INTRODUCTION:

Gingival trauma is a common oral health problem caused by various factors, such as mechanical injury, periodontal disease, or dental procedures. Effective treatment and rapid healing of gingival trauma are essential to prevent complications and ensure optimal oral health¹.

Following a gingivectomy procedure, various aspects manifest, including heightened bleeding, infection, pain and discomfort, reoccurrence of periodontal disease, hypersensitivity, diminished gum recession, aesthetic concerns, and potential patient discontent². In the biological aspect of healing, the spread of infection and hypersensitivity are the factors most considered because they relate to the degree of recovery³. Secondary infections emergefrom postoperative treatment and protective factors against surgical wounds⁴. Using a periodontal pack on the traumatized gingiva and protecting against infection also helps accelerate wound healing⁵. However, there have also been reports of functional failure of the periodontal pack covering the surgical wound, causing an increase in infection and re-treatment⁶. It also slows wound healing, interfering with patient comfort after periodontal surgery.

This problem is still being discussed now after periodontal surgery. Many researchers continue developing strategies, including using antibiotics and painkillers to prevent and enhance healing responses. However, this effort triggers a new problem:Antibiotics tend to affect the balance of commensal bacteria in the oral cavity⁷. It can even increase the occurrence of hypersensitivity to the gum tissue⁸. Films derived from natural materials continue to be developed as a wound cover after surgery and as a drug delivery to maintain tissue and cell proliferation until healing occurs⁹. There is increasing interest in applying innovative approaches, such as chitosan, to improve the healing process in oral tissues¹⁰.

Chitosan plays an essential role in wound healing through various synergistic mechanisms.Its hemostatic properties help stop bleeding quickly, a crucial first step in wound care¹¹. Furthermore, chitosan utilizes its positive charge to disrupt bacterial membranes, reducing the risk of infection with its antibacterial properties.It keeps the wound environment clean and conducive to healing¹². Chitosan also promotes cellular activity by supporting fibroblast adhesion and proliferation, which is essential for synthesizing extracellular matrix and collagen, which are vital components in tissue regeneration¹³. In addition, chitosan’s ability to regulate wound moisture supports creating an optimal moist environment for an efficient healing process.The advantages of chitosan are not only limited to its intrinsic properties but also its ability to act as a carrier for drugs or growth factors that can accelerate wound healing¹⁴. Its biodegradability allows chitosan to integrate with tissue without causing significant side effects, eliminating the need for material removal and minimizing disruption to the healing area¹⁵.

Chitosan has been developed by Gani (2023) in the form of films for application to wounds¹⁶. As the leadingfilm component, chitosan has properties that positively influence the healing process¹⁷. In theory, chitosan, in forming a film, can function as a barrier to infectious agents and protect cells and tissue in the wound area¹⁵. The chitosan film creates a microenvironment that isolates the surgical wound from bacteria and external debris, reduces the risk of infection, and allows healing cells, such as epithelial and fibroblast cells, to develop without interference¹⁸. In addition, chitosan is also known to stimulate fibroblast cell proliferation and extracellular matrix synthesis, which supports better tissue formation¹⁹. This study aims to evaluate the effectiveness of chitosan film as a stimulant for gingival wound healing by increasing local drug delivery.

Material and Methods:

Ethical considerations:

This research has passed ethical clearance No 341/KE/FKG/2022 from the Faculty of Dentistry, Syiah Kuala University, Darussalam, Banda Aceh, Indonesia.The research material comprised 25 model animals (Rattus novergicus) divided into five groups.Each treatment group was given the same treatment before Gingival trauma. It also uses a film chitosan, which was made in the Chemistry Laboratory, Faculty of Teacher Training and Education, Syiah Kuala University, Banda Aceh, Indonesia.

Animal Model of Gingiva Trauma:

This study used Rattus novergicus aged 8-10 weeks with a body weight of 150-200 grams.Before treatment, mice were acclimatized for seven days in a conductive atmosphere (temperature, water, food, light-dark cycle, and noise).Treatment of the gingival trauma model begins with anesthesia Ketamine base 100mg/Kg Body Weight and Xylazine 5mg/Kg Body Weight, intramuscularly²⁰. Start by determining the bleeding point with a pocket marker for gingival trauma. Then, incisions were made on the facial and lingual/palatal parts using a Kirkland knife number 12 and 15, while on the proximal portion using an Orban knife.The incision is made apical to the bleeding point at an angle of 45 to the coronal direction. Then, gingival trauma is performed, and a film is applied to the incision area and covered with a periodontal pack at the incision area. Then, a microscopic examination of fibroblast cells, epithelial cells, toxic cells, osteoblast cells, and alveolar bone osteoclasts was carried out.

