Drug delivery systems for intra-articular treatment of osteoarthritis.

Review

Drug delivery systems for intra-articular treatment of osteoarthritis 1.

Overview

2.

Structure and function of synovial joint

3.

Pathophysiology and treatment modality for OA

Expert Opin. Drug Deliv. Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 05/18/14 For personal use only.

4.

Rationale for IA drug delivery in OA

5.

Current IA treatment for OA

6.

Delivery systems investigated for IA OA treatment

7.

Conclusion

8.

Expert opinion

Mi Lan Kang & Gun-Il Im Dongguk University Ilsan Hospital, Department of Orthopedics, Goyang, Korea

Introduction: Intra-articular (IA) drug delivery is very useful in the treatment of osteoarthritis (OA), the most common chronic joint affliction. However, the therapeutic effect of IA administration depends mostly on the efficacy of drug delivery. Areas covered: The present article reviews the current status of IA therapy for OA treatment as well as its rationale. Outlines of drug delivery parameters such as release profile, retention time, distribution, size and transport that influence the drug’s biological performance in the joints are summarized. New delivery systems, currently under investigation, including liposome, nanoparticle, microparticle and hydrogel formulations are introduced. Functionalized drug delivery systems by targeting and thermoresponsiveness that are being investigated for OA treatment via IA therapy are also addressed. Expert opinion: Several delivery systems, including liposome, microparticles, nanoparticles and hydrogels, have been investigated for the sustained drug delivery to the joints. These can be advanced by the use of functionalized drug delivery systems that can lead targeting to specific regions and thermoresponsiveness for prolonged drug release in the joints. Further advances will bring forth new biocompatible and biodegradable materials as a drug carrier or new combination regimens. Future innovations in this field should be directed toward the development of adapted delivery systems that can induce tissue regeneration in OA patients. Keywords: drug delivery system, drug targeting, intra-articular administration, joints, osteoarthritis, thermoresponsiveness Expert Opin. Drug Deliv. (2014) 11(2):269-282

1.

Overview

Osteoarthritis (OA) is the most common arthritis, which is also called degenerative arthritis or degenerative joint disease. OA is a chronic affliction characterized by the breakdown and subsequent loss of articular cartilage. Although OA, except for the final stage, is generally treated by systemic drug administration, intra-articular (IA) drug delivery can be very useful when a small number of joints are affected or when the disease does not respond to systemic medications [1]. IA drug administration has many advantages such as the direct targeting of selected joints, initial high local drug concentrations, lower total drug dose, avoidance of systemic side effects and fewer drug interactions. Therefore, IA therapy not only reduces the costs of treatment but also improves the efficacy of therapy for OA patients. Currently, there are two major substance classes that are approved and broadly used for OA treatment via IA injection: glucocorticoids and sodium hyaluronate/hyaluronic acid (HA). However, the duration of pain relief with these drugs is relatively short and these drugs do not provide adequate pain relief due to rapid clearance and short residence time of the drugs in the synovial joint. Therefore, the development of IA 10.1517/17425247.2014.867325 © 2014 Informa UK, Ltd. ISSN 1742-5247, e-ISSN 1744-7593 All rights reserved: reproduction in whole or in part not permitted

269

M. L. Kang & G.-I. Im

Article highlights. . .

.

.


.

Intra-articular (IA) administration is a very useful therapy by the direct targeting of osteoarthritic joints. IA therapy should consider appropriate drug delivery systems for overcoming shortcoming such as rapid clearance and short residence time of drugs in the joint. Several types of IA delivery systems such as microparticles, nanoparticles, liposome and hydrogels were investigeted for the treatment of osteoarthritis. IA delivery systems can be advanced by their functionalization using targeting strategy to specific regions of the joint. Phase transition by thermoresponsive delivery systems can form a drug depot in the joint and leads to prolonged and controlled drug release.

This box summarizes key points contained in the article.

drug delivery systems that can release the therapeutic agent gradually and provide locally sustained drug action is a crucial step for successful OA treatment. Different carrier formulations such as hydrogel, liposomes and nano- or microparticles are constantly being developed to achieve long-term drug retention within the synovial joint. The objective of this review is to provide a general overview and discuss recent advances in the field of IA drug delivery systems for OA treatment. 2.

Structure and function of synovial joint

Joints are classified into synarthroses, amphiarthroses and diarthroses (synovial joints) according to the type of movement and location of each movement. Diarthroses are most frequently affected by OA [2]. All synovial joints have a synovial cavity space between articulating bones that is occupied by synovial fluid (SF), which is a clear and viscous liquid (Figure 1). SF is formed primarily by ultrafiltration of plasma across the fenestral membranes of capillary, driven by a net imbalance in the ‘Starling pressures’ acting across the membrane. The imbalance in the Starling pressure is the pressure drop from capillary plasma to synovial interstitium, minus the difference in effective colloidal osmotic pressure across the capillary wall [3]. The articular capsule, another component of the synovial joint, consists of two layers: the outer fibrous membrane that contains ligaments and the inner synovial membrane that secretes the lubricating, shockabsorbing and joint-nourishing SF [4]. Hyaline cartilage covers the articulating surfaces of bones within synovial joints. It absorbs shock to the joint and reduces friction during movement [5]. Synovial membrane or synovium is the soft tissue lining the cavity of the synovial joint. Two main types of cells are found in the synovial membrane: macrophage-like type A synoviocytes, which have a prominent Golgi complex and many vesicles, and fibroblast-like type B synoviocytes, which 270

produce a protein-rich secretion [6]. Both of them phagocytose foreign materials [7]. Several factors determine the exchange of drugs and small solutes between plasma and synovial effusions. Synovial factors include synovial pathophysiology, trans-synovial absorption rates, while the drug factors comprise the drug dissociation constant, molecular radius, serum half-life, protein binding and drug solubility [8]. The movement of protein drugs is mainly limited by the capillary permeability, whereas the movement of small molecule drugs is determined by diffusion across the interstitial space. SF contains a considerable amount of HA, a polymer of disaccharides and lubricin, which imparts viscoelasticity to SF. SF reduces friction between the articular cartilage surfaces during joint motion. As the articular cartilage is free of blood vessels, the nutrition of the tissue depends on the diffusion of nutrients from SF. A significant increase in SF volume and a simultaneous decrease in the concentration and molecular weight of HA decrease SF viscosity in OA patients. An increased in SF volume increases IA pressure, resulting in joint pain (Table 1). Articular cartilage is composed of chondrocytes and extracellular matrix (ECM), which is composed of collagen fibers, proteoglycan and elastin fibers. Chondrocytes are terminally differentiated cells that produce and maintain ECM. Chondrocyte proliferation, differentiation and homeostasis are not only governed by growth factors but are also regulated by the ECM, which provides important signals for chondrocyte behavior [9,10]. The chondrocytes sense changes in matrix composition and compensate for those changes to maintain cartilage homeostasis [9,11].

Pathophysiology and treatment modality for OA

3.

