BOSNlAN lOUlNAl Ol BASlC MlDlCAl SCllNClS 2010, 10 (3).

186-191

Abstract
Diabetic patients increase their bodvs susceptibilitv to intection and diabetes is a risk
tactor tor periodontal diseases and oral intection. Althouh manv studies shoved the
mechanism ot impaired vound healin in diabetes, there are still aruments to shed
liht on vhat kind ot tactors, includin local and svstemic tactors are involved in the
protracted vound healin. Tis reviev article summarizes reports on the vound heal-
in in diabetes and discusses the mechanism ot the protracted vound healin ot the
oral mucosa in diabetes. Delaved vascularization, reduction in blood ov, decline in in-
nate immunitv, decreases in rovth tactor production, and psvcholoical stresses mav
be involved in the protracted vound healin ot the oral mucosa in diabetics.
llY WOlDS. Diabetes, oral mucosa, vound healin
THE MECHANISM
OF PROTRACTED
WOUND HEALING
ON ORAL MUCOSA IN
DIABETES. REVIEW
Yoshihiro Abiko
1
* and Denis Selimovic
2
*
Department ot Dental Science, Division ot Oral Medicine and Patholov,
lnstitute ot Personalized Medical Science, Health Sciences Universitv ot
Hokkaido, .-, Ainosato, lita-ku, Sapporo, Hokkaido, oo.8o;., lapan
Department ot Oral Medicine and Surerv, Universitv Hospitals ot Strasbour,
+, Place de lHopital and lnstitute National de la Sante et lecherche Medicale
(lNSllM U,;;), Btiment , ++, lue Huemann, 6; ooo Strasbour, lrance
Correspondin author
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YOSHlHllO ABllO AND DlNlS SlllMOVlC. THl MlCHANlSM Ol PlOTlACTlD WOUND HlAllNG ON OlAl MUCOSA lN DlABlTlS. llVllW
Introduction
Diabetes is tound almost in everv population, and the
prevalence vill continue to increase loballv vithout
ettective prevention and control prorams. Diabetic
patients increase their bodvs susceptibilitv to intection
and diabetes is a risk tactor tor periodontal diseases
and oral intection. Since the diabetes otten protracts
vound healin leadin to secondarv intection, the
individual surical procedure should be caution-
arv underone a chane. Manv studies shoved the
mechanism ot impaired vound healin in diabe-
tes. There are, hovever, still aruments to shed liht
on vhat kind ot tactors, includin local and svstemic
tactors are involved in the protracted vound heal-
in. This reviev vill discuss on the mechanism ot
protracted vound healin ot oral mucosa in diabetes.
Factors aecting wound healing of oral mucosa
Oral mucosa is covered vith stratied squamous epi-
thelium, and the connective underneath the epithelium
consists ot tibroblasts, collaens and capillaries. The
process ot vound healin involves hemostasis, inam-
mation, cell proliteration and remodelin. The tirst
phase ot hemostasis beins immediatelv atter vound-
in, vith vascular construction and tibrin clot torma-
tion. Te inammatorv phase is characterized bv the
sequential inltration ot neutrophil, macrophaes, and
lvmphocvtes. The proliteration phase overlaps vith
the intlammatorv phase, and is characterized bv epi-
thelial proliteration and miration over the provisional
matrix vithin the vound, vascularization, collaen
svnthesis and extracellular matrix tormation. Te col-
laen remodelin, and vascular maturation and reres-
sion occurs in the remodelin phase. Multiple local
and svstemic tactors impair their vound healin. Sup-
plv ot oxven, intection and torein bodv are the lo-
cal tactors. Aein, sex, stress, tailure ot circulation,
obesitv, medications such as steroid and anti-cancer
dru, alcohol, smokin, immunosuppresed state, nu-
trition and manv tvpes ot svstemic diseases can be a
svstemic tactor tor it. Diabetes, manv tvpes ot brosis,
aundice and uremia include the svstemic diseases (+).
Circulation and vascularization in diabetes
Diabetic patient contract a vascular disorder, includin
obstructed vascular sclerosis, leadin to decrease ot vas-
cular circulation (.). Te decrease ot vascular circulation
cause hvpoxia vhich induces to impair vound healin.
Hvpoxia enhances initial inammatorv reactions and in-
creases oxidant tree radical, vhich delavs vound healin
(,|). Oxidant tree radical is also induced bv an increase
in blood suar level (,) and promote advanced lvca-
tion end-products(AGls) inhibitin vascularization (6).
Oxidant radical induces incomplete tormation and dis-
traction ot ap unctions ot blood vessels (;,8,,,+o). ll-
evated blood-suar levels directlv cause incomplete tor-
mation ot ap unctions even thouh no oxidant stresses
(++), and also promotes the production ot TNl-alpha
(TNl-) involved in inhibition ot hemanioenesis
(+.). Manv tactors decrease microvascular circulation
and therebv cause impaired vound healin in diabetes.
