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\def\RunningAuthor{Divya Sanjeevi Ramakrishnan et al.}
\firstPage{6155}
\articleType{Review Article}
\receivedDate{25 May 2020}
\acceptedDate{16 Jul 2020}
\revisedDate{16 Jun 2020}
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\title{\textbf{Efficacy of hyaluronic acid gel in management of post-operative complications after removal of third molar - A Systematic review}}
\author{Divya~Sanjeevi~Ramakrishnan\textsuperscript{*},  
            Sudarssan~Subramaniam~Gouthaman,  
            Janani~Kandamani, 
            Senthilnathan~Periasamy~\\[5pt]{Department of Oral and Maxillofacial Surgery, Saveetha Dental College, Saveetha University, Chennai, Tamil Nadu, India}}

\begin{abstract}
The surgical removal of third molar is the commonly performed procedure in oral and maxillofacial surgery. It takes several days to recover from the complications following removal of the third molar. The common postoperative complications are pain, swelling, trismus, alveolar osteitis after third molar removal. The aim of this systematic review was to thoroughly analyse the existing literature to evaluate the effect of intra socket versus extra socket application of hyaluronic acid gel in management of postoperative complications after third molar removal. The objective of this systematic review is to assess the efficacy of intra socket versus extra socket application of hyaluronic acid gel compared to placebo or no treatment in management of post-operative complications after removal of third molar. The data bases of PubMed, Cochrane and google scholar were searched for the related topics along with a complimentary manual search of all oral surgery journals till October 2018. The data collection form was based on analysis of included studies for their quality assessment and publication bias. The primary outcome measure was post-operative pain and the secondary outcome measures were post-operative swelling \& post-operative mouth opening. Three articles were selected based on the inclusion criteria. The included studies were randomized controlled trials. The clinical evidence from this review shows hyaluronic acid gel application is found to be beneficial in reducing pain, swelling \& trismus after surgical removal of third molar. After contemplating its pivotal role in various anti- inflammatory diseases, it is prudent to consider as an alternative in managing postoperative sequelae of third molar removal.\textbf{\space }
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Complications of third molar removal,\newline Healing of extraction socket,\newline Hyaluronic acid gel,\newline Third molar removal
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Divya~Sanjeevi~Ramakrishnan~\\ Phone:\ +91 8870497174~\\  Email:\ divyaramakrishnan55@gmail.com
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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        \makeatother
        
    
\section{ Introduction}
The mandibular third molar is the commonest tooth impacted in the oral cavity. The frequent cause for failure of eruption in the alveolar arch is due to lack of space as a pattern of evolution.Complications are inevitably associated with such surgical removal of third molars. The frequency and severity of the complications associated with surgical procedures are influenced by various factors that are related to the procedure, patient, and surgeon \unskip~\citep{839824:19888485}. Following the days after third molar surgery, pain, facial swelling, alveolar osteitis \unskip~\citep{839824:19888494} and restriction of mouth opening, reduced quality of life were the notable changes \unskip~\citep{839824:19888496}. Variable amount of oedema or swelling is expected after any surgical procedurs,\unskip~\citep{839824:19888493} leading to trismus or reduced mouth opening \unskip~\citep{839824:19888492}. The maximum size of the swelling is seen at 1{\textendash}2 days after procedure, begins to subside on the third or fourth day and resolves by the end of the first week. Postoperative trismus, swelling, and pain levels \unskip~\citep{839824:19888483},varies with the age, gender, operating time and surgical difficulty of the impacted teeth \unskip~\citep{839824:19888488}. Various agents have been investigated to prevent or reduce these postoperative sequelae \unskip~\citep{839824:19888503}. Management of such postoperative inflammation and associated symptoms requires adequate anti-inflammatory and antibiotic therapy \unskip~\citep{839824:19888498}.

Hyaluronan or hyaluronic acid (HA) is a biomaterial that has been shown to accelerate the wound healing. Karl Meyer and John Palmer in 1934 discovered HA by segregating from vitreous body of a cow. Beginning in 1960s, HA-based compounds were constituted for skin lesions, 1980s for cataract corrective surgeries. By 1980s advanced toward joint injections, finally in 1990s, hyaluronic acid emerged in aesthetic field where at present it is highly recognized. The name hyaluronic acid is derived from Greek word denoting ``glass \& sugar''. 