OA is prevalent after 65 years of age, reaching an incidence of 60% in men and 70% in women [12]. It is characterized by progressive focal degeneration of the articular cartilage, osteophyte formation, subchondral sclerosis, synovial inflammation and hypertrophy of the joint capsule. Although the exact cause of OA is unknown, contributing factors include aging and hereditary, developmental and metabolic factors and mechanical deficits. When OA has no recognized cause, it is referred to as primary OA. If the cause of the OA is known, then it is referred to as secondary OA. Conditions that lead to secondary OA include congenital abnormalities, hormone disturbances, crystal deposits, inflammatory diseases, all chronic forms of arthritis, repeated trauma or surgery to the joint structures, injury to the joints or ligaments, obesity and septic arthritis [13]. Metabolic changes, genetic mutations, metalloproteinase, and inflammatory mediators as factors in the pathogenesis of OA have been investigated to treat OA in the early stages of the disease. However, no exact therapeutic measure has been obviously shown to prevent the development of OA so far. OA with mild pain may be controlled initially by the use of simple analgesics such as acetaminophen, propoxyphene and

Expert Opin. Drug Deliv. (2014) 11(2)

Drug delivery systems for intra-articular treatment of osteoarthritis

Normal

Osteoarthiritis

Joint capsule Osteophyte Synovial membrane


Sclerotic bone Joint cavity (filled with synovial fluid)

Cartilage debris Irregular joint space

Articular carilage Bone cysts

Bone

Figure 1. Appearance of normal and osteoarthritic synovial joint.

Table 1. Characteristics of human SF under normal and OA conditions [21,108]. Parameter Physical parameters Volume (ml) Temperature ( C) Viscosity (mPas) Cellular components Leukocytes (cells 109/l) Neutrophil (% of leukocytes) Biochemical parameters Total protein (g/100 ml) HA (g/100 ml) MW of HA (MDa)

Normal

OA

0.5 -- 2.0 ~ 34 > 300

> 3.5 > 36 < 300

< 0.2 ~ 10

40 kDa produced an analgesic effect, HA of 860 and 2300 kDa produced higher and long-lasting analgesic effect [32]. While both HA and corticosteroids have become the most commonly used drugs for IA injection in OA treatment, HA has shown good long-term effects compared to corticosteroids such as hexacetonide and methylprednisolone acetate in some studies [35,36]. Another study reported that while corticosteroids have a tendency to produce faster pain relief, HA has long-lasting effects with better symptomatic relief at 6 months [37]. However, the recent American Academy of Orthopedic Surgeons recommended against the use of HA via IA injection based on lack of efficacy as demonstrated from a meta-analysis of 14 studies [38]. Furthermore, IA delivery of HA requires multiple injections for efficiency, and this is unavoidably associated with pain and noncompliance in patients [39]. On the other hand, the side effects of HA injections are mild in general and adverse effects are usually restricted to local reactions. Inhibitors of MMPs have been developed for an IA injection and preclinically evaluated. SB203580, a selective p38 mitogen-activated protein kinase inhibitor, was selective on the expression of MMP-13 in a rat model of OA induced by anterior cruciate ligament transection [40]. A non-Zn-chelating, selective MMP-13 inhibitor was also developed and proved to have long durability in the joint and penetrates cartilage effectively with remarkable efficacy [41].




Lastly, platelet-rich plasma (PRP) has recently emerged as another IA therapeutic modality to treat knee OA [42]. PRP is an autologous blood product produced by the centrifugation of whole blood, containing a higher concentration of platelets than baseline values. The discovery of physiologic role of platelets in the natural healing process has led to the investigation of PRP as a treatment for a variety of musculoskeletal indications [43]. Platelets contain storage pools of growth factors, cytokines, chemokines and many other mediators. Growth factors are released from the granules of platelets and induce chemotaxis, cell migration, angiogenesis, proliferation, differentiation and matrix production [44,45]. Several in vivo animal studies have shown the potential beneficial effects of PRP in suppressing the progression of OA [46-48]. While the PRP treatment had started without sufficient scientific evidences, recent results from well-designed clinical trials support IA therapy of PRP for knee OA. Prospective studies demonstrated the usefulness of IA therapy of PRP versus placebo [49] and versus HA injections [50-53] in treating symptomatic knee OA. PRP injection is apparently more effective in early stage OA than in advanced disease [53,54].

Delivery systems investigated for IA OA treatment

6.

To achieve sustained release and slow absorption of drugs within the SF, different established formulations such as suspension, hydrogels, liposomes and nano- or microparticles have been developed. This section summarizes the current investigations of IA drug delivery systems for OA treatment (Table 3), categorizing the delivery systems into molecules and biomaterials and into different functionalization such as drug targeting and thermoresponsiveness. Molecules and biomaterials Basic fibroblast growth factor (bFGF) is regarded as one of the most potent mitogens for chondrocytes in vitro [55], and it is effective in localized articular cartilage injury [56]. However, it has been reported that bFGF is rapidly diffused from the injection site and metabolized [57], and it shows both anabolic and catabolic actions in the articular cartilage depending on its concentration [58]. Sustained release of bFGF from gelatin hydrogel microspheres in the knee joint cavity was evaluated by Inoue et al. [59]. The amount of 125I-labeled bFGF microspheres was found to be significantly higher in the joint than the 125I-labeled bFGF solution. bFGF contained in gelatin hydrogel microspheres induced anabolic effects on the cartilage and suppressed the progression of OA after IA injection in the anterior cruciate ligament transection rabbit model. Ionic bonds that are formed when bFGF is impregnated with acid gelatin are broken in the process of gelatin degradation, and consequently, it is possible to have a slow and continuous release of bFGF. Local delivery of growth factors is proper to avoid systemic adverse effects, but it has been difficult to determine the dose 6.1

and release rate of the growth factor at the site of injury. Calcium alginate beads were evaluated as an IA delivery system of transforming growth factor-b (TGF-b), a powerful chondrogenic factor, in OA treatment, particularly in relation to its ability to control the release rate [60]. The alginate beads allowed the controlled release of TGF-b at a slow and steady rate of 0.25% per hour for the 1 µg/ml beads. Alginate hydrogels have a long history in the development of controlled delivery systems in the pharmaceutical industry, although their poor in vivo degradability makes them poor choice as a drug delivery vehicle [61]. However, the mechanism leading to the constant and sustained release of TGF-b from the alginate bead is unclear. It has been suggested that degradation of calcium alginate gels through the loss of divalent calcium ions to chelating anions in the surrounding medium and through diffusion from the gel along the concentration gradient could be responsible for the gradual release profiles of TGF-b [62]. Micro- or nanoparticles made of biodegradable polymers have been investigated as a method for the controlled release of drugs in IA injection. Besides the need for a biocompatibility, the release profile of the encapsulated compound needs to be reproducible and independent of the force load of the joint [21]. Poly(lactic-co-glycolic acid) (PLGA) has been a widely used copolymer for multiple medical purposes because of their proven safety, minimal toxicity and flexible physicochemical properties. There are several reports that have evaluated PLGA as a drug delivery system via the IA route for OA treatment [63-65]. Triamcinolone acetonide in 75:25 PLGA microspheres maintained a gradient between synovial and systemic concentrations for the duration of 6 weeks in 24 knee OA patients [66]. Lornoxicam (Lnxc)-loaded PLGA microspheres (Lnxc-MS) for OA treatment by IA therapy showed effective pharmacodynamics including reduced joint swelling and repair of cartilage damage in the papain-induced rat OA model [63]. Lnxc, an NSAID of the oxicam class, has effective anti-inflammatory, analgesic and antipyretic effects [67]; however, Lnxc injections leak quickly into the systemic circulation owing to the short residence time and half-life [68]. Lnxc-MS showed considerable potential to create several useful effects of Lnxc such as sustained release, increased retention time in the joint, reduced clearance time from the joint and decreased plasma concentrations compared to the Lnxc suspension [63]. While drug concentration declined below the limit of quantitation 48 h after injection with the suspension, Lnxc in the joint tissue of animals injected with the PLGA microspheres remained at a high level for a longer time, until 96 h. The rapid clearance of Lnxc from the joint cavity causes a decrease in drug concentration in the joint cavity and consequently there is less efficiency of therapeutic effects, whereas the microsphere formulations with a higher drug concentration in the joint tissue can lead to greater therapeutic efficiency. Recently, we have reported that sulforaphane-loaded PLGA microspheres (SFN-PLGA) have successful anti-inflammatory activity in articular chondrocytes, and this formulation delays the progression of surgically induced OA in rats after IA


