Microneedle Radiofrequency Induces Extracellular Matrix Remodeling Through Fibroblast Activation: A Histological Study in a Porcine Model
Yidan Xu
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorYi Zhang
Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorHao Wang
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorHuimiao Tang
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorWanxin Zeng
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorCorresponding Author
Xiang Wen
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Correspondence: Xiang Wen ([email protected])
Search for more papers by this authorYidan Xu
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorYi Zhang
Laboratory of Stem Cell and Tissue Engineering, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorHao Wang
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorHuimiao Tang
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorWanxin Zeng
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Laboratory of Dermatology, Clinical Institute of Inflammation and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorCorresponding Author
Xiang Wen
Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
Correspondence: Xiang Wen ([email protected])
Search for more papers by this authorYidan Xu and Yi Zhang contributed equally to this study.
ABSTRACT
Objectives
Microneedle radiofrequency (MRF) is a promising skin rejuvenation treatment. However, the mechanisms underlying its effects on extracellular matrix (ECM) remodeling remain unclear. This study aimed to investigate the immediate histological effects of MRF under varying settings, its short-term impact on collagen and elastin synthesis, and the roles of fibroblasts and adipose-derived stem cells (ADSCs).
Materials and Methods
Porcine abdominal skin was treated with an MRF device containing 49 insulated microneedles using varying energy parameters (8–12 W; 100–300 ms). Immediate histological responses to treatment were evaluated through hematoxylin and eosin (H&E) staining. Short-term changes in collagen and elastin synthesis at Days 7 and 28 posttreatment were assessed via picrosirius red and Victoria blue staining. Additionally, expression and distribution of ECM remodeling-related proteins (MMPs, TGF-β, EGF, Ki67) and ADSCs were analyzed by multiplex immunohistochemistry (mIHC) and western blot analysis.
Results
H&E staining revealed thermal coagulation zones in the dermis immediately after MRF treatment, with zone size increasing with higher power and longer pulse durations (p < 0.05). By Day 28, Collagen I and III densities and organization significantly improved, with the Collagen I/III ratio rising to 7.05 ± 1.21 in the treatment area (p < 0.01) and 3.90 ± 0.37 in the surrounding dermis (p < 0.001). Elastic fibers also showed increased density. mIHC staining demonstrated significant upregulation of MMP-1, MMP-3, and MMP-13 expression in treated and surrounding dermal regions by Day 7 (p < 0.01); however, by Day 28, MMP-1, MMP-9, and MMP-13 expression significantly decreased (p < 0.05), whereas MMP-3 remained elevated. Furthermore, expression levels of TGF-β, EGF, and Ki67 significantly increased by Day 28 (p < 0.05). mIHC analysis of the fibroblast marker FSP-1 coexpression, along with Western blot analysis of Collagen I, Collagen III, MMP-1, MMP-3, TGF-β, and EGF, revealed similar trends. Notably, significant expression of ADSC markers was detected at Day 7 posttreatment (p < 0.01).
Conclusions
MRF predominantly promotes the synthesis of Collagen I and Collagen III, increasing the Collagen I/III ratio, and regulates the expression of MMP-1, MMP-3, MMP-9, TGF-β, and EGF. These factors collectively drive fibroblast activation, migration, and ECM remodeling. These changes are indicative of the potential for MRF to support skin regeneration and rejuvenation. Preliminary findings suggest that ADSCs may contribute to these regenerative processes.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
The authors confirm that the data supporting the findings of this study are available from corresponding author.
Supporting Information
| Filename | Description |
|---|---|
| lsm70033-sup-0001-SuppInfo.docx2.1 MB | SuppInfo. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1L. Gardeazabal and A. Izeta, “Elastin and Collagen Fibres in Cutaneous Wound Healing,” Experimental Dermatology 33, no. 3 (2024): e15052, https://doi.org/10.1111/exd.15052.
- 2J. M. Sorrell and A. I. Caplan, “Fibroblast Heterogeneity: More Than Skin Deep,” Journal of Cell Science 117, no. 5 (2004): 667–675, https://doi.org/10.1242/jcs.01005.
