Scholarly article on topic 'Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities'

Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities Academic research paper on "Chemical sciences"

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Academic research paper on topic "Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities"

Polymers 2014, 6, 799-819; doi:10.3390/polym6030799



ISSN 2073-4360


Drugs and Polymers for Delivery Systems in OA Joints: Clinical Needs and Opportunities

1 2 12 1 Maarten Janssen , George Mihov , Tim Welting , Jens Thies and Pieter Emans '*

1 Department of Orthopaedic Surgery, Maastricht University Medical Center, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands; E-Mails: (M.J.); (T.W.)

2 DSM Biomedical, Koestraat 1, 6167 RA Geleen, the Netherlands; E-Mails: (G.M.); (J.T.)

* Author to whom correspondence should be addressed; E-Mail:; Tel.: +31-43-387-5038; Fax: +31-43-387-4893.

Received: 31 January 2014; in revised form: 2 March 2014 /Accepted: 3 March 2014 / Published: 13 March 2014

Abstract: Osteoarthritis (OA) is a big burden of disease worldwide and one of the most common causes of disability in the adult population. Currently applied therapies consist of physical therapy, oral medication, intra-articular injections, and surgical interventions, with the main goal being to reduce pain and improve function and quality of life. Intra-articular (IA) administration of drugs has potential benefits in OA treatment because it minimizes systemic bioavailability and side effects associated with oral administration of drugs without compromising the therapeutic effect in the joint. However, IA drug residence time is short and there is a clinical need for a vehicle that is able to provide a sustained release long enough for IA therapy to fulfill its promise. This review summarizes the use of different polymeric systems and the incorporated drugs for IA drug delivery in the osteoarthritic joint with a primary focus on clinical needs and opportunities.

Keywords: osteoarthritis; drug delivery systems; DMOAD

1. Introduction

1.1. The Osteoarthritic Joint

Osteoarthritis (OA) is a progressive disease in which degeneration of joint cartilage and eventually the underlying subchondral bone may cause pain, stiffness, and inflammation.

The precise cause of OA is unknown, but it is believed to be a combination of both mechanical and biological events affecting the joint [1]. OA mostly affects the knees, hips, hands, feet, and spine, but other joints can also be affected [2,3]. OA is the most common form of arthritis and the leading cause of chronic disability in the United States [4]. It ranks fourth in health impact in women and eighth in men in the Western world (US and Europe) [5]. Due to aging and increasing life expectancy, OA is expected to become the world's fourth-leading cause of disability in 2020 [6]. Because effective treatments are lacking, it is a growing socio-economic problem. The costs (medical and productivity loss) are 871 euros per patient, per month, in the Netherlands [6].

1.2. Current Treatment

Currently available treatment options for OA primarily focus on pain relief and improving function. Non-pharmacological therapy is widespread but differs per joint and the American College of Rheumatology (ACR) only strongly recommends weight loss if overweight, and participation in either cardiovascular or resistance exercise [7]. Pharmacologicaltherapy begins with oral administration of paracetamol either combined or substituted with NSAIDs or COX-2 inhibitors and a weak opioid (e.g., tramadol) depending on patient characteristics [8]. Major disadvantages of oral administration of these drugs are the limited bio-availability and the risk of side effects (e.g., liver damage, GI-ulcer/bleeding, and constipation). As OA has a localized nature, intra-articular administration of drugs provides an excellent opportunity to improve treatment. Glucocorticoid and hyaluronic acid (HA) injections are not impeded by the disadvantages of the oral route and are already common practice. However, although these injections provide a fairly good relief of symptoms and improve function over the short- and medium-term, there is little to no disease modification, and the beneficial results are often not long-lived.

Therefore to date OA continues progressing for almost all patients. At end-stage disease, surgical interventions, and finally joint replacement (e.g., total knee arthroplasty [TKA]) is indicated in many patients. However, the exponential increase in knee joint replacements is becoming an inevitable medical and economic problem [9]. The number of TKAs continues to grow each year and as these increase in number, the amount of revision TKAs continues to increase substantially as well [10]. While a primary TKA is cost-effective, revision surgery of TKA has a less favorable outcome for both the healthcare status of the patient and the economic benefit [11]. To prevent this situation a therapy that postpones primary joint arthroplasty is needed.

1.3. Clinical Needs

To improve treatment of OA there is a need for new strategies. Development of disease modifying osteoarthritis drugs (DMOADs) is one of those strategies. The mechanism of action of DMOADs is directed at reducing, halting, or reversing progression of OA or even preventing OA by either

inhibiting different causative pathways (catabolic activity) or stimulating repair mechanisms (anabolic activity) [12]. To date the pharmaceutical industry has failed to provide effective and safe DMOADs for clinical use [13]. The main reasons are that despite their specific targeted action DMOADs still can cause side effects when administered systemically [14-16], or when injected intra-articular have a short residence time within the joint [17,18]. It remains unclear how long particular drugs have to remain in the joint for an effective pain relief and/or disease modification after an intra-articular injection. Without a drug delivery system (DDS), synovial disappearance time of a drug in the joint is often short and except for cross-linked HA usually drugs do not reside much longer than 24 hours [18]. Direct intra-articular drug delivery allows for an effective concentration where it is needed with a minimum of drugs. Moreover it negates the main disadvantages of systemic administration; a low (oral) bioavailability or systemic side effects. However, due to the rapid clearance of most intra-articular injected drugs, frequent injections would be needed to maintain an effective concentration [19]. Frequent intra-articular injections are undesired due to the pain and discomfort they may cause and the risk of introducing an infection to the joint. Therefore a DDS for DMOADs combined with an intra-articular injection seems to be needed to cause prolonged drug residence time and a stable concentration within the therapeutic window with a single injection as compared to repeated injections in which the concentration may vary between a toxic and a subtherapeutic level (Figure 1). As a result, this leads to a reduction of side effects and may lead to an improved patient compliance [20].

Figure 1. Therapeutic window of administered drugs. The solid line shows the release profile of a repeatedly dosed free drug with a high variation in available drug concentrations ranging from subtherapeutic to toxic levels. The dashed line shows a possible release profile of a drug delivery system which lies within the therapeutic range.

.Free drug kinetics

Toxic range

c o P rö

Therapeutic range

o c o o

Subtherapeutic range

Furthermore, there is a need for diagnostic improvement, currently the role of biomarkers for diagnosis of OA is still under debate [21]. Regulatory approval in clinical trials still requires changes

in radiographic joint space width and an impact on symptoms [22,23]. However, as MRI allows for direct visualization and measurements of cartilage [23,24] the FDA recently recognized the improvement of MRI as an OA imaging biomarker. Other OA associated processes (e.g., osteophytes, subchondral bone changes, and trabecular structure) can likewise be assessed by MRI [13]. With MRI, different phenotypes of OA can be identified and the success of treatment may be tailored depending on the phenotype and its effect can be monitored in more detail [25].

In this review we provide an overview of (candidate) drugs that are needed for an effective OA treatment and can be incorporated in a DDS and which polymers are required to provide for such system.

