INTRODUCTION:

Diabetes Mellitus (DM) is one of the chronic diseases where the patient is unable to control the glucose levels in the blood. Furthermore, the body will experience a hyperglycemia. DM can occur due to various factors such as damage to the pancreas (type I diabetes) and insulin resistance (type II diabetes)¹. DM is a global epidemic or pandemic disease that affects many people in the world. According to data from International Diabetes Federation (IDF) in 2013, DM is a disease that affects around 382 million people in the world with an increase in the number of patients reaching to 451 million in 2017.

Based on data from WHO, in 2030 people with DM will increase by around 10% of adults in the world. In Indonesia, DM patients reach 12 million people in the age range above 15 years old². Oral health condition in DM patient is usually poor because of the systemic complications caused by high levels of glucose in the blood and the body's inability to control glucose in the blood³. Dental extraction procedure in DM patient is necessary to be considered due to the post-extraction wound healing process is different compared to normal patient. Tooth extraction will cause injury to the tooth socket and wound healing will be occur. Wound healing stage consists of hemostasis, inflammation, proliferation, and remodeling⁴. In DM patients, there is an increase in ROS levels which causes the prolonged and uncontrolled of inflammatory response which consequently increasing the tissue damage. Drugs for DM patient which aim to accelerate the wound healing have been on the market, but the side effects should be considered. The side effects that can be occurs are erythema and skeletal bone fragility^5,6.

Compared with previous treatment, curcumin loaded chitosan nanoparticle in the post-extraction wounds of patients with type-II DM has the advantage to decrease the ROS level⁷. In addition, chitosan as a drug carrier has the advantages for increasing the bioavailability of curcumin⁸. Both curcumin and chitosan are natural ingredients that are easy to find and do not cause side effects^9,10.

Diabetes Mellitus and Wound Healing:

The oral cavity of DM patient is different compared to normal individual¹. Oral cavity in DM patient tends to have a complicated health problem. Minor surgery such as tooth extraction should be considered in DM patient. However, tooth extraction will cause injury and lead to new problems due to the delayed wound healing process in DM patient^3,4,5.

In normal people, the wound heals through several stages, they are hemostasis, inflammation, proliferation, and remodeling. In hemostasis stage, there is vasoconstriction of arteries which is followed by platelet aggregation to the injured area resulting in a degranulation. Platelets will cover the wound with the help of a thrombus, then fibrin thread will occur to form a plug. The process of hemostasis runs for approximately 48 hours. Inflammatory stage works in conjunction with hemostasis. At this stage, there is infiltration of neutrophils, monocytes, and lymphocytes⁴. Monocytes will differentiate into macrophages which are responsible for the formation of phagocytosis of bacteria from the outside of body. In a recent study, macrophage dysfunction affects the wound healing process. The inflammatory process occurs at its peak for 3-4 days¹¹. During this process, usually it is accompanied by pain and erythema. Next stage is proliferation, at this stage there is a re-epithelialization process when the epithelial layer begins to grow again to make the injured layer return to normal. At this stage, angiogenesis will also occur which is the formation of blood vessel capillaries. In this angiogenesis process as well, the different speed of healing wounds of normal people and DM patients occur¹². In addition, collagen synthesis and extracellular matrix formation are also formed. The proliferation stage occurs for 2-3 weeks. The last stage is the remodeling which can occur for years according to the systemic state of the patient's body. The duration of the remodeling process is determined by collagen remodeling, the regression and the maturation of vascular blood vessels^11,12.

People with DM experience angiogenesis and neovascularization dysfunction caused by hyperglycemia. Angiogenesis and neovascularization dysfunction is a condition in the blood plasma that has a lot of glucose but cannot enter the cell, therefore the cell experiences an energy deficit to carry out the wound healing process. Angiogenesis and neovascularization dysfunction will also cause hypoxia (lack of oxygen) then form ROS and Advanced Glycation End products (AGEs) which affect the wound healing. Therefore, AGEs require metabolism to take place quickly and continuously, thus, it can cover the shortage of these cell needs. In the scheme, it can answer the reasons for DM patients experiencing many problems. If the process of vascularization and angiogenesis is disrupted, the network lacks energy intake because the food source is not perfectly obtained by the cell. In addition, DM patients usually experience neuropathy or a state of disturbance at the innervation that can be seen in the periodontal tissue caused by the inability of periodontal tissue to maintain the position of the teeth in the oral cavity. Furthermore, the immune impairment experienced by DM patient will cause the opportunistic pathogens in the oral cavity to multiply such as caries and periodontitis. Therefore, people with DM usually experience periodontal tissue disorders, caries, and severe teeth mobility¹⁵. The main cause of disruption in the post-extraction wound healing for DM patients is the increased levels of ROS. The role of ROS in the wound healing is to control bacterial growth, thus, it cannot cause any infection. The increased level of ROS in a long period can lead to oxidative stress to increase, as a result, it delays the wound healing. The delayed wound healing due to the oxidative stress will increase neutrophil infiltration, ROS and the inflammatory mediators particularly Tumor Necrosis Factor-α (TNF-α) and Interleukin-1 (IL-1). ROS also can cause lipid peroxidation, DNA damage, and enzyme inactivation. Furthermore, it will increase the amount of Phosphorylate Phosphatidylinositol 3 Kinase (PI3K) which activates the Nuclear Factor Kappa Beta (NF-kB). Activation of NF-kB can migrate to the nucleus and activate the transcription of genes that play a role in inflammation, consequently, it will lead to the prolonging inflammation and tissue destruction^13,14.

