INTRODUCTION:

Pressure Ulcer occurs due to external pressure that presses the blood vessels or due to friction and shearing forces that tear and injure blood vessels. Greater external pressure from capillary pressure and arteriolar pressure interferes the blood flow in capillary pads. When pressure is applied to the skin over the skin protrusion for two hours, ischemia and hypoxia tissue as a result of external pressure cause irreversible tissue damage¹.

When a wound occurs, several effects will appear including loss of whole or part of organ function, sympathetic stress response, bleeding and blood clotting, bacterial contamination and cell death².

Black cumin (Nigella sativa) is wrong one plant herbs which have various effect pharmacology, including: as antioxidants, antidiabetic, hypoallergenic, anti-inflammatory, and as an immunomodulator, so that caraway black (Nigella sativa) is often used as herbal medicine³.

Black cumin oil is known to contain compounds that have antibacterial activity such as thymoquinone and -pinene. Thymoquinone is able to inhibit bacterial growth by inhibiting csprotein and RNA synthesis⁴. Black cumin oil is known to have antibacterial activity against P. acnes with a minimum inhibitory concentration (MIC) of 0.5 %⁵. The main content of black cumin oil, namely thymoquinone, has been studied to have a pharmacological effect as an antibacterial⁶.

The use of nanotechnology in the food and pharmaceutical fields has a tendency to increase. Nanotechnology is a technology that is able to prepare active drug particles on a nanoscale. The shape and size of the particles are one of the factors that affect the effectiveness of the drug, because the particle size is very influential in the processes of solubility, absorption, and distribution of drugs⁷. Increasing the amount of drug in the blood during systemic administration will also increase the risk of side effects and side effects, until the risk of reaching the toxic level. In many cases, an increase in the blood level of the drug is required for the drug to produce a pharmacological effect. Therefore, nanoparticles provide a good solution because they can provide pharmacological effects at smaller (efficient) doses⁸.

Emulgel is an emulsion of either oil in water or water in oil that is made into a gel by adding a gelling agent. Emulgel is one form of a good drug delivery system⁹, generally providing a faster drug release than ointments and creams. In addition, emulgel is suitable for active ingredients that are hydrophobic and can reduce the oily impression when applied. This study aims to obtain a topical preparation of black cumin seed oil that has anti-inflammatory activity on pressure wound healing.

RESEARCH METHODS:

a. Equipment:

The equipment used in this study were: sterile scalpel, caliper, razor, gauze, gloves, cotton, analytical balance, porcelain cup, watch glass, object glass, mortar and pestle, beaker glass, spatula, dropper, spatula, parchment paper, pH meter, plastic pot, rabbit cage.

b. Ingredient:

The materials used in this study were: Carbopol, Triethanolamine (TEA), methyl paraben, propylene glycol, black cumin oil extract, 70% ethanol, Neocenta Gel, esthesia cream® (PT.Genero Pharmaceuticals), aquadest.

c. Gel Preparation Formula:

Black cumin seed oil emulgel preparations were made in three formulas (Table 1). The ingredients are weighed according to the existing formula. 0.5g of Carbopol was developed for 30minutes and stirred until homogeneous (mixture 1). Then TEA was added to the mixture 1 and then ground until evenly dispersed. Added methyl paraben, propylene glycol, and aquadest add 50ml little by little with continuous stirring to form a gel. Then black cumin extract was added to the mortar and ground until homogeneous. The same procedure is also carried out in making the next formula.

This research received ethical clearance from the health research ethics committee of Faculty of Medicine University of Muhammadiyah Sumatera Utara with no594/KEPK/FKUMSU/2021dated 26^th August 2022.

