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Santhosh kumar, Suhas Manoharan, Nabeel Nazar. Dry Socket and Its Management - An Overview. Int J Dentistry Oral Sci. 2021;08(04):2158-2161.
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Dry Socket and Its Management - An Overview
Research Article
International Journal of Dentistry and Oral Science (IJDOS)
ISSN: 2377-8075
*Corresponding Author:
Santhosh kumar,
Reader, Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University
162, Poonamallee High Road, Velappanchavadi, Chennai 600077 Tamil Nadu, India.
Tel: 9994892022
Email Id: santhoshsurgeon@gmail.com
Received: March 01, 2021
Accepted: March 20, 2021
Published: April 02, 2021
Citation: Santhosh kumar, Suhas Manoharan, Nabeel Nazar. Dry Socket and Its Management - An Overview. Int J Dentistry Oral Sci. 2021;08(04):2158-2161.
Copyright: Santhosh kumar©2021. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distri-
bution and reproduction in any medium, provided the original author and source are credited.
Introduction
Alveolar Osteitis (AO) or dry socket is a complication that oc-
curs after extraction of tooth especially third molars. This post-
surgical complication also called as dry socket is most commonly
seen after 2-3 days after extraction of the tooth. The terminology
‘dry socket’ was rst specied in literature in 1896 [1]. Other com-
monly used terms include alveolitissicca dolorosa, localised Ostei-
tis, alveolar Osteitis, necrotic socket or septic socket and alveola-
gia. This complication may cause repeated visits to the clinician
and maybe of great inconvenience to both patient and clinician.
Such a complication results in severe pain and eventually lead-
ing to increased cost of treatment for both patient and operator.
Dry socket generally results in pain on the second to fourth day
following dental extraction. Post extraction ache normally occurs
after the anaesthesia or analgesia has worn off, or has a more
delayed onset [2]. Examination normally entails gentle irrigation
with warm saline and probing of the socket to establish the diag-
nosis. On occasion, part of the root of the teeth or a chunk of
bone fractures off and is retained in the socket.
Alveolar Osteitis (AO) is simply an inammation of the alveolar
process of maxilla or mandible. Though self-limiting, the condi-
tion sometimes lasts up to 7 days post extraction characterized by
dull aching radiating pain which may reach the temple, eye or neck.
At times the pain can be so severe that it cannot even be relieved
by analgesics [3]. Halitosis is a common symptom. The term al-
veolar Osteitis is taken into consideration synonymous with "dry
socket"; however, some believe that dry socket means a focal or
localized alveolar Osteitis [4]. An instance of any other kind of
Osteitis is focal sclerosing/condensing Osteitis. The phrase dry
socket is used due to the fact that the socket has a dry appear-
ance once the blood clot is lost and particles are washed away.
Alveolar Osteitisusually does not show any signs such as fever or
Abstract
Alveolar Osteitis (AO) is an inammation of the alveolar process of maxilla or mandible. Though self-limiting, the condition
sometimes lasts up to 7 days post extraction characterized by dull aching radiating pain which may reach the temple, eye or
neck. This article discusses the etiology, pathogenesis, risk factors for dry socket and also elaborates the various methods and
techniques in the prevention and management of dry socket. Etiology of alveolar Osteitis has not been well established; with
ranging descriptive denitions and diagnostic criteria exist to elucidate alveolar Osteitis. Alveolar Osteitis is a complication that
can be avoided by taking necessary preventive measures. It can be prevented by use of antibiotics, irrigation, and maintenance
of oral hygiene. Despite lots of research being done, there is no clarity regarding the management of dry socket. Though
there is no specic treatment for alveolar osteitis, eugenol dressings and curettage cut back the incidence of it. Studies did lack
proper analysis and clear answers regarding the management of dry socket. There is yet no universally accepted preventive
measure or management and further detailed studies are necessary to establish concrete conclusions.
Keywords: Dry socket; AlveolarOsteitis; Management; Fibrinolysis; Dental Extractions; Alvogyl; Eugenol; Complication.
Santhosh kumar1*, Suhas Manoharan2, Nabeel Nazar3
1 Reader, Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospital, Saveetha University.
2 Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospital, Saveetha University.