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\label{f-046f9734f5aa}
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\egroup
Hyaluronic acid is distinguished for its cellular metabolism and other biological processes of tissue repair .It is found in many tissues with its highest concentrations in connective tissues including the synovial fluid in human and all tissue and body fluids of vertebrates. It has been described to play an crucial roles in wound healing by inducing early granulation tissue formation by promoting re-epithelialization and also angiogenesis during the healing phase \unskip~\citep{839824:19888479}. Thus, HA has been used to prevent or reduce postoperative inflammation and associated symptoms \unskip~\citep{839824:19888506}. The effects such as non-immunogenic and non-toxicity allows it to be used in many fields, such as ophthalmology, dermatology, and rheumatology. HA is available in gel or liquid forms to be applied topically in the oral cavity \unskip~\citep{839824:19888500,839824:19888499}. Transforming growth factor (TGF) \ensuremath{\beta }-1, basic fibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) all stimulate hyaluronic acid production by fibroblasts. Furthermore, their effects appear to be synergistic and not related to mitosis and, by extension, proliferation \unskip~\citep{839824:19888504}. It would, therefore, appear that at least some of the effects of these growth factors upon cell proliferation and migration are mediated through the hyaluronic acid pathway \unskip~\citep{839824:19888490}. The circumstance is even though not clear, there would have all the profits by exogenous utilization of hyaluronic acid on extracellular matrix remodelling \unskip~\citep{839824:19888478}.


\begin{table*}[!htbp]
\caption{\boldmath {Risk of Bias -Major and Minor Criteria} }
\label{tw-7c00ea8537e4}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06600000000000001\linewidth-2\tabcolsep}p{\dimexpr.11639999999999999\linewidth-2\tabcolsep}p{\dimexpr.1077\linewidth-2\tabcolsep}p{\dimexpr.1099\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}p{\dimexpr.10\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Author \& Year & Randiomi- Sation & Allocation Concealment & Assessor Blinding & Dropouts Described  & Sample Justified & Baseline Comparision & I/E crtiteria & Method Error\\
\tblmidrule 
1. &
  \unskip~\cite{839824:19888495} &
  yes &
  no &
  yes &
  none &
  no &
  yes &
  yes &
  no\\
2 &
  \unskip~\cite{839824:19888501} &
  yes &
  no &
  no &
  none &
  yes &
  yes &
  yes &
  No\\
3 &
  \unskip~\cite{839824:19888481} &
  yes &
  no &
  yes &
  none &
  no &
  yes &
  yes &
  no\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {General Characteristics of The Included Studies} }
\label{tw-0ae970619efd}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06359999999999999\linewidth-2\tabcolsep}p{\dimexpr.14880000000000003\linewidth-2\tabcolsep}p{\dimexpr.1476\linewidth-2\tabcolsep}p{\dimexpr.1314\linewidth-2\tabcolsep}p{\dimexpr.1086\linewidth-2\tabcolsep}p{\dimexpr.1159\linewidth-2\tabcolsep}p{\dimexpr.1062\linewidth-2\tabcolsep}p{\dimexpr.1779\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Author \& year & Title of the article  & Study design & Sample size & Mean Age \& gender  & Control group  & Intervention group\\
\tblmidrule 
1. &
  \unskip~\cite{839824:19888495} &
  The Effect of Cross-Linked Hyaluronic Acid in Surgical Extraction of Impacted Mandibular Third Molars  &
  Randomised split mouth study &
  N=14 &
  25.25 \ensuremath{\pm} 3.1 \mbox{}\protect\newline Years \mbox{}\protect\newline (males =7, \mbox{}\protect\newline females=7) &
  placebo &
  Intra \mbox{}\protect\newline Socket  \mbox{}\protect\newline Application of hyaluronic acid gel.\\
2. &
  \unskip~\cite{839824:19888501} &
  Effects of hyaluronic acid on bleeding following third molar extraction  &
  Randomised cross over study  &
  N=40 &
  18-35 years &
  placebo &
  Extra  \mbox{}\protect\newline Socket application (edge of the socket).\\
3. &
  \unskip~\cite{839824:19888481} &
  The antioxidant and anti-inflammatory efficiency of \mbox{}\protect\newline hyaluronic acid after third molar extraction  &
  Randomised cross over study &
  N=40 &
  26.6 \ensuremath{\pm} 6.3 year &
  placebo &
  Extra  \mbox{}\protect\newline Socket application (edge of the socket). \\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}
 \textbf{\space }


