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Rheological Properties of Synovial Fluid due to Viscosupplements: A

Review for Osteoarthritis Remedy

S. More , A. Kotiya , A. Kotia , S.K. Ghosh , L.A. Spyrou ,

I.E. Sarris

PII: S0169-2607(20)31477-2
DOI: https://doi.org/10.1016/j.cmpb.2020.105644
Reference: COMM 105644

To appear in: Computer Methods and Programs in Biomedicine

Received date: 15 April 2020

Accepted date: 30 June 2020

Please cite this article as: S. More , A. Kotiya , A. Kotia , S.K. Ghosh , L.A. Spyrou ,
I.E. Sarris , Rheological Properties of Synovial Fluid due to Viscosupplements: A Review
for Osteoarthritis Remedy, Computer Methods and Programs in Biomedicine (2020), doi:
https://doi.org/10.1016/j.cmpb.2020.105644

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Highlights

 Synovial fluid concentration, molecular weight and rheological properties

 Recent advancements of rheological properties of viscosupplementation

 Commercial viscosupplements and the role of polymeric properties

 Clinical studies on the effectiveness and challenges of viscosupplements

1
 Rheological Properties of Synovial Fluid due to Viscosupplements: A Review for
Osteoarthritis Remedy

S. More 1, A. Kotiya2, A. Kotia1, S.K. Ghosh3, L.A. Spyrou4, I.E. Sarris5,

1
School of Mechanical Engineering, Lovely Professional University Punjab, India
2
Central Research Institute (H), Noida, India
3
Indian Institute of Technology (Indian School of Mines) Dhanbad, India
4
Institute for Bio-Economy and Agri-Technology, Center for Research and Technology Hellas,
38333 Volos, Greece
5
Department of Mechanical Engineering, University of West Attica, 12210 Athens, Greece

Abstract

The synovial fluid is a transparent electrolyte solution included in joints to provide lubrication
helping the proper movement. It exhibits complex rheological properties due to the interaction
among its constituents i.e. hyaluronic acid, albumin, lubricin and phospholipids. In degenerative
osteoarthritis and inflammatory rheumatoid arthritis diseases, the quantity of synovial fluid and
lubrication efficiency significantly deteriorates. In that case, viscosupplementation with intra-
articular hyaluronic acid may be prescribed to replenish the concentration, the molecular weight
and the rheological properties of natural synovial fluid. The present review concentrates on the
recent advancements in viscosupplementation with emphasis into their rheological properties, its
effects on the rheological behavior of synovial fluid, and finally its clinical effectiveness.
Initially, the properties of synovial fluid are summarized, and then a discussion on commercial
viscosupplements, the role of polymeric properties and their rheological properties are reviewed.
Moreover, a detailed discussion on the clinical effectiveness and challenges of viscosupplements
are provided.

Keywords: synovial fluid, viscosupplements, rheology, viscosity, elasticity, hyaluronic acid

Content:

1. Introduction
2. Relevant articles selection criteria

2
 3. Role of synovial fluid
4. Viscosupplements
1. Commercial viscosupplements
2. Role of polymeric properties
3. Effect of viscosupplementation on the rheological properties of synovial fluid
4. Clinical effectiveness and challenges of viscosupplements
5. Conclusions

1. Introduction

Osteoarthritis (OA) is a degenerative disease that affects the mechanical and rheological
behavior of synovial fluid (SF). In turn, OA causes musculoskeletal disorders, pain and mobility
limitations, thus reducing patient’s independence and overall quality of life. The most commonly
affected joints are the hip and knee joints, owing to large loads carried by them [1-6]. Other
joints, i.e. shoulder, waist and ankle joints are also severely affected. Figure 1 presents all joints
of human body that are affected by OA. Each and every joint within the frame contains synovial
fluid as joint lubricant. This joint fluid is also called synovia due to its similarity to egg’s white
[7]. The primary property of this liquid is to grease up the joint and to allow for easier
movement. Thus, it contributes to joint lubrication and bearing functions by facilitating the
movement and reducing the discomfort. Each end of adjacent bones is covered with a smooth
and soft layer of cartilage, thereafter, joint encapsulate contains non-sticky SF as lubrication
fluid.

The main purpose of the conventional OA treatment is to reduce severe pain and keep up joint
portability. The most common non-surgical treatment includes the use of non-steroidal anti-
inflammatory drugs (NSAIDs) and intra-articular hyaluronic acid (IA-HA) injection that is
referred as viscosupplementation [8]. The aim of viscosupplementation is to reduce pain and
restore the rheological properties of the synovial fluid.

3
 Figure 1: Major Synovial joints in human body.

In OA the hyaluronic acid (HA) is depolymerized, causing deterioration in elastic and viscous
properties of SF [9]. In comparison to healthy SF, degenerated SF due to OA has lower viscosity
[10]. This reduction in lubrication properties of SF is due to decrease in molecular size and
concentration of HA [10-12].