3 Reader, Department of Oral and Maxillofacial Surgery, Saveetha Dental College and Hospital, Saveetha University.
Santhosh kumar, Suhas Manoharan, Nabeel Nazar. Dry Socket and Its Management - An Overview. Int J Dentistry Oral Sci. 2021;08(04):2158-2161.
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lymphadenitis; only erythema and minimal oedema is present in
the soft tissues around the socket. Signs may include an empty
socket, which is partially or totally devoid of blood clot. Bone
may be visible or the socket may contain food debris which on
removal exposes the bone [5]. The exposed bone is sensitive and
painful on touch. Inamed soft tissues surrounding the socket
may overlie the socket and hide the dry socket from examination.
Etiology Of Dry Socket
Most authors concur that surgical injury assume a huge part in
formation of AO. Surgical extractions, in contrast with nonsurgi-
cal extractions, result in higher incidence rate of AO [6]. Lilly et
al. [7] found that surgical extractions involving reection of ap
and removal of bone will probably cause AO. Numerous investi-
gations assert that administrator's experience is a hazard factor for
development of AO. Larsen [8] presumed that specialist's naiveté
could be identied with a greater injury amid the extraction, par-
ticularly surgical extraction of mandibular third molars. Alexan-
der [1] and Oginni et al. [9] announced a higher occurrence of AO
following extractions performed by the less experienced admin-
istrators. Subsequently the aptitude and experience of the admin-
istrator ought to be contemplated. It is also believed that alveolar
Osteitis is a common occurrence post extraction of mandibular
third molars. It isexplained that reduced vascularity, decreased
ability to produce granulation tissue and increased bone density
maybe the causative factors [10]. However, there is no proof re-
garding decreased vascularity and alveolar Osteitis. The reason for
such site-specic occurrence maybe due to alarge percentage of
mandibular third molar extractions [11].
Physical removal or dislodgement of the clot is also a popularly
discussed theory which maybe probably due to negative pressure
created during situation like sucking through a straw. However,
there is no solid evidence regarding this issue. The cause of dry
socket is not absolutely understood [12]. Typically, following ex-
traction of a tooth, blood is extravagated into the socket, and a
blood clot is formed. This blood clot is replaced with granulation
tissue which consists of broblasts and endothelial cells derived
from remnants of the periodontal membrane, surrounding alveo-
lar bone and gingival mucosa. In time this in turn is changed to
coarse, brillar bone and ultimately to mature, woven bone. The
clot may fail to form due to poor blood supply. The poor blood
supply maybe due tofactors such as smoking, anatomical site,
bone density and conditions which cause sclerotic bone to form.
The clot can also be misplaced due to excessive mouth rinsing,
or collapse in advance due to brinolysis [13] Fibrinolysis is the
degeneration of the clot and can be because of the conversion
of plasminogen to plasmin and formation of kinins. Elements
which promote brinolysis include local trauma, oestrogens, and
pyroxenes from microorganism [14].
Microorganism may additionally colonize the socket, and result in
dissolution of the clot. Bacterial breakdown and brinolysis are
the important contributing factors to the lack of the clot. Bone
tissue is uncovered to the oral environment, and a localized in-
ammatory reaction takes vicinity with in the adjoining marrow
areas. This localizes the irritation to the walls of the socket, which
becomes necrotic. The necrotic bone in the socket is slowly sepa-
rated by osteoclasts and fragmentary sequestra may also form.
The bones of the jaws seem to have a few evolutionary resist-
ances to this procedure [15].
Pathogenesis Of Dry Socket
Recovery from Alveolar Osteitis is slow and gradual because tis-
sue should develop from the surrounding gingival mucosa, which
takes longer than the regular formation of a blood clot.
Rozantis et al [16] studied the relationship between streptococ-
cus mutans and alveolar Osteitis. Delayed healing was seen in
extraction sites after microorganisms were inoculated in to the
extraction sites. Bacteria and microorganisms are known to cause
alveolar Osteitis. Patients with poor oral hygiene, periodonti-
tis, pericoronitis and other advanced periodontal conditions are
known to show increased incidence of alveolar Osteitis [17].
