Biomechanical contributions to cataract development and implications for treatment strategies

Abstract

Background

Cataracts remain the leading cause of blindness worldwide, primarily due to the progressive opacification of the crystalline lens. While surgical removal is the only definitive treatment, no pharmacological therapies have proven effective in reversing or significantly delaying disease progression.

Main text

Alterations in the biomechanical properties of the lens and their role in cataract formation. Biomechanics plays a crucial role in maintaining the normal structure and function of living organisms. As a mechanical material, the lens is subject to long-term regulation by the ciliary body, with its mechanical deformability being closely linked to the function of visual accommodation. Additionally, with age, the mechanical properties of the lens and its components undergo gradual changes, resulting in increased stiffness, reduced elasticity, and impaired accommodative capacity. These changes highlight the potential role of lens biomechanics in the onset and progression of cataracts. Understanding the patterns of biomechanical alterations during cataract formation may improve early diagnosis, enable better prediction of disease progression, optimize surgical approaches, and contribute to the development of non-surgical interventions, including pharmacological therapies and novel intraocular lens designs.

Conclusions

Focusing on biomechanical changes during the onset and progression of cataracts is essential for the development of new diagnostic and therapeutic strategies. This paper provides an overview of the anatomical structure of the lens, reviews existing literature on age-related biomechanical changes in the lens and their direct link to cataract pathogenesis, and discusses future research directions and applications of biomechanics in cataract research.

1. Introduction

Cataract is an ocular disease characterized by the progressive loss of lens transparency, resulting in blurred vision and limitations in daily activities.¹ As the leading cause of irreversible visual impairment and blindness globally, cataracts present a significant public health threat.² According to data released by the World Health Organization (WHO) in 2023, approximately 95 million people worldwide experience moderate-to-severe visual impairment due to cataracts, accounting for one-third of all cases of vision impairment cases. Additionally, around 20 million individuals are blind as a result of cataracts, representing over half of global blindness cases. Notably, more than 80% of these cases are found in individuals aged 50 and older.³ The prevalence of age-related cataracts strongly correlates with advancing age.

Cataracts can be classified based on the anatomical location of lens opacification into cortical cataracts, nuclear cataracts, and posterior subcapsular cataracts (PSC). The pathogenesis of cataracts involves the interplay of multiple factors. Research suggests that oxidative stress-incuded free radical damage serves as a common pathway underlying various cataractogenic factors.⁴ Additionally, dysregulated apoptosis of lens epithelial cells (LECs) and aggregation of structural proteins play critical roles in cataract formation.^5,6 Currently, surgical intervention remains the only established treatment for cataracts.⁷ While this technique has reached a relatively mature stage, postoperative complications, such as posterior capsule opacification (PCO) and insufficient accommodative function of intraocular lenses (IOLs),^1,2 continue to occur. Despite ongoing investigations into antioxidants and molecular chaperone modulators, no FDA-approved drugs currently exist that effectively reverse or delay cataract progression.³

The lens is a crucial component of the eye’ s refractive system, responsible for focusing light onto the retina to produce clear images. Its tissue transparency, refractive index, and biomechanical properties are essential for maintaining the eye’ s focusing function. The lens primarily adjusts its shape to accommodate visual demands at varying distances while maintaining high transparency to ensure efficient light transmission. However, with aging and the accumulation of pathological factors, the mechanical properties of the lens gradually undergo degenerative changes, including a decrease in elastic modulus and an increase in stiffness.⁸ These alterations not only impair accommodative ability but may also reduce transparency, contributing to the formation and progression of cataracts.^9,10 This review explores the biomechanical properties of the lens and the dynamic changes that occur during cataract formation, offering new insights for the diagnosis and treatment of cataracts.

2. Lens structure

The ocular lens is a transparent, biconvex ellipsoid located in the anterior segment of the eye. It consists of three main anatomical components: the lens capsule, a monolayer of epithelial cells, and concentrically arranged lens fibers. The lens is suspended in its anatomical position along the visual axis by zonular fibers, which connect it to the ciliary body and maintain tension, as shown in Fig. 1.

Fig. 1.

Schematic representation of ocular lens anatomy and positioning: (A) Anatomical location of the lens within the anterior segment of the eye. (B) Detailed structural composition showing: lens capsule, lens epithelium cells, lens fibers, and zonular fibers.

