Ef icacy of hyaluronic acid gel in management of post-operative complications after removal of third molar-A Systematic review

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 inmanagement of postoperative complications after third molar removal. The objective of this systematic review is to assess the ef icacy 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.Thedata collection formwasbased 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 bene icial in reducing pain, swelling & trismus after surgical removal of third molar. After contemplating its pivotal role in various antiin lammatory diseases, it is prudent to consider as an alternative in managing postoperative sequelae of third molar removal.


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 in luenced by various factors that are related to the procedure, patient, and surgeon (Göktay et al., 2011). Following the days after third molar surgery, pain, facial swelling, alveolar osteitis (Blum, 2002) and restriction of mouth opening, reduced quality of life were the notable changes (Berge, 1997). variable amount of oedema or swelling is expected after any surgical procedurs, (Filho, 2008) leading to trismus or reduced mouth opening (Hupp et al., 2018).The maximum size of the swelling is seen at 1-2 days after procedure, begins to subside on the third or fourth day and resolves by the end of the irst week. Postoperative trismus, swelling, and pain levels (Trindade et al., 2011),varies with the age, gender, operating time and surgical dificulty of the impacted teeth (Lago-Méndez et al., 2007) .Various agents have been investigated to prevent or reduce these postoperative sequelae (Hammad et al., 2011). Management of such postoperative in lammation and associated symptoms requires adequate anti-in lammatory and antibiotic therapy (Ren and Malmstrom, 2007).
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, inally in 1990s, hyaluronic acid emerged in aesthetic ield where at present it is highly recognized. The name hyaluronic acid is derived from Greek word denoting "glass & sugar".
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 luid in human and all tissue and body luids 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 (Mendes et al., 2008).Thus, HA has been used to prevent or reduce postoperative in lammation and associated symptoms (Koray et al., 2014) .The effects such as non-immunogenic and non-toxicity allows it to be used in many ields, such as ophthalmology, dermatology, and rheumatology. HA is available in gel or liquid forms to be applied topically in the oral cavity (Prestwich, 2011;Fatini et al., 1968). Transforming growth factor (TGF) β-1, basic ibroblast growth factor (b-FGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) all stimulate hyaluronic acid production by ibroblasts. Furthermore, their effects appear to be synergistic and not related to mitosis and, by extension, proliferation (Mesa, 2002).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 (Greco et al., 1998).
The circumstance is even though not clear, there would have all the pro its by exogenous utilization of hyaluronic acid on extracellular matrix remodelling (Mast et al., 1993).

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.

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, Postoperative mouth opening is evaluated following third molar surgery

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.

Review articles
Animal studies

In vitro studies
Studies not meeting inclusion criteria were excluded.

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 identi ied from the search were assessed independently by two review     Con licts concerning inclusion of the studies were resolved by discussion. Eleven studies were identi ied 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 1).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 con licts concerning risk of bias were sorted by discussion.  Gocmen et al (2015), and high for Gocmen et al (2017).

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 2  and 3).The various outcome measures assessed in the included studies were categorised in Table 4.
According to Amr bayoumi (Bayoum et al., 2018), a total of fourteen patients were included in this study. The mean age of the participants was 25.25 ± 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 lap 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 th postoperative day for HA group (P<0.001).the facial swelling for the HA group on the 7 th postoperative day was signi icantly less (P<0.05).The mean pain VAS scores declined gradually in both groups, whereas it is signi icant on postoperative day seven for HA group.
According to Gocmen et al (Gocmen et al., 2017), 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 st hr, 3 rd , 7 th day. MIO and VAS were not statistically signi icant between groups at 1 st hour, 3 rd day and 7 th day. However 3 rd day outcomes of facial swelling was increased for HA group.
According Gocmen et al (Gocmen et al., 2015), with total of 40 patients included and mean age was 26.6 ± 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 st , 7 th day. No statistically signi icant differences for VAS and MIO scores between the groups at postoperative 7 th day. However mean VAS scores for both groups after 1 week was signi icantly reduced (p <0.05).
Following extraction, formation of the blood clot is a fundamental step for socket repair. The formation of ibrin network provides a stable matrix as a base for lymphocytes, macrophages and neutrophils migration, characterizing the acute in lammatory response. Thin collagen ibrils formed by ibroblasts join to newly formed capillaries to form the granulation tissue (Yugoshi et al., 2002) . 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 (Kanyama et al., 2003).Socket healing events result in a thick bony trabecular network containing small medullary spaces at 21 days (Devlin and Sloan, 2002). 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-in lammatory 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 ibrin (Yelamali and Saikrishna, 2015) platelet-rich plasma (Dutta et al., 2015) and hyaluronic acid (Koray et al., 2014) 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 (Itoh, 2001) demineralized or bone graft (Bakoš et al., 1999) .Others demonstrated that topical HA pro-moted healing (Mariggiò et al., 2009) and reduced patient discomfort when used as an adjuvant treatment for gingivitis and chronic periodontitis, or postoperatively, following dental implant/sinus elevation procedures (Ballini et al., 2009).Topical HA also seems to have been effective in treating oral ulcers (Sandy-Hodgetts et al., 2015).
One study (Bayoumi et al., 2015) 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 signi icant difference between the groups after mandibular third molar extraction with topical application of sodium hyaluronate gel and an amino acid is seen (Guazzo, 2018). Study conducted by Yilmaz et al (Yilmaz, 2017)showed that local administration of HA into the extraction socket may alleviate the pain. However Afat et al (Afat et al., 2018) 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 ibroblasts.

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 postsurgical sequelae such as pain, swelling and trismus. Intra socket application of cross linked hyaluronic acid gel is an effective alternative in reducing postoperative pain, dry socket & trismus whereas the extra socket application of hyaluronic acid gel is not as ef icient.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-in lammatory, antioxidant effect should evaluated at larger sample size & various forms of hyaluronic acid at different dosage should also be considered.