Arya Tjipta Prananda
Rony Abdi Syahputra- 1Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia
- 2Department of Pharmacology, Faculty of Pharmacy, Universitas Sumatera Utara, Medan, Indonesia
Keloid formation is a pathological scarring process marked by excessive fibroblast activity, overproduction of extracellular matrix (ECM), and chronic inflammation, presenting significant challenges in management despite existing treatments like corticosteroid injections, surgical excision, and cryotherapy. This review evaluates Photobiomodulation Therapy (PBMT) as a promising non-invasive approach for keloid treatment. PBMT utilizes non-thermal light in the red to near-infrared spectrum, which enhances mitochondrial activity, reduces reactive oxygen species (ROS), and regulates fibroblast proliferation and apoptosis. It also exhibits anti-fibrotic properties by inhibiting TGF-β1 expression, collagen synthesis, and Smad signaling, while modulating inflammation through reduced pro-inflammatory cytokines (IL-6, TNF-α) and enhanced macrophage activity. Preclinical evidence in animal models and fibroblast cultures demonstrates PBMT’s ability to reduce scar size, collagen deposition, and fibroblast activity. Clinical studies, including randomized controlled trials (RCTs) and case reports, show significant improvements in keloid height, elasticity, and texture, with reductions in pain and pruritus, as well as lower recurrence rates compared to conventional therapies. PBMT is well-tolerated with minimal adverse effects, such as transient redness or mild itching, and is safe for all skin types, including those with darker pigmentation. In conclusion, PBMT offers a promising, safe, and effective alternative for keloid management by targeting key fibrotic, inflammatory, and angiogenic processes. However, further large-scale randomized controlled trials with standardized protocols are necessary to confirm its long-term efficacy and integrate it into clinical practice.
Introduction
Keloids are pathological scars resulting from dysregulated wound healing, marked by excessive deposition of fibrous tissue that extends beyond the original wound margins (1, 2). In contrast to hypertrophic scars, keloids exhibit continuous growth in the absence of additional trauma (3). Clinically, keloids may present with pain, pruritus, and stiffness, potentially limiting mobility when located near joints, and contributing to psychological distress, particularly when situated in visible areas (4). They are more prevalent among individuals with darker skin phototypes and those with a genetic predisposition, typically developing between the ages of 10 and 30 years (5–9). As such, keloids constitute both cosmetic and clinical challenges.
The pathophysiology of keloids involves disrupted wound healing, particularly during the proliferation and remodeling phases, leading to excessive extracellular matrix (ECM) production—mainly type I and III collagen—and thick, irregular scars (10, 11). A key factor is fibroblast hyperactivity, resulting in increased synthesis of ECM components such as collagen, fibronectin, and proteoglycans (12). In keloid tissue, both fibroblasts and myofibroblasts are present and contribute to pathological scarring. Myofibroblasts typically arise through TGF-β1–induced differentiation of fibroblasts during wound healing, although contributions from other precursor cells—including pericytes and mesenchymal stem cells—have been proposed. In normal wound healing, myofibroblasts appear transiently to facilitate wound contraction and then undergo apoptosis. In keloids, this resolution phase is impaired, leading to persistent myofibroblast presence and continuous ECM deposition (13, 14). Vascular Endothelial Growth Factor (VEGF) supports angiogenesis, aiding keloid growth (15, 16), while chronic inflammation and cytokines like IL-6, IL-8, and TNF-α exacerbate the process.
Keloid treatment remains clinically challenging due to limited efficacy and high recurrence rates. Intralesional corticosteroids, particularly triamcinolone acetonide, are widely used to inhibit fibroblast proliferation and collagen synthesis but are associated with adverse effects such as skin atrophy, hypopigmentation, pain, and frequent recurrence (17–19). Surgical excision alone results in recurrence rates of 50–80% due to post-operative fibroblast activation and collagen overproduction (20). Cryotherapy shows inconsistent results and often induces hypopigmentation, especially in darker skin types. Radiotherapy is effective adjunctively but poses long-term carcinogenic risks. Silicone gel therapy relies heavily on patient adherence, limiting its practicality. These limitations highlight the urgent need for safer and more effective therapeutic strategies.
In recent years, Photobiomodulation Therapy (PBMT), or Low-Level Laser Therapy (LLLT), is a non-thermal light-based treatment that uses low-energy lasers or LEDs to modulate cellular and molecular processes involved in keloid formation (21). Unlike tissue-destructive laser ablation, PBMT works by stimulating cellular activity through the absorption of light by intracellular chromophores, such as cytochrome c oxidase in mitochondria (Figure 1). By stimulating mitochondrial chromophores like cytochrome c oxidase, PBMT enhances ATP production and reduces reactive oxygen species (ROS), promoting cellular repair and balanced fibroblast activity (22). In keloid management, PBMT inhibits fibroblast proliferation, reduces collagen synthesis (23), and suppresses TGF-β1 expression (24). Its anti-inflammatory effects decrease IL-6 and TNF-α levels, while downregulation of VEGF disrupts angiogenesis, collectively limiting scar overgrowth.
Figure 1. Mechanism of Photobiomodulation Therapy (PBMT). Photobiomodulation Therapy (PBMT) activates cytochrome c oxidase in mitochondria, boosting ATP and nitric oxide (NO) production, which promotes vasodilation. This also generates ROS, activating the PI3K/AKT pathway to support cell survival, proliferation, and differentiation. ROS and ATP-driven cAMP stimulate PKA, influencing the RAS–RAF–MEK–ERK cascade and regulating sirtuins (SIRT), which epigenetically modulate gene expression by deacetylating histones and transcription factors like NF-κB. This suppresses pro-inflammatory cytokines (e.g., TNF-α, IL-6), inhibits fibrosis, and improves mitochondrial function. Overall, PBMT enhances repair, metabolism, and regeneration through coordinated mitochondrial and signaling pathway activation.
