: a phase IIb trial of a novel extended-release microsphere formulation of triamcinolone acetonide for intraarticular injection in knee osteoarthritis. Arthritis Rheumatol 2018;70:204–11. [129] Li H, Hu C, Yu H, Chen C. Chitosan composite scaffolds for articular cartilage defect repair: a review. RSC Adv 2018;8:3736–49. [130] Oryan A, Sahvieh S. Effectiveness of chitosan scaffold in skin, bone and cartilage healing. Int J Biol Macromol 2017;104:1003–11. [131] Stanish WD, McCormack R, Forriol F, Mohtadi N, Pelet S, Desnoyers J, et al. Novel scaffold-based BST-CarGel treatment results in superior cartilage repair compared with microfracture in a randomized controlled trial. J Bone Joint Surg Am 2013;95:1640–50. [132] Fan M, Ma Y, Tan H, Jia Y, Zou S, Guo S, et al. Covalent and injectable chitosan-chondroitin sulfate hydrogels embedded with chitosan microspheres for drug delivery and tissue engineering. Mater Sci Eng C Mater Biol Appl 2017;71:67–74. [133] Wei W, Yuan L, Hu G, Wang L-Y, Wu J, Hu X, et al. Monodisperse chitosan microspheres with interesting structures for protein drug delivery. Adv Mater 2008;20:2292–6. [134] Mapp PI, Walsh DA. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat Rev Rheumatol 2012;8:390–8. [135] Lin CC, Anseth KS. PEG hydrogels for the controlled release of biomolecules in regenerative medicine. Pharm Res 2009;26:631–43. [136] Risbud MV, Sittinger M. Tissue engineering: advances in in vitro cartilage generation. Trends Biotechnol 2002;20:351–6. [137] Makris EA, Gomoll AH, Malizos KN, Hu JC, Athanasiou KA. Repair and tissue engineering techniques for articular cartilage. Nat Rev Rheumatol 2015;11:21–34. [138] Lana JFSD, Weglein A, Sampson SE, Vicente EF, Huber SC, Souza CV, et al. Randomized controlled trial comparing hyaluronic acid, platelet-rich plasma and the combination of both in the treatment of mild and moderate osteoarthritis of the knee. J Stem Cells Regen Med 2016;12:69–78. [139] Piuzzi N, Chughtai M, Khlopas A, Harwin S, Miniaci A, Mont M, et al. Platelet-rich plasma for the treatment of knee osteoarthritis: a review. J Knee Surg 2017;30:627–33. [140] Zhong W, Sumita Y, Ohba S, Kawasaki T, Nagai K, Ma G, Asahina I. In vivo comparison of the bone regeneration capability of human bone marrow concentrates vs. platelet-rich plasma. PLoS One 2012;7:e40833. [141] Bennell KL, Hunter DJ, Paterson KL. Platelet-rich plasma for the management of hip and knee osteoarthritis. Curr Rheumatol Rep 2017;19:24.

183

[142] Cook CS, Smith PA. Clinical update: why PRP should be your first choice for injection therapy in treating osteoarthritis of the knee. Curr Rev Musculoskelet Med 2018;11:583–92. [143] Masoudi E, Ribas J, Kaushik G, Leijten J, Khademhosseini A. Platelet-rich blood derivatives for stem cell-based tissue engineering and regeneration. Curr Stem Cell Rep 2016;2:33–42.
