Topical Skin Boosters in Aesthetic Practice: Pharmacokinetic Challenges, Delivery Platforms, Evidence Gaps, and Future Directions

Abstract

Although the term “topical skin booster” has gained significant traction in Korean aesthetic medicine, the category remains loosely defined and often disconnected from established principles of transdermal pharmacology. To address this ambiguity, we critically reviewed the mechanistic foundations and clinical evidence surrounding these formulations, using the 500 Da permeability heuristic as an initial physicochemical screening framework rather than an absolute cutoff. We assessed key delivery platforms, including microneedling, ablative fractional lasers, radiofrequency microneedling, and cold atmospheric plasma. The available evidence indicates that macromolecular actives such as hyaluronic acid and polydeoxyribonucleotides generally face substantial barriers to passive penetration, whereas small-molecule agents have a stronger physicochemical rationale for topical use. We propose a hypothesis-generating “signal-and-support” framework for biologically plausible multi-ingredient formulation design. The field remains constrained by inconsistent, claim-specific verification of cutaneous exposure and dermal delivery, particularly for macromolecular actives. More rigorous target-compartment pharmacokinetic and target-engagement studies are needed to distinguish mechanistic plausibility from verified dermal delivery and clinical benefit.

1. Introduction

In recent years, the term “skin booster” has rapidly expanded in visibility within Korean aesthetic medicine. Originally, the “skin booster” label was exclusively used to describe intradermal microinjections of hyaluronic acid (HA); however, this terminology has subsequently extended into topically applied serums and gels under the name of “topical skin booster.” Contemporary topical skin boosters increasingly incorporate a wide spectrum of bioactive compounds that were traditionally limited to injectable applications. These include low-molecular-weight HA, polydeoxyribonucleotides (PDRN), and emerging classes of biologically derived molecules such as growth factors, peptides, and exosomes. However, this rapid expansion has led to a loosely defined category that is currently driven more by commercial positioning than by clear, standardized pharmacologic criteria. From a strict clinical standpoint, the fundamental conceptual problem with topical skin boosters is the formidable biological barrier of the skin itself.

This critical narrative review re-examines topical skin boosters within the broader framework of topical drug delivery, with particular attention to macromolecular agents such as HA and PDRN and to device-assisted strategies intended to overcome the cutaneous barrier. It also considers representative contemporary Korean formulations to illustrate how current formulation strategies translate these concepts into real-world aesthetic practice. Specifically, the review addresses four principal questions: (1) Which physicochemical constraints govern the passive penetration of topical skin booster ingredients? (2) To what extent do currently used barrier-modifying technologies overcome these constraints? (3) What level of evidence supports penetration, dermal deposition, target engagement, and clinical efficacy for major skin booster ingredients? and (4) Which formulation and delivery strategies are most likely to advance the field toward pharmacokinetically verifiable dermal delivery?

2. Literature Search Methodology

This article was designed as a critical narrative review. The literature search and reporting approach was informed by the Scale for the Assessment of Narrative Review Articles (SANRA), with particular attention to transparent description of the literature search, appropriate referencing of key statements, consideration of the level of evidence, and presentation of outcome data relevant to the review questions [1].

A targeted literature search was conducted in PubMed/MEDLINE, with the final search performed on 23 July 2026. No restriction on publication year was applied, and only English-language publications were included. Search terms were iteratively combined to address three principal thematic domains: (1) physicochemical determinants of passive cutaneous penetration and the 500 Da permeability heuristic; (2) device-assisted and barrier-modifying delivery approaches, including microneedling, ablative fractional laser (AFXL), radiofrequency (RF) microneedling, and cold atmospheric plasma (CAP); and (3) clinically relevant topical skin booster ingredients and formulation strategies, including hyaluronic acid, PDRN, extracellular vesicles (EVs), peptides, antioxidants, and pigment-modulating agents. Google Scholar was used as a supplementary discovery and citation-tracking tool rather than for quantitative record accounting.

Publications were considered relevant when they addressed at least one of the following: physicochemical determinants of cutaneous penetration; direct or indirect assessment of device-assisted topical delivery; tissue deposition, biodistribution, or target engagement of skin-rejuvenation ingredients; clinical outcomes of topical agents used with barrier-modifying procedures; or formulation technologies relevant to macromolecular cutaneous delivery. Publications unrelated to cutaneous delivery, lacking information relevant to the mechanistic or clinical questions of this review, or consisting solely of unsupported commercial or promotional claims were excluded. Human clinical evidence was prioritized where available, while preclinical, ex vivo, and mechanistic studies were included when they provided relevant information regarding penetration pathways, tissue deposition, target engagement, or formulation–device interactions. For claims concerning clinical efficacy or target-compartment delivery, greater interpretive weight was given to controlled human studies and to studies providing direct analyte-specific localization or exposure measurements; preclinical and ex vivo studies were used primarily to assess mechanistic plausibility and transport pathways, whereas reviews were used mainly to contextualize established concepts and identify the pertinent primary literature. Reference lists of relevant articles were additionally examined to identify pertinent primary studies. Because the objective was critical and integrative synthesis rather than exhaustive evidence retrieval, study selection was guided by relevance to the mechanistic, pharmacokinetic, and translational questions addressed in this review rather than by a prespecified systematic-review protocol. The detailed search strategies, eligibility principles, and literature identification/selection flow are provided in Supplementary File S1.

3. Origins of the Term “Topical Skin Boosters”

Originally introduced in 2015 to describe intradermal microinjections of non-cross-linked HA, “skin boosters” were initially intended to improve hydration, elasticity, and texture through direct dermal deposition—bypassing the stratum corneum (SC) to provide more predictable local dermal exposure [2]. Recent comparative reviews reflect the diversification of injectable skin booster practice to include both HA-based and polynucleotide/PDRN-based products [3,4]. The terminology was later extended to topical serums and gels containing bioactives associated with injectable products. Today, “topical skin booster” commonly refers to HA-based serums using low-molecular-weight HA for improved penetration, as well as newer formulations incorporating growth factors, exosomes, PDRN, or polymer–HA hybrids designed for topical or microneedle-assisted delivery [5]. In Korea, where the skin booster concept has substantial commercial visibility, the term is applied across heterogeneous topical products. Because “skin booster” is a commercial and clinical descriptor rather than a standardized pharmacologic category, the evidentiary burden should be determined by product composition, route of administration, intended use, and the specific claim being made. Moreover, no universally accepted definition exists for topical products marketed under the broader skin booster concept, and the category is often characterized by commercial positioning rather than clearly defined pharmacologic criteria [6]. At present, the term “topical skin booster” is applied variably to products spanning post-procedure recovery serums, daily humectant formulations, and agents intended for device-assisted transcutaneous delivery [5].

Given the terminological heterogeneity surrounding skin boosters, this review adopts an operational definition based on route and intended use. A topical skin booster is defined as a bioactive formulation applied to the skin surface to improve skin quality, either on intact skin or as an adjunct to a procedure that transiently modifies the cutaneous barrier. Four delivery paradigms that are frequently conflated under the broader skin booster concept are therefore distinguished (

Table 1. Operational classification of skin booster paradigms used in this review.

