[Academic Presentation] Photodynamic Therapy for Photoaging and Its Effects on the Skin Barrier

Skin aging is classified into intrinsic aging and extrinsic aging. Intrinsic aging refers to the natural aging process that occurs with advancing age, whereas extrinsic aging results from environmental factors. Since prolonged, repeated exposure to ultraviolet radiation in sunlight is the most significant environmental contributor to skin aging, extrinsic aging is also known as photoaging. The hallmark features of photoaged skin include skin laxity, roughness, wrinkles, pigmented spots, and telangiectasia; these not only compromise aesthetic appearance but may also progress to precancerous lesions and cutaneous neoplasms. At the histological level, photoaged skin exhibits epidermal atrophy with thinning of the spinous layer, or epidermal thickening with hyperplasia of the spinous layer; the dermo‑epidermal junction becomes flattened, and epidermal ridges are obliterated. The most distinctive alteration is the degenerative change in the dermal collagen architecture: the abundance of type I collagen, the most prevalent collagen in the dermis, declines, reducing skin resilience and tensile strength and impairing its ability to maintain a plump, well‑hydrated appearance. Type I collagen and elastic fibers undergo degeneration, becoming abnormally thickened and curled, while amorphous elastin‑like material accumulates, leading to a loss of the skin’s original elasticity and compliance, thereby resulting in laxity and wrinkling. Consequently, combating photoaging and restoring the abnormal collagen architecture represent the primary therapeutic goals.

In a broad sense, skin barrier function encompasses physical barriers, pigmentary barriers, neural barriers, and other barrier‑related mechanisms that contribute to skin homeostasis. However, this article focuses on the narrow definition of the skin barrier, which typically refers solely to the physical or mechanical barrier structure—a “brick‑and‑mortar” architecture composed of the hydrolipidic film and the intercellular lipids between keratinocytes. The outermost line of defense in this barrier is the hydrolipidic film; its lipids not only lubricate the skin but also help reduce transepidermal water loss, while the natural moisturizing factors it contains play a crucial role in maintaining skin hydration. Keratinocytes serve as the “bricks” in this brick‑and‑mortar structure; their cytoplasm contains tightly packed, robust keratin filament bundles, which, together with an insoluble cornified envelope, collectively perform the barrier’s protective functions. Intercellular lipids, acting as the “mortar” between these bricks, adopt a characteristic lipid bilayer membrane structure and constitute a potent barrier that regulates the passage of substances into and out of the epidermis.

The skin barrier, on the one hand, protects the skin from invasion by external adverse factors, and on the other hand, prevents the loss of water, nutrients, electrolytes, and other substances from both the skin and the body, thereby helping to maintain a relatively stable internal environment. Impairment of the skin barrier is manifested as reduced transepidermal water loss (TEWL), decreased stratum corneum hydration, altered pH, and abnormal lipid content and composition. Damage to the skin barrier can lead to conditions such as dry skin, skin aging, atopic dermatitis, psoriasis, and solar dermatitis. Acute ultraviolet exposure can weaken the skin barrier, severely compromising the mechanical integrity, cohesion, and resilience of keratinocytes, thus disrupting barrier function. Chronic UV exposure reduces stratum corneum hydration and increases TEWL, resulting in impaired barrier function in photoaged skin. In naturally aged skin, diminished proliferation of basal layer keratinocytes leads to epidermal thinning, flattening of the dermo‑epidermal junction, and shortening of epidermal ridges—changes that also occur in photoaged skin. The flattening of the dermo‑epidermal junction decreases the contact area between the two layers, limiting nutrient exchange and affecting keratinocyte proliferation and activity, thereby indirectly impairing barrier function. In naturally aged skin, stratum corneum hydration may slightly decrease or remain stable, with TEWL unchanged and sebum levels reduced; similar alterations in barrier function may also be observed in photoaged skin. Barrier dysfunction likewise accelerates skin aging. Consequently, impaired skin barrier function and photoaging often coexist and mutually exacerbate each other.

Photodynamic therapy (PDT) is a novel treatment that combines a photosensitizer with an appropriate light source to induce a photodynamic effect, selectively ablating diseased tissue in the presence of oxygen. In dermatology, it is used to treat precancerous skin lesions, cutaneous neoplasms, genital warts, acne, and other conditions. In 2002, Ruiz‑Rodríguez et al. first introduced the concept of photodynamic skin rejuvenation, and in 2010, Bruscino et al. reported for the first time that PDT, while treating actinic keratosis, also exerts a skin‑rejuvenating effect. Subsequently, several studies have demonstrated that PDT can ameliorate collagen structural abnormalities associated with photoaging, with varying degrees of efficacy depending on the light source; moreover, microneedling pretreatment can enhance PDT’s ability to improve photoaging‑related skin changes. Given that photoaging and impaired skin barrier function often coexist, restoring the skin barrier constitutes a fundamental component of therapy for photoaging and other light‑induced skin disorders. Multiple studies have shown that, alongside its beneficial effects on photoaging, PDT also improves skin barrier integrity.