Viscosupplementsare utilized for diminishing agony and enhancing joint movement in patients
with OA by restoring the physiological homeostasis of the OA joint [11, 13]. The HA-protein
complex is the main factor being responsible for increasing viscoelastic properties of SF [10].
Viscosupplements significantly modify the rheological properties of SF. A rheological analysis
includes the study of deformation, as well as, fluid flow under varying shear stress and shear

4
rate. The rheological analysis of the shear properties of SF is usually performed by using a
rheometer, which measures the flow resistance in fluids by control of stress or shear rate [11,
13]. Cone and plate, parallel plate, concentric cylinder and double gap concentric cylinder are
among various types of commercial rheometers available for analyzing SF [13]. Relaxation time
is an indicative measure of time dependency of fluid response under the presence of high
molecular weight (MW) viscosupplements. Shear thinning and non-Newtonian behavior of SF
with viscosupplementation have been previously reported [14].

The scope of this study is to review the rheological properties of viscosupplements, their effect
on the rheological behavior of synovial fluid, as well as, their clinical effectiveness. Initially a
discussion on the composition of SF and its role in joint lubrication is presented. Subsequently
commercially available viscosupplements and their polymeric properties are elaborated. IA-HA
injection makes significant modification in rheological properties of SF. Last sections deal with
the effect of viscosupplementation on rheological properties and evaluate effectiveness of
viscosupplementation in OA clinical practice.

2. Relevant Articles Selection Criteria

In order to select the most important articles for the theme of the present review, the search
engines Google Scholar, Scopus and ScienceDirect were utilized. The combination of the
keywords “synovial fluid”, “viscosupplements” and “rheology” were used. The date for the last
search was February4, 2020. Figure 2 shows a flow chart for the relevant research article
identification and selection. Two selection stages are used as described below:

 In first stage, bibliography is searched according to articles title and abstract.

Subsequently, existing articles are filtered for the purpose of selecting the adequate ones
that meet the following three basic criteria, namely: a) the subject is related to OA
remedy, b) rheological properties of synovial fluid are examined, and c) the subject is
related to viscosupplements. Additional papers were also identified from reference list.
After review and exclusion from the database source, 136 papers are remained.
 In second stage abstract screening of these papers is performed, which shortlisted 102
potential articles. In the next stage, the whole content of these articles is read in order to
decide whether are relevant or not. This process finalized with 80 potential articles.

5
 Figure 2: Flow chart for research article identification and selection strategy.

3. Role of synovial fluid

The composition of SF is similar to dialysate of blood serum as it have same electrolyte and
other lower molecular substance. The composition of protein and hyaluronate is the main
difference between SF and blood serum [15]. In healthy joints, soft articular cartilage and SF are
closely functionalized to provide some of the lowest coefficients of friction found in nature [16].
SF provides shock absorption, lubrication, and nutrition to adjacent articular cartridge. Non-
Newtonian behavior with shear thinning, elasticity and high viscosity are characteristics of
normal SF [17]. Synovial fluid is mainly composed of four constituents i.e. serum albumin (egg
white), HA, lubricin (mucinous glycoproteins) and globulin [18]. HA contained in SF majorly
determines its rheological properties [19]. SF is secreted into joint cavity by the inner membrane
of synovial joint (synovial membrane). The quantity of SF in joints is varied according to its size
e.g. knee joint contains about 3.5 ml SF [13]. Its physical appearance is transparent with slight
straw yellowish.

6
The complex nature of human musculoskeletal movements requires SF to provide lubrication
boundary to elasto-hydrodynamic lubrication regime. Figure 3 shows a typical Stribeck curve, to
display various lubrication regimes. In boundary lubrication regime, a monolayer or thin film of
lubricant exist in between mating surfaces. It exists in heavy load and low shear rate conditions.
Mixed and elasto-hydrodynamic regimes have relatively lower friction coefficients [20], due to
presence of a thicker layer of lubricant.

Figure 3: Stribeck curve.

Lubricin and HA are the main macromolecules responsible for the SF lubrication [12]. The high
viscosity of SF enables it to easy transition from boundary lubrication to elasto-hydrodynamic
regime [22-23]. This transition is possible due to HA-lubricin interaction, by increasing viscosity
at the cartilage surface and hence improving load carrying capacity [21]. Boundary lubrication in
SF is mainly provided by lubricin [22]. In SF, carboxy-terminus of lubricin brings it to articular
surface, and water is drawn though hydrophilic oligosaccharides brush to lower boundary
lubrication coefficient [24-25].
SF has the property to increase its thickness almost abruptly to more than 3 times under shearing
and form dense aggregates, as shown in Figure 4.These aggregates have sufficient long life, and
provide effective surface protection [18]. Their shear induced self-replenishing mechanism is

7
responsible for effective functioning of joint lubrication. The identification of the role of HA,
lubricin or albumin individually or as a group, and also their effect on SF aggregation between
cartilage surfaces constitute a field of continuous research.

Figure 4: Synovial fluid under shearing [18].