Operational Definition	Skin Barrier Status at Delivery	Primary Delivery Mechanism	Expected Exposure	Role in This Review
Bioactive formulation applied to intact skin without intentional barrier disruption	Intact	Passive diffusion; formulation-dependent enhancement	Predominantly surface/SC and epidermal exposure; dermal exposure strongly dependent on physicochemical properties	Evaluated for passive penetration and formulation-dependent delivery
Post-procedure topical adjunct	Topical formulation applied during or after a procedure that transiently disrupts or modifies the barrier	Disrupted or transiently modified	Diffusion through procedure-created or modified pathways	Potentially increased viable epidermal/dermal exposure
Active-loaded microneedle patch	Microneedle system in which the active is incorporated into, coated onto, or delivered through the microneedle itself	Mechanically bypassed	Direct intradermal/intraepidermal deposition via microneedle architecture	Device-controlled local tissue delivery
Intradermal injectable skin booster	Formulation introduced directly into the dermis by needle injection	Stratum corneum bypassed	Direct injection	Predictable local dermal deposition

): daily intact-skin topical formulations, post-procedure topical adjuncts, active-loaded microneedle systems, and intradermal injectable skin boosters. Only the first two are classified here as topical skin booster applications; active-loaded microneedle systems are treated as a mechanistically distinct device-mediated category, whereas intradermal injections serve as a pharmacokinetic and clinical reference route because they bypass the SC entirely. Products intended primarily for cleansing, camouflage, or basic moisturization without an explicit bioactive or skin-rejuvenation rationale are outside the scope of this review.

4. The Fundamental Conceptual Problem

From a strict clinical and pharmacologic standpoint, the scientific basis for labeling these topical agents as skin boosters is not easily justified. The key advantage of skin-boosting or biorevitalizing injectables is their ability to bypass the epidermis, the primary barrier that prevents transdermal delivery of high-molecular-weight biologics [6]. However, topical delivery of these macromolecules remains constrained by the skin barrier. Passive penetration of high-molecular-weight HA is markedly restricted and molecular-weight dependent, while evidence that native PDRN crosses intact human SC at therapeutically relevant levels remains sparse [7,8]. Injectable particulate biostimulators such as poly-L-lactic acid (PLLA) and polycaprolactone (PCL) derive part of their neocollagenic effect from tissue-level controlled foreign-body responses after implantation [9]. This implantation-dependent mechanism should not be assumed for topically applied polymer particles that have not been demonstrated to reach viable tissue.

The “500 Da rule,” first proposed by Bos and Meinardi in 2000 [10], remains a widely cited empirical heuristic in cutaneous pharmacology. Their analysis noted that compounds associated with clinically relevant passive skin penetration were generally below approximately 500 Da. This observation is best treated as a screening heuristic rather than evidence that all larger compounds are categorically excluded. The physiological basis lies in the SC, a 15–20 µm lipid–protein barrier that serves as the principal rate-limiting step for passive diffusion (Figure 1). For compounds near or above this empirical size range, any passive permeation depends strongly on other physicochemical attributes. Efficient passive permeation requires an appropriate balance of molecular size, lipophilicity, aqueous solubility, and unionized fraction [11], implying hydrophilic macromolecules are not expected to cross the intact SC without mechanical or chemical assistance [12]. Collectively, these parameters define a physicochemical landscape in which passive transcutaneous delivery becomes progressively less favorable as molecular size and hydrophilicity increase. For the purposes of this review, the 500 Da rule is operationalized as an initial physicochemical screening heuristic for the likelihood of passive permeation across the intact SC, rather than as an absolute cutoff for cutaneous delivery. Exceeding this approximate molecular-size threshold does not preclude delivery but increases the evidentiary burden for demonstrating meaningful exposure within the intended cutaneous compartment. Accordingly, the heuristic is used to calibrate the level of evidence required to substantiate delivery claims, not to predetermine whether delivery can occur.

We therefore distinguish penetration, permeation, target-compartment deposition, target engagement, and clinical efficacy as complementary evidentiary domains rather than interchangeable endpoints [13] (

Table 2. Proposed evidentiary framework for evaluating topical skin booster delivery claims.

Pillar	Domain	Evidentiary Level/Representative Endpoint
Pillar 1	Drug delivery/exposure	Level 1—Mechanistic plausibility (barrier/pathway evidence)
		Level 2—Tracer- or model-based localization
		Level 3—Native-analyte tissue deposition
		Level 4—Quantitative target-compartment exposure
Pillar 2	Target engagement	Level 5—Molecular/cellular target engagement
Pillar 3	Clinical efficacy	Level 6—Prespecified clinical efficacy endpoint

Conceptually informed by the three-pillar framework of reference [15].

). Demonstration of SC passage is only one component of local cutaneous bioavailability assessment and, by itself, does not establish equivalent exposure at the intended viable epidermal or dermal target site [14]. To clarify their relationship, the three-pillar framework in Table 2 encompasses six sequential evidentiary levels: Pillar 1 (drug delivery/exposure) comprises mechanistic plausibility, tracer- or model-based localization, native-analyte tissue deposition, and quantitative target-compartment exposure; Pillar 2 addresses target engagement; and Pillar 3 addresses clinical efficacy. Evidence at one level may support, but does not by itself establish, the subsequent level. In this review, “penetration” denotes entry of an analyte into one or more cutaneous layers, whereas “permeation” denotes movement through the skin barrier or tissue. “Deposition” denotes demonstrable localization of the analyte within a defined tissue compartment, and “dermal exposure” is reserved for evidence of analyte presence within the dermis, with quantitative concentration–time information specified when available. “Delivery” is used as a broader umbrella term and is qualified by the measured endpoint whenever possible.

5. Transcending the 500 Da Limit: Breaking the Stratum Corneum Barrier

While the 500 Da rule should be regarded as a useful heuristic rather than an immutable biological cutoff, it nevertheless highlights one important constraint underlying many topical skin booster claims. Passive cutaneous transport is governed by the combined effects of molecular size, lipophilicity, ionization, aqueous solubility, vehicle composition, thermodynamic activity, and barrier condition; molecular size, therefore, should not be interpreted in isolation. Nevertheless, many proposed skin booster bioactives are both large and highly hydrophilic, a physicochemical combination that makes efficient passive permeation across intact SC particularly unfavorable. Accordingly, such macromolecular actives generally exhibit negligible or highly limited passive penetration unless the barrier is circumvented or permeability is enhanced by an appropriate delivery strategy [16].

The most widely studied and clinically relevant approach involves deliberate disruption or bypass of the SC (

Table 3. Procedural modalities for bypassing the stratum corneum and their mechanistic basis.

Modality	Physical Principle	Effect on the SC
Physical microneedling	Mechanical	SC puncture
Fractional CO2 laser (10,600 nm)	Thermal	SC ablation + coagulation
Fractional Er:YAG laser (2940 nm)	Thermal	SC ablation
Fractional thulium laser (1927 nm)	Thermal	SC coagulation
Fractional picosecond laser	Photomechanical	Non-ablative barrier perturbation; parameter-dependent
RF microneedling	Thermomechanical	Mechanical puncture ± RF-induced coagulation, depending on needle design and treatment parameters
Electroporation	Electrical	SC modification
Sonophoresis	Acoustic	SC disruption/fluidization

CO₂, carbon dioxide; Er:YAG, erbium-doped yttrium aluminium garnet; RF, radiofrequency; SC, stratum corneum. Note: The listed tissue effects are schematic representations of predominant mechanisms and should not be interpreted as uniform across devices. Actual barrier and tissue responses vary according to wavelength, optical configuration, fluence, pulse characteristics, needle design and insulation, treatment depth, energy settings, and other device-specific parameters.