\begin{table*}[!htbp]
\caption{\boldmath {General Characteristics of The Included Studies} }
\label{tw-6e44d8971ce3}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.08570000000000002\linewidth-2\tabcolsep}p{\dimexpr.2043\linewidth-2\tabcolsep}p{\dimexpr.21980000000000008\linewidth-2\tabcolsep}p{\dimexpr.18019999999999992\linewidth-2\tabcolsep}p{\dimexpr.31000000000000007\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Author \& year & Dosage of hyaluronic acid gel & Outcomes meauresd at POD day & Variables of interest\\
\tblmidrule 
1. &
  \unskip~\cite{839824:19888495} &
  0.33 ml cross-linked HA gel (HyaDENT BG{\textsuperscript{\textregistered}}, 20 mg HA/ml)  &
  2nd ,4th ,7th day &
  Pain by VAS Score , Swelling measured by orotragal and Mentotragal distances. Mouth opening was recorded by measuring Interincisal distance \\
2. &
  \unskip~\cite{839824:19888501} &
  A 0.2 ml HA gel (0.8\% [w/v]; Gengigel, Ricerfarma, Italy) following tooth removal (n=20). &
  POD 1st hour,3rd day,7th day &
  Pain by VAS Score , Swelling measured by orotragal and Mentotragal distances. Mouth opening was recorded by measuring Interincisal distance \\
3. &
  \unskip~\cite{839824:19888481} &
  0.8\% [w/v]; Gengigel, Ricerfarma, Italy) following tooth removal  &
  Immediately after extraction, POD 7th day. &
  Pain by VAS Score, Mouth opening was recorded by measuring Interincisal distance.\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

\begin{table*}[!htbp]
\caption{\boldmath {Outcome Measures Assessed in The Included Studies} }
\label{tw-76f9b098fc39}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.06929999999999999\linewidth-2\tabcolsep}p{\dimexpr.1557\linewidth-2\tabcolsep}p{\dimexpr.195\linewidth-2\tabcolsep}p{\dimexpr.1222\linewidth-2\tabcolsep}p{\dimexpr.1389\linewidth-2\tabcolsep}p{\dimexpr.1589\linewidth-2\tabcolsep}p{\dimexpr.16\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}S.No & Author Name & Outcomes Measured & Other Outcomes & Pain & Maximum Incisal Opening & Facial Swelling\\
\tblmidrule 
1. &
  \unskip~\cite{839824:19888495} &
  Cross-Linked Hyaluronic Acid in Surgical Extraction of Impacted Mandibular Third Molars &
  Not specified &
  VAS score &
  Difference between interinicisal distance before and after surgery &
  Swelling measured by orotragal and mentotragal distances\\
2. &
  \unskip~\cite{839824:19888501} &
  Effects of hyaluronic acid on bleeding following third molar extraction &
  Bleeding time &
  VAS score &
  Difference between interinicisal distance before and after surgery &
  Swelling measured by orotragal and mentotragal distances\\
3. &
  \unskip~\cite{839824:19888481} &
  The antioxidant and anti-inflammatory efficiency of hyaluronic acid after third molar extraction &
  LPO levels were determined by \mbox{}\protect\newline Ledwozyw's method \& GSH measurements were performed  &
  VAS score &
  Difference between interinicisal distance before and after surgery &
  Not measured\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

    
\section{Materials and Methods}
The Data Bases of PubMed Advanced, Cochrane and Google scholar were searched until October 2018 using controlled vocabulary and free text terms. This electronic search includes text articles only in English language, human species and to include all the randomized control studies that are relevant for the inclusion criteria of this systematic review. 

\textbf{Inclusion criteria}

Randomized controlled trials

Clinical trials

Patients undergoing surgical removal of impacted upper \& lower third molar.