- 3D. G. Janson, G. Saintigny, A. van Adrichem, C. Mahé, and A. El Ghalbzouri, “Different Gene Expression Patterns in Human Papillary and Reticular Fibroblasts,” Journal of Investigative Dermatology 132, no. 11 (2012): 2565–2572, https://doi.org/10.1038/jid.2012.192.
- 4R. B. Diller and A. J. Tabor, “The Role of the Extracellular Matrix (ECM) in Wound Healing: A Review,” Biomimetics 7, no. 3 (2022): 7030087. https://doi.org/10.3390/biomimetics7030087.
- 5J. Gosline, M. Lillie, E. Carrington, P. Guerette, C. Ortlepp, and K. Savage, “Elastic Proteins: Biological Roles and Mechanical Properties,” Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences 357, no. 1418 (2002): 121–132.
- 6H. E. Talbott, S. Mascharak, M. Griffin, D. C. Wan, and M. T. Longaker, “Wound Healing, Fibroblast Heterogeneity, and Fibrosis,” Cell Stem Cell 29, no. 8 (2022): 1161–1180, https://doi.org/10.1016/j.stem.2022.07.006.
- 7M. A. Cole, T. Quan, J. J. Voorhees, and G. J. Fisher, “Extracellular Matrix Regulation of Fibroblast Function: Redefining Our Perspective on Skin Aging,” Journal of Cell Communication and Signaling 12, no. 1 (2018): 35–43, https://doi.org/10.1007/s12079-018-0459-1.
- 8C. R. Lovell, K. A. Smolenski, V. C. Duance, N. D. Light, S. Young, and M. Dyson, “Type I and III Collagen Content and Fibre Distribution In Normal Human Skin During Ageing,” British Journal of Dermatology 117, no. 4 (1987): 419–428.
- 9M. Wlaschek, P. Maity, E. Makrantonaki, and K. Scharffetter-Kochanek, “Connective Tissue and Fibroblast Senescence in Skin Aging,” Journal of Investigative Dermatology 141, no. 4S (2021): 985–992, https://doi.org/10.1016/j.jid.2020.11.010.
- 10W. Manuskiatti, P. Pattanaprichakul, S. Inthasotti, et al., “Thermal Response of In Vivo Human Skin to Fractional Radiofrequency Microneedle Device,” BioMed Research International 2016 (2016): 1–7, https://doi.org/10.1155/2016/6939018.
- 11V. Vejjabhinanta, R. Wanitphakdeedecha, P. Limtanyakul, and W. Manuskiatti, “The Efficacy in Treatment of Facial Atrophic Acne Scars in Asians With a Fractional Radiofrequency Microneedle System,” Journal of the European Academy of Dermatology and Venereology 28, no. 9 (2014): 1219–1225, https://doi.org/10.1111/jdv.12267.
- 12Q. Jia, H. Zhao, Y. Wang, Y. Cen, and Z. Zhang, “Mechanisms and Applications of Adipose-Derived Stem Cell-Extracellular Vesicles in the Inflammation of Wound Healing,” Frontiers in Immunology 14 (2023): 1214757, https://doi.org/10.3389/fimmu.2023.1214757.
- 13W. Dou, Q. Yang, Y. Yin, et al., “Fractional Microneedle Radiofrequency Device and Fractional Erbium-Doped Glass 1,565-nm Device Treatment of Human Facial Photoaging: A Prospective, Split-Face, Random Clinical Trial,” Journal of Cosmetic and Laser Therapy 23, no. 5–6 (2021): 142–148, https://doi.org/10.1080/14764172.2022.2033783.
- 14R. R. Maia, A. C. Sarmento, R. M. V. Silva, et al., “Comparative Effects of Fractional Radiofrequency and Microneedling on the Genitalia of Postmenopausal Women: Histological and Clinical Changes,” Clinics 77 (2022): 100117, https://doi.org/10.1016/j.clinsp.2022.100117.