273


Table 3. Drug delivery systems developed up to this date for the IA treatment of OA. Type


Nanoparticle

Hydrogel

Liposome

Nature of the matrix

Diameter of particles

Targeted drugs

In vivo tests

PLGA

30.2 ± 12 or 36.6 ± 11 nm

Insulin

Healthy mouse

PLGA covered by HA

Not defined

Model drug, dextran--FITC

Healthy rat

Tetraethylene glycol methacrylate/cyclohexyl methacrylate

270 ± 5 nm

IL-1 receptor antagonist

Healthy rat

Poly(propylene sulfide)

38 nm

Collagen II a1-binding ligand, WYRGRL

Healthy mouse

HA/perlecan bearing heparan sulfate chains a-CD-EG4400

-

BMP2

Papain-induced OA mouse

-

Chondroitin sulfate

Surgically induced OA rabbit

Liposomes carrying HA

Not defined

Dexamethasone/ diclofenac

Monosodiumiodoacetateinduced OA rat

Liposome

4.98 µm

Celecoxib/HA


Comments

Ref.

Rapid burst release in vitro Insulin activity (stimulation of ECM synthesis) after release from microsphere No characterization of the nanoparticles. Detection in synovial membrane but not in patellae. Inflammatory response (IL-1 b and TNF-a) Study sould be confirmed in OA model animals using the drug to treat OA Targeting synoviocyte cells via surface IL-1 receptors Inhibition of IL-1-mediated signaling. Prolonged retention (particle-tethered IL-1Ra, t1/2 = 3.01 days; soluble IL-1Ra, t1/2 = 0.96 days) Targeting articular cartilage via collagen II a1-binding ligand. Entering the articular cartilage ECM of nanoparticles with mean diameter of < 38 nm but not nanoparticle with mean diameter of 96 nm Stimulation of proteoglycan and cartilage matrix synthesis

[62]

Slow in vitro release (80% for 1 week; remaining 20% for 30 days). Improvement of biomechanical and histological properties of repaired cartilage No characterization of the liposomes. Inhibition of cyclooxygenases activity (diclofenac) and cyclooxygenases protein expression (dexamethasone) Reduced inflammation High encapsulation efficiency (99.5%). Slow release of loposomal celecoxib(Clx)--HA combination than Clx only from the liposome. Efficiency in pain control and cartilage protection

[109]

[92]

[90]

[91]

[82]

[74]

[75]

bFGF: Basic fibroblast growth factor; ELP: Elastin-like polypeptide; FITC: Fluorescein isothiocyanate; HA: Hyaluronic acid ; IA: Intra-articular; IL-1Ra: IL-1 receptor antagonist; MW: Molecular weight; OA: Osteoarthritis; PLGA: Poly(lactic-co-glycolic acid); TGF-b: Transforming growth factor-b.

274



Table 3. Drug delivery systems developed up to this date for the IA treatment of OA (continued). Type


Microparticle

Miscellaneous

Nature of the matrix

Diameter of particles

Targeted drugs

In vivo tests

PLGA

Not defined

Lornoxicam

Healthy rat

PLGA

69 ± 25 µm

PTH (1 -- 34)

Papain-induced OA rat

PLGA

14.5 ± 0.81 µm

Sulforaphane

Surgically induced OA rat

PLGA

9.0 ± 0.2 or 5.0 ± 0.1 µm

Naproxen sodium

Ovalbumin and Freund’s complete adjuvantinduced OA rabbit

Gelatin hydrogel

70 µm

bFGF

Healthy rabbit

Collagomers

Microparticle dimension in SEM image

Diclofenac

Monosodiumiodoacetateinduced OA rat

Calcium alginate

Not defined

TGF-b


ELPs

Not defined

Model genes encoding Val/Gly/Ala or Val only

Healthy rat

Comments

Ref.

Decrease of drug’s systemic toxicity and increase of retention time in joint Reduction of joint swelling Repair of articular cartilage damage Encapsulation efficiency (62.7%). Burst release up to early 2 days and sustained release for 19 days. Reduced the number of administration times Slow in vitro release (6% of sulforaphane from microspheres for 30 days). In vitro and in vivo chondroprotective effect Fast release from low-MW PLGA microspheres compared with high-MW PLGA microsphers. Increased residence time of PLGA microspheres comapred with BSA microspheres in joint Retention in the joint cavity (3% remaining after 7 days) Localization bFGF in soft tissue (including synovium) but not in articular cartilage Indicated induced anabolic effects on cartilage and suppression of the progression of OA High encapsulation efficiency (85%). Slow in vitro drug release (t1/2 = 11 days). High affinity to target cells (k D = 2.6 nM collagen) Anti-inflammatory activity over 3 weeks Slow in vitro release of TGF-b from alginate (30 to 40% retention after 5 days) Improved repair of the articular cartilage defects Thermogelling biopolymer (ELP) that aggregate upon IA injection. Prolonged retention in the joint cavity (nonaggregated ELP, t1/2 = 3.4 h; aggregated ELP, t1/2 = 3.7 days)

[63]

[64]

[65]

[110]

[59]

[81]

[60]

[96]

bFGF: Basic fibroblast growth factor; ELP: Elastin-like polypeptide; FITC: Fluorescein isothiocyanate; HA: Hyaluronic acid ; IA: Intra-articular; IL-1Ra: IL-1 receptor antagonist; MW: Molecular weight; OA: Osteoarthritis; PLGA: Poly(lactic-co-glycolic acid); TGF-b: Transforming growth factor-b.


275



delivery [65]. SFN, a molecule within the isothiocyanate group of organosulfur compounds, has been known to prevent, delay or reverse carcinogenesis [69]. SFN also has antiinflammatory activity such as downregulation of expression of lipopolysaccharide-stimulated inducible iNOS, COX-2 and TNF-a [70]. Our results showed that SFN-PLGA microspheres are an effective drug formulation in OA treatment when given via the IA route [65]. Insulin was encapsulated in PLGA microspheres for IA injection [62]. The release profiles of insulin indicated a biphasic release pattern, with almost 40% of the total insulin released in the first 24 h and a second release phase over the next 15 days, at which point 89% of the total insulin had been released. Slow release of insulin was found to mimic the effects of anabolic growth factor, insulin growth factor-1 (IGF-1), by activating the IGF-1 receptor. It was able to stimulate proteoglycan synthesis, inhibit prostaglandin and nitric oxide release and overcome the detrimental effects of IL-1 [62]. Another study has shown that amino acid polypeptide of N-terminal fragment 1 -- 34 of parathyroid hormone [PTH (1 -- 34)]-loaded PLGA microspheres sustainably released PTH (1 -- 34) for 19 days and suppressed the papain-induced OA change in rat knee cartilage [64]. These researchers reported previously that PTH (1 -- 34) acts on human articular chondrocytes to suppress their terminal differentiation as well as reducing papain-induced OA in rats [71]. Administration of PTH (1 -- 34) requires an injection once every 3 days during the treatment period [71]. PLGA microspheres effectively prolonged the treatment duration of an IA injection for OA treatment through the sustained release of PTH (1 -- 34) from the delivery system [64]. PLGA has been shown to degrade mainly by simple hydrolysis of the ester bond into acidic monomers. There are data to suggest that PLGA produce an acidic degradation product that can result in high local acidity [72,73]. The selective accumulation of the acidic degradation product can induce heterogeneous catalytic degradation in the interior of the drug delivery systems [72,73]. The processes of degradation can be proinflammatory through the release of acidic moieties, residual catalysts and micron- or sub-micron-sized particles [24]. This potential disadvantage should be taken into account in using PLGA as a vehicle for IA drug delivery. Liposomes are artificially prepared vesicles, composed of lipid bilayer. They are naturally occurring, biodegradable and nontoxic biomaterial. Liposomes are also useful for local delivery of therapeutic agents to the sites of interest. There are several reports that evaluate liposomes as IA drug delivery systems for OA treatment [74,75]. Celecoxib (Clx), a COX2 inhibitor and anti-inflammatory agent, is widely used as a drug of choice for OA treatment because of its low gastrointestinal side effects [76]. However, it has been reported that use of Clx increase the risk of serious cardiovascular events especially with the chronic use and higher doses of this drug [77]. Encapsulation of Clx in multilamellar vesicles composed of DSPC (1,2-distearoyl-sn-glycero276