Violent curettage or irrigation of the socket may also cause dis-
lodgement of the clot formed and cause a dry socket. There also
theories suggestive of a female predilection. Alveolar Osteitis is
associated with the usage of oral contraceptives. Oral contracep-
tives became popular in the early 1960s and a positive correlation
was seen between occurrence of alveolar Osteitis and usage of
oral contraceptives [18]. This correlation is due to oestrogen lev-
els as the oestrogen hormone plays a major role in brinolysis. It
is believed that oestrogen activates the brinolytic process lead-
ing to increases in certain factors such as II. VII, VIII and X and
plasminogen causing lysis of the blood clot.
Moreover, in a series of 4000 extractions, it was found that there
was clear female predilection irrespective of the usage of oral
contraceptives [18]. A brin clot is made of thromb in and -
brinogen in a post extraction socket and over this, the epithelium
migrates. New blood vessels grow into the clot during granulation
tissue formation and this clot degrades through the activity of
broblast and brinolysis through the plasmin before the start
of osteoproliferation. Birn [19] discovered that the plasmin like
activity in dry sockets was not present at normal extraction sites.
Kinases are liberated during inammation through direct or indi-
rect activation of plasminogen in the blood. These kinases cause
lysis and destruction of the blood clot. Tissue or plasma activa-
tors activate and convert the plasminogen to brin, resulting in
the dissolution of the clot by disintegration of brin. This plasmi-
nogen pathway activation, can be direct (physiologic) or indirect
(non-physiologic). Direct activators are released to the alveolar
bone cells after trauma. Indirect activators are released by bacte-
ria. Direct extrinsic activators are tissue plasminogen activators
and endothelial plasminogen activators. Direct intrinsic activators
include the components of plasma such as factor XII, urokinase
[20].
Risk Factors For Dry Socket
Patients with systemic illness such as diabetes or otherimmuno-
compromised conditions also have higher incidences of alveolar
Osteitis due to impaired healing of the wound. It is also seen that
incidence of dry socket increases with age. Hence it is advised to
perform any mandibular third molar extraction before the age of
24yrs especially among females to prevent occurrence of alveolar
Osteitis. Smoking is alsoa major risk factor for alveolar Osteitis.
Remnants of tooth root or bone fragments can also result in dis-
turbed or poor wound healing which may cause alveolar Osteitis.
Radiotherapy might decrease the blood supply to alveolar bone
which may lead to occurrence of a dry socket [21].
It was inferred that utilization of local anaesthesia with vaso-
Santhosh kumar, Suhas Manoharan, Nabeel Nazar. Dry Socket and Its Management - An Overview. Int J Dentistry Oral Sci. 2021;08(04):2158-2161.
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constrictors will increase the incidence of AO. It was also found
that AO frequency will increase with inltration anaesthesia as
a result of the ischemia that ends up in poor or reduced blood
supply [22]. However, the studies that followed indicated that the
ischemia remains for only about two hours and is replaced by
reactive hyperaemia, which makes it inapplicable for disintegra-
tion of the blood clot [23]. One study conveyed that there is no
signicant difference in AO prevalence following extraction of
teeth requiring inltration anaesthesia versus regional block an-
aesthesia with vasoconstrictor [24]. It is presently accepted that
local ischemia owing to vasoconstrictve effect of local anaesthesia
has no role in the development of AO. Limited proof suggests
higheroccurrence of AO during single extractions on contrast to
multiple extractions. According to one study, AO prevalence was
7.3% following single extractions and 3.4% following multiple
extractions [25]. This difference could be as a result of less pain
tolerance in patients who come for single tooth extractions. Also,
it could be that most patients with multiple extractions have peri-
odontally compromised teeth or unhealthy dentition.
Prevention Of Dry Socket
As AO is a commonly occurring complication after tooth extrac-
tions, a lot studies have been done and many theories and tech-
niques have been put forward to help in preventing alveolar os-
teitis. But still no single method or technique has been universally
accepted in the prevention of AO. Systemic and topical antibiot-
ics have been proposed to prevent AO, however there are argu-
ments claiming that regular use of topical antibiotics have led to
resistance among certain strains of bacteria. Topical tetracycline
claimed to be effective but it showed foreign body reaction on
topical application. Commonly used systemic antibiotics to treat
AO are clindamycin, erythromycin and metronidazole [26].