PBMT offers several advantages over conventional therapeutic modalities, including its non-invasive nature, minimal risk of side effects, and versatility in combination with other treatments (25). PBMT can be used as a standalone or adjunctive therapy to enhance the efficacy of keloid management. Preclinical and clinical studies have demonstrated PBMT’s ability to significantly reduce keloid size, thickness, and hardness, improve tissue elasticity, and alleviate symptoms such as pain and itching (26, 27). Additionally, some studies report lower recurrence rates following PBMT treatment compared to other modalities. However, challenges remain, particularly regarding the variability of therapy protocols, including light wavelength, energy dose, session duration, and frequency. Standardizing PBMT parameters is crucial to ensure consistent and reproducible therapeutic outcomes across different populations.
This review provides a comprehensive analysis of the mechanisms underlying PBMT’s action, evaluates the scientific evidence from preclinical and clinical studies, and highlights future research directions. The focus is on understanding how PBMT modulates the cellular and molecular processes involved in keloid formation while critically assessing its clinical effectiveness and safety profile. By synthesizing current knowledge, this review aims to clarify PBMT’s potential role in keloid management and identify key areas for further investigation.
Pathophysiology of keloid formation and the need for alternative therapeutics
Normal wound healing
Wound healing is a dynamic, multi-phase process involving hemostasis, inflammation, proliferation, and remodeling, each essential for restoring tissue integrity (28). Hemostasis starts immediately after injury with platelet activation, coagulation, and fibrin clot formation to stop bleeding and support cell migration, during which platelets release growth factors like PDGF and TGF-β to recruit inflammatory cells and promote healing (29–31). The inflammatory phase begins within hours and lasts 2–3 days, during which neutrophils and macrophages clear debris and pathogens while releasing cytokines (IL-1β, IL-6, TNF-α) and growth factors to stimulate fibroblast activity and angiogenesis (32, 33). In the proliferation phase, fibroblasts produce ECM components such as collagen and fibronectin, epithelial cells migrate to cover the wound, and VEGF-driven angiogenesis ensures nutrient supply (34, 35). Remodeling involves the replacement of type III collagen with type I, mediated by MMPs, resulting in stronger scar tissue (36). Keloids result from dysregulation in the proliferation and remodeling phases, leading to abnormal ECM accumulation and scarring; hyperactive fibroblasts, stimulated by elevated levels of TGF-β1 and VEGF, drive excessive collagen synthesis—particularly types I and III—while reduced ECM degradation due to altered MMP activity and increased TIMPs promotes fibrotic tissue extending beyond the wound margin (37, 38), highlighting the complexity of keloid formation and its clinical challenges.
Wound healing disorders in keloids
In keloids, dysregulated wound healing during the proliferation and remodeling phases is driven by fibroblast hyperactivity, excessive collagen I and III production, and imbalanced ECM turnover (39, 40). TGF-β1/β2 enhance fibroblast proliferation, differentiation of fibroblasts into myofibroblasts, and collagen synthesis while suppressing MMPs critical for ECM degradation (41). MMP regulation is complex—MMP1/MMP13 initiate collagen I breakdown, while low TIMP2 levels can activate MMP2. Broad MMP inhibition, such as targeting MMP9 in cancer, has failed due to adverse effects. VEGF promotes abnormal angiogenesis, sustaining fibrotic tissue, while IL-6 and IL-8 perpetuate inflammation and fibroblast activation. Myofibroblast resistance to apoptosis leads to ongoing collagen accumulation (42). Thus, ECM dysregulation in keloids involves both collagen overproduction and impaired degradation.
Abnormal ECM remodeling in keloids
In keloids, ECM remodeling is profoundly impaired, leading to excessive collagen deposition and disorganized tissue architecture. Unlike the criss-cross collagen arrangement in healthy skin, keloids show thick, irregular, and haphazard collagen bundles due to reduced decorin and elevated collagen V, which disrupts fibril assembly. In healthy dermis, the dense and well-organized collagen matrix contributes to a biophysical phenomenon known as molecular crowding. This high-density environment restricts fibroblast proliferation by physically limiting cellular space and hindering the diffusion of signaling molecules, thus acting as a natural brake on overactivation. In contrast, artificial dermis in 3D skin models lacks such structural constraints, often allowing unregulated fibroblast activity. The normal replacement of type III with type I collagen during scar maturation is impaired, resulting in persistent type III and excessive type I collagen that form stiff, inflexible tissue (43). ECM imbalance is worsened by GAG overproduction, especially hyaluronic acid (HA), which binds water, increases osmotic pressure, expands ECM volume, and activates pro-fibrotic signaling via CD44. Notably, increased HA incorporation may reduce molecular crowding by hydrating and spacing the ECM, facilitating better diffusion of regulatory molecules and potentially modulating fibroblast activity. Other GAGs, like chondroitin sulfate, and fibronectin overproduction further stiffen the matrix and promote ECM persistence (37). Reduced decorin enhances TGF-β activity, while abnormal HA-CD44 signaling sustains fibroblast proliferation. Concurrently, decreased MMPs and elevated TIMPs inhibit ECM degradation, leading to keloids’ dense, rigid texture and invasive growth (44).
Challenges in standard keloid treatments and the potential of PBMT as a therapeutic alternative
Keloid treatment remains challenging due to high recurrence rates and the lack of standardized protocols. Keloids often recur even after surgical excision, with recurrence rates reaching 50–80% without adjuvant therapies such as corticosteroids or radiotherapy (20, 45). Treatment outcomes vary with lesion site, size, patient age, and genetics, complicating management. The absence of consensus on optimal dosing, duration, or combination therapies highlights the need for more effective, minimally invasive approaches. Photobiomodulation therapy (PBMT) offers promise by enhancing mitochondrial function via cytochrome c oxidase activation, promoting ATP production and NO-mediated vasodilation, modulating redox balance, reducing inflammatory cytokines, and regulating PI3K/AKT and RAS–MEK–ERK pathways involved in fibroblast activity and ECM remodeling. PBMT may serve as a viable adjunct or alternative to current treatments, warranting further comparative studies on efficacy and safety.
