Knee Surg Sports Traumatol Arthrosc (2010) 18:901–907
DOI 10.1007/s00167-009-1039-y
KNEE
Efficacy of intra-articular polynucleotides in the treatment of knee
osteoarthritis: a randomized, double-blind clinical trial
Roberto Vanelli • Pietro Costa •
Stefano Marco Paolo Rossi • Francesco Benazzo
Received: 19 June 2009 / Accepted: 22 December 2009 / Published online: 29 January 2010
Ó Springer-Verlag 2010
Abstract This randomized, double-blind clinical trial
was conducted over 16 weeks to assess the efficacy and
safety profile of intra-articular polynucleotides gel injec-
tions in the treatment of knee osteoarthritis associated
with persistent knee pain. 60 patients were enrolled and
randomized to receive intra-articular polynucleotides
(n = 30) or hyaluronan (n = 30); patients received five
weekly intra-articular knee injections and the follow-up
period was 3 months after the end of treatment. Primary
endpoint was to determine polynucleotides (PN) efficacy in
reducing knee pain at the end of the study, over baseline
value and over standard hyaluronan viscosupplementation
(HA). Pain levels were measured using a 0–10 cm Visual
Analogue Scale (VAS). Secondary endpoints included
Knee Osteoarthritis Outcome Score (KOOS), NSAIDs
consumption, crackling during movement and articular
mobility limitation. The mean global VAS pain decreased
from 5.7 ± 1.9 cm (T0) to 1.9 ± 1.5 cm (T16) in poly-
nucleotide group and from 4.9 ± 2.0 cm (T0) to
2.1 ± 1.4 cm (T16) in hyaluronan group. The reduction in
pain was statistically significant for both groups. KOOS
increases from baseline values were statistically significant
in both groups. No significant adverse events were reported.
These findings suggest that intra-articular polynucleotides
can be a valid alternative to traditional hyaluronan supple-
mentation for the treatment of knee osteoarthritis.
Keywords Polynucleotides
Condrotide