2. Candidate Drugs for OA Treatment

Many different drugs have been investigated for OA treatment. However there are limitations to which drugs can be incorporated in a DDS. The incorporated drug has to be able to withstand the manufacturing process of the carrier vehicle (i.e., compression, heat, stirring, etc.). As the final goal of manufacturing these vehicles (particles) is injecting them intra-articularly, the DDSs have to be sterilized. Not only should the DDSs be able to withstand this process, but so should the incorporated drugs.

2.1. NSAIDs, Coxibs, Glucocorticoids, and Hyaluronan

Drugs currently used in DDSs in the OA joint are mostly derived from the drugs normally used in OA treatment (NSAIDs, Coxibs, Glucocorticoids, and HA). Fourteen studies show incorporation of an NSAID [26-39] and two studies incorporated Celecoxib (Cxb) [40,41] in their carrier. Glucocorticoids were incorporated in six different studies [42-47] and HA in three [48-50]. An overview of these, and other studies is presented in Table 1.

The rationale for the use of these drugs is that their mechanism of action has been abundantly investigated in the perspective of OA treatment, their ability to give symptomatic relief and their potential to slow down disease progression. Moreover, these drugs have often already been approved by the regulatory bodies for parenteral administration, which may ease their DDS regulatory process.

An important note, however, is that these drugs were developed and studied for use in oral OA treatment or an intra-articular injection without a DDS. Since then, great progress has been made in DDSs, and as such more other potential drugs may be used for treatment of OA. Due to systemic side effects, short half time, etc., many of these candidates have been thought not suitable for OA treatment in the past. With the introduction of different drug delivery systems DMOADs and other new candidate drugs may ultimately provide a more effective treatment.

Table 1. Overview of investigated polymers and drugs in drug delivery systems (DDSs). ACLT—Anterior cruciate ligament transection, MT—Meniscal tear, FCA—Freunds Complete Adjuvant, MIA—monosodium iodoacetate, SPIONs—Superparamagnetic iron oxide nanoparticles, DPPE—dipalmitoyl phosphatidylethanolamine, FITC—Fluorescein isothiocyanate, PC:DOPE— phosphatidylcholine:dioleoylphosphatidylethanolamine, TEGM-CHM—Tetraethylene glycol methacrylate-cyclohexyl methacrylate, MEH-PPV—poly[2-methoxy-b-(2-ethylhexyloxy)-1,4-phenylenevinylene], PCLA-PEG-PCLA—poly(s-caprolactone-co-lactide)-b-

poly(ethylene glycol)-bpoly(s-caprolactone-co-lactide), PVA—polyvinyl alcohol.

Author Year Type DDS Composition Drug Particle Diameter Model OA Induction Outcome

Ibim 1998 Microsphere PolyPhosphazene Colchicine Not stated in vitro N.A. Prolonged release, possible toxicity


Brown 1998 Microsphere Gelatin/chondroitin 6-sulfate 14C-albumin, 14C-inulin, 14C-diazepam 1-60 ^m in vitro/mice none partially biocompatible

Tuncay 2000 Microsphere PLGA Diclofenac 5-10 ^m in vitro/rabbit Ovalbumin/FCA No significant difference in inflammation

Tuncay 2000 Microsphere Albumin Diclofenac ±15 ^m in vitro/rabbit Ovalbumin/FCA Promising at day 30

Bozdag 2001 Microsphere PLGA, albumin Naproxen 10 ^m in vitro/rabbit Ovalbumin/FCA PLGA better than albumin

Bragdon 2001 Microsphere PLGA Paclitaxel 50 ^m ex vivo horse MCP none Biocompatible

Horisawa 2002 Nano/ microsphere PLGA Fluoresceinamine 265 nm/26.5 ^m Rat none Fagocytosis is size dependent

Horisawa 2002 Nanosphere PLGA Betamethasone 300-490 nm in vitro/rabbit Ovalbumin/FCA Prolonged efficacy

Liang 2003 Microsphere PLLA Methotrexate 83.7-187.6 ^m in vitro/rabbit None mild inflammation, prolonged release

Fernandez-Carballido 2004 Microsphere PLGA Ibuprofen, PEG oil (Labrafil) 39.69 ^m in vitro N.A. Labrafil reduces burst release, prolonged release

Liggins 2004 Microsphere PLGA, PLA, PCL, Chitosan Paclitaxel 1-20 ^m, 10-35 ^m, 35-105^m Rabbit BSA/FCA, Carrageenan Chitosan not biocompatible, small PLGA particles give greater inflammation.

Thakkar 2004 Microsphere Chitosan Celecoxib 8 ^m Rat FCA Chitosan is biocompatible, improved retention

Fernandez-Carballido 2004 Microsphere PLGA Ibuprofen, PEG oil (Labrafil) 39.31 ^m in vitro N.A. Storage of PLGA/Ibuprofen particles does not change characteristics

Park 2005 Hydrogel Hyaluronic acid Hyaluronic acid Ultrasound 3000 kDA Rabbit ACLT/MT Combination of HYA and US is more effective than monotherapy

Betre 2006 Aggregate Elastin-like polypeptides none N.A. rat None Biocompatible, prolonged residence time

Tsai 2007 Nanosphere Nanogold none 5, 13 nm Rat Collagen RA reduction

Zhang 2007 Micelle PNIPAAm/EAB-PPP Indomethacin Not stated in vitro/rat FCA, Carrageenan Prolonged release/effect

Chondral defect Biocompatible, improved

Hui 2007 Hydrogel a-CD-EG 4400 Chondroitin sulfate N.A. Rabbit biomechanical and histologic properties

Lu 2007 Microsphere Gelatin Flurbiprofen 2.5-12.3 ^m Rabbit None Prolonged residence IA, biocompatibility unclear

Thakkar 2007 Nanoparticles Glycerol behenate Celecoxib 257 nm Rat FCA Prolonged residence, biocompatible

Rothenfluh 2008 Nanoparticles Poly(propylene sulphide) WYRGRL (Col II-binding peptide) 38, 96 nm Mice None Retention of the small particles in cartilage matrix

Butoescu 2008 Microparticles PLGA Dexamethasone/SPI ONs ~10 ^m in vitro N.A. Possible to incorporate 2 active substances

Biocompatible, uptake of 1 and 10

Butoescu 2009 Microparticles PLGA Dexamethasone/SPIONs 1, 10 ^m Mice None ^m particles, prolonged action of magnetic particles

Elron-Gross 2009 Collagomers Collagen :DPPE Diclofenac Not stated Rat MIA Better and sustained reduction of inflammation

Butoescu 2009 Microparticles PLGA Dexamethasone/SPIONs ~10 ^m Mice N.A. (dorsal air pouch) Sustained release, first order kinetics

Saravanan 2011 Microsphere Gelatin Diclofenac sodium 1-60 ^m Rabbit None Prolonged release

Zille 2010 Nanoparticles PLGA, PLA, HA FITC-dextran Not stated Rat None Weak hyperplasia, no inflammation

Zhang 2011 Microspheres PLGA Lornoxicam 7.47 ^m Rabbit/rat None Prolonged retention

Panusa 2011 Microspheres PLGA Methylprednisolone 3-60 ^m Rat Carrageenan Prolonged retention, less inflammation

Zarnescu 2011 Liposomes PC:DOPE:cholest erol:stearylamine Chondroitin sulfate Not stated in vitro N.A. Interacts with collagen

