''Efficacy of Locally Delivered Hyaluronic Acid Gel as an Adjunctive to Non-Surgical Management of Periodontitis
Condition: Periodontitis
MeSH terms: Periodontitis
Study type: Interventional
Phase: Phase 4

Summary: 
      Hyaluronic Acid (HA) is an addition to the local chemotherapeutic agents. Hyaluronic acid was
      discovered by Meyer and Palmer. HA is widely found in the extracellular matrix and it plays
      an essential role in controlling cell behavior including random motility, metabolic
      reactions, chemotaxis, proliferation and invasion. HA is released by many cells including
      fibroblasts (Dahiya et al., 2013).

      Hyaluronic acid can be found in the skin, eyes and the periodontium. In addition, it appears
      in body fluids like serum, gingival crevicular fluid and saliva. Hyaluronic acid is created
      in the periodontium by HA synthase enzyme present in numerous cells like fibroblast and
      cementoblast (Fraser et al., 1997).

      There is evidence that hyaluronic acid is bacteriostatic, fungostatic, anti-inflammatory,
      osteoconduvtive and pro-angiogenic. These dissimilar properties illustrate the ability of
      hyaluronic acid to be an ideal material for wound healing (Carlson et al., 2004).
    

Detailed description: 
      Periodontitis is a chronic multifactorial inflammatory disease, associated with the dental
      plaque biofilms, its distinct feature is destruction of the tooth supporting apparatus. Its
      main features include: damage of the periodontal tissue, that's manifested by clinical
      attachment loss, alveolar bone loss, periodontal pocketing and bleeding gum (Armitage, 1999).

      A new periodontitis classification scheme has been approved, in which forms of the disease
      previously known as "chronic" or "aggressive" are now gathered under a single term
      ("periodontitis") and are more characterized based on a multi-dimensional staging and grading
      system. Staging is basically reliant on the severity of disease as well as on the difficulty
      of disease management, on the other hand , grading offers additional information about
      biological aspects of the disease including a history-based analysis of the rate of
      periodontitis progression; risk assessment for further progression and analysis of likely
      poor outcomes of treatment (Caton et al., 2018; Papapanou et al., 2018).

      Host-Microbial interaction is having a huge effect on the nature of periodontal disease
      progression. The microbial biofilm elicits the host to release inflammatory mediators that
      have a negative effect on the connective tissues. The biofilm or dental plaque is required
      but not enough to induce periodontitis, since it is the host inflammatory response to this
      microbial challenge that eventually can be the reason for destruction of the periodontium
      (Haffajee and Socransky, 1994; Page , 1997; Darveau, 2010).

      Physical removal of dental plaque through debridement and/or using antimicrobial agents is
      the most prevalent management of periodontitis. Initially, scaling and root planing (SRP) is
      done with the means of hand or ultrasonic instruments to debride the root surface, allowing
      the development of a long junctional epithelium. Clinically, in case of lack of accessibility
      like extensive tissue loss, deep periodontal pocket and furcation involvement make it unclear
      to determine the efficacy of the debridement (Lindhe, 1985).

      The use systemic antibiotics (ABs) can contribute in treatment goals without surgical
      treatment. However, their usage is limited to particular patients for those who have
      previously two courses of SRP with no improvement in periodontal pocket depth. Additionally,
      the side effects and rise in AB resistance over time have reduced the number of cases managed
      in this way (Walters et al., 2015).

      Local antimicrobial therapy includes the direct placement of an antimicrobial agent into sub
      gingival sites, limiting the effect of the agent on non-oral body sites. The main goal in
      using an intra-pocket device for the delivery of an antibacterial agent is maintenance of
      therapeutic levels of the drug for the required period of time. This method has direct
      influence on the pathogens, without any damage to the tissues (Garg, 2015).

      The first local drug delivery system in periodontal treatment was ActiciteTM. The first non
      resorbable system. Although quite effective, the delivery of this system in the periodontal
      pockets required extra skills and another visit to the dentist in order to be removed. The
      drawbacks of the non-resorbable systems headed to the advance of resorbable systems for
      antimicrobial delivery like ATRIDOXTM, gel containing 10 % doxycyline hyclate. Progresses in
      the formulation of local delivery systems lead to the manufacture of ARESTINTM, sustained
      release product consist of minocycline (Krayer et al., 2010).