Turnover Joint
Osteoarthritis
Hyaluronic acid

Intra-articular
R. Vanelli
P. Costa
S. M. P. Rossi (&)
F. Benazzo
IRCCS Foundation, Orthopaedic and Traumatology Department,
S. Matteo Hospital Institute, University of Pavia, Pavia, Italy
e-mail: rossi.smp@gmail.com
Introduction
Osteoarthritis (OA) is a chronic joint disease characterized
by degeneration of the articular cartilage, changes in the
physico-chemical properties of the synovial fluid and
macroscopical modifications of the joint. Scientific and
clinical data gathered so far have correlated the onset and the
progression of osteoarthritis to both mechanical and bio-
logical factors [22]. Among the different kinds of arthritic
diseases, OA is the most frequent: it is estimated that
25–30% of people over 45 years old are affected by it [9].
Many different therapies are available nowadays for the
treatment of OA and other osteochondral defects, ranging
from non-pharmacologic therapy to pharmacological
approaches (viscosupplementation, oral supplements or
topical treatments), but a flawless treatment is still to be
found.
Non-pharmacologic approaches for patients with knee
OA may include weight loss (if overweight), exercise
programs, appropriate footwears and assistive devices for
activities of daily living (ADL). Pharmacologic therapies
for relieving pain include oral acetaminophen, NSAIDs and
other analgesics like tramadol, intra-articular glucocorti-
coids and viscosupplementation with hyaluronic acid.
Other options are oral supplements (like glucosamine or
chondroitin) and topical treatments like capsaicin methyl-
salicylate [2].
Patients with severe symptomatic OA who have pain
that has failed to respond to medical therapy and who have
progressive limitation in ADL should be referred to an
orthopaedic surgeon for evaluation. Surgical options
include traditional arthroscopic debridement, total joint
arthroplasty and innovative techniques such as autologous
chondrocytes implantation (ACI) [21] or cartilage repair
using mesenchymal stem cells [13].
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Intra-articular Hyaluronic Acid (HA) supplementation is
a simple and widespread way to treat minor and moderate-
degree osteoarthritic joints [3]. HA is able to enhance
the viscoelasticity of the synovial fluid, thereby protecting
the cartilage from mechanical stresses and relieving the
patient’s pain. However, the efficacy of intra-articular HA
remains controversial: despite the fact that several clinical
trials have claimed a disease-modifying effect for HA,
subsequent meta-analyses have cast doubts on this fact [4].
Quite possibly, the lack of a real effectiveness for short-
term relief agents comes from the fact that a predominant
part of their activity is due only to their gliding and
lubricant effects, whereas OA is a multi-factorial disease
originating from a complex pattern of biochemical, meta-
bolic and inflammatory factors.
The ideal intra-articular treatment for OA should not
only provide a mechanical protection of the cartilage sur-
face, but also restore chondrocytes’ homeostasis by
restoring the physiological articular micro-environment
and supplying nutrients.
These considerations led to the development of an
innovative medical product for intra-articular therapy of
degenerative pathologies of the cartilage (product name:
Condrotide-Turnover Joint). The product is composed of
polynucleotides (20 mg/ml), polymeric molecules which
are able to bind a large amount of water and to re-organize
their structure by orienting and coordinating water mole-
cules to form a 3-D gel.
These polymeric molecules, when infiltrated intra-
articularly, can deeply moisturize articular surfaces. They
undergo enzymatic cleavage and progressively release in
the articular cavity both water molecules and smaller-sized
oligonucleotides that retain their moisturizing and visco-
elastic properties thereby maintaining the effect longer.
Polynucleotides (PN) are extracted from natural sources
(fish sperm). It is already known in literature [5–20] that
the derivatives of enzyme degradation of polynucleotide
chains (simple nucleotides, nucleosides, nitrogen bases) are
physiologically present in the extra-cellular environment
and are useful substrates for cells. Intra-articular infiltration
progressively enriches the synovial fluid of PN and thus of
nucleotides, purine and pyrimidine bases that cells can use
to promote their metabolism.
The product is a CE-marked (Conformite´ Europe´enne)
Class III Medical Device whose tolerability and safety of
use has been confirmed both by in vitro and in vivo bio-
compatibility tests requested by 93/42/EEC (European
Economic Community) Directive and carried out in com-
pliance with International Organization for Standardization
(ISO)-10993 guidelines. The product is sterile and
apyrogenic.
This is the first clinical trial to assess the efficacy of an
intra-articular preparation based on polynucleotides in the
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Knee Surg Sports Traumatol Arthrosc (2010) 18:901–907
treatment of osteoarthritis (OA) associated with persistent
pain by comparing its effects with standard HA
viscosupplementation.
Materials and methods
The product under study is a gel consisting of highly
purified—natural origin long chain polynucleotides (con-
centration 20 mg/ml). It is provided in a pre-filled glass
syringe with 2 ml of high molecular weight sterile and
apyrogenic polynucleotides (batch no. 605553), trade name
Turnover Joint and Condrotide. Polynucleotides are
derived from trout fed for human nutrition. The extractive
procedure is an original method of Mastelli S.r.l. (Italy).
The other group was treated with HA in pre-filled glass
syringe with 2 ml of 8 mg/ml hyaluronic acid (Sinovial,
batch no. 050727, Laboratoires Genévrier, Sophia Antipolis,
France).
This randomized, double-blind, clinical trial was carried
out from 2006 to 2007 in the Orthopaedic and Traumato-
logical Clinic of the University of Pavia (Italy). The
Clinical Investigation Plan, the Informed Consent Form
and the Case Report Form were approved by the Ethics