Table 1. Black Cumin Oil Extract Gel Formula with Various Gel Preparations

Material Name	Utility	Gel Formula
Material Name	Utility	Formula 1	Formula 2	Formula 3
Black Cumin Oil Extract	Active Ingredients	-	0.1 g	10 gr
Carbopol	Gel Shaper	0.5 gr	0.5 gr	0.5 gr
Triethanolamine (TEA)	Alkali	1 gr	1 gr	1 gr
Methyl Paraben	Preservative	0.25 gr	0.25 gr	0.25 gr
Propylene glycol	Humectants	0.5 gr	2.5 gr	2.5 gr
Aquadest	Carrier	50 ml	50 ml	50 ml

Information:

Formula 1: Gel Base

Formula 2: Gel formula with black cumin extract without nanoparticles 0.1gr

Formula 3: Gel formula with extract of caraway oil nanoparticles 10gr

RESULT:

a. Organoleptic test results

Table 2: Gel Preparations Organoleptic Test Results

F	Formula	Form	Color	Smell
1	Negative Control (gel base)	Semi Solid	Clear White	No smell
2	Nanoparticle-Free Gel 0.1gr	Semi Solid	Yellowish white	Characteristic Smell of Black Cumin Seed Oil
3	Gel Nanoparticles 10 gr	Semi Solid	White	Typical Smell of Black Cumin Seed Oil

Based on Table 2, all formulas have a semisolid form with clear and odorless color on the negative control, a yellowish white color, and a characteristic odor of black cumin seed oil on a nanoparticle-free gel, as well as a white color and a characteristic odor of black cumin seed oil on a nanoparticle gel. Each gel type's color is obtained from the active ingredients used and the scent contained in each gel.

b. Homogeneity Check

Table 3: Results of Homogeneity Test of Gel Preparations

Formula	Homogeneity
Formula 1 (Gel Base	Homogeneous
Formula 2 (Gel Without Nanoparticles 0.1 g)	Homogeneous
Formula 3 Gel Nanoparticles 10 gr)	Homogeneous

Table 3 shows that all the mean pH values of the formulas have typical values. It checks pH values for four weeks using a pH meter. The minimum and maximum limits are in the interval 4.5 – 6.6. This test is the basis for determining a safe pH value when used on the skin. A pH value that is too high can irritate the skin and vice versa. If the pH value is too low, the skin will lose fluid due to the pH difference.

c. pH Check

Table 4: Gel Preparation pH Test Results

F	Preparation	pH				Average
F	Preparation	Week 1	Week 2	Week 3	Week 4	Average
1	Gel Base (Negative Control)	5.5	5.6	5.7	5.9	5.68
2	Gel Without Nanoparticles 0.1 gr	5.5	5.7	58	5.9	5.73
3	Gel nanoparticles 10 gr	5.0	5.2	5.2	5.9	5.38

Table 4 shows that all formulas' average pH values have typical values. It examined the pH value for four weeks using a pH meter. The minimum and maximum limits were at intervals of 4.5 – 6.6. This test is the basis for determining a safe pH value when using it on the skin. A pH value that is too high can irritate the skin, and vice versa. If the pH value is too low, it will cause the skin to lose fluids due to the difference in pH.

d. Spreadability Test

Table 5: The Result of the Spreadability of the Preparations

F	Gel preparation	Initial Diameter (cm)	Diameter + load 50 grams	Diameter + load 100 grams	Diameter + 150 gram load
1	Gel Base (Negative Control)	4.3cm	4.7 cm	5.2 cm	5.4 cm
2	Gel Without Nanoparticles 0.1 gr	3.9 cm	3.9 cm	4.9 cm	5.3 cm
3	Gel Nanoparticles 10 gr	3.7 cm	4.1 cm	4.2 cm	5.7 cm

Table 5 shows that all formulas have good dispersion, as evidenced by values between 5 to 7 cm. This test aims to determine the spreadability of the formulation on the skin, where this test uses a load of 50g, 100g, and 150g.

e. PSA Test:

Table 6: Size of black cumin emulsion nanoparticles based on surfactant concentration.

Sample	Particle Size (nm)	Polydispersity Index	Zeta Value Potential (mV)
Formula I	122.7 nm	0.59	66.9

Oil-in-water nanoemulsions are oil droplets with a diameter of 1-500 nm, dispersed in a continuous aqueous phase and the droplets are surrounded by emulsifying molecules¹⁰. The size of the droplets produced depends on several factors, including the type of homogenizer used, manufacturing temperature, energy intensity and time, as well as the condition of the sample in the form of oil, oil concentration, type of emulsifier/surfactant used and physicochemical properties. Samples (interfacial tension and viscosity)¹¹.

