The “Three-Tier Regulatory Network” of Orthokeratology in Myopia Control: Evidence Weight of Underlying Mechanisms, Controversies, and New Perspectives for Clinical Translation--A Review

Introduction

Myopia has become a global public health issue. Orthokeratology (Ortho-K) temporarily reshapes the corneal morphology through overnight wear, providing clear unaided vision during the day while effectively controlling myopia progression. But, its exact mechanism has yet to be fully clarified. Traditional views have primarily focused on the induced peripheral retinal defocus; however, accumulating evidence indicates that this is a multi-pathway, dynamically interactive process involving optics, biomechanics, neurobiology, and molecular biology.^1,2

Current research is limited by a simplistic enumeration of pathways and a lack of in-depth analysis of core driving factors and cross-regulatory interactions between pathways. For example, how do peripheral defocus signals regulate axial growth through the retinal-choroidal-scleral signaling pathway? What interactions exist between corneal biomechanical changes and neurobiological responses? These critical scientific questions urgently require answers through the integration of multi-omics technologies and cross-scale research. Furthermore, individual efficacy differences observed in clinical practice (eg., poor efficacy in allergic children) also need molecular mechanistic explanations.³ With the development of artificial intelligence (AI) technologies, machine learning-based predictive models have begun to be applied to Ortho-K efficacy prediction and lens parameter optimization, providing new ideas for personalized treatment.^4,5

By analyzing the latest literature from 2021 to 2025, this review systematically outlines the core mechanisms of Ortho-K in slowing myopia and innovatively proposes a “three-tier regulatory network” model based on evidence weight, covering from the initial drivers of the direct lens stimulation on the cornea and peripheral defocus, to the intermediate integration of retinal-choroidal changes, and the ultimate effect of scleral remodeling, while also assessing the evidence levels of each pathway. Additionally, it addresses key controversies in the current field (such as individual response differences) and explores future research directions in combination with cutting-edge technologies like AI personalized design and single-cell sequencing. Finally, based on mechanistic studies, it provides feasible translational recommendations for optimizing clinical practice and personalized treatment strategies.

This review fills critical gaps in current research, which is limited by simplistic enumeration of regulatory pathways and lack of systematic analysis of core driving factors, cross-pathway interactions, and evidence-based prioritization of mechanisms. The proposed three-tier regulatory network provides a unified conceptual framework for understanding the complex anti-myopia mechanism of Ortho-K, which can not only guide the optimization of clinical lens design and personalized treatment, but also provide new theoretical directions for basic research on myopia. Given the global pandemic of adolescent myopia, this work has important public health value for improving the overall efficacy of myopia control and reducing the risk of myopia-related blinding complications.

Methods

A comprehensive literature review was conducted using the database of PubMed, Embase, and Web of Science. The primary search terms included “orthokeratology”, “ortho-k”, “OK lens”, “mechanism”, “myopia”, “Artificial Intelligence”. The search was restricted to studies published between January 2021 and December 2025, with additional filters applied to include articles published in the English language. Articles focusing on non-myopia or unrelated ocular conditions were excluded. A total of 195 peer-reviewed manuscripts were analyzed, consisting of systematic reviews, randomized controlled trials, cohort studies, case-control studies, and case reports. To ensure comprehensive data capture, the reference lists of all included publications were also manually screened for additional relevant studies.

Construction of the “Three-Tier Regulatory Network” Model of Ortho-k in Myopia Control

Model Framework and Core Driving Tier Analysis

By reviewing the latest literature from the past 5 years (2021–2025), we systematically outline the core mechanisms of Ortho-K in slowing myopia progression and innovatively propose a “Initial driver - Intermediate signal integration - Terminal effect” three-tier regulatory network modelbased on existing evidence weight (Figure 1).

Figure 1 Schematic diagram of the Initial driver - Intermediate signal integration - Terminal effect three-tier regulatory network of orthokeratology (Ortho-K) in myopia control. (a) Initial Driver Tier: The dual upstream activation factors triggered by Ortho-K lenses (with AI-personalized design optimization) include direct mechanical contact stimulation on the cornea and induction of peripheral retinal optical defocus, the core trigger signals of the myopia control regulatory cascade. (b) Intermediate Signal Integration Tier: Initial driver signals initiate multi-tissue/cell signal conversion and amplification, involving activation of the corneal nerve reflex arc and structural/hemodynamic changes (blood flow and thickness alterations) in the retinal-choroidal complex. (c) Terminal Effect Tier: Integrated upstream signals converge on the sclera to regulate key biological processes including scleral collagen remodeling and extracellular matrix reconstruction, the final common pathway for myopia control. (d) Clinical Outcome: The multi-tier regulatory network ultimately exerts the therapeutic effect of inhibiting ocular axial elongation, thereby achieving effective myopia control in adolescents. All arrows in the figure indicate the direction of signal transduction and regulatory cascade among different tiers and ocular tissues.

