Why This Article Matters
Orthokeratology (Ortho-K) has long relied on the traditional “peripheral defocus” hypothesis, which frequently falls short of explaining the significant variability in individual clinical responses we observe in pediatric myopic patients. This review is highly relevant for the myopia experts community because it transitions our understanding from a purely optical model to a comprehensive “Three-Tier Regulatory Network”. It provides an integrated conceptual framework linking optical, biomechanical, neurovascular, and scleral mechanisms, offering a biologically plausible rationale for future personalized approaches to orthokeratology.
Summary
In this narrative review, Han et al. synthesize literature from 2021 to 2025 to elucidate the complex mechanisms underlying Ortho-K for myopia control. Moving beyond the optical defocus theory, the authors propose a hierarchical "Three-Tier Regulatory Network." The initial driver tier includes the mechanical stimulation of the cornea and the peripheral retinal defocus induced by the lens. These cues activate the intermediate signal integration tier, characterized by corneal nerve reflexes and retinal-choroidal structural and hemodynamic shifts (such as increased choroidal thickness and vascular density). These signals eventually converge on the terminal effect tier, triggering scleral collagen remodeling to inhibit axial elongation. The review discusses the interactions and proposed mechanism between optical defocus, corneal biomechanics, neurovascular regulation, and molecular signaling pathways, while also considering the evidence levels of each pathway.
The authors also explore problematic and difficult clinical situations in myopia management, such as individual response variations (e.g., “low responders”) and the potential genetic and cellular bases for these differences. Furthermore, the review highlights the emerging role of new technologies such as Artificial Intelligence (AI) in personalizing lens design based on corneal topography and biomechanics and outlines the synergistic mechanistic pathways of combining Ortho-K with low-concentration atropine.
Commentary
Limitations
As a narrative rather than systematic review, the weighting of the evidence remains somewhat subjective, as no formal assessment of study quality or risk of bias was performed. Much of the terminal effect data regarding scleral remodeling still relies heavily on animal models, and translating these cellular findings directly to human scleral tissue dynamics requires caution. Furthermore, while the synergistic mechanism of combined atropine and Ortho-K is well-argued theoretically, robust long-term clinical trial data in diverse European cohorts is still maturing.
Clinical relevance
The expansion of the concept of orthokeratology from a predominantly optical intervention to a complex cascade of biochemical and neurovascular remodeling provides clinicians with a broader framework for interpreting treatment response and understanding the biological basis of myopia control. Another major challenge often highlighted by practitioners is the management of "poor responders" to orthokeratology. This article directly addresses this clinical hurdle by mapping out why these variations occur – shifting the focus from patient compliance to inherent neurovascular, biomechanical, or genetic differences. For those practitioners managing high-volume pediatric clinics, the proposed dynamic follow-up flowchart (which incorporates objective visual quality and early combination therapy) provides a useful conceptual framework for individualized follow-up.
Comparison with existing evidence
The review is broadly consistent with the rigorous standards set by recent International Myopia Institute (IMI) reports, while proposing a biological rationale for early combination therapy with low-dose atropine in patients showing rapid axial elongation, although this strategy still requires prospective clinical validation.
Unanswered questions
Future research must prioritize identifying accessible and validated clinical biomarkers – perhaps via OCTA choroidal metrics, corneal topography and intraocular higher-order aberrations assessment – that can predict individual responses before initiating treatment, allowing us to define the optimal timing for combination therapies tailored to specific biomechanical phenotypes and correct integration of those biomarkers with tools such growth curves and AI-integrated prediction models.
Key Take-Home Messages
- Ortho-K efficacy is driven by a multi-level network: initial optical/mechanical drivers, intermediate neurovascular integration, and terminal scleral remodeling.
- Individual variability in treatment response is likely rooted in baseline biomechanical, genetic, and choroidal vascular differences, necessitating personalized risk stratification.
- AI models integrating corneal topography and biomechanics are emerging as promising tools for predicting efficacy and optimizing lens parameters (e.g., utilizing smaller back optic zone diameters for enhanced control).
- Early combination therapy with low-dose atropine represents a biologically plausible strategy for poor responders, although prospective clinical validation is still needed.
Conflict of Interest Statement
The author declares no conflict of interest related to this article.
Strengths
The primary strength of this review is its cohesive conceptual framework. By organizing the mechanisms into a three-tier network, Han et al. provide an integrated framework encompassing optical, biomechanical, and neurovascular theories. The integration clinical imaging modalities such as OCT angiography and corneal topography with cutting-edge concepts like AI-driven lens optimization and advanced genetic testing like single-cell RNA sequencing elevates the discourse from empirical observation to precision medicine.