Committee of the Clinical Centre. Patient entered in the
study after reading and signing an informed consent form.
The trial was carried out according to 1964 Helsinki
Declaration principles, and its subsequent endorsement.
The trial was registered in the International Standard
Randomised Controlled Trial Register with the number
ISRCTN77293496.
A total of 60 patients were enrolled in this clinical trial.
The main inclusion criteria were subjects between 18 and
80 years, having developed persistent pain for at least
2 months and affected by knee osteoarthritis (diagnosis
based on the ACR-American College of Rheumatology
classification [1]).
Exclusion criteria included alcohol or drug abuse,
pregnancy or breastfeeding, hypersensibility to study
products, hyaluronic acid or steroid infiltration therapy
ongoing or suspended for less than 3 months, systemic
treatment with anticoagulants and steroids ongoing or
suspended for less than 1 month, previous bone fractures or
severe traumas of the interested knee, presence of rheu-
matoid arthritis and of relevant haematological
pathologies.
There were no restrictions on the use of NSAIDs during
the study period; at each visit, the physician recorded on
the Case Report Form (CRF) the consumption of anti-
inflammatory drugs. Oral and parenteral corticosteroids
were prohibited during the study period.
After the inclusion visit, patients were randomized in
one of the two study groups, i.e., Group A—
Knee Surg Sports Traumatol Arthrosc (2010) 18:901–907
Fig. 1 Study outline
polynucleotides or Group B—hyaluronic acid. The study
outline is presented in Fig. 1.
Patients of Group A received five 2-ml intra-articular
injections with an interval of 1 week between the injections
(from week 0 to week 4) of 40 mg/2 ml polynucleotides.
In an analogous way, Group B patients received five 2-ml
intra-articular injections with an interval of 1 week between
the injections (from week 0 to week 4) of 16 mg/2 ml
hyaluronic acid.
Injections were performed by highly skilled medical
personnel, under aseptic conditions and following the
standard technical rules for intra-articular administration.
All clinical parameters were evaluated immediately before
the first treatment (T0) and before each subsequent injec-
tion (T1, T2, T3, T4 visits). In addition, patients returned
for two follow-up visits after 8 weeks (T8) and 16 weeks
(T16) from the beginning of the study (respectively, 1 and
3 months after the end of the intra-articular treatment).
During follow-up visits, all primary and secondary end-
points (subsequently described) were evaluated and recor-
ded on the CRF, as well as the occurrence of adverse
events.
To ensure the double-blind condition, a blind-observer
technique was applied; clinical evaluations were performed
by a different physician from the one who carried out the
injections and who could therefore identify which treat-
ment was being administered to the subject. This way,
neither the investigator nor the patient could identify the
injected product.
The primary endpoint of the study was the change in the
pain level at rest, at weight-bearing and during physical
activity, from baseline to T16. The level of knee pain was
evaluated using a 0- to 10-cm Visual Analogue Scale––
VAS [7]. Secondary endpoints included the evaluation of
KOOS results, NSAIDs consumption, crackling during
movement and articular mobility limitation (LMA). At
903
each visit, the safety profile of the devices was assessed by
recording adverse events. To measure the levels of crack-
ling and LMA, an arbitrary scale (ranging from 0 to 3) was
used by the physician (0 = absent, 1 = mild, 2 = mod-
erate, 3 = severe).
To monitor NSAIDs consumptions, the clinician repor-
ted on the CRF, during each visit, the number of days of the
preceding week in which the patients have used NSAIDs,
specifying the brand name and the dose.
KOOS questionnaires were filled out by patients during
the inclusion visit (T0), at the end of the treatment period
(T4) and during the follow-up visits (T8 and T16), referring
to the week before the visit.
The KOOS (Knee injury and Osteoarthritis Outcome
Score) is a scale developed as an extension of Western
Ontario and McMaster Universities Osteoarthritis Index
(WOMAC), to create a validated instrument to determine
the efficacy of clinical treatments [15, 16].
The KOOS is a questionnaire that covers five patients-
relevant dimension: Pain, Other Disease Specific Symp-
toms, Activity of Daily Living Functions (ADL), Sport/
Recreation Functions and knee-related Quality of Life
(QOL); for each question, 5 alternatives are presented,
whose score ranges from 0 to 4 points.
Statistical analysis
The size of the study population (60 patients divided in two
30-patients group) was calculated using a t-test with a
desired power of 80%, an alpha of 5%, a standard deviation
of 3.0 cm to reveal a difference of 1.6 cm in the pain
reduction measured on the VAS [7] scale and foreseeing a
5% drop-out rate.
A notched box plot statistical model was applied to
interpret the study results. For each box (Figs. 3, 4), the
upper and the lower sides represent, respectively, the 75%
and the 25% percentiles of the distribution; the length of
the box corresponds to the interquantile range (IQR). The
median (50% percentile) is represented by the parallel line
which divides the box in two halves, while circles corre-
spond to outside values (green = mild outliers; red =
severe outliers). Values are considered statistically differ-
ent (CI 95%) when notched boxes do not possess any
y-coordinate in common.
For statistical analysis of KOOS results, a Tukey–
Kramer multiple comparison test was applied (alpha =
0.05, CV = 4.3510).
Statistical analysis was applied to evaluate differences
within each group at different timepoints; a statistical
comparison between Group A and Group B was not per-
formed due to the different variability of the two popula-
tions, which has not allowed a split-plot evaluation.
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904 Knee Surg Sports Traumatol Arthrosc (2010) 18:901–907