Eswaramo orthy 2012 Microspheres PLGA Parathyroid hormone 51-85 ^m Rat Papain/Cyst ein Biocompatible, improved GAG and Col II levels

te Boekhorst 2012 Nanoparticles PLGA siRNA (against RA) 235-285 nm Mice Collagen antibody Positive effect on RA depending on dose

Kawadkar 2012 Microspheres Genipin cross-linked chitosan Flurbiprofen 5.18-9.74 ^m Rat Carrageenan Biocompatible, prolonged retention Biocompatible, effect comparable

Zhang 2012 Microspheres PLGA Lornoxicam Not stated Rat Papain with weekly injections of Lornoxicam

Whitmire 2012 Nanoparticles TEGM-CHM Interleukin-1 Ra 300 nm Rat MIA Prolonged retention, no negative effects on cartilage

Gaignaux 2012 Microparticles PLGA Clonidine 10-30 ^m in vitro N.A. Possible to incorporate small hydrophilic drug in PLGA

Présumey 2012 Microspheres PLGA anti-TNF siRNA 23.5 ^m Mice Collagen Biocompatible, prolonged inhibition of TNA-a

Prolonged retention of

Chen 2012 Microspheres/hydrogel Chitosan Brucine 0.5-4.5 цш Rat/rabbit Collagenase microsphere/hydrogel composite, inhibiting inflammation

Morgen 2012 Nanoparticles Dextran propionate/MEH-PPV Fluorescent labeled peptide 100-150 nm Rat None Prolonged retention of peptide, biocompatible

Kawadkar 2013 Microspheres Genipin cross-linked gelatin Flurbiprofen 6.39 цш Rat Carrageenan Biocompatible, prolonged release

Ryan 2013 Nanocomplex HA-chitosan Salmon calcitonin (sCT) 100-200 nm Mice K/BxN serum sCT-HA-chitosan nanoparticles reduces inflammation and

preserves bone and cartilage

Ko 2013 Microspheres PLGA Sulforaphane 14.5 цш Rat ACLT Prolonged retention, inhibition of inflammation

Sandker 2013 Hydrogel PCLA-PEG-PCLA None N.A. Rat None Hydrogel degrades after 3+ weeks

Bédouet 2013 Microsphere PLGA cross-linked PEG None 40-100 цш Sheep None Slow degradation, little inflammation from MS

Chen 2013 Nanoparticles in microspheres PLGA-PVA Brucine 12.38 цш Rat None Prolonged retention, less burst release

Bédouet 2014 Microspheres PEG-hydrogel Ibuprofen 40-100 цш ex vivo sheep LPS Prolonged retention, less burst release, inhibition of inflammation

2.2. DMOADs

Pathological processes in OA consist of inflammation, cartilage degradation and subchondral bone changes [13]. Inflammation can be caused by a variety of cytokines such as Interleukins (ILs) [51], Tumor Necrosis Factors (TNFs), and Nitric Oxide (NO) [52], whereas, cartilage degradation is mainly caused by enzymes, such as Matrix Metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) [52]. Furthermore, a strong correlation between subchondral bone changes and OA development has been described [53,54].

Based on their method of action, roughly three groups of DMOADs can be identified: (i) inhibitors of degrading enzymes and inflammation, (ii) growth factors, and (iii) drugs which target subchondral bone changes. Most DMOADs are proteins or protein derived peptides with different properties when applied in therapeutic use (Table 2). Diffusion transport of proteins and large peptides is generally slow and due to their weak non-covalent interaction and fragile tertiary structure proteins usually have a low in vivo stability. Enzymatic or proteolytic degradation causes short half-lives when administered without a DDS. In addition, a DDS can protect the protein or peptide against degrading environmental factors when prepared or stored [55]. However, maintaining the structure and function of often fragile protein based drugs during DDS processing, formulation, sterilization and subsequent degradation and release is far from trivial and as a result very few protein based DDS products are on the market today. Peptides are already successfully incorporated in DDSs in other fields of research (e.g., Airway and Gastro-intestinal drug delivery) [56,57]. These positive results are promising for the application of peptidal DMOADs in a DDS. Even DMOADs and drugs that can be administered systemically or by injection (bisphosphonates and Platelet-rich plasma (PRP) respectively) seem to benefit from a DDS [58,59]. These results also suggest that there might be a beneficial effect of targeting subchondral bone in OA treatment, but more evidence is needed, especially in drug delivery systems.

2.3. Cytostatic Drugs

Cytostatic drugs are able to inhibit inflammation and can even be chondroprotective [60], though they are not used in OA treatment because of their high toxicity and often severe side effects when administered systemically. Some studies, however, showed beneficial effects of IA administration of paclitaxel and methotrexate without apparent toxicity and side effects in an animal model [61,62]. In line with other classes of drugs there is potential for cytostatic drugs when administered via an intra-articular drug delivery system [61].

When categorizing candidate drugs/DMOADs for use in a DDS, attention should be paid to their chemical nature and the possibilities to incorporate them in a drug delivery system. The complexity in designing effective DDSs for a certain drug increases with the size and complexity of that drug.

Table 2. Most investigated disease modifying osteoarthritis drugs (DMOADs), based on their target of action. The chemical nature of a DMOAD is important for incorporation in a DDS.

DMOADs Chemical Nature

Enzyme inhibitors

MMP inhibitors (TIMP 1-4) Protein/Peptide

Aggrecanase inhibitors (ADAMTS) Small molecule

Cytokine inhibitors

IL-1 inhibitors (IL-1 Ra) Protein

TNF-a antagonists Antibody

iNOS inhibitors Various

Growth factors

Fibroblast Growth Factor (FGF)-18 Protein/Peptide

Bone morphogenetic protein (BMP)-7 Protein/Peptide

Platelet-rich plasma (PRP) Plasma

Drugs targeting subchondral bone

Calcitonin Peptide

Bisphosphonates Bisphosphonate

3. Drug Delivery Systems

3.1. History

The importance of a drug delivery system has long been recognized. In the mid-1960s, Folkman discovered that a silicone rubber tube acted as a constant rate drug delivery device in rabbit anesthesia [63]. In 1987, Ratcliffe et al. provided the first evidence that (albumin) microspheres can delay clearance of a drug from the joint [64]. In the search for a method to provide an ideal (intra-articular) drug delivery system, many different carriers have been investigated. At first focus was on achieving a "zero order release" usually in macroparticulate systems (e.g., ocular, vaginal, or trans- and, sub-dermal particles). In the 1980s and 1990s, a gradual shift towards microparticles and a sustained or long-term drug release occurred [63]. From the 1990s and onwards, the development of DDSs went a step further with the introduction of nanoparticles. Conventional techniques, such as compression, spray and dip coating, and encapsulation, can be used to incorporate drugs in a drug delivery system [65].

DDSs can have a different structure and morphology, all with different characteristics in drug loading, release and response to the physiological environment (Figure 2). In addition, in the case of micro-particulate systems, the size of the particles is also important as particles of 1-10 |im could be taken up by synoviocytes probably through phagocytosis [45]. Depending on the goal of treatment this can be unwanted. When designing a DDS, close attention should, thus, be paid to the drug that will be incorporated, physiological environment of the target location, biocompatibility and desired duration of drug release.