The best emulsion formulation is indicated by the smallest droplet size based on the results of particle size analysis (Particle Size Analyzer- HORIBA SZ-100). In the cumin oil extract formulation, the particle size of 122.7 nm has a polydispersity index of 0.57 -0.59 which means that the formulation has a particle distribution with a very good level of particle size uniformity. In contrast to the value of zeta potential (mV) this is a parameter of electric charge between colloidal particles. The higher the zeta potential value, the more stable a colloidal solution is because the higher the zeta potential value, the more it will prevent flocculation or incorporation of colloidal particles.

f. Activity Test:

Table 7: Results of Visual Observation of Pressure Wounds

Formula	Information	Day Physiological Observations
Formula	Information	1	3	6	10	14
Formula 1 (Gel Base)	Discoloration	R	B	B	P	P
	The formation of a scab	-	+	+	+	+
	New skin is formed	-	-	-	+	+
	Wounds Heal	-	-	-	-	+
Formula 2 (Gel Without Nanoparticles 0.1 g)	Discoloration	R	B	P	P	P
	The formation of a scab	-	+	+	+	+
	New Skin Formed	-	-	-	-	+
	Wounds Heal	-	-	-	-	+
Formula 3 (Gel Nanoparticles 10 gr)	Discoloration	R	B	B	P	P
	The formation of a scab	-	+	+	+	+
	New Skin Formed	-	-	+	+	+
	Wounds Heal	-	-	-	+	+
Positive Control (Comparison)	Discoloration	R	B	P	P	P
	The formation of a scab	-	+	+	+	+
	New Skin Formed	-	-	-	+	+
	Wounds Heal	-	-	-	+	+

Description: R (Read); B (Brown); P (Pink); W (White); There is (+); There isn't any (-)

Wound observations were performed five times in 14 days, namely on days 1, 3, 6, 10, and 14, to see the physical changes in the treatment area. The test rabbits observed the progress of the wound healing process visually, and the observations started from day 1 to day 14 in each group. Visual observations included changes in the colour of wound formation from scabs to closed wounds. Scab formation in each test rabbit started on day 3. The appearance of new skin in the negative control group and the test preparation started on day 10. The colour change in the negative and test group preparations occurred when the wound began to dry, and the wound healing process began. The formation of a scab indicates that the wound-healing process is entering the early stages of proliferation. Visual observation can be used as a reference to show the condition of the wound when it is first moist, visible scab formation or granulation tissue begins to dry. On the third day, the test group was negative, and the test group preparations formed an average scab. On the 6th day, in both the negative test group and the test group, the thick scabs on the brown wound detached and turned pink. This condition indicates that it will enter the healing stage, which forms the skin. This shows the growth of new cells on the skin, thus helping to accelerate the release of the scab and get closer to the edge of the wound. On the 14th day, both the test group and the control group were negative. The damage had healed and formed a new layer of white skin.

Wound Diameter Observation

Table 8: Average Wound Diameter Day- 0 to Day-14

Wound Diameter (cm)	Formula 1 (Gel base)	Formula 2 Gel Without Nanoparticles 0.1 gr	Formula 3 Gel Nanoparticles 10 gr	Positive Control (Neocenta Gel)
Day 0	2.0	2.0	2.0	2.0
Day 1	1.8	1.8	1.8	1.8
Day 2	1.7	1.7	1.7	1.6
Day 3	1.5	1.5	1.5	1.4
Day 4	1.3	1.3	1.2	1
Day 5	1.1	1.1	0.8	0.5
Day 6	0.8	0.8	0.5	0.4
Day 7	0.6	0.6	0.3	0.2
Day 8	0.5	0.5	0.2	0.1
Day 9	0.4	0.5	0.1	0
Day 10	0.3	0.4	0
Day 11	0.2	0.3
Day 12	0.2	0.2
Day 13	0.1	0.1
Day 14	0	0

