Exploring the early healing potential of a novel thermosensitive hyaluronic acid gel with octenidine preservation system as an adjunct to non-surgical periodontal treatment: a split-mouth blinded pilot study with proteomic analysis

Oral diseases, surpassing all noncommunicable diseases in global prevalence,
have become a major health concern, with caries and severe periodontitis at the
forefront, affecting roughly 2 billion and 1 billion people worldwide,
respectively. Periodontitis, a severe gum infection capable of destroying the
bone supporting teeth, signifies a threat to global health, linking to systemic
diseases and underscoring the importance of oral hygiene and regular check-ups.
This necessitates an integrated approach to oral health, highlighting the need
for preventive measures, addressing oral health inequalities, and incorporating
oral health into general healthcare systems for comprehensive management.

Currently available conventional treatment for periodontitis includes root
surface debridement (RSD) or scaling and root planing (SRP), which remove
subgingival plaque and tartar, thereby removing the causative factor for
periodontal disease and inhibiting the natural healing process of the gums
becomes possible. However, new bacteria can infiltrate the pockets after RSD or
SRP and hinder the healing process.

To improve gingival healing and prevent recurrence of inflammation within the
periodontal pockets, additional treatments have been developed, intended for
use after RSD or SRP. These methods include antimicrobial laser therapy, host
modulating agents that inhibit host collagen-degrading enzymes that cause
tissue loss due to the inflammatory response, or the use of antibiotic or
antibacterial agents that aid in the inhibition of bacterial recolonization in
the periodontal pockets. The latter are available as rinses, toothpastes, or
sustained-release products, which are inserted into the periodontal pockets and
remain there for days or weeks. In addition, systemic antibiotics can be
administered, with or without topical treatment. Another additional treatment
option is the use of barrier agents that fill the periodontal pockets and
prevent infiltration of bacteria from the oral cavity into the pockets.

Although the effectiveness of SRP has been proven to be statistically
significant in numerous clinical studies, several complementary treatments have
been shown to provide greater improvement in clinical parameters such as pocket
depth, clinical attachment level and bleeding on probing.

The medical device under investigation, Pocket-X Gel, is a product of
Israel-based Tree of Life Pharma Ltd. This device is designed to gel in place
and serves as a physical barrier against the recolonization of bacteria in
periodontal pockets after SRP. The gel is biodegradable and remains in the
periodontal pocket for one to three weeks before breaking down or being
expelled as part of the gums' natural healing process.

The study aims to assess the effectiveness of this patented Class IIa medical
device in reducing bacterial load and promoting periodontal healing, which may
provide a valuable alternative to traditional antibiotic treatments. This is of
paramount importance in an era when the reduction of antibiotic use is
extremely important. The study states two hypotheses: the null hypothesis (H0)
claims that there will be no significant difference in clinical outcomes
between the standard non-surgical treatment and the treatment with the
integration of Pocket-X Gel, while the alternative hypothesis (H1) states a
significant improvement in periodontal health is expected with the additional
use of this thermosensitive hyaluronic acid gel.

This pilot study aims to assess the feasibility, safety and preliminary
efficacy of a novel thermosensitive hyaluronic acid gel with an octenidine
preservative system as an adjunct to standard non-surgical periodontal
treatment. The use of a blinded design will strengthen the validity of the
study. The primary outcome of this study is a proteomic analysis of the
patients' gingival crevicular fluid so that we can understand in depth how (and
if) the gel promotes soft tissue healing after standard non-surgical
periodontal treatment.
Proteomic analysis provides a comprehensive view of the proteins in a
biological sample, providing insights into cellular functions, disease markers
and drug targets. It identifies differentially expressed proteins,
post-translational modifications and interactions, and contributes to our
understanding of complex biological processes. It is a very sensitive
technique, therefore all collected samples will be sent to a specialized
laboratory in Utrecht for analysis.
The secondary outcomes of our study are the clinical periodontal markers, which
will be measured twice (baseline and control after 6 weeks): Probing Pocket
Depth (PPD), Bleeding On Probing (BOP), Clinical Attachment Loss (CAL).

The pilot study allows us to use a smaller sample of participants (n=10)
without a power calculation. We aim to recruit the patients within the timeline
of the OHS Periodontology MSc. The patients will be recruited at the
Periodontology Department of ACTA. Patients who come for an intake, diagnosed
with Periodontintis stage III or IV, who meet the inclusion criteria will be
asked to participate in this study. The study is prospective, randomized
split-mouth and blinded (patients).

User
- Recruitment of patients: patients who meet the inclusion criteria will be
asked if they want to participate in this study (thinking period 2 weeks). They
will be provided with the product's folder, extensive information about the
research and the procedures, and an informed consent. The protocol is developed
in order to provide as little inconvenience as possible to the patients in
terms of time investment.
- Baseline: Full Periodontal status (POD, BOP, CAL) and Gingival Crevicular
Fluid (GCF) sampling. The measurements and GCF collection will be performed by
the head investigator (I.K. Vragkali). The treatment of the test and control
sites as well as the application of the product will be performed by the head
investigator I.K. Vragkali, in order to provide standardization during the
procedures.
- Patients will undergo the standard non- surgical periodontal treatment in 2
or 4 appointments (1 week apart) with adjunctive use of the product (Pocket-X
gel) in a randomized split-mouth manner (1 quadrant with test product and 1
quadrant with placebo saline solution). Application of gel will be performed at
the end of the 1st treatment appointment.
- At the second appointment (before the treatment), the second GCF sample will
be taken.
- The patients will be required to come back for the 3rd GCF sampling after 3
weeks. This may be an additional appointment compared to the standard
procedure, depending on if the patients would have their treatment in 2 or 4
appointments.
- During the 6 weeks check-up, the last (4th) GCF sample will be taken and new
periodontal measurements will be performed (periodontal status).

The patients will undergo standard non-surgical periodontal treatment as it is
offered to everyone who comes to our clinic. They will get a full mouth
periodontal status, which is also a standartd procedure. The extra procedure
that they will have to undergo is the Crevicular Gingival Fluid (CGF) sampling.
GCF will be sampled using paper strips (Periopaper ® , Oraflow Inc., New York,
USA) placed at the gingival margin of the test sites for 30 seconds. It is a
painless procedure which will not burden the patient whatsover.

The gel comes in a pre-filled syringe with two application tips and is applied
as a liquid by a dental professional. On contact with body temperature in the
periodontal pocket, it turns into a gel, which effectively fills the pocket and
blocks bacterial entry. The syringe is intended for single use on one patient,
with the ability to treat multiple pockets on one individual. The ingredients
are water, Poloxamer 407, hyaluronic acid, phenoxyethanol and octenidine
dihydrochloride - all recognized as safe for oral use.

- There is minimal risk expected and/or associated with this research. In case
of unknown allergies: Allergy to hyaluronic acid is reported to be rare and
mostly associated with dermal fillers/injectables.
- There may be some post-treatment discomfort and sensitivity of the dentition,
which would have happened anyway without the application of the product.
- There is possibly no additional effect in terms of early healing.


Benefits:
- The participants will receive the product for free.
- Potenitally improved healing of the periodontal tissues