HA is a high molecular weight glycosaminoglycan of extracellular matrix and its solution is

highly viscous exiting a non-Newtonian behavior. It is composed of alternating D-glucuronic
acid and N-acetyl D-glucosamine connected by β-1,3 and β-1,4 glycosidic bonds, respectively,
with a 6000-8000 kDa MW. HA transmits the force of contraction and facilitate smooth gliding
of loose connective tissues [26]. Inflammatory (rheumatoid-arthritis) and degenerative (OA)
joint diseases cause reduction in HA concentration and MW, which significantly affects the
lubrication properties [27]. Figure 5 shows a schematic representation of healthy and OA joint
for comparison, where SF concentration, lubricin, HA and MW are reduced in OA. The
reduction in HA and lubricin significantly deteriorates the boundary lubrication and results in
reduced load carrying capacity. Estrella et al. [28] reported that the profile of lubricin is altered
in OA, having as a consequence to reduce negative charge density on surface of lubricin, which
in turn results in diminished lubrication ability.

8
 Figure 5: Comparison between healthy and OA joints with respect to synovial fluid layer.

Rheological studies of SF help to investigate the lubrication conditions within a joint and unveil
the potential treatment options for joint diseases. Madkhali et al. [29] observed that zero shear
viscosity of SF was affected in OA joints and varied from 0.05-14.05 Pa-s (mean 1.73 Pa-s and
standard deviation 2.75 Pa-s), where in healthy joints, zero shear viscosity was in the range of 1-
175 Pa-s [30]. Shear rate in human joints varies in the range of 0.01s-1 to 105s-1. Also, shear
thinning ratios for healthy SF and OA-affected joints are in the range of 70-250 and 5-40,
respectively [27]. Table 1 lists the rheological properties reported by various authors on normal
and diseased SF cases. Anadere et al. [10] used oscillating capillary viscometer to measure
viscosity of 75 samples of SF. Mean viscosity with meniscus defect was observed to be
40.12±13.2 cP, where its value in traumatic decrease was found to be 13.14±8.6 cP. Ferguson et
al. [31] analyzed SF from both left and right knee of 10 subjects and observed significant
differences in apparent viscosity of SF from left and right knee, as well as behavior with non-
Newtonian characteristics.

9
1 Table 1: Viscosity measurements and rheological features of the synovial fluid reported by various viscometers

Sr. Temperature Loading

No. Viscometer Used of Analysis SF Sample Size Results Reference
(oC) Conditions
Oscillating
Mean viscosity (meniscus defect: 40.12±13.2
capillary 75 subjects(7- meniscus
1. 0
23 C cP; OA: 31.0±15.0 cP; traumatic: 13.14±8.6 Anadere et al. [10]
viscometer defect, 12-OA, 18- Shear rate of 10 s-l
cP; RA: Seronegative 19.5±7.2 cP,
traumatic, 34- RA
Seropositive 9.91±3.8 cP)

Oscillatory OA joint fluids showed increased viscosity,

2. Gomez et al. [35]
flow capillary 24 subjects (OA, RA, Shear rates 3-300
20 - 25 C 0
mixed connective tissue s-l elasticity and intrinsic viscosity as
viscoelasticity disease, and pseudo compared to rheumatoid arthritis fluids.
meter gout)

Differences found at the rheological

Shearing forces
properties of healthy and rheumatoid arthritis Balazs et al. [12]
Capillary 503 subjects (268 normal of 7 -17 dynes
3. 25 0C
viscometer and remaining RA) SF due to concentration, MW and molecular
cm-2
interaction
Weissenberg
4. Rheogoniomete Shear rate Non-Newtonian character is found for SF Ferguson et al. [31]
r model 10 subjects (OA, RA 1.12-560 s-1
R16.(cone & 250C and traumatic synovial
plate effusion)
viscometer)

10
 R17 Elastic compliance (cm2dyne-1) at 18 oC for Caygil et al. [33]
Shear rate range of
Weissenberg 7.35 * 10 to 7.35 * normal fluids (0.384-1.728) & rheumatoid
5. 102sec -1
Rheogoniomet fluid (0.427). Elastic properties of synovial
er 8 subjects (4 Normal, fluid are shown to play a negligible role in
18 0C & 28 0C
4 Pathological) the action of a human knee joint under
conditions when the deformability of the
cartilage is significant.

RA case Newtonian properties with

6. Rotational cone-
o o viscosity below 10 centipoises, traumatic
in-cone 29 C & 36 C 8 subjects (traumatic Shear rate Blosh et al. [32]
viscometer arthritis and RA) arthritis cases shows thixotropic behavior
0.01-200 s-1
with viscosity 1000-10000 centipoise
47 patients (21 Functional behavior & characteristic for
Shear rate
rheumatoid
7. Bohlin VOR normal SF broke down in the SF of Safari et al. [34]
factor (RF) positive range up to
rheometer 27 oC arthritis, 5 RF rheumatoid arthritis and It was also absent in
12530 l/s
negative, 6 Normal, 3
the SF of knee joints with meniscus lesions
treated with
glucocorticoid and ligament defects.
injections, from 6
with ligament defects
and from 6 with
meniscus lesion)
HA concentration in normal SF was found
32 subjects (OA Frequencies
8. Micro-Fourier 2-2.5 to 4 mg/ml, whereas in OA knee 1-2 Bagga et al. [36]
rheometer grades 1 to 2 ranging from 0
20 to 25 0C mg/ml; Elasticity at 2.5 Hz for normal and
(Osteoarthritis to 20 Hz
OA SF were measured as 23 Pa and 7 Pa
Research Society
respectively.
International)