Immunoresponses in diabetes
lntections are ot particular concern tor diabetic patients.
local intection directlv causes impaired vound healin,
and the delaved vound healin increases susceptibilitv
to intections. Diabetic patients are under state ot immu-
nosuppression, vhich is related to the hiher suscepti-
bilitv to intection. Previous reports shoved the suppres-
sion ot innate immunitv in the diabetics (+). Decreased
number ot neutrophils mirated throuhout trom blood
capillaries vere reported in diabetics. lncreased amount
ot AGl depositions causes the decreased number ot
inltrated neutrophils (+|). Te AGl directlv inhibits
the chemotactic activitv ot neutrophils. A previous re-
port shoved that chemotactic attractant ot neutrophils
vas sinicantlv lover in the diabetics vith more than
lucose concentration ot +.mmoll than in healthv
individuals (+,). Te chemotactic attractant ot mono-
cvtes are also declined (+6). Neutrophils and monocvtes
plav a kev role in innate immunitv and act as a bride
betveen innate and adaptive immunitv. Te dvstunc-
tions ot those cells mav be a crucial in the suppression ot
host immunitv in diabetic patients. Te dvstunction ot
neutrophil chemotaxis can be controlled bv lover hih
blood-suar levels in diabetic patients (+;). ln addition
to neutrophils and monocvtes, antimicrobial peptides
produced also bv epithelial cells act as an important part
ot innate immunitv. Several tvpes ot antimicrobial pep-
tides includin beta-detensins, cathelicidin and psoriasin
are produced bv oral epithelium (+8,+,). Te expression
levels ot beta-detensins are altered bv the concentration
ot insulin, lucose or adiponectin (.o,.+). Te alteration
ot concentration ot lucose and insulin in the blood mav
decrease the tunction ot innate immunitv, inhibitin
the vound healin. Saliva that covers the surtace ot oral
epithelium tunctions as innate immunitv bv antimicro-
bial eects vith rinsin the surtace ot oral epithelium
(..). ln diabetics, tunctional alteration ot saliva such as
tlov rate and its component attect their vound heal-
in (See more detain in the next section). Te previous
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YOSHlHllO ABllO AND DlNlS SlllMOVlC. THl MlCHANlSM Ol PlOTlACTlD WOUND HlAllNG ON OlAl MUCOSA lN DlABlTlS. llVllW
investiations on abnormal ot the adaptive immunitv
have mainlv tocused on tvpe l diabetes (.,.|). Tvpe ll
diabetes and obesitv increase the blood concentration ot
inammatorv cvtokines such as ll-6 and TNl-, vhich
is involved in the insulin resistance (.,,.6). Te diabetic
rats inected bv inactivated P. inivalis induced more
proloned inammation than the control (.;). Te in-
ammatorv cascade response is inhibited bv TNl- in
the diabetics, implvin abnormal reulation ot inam-
matorv cvtokines includin TNl- in diabetes (.8).
lncreased level ot TNl- is also induced bv the hih
level ot AGl (.,). AGls induces production ot manv
other tvpes ot cvtokines and chemokines, suestin
that AGl is involved in the abnormal ot the adaptive
immunitv (o). Certain concentration ot AGl inhibits
production ot tvpe l and lll collaens (+) and otten in-
duces cell apoptosis (.;). AGl mav impair the vound
healin ovin to induction ot excessive immunore-
sponses and neative reulations ot the cell phvsiolov.
Salivary components and ow in diabetes
Saliva has manv tunctions includin diestion, buer-
in capacitv, antimicrobial activitv, selt-cleanin action
ot the surtace ot oral mucosa keepin the phvsioloi-
cal oral ora in balance. Manv ot blood data that can
be detected in diabetics are also detected in saliva. ln-
creased level ot suar and AGl are tolloved bv hih
level ot lucose and AGl in saliva (.,,|) . A most
crucial chane ot saliva in diabetic patients is lover ov
rate caused bv hvpotunction ot salivarv land (,-|o).
Saliva contains manv kinds ot antimicrobial peptides
and proteins (..,+8,|+), and the lover ov rate causes
bacterial intection. The components ot saliva are al-
tered in diabetics. Saliva in diabetics contains less lu-
tathione and melatonin that tunction as a scavener tor
tree radicals than that in health individuals (|.,|,||).
Te diabetic patients produce more tree radicals at the
vound under elevated blood-suar and hvpooxidation
conditions than normal (,|). Te lover level ot scav-
eners and the hiher level ot tree radicals mav induce
more oxidative stress causin the protracted vound
healin in diabetes. Te hih concentration ot MMP-8,
a tvpe ot collaenase, is detected in saliva ot diabetics
(|,,|6). The excess amount ot enzvmes tor derada-
tion ot extracellular matrices impairs vound healin
(+). Te hih level ot MMP-8 mav be involved in the
impaired vound healin. The diabetics have less epi-
dermal rovth tactor (lGl) in saliva. lGl mainlv pro-
duced bv submandibular lands tulll manv tunctions,
includin cell rovth and ditterentiation in oral tis-
sues. lGl promotes re-epithelialization ot oral mucosa
(|;). Te less lGl in saliva mav also be involved in the
protracted vound healin on oral mucosa in diabetes.