An author suggested that placing any medicament into the alveo-
lus will show certain degree of improvement in case of alveolar
Osteitis [27]. Analgesics such as acetaminophen with oxycodone,
codeine or hydroxycodone maybe used. Many studies also sug-
gest the usage of 0.12% chlorhexidine mouthwash after extrac-
tion of mandibular third molars result in decreased occurrence
of dry socket [28-32]. Also, usages of antibrinolytic agents such
as para-hydroxybenzoic acid or PHBA and tranexamic acid have
shown to reduce the incidence of alveolar Osteitis. PHBA is
known to have anti-microbial effects but is known to impair bone
healing from animal studies. Meanwhile, tranexamic acid is not
widely accepted and is not proved to reduce the incidence of al-
veolar Osteitis. The usage of an antiseptic agent 9-aminoacridine
was speculated to reduce the incidence of AO however there is
no evidence to support this claim. Eugenol was promoted to be
used along with dressings but the irritant effect leading to delayed
wound healing has been well described in literature and hence
is not commonly preferred to prevent the incidence of alveolar
Osteitis [33-35].
Management Of Dry Socket
Management of alveolar Osteitis is not as speculative as preven-
tion. Alveolar Osteitis is a self-healing condition and there is no
established treatment for alveolar Osteitis. Analgesics and antibi-
otics are recommended to relieve pain. Medicated dressings are
also mentioned in literature however, intra alveolar dressings are
known to delay the wound healing process. Alvogyl containing
butamben ananaesthetic, eugenol an analgesic and iodoforman
antimicrobial agent are used to pack the sockets. However certain
studies claim packing with alvogyl caused marked inammation
and retarded healing [36, 37].
Summary
Alveolar Osteitis is a complication that can be avoided by tak-
ing necessary preventive measures. Despite lots of research be-
ing done, there is no clarity regarding the management of dry
socket. Very little progress has been created in addressing this
usually encountered and unsightly surgical condition in patients.
Literature related to alveolar Osteitis is not consistent and is con-
icting. Studies are poorly done, have variable styles and applied
mathematics, biases, lack analysis, or encompass individual opin-
ions. Etiology of alveolar Osteitis has not been well established;
with ranging descriptive denitions and diagnostic criteria exist
to elucidate alveolar Osteitis. This lack of over simplied answer-
consistent with one author, is the result of the initiation of -
brinolytic method which seems to be associated with associate
interfacing of multiple freelance factors. Analysis done to prevent
this complication have yielded no single universally acceptable
technique or success. However, a large number of intra-alveolar
medicaments are instructed in the literature and are offered on the
market. Even if complications or severe reactions from prepa-
rations placed with in the socket are rare, most have rumoured
some negative reactions. If adverse reactions do occur, this body
of literature does not offer enough support for the treating practi-
cian. The formula to management of this complication ought to
begin with patient education and patients with classiable risk fac-
tors ought to learn intimately concerning this anticipated compli-
cation. Any investigation and well-designed studies are necessary
to draw rm conclusions and to clarify this complication.
Conclusion
The prevalence of dry socket is inevitable. It can be prevented
by use of antibiotics, irrigation, and maintenance of oral hygiene.
Though there is no specic treatment for alveolar osteitis, eugenol
dressings and curettage cut back the incidence of it. Studies did
lack proper analysis and clear answers regarding the management
of dry socket. There is yet no universally accepted preventive
measure or management. Further studies and investigations need
to be done to establish concrete conclusions.
References
[1]. Alexander RE. Dental extraction wound management: a case against
medicating postextraction sockets. J Oral Maxillofac Surg. 2000 May
1;58(5):538-51.PubmedPMID: 10800910.
[2]. Birn H. Etiology and pathogenesis of brinolyticalveolitis (“dry socket”).
International journal of oral surgery. 1973 Jan 1;2(5):211-63.
[3]. Brekke JH, Bresner M, Reitman MJ. Eect of surgical trauma and polylac-
tate cubes and granules on the incidence of alveolar osteitis in mandibular
third molar extraction wounds. J Can Dent Assoc. 1986 Apr;52(4):315-9.
PubmedPMID: 3518884.
