# Efficacy and Tolerability of a Microneedling Device Plus Exosomes for Treating Melasma
## 1 Introduction
### Exosomes in Dermatology
#### 1.4.1 Human Stem Cell-Derived Exosomes  
Exogenous exosomes, such as stem cell exosomes, can serve as novel treatment options to repair and rejuvenate skin tissues [28]. Exosomes can be isolated and purified from different sources, such as blood, urine, mesenchymal stem cells, and adipose tissue stem cells. The isolation and characterization of exosomes involve techniques such as ultracentrifugation, size-exclusion chromatography, and flow cytometry. Human umbilical cord mesenchymal stem cell exosomes (hUCMSC-Exos) have been shown to promote wound healing by delivering Wnt, which activates the Wnt/\(\beta\)-catenin pathway in skin cells. Additionally, they protect skin cells from apoptosis induced by acute heat stress through the activation of AKT pathway [29]. Studies conducted both in vitro and in vivo have highlighted the therapeutic potential of exosomes in treating photodamaged skin by reducing TNF-\(\alpha\) levels and increasing TGF-\(\beta\) and tissue inhibitor of MMP (TIMP). This results in an increase in collagen I and elastin, and a reduction in collagen III [30].  
Exosomes originating from keratinocytes have been found to enhance melanocyte pigmentation through miR-3196 and MITF-dependent signaling pathways, or via miR-203 and MITF-independent pathways. Conversely, keratinocyte-derived exosomes overexpressing miR-330-5p have been observed to reduce melanin production and TYR expression in melanocytes. Furthermore, miR-675 from keratinocyte exosomes contributes to H19 lncRNA downregulation-stimulated melanogenesis by inhibiting MITF expression [27]. Exosomes derived from human adipose tissue-derived mesenchymal stem/strom cells (ASC-exosomes) can decrease intracellular melanin content in vitro by affecting downstream factors of TYR (TYRP-1, TYRP-2). However, clinically relevant brightening effects are not evident, suggesting an enhancement in transdermal delivery for more meaningful efficacy [31]. A 12-week split-face study demonstrated that combined treatment with human adipose tissue stem cell-derived exosomes (HASC) and microneedling is effective for facial skin aging, showing improvement in skin hydration, elasticity, and pigmentation. In particular, the melanin index significantly decreased in the skin area treated with exosomes and microneedling compared to the area treated with microneedling alone [32]. Another study explored the therapeutic benefits and the percutaneous penetration of hUCMSC-Exos in conjunction with microneedles, 1565 nm nonablative fractional laser (NAFL), and a plasma device called Peninsula Blue Aurora Shumin Master (PBASM) for the treatment of melanoma in both rat models and human subjects. In the animal study, about the effect of penetration, hUCMSC-Exos can penetrate the deep dermis under microneedles, NAFL, and PBASM treatments. All the patients showed significant clinical improvement in melanoma compared to baseline, assessed through the MASI score, degree of improvement rate, and physician global assessment score (PGA). No statistically significant differences were found among the three therapeutic approaches [33].