At the initial core driving tier, optical defocus (especially the relative myopic defocus of peripheral retina) and corneal biomechanical direct contact stimulation constitute the upstream activation factors. Multiple studies have confirmed that lenses designed with a small optical zone (5.0mm) can produce a stronger myopic defocus effect in the 10°-20° region, while traditional optical zones (6.0mm) exhibit more significant defocus effects in the 40°-53° region and temporal area.⁶ This differentiated defocus distribution pattern shows through meta-analysis that small optical zone lenses have superior control over axial growth and quantify the weight of optical defocus as a “trigger” signal.⁷ Additionally, finite element model analysis reveals that Ortho-k lenses change the dynamics of intraocular tension, particularly reducing the tension of the posterior ciliary muscle-lens complex, providing a biomechanical basis for the observed short-term axial shortening.⁸

The intermediate signal integration tier plays a crucial role in signal conversion and amplification. The corneal nerve reflex arc plays an important role at this level, with its activation affecting ciliary muscle tension and accommodation function. Changes in retinal blood flow and thickness also play important roles in the intermediate signal integration tier, as the regulation of retinal blood flow can influence neuro-metabolic demands and signal transmission efficiency, while changes in retinal thickness reflect structural adjustments and functional states of neural tissue. Optical coherence tomography angiography (OCTA) studies show that after six months of wear, the vascular density of superficial and deep capillary plexuses significantly increases, suggesting participation in neurovascular regulation.⁹ Additionally, changes in choroidal thickness are also important indicators, as Ortho-k lenses can induce more significant choroidal thickening compared to multifocal spectacle lenses, which may be related to the regulatory expression of bioactive factors such as dopamine and vasoactive intestinal peptide (VIP).¹⁰

The terminal effect tier focuses on scleral remodeling, particularly the metabolic activity of posterior scleral fibroblasts and the reconstruction of extracellular matrix components (such as collagen and glycosaminoglycans). Long-term follow-up data shows that increasing the compressive factor (1.75 D) in lens design can slow axial elongation by 34% within two years, indicating the persistence and cumulative effect of scleral remodeling.¹¹ Proteomics analysis detected 423 proteins on the lens surface, including signaling molecules that may be related to scleral metabolic regulation, providing molecular-level clues for understanding the terminal effect.¹² This tier acts as a common target for the joint action of various pathways, ultimately manifested as a reduction in the rate of axial growth.

Evidence of Interactions Between Pathways and the Regulatory Network

There exists a complex cross-talk mechanism between the “optical-biomechanical-neurovascular” Pathways of Ortho-k. Finite element analysis demonstrates that lenses with different back optical zone diameters (BOZD) produce differentiated biomechanical effects: 5.0mm BOZD lenses generate higher central contact pressure and a smaller mechanical treatment zone diameter, while 6.0mm BOZD lenses lead to maximum stress shifting from the center to the periphery.¹³ This biomechanical change may modulate the quality of defocus signals by affecting higher-order corneal aberrations, forming interactions between optical and biomechanical pathways. Multispectral refractive topography studies show that after wearing Ortho-k lenses, the amount of peripheral retinal defocus in the 15°-53° regions is significantly lower than that in the spectacle group, suggesting that biomechanical remodeling may optimize the distribution pattern of defocus signals.¹⁴

Regarding the “prioritization” And “timing” Of the regulatory network, short-term studies (1 week) have observed an average axial shortening of 0.028mm, indicating the rapid response of biomechanical and neuro-reflex pathways.⁸ While changes in choroidal thickness and retinal vascular density after six months reflect the progressive adaptation of the neurovascular pathway.^9,10 Genetic studies further reveal that nonsynonymous variants of retinal disease-related genes (eg., RIMS2 and LCA5) are associated with slower myopic progression, suggesting that the activity of various pathways may vary based on genetic determinants among individuals.¹⁵

Current research still has gaps in direct evidence of “pathway interactions.” In particular, how corneal nerve stimulation influences choroidal blood flow through neuro-reflexes and how these immediate changes translate into long-term remodeling of the sclera remain to be validated by multi-modal synchronous monitoring technologies. Future studies should integrate corneal topography, aberration analysis, choroidal thickness, and blood flow synchronous measurements to comprehensively analyze the spatiotemporal dynamics of this complex regulatory network.¹⁶ Additionally, the development of soft Ortho-k lenses (elastic modulus 33–535MPa) provides a new experimental tool for exploring the precise balance between biomechanical parameters and optical effects.¹⁷