The percentage of wound healing was observed in the control group and the test group at time intervals from day 1 to day 14 to see changes in the wound in rabbits, indicating that wound healing occurred. Rabbits: an incision measured the average wound length in rabbits from day 0 to day 14. The wound diameter in each preparation has a different wound diameter. The amount of wound healing with F1 occurred on the 14th day, the wound healing time with F2 happened on the 13th day, the wound healing time with F3 occurred on the 9th day, and the duration of wound healing with the help of Neocenta Gel (positive control) occurred on the 8th day.

g. Significance Test of Differences in Wound Healing Effectiveness:

Table 9: Significance Test for Differences in Healing Effectiveness

Wound Length Group
Tukey HSD ^a	Comparison	15	0.600
	Gel Nanoparticles 10 gr	15	0.673
	Gel Base	15	0.833
	Gel Without Nanoparticles 0.1 gr	15	0.853
	Sig.		0.765
Means for groups in homogeneous subsets are displayed.
a. Uses Harmonic Mean Sample Size = 15,000.

The data above shows that the average of the four treatment groups was not significantly different (p=0.765 > 0.05).

DISCUSSION:

Applying an emulsion with nanoparticles directly to skin wounds speeds up the healing process and doesn't show any signs of toxicity. The results showed that the polymer layer formed over the wound protected it from ambient pathogens and became an integral part of the newly formed skin layer. The removal of clumps of film-coated bristles adhering to the abrasion surface due to the film binding the strands to the abrasion surface caused new blisters to appear within 8 hours, thus indicating the infiltration of dermal fibroblast cells and epidermal keratinocyte cells into the polymer film matrix due to disruption of the skin-film interface. None of the analysed emulsions produced a noticeable, undesirable effect on the abrasion area. No redness, irritation, or inflammation was observed in mice treated topically with the nanoparticle emulsion, and all rabbits appeared healthy and active during the study. Most mice did not notice the film on the dorsal surface, and no rabbits were seen rubbing the area with another object to remove the coating. This indicated that the rabbits were very tolerant of the film and did not feel any pain or discomfort from the treatment. No clumps of polymer were observed in the subcutaneous area or below, and no clusters were observed within the skin layer. However, this does not rule out the possibility that the nanoparticles can migrate through several layers of the skin; this is a problem we hope to address to determine the degree of infiltration of nanoparticles into the epidermis and possibly the dermal layer. When a solid film forms on the abrasive surface, the area retains its moist, fresh consistency without becoming dry or stiff. The film blends seamlessly with the skin and contains the same mechanical properties as intact skin, allowing the animal to move naturally without pulling or restricting movement. This indicates that the film can maintain the wound bed with the moisture and oxygen needed to increase the healing rate.

Nigella sativa fruit is a capsule-based fruit that contains many black trigonal seeds. It has various therapeutic effects mainly attributed to its anti-inflammatory, antioxidant, anticancer, antibacterial, nephroprotective, and neuroprotective properties, which have been revealed in several in vivo studies¹². The positive effect of Nigella sativa in skin wound healing is mainly due to the induction of angiogenesis, increased fibroblast proliferation, and subsequent collagen synthesis ¹³. In addition, Nigella sativa has been reported to reduce the presence of white blood cells, tissue damage, and bacterial infections¹⁴. The most prominent active component of NS is thymoquinone (TQ)¹⁵. According to a review by Khader et al., four favorable traits describe TQ based on 406 evaluated empirical evidence. These properties are anti-inflammatory, antioxidant, anticancer, and hepatoprotective¹⁶. In addition, Darakhshan et al. (2015)¹⁷ stated that TQ has antihistamine, antimicrobial, gastroprotective, nephroprotective, and neuroprotective properties.