Classical photodynamic therapy employs 635-nm red light as the light source, which penetrates deeply and matches the absorption peak of protoporphyrin IX. Red light itself also exerts a certain skin‑rejuvenating effect. Ji et al. conducted a comparative study on photoaged skin on the extensor surface of the forearm, comparing red‑light–photodynamic therapy with red‑light monotherapy. The results showed that both treatments improved histological abnormalities, including disorganized collagen arrangement and elastin fiber degeneration. However, compared with the red‑light–only group, the red‑light–photodynamic group demonstrated more pronounced improvements in the clinical appearance of photoaged lesions, a more significant increase in stratum corneum hydration, and a greater reduction in transepidermal water loss. These findings indicate that, relative to red‑light monotherapy, photodynamic therapy not only yields superior skin‑rejuvenating effects but also enhances skin barrier function to a greater extent.

Intense pulsed light (IPL) is a commonly used source for skin rejuvenation, with wavelengths ranging from 500 nm to 1200 nm—covering the absorption peak of PpIX—and thus serving as an ideal therapeutic light source for photodynamic therapy. A zonal study of photoaged skin on the neck conducted by Zhang Haiyan et al. demonstrated that, compared with both the IPL‑only group and the red‑light group, the photodynamic therapy group exhibited improvements in skin brightness, elasticity, and thickness, along with reductions in melanin index; moreover, these improvements were more pronounced in the photodynamic therapy group. During 12‑week follow-up, the IPL‑photodynamic therapy group showed sustained increases in stratum corneum water content and decreases in transepidermal water loss, whereas the red‑light‑photodynamic therapy group initially displayed transient reductions in stratum corneum hydration and increases in transepidermal water loss, likely reflecting disruption of the skin barrier caused by side effects such as erythema and edema. By the later stages of follow-up, both parameters had improved beyond baseline levels, suggesting that photodynamic therapy ultimately exerts a beneficial effect on the skin barrier. Although the skin barrier is also associated with sebum levels, this study did not detect any significant changes in sebum content following photodynamic treatment. Results from a hemifacial controlled trial by Yang et al. further indicated that the photodynamic therapy group experienced a more marked reduction in photoaging scores than the IPL‑only group, and that increases in forehead and periorbital pH values and enhancements in stratum corneum hydration were significantly greater than those observed in the IPL‑only group, demonstrating that IPL‑photodynamic therapy not only treats photoaging but also improves skin barrier function, with effects surpassing those of IPL alone.

Studies by Gold et al. have shown that short‑duration (30–60 min) IPL‑photodynamic therapy yields greater improvement in photoaged skin lesions compared with IPL alone, demonstrating superior efficacy over IPL monotherapy for crow’s feet, pigmented spots, textural roughness, and telangiectasia, as well as a higher clearance rate of actinic keratosis lesions. Furthermore, Clementoni et al. treated 21 patients by pre‑treating facial skin with a microneedle roller prior to topical application, followed by irradiation with red light and IPL sources; at 3 and 6 months post‑treatment, photaging scores improved significantly. Moreover, compared with baseline, 90% of patients exhibited a clinical improvement exceeding 50% at 6 months. These findings suggest that microneedle roller pretreatment is well tolerated, enhances ALA absorption and penetration into the skin, and augments clinical outcomes.

The discomfort associated with photodynamic therapy primarily stems from adverse reactions such as pain, erythema, edema, and crusting during or after treatment; intense pulsed light may elicit milder side effects. Weighing the balance between adverse effects and therapeutic efficacy, low‑dose photodynamic therapy is better suited for treating photoaging. Kosaka et al. have demonstrated that using a lower concentration of 5‑aminolevulinic acid (ALA) and a shorter application time can reduce the incidence of adverse reactions; they recommend employing 5% ALA with a 2‑hour application duration for photodynamic skin rejuvenation.

Although numerous studies have demonstrated that photodynamic therapy can improve the skin barrier while treating photoaging, it is not yet used as a standalone treatment to enhance skin barrier function in clinical practice. Nevertheless, among the various therapeutic approaches for cutaneous photoaging, actinic keratosis, and acne, photodynamic therapy offers the additional benefit of improving the skin barrier.