An ideal drug delivery system complies with adequate disease modification, biodegradability, and biocompatibility, while responding to feedback and its physiological environment [65].

Figure 2. Different structures and morphology of DDSs (not-exhaustive). Each structure has its advantages and disadvantages to incorporate and release different types of drugs for intra-articular treatment of OA.

Micro-/nano-capsule Micro-/nano-sphere Polymer-drug conjugate

Micelle Liposome Hydrogel

O = Drug

3.2. Hurdles in Drug Delivery System Design

Using polymers for intra-articular drug delivery offers a great variety of opportunities to address OA-progression. However, poly(lactic-co-glycolic acid) (PLGA) and NSAIDs emerge, more often, in different studies, the field of polymers for intra-articular drug delivery is very fragmented. Particle size varies tremendously between particles of only a few nanometers and particles of more than 100 pm. Different particle sizes results in different DDS kinetics and drug release statistics, particles smaller than 10 pm can readily be phagocytized by synoviocytes, whereas particles larger than 20 pm can trigger a giant cell response, but not necessarily an inflammatory response. According to Butoescu et al., an optimal particle size for IA drug delivery would be between 5 and 10 pm [66]. Together with size, method of production of a DDS can influence drug characteristics where especially the large proteins are vulnerable to environmental challenges [67]. For clinical application biocompatibility of a drug and DDS in the joint is of great importance. Polyesters like Poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and PLGA are already widely used and are deemed biocompatible in drug delivery, but their breakdown products are acidic and can lower the pH in the environment which subsequently can cause drug stability problems and inflammation of the surrounding tissue [68]. Ideally, a drug delivery system has to be fully degradable whereas residue from particles can also cause inflammation of the joint.

3.3. Polymers

To avoid inflammation of the injected joint, a polymer carrier has to be biocompatible. The largest group of carriers consists of biodegradable polymeric particles, as well from natural, synthetic, or combined origin. Polymeric particles have the big advantage that they can be altered to fit their

purpose. Depending on manufacturing technique particles can either be microcapsules (a reservoir with a separate polymeric shell) or microspheres (matrix type with a homogenous mixture of a polymer and the encapsulated drug). The latter one having excellent sustained release characteristics [69].

There is a great diversity in both DDSs and in the drugs encapsulated. Natural polymers are widely available and often biodegradable. However, reproducibility is low and they often have a high immunogenicity [68]. Natural polymers investigated for IA drug delivery include Chitosan which was shown to be able to incorporate Cxb or Flurbiprofen and extend their residence time in the joint [28,41,70], Diclofenac Sodium loaded albumin microspheres provided a significant reduction of arthritis after 30 days of incubation in a rabbit knee [38], gelatin microspheres are able to incorporate different NSAIDs or proteins, and Saravanan et al. found gelatin microspheres to be more stable than albumin, but residence times are still relatively short [30,33,71].

Synthetic polymers in general are less biocompatible but their characteristics can easily be altered [68]. For IA drug delivery, mostly the polymers that have proven to be biocompatible were investigated. PLA has been shown to be biocompatible in rabbit knees [61,62], polyethylene glycol (PEG), often combined with other polymers (e.g., polycaprolactone (PCL)) is biocompatible and able to control release characteristics of the incorporated drug [72-75], however, by far, the most used synthetic polymer is PLGA. This synthetic polymer has a good biocompatibility and is able to incorporate many different types of drugs [29,31,35-37,39,42-46,50,60,61,72-74,76-84]. Several studies have been published on the incorporation of proteins in different DDSs, a common problem in the classical models (e.g., PLGA), however, is the initial burst release, which can cause local toxic drug concentrations, and the acidic breakdown products can influence protein stability followed by a very slow or no release at all [68,85,86].

The evolution of bio- degradable materials from aliphatic polyesters to nitrogen bearing polymers such as polyurethanes and polyester amides (PEAs) has been accompanied with better control over degradation and release properties. PEAs are based on a-amino acids, aliphatic dicarboxylic acids, and aliphatic a-ro diols [87]. Among this class of polymers it is the AA-BB hetero-chain polymers that offer the greatest versatility in terms of molecular level design to tailor drug release properties. Furthermore, the incorporation of amino acid-based building blocks offers more than providing metabolizable building blocks [88,89], they provide one or more functional groups along the polymer chain. This allows further modification of the polymer to tailor its physicochemical properties and performance as drug eluting matrices. An important advantage of these polymers is related to the fact that, by design, they predominantly degrade via an enzymatic mechanism and, due to consequential surface erosion, drug release follows nearly zero-order kinetics. PEAs are currently being applied in several developmental DDSs and are in clinical trials for a cardiovascular drug eluting stent [90].

3.4. Liposomes

Liposomes are artificial vesicles composed of one or more concentric phospholipid bilayers and used especially to deliver microscopic drugs to body cells. Liposomes can be used as a carrier for intra-articular drug delivery, but far less research has been done on this carrier as compared to polymer-based microspheres. However, the first reports of liposomes as drug carriers appeared in the 1970s and there are still few results reported on liposomes for intra-articular application. In 2001,

Trif et al. reported a positive effect of human Lactoferrin encapsulated in liposomes in collagen-induced arthritis in mice [91]. Elron-Gross et al. reported a reduction of inflammation in a monosodium iodoacetate (MIA) induced OA rat knee after a liposomal dexamethasone and diclofenac combination injection as compared to control assessed by MRI, in 2009 [32,92], and Dong et al. found a combination of Cxb incorporated liposomes and HA to be more effective in pain control and cartilage protection than a single Cxb injection, Cxb liposome, and HA treatment alone [93]. Although liposomes are well established, and are effective and biocompatible, IA residence time is relatively short compared to other DDSs [18].

3.5. Hydrogels

Hydrogels are insoluble, water swollen, cross-linked, three-dimensional structures of polymer chains [94]. HA, which is already common practice in many clinics, can be seen as a hydrogel. Depending on its molecular weight, and whether it is cross-linked or not, HA has different characteristics. The working mechanism of HA is believed to depend on its viscosity, lubricity and restoring some of the normal joint physiology. Other than HA, only a few hydrogels are used for IA drug delivery. Bedouet et al. developed a PEG-hydrogel-Microsphere in order to minimize the amount of foreign material injected [73], and in another study by Bedouet et al. they sought to deal with the burst release of intra-articular DDSs by developing a methacrylate derivative of ibuprofen with a hydrophilic PEG-hydrogel, which slowly released the ibuprofen [72]. Another method to deal with burst release was provided by Chen et al., by loading brucine in a chitosan microsphere and dispersed that microsphere in a chitosan hydrogel [95]. A more investigative approach was used by Sandker et al., who incorporated 2-(2',3',5',-triiodobenzoyl) moieties (TIB) to make their poly(s-caprolactone-co-lactide)-b-poly(ethylene glycol)-bpoly(s-caprolactone-co-lactide) (PCLA-PEG-PCLA) hydrogel radiopaque for long term in vivo visualization [75].