3-phosphocholine) and variable amounts of cholesterol was developed to circumvent the low bioavailability and systemic side effects of oral Clx formulations [78]. To improve efficacy for OA treatment while reducing the adverse events of Clx, Dong et al. developed a new hybrid formulation of Clx-loaded liposome embedded in HA gel [75]. The liposomal Clx embedded in HA gel formulation showed sustained and prolonged release profiles of Clx and greater efficiency in pain control and cartilage protection in rabbit OA models compared with liposome-only formulations. The IA delivery of the liposomal Clx and HA combination may lead to a reduction in cardiovascular events by minimizing the dose and exposure time of the drug. Hydrolysis and oxidation of phospholipid liposomes in degradation processes could induce an interaction of their degradation product and serum components in vivo [79]. The degradation of the liposomal drug carrier and the release rate of the drugs would be determined by the liability of the lipid substrate toward hydrolysis catalyzed by phospholipase A2 (PLA2) as well as on the local concentration of PLA2 in the diseased tissue [80]. Collagomers, novel IA delivery systems based on collagenlipid conjugates, were developed and evaluated to circumvent severe adverse effects and risks of gastrointestinal toxicity of diclofenac in OA treatment [81]. The formulations were prepared by conjugation of collagen type I and dipalmitoyl phosphatidyl ethanolamine using glutaraldehyde as a crosslinker. Diclofenac, one of the NSAIDs, encapsulated in the collagomers showed slow drug release (T1/2 = 11 days), as well as a high affinity for target cells (kD = 2.6 nM collagen) and anti-inflammatory activity in OA rat models. Daily oral administration of NSAIDs can lead to adverse effects including GI toxicity, gastric ulcers and anaphylaxis [21]. Therefore, the IA delivery of diclofenac encapsulated in collagomers may reduce adverse effects and risks of gastrointestinal toxicity by minimizing contact between the free drug and the gastrointestinal tract. Another hybrid IA delivery system using HA involves covalent immobilization with a module of perlecan (PlnD1) bearing heparan sulfate (HS) chains and HA microgels to deliver bone morphogenetic protein 2 (BMP2) [82]. BMP2 plays a critical role in the establishment of normal cartilage during development and also enhances reparative processes and synthesis of ECM components in damaged articular cartilage [83,84]. PlnD1 acts as a depot for BMP2 storage through their HS chains that bind BMP2, producing the controlled release of the drug [85], protecting it from proteolytic degradation as well as potentiating the chondrogenic bioactivity of BMP2 [86]. PlnD1 was conjugated with HA via the core protein through a polyethylene glycol linker to avoid its diffusion and susceptibility to degradation of the PlnD1 and potentiate the cartilage repair effect of BMP2 in a murine model with early OA. The degradation products of HA, oligosaccharides and very-low-molecular-weight HA, exhibit pro-angiogenic



properties [87]. HA degradation products are known to contribute to scar formation. When hyaluronidase is added to generate HA fragments, scar formation increases. These data support the theory that while high-molecular-weight HA promotes cell quiescence and supports tissue integrity, HA degradation product is a signal that injury has occurred and initiates an inflammatory response [88]. Targeting delivery systems Target drug delivery system is a special form of drug delivery system where the pharmacologically active agent or medicament is selectively targeted or delivered only to its site of action or absorption [89]. An ideal site-selective drug delivery approach not only increases the therapeutic efficacy of drug but also decreases the toxicity associated with drug. This allows lower doses of drug to be used in therapy. Targeting the ECM of articular cartilage depends on the ability of drug delivery systems to enter the cartilage collagen matrix and to reside there. Promising targeting strategies have been reported such as IL-1 receptor antagonist (IL-1Ra)-conjugated nanoparticles [90], phage-panned peptide-targeted nanoparticles [91], and HA-coated PLGA particles [92]. A self-assembled submicron scale particle, which composed of a new block copolymer synthesized by polymerization of the hydrophilic monomer tetraethylene glycol methacrylate and the hydrophobic monomer cyclohexyl methacrylate, provides targeted delivery by protein tethering [90]. The IL-1Ratethered polymeric nanoparticles not only retained IL-1Ra bioactivity and their ability to target synoviocytes but also modulated NF-kB activation after IL-1b stimulation, clearly indicating that the conjugated IL-1Ra maintained its ability to block the IL-1 signaling pathway [90]. The retention time and distribution of IL-1Ra when conjugated to nanoparticles and delivered through the IA route were successfully increased. Rats that received IL-1Ra-conjugated nanoparticles showed significant retention time in the joint space for up to 14 days (3.01 ± 0.09 days half-life), while those receiving soluble IL-1Ra protein exhibited rapid clearance (0.96 ± 0.08 day half-life). The conjugation of IL-1Ra protein to nanoparticles induced increase in the retention time in the joint as well as the improvement of distribution throughout the IA space and cartilage [90]. Obtaining long retention times in the synovial joint space is a crucial step in achieving successful results in OA treatment using IA drug delivery systems. The functionalization of delivery systems by chemical surface modifications can lead to high binding of the drug to specific targets in the joint, thus increasing residence times. Drug targeting of the cartilage matrix has been developed and evaluated using functionalized nanoparticles containing ligand peptide WYRGRL, which targets collagen II a1 [91]. The nanoparticles bound to the extracellular compartment of articular cartilage following IA injection and showed increased retention time within the ECM, up to 72-fold more than nanoparticles displaying a scrambled peptide. This approach provides a way for targeting