      Local delivery antibiotics that are commercially available as controlled release devices had
      many disadvantages including limited spectrum of antimicrobial activity in some periodontal
      polymicrobial infections, risk of generating antimicrobial resistance and massive acquisition
      cost (Sltos , 2002).

      The most extensive used and studied antiseptic in oral diseases is chlorhexidine.
      Chlorhexidine displays high affinity towards bacteria .The highest advantages of
      chlorhexidine application after SRP or surgical periodontal treatment include better-quality
      in wound healing and general plaque control (Horz & Conrads, 2007). However, even with the
      advantages, the application may end with staining of the teeth, taste disturbances and
      increase of calculus formation (Zanatta et al., 2010).

      Hyaluronic Acid (HA) is an addition to the local chemotherapeutic agents. Hyaluronic acid was
      discovered by Meyer and Palmer. HA is widely found in the extracellular matrix and it plays
      an essential role in controlling cell behavior including random motility, metabolic
      reactions, chemotaxis, proliferation and invasion. HA is released by many cells including
      fibroblasts (Dahiya et al., 2013).

      Hyaluronic acid can be found in the skin, eyes and the periodontium. In addition, it appears
      in body fluids like serum, gingival crevicular fluid and saliva. Hyaluronic acid is created
      in the periodontium by HA synthase enzyme present in numerous cells like fibroblast and
      cementoblast (Fraser et al., 1997).

      There is evidence that hyaluronic acid is bacteriostatic, fungostatic, anti-inflammatory,
      osteoconduvtive and pro-angiogenic. These dissimilar properties illustrate the ability of
      hyaluronic acid to be an ideal material for wound healing (Carlson et al., 2004).

      The anti-inflammatory action of hyaluronic acid is related to the role of exogenous
      Hyaluronan as a scavenger by draining metaloprotinases, prostaglandins and other bio-active
      molecules (Laurant et al., 1995). Moreover, hyaluronic acid is anti-edematous due to its
      osmotic activity. The high concentration of medium and lower molecular weight hyaluronic acid
      has a possible bacteriostatic role especially on aggregatibacter actinomyecetemcomitans and
      staph aureus strains which are usually found in periodontal wounds (Pirnazar et al., 1999).

      In patients with chronic periodontitis, the adjunctive application of hyaluronic acid to non
      -surgical periodontal treatment including (scaling and root planning) results in much higher
      clinical improvement including probing depth and bleeding on probing (Bertl, 2015).

      A clinical trial by (Yi Xu et al ., 2004) used HA gel as an adjunctive to scaling and root
      planning in treatment of chronic periodontitis , regarding the clinical parameters and
      microbiological analysis had revealed that HA gel has an essential role in improvement of all
      clinical parameters but in contrary, microbiological analysis using conventional PCR revealed
      that hyaluronic acid has no effect on the bacteria .

      Based on the previously mentioned properties hyaluronic acid, We hypothesized that hyaluronic
      acid has a major role to be used as an adjunctive to non-surgical treatment in periodontitis
      patients.
    

Intervention name(s): Hyaluronic acid; non surgical periodontal therapy
Intervention type(s): Drug; Procedure
Intervention description(s): Hyaluronic Acid (HA) is an addition to the local chemotherapeutic agents. Hyaluronic acid was discovered by Meyer and Palmer. HA is widely found in the extracellular matrix and it plays an essential role in controlling cell behavior including random motility, metabolic reactions, chemotaxis, proliferation and invasion. HA is released by many cells including fibroblasts; NSPT, with or without adjunctive therapies, is an effective treatment for periodontitis. It reduces PD and results in formation of some new attachment; however, it also has several limitations, and surgical therapy might be required to control inflammation and optimize outcomes. When used for non-surgical scaling and root planing, periodontal curettes can reach a mean PD of up to approximately 5.5 mm. The mean PD in which a plaque-free and calculus-free surface can be established is <4 mm
Other intervention name(s): hyaluronan
Intervention MeSH terms: Hyaluronic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: topical application of hyaluronic acid in patients with periodontitis 1 day after scaling
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment