Ácido hialurônico perspectivas em odontologia

Prévia do material em texto

International Journal of 
Immunopathology and Pharmacology
2016, Vol. 29(4) 572 –582
© The Author(s) 2016
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DOI: 10.1177/0394632016652906
iji.sagepub.com
Introduction
Hyaluronic acid (HA) is a naturally occurring non-
sulfated glycosaminoglycan with a high molecular 
weight of 4000-20,000,000 Da. The structure of 
HA consists of polyanionic disaccharide units of 
glucuronic acid and N-acetyl glucosamine con-
nected by alternating bl-3 and bl-4 bonds. It is a 
linear polysaccharide of the extracellular matrix of 
connective tissue, synovial fluid, embryonic mes-
enchyme, vitreous humor, skin, and many other 
organs and tissues of the body.1
HA is a key element in the soft periodontal tis-
sues, gingiva, and periodontal ligament, and in the 
hard tissue, such as alveolar bone and cementum.2 
It has many structural and physiological functions 
within these tissues.
It can play a regulatory role in inflammatory 
response: the high-molecular-weight HA synthe-
sized by hyaluronan synthase enzymes in the peri-
odontal tissues, gingiva, periodontal ligament, and 
in alveolar bone3 undergoes extensive degradation 
Hyaluronic acid: Perspectives in dentistry. 
A systematic review
Manuele Casale,1 Antonio Moffa,1 Paola Vella,1 Lorenzo Sabatino,1 
Francesco Capuano,1 Beatrice Salvinelli,2 Michele Antonio Lopez,3 
Francesco Carinci4 and Fabrizio Salvinelli1
Abstract
To date, topical therapies guarantee a better delivery of high concentrations of pharmacologic agents to the soft 
periodontal tissue, gingiva, and periodontal ligament as well as to the hard tissue such as alveolar bone and cementum. 
Topical hyaluronic acid (HA) has recently been recognized as an adjuvant treatment for chronic inflammatory disease 
in addition to its use to improve healing after dental procedures. The aim of our work was to systematically review 
the published literature about potential effects of HA as an adjuvant treatment for chronic inflammatory disease, in 
addition to its use to improve healing after common dental procedures. Relevant published studies were found in 
PubMed, Google Scholar, and Ovid using a combined keyword search or medical subject headings. At the end of our 
study selection process, 25 relevant publications were included, three of them regarding gingivitis, 13 of them relating 
to chronic periodontitis, seven of them relating to dental surgery, including implant and sinus lift procedures, and the 
remaining three articles describing oral ulcers. Not only does topical administration of HA play a pivotal key role in the 
postoperative care of patients undergoing dental procedures, but positive results were also generally observed in all 
patients with chronic inflammatory gingival and periodontal disease and in patients with oral ulcers.
Keywords
burning mouth, gingivitis, healing, hyaluronan, hyaluronic acid, implant, mucositis, oral mucous regeneration, oral 
wound, periodontitis, sodium hyaluronate, stomatitis, teeth
Date received: 10 February 2016; accepted: 3 May 2016
1 Unit of Otolaryngology, University Campus Bio-Medico, Rome, Italy
2 European University of Madrid, Madrid, Spain
3 University of San Marino State, Italy
4 Department of Morphology, Surgery and Experimental Medicine, 
University of Ferrara, Ferrara, Italy
Corresponding author:
Manuele Casale, Unit of Otolaryngology, Campus Bio-Medico 
University, School of Medicine, Via Alvaro del Portillo 21, 00128 Rome, 
Italy. 
Email: m.casale@unicampus.it
652906 IJI0010.1177/0394632016652906International Journal of Immunopathology and PharmacologyCasale et al.
research-article2016
Editorial
mailto:m.casale@unicampus.it
Casale et al. 573
to lower molecular weight molecules in chronically 
inflamed tissue, such as gingival tissue inflamma-
tion4 or in the postoperative period after implant or 
sinus lift surgery.
High-molecular-weight HA is fragmented 
under the influence of reactive oxygen species 
(ROS), including the superoxide radical and 
hydroxyl radical species observed during perio-
dontal diseases;5 these radicals are generated 
primarily by infiltrating polymorphonuclear leu-
kocytes and other inflammatory cells during 
bacterial phagocytosis.
Low-molecular-weight fragments play a role in 
signaling tissue damage and mobilizing immune 
cells, while the high-molecular-weight HA sup-
presses the immune response preventing excessive 
exacerbations of inflammation.6
Low-molecular-weight HA appears to be par-
ticularly prominent in the gingival tissues of 
patients during the initial stages of periodontitis,7 
possibly as a result of the action of bacterial 
enzymes (hyaluronidases).8
It supports the structural and homeostatic integ-
rity of tissues9 regulating osmotic pressure and tis-
sue lubrication.
HA is one of the most hygroscopic molecules 
known in nature. When HA is incorporated into an 
aqueous solution, hydrogen bonding occurs 
between adjacent carboxyl and N-acetyl groups; 
this feature allows HA to maintain conformational 
stiffness and to retain water.
HA also presents important viscoelastic proper-
ties reducing the penetration of viruses and bacte-
ria into the tissue.10
The molecule is also a key component in the 
series of stages associated with the wound-healing 
process in both mineralized and non-mineralized 
tissues (inflammation, granulation tissue formation, 
epithelium formation, and tissue remodeling).11,12
As a consequence of the many functions attrib-
uted to HA, advances have been made in the devel-
opment and application of HA-based biomaterials in 
the treatment of various inflammatory conditions.9
Therefore, based on the multifunctional roles 
that HA has in wound healing generally, and that 
gingival and bone healing follow similar biological 
principles, it is conceivable that HA has compara-
ble roles in the healing of the mineralized and non-
mineralized tissues of the periodontium.11,13
To date, the use of HA is widely spread in sev-
eral other branches of medicine and neither 
contraindications nor interactions with drugs have 
been reported.14–17
We conducted in June 201518 a systematic 
review on the potential benefits of topical HA in 
the treatment of both acute and chronic inflamma-
tory diseases of the upper aerodigestive tract 
(UADT). In recent years, formulations of HA have 
been developed for topical administration as a 
coadjutant treatment in acute and chronic tooth and 
gingival disease, such as in the healing of tissue 
after oral surgery, based on the large quantity of 
evidence based on data available on the role of HA 
in the field of dentistry in animal models.19
In the literature, there are some reviews on the 
role of HA in the field of dentistry. However, these 
studies are not complete and cover only some clini-
cal applications such as HA application in perio-
dontal disease.20
The aim of the study is: to systematically review 
the published literature regarding all the therapeu-
tic effects of HA on acute and chronic inflamma-
tory disease in oral cavity; to clarify and classify 
the main application areas of HA in dentistry, the 
pathophysiological basis, and the schedule of post-
operative HA application; and to evaluate the most 
effective parameters of HA use in the field of 
odontostomathology.
Methods
Research and study selection
Relevant published studies were searched for in 
PubMed, Google Scholar, and Ovid using either 
the following keywords or, in case of the PubMed 
database, medical subject headings: (“hyaluronic 
acid” and “periodontitis”), (“hyaluronic acid” and 
“gingivitis”), (“hyaluronic acid” and “mucositis”), 
(“hyaluronic acid” and “implant”), (“hyaluronic 
acid” and “ teeth”), (“hyaluronic acid” and “ gin-
giva”), (“hyaluronic acid “ and “oral mucous 
regeneration”), (“hyaluronic acid” and “oral 
wound”), (“hyaluronic acid” and “stomatitis”), 
(“hyaluronic acid” and “healing”), (“hyaluronic 
acid” and “oral ulcers”), and (“hyaluronic acid” 
and “oral scars”) with nolimit selected for the year 
of publication.
Literature search was performed according to 
PRISMA guidelines with the following main eli-
gibility criteria: only English; human controlled 
trials; and effect size of HA evaluated histologi-
cally or clinically in patients with dental disease.
574 International Journal of Immunopathology and Pharmacology 29(4)
Literature reviews, technical notes, letters to 
editors, and instructional course were excluded.
Two authors (CM and MA) independently 
assessed the full-text version of each publication, 
making their selection on the basis of content and 
excluding papers that did not include the specifi-
cally required content.
The reference lists of articles that meet the first 
criteria were fully reviewed to identify useful articles 
that were not included in the initial electronic search.
During the research phase, in each of the jour-
nals, articles strictly coherent with the topic were 
first identified, while studies on animal models 
were excluded after the primary selection. Similarly, 
in vitro studies were excluded at this stage.
Studies that were based on the use of HA in oral 
mucositis resulting from chemotherapy or irradia-
tion, from allogeneic hematopoietic stem cells 
transplantation, and in the treatment of palliative 
care patients were subsequently removed from the 
selected list.
At the end of our study selection process, 25 rel-
evant publications were included, as showed in 
Figure 1.
Results
Features of each single study are reported in Table 1.
HA in gingivitis
Nowadays HA is a useful adjuvant treatment in 
gingivitis therapy.
Jentsch et al.21 showed that topical treatment 
with 0.2% HA twice daily for a 3-week period had 
a beneficial effect in the patients affected by gingi-
vitis, improving the plaque indices, papillary 
bleeding index (PBI), and gingival crevicular fluid 
(GCF) variables.
Pistorius et al.22 revealed that the topical appli-
cation of a spray containing HA (5 times daily for 
1 week) led to a reduction in the sulcus bleeding 
index (SBI), PBI values, and the GCF.
Similarly, Sahayata et al.23 observed that local 
application of 0.2% HA gel on inflamed gingiva, 
twice daily for a 4-week period, in addition to scal-
ing and routine oral hygiene, provided a significant 
improvement in the gingival index (GI) and PBI 
when compared with both the placebo control 
group (scaling plus placebo gel) and negative con-
trol group (scaling only).
HA in chronic periodontitis
The local use of HA gel, twice a day for 1 month, 
in patients with chronic periodontitis, reduced the 
proliferation index of the gingival epithelium 
(expression of Ki-67 antigen), the inflammatory 
process and improved periodontal lesions.24
However, several studies suggested that a com-
bined treatment composed of full-mouth scaling 
and root planing (SRP) and the topical administra-
tion of HA had a beneficial effect on periodontal 
health in chronic periodontitis.
Subgingival administration of 1 mL 0.2 mL 
0.8% HA gel once a week for 6 weeks ameliorated 
the sulcus fluid flow rate (SFFR);25 Johannsen 
et al.26 noted two subgingival administrations of 
0.2 mL 0.8% HA gel (at baseline and after 1 week) 
significantly reduced bleeding in the HA group 
when compared with the control group.
Similarly, Polepalle et al.27, showed that subgin-
gival placement of 0.2 mL 0.8% HA gel premolars 
and canine teeth, following SRP, for 1 week, led to 
a significant reduction in bleeding on probing 
(BOP), plaque index, bleeding on probing pocket 
depth (PPD), clinical attachment level (CAL), and 
colony-forming units (CFUs) compared with the 
control site treated with SRP only.
Gontiya et al.28 using the same treatment as 
Polepalle, Xu, and Johannsen, showed that the sub-
gingival application of 0.2% hyaluronic acid gel 
(GENGIGEL®) with SRP in chronic periodontitis 
patients improved the GI and bleeding index (BI) 
when compared with control sites, as confirmed by 
Figure 1. Process of inclusion of the studies.
Casale et al. 575
T
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om
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t 
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t 
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t 
4 
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ho
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ta
tis
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ly
 
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gn
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ra
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om
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 p
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s 
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ar
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ite
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pr
em
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rs
t 
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d 
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ua
dr
an
ts
T
he
 p
at
ie
nt
s 
re
ce
iv
ed
 S
R
P 
at
 b
as
el
in
e,
 a
nd
 
2,
 4
, a
nd
 6
 w
ee
ks
. T
he
 p
at
ie
nt
s 
ap
pl
ie
d 
in
 
th
e 
te
st
 s
ite
s 
1 
m
L 
0.
2%
 H
A
 a
t 
ba
se
lin
e,
 a
nd
 
at
 w
ee
ks
 1
, 2
, 3
, 4
, 5
, a
nd
 6
Su
lc
us
 fl
ui
d 
flo
w
 r
at
e 
(S
FF
R
) 
an
d 
su
lc
us
 
bl
ee
di
ng
 in
de
x 
w
er
e 
ev
al
ua
te
d 
at
 b
as
el
in
e 
an
d 
af
te
r 
1,
 2
, 3
, 4
, 5
, 6
, a
nd
 1
2 
w
ee
ks
; 
pr
ob
in
g 
de
pt
h 
an
d 
cl
in
ic
al
 a
tt
ac
hm
en
t 
le
ve
l 
at
 b
as
el
in
e 
an
d 
6 
an
d 
12
 w
ee
ks
. D
en
tis
ts
 a
ls
o 
to
ok
 s
ub
gi
ng
iv
al
 p
la
qu
e 
sa
m
pl
es
, i
n 
or
de
r 
to
 
de
te
rm
in
e 
th
e 
pr
es
en
ce
 o
f A
ct
in
ob
ac
ill
us
, 
ac
tin
om
yc
et
em
co
m
ita
ns
, P
or
ph
yr
om
on
as
 
gi
ng
iv
al
is
, P
re
vo
te
lla
 in
te
rm
ed
ia
, T
an
ne
re
lla
 
fo
rs
yt
he
ns
is
, a
nd
 T
re
po
ne
m
a 
de
nt
ic
ol
a,
 a
t 
ba
se
lin
e 
an
d 
6 
an
d 
12
 w
ee
ks
T
hi
s 
st
ud
y 
sh
ow
ed
 a
n 
im
pr
ov
em
en
t 
of
 a
ll 
cl
in
ic
al
 
va
ri
ab
le
s 
in
 b
ot
h 
gr
ou
ps
. T
he
re
 a
re
 n
ot
 c
lin
ic
al
 
an
d 
m
ic
ro
bi
ol
og
ic
al
 d
iff
er
en
ce
s 
be
tw
ee
n 
te
st
 a
nd
 
co
nt
ro
l s
ite
s
Jo
ha
nn
se
n 
et
 a
l.
11
 p
at
ie
nt
s;
 
ag
e 
ra
ng
e,
 
42
–6
3 
ye
ar
s
C
on
tr
al
at
er
al
 p
ai
rs
 o
f p
re
m
ol
ar
 a
nd
 
ca
ni
ne
 t
ee
th
 in
 t
he
 m
ax
ill
a 
or
 t
he
 
m
an
di
bl
e 
w
er
e 
ra
nd
om
iz
ed
 t
o 
re
ce
iv
e 
th
e 
te
st
 t
re
at
m
en
t 
(a
dj
un
ct
iv
e 
H
A
 g
el
) 
or
 t
o 
se
rv
e 
as
 S
R
P 
co
nt
ro
ls
T
he
 p
at
ie
nt
s 
re
ce
iv
ed
 S
R
P 
at
 b
as
el
in
e,
 a
nd
 
2,
 4
, a
nd
 6
 w
ee
ks
. T
he
 p
at
ie
nt
s 
ap
pl
ie
d 
in
 
th
e 
te
st
 s
ite
s 
1 
m
L 
0.
2%
 H
A
 a
t 
ba
se
lin
e,
 a
nd
 
at
 w
ee
ks
 1
, 2
, 3
, 4
, 5
, a
nd
 6
Su
lc
us
 fl
ui
d 
flo
w
 r
at
e 
(S
FF
R
) a
nd
 s
ul
cu
s 
bl
ee
di
ng
 
in
de
x 
w
er
e 
ev
al
ua
te
d 
at
 b
as
el
in
e 
an
d 
af
te
r 
1,
 
2,
 3
, 4
, 5
, 6
, a
nd
 1
2 
w
ee
ks
; p
ro
bi
ng
 d
ep
th
 a
nd
 
cl
in
ic
al
 a
tt
ac
hm
en
t l
ev
el
 a
t b
as
el
in
e 
an
d 
6 
an
d 
12
 
w
ee
ks
. D
en
tis
ts
 a
lso
 to
ok
 a
 s
ub
gi
ng
iv
al
 p
la
qu
e 
sa
m
pl
es
, i
n 
or
de
r 
to
 d
et
er
m
in
e 
th
e 
pr
es
en
ce
 
of
 A
ct
in
ob
ac
ill
us
, a
ct
in
om
yc
et
em
co
m
ita
ns
, 
Po
rp
hy
ro
m
on
as
 g
in
gi
va
lis
, P
re
vo
te
lla
 in
te
rm
ed
ia
, 
T
an
ne
re
lla
 fo
rs
yt
he
ns
is,
 a
nd
 T
re
po
ne
m
a 
de
nt
ic
ol
a,
 a
t b
as
el
in
e 
an
d 
6 
an
d 
12
 w
ee
ks
T
hi
s 
st
ud
y 
sh
ow
ed
 a
n 
im
pr
ov
em
en
t 
of
 a
ll 
cl
in
ic
al
 
va
ri
ab
le
s 
in
 b
ot
h 
gr
ou
ps
. T
he
re
 a
re
 n
ot
 c
lin
ic
al
 
an
d 
m
ic
ro
bi
ol
og
ic
al
 d
iff
er
en
ce
s 
be
tw
ee
n 
te
st
 a
nd
 
co
nt
ro
l s
ite
s
576 International Journal of Immunopathology and Pharmacology 29(4)
A
ut
ho
rs
M
ea
n 
ag
e
H
A
 g
ro
up
C
on
tr
ol
 g
ro
up
T
re
at
m
en
t
Pa
ra
m
et
er
s 
ev
al
ua
te
d
C
lin
ic
al
 e
vi
de
nc
es
H
A
 in
 g
in
gi
vi
tis
Po
le
pa
lle
 
et
 a
l.
30
–6
0 
ye
ar
s
In
 t
hi
s 
sp
lit
 m
ou
th
 s
tu
dy
, 7
2 
te
et
h 
(3
6 
te
st
 s
ite
s 
an
d 
36
 c
on
tr
ol
 s
ite
s)
 in
 
18
 p
at
ie
nt
s 
w
ith
 m
od
er
at
e 
to
 s
ev
er
e 
ch
ro
ni
c 
pe
ri
od
on
tit
is
T
es
t 
si
te
s 
re
ce
iv
ed
 s
ub
gi
ng
iv
al
 
ad
m
in
is
tr
at
io
n 
of
 0
.2
 m
L 
of
 0
.8
%
 H
A
 
fo
llo
w
in
g 
SR
P 
an
d 
1 
w
ee
k 
la
te
r
Bl
ee
di
ng
 o
n 
pr
ob
in
g 
(B
O
P)
, A
PI
, p
ro
bi
ng
 
po
ck
et
 d
ep
th
 (
PP
D
), 
an
d 
cl
in
ic
al
 a
tt
ac
hm
en
t 
le
ve
l (
C
A
L)
 w
er
e 
as
se
ss
ed
 a
t 
ba
se
lin
e,
 1
, 4
, 
an
d 
12
 w
ee
ks
. C
ol
on
y-
fo
rm
in
g 
un
its
 (
C
FU
) 
pe
r 
m
L 
w
er
e 
as
se
ss
ed
 a
t 
ba
se
lin
e,
 a
ft
er
 S
R
P,
 
an
d 
af
te
r 
2 
w
ee
ks
T
he
re
 w
as
 a
 s
ig
ni
fic
an
t 
re
du
ct
io
n 
in
 B
O
P,
 A
PI
, 
PP
D
, a
nd
 C
A
L 
in
 t
he
 t
es
t 
si
te
s 
th
an
 c
on
tr
ol
 
gr
ou
p.
 In
 t
he
 t
es
t 
si
te
s 
th
er
e 
w
as
 a
ls
o 
a 
si
gn
ifi
ca
nt
 
re
du
ct
io
n 
of
 C
FU
s
G
on
tiy
a 
et
 a
l.
A
ge
 r
an
ge
, 
25
–5
5 
ye
ar
s
26
 p
at
ie
nt
s 
w
ith
 c
hr
on
ic
 p
er
io
do
nt
iti
s 
pa
tie
nt
s 
(1
20
 s
ite
s 
se
le
ct
ed
). 
T
he
 s
ite
s 
w
er
e 
di
vi
de
d 
in
 t
w
o 
gr
ou
ps
: c
on
tr
ol
 a
nd
 
ex
pe
ri
m
en
ta
l s
ite
s 
(H
A
 g
el
)
T
he
 t
es
t 
si
te
s 
re
ce
iv
ed
 1
 m
L 
of
 0
.2
%
 H
A
 
ge
l a
t 
ba
se
lin
e 
an
d 
at
 t
he
 e
nd
 o
f w
ee
ks
 1
, 2
, 
an
d 
3.
 M
ar
gi
na
l g
in
gi
va
l b
io
ps
y 
w
as
 o
bt
ai
ne
d 
fr
om
 e
xp
er
im
en
ta
l a
nd
 c
on
tr
ol
 s
ite
s,
 
pr
ov
id
in
g 
tis
su
e 
fo
r 
hi
st
ol
og
ic
 e
xa
m
in
at
io
ns
C
lin
ic
al
 p
ar
am
et
er
s 
G
I, 
PB
I, 
PP
D
, a
nd
 R
el
at
iv
e 
A
tt
ac
hm
en
t 
Le
ve
l (
R
A
L)
 e
va
lu
at
ed
 a
t 
ba
se
lin
e 
(d
ay
 0
), 
an
d 
w
ee
ks
 4
, 6
, a
nd
 1
2
T
he
 t
es
t 
si
te
s 
sh
ow
ed
 s
ta
tis
tic
al
ly
 s
ig
ni
fic
an
t 
im
pr
ov
em
en
t 
in
 G
I a
nd
 P
BI
 a
t 
6 
an
d 
2 
w
ee
ks
 t
ha
n 
co
nt
ro
l s
ite
s
R
aj
an
 e
t 
al
.
H
A
 g
ro
up
 (
33
 s
ite
s)
 in
 3
3 
pa
tie
nt
s
T
he
 p
at
ie
nt
s 
re
ce
iv
ed
 S
R
P 
in
 t
he
 c
on
tr
ol
 
an
d 
te
st
s 
si
te
s 
at
 b
as
el
in
e.
 In
 t
he
 t
es
t 
si
te
s 
th
e 
pa
tie
nt
s 
ap
pl
ie
d 
0.
2%
 H
A
 g
el
 
(G
en
gi
ge
l®
) 
af
te
r 
SR
P 
an
d 
1 
w
ee
k 
po
st
 
tr
ea
tm
en
t
T
he
 c
lin
ic
al
 p
ar
am
et
er
s 
ev
al
ua
te
d:
 G
I, 
A
PI
, 
BO
P,
 P
PD
, C
A
L 
at
 t
hr
ee
 a
pp
oi
nt
m
en
ts
: 
be
fo
re
 S
R
P,
 4
 w
ee
ks
 a
nd
 1
2 
w
ee
ks
 a
ft
er
 S
R
P
In
 t
he
 H
A
 g
ro
up
, t
his 
co
m
bi
ne
d 
tr
ea
tm
en
t 
sh
ow
ed
 
a 
si
gn
ifi
ca
nt
 im
pr
ov
em
en
t 
in
 a
ll 
cl
in
ic
al
 p
ar
am
et
er
s:
 
BO
P,
 P
PD
, a
nd
 C
A
L,
 a
t 
12
 w
ee
ks
 p
os
t 
th
er
ap
y 
in
 c
om
pa
ri
so
n 
to
 t
he
 c
on
tr
ol
 g
ro
up
 t
re
at
ed
 w
ith
 
SR
P 
on
ly
Pi
llo
ni
 e
t 
al
.
M
ea
n 
ag
e 
41
.9
 
±
 1
5.
1 
ye
ar
s
19
 a
du
lt 
pa
tie
nt
s 
w
ith
 m
ild
 c
hr
on
ic
 
pe
ri
od
on
tit
is
 a
nd
 s
ha
llo
w
 p
oc
ke
ts
 in
 t
w
o 
di
ffe
re
nt
 q
ua
dr
an
ts
 (
on
e 
qu
ad
ra
nt
 w
ith
 
H
A
 g
el
 a
nd
 t
he
 o
th
er
 q
ua
dr
an
t 
w
ith
ou
t)
A
ft
er
 S
R
P,
 d
ai
ly
 a
nd
 fo
r 
3 
w
ee
ks
, H
A
 g
el
 
w
as
 a
pp
lie
d 
in
 t
he
 t
es
t 
si
te
s 
(o
ne
 q
ua
dr
an
t)
 
w
ith
 a
 t
oo
th
br
us
h
T
he
se
 c
lin
ic
al
 p
ar
am
et
er
s 
w
er
e 
ev
al
ua
te
d 
be
fo
re
 S
R
P 
an
d 
re
pe
at
ed
 a
t 
14
 a
nd
 2
1 
da
ys
: 
A
PI
, B
O
P,
 P
PD
, G
I, 
PA
L 
(p
ro
bi
ng
 a
tt
ac
hm
en
t 
le
ve
l)
T
he
 t
re
at
m
en
t 
w
ith
 H
A
 g
el
 s
ho
w
ed
 a
 g
re
at
er
 
ef
fe
ct
. B
O
P 
ha
d 
a 
de
cr
ea
se
 o
f 9
2.
7%
 a
nd
 G
I 
of
 9
6.
5%
, w
he
re
as
 c
on
tr
ol
s 
75
.8
%
 a
nd
 7
9.
0%
, 
re
sp
ec
tiv
el
y.
 T
he
 d
iff
er
en
ce
 o
f P
PD
 in
 b
ot
h 
ar
ea
s 
w
as
 s
ta
tis
tic
al
ly
 s
ig
ni
fic
an
t 
in
 fa
vo
r 
of
 t
he
 H
A
 g
el
 
tr
ea
te
d 
zo
ne
Ei
ck
 e
t 
al
.
42
 p
at
ie
nt
s 
(1
8 
m
en
, 2
4 
w
om
en
; a
ge
 
ra
ng
e,
 4
1–
72
 
ye
ar
s)
. O
nl
y 
34
 c
om
pl
et
ed
 
th
e 
st
ud
y
17
 p
at
ie
nt
s
17
 p
at
ie
nt
s
A
ft
er
 t
he
 S
R
P,
 a
 g
el
 c
on
ta
in
in
g 
0.
8%
 
H
A
 (
18
00
 k
D
a)
 w
as
 in
tr
od
uc
ed
 in
to
 a
ll 
pe
ri
od
on
ta
l p
oc
ke
ts
 in
 t
he
 H
A
 g
ro
up
. 
In
 a
dd
iti
on
, t
he
 p
at
ie
nt
s 
ap
pl
ie
d 
a 
ge
l 
co
nt
ai
ni
ng
 0
.2
%
 H
A
 (
10
00
 k
D
a)
 o
nt
o 
th
e 
gi
ng
iv
al
 m
ar
gi
n 
tw
ic
e 
da
ily
 d
ur
in
g 
th
e 
fo
llo
w
in
g 
14
 d
ay
s.
 T
he
 c
on
tr
ol
 g
ro
up
 w
as
 
tr
ea
te
d 
w
ith
 S
R
P 
on
ly
; n
o 
pl
ac
eb
o 
w
as
 u
se
d
Pr
ob
in
g 
de
pt
h 
(P
D
) 
an
d 
C
A
L 
w
er
e 
re
co
rd
ed
 
at
 b
as
el
in
e 
an
d 
af
te
r 
3 
an
d 
6 
m
on
th
s,
 a
nd
 
su
bg
in
gi
va
l p
la
qu
e 
an
d 
su
lc
us
 fl
ui
d 
sa
m
pl
es
 
w
er
e 
ta
ke
n 
fo
r 
m
ic
ro
bi
ol
og
ic
 a
nd
 b
io
ch
em
ic
al
 
an
al
ys
is
PD
 a
nd
 C
A
L 
w
er
e 
re
co
rd
ed
 a
t 
ba
se
lin
e 
an
d 
af
te
r 
3 
an
d 
6 
m
on
th
s,
 a
nd
 s
ub
gi
ng
iv
al
 p
la
qu
e 
an
d 
su
lc
us
 
flu
id
 s
am
pl
es
 w
er
e 
ta
ke
n 
fo
r 
m
ic
ro
bi
ol
og
ic
 a
nd
 
bi
oc
he
m
ic
al
 a
na
ly
si
s
C
ha
uh
an
 e
t 
al
.
60
 p
at
ie
nt
s 
(3
0–
65
 y
ea
rs
)
G
ro
up
 1
 (
20
 p
at
ie
nt
s)
 S
R
P,
 G
ro
up
 2
 