Results Table 2 VAS scores (pain at rest) for Group A and Group B
Pain at rest Group A (PN) (cm) Group B (HA) (cm)
A total of 59 patients completed the study (Group A = 29
subjects, Group B = 30 subjects). There was one drop-out T0 4.5 ± 3.0 2.9 ± 2.4
in Group A due to personal reasons. T1 3.4 ± 2.8 2.7 ± 2.1
The demographic data of the study population are T2 3.0 ± 2.4 2.2 ± 1.7
reported in Table 1. T3 2.7 ± 2.5 1.9 ± 1.6
The mean global VAS pain decreased from T4 2.2 ± 2.5 1.7 ± 1.5
5.7 ± 1.9 cm (T0) to 1.9 ± 1.5 cm (T16) in Group A and T8 1.7 ± 1.9 1.7 ± 1.9
from 4.9 ± 2.0 cm (T0) to 2.1 ± 1.4 cm (T16) in Group T16 1.3 ± 1.5 1.2 ± 1.3
B. Changes were statistically significant for both groups. Data are presented as mean ± SD
A statistical analysis to evaluate differences between
Group A and Group B was not performed due to the
Table 3 VAS scores (pain at weight-bearing) for Group A and
different variability of the two populations. Group B
Tables 2, 3 and 4 report the VAS scores divided in the
Pain at weight-bearing Group A (PN) (cm) Group B (HA) (cm)
three different subscales (at rest, during load and during
physical activity). T0 5.5 ± 2.3 5.0 ± 2.8
Regarding the pain at rest, Group A showed a faster T1 5.1 ± 2.4 4.3 ± 2.4
reduction in pain over Group B (Table 2), whilst the two T2 4.2 ± 2.4 3.7 ± 2.0
groups (Group A and B) showed a similar behaviour con- T3 3.9 ± 2.4 3.8 ± 1.8
cerning pain at weight-bearing (Table 3). T4 3.8 ± 2.2 3.2 ± 1.8
A similar trend between Groups A and B is also T8 2.8 ± 1.8 2.5 ± 1.7
observed in pain scores during physical activity (Table 4). T16 2.1 ± 1.6 2.1 ± 1.4
Mean KOOS scores, divided in the five subscales (Pain,
Data are presented as mean ± SD
Symptoms, ADL, Sport/Rec, QOL) are reported in Table 5.
The improvement of KOOS scores (T16 vs. T0) is statis-
Table 4 VAS scores (pain during physical activity) for Group A and
tically significant for both groups. Sport/Rec subscale was
Group B
not subject to statistical analysis due to the small number of
patients (N = 14 for Group A and N = 10 for Group B) Pain during physical Group A (PN) (cm) Group B (HA) (cm)
activity
who performed sport activities during normal life at all
(average population age was over 60 years); nevertheless, T0 6.9 ± 1.9 7.0 ± 2.2
the data show a trend towards improvement in Group A T1 5.7 ± 1.9 6.2 ± 2.0
(from 24.6 ± 20.0 to 38.9 ± 26.7) over Group B (from T2 4.9 ± 1.9 5.4 ± 2.0
30.0 ± 12.5 to 33.6 ± 25.6) when comparing baseline T3 4.7 ± 2.2 4.7 ± 2.0
with T16 values. T4 3.8 ± 2.4 4.1 ± 2.1
Plotting the differences between T16 and T0 of both T8 3.2 ± 1.8 3.6 ± 2.1
groups (Fig. 2), it becomes obvious that the improvement T16 2.4 ± 1.8 3.1 ± 2.2
of KOOS scores is higher in PN group than in HA group in
Data are presented as mean ± SD
all subscales; this is particularly evident for Symptoms and
Sport/Rec subscales.
Crackling and LMA results are presented in Figs. 3 and 4.
NSAIDs consumption (Fig. 5) was recorded throughout
the study by recording on the CRF during each visit the
Table 1 Demographic data of study population number of days in which the patients have taken anti-
Parameter Group A (PN) Group B (HA) inflammatory drugs in the previous week.
Results show a minor use of NSAIDs in PN group when
Number of patients 29 30
compared to HA group from T1 to T16, mainly evident at
Gender (M/F) 10 M/19 F 10 M/20 F
T4 and T8.
Age (years) 60 (37–79) 67 (46–82)
It is remarkable to note that in Group A, only 1 patient
Weight (kg) 69.5 (60–100) 78 (54–125)
out of 29 (3%) used NSAIDs at the end of the study, while
Height (cm) 160 (150–185) 165 (150–187)
in Group B, 8 patients out of 30 (27%) continued to
BMI (kg/m2) 26.7 (23.9–36.1) 28.8 (20.9–35.7)
use anti-inflammatory drugs, with one patient assuming
Data are presented as median and range values NSAIDs 4 days in the week before T16 visit.