[4]. Colby RC. e general practitioner's perspective of the etiology, prevention,
and treatment of dry socket. Gen Dent. 1997 Sep-Oct;45(5):461-7. Pub-
medPMID: 9515413.
[5]. Field EA, Speechley JA, Rotter E, Scott J. Dry socket incidence compared
after a 12 year interval. Br J Oral Maxillofac Surg. 1985 Dec;23(6):419-27.
Pubmed PMID: 2933062.
[6]. Torres-Lagares D, Serrera-Figallo MA, Romero-Ruíz MM, Infante-Cossío
P, García-Calderón M, Gutiérrez-Pérez JL. Update on dry socket: a review
Santhosh kumar, Suhas Manoharan, Nabeel Nazar. Dry Socket and Its Management - An Overview. Int J Dentistry Oral Sci. 2021;08(04):2158-2161.
2161
OPEN ACCESS https://scidoc.org/IJDOS.php
of the literature. Med Oral Patol Oral Cir Bucal. 2005 Jan-Feb;10(1):81-5;
77-81. English, Spanish. Pubmed PMID: 15627911.
[7]. Lilly HA, Lowbury EJ, Wilkins MD, Zaggy A. Delayed antimicrobial ef-
fects of skin disinfection by alcohol. J Hyg (Lond). 1979 Jun;82(3):497-500.
Pubmed PMID: 448066.
[8]. Larsen PE. Alveolar osteitis after surgical removal of impacted mandibular
third molars: Identication of the patient at risk. Oral Surg Oral Med Oral
Pathol. 1992 Apr;73(4):393-7. Pubmed PMID: 1574298.
[9]. Oginni FO, Fatusi OA, Alagbe AO. A clinical evaluation of dry socket in a
Nigerian teaching hospital. J Oral Maxillofac Surg. 2003 Aug;61(8):871-6.
Pubmed PMID: 12905436.
[10]. Blum IR. Contemporary views on dry socket (alveolar osteitis): a clinical
appraisal of standardization, aetiopathogenesis and management: a critical
review. Int J Oral Maxillofac Surg. 2002 Jun;31(3):309-17. Pubmed PMID:
12190139.
[11]. Amaratunga ND, Senaratne CM. A clinical study of dry socket in Sri
Lanka. Br J Oral Maxillofac Surg. 1988 Oct;26(5):410-8. Pubmed PMID:
3056513.
[12]. Jaafar N, Nor GM. e prevalence of post-extraction complications in an
outpatient dental clinic in Kuala Lumpur Malaysia--a retrospective survey.
Singapore Dent J. 2000 Feb;23(1):24-8. Pubmed PMID: 11602946.
[13]. Rud J. Removal of impacted lower third molars with acute pericoronitis
and necrotising gingivitis. Br J Oral Surg. 1970 Mar;7(3):153-60. Pubmed
PMID: 5272558.
[14]. Peñarrocha M, Sanchis JM, Sáez U, Gay C, Bagán JV. Oral hygiene and
postoperative pain after mandibular third molar surgery. Oral Surg Oral
Med Oral Pathol Oral RadiolEndod. 2001 Sep;92(3):260-4. Pubmed
PMID: 11552141.
[15]. Ygge J, Brody S, Korsan-Bengtsen K, Nilsson L. Changes in blood coagula-
tion and brinolysis in women receiving oral contraceptives. Comparison
between treated and untreated women in a longitudinal study. Am J Obstet
Gynecol. 1969 May 1;104(1):87-98. Pubmed PMID: 4180662.
[16]. J. Rozanis, I. D. Schoeld, B. A. Warren, “Is dry socket preventable?” Dental
Journal.1977; 43(5):233–236.
[17]. MacGregor AJ. Aetiology of dry socket: a clinical investigation. Br J Oral
Surg. 1968 Jul;6(1):49-58. Pubmed PMID: 5244107.
[18]. Blondeau F, Daniel NG. Extraction of impacted mandibular third molars:
postoperative complications and their risk factors. J Can Dent Assoc. 2007
May;73(4):325. Pubmed PMID: 17484797.
[19]. Birn H. Bacteria and brinolytic activity in “dry socket”. ActaOdontologi-
caScandinavica. 1970 Jan 1;28(6):773-83.