Working mechanism of photobiomodulation therapy
Light absorption and cellular effects
PBMT uses 600–1,100 nm light (red to near-infrared) to non-invasively modulate cellular activity by enhancing mitochondrial function and ATP production through cytochrome c oxidase activation (46, 47). ATP supports key processes like proliferation, migration, and tissue repair. In keloids, PBMT regulates fibroblast activity, reduces ROS to prevent oxidative stress and collagen overproduction, and modulates the cell cycle to limit excessive ECM components such as type I and III collagen (48).
Anti-fibrotic mechanisms in keloids
Photobiomodulation therapy (PBMT) demonstrates significant anti-fibrotic effects by modulating key pathophysiological mechanisms involved in keloid formation, including fibroblast activity, collagen synthesis, and pro-fibrotic signaling pathways. PBMT suppresses fibroblast proliferation by regulating intracellular pathways such as Akt/PI3K and ERK/MAPK, leading to G1 cell cycle arrest and apoptosis in hyperactive fibroblasts (49). It also downregulates the expression of collagen-encoding genes, such as COL1A1 and COL3A1, which code for type I and type III collagen respectively, and inhibits pro-fibrotic enzymes, thereby reducing collagen synthesis and preventing excessive extracellular matrix (ECM) accumulation (50). Additionally, PBMT attenuates the expression of transforming growth factor-beta 1 (TGF-β1), a central mediator in keloid pathogenesis, and inhibits its downstream Smad signaling pathway, further decreasing fibroblast activation and collagen production (51). Collectively, these mechanisms contribute to the restoration of ECM homeostasis and the attenuation of fibrotic progression.
Immunomodulating effects
Chronic inflammation is a key factor in the initiation and persistence of keloid formation. PBMT exerts significant immunomodulatory effects by regulating the inflammatory response, thus fostering a wound healing microenvironment that minimizes excessive fibrosis. A primary mechanism is the reduction of pro-inflammatory cytokines, including IL-6, TNF-α, and IL-8, which stimulate fibroblast activity and collagen synthesis. By suppressing these cytokines, PBMT alleviates chronic inflammation that contributes to keloid pathogenesis. Additionally, PBMT promotes macrophage activation, particularly the transition to the M2 phenotype, which has anti-inflammatory and pro-regenerative properties. M2 macrophages aid in cellular debris clearance and the release of growth factors supporting wound healing (52, 53). This macrophage polarization also facilitates more balanced ECM remodeling, significantly reducing the risk of excessive ECM accumulation (54).
Vascular effects
Excessive angiogenesis, driven by elevated VEGF expression, is a hallmark of keloid formation. PBMT regulates angiogenesis by suppressing VEGF expression and associated signaling pathways, thereby inhibiting the formation of new blood vessels in the wound area (55). This reduction in angiogenesis limits the nutrient supply required for fibroblast activity and ECM accumulation. Additionally, PBMT stabilizes existing blood vessel structures, reducing vascular leakage and preventing excessive blood supply to the wound, thus promoting balanced vascularization and supporting wound healing without exacerbating fibrous tissue growth (56).
Summary of PBMT vs. other energy-based modalities
PBMT offers several advantages over other energy-based therapies, such as laser ablation, fractional CO₂ laser, and intense pulsed light (IPL). Laser resurfacing, for instance, uses thermal energy to destroy surface tissue but often results in secondary inflammation, hyperpigmentation, and prolonged recovery (57). Fractional CO₂ lasers stimulate ECM remodeling through thermal micro-columns but are frequently associated with pain and localized inflammation (58). IPL targets pigmentation and vascularization but is less effective in suppressing fibroblast activity. In contrast, PBMT operates non-thermally and non-invasively, addressing cellular and molecular mechanisms of keloid pathogenesis. PBMT suppresses TGF-β1, reduces collagen synthesis, and modulates inflammation and angiogenesis, with minimal side effects (59). This makes PBMT a safer, more flexible, and effective option, either as a standalone treatment or in combination with other therapies (Figure 2). PBMT offers a distinct, non-invasive mechanism and is often combined with non-energy-based therapies for enhanced outcomes. Corticosteroids and 5-fluorouracil (5-FU), commonly used to suppress fibroblast activity, are effective but may cause adverse effects such as skin atrophy, hypopigmentation, pain, or ulceration. Agents like bleomycin and verapamil also target keloid fibroblasts but show variable efficacy and safety. PBMT can enhance these treatments by improving drug penetration, reducing inflammation, and supporting scar remodeling, making it a promising standalone or adjunct option, particularly for resistant keloids.
Figure 2. Photobiomodulation therapy advantages vs. other energy based modalities disadvantages.
Evidence from preclinical and clinical studies
Preclinical studies
PBMT has shown efficacy in treating pathological scarring, including keloids. In animal models, it significantly reduced scar size and thickness; for example, 810 nm light inhibited fibroblast proliferation and collagen deposition in mice and rabbits (60). Histology revealed thinner scars with normalized collagen patterns, along with increased MMP activity for ECM remodeling (61). PBMT also reduced inflammation and improved tissue elasticity, indicating antifibrotic effects. In vitro, 660 nm and 830 nm PBMT suppressed keloid fibroblast proliferation by modulating the cell cycle and reducing S-phase cells (62, 63). It also downregulated TGF-β1, key in keloid pathogenesis (64), and induced fibroblast apoptosis via cytochrome c and caspase-3 activation (65). These findings support PBMT’s potential as a targeted therapy for keloids.