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Knee Surg Sports Traumatol Arthrosc (2010) 18:901–907 905

Table 5 KOOS subscales scores

KOOS subscales Group A (PN) Group B (HA)
T0 T16 T0 T16

Pain 42.0 ± 21.6 63.3 ± 19.7 43.5 ± 18.6 63.0 ± 23.6

Symptoms 53.8 ± 17.9 66.2 ± 18.2 58.4 ± 13.7 63.6 ± 15.9
Activity of Daily Living (ADL) 50.3 ± 18.5 65.2 ± 17.4 55.1 ± 12.4 67.1 ± 20.4
Sport/Recreation (Sport/Rec) 24.6 ± 20.0 38.9 ± 26.7 30.0 ± 12.5 33.6 ± 25.6
Quality of Life (QOL) 34.0 ± 17.8 53.1 ± 18.8 35.0 ± 15.8 49.7 ± 21.5
Data are presented as mean ± SD

Fig. 2 The difference between

T16 and T0 KOOS scores is
reported for Group A and Group
B. Data are presented as mean

Fig. 3 Crackling evaluation in

Group A and Group B
(notched box plot)

Fig. 4 LMA evaluation in

Group A and Group B
(notched box plot)

No serious adverse events were reported during the only one patient of Group A developed mild joint pain after
study; the intra-articular administration of the two products the last PN injection (T4), which subsided within 1 h.
did not cause any systemic undesired event in any patient; There was one drop-out in the PN group due to personal