11
4. Viscosupplements
Viscosupplementation is characterized as a method during which pathological SF is supplanted
by viscoelastic fluids using hyaluronan or its derivatives [11]. The prime motivation of
viscosupplementation is to restore SF rheological and chemical composition [13]. In OA
condition, HA quantity and its MW drastically reduces, which corresponds to reduced SF
viscosity. Viscosupplementation provides the addition of HA with high MW. This restores
natural load carry capacity of joint and also provides wound healing with prevention of excessive
scar formation [11, 37].
Intra-articular hyaluronic acid (IA-HA) or hylan injection is usually employed as a
viscosupplementation for restoring SF’s behavior. The viscoelastic properties of hyaluronic acid
are found to be connected with its MW and can be helpful for the non-inflammatory restoration
of SF properties [29]. HA is a natural biopolymer that shows very promising properties, making
it ideally suited for supplementation of joint fluids. Solutions of HA has Newtonian behavior at
low-shear rates and a remarkable decrease in viscosity as the shear-rate increases, where the
polymer chains tend to entangle at low concentration, showing viscoelastic behavior [38]. The
network-forming ability of HA in solutions gives rise to the non-Newtonian behavior, while the
cross linking of the polymer chains provides longer retention time [39], resistance to free radical
degradation [40], an increase of rheological properties [41].

4.1 Commercial viscosupplements

Commercially available viscosupplements vary in respect of MW, molecular linking (cross link,
linear), shear viscosity, cross over frequency and resident time in the joint [36]. The preliminary
Hyalgan and Artz were two hyaluronic preparations with low average MW that were
commercially available in 1986. Later, various other hyaluronic preparations derived to provide
treatment in immeasurable degenerative OA patients [43]. HA are blended as high MW
polymers, with a range of MW around 1000-8000 kDa. In case of increase in HA content, there
is a decrease in normal molecular mass of SF, which results in diminishing viscosity and
elasticity [38]. Both high MW of HA and high concentration of HA is necessary for normal joint
function [17]. However, some studies revealed that the injection of HA of more than 3000 kDa
has more treatment related adverse effects as compared to HA with MW less than 1500 kDa
[44].

12
 The main parameters used for defining viscosupplement properties are MW, HA source, cross-
linking, concentration, zero shear rate viscosity, shear thinning ratio and crossover frequency. A
basic definition of this parameter can be as follows [42]:

 Molecular Weight – Average mass of HA molecules, measured in deltons,

 Cross-linking – Nature of covalent bonding, that effects viscosity,
 Zero shear rate viscosity – viscosity at almost zero (0.01 s-1) shear rate, measures
resistance to permanent deformation under creep load,
 Shear thinning ratio – Reduction in viscosity with shear rate,
 Crossover frequency – Change in viscoelastic property with varying force that indicates
change in viscoelastic properties during walking and running.
Table 2 lists some of the properties of commercially available viscosupplements. It shows that
the majority of viscosupplements are derived from bacterial sources. Hyalgan and Supartz have
zero shear viscosity of 0.27 Pa-s and 3.07 Pa-s, respectively, whereas the crossover frequency of
Supartz, Monovisc and Euflexxa are 3.98 Hz, 2.51 Hz and 0.10 Hz, respectively [42].

.Table 2:List of main commercially available viscosupplements

Sr. No Component Molecular weight (kDa ) HA source Concentration(mg/ml)
1. Hyalgan® 500-730 Rooster combs 10
2. Hyalubrix® 1500 Bacterial 15
3. Synvisc® 6000-7000 Bacterial 8
4. Durolane® 1000 Bacterial 20
5. Monovisc® 1000-2900 Bacterial 20
6. Supartz® 620–1170 Avian (naturally 1
derived)
7. Orthovisc® 1000-2900 Avian (naturally 1.5
derived)
8. Euflexxa® 2400-3600 Bacterial 1
9. Suprahyal® 500-1000 Bacterial 10
10. Suplasyn® 500-730 Bacterial 10
11. Ostenil® 1000-2000 Bacterial 20

13
12. Viscoseal® 1600 Bacterial 10
13. Synvisc-One® 6000-7000 chicken combs -
14. Gel-One® No molecular weight value was found, as highly cross- -
linked, gel-like structure

4.2 Role of polymeric properties

The concentration and average MW dramatically influence the rheological properties of
hyaluronan preparations, such as viscosity, elasticity, the solidity of the fluid. It was shown that
three weekly injections of Hylan G-F20 (Synvisc) recover for a long term, between three and six
months, the SF parameters of HA concentration and viscoelasticity [45]. The injection of 6 ml
Hylan G-F 20 of high MW in cross-linked of hyaluronans, has been incontestable to protect and
viable for the treated of OA agony of the joint in the patients. Likewise, it had been well-endured
and effective in treating symptomatic knee osteoarthritis with imperative long methods to
improve results [46]. Mathieu et al. investigated SF rheology by using two different formulations
of viscosupplements; one with medium-MW linear HA of bacterial origin which is prepared by
linear HA solution 10 g/L with the directly disintegration of hyaluronic acid in 0.15 mol/L NaCl
and the second with high-MW cross-linked HA, Hylan G-F 20 (Synvisc) [47]. When mixed with
the linear HA, SF turns out to be no more non-Newtonian, though the non-Newtonian conduct
was strengthened once blended with the cross-linked HA.
The injections of Hylan or hyaluronic acid was found to reduce agony for ≤ 26 weeks, which is
longer time than the transient relaxations from NSAID medicine and corticosteroid injections
[48]. IA-HA injection re-establishes the viscoelasticity and protection given by synovial HA,
which is diminished with OA, and additionally diminishes joint torment and improves joint
movements.