Clinical studies
Clinical studies strongly support PBMT’s effectiveness in reducing keloid size, thickness, and symptoms. Evidence from RCTs, observational studies, and case reports aligns with pre-clinical findings. For example, PBMT using 810 nm at 4 J/cm2 for 12 weeks significantly reduced keloid height and improved skin tone (66). Other studies using 660 nm and 830 nm wavelengths also showed enhanced skin elasticity, reduced pain, and improved texture with lower recurrence risk (67, 68). These outcomes confirm PBMT’s role in inhibiting fibroblast overgrowth and promoting ECM remodeling.
PBMT is a safe, well-tolerated, non-invasive treatment with minimal, temporary side effects such as redness or warmth (69). It is especially suitable for darker skin types prone to post-inflammatory hyperpigmentation and scarring, as it modulates inflammation without damaging the epidermis (70). With minimal recovery time and a favorable safety profile, PBMT is a reliable alternative to invasive keloid therapies (71).
Challenges and limitations of PBMT
Despite the promising potential of photobiomodulation therapy (PBMT) in keloid management, several challenges and limitations must be addressed to optimize its clinical implementation. A key issue is the variability in PBMT protocols, including differences in energy dose, light wavelength, session duration, and frequency, with studies reporting wavelengths between 600 and 1,100 nm, energy levels of 4–8 J/cm2, and varying session durations (72, 73), making comparisons difficult and hindering the establishment of optimal parameters. Standardizing these protocols through systematic research is essential. Furthermore, the lack of large-scale, multicenter clinical trials remains a significant limitation, as existing studies often involve small sample sizes, limited designs, and short follow-up periods, thus reducing the generalizability of findings. To support PBMT’s inclusion in clinical guidelines, large-scale randomized controlled trials (RCTs) with diverse populations are necessary. Additionally, individual variability in response to PBMT—shaped by factors such as genetics, scar location, size, skin type, and age (25)—complicates outcome prediction and underscores the need for personalized treatment strategies. Overall, addressing protocol inconsistencies, expanding clinical evidence through robust trials, and adopting personalized approaches will be crucial to enhance the efficacy, safety, and clinical adoption of PBMT for keloid treatment.
Future perspectives and research directions
Photobiomodulation therapy (PBMT) shows strong potential as a primary treatment for keloids, though further research is needed to refine its clinical application. A major challenge lies in optimizing PBMT parameters such as wavelength (600–1,100 nm), energy density, session duration, and frequency, as existing studies vary significantly in these aspects. Systematic research and well-designed clinical trials are essential to establish protocols that ensure therapeutic efficacy without adverse effects. Combining PBMT with other treatments—such as corticosteroid injections to inhibit fibroblast proliferation or platelet-rich plasma (PRP) to promote tissue regeneration—may offer synergistic benefits (74), though the optimal sequence, dose, and frequency for such combinations remain to be defined.
In-depth molecular and genetic research is also critical to understanding PBMT’s role in keloid pathogenesis. Studies focusing on its effects on TGF-β signaling, collagen synthesis, and pro-fibrotic pathways such as Smad and PI3K/Akt could support the integration of PBMT with targeted molecular therapies (75). A personalized treatment approach is necessary, as individual responses to PBMT may vary based on ethnicity, keloid characteristics, age, and genetic factors. Moreover, intercompartmental signaling—particularly interactions between keratinocytes, fibroblasts, and immune cells—may influence keloid formation, though this remains poorly understood. In individuals with darker skin, melanocyte-derived factors like endothelin-1 and α-MSH may stimulate keratinocyte proliferation, potentially affecting PBMT outcomes (76). Addressing these factors through personalized protocols and interdisciplinary collaboration will be key to advancing PBMT as a standardized, effective therapy for keloid management.
In addition to PBMT, pharmacological agents that influence vascular function—such as statins—may warrant investigation. Statins, known for their vasodilatory and anti-inflammatory properties through nitric oxide modulation and endothelial stabilization, could hypothetically impact keloid vascularization and wound healing (77). However, the potential benefits must be weighed against possible long-term effects on skin integrity and aging, as statins have been associated with altered collagen turnover and reduced dermal thickness in some contexts. Future studies should explore these aspects to determine whether statins play a supportive or detrimental role in dermal remodeling.
Additionally, differences in vitamin D synthesis among skin phototypes may influence keloid susceptibility. Individuals with darker skin have lower efficiency in synthesizing vitamin D due to reduced UVB-mediated cutaneous conversion (78, 79). Given vitamin D’s role in regulating immune responses, fibroblast activity, and TGF-β1 expression, its deficiency might contribute to heightened keloid formation (80). Thus, activated (hydroxyated) vitamin D should be further investigated as a possible adjunctive therapy for individuals with dark skin prone to keloid development.
Furthermore, ultrastructural studies of the extracellular matrix (ECM)—using modalities like transmission electron microscopy (TEM) or second harmonic generation (SHG) imaging—could provide crucial insights into the microarchitectural changes in collagen organization pre- and post-PBMT. Keloids are characterized by dense, disorganized collagen fibers; detecting structural improvements over the course of treatment could validate PBMT’s long-term remodeling effects (81). These findings may also hold significance for broader matrix biology research, particularly in understanding fibrotic mechanisms across different tissues.
Conclusion
Photobiomodulation therapy (PBMT) is a promising, non-invasive treatment for keloid management, acting through mitochondrial stimulation to enhance ATP production, reduce oxidative stress, and modulate fibroblast activity. It exhibits anti-fibrotic, immunomodulatory, and anti-angiogenic effects, supported by both preclinical and clinical studies showing reduced keloid size, symptoms, and recurrence with minimal side effects. While further research is needed to standardize treatment protocols and optimize dosing parameters, PBMT holds strong potential as a safe and effective alternative or adjunct to conventional therapies, particularly when integrated into combination regimens with agents like corticosteroids, retinoids, or platelet-rich plasma.