Hyaluronic acid Gel is used for the management of postoperative complications after third molar surgery.

Placebo

Post-operative pain, Post-operative swelling, Post- operative mouth opening is evaluated following third molar surgery

\textbf{Exclusion criteria}

The following studies were excluded,

Other than gel forms of hyaluronic acid are excluded.

Studies with combination of hyaluronic acid with other drugs are excluded.

Case reports / Case series

Pilot studies

Review articles

Animal studies

In vitro studies

Studies not meeting inclusion criteria were excluded.

\textbf{Search Methodology}

Electronic search was carried out using the keywords in the Search engines- PubMed, Cochrane and Google Scholar which yielded a total of 19 articles. Hand search yielded two articles which were the same as those obtained in PubMed. Based on predetermined inclusion and exclusion criteria, the titles of the studies identified from the search were assessed independently by two review authors (Dr.Divya S.R, Dr.Senthilnathan periasamy). Conflicts concerning inclusion of the studies were resolved by discussion. Eleven studies were identified from the search after excluding duplications. Eight articles were excluded after reading titles and abstracts. Full text articles were retrieved for three relevant studies (Figure~\ref{f-046f9734f5aa}). The reference list of the full text articles were reviewed for identifying additional studies. Quality assessment criteria evaluated for the studies by two review authors in accordance with PRISMA guidelines. The risk of bias for each study was independently assessed by the review authors and conflicts concerning risk of bias were sorted by discussion.

\textbf{\textbf{Quality of Evidence}}

Out of three articles included in this review, all three articles shows as level 2 evidence \unskip~\citep{839824:19888495,839824:19888481,839824:19888501}. Type of randomization \& allocation concealment method were not mentioned in all three articles \unskip~\cite{839824:19888481,839824:19888501,839824:19888495}. Assessor blinding was done in \unskip~\cite{839824:19888495}  \& \unskip~\cite{839824:19888481}  study. Sample size justification was given in \unskip~\cite{839824:19888501}  study. There was no method error in all studies. The risk of bias is moderate for two studies, \unskip~\cite{839824:19888495,839824:19888481}, and high for \unskip~\cite{839824:19888501}.
    
\section{Results and Discussion}
There were 2 randomized controlled trials \& 1 clinical trial is included in this systematic review. The data extraction is done for all 3 studies (Tables~\ref{tw-0ae970619efd} and~\ref{tw-6e44d8971ce3}). The various outcome measures assessed in the included studies were categorised in Table~\ref{tw-76f9b098fc39}.

According to Amr bayoumi \unskip~\citep{839824:19888495}, a total of fourteen patients were included in this study. The mean age of the participants was 25.25 \ensuremath{\pm} 3.1years (range: 22-32 years).

Once after the surgical removal of third molar, 0.33 ml cross-linked  HA gel was set into study socket and plain Gelfoam in the control socket. Finally closure of flap using 3-0 Vicryl sutures. All the outcome variables were measured on post-operative second, fourth and seventh day. The mean MMO was significantly increased all through the study period and most distinct difference is seen at 7\ensuremath{^{th}} postoperative day for HA group (P{\textless}0.001).the facial swelling for the HA group on the 7\ensuremath{^{th}} postoperative day was significantly less (P{\textless}0.05).The mean pain VAS scores declined gradually in both groups, whereas it is significant on postoperative day seven for HA group. 

According to Gocmen et al  \unskip~\citep{839824:19888501}, total of forty patients was included and mean patient age was 24.8 years (18-35 years). 0.8\% HA was applied on the edge of the extraction socket for the HA group and no intervention for control group. The pain score by VAS, and MIO, swelling measured at POD 1\ensuremath{^{st}} hr, 3\ensuremath{^{rd}}, 7\ensuremath{^{th}} day. MIO and VAS were not statistically significant between groups at 1\ensuremath{^{st}} hour, 3\ensuremath{^{rd}} day and 7\ensuremath{^{th}} day. However 3\ensuremath{^{rd}} day outcomes of facial swelling was increased for HA group.