Photodynamic therapy significantly improves wrinkles, skin laxity, and other signs of photoaging. At the microstructural level, its primary effect lies in remodeling dermal collagen, particularly types I and III. Marmur, Orringer, and others have demonstrated at the ultrastructural level that ALA‑photodynamic therapy markedly increases both type I and type III collagen in the dermis, with these changes correlating to improvements in the clinical appearance of photoaged skin. Bjerring used 0.5% ALA and a single session of IPL photodynamic treatment at a dose of 7 J/cm²; histological analysis of human skin 72 hours later revealed a 208% increase in type III collagen production in the irradiated group after 15 minutes of topical application, and a 483% increase after 3 hours of application. In animal models, Park et al. showed that following UV exposure, mice exhibited reduced collagen content and increased deposition of elastin‑like substances; from day 2 to day 21 after ALA‑photodynamic treatment, collagen levels rose while elastin‑like material decreased. Furthermore, Lv et al., employing photodynamic intervention in a photoaging animal model, found that ALA‑photodynamic therapy could prevent the onset of photoaging in hairless mice. Using two‑photon microscopy to assess dermal collagen, they observed that the photopreventive intervention group not only displayed increased collagen density but also more uniform and smoother collagen fiber organization.

At the cellular level, fibroblasts are the primary collagen‑producing cells in the dermis; however, in photoaged skin, these fibroblasts exhibit reduced proliferative capacity and diminished collagen synthesis due to exposure to abundant degraded collagen. Following UV irradiation, dermal fibroblasts undergo morphological enlargement accompanied by endoplasmic reticulum swelling, whereas ALA‑photodynamic therapy can restore their morphology toward a more normal phenotype. Studies by Zhou et al. have shown that ALA‑photodynamic therapy not only elevates matrix metalloproteinase (MMP) levels in photoaged fibroblasts but also induces oxidative damage and apoptosis in these cells, while sparing normal fibroblasts to a certain extent. Furthermore, research has investigated the molecular effects of photodynamic therapy on fibroblasts: Yong et al., in in vitro experiments examining the molecular mechanisms underlying photodynamic skin rejuvenation, found that ALA‑photodynamic therapy enhances fibroblast viability and proliferation, increases type I collagen expression, and activates the ERK signaling pathway via the generation of reactive oxygen species (ROS).

Furthermore, as research on the interactions between the epidermis and dermis has advanced, mounting evidence indicates that photodynamic therapy can also exert indirect effects on dermal fibroblasts, thereby promoting collagen remodeling. In photoaged skin, the accumulation of partially degraded and fragmented collagen fibers inhibits collagen synthesis; thus, matrix metalloproteinases (MMPs) are essential for both the degradation of aged collagen and the synthesis of new collagen. An early, transient increase in MMP‑3 further degrades already fragmented collagen. Studies by Karrer et al. have shown that ALA‑photodynamic therapy not only directly induces MMP production in dermal fibroblasts but also, by acting on epidermal keratinocytes to release soluble factors, indirectly stimulates fibroblasts to synthesize MMPs. Similarly, Kim et al. demonstrated that treating keratinocytes with a low dose of ALA‑photodynamic therapy and then using their conditioned medium to stimulate fibroblasts resulted in increased collagen synthesis by the fibroblasts, accompanied by elevated levels of IL‑1α, IL‑6, and TNF‑α in the supernatant. These findings suggest that ALA‑photodynamic therapy exerts its effects not only through direct action on fibroblasts involved in collagen remodeling but also via an indirect pathway mediated by epidermal keratinocytes.

The effects of photodynamic therapy on pigmented lesions associated with cutaneous photoaging may stem from its photodynamic action, which induces varying degrees of apoptosis and necrosis in hyperplastic epidermal cells, ultimately leading to the fading or disappearance of these lesions. Photodynamic therapy also improves stratum corneum hydration; however, the underlying mechanisms by which it reduces transepidermal water loss remain poorly elucidated, possibly involving the clearance of abnormal epidermal cells and the subsequent normalization of epidermal homeostasis. In the treatment of actinic keratosis, photodynamic therapy eliminates malignant keratinocytes via pathways linked to necrosis and apoptosis, while PpIX accumulates in keratinocytes surrounding the lesion. Sublethal photodynamic exposure can promote the turnover of epidermal keratinocytes. Alternatively, aberrant keratinocytes may selectively absorb the photosensitizer, triggering a photodynamic effect that leads to their shedding, thereby allowing normal epidermal cells to regenerate. This process alleviates the dryness and roughness characteristic of photoaged skin, remodels the “brick-and-mortar” architecture of the skin barrier, and restores barrier function. Studies have shown that following MAL‑PDT, skin thickness increases and the thickness of the subepidermal hypoechoic band measured by ultrasound decreases, indicating an increase in epidermal thickness that helps reinforce the skin barrier. The underlying mechanism may involve photodynamic stimulation of the regeneration of normal epidermal keratinocytes.