In-Depth Analysis of Core Pathways and Evidence Level Assessment

Optical Defocus Pathway: From Theory to Quantitative Validation

The optical defocus theory is currently the most widely accepted and evidence-supported core hypothesized mechanism by which Ortho-k slows myopia progression. This theory posits that Ortho-k suppresses axial growth by inducing relatively myopic defocus signals in the peripheral retina through changes in the curvature of the anterior corneal surface.¹⁸ Research has confirmed that Ortho-k significantly alters higher-order aberrations, particularly that the increase in spherical aberration (approximately 0.1–0.3 μm) plays a key role in modulating defocus signals, enhancing the retina’s sensitivity to defocus signals.¹⁹ A meta-analysis of multiple randomized controlled trials (RCTs) shows that compared to single-vision spectacles, Ortho-k can achieve significantly better control of axial elongation in children with low to moderate myopia.the annual average axial growth of the eye in patients with myopia ranging from −1.00 to −4.00 D slows down by 0.15–0.25 mm (effect size d=0.62, 95% CI 0.51–0.73).¹¹ However, subgroup analysis indicates that patients with high myopia (>-6.00 D) exhibit significant differences in treatment efficacy, with a reduction of approximately 30% in axial control effectiveness, suggesting the presence of a “ceiling effect” In defocus signals.²⁰ It is noteworthy that the amount of defocus and the control effect are not simply linearly related; when peripheral defocus exceeds +2.75 D, the myopia control effect no longer increases with the amount of defocus.²¹ Indicating that apart from optical defocus, other pathways such as biomechanical stimulation and neural reflexes may be involved in regulation.

Corneal Biomechanics and Neural Reflex Pathways

Following Ortho-k wear, the corneal epithelium exhibits characteristic topographical thickness alterations: mild thinning in the central base curve zone and compensatory thickening in the mid-peripheral reverse curve zone, with gradual normalization toward the limbus. These changes emerge 7–14 days post-initiation and are fully reversible upon treatment cessation.²² BrdU labeling in rabbits demonstrated significantly higher mitotic activity of basal epithelial cells in the central compressed zone versus the mid-periphery, indicating mechanical stress-induced epithelial proliferation to maintain integrity. Enzyme histochemistry showed mild elevations in central lactate dehydrogenase and mid-peripheral alkaline phosphatase/β-glucuronidase activities, with normal glycogen distribution, confirming only adaptive metabolic changes without functional impairment.²² Finite element analysis (FEA) quantified regional corneal stress responses: target myopia reduction magnitude was the strongest determinant of central corneal stress (partial η²=0.9382), followed by corneal curvature (partial η²=0.5650) and thickness (partial η²=0.1975), while corneal curvature dominated peripheral stress (partial η²=0.5220).²³ High-fidelity simulations revealed peak corneal displacement and stress localized 2.4–2.5 mm from the apex, indicating the Ortho-k base curve mediates both central flattening and mid-peripheral steepening, revising the traditional view that mid-peripheral reshaping is solely reverse curve-dependent.²⁴

Biomechanical stimulation triggers multi-tiered neural reflexes via corneal mechanoreceptors, indirectly regulating ocular growth. Sustained stress from Ortho-k activates epithelial nerve terminals, which transmit signals via the trigeminal ophthalmic division to modulate ciliary muscle contractility. Clinical studies show 1-month Ortho-k significantly reduces accommodative lag, improves accommodative amplitude and facility, and lowers the AC/A ratio, mitigating retinal hyperopic defocus and retarding axial elongation.²⁵ Concurrently, neural signals propagate along the retina-choroid-sclera axis to regulate choroidal vasomotion and stromal remodeling. After 1 month of Ortho-k, total choroidal volume, vascular volume (CVV), and stromal volume (CSV) increase significantly, while the choroidal vascularity index (CVI) of the medium-vessel choroidal layer (MVCL) decreases, indicating asynchronous vascular-stromal remodeling.²⁶ A prospective cohort study confirmed that 1-month CVI changes in the MVCL temporal outer and nasal inner rings independently predict 1-year axial length (AL) elongation. A model combining these CVI changes with age and sex achieved an AUC of 0.905, identifying choroidal neurovascular responses as a critical intermediate in the transduction of biomechanical signals into myopia control effects.²⁶