Importantly, consideration of individual factors—such as skin phototype and vitamin D status—may improve treatment outcomes and help explain the higher prevalence of keloids in darker-skinned populations. Additionally, ultrastructural evaluation of extracellular matrix remodeling may serve as a valuable biomarker of long-term efficacy, offering insights not only for scar modulation but also for broader fibrotic conditions. These perspectives underscore PBMT’s expanding relevance in both dermatological and regenerative medicine contexts.
Author contributions
RS: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing. AP: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The authors declare that no Gen AI was used in the creation of this manuscript.
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References
1. Huang, C, and Ogawa, R. Keloidal pathophysiology: current notions. Scars, Burns Healing. (2021) 7:2059513120980320. doi: 10.1177/2059513120980320
2. Limandjaja, GC, Niessen, FB, Scheper, RJ, and Gibbs, S. Hypertrophic scars and keloids: overview of the evidence and practical guide for differentiating between these abnormal scars. Exp Dermatol. (2021) 30:146–61. doi: 10.1111/exd.14121
3. Yordanov, YP, and Shef, A. Hypertrophic scars and keloids – contemporary concepts and treatment options. Acta Med Bulg. (2014) 41:57–74. doi: 10.2478/amb-2014-0008
4. Yamawaki, S. Scar evaluation In: Ogawa R, editor. Total scar management : Springer Singapore (2020). 71–82. Available at: https://link.springer.com/chapter/10.1007/978-981-32-9791-3_6
5. Delaleu, J, Charvet, E, and Petit, A. Keloid disease: review with clinical atlas. Part I: definitions, history, epidemiology, clinics and diagnosis. Annales de Dermatologie et de Venereologie. (2023) 150:3–15. doi: 10.1016/j.annder.2022.08.010
6. Liang, Z, Zhang, M, Hao, Y, Shan, M, Liu, H, Xia, Y, et al. Risk factors associated with keloid infections: a five-year retrospective study. Int Wound J. (2023) 20:2215–23. doi: 10.1111/iwj.14099
7. Liu, S, Yang, H, Song, J, Zhang, Y, Abualhssain, ATH, and Yang, B. Keloid: genetic susceptibility and contributions of genetics and epigenetics to its pathogenesis. Exp Dermatol. (2022) 31:1665–75. doi: 10.1111/exd.14671
8. Naik, PP, and Farrukh, SN. Influence of ethnicities and skin color variations in different populations: a review. Skin Pharmacol Physiol. (2022) 35:65–76. doi: 10.1159/000518826
9. Zhu, Z, Kong, W, Wang, H, Xiao, Y, Shi, Y, Gan, L, et al. Clinical status of hospitalized keloid cases from 2013 to 2018. Burns J Int Soc Burn Inj. (2022) 48:1874–84. doi: 10.1016/j.burns.2021.12.007
10. Sorg, H, and Sorg, CGG. Skin wound healing: of players, patterns, and processes. Eur Surg Res. (2023) 64:141–57. doi: 10.1159/000528271
11. Tripathi, S, Soni, K, Agrawal, P, Gour, V, Mondal, R, and Soni, V. Hypertrophic scars and keloids: a review and current treatment modalities. Biomed Dermatol. (2020) 4:11. doi: 10.1186/s41702-020-00063-8
12. Elsaie, ML. Update on management of keloid and hypertrophic scars: a systemic review. J Cosmet Dermatol. (2021) 20:2729–38. doi: 10.1111/jocd.14310
13. Feng, F, Liu, M, Pan, L, Wu, J, Wang, C, Yang, L, et al. Biomechanical regulatory factors and therapeutic targets in keloid fibrosis. Front Pharmacol. (2022) 13:906212. doi: 10.3389/fphar.2022.906212
14. Li, X-Y, Weng, X-J, Li, X-J, and Tian, X-Y. TSG-6 inhibits the growth of keloid fibroblasts via mediating the TGF-β1/Smad signaling pathway. J Invest Surg. (2021) 34:947–56. doi: 10.1080/08941939.2020.1716894
15. Huang, C, and Ogawa, R. Systemic factors that shape cutaneous pathological scarring. FASEB J. (2020) 34:13171–84. doi: 10.1096/fj.202001157R
16. Nour, S, Imani, R, Chaudhry, GR, and Sharifi, AM. Skin wound healing assisted by angiogenic targeted tissue engineering: a comprehensive review of bioengineered approaches. J Biomed Mater Res A. (2021) 109:453–78. doi: 10.1002/jbm.a.37105
17. Lee, J, and Kim, J. Minimal-invasive technologies for treatment of HTS and keloids: corticosteroids In: Téot L, Mustoe TA, Middelkoop E, Gauglitz GG, editors. Textbook on scar management : Springer International Publishing (2020). 243–50. Available at: https://www.ncbi.nlm.nih.gov/books/NBK586094/
18. Rimmer, SN, Chandy, RJ, Khan, D, and Feldman, SR. Recurrence rates in the treatment of keloids and hypertrophic scars with intralesional triamcinolone combined with other intralesional agents. Arch Dermatol Res. (2023) 315:2757–67. doi: 10.1007/s00403-023-02662-x
19. Sheng, M, Chen, Y, Li, H, Zhang, Y, and Zhang, Z. The application of corticosteroids for pathological scar prevention and treatment: current review and update. Burns Trauma. (2023) 11:tkad009. doi: 10.1093/burnst/tkad009
20. Lee, JW, and Seol, KH. Adjuvant radiotherapy after surgical excision in keloids. Medicina (Kaunas). (2021) 57:730. doi: 10.3390/medicina57070730
21. Brochado, FT, Mármora, BC, Campos, PS, Schmidt, TR, Fernandes, KPS, Bussadori, SK, et al. Effects of different protocols of defocused high-power laser on the viability and migration of myoblasts—a comparative in vitro study. Lasers Med Sci. (2022) 37:3571–81.