Curcumin:

Curcumin is an active ingredient contained in Curcuma longa (Turmeric)¹⁵. In Indonesia, turmeric is widely used as a spice in cooking and as traditional medicine. The content of curcumin in turmeric also has a role as anti-inflammatory, anti-oxidant, anti-neoplastic, and wound healing accelerator. Curcumin plays an important role in every stage of wound healing, especially in DM patient^7,14,16.

Although it has many advantages in improving the healing, curcumin also has limitations in pharmacological properties, which are poor bioavailability, rapid metabolism of the body, and fast half-life¹⁶. These limitations are the main problem in using curcumin in treatment^17,18,19. Curcumin acts as an antioxidant which acts in decreasing the ROS level. Potential antioxidant ability is shown by curcumin through the electron migration by donating H atoms of two methoxy phenol groups which causes ROS to be stable and not reactive. With the stable ROS, it causes a decrease in the formation of lipid peroxidase that can be harmful to DNA, inactivation of enzymes, the decreased expression of NF-kB and inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8, monocyte chemoattractant proteins and inhibitory protein migration)^13,14.

Curcumin not only plays an important role in the inflammatory phase, but also all stages of wound healing. During the proliferation stage, curcumin increases the migration of fibroblasts, granulation tissue formation, collagen deposition, and re-epithelialization. In addition, curcumin has a role of performing apoptosis to eliminate the unwanted inflammatory cells towards the location of the wound. In the remodeling stage, fibroblast deposition at the wound site removes the transforming growth factor-β (TGF-β) cytokine to increase the wound contraction, thus, accelerate the healing. The previous study mentioned that the granulation tissue diabetic rat topical curcumin showed an increase in TGF-β expression¹⁹. Although it has advantages in improving wound healing, curcumin has a disadvantage in low bioavailability because it is easily degraded by the body which can cause its half-life to be absorbed. Therefore, a drug carrier is needed, one of which is chitosan nanoparticles to improve the curcumin bioavailability²⁰.

Chitosan:

Chitosan is a cationic polysaccharide from deacetylation of chitin and glucosamine units, and it is a natural material derived from the waste of crustacean shells. This cationic polysaccharide is easy to find, biocompatible in the body, low in immunogenicity, biodegradable, and has good pharmacological properties^21,22.

According to the US FDA the use of chitosan has been approved for use in the tissue engineering and as a drug carrier²³. One of chitosan’s uses as a medicine carrier is to change it in the form of nanoparticles and nanoparticles are colloidal particles with a size of around 1-1000 nm²². Chitosan nanoparticles as carriers serve to assist the administration of drugs in order to work effectively in the desired place by regulating the drug’s release stability, increasing efficacy, and reducing toxicity⁸.

Chitosan nanoparticles act as penetration enhancers of curcumin by opening the narrow boundaries in the epithelium. The transport of chitosan nanoparticles is through the transcellular transport (inside cells) and the paracellular transport (in the gap between cells). This causes curcumin to work according to the desired location. Chitosan has mucoadhesive properties that able to do adhesion with mucus and release curcumin from time to time, these properties are obtained because chitosan is cationic, and the mucous layer is negatively charged which leads electrostatic attraction. This sensitivity controls the release of curcumin in nanoparticles which increases the bioavailability of curcumin^8,9,23.

Chitosan Curcumin Loaded Nanoparticle:

Administration of curcumin loaded chitosan nanoparticles topically was chosen to increase the effectiveness of curcumin in order to work directly at the location of the extracted tooth. Curcumin has poor water solubility and stability; thus, it needs to be inserted into the nanoparticles and put into scaffold. The synthesis of curcumin loaded chitosan nanoparticle is carried out by dissolving 8 mg of curcumin with 10mL absolute ethanol to obtain 800μg/mL, then added with 2% acetic acid. Next, to get the appropriate pH 5, chitosan is given 2 M NaOH. After that, curcumin is dropped along with sodium tripolyphosphate (TPP) in chitosan solution and then stirred as much as 1000rpm for 45 minutes to produce a suspension of chitosan nanoparticles. The chitosan nanoparticle suspension is inserted into the silicon grid and finally dried at room temperature^24,25.

CONCLUSION:

Curcumin loaded chitosan nanoparticle has the potential to accelerate the post-extraction wound healing in DM patients by decreasing ROS levels in all stages of wound healing. Further research is needed regarding other active ingredients in curcumin loaded chitosan nanoparticles to accelerate the post-extraction wound healing more specifically. This latest innovation is expected to be implemented significantly and can accelerate the post-extraction wound healing in people with diabetes mellitus.

ACKNOWLEDGEMENT:

The Author would like to thank Faculty of Dental Medicine, Airlangga University for the support.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

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Received on 16.07.2019 Modified on 23.08.2019

Research J. Pharm. and Tech 2020; 13(2):1039-1042.

DOI: 10.5958/0974-360X.2020.00191.2