(2
0 
pa
tie
nt
s)
 S
R
P 
+
 H
A
, G
ro
up
 3
 (
20
 
pa
tie
nt
s)
 S
R
P 
+
 c
hl
or
he
xi
di
ne
 (
C
H
X
)
In
 G
ro
up
 1
, t
he
 p
at
ie
nt
s 
re
ce
iv
ed
 o
nl
y 
SR
P 
tr
ea
tm
en
t; 
in
 G
ro
up
s 
2 
an
d 
3,
 t
he
 
pa
tie
nt
s,
 a
t 
le
as
t 
ei
gh
t 
te
et
h,
 a
ls
o 
re
ce
iv
ed
 
to
pi
ca
l a
pp
lic
at
io
n 
of
 H
A
 g
el
 a
nd
 C
H
X
 g
el
, 
re
sp
ec
tiv
el
y
C
lin
ic
al
 p
ar
am
et
er
s:
 G
I, 
PP
D
, a
nd
 C
A
L 
ev
al
ua
te
d 
at
 b
as
el
in
e 
an
d 
3 
m
on
th
s,
 A
PI
 
ev
al
ua
te
d 
at
 b
as
el
in
e,
 1
 m
on
th
, a
nd
 3
 
m
on
th
s.
 S
ys
te
m
ic
/h
em
at
ol
og
ic
al
 p
ar
am
et
er
s,
 
bl
oo
d 
sa
m
pl
es
 fo
r 
la
bo
ra
to
ry
 t
es
ts
 fo
r 
to
ta
l 
le
uc
oc
yt
e 
co
un
t 
(T
LC
), 
di
ffe
re
nt
ia
l l
eu
co
cy
te
 
co
un
t 
(D
LC
), 
an
d 
C
-r
ea
ct
iv
e 
pr
ot
ei
n 
(C
R
P)
 
ev
al
ua
te
d 
at
 b
as
el
in
e,
 2
4 
h,
 a
nd
 a
t 
1 
m
on
th
 
an
d 
3 
m
on
th
s
A
t 
3 
m
on
th
s,
 c
ha
ng
e 
in
 P
PD
 a
nd
 C
A
L 
w
as
 m
or
e 
in
 G
ro
up
 2
 t
ha
n 
G
ro
up
 3
, b
ut
 t
he
 d
iff
er
en
ce
 w
as
 
no
n-
si
gn
ifi
ca
nt
En
gs
tr
öm
 
et
 a
l.
15
 p
at
ie
nt
s 
N
o 
su
rg
ic
al
 g
ro
up
: 
ni
ne
 p
at
ie
nt
s 
(m
ea
n 
ag
e,
 4
8 
ye
ar
s)
. S
ur
gi
ca
l 
gr
ou
p:
 s
ix
 
pa
tie
nt
s 
(m
ea
n 
ag
e,
 4
9 
ye
ar
s)
In
 e
ac
h 
of
 1
5 
in
di
vi
du
al
s,
 t
w
o 
te
et
h 
w
er
e 
ch
os
en
. I
n 
th
e 
su
rg
ic
al
 g
ro
up
 (
si
x 
pa
tie
nt
s)
, a
 b
io
ab
so
rb
ab
le
 m
em
br
an
e 
w
as
 u
se
d 
fo
r 
bo
th
 t
es
t 
an
d 
co
nt
ro
l 
si
te
s,
 a
nd
 H
A
 w
as
 p
la
ce
d 
in
 t
he
 
in
tr
ab
on
y 
po
ck
et
 o
f t
he
 t
es
t 
si
te
. I
n 
th
e 
no
n-
su
rg
ic
al
 g
ro
up
 (
ni
ne
 p
at
ie
nt
s)
, t
he
 
pe
ri
od
on
ta
l p
oc
ke
ts
 w
er
e 
sc
al
ed
 a
nd
 H
A
 
w
as
 a
dm
in
is
te
re
d 
th
re
e 
tim
es
 w
ith
 a
n 
in
te
rv
al
 o
f 1
 w
ee
k 
in
 t
he
 t
es
t 
po
ck
et
s
In
 t
he
 s
ur
gi
ca
l g
ro
up
, f
ul
l-t
hi
ck
ne
ss
 fl
ap
 
w
as
 e
le
va
te
d 
an
d 
th
e 
pa
tie
nt
s 
re
ce
iv
ed
 
SR
P.
 In
 b
ot
h 
th
e 
te
st
 a
nd
 c
on
tr
ol
 s
ite
s,
 
bo
ne
 p
oc
ke
ts
, w
er
e 
co
ve
re
d 
w
ith
 a
 m
at
ri
x 
ba
rr
ie
r 
ba
se
d 
on
 b
io
ab
so
rb
ab
le
 p
ol
ya
ct
ic
 
ac
id
 m
ix
ed
 w
ith
 c
itr
ic
 a
ci
d 
st
er
. I
n 
ad
di
tio
n,
 
H
A
 w
as
 a
dm
in
is
te
re
d 
on
 t
es
t 
si
te
s.
 In
 t
he
 
no
 s
ur
gi
ca
l g
ro
up
: T
re
at
m
en
t 
in
cl
ud
in
g 
SR
P 
of
 b
ot
h 
te
st
 a
nd
 c
on
tr
ol
 t
ee
th
. H
A
 w
as
 
ad
m
in
is
te
re
d 
in
 t
he
 t
es
t 
si
te
s 
th
re
e 
tim
es
 a
t 
1-
w
ee
k 
in
te
rv
al
s
A
lv
eo
la
r 
bo
ne
 h
ei
gh
t 
an
d 
bo
ne
 h
ea
lin
g 
pa
tt
er
ns
, g
in
gi
va
l c
re
vi
cu
la
r 
flu
id
 
im
m
un
og
lo
bu
lin
 (
Ig
g,
 C
3,
 a
nd
 p
ro
st
ag
la
nd
in
 
E2
 [
PG
E2
])
 r
es
po
ns
es
, P
PD
, B
O
P,
 a
nd
 t
he
 
pr
es
en
ce
 o
f p
la
qu
e 
ev
al
ua
te
d 
at
 b
as
el
in
e 
be
fo
re
 t
re
at
m
en
t, 
an
d 
at
 2
 w
ee
ks
, a
nd
 1
, 3
, 6
, 
an
d 
12
 m
on
th
s 
af
te
r 
tr
ea
tm
en
t
T
he
 o
bs
er
ve
d 
di
ffe
re
nc
e 
in
 b
on
e 
he
ig
ht
 b
et
w
ee
n 
te
st
 a
nd
 c
on
tr
ol
 s
ite
s 
in
 t
he
 s
ur
gi
ca
l g
ro
up
 a
ft
er
 
12
 m
on
th
s 
w
as
 le
ss
 t
ha
n 
1 
m
m
, w
hi
ch
 w
as
 o
nl
y 
de
te
ct
ab
le
 o
n 
ra
di
og
ra
ph
s.
 A
 d
ec
re
as
e 
in
 b
on
e 
he
ig
ht
 w
as
 fo
un
d 
fo
r 
bo
th
 g
ro
up
s 
af
te
r 
sc
al
in
g.
 
Pr
ob
in
g 
de
pt
h 
re
du
ct
io
n 
af
te
r 
th
e 
su
rg
ic
al
 
tr
ea
tm
en
t, 
as
 w
el
l a
s 
af
te
r 
sc
al
in
g 
an
d 
ro
ot
 p
la
ni
ng
, 
w
as
 a
s 
ex
pe
ct
ed
T
ab
le
 1
. 
(C
on
tin
ue
d)
 (C
on
tin
ue
d)
Casale et al. 577
A
ut
ho
rs
M
ea
n 
ag
e
H
A
 g
ro
up
C
on
tr
ol
 g
ro
up
T
re
at
m
en
t
Pa
ra
m
et
er
s 
ev
al
ua
te
d
C
lin
ic
al
 e
vi
de
nc
es
H
A
 in
 g
in
gi
vi
tis
Br
ig
ug
lio
 e
t 
al
.
C
on
tr
ol
 g
ro
up
 
(4
2.
3 
±
 8
.4
 
ye
ar
s)
, H
A
 
gr
ou
p 
(4
7.
7 
±
 
8.
1 
ye
ar
s)
In
 t
hi
s 
sp
lit
 m
ou
th
 s
tu
dy
, 7
2 
te
et
h 
(3
6 
te
st
 s
ite
s 
an
d 
36
 c
on
tr
ol
 s
ite
s)
 in
 
18
 p
at
ie
nt
s 
w
ith
 m
od
er
at
e 
to
 s
ev
er
e 
ch
ro
ni
c 
pe
ri
od
on
tit
is
A
ft
er
 t
he
 m
ai
nt
en
an
ce
 p
er
io
d,
 t
he
 p
at
ie
nt
s 
w
er
e 
im
m
ed
ia
te
ly
 p
la
nn
ed
 fo
r 
su
rg
er
y.
 