4. Discussion

Drug delivery systems have been around for about half a century. Since then, a number of new developments have been made, starting from macroscopic particulates to advanced nanometer sized DDSs that adapt to changes in their physiological environment. Since the discovery of polymeric DDSs as a therapeutic application, a massive increase in citations can be seen on PubMed [68] and an incredible amount of progress has been made in their development. However, it was not until 1987 that the pioneering work of Ratcliffe et al. [64] proposed a DDS for IA treatment of OA and this became an increasing field of interest in the late 1990s. As can be seen in Table 1 the most used polymer for DDSs is PLGA, Although PLGA is biocompatible and biodegradable, and has been approved by the FDA many years ago, disadvantages are the initial burst release and the acidic microenvironment it creates on its breakdown which could cause inflammation and can lead to stability problems of the incorporated drugs (e.g., proteins) [68,96]. The search for improvement of biocompatibility, release characteristics and drug incorporation led to an improved PLGA manufacturing process but also to the discovery of new polymers for intra-articular treatment of OA [89,96].

The initial treatment was mainly focused on relieving OA symptoms. Most of the incorporated drugs were NSAIDs or glucocorticoids. Drugs which not only target symptoms but also the disease

process of OA have been incorporated in DDS more recently. Incorporation of DMOADs is even harder as these drugs are still in a developmental stage and most DMOADs are proteins or peptides (Table 2), which makes them vulnerable to environmental challenges in the manufacturing process of DDSs [13]. As such, a drug which targets pain, such as NSAIDs or glucocorticosteroids, released from a DDS are more likely to find their (clinical) application in the near future compared to DMOADs.

The search for the ideal osteoarthritic drug and a biocompatible and biodegradable DDS has been subject of many studies. The focus of most studies was mainly on optimization of DDSs and the ongoing development of the ideal drugs to target OA. To date, this has led to a few ongoing or completed clinical trials on the implementation of polymers for a DDS in OA treatment [97].

5. Conclusions

The optimization of existing DDSs is ongoing and new DDSs are still being developed. It seems to be that the ideal DDS for intra-articular OA treatment has not yet been found. However, many hurdles in the developmental process have been taken care of and implementation of DDSs for clinical applications, such as ophthalmology, cardiology, oncology, etc., give us examples of the possibilities. Given the developments in the field of DDS and the increasing amount of drugs that may be released from a DDS, it is expected that more clinical trials will start to fulfill the need for OA treatment with a DDS.

Conflicts of Interest

The authors declare no conflict of interest. References

1. Zhang, Y.; Jordan, J.M. Epidemiology of osteoarthritis. Clin. Geriatr. Med. 2010, 26, 355-369.

2. van Saase, J.L.; van Romunde, L.K.; Cats, A.; Vandenbroucke, J.P.; Valkenburg, H.A. Epidemiology of osteoarthritis: Zoetermeer survey. Comparison of radiological osteoarthritis in a Dutch population with that in 10 other populations. Ann. Rheum. Dis. 1989, 48, 271-280.

3. Buckwalter, J.A.; Saltzman, C.; Brown, T. The impact of osteoarthritis: implications for research. Clin. Orthop. Relat. Res. 2004, 427, S6-S15.

4. CDC. Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation— United States, 2007-2009. MMWRMorb. Mortal. Wkly. Rep. 2010, 59, 1261-1265.

5. Haq, I.; Murphy, E.; Dacre, J. Osteoarthritis. Postgrad. Med. J. 2003, 79, 377-383.

6. Hermans, J.; Koopmanschap, M.A.; Bierma-Zeinstra, S.M.; van Linge, J.H.; Verhaar, J.A.; Reijman, M.; Burdorf, A. Productivity costs and medical costs among working patients with knee osteoarthritis. Arthritis Care Res. 2012, 64, 853-861.

7. Hochberg, M.C.; Altman, R.D.; April, K.T.; Benkhalti, M.; Guyatt, G.; McGowan, J.; Towheed, T.; Welch, V.; Wells, G.; Tugwell, P. 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, 465-474.

8. Zhang, W.; Doherty, M.; Arden, N.; Bannwarth, B.; Bijlsma, J.; Gunther, K.P.; Hauselmann, H.J.; Herrero-Beaumont, G.; Jordan, K.; Kaklamanis, P.; Leeb, B.; Lequesne, M.; Lohmander, S.; Mazieres, B.; Martin-Mola, E.; Pavelka, K.; Pendleton, A.; Punzi, L.; Swoboda, B.; Varatojo, R.; Verbruggen, G.; Zimmermann-Gorska, I.; Dougados, M. EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann. Rheum. Dis. 2005, 64, 669-681.

9. Bitton, R. The economic burden of osteoarthritis. Am. J. Manag. Care 2009, 15, S230-235.

10. Dixon, T.; Shaw, M.; Ebrahim, S.; Dieppe, P. Trends in hip and knee joint replacement: socioeconomic inequalities and projections of need. Ann. Rheum. Dis. 2004, 63, 825-830.

11. Lavernia, C.; Lee, D.J.; Hernandez, V.H. The increasing financial burden of knee revision surgery in the United States. Clin. Orthop. Relat. Res. 2006, 446, 221-226.

12. Pelletier, J.P.; Martel-Pelletier, J.; Raynauld, J.P. Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: Today and tomorrow. Arthritis Res. Ther. 2006, 8, doi:10.1186/ar1932.

13. Qvist, P.; Bay-Jensen, A.C.; Christiansen, C.; Dam, E.B.; Pastoureau, P.; Karsdal, M.A. The disease modifying osteoarthritis drug (DMOAD): Is it in the horizon? Pharmacol. Res. 2008, 58, 1-7.

14. King, J.; Zhao, J.; Clingan, P.; Morris, D. Randomised double blind placebo control study of adjuvant treatment with the metalloproteinase inhibitor, Marimastat in patients with inoperable colorectal hepatic metastases: significant survival advantage in patients with musculoskeletal side-effects. Anticancer Res. 2003, 23, 639-645.

15. Hudson, M.P.; Armstrong, P.W.; Ruzyllo, W.; Brum, J.; Cusmano, L.; Krzeski, P.; Lyon, R.; Quinones, M.; Theroux, P.; Sydlowski, D.; Kim, H.E.; Garcia, M.J.; Jaber, W.A.; Weaver, W.D. Effects of selective matrix metalloproteinase inhibitor (PG-116800) to prevent ventricular remodeling after myocardial infarction: results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) trial. J. Am. Coll. Cardiol. 2006, 48, 15-20.

16. Rudolphi, K.; Gerwin, N.; Verzijl, N.; van der Kraan, P.; van den Berg, W. Pralnacasan, an inhibitor of interleukin-1beta converting enzyme, reduces joint damage in two murine models of osteoarthritis. Osteoar. Cartil. 2003, 11, 738-746.

17. Edwards, S.H. Intra-articular drug delivery: the challenge to extend drug residence time within the joint. Vet. J. 2011, 190, 15-21.

18. Larsen, C.; Ostergaard, J.; Larsen, S.W.; Jensen, H.; Jacobsen, S.; Lindegaard, C.; Andersen, P.H. Intra-articular depot formulation principles: role in the management of postoperative pain and arthritic disorders. J. Pharm .Sci. 2008, 97, 4622-4654.