4.3. Effect of viscosupplementation on the rheological properties of synovial fluid

Viscosupplements with moderate to high MW in HA provide enhancement in rheological
properties. Bhuanantanondh et al. investigated the rheological properties of osteoarthritic SF
with viscosupplements on SF by using a Kinexus rheometer and Bohlin Gemini
HRnanorheometerat 37°C of stainless-steel geometry, 40 mm cone diameter, with 1° cone angle
and plate [13]. The measurements of viscoelasticity were performed with an oscillating capillary

14
viscometer. The sinusoidal frequency applied in these measurements was 2 Hz, which is
representative of the brisk joint movement. The shear rate dependence of varied SF solutions was
investigated at 23OC by Anadere et al. [10]. The main examinations of the rheological properties
of SF were made by using a Kinexus Ultra rheometer at 25 and 37°C by using stainless steel
cone and plate geometry. Three additional samples were investigated at 20, 29, and 35°C to
further investigate the effects of temperature.
Madkhali et al. [29] used a rotational Kinexus Ultra rheometer, where the cone and plate
geometry is used to accommodate less test sample volumes. Balazs et al. [11], performed a
scientific analysis of the rheological properties of hyaluronan between the healthy and
pathological human and found that properties like the viscous modulus, (G’),and the modulus of
elasticity (G”) depend on the deformation frequency to which the SF is exposed, and that at a
well-defined frequency called crossover frequency, when the values of G’ and G’’ reached
equality. Below the crossover frequency the solutions behave as viscous fluids, whereas above it,
as elastic solids. This practically indicates the mechanical energy to which the hyaluronan
solution is exposed will dissipate in viscous flow below the crossover frequency, whereas is
stored as elastic deformation for higher one.
Micro-Fourier rheometer is one the widely used instrument for measurement of SF rheological
properties. In this a small quantity of fluid is placed on the metal plate, which is then subject to
compression over 0 to 20 Hz range of experimental frequencies [45]. CSL 500 controlled
rheometer is preferred equipment used for SF rheology analysis [49]. Bohlin VOR rheometer
provides controlled temperature (37oC, 25oC) measurement of rheological properties of SF. It
have cone and plate (CP 5/30 cell) with coaxial cylinders geometry [50]. Bloch et al. investigated
the rheological properties of synovial fluid by using a rotational cone-in-cone viscometer [32].
Caygill et al. evaluated the lubrication properties of the synovial fluid in four normal and four
pathological samples by victimization R17 WeissenbergRheogoniometer, which has 2o cone and
plate system, with 5 cm diameter [33].
Dodero et al. [51] measured the rheological properties of SF by using an AR-G2 type rotational
rheometer with a 60 mm cone diameter, 1° cone and plate geometry. Rotational Viscometer (LS
100, LS 2) is used for measuring shear rate in the range of 0.001-10s-1 and a rheometrics
mechanical spectrometer (RMX 7200) in the range of 10-1000 s-1 [17]. Moreover, the
rheological behavior of synovial fluid is additionally investigated by including two hyaluronic

15
acid concentrations means, a linear and a cross-linked, was analyzed with an AR 1000 type
rheometer with 4 cm diameter and 3.59o cone and plate geometry at 25oC [47]. Furthermore, the
MW of HA was measured by Miyazaki et al. [52] utilizing a cone and plate E type rotational
viscometer with 24 mm diameter and 1o34’ geometry. Safari et al. [34] assessed of rheumatic
diseases of SF is made by investigation of the viscoelastic parameters by using a Bohlin VOR
rheometer with parallel plate geometry at 27° C. Table 3 enlisted the outcomes of some selected
studies that are shorted based on various kinds of viscosupplements, rheometer and experimental
conditions.

16
 Table 3: Rheological studies on synovial fluid under viscosupplements

Sr. Loading
Viscosupplements Viscometer Temperature SF Sample Size Results Reference
No. used of Analysis Conditions
(oC)
Orthovisc, Bohlin Gemini 22 subjects (20 High-MW viscosupplements
grade 4 OA, 1 Bhuanantano
1. nano
Suplasyn, HR - 37 ºC showed more viscoelasticity
grade 3 OA and Shear rates ndh, et
Synvisc rheometer & 1 grade 2 OA) compared to low-MW
ranged from al. [13]
Kinexus viscosupplements
0.01 - 1000 s-1
rheometer

Orthovisc (Non- Using a Kinexus Shear rates Viscoelasticity was found lower Madkhali
38 subjects (OA)
crossed-linked Ultra rheometer 20, 29 and ranging from in OA affected SF than healthy et al. [29]
2.
HA) 37°C 10−2 to 103 s−1 SF samples.