22. Schiliro, C, and Firestein, BL. Mechanisms of metabolic reprogramming in cancer cells supporting enhanced growth and proliferation. Cells. (2021) 10:1056. doi: 10.3390/cells10051056
23. Genah, S, Cialdai, F, Ciccone, V, Sereni, E, Morbidelli, L, and Monici, M. Effect of NIR laser therapy by MLS-MiS source on fibroblast activation by inflammatory cytokines in relation to wound healing. Biomedicines. (2021) 9:307. doi: 10.3390/biomedicines9030307
24. Keshri, GK, Yadav, A, Verma, S, Kumar, B, and Gupta, A. Effects of pulsed 810 nm Al-Ga-as diode laser on wound healing under immunosuppression: a molecular insight. Lasers Surg Med. (2020) 52:424–36. doi: 10.1002/lsm.23156
25. Hernández-Bule, ML, Naharro-Rodríguez, J, Bacci, S, and Fernández-Guarino, M. Unlocking the power of light on the skin: a comprehensive review on photobiomodulation. Int J Mol Sci. (2024) 25:4483. doi: 10.3390/ijms25084483
26. Glass, GE. Photobiomodulation: the clinical applications of low-level light therapy. Aesthet Surg J. (2021) 41:723–38. doi: 10.1093/asj/sjab025
27. Van Tran, V, Chae, M, Moon, J-Y, and Lee, Y-C. Light emitting diodes technology-based photobiomodulation therapy (PBMT) for dermatology and aesthetics: recent applications, challenges, and perspectives. Opt Laser Technol. (2021) 135:106698. doi: 10.1016/j.optlastec.2020.106698
28. Čoma, M, Fröhlichová, L, Urban, L, Zajíček, R, Urban, T, Szabo, P, et al. Molecular changes underlying hypertrophic scarring following burns involve specific deregulations at all wound healing stages (inflammation, proliferation and maturation). Int J Mol Sci. (2021) 22:897. doi: 10.3390/ijms22020897
29. Dos Santos, RG, Santos, GS, Alkass, N, Chiesa, TL, Azzini, GO, da Fonseca, LF, et al. The regenerative mechanisms of platelet-rich plasma: a review. Cytokine. (2021) 144:155560. doi: 10.1016/j.cyto.2021.155560
30. Karolczak, K, and Watala, C. Blood platelets as an important but underrated circulating source of TGFβ. Int J Mol Sci. (2021) 22:4492. doi: 10.3390/ijms22094492
31. Yang, F, Bai, X, Dai, X, and Li, Y. The biological processes during wound healing. Regen Med. (2021) 16:373–90. doi: 10.2217/rme-2020-0066
32. Westman, J, Grinstein, S, and Marques, PE. Phagocytosis of necrotic debris at sites of injury and inflammation. Front Immunol. (2019) 10:3030. doi: 10.3389/fimmu.2019.03030
33. Xiaojie, W, Banda, J, Qi, H, Chang, AK, Bwalya, C, Chao, L, et al. Scarless wound healing: current insights from the perspectives of TGF-β, KGF-1, and KGF-2. Cytokine Growth Factor Rev. (2022) 66:26–37. doi: 10.1016/j.cytogfr.2022.03.001
34. Huang, J, Heng, S, Zhang, W, Liu, Y, Xia, T, Ji, C, et al. Dermal extracellular matrix molecules in skin development, homeostasis, wound regeneration and diseases. Semin Cell Dev Biol. (2022) 128:137–44. doi: 10.1016/j.semcdb.2022.02.027
35. Peña, OA, and Martin, P. Cellular and molecular mechanisms of skin wound healing. Nat Rev Mol Cell Biol. (2024) 25:599–616. doi: 10.1038/s41580-024-00715-1
36. Laronha, H, and Caldeira, J. Structure and function of human matrix metalloproteinases. Cells. (2020) 9:1076. doi: 10.3390/cells9051076
37. Eremenko, E, Ding, J, Kwan, P, and Tredget, EE. The biology of extracellular matrix proteins in hypertrophic scarring. Adv Wound Care. (2022) 11:234–54. doi: 10.1089/wound.2020.1257
38. Nicolini, G, Balzan, S, and Forini, F. Activated fibroblasts in cardiac and cancer fibrosis: an overview of analogies and new potential therapeutic options. Life Sci. (2023) 321:121575. doi: 10.1016/j.lfs.2023.121575
39. Betarbet, U, and Blalock, TW. Keloids: a review of etiology, prevention, and treatment. J Clin Aesthet Dermatol. (2020) 13:33–43. https://www.ncbi.nlm.nih.gov/pubmed/32308783
40. Wang, Y, Zheng, L, Zhang, L, Tai, Y, Lin, X, and Cai, Z. Roles of MMP-2 and MMP-9 and their associated molecules in the pathogenesis of keloids: a comprehensive review. Front Pharmacol. (2024) 15:1444653. doi: 10.3389/fphar.2024.1444653
41. Shoari, A. Potential of MMP-2 and MMP-9 gelatinase blockade as a therapeutic strategy in fibrosarcoma treatment: a decadal review. Targets. (2024) 2:104–25. doi: 10.3390/targets2020007
42. Younesi, FS, Miller, AE, Barker, TH, Rossi, FMV, and Hinz, B. Fibroblast and myofibroblast activation in normal tissue repair and fibrosis. Nat Rev Mol Cell Biol. (2024) 25:617–38. doi: 10.1038/s41580-024-00716-0
43. Kohlhauser, M, Mayrhofer, M, Kamolz, L-P, and Smolle, C. An update on molecular mechanisms of scarring-a narrative review. Int J Mol Sci. (2024) 25:11579. doi: 10.3390/ijms252111579