19. Owen, S.G.; Francis, H.W.; Roberts, M.S. Disappearance kinetics of solutes from synovial fluid after intra-articular injection. Br. J. Clin .Pharmacol. 1994, 38, 349-355.

20. Shuid, A.N.; Ibrahim, N.; Mohd Amin, M.C.; Mohamed, I.N. Drug delivery systems for prevention and treatment of osteoporotic fracture. Curr. Drug Targets 2013, 14, 1558-1564.

21. Lotz, M.; Martel-Pelletier, J.; Christiansen, C.; Brandi, M.L.; Bruyere, O.; Chapurlat, R.; Collette, J.; Cooper, C.; Giacovelli, G.; Kanis, J.A.; Karsdal, M.A.; Kraus, V.; Lems, W.F.; Meulenbelt, I.; Pelletier, J.P.; Raynauld, J.P.; Reiter-Niesert, S.; Rizzoli, R.; Sandell, L.J.; Van Spil, W.E.;

Reginster, J.Y. Value of biomarkers in osteoarthritis: current status and perspectives. Ann. Rheum. Dis. 2013, 72, 1756-1763.

22. Committee for Medicinal Products for Human Use. Guideline on clinical investigation of medicinal products used in the treatment of osteoarthritis. 2010. Available online: (accessed on 28 January 2014)

23. Conaghan, P.G.; Hunter, D.J.; Maillefert, J.F.; Reichmann, W.M.; Losina, E. Summary and recommendations of the OARSI FDA osteoarthritis Assessment of Structural Change Working Group. Osteoar. Cartil. 2011, 19, 606-610.

24. Pelletier, J.P.; Cooper, C.; Peterfy, C.; Reginster, J.Y.; Brandi, M.L.; Bruyere, O.; Chapurlat, R.; Cicuttini, F.; Conaghan, P.G.; Doherty, M.; Genant, H.; Giacovelli, G.; Hochberg, M.C.; Hunter, D.J.; Kanis, J.A.; Kloppenburg, M.; Laredo, J.D.; McAlindon, T.; Nevitt, M.; Raynauld, J.P.; Rizzoli, R.; Zilkens, C.; Roemer, F.W.; Martel-Pelletier, J.; Guermazi, A. What is the predictive value of MRI for the occurrence of knee replacement surgery in knee osteoarthritis? Ann. Rheum. Dis .2013, 72, 1594-1604.

25. Kinds, M.B.; Marijnissen, A.C.; Viergever, M.A.; Emans, P.J.; Lafeber, F.P.; Welsing, P.M. Identifying phenotypes of knee osteoarthritis by separate quantitative radiographic features may improve patient selection for more targeted treatment. J. Rheumatol. 2013, 40, 891-902.

26. Serra Moreno, J.; Agas, D.; Sabbieti, M.G.; Di Magno, M.; Migliorini, A.; Loreto, M.A. Synthesis of novel pyrrolyl-indomethacin derivatives. Eur. J. Med. Chem. 2012, 57, 391-397.

27. Kawadkar, J.; Jain, R.; Kishore, R.; Pathak, A.; Chauhan, M.K. Formulation and evaluation of flurbiprofen-loaded genipin cross-linked gelatin microspheres for intra-articular delivery. J. Drug Target. 2013, 21, 200-210.

28. Kawadkar, J.; Chauhan, M.K. Intra-articular delivery of genipin cross-linked chitosan microspheres of flurbiprofen: preparation, characterization, in vitro and in vivo studies. Eur. J. Pharm. Biopharm. 2012, 81, 563-572.

29. 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, 255-263.

30. Saravanan, M.; Bhaskar, K.; Maharajan, G.; Pillai, K.S. Development of gelatin microspheres loaded with diclofenac sodium for intra-articular administration. J. Drug Target. 2011, 19, 96-103.

31. Zhang, Z.; Bi, X.; Li, H.; Huang, G. Enhanced targeting efficiency of PLGA microspheres loaded with Lornoxicam for intra-articular administration. Drug Deliv. 2011, 18, 536-544.

32. Elron-Gross, I.; Glucksam, Y.; Biton, I.E.; Margalit, R. A novel Diclofenac-carrier for local treatment of osteoarthritis applying live-animal MRI. J. Control. Release 2009, 135, 65-70.

33. Lu, Y.; Zhang, G.; Sun, D.; Zhong, Y. Preparation and evaluation of biodegradable flubiprofen gelatin micro-spheres for intra-articular administration. J. Microencapsul. 2007, 24, 515-524.

34. Zhang, J.X.; Yan, M.Q.; Li, X.H.; Qiu, L.Y.; Li, X.D.; Li, X.J.; Jin, Y.; Zhu, K.J. Local delivery of indomethacin to arthritis-bearing rats through polymeric micelles based on amphiphilic polyphosphazenes. Pharm. Res. 2007, 24, 1944-1953.

35. Bozdag, S.; Calis, S.; Kas, H.S.; Ercan, M.T.; Peksoy, I.; Hincal, A.A. In vitro evaluation and intra-articular administration of biodegradable microspheres containing naproxen sodium. J. Microencapsul. 2001, 18, 443-456.

36. Fernandez-Carballido, A.; Herrero-Vanrell, R.; Molina-Martinez, I.T.; Pastoriza, P. Sterilized ibuprofen-loaded poly(D,L-lactide-co-glycolide) microspheres for intra-articular administration: effect of gamma-irradiation and storage. J. Microencapsul. 2004, 21, 653-665.

37. Fernandez-Carballido, A.; Herrero-Vanrell, R.; Molina-Martinez, I.T.; Pastoriza, P. Biodegradable ibuprofen-loaded PLGA microspheres for intraarticular administration. Effect of Labrafil addition on release in vitro. Int J. Pharm. 2004, 279, 33-41.

38. Tuncay, M.; Calis, S.; Kas, H.S.; Ercan, M.T.; Peksoy, I.; Hincal, A.A. In vitro and in vivo evaluation of diclofenac sodium loaded albumin microspheres. J. Microencapsul. 2000, 17, 145-155.

39. Tuncay, M.; Calis, S.; Kas, H.S.; Ercan, M.T.; Peksoy, I.; Hincal, A.A. Diclofenac sodium incorporated PLGA (50:50) microspheres: formulation considerations and in vitro/in vivo evaluation. Int. J. Pharm. 2000, 195, 179-188.

40. Thakkar, H.; Kumar Sharma, R.; Murthy, R.S. Enhanced retention of celecoxib-loaded solid lipid nanoparticles after intra-articular administration. Drugs R D 2007, 8, 275-285.

41. Thakkar, H.; Sharma, R.K.; Mishra, A.K.; Chuttani, K.; Murthy, R.S. Celecoxib incorporated chitosan microspheres: in vitro and in vivo evaluation. J. Drug Target. 2004, 12, 549-557.

42. Panusa, A.; Selmin, F.; Rossoni, G.; Carini, M.; Cilurzo, F.; Aldini, G. Methylprednisolone-loaded PLGA microspheres: A new formulation for sustained release via intra-articular administration. A comparison study with methylprednisolone acetate in rats. J. Pharm. Sci. 2011, 100, 4580-4586.

