COMBINED CORRECTION OF AGE-RELATED SKIN CHANGES USING FRACTIONAL RADIOFREQUENCY MICRONEEDLING AND EXOSOME THERAPY

SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 89 COMBINED CORRECTION OF AGE-RELATED SKIN CHANGES USING FRACTIONAL RADIOFREQUENCY MICRONEEDLING AND EXOSOME THERAPY U. Sabirov1, N. Khodjaeva2, I. Nazarova3 DSc., Professor, Republican specialized scientific and practical medical center of dermatovenereology and cosmetology, dermatology, Tashkent, Uzbekistan1 DSc., Republican specialized scientific and practical medical center of dermatovenereology and cosmetology, dermatology, Tashkent, Uzbekistan2 Republican specialized scientific and practical medical center of dermatovenereology and cosmetology, dermatology, Tashkent, Uzbekistan3 https://doi.org/10.5281/zenodo.18065303 Abstract. Involutionary processes in the human body are often accompanied by a single visible manifestation—a change in appearance. There is a pressing need to find new treatment methods that will focus on the timely and rational correction of age-related skin changes and enable a comprehensive impact on the mechanisms of skin aging. Hardware physiotherapy technologies and innovative preparations with exosomes have powerful regenerative potential, initiating and supporting physiological tissue regeneration. Despite the significant amount of data on combined aesthetic correction protocols, there is only limited information on the combined use of fractional microneedle radiofrequency therapy and exosomes. Patients were divided into 3 observation groups depending on the treatment method received. Fractional microneedle radiofrequency therapy was performed twice using the Exion BTL device at 4-week intervals with preliminary topical anesthesia. Salmon-derived exosome therapy was performed three times at 3week intervals between procedures. Combined therapy combined the use of the above methods. The regression of clinical signs of skin aging was assessed based on computer diagnostics of skin condition, high-frequency ultrasound examination of the skin (HFUS) and cutometry. A comparative analysis of the effects of various methods of correcting involutive changes in facial skin showed that the use of combined therapy provides the most pronounced clinical effect in relation to all assessed signs of skin aging. Combined therapy was accompanied by a significant increase in the indicators of 3-spectral computer diagnostics and cutometry. The reconstructive effect on skin morphological structures according to ultrasonography was also significantly higher for the combined treatment method compared to radiofrequency therapy (p < 0.01) and topical therapy with exosomes (p < 0.05). The combined use of fractional microneedle radiofrequency therapy and exosomes provides more effective and prolonged correction of agerelated skin changes compared to the individual components of the method. Keywords: skin aging, microneedle radiofrequency therapy, exosomes, high-frequency ultrasound examination (HFUS). Introduction Skin aging is a complex multifactorial biological process characterized by progressive structural and functional changes in all layers of the skin. The relevance of developing effective methods for correcting age-related changes is due not only to increased aesthetic demands in modern society, but also to significant medical aspects, including barrier function disorders, SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 90 increased dryness, an increased risk of developing dermatoses, and a significant decrease in regenerative potential in middle-aged and elderly patients [7, 8, 16]. Age-related skin changes demonstrate a clear dynamic of development, determined by genetic and epigenetic factors. At the age of 25-35, initial, predominantly functional manifestations are observed: moderate dryness due to decreased activity of the sebaceous and sweat glands, the appearance of fine expression lines in the periorbital area, a slight decrease in elasticity, and slight thinning of the skin. Studies show that histological changes in the dermis begin at this age—a 5-7% decrease in the number of fibroblasts and a 10-15% decrease in type I collagen synthesis compared to the age of 20 [7, 17]. Between the ages of 35 and 45, more pronounced structural changes are observed: deepening of nasolabial folds, formation of wrinkles in the perioral area, appearance of telangiectasia, and initial manifestations of soft tissue ptosis. According to recent studies, at this age, the rate of collagen degradation increases by 25-30% annually, while the synthesis of new collagen decreases by 15-20% [7]. After 45-50 years of age, pronounced involutional changes are observed: deep static wrinkles, significant ptosis, atrophy of subcutaneous tissue, and changes in skin pigmentation and texture. By the age of 60, the total collagen content in the skin decreases by 50-60%, and elastin by 30-40% compared to younger age, while the number of fibroblasts decreases by 40-50% and their synthetic activity significantly decreases [8, 17]. The pathophysiology of skin aging involves a complex interaction of intrinsic (chronological) and extrinsic (external) mechanisms leading to cumulative damage to all structural components of the skin. Progressive changes are observed in the epidermis: atrophy with a 2050% decrease in the number of Langerhans cells, impaired keratinocyte cohesion, and an increase in cell renewal time from 28 to 40-60 days [7]. Dermal changes are characterized by progressive atrophy with a 10-20% decrease in the number of fibroblasts in the decade after age 30, a decrease in their synthetic activity, fragmentation of elastin fibers, and degradation of the collagen matrix. The annual loss of collagen is 1-2%, with a particularly significant decrease in the content of type VII collagen, which is necessary for the attachment of the basement membrane [7, 18]. The key pathogenetic link is the imbalance between the synthesis and degradation of extracellular matrix components, caused by increased expression of matrix metalloproteinases (MMP-1, MMP-3, MMP-9) and decreased activity of their tissue inhibitors [7, 16]. Modern diagnostics of age-related skin changes have advanced significantly thanks to the introduction of high-precision non-invasive imaging methods. High-frequency ultrasound (20-100 MHz) allows for accurate assessment of dermal thickness and collagen fiber density, demonstrating a 20-35% reduction in dermal thickness by the age of 60 [15]. Optical coherence tomography provides detailed visualization of the dermo-epidermal junction, showing its flattening by 30-50% with aging. Confocal microscopy assesses cellular changes in vivo, revealing a decrease in the number of Langerhans cells and a disruption in the architecture of the epidermis [15, 19]. Additional methods, such as measuring the biomechanical properties of the skin using cutometry, mexametry, corneometry, and micro-relief assessment using 3D imaging, provide comprehensive data on structural changes, allowing for an objective assessment of the effectiveness of anti-aging measures [15]. Among invasive methods for correcting age-related changes, microneedle radiofrequency lifting (MRFL) is an innovative technology that combines microperforation of tissue with needles of various lengths (0.5-3.5 mm) with controlled delivery of radiofrequency energy (0.5-10 MHz) to the dermis [11, 13]. The mechanism of action involves multi-level processes: stimulation of SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 91 dermal remodeling through the activation of fibroblasts and induction of collagen synthesis types I, III, and VII, thermal stimulation of neocollagenesis without damaging the epidermis through a mechanism of controlled thermal damage, and a 40-60% increase in the synthesis of hyaluronic acid and extracellular matrix components [11, 13, 14]. Studies demonstrate the complex molecular mechanisms of micro-needle radiofrequency lifting. Activation of the Wnt/β-catenin signaling pathway leads to increased fibroblast proliferation and extracellular matrix synthesis [13]. At the same time, the activity of matrix metalloproteinases is modulated, with a 45-50% decrease in MMP-1 and an increase in the synthesis of tissue metalloproteinase inhibitors [11, 20]. Metaanalyses confirm a statistically significant improvement in skin aging indices on standardized scales, with collagen density increasing by 35-45% three months after the course of procedures, with a clinically significant improvement in skin elasticity by 25-30% and a reduction in wrinkle depth by 40-50% [11, 13, 20]. Recently, increasing attention has been paid to cellular technologies in the context of regenerative medicine, in particular, the use of exosomes. Exosomes are extracellular vesicles measuring 30-150 nm, secreted by mesenchymal stem cells and containing more than 850 biologically active molecules (mRNA, microRNA, cytokines, growth factors) [3, 4]. The mechanisms of anti-aging action include multifactorial effects on various cellular and molecular pathways: stimulation of fibroblast proliferation and migration via the TGF-β/Smad pathway, inhibition of apoptosis through the transfer of anti-apoptotic microRNAs (miR-21, miR-29), and enhancement of antioxidant defense through activation of Nrf2-mediated pathways [3, 4, 21]. Recent studies demonstrate the ability of exosomes to suppress the expression of matrix metalloproteinases MMP-1 and MMP-3 by 60-70% through the regulation of MAPK and NF-κB signaling pathways [3, 21]. At the same time, exosomes stimulate angiogenesis through VEGFmediated mechanisms, increasing the density of the capillary network by 25-30% [4, 6]. Studies demonstrate a significant increase in the synthesis of type I collagen (by 67%) and hyaluronic acid (by 42%) when exosomes are used in fibroblast culture [1, 3]. Clinical studies confirm a long-term remodeling effect with results lasting up to 21 months and an improvement in hydration by 55%, elasticity by 45%, and skin density by 38% [6, 21]. Currently, a combined approach that combines microneedle radiofrequency lifting and exosome therapy based on proven synergistic effects is of particular interest. Microchannels created by microneedles ensure optimal transdermal