44. Schoberleitner, I, Lackner, M, Coraça-Huber, DC, Augustin, A, Imsirovic, A, Sigl, S, et al. SMI-capsular fibrosis and biofilm dynamics: molecular mechanisms, clinical implications, and antimicrobial approaches. Int J Mol Sci. (2024) 25:11675. doi: 10.3390/ijms252111675
45. Ekstein, SF, Wyles, SP, Moran, SL, and Meves, A. Keloids: a review of therapeutic management. Int J Dermatol. (2021) 60:661–71. doi: 10.1111/ijd.15159
46. Amaroli, A, Pasquale, C, Zekiy, A, Utyuzh, A, Benedicenti, S, Signore, A, et al. Photobiomodulation and oxidative stress: 980 nm diode laser light regulates mitochondrial activity and reactive oxygen species production. Oxidative Med Cell Longev. (2021) 2021:6626286. doi: 10.1155/2021/6626286
47. Galache, TR, Sena, MM, Tassinary, JAF, and Pavani, C. Photobiomodulation for melasma treatment: integrative review and state of the art. Photodermatol Photoimmunol Photomed. (2024) 40:e12935. doi: 10.1111/phpp.12935
48. Yadav, A, Verma, S, Keshri, GK, and Gupta, A. Role of 904 nm superpulsed laser-mediated photobiomodulation on nitroxidative stress and redox homeostasis in burn wound healing. Photodermatol Photoimmunol Photomed. (2020) 36:208–18. doi: 10.1111/phpp.12538
49. Cavalcanti, MFXB, Cabette, RA, Moraes, AC, Diomede, F, Trubiani, O, and Maria, DA. The effects in vitro of photobiomodulation over fibroblasts and extracellular matrix. Photobiomodul Photomed Laser Surg. (2024) 42:140–7. doi: 10.1089/photob.2023.0123
50. Mohamed, AE, Mahmoud, AM, Mohamed, WR, and Mohamed, T. Femtosecond laser attenuates oxidative stress, inflammation, and liver fibrosis in rats: possible role of PPARγ and Nrf2/HO-1 signaling. Life Sci. (2022) 307:120877. doi: 10.1016/j.lfs.2022.120877
51. Hameedi, SG, Saulsbery, A, and Olutoye, OO. The pathophysiology and management of pathologic scarring-a contemporary review. Adv Wound Care. (2024). 14:48–64. doi: 10.1089/wound.2023.0185
52. Nazari, M, Taremi, S, Elahi, R, Mostanadi, P, and Esmeilzadeh, A. Therapeutic properties of M2 macrophages in chronic wounds: an innovative area of biomaterial-assisted M2 macrophage targeted therapy. Stem Cell Rev Rep. (2024) 21:390–422. doi: 10.1007/s12015-024-10806-3
53. Sim, SL, Kumari, S, Kaur, S, and Khosrotehrani, K. Macrophages in skin wounds: functions and therapeutic potential. Biomol Ther. (2022) 12:1659. doi: 10.3390/biom12111659
54. Zhao, X, Chen, J, Sun, H, Zhang, Y, and Zou, D. New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction. Cell Biosci. (2022) 12:117. doi: 10.1186/s13578-022-00856-w
55. Zhang, G, Yi, L, Wang, C, Yang, P, Zhang, J, Wang, J, et al. Photobiomodulation promotes angiogenesis in wound healing through stimulating the nuclear translocation of VEGFR2 and STAT3. J Photochem Photobiol B. (2022) 237:112573. doi: 10.1016/j.jphotobiol.2022.112573
56. Mgwenya, TN, Abrahamse, H, and Houreld, NN. Photobiomodulation studies on diabetic wound healing: an insight into the inflammatory pathway in diabetic wound healing. Wound Repair Regen. (2025) 33:e13239. doi: 10.1111/wrr.13239
57. Bard, RL, and Rokhsar, C. Into the world of laser resurfacing In: Bard RL, editor. Image-guided aesthetic treatments : Springer International Publishing (2023). 97–110. Available at: https://link.springer.com/chapter/10.1007/978-3-031-36266-8_8
58. Wu, H-H, Chen, M-Q, Liu, J-H, Song, L-L, Luo, D-Q, Lu, J-F, et al. Combination of fractional carbon dioxide laser with recombinant human collagen in periocular skin rejuvenation. J Cosmet Dermatol. (2024) 23:124–33. doi: 10.1111/jocd.15942
59. Ailioaie, LM, and Litscher, G. Molecular and cellular mechanisms of arthritis in children and adults: new perspectives on applied photobiomodulation. Int J Mol Sci. (2020) 21:6565. doi: 10.3390/ijms21186565
60. Keshri, GK, Kumar, G, Sharma, M, Bora, K, Kumar, B, and Gupta, A. Photobiomodulation effects of pulsed-NIR laser (810 nm) and LED (808 ± 3 nm) with identical treatment regimen on burn wound healing: a quantitative label-free global proteomic approach. J Photochem Photobiol. (2021) 6:100024. doi: 10.1016/j.jpap.2021.100024
61. Pilar, EFS, Brochado, FT, Schmidt, TR, Leite, AC, Deluca, AA, Mármora, BC, et al. Modulation of gene expression in skin wound healing by photobiomodulation therapy: a systematic review in vivo studies. Photodermatol Photoimmunol Photomed. (2024) 40:e12990. doi: 10.1111/phpp.12990
62. Kasowanjete, P, Abrahamse, H, and Houreld, NN. Photobiomodulation at 660 nm stimulates in vitro diabetic wound healing via the Ras/MAPK pathway. Cells. (2023) 12:1080. doi: 10.3390/cells12071080
63. Mgwenya, TN, Abrahamse, H, and Houreld, NN. Modulatory effects of 830 nm on diabetic wounded fibroblast cells: an in vitro study on inflammatory cytokines. Photobiomodul Photomed, Laser Surgery. (2024) 42:676–92. doi: 10.1089/photob.2024.0041