), thereby creating transient pathways that permit the delivery of macromolecules otherwise excluded from passive diffusion across intact skin [17]. Even simple microneedling transiently compromises the SC barrier, while more advanced modalities—including AFXL and RF microneedling—can further augment permeability and clinical effects. By creating temporary microchannels, these procedures substantially reduce the barrier imposed by the SC and permit enhanced delivery of selected macromolecular agents. Importantly, evidence of enhanced macromolecular transport should be interpreted as specific to the formulation, molecular form and labeling strategy, delivery device, treatment parameters, and experimental model actually studied; such findings should not be generalized to untested topical formulations or related macromolecules.

5.1. Microneedling-Enhanced Transepidermal Transport of Macromolecules

Mechanical disruption of the SC using microneedling and related microneedle platforms is a well-established technique for creating transient microchannels that bypass the SC and facilitate transcutaneous transport of topically applied agents [18]. Microchannel formation, however, establishes a potential transport pathway rather than analyte-specific delivery to a defined tissue compartment; increased permeability or tracer transport should therefore be distinguished from tissue deposition, target engagement, and clinical efficacy. Nominal microneedle length influences the skin compartment accessed (Figure 2), but actual insertion depth and channel behavior vary with device mechanics, anatomical site, skin thickness, needle geometry, and insertion technique [19,20].

Early studies characterized the formation and closure of microneedle-created channels [21] and established the clinical and histologic basis of percutaneous collagen induction [22,23]. Subsequent drug-delivery studies showed that these channels can enhance transcutaneous transport of topically applied compounds [24,25]. Together, these data support microneedling as a barrier-bypass strategy, while the magnitude of transport remains molecule-specific.

Figure 2. Conceptual relationship between microneedle length and penetration into human skin. Longer microneedles generally permit access to deeper cutaneous compartments, but actual insertion depth may be substantially less than nominal needle length because of skin deformation and device-specific insertion mechanics. Penetration depth also varies with anatomical site, skin thickness, needle geometry, and insertion technique; therefore, the depicted ranges should be interpreted schematically rather than as fixed anatomical thresholds. Conceptual ranges informed by [26].

Figure 2. Conceptual relationship between microneedle length and penetration into human skin. Longer microneedles generally permit access to deeper cutaneous compartments, but actual insertion depth may be substantially less than nominal needle length because of skin deformation and device-specific insertion mechanics. Penetration depth also varies with anatomical site, skin thickness, needle geometry, and insertion technique; therefore, the depicted ranges should be interpreted schematically rather than as fixed anatomical thresholds. Conceptual ranges informed by [26].

The resulting permeability window is brief: microneedle-induced channels begin to reseal within minutes, with substantial barrier recovery over the following hours and complete closure within hours to days depending on occlusion and experimental conditions [21].

HA has been extensively investigated in microneedle-based delivery systems. Fluorescence-tracer, confocal imaging, and ex vivo permeation studies provide proof-of-principle for enhanced transport or tissue localization under specific experimental conditions [27], but much of this evidence derives from HA-containing dissolving microneedles, fluorescently labeled HA, or model compounds rather than separately applied native high-molecular-weight HA after conventional microneedling [28]. Device geometry and effective insertion depth further influence transport [20,29]. Accordingly, current evidence supports pathway-level transport or localization rather than quantitative dermal exposure or target engagement of separately applied native high-molecular-weight HA, and findings from specialized or labeled systems should not be generalized to conventional topical HA.

PDRN has been studied as a microneedling adjunct in an animal model and an early clinical trial [30,31], supporting biological plausibility but not establishing the amount, depth, molecular integrity, or biologically active concentration reaching the target tissue. Favorable clinical outcomes have likewise been reported when exosome-containing formulations are applied after microneedling [32,33], but these studies do not demonstrate intact-vesicle deposition or functional cargo delivery to a defined viable skin compartment. For both PDRN- and EV-containing formulations, mechanistic plausibility and adjunctive clinical benefit therefore remain distinct from direct evidence of target-compartment exposure or target engagement.

Overall, microneedling creates transient barrier-bypass pathways and can enhance transport of selected compounds and macromolecular model systems, but the magnitude and depth of transport remain molecule-, formulation-, and device-specific. Current evidence does not establish that microneedle-assisted topical delivery of HA-, PDRN-, or EV-containing formulations achieves target-compartment exposure or pharmacokinetic performance comparable to direct intradermal injection, which remains the more predictable route for dermal drug exposure (

Table 4. Summary of evidence hierarchy on microneedling for macromolecular delivery.

Claim	Level of Evidence	Quality	Reference
Microneedling creates SC bypass channels	Established mechanistic evidence (histology, confocal imaging, TEWL, impedance; human and preclinical studies)	Strong	[16,21]
Microneedling enhances penetration of topically applied small molecules	Established mechanistic evidence + human in vivo studies	Strong	[12,24,25]
Microneedling can enhance transport/localization in selected HA or model systems, but dermal deposition of separately applied topical HMW-HA remains insufficiently demonstrated	Preclinical/ex vivo evidence; indirect clinical evidence	Weak–Moderate	[16]
Microneedling may facilitate cutaneous transport of topical PDRN, but analyte-specific target-compartment exposure and superiority over topical PDRN alone have not been directly established	Preclinical evidence + indirect/early clinical evidence	Weak	[30,31,34]
Clinical equivalence between barrier-assisted topical delivery of macromolecules and direct intradermal injection	Not demonstrated; available head-to-head studies remain sparse	Absent–Insufficient

HA, hyaluronic acid; HMW, high molecular weight; PDRN, polydeoxyribonucleotide; SC, stratum corneum; TEWL, transepidermal water loss.

).

5.2. Ablative Fractional Laser Resurfacing

Laser-assisted drug delivery (LADD) has emerged as a well-established therapeutic platform in dermatology, leveraging controlled fractional laser-induced disruption of the skin barrier to enhance the cutaneous and transdermal delivery of topically applied agents [35]. The foundational framework of LADD is based predominantly on AFXL technology, particularly the 10,600 nm carbon dioxide (CO₂) and 2940 nm erbium: yttrium–aluminum–garnet (Er:YAG) laser systems, which generate controlled microscopic treatment zones that transiently bypass the SC and facilitate topical drug delivery [35]. These vertically oriented, water-filled microchannels provide a transient pathway for topical agents to bypass the SC, particularly facilitating the delivery of hydrophilic molecules that otherwise penetrate intact skin poorly [36] (Figure 3). Furthermore, the peripheral zone of thermal coagulation surrounding each microscopic ablation column may serve as a transient drug reservoir, modulating the retention and subsequent diffusion of topically applied therapeutics [35,36].

Unfortunately, the clinical optimization of LADD is limited by the temporal dynamics of epidermal resealing. A 2017 channel-kinetics investigation using optical coherence tomography and transepidermal water loss (TEWL) mapped microchannel morphology over time [37]. AFX-induced channels were fully patent only for ~30 min, the peak channel-mediated transport window. Patency dropped to ~75% by 6 h and to <3% by 24–48 h. Fluorescence similarly diminished within 30 min and was no longer detectable by 48 h, indicating that the immediate post-treatment window—particularly the first ~30 min—represents the period of maximal transport potential [37].