Choroidal Changes and Retinal Signal Regulation

The phenomenon of choroidal thickening after wearing Ortho-k is one of the most consistent findings in research. In the short term (1 day to 1 month), the extent of choroidal thickening ranges from 10–30 μm, with the subfoveal area showing the most significant thickening (18.5±6.2 μm).²⁷ This thickening is related to increased blood flow, with laser doppler showing a 7.5% increase in choroidal vascular index (CVI) (p<0.01), possibly affecting the release of signaling molecules such as dopamine by improving retinal oxygen supply.²⁸ Animal experiments have confirmed that Ortho-k can upregulate retinal dopamine content (+38%) and its metabolite dopac levels (+27%).²⁹ However, the correlation between choroidal thickening and long-term axial control effectiveness remains controversial: Some studies have found that for every 50 μm increase in baseline CHT, annual axial growth decreases by 0.06 mm (β=−0.12, p=0.03).³⁰ While others found no significant association (p>0.15).³¹ This inconsistency may arise from differences in measurement methods (EDI-OCT vs SS-OCT) or individual variability in mechanochemical signal transduction. Notably, choroidal changes exhibit a circadian rhythm, with the daytime CHT fluctuation amplitude (8.3 μm) in Ortho-k wearers significantly greater than that of the control group (4.7 μm, p=0.012), suggesting that circadian pathways may be involved in regulation.³²

Mechanisms of Scleral Remodeling

The core pathological basis of axial myopia is scleral remodeling, which manifests as an imbalance between the synthesis and degradation of the extracellular matrix (ECM), decreased type I collagen content, and elevated matrix metalloproteinase-2 (MMP-2) activity.³³ The hypoxia-inducible factor-1α/hypoxia-inducible factor-2α (HIF-1α/HIF-2α) signaling pathway activated by scleral hypoxia is the key driving factor for this process.³³ The mechanisms by which Ortho-k controls myopia involve multidimensional regulation: the traditional theory holds that Ortho-k generates peripheral myopic defocus through corneal reshaping, thereby inhibiting axial elongation of the eyeball;³⁴ recent studies have confirmed that the mechanical pressure exerted by Ortho-k can be transmitted through the ocular wall, reducing the tension of the posterior ciliary muscle-lens complex and inducing an average short-term axial shortening of 0.028 mm within one week;³⁵ meanwhile, Ortho-k can significantly increase subfoveal choroidal thickness (SFChT), and the degree of thickening is negatively correlated with axial elongation, which inhibits abnormal scleral remodeling by ameliorating scleral hypoxia;³⁶ furthermore, magnetic resonance imaging (MRI) has revealed that 12 months of Ortho-k wear can transform the eyeball from a prolate shape to an oblate shape, with only mild elongation observed in regions beyond 20° of the periphery, thus restricting scleral expansion from a biomechanical perspective.³⁷ It should be noted that relevant studies on human scleral tissue are still very limited, and their specific mechanisms in the human body need further verification.

Mechanism Exploration of Individual Response Differences and Core Controversies

Phenotypes of Poor Clinical Response and Potential Influencing Factors

Ortho-k has shown significant inter-individual efficacy differences in delaying myopia progression, with some patients categorized as “non-responders” or “low responders” (low responders are usually defined as axial elongation ≥0.30 mm in the first year of treatment). Clinical research data indicate that this poor response phenotype may be associated with a range of baseline characteristics. Firstly, the initial degree of myopia in patients is a key factor. A retrospective study of Ortho-k wearers showed that in “low responders” With an axial growth of ≥0.30 mm in the first year of treatment, baseline myopia may influence subsequent treatment effects.³⁸ Secondly, age is another important variable; some studies have pointed out that older baseline age in children with poor Ortho-k response may be associated with less axial growth.³⁸ Additionally, pupil size, corneal morphology, and biomechanical properties (such as stiffness) may also affect the shaping effects of Ortho-k and the stability of optical defocus signals, thereby influencing myopia control outcomes. For example, one study explored the effects of different degrees of myopia on corneal biomechanical characteristics, suggesting that corneal stiffness may decrease with increasing myopia.³⁹ Baseline choroidal thickness, as an indicator reflecting ocular blood flow and metabolic status, has also been examined for its relationship with Ortho-k efficacy. The lag time of regulation represents an important visual function parameter in the occurrence and development of myopia, and its baseline levels may be related to individual sensitivity to optical interventions. Although existing studies have not systematically conducted subgroup analyses on all factors, trends indicate that these factors do not act independently but rather form a complex network influencing efficacy. For instance, when evaluating the effects of Ortho-k combined with low-concentration atropine on low responders, researchers simultaneously considered baseline age, treatment compliance, and other factors.^40,41 Therefore, identifying the phenotype of poor clinical response to Ortho-k and clarifying its potential influencing factors is the first step toward achieving precision intervention.

Controversies and Exploration at the Molecular and Genetic Levels

The differences in individual responses to Ortho-k efficacy may be deeply rooted in molecular and genetic levels, constituting one of the core controversies in this field. A key scientific question is: Do these differences partially arise from inherent sensitivity differences of target cells (such as scleral fibroblasts) to upstream regulatory signals (such as optically induced choroidal thickening, retinal dopamine release, etc).? Scleral fibroblasts are key executors of extracellular matrix remodeling in the posterior segment of the eye, and the balance of their proliferation, differentiation, collagen synthesis, and degradation directly determines the biomechanical properties of the sclera and the axial length.^35,42 If scleral fibroblasts from different individuals exhibit varied response thresholds to the same “stop growth” Signals, then even if they receive the same ortho-the effectiveness of k treatment in controlling the eye axis may vary significantly. This suggests that the “endpoint” Of myopia control efficacy may depend on the cell biological characteristics of scleral tissue.