64. Fernandez-Guarino, M, Naharro-Rodriguez, J, and Bacci, S. Aberrances of the wound healing process: a review. Cosmet. (2024) 11:209. doi: 10.3390/cosmetics11060209
65. Salehpour, F, Sadigh-Eteghad, S, Mahmoudi, J, Kamari, F, Cassano, P, and Hamblin, MR. Action mechanisms of photobiomodulation in neuronal cells and the brain In: Synthesis lectures on biomedical engineering : Springer Nature Switzerland (2023). 49–85. Available at: https://link.springer.com/chapter/10.1007/978-3-031-36231-6_4
66. Barolet, D. Photobiomodulation in dermatology: harnessing light from visible to near infrared. Med Res Arch. (2018) 6:1–30. doi: 10.18103/mra.v6i1.1610
67. Kim, YH, Kim, HK, Choi, JW, and Kim, YC. Photobiomodulation therapy with an 830-nm light-emitting diode for the prevention of thyroidectomy scars: a randomized, double-blind, sham device-controlled clinical trial. Lasers Med Sci. (2022) 37:3583–90. doi: 10.1007/s10103-022-03637-6
68. Mota, LR, Duarte, I d S, Galache, TR, Pretti, KMDS, Neto, OC, Motta, LJ, et al. Photobiomodulation reduces periocular wrinkle volume by 30%: a randomized controlled trial. Photobiomod Photomed Laser Surg. (2023) 41:48–56. doi: 10.1089/photob.2022.0114
69. Hamblin, MR. Mechanisms and applications of the anti-inflammatory effects of photobiomodulation. AIMS Biophys. (2017) 4:337–61. doi: 10.3934/biophy.2017.3.337
70. Pires, JA, Bragato, EF, Momolli, M, Guerra, MB, Neves, LM, de Oliveira Bruscagnin, MA, et al. Effect of the combination of photobiomodulation therapy and the intralesional administration of corticoid in the preoperative and postoperative periods of keloid surgery: a randomized, controlled, double-blind trial protocol study. PLoS One. (2022) 17:e0263453. doi: 10.1371/journal.pone.0263453
71. Mosca, RC, Santos, SN, Nogueira, GEC, Pereira, DL, Costa, FC, Pereira, JX, et al. The efficacy of photobiomodulation therapy in improving tissue resilience and healing of radiation skin damage. Photo-Dermatology. (2021) 9:10. doi: 10.3390/photonics9010010
72. Amiri, P, and Fekrazad, R. Efficacy of photobiomodulation therapy on Bell’s palsy symptoms: a systematic review. Lasers Med Sci. (2024) 39:288. doi: 10.1007/s10103-024-04240-7
73. Khorsandi, K, Hosseinzadeh, R, Abrahamse, H, and Fekrazad, R. Biological responses of stem cells to photobiomodulation therapy. Curr Stem Cell Res Ther. (2020) 15:400–13. doi: 10.2174/1574888X15666200204123722
74. Yadav, JP, Singh, AK, Grishina, M, Pathak, P, Verma, A, Kumar, V, et al. Insights into the mechanisms of diabetic wounds: pathophysiology, molecular targets, and treatment strategies through conventional and alternative therapies. Inflammopharmacology. (2024) 32:149–228. doi: 10.1007/s10787-023-01407-6
75. Han, B, Fan, J, Liu, L, Tian, J, Gan, C, Yang, Z, et al. Adipose-derived mesenchymal stem cells treatments for fibroblasts of fibrotic scar via downregulating TGF-β1 and Notch-1 expression enhanced by photobiomodulation therapy. Lasers Med Sci. (2019) 34:1–10. doi: 10.1007/s10103-018-2567-9
76. James, AJ, Torres-Guzman, RA, Chaker, SC, Sigel, ME, Perdikis, G, Supp, DM, et al. Global insights into keloid formation: an international systematic review of regional genetic risk factors and commonalities. Wound Repair Regen. (2024) 32:746–57. doi: 10.1111/wrr.13203
77. Chello, C, Nenna, A, Chello, M, Satriano, UM, Cardetta, F, Lusini, M, et al. Statin treatment and hypertrophic scarring after cardiac surgery. Wound Repair Regen. (2021) 29:129–33. doi: 10.1111/wrr.12878
78. Bocheva, G, Slominski, RM, and Slominski, AT. The impact of vitamin d on skin aging. Int J Mol Sci. (2021) 22:9097. doi: 10.3390/ijms22169097
79. Libon, F, Cavalier, E, and Nikkels, AF. Skin color is relevant to vitamin D synthesis. Dermatology. (2013) 227:250–4. doi: 10.1159/000354750
80. Hahn, JM, Combs, KA, Powell, HM, and Supp, DM. A role for vitamin D and the vitamin D receptor in keloid disorder. Wound Repair Regen. (2023) 31:563–75. doi: 10.1111/wrr.13109
Keywords: keloid, photobiomodulation therapy, low-level laser therapy, fibroblast, TGF-β1, collagen synthesis, wound healing, scar management
Citation: Prananda AT and Syahputra RA (2025) Photobiomodulation therapy in keloid management: a comprehensive review. Front. Med. 12:1550662. doi: 10.3389/fmed.2025.1550662
Edited by:
Dirk Breitkreutz, German Cancer Research Center (DKFZ), GermanyReviewed by:
Rolando Perez-Lorenzo, Columbia University, United StatesShuang Chang, Vanderbilt University, United States
Copyright © 2025 Prananda and Syahputra. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Rony Abdi Syahputra, cm9ueUB1c3UuYWMuaWQ=