The clinical evidence base for LADD is strongest for relatively low-molecular-weight therapeutics, including corticosteroids, 5-fluorouracil, aminolevulinic acid, and methotrexate [35]. These compounds possess physicochemical properties that are inherently favorable for cutaneous transport, and AFXL can further enhance their cutaneous transport by transiently bypassing the SC [35]. Melasma has become a major focus of LADD-related clinical research in dermatology. Split-face randomized trials have evaluated fractional CO₂ laser combined with tranexamic acid delivered topically or by microinjection, depending on the study protocol [38,39]. Other comparative trials have specifically evaluated laser-assisted topical tranexamic acid against topical ascorbic acid [40,41]. One study found that combining low-power fractional CO₂ with Q-switched neodymium-doped yttrium aluminium garnet (QS-Nd:YAG) laser “toning” reduced punctate leukoderma risk while maintaining comparable melasma-improving efficacy to QS-Nd:YAG alone [42]. Waibel et al. [43] further demonstrated in a randomized split-face trial that immediate application of a vitamin C/E/ferulic acid serum following fractional ablative CO₂ laser resurfacing accelerated clinical wound healing, reduced postoperative erythema and edema, and significantly increased local basic fibroblast growth factor expression, supporting the concept that LADD can augment early regenerative responses. Pretreatment with fractional Er:YAG laser has been shown to improve topical anesthetic efficacy, yielding substantially lower pain scores than topical anesthesia alone [44]. For hypertrophic scars and keloids, clinical series and reports support the feasibility of AFXL-assisted corticosteroid delivery as an alternative adjunct to direct intralesional injection [45,46], though one randomized trial reported no clear long-term advantage over laser monotherapy [47].

Peptides weighing several hundred daltons have been shown to penetrate effectively when topically applied to AFXL-treated skin. A low-fluence fractional Er:YAG laser enhanced peptide skin permeation by increasing follicular uptake, and the magnitude of this effect depended on peptide size and sequence, with smaller, more hydrophilic peptides showing the greatest enhancement [48]. Similarly, a randomized, blinded split-face study found that applying a tripeptide/hexapeptide anhydrous gel before and after AFXL accelerated barrier recovery and improved acne-scar outcomes compared with moisturizer control [49]. This demonstrates an adjunctive clinical effect but does not directly quantify peptide deposition within the skin.

Clinical studies suggest that AFXL can facilitate biological effects of topically applied agents even in the kilodalton range, most notably botulinum neurotoxin type A, although direct target-compartment quantification and the overall evidence for active-specific dermal delivery of such high–molecular-weight compounds remain limited. A randomized split-face trial demonstrated that combining fractional CO₂ laser with topical application of reconstituted botulinum neurotoxin yields superior improvements in skin roughness, hydration, elasticity, and overall rejuvenation compared with laser treatment alone [50]. AFXL-assisted delivery of topical botulinum neurotoxin has likewise shown promise in a small case series, achieving safe reductions of approximately 50–80% in palmar sweating over three months in patients with primary palmar hyperhidrosis [51]. This finding was confirmed in a couple of randomized, intrapatient trials in patients with primary localized hyperhidrosis [52,53,54].

AFXL creates aqueous microchannels that can facilitate transport of a broader range of agents, including selected hydrophilic macromolecules; however, the extent and depth of transport and tissue localization remain analyte-, formulation-, and parameter-specific [35,36,55]. Nguyen et al. [55] provided one of the strongest in vivo demonstrations of AFXL-enhanced HA tissue localization using multiphoton tomography with fluorescence lifetime imaging. Topically applied HA was visualized throughout the viable epidermis and into the upper dermis 30 min after fractional CO₂ laser treatment, with residual HA detectable 30 days later [55]. These findings provide direct in vivo evidence that AFXL can facilitate localization of selected HA formulations in the viable epidermis and upper dermis under studied conditions [55], although the concentration–time profile and functional target engagement require further investigation. Their follow-up analysis showed that both CO₂ and 1927 nm thulium fractional lasers enhance topical HA penetration into the upper dermis, with CO₂ producing larger HA aggregates but more prolonged inflammation, whereas thulium produced comparable upper-dermal localization with substantially less downtime [56]. Clinically, a randomized split-face study demonstrated that applying HA immediately after ablative fractional CO₂ laser treatment yielded greater improvements in skin texture and firmness than saline, supporting the clinical feasibility of combining AFXL with topical HA for facial rejuvenation but not independently establishing HA deposition [57]. Combined fractional Er:YAG treatment with topical HA has also been described in limited clinical reporting [58]. In evidentiary terms, the imaging data support spatial localization of HA under the studied conditions, whereas quantitative target-compartment pharmacokinetics and biological target engagement remain separate, incompletely characterized endpoints. These findings should therefore be interpreted within the specific HA preparation, labeling approach, laser parameters, and imaging model studied and should not be extrapolated to all topical HA formulations or treatment settings.

For PDRN and related polynucleotides, strong evidence for LADD is still lacking. A randomized comparative trial found that combining fractional CO₂ laser treatment with a topical formulation containing polynucleotide together with exosome-mimetic nanovesicles produced greater acne-scar improvement, fewer adverse effects, and higher patient satisfaction than CO₂ laser monotherapy [59]. Because the adjunct contained multiple biologically active components, the observed benefit cannot be attributed to polynucleotide alone, and direct dermal exposure was not quantified. Nonetheless, animal models have demonstrated that applying PDRN following AFXL can accelerate wound healing, increase granulation-tissue thickness, and increase neovascularization compared with fractional treatment alone [60].

5.3. Radiofrequency Microneedling

RF microneedling has emerged as a distinct and mechanistically unique modality within the paradigm of device-assisted drug delivery [61]. Unlike standard mechanical microneedling or AFXL, RF microneedling induces two simultaneous yet distinct tissue events that govern drug permeation. The physical penetration of the needles generates mechanical microchannels that bypass the SC, functioning identically to traditional microneedling to facilitate the initial entry of topically applied agents. Concurrently, the deposition of RF energy creates thermal coagulation zones around each needle tip [62] (Figure 4). This perilesional, thermally altered tissue resembles the coagulative collar seen in AFXL [63].

However, the spatial distribution of these tissue events critically influences transdermal bioavailability. Modern insulated-needle RF microneedling platforms largely spare the epidermis by confining RF-induced thermal injury to the dermis. Consequently, unlike AFXL that generates continuous thermally ablated columns, topical drug delivery after insulated RF microneedling is thought to occur primarily through the transient mechanical needle-entry microchannels [63,64], while the contribution of the surrounding RF-induced coagulation zone to molecular transport remains incompletely defined. The available device-physics literature supports epidermal sparing with insulated needles but does not establish a quantified open-channel geometry or lifetime [64]. Accordingly, the window for enhanced passive topical delivery may differ from that achieved with AFXL-assisted drug delivery, but its magnitude and duration remain uncertain. Broader reviews of transdermal biologic delivery likewise emphasize persistent evidence gaps for macromolecular transport across noninjectable platforms [65].

In melasma, randomized studies have tested RF microneedling with adjunctive topical small-molecule therapy [66], and combination protocols with autologous platelet-rich plasma (PRP) have also reported clinical benefit [67]. A split-face, double-blind, randomized controlled trial evaluated the application of topical insulin, a peptide of approximately 5.8 kDa, immediately following fractional RF microneedling for atrophic acne scars [68]. At the three-month follow-up, the treatment side demonstrated statistically significant improvements in clinical scar grading alongside histologically confirmed increases in dermal collagen density. This study provides indirect pharmacodynamic evidence consistent with enhanced delivery of a peptide substantially larger than 500 Da, although intradermal insulin exposure was not directly quantified. Topical exosome treatments applied immediately after RF microneedling have recently been described in case series as producing marked improvements in acne, including notable reductions in both overall severity and lesion counts [69], while preliminary split-face studies using plant-derived EV preparations suggest additional benefits for skin remodeling and texture [70]. Nevertheless, these clinical outcome studies do not directly demonstrate vesicle transport or target-compartment exposure. The evidence base for RF microneedling-assisted delivery of topical adjuncts remains largely preliminary and suggestive. A randomized split-face study by Cheng et al. [71] reported that combining bipolar RF with microneedle-assisted application of an extracellular matrix (ECM) produced significantly greater improvements in periorbital wrinkle severity, skin elasticity, and skin thickness than microneedle-assisted application alone. The authors attributed these synergistic effects to the complementary actions of potential adjunct transport through needle-created pathways and RF-induced dermal remodeling, although direct tissue penetration of the ECM components was not measured.