In
 t
he
 t
es
t 
gr
ou
p,
 t
he
 t
re
at
ed
 s
ite
s 
w
er
e 
fil
le
d 
w
ith
 H
A
 a
ft
er
 t
he
 s
ur
gi
ca
l a
cc
es
s 
an
d 
cl
ea
ni
ng
 p
ha
se
s 
w
er
e 
ca
rr
ie
d 
ou
t. 
A
 s
im
ila
r 
pr
oc
ed
ur
e 
w
as
 p
er
fo
rm
ed
 for 
th
e 
co
nt
ro
l 
gr
ou
p,
 w
ith
ou
t 
th
e 
H
A
 a
pp
lic
at
io
n
T
he
 fo
llo
w
in
g 
cl
in
ic
al
 p
ar
am
et
er
s 
w
er
e 
re
co
rd
ed
 im
m
ed
ia
te
ly
 p
ri
or
 t
o 
th
e 
su
rg
er
y 
an
d 
re
pe
at
ed
 1
2 
an
d 
24
 m
on
th
s 
la
te
r:
 A
PI
, 
BO
P,
 P
D
, a
nd
 C
A
L
T
he
 t
re
at
m
en
t 
of
 in
fr
ab
on
y 
de
fe
ct
s 
w
ith
 
hy
al
ur
on
ic
 a
ci
d 
of
fe
re
d 
an
 a
dd
iti
on
al
 b
en
ef
it 
in
 
te
rm
s 
of
 c
lin
ic
al
 a
tt
ac
hm
en
t 
le
ve
l g
ai
n,
 p
ro
bi
ng
 
de
pt
h 
re
du
ct
io
n,
 a
nd
 p
re
di
ct
ab
ili
ty
 c
om
pa
re
d 
to
 
tr
ea
tm
en
t 
w
ith
 o
pe
n 
fla
p 
de
br
id
em
en
t
Be
vi
la
cq
ua
M
ea
n 
ag
e,
 5
1 
±
 9
.8
 y
ea
rs
11
 p
at
ie
nt
s 
w
ith
 m
od
er
at
e-
se
ve
re
 
ch
ro
ni
c 
pe
ri
od
on
tit
is
, w
ho
 h
ad
 fo
ur
 s
ite
s 
w
ith
 p
oc
ke
t: 
22
 s
ite
s 
in
 t
he
 C
on
tr
ol
 
G
ro
up
 a
nd
 2
2 
si
te
s 
in
 t
he
 H
A
 g
ro
up
T
he
 p
at
ie
nt
s 
in
 t
he
 H
A
 g
ro
up
, r
ec
ei
ve
d 
0.
5 
m
L 
of
 a
m
in
o 
ac
id
s 
an
d 
H
A
 g
el
 (
A
m
in
og
am
 
Ò
 A
) 
w
hi
le
 t
he
 p
at
ie
nt
s 
in
 t
he
 c
on
tr
ol
 
gr
ou
p 
re
ce
iv
ed
 0
.5
 m
L 
of
 p
la
ce
bo
 g
el
 
(A
m
in
og
am
 Ò
 B
). 
A
m
in
og
am
 A
 a
nd
 
A
m
in
og
am
 B
 w
er
e 
ap
pl
ie
d 
in
 t
he
 t
es
t 
si
te
s 
fo
llo
w
in
g 
th
e 
sa
m
e 
pr
oc
ed
ur
e 
at
T
he
 c
lin
ic
al
 v
ar
ia
bl
es
 e
va
lu
at
ed
: A
PI
, 
BO
P,
 C
A
L,
 P
PD
, L
ev
el
 c
al
pr
ot
ec
tin
 a
nd
 
m
ye
lo
pe
ro
xi
da
se
 (
M
PO
), 
gi
ng
iv
al
 c
re
vi
cu
la
r 
flu
id
 v
ol
um
e 
(G
C
F)
 a
t 
da
ys
 4
5 
an
d 
90
. T
he
 
qu
an
tit
y 
of
 c
al
pr
ot
ec
tin
, M
PO
, a
nd
 G
C
F 
w
as
 
ev
al
ua
te
d 
an
d 
re
co
rd
ed
 a
t 
te
st
 a
nd
 c
on
tr
ol
 
si
te
s 
at
 7
 a
nd
 4
5 
da
ys
T
he
 H
A
 g
ro
up
 e
xp
er
ie
nc
ed
 a
t 
ba
se
lin
e 
at
 a
nd
 4
5 
da
ys
 a
 s
ig
ni
fic
an
t 
re
du
ct
io
n 
in
 p
ro
bi
ng
 d
ep
th
 a
nd
 
bl
ee
di
ng
 o
n 
pr
ob
in
g 
th
an
 c
on
tr
ol
 g
ro
up
. A
ls
o 
bo
th
 
gr
ou
ps
 h
ad
 a
 s
ig
ni
fic
an
t 
re
du
ct
io
n 
in
 μ
g/
sa
m
pl
e 
of
 
ca
lp
ro
te
ct
in
 a
nd
 m
ye
lo
pe
ro
xi
da
se
 a
ft
er
 1
 w
ee
k 
an
d 
an
 in
cr
ea
se
 a
t 
45
 d
ay
s
K
ar
im
 e
t 
al
.
14
 p
at
ie
nt
s 
w
ith
 c
hr
on
ic
 p
er
io
do
nt
iti
s 
ha
vi
ng
 fo
ur
 in
te
rp
ro
xi
m
al
 in
tr
ab
on
y 
de
fe
ct
s 
w
er
e 
in
cl
ud
ed
 in
 t
hi
s 
sp
lit
-m
ou
th
 
st
ud
y 
(fo
r 
ea
ch
 p
at
ie
nt
, t
w
o 
si
te
s 
in
 t
es
t 
gr
ou
p 
[H
A
 g
el
] 
an
d 
tw
o 
si
te
s 
in
 c
on
tr
ol
 
gr
ou
p 
[p
la
ce
bo
] 
ge
l)
T
es
t 
si
te
s 
tr
ea
te
d 
w
ith
 m
od
ifi
ed
 W
id
m
an
 
fla
p 
(M
W
F)
 s
ur
ge
ry
 in
 c
on
ju
nc
tio
n 
w
ith
 
ei
th
er
 0
.5
 m
L 
of
 0
.8
%
 H
A
 g
el
 a
nd
 c
on
tr
ol
 
si
te
s 
tr
ea
te
d 
w
ith
 t
he
 s
am
e 
pr
oc
ed
ur
e 
an
d 
pl
ac
eb
o 
ge
l
BO
P,
 A
PI
, P
PD
, a
nd
 C
A
L 
w
er
e 
as
se
ss
ed
 a
t 
ba
se
lin
e,
 1
, 4
, a
nd
 1
2 
w
ee
ks
. C
FU
s 
pe
r 
m
L 
w
er
e 
as
se
ss
ed
 a
t 
ba
se
lin
e,
 a
ft
er
 S
R
P 
an
d 
af
te
r 
2 
w
ee
ks
T
he
re
 w
as
 a
 s
ig
ni
fic
an
t 
re
du
ct
io
n 
in
 B
O
P,
 A
PI
, 
PP
D
, a
nd
 C
A
L 
in
 t
he
 t
es
t 
si
te
s 
th
an
 c
on
tr
ol
 
gr
ou
p.
 In
 t
he
 t
es
t 
si
te
s 
th
er
e 
w
as
 a
ls
o 
a 
si
gn
ifi
ca
nt
 
re
du
ct
io
n 
of
 C
FU
s
H
A
 in
 im
pl
an
t 
su
rg
er
y 
an
d 
si
nu
s 
lif
t
A
ra
új
o 
N
ob
re
 
et
 a
l.
M
ea
n 
ag
e,
 5
8.
6 
±
 9
.5
1 
ye
ar
s
15
 p
at
ie
nt
s 
w
ith
 H
A
 g
el
15
 p
at
ie
nt
s 
w
ith
 C
H
X
 
ge
l
T
hi
rt
y 
ed
en
tu
lo
us
 p
at
ie
nt
s,
 w
ith
 B
rå
ne
m
ar
k 
Sy
st
em
 im
pl
an
ts
 p
la
ce
d 
in
 t
he
 m
an
di
bl
e,
 
w
er
e 
ra
nd
om
ly
 a
ss
ig
ne
d 
to
 t
w
o 
gr
ou
ps
 (
H
A
 
an
d 
C
H
X
)
T
he
 c
lin
ic
al
 p
ar
am
et
er
s 
ev
al
ua
te
d:
 m
od
ifi
ed
 
pl
aq
ue
 in
de
x 
(m
Pl
I),
 m
od
ifi
ed
 b
le
ed
in
g 
in
de
x 
(m
BI
), 
PP
D
 in
 m
L,
 s
up
pu
ra
tio
n 
(S
up
), 
cl
in
ic
al
 