6.2

poorly accessible avascular tissue and may be of use in small molecule and biomolecular therapy in OA. Nanoparticles of poly(D, L-lactic acid) or PLGA covered with chemically esterified amphiphilic HA can improve the interaction between chondrocytes and nanoparticles, leading to better drug targeting [92]. This is because HA, which is a natural polysaccharide already present in the articular cartilage, interacts with the CD44 receptors of the cells. A previous in vitro study demonstrated that these nanoparticles were internalized by both chondrocytes and synoviocytes cells, probably due to the HA covering of these particles [93]. Thermoresponsive delivery systems IA drug delivery systems should address the problem of the short residence times due to the rapid uptake of the injected drugs within the joint space, which causes low bioavailability and adverse side effects. Among them, thermoresponsive polymers that exhibit a drastic and discontinuous change in their physical properties with temperature are emerging as a promising method [94]. Elastin-like polypeptides (ELPs), which consist of a repeating penta peptide sequence, present in native elastin are one of the thermoresponsive polymers that exhibit a phase transition above their transition temperature (Tt), which is characterized by the formation of micron- and submicron-sized aggregates [95]. The thermally responsive IA delivery systems using ELPs were designed to aggregate upon IA injection at 37 C and form a drug depot that could slowly disaggregate, with clearance from the joint space over time [96]. The report showed that the aggregating ELP had a 25-fold longer half-life in the joint than proteins of similar molecular weight, suggesting that IA delivery of ELP-based fusion proteins may be a possible strategy for the prolonged release of protein drugs in OA treatment. The kinetics and levels of ELPs in blood and joint tissue reveal that the aggregating ELPs concentrate in the injection site, and slowly disaggregate, promoting the sustained release, distribution and clearance of the drug. Researchers have suggested that IA delivery of ELPs-based fusion proteins may be a possible strategy for the biocompatible and sustained release of disease-modifying protein drugs for OA treatment [96]. IL-1Ra has been shown to inhibit the progression of OA lesions in OA animal models [97] and to reduce the pain and swelling of inflammatory arthritis in humans [98]. Several reports have focused on the delivery of the IL-1Ra gene directly to the joint [99] and the delivery of a high-dose IL-1Ra (150 mg/injection) through the IA route [100] without using any delivery systems that overcome the rapid clearance of the drug. In an ongoing report, thermally responsive drug depot for IA delivery of IL-1Ra through fusion to ELP is being investigated [101]. It was claimed that this formulation forms a drug depot that produces sustained anti-cytokine therapeutic release while preserving partial bioactivity. It was also claimed that this formulation permitted the use of smaller doses and longer dosing intervals compared to IL-1Ra alone [101]. 6.3


277



6.4

Drug size and transport

The synovium constitutes the main barrier for drug transport out of the joint cavity. In the joint cavity, solute drug molecules released from the immobilized depot undergo a number of reactions and distribution processes before eventually being cleared from the synovial space [18]. The ECM is the major diffusional barrier for the entry of small molecules, while the endothelium is the critical barrier for passage of proteins [18]. Therefore, the size of drug formulations and their transport through the joint determine their capability for tissue penetration and cellular uptake. Thus, the size of the formulation is a major issue of IA drug delivery. Particulates delivered through the IA route may be transported by the following pathway. First there is phagocytosis by synovial membrane macrophages which may be accompanied by release of the encapsulated drug within the targeted synovial macrophages [102]. In this case, particles of size < 250 nm can escape freely from the joint cavity, whereas those with a diameter between 1 and 4 µm are effectively phagocytosed by the synovial macrophages [102-104]. Dong et al. have developed Clx loaded liposomes embedded in HA gel for an IA delivery system, which showed an optimal particle size of 4.98 µm [75]. Another report showed that > 90% of the PTH/PLGA microspheres with a larger size for IA delivery were 51 -- 85 µm in diameter [64]. Second is the entry of nanoparticulates into the cartilage matrix by convective transport during cartilage compression and penetration of nanoparticulates between the collagen fibers of the ECM [90,91]. Nanoparticles with a mean volume diameter of 31 and 38 nm were able to enter the articular cartilage ECM, whereas larger nanoparticles with a mean volume diameter of 96 nm could not [91]. This significant difference was attributed to the 60 nm pore size of the dense collagen network. The third pathway is the microparticles remaining within the SF by adhering to the cartilage and synovium or becoming entrapped within the synovial folds. The drug is released from the microparticles into the SF and the free drug is transported via passive diffusion into joint tissues, lymphatic channels and capillaries and then into the systemic circulation [105,106]. A previous report emphasized that the appropriate size of microspheres for IA injection in rats was 35 -- 105 µm and that this caused no harmful effects [107]. 7.

Conclusion

IA drug delivery is very useful for the OA treatment since joint is a main site of the disease developed. However, soluble drugs administered through the IA route are rapidly absorbed into the blood circulation [20] and cleared by trans-synovial flow into the synovial lymph vessels [21]. Therefore, appropriate drug delivery systems that improve drug residence time in joint and act as a drug depot for sustained release are needed. There are many types of IA drug delivery systems including nano-/microparticles, liposome, hydrogel and micelle that 278

were developed for OA treatment. The polymer that was used the most in raw materials of IA drug delivery systems was PLGA [63-65,62,92], owing to their excellent biocompatibility and biodegradability approved by the US FDA for clinical applications. The developments of IA drug delivery systems for OA treatment has been also improved by functionalized characteristics including drug targeting [90-92] and thermoresponsiveness [96,101]. The target drug delivery systems could increase residence times of drugs in the joint by binding of the drugs to specific sites [90-92]. The thermally responsive IA drug delivery systems acted as a drug depot by aggregation at body temperature and thus drug residence time could increase [96,101]. The size of drug formulations and their transport through the joint determines their capability for tissue penetration and cellular uptake. An appropriate size of drug formulations for IA delivery is still controversial. While the size smaller than 60 nm was suggested for their transportation through the dense collagen network in the ECM [90,91], the larger size of 51 -- 85 µm [64] and 4.98 µm [75] were suggested as an optimal size for IA drug delivery. 8.

Expert opinion

IA drug delivery for OA treatment is a targeted drug delivery to the affected tissues. It aims to minimize the attendant side effects of systemically administered drugs including high cost, limited efficacy and lack of patient compliance. Many researchers are engaged in ongoing efforts to find ways to exploit the characteristics of the IA route through the development of various delivery systems such as HA formulations, microparticles, nanoparticles, hydrogels and liposomes for OA treatment. These developments also provide a means to utilize IA administration for new drug candidates that cannot be administered with good efficacy and safety via the systemic route. The development of IA drug delivery systems for OA treatment can be advanced by the use of functionalized drug delivery systems that can lead targeting of specific regions of the joint. Consequently, drug targeting delivery may induce sustained or controlled release of the drug and increased retention time of the drug in the joint. While many studies targeted synovium in the treatment of inflammatory arthritis, the primary affected site of the OA process is the cartilage matrix. Therefore, drug targeting to the component of cartilage matrix in the joint may be a significant consideration for the future therapeutic approaches in OA treatment. The strategy of drug targeting delivery via IA administration also includes conjugating of delivery systems and a bioaffinity ligand such as receptor antagonist or aptamer that can bind to specific receptors expressed on chondrocyte in the cartilage matrix. Other promising method of functionalized drug delivery systems has significant characteristics of phase transition by the use of thermoresponsive biomaterials. It exhibits a drastic




and discontinuous change of their physical properties above their transition temperature. The thermally responsive IA drug delivery systems can be designed to aggregate at body temperature and form a drug depot that could slowly disaggregate, with promoting the sustained release, distribution and clearance of the drug. Research is being extended to the development of new drug moieties known to modify OA or other biological molecules having biocompatible and biodegradable properties. The assessments of biocompatibility should include evaluation of swelling, inflammation and histopathological analysis in the joint. Further advancements in this field should involve a better understanding of the cartilage homeostasis and pathology as well as new biocompatible and biodegradable delivery systems. In spite of the extensive research done in this field, there are few published reports about new IA drug delivery systems for OA treatment in humans. These systems need to be further refined to enable preclinical and clinical trials using well-defined scoring systems for evaluation of biocompatibility. Bibliography

Caldwell JR. Intra-articular corticosteroids. Guide to selection and indications for use. Drugs 1996;52:507-14

2.