Clinically, one of the major methodological limitations of the current RF microneedling literature is the intrinsic regenerative activity of the procedure itself. Independent of any adjunctive topical therapy, needle penetration and RF-induced thermal coagulation activate wound-healing pathways that promote neocollagenesis, neoelastogenesis, ECM remodeling, and regenerative immune responses [72,73]. Accordingly, clinical improvements observed in uncontrolled or open-label combination studies constitute indirect pharmacodynamic indications rather than proof of adjunct delivery, reinforcing the need for split-face randomized controlled trials. Furthermore, the channel-kinetics framework established for AFXL, which quantified open-channel dwell times [37], has not been replicated for RF microneedling. In the literature identified by this review, we found no peer-reviewed study that directly quantified the exact dimensions, temporal patency, or absolute molecular-weight limits of RF-induced microchannels.

5.4. Cold Atmospheric Plasma

Unlike microneedling or AFXL, CAP does not primarily enhance permeability by creating persistent physical channels. Experimental studies instead indicate that CAP can transiently modify SC lipid organization, membrane and junctional permeability, and other aspects of barrier physiology through reactive oxygen and nitrogen species, charged species, and transient electric fields (Figure 5) [74,75,76,77]. CAP-associated changes in surface pH and cutaneous microcirculation have also been reported [78,79,80], although their direct contribution to topical drug transport remains uncertain. These observations establish biological plausibility for transient barrier modulation but should not, by themselves, be interpreted as evidence that a particular active reaches a defined viable-skin compartment at a clinically relevant concentration.

CAP evidence can be considered at four levels: (1) barrier modification or increased nonspecific permeability; (2) enhanced transport of a defined analyte across or into skin; (3) localization or quantification within a specified target compartment; and (4) target engagement or clinical benefit. These levels are not interchangeable: changes in TEWL, lipid organization, junctional proteins, or electrical permeability establish barrier modulation, not dermal delivery of a specific active. Because barrier recovery and transport kinetics vary by endpoint, analyte, device, and experimental system [77,81], no universal CAP “delivery window” can presently be defined.

The most direct analyte-specific evidence for CAP-assisted topical transport is currently strongest for selected relatively small molecules whose overall physicochemical and formulation characteristics are compatible with cutaneous transport. For lidocaine, quantitative permeation experiments demonstrated an approximately 1.97-fold increase in transdermal flux after CAP pretreatment [82], and a randomized split-face clinical study subsequently showed greater topical anesthetic effect [83]. Experimental studies have also reported enhanced percutaneous absorption of model compounds in porcine skin [84], enhanced niacinamide transport [81], and clinical use of a combined cold-plasma/electroporation/microjet platform to augment nano-molecule delivery [85]. In a hairless-mouse model, low-intensity CAP combined with topical ascorbic acid produced greater pigment reduction than either intervention alone, supporting preclinical synergy rather than direct ascorbate pharmacokinetic proof [86]. For selected supra-500 Da analytes, experimental studies have demonstrated enhanced transport or tissue localization of epidermal growth factor, cyclosporine A, and 3–5 kDa dextran under specific CAP conditions [77,87,88]. These findings provide proof-of-feasibility for particular analyte-device combinations rather than evidence of a general molecular-size range that CAP can reliably deliver.

For skin-booster macromolecules such as HA and PDRN, the evidence is substantially less mature. Human skin-explant data support CAP-enhanced transport of topically applied HA [89], while nanocarrier and plasma-engineered formulations have shown increased transport or cellular uptake in experimental systems [8,76,90]. However, these findings remain formulation-specific and do not establish quantitative in vivo dermal exposure of native topical HA or PDRN. Clinical reports using a PCL microsphere formulation likewise demonstrate feasibility rather than direct particle deposition [91]. No randomized human study identified in this review directly quantified dermal HA or PDRN after CAP-assisted topical application.

The CAP literature reviewed here includes both argon- and helium-fed systems, underscoring substantial device heterogeneity. Reproducible CAP-assisted topical-delivery protocols will therefore require more precise dosimetry-controlled output, including standardized reactive-species flux, exposure duration, and treatment area.

Table 5. Summary of available evidence and key uncertainties for device-assisted topical delivery of representative skin booster actives.

Platform	Representative Evidence	Direct Analyte-Specific Tissue Quantification	Most Defensible Conclusion	Key References
MN	HA: ex vivo/imaging; PDRN: preclinical/early clinical	Limited; direct dermal quantification of separately applied HMW-HA/PDRN lacking	SC bypass is established, but dermal delivery of separately applied HA/PDRN remains insufficiently demonstrated	[19,27,28,30,31]
AFXL	HA: human in vivo imaging; LMW drugs: multiple clinical trials	Limited; spatial HA localization demonstrated, but concentration–time data remain sparse	Strongest evidence among reviewed platforms for localized cutaneous delivery; quantitative target-compartment pharmacokinetics remains incompletely characterized and formulation-specific	[37,44,55,56,57]
RFMN	Insulin RCT; ECM-mixture split-face study	No direct analyte-specific exposure measurement identified	Adjunctive effects are difficult to distinguish from intrinsic RF/needling remodeling without direct exposure measurements	[68,71]
CAP	Small molecules: quantitative flux/clinical pharmacodynamics; HA: analyte-specific explant evidence	Analyte-specific quantitative or spatial evidence available for selected small molecules and ex vivo HA; no direct in vivo dermal quantification of HA/PDRN identified	Best supported for selected small molecules; macromolecular delivery remains predominantly preclinical/ex vivo and analyte-specific	[82,83,89]

AFXL, ablative fractional laser; CAP, cold atmospheric plasma; ECM, extracellular matrix; HA, hyaluronic acid; HMW, high-molecular-weight; LMW, low-molecular-weight; MN, microneedling; PDRN, polydeoxyribonucleotide; RCT, randomized controlled trial; RFMN, radiofrequency microneedling; SC, stratum corneum; evidence categories refer to the highest level of evidence identified for the stated analyte–platform pairing and do not imply equivalence across formulations, devices, treatment parameters, skin models, or clinical indications. “Direct native-analyte quantification” refers to measurement of the relevant active in a defined skin compartment. Tracer localization, labeled-formulation imaging, and clinical outcomes provide complementary but non-interchangeable evidence and should not alone be interpreted as quantitative pharmacokinetic confirmation.

summarizes the highest level of evidence identified for representative analyte-platform pairings and explicitly separates barrier modification, analyte-specific transport or localization, target-compartment exposure, and adjunctive clinical outcomes.

6. Real-World Formulation Paradigms: Multi-Ingredient Architectures in Clinical Practice

From a formulation perspective, contemporary multi-ingredient topical skin boosters can be interpreted as an attempt to accommodate percutaneous-delivery and stability constraints while addressing multiple biological processes relevant to skin aging [92]. Cutaneous aging is a multifactorial process arising from interacting intrinsic and extrinsic mechanisms, including impaired barrier and hydration homeostasis, oxidative stress and cellular senescence, enzyme-mediated ECM degradation, and dysregulation of melanocyte function [93]. Because these processes operate through partially distinct but interconnected pathways across multiple cutaneous compartments, broad-spectrum rejuvenation provides a biological rationale for multimodal, multi-target interventions rather than exclusive reliance on a single mechanistic target [94].