im
pl
an
t 
m
ob
ili
ty
 (
m
ob
). 
Bo
th
 g
ro
up
s 
w
er
e 
fo
llo
w
ed
 u
p 
fo
r 
6 
m
on
th
s,
 a
nd
 t
he
 c
lin
ic
al
 
ob
se
rv
at
io
ns
 w
er
e 
pe
rf
or
m
ed
 o
n 
da
y 
10
, a
nd
 
at
 2
, 4
, a
nd
 6
 m
on
th
s 
po
st
 s
ur
ge
ry
H
A
 a
nd
 C
H
X
 s
ho
w
ed
 g
oo
d 
ef
fe
ct
s 
in
 m
ai
nt
ai
ni
ng
 
a 
he
al
th
y 
pe
ri
-im
pl
an
t 
co
m
pl
ex
. S
ta
tis
tic
al
ly
 
si
gn
ifi
ca
nt
 d
iff
er
en
ce
s 
w
er
e 
fo
un
d 
in
 t
he
 H
A
 
gr
ou
p 
fo
r 
m
od
ifi
ed
 b
le
ed
in
g 
in
de
x 
on
 t
he
 s
ec
on
d 
ob
se
rv
at
io
n.
 M
od
ifi
ed
 p
la
qu
e 
in
de
x 
an
d 
m
od
ifi
ed
 
bl
ee
di
ng
 in
de
x 
re
ve
al
ed
 a
 p
ot
en
tia
lly
 b
et
te
r 
re
su
lt 
fo
r 
C
H
X
 a
t 
6 
m
on
th
s
V
an
de
n 
Bo
ga
er
de
A
ge
 r
an
ge
, 
36
–6
7 
ye
ar
s
19
 d
ef
ec
ts
 w
er
e 
tr
ea
te
d
Es
te
ri
fie
d 
H
A
 in
 t
he
 fo
rm
 o
f f
ib
er
s 
w
as
 
pa
ck
ed
 in
to
 t
he
 p
er
io
do
nt
al
 d
ef
ec
ts
T
he
 P
PD
s,
 g
in
gi
va
l r
ec
es
si
on
, a
nd
 C
A
L 
w
er
e 
ev
al
ua
te
d 
be
fo
re
 t
re
at
m
en
t 
an
d 
af
te
r 
1 
ye
ar
A
ft
er
 1
 y
ea
r 
th
er
e 
w
er
e 
th
es
e 
fo
llo
w
in
g 
re
su
lt:
 
PP
D
 r
ed
uc
tio
n,
 g
in
gi
va
l r
ec
es
si
on
 in
cr
ea
se
, a
nd
 
C
A
L 
ga
in
Ba
lli
ni
 e
t 
al
.
M
ea
n 
ag
e 
of
 
43
.8
 y
ea
rs
 fo
r 
w
om
en
, 4
0.
0 
ye
ar
s 
fo
r 
m
en
, 
an
d 
42
 y
ea
rs
 
fo
r 
al
l g
ro
up
s
19
 d
ef
ec
ts
 w
er
e 
tr
ea
te
d.
 N
in
e 
pa
tie
nt
s 
w
ith
 p
er
io
do
nt
al
 d
ef
ec
ts
 t
re
at
ed
 b
y 
an
 
es
te
ri
fie
d 
lo
w
-m
ol
ec
ul
ar
 H
A
 p
re
pa
ra
tio
n 
(E
H
A
) 
an
d 
au
to
lo
go
us
 g
ra
ft
in
g
0.
5 
cc
 o
f a
ut
ol
og
ou
s 
bo
ne
 b
le
nd
ed
 w
ith
 t
w
o 
bu
nd
le
s 
of
 E
H
A
 fi
be
rs
 a
nd
 a
 fe
w
 d
ro
ps
 o
f 
ph
ys
io
lo
gi
ca
l s
ol
ut
io
n 
w
as
 p
os
iti
on
ed
 in
 t
he
 
si
te
. F
in
al
ly
, t
he
 fl
ap
 w
as
 r
e-
po
si
tio
ne
d 
an
d 
su
tu
re
d 
w
ith
 s
in
gl
e 
st
itc
he
s.
 A
ft
er
 s
ur
ge
ry
, 
pa
tie
nt
s 
ri
ns
ed
 t
he
ir
 m
ou
th
s 
tw
ic
e 
da
ily
 
w
ith
 1
0 
m
L 
of
 0
.2
 %
 C
H
X
 fo
r 
6 
w
ee
ks
T
he
 c
lin
ic
al
 p
ar
am
et
er
s 
ev
al
ua
te
d:
 F
M
PS
 (
fu
ll 
m
ou
th
 p
la
qu
e 
su
rf
ac
es
), 
FM
BS
 (
fu
ll 
m
ou
th
 
pl
aq
ue
 s
ur
fa
ce
s)
, P
PD
 (
pe
ri
od
on
ta
l p
oc
ke
t 
de
pt
h)
, R
: g
in
gi
va
l r
ec
es
si
on
, t
he
 c
em
en
t 
en
am
el
 ju
nc
tio
n 
(C
EJ
), 
C
A
L,
 IB
PD
 (
in
tr
ab
on
y 
po
ck
et
 d
ep
th
). 
D
at
a 
w
er
e 
ob
ta
in
ed
 a
t 
ba
se
lin
e 
be
fo
re
 t
re
at
m
en
t 
an
d 
af
te
r 
10
 d
ay
s,
 a
nd
 a
t 
6,
 
9,
 a
nd
 2
4 
m
on
th
s 
af
te
r 
tr
ea
tm
en
t
C
lin
ic
al
 r
es
ul
ts
 s
ho
w
ed
 a
 m
ea
n 
ga
in
 o
f C
A
L 
(g
C
A
L)
 o
f 2
.6
 m
m
 o
f t
he
 t
re
at
ed
 s
ite
s,
 c
on
fir
m
ed
 
by
 r
ad
io
gr
ap
hi
c 
ev
al
ua
tio
n
K
or
ay
 e
t 
al
.
34
 p
at
ie
nt
s 
(1
5 
m
en
, 1
9 
w
om
en
; m
ea
n 
ag
e,
 2
3.
35
 ±
 
3.
89
 y
ea
rs
)
34
 p
at
ie
nt
s 
w
ith
 b
ila
te
ra
l s
ym
m
et
ri
ca
lly
 
im
pa
ct
ed
 m
an
di
bu
la
r 
th
ir
d 
m
ol
ar
s 
di
vi
de
d 
in
 t
he
 B
nz
H
C
l g
ro
up
 a
nd
 t
he
 
H
A
 g
ro
up
A
ll 
pa
tie
nt
s 
un
de
rw
en
t 
tw
o 
su
rg
ic
al
 
op
er
at
io
ns
: i
n 
th
e 
fir
st
 o
pe
ra
tio
n,
 t
he
 r
ig
ht
 
th
ir
d 
m
ol
ar
 w
as
 e
xt
ract
ed
 w
hi
le
 in
 t
he
 
se
co
nd
 o
pe
ra
tio
n,
 t
he
 le
ft
 t
hi
rd
 m
ol
ar
 w
as
 
ex
tr
ac
te
d.
 A
ft
er
 b
ot
h 
op
er
at
io
ns
, t
he
 g
ro
up
 
ap
pl
ie
d 
th
e 
tw
o 
pu
m
ps
 t
o 
th
e 
ex
tr
ac
tio
n 
ar
ea
 t
hr
ee
 t
im
es
 a
 d
ay
, f
or
 7
 d
ay
s 
(B
nz
H
C
l 
sp
ra
y 
or
 H
A
 s
pr
ay
)
Sw
el
lin
g 
w
as
 e
va
lu
at
ed
 u
si
ng
 a
 t
ap
e 
m
ea
su
re
 
m
et
ho
d,
 p
ai
n 
w
ith
 a
 v
is
ua
l a
na
lo
gu
e 
sc
al
e 
(V
A
S)
, a
nd
 t
ri
sm
us
 b
y 
m
ea
su
ri
ng
 t
he
 
m
ax
im
um
 in
te
r-
in
ci
sa
l o
pe
ni
ng
. A
ss
es
sm
en
ts
 
w
er
e 
m
ad
e 
on
 t
he
 d
ay
 o
f s
ur
ge
ry
 a
nd
 o
n 
da
ys
 
2 
an
d 
7 
af
te
r 
su
rg
er
y
T
he
 p
at
ie
nt
s 
w
ith
 H
A
 s
pr
ay
 e
xp
er
ie
nc
ed
 
st
at
is
tic
al
ly
 s
ig
ni
fic
an
t 
re
su
lts
 fo
r 
th
e 
sw
el
lin
g 
an
d 
tr
is
m
us
 v
al
ue
s 
th
an
 t
ho
se
 w
ith
 t
he
 B
nz
H
C
l s
pr
ay
T
ab
le
 1
. 
(C
on
tin
ue
d)
578 International Journal of Immunopathology and Pharmacology 29(4)
A
ut
ho
rs
M
ea
n 
ag
e
H
A
 g
ro
up
C
on
tr
ol
 g
ro
up
T
re
at
m
en
t
Pa
ra
m
et
er
s 
ev
al
ua
te
d
C
lin
ic
al
 e
vi
de
nc
es
H
A
 in
 g
in
gi
vi
tis
R
om
eo
 e
t 
al
.
45
.5
 y
ea
rs
H
A
 g
ro
up
: 3
1 
pa
tie
nt
s
C
on
tr
ol
 g
ro
up
: 1
8 
pa
tie
nt
s
In
 b
ot
h 
gr
ou
ps
, e
xc
is
io
na
l b
io
ps
y 
w
as
 