43. Butoescu, N.; Jordan, O.; Burdet, P.; Stadelmann, P.; Petri-Fink, A.; Hofmann, H.; Doelker, E. Dexamethasone-containing biodegradable superparamagnetic microparticles for intra-articular administration: physicochemical and magnetic properties, in vitro and in vivo drug release. Eur. J. Pharm. Biopharm. 2009, 72, 529-538.

44. Butoescu, N.; Jordan, O.; Petri-Fink, A.; Hofmann, H.; Doelker, E. Co-encapsulation of dexamethasone 21-acetate and SPIONs into biodegradable polymeric microparticles designed for intra-articular delivery. J. Microencapsul. 2008, 25, 339-350.

45. Butoescu, N.; Seemayer, C.A.; Foti, M.; Jordan, O.; Doelker, E. Dexamethasone-containing PLGA superparamagnetic microparticles as carriers for the local treatment of arthritis. Biomaterials 2009, 30, 1772-1780.

46. Horisawa, E.; Hirota, T.; Kawazoe, S.; Yamada, J.; Yamamoto, H.; Takeuchi, H.; Kawashima, Y. Prolonged anti-inflammatory action of DL-lactide/glycolide copolymer nanospheres containing betamethasone sodium phosphate for an intra-articular delivery system in antigen-induced arthritic rabbit. Pharm. Res. 2002, 19, 403-410.

47. Pavanetto, F.; Genta, I.; Giunchedi, P.; Conti, B.; Conte, U. Spray-dried albumin microspheres for the intra-articular delivery of dexamethasone. J. Microencapsul. 1994, 11, 445-454.

48. Morgen, M.; Tung, D.; Boras, B.; Miller, W.; Malfait, A.M.; Tortorella, M. Nanoparticles for improved local retention after intra-articular injection into the knee joint. Pharm. Res. 2013, 30, 257-268.

49. Park, SR.; Park, S.H.; Jang, K.W.; Cho, H.S.; Cui, J.H.; An, H.J.; Choi, M.J.; Chung, S.I.; Min, B.H. The effect of sonication on simulated osteoarthritis. Part II: alleviation of osteoarthritis pathogenesis by 1 MHz ultrasound with simultaneous hyaluronate injection. Ultrasound Med. Biol. 2005, 31, 1559-1566.

50. Zille, H.; Paquet, J.; Henrionnet, C.; Scala-Bertola, J.; Leonard, M.; Six, J.L.; Deschamp, F.; Netter, P.; Verges, J.; Gillet, P.; Grossin, L. Evaluation of intra-articular delivery of hyaluronic acid functionalized biopolymeric nanoparticles in healthy rat knees. Biomed. Mater. Eng. 2010, 20, 235-242.

51. Jotanovic, Z.; Mihelic, R.; Sestan, B.; Dembic, Z. Role of interleukin-1 inhibitors in osteoarthritis: an evidence-based review. Drugs Aging 2012, 29, 343-358.

52. Lee, A.S.; Ellman, M.B.; Yan, D.; Kroin, J.S.; Cole, B.J.; van Wijnen, A.J.; Im, H.J. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 2013, 527, 440-447.

53. Weinans, H.; Siebelt, M.; Agricola, R.; Botter, S.M.; Piscaer, T.M.; Waarsing, J.H. Pathophysiology of peri-articular bone changes in osteoarthritis. Bone 2012, 51, 190-196.

54. Intema, F.; Hazewinkel, H.A.; Gouwens, D.; Bijlsma, J.W.; Weinans, H.; Lafeber, F.P.; Mastbergen, S.C. In early OA, thinning of the subchondral plate is directly related to cartilage damage: results from a canine ACLT-meniscectomy model. Osteoar. Cartil. 2010, 18, 691-698.

55. Tan, M.L.; Choong, P.F.; Dass, C.R. Recent developments in liposomes, microparticles and nanoparticles for protein and peptide drug delivery. Peptides 2010, 31, 184-193.

56. Gupta, S.; Jain, A.; Chakraborty, M.; Sahni, J.K.; Ali, J.; Dang, S. Oral delivery of therapeutic proteins and peptides: a review on recent developments. Drug Deliv. 2013, 20, 237-246.

57. Jain, A.; Gulbake, A.; Shilpi, S.; Hurkat, P.; Jain, S.K. Peptide and protein delivery using new drug delivery systems. Crit. Rev. Ther. Drug Carrier. Syst. 2013, 30, 293-329.

58. Laslett, L.L.; Kingsbury, S.R.; Hensor, E.M.; Bowes, M.A.; Conaghan, P.G. Effect of bisphosphonate use in patients with symptomatic and radiographic knee osteoarthritis: Data from the Osteoarthritis Initiative. Ann. Rheum. Dis. 2013.

59. Saito, M.; Takahashi, K.A.; Arai, Y.; Inoue, A.; Sakao, K.; Tonomura, H.; Honjo, K.; Nakagawa, S.; Inoue, H.; Tabata, Y.; Kubo, T. Intraarticular administration of platelet-rich plasma with biodegradable gelatin hydrogel microspheres prevents osteoarthritis progression in the rabbit knee. Clin. Exp. Rheumatol. 2009, 27, 201-207.

60. Bragdon, B.; Bertone, A.L.; Hardy, J.; Simmons, E.J.; Weisbrode, S.E. Use of an isolated joint model to detect early changes induced by intra-articular injection of paclitaxel-impregnated polymeric microspheres. J. Invest. Surg. 2001, 14, 169-182.

61. Liggins, R.T.; Cruz, T.; Min, W.; Liang, L.; Hunter, W.L.; Burt, H.M. Intra-articular treatment of arthritis with microsphere formulations of paclitaxel: biocompatibility and efficacy determinations in rabbits. Inflamm. Res. 2004, 53, 363-372.

62. Liang, L.S.; Jackson, J.; Min, W.; Risovic, V.; Wasan, K.M.; Burt, H.M. Methotrexate loaded poly(L-lactic acid) microspheres for intra-articular delivery of methotrexate to the joint. J. Pharm. Sci. 2004, 93, 943-956.

63. Hoffman, A.S. The origins and evolution of "controlled" drug delivery systems. J. Control. Release 2008, 132, 153-163.

64. Ratcliffe, J.H.; Hunneyball, I.M.; Wilson, C.G.; Smith, A.; Davis, S.S. Albumin microspheres for intra-articular drug delivery: investigation of their retention in normal and arthritic knee joints of rabbits. J. Pharm. Pharmacol. 1987, 39, 290-295.

65. Liechty, W.B.; Kryscio, D.R.; Slaughter, B.V.; Peppas, N.A. Polymers for drug delivery systems. Annu. Rev. Chem. Biomol. 2010, 1, 149-173.

66. 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, 205-218.

67. Sinha, V.R.; Trehan, A. Biodegradable microspheres for protein delivery. J. Control. Release 2003, 90, 261-280.

68. Grund, S.; Bauer, M.; Fischer, D. Polymers in Drug Delivery—State of the Art and Future Trends. Adv. Eng. Mater. 2011, 13, B61-B87.

69. Wang, L.; Liu, Y.; Zhang, W.; Chen, X.; Yang, T.; Ma, G. Microspheres and microcapsules for protein delivery: strategies of drug activity retention. Curr. Pharm. Des. 2013, 19, 6340-6352.