The lens capsule is an acellular, elastic basement membrane that fully encases the lens, exhibiting elasticity, stiffness, and toughness.^11,12 Based on its morphological structure, it can be divided into three parts: the anterior lens capsule, the posterior lens capsule, and the equatorial capsule, located at the junction of the anterior and posterior regions.¹³ Biochemically, the capsule is primarily composed of type IV collagen and laminin, with additional extracellular matrix (ECM) components, Including nidogen, heparan sulfate proteoglycans (HSPG), and SPARC (secreted protein acidic and rich in cysteine), which together maintain its structural integrity.14, 15, 16, 17 The lens capsule exhibits regional variations in thickness, being thickest in the midperipheral anterior region (21 ​μm), intermediate at the anterior pole (13 ​μm), and thinnest at the posterior pole (4 ​μm).¹⁸

LECs, the only mitotically active cell population in the lens, line the inner surface of the anterior lens capsule. They migrate toward the equatorial region, where they proliferate and differentiate into fiber cells to support lens growth.¹⁹

Fiber cells differentiate from lens epithelium through nuclear and organelle degradation. These cells undergo significant elongation and develop a highly ordered, lamellar architecture, resembling onion-skin layers.²⁰ Structurally, the lens consists of two distinct layers: the cortex and the nucleus. The outer cortical region contains newly formed fiber cells arranged in regular arrays with high water content, while the central nuclear region is composed of densely packed, aged fiber cells that progressively harden due to dehydration and age-related compaction.²¹

The zonular apparatus consists of tubular fibrillar structures that connect the ciliary body to the crystalline lens. These oriented fibers, originating from the vitreous base, form loosely organized fiber bundles that undergo coordinated tension modulation during ciliary muscle contraction. The zonular apparatus is essential for lens suspension and accommodation, and its fibers are generally divided into anterior, posterior, and equatorial groups.²² The anterior zonules, arising from the ciliary processes, insert into the anterior lens capsule and are essential for suspending the lens and modulating its shape during accommodation.²² The posterior zonules extend along the vitreous surface before attaching to the posterior capsule, helping stabilize the vitreolenticular interface and coordinate lens–vitreous movement.22, 23, 24 The equatorial zonules anchor directly into the lens equator, maintaining its position on the visual axis and transmitting balanced tension for precise focusing.²⁵

3. Lens biomechanics properties

To understand the biomechanical behavior of the crystalline lens, it is important to begin with some fundamental mechanical concepts. When subjected to external forces, the lens undergoes deformation, which can be described in terms of stress (the internal force per unit area) and strain (the relative change in dimension). Importantly, the functional significance of this deformation lies in the ability of the ciliary muscle, through the zonular fibers, to exert tension on the lens, thereby altering its curvature. This dynamic adjustment effectively regulates the focal length of the lens, enabling the eye to achieve clear imaging across varying distances.²⁶

Elasticity refers to the ability of a material to recover its original form once the load is removed, and several parameters are commonly used to quantify this property. Young's modulus (E) characterizes the stiffness of a material under uniaxial loading, while the shear modulus (G) reflects resistance to shear deformation. Poisson's ratio (ν) describes the coupling between axial loading and transverse contraction, and in the crystalline lens, it typically approaches the theoretical limit of incompressibility (≈0.5).²⁷ In addition, the bulk modulus (K) measures resistance to uniform compression, whereas the longitudinal modulus (M) reflects stiffness under uniaxial tension or compression. Fig. 2 illustrates the measurement framework for these elastic moduli.

Fig. 2.

Measurement diagram showing loading directions (F) and deformation for Young’ s modulus, Shear modulus, Longitudinal modulus, and Bulk modulus determination.

Together, these elastic constants determine how the lens responds to forces transmitted through the capsule and fiber network, which is essential for both its accommodative function and the maintenance of transparency. The lens is not a perfectly homogeneous or isotropic structure; instead, its layered architecture and anisotropy give rise to more complex mechanical behavior.²⁸

3.1. Techniques of lens biomechanics

Over the past decade, the study of lens biomechanics has evolved considerably, moving from conventional in vitro testing to more sophisticated, non-invasive in vivo approaches. Traditional methodologies—such as rotational analysis,²⁹ micro/nano-indentation,³⁰ uniaxial compression,³¹ and acoustic interferometry³²—provided the foundational understanding of bulk and regional elastic properties of the crystalline lens. While valuable, these approaches are inherently limited by their destructive nature and inability to capture dynamic changes under physiological conditions.