pe
rf
or
m
ed
 in
 o
ra
l s
of
t 
tis
su
es
. I
n 
th
e 
H
A
 
gr
ou
p,
 t
he
 p
at
ie
nt
s 
re
ce
iv
ed
 H
A
 g
el
 a
ft
er
 
la
se
r 
su
rg
er
y;
 in
 t
he
 c
on
tr
ol
 g
ro
up
, t
he
 
pa
tie
nt
s 
re
ce
iv
ed
 n
o 
tr
ea
tm
en
t 
in
vo
lv
in
g 
a 
dr
ug
 o
r 
ge
l
N
um
er
ic
 r
at
in
g 
sc
al
e 
(N
R
S)
 w
as
 u
se
d 
to
 
ev
al
ua
te
 p
ai
n 
ex
pe
ri
en
ce
d 
af
te
r 
su
rg
er
y 
(p
ai
n 
in
de
x 
[P
I]
). 
T
he
 le
si
on
 a
re
a 
w
as
 m
ea
su
re
d 
af
te
r 
su
rg
er
y 
(T
0)
 a
nd
 a
ft
er
 7
 d
ay
s 
(T
1)
. A
 
pe
rc
en
ta
ge
 h
ea
lin
g 
in
de
x 
(P
H
I) 
w
as
 c
al
cu
la
te
d 
in
di
ca
tin
g 
he
al
in
g 
ex
te
ns
io
n 
in
 7
 d
ay
s
H
A
 c
as
es
 s
ho
w
ed
 a
n 
av
er
ag
e 
PH
I o
f 2
6.
50
–
64
.3
8%
, w
he
re
as
 t
he
 a
ve
ra
ge
 P
H
I i
n 
th
e 
C
G
 w
as
 
27
.8
4–
47
.8
8%
. M
ea
n 
PI
 w
as
 0
.9
6–
2.
67
 fo
r 
H
A
 
an
d 
0.
86
–2
.7
5 
fo
r 
C
G
. A
 s
ta
tis
tic
al
ly
 s
ig
ni
fic
an
t 
di
ffe
re
nc
e 
w
as
 d
et
ec
te
d 
be
tw
ee
n 
th
e 
gr
ou
ps
 fo
r 
PH
I, 
w
he
re
as
 n
o 
di
ffe
re
nc
e 
w
as
 d
et
ec
ta
bl
e 
fo
r 
PI
K
um
ar
 e
t 
al
.
T
hi
s 
w
as
 a
 r
an
do
m
iz
ed
 c
lin
ic
al
 t
ri
al
 w
ith
 
sp
lit
-m
ou
th
 d
es
ig
n,
 w
he
re
 1
0 
pa
tie
nt
s 
w
ith
 2
0 
si
te
s 
of
 M
ill
er
s 
C
la
ss
 I 
re
ce
ss
io
n 
w
er
e 
tr
ea
te
d 
an
d 
fo
llo
w
ed
 u
p 
fo
r 
a 
pe
ri
od
 o
f 6
 m
on
th
s
H
A
 s
ite
s 
w
er
e 
tr
ea
te
d 
w
ith
 H
A
 g
el
 0
.2
%
 
w
ith
 c
or
on
al
ly
 a
dv
an
ce
d 
fla
p 
(C
A
F)
 w
hi
le
 
co
nt
ro
l s
ite
s 
w
er
e 
tr
ea
te
d 
w
ith
 C
A
F 
al
on
e
R
ec
es
si
on
 d
ep
th
 (
R
D
) 
w
as
 m
ea
su
re
d 
re
gu
la
rl
y 
at
 b
as
el
in
e 
an
d 
1,
 3
, 6
, 1
2,
 a
nd
 2
4 
w
ee
ks
 
po
st
op
er
at
iv
el
y.
 P
PD
 a
nd
 C
A
L 
w
er
e 
al
so
 
m
ea
su
re
d 
al
on
g 
w
ith
 R
D
 a
t 
ba
se
lin
e 
an
d 
12
 
an
d 
24
 w
ee
ks
T
he
re
 w
as
 a
 s
ig
ni
fic
an
t 
ch
an
ge
 in
 R
D
, P
PD
, 
C
A
L,
 a
nd
 p
er
ce
nt
ag
e 
of
 r
oo
t 
co
ve
ra
ge
 in
 b
ot
h 
gr
ou
ps
 w
he
n 
co
m
pa
re
d 
to
 t
he
 b
as
el
in
e 
va
lu
es
. 
T
he
re
 w
as
 n
o 
st
at
is
tic
al
ly
 s
ig
ni
fic
an
t 
di
ffe
re
nc
e 
be
tw
ee
n 
th
e 
ex
pe
ri
m
en
ta
l a
nd
 c
on
tr
ol
 s
ite
s 
in
 
te
rm
s 
of
 R
D
, P
PD
, a
nd
 C
A
L.
 T
ho
ug
h 
th
er
e 
is
 n
o 
st
at
is
tic
al
ly
 s
ig
ni
fic
an
t 
di
ffe
re
nc
e 
ro
ot
 c
ov
er
ag
e 
in
 
th
e 
ex
pe
ri
m
en
ta
l g
ro
up
, i
t 
ap
pe
ar
ed
 t
o 
be
 c
lin
ic
al
ly
 
m
or
e 
st
ab
le
 c
om
pa
re
d 
w
ith
 t
he
 c
on
tr
ol
 g
ro
up
 
af
te
r 
24
 w
ee
ks
H
A
 in
 o
ra
l u
lc
er
s
Le
e 
et
 a
l.
40
 y
ea
rs
33
 p
at
ie
nt
s 
:1
7 
pa
tie
nt
s 
w
ith
 B
eh
ce
t’s
 
di
se
as
e,
 a
nd
 1
6 
pa
tie
nt
s 
w
ith
 r
ec
ur
re
nt
 
ap
ht
ho
us
 u
lc
er
at
io
ns
Pa
tie
nt
s 
w
er
e 
tr
ea
te
d 
w
ith
 H
A
 0
.2
%
 g
el
 
tw
ic
e 
a 
da
y 
fo
r 
2 
w
ee
ks
Su
bj
ec
tiv
e 
as
se
ss
m
en
t: 
nu
m
be
r 
of
 u
lc
er
s,
 
he
al
in
g 
pe
ri
od
 a
nd
 V
A
S;
 O
bj
ec
tiv
e 
as
se
ss
m
en
t: 
nu
m
be
r 
an
d 
m
ax
im
al
 s
iz
e 
of
 u
lc
er
A
 s
ub
je
ct
iv
e 
re
du
ct
io
n 
in
 t
he
 n
um
be
r 
of
 u
lc
er
s 
w
as
 r
ep
or
te
d 
by
 7
2.
7%
 o
f p
at
ie
nt
s.
 A
 d
ec
re
as
e 
in
 t
he
 u
lc
er
 h
ea
lin
g 
pe
ri
od
 w
as
 r
ep
or
te
d 
by
 
72
.7
%
 o
f p
at
ie
nt
s;
 7
5.
8%
 o
f p
at
ie
nt
s 
ex
pe
ri
en
ce
d 
im
pr
ov
em
en
t 
in
 V
A
S 
fo
r 
pa
in
. O
bj
ec
tiv
e 
in
sp
ec
tio
n 
of
 t
he
 u
lc
er
s 
sh
ow
ed
 a
 r
ed
uc
tio
n 
of
 n
um
be
rs
 in
 
57
.6
%
 o
f p
at
ie
nt
s,
 a
nd
 7
8.
8%
 o
f t
he
 u
lc
er
s 
sh
ow
ed
 
a 
de
cr
ea
se
 in
 a
re
a.
 A
m
on
g 
th
e 
in
fla
m
m
at
or
y 
si
gn
s,
 
sw
el
lin
g 
an
d 
lo
ca
l h
ea
t 
w
er
e 
si
gn
ifi
ca
nt
ly
 im
pr
ov
ed
 
af
te
r 
tr
ea
tm
en
t
N
ol
an
 e
t 
al
.
H
A
 g
ro
up
 
(3
7 
ye
ar
s)
; 
C
on
tr
ol
 g
ro
up
 
(3
6 
ye
ar
s)
H
A
 g
ro
up
: 6
0 
pa
tie
nt
s
C
on
tr
ol
 g
ro
up
: 5
6 
pa
tie
nt
s
Pa
tie
nt
s 
in
 t
he
 H
A
 g
ro
up
 w
er
e 
tr
ea
te
d 
w
ith
 