Nagerl H, Kubein-Meesenburg D, Cotta H, et al. Biomechanical principles of diarthroses and synarthroses. III: mechanical aspects of the tibiofemoral joint and role of the cruciate ligaments. Z Orthop Ihre Grenzgeb 1993;131:385-96

Declaration of interest The authors state no conflict of interest and have received a grant from the National Research Foundation of Korea (2009-0092196) in preparation of this manuscript.

synovial cells of the rat knee joint to intra-articularly injected latex particles. Kaibogaku Zasshi 1999;74:525-35

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Finally, tissue engineering strategies integrate the concepts of medicine, chemistry, biology, pharmaceutics and engineering. These approaches can use a combination of cells, biometrics, scaffolds, delivery vehicles and signaling molecules for OA treatment. Research in this field should be directed toward the development of adapted drug delivery systems that can induce tissue regeneration in OA patients. The strategy includes IA delivery of medications or genes that can promote the chondrogenic differentiation of stem cells residing in synovium or bone marrow.

8.

Wallis WJ, Simkin PA. Antirheumatic drug concentrations in human synovial fluid and synovial tissue. Observations on extravascular pharmacokinetics. Clin Pharmacokinet 1983;8:496-522

9.

van der Kraan PM, Buma P, van Kuppevelt T, et al. Interaction of chondrocytes, extracellular matrix and growth factors: relevance for articular cartilage tissue engineering. Osteoarthritis Cartilage 2002;10:631-7

Levick JR, McDonald JN. Fluid movement across synovium in healthy joints: role of synovial fluid macromolecules. Ann Rheum Dis 1995;54:417-23

10.

4.

Werner CM, Nyffeler RW, Jacob HA, et al. The effect of capsular tightening on humeral head translations. J Orthop Res 2004;22:194-201

11.

Goldring MB. The role of the chondrocyte in osteoarthritis. Arthritis Rheum 2000;43:1916-26

12.

5.

Pieper KS, Fehrmann P, Vergani G, et al. On the functional organisation of hyaline articular cartilage. Ital J Anat Embryol 1995;100(Suppl 1):113-19

Sarzi-Puttini P, Cimmino MA, Scarpa R, et al. Osteoarthritis: an overview of the disease and its treatment strategies. Semin Arthritis Rheum 2005;35:1-10

13.

Swiechowicz S, Ostalowska A, Kasperczyk A, et al. Evaluation of hyaluronic acid intra-articular injections in the treatment of primary and secondary osteoarthritis of the knee. Pol Orthop Traumatol 2012;77:105-9

3.

6.

7.

Wilkinson LS, Pitsillides AA, Worrall JG, et al. Light microscopic characterization of the fibroblast-like synovial intimal cell (synoviocyte). Arthritis Rheum 1992;35:1179-84 Senda H, Sakuma E, Wada I, et al. Ultrastructural study of cells at the synovium-cartilage junction: response of

14.

van der Kraan PM, van den Berg WB. Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration? Osteoarthritis Cartilage 2012;20:223-32

Flood J. The role of acetaminophen in the treatment of osteoarthritis. Am J


Manag Care 2010;16(Suppl Management):S48-54 15.

Chen YF, Jobanputra P, Barton P, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess 2008;12:1-278

16.

Qvist P, Bay-Jensen AC, Christiansen C, et al. The disease modifying osteoarthritis drug (DMOAD): is it in the horizon? Pharmacol Res 2008;58:1-7

17.

Richmond JC. Surgery for osteoarthritis of the knee. Rheum Dis Clin North Am 2013;39:203-11

18.

Larsen C, Ostergaard J, Larsen SW, et al. Intra-articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J Pharm Sci 2008;97:4622-54 Comprehensive review on the basis of rational design of intra-articular drug delivery systems for polonged release.

..

19.

Abramson S. Drug delivery in degenerative joint disease: where we are and where to go? Adv Drug Deliv Rev 2006;58:125-7

20.

Neander G, Eriksson LO, Wallin-Boll E, et al. Pharmacokinetics of intraarticular indomethacin in patients with osteoarthritis. Eur J Clin Pharmacol 1992;42:301-5

279


21.

..


22.

23.

24.

Gerwin N, Hops C, Lucke A. Intraarticular drug delivery in osteoarthritis. Adv Drug Deliv Rev 2006;58:226-42 Review of intra-articular drug treatment in osteoarthritis with emphasis on glucocorticoids and hyaluronic acid. Owen SG, Francis HW, Roberts MS. Disappearance kinetics of solutes from synovial fluid after intra-articular injection. Br J Clin Pharmacol 1994;38:349-55 Coleman PJ, Scott D, Ray J, et al. Hyaluronan secretion into the synovial cavity of rabbit knees and comparison with albumin turnover. J Physiol 1997;503:645-56 Bergsma JE, de Bruijn WC, Rozema FR, et al. Late degradation tissue response to poly(L-lactide) bone plates and screws. Biomaterials 1995;16:25-31

25.

Williams DF. The Williams dictionary of biomaterials. Liverpool University Press; Liverpool: UK: 1999

26.

Williams DF. On the mechanisms of biocompatibility. Biomaterials 2008;29:2941-53

27.

28.

29.

30.

Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebocontrolled trial. Arthritis Rheum 2003;48:370-7 Neustadt DH. Intra-articular injections for osteoarthritis of the knee. Cleve Clin J Med 2006;73:897-8 Saxne T, Heinegard D, Wollheim FA, et al. Therapeutic effects on cartilage metabolism in arthritis as measured by release of proteoglycan structures into the synovial fluid. Ann Rheum Dis 1986;45:491-7 Hepper CT, Halvorson JJ, Duncan ST, et al. The efficacy and duration of intraarticular corticosteroid injection for knee osteoarthritis: a systematic review of level I studies. J Am Acad Orthop Surg 2009;17:638-46

31.

Arroll B, Goodyear-Smith F. Corticosteroid injections for osteoarthritis of the knee: meta-analysis. BMJ 2004;328:869

32.

Raynauld JP, Buckland-Wright C, Ward R, et al. Safety and efficacy of long-term intraarticular steroid injections

280

in osteoarthritis of the knee: a randomized, double-blind, placebocontrolled trial. Arthritis Rheum 2003;48:370-7

43.

Smyth SS, McEver RP, Weyrich AS, et al. Platelet functions beyond hemostasis. J Thromb Haemost 2009;7:1759-66

33.

Balazs EA, Watson D, Duff IF, et al. Hyaluronic acid in synovial fluid. I. Molecular parameters of hyaluronic acid in normal and arthritis human fluids. Arthritis Rheum 1967;10:357-76

44.

Foster TE, Brooks JR. Functional groups based on leaf physiology: are they spatially and temporally robust? Oecologia 2005;144:337-52

45.

34.

Rydell N, Balazs EA. Effect of intraarticular injection of hyaluronic acid on the clinical symptoms of osteoarthritis and on granulation tissue formation. Clin Orthop Relat Res 1971;80:25-32

Anitua E, Andia I, Ardanza B, et al. Autologous platelets as a source of proteins for healing and tissue regeneration. Thromb Haemost 2004;91:4-15

46.

35.

Listrat V, Ayral X, Patarnello F, et al. Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan) in osteoarthritis of the knee. Osteoarthritis Cartilage 1997;5:153-60

Mifune Y, Matsumoto T, Takayama K, et al. The effect of platelet-rich plasma on the regenerative therapy of muscle derived stem cells for articular cartilage repair. Osteoarthritis Cartilage 2013;21:175-85

47.

36.

Jones AC, Pattrick M, Doherty S, et al. Intra-articular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis. Osteoarthritis Cartilage 1995;3:269-73

Kwon DR, Park GY, Lee SU. The effects of intra-articular platelet-rich plasma injection according to the severity of collagenase-induced knee osteoarthritis in a rabbit model. Ann Rehabil Med 2012;36:458-65

48.

