Creative Touch Permanent Makeup and Aesthetics

Transforming growth factor beta (TGF-β) is the master regulator of dermal wound healing and ECM remodelling, signalling through the Smad2/3 pathway to drive fibroblast activation, collagen synthesis, and myofibroblast differentiation. Three isoforms with distinct roles: TGF-β1 and TGF-β2 drive fibrotic, scar-forming healing in adult wounds; TGF-β3 is anti-fibrotic, promotes regenerative healing, and characterises the scarless fetal wound environment. The TGF-β1 to TGF-β3 ratio at the wound site is the primary determinant of scar quality. In aesthetic treatments, controlled TGF-β1 activation produces therapeutic collagen remodelling; uncontrolled activation produces fibrosis. TGF-β signalling declines with age through receptor downregulation and Smad7 inhibition, reducing fibroblast responsiveness. PLLA biostimulators act primarily through TGF-β/Smad pathway upregulation.

TGF-β is secreted by virtually every cell type involved in skin repair – platelets (the first source at wound activation), macrophages, T-regulatory cells, keratinocytes, and fibroblasts – in a latent form bound to a latency-associated peptide (LAP) that holds it inactive until released by proteases, reactive oxygen species, or mechanical tension. This latency mechanism provides a local activation threshold: TGF-β does not act at a distance from its source but is activated in the specific tissue microenvironment where it is needed, making its effects spatially and temporally regulated in a way that systemically circulating cytokines are not. ^[3]

The Smad Signalling Pathway

TGF-β signals through a canonical intracellular pathway that is both well-characterised and clinically relevant – because multiple aesthetic treatment mechanisms act by upregulating it. Extracellular TGF-β binds a heterodimeric receptor complex of TGF-β receptor type I (TβRI) and type II (TβRII) at the cell surface. TβRII transphosphorylates TβRI, which then phosphorylates receptor-regulated Smads (Smad2 and Smad3) at their C-terminal serine residues. Phosphorylated Smad2/3 form a complex with the common mediator Smad4, and this trimeric complex translocates to the nucleus, where it binds promoter regions of target genes – including COL1A1 and COL1A2 (type I collagen), COL3A1 (type III collagen), fibronectin, TIMP-1 and TIMP-2 (tissue inhibitors of metalloproteinases), and alpha-smooth muscle actin (α-SMA, the marker of myofibroblast differentiation). ^[6]

The net genomic output is fibroblast activation, collagen synthesis, ECM deposition, and suppression of the matrix metalloproteinases (MMPs) that would otherwise degrade the newly synthesised matrix. Non-canonical (Smad-independent) pathways – including MAPK/ERK, PI3K/Akt, and RhoA – operate in parallel and modulate the magnitude and context-specificity of the Smad response. PLLA biostimulators have been shown to upregulate TGF-β levels dose-dependently, driving p-Smad2 and p-Smad3 phosphorylation and increasing COL1A1, COL1A2, elastin, TIMP-1, and TIMP-2 expression in dermal fibroblasts – with the collagen synthesis effect blocked when TGF-β receptor is inhibited by SB431542, confirming TGF-β/Smad as the primary mechanistic pathway of PLLA’s clinical effect. ^[7]

The Three Isoforms

TGF-β exists as three isoforms – TGF-β1, TGF-β2, and TGF-β3 – that signal through the same receptor complex and Smad2/3 pathway but produce meaningfully different biological outcomes depending on their relative concentrations, the tissue context, and the wound healing phase. ^[3]

TGF-β1

TGF-β1 is the dominant isoform in adult wound healing and the primary driver of the fibrotic healing response. Released initially from degranulating platelets at wounding, it recruits macrophages and inflammatory cells to the wound site, drives the inflammatory phase, and then initiates the transition to the proliferative phase by activating fibroblast chemotaxis and myofibroblast differentiation. Its sustained elevation drives ECM deposition, collagen crosslinking, and the contraction characteristic of normal scar formation. When TGF-β1 signalling is excessive or unresolved – through chronic inflammation, repeated injury, or dysregulated feedback – it drives pathological fibrosis: hypertrophic scars, keloids, and the dermal contracture of chronic wounds. ^[6]

Skin that heals with prominent scar formation is characterised by a high TGF-β1 to TGF-β3 ratio. In aesthetic treatment contexts, TGF-β1 is the principal mediator of the collagen neosynthesis response to RF microneedling, fractional laser, and needling procedures – the intended therapeutic effect. The clinical challenge is that the same signalling cascade that produces this beneficial remodelling, when triggered in the wrong tissue, at the wrong depth, or in a genetically predisposed individual, produces the same outcome as a pathological wound: fibrosis.