According Gocmen et al \unskip~\citep{839824:19888481}, with total of 40 patients included and mean age was 26.6 \ensuremath{\pm} 6.3 years. Applications of 0.8\% HA gel at the edge socket area for study group and no intervention for control group. The outcome variables were evaluated at POD 1\ensuremath{^{st}}, 7\ensuremath{^{th}} day. No statistically significant differences for VAS and MIO scores between the groups at postoperative 7\ensuremath{^{th}} day. However mean VAS scores for both groups after 1 week was significantly reduced (p {\textless}0.05).

Following extraction, formation of the blood clot is a fundamental step for socket repair. The formation of fibrin network provides a stable matrix as a base for lymphocytes, macrophages and neutrophils migration, characterizing the acute inflammatory response. Thin collagen fibrils formed by fibroblasts join to newly formed capillaries to form the granulation tissue \unskip~\citep{839824:19888507}. Bone resorption in bone crests in the beginning, while bone deposition is seen at the base of the socket. Mesenchymal cells originated from remnant periodontal ligament and medullar bone differentiate into osteoblastic cells that secrete bone matrix, observed after a week \unskip~\citep{839824:19888486}. Socket healing events result in a thick bony trabecular network containing small medullary spaces at 21 days \unskip~\citep{839824:19888508}. Sequelae after removal of third molars such as nerve injury, pain, swelling, trismus \& dry socket can cause an effect on quality of life. Routine management of such complications include anti-inflammatory drugs, steroids, and analgesics. However prescription of such drugs has its own adverse effects. To promote soft and hard tissue healing, the topical application of antibiotics such as tetracycline and minocycline, or chlorhexidine, platelet-rich fibrin \unskip~\citep{839824:19888480} platelet-rich plasma \unskip~\citep{839824:19888484} and hyaluronic acid \unskip~\citep{839824:19888506} have been used after third molar surgery.

Hyaluronic acid based gels have been used for healing of bone defects , with bone morphogenetic protein 2 (BMP-2), bone matrix, hydroxyapatite \unskip~\citep{839824:19888505}  demineralized or bone graft \unskip~\citep{839824:19888502}. 

Others demonstrated that topical HA promoted healing \unskip~\citep{839824:19888489} and reduced patient discomfort when used as an adjuvant treatment for gingivitis and chronic periodontitis, or postoperatively, following dental implant/sinus elevation procedures \unskip~\citet{839824:19888487}. Topical HA also seems to have been effective in treating oral ulcers \unskip~\citep{839824:19888509}.

One study \unskip~\citet{839824:19888491} showed that there were no difference between study and control groups when a non-cross linked HA used in the socket and it dissolved within 12 hours. 

No statistically significant difference between the groups after mandibular third molar extraction with topical application of sodium hyaluronate gel and an amino acid is seen \unskip~\citep{839824:19888482}. Study conducted by Yilmaz et al \unskip~\citep{839824:19888497}showed that local administration of HA into the extraction socket may alleviate the pain. 

However Afat et al \unskip~\citep{839824:19888477} proved that postoperative oedema can be minimized after third molar surgery when L-PRF combined with HA as L-PRF ensures that certain amount of HA is remained in the socket for a longer duration. When HA is used for dry socket, it acts as stabiliser for matrix formed during healing phase and stimulates migration and proliferation of fibroblasts. 
    
\section{Conclusions}
 Within the limitations of this systematic review, it provides a basis for the routine administration of hyaluronic acid gel to reduce the intensity of post-surgical sequelae such as pain, swelling and trismus. Intra socket application of cross linked hyaluronic acid gel is an effective alternative in reducing post-operative pain, dry socket \& trismus whereas the extra socket application of hyaluronic acid gel is not as efficient.The number of good quality randomized controlled trials included in this review is very limited \& the dosage and type of hyaluronic acid gel is used in the articles of this review are also inconsistent. the method of application of hyaluronic acid gel such as either intra socket or extra socket as well as use of cross linked HA, should be taken into consideration \& comparison of these would prove the reliable method .Use of hyaluronic acid gel in regard to other post-operative parameters such as, bleeding, anti-inflammatory, antioxidant effect should evaluated at larger sample size \& various forms of hyaluronic acid at different dosage should also be considered.

\textbf{Conflict of Interest}

The authors declare that they have no conflict of interest for this study.

\textbf{Funding Support}

The authors declare that they have no funding support for this study.


    

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