Immune Cell Assay:

Examination of blood immune cells from animal models of gingival trauma using a thin smear blood preparation approach based on the working principles of Adewoyin (2014)²¹. In the first stage, a glass object with a drop of blood is placed on a table or flat surface. Then, attach the object glass by pressing your left index finger on the end of the glass without the identification sticker. Then, another glass object is prepared, which functions as a pusher. Next, the glass pusher is placed on top of the second drop of blood at a 45^oC angle. Then, let the blood spread to all ends of the glass object. Then, the pushing glass object is pulled back about 5mm and moved forward while maintaining an angle of 45 degrees.Then, the smear was allowed to dry at room temperature after being soaked in 76% methanol for 30 minutes, given 3% Giemsa solution for 30 minutes, washed with running water, placed on its side, and allowed to dry. Further observations were carried out under a microscope with 400x magnification.

Fibroblast Assessment:

The analysis of fibroblast cells used for histopathological assessment after euthanizing the animal model with intraperitoneal ketamine gingival samples was taken and processed. The samples were initially fixed in 10% Neutral Buffered Formalin and then embedded in tissue cassettes for sectioning. Dehydration was accomplished in two 1.5-hour acetone processes, followed by two benzol stages of the same duration. A 1.5-hour benzol-paraffin combination was used for paraffinization, followed by 1.5 h of pure paraffin. The samples were encapsulated in paraffin blocks, sectioned at 5µm thickness with a microtome, and stretched in warm water to remove wrinkles. After 18 hours of drying on glass slides at 60°C, the sections were stained with Mayer's Hematoxylin for 8 minutes and Eosin for 2-3min, then dehydrated in alcohol and cleared in xylol. The final procedure was to cover the tissues with a glass coverslip for viewing under an Olympus electric microscope²².

ELISA Assay:

Assessment of IL-1β Assay using Elisa kits from Elabscience Biotechnology Inc, Texas, USA).The protein titers were assessed, and 96 well plates labeled with antibodies were added to the standard solution and sample (gingival tissue supernatant), each 100μL (Duplo).Then, it was covered with a sealing plate and incubated for 90 min at 37°C.Then, the liquid was removed, and 100µL of Biotinylated Detection Ab solution was added to each well and covered with a plate sealer.Then resuspended and incubated for 60min at 37°C.Then, washed with 350µL of washing buffer into each well for 1-2min and aspirated and patted on absorbent paper until the wells were dry. They were washing steps three times.Then, 100µL of conjugated HRP concentrate solution was added to each well, covered with a plate sealer, and then incubated for 30 mins at 37°C. Then, aspirated and washed with wash buffer three times.Then 90µL of substrate reagent was added to each well, covered with a plate sealer, and incubated for about 15 min at 37°C. Then, 50µL Stop solution was added to each well and read at a wavelength of 450nm.

Statistical Analysis:

Differences in the quantity and quality of the number of immune cells, fibroblast cells, and titer of IL-1β were analyzed using One-way ANOVA, with a significance limit of p<0.05.(IBM SPSS Statistics 23.0).

Result and Discussion:

Chitosan films containing antioxidants can be crucial in healing surgical wounds. Antioxidants help protect body tissue from damage caused by excessive oxidative reactions, which can occur during inflammation, injury, or wound healing.When healing surgical wounds, chitosan films with antioxidants can protect against oxidative stress, reduce inflammation, stimulate tissue regeneration, prevent infection, increase angiogenesis, and reduce scar tissue formation²³. Chitosan and Moringa leaves, besides containing high levels of antioxidants, also have anti-inflammatory compounds. This property is reported to play a role in maintaining the stability of the immune response and preventing tissue toxicity due to the ROS response when infection occurs²⁴. These results indicate that films used for therapy in gingival surgery can be used as antioxidants to improve postoperative healing because antioxidants help reduce cell damage caused by unstable molecules called free radicals²⁵.

Table 1 reports that the chitosan film provides a good immunotolerance response in increasing healing after gingival trauma. Films can reduce inflammatory cell response and promote healing (Fig 1). While the negative control shows inflammatory cells above standard limits, meaning an infection response is still occurring.Even though treatment for seven days has not demonstrated complete healing in the gingival area, it was indicated that Eusionophil cells were still found to suggest that the allergic response process was still ongoing.However, these films generally help improve wound healing in post-periodontal surgery gingival trauma models.