Beyond target diversity, rational multi-ingredient formulations can be designed around the physicochemical constraints imposed by the SC. One strategy is to combine molecules of different molecular sizes and biological roles: low-molecular-weight actives such as niacinamide and ascorbic acid have well-characterized epidermal and dermal biological effects [95,96], whereas high-molecular-weight polymers exhibit more restricted passive penetration [7]. High-molecular-weight HA therefore predominantly contributes surface hydration and barrier-associated effects [97], while macromolecular bioactives such as PDRN may require penetration-enhancing formulations or physical barrier-disruption technologies to achieve efficient delivery into viable skin [30]. This complementary permeation profile can be further optimized through vehicle-specific excipients, including chemical penetration enhancers and rationally designed co-solvent systems [98]. These components can independently or synergistically modify SC diffusivity and drug partitioning, while supersaturating formulations increase thermodynamic activity and thereby the chemical-potential gradient driving transfer from the vehicle into and across the skin [99] (Figure 6).

Crucially, these formulations leverage the pharmacological principle of cascade amplification. Biological processes such as melanogenesis and neocollagenesis are governed by complex, partially redundant networks comprising parallel and convergent signaling pathways followed by sequential biosynthetic and enzymatic cascades [100,101]. For collagen biosynthesis, formation of a mature matrix requires multiple downstream post-translational processes, including ascorbate-dependent proline and lysine hydroxylation, triple-helix formation and secretion, extracellular procollagen processing, and lysyl-oxidase-mediated fibril cross-linking [102]. Oxidation-sensitive bioactive ingredients also impose specific formulation requirements. Rational co-antioxidant systems can improve chemical stability and preserve biological activity prior to cutaneous penetration; a well-characterized example is the combination of vitamins C and E with ferulic acid, in which ferulic acid stabilizes the antioxidant formulation and substantially enhances its photoprotective efficacy [103].

Ultimately, the multi-ingredient design of advanced aesthetic topicals reflects an increasingly integrated formulation paradigm that combines pathway-targeted complementarity with optimization of cutaneous delivery and chemical stabilization of labile bioactive ingredients [94]. Multi-component topical skin booster formulations can incorporate actives directed at hydration, inflammation, pigmentation, regenerative signaling, and extracellular-matrix support [30]. To enhance storage stability and reduce unwanted interactions among formulation components [104], selected actives can be kept separate from the aqueous vehicle as lyophilized components and reconstituted immediately before use. A dual-vial configuration is one formulation option for dry-state storage followed by reconstitution immediately before topical application.

Table 6. Illustrative functional classification of active components encountered in multi-component topical skin booster formulations and their proposed formulation or biological rationale.

Functional Category	Active Component	Illustrative Role/Rationale in Topical Skin Booster Formulations
Hydration	Sodium hyaluronate (multi-molecular weight), acetylated sodium hyaluronate, panthenol, sucrose, trehalose, serine, glycine, threonine, alanine, polyglutamic acid, ceramides, betaine, beta-glucan	HA/polyglutamic acid: humectancy and water retention; panthenol/ceramides/beta-glucan: barrier support; sugars and NMF-related amino acids: osmolyte/humectant support.
Anti-inflammatory	Niacinamide, panthenol, glutathione, ascorbic acid, histidine, cysteine, methionine, Centella asiatica derivatives (madecassoside, asiaticoside), allantoin, dipotassium glycyrrhizate, Houttuynia cordata extract	Niacinamide, panthenol, Centella derivatives, allantoin and glycyrrhizate: barrier-calming/anti-inflammatory rationale; glutathione, ascorbate and sulfur-containing amino acids: antioxidant/redox support.
Anti-pigmentation	Arbutin/alpha-arbutin, tranexamic acid, glutathione (reduced), niacinamide, ascorbic acid and stable derivatives (e.g., ethyl ascorbic acid), kojic acid, nonapeptide-1	Tranexamic acid, arbutin/kojic acid, niacinamide, vitamin C, glutathione and nonapeptide-1: pigment-modulating rationale through distinct melanogenesis, pigment-transfer or redox-related pathways.
Regenerative Signaling	Sodium DNA (PDRN fragments), plant-derived EVs, ginseng-derived EVs, lactobacillus-derived EVs, human adipose-derived exosomes, human amniotic fluid-derived exosomes, growth factors (EGF, FGF, IGF), biomimetic peptides (acetyl hexapeptide-8, palmitoyl tripeptide-1), arginine, lysine, proline, leucine, isoleucine, valine, phenylalanine, tyrosine	PDRN: purinergic/nucleotide-salvage-related signaling; EVs/exosomes: proposed paracrine cargo signaling; growth factors/peptides: receptor- or sequence-specific signaling. Amino acids provide supportive substrate/microenvironmental roles rather than proven regenerative effects.
ECM Substrate Support	Glycine, proline, lysine, glutamic acid, aspartic acid, sodium hyaluronate, trehalose, poly-L-lactic acid, polycaprolactone, hydrolyzed collagen, proteoglycans, copper tripeptide-1	Glycine/proline/lysine: collagen-related substrate rationale; HA/proteoglycans/hydrolyzed collagen: matrix hydration/support; copper tripeptide-1: repair/ECM-signaling rationale; PLLA/PCL: scaffold/biostimulatory rationale mainly established after tissue placement, not simple topical application.

ECM, extracellular matrix; EV, extracellular vesicle; HA, hyaluronic acid; NMF, natural moisturizing factor; PDRN, polydeoxyribonucleotide; PCL, polycaprolactone; PLLA, poly-L-lactic acid; functional categories reflect established or proposed roles of individual ingredients and do not establish their relative or causal contribution to the effects of a complete multi-ingredient formulation; entries summarize component-level rationale and do not establish clinical benefit from topical use.

provides an illustrative functional classification of ingredient categories relevant to the formulation archetypes discussed here.

6.1. Translational Formulation Strategies

To bridge theoretical pharmacokinetic principles with contemporary formulation practice, the following sections use two commercially available formulation types as illustrative archetypes. They were purposively selected to contrast macromolecule-centered regenerative formulations with predominantly low-molecular-weight multi-active formulations and were not selected through market-share ranking or comparative efficacy assessment. Their inclusion is intended to illustrate formulation logic rather than treatment prevalence and does not imply endorsement or superiority over other products. For multi-ingredient commercial formulations, component-level evidence is used here to describe plausible biological roles rather than to assign observed formulation-level effects to individual ingredients; such attribution requires a study design that isolates the contribution of the component concerned.

6.1.1. Formulation Archetype 1: Macromolecule-Centered Regenerative Formulations

One illustrative archetype is a macromolecule-centered regenerative formulation built around PDRN or related polynucleotide components. The biological effects of these nucleic-acid-derived polymers are partly attributed to adenosine A2A-receptor signaling and nucleotide-salvage pathways, with downstream anti-inflammatory and fibroblast-related effects [105]. Such formulations may pair DNA-derived components with EV-related ingredients to engage complementary paracrine signaling pathways involving proteins, lipids, and regulatory RNAs that can modulate inflammation, angiogenesis, fibroblast activity, wound repair, and extracellular-matrix remodeling [106,107]. Complementing these signaling pathways, many formulations incorporate ECM–supportive components that may help reestablish a structural and biochemical microenvironment favorable to tissue repair and remodeling [108]. We propose the term “signal-and-support” to describe this conceptual formulation architecture, in which pathway-directed signaling components are combined with ingredients intended to support the surrounding tissue microenvironment. This framework is hypothesis-generating rather than an established or validated pharmacological model and requires prospective experimental validation.