- 15J. Feng, L. Zhang, J. Qi, and L. Huang, “Histological Damage Characteristics and Quantitive Analysis of Porcine Skin With Non-Insulated Microneedle Radiofrequency,” Skin Research and Technology Jun 29, no. 6 (2023): e13396, https://doi.org/10.1111/srt.13396.
- 16B. M. Hantash, B. Renton, R. L. Berkowitz, B. C. Stridde, and J. Newman, “Pilot Clinical Study of a Novel Minimally Invasive Bipolar Microneedle Radiofrequency Device,” Lasers in Surgery and Medicine 41, no. 2 (2009): 87–95, https://doi.org/10.1002/lsm.20687.
- 17Z. Zheng, B. Goo, D.-Y. Kim, J.-S. Kang, and S. B. Cho, “Histometric Analysis of Skin-Radiofrequency Interaction Using a Fractionated Microneedle Delivery System,” Dermatologic Surgery 40, no. 2 (2014): 134–141, https://doi.org/10.1111/dsu.12411.
- 18H. Wang, M. R. Hamblin, Y. Zhang, Y. Xu, and X. Wen, “Histological Evaluation of Monopolar and Bipolar Radiofrequency Microneedling Treatment in a Porcine Model,” Lasers in Surgery and Medicine 56, no. 3 (2024): 288–297, https://doi.org/10.1002/lsm.23768.
- 19T. Puiu, T. F. Mohammad, D. M. Ozog, and P. V. Rambhatla, “A Comparative Analysis of Electric and Radiofrequency Microneedling Devices on the Market,” Journal of Drugs in Dermatology 17, no. 9 (2018): 1010–1013.
- 20E. Dayan, C. Chia, A. J. Burns, and S. Theodorou, “Adjustable Depth Fractional Radiofrequency Combined With Bipolar Radiofrequency: A Minimally Invasive Combination Treatment for Skin Laxity,” supplement, Aesthetic Surgery Journal 39, no. Suppl 3 (2019): S112–S119, https://doi.org/10.1093/asj/sjz055.
- 21J. Kim, S. G. Lee, S. Choi, et al., “Combination of Fractional Microneedling Radiofrequency and Ablative Fractional Laser Versus Ablative Fractional Laser Alone for Acne and Acne Scars,” Yonsei Medical Journal 64, no. 12 (2023): 721–729, https://doi.org/10.3349/ymj.2023.0234.
- 22H.-W. Ryu, S.-A. Kim, H. R. Jung, Y.-W. Ryoo, K.-S. Lee, and J.-W. Cho, “Clinical Improvement of Striae Distensae in Korean Patients Using a Combination of Fractionated Microneedle Radiofrequency and Fractional Carbon Dioxide Laser,” Dermatologic Surgery 39, no. 10 (2013): 1452–1458, https://doi.org/10.1111/dsu.12268.
- 23W. Manuskiatti, P. Pattanaprichakul, S. Inthasotti, et al., “Thermal Response of in Vivo Human Skin to Fractional Radiofrequency Microneedle Device,” BioMed Research International 2016 (2016): 1–7, https://doi.org/10.1155/2016/6939018.
- 24M. el-Domyati, T. S. el-Ammawi, W. Medhat, et al., “Radiofrequency Facial Rejuvenation: Evidence-Based Effect,” Journal of the American Academy of Dermatology 64, no. 3 (2011): 524–535, https://doi.org/10.1016/j.jaad.2010.06.045.
- 25L. J. England, M.-H. Tan, P. R. Shumaker, et al., “Effects of Monopolar Radiofrequency Treatment over Soft-Tissue Fillers in An Animal Model,” Lasers in Surgery and Medicine 37, no. 5 (2005): 356–365.
- 26C. Park, J. Hong, H. G. Ryu, et al., “Monopolar Radiofrequency for Dermal Temperature Regulation and Remodeling: A Porcine Model Study,” Journal of cosmetic dermatology 23 (2024): 3955–3960, https://doi.org/10.1111/jocd.16495.
- 27Z. Zheng, B. Goo, D. Y. Kim, J. S. Kang, and S. B. Cho, “Histometric Analysis of Skin-Radiofrequency Interaction Using a Fractionated Microneedle Delivery System,” Dermatologic Surgery 40, no. 2 (2014): 134–141, https://doi.org/10.1111/dsu.12411.