Orthovisc was found 10 times Mazzucco et

CSL 500 58 Subjects (OA) Shear rates
ranged from 0.01 more viscous than Supartz al. [49]
3. Orthovisc, Supartz controlled stress to 1000 s-1 with higher MW and
rheometer. -
concentration.

Synvisc, Hyalgan, Cannon- Shear rates of Hyalgan showed lower

-1
4. Orthovisc Ubbelohde 0.002 s &100 elastoviscosity compared to Gomis et al.
[53]
semi micro - s-1 Synvisc and Orthovisc
25°C
dilution
viscometer
and Couette-

17
 type
viscometer

Significant improvement was

found in SF HA concentration
5. Hylan GF-20 Stored at – 32 subjects (OA Frequencies Bagga et al.
Micro-Fourier
80°C until 1 to 2) ranging from 0 to and complex shear modulus at [36]
rheometer
analysis 20 Hz 3-month post-administration of
Hylan GF-20
Linear HA of Cross linked HA (Hylan G- Mathieu et
6. 13 subjects (12 Shear rates from F20) was found much more al. [47]
bacterial origin; AR 1000 0
25 C OA knee and 1
Cross-linked HA Rheometer OA shoulder) 0.1 to 50 s-1 efficient in improving rheological
Hylan G-F 20 behavior of OA SF than linear
one
HA solutions show liquid-like
Sodium behavior at low frequencies and
7. hyaluronate Dodero et al.
gel-like behavior at high [51]
(average molecular AR-G2 rotational - Frequency from
200 C
weight of 90 kDa, rheometer 0.01 to 40 Hz frequencies; Also, increasing
1100 kDa, 1800 MW & concentration, HA
kDa, and 4000 kDa
solutions show higher viscosity.
Cone-plate shearing rate MW decreased with a decrease
Two HA sample
8. rotational - at 0.5, 20, in the NaCl concentration & Miyazaki et
(sodium salts) with 370C
6 6
2.6*10 and 1.1*10 viscometer. and 100 rpm polymer concentrations of al. [52]
avg molecular
samples affected viscosity.
weight

18
4.4 Clinical effectiveness and challenges of viscosupplements
Clinical studies provide details on the performance and effectiveness of viscosupplements.
Lundsgaard et al. [8] observed the effect of intra-articular sodium hyaluronate versus
physiological saline on patients with OA. A sample of 251 patients with knee OA was treated
with four weekly IA-HA injections, followed by 26 weeks follow up. They observed that IA-HA
is not having any significant improvement over saline placebo. In this, the effects of various
viscosupplements are recorded and also some patient observations (short form-12, Western
Ontario McMaster index) are considered to clearly determine the effectiveness in treatment.
Berenbaum et al. [54] compare two IA-HA solutions having different molecular weights. They
observed that three weekly injections of intermediate (800-1500 kDa) MW in HA is found
superior to low (500-730kDa) MW HA. Pavelka and Uebelhart [55] performed a comparative
study on the efficacy of purified IA-HA versus hylan G-F20and observed that both treatments
were equivalent in term of efficacy and safety. OA Research Society International (OARSI)
provides guidelines for effective and assessable treatment [56].
Puhl et al. [57] studies the efficacy and safety of IA-HA injection for treatment of patient with
OA of knee. A sample of 290 patients is observed that is received intra-articular injections in
weekly intervals and better response to active treatment is recorded, with side-effects confined
only to local reactions. Dey et al. [58] evaluate the effectiveness and tolerance of IA-HA in a
double blind, randomized, multicenter parallel group study. They observed that HA treatment
was significantly more effective in mild to moderate OA. Huang et al. [59] performed study on
the effect of intra-articular sodium hyaluronate on Asian population. They observed pain
relieving and improvement in function of knee with this treatment. In a similar study, the issue of
pseudosceptic arthritis is also reported in some cases post HA treatment. It is a rare complication
associated with hyaluronic acid injections, which normally involve inflammatory reactions at the
injection site. Aydin et al. [60] described three case studies of viscosupplementation of the knee
and observed acute pseudoseptic arthritis caused by hyaluronic acid. Roos et al. [61] reported the
case of acute pseudoseptic arthritis after repeated sodium hyaluronan injection. Their study
revealed cases of aseptic arthritis without crystal deposition, but none of the cases with
Curavisc®, which is a non-cross linked hyaluronam, naturally derived from fermentation.
However, the study of Tahiri et al. [62] revealed the acute septic arthritis in very first infiltration
within the first course after using Curavisc®. Table 4 lists the clinical studies considering the use

19
of viscosupplements. The studies present in general conflicting results, thus the clinical efficacy
of viscosupplementation is uncertain [56].

