Kang 2013

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 drugs 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
<3
< 25
10 -- 30
3.5
4 -- 10
15 -- 35
< 2.2
1 -- 2
HA: Hyaluronic acid; MW: Molecular weight; OA: Osteoarthritis;

SF: Synovial fluid.
tramadol, which are the first line of OA treatment [14]. If these

analgesics do not sufficiently control the pain, a NSAID can be
used. NSAIDs have similar effectiveness, but they differ in
their major side effects such as gastrointestinal bleeding. The
most common side effects of NSAIDs include gastrointestinal
distress, that is, stomach upset, cramping diarrhea, ulcers and
even bleeding. The COX2-specific NSAIDs have lower rates
of gastrointestinal side effects but are associated with higher
rates of cardiovascular disease including myocardial infarction [15]. Because of these side effects of NSAIDs, physicians
are increasingly considering IA treatment when oral therapies
are not effective or show considerable systemic side effects.

Another group of drugs are disease-modifying OA drugs.
They are drugs with the ability to slow down the disease
process of OA or maybe even arrest it completely, including
compounds that inhibit matrix-metalloproteinases (MMPs),
bisphosphonates, cytokine blockers and calcitonin and inhibitors of inducible nitric oxide synthase (iNOS), doxycycline, glucosamine and diacerein [16]. Surgical treatments including joint
replacement are indicated in advanced OA with significant disability and for those patients in whom more conservative
management has failed [17].
4.
Rationale for IA drug delivery in OA
The localized nature of OA makes IA injection an attractive

modality as the drug can be directly given to the main site
where the disease has developed. This is the most important reason for using IA injection to treat OA. The advantages and
disadvantages of IA injection are summarized in Table 2.
Drugs are injected into the synovial joint using a needle.
A minimum amount of the drug is usually required and exposure of the drug to unaffected sites is minimized with this
route of administration [18]. Therefore, IA injection achieves
high drug concentrations at the site of action with limited systemic toxicity. In addition, it enables the administration of
drugs, which have good efficacy but low oral bioavailability
such as proteins or drugs with low solubility [19].
In general, soluble drugs administered through the IA route
are rapidly absorbed into the blood circulation [20]. The most
important clearance mechanism for high-molecular-weight
271
Table 2. Advantages and disadvantages of

intra-articular administration.
Advantages
Application of drugs directly
into joint
Possibility of initial high drug
concentrations at the site of
action
Requiring only a low amount
of drugs
Minimizing drug exposure of
inappropriate sites
Feasibility of applying drugs
with low oral bioavailability
Reduction of systemic side
effects
Reduction of treatment
expenses
Disadvantages
Discomfort and pain for
patient
Increased risk of serious joint
infections, sepsis or cartilage
damage
Short retention time and
rapid clearance of drugs in
joint
substances located in the SF is trans-synovial flow into

the synovial lymph vessels, when it is transported into the
systemic circulation via the superior vena cava [21].
Clearance and distribution of injected drugs from the SF
mainly depend on their molecular size and solubility. Water
and protein in the SF is completely replaced within a period
of approximately 2 h; albumin from the SF of OA patients
was cleared at a rate of about 0.04 ml/min, corresponding to a
turnover of about 1 h [21,22]. The clearances obtained for the solutes of NSAIDs such as diclofenac, salicylate and paracetamol
in SF were shown to be as short as 1 -- 5 h [22]. Cortisone, naproxen or ketoprofen administered via IA injection have halflives of 1 -- 2 h in solutions or suspensions, and HA has a
half-life of 22 -- 26 h [23]. Drug delivery systems should address
shortcomings of rapid clearance by increasing the drug residence time in the synovial cavity and ensuring sustained release
and slow absorption of the active substance in the joints.
Biodegradability is also a major concern in the choice of
drug delivery vehicles for successful IA treatment. Residual
polymer and degradation products remaining within the
joint, particularly in OA patients, may induce side-effects
such as inflammation in the joint [24]. Biocompatibility, which
generally refers to the ability of a material to perform with an
appropriate host response in a specific situation, is an important issue for the development of drug delivery systems [25].
Formulation, method of use, location in the body and condition being treated as well as biodegradation should be considered in defining biocompatibility of a drug delivery
system [26]. Appropriate IA drug delivery systems for OA
treatment should be selected and applied in consideration of
the exceptional environment of a joint cavity.
5.
Current IA treatment for OA
Corticosteroids are the first substances that have provided

valuable symptomatic treatment for patients with knee OA
272
associated with synovitis and effusion [27]. Corticosteroids