- 28A. N. B. Kauvar and A. Gershonowitz, “Clinical and Histologic Evaluation of a Fractional Radiofrequency Treatment of Wrinkles and Skin Texture With Novel 1-mm Long Ultra-Thin Electrode Pins,” Lasers in Surgery and Medicine 54, no. 1 (2022): 54–61, https://doi.org/10.1002/lsm.23452.
- 29I. K. Jeon, S. E. Chang, G.-H. Park, and M. R. Roh, “Comparison of Microneedle Fractional Radiofrequency Therapy With Intradermal Botulinum Toxin a Injection for Periorbital Rejuvenation,” Dermatology 227, no. 4 (2013): 367–372, https://doi.org/10.1159/000356162.
- 30C. Huang, M. Mao, Y. Peng, et al., “Efficacy and Safety of Single Microneedle Radiofrequency Vs. Photodynamic Therapy on Moderate-to-Severe Acne Vulgaris: A Prospective, Randomized, Controlled Study,” Chinese Medical Journal 137, no. 8 (2024): 1006–1008, https://doi.org/10.1097/CM9.0000000000002911.
- 31A. A. M. Emam, H. A. Nada, M. A. Atwa, and N. Z. Tawfik, “Split-Face Comparative Study of Fractional Er:YAG Laser Versus Microneedling Radiofrequency in Treatment of Atrophic Acne Scars, Using Optical Coherence Tomography for Assessment,” Journal of Cosmetic Dermatology 21, no. 1 (2022): 227–236, https://doi.org/10.1111/jocd.14071.
- 32Y. Zhang, Y. Li, C. Li, and J. Tian, “Experience of Negative Pressure Fractional Microneedle Radiofrequency Therapy for Axillary Osmidrosis: A Case Study,” Archives of Dermatological Research 317, no. 1 (2024): 66, https://doi.org/10.1007/s00403-024-03560-6.
- 33Y. R. Helfrich, D. L. Sachs, and J. J. Voorhees, “Overview of Skin Aging and Photoaging,” Dermatology Nursing 20, no. 3 (2008): 177–183.
- 34B. D. Zelickson, D. Kist, E. Bernstein, et al., “Histological and Ultrastructural Evaluation of the Effects of a Radiofrequency-Based Nonablative Dermal Remodeling Device: A Pilot Study,” Archives of Dermatology 140, no. 2 (2004): 204–209.
- 35M. el-Domyati, T. S. el-Ammawi, W. Medhat, et al., “Radiofrequency Facial Rejuvenation: Evidence-Based Effect,” Journal of the American Academy of Dermatology 64, no. 3 (2011): 524–535, https://doi.org/10.1016/j.jaad.2010.06.045.
- 36J. H. Chung, J. Y. Seo, H. R. Choi, et al., “Modulation of Skin Collagen Metabolism in Aged and Photoaged Human Skin In Vivo,” Journal of Investigative Dermatology 117, no. 5 (2001): 1218–1224.
- 37L. Zhang, S. Zhang, H. Song, and B. Li, “Ingestion of Collagen Hydrolysates Alleviates Skin Chronological Aging in an Aged Mouse Model by Increasing Collagen Synthesis,” Food & Function 11, no. 6 (2020): 5573–5580, https://doi.org/10.1039/d0fo00153h.
- 38L. Zhang, S. Zhang, H. Song, and B. Li, “Ingestion of Collagen Hydrolysates Alleviates Skin Chronological Aging in an Aged Mouse Model by Increasing Collagen Synthesis,” Food & Function 11, no. 6 (2020): 5573–5580, https://doi.org/10.1039/d0fo00153h.
- 39J. Uitto, A. J. Perejda, R. P. Abergel, M. L. Chu, and F. Ramirez, “Altered Steady-State Ratio of Type I/III Procollagen Mrnas Correlates With Selectively Increased Type I Procollagen Biosynthesis in Cultured Keloid Fibroblasts,” Proceedings of the National Academy of Sciences of the United States of America 82, no. 17 (1985): 5935–5939.