Figure 1. Representative immune cells exposed during the gingival healing process after periodontal surgery treated with 30% film.(A) Neutrophils, (B) Basophils, (C) Lymphocytes, (D) Eusinophils, and (E) Monocytes.400x magnification

Table 1. Response of blood immune cells of post gingiva trauma

Chitosan Film	N	Inflammatory cells (%) 7 days																			*p-Value
		Neutrophils				Basophils				Lymphocytes				Eosinophils				Monocytes
		SD		Amount		SD		Amount		SD		Amount		SD		Amount		SD		Amount
CF10%	5	0.58		45		1.37		3		1.27		42		1.73		2		0.23		11	0.001
CF20%	5	1.73		47		0.52		3		1.35		37		1.21		2		1.47		10
CF30%	5	1.15		35		0.12		1		0.26		26		1.36		2		1.01		8
CF	5	1.23		52		2.45		4		0.11		46		3.11		2		2.87		11
Negative control	5	2.13		72		3.17		15		1.21		68		2.01		7		2.31		17
**P-Value	25	0.059				0.022				0.031				0.042				0.031
Chitosan Film	N	Inflammatory cells (%) 14 days																			*p-Value
		Neutrophils			Basophils				Lymphocytes				Eosinophils				Monocytes
		SD	Amount		SD		Amount		SD		Amount		SD		Amount		SD		Amount
CF10%	5	0.21	32		0.17		2		1.14		21		1.06		1		0.10		4		0.001
CF20%	5	1.03	29		0.42		2		1.67		19		1.34		1		1.72		3
CF30%	5	1.25	25		0.22		1		0.17		15		1.37		1		1.16		2
CF	5	0.13	32		1.05		2		0.20		22		2.01		1		1.26		6
Negative control	5	1.13	87		2.07		17		1.71		88		2.71		9		1.21		21
*P-Value	25	0.032			0.012				0.021				0.031				0.016

* One Way Anova; CF (Chitosan film)

Table 2. Fibroblast cells in gingival tissue

Chitosan Film	N	Fibroblast cell (unit/cell)								p-Value
		7 days				14 days
		Mean	SD	%	Recovery	Mean	SD	%	Recovery
CF10%	5	10.32	1.73	23%	Healing process	10.33	2.31	19%	Medium healed	0.001
CF20%	5	10.21	0.00	23%	Healing process	12.78	0.58	24%	Healed
CF30%	5	10.11	2.13	23%	Healing process	12.67	2.08	24%	Healed
CF	5	9.27	1.14	21%	Healing process	11.23	0.25	21%	Healed
Negative control	5	4.33	0.58	10%	Healing process	6.67	1.53	12%	Not healed yet
*p-value		0,037				0,021
*p-value		0,001

* One Way ANOVA; CF (Chitosan film)

In the context of this research, the role of antioxidants contained in the combination of Chitosan and Moringa leaf extract was revealed in reducing the immune cell response during infection. Antioxidants can neutralize free radicals and reactive oxygen molecules that can form during inflammation or infection²⁶. An excessive immune cell response can cause detrimental inflammation and damage healthy cells and tissue in infectious conditions.This study’s results indicate that using chitosan films containing antioxidants can produce a response that reduces excessive immune cell activity during infection. By reducing the exaggerated reaction of immune cells, this combination of chitosan and moringa leaf extract may help prevent unwanted inflammation and reduce cell and tissue damage that can occur during infection.

Figure 2 shows fibroblast cells on the 14^th day of treatment.The number of fibroblast cells increased from day 7 and 14. It references healing in gingival trauma post-periodontal surgery (Table 2). In general, fibroblast cells are one of the critical components in the wound healing process, contributing to regeneration, scar tissue formation, and restoration of the function of damaged tissue.In addition, fibroblast cells assist in tissue remodeling during the advanced healing stage.²⁷ The scar tissue formed initially by fibroblasts is subject to change and maturation, and the role of fibroblast cells in composing the extracellular matrix continues during this process.²⁸. Fibroblast cells are essential in forming extracellular matrix, collagen production, and scar tissue formation in the proliferation phase of wound healing ²⁹. The film of Chitosan has become an exciting approach to promoting wound healing by increasing fibroblast cell activity.This film can provide an optimal microenvironment for the proliferation and migration of fibroblast cells, two critical stages in wound healing.

Figure 2. Histology assessment of fibroblast cells. (A) Chitosan film10% (B) Chitosan film 20% (C) Chitosan film 30% (D) Chitosan film. 400x Magnification LED Fluorescence Microscope.