TGF-β2

TGF-β2 is the least well-characterised isoform in dermal repair but shares the pro-fibrotic profile of TGF-β1 in adult wounds. It is particularly important in ocular tissue repair and is the primary isoform implicated in post-surgical fibrosis in ophthalmological contexts. In skin, TGF-β2 functions alongside TGF-β1 in ECM deposition during the proliferative phase; its independent contribution to fibrotic versus regenerative outcomes in dermal wounds is less clearly distinguished from TGF-β1 than TGF-β3’s anti-fibrotic role. ^[4]

TGF-β3

TGF-β3 is the isoform most directly relevant to the goal of regenerative rather than fibrotic healing and is the focus of the most clinically significant mechanistic research in scarless wound repair. Fetal wounds heal without scar – a phenomenon characterised by high TGF-β3 and low TGF-β1 expression at the wound site. As gestation progresses and the wound environment shifts toward the adult phenotype, TGF-β3 levels decline and TGF-β1 rises, and the quality of healing transitions from scarless to scar-forming. ^[5]

TGF-β3 is a less potent inducer of fibroblast-to-myofibroblast differentiation than TGF-β1, and reduces macrophage infiltration at the wound site – macrophage-driven TGF-β1 secretion being a primary amplification loop for the fibrotic response. It upregulates fibronectin (Fn1) and hyaluronic acid synthases HAS1 and HAS2, which promote cell attachment and migration and produce the hyaluronan-rich ECM characteristic of scarless fetal repair. ^[1] In adult wounds, tissues with minimal scarring – oral mucosa, vocal fold mucosa – exhibit a significantly lower TGF-β1 to TGF-β3 ratio than skin, and exogenous TGF-β3 delivery to adult wounds has demonstrated scar reduction in animal models. ^[3]

The clinical implication is that therapeutic approaches which shift the TGF-β1/TGF-β3 ratio toward TGF-β3 – whether through exogenous TGF-β3 delivery, anti-TGF-β1 neutralising antibodies, or interventions that reduce macrophage-driven TGF-β1 amplification – represent a theoretically sound approach to reducing scar formation. This remains an active area of translational research rather than established clinical practice, but it informs the mechanistic framing of scar management discussions in aesthetics.

The Dual Role Paradox

The central clinical insight of TGF-β biology is that the same molecule – at different concentrations, in different tissue contexts, and at different points in the healing timeline – produces either the therapeutic outcome aesthetics treatment is designed to achieve or the adverse outcome it is designed to avoid. Controlled, transient TGF-β1 activation at the dermis – as produced by RF microneedling, fractional ablation, or collagen biostimulator placement – initiates a proportionate wound healing response that resolves into organised collagen remodelling. Uncontrolled, prolonged, or excessive TGF-β1 activation – as produced by treatment at the wrong depth, in skin with compromised barrier function, or in individuals with predisposition to aberrant fibroblast response – initiates the same pathway that produces hypertrophic scarring.

This is why treatment depth, device calibration, skin health status at treatment, and patient selection criteria for procedures that depend on TGF-β-mediated remodelling are not merely precautionary – they are the variables that determine which arm of the TGF-β response is activated. The isoform ratio at the wound site shifts with the degree and duration of tissue disruption: controlled micro-injury favours a balanced TGF-β1/TGF-β3 response and proportionate remodelling; deep or extensive injury shifts the ratio toward TGF-β1 dominance and fibrotic risk.

TGF-β in Skin Ageing

TGF-β signalling in dermal fibroblasts declines with age through multiple mechanisms: reduced TβRI and TβRII receptor expression, reduced Smad2/3 phosphorylation efficiency, and increased expression of Smad7 – the inhibitory Smad that competes with Smad2/3 for receptor binding and limits the transcriptional response. ^[2] The practical consequence is that aged fibroblasts mount a weaker collagen synthesis response to the same TGF-β stimulus than younger fibroblasts – contributing to the slower wound healing, reduced treatment response, and declining ECM maintenance that characterises photoaged and intrinsically aged skin. This is one mechanistic explanation for why collagen-stimulating treatments produce more gradual and less dramatic results in older clients, and why energy-based treatments that amplify TGF-β signalling may need to be sequenced or repeated differently in older skin than in younger.