- 40C. J. Zhou and Y. Guo, “Mini Review on Collagens In Normal Skin and Pathological Scars: Current Understanding and Future Perspective,” Frontiers in Medicine 11 (2024): 1449597, https://doi.org/10.3389/fmed.2024.1449597.
- 41R. M. Herman, M. Berho, M. Murawski, et al., “Defining the Histopathological Changes Induced by Nonablative Radiofrequency Treatment of Faecal Incontinence–A Blinded Assessment in an Animal Model,” Colorectal Disease 17, no. 5 (2015): 433–440, https://doi.org/10.1111/codi.12874.
- 42P. Affinito, S. Palomba, C. Sorrentino, et al., “Effects of Postmenopausal Hypoestrogenism on Skin Collagen,” Maturitas 33, no. 3 (1999): 239–247.
- 43J. Huang, S. Heng, W. Zhang, et al., “Dermal Extracellular Matrix Molecules in Skin Development, Homeostasis, Wound Regeneration and Diseases,” Seminars in Cell & Developmental Biology 128 (2022): 137–144, https://doi.org/10.1016/j.semcdb.2022.02.027.
- 44D. H. Suh, H.-J. Ahn, J.-K. Seo, S. J. Lee, M. K. Shin, and K. Y. Song, “Monopolar Radiofrequency Treatment for Facial Laxity: Histometric Analysis,” Journal of Cosmetic Dermatology 19, no. 9 (2020): 2317–2324, https://doi.org/10.1111/jocd.13449.
- 45Y. Tanaka, Y. Tsunemi, M. Kawashima, N. Tatewaki, and H. Nishida, “Treatment of Skin Laxity Using Multisource, Phase-Controlled Radiofrequency in Asians: Visualized 3-dimensional Skin Tightening Results and Increase in Elastin Density Shown Through Histologic Investigation,” Dermatologic Surgery 40, no. 7 (2014): 756–762, https://doi.org/10.1111/dsu.0000000000000047.
- 46P. Pittayapruek, J. Meephansan, O. Prapapan, M. Komine, and M. Ohtsuki, “Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis,” International Journal of Molecular Sciences 17, no. 6 (2016): 868. https://doi.org/10.3390/ijms17060868.
- 47Q. Wen, S. M. Mithieux, and A. S. Weiss, “Elastin Biomaterials in Dermal Repair,” Trends in Biotechnology 38, no. 3 (2020): 280–291, https://doi.org/10.1016/j.tibtech.2019.08.005.
- 48Y. P. Hwang, J. H. Choi, H. G. Kim, et al., “Cultivated Ginseng Suppresses Ultraviolet B-Induced Collagenase Activation via Mitogen-Activated Protein Kinases and Nuclear Factor κB/Activator Protein-1-Dependent Signaling In Human Dermal Fibroblasts,” Nutrition Research 32, no. 6 (2012): 428–438, https://doi.org/10.1016/j.nutres.2012.04.005.
- 49B. K. Pilcher, J. A. Dumin, B. D. Sudbeck, S. M. Krane, H. G. Welgus, and W. C. Parks, “The Activity of Collagenase-1 Is Required for Keratinocyte Migration on a Type I Collagen Matrix,” Journal of Cell Biology 137, no. 6 (1997): 1445–1457.
- 50M. J. Toriseva, R. Ala-aho, J. Karvinen, et al., “Collagenase-3 (MMP-13) Enhances Remodeling of Three-Dimensional Collagen and Promotes Survival of Human Skin Fibroblasts,” Journal of Investigative Dermatology 127, no. 1 (2007): 49–59, https://doi.org/10.1038/sj.jid.5700500.
- 51M. S. Ågren, I. N. Jorgensen, M. Andersen, J. Viljanto, and P. Gottrup, “Matrix Metalloproteinase 9 Level Predicts Optimal Collagen Deposition During Early Wound Repair In Humans,” Journal of British Surgery 85, no. 1 (1998): 68–71.