[20]. Moore JW, Brekke JH. Foreign body giant cell reaction related to placement
of tetracycline-treated polylactic acid: Report of 18 cases. Journal of Oral and
Maxillofacial Surgery. 1990 Aug 1;48(8):808-12.
[21]. Bystedt H, Nord CE, Nordenram A. Eect of azidocillin, erythromycin,
clindamycin and doxycycline on postoperative complications after surgi-
cal removal of impacted mandibular third molars. Int J Oral Surg. 1980
Jun;9(3):157-65. Pubmed PMID: 6777314.
[22]. Larsen PE. e eect of a chlorhexidine rinse on the incidence of alveolar
osteitis following the surgical removal of impacted mandibular third molars.
J Oral Maxillofac Surg. 1991 Sep;49(9):932-7. PubmedPMID: 1886022.
[23]. Hermesch CB, Hilton TJ, Biesbrock AR, Baker RA, Cain-Hamlin J, McCla-
nahan SF, Gerlach RW. Perioperative use of 0.12% chlorhexidinegluconate
for the prevention of alveolar osteitis: ecacy and risk factor analysis. Oral
Surg Oral Med Oral Pathol Oral RadiolEndod. 1998 Apr;85(4):381-7. Pub-
med PMID: 9574945.
[24]. Tjernberg A. Inuence of oral hygiene measures on the development of al-
veolitissicca dolorosa after surgical removal of mandibular third molars. Int J
Oral Surg. 1979 Dec;8(6):430-4. Pubmed PMID: 120340.
[25]. Birn H. Antibrinolytic eect of Apernyl® in “dry socket”. International
journal of oral surgery. 1972 Jan 1;1(4):190-4.
[26]. Malay KK, Duraisamy R, Brundha MP, Kumar MP. Awareness regarding
anemia among 1 st year dental undergraduate students. Drug Invention To-
day. 2018 Aug 1;10(8).
[27]. Kumar MS. Knowledge, attitude and practices towards oral health among
law students in Chennai. Journal of Pharmaceutical Sciences and Research.
2016 Jul 1;8(7):650.
[28]. Kumar MP. Dental management of patients on antiplatelet therapy: Litera-
ture update. Asian J Pharm Clin Res. 2016;9(3):26-31.
[29]. Kumar S. Newer delivery systems for local anesthesia in dentistry. J Pharm
Sci Res. 2015;7(5):252-5.
[30]. Ahamed A, Kumar MS. Knowledge, attitude and perceived condence in
handling medical emergencies among dental students. J IntSocPrev Com-
munity Dent. 2017 Nov-Dec;7(6):364-369. PubmedPMID: 29387622.
[31]. Kumar S. Knowledge, attitude and practices of dental students toward dental
management of patients on antiplatelet therapy. Asian J Pharm Clin Res.
2016;9(30):270-6.
[32]. Gayathri MM. Knowledge, Awareness and Attitude among dental students
about hepatitis B infection. Journal of Pharmaceutical Sciences and Re-
search. 2016 Mar 1;8(3):168.
[33]. Kumar SM. Knowledge, Attitude and practices regarding needlestick inju-
ries among dental students. Asian Journal of Pharmaceutical and Clinical
Research. 2016;9(4):312-5.
[34]. Ritzau M. e prophylactic use of tranexamic acid (Cyklokapron®) on al-
veolitissicca dolorosa. International Journal of Oral Surgery. 1973 Jan
1;2(5):196-9.
[35]. Johnson WS, Blanton EE. An evaluation of 9-aminoacridine/gelfoam to re-
duce dry socket formation. Oral Surgery, Oral Medicine, Oral Pathology.
1988 Aug 1;66(2):167-70.
[36]. Sivakumar N, Sundari KK, Chandrasekar S, Kumar MP. A review on smile
arc-An orthodontist's perspective. Drug Invention Today. 2018 Sep 2;10.
[37]. Bloomer CR. Alveolar osteitis prevention by immediate placement of medi-
cated packing. Oral Surg Oral Med Oral Pathol Oral RadiolEndod. 2000
Sep 1;90(3):282-4.PubmedPMID: 10982947.