To explore the genetic basis, researchers have begun to focus on the role of gene polymorphisms. Genetic variations associated with scleral collagen metabolism (such as collagen genes) and dopamine signaling pathways (such as dopamine receptor genes) may regulate individual responses to myopia interventions by affecting the stability of the extracellular matrix and the efficiency of neurotransmitter signaling.⁴³ Utilizing genome-wide association studies (GWAS) to identify efficacy-related genetic loci is a powerful method. Although there have not yet been specific GWAS reports targeting the efficacy of Ortho-k, this technology has been widely used to find genetic association loci for complex traits (such as myopia itself and responses to drugs or training).^44,45 In the future, by collecting genotype and phenotype data from a large number of Ortho-k responders and non-responders for GWAS analysis, key genetic variations related to efficacy are expected to be discovered.

The most promising cutting-edge direction to resolve this controversy is single-cell RNA sequencing (scRNA-seq) technology. This technology can reveal the heterogeneity of tissue cells and gene expression profiles at single-cell resolution.^46,47 By applying scRNA-seq technology, we can systematically compare the scleral and choroidal tissues of myopic eyes with normal eyes, as well as Ortho-k responders and non-responders. Through this comparison, we can identify cell subpopulations that are specifically activated or inhibited in responders (for example, specific functional subtypes of scleral fibroblasts or immune cells) and analyze their unique gene expression networks and signaling pathways. This not only directly validates the hypothesis of “differences in target cell sensitivity” But also identifies key molecular targets driving efficacy differences, thereby providing revolutionary insights for developing predictive biomarkers and new targeted therapies, advancing myopia control from empirical treatment to precision medicine.^48,49

Mechanistic Research Driven by AI and New Technologies and Personalized Interventions

Application of AI in Lens Personalization Design and Efficacy Prediction

In recent years, AI technology has shown tremendous potential in the personalized design and efficacy prediction of Ortho-k. Machine learning models have achieved precise optimization of lens design by integrating multi-source data, including corneal topography, biomechanical parameters measured by Corvis ST, refractive parameters, and patient basic information. Research has shown that AI models based on random forest algorithms perform excellently in analyzing corneal topography data, accurately identifying corneal morphological features, and providing key evidence for reverse geometric parameter design.⁵⁰ In terms of efficacy prediction, the latest research in 2024 shows that AI models can predict the trend of axial length changes within one month after wearing by analyzing pre-treatment corneal biomechanical responses (such as dynamic deformation amplitude) and topographic features, achieving an accuracy rate of 96%.⁵¹ This predictive ability provides important decision-making support for clinicians, helping to identify patient groups most likely to benefit from Ortho-k treatment. More importantly, AI technology establishes mathematical models of input-output relationships, offering new ideas for revealing the multi-pathway mechanistic network of myopia control. For example, by analyzing the correlation between different parameter combinations (such as corneal stiffness, central thickness, and peripheral defocus amount) and the effect of axial length growth inhibition, AI models can infer the relative contribution weights of each pathway.⁵² Another study developed a machine learning-based tool to predict key parameters such as the total lens diameter and base curve, with prediction accuracy superior to that of traditional manufacturers’ initial lens selectors.⁵³ However, current AI models still face challenges such as data heterogeneity and small sample overfitting, requiring more prospective multicenter studies to enhance generalization ability.

Integrated Analysis of Multimodal Imaging and Biomechanical Modeling

The combination of multimodal imaging technology and biomechanical modeling provides a revolutionary tool for visualizing changes in the intraocular microenvironment after Ortho-k intervention. By combining choroidal capillary density and blood flow index measured by Optical Coherence Tomography Angiography (OCTA) with dynamic lens-ciliary body structures evaluated by Ultrasound Biomicroscopy (UBM), and using Finite Element Analysis (FEA) to model in vivo biomechanical environmental changes, the multiple effects brought about by orthokeratology lenses can be quantified. For example, studies have assessed corneal biomechanics using devices such as Corvis ST and found that corneal stiffness parameters (eg., SP-A1) change after lens wear. These changes are associated with alterations in corneal morphology and thickness, rather than a true change in corneal tissue rigidity.⁵⁴ This integrated technology has irreplaceable value for visualizing and quantifying “pathway interactions”. For instance, OCTA studies have shown that local retinal vascular density increases after orthokeratology lens wear, particularly in the macular region.⁵⁵ Meanwhile, changes in choroidal blood flow are also closely related to axial elongation.⁵⁶ If spatial overlay analysis is performed between these regions of blood flow changes and the high-stress regions calculated by FEA, a high degree of overlap may be found between the two, thereby confirming the biological plausibility of “hemodynamic-mechanical” coupling. This multimodal integrated analysis is an important tool for future mechanistic research. It can reveal the interactions between different pathways and provide a basis for more precise personalized interventions.