Nevertheless, a key limitation of PDRN-based topical products is the poor passive permeability expected for hydrophilic DNA macromolecules. Device-based interventions such as microneedling and AFXL can create transient pathways for macromolecular transport, while RF microneedling adds an independent dermal-remodeling stimulus [109]. Recent formulation strategies include low-molecular-weight PDRN [110,111] as well as nanoscale carrier systems designed to improve stability and delivery [112]. These component-level pathway assignments represent mechanistic plausibility and should not be interpreted as evidence that topical application of the finished formulation achieves corresponding target-compartment exposure or target engagement in vivo.

An illustrative multi-component archetype formulation in Korea (Figure 7) combines PDRN with EV-related ingredients, amino acids, vitamins, antioxidants, and supportive actives. Available studies provide component-level or formulation-adjacent preclinical evidence [30,113]. Studies have also reported modulation of macrophage–fibroblast crosstalk and increased collagen production, providing indirect mechanistic support for regenerative-signaling concepts [114]. Recent injectable animal studies further show that plant-derived EV preparations and PDRN-containing regenerative formulations can enhance wound healing, collagen deposition, and angiogenic responses after direct tissue administration [115,116]; these findings support biological plausibility but do not establish topical delivery or target-compartment exposure. Antioxidant and pigment-regulating agents—such as glutathione, vitamin C, niacinamide, arbutin, and tranexamic acid—may be incorporated to address oxidative stress and dyschromia [30,113]. Barrier-recovery ingredients such as panthenol and copper–zinc complexes—shown to restore epidermal homeostasis and temper excessive or prolonged inflammatory signaling [117,118]—are also included to provide a supportive microenvironment for tissue regeneration.

Overall, these formulations reflect an effort to integrate regenerative signaling with microenvironmental support, moving beyond approaches centered only on hydration. However, despite the strong biological rationale and encouraging preclinical findings supporting these multi-target designs, their clinical synergistic effects and actual target engagement have not yet been directly demonstrated. A substantial gap therefore remains between preclinical promise and rigorously verified clinical evidence confirming real-world delivery and target engagement in human subjects. In addition, pharmacokinetic behavior established for an isolated ingredient cannot be assumed to apply when that ingredient is incorporated into a complex commercial formulation [119]; the finished formulation itself must be evaluated as the relevant pharmacokinetic unit.

Accordingly, the signal-and-support framework should presently be regarded as an organizing hypothesis for formulation design rather than evidence of synergistic pharmacological activity. When a complete multi-ingredient formulation is evaluated, observed biological or clinical effects should be attributed to the formulation as a whole unless component-isolation, appropriate comparator, or factorial designs permit the contribution of individual ingredients to be distinguished.

6.1.2. Formulation Archetype 2: Low-Molecular-Weight Multi-Active Formulations

A second illustrative archetype centers on low-molecular-weight antioxidants and pigment-modulating agents intended to influence the epidermal microenvironment. These ingredient classes address melanocyte dysregulation and oxidative stress, both of which contribute to visible features of skin aging [120,121]. Notably, most of these auxiliary antioxidant and pigment-modulating compounds fall within a molecular-size range that removes one major physicochemical constraint on passive cutaneous transport, although their actual permeability remains dependent on properties such as lipophilicity, ionization, solubility, concentration, vehicle composition, thermodynamic activity, and skin-barrier condition. For example, glutathione—a tripeptide antioxidant that serves as a key intracellular redox regulator—has a molecular weight of approximately 307 Da [122]. Vitamin C (L-ascorbic acid), at approximately 176 Da, is an even smaller hydrophilic molecule that serves as an essential cofactor for collagen prolyl and lysyl hydroxylases while contributing to intracellular antioxidant defense [123]. Niacinamide (nicotinamide), the amide form of vitamin B3, is a small hydrophilic molecule (122.12 Da) with well-characterized regulatory effects on epidermal barrier homeostasis and inflammatory pathways [95]. Tranexamic acid—widely used for melasma and shown in vitro to modulate melanogenesis and angiogenesis through VEGF-receptor-related effects [124]—is another small hydrophilic molecule, with a molecular weight of approximately 157 Da.

Collectively, these compounds have a stronger overall physicochemical rationale for topical delivery than large hydrophilic polymers, not because molecular size alone predicts permeability, but because molecular size can be considered together with compound-specific physicochemical properties, formulation characteristics, thermodynamic activity, and barrier condition. More broadly, a recent survey of Korean board-certified dermatologists shows that modern skin-rejuvenation practice commonly combines low-molecular-weight topical agents with energy-based devices or injectables as part of individualized multimodal treatment strategies [125].

Concentrated low-molecular-weight actives can increase thermodynamic activity and thereby increase the driving force for partitioning from the vehicle into skin [126]. An illustrative low-molecular-weight archetype can combine glutathione, ascorbic acid, tranexamic acid, and niacinamide. This archetype is used here to illustrate formulation logic rather than treatment prevalence. For formulations used episodically as procedural adjuncts, the durability of target-compartment exposure after a single application remains uncertain.

6.2. Emerging Mechanistically Distinct Topical Concepts

Spicule-based systems have emerged as micromechanical topical-delivery platforms. Natural siliceous or soluble micro-spicules can transiently perturb the SC and carry or facilitate transport of co-applied actives; porcine-skin transport studies and a randomized split-face trial using micro-spicule-associated epidermal growth factor support proof-of-concept, although the evidence remains formulation- and platform-specific [5,127,128]. Another emerging approach involves incorporating “volumizing ingredients,” such as sarsasapogenin, into topical formulations to promote tissue fullness. This strategy is based on manufacturer-associated evidence suggesting that sarsasapogenin may stimulate adipocyte differentiation and lipid accumulation; however, independent clinical validation remains limited [129].

7. Gaps and Needs

Across physical barrier-disruption modalities, a major methodological limitation is that standardized target-compartment pharmacokinetic methods are not consistently applied across device-assisted topical-delivery studies [130]. Most clinical studies rely on surrogate biophysical metrics or global photographic improvement scales—endpoints incapable of distinguishing device-induced neocollagenesis from any incremental effect attributable to topically delivered macromolecular agents. Only a limited number of investigations have incorporated tissue-level or spatially resolved assessments of device-assisted topical delivery. For example, recent multiphoton fluorescence-lifetime imaging studies directly visualized HA deposition across the epidermis and into the upper dermis following fractional laser treatment [55,56], whereas even rigorous randomized trials—such as the split-face study of topical insulin after RFMN by Rattananukrom et al. [68]—have generally relied on clinical and imaging endpoints without direct quantification of intradermal drug exposure. In the absence of direct analyte-specific pharmacokinetic verification, claims specifically attributing clinical efficacy to dermal delivery of the proposed active cannot be rigorously substantiated.

We therefore propose a tiered, analyte-, platform-, and claim-specific framework for evaluating topical skin booster delivery. The framework distinguishes complementary evidentiary domains ranging from pathway- or tracer-based evidence of barrier passage or transport, through layer-specific quantitation of the native analyte and evidence of target engagement, to controlled clinical outcomes. Terminology should be calibrated to the highest evidentiary level directly supported for each analyte–platform pairing: barrier modification is not equated with analyte delivery, analyte localization is not equated with quantitative target-compartment exposure, and clinical improvement is not interpreted as proof of dermal deposition without direct exposure measurements. For instance, when a study reports only barrier passage, flux measurements, or spatial localization, it is suggested to use those specific terms rather than implying dermal exposure or delivery to a particular target compartment.