37.

Leopold SS, Redd BB, Warme WJ, et al. Corticosteroid compared with hyaluronic acid injections for the treatment of osteoarthritis of the knee. A prospective, randomized trial. J Bone Joint Surg Am 2003;85-A:1197-203

Saito M, Takahashi KA, Arai Y, et al. Intraarticular administration of plateletrich plasma with biodegradable gelatin hydrogel microspheres prevents osteoarthritis progression in the rabbit knee. Clin Exp Rheumatol 2009;27:201-7

38.

American Academy of Orthopedic Surgeons. Treatment of Osteoarthritis of the Knee. 2013 Annual Meeting; Rosemont, IL, USA

49.

39.

Brandt KD, Smith GN Jr, Simon LS. Intraarticular injection of hyaluronan as treatment for knee osteoarthritis: what is the evidence? Arthritis Rheum 2000;43:1192-203

Patel S, Dhillon MS, Aggarwal S, et al. Treatment with platelet-rich plasma is more effective than placebo for knee osteoarthritis: a prospective, doubleblind, randomized trial. Am J Sports Med 2013;41:356-64

50.

Chen WD, Jiang Q, Chen DY, et al. Effects of intra-articular injection of p38 mitogen-activated protein kinase inhibitor on matrix metalloproteinase in articular cartilage of a rat model of osteoarthritis. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2007;29:777-81

Cerza F, Carni S, Carcangiu 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

51.

Spakova T, Rosocha J, Lacko M, et al. Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid. Am J Phys Med Rehabil 2012;91:411-17

52.

Say F, Gurler D, Yener K, et al. Platelet-Rich Plasma injection is more effective than hyaluronic acid in the treatment of knee osteoarthritis. Acta Chir Orthop Traumatol Cech 2013;80:278-83

53.

Kon E, Mandelbaum B, Buda R, et al. Platelet-rich plasma intra-articular

40.

41.

42.

Gege C BB, Bluhm H, Boer J, et al. Discovery and evaluation of a anterior cruciate ligament transection) inhibitor for potential intra-articular treatment of osteoarthritis. J Med Chem 2012;55:709-916 Filardo G, Kon E. PRP: more words than facts. Knee Surg Sports Traumatol Arthrosc 2012;20:1655-6




injection versus hyaluronic acid viscosupplementation as treatments for cartilage pathology: from early degeneration to osteoarthritis. Arthroscopy 2011;27:1490-501 54.

Jang SJ, Kim JD, Cha SS. Platelet-rich plasma (PRP) injections as an effective treatment for early osteoarthritis. Eur J Orthop Surg Traumatol 2013;23:573-80

55.

Kato Y, Iwamoto M, Koike T. Fibroblast growth factor stimulates colony formation of differentiated chondrocytes in soft agar. J Cell Physiol 1987;133:491-8

56.

57.

58.

59.

60.

61.

63.

64.

Yamamoto T, Wakitani S, Imoto K, et al. Fibroblast growth factor-2 promotes the repair of partial thickness defects of articular cartilage in immature rabbits but not in mature rabbits. Osteoarthritis Cartilage 2004;12:636-41 Kawaguchi H, Kurokawa T, Hanada K, et al. Stimulation of fracture repair by recombinant human basic fibroblast growth factor in normal and streptozotocin-diabetic rats. Endocrinology 1994;135:774-81 Sah RL, Chen AC, Grodzinsky AJ, et al. Differential effects of bFGF and IGF-I on matrix metabolism in calf and adult bovine cartilage explants. Arch Biochem Biophys 1994;308:137-47 Inoue A, Takahashi KA, Arai Y, et al. The therapeutic effects of basic fibroblast growth factor contained in gelatin hydrogel microspheres on experimental osteoarthritis in the rabbit knee. Arthritis Rheum 2006;54:264-70 Mierisch CM, Cohen SB, Jordan LC, et al. Transforming growth factor-beta in calcium alginate beads for the treatment of articular cartilage defects in the rabbit. Arthroscopy 2002;18:892-900 Rowely J MG, Mooney D. Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials 1999;20:45-53 Zhang Z, Huang G. Intra-articular lornoxicam loaded PLGA microspheres: enhanced therapeutic efficiency and decreased systemic toxicity in the treatment of osteoarthritis. Drug Deliv 2012;19:255-63 Eswaramoorthy R, Chang CC, Wu SC, et al. Sustained release of PTH(1-34) from PLGA microspheres suppresses osteoarthritis progression in rats. Acta Biomater 2012;8:2254-62

65.

Ko JY, Choi YJ, Jeong GJ, et al. Sulforaphane-PLGA microspheres for the intra-articular treatment of osteoarthritis. Biomaterials 2013;34:5359-68

66.

Bodick N, Lufkin J, Willwerth C, et al. FX006 Prolongs the Residency of Triamcinolone Acetonide in the Synovial Tissues of Patients with Knee Osteoarthritis. Osteoarthritis Cartilage 2013;21(Suppl):s144-5

67.

68.

Rawal N, Kroner K, Simin-Geertsen M, et al. Safety of lornoxicam in the treatment of postoperative pain: a postmarketing study of analgesic regimens containing lornoxicam compared with standard analgesic treatment in 3752 day-case surgery patients. Clin Drug Investig 2010;30:687-97 Balfour JA, Fitton A, Barradell LB. Lornoxicam. A review of its pharmacology and therapeutic potential in the management of painful and inflammatory conditions. Drugs 1996;51:639-57

69.

Juge N, Mithen RF, Traka M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci 2007;64:1105-27

70.

Heiss E, Herhaus C, Klimo K, et al. Nuclear factor kappa B is a molecular target for sulforaphane-mediated antiinflammatory mechanisms. J Biol Chem 2001;276:32008-15

62.

71.

Cai L, Okumu FW, Cleland JL, et al. A slow release formulation of insulin as a treatment for osteoarthritis. Osteoarthritis Cartilage 2002;10:692-706 Chang JK, Chang LH, Hung SH, et al. Parathyroid hormone 1-34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats. Arthritis Rheum 2009;60:3049-60

72.

Yoshioka T, Kawazoe N, Tateishi T, et al. In vitro evaluation of biodegradation of poly(lactic-coglycolic acid) sponges. Biomaterials 2008;29:3438-43

73.

Yang Y, Tang G, Zhao Y, et al. Effect of cyclic loading on in vitro degradation of poly(L-lactide-co-glycolide) scaffolds. J Biomater Sci Polym Ed 2010;21:53-66

74.

Elron-Gross I, Glucksam Y, Margalit R. Liposomal dexamethasone-diclofenac combinations for local osteoarthritis treatment. Int J Pharm 2009;376:84-91


75.

Dong J, Jiang D, Wang Z, et al. Intra-articular delivery of liposomal celecoxib-hyaluronate combination for the treatment of osteoarthritis in rabbit model. Int J Pharm 2013;441:285-90

76.

Clemett D, Goa KL. Celecoxib: a review of its use in osteoarthritis, rheumatoid arthritis and acute pain. Drugs 2000;59:957-80

77.

Solomon SD, McMurray JJ, Pfeffer MA, et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-80

78.

Deniz A, Sade A, Severcan F, et al. Celecoxib-loaded liposomes: effect of cholesterol on encapsulation and in vitro release characteristics. Biosci Rep 2010;30:365-73

79.

Foradada M, Pujol MD, Bermudez J, et al. Chemical degradation of liposomes by serum components detected by NMR. Chem Phys Lipids 2000;104:133-48

80.