Synergistic Mechanisms of Combination Therapy and Strategy Optimization

Synergistic Mechanism of Ortho-k and Low-Concentration Atropine

In clinical practice for myopia prevention and control, the combined use of Ortho-k and low-concentration atropine is becoming increasingly common, and its effect is not merely a simple “1+1=2” Addition, but rather contains complex synergistic or complementary mechanisms. Beyond single therapies, combination treatment aims to construct a more robust myopia delay network through multi-target and multi-pathway interventions. This synergy may stem from complementary action levels: Ortho-k primarily intervenes in the initial stages of myopia progression through its upstream optical defocus effects and corneal biomechanical remodeling, while low-concentration atropine may directly act on the terminal effect level of myopia regulation—the sclera. Studies have shown that atropine, in addition to its traditional accommodative paralysis effects, may also exert its effects through non-accommodation-dependent pathways, such as acting on M receptors on the sclera to directly regulate the proliferation of scleral fibroblasts and extracellular matrix remodeling, thereby counteracting axial length elongation.⁵⁷ This combination of “optical/biomechanical drive” And “biochemical receptor regulation” Constitutes a “multi-target” Intervention strategy aimed at different stages of myopia occurrence and development. Moreover, the regulatory effect of atropine on the ocular surface microenvironment should not be overlooked. It may create a more favorable corneal biomechanical and neural signaling environment for Ortho-k wear by affecting tear film stability and regulating the spectrum of ocular surface inflammatory factors. For example, a stable tear film helps maintain a more uniform contact and force transmission between the lens and cornea, while reduced ocular surface inflammation may optimize the integrity of the corneal epithelium and downstream biological signal transduction.⁵⁸ Although high-quality clinical studies directly targeting the effects of Ortho-k combined with atropine on tear cell cytokines and corneal epithelium are still being accumulated, drawing from research ideas in other fields of combination therapy and exploring the interactions between the two at the cellular and molecular levels will provide crucial new evidence to elucidate their synergistic mechanisms and guide more precise clinical combination scheme optimization.

Mechanistic Basis of Other Potential Combination Strategies

In addition to combination with low-concentration atropine, the potential synergistic mechanisms between Ortho-K and other interventions are also worthy of exploration. Multifocal soft contact lenses (MSCLs) provide myopic defocus stimulation across the entire visual field through their concentric or aspheric designs. Theoretically, they can compensate for the blind spots of Ortho-K defocus rings in the peripheral visual field, thereby comprehensively optimizing the distribution of defocus signals on the retina.⁵⁹ This “dual optical defocus” strategy aims to maximize the signal input for inhibiting axial elongation. However, there is currently limited clinical evidence on the efficacy of the combined use of Ortho-K and multifocal soft contact lenses, and there are concerns about the superimposed risk of corneal hypoxia. Since both are contact lenses, simultaneous wear will significantly reduce corneal oxygen supply and increase the risk of corneal complications.⁶⁰

Increased outdoor activity is a well-recognized effective method for delaying myopia progression, and its mechanism is mainly related to natural light stimulating the retina to release dopamine. As an inhibitory signal for axial growth, dopamine plays a key role in myopia control.⁶¹ The combination of Ortho-K and increased outdoor activity can theoretically form “optical-biochemical” dual signal inhibition: Ortho-K provides optical defocus signals, while natural light provides biochemical signals by upregulating dopamine levels, and the two synergistically inhibit axial elongation through different pathways. Indirect evidence supporting this synergistic effect comes from seasonal studies, which show that the myopia control effect in summer (with longer daylight hours and more outdoor activities) is better than that in winter, and the effect size of axial length control in high-insolation seasons can increase by approximately 15%.⁶¹ This combined strategy is safe and easy to implement, making it a highly promising component of future myopia management programs. However, the quantification of its specific synergistic effects and the optimal implementation model still require further research.