Chitosan has been known for stimulating cell growth, including fibroblast cells, which produce an extracellular matrix important in tissue regeneration³⁰. Chitosan’s anti-inflammatory properties have also been shown to reduce inflammation around wounds, creating an environment more conducive to efficient healing³¹. Not only that, the hemostatic properties of chitosan play a role in controlling bleeding in wounds. At the same time, its ability to help form the extracellular matrix provides the framework needed for tissue regeneration. Fibroblast cells play a significant role in the wound-healing process.The wound healing process involves a series of complex steps, and fibroblasts are one of the cell types that play a role in the regeneration and healing of damaged tissue.³²

Table 3 reports the quantity of tissue IL1-β titers after gingival trauma treatment for 14 days. The 30% film group could reduce the inflammatory response better (32.632pg/mL).At the same time, the 10% (44.329 pg/mL) and 20% (42.980pg/mL) film groups had the same ability as the chitosan film group.However, based on the quantity of IL1-β titers, these three groups were within the normal range of 32-47pg/mL compared to the negative control group (121,268pg/mL).Based on the quantity of IL1-β titers, the four treatment groups showed recovery status.While the negative control group still showed infection.The amount of IL1-β titers between the treatment groups showed significant differences (p<0.05;0.047).

Table 3. IL-1β titer in gingival tissue

Chitosan Film	N	IL-1β (pg/mL)				p-value
Chitosan Film	N	SD	Mean	Freq	Status	p-value
CF10%	10	2.80	44.3298	15%	Healed	0.047
CF20%	10	3.44	42.9808	15%	Healed
CF30%	10	2.43	32.632	11%	Healed
CF	10	2.09	47.8054	17%	Healed
Negative control	10	3.18	121.268	42%	Still infection

* One Way Anova; CF (Chitosan Film)

The chitosan film prevents pro-inflammatory cytokine responses (Table 3).These results correlate with the immune cell response (Table 1).These findings indicate that chitosan films suppress inflammation after periodontal surgery. IL-1β is a prototypical pro-inflammatory cytokine that stimulates both local and systemic responses.However, this effect is detrimental in some circumstances, such as chronic inflammatory diseases and septic shock.The role of interleukins is to provide information to the immune system to increase its response to pathogens³³. Chitosan with the compounds 2-Pentanone, 4-hydroxy-4-methyl-1,5-diphenyl- and Butane, 1,1-diethoxy-3-methyl- can effectively induce IL-1β signals to respond to inflammation.Indirectly, the involvement of chitosan in the wound-healing process significantly reduces inflammation³⁴

Based on the findings of this study, it can be justified that the mechanism of inhibiting the release of interleukin-1 beta (IL-1β) by the antioxidant chitosan involves a series of complex interactions that lead to a reduction in the expression and release of this pro-inflammatory cytokine.This process involves several stages involving cellular activities and molecular interactions. The antioxidant chitosan inhibits the production of free radicals and oxidative stress in cells.Free radicals and oxidative stress can trigger inflammatory signaling pathways that release IL-1β³⁵. By reducing oxidative stress, antioxidants help reduce the activation of inflammatory pathways³⁶. Chitosan can interact with cell surface receptors involved in immune responses, such as Toll-like receptors (TLR).Chitosan binding to TLRs can inhibit the activation of signaling pathways that lead to IL-1β production.In this case, chitosan acts as a modulating agent that inhibits excessive inflammatory responses³⁷.

Conclusions:

The conclusion of the innovative use of chitosan film as a drug delivery system aimed at accelerating gingival wound healing shows significant results.These findings indicate that chitosan films facilitate wound healing by stabilizing immune cell responses and actively contribute to tissue repair by increasing the proliferation of fibroblast and osteoblast cells. In addition, the observed decrease in IL-1βlevels indicates the anti-inflammatory potential ofchitosan film, which helps reduce inflammation and potential subsequent tissue damage. With these promising results, chitosan film can be considered an innovative therapeutic strategy in periodontal surgery.

Conflict of Interest:

The authors declare no conflicts of interest.

Acknowledgment:

The funding for this research was provided by DRTPM Kemdikbudristek of the Indonesian Government, following the research program implementation contract for 2023, identified explicitly as No. 062/ES/PG.02.00.PL/2023.

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Received on 08.11.2023 Modified on 14.03.2024

Research J. Pharm. and Tech 2024; 17(11):5305-5310.

DOI: 10.52711/0974-360X.2024.00812