Davidsen J, Jorgensen K, Andresen TL, et al. Secreted phospholipase A(2) as a new enzymatic trigger mechanism for localised liposomal drug release and absorption in diseased tissue. Biochim Biophys Acta 2003;1609:95-101

81.

Elron-Gross I, Glucksam Y, Biton IE, et al. A novel Diclofenac-carrier for local treatment of osteoarthritis applying liveanimal MRI. J Control Release 2009;135:65-70

82.

Srinivasan PP, McCoy SY, Jha AK, et al. Injectable perlecan domain 1-hyaluronan microgels potentiate the cartilage repair effect of BMP2 in a murine model of early osteoarthritis. Biomed Mater 2012;7:024109

83.

Blaney Davidson EN, Vitters EL, van Lent PL, et al. Elevated extracellular matrix production and degradation upon bone morphogenetic protein-2 (BMP-2) stimulation point toward a role for BMP-2 in cartilage repair and remodeling. Arthritis Res Ther 2007;9:R102

84.

Dell’Accio F, De Bari C, El Tawil NM, et al. Activation of WNT and BMP signaling in adult human articular cartilage following mechanical injury. Arthritis Res Ther 2006;8:R139

85.

Ruppert R, Hoffmann E, Sebald W. Human bone morphogenetic protein 2 contains a heparin-binding site which

281


polymers. J Phys Chem 1997;B 101:11007-28

modifies its biological activity. Eur J Biochem 1996;237:295-302


86.

Yang W, Gomes RR, Brown AJ, et al. Chondrogenic differentiation on perlecan domain I, collagen II, and bone morphogenetic protein-2-based matrices. Tissue Eng 2006;12:2009-24

87.

Mio K, Stern R. Inhibitors of the hyaluronidases. Matrix Biol 2002;21:31-7

88.

Chen WY, Abatangelo G. Functions of hyaluronan in wound repair. Wound Repair Regen 1999;7:79-89

89.

Petrak K. Essential properties of drugtargeting delivery systems. Drug Discov Today 2005;10:1667-73

90.

Whitmire RE, Wilson DS, Singh A, et al. Self-assembling nanoparticles for intra-articular delivery of antiinflammatory proteins. Biomaterials 2012;33:7665-75 Study of intra-articular drug delivery using receptor antagonist to targetspecific receptor on synoviocyte.

.

91.

.

92.

93.

Rothenfluh DA, Bermudez H, O’Neil CP, et al. Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nat Mater 2008;7:248-54 Study of intra-articular drug delivery using peptide ligand to target components of articular cartilage. Zille H, Paquet J, Henrionnet C, et al. Evaluation of intra-articular delivery of hyaluronic acid functionalized biopolymeric nanoparticles in healthy rat knees. Biomed Mater Eng 2010;20:235-42 Laroui H, Grossin L, Leonard M, et al. Hyaluronate-covered nanoparticles for the therapeutic targeting of cartilage. Biomacromolecules 2007;8:3879-85

94.

Mark A, Ward TKG. Thermoresponsive polymers for biomedical applications. Polymers 2011;3:1215-42

95.

Urry DW. Physical chemistry of biological free energy transduction as demonstrated by elastic protein-based

282

96.

.

97.

polymeric microspheres. Pharm Res 2008;25:1815-21

Betre H, Liu W, Zalutsky MR, et al. A thermally responsive biopolymer for intra-articular drug delivery. J Control Release 2006;115:175-82 Study of thermoresponsive intraarticular drug delivery using polypeptides that undergo a phase transition above their transition temperature.

104. Edwards SH, Cake MA, Spoelstra G, et al. Biodistribution and clearance of intra-articular liposomes in a large animal model using a radiographic marker. J Liposome Res 2007;17:249-61

Caron JP, Fernandes JC, Martel-Pelletier J, et al. Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum 1996;39:1535-44

106. Nishide M, Kamei S, Takakuea Y, et al. Fate of biodegradable dl-lactic acid oligomer microspheres in the articulus. J Bioactive Compat Polymers 1999;14:385-98

98.

Bresnihan B, Cobby M. Clinical and radiological effects of anakinra in patients with rheumatoid arthritis. Rheumatology (Oxford) 2003;42(Suppl 2):ii22-8

99.

Evans CH, Gouze JN, Gouze E, et al. Osteoarthritis gene therapy. Gene Ther 2004;11:379-89

100. Chevalier X, Giraudeau B, Conrozier T, et al. Safety study of intraarticular injection of interleukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. J Rheumatol 2005;32:1317-23 101. Shamji MF, Betre H, Chen J, et al. Development of a thermally responsive drug depot for intra-articular delivery of interleukin-1 receptor antagonist to attenuate inflammatory events in osteoarthritis. Osteoarthritis Cartilage 2007;15(Suppl C):C226-C7 102. Hirota K, Hasegawa T, Hinata H, et al. Optimum conditions for efficient phagocytosis of rifampicin-loaded PLGA microspheres by alveolar macrophages. J Control Release 2007;119:69-76 103. Champion JA, Walker A, Mitragotri S. Role of particle size in phagocytosis of


105. Ramesh DV, Tabara Y, Ikada Y. Biodegradable microspheres for local drug release in the articulus. J Bioactive Compat Polymers 1999;14:137-49

107. Liggins RT, Cruz T, Min W, et al. Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits. Inflamm Res 2004;53:363-72 108. Zaffagnini S, Allen AA, Suh JK, et al. Temperature changes in the knee joint during arthroscopic surgery. Knee Surg Sports Traumatol Arthrosc 1996;3:199-201 109. Hui JH, Chan SW, Li J, et al. Intra-articular delivery of chondroitin sulfate for the treatment of joint defects in rabbit model. J Mol Histol 2007;38:483-9 110. Bozdag S, Calis S, Kas HS, et al. In vitro evaluation and intra-articular administration of biodegradable microspheres containing naproxen sodium. J Microencapsul 2001;18:443-56

Affiliation

Mi Lan Kang PhD & Gun-Il Im† MD † Author for correspondence Dongguk University Ilsan Hospital, Department of Orthopedics, Goyang 410-773, Korea Tel: +82 31 961 7315; Fax: +82 31 961 7314; E-mail: [email protected]

Pulmonary drug delivery systems for tuberculosis treatment.

Gastroretentive drug delivery systems for the treatment of Helicobacter pylori.

Local drug delivery systems for the treatment of periodontal disease.

Drug delivery systems 5A. Oral drug delivery.

Drug delivery systems. 6. Transdermal drug delivery.

Implantable drug-delivery systems.

Advanced drug delivery systems for therapeutic applications.

In situ gelling systems for drug delivery.

Lipid-Based Drug Delivery Systems.

ATP-Responsive Drug Delivery Systems.

MEMS: Enabled Drug Delivery Systems.

Kidney-targeted drug delivery systems.

pH-responsive drug-delivery systems.

Implantable neurosurgical drug delivery systems.

Self-nanoemulsifying drug delivery systems as novel approach for pDNA drug delivery.

Nanotechnology-based drug delivery systems for the treatment of Alzheimer's disease.

Advanced drug delivery systems for local treatment of the oral cavity.

Nanotechnology-based drug delivery systems for treatment of oral cancer: a review.

Targeted liposomal drug delivery systems for the treatment of B cell malignancies.

Drug Delivery Systems for Imaging and Therapy of Parkinson's Disease.

A review of drug delivery systems for capsule endoscopy.

Therapeutic applications of electrospun nanofibers for drug delivery systems.

Radiation sterilization of new drug delivery systems.

Drug delivery systems for ovarian cancer treatment: a systematic review and meta-analysis of animal studies.