20
 Table 4: Studies on testing the clinical effectiveness of viscosupplements

Sr. SF
Viscosupplement
No. Testing Method Age Sample Testing Conditions Result Reference
/HA
Size
4 weekly intra-articular IA-HA does not make
Radiographic, injections of Sodium significant improvement in
Sodium Routine blood and Lundsga
Over 59 251 hyaluronate 2 ml term of pain relief compared
1 hyaluronate urine laboratory test subjects ard et al.
year. (Hyalgan 10.3 mg/ml) & to physiological saline
(OA) followed patients for 26 placebo. [8]
weeks.
Sodium 5 weekly intra-articular 5 weekly IA-HA injection
hyaluronate 200 injections of sodium provide pain relief and improve
Visual analog scale, Age > 50 Huang et al.
2 (Hyalgan) subjects hyaluronate 10 mg/ ml function of degenerative knee
scores years [63]
(OA) & evaluated at Week 5, joint
13, and 25.
2 ml Hyalgan (10 5 IA injections of hyaluronan
Sodium Intention to treat mg/ml) Intra-articular did not improve pain,
hyaluronate; (ITT) and per 337 injections weekly for 5 function, paracetamol
mean age 60 Jorgensen et
3 protocol (PP) used subjects weeks and followed up
Hyalgan Year. consumption or other efficacy al. [73]
as efficacy analyzer (OA) to 1 year
parameters 3, 6, 9 and 12
parameters months after the treatment
mean age 56 67 3 injections with Additional benefits observed
Orthovisc® WOMAC score years and age subjects weekly with 30 mg with IA-HA followed by
range 40 - 65 OA sodium hyaluronate arthroscopic debridement to
(Sodium
years (men – dissolved in 2 ml
provide enhanced short-term
hyaluronate) 21; physiological saline & Heybeliet al.
4 women evaluated before and benefits, but such
[72]
– 46) after 6, 12, and 24 combination needs to justify
weeks. by controlled studies with
longer follow-up and large
patient groups.

21
 WOMAC, 4 injections at weekly
Orthovisc Investigator global patients were 372 2ml (30 mg) & follow- Orthovisc (High MW) found Neustadt et
5 ≥ 40 years of subjects up evaluation at Weeks safe and effective in reducing al. [78]
score, Patientglobal
age (OA) 8, 12, 16, 22, and 28 pain for knee OA
score after the first injection.
VAS scale (pain, age 40-75 240 Hyaluronan treatments were
function, motion, years subjects 3 IA injections once a pooled; there was a Lohmander
activity), algo OA week 2.5 ml & were significantly longer duration of
et al. [74]
6 Hyaluronan functional index, and (male- followed for 52 weeks.
clinical benefit for hyaluronan
global evaluation 106,
female- treatment than for placebo.
134)
- 106 2ml IA injections using Improvement in knee pain and
Hyaluronic WOMAC index subjects 20 mg/ml HA sodium function with IA-HA shows Robert et al.
7
Score and VAS (OA) salt once weekly for superior results than placebo. [75]
acid (HA)
3weeks
WOMAC score, Group 1: High MW Efficacy and safety with high
Patients age 238
High MW HA and Visual Analog HA, once a week for 3 and low MW HA was found
over 40 years subjects
low MW HA Scale(VAS) (OA) weeks & Group 2: similar.
8
Low MW HA, one a Lee et al.
week for 5 weeks. [20]

3 injections of HA or IA-HA found effective in

placebo were given at improvement of OA effected
48 weeks 1, 2, & 3. knee joint, but there was no
HA VAS, WOMAC Kul-Panzaet
9 - subjects Group1–IA-HA
significant statistical al. [45]
(OA) (1.5mDa), Group 2 –
0.9% saline placebo difference in term of function
compared to placebo
WOMAC, SF-12, IA Hylan G-F 20 injection
Patient global Age 30+ 394 6-mL intra-articular found tolerable and effective
Hylan G-F 20 years subjects injection of Hylan G-F Pal et al.
assessment (PTGA), for OA knee treatment with
10 (OA) 200 & evaluated at
and clinical weeks 1, 4, 12, 26, 39, significant long durability (1 [46]
observerglobal and 52. year)
assessment

22
 (COGA) scores
Radiographic IA of 2.0 ml of Hylan Hylan G-F 20 is a safe and
Avg. age 18- 102
Hylan G-F 20 examination G-F 20 &12 weeks in effective treatment for OA of
75 years; subjects
duration, with a follow- the knee and can be used
>30% above (OA)
up at 26 weeks.
normal body either as a replacement for or
11
weight an adjunct to NSAID therapy. Adams et
al. [48]

Monitor with visual 100 3 IA injections of 2 ml

Hylan G-F 20 analogue scale and Mean age 62 subjects hylan G-F 20 were Hylan G-F 20 was found Wobig et al.

12 clinical variable used year, (OA) administered 1 week. effective and tolerable in the [64]
to asses patients management of chronic
idiopathic OA.