Clinical Translation Suggestions Based on Mechanistic Research

Efficacy Prediction and Patient Stratification Management

In the clinical application of Ortho-k, there is significant heterogeneity in patient responses to treatment, highlighting the need for establishing effective efficacy prediction and stratification management strategies. Drawing on other medical fields, such as oncology and immunotherapy, the integration of multidimensional clinical data to build risk stratification models has become central to precision medicine.⁶² For Ortho-k treatment, attempts could be made to integrate baseline parameters such as age, degree of myopia, axial length/corneal curvature radius ratio (AL/CR), corneal biomechanical indicators (eg., SP-A1), and subfoveal choroidal thickness (SFChT) to form a simple risk assessment model. A prospective cohort study found that a smaller Treatment Zone Diameter (TZD) is a protective factor against axial elongation. When TZD is less than 3.82 mm, annual axial length growth can be controlled to below 0.2 mm.⁶³ In addition, the characteristics of corneal refractive power distribution also have predictive value. Studies have confirmed that the corneal power exponent is significantly correlated with one-year axial length growth, and when combined with baseline age, it can explain 75.2% of the variation in axial length.⁶⁴

In terms of patient stratification, baseline characteristics such as age, myopic refractive error, and corneal morphology have a significant impact on treatment efficacy. For example, younger children (<12 years old) have faster axial length growth, while patients with higher baseline myopia and flatter corneal asphericity have a higher risk of treatment discontinuation.⁶⁵ Therefore, in clinical practice, indicators such as patient age, refractive status, corneal topography parameters (eg., e-value, treatment zone area), and higher-order aberrations should be comprehensively evaluated. Patients should be divided into high-, medium-, and low-response groups, and differentiated treatment goals and follow-up plans should be formulated. For patients with predicted poor efficacy, combination with low-concentration atropine or switching to a lens design with a smaller optical zone diameter can be considered to achieve an individualized myopia management strategy.

Personalized Fitting and Parameter Optimization

Mechanistic studies have revealed differences in myopia control efficacy among different lens designs, which provides a theoretical basis for personalized fitting. Studies on corneal refractive power distribution have shown that smaller and more aspheric treatment zones are beneficial for slowing axial elongation in children, and this effect is independent of baseline refractive error.⁶⁶ Specifically regarding lens parameters, the Back Optical Zone Diameter (BOZD) is a critical variable. Multiple studies have confirmed that CRT lenses with a 5.0 mm BOZD produce a smaller treatment zone area, higher mean Relative Corneal Refractive Power (mRCRP), and greater higher-order aberrations compared to those with a 6.0 mm BOZD, thereby reducing annual axial length growth by approximately 51.8%.⁶³

However, there are differences in efficacy among lenses of different brands and designs. A three-year retrospective study showed that lenses with VST (Vision Shaping Treatment) design (eg., Euclid) are superior to CRT design in delaying axial elongation.⁶⁷ In terms of fitting technology, Artificial Intelligence (AI)-assisted methods have shown great potential. AI models based on corneal topography results can more accurately predict the final parameters of CRT lenses, with a correlation coefficient of up to 0.958 (for base curve radius) between predicted values and actual ordered parameters, which is significantly superior to traditional methods.⁶⁸ Similarly, machine learning algorithms also outperform the traditional slide rule method in predicting the Reverse Zone Depth (RZD) and Landing Zone Angle (LZA) of lenses.⁶⁹ Therefore, during clinical fitting, based on the patient’s corneal morphology (eg., e-value, corneal astigmatism, corneal height difference at 8mm chord length) and combined with AI-assisted tools, priority should be given to lens designs that can produce smaller, more centered treatment zones with steeper refractive power gradients to achieve optimal myopia control efficacy.⁷⁰

Follow-Up Assessment and Plan Adjustment

An effective follow-up assessment system is the cornerstone of ensuring the long-term safety and effectiveness of Ortho-K. The assessment content should transcend traditional measurements of refractive error and axial length, delving into all aspects that ensure the normal “operation” of its optical and biological mechanisms. It is recommended to systematically increase the following assessment dimensions in routine follow-ups: first, corneal health status, evaluated through fluorescein staining to assess the integrity of the corneal epithelium, which is the primary defense against serious complications such as infectious keratitis.⁷¹ Second, the position and morphology of the defocus ring, accurately assessed using corneal topography to determine whether the treatment zone, reverse curve, and peripheral defocus ring are centered, symmetrical, and complete, form the structural basis for generating effective peripheral defocus to delay axial length growth.⁷² Third, visual quality can be assessed by measuring intraocular higher-order aberrations or collecting patients’ subjective reports of glare, halo, and other visual disturbances; poor visual quality may affect patient compliance and indicate potential issues with lens fitting. These multidimensional assessments collectively form a comprehensive follow-up network. Based on this, a reference for the timing of combined treatment decisions can be established. For patients using Ortho-K with a single axial length growth still >0.3 mm, it indicates that the intervention effect through the “corneal shaping-defocus” main pathway may have reached a plateau. At this time, early combination with low-concentration atropine treatment can be considered based on mechanisms.⁷³ Atropine primarily acts on M receptors in the retina and choroid, affecting the release of neurotransmitters such as dopamine, thus achieving synergistic intervention in axial length growth through a different pathway of “neurotransmitter regulation”. This “strong synergy” strategy based on mechanistic pathways aims to achieve synergistic effects rather than passively waiting for single treatments to completely fail before seeking remedies, reflecting a dynamic and precise clinical decision-making mindset (Figure 2).