X, Garcia-Balletbo
M. Infiltra[144] Wang-Saegusa A, Cugat R, Ares O, Seijas R, Cusco tion of plasma rich in growth factors for osteoarthritis of the knee short-term effects on function and quality of life. Arch Orthop Trauma Surg 2011;131: 311–7. [145] Levy DM, Petersen KA, Scalley Vaught M, Christian DR, Cole BJ. Injections for knee osteoarthritis: corticosteroids, viscosupplementation, platelet-rich plasma, and autologous stem cells. Arthrosc J Arthrosc Relat Surg 2018;34:1730–43. [146] Le ADK, Enweze L, DeBaun MR, Dragoo JL. Current clinical recommendations for use of platelet-rich plasma. Curr Rev Musculoskelet Med 2018;11:624–34. [147] Dhillon MS, Patel S, Bansal T. Improvising PRP for use in osteoarthritis kneeupcoming trends and futuristic view. J Clin Orthop Trauma 2018;10:32–5. [148] Filardo G, Kon E, Pereira Ruiz MT, Vaccaro F, Guitaldi R, Di Martino A, et al. Platelet-rich plasma intra-articular injections for cartilage degeneration and osteoarthritis: single- versus double-spinning approach. Knee Surg Sports Traumatol Arthrosc 2012;20:2082–91. [149] Braun HJ, Kim HJ, Chu CR, Dragoo JL. The effect of platelet-rich plasma formulations and blood products on human synoviocytes: implications for intra-articular injury and therapy. Am J Sports Med 2014;42:1204–10. [150] Anitua E, Troya M, Zalduendo MM, Orive G. The effect of different drugs on the preparation and biological outcomes of plasma rich in growth factors. Ann Anat Anat Anzeiger: Off Organ Anat Ges 2014;196:423–9. [151] Yin W-J, Xu H-T, Sheng J-G, An Z-Q, Guo S-C, Xie X-T, et al. Advantages of pure platelet-rich plasma compared with leukocyte- and platelet-rich plasma in treating rabbit knee osteoarthritis. Med Sci Monit 2016;22:1280–90. [152] Riboh JC, Saltzman BM, Yanke AB, Fortier L, Cole BJ. Effect of leukocyte concentration on the efficacy of platelet-rich plasma in the treatment of knee osteoarthritis. Am J Sports Med 2016;44:792–800. [153] Spakov
a T, Rosocha J, Lacko M, Harvanov
a D, Gharaibeh A. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil 2012;91:411–7. [154] Cerza F, Carni S, Carcangiu A, Di Vavo I, Schiavilla V, Pecora A, et al. Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. Am J Sports Med 2012;40:2822–7. [155] Kurapati K, Tapadia S, Rao M, Anbarasu K, Verma VK, Beevi SS. Efficacy of intraarticular injection of platelet rich plasma and hyaluronic acid in early knee osteoarthritis case series. Eur J Mol Clin Med 2018;5:30–6. [156] Andia I, Abate M. Knee osteoarthritis: hyaluronic acid, platelet-rich plasma or both in association? Expert Opin Biol Ther 2014;14:635–49. [157] Saturveithan C, Premganesh G, Fakhrizzaki S, Mahathir M, Karuna K, Rauf K, et al. Intra-articular hyaluronic acid (HA) and platelet rich plasma (PRP) injection versus hyaluronic acid (HA) injection alone in patients with grade III and IV knee osteoarthritis (OA): a retrospective study on functional outcome. Malays Orthop J 2016;10:35–40. [158] Bacakova L, Zarubova J, Travnickova M, Musilkova J, Pajorova J, Slepicka P, et al. Stem cells: their source, potency and use in regenerative therapies with focus on adipose-derived stem cells a review. Biotechnol Adv 2018;36:1111–26. [159] Orth P, Rey-Rico A, Venkatesan JK, Madry H, Cucchiarini M. Current perspectives in stem cell research for knee cartilage repair. Stem Cells Cloning: Adv Appl 2014;7:1–17. [160] Vinatier C, Guicheux J. Cartilage tissue engineering: from biomaterials and stem cells to osteoarthritis treatments. Ann Phys Rehabil Med 2016;59:139–44. [161] Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol 2014;32:252–60. [162] Freitag J, Bates D, Boyd R, Shah K, Barnard A, Huguenin L, et al. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy a review. BMC Musculoskelet Disord 2016;17:230. [163] Kong L, Zheng LZ, Qin L, Ho KKW. Role of mesenchymal stem cells in osteoarthritis treatment. J Orthop Translat 2017;9:89–103. [164] Yubo M, Yanyan L, Li L, Tao S, Bo L, Lin C. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS One 2017;12:e0175449. [165] Chang YH, Liu HW, Wu KC, Ding DC. Mesenchymal stem cells and their clinical applications in osteoarthritis. Cell Transplant 2016;25:937–50.