Patient satisfaction Hylan G-F 20 of 3 Clinical effectiveness and

was measured on weekly injections and general patient satisfaction are
392 better amongst patients who
Hylan G-F 20, VAS, WOMAC, Sodium Hyaluronate of Raman et al.
13 - subjects received Hylan G-F 20.
Synvisc Oxford knee score 5 weekly injections [66]
(OA)
and EuroQolEQ-5D
scores.
WOMAC score, Age 18+ 506 3 Injections into the Effectiveness of Synvisc was
Lequesne index and years subjects target knee spaced 1 more compare to conventional
Hylan G-F 20 (knee week apart & evaluation treatment without additional Kahanet al.
14 short form -12 (SF-
(Synvisc) OA) before treatment and cost. [68]
12),quality-of-life
after 1, 3, 6 and 9
questionnaire months
6 ml IA injection & Singe 6 ml IA injection of
Hylan G-F 20 WOMAC score; 253 results evaluated at 4, 8, Hylan G-F-20 was found
age 40 years
15 clinical observer subjects Chevalier et
or greater 12, 18 and 26 week post effective, with modest
globalassessment (OA) al. [71]
injection difference compared to placebo
Hylan G-F 20, Magnetic resonance Ages mean 30 3 IA injections of 2 ml IA-HA injections provided
16 imaging (MRI) 50 and 52 subjects & evaluated after the effective for knee OA Cubukcu et
Synvisc al. [77]

23
 (AO) 1st, 2nd, 3rd, and 8th
weeks
age 50 to 321 3 weekly injections, Euflexaa (Bio-HA) provide
Euflexxa, Synvisc, WOMAC index pain 80years subjects with follow-upbetter pain relief and improve
Hylan G-F 20 scale (OA) evaluations at weeks 3, joint function for knee OA, Kirchner et
17 al. [79]
6 and 12 without local reactions
associatedwith IA-HA (cross-
linked) products
Primary outcome 3 weekly injections, F60027 &Hylan G-F 20 were
measure comparison with follow-up equally effective in reducing
Hyaluronans between F60027 evaluations up to 24 functional impairment and
F60027, &Hylan G-F 20 to weeks. relieving pain in KOA patients
276
Hylan G-F20 lequesne index sore age 50-75 and well tolerated. Maheu et al.
18 subjects
range from 0 to 24 years [65]
(OA)
and secondary
efficacy criteria with
compareto100 mm
VAS.
GO- ON®(800– WOMAC pain GO-ON 25 mg/2.5 ml or
Treatment with GO-ON®
1500 kDa), subscale as primary Hyalgan 20 mg/2 ml (intermediate MW HA) found
Hyalgan (500– outcome (0–100 injected at 3-weekly superior compared to Hyalgan
453
730kDa) mm)& OA Research Age 50-80 intervals. (low MW HA) in 3 weekly Berenbaum
19 subjects
Society-outcome years injections. et al. [54]
(AO)
measures in
rheumatology
(OARSI- MERACT).
Western Ontario Men & 240 5 injections 2.5 ml IA-HA injection found
Supartz® McMaster(WOMAC) women age subjects administered (1 per effective than saline in mild to Day et al.
20 (Hyaluronan) 40-75 years (AO) week) and follow-up moderate OA [58]
for 13 weeks
Primary outcomes age 60+ 210 3 injection, once a week Neither hyaluronan preparation
21
measured with years subjects for either of Artzal provide durable clinical benefits

24
 Kaplan–Meier (AO) (native high- molecular- than placebo
survival analysis for weight Hyaluronan),
Artzal, 0-52 weeks; Synvisc (cross- linked
Synvisc Secondary outcomes hyaluronan) or with Karlsson et
measured in term of placebo; Follow-up for al. [67]
resting and max. 52 weeks.
pain; other Lequesne
index,WOMAC and
SF-36 scores
Non-animal 3 to 5 injections at NASHA was not found superior
stabilized WOMAC score, 18 weekly intervals at than placebo in the primary
22 hyaluronic Likert Scale and - subjects different quantity. efficacy analysis. Ray et al.
patients overall global (OA) [69]
acid (NASHA)
disease status.
VAS scale, WOMAC Mean Age 60 588 3 ml IA injection & IA-Bio HA provide better pain
Altman et al.
23 Euflexx® score year subjects follow-up visits at 2, 6, relief in OA knee compared to
[70]
(OA) 13, and 26 weeks. IA buffered saline
Euflexxa® Clinical assessment, Ages of 60 49 5 injections at weekly at Providing 20 week relief for
24 (Sodium salt of and 85 subjects 10 mg/ml & assessment OA patients. Tamir et al.
HA) Statistical analysis (OA) at weeks 6, 12 and 20 [76]

25
 6. Conclusions

The present review concentrates on the recent advancements in viscosupplementation with

emphasis into their rheological properties, its effects on the rheological behavior of synovial
fluid, and finally its clinical effectiveness. A systematic selection criterion is used to determine
the most appropriate articles. Initially, the SF composition is discussed and the lubrication
properties of hyaluronic acid and lubricin that are jointly functioning to provide boundary
lubrication. In degenerative diseases like osteoarthritis, quantity and lubrication properties of
both hyaluronic acid and lubricin are reduced, which limit joints load carrying capacity.
Moreover, the commercially available viscosupplements and their rheological property are
discussed. Finally, a detailed discussion on clinical studies, which evaluates the effectiveness and
challenges of viscosupplements, is provided. Although proof has been presented that the
viscosupplements improve the rheological properties of SF, their clinical efficacy still needs
further investigation.

26
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32
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