Growth factors in diabetes
ln addition to lGl in saliva, manv other rovth tac-
tors includin insulin-like rovth tactor (lGl), trans-
tormin rovth tactor (TGl), platelet-derived rovth
tactor (PDGl) and nerve rovth tactor (NGl) pro-
duced at the vound promotes the healin (|8). The
lover levels ot lGl-+, TGl-b+ and NGl produced at
the vound vere reported in both diabetic animals
and human. Te decreased expression ot these rovth
tactors mav be involved in the protracted vound heal-
in. lGl-+, an isotorm ot lGl, stimulates chemotaxis
ot endothelial cells and proliteration ot keratinocvtes
and tibroblasts, vhich promote re-epithelization and
extension ot vound (|,,,o,,+). Delaved expression ot
lGl-+ and lGl-+ receptor mlNAs vas observed in the
process ot the vound healin in diabetic mice (,.,,,,|).
Decreased expression levels ot those mlNAs vere
also observed in toot ulcer in the diabetic patients (,,).
TGl-b+, an isotorm ot TGl-b, promotes chemotaxis
ot monocvtes, macrophaes, neutrophils, lvmphocvtes,
keratinocvtes and broblasts, and production ot rovth
tactors trom those cells. These accelerate vasculariza-
tion, deposition ot extracellular matrices and inhibition
ot deradation ot extracellular matrices (,6,,;). The
production level ot TGl-b+ vas decreased in the pro-
cess ot vound healin in diabetic rats (,|). Decreased
production level ot TGl-b + vas observed in toot ul-
cer in diabetic patients (,8,,,,6o). PDGl, like TGl-b,
promotes vascularization and deposition ot extracel-
lular matrices. PDGl production is decreased in the
chronic toot ulcer (6+). Te expression levels ot PDGl
and its receptor vere decreased also in diabetic rats
and mice model (6.,6). TGl-b stimulates the expres-
sion ot PDGl (6|). Te decreased expression ot PDGl
mav be linked to the decreased expression ot TGl-b in
diabetics. NGl oriinallv discovered as a neurotrophic
tactor is expressed in broblasts, endothelial cells and
keratinocvtes (6,,66,6;), vhich is involved in immu-
noresponse and vascularization (68,6,). NGl induces
proliterations ot keratinocvtes and endothelial cells,
monocvtic dierentiation and activation ot neutrophils
(6,,;o,;+,;.). lxpression ot NGl vas also decreased in
the skin both on diabetic patients and rats (;-;;). An-
other rovth tactor, keratinocvte rovth tactor (lGl)
is decreased in diabetic mouse (;8). ll-6 stimulates lGl
production trom tibroblasts and the expression level
ot ll-6 is decreased in the vound ot diabetic patients
(;,). As stated above, most ot the rovth tactors that
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YOSHlHllO ABllO AND DlNlS SlllMOVlC. THl MlCHANlSM Ol PlOTlACTlD WOUND HlAllNG ON OlAl MUCOSA lN DlABlTlS. llVllW
promote vound healin are decreased. Te decreased
expression ot these rovth tactors mav lead to poor and
delaved vound healin on the oral mucosa in diabetes.
Psychological stresses in diabetes
Diabetic patients are otten under psvcholoical stress
(8o,8+). Psvcholoical stress causes a substantial delav
in vound healin (+). Te psvcholoical stress mav be
associated vith protracted vound healin in diabetic
patients. Tere are several possible mechanisms hov
psvcholoical stress causes a delav in vound healin.
Te stress results in the dereulation ot the immune svs-
tem, mediated primarilv throuh the hvpothalamic-pi-
tuitarv-adrenal (HPA). Te dereulation ot the immune
svstem increases susceptibilitv to intection leadin to
poor vound healin in diabetes (8.,8). Te psvcholoi-
cal stressors mav lead to emotional states such as anxi-
etv and depression, vhich adverselv aects endocrine
and immune tunction. Te stress mav make individuals
to have unhealthv habits, includin inadequate nutri-
tion and a reater propensitv tor abuse ot alcohol and
ciarettes. Tese tactors mav neativelv modulate the
process ot vound healin. Te stress also causes hvper-
lvcemia vith increasin ot norepinephrine and epi-
nephrine via svmpathetic-adrenal medullarv (+). Stress
tactors mav inuence neativelv the diabetic condition
and have an even vorse eect on the vound healin.
Future prospects
Multiple tactors are involved in protracted vound heal-
in on oral mucosa in diabetes. Te severitv and patho-
phvsioloical conditions in diabetes are ot reat varietv
amon individuals. The values ot blood-suar, hemo-
lobin A+c (Hb+c) and +,,-anhvdrolucitol (+,,-AG)
ditter amon diabetic patients. The pathophvsioloi-
cal conditions and their molecular bioloical mecha-
nisms ditter betveen tvpes l and ll diabetes. These
individual ditterences mav be crucial tactors tor the
protected vound healin. Tere is not enouh clinical
and experimental evidence hov the individual ditter-
ences attect the multiple tactors. lurther clinical in-
vestiations need to claritv the eect ot the individual
ditterences on the multiple tactors. The uideline tor
oral surical procedures in diabetes should be reevalu-
ated and then nevlv tormulated usin these clinical data.
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