- 52R. R. Driskell, B. M. Lichtenberger, E. Hoste, et al., “Distinct Fibroblast Lineages Determine Dermal Architecture in Skin Development and Repair,” Nature 504, no. 7479 (2013): 277–281, https://doi.org/10.1038/nature12783.
- 53M. Okada, A. Suzuki, H. Yamawaki, and Y. Hara, “Levosimendan Inhibits Interleukin-1β-Induced Cell Migration and MMP-9 Secretion in Rat Cardiac Fibroblasts,” European Journal of Pharmacology 718, no. 1–3 (2013): 332–339, https://doi.org/10.1016/j.ejphar.2013.08.013.
- 54N. Kitanaka, R. Nakano, M. Sakai, et al., “ERK1/ATF-2 Signaling Axis Contributes to Interleukin-1β-Induced MMP-3 Expression in Dermal Fibroblasts,” PLoS One 14, no. 9 (2019): e0222869, https://doi.org/10.1371/journal.pone.0222869.
- 55S. Pan, Z. Zhang, C. Li, and D. Yang, “Interleukin-25 Regulates Matrix Metalloproteinase-2 and -9 Expression in Periodontal Fibroblast Cells Through ERK and P38MAPK Pathways,” Cell Biology International 44, no. 11 (2020): 2220–2230, https://doi.org/10.1002/cbin.11430.
- 56X. Jiang, H. Ge, C. Zhou, X. Chai, and H. Deng, “The Role of Transforming Growth Factor β1 in Fractional Laser Resurfacing With a Carbon Dioxide Laser,” Lasers in Medical Science 29, no. 2 (2014): 681–687, https://doi.org/10.1007/s10103-013-1383-5.
- 57K.-A. Byun, H. M. Kim, S. Oh, S. Batsukh, K. H. Son, and K. Byun, “Radiofrequency Treatment Attenuates Age-Related Changes in Dermal-Epidermal Junctions of Animal Skin,” International Journal of Molecular Sciences 25, no. 10 (2024): 5178, https://doi.org/10.3390/ijms25105178.
- 58G. J. Fisher, Y. Shao, T. He, et al., “Reduction of Fibroblast Size/Mechanical Force Down-Regulates TGF-β Type II Receptor: Implications for Human Skin Aging,” Aging Cell 15, no. 1 (2016): 67–76, https://doi.org/10.1111/acel.12410.
- 59J. Liu, Y. Wang, Q. Pan, et al., “Wnt/β-catenin Pathway Forms a Negative Feedback Loop During TGF-β1 Induced Human Normal Skin Fibroblast-to-Myofibroblast Transition,” Journal of Dermatological Science 65, no. 1 (2012): 38–49, https://doi.org/10.1016/j.jdermsci.2011.09.012.
- 60W. Baszanowska, M. Niziol, I. Oscilowska, J. Czyrko-Horczak, W. Miltyk, and J. Palka, “Recombinant Human Prolidase (rhPEPD) Induces Wound Healing in Experimental Model of Inflammation Through Activation of EGFR Signalling in Fibroblasts,” Molecules 28, no. 2 (2023): 851. https://doi.org/10.3390/molecules28020851.
- 61D. H. You and M. J. Nam, “Effects of Human Epidermal Growth Factor Gene-Transfected Mesenchymal Stem Cells on Fibroblast Migration and Proliferation,” Cell Proliferation 46, no. 4 (2013): 408–415, https://doi.org/10.1111/cpr.12042.
- 62O. I. Badr, A. Anter, I. Magdy, et al., “Adipose-Derived Mesenchymal Stem Cells and Their Derived Epidermal Progenitor Cells Conditioned Media Ameliorate Skin Aging in Rats,” Tissue Engineering and Regenerative Medicine 21, no. 6 (2024): 915–927, https://doi.org/10.1007/s13770-024-00643-3.
- 63M. Ichihashi, M. Tanaka, T. Iizuka, et al., “A Single Intradermal Injection of Autologous Adipose-Tissue-Derived Stem Cells Rejuvenates Aged Skin and Sharpens Double Eyelids,” Journal of Personalized Medicine 13, no. 7 (2023): 1162, https://doi.org/10.3390/jpm13071162.