Many wound healing models have been developed to evaluate the efficacy of wound healing therapy. At the pre-clinical level, animal models for various skin depths and comorbidities are available¹⁸. In terms of wound depth, the wound can be superficial, partial thickness, or total thickness¹⁹. The process through which skin or other human tissue recovers from harm is known as wound healing. Wound healing is a very well-organized and exacting procedure^20-26. External injuries occur only at the epidermis level, such as abrasions, whereas partial thickness injuries involve the epidermis and dermis, such as lacerations or burns. Finally, a full-thickness skin wound involves all layers of the skin and can extend to muscle and bone, such as a cut or gunshot wound.

Regarding comorbidities, many conditions contribute to worsening impaired wound healing¹⁵. These include diabetes mellitus, immune compromised diseases, severe bacterial infections, and others. Therefore, further clinical intervention is needed to reduce the symptoms and complications of this particular condition. Any wound-healing failure within three months after skin injury is considered a chronic wound²⁷. Alternatively, an acute wound is a rapid wound that occurs suddenly due to trauma, including abrasions, lacerations, penetrations, degloving, or burns¹⁸.

Evaluate the therapeutic outcome of a wound healing intervention from a combination of macroscopic and histological observations, biochemical and biomechanical measurements, and evaluation of cellular and immunologic responses to estimate the effect of therapy on the progression of wound repair²⁸. Macroscopic evaluation, also known as gross morphological observation, provides an early indication of wound healing efficiency. Parameters that can be obtained from this observation include total healing time, wound contraction, and wound closure¹⁹. It is important to note that wound closure does not guarantee quality skin regeneration²⁹. Thus, microscopic evaluation of skin regeneration is critical. The advantage of using animal models for wound healing is their ability to extract skin tissue for histological observation¹⁵. Each animal model has advantages and disadvantages, so it isn't easy to meet all the requirements and needs for a thorough evaluation. For example, the use of a rabbits model can provide a rough idea of the effectiveness of wound care but does not reflect the overall results that are representative of the human model, as this model is dominated by myofibroblast-mediated contraction and is fundamentally different from the structure of human skin³⁰. Skin structure changes that represent different wound healing phases can be evaluated through histological observations. The hemostatic phase begins immediately or until approximately three hours after tissue injury to stop bleeding and can be observed with scab formation at the injury site³¹. Furthermore, the inflammatory phase is usually characterized by immune cell infiltration, swelling, and redness of the dermis layer. The inflammatory phase can be acute or chronic, depending on whether it lasts several days or months. The proliferative phase's success, lasting from four hours to 14 days, can be measured by granulation tissue formation and epithelialization³². Finally, the remodeling phase can restore skin tissue to its pre-injury state. This phase usually starts on the eighth day and can last up to a year, depending on the patient's condition and metabolism. Recent findings have linked oxidative stress with impaired wound healing³³. Under normal conditions, the production of free radicals through cellular metabolism is balanced by antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRx), and glutathione-S-transferase. (GST)³⁴. These excess free radicals can damage molecular structures such as proteins, lipids, and DNA³⁵. Hemostasis, inflammation, proliferation, and remodelling are all components of the complicated and dynamic process of wound healing. Devitalized and missing cellular components and tissue layers are rebuilt throughout this phase³⁶. This damage, in turn, disrupts the normal wound-healing process, which is highly dependent on many cellular and molecular mediators. Therefore, interventions that can reduce this damage will positively impact wound healing. In this review, a systematic search of electronic databases, namely Medline via hosts EBSCO and Scopus, was performed to identify published research articles regarding the positive effects of Nigella sativa on skin wound healing. These findings were critically assessed and presented regarding wound healing outcome measures.

CONCLUSION:

This study shows that, depending on metabolic conditions, Nigella sativa could be very important for speeding up wound healing. Nigella sativa speeds up the healing of wounds because its active ingredients are anti-inflammatory, antioxidant, and antibacterial. More research needs to be done to figure out how Nigella sativa from different plants helps wounds heal.

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Received on 10.11.2022 Modified on 30.01.2023

Research J. Pharm. and Tech 2024; 17(3):1370-1375.

DOI: 10.52711/0974-360X.2024.00216