A therapeutic modality currently being developed for melasma is secretome. Secretome is a bioactive molecule secreted by mesenchymal stem cells in a conditioned medium containing a large number of growth factors, cytokines, various macromolecules, and extracellular vesicles, including microvesicles and exosomes, that can stimulate various biological reactions, particularly in modulating new tissue formation. Secretome can provide a depigmenting effect by increasing the proliferation and migration of epidermal keratinocytes, which contain melanin pigment, in line with increased fibroblast synthesis.

Secretomes contain various cytokines and growth factors, one of which is transforming growth factor (TGF)-β. TGF-β is primarily secreted by fibroblasts (FB) and, to a lesser extent, by keratinocytes, and plays a crucial role in regulating melanocyte function. TGF-β has been reported to inhibit cAMP/protein kinase A signaling and induce GLI2, which then suppresses microphthalmia-associated transcription factor (MITF), a central transcription factor in melanogenesis. A study by Moon et al. in Korea examined TGF-β3. Moon et al. examined the effects of TGF-β3 on melanogenesis in human melanocytes co-cultured with skin cells irradiated with ultraviolet (UV) light, and in UV-irradiated human skin. The results showed that UVB irradiation or stem cell factor (SCF)/endothelin-1 (ET-1) increased melanogenesis. TGF-β3 effectively inhibited melanin accumulation and tyrosinase activity by downregulating the extracellular signal-regulated kinase (ERK)/microphthalmia-associated transcription factor (MITF) pathway. TGF-β3 increased the expression of keratinocyte differentiation markers.

Mechanistically, TGF-β3 inhibits melanogenesis by inhibiting MITF expression, which is regulated by ERK. TGF-β1 reduces MITF but at the risk of inducing skin fibrosis. However, in the study by Moon et al., the aforementioned TGF Beta 1 function was not found in TGF-β3. Furthermore, TGF-β3 restored skin differentiation function in UV-irradiated keratinocytes.

To date, there have been no clinical trials comparing intradermal injection of concentrated secretome with intradermal injection of concentrated secretome with the addition of TGF-β3 as a melasma therapy in Indonesia, thus encouraging researchers to conduct further research.

Melasma is a pigmentation disorder in the form of brownish macules with irregular edges caused by dysfunctional melanogenesis. Melasma is more common in women with Fitzpatrick skin types IV-VI, namely those of Asian, Hispanic, and African descent, especially on sun-exposed areas of the face. Various epidemiological studies report that melasma can occur in all ethnicities, but the prevalence of melasma tends to be higher in East Asian (Japanese, Korean, and Chinese), Indian, Pakistani, Middle Eastern, and Mediterranean-African populations. In a 2014 study, melasma patients in Asia tended to be aged 21-64 years. The prevalence of melasma varies from place to place depending on race, skin phototype, and intensity of sun exposure. 4 Based on the distribution of lesions, melasma is clinically divided into 3 types: centrofacial (65%), malar (20%), and mandibular (15%).

Melasma is a disorder with multifactorial causes. Several trigger factors for melasma include genetic predisposition, exposure to ultraviolet (UV) light, hormonal influences, pregnancy, cosmetic use, consumption of photosensitizing medications, stress, and oxidative stress. One of the main triggering factors that can worsen melasma lesions is UV light.

Melasma impacts a person's appearance, causing psychosocial and emotional disturbances and a decreased quality of life. Generally, melasma patients often complain of embarrassment, low self-confidence, dissatisfaction, and a lack of desire to travel.According to the WHO, quality of life is an individual's perception of their position in life, both in the context of culture, value systems, goals, expectations, standards, and concerns. In 2003, Balkhrisnan et al. developed a Melasma Quality of Life Scale (MELASQoL) questionnaire consisting of 10 questions to assess the effects of melasma on emotional aspects, social relationships, and daily activities.12 The MELASQoL questionnaire contains questions covering 3 domains, namely emotional conditions (questions 1-4), social life (questions 5-7, and 10), and recreation (questions 8-9). A study by Aditya et al. has validated and assessed the reliability of the MELASQoL questionnaire prepared in Indonesian, namely MELASQoL-INA. The higher the MELASQoL score, the lower the person's quality of life.

Various treatment modalities are available for melasma, but none are satisfactory, and relapses often occur after therapy is discontinued.15,16 The mainstay of melasma therapy is sun avoidance and the use of broad-spectrum sunscreen. Other primary treatments for melasma include eliminating causative factors and using bleaching agents, such as hydroquinone (HQ). Hydroquinone at a concentration of 2-5% as a single therapy or in combination with tretinoin and topical corticosteroids (triple combination cream) is the gold standard for melasma therapy. However, this therapy has side effects if used long-term and without proper monitoring. Therefore, a more effective treatment modality is needed for melasma treatment.