- 64S. Menkes, M. Luca, G. Soldati, and L. Polla, “Subcutaneous Injections of Nanofat Adipose-Derived Stem Cell Grafting in Facial Rejuvenation,” Plastic and Reconstructive Surgery - Global Open 8, no. 1 (2020): e2550, https://doi.org/10.1097/GOX.0000000000002550.
- 65F. Castiglione, P. Hedlund, E. Weyne, et al., “Intratunical Injection of Human Adipose Tissue-Derived Stem Cells Restores Collagen III/I Ratio in a Rat Model of Chronic Peyronie's Disease,” Sexual Medicine 7, no. 1 (2019): 94–103, https://doi.org/10.1016/j.esxm.2018.09.003.
- 66W. Hur, H. Y. Lee, H. S. Min, et al., “Regeneration of Full-Thickness Skin Defects by Differentiated Adipose-Derived Stem Cells Into Fibroblast-Like Cells by Fibroblast-Conditioned Medium,” Stem Cell Research & Therapy 20 8, no. 1 (2017): 92, https://doi.org/10.1186/s13287-017-0520-7.
- 67Z. Q. Zhou, Y. Chen, M. Chai, et al., “Adipose Extracellular Matrix Promotes Skin Wound Healing by Inducing the Differentiation of Adipose‑Derived Stem Cells Into Fibroblasts,” International Journal of Molecular Medicine 43, no. 2 (2019): 890–900, https://doi.org/10.3892/ijmm.2018.4006.
- 68K.-X. Tan, T. Chang, and X. Lin, “Secretomes as An Emerging Class of Bioactive Ingredients for Enhanced Cosmeceutical Applications,” Experimental Dermatology 31, no. 5 (2022): 674–688, https://doi.org/10.1111/exd.14570.
- 69V. Benítez-Roig and M. A. Trelles, “Procedure and Results on Lower Face and Neck Rejuvenation Using a Temperature-Controlled Bipolar Fractional Radiofrequency Microneedling Device,” Lasers in Surgery and Medicine 54, no. 5 (2022): 639–647, https://doi.org/10.1002/lsm.23517.
- 70Y. Gao, Q. Che, Q. He, et al., “Treatment of Periorbital Aging With Negative Pressure Fractional Microneedle Radiofrequency: A Self-Controlled Clinical Trial,” Journal of Cosmetic Dermatology 23, no. 4 (2024): 1269–1276, https://doi.org/10.1111/jocd.16091.
- 71Z. Ding, Y. Guo, Y. Guo, et al., “Efficacy and Safety of Fractional Microneedle Radiofrequency for Atrophic Acne Scars: A Real-World Clinical Study of 126 Patients,” Lasers in Surgery and Medicine 56, no. 2 (2024): 150–164, https://doi.org/10.1002/lsm.23759.
- 72Y. I. Lee, E. Kim, D. W. Lee, et al., “Synergistic Effect of 300 μm Needle-Depth Fractional Microneedling Radiofrequency on the Treatment of Senescence-Induced Aging Hyperpigmentation of the Skin,” International Journal of Molecular Sciences 22, no. 14 (2021): 7480, https://doi.org/10.3390/ijms22147480.
- 73X. Wu, Y. Liu, J. Zhu, W. Yu, and X. Lin, “A Prospective Trial of the Microneedle Fractional Radiofrequency System Application in the Treatment of Infraorbital Dark Circles,” Clinical, Cosmetic and Investigational Dermatology 15 (2022): 1293–1300, https://doi.org/10.2147/CCID.S372409.
- 74B. Wang, Y. Deng, P. Li, et al., “Efficacy and Safety of Non-Insulated Fractional Microneedle Radiofrequency for Treating Difficult-to-Treat Rosacea: A 48-week, Prospective, Observational Study,” Archives of Dermatological Research 314, no. 7 (2022): 643–650, https://doi.org/10.1007/s00403-021-02259-2.