delivery of exosomes with bioavailability of up to 85% [2, 5]. Radiofrequency stimulation not only enhances tissue permeability for exosomes, but also creates optimal conditions for the realization of their regenerative potential by activating cellular signaling pathways and stimulating neocollagenesis [2, 5, 22]. In turn, exosomes potentiate and prolong the neocollagenogenic effect of MRFL through the activation of dermal stem cells and modulation of the microenvironment [5, 21]. Combination therapy provides synergistic activation of several regeneration signaling pathways (TGF-β, Wnt, Nrf2), leading to more pronounced and sustainable clinical results [2, 5]. Studies demonstrate the statistically significant superiority of combination therapy over monotherapy: improvement in skin density by 45% versus 28%, reduction in wrinkle depth by 62% versus 41%, and enhancement of collagen synthesis by 75% versus 48% [2, 22]. Histological studies confirm a 55% increase in the number of fibroblasts and a 40% increase in neovascularization with the combined approach [5, 22]. Thus, combined correction of age-related skin changes using microneedle radiofrequency lifting and exosome therapy is a promising and scientifically sound direction in modern aesthetic medicine. This approach is based on a deep understanding of the pathophysiology of aging and SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 92 the molecular mechanisms of regeneration, and its effectiveness is confirmed by a growing body of experimental and clinical data. Further research should focus on optimizing treatment protocols, studying long-term effects, assessing safety, and developing personalized approaches that take into account the individual characteristics of skin aging and the genetic predispositions of patients. Materials and methods A prospective comparative study was conducted at the dermatocosmetology department of the Republican Specialized Scientific and Practical Medical Center for Dermatovenereology and Cosmetology with 30 female patients aged 30 to 65 who were receiving outpatient treatment for clinically pronounced signs of skin aging. All participants were randomized into three intervention groups: - Group 1 (n=10) received monotherapy with microneedle radiofrequency lifting; - Group 2 (n=10) received monotherapy with topical application of exosomes; - Group 3 (n=10) received combination therapy with microneedle radiofrequency lifting followed by exosome application in a single treatment session. Fractional microneedle bipolar radiofrequency therapy was performed using the Exion BTL device. Topical anesthesia with a 5% lidocaine cream was applied 40 minutes before the procedure. The treatment was performed using a disposable sterile attachment with 36 needles insulated along their entire length. The parameters of the procedure were set individually, taking into account the anatomical features of the treatment areas and the skin type of the patients: the penetration depth of the needles varied from 0.5 to 3.5 mm, and the energy density from 30 to 70 J. The course of treatment consisted of two procedures with an interval of 4 weeks. For exosome therapy, the E50 Skin Booster (PrimaCure Co, Republic of Korea) was used, which contains salmon-derived exosomes. For each treatment session, 5 ml of the booster solution was applied using an AutoDP device (dermopen). After application, the drug remained on the skin for natural absorption for at least 6 hours. The course of therapy included two procedures with an interval of 3 weeks. In the combined therapy group, the procedure was performed in the following sequence: first, microneedle radiofrequency lifting was performed using the method described above, after which the exosome preparation was applied directly to the treated surface. The course consisted of two treatment sessions with an interval of 4 weeks. A set of modern non-invasive diagnostic methods was used to objectively evaluate the results of treatment: 1. Three-spectrum computer diagnostics using the Opatra Skin Analyzer system (UK); 2. Cutometry using the Multi Skin Test MC1000 device; 3. High-frequency ultrasound scanning using the DUB Skin Scanner (TPM GmbH, Germany) with a linear sensor at frequencies of 33 MHz and 75 MHz. The effectiveness was assessed before the start of treatment and 2 months after the end of the therapy course. For a subjective assessment of the results, the Global Aesthetic Improvement Scale (GAIS) was used, which was completed by an independent expert.The data obtained were statistically processed using parametric and nonparametric statistical methods with the determination of the significance of differences (p < 0.05). Results The study demonstrated a statistically significant improvement in skin condition in all observation groups. The distribution of patients by skin aging types according to Kalgunenko's classification showed a predominance of the deformation type, which was diagnosed in 15 patients SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 93 (50%). The fine-wrinkle type was observed in 6 patients (20%), the tired type in 4 (13.3%), and the