70. Ryan, S.M.; McMorrow, J.; Umerska, A.; Patel, H.B.; Kornerup, K.N.; Tajber, L.; Murphy, E.P.; Perretti, M.; Corrigan, O.I.; Bray den, D.J. An intra-articular salmon calcitonin-based nanocomplex reduces experimental inflammatory arthritis. J. Control. Release 2013, 167, 120-129.

71. Brown, K.E.; Leong, K.; Huang, C.H.; Dalal, R.; Green, G.D.; Haimes, H.B.; Jimenez, P.A.; Bathon, J. Gelatin/chondroitin 6-sulfate microspheres for the delivery of therapeutic proteins to the joint. Arthritis Rheum. 1998, 41, 2185-2195.

72. Bedouet, L.; Moine, L.; Pascale, F.; Nguyen, V.N.; Labarre, D.; Laurent, A. Synthesis of hydrophilic intra-articular microspheres conjugated to ibuprofen and evaluation of antiinflammatory activity on articular explants. Int. J. Pharm. 2014, 459, 51-61.

73. Bedouet, L.; Pascale, F.; Moine, L.; Wassef, M.; Ghegediban, S.H.; Nguyen, V.N.; Bonneau, M.; Labarre, D.; Laurent, A. Intra-articular fate of degradable poly(ethyleneglycol)-hydrogel microspheres as carriers for sustained drug delivery. Int. J. Pharm. 2013, 456, 536-544.

74. Gaignaux, A.; Reeff, J.; Siepmann, F.; Siepmann, J.; De Vriese, C.; Goole, J.; Amighi, K. Development and evaluation of sustained-release clonidine-loaded PLGA microparticles. Int. J. Pharm. 2012, 437, 20-28.

75. Sandker, M.J.; Petit, A.; Redout, E.M.; Siebelt, M.; Muller, B.; Bruin, P.; Meyboom, R.; Vermonden, T.; Hennink, W.E.; Weinans, H. In situ forming acyl-capped PCLA-PEG-PCLA triblock copolymer based hydrogels. Biomaterials 2013, 34, 8002-8011.

76. Chen, Z.; Liu, D.; Wang, J.; Wu, L.; Li, W.; Chen, J.; Cai, B.C.; Cheng, H. Development of nanoparticles-in-microparticles system for improved local retention after intra-articular injection. DrugDeliv. 2013, doi:10.3109/10717544.2013.848495.

77. Eswaramoorthy, R.; Chang, C.C.; Wu, S.C.; Wang, G.J.; Chang, J.K.; Ho, M.L. Sustained release of PTH(1-34) from PLGA microspheres suppresses osteoarthritis progression in rats. Acta Biomater. 2012, 8, 2254-2262.

78. Horisawa, E.; Kubota, K.; Tuboi, I.; Sato, K.; Yamamoto, H.; Takeuchi, H.; Kawashima, Y. Size-dependency of DL-lactide/glycolide copolymer particulates for intra-articular delivery system on phagocytosis in rat synovium. Pharm. Res. 2002, 19, 132-139.

79. Ko, J.Y.; Choi, Y.J.; Jeong, G.J.; Im, G.I. Sulforaphane-PLGA microspheres for the intra-articular treatment of osteoarthritis. Biomaterials 2013, 34, 5359-5368.

80. Mountziaris, P.M.; Sing, D.C.; Chew, S.A.; Tzouanas, S.N.; Lehman, E.D.; Kasper, F.K.; Mikos, A.G. Controlled release of anti-inflammatory siRNA from biodegradable polymeric microparticles intended for intra-articular delivery to the temporomandibular joint. Pharm. Res. 2011, 28, 1370-1384.

81. Mountziaris, P.M.; Sing, D.C.; Mikos, A.G.; Kramer, P.R. Intra-articular microparticles for drug delivery to the TMJ. J. Dent. Res. 2010, 89, 1039-1044.

82. Mountziaris, P.M.; Tzouanas, S.N.; Sing, D.C.; Kramer, P.R.; Kasper, F.K.; Mikos, AG. Intra-articular controlled release of anti-inflammatory siRNA with biodegradable polymer microparticles ameliorates temporomandibular joint inflammation. Acta Biomater. 2012, 8, 3552-3560.

83. Presumey, J.; Salzano, G.; Courties, G.; Shires, M.; Ponchel, F.; Jorgensen, C.; Apparailly, F.; De Rosa, G. PLGA microspheres encapsulating siRNA anti-TNFalpha: efficient RNAi-mediated treatment of arthritic joints. Eur. J. Pharm. Biopharm. 2012, 82, 457-464.

84. te Boekhorst, B.C.; Jensen, L.B.; Colombo, S.; Varkouhi, A.K.; Schiffelers, R.M.; Lammers, T.; Storm, G.; Nielsen, H.M.; Strijkers, G.J.; Foged, C.; Nicolay, K. MRI-assessed therapeutic effects of locally administered PLGA nanoparticles loaded with anti-inflammatory siRNA in a murine arthritis model. J. Control. Release 2012, 161, 772-780.

85. Giteau, A.; Venier-Julienne, M.C.; Aubert-Pouessel, A.; Benoit, J.P. How to achieve sustained and complete protein release from PLGA-based microparticles? Int. J. Pharm. 2008, 350, 14-26.

86. Allison, S.D. Analysis of initial burst in PLGA microparticles. Expert Opin. Drug Deliv. 2008, 5, 615-628.

87. Castaldo, L.; Corbo, P.; Maglio, G.; Palumbo, R. Synthesis and preliminary characterization of polyesteramides containing enzymatically degradable amide bonds. Polym. Bull. 1992, 28, 301-307.

88. Dias, A.J.A.A.; Petit, A. Microparticles comprising a crosslinked polymer. Patent WO2007107358, 27 September 2007.

89. Dias, A.J.A.A.; Plum, B.J.M.; Quaedvlieg, P.J.L.M.; Wiertz, R.W. Carbamate, thiocarbamate or carbamide comprising a biomolecular moiety. Patent WO2008055666, 15 May 2008.

90. Svelte Medical Systems. Available online: article=113 (accessed on 12 March 2014).

91. Trif, M.; Guillen, C.; Vaughan, D.M.; Telfer, J.M.; Brewer, J.M.; Roseanu, A.; Brock, J.H. Liposomes as possible carriers for lactoferrin in the local treatment of inflammatory diseases. Exp. Biol. Med. 2001, 226, 559-564.

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

93. 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, 285-290.

94. Kopecek, J. Hydrogel biomaterials: A smart future? Biomaterials 2007, 28, 5185-5192.

95. Chen, Z.P.; Liu, W.; Liu, D.; Xiao, Y.Y.; Chen, H.X.; Chen, J.; Li, W.; Cai, H.; Cai, B.C.; Pan, J. Development of brucine-loaded microsphere/thermally responsive hydrogel combination system for intra-articular administration. J. Control. Release 2012, 162, 628-635.

96. Athanasiou, K.A.; Niederauer, G.G.; Agrawal, C.M. Sterilization, toxicity, biocompatibility and clinical applications of polylactic acid/polyglycolic acid copolymers. Biomaterials 1996, 17, 93-102.

97. ClinicalTrials. Available online: (accessed on 4 March 2014).

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