inhibit prostaglandin synthesis and decrease the activity of
collagenase and other MMPs [28]. IA injections of corticosteroid also reduce the production of inflammatory cytokines
including IL-1 and TNF-a [29]. On the other hand, there
are possible adverse reactions associated with IA injection of
corticosteroids, and these include injury to the joint tissues
especially with repeated injections and the stimulation of
inflammation by crystallized corticosteroids [30]. IA injection
of hydrocortisone leads to pain relief that may last between
a few weeks and a few months [31]. A single IA injection of triamcinolone hexacetonide in knee also provides short-term
pain relief in knee OA. Increased benefit was associated with
both clinical evidence of joint effusion and successful aspiration of SF at the time of injection [27]. Furthermore, longterm treatment of knee OA with repeated triamcinolone
acetonide injections appears to be clinically effective for symptom relief with no deleterious effects on the anatomical structure of the knee [32].
HA is another IA injection material used frequently for
OA treatment. HA naturally exists in the SF. In patients
with knee OA, both the concentration and the molecular
weight of HA are decreased, reducing the viscoelasticity of
the SF [33]. The rationale behind IA injections of HA is the
restoration of the viscoelasticity of SF. Injected HA supplements the flow of SF, regulates the synthesis of endogenous
HA as well as inhibits its degradation and finally relieves
joint pain [34]. Duration of action differs depending on the
molecular weight of HA. While HA with a molecular weight
of > 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 g/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 m
Celecoxib/HA
Surgically
induced OA
rabbit
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 m
PTH (1 -- 34)
Papain-induced
OA rat
PLGA
14.5
0.81 m
Sulforaphane
Surgically
induced OA rat
PLGA
9.0 0.2 or
5.0 0.1 m
Naproxen
sodium
Ovalbumin and
Freunds complete adjuvantinduced OA
rabbit
Gelatin
hydrogel
70 m
bFGF
Healthy rabbit
Collagomers
Microparticle
dimension in
SEM image
Diclofenac
Monosodiumiodoacetateinduced OA rat
Calcium
alginate
Not defined
TGF-b
Surgically
induced OA
rabbit
ELPs
Not defined
Model genes
encoding
Val/Gly/Ala or
Val only
Healthy rat
Comments
Ref.
Decrease of drugs 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 m 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 m [75]. Another report showed that
> 90% of the PTH/PLGA microspheres with a larger size
for IA delivery were 51 -- 85 m 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 m 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 m [64] and 4.98 m [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.
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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: gunil@duih.org

Kang 2013

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Review

Drug delivery systems for

Structure and function of

Rationale for IA drug delivery

Current IA treatment for OA

Delivery systems investigated

Mi Lan Kang & Gun-Il Im

Introduction: Intra-articular (IA) drug delivery is very useful in the treatment

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

Intra-articular (IA) administration is a very useful therapy

This box summarizes key points contained in the article.

drug delivery systems that can release the therapeutic agent

Structure and function of synovial joint

Joints are classified into synarthroses, amphiarthroses and

produce a protein-rich secretion [6]. Both of them phagocytose

Pathophysiology and treatment modality

OA is prevalent after 65 years of age, reaching an incidence of

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

Drug delivery systems for intra-articular treatment of osteoarthritis

Figure 1. Appearance of normal and osteoarthritic synovial joint.

Table 1. Characteristics of human SF under normal and

HA: Hyaluronic acid; MW: Molecular weight; OA: Osteoarthritis;

tramadol, which are the first line of OA treatment [14]. If these

are not effective or show considerable systemic side effects.

Rationale for IA drug delivery in OA

The localized nature of OA makes IA injection an attractive

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

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

Table 2. Advantages and disadvantages of

substances located in the SF is trans-synovial flow into

Current IA treatment for OA

Corticosteroids are the first substances that have provided

associated with synovitis and effusion [27]. Corticosteroids

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

Drug delivery systems for intra-articular treatment of osteoarthritis

Lastly, platelet-rich plasma (PRP) has recently emerged as

Delivery systems investigated for IA OA

To achieve sustained release and slow absorption of drugs

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

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

Rapid burst release in vitro

Slow in vitro release (80%

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

Drug delivery systems for intra-articular treatment of osteoarthritis

Decrease of drugs systemic

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

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

delivery [65]. SFN, a molecule within the isothiocyanate group

3-phosphocholine) and variable amounts of cholesterol was

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

Drug delivery systems for intra-articular treatment of osteoarthritis

poorly accessible avascular tissue and may be of use in small

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

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

Drug size and transport

The synovium constitutes the main barrier for drug transport

IA drug delivery is very useful for the OA treatment since

were developed for OA treatment. The polymer that was

IA drug delivery for OA treatment is a targeted drug delivery

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

Drug delivery systems for intra-articular treatment of osteoarthritis

and discontinuous change of their physical properties above

Caldwell JR. Intra-articular

synovial cells of the rat knee joint to