combined type in 5 (16.7%). Statistical analysis confirmed the homogeneity of the groups in terms of baseline characteristics. The results of three-spectral computer diagnostics revealed a significant improvement in the integral assessment of skin condition. The greatest dynamics were recorded in the combined therapy group, where the overall assessment improved by 12% (p < 0.05). In the monotherapy group with microneedle RF lifting, the indicator increased by 8%, while in the monotherapy group with exosomes, it increased by 6%. A detailed analysis of individual skin parameters showed a marked positive trend in all assessed indicators. In the combination therapy group, the maximum improvement in wrinkles was 15% and in pores 12% (Fig 1). In the RF lifting monotherapy group, these indicators were 10% and 8%, respectively, and in the exosome monotherapy group, 8% and 5%. UV damage parameters improved most significantly in the exosome monotherapy group (10%), while in the combination group and the RF lifting group, the improvement was 8% and 5%, respectively (Fig 2). The telangiectasia index improved by 8% in the combination group, by 7% in the RF lifting group, and by 6% in the exosome group. Wrinkles baseline Wrinkles 2 month Pores baseline Pores 2 month Fig 1. Results of computer diagnostics based on wrinkle and pore parameters in a 38-year-old female patient who received combined treatment. UV damage baseline UV damage 2 month Teleangiectasia baseline Teleangiectasia 2 month Fig 2. Results of computer diagnostics based on UV damage and teleangiectasia parameters in a 38-year-old female patient who received combined treatment. Cutometry data revealed an initial decrease in skin elasticity relative to the age norm in 68% of patients. After completing the course of therapy, a significant improvement in elasticity indicators was recorded: by 23% in the combined therapy group (p < 0.05), by 15% in the RF SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 94 lifting group, and by 10% in the exosome group. Statistical analysis confirmed the significance of the differences between the combination therapy group and the monotherapy groups. The high-frequency ultrasound test findings revealed considerable favorable alterations in the skin's structural properties across all treatment groups, with the most pronounced enhancements noted in the combination therapy group (Table 1). This group exhibited a 15% augmentation in dermal thickness, a 28% enhancement in acoustic density (p < 0.05), and a 17% advancement in the epidermal microrelief index. A comparison examination of the percentage improvement (Table 2) indicated that skin thickening in the combination group was double that of the exosome monotherapy group, and the rise in acoustic density was 40% superior to that of the RF-lifting monotherapy group. The condition of patients' skin during ultrasound scanning before and after the procedure was assessed at four fixed points on the skin of the face: the forehead, cheekbone area, nasolabial area, and chin. The micro-relief of the epidermis was assessed using a 75 MHz sensor, and the thickness of the epidermis and dermis layers and their acoustic density were assessed using a 33 MHz sensor. The maximum result for epidermal micro-relief was observed in patients in the combined protocol in the forehead and cheekbone areas (Fig 3), while significant thickening of the dermis and an increase in its acoustic density were observed in the forehead and nasolabial areas, also in patients in group 3 (Fig 4). Parameter Freq. MHz Uni t Group 1: RF Group 2: Exosomes Group 3: Combination (Baseline / Post) Dermal Thickness 33 mm 1.54 ± 0.12 / 1.65 ± 0.10 1.56 ± 0.11 / 1.68 ± 0.09 1.52 ± 0.13 / 1.75 ± 0.11 Dermal Density 33 AU 82.5 ± 6.3 / 99.0 ± 5.8 85.1 ± 5.9 / 103.8 ± 6.1 *83.2 ± 6.5 / 106.5 ± 5.5 * Microrelief Index 75 AU 115.3 ± 8.1 / 126.8 ± 7.5 117.5 ± 7.8 / 131.6 ± 7.0 116.4 ± 8.4 / 136.2 ± 6.8 Table 1. HFUS Skin Parameters Preand Post-Treatment Parameter RF Mono Exo Mono Combinatio n Key Comparative Finding Dermal Thickness +7% +8% +15% 2x > Exosomes Dermal Density +20% +22% +28%* 40% > RF Microrelief +10% +12% +17% Superior to mono Table 2. Efficacy Comparison (% Improvement from Baseline) SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 95 Abbreviations and Notes:  HFUS: High-Frequency Ultrasound.  Freq.: Frequency.  AU: Arbitrary Units (for echogenicity and microrelief indices).  RF: Radiofrequency (Microneedling RF-Lifting).  Exo: Exosomes.  Mono: Monotherapy.  Data presented as Mean ± SD.  *p < 0.05 vs. baseline. Forehead baseline Forehead 2 month Cheekbone area baseline Cheekbone area 2 month Fig 3. Results of high-frequency ultrasound examination using a linear sensor at frequency 75 MHz in the forehead and cheekbone areas in a 38-year-old female patient who received combined treatment. Forehead baseline Forehead 2 month Nasolabial area baseline Nasolabial area 2 month Fig 4. Results of high-frequency ultrasound examination using a linear sensor at frequency 33 MHz in the forehead and nasolabial areas in a 38-year-old female patient who received combined treatment. Assessment of clinical efficacy using the GAIS scale confirmed the advantage of the combined method. A significant improvement was recorded in 90% of patients in the combination therapy group (p < 0.05), while in the RF lifting and exosome monotherapy groups, this figure was 70% and 60%, respectively. Statistical analysis revealed significant differences between the combination therapy group and the monotherapy groups. No side effects were observed in patients. The results obtained convincingly demonstrate the synergistic effect of the combined use of microneedle radiofrequency lifting and exosome therapy. The greatest effectiveness of the combined protocol is particularly evident in terms of improving skin elasticity and structural parameters of the dermis, which is confirmed by instrumental studies. Statistical analysis confirmed the reliability of the advantages of the combined technique in terms of key evaluation SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 96 parameters. The identified patterns justify the promising application of the combined approach in the clinical practice of aesthetic dermatology for the correction of age-related skin changes. Discussion The study demonstrates the marked effectiveness of the combined use of microneedle radiofrequency lifting and exosome therapy in correcting age-related skin changes. The results obtained are consistent with current understanding of the pathophysiology of skin aging and the mechanisms of action of the techniques studied. The synergistic effect of the combined protocol, manifested in a significant superiority in all evaluated parameters, can be explained by the complementarity of the mechanisms of action. Microneedle radiofrequency lifting, on the one hand, creates microchannels for optimal delivery of biologically active substances, and on the other hand, initiates a cascade of reparative processes through controlled thermal exposure and activation of the Wnt/β-catenin signaling pathway. Exosomes, in turn, provide targeted modulation of cellular metabolism by transferring regulatory microRNAs and growth factors, which potentiates and prolongs the neocollagenogenic response. Particular attention should be paid to the marked improvement in skin elasticity in the combination therapy group (23%), which is almost 1.5 times higher than the results of radiofrequency lifting monotherapy. This fact can be explained by the combined effect on various components of the extracellular matrix: thermal stimulation mainly activates the synthesis of collagen fibers, while exosomes have a complex effect on the synthesis of elastin and glycosaminoglycans. Ultrasound data showing a 28% increase in dermal acoustic density in the combination therapy group correlates with the histological changes described in the studies by Liang et al. [1] and Theodorakopoulou et al. [2]. The results obtained indicate a significant improvement in the organization of the collagen matrix, which is a key factor in the correction of age-related atrophy of the dermis. The advantages of the combined approach were particularly evident in the GAIS scale assessment, where 90% of patients reported significant improvement. This indicator not only confirms the objective data of instrumental studies, but also reflects high patient satisfaction, which is an important aspect in aesthetic medicine. It should be noted that the combined technique demonstrated an optimal safety profile, which is consistent with the data of Jafarzadeh et al. [4] on the good tolerability of both radiofrequency techniques and exosome therapy. The absence of significant side effects during the study allows this protocol to be recommended for widespread clinical use. A promising area for further research is the study of long-term treatment outcomes, as well as the optimization of procedure parameters for different types of skin aging and age groups. Conclusions The study convincingly demonstrates the clinical efficacy of the combined use of microneedle radiofrequency lifting and exosome therapy in correcting age-related skin changes. The results obtained indicate a pronounced synergistic effect of this approach, which is confirmed by a significant improvement in both objective instrumental indicators and subjective patient assessments. The study results revealed a significant superiority of the combined technique in terms of key parameters of skin condition. The greatest effectiveness was noted in terms of improving skin elasticity and structural characteristics of the dermis, which is confirmed by comprehensive instrumental diagnostics data. The optimal safety profile of the technique used and its good tolerability by patients deserve special attention. The clinical significance of the study is emphasized by high patient satisfaction scores, as assessed using a standardized scale. The results SCIENCE AND INNOVATION INTERNATIONAL SCIENTIFIC JOURNAL VOLUME 4 ISSUE 12 DECEMBER 2025 ISSN: 2181-3337 | SCIENTISTS.UZ 97 obtained allow us to recommend a combined protocol for widespread use in aesthetic dermatology practice. 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