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Fig. 5 NSAIDs consumption expressed as number of days of the
week before the visit in which anti-inflammatory drugs were used
reasons. No infections developed as a consequence of the
intra-articular injections.
Discussion
OA is a widespread chronic disease, which interests a large
part of the population and whose incidence is likely to
grow steadily in the future due to the increase in life
expectancy and ageing [23]. By the year 2020, osteoar-
thritis will become the fourth leading cause of disability
worldwide; and today, it accounts for nearly the 3% of total
years of living with disability globally [12]. Although
many people consult their general practitioners because of
osteoarthritis, many others do not, considering osteoar-
thritis like an inevitable consequence of ageing; a common
opinion is that ‘‘nothing can be done’’ about pain and other
OA symptoms. This general perception is also due to the
poor efficacy of available therapies; regarding surgical
options, the innovative techniques of autologous chondro-
cytes implantation (ACI) have so far failed to demonstrate
superiority when compared to traditional mosaicoplasty or
microfractures [8]. In addition, these procedures are quite
expensive and can be performed only on a small number of
patients.
Several pharmacological approaches are used for the
treatment of OA, like intra-articular hyaluronan or corti-
costeroid, NSAIDs, oral supplements (e.g., glucosamine or
chondroitin [14]) and topical treatments (e.g., capsaicin
[2]). For some of these therapies, a considerable amount of
clinical data is available, often claiming a substantial
efficacy in dealing with osteoarthritis symptomatology.
Nevertheless, successive meta-analyses have shown that
some of these treatments show a small benefit over placebo.
NSAIDs (and in particular paracetamol), in turn, possess a
good efficacy profile but are not indicated for chronic
treatments due to their serious potential side effects.
These considerations have urged the scientific commu-
nity to research new effective, safe and long-lasting ther-
apeutics to alleviate OA symptomatology.
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Knee Surg Sports Traumatol Arthrosc (2010) 18:901–907
In this randomized, double-blind clinical trial, we have
verified that intra-articular polynucleotides are able to
decrease substantially the pain associated with osteoar-
thritis and to enhance the global quality of life of patients
(as demonstrated by KOOS questionnaire).
Polynucleotides are physiological molecules endowed
with remarkable viscoelastic and trophic properties that
represent an innovation in the field of intra-articular
viscosupplementation.
Overall efficacy of polynucleotides, both in terms of
pain reduction and KOOS results, was comparable to
hyaluronic acid.
The mean global VAS pain decreased significantly from
T0 to T16 in both groups. In the same way, KOOS scores
showed significant improvements between baseline and
T16 values in both groups.
Other secondary parameters (i.e., crackling, LMA and
NSAIDs consumption) seem to show, at some time-
points, a greater efficacy of PN over HA, although a
statistical comparison between the two groups was not
performed.
The principal limitation of this study is represented by
the short follow-up period (3 months): another clinical
study with an extended follow-up might confirm these
preliminary results and should also investigate whether the
efficacy of polynucleotides can be maintained changing the
posologic scheme (e.g., three injections only).
Conclusions
In conclusion, we were the first group to investigate the use
of intra-articular polynucleotides and to evaluate their
efficacy in the treatment of symptomatic osteoarthritis.
The results obtained suggest that polynucleotides can be
considered as an alternative to hyaluronic acid for the
treatment of symptomatic osteoarthritis; we reckon that this
product may prove useful to extend the range of treatments
available in this therapeutical field.
Acknowledgments The study took place at the IRCCS Foundation,
Orthopaedic and Traumatology Department, S. Matteo Hospital
Institute, University of Pavia, Italy. This work was supported by
Mastelli s.r.l., Sanremo Italy. Special thanks to Dr. Giulia Cattarini
and Dr. Andrea Armando for their assistance with the study and
manuscript. Authors would also like to thank Prof. Martino Recchia
for the statistical analysis.
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