H
A
 g
el
 0
.2
%
 w
hi
le
 p
at
ie
nt
s 
in
 t
he
 c
on
tr
ol
 
gr
ou
p 
w
ith
 p
la
ce
bo
 (
2–
3 
tim
es
 p
er
 d
ay
 fo
r 
th
e 
ne
xt
 7
 d
ay
s)
M
ea
n 
nu
m
be
r 
of
 u
lc
er
s;
 u
lc
er
 h
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Casale et al. 579
a gingival biopsy, which showed a significant 
reduction of inflammatory infiltrate.
Rajan et al.29 showed that HA applied immedi-
ately after SRP and 1 week post therapy, has a ben-
eficial effect on periodontal health in patients with 
chronic periodontitis. In the HA group, this com-bined treatment showed a significant improvement 
in all clinical parameters: BOP, PPD, and CAL, at 
12 weeks post therapy in comparison to the control 
group treated with SRP only.
HA gel applied topically after SRP by massag-
ing the gingiva with a soft bristled toothbrush for 3 
weeks reduced the gingival inflammation improv-
ing all clinical parameters: PLI (plaque index), 
BOP, PPD, GI, and probing attachment level 
(PAL), compared with patients treated using nor-
mal oral hygiene procedures.30
Eick et al.31 evaluated the effect of the associa-
tion of topical HA with different molecular weights. 
Immediately after the SRP, a gel containing 0.8% 
HA (1800 kDa) was introduced into all periodontal 
pockets; in addition, the patients applied a gel con-
taining 0.2% HA (1000 kDa) onto the gingival 
margin twice daily for the following 14 days; in 
comparison with the control group (SRP only), the 
HA group showed a positive effect on PPD reduc-
tion and the prevention of recolonization by perio-
dontopathogens (such as Campylobacter, Prevotella 
intermedia, and Porphyromonas gingivalis).
Chauhan et al.,32 in their clinical trials, enrolled 
60 patients, randomly divided into three groups: 
the patients in group 1 received complete SRP and 
subgingival debridement, while the patients in 
groups 2 and 3, received topically applied HA gel 
and chlorhexidine (CHX) gel, respectively, after 
SRP procedure.
In all the three groups, a significant reduction in 
PPD and gain in CAL were observed between 
baseline and 3-month follow-up; however, at 3 
months, the change in PPD and CAL was more in 
group 2 than group 3, but the difference was 
non-significant.
Engström et al.33 investigated in their study 
the anti-inflammatory effect and the effect on 
bone regeneration of HA in surgical and non-
surgical groups in the patients with chronic 
periodontitis.
In the surgical group, a bioabsorbable mem-
brane was used for both test and control sites, 
and HA was placed in the infrabony pocket of 
the test site.
In the non-surgical group, the periodontal pock-
ets were scaled and HA was administered three 
times with an interval of 1 week in the test 
pockets.
They observed difference in bone height between 
test and control sites in the surgical group after 12 
months, less than 1 mm, which was only detectable 
on radiographs. No statistical difference was found 
on radiographs in the non-surgical group, where a 
decrease in bone height was found for both groups 
after scaling.
PPD reduction after the surgical treatment, as 
well as after SRP, was as expected. They showed 
that HA in contact with bone and soft tissues had 
no influence on the immune system in this study.
HA has also been used in conjunction with open 
flap debridement (OFD) for the treatment of infra-
bony defects, offering an additional benefit in 
terms of CAL gain, PPD reduction, and predicta-
bility compared to patients with chronic periodon-
titis who underwent OFD treatment alone.34
Bevilacqua et al.35 proved that the subgingival 
application of 0.5 mL of amino acids and HA gel 
following ultrasonic mechanical instrumentation is 
beneficial for improving periodontal parameters in 
patients with moderate to severe chronic periodon-
titis in comparison to patients treated with only 
ultrasonic debridement. This combined treatment 
reduced PPD and BOP.
The topical application of 0.8% HA gel in addi-
tion to modified Widman flap (MWF) surgery 
improved the CAL and gingival recession (GR) 
more than MWF surgery alone or the application 
of a placebo gel, as indicated in the study carried 
out by Karim et al.36
The use of HA in implant surgery and sinus lift
Araújo Nobre et al.37 compared the health status of 
the peri-implant complex during the healing period 
of immediate function implants, using HA or CHX 
gels. They found a statistically significant lower 
modified bleeding index in the HA group in com-
parison with the control group treated with CHX. It 
might be advantageous to purpose combined treat-
ment using HA 0.2% gel in the first 2 months and 
0.2% CHX from months 2 to 6.
Vanden Bogaerde et al.38 investigated the clini-
cal efficacy of treating deep periodontal defects 
using esterified HA in packed fibers in the defect. 
One year after treatment, the mean PPD was 
580 International Journal of Immunopathology and Pharmacology 29(4)
reduced, GR has increased, and attachment gain 
was recorded.
Ballini et al.39 suggested that autologous bone 
combined with an esterified low-molecular HA 
preparation seems to have good capabilities in accel-
erating new bone formation in infrabony defects.
The topical administration of a 0.2% HA spray 
three times a day, for 7 days following impacted 
third molar surgery to the extraction area, appears to 
offer a beneficial effect in the management of swell-
ing and trismus during the immediate postoperative 
period when compared with the topical administra-
tion of 0.15% benzydamine hydrochloride spray.40
Romeo et al.41 showed that the use of a gel con-
taining amino acids and 1.33% HA, topically 
applied three times per day for 1 week, can pro-
mote faster secondary intention healing in laser-
induced wounds in patients who underwent an 
excisional biopsy of the oral soft tissues than the 
rate of healing the control group. It could consider-
ably quicken the repair processes although it does 
not seem to affect pain perception.
In contrast to the above mentioned authors, Galli 
et al.,42 conducted a study using a Likert scale 10 
days postoperatively and found that a single appli-
cation of 0.8% HA does not appear to improve 
wound healing when applied to the surgical inci-
sions in the oral cavity.
Finally, Kumar et al.43 evaluated the efficacy of 
HA gel in root coverage procedures as an adjunct 
to coronally advanced flap (CAF) procedure.
In this split mouth study design, 10 patients with 
20 sites of Millers Class I recession were treated 
and followed-up for a period of 6 months.
Experimental sites were treated with HA gel 
0.2% and CAF while control sites were treated 
with CAF alone.
There was a significant change in RD, PPD, CAL, 
and percentage of root coverage in both groups when 
compared to the baseline values, but there was no 
statistically significant difference between HA sites 
and control sites in terms of RD, PPD and CAL.
Though there is no statistically significant dif-
ference, root coverage in the HA sites appeared to 
be clinically more stable than the control site 
treated with CAF alone after 24 weeks.
HA in oral ulcers
Several studies focused their attention on use of 
HA as topical treatment for oral ulcers.
In particular Nolan44 showed that topical appli-
cation of 0.2% HA gel twice daily for 2 weeks 
seems to be an effective and safe therapy in patients 
with recurrent aphthous ulcers (RAU).
Lee et al.45 investigated the efficacy of the topi-
cal application of 0.2% HA gel for oral ulcers in 
patients with RAU and the oral ulcers of Behçet’s 
disease (BD). In this study, HA gel application 
improved subjective parameters (number of ulcers, 
healing period, visual analogue scale [VAS] for 
pain), and objective parameters (number of ulcers, 
maximal area of ulcer, and inflammatory signs 
such as swelling and local heat).
Discussion
Hyaluronan is a non-sulfated glycosaminoglycan 
found in the extracellular matrix of all vertebrate 
tissues, which plays a multifunctional role in scar-
free wound healing, while also paramount role in 
physiology in the oral cavity and in the field of 
dentistry. The data, which have emerged from our 
analysis of the literature, allow us to suggest that 
hyaluronan may play a potential role in periodontal 
tissue healing and as an aid to the treatment of peri-
odontal disease.
HA promotes a remission of symptoms, not 
only in the marginal gingiva, but also in the 
deeper-seated periodontal tissues, via the known 
mechanisms established for hyaluronan in wound 
healing.
Topical HA can be useful as a coadjutanttreat-
ment in gingivitis, chronic periodontitis, as well as 
during the postoperative period both for implant 
and sinus lift procedures for faster healing and to 
reduce the patients’ discomfort during the postop-
erative period. Finally, topical HA may be a valu-
able treatment for oral ulcers.
We would like to emphasize that topical treat-
ments are more effective in their ability to deliver 
high concentrations of pharmacological agents to 
the teeth and oral mucosa, rather than systemic 
administration.
Further laboratory-based research and large-
scale randomized controlled clinical trials imply 
that HA may be a suitable carrier of cells from peri-
odontal tissue, promoting tissue regeneration in the 
augmentation of both mineralized and non-miner-
alized periodontal tissue.
More studies are necessary to identify the best 
way of administration (spray, gel, nebulization, 
Casale et al. 581
and so on) in addition to the best method of 
scheduling postoperative treatment for each den-
tal condition.
Conclusion
Today HA is widely used in many branches of 
medicine with interesting potential applications in 
dentistry for the treatment of acute and chronic 
inflammatory disease.
Data obtained from the present review of 20 
clinical studies demonstrate that, due to its positive 
action on tissue repair and wound healing, topical 
administration of HA could play a role not only in 
postoperative dental surgery, but also in the treat-
ment of patients affected by gingivitis and perio-
dontitis, with a significant improvement in their 
quality of life. Further laboratory-based research 
and large-scale randomized controlled clinical tri-
als on a larger scale are advisable to confirm these 
promising results.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest 
with respect to the research, authorship, and/or publication 
of this article.
Funding
This research received no specific grant from any fund-
ing agency in the public, commercial, or not-for-profit 
sectors.
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