Technological advances have resulted in the development of cosmeceutical products derived from natural and synthetic ingredients, some of which have been clinically and empirically tested and successfully commercialized. In Indonesia, the cosmetics industry market is growing relatively rapidly, with total cosmetic product sales in 2017 (Rp9.76 trillion) increasing by 12.9% compared to 2016 (Rp8 trillion), and cosmetic exports increasing by 20% with a transaction value of US$406 million. This indicates that researchers and developers in the cosmetics industry are continuously innovating to find new compound combinations or other modalities to support the growth of the cosmetics market.

One therapeutic modality currently being developed for melasma is secretome. Secretome is a bioactive molecule secreted by mesenchymal stem cells in a conditioned medium containing a large number of growth factors, cytokines, and various macromolecules, as well as extracellular vesicles, including microvesicles and exosomes, that can stimulate various biological reactions, particularly in modulating various new tissue formations. Secretome can provide a depigmenting effect by increasing the proliferation and migration of epidermal keratinocytes, which contain melanin pigment, in line with increased fibroblast synthesis.

Secretomes contain various cytokines and growth factors, one of which is transforming growth factor (TGF)-β. TGF-β is predominantly secreted by fibroblasts (FB) and to a lesser extent by keratinocytes and plays a crucial role in regulating melanocyte function. TGF-β has been reported to inhibit cAMP/protein kinase A signaling and induce GLI2, which in turn suppresses microphthalmia-associated transcription factor (MITF), a central transcription factor in melanogenesis. A study by Moon et al. in Korea examined TGF-β3. Moon et al. examined the effects of TGF-β3 on melanogenesis in human melanocytes co-cultured with skin cells irradiated with ultraviolet (UV) light, and in UV-irradiated human skin. The results showed that UVB irradiation or stem cell factor (SCF)/endothelin-1 (ET-1) increased melanogenesis. TGF-β3 effectively inhibited melanin accumulation and tyrosinase activity by downregulating the extracellular signal-regulated kinase (ERK)/microphthalmia-associated transcription factor (MITF) pathway. TGF-β3 increased the expression of keratinocyte differentiation markers.

Mechanistically, TGF-β3 inhibits melanogenesis by inhibiting MITF expression, which is regulated by ERK. 27,28 TGF-β1 reduces MITF but at the risk of inducing skin fibrosis. However, in the study by Moon et al., mentioned function of TGF Beta 1 was not found in TGF-β3. Furthermore, TGF-β3 restored skin differentiation function in UV-irradiated keratinocytes.

To date, no clinical trials have compared intradermal injection of concentrated secretome with intradermal injection of concentrated secretome with the addition of TGF-β3 as a melasma therapy in Indonesia, prompting researchers to conduct further research. The examination parameters include the mMASI score, mexameter score, dermoscopy, and Wood's lamp. Wood's lamp examination is used to help identify the location of melanin pigment in melasma lesions. Dermoscopy is a non-invasive examination to visualize subsurface structures that are invisible to the naked eye. Mexameter is a fast, easy, and accurate spectrometer measurement technique for measuring the melanin index and erythema index in skin based on light reflection and absorption. The mexameter examination functions to measure the severity of melasma objectively.33 The severity of melasma and evaluation of therapy response can be assessed subjectively using the mMASI score.

Inclusion Criteria:

• Women diagnosed with melasma.
• Women without melasma and have areas of skin that are clinically free of lesions for SP control.
• 30-60 years old.
• Fitzpatrick skin type IV-V.
• Willing to be a research subject by signing a research consent form (Informed Consent).

Exclusion Criteria:

• Pregnant and breastfeeding women.
• Currently using hormonal contraception or have ever used contraception hormones in the last 6 months.
• Using topical therapy for melasma, for example corticosteroids, tretinoin, hydroquinone, and other therapies that whiten or brighten the skin in the last 2 weeks.
• Using topical triple combination cream therapy for at least 3 months and did not show significant improvement
• Using systemic therapy for melasma, for example antioxidants or tranexamic acid in the last 4 weeks.
• History of superficial peeling therapy in the last 4 weeks.
• History of deep peeling therapy, laser or mechanical abrasion in the last 6 months.
• Using drugs that are photosensitizers such as tetracycline, phenytoin, carbamazepine, spironolactone.
• History of blood clotting disorders or on blood thinning therapy.
• Allergy to tranexamic acid.
• Have other skin complaints that may interfere with the evaluation of melasma, for example post-inflammatory hyperpigmentation, Hori's nevus, Ota's nevus, pigmented contact dermatitis, and other pigmentation disorders
• Difficulty complying with treatment.