Rather than requiring direct pharmacokinetic verification as a mandatory endpoint in every study, the evidence required should be calibrated to the physicochemical properties of the active ingredient, the delivery platform, and the specific claim being evaluated. Importantly, these tiers are complementary rather than interchangeable: controlled clinical efficacy does not substitute for direct pharmacokinetic evidence when the claim specifically concerns cutaneous delivery or dermal bioavailability, just as demonstration of tissue deposition alone does not establish target engagement or clinical benefit.

Methodological approaches applicable to this framework include quantitative analytical chemistry with layer-specific tissue sampling, mass-spectrometry imaging, calibrated confocal laser scanning microscopy using fluorescently labeled compounds, and label-free spectroscopic techniques such as confocal Raman microscopy. Direct measurements of analyte deposition or target-compartment exposure may be complemented by biopsy-based histology, immunohistochemistry, and molecular assays to assess downstream target engagement. Non-invasive optical methods can provide additional spatial and longitudinal information, although their ability to quantify the active compound itself requires validation for each analyte (

Table 7. Comparison of analytical methods for assessing skin penetration of topically applied skin booster formulations.

Method	Drug Exposure	Spatial Localization
HPLC/LC-MS/MS	Quantitative	Only with layer-specific sampling
Mass-spectrometry imaging	Semiquantitative–quantitative	Excellent
Fluorescence CLSM	Semi-quantitative	Excellent
Confocal Raman microspectroscopy	Semiquantitative–quantitative	Excellent
RT-PCR	No	Limited to sampled compartment
Reflectance confocal microscopy	No	Morphological
Skin biopsy, IHC	No	Excellent morphology
Microdialysis	Quantitative	Dermal compartment

CLSM, confocal laser scanning microscopy; HPLC/LC-MS/MS, high-performance liquid chromatography–tandem mass spectrometry; IHC, immunohistochemistry; RT-PCR, reverse transcription polymerase chain reaction.

). Even in pilot-scale studies, combining orthogonal methods across relevant evidentiary tiers could substantially strengthen the evidence base and enable more meaningful comparisons among delivery platforms.

Future development of topical skin boosters may move from empirically repurposed cosmeceuticals toward more integrated formulation–device systems, in which molecular size, hydrophilicity, viscosity, concentration, stability, and excipient composition are optimized for the transport environment created by a specific delivery platform [131]. AFXL generates open microchannels whose depth and morphology interact with drug solubility, molecular size, and tissue-binding properties to determine biodistribution [132], whereas microneedle-based systems and RF microneedling create distinct mechanical and thermal transport environments whose formulation requirements remain incompletely characterized. CAP represents a mechanistically different approach, transiently modifying SC lipid chemistry and permeability and showing enhanced transport for selected hydrophilic analytes under specific experimental conditions [75]. These device-specific requirements may motivate dedicated post-procedure formulations with analyte- and platform-specific pharmacokinetic characterization, reducing empirical cross-platform use of formulations that have not been specifically evaluated for a given device and making direct comparative pharmacokinetic studies increasingly important. In parallel, regulatory-science discussions of active-loaded microneedle dosage forms provide a precedent for treating the formulation and delivery architecture as an integrated product-development problem [133], with implications for next-generation topical skin booster product development.

A final point is the growing focus on modifying bioactive macromolecules themselves so they can bypass the SC without any barrier disruption. Biomimetic lipid nanocarriers provide one such approach: ultradeformable vesicles such as transfersomes can exploit their membrane flexibility to traverse narrow intercellular pathways [134], whereas ethanol-rich ethosomes combine vesicular deformability with ethanol-mediated fluidization of stratum-corneum lipids [135]. Solid-lipid nanoparticles and related lipid carriers operate somewhat differently, enhancing cutaneous deposition and drug partitioning partly through film formation, occlusion, and increased stratum-corneum hydration [136]. Integrating nanocarrier design with experimentally characterized properties of PDRN formulations—including particle size, surface charge, and formulation stability [137]—represents a priority research direction for developing non-invasive topical formulations capable of achieving verifiable dermal-level macromolecule deposition. A complementary strategy modifies the bioactive itself. Bioreversible prodrug approaches can transiently alter lipophilicity, ionization, or charge to improve partitioning into and diffusion across the stratum corneum, followed by enzymatic or chemical regeneration of the active parent molecule within the skin [138]. Alternatively, bioactives may be conjugated to, complexed with, or coadministered with cell- or skin-penetrating peptides that facilitate transport of otherwise poorly permeable cargoes, including peptides and proteins, across intact skin [139].

8. Regulatory Considerations for Topical Skin Boosters in Korea

Regulatory classification of topical skin boosters is jurisdiction-specific and depends on intended use, route of administration, composition, and product claims. In Korea, topical skin boosters marketed as cosmetics fall within a framework limited to external application; intradermal or other parenteral use therefore falls outside the authorized cosmetic route of administration [140]. Additional restrictions apply to emerging biologically derived ingredients: current Korean guidance does not permit human-cell- or human-tissue-derived exosomes as cosmetic ingredients and restricts labeling or advertising that may imply their presence [141]. Non-human-derived EV-related claims are treated separately but remain subject to substantiation and general requirements against misleading advertising [141].

9. Limitations of This Review

Many critical limitations must be acknowledged to properly contextualize the findings of this review. First, this article was constructed as a narrative review rather than a strict systematic analysis. Because literature selection and synthesis were not governed by rigid methodological protocols, there is an inherent potential for selection bias. Because the evidence base is rapidly evolving, current conclusions and mechanistic interpretations should be viewed as provisional, as newly emerging device- and formulation-specific data may quickly reshape the overall evidentiary landscape. Meaningful cross-study comparisons are also severely hampered by vast heterogeneity in both device parameters and product formulations. In addition, contemporary topical skin boosters often rely on complex, multi-ingredient formulations, making it difficult to evaluate the specific pharmacokinetic behavior or clinical contribution of any single active component within these mixtures. Finally, the real-world case studies and formulation trends highlighted in this review are deeply rooted in the Korean aesthetic market. Because this specific commercial landscape is governed by regional cosmetic and medical device regulations, the direct international generalizability of these exact product paradigms may be limited.

10. Conclusions

Topical skin boosters represent an evolving approach to skin rejuvenation, but their clinical adoption has outpaced direct characterization of cutaneous exposure, particularly for macromolecular actives. Because passive permeation of many large, hydrophilic macromolecular actives across the intact SC is highly constrained under conventional topical conditions, meaningful exposure within deeper cutaneous compartments generally requires an effective penetration-enhancing strategy, such as physical barrier bypass, transient barrier modulation, or appropriately engineered carrier systems. Future development should therefore move beyond the nonspecific “regenerative serum” paradigm toward rational formulation–device integration and delivery systems designed around the physicochemical properties and intended tissue targets of individual actives.

To evaluate such strategies, we propose a tiered, analyte-, platform-, and claim-specific evidentiary framework rather than a universal requirement for direct pharmacokinetic verification in every study. Relevant evidence may include pathway or tracer studies demonstrating barrier passage or transport, layer-specific quantitation of the native analyte, demonstration of target engagement, and controlled clinical outcomes. These domains are complementary rather than interchangeable: clinical efficacy alone does not establish dermal deposition, just as tissue deposition alone does not establish target engagement or clinical benefit. The evidentiary requirements should therefore be calibrated to the physicochemical properties of the active ingredient, the delivery platform, and the specificity of the claim being made. Within this framework, the central question is not simply whether a topical skin booster produces a clinical effect, but whether the available evidence is sufficient to support the specific delivery, mechanistic, or efficacy claim being made.