Figure 2 Flowchart of dynamic follow-up assessment and personalized treatment plan adjustment for Ortho-K in clinical myopia control practice. The clinical management process starts with overnight wear of Ortho-K lenses, and routine follow-up and multi-dimensional assessment are the core of subsequent management: (1) Corneal Health Assessment: Evaluate corneal epithelial integrity via fluorescein sodium staining to ensure stable corneal tissue health; (2) Defocus Ring Evaluation: Detect the position and morphology of the defocus ring (including treatment zone, reverse arc zone, and peripheral defocus ring) to confirm centering, symmetry and optimal structural state of the defocus ring; (3) Visual Quality Assessment: Measure intraocular higher-order aberrations and collect patient-reported outcomes (e.g., presence of glare/halo) to evaluate subjective and objective visual quality. For patients with axial length growth ≤0.3 mm/year and improved visual quality, Ortho-K monotherapy is continued with routine follow-up. For patients with axial length growth >0.3 mm/year, early combination therapy with low-dose atropine (0.01%) is initiated to achieve pathway synergy, ultimately enhancing the overall myopia control efficacy. All decision nodes in the flowchart are based on the three-tier regulatory network mechanism of Ortho-K and clinical evidence-based medicine. Arrows in the flowchart indicate the direction of clinical decision-making and management processes.

Future Perspectives

As an effective intervention for controlling myopia in adolescents, Ortho-K has evolved beyond the early simplistic optical defocus hypothesis to a dynamic regulatory network that integrates multiple levels and pathways. This deepened understanding not only solidifies its clinical application foundation but also poses clear requirements for the innovation of future research paradigms and clinical practice strategies.

Confronted with this complex network, future mechanistic research needs to focus on unraveling the “black box.” On one hand, new technologies should be actively embraced. Using AI to analyze multimodal ocular biomechanical and imaging data (such as corneal stress distribution and blood flow in the choroidal capillary layer), combined with single-cell sequencing technology of scleral tissue, may establish more precise correlations between macro-characterization and micro-molecular events, thereby elucidating the specific details of pathway interactions and identifying key gene polymorphisms or biomarkers that affect efficacy. On the other hand, a deep integration of basic research and clinical practice must be promoted. This requires a fundamental transformation of the clinical translation pathway: fittings should shift from a rough model reliant on empirical formulas to a personalized lens design that integrates corneal morphology, biomechanical properties, and baseline risk of axial growth; efficacy assessments should expand from merely focusing on axial length as a lagging indicator to incorporating intermediate signals such as choroidal thickness and vascular index into a multidimensional dynamic monitoring system; intervention strategies should evolve from a “one-size-fits-all” fixed review cycle to individualized and dynamically adjustable plans based on early (eg., 1–3 months post-wearing) response prediction models, including promptly initiating combinations with low-concentration atropine and other methods where necessary, to achieve synergistic effects.

Globally, the standardized application of this three-tier regulatory model is expected to reduce the heterogeneity of Ortho-K clinical practice, improve the predictability of treatment efficacy, and promote the transformation of myopia control from empirical treatment to precision medicine. This will ultimately contribute to reducing the global burden of myopia and protecting the visual health of children and adolescents worldwide.

Conclusion

In summary, based on the latest research evidence from 2021 to 2025, this review systematically constructs the “initial driver-intermediate integration-terminal effect” three-tier regulatory network model of myopia control by orthokeratology, and clarifies the evidence weight of each pathway: the optical defocus and corneal biomechanical stimulation in the initial driver layer have the most sufficient evidence and are the core of initiating the regulatory cascade; the neurovascular regulation in the intermediate signal integration layer has relatively consistent evidence; while the molecular mechanism of terminal scleral remodeling is still mainly based on animal experimental evidence, and human research needs to be further deepened.

The mechanistic research on myopia control through Ortho-k has entered an AI-driven era of system biology. Balancing different research perspectives lies in recognizing that corneal shaping and optical defocus are merely the “triggers” that initiate this cascade reaction, while subsequent biomechanical and molecular pathways serve as the “amplifiers” and “regulators” that determine the intensity and duration of the response. The future direction lies in interdisciplinary collaboration to map a more refined individualized mechanistic landscape, thereby truly realizing the leap from “population effectiveness” to “individual precision,” ultimately enhancing the overall efficacy, safety, and predictability of myopia control, providing a more solid guarantee for the eye health of children and adolescents.