Recent progress has been driven by breakthroughs in advanced imaging and integrative modeling. Among them, Brillouin light scattering microscopy has emerged as a pivotal technique, enabling non-destructive, three-dimensional mapping of lens stiffness. This approach has revealed age-dependent regional disparities in stiffness.³³ Such spatial variability provides new biomechanical insights into the early mechanisms of cataract formation. Moreover, optical coherence tomography (OCT) elastography has progressed from experimental validation to clinical application, making it possible to characterize lens biomechanics in vivo under non-contact conditions. Studies have shown that Optical Coherence Elastography (OCE) can reveal age-related regional stiffness variations, providing new biomechanical insights into the early mechanisms of cataract formation.³⁴ In vitro modeling also offers key insights: phase-sensitive OCE combined with acoustic radiation force (ARF) revealed that the lens capsule significantly amplifies viscoelastic responses, underscoring the necessity of considering capsule–cortex coupling when discussing lens stiffening in cataract formation.³⁵ Importantly, a recent bibliometric analysis highlighted the rapid growth of artificial intelligence applications in ophthalmic research over the past five years. Integrating AI with OCT elastography is expected to enhance data processing and automated analysis, accelerating the translation of biomechanical parameters into cataract prediction and personalized treatment strategies.³⁶ Beyond imaging approaches, atomic force microscopy (AFM) has provided new insights into the microscale biomechanics of the lens capsule. Recent findings indicate an age-related decline in the stiffness ratio between the inner and outer capsule surfaces, suggesting structural remodeling of its biomechanical gradient during aging.^37,38 Meanwhile, finite element analysis (FEA) has advanced our understanding of lens deformation under physiological loading, with recent models showing how changes in zonular tension affect lens curvature, thickness, and optical power—highlighting the role of zonular mechanics in lens biomechanics.³⁹ Table 1 summarizes the main in vitro and in vivo approaches for assessing lens biomechanics.

Table 1.

In vitro and in vivo approaches for assessing lens biomechanics.

Method	Category	Spatial Resolution	Primary Parameters
Rotational Analysis	In vitro	∼100 ​μm	Shear modulus
Micro-indentation	In vitro	50 ​μm	Regional elastic modulus
Uniaxial Compression	In vitro	Bulk measurement	Young's modulus
Bubble Acoustics	In vitro	200 ​μm	Viscoelasticity
Brillouin Scattering	In vivo	10 ​μm	Longitudinal modulus
OCT	In vivo	15 ​μm	Strain distribution
AFM	In vitro	<1 ​μm	Surface elastic modulus
FEA	Computational	Adjustable mesh size	Stress/strain distribution

3.2. Lens and biomechanics

The biomechanical properties of the crystalline lens undergo significant age-dependent changes, which have been experimentally validated across multiple species.^26,40 Gang Shi et al. reported that elastic wave velocity increased from 1.21 ​± ​0.04 ​m/s in young lenses to 1.85 ​± ​0.05 ​m/s in mature lenses, corresponding to an elevation in Young’ s modulus from 5.97 ​± ​0.89 ​kPa to 13.45 ​± ​0.74 ​kPa.²⁶ Similar trends were observed in rabbit⁴¹ and murine models,⁸ further emphasizing the evolutionary conservation of lens biomechanical aging.

However, these age-dependent changes are region-specific, with striking differences between the cortex and nucleus, as summarized in Table 2. Heys et al. observed that the nucleus stiffens by approximately 930-fold with age (from 25.7 ​Pa to 23,954 ​Pa), whereas the cortex stiffens by only 53-fold (from 48.5 ​Pa to 2577 ​Pa).³⁰ Notably, they identified a stiffness crossover point at 30–35 years, when nuclear stiffening surpasses cortical stiffening. Wilde et al. further demonstrated that, although the cortex is stiffer in young lenses, the nucleus undergoes more rapid hardening, becoming mechanically dominant after age 45.⁴² Comparable findings in ovine lenses confirm the evolutionary conservation of this pattern.⁴³ Collectively, these findings strongly suggest that the progressive breakdown of the cortico-nuclear stiffness gradient plays a critical role in cataract formation.

Table 2.

Biomechanical properties comparison: Cortex and nucleus.

Characteristic	Cortex	Nucleus
Young's Modulus	0.05–0.08 ​kPa (Youth)	0.05–0.08 ​kPa (Youth)
	2–5 ​kPa (>60 ​yrs)	18–25 ​kPa (>60 ​yrs)
Hardening Pattern	Linear increase, dominant before age 40	Accelerated increase after 40 ​yrs, dominant after 50 ​yrs
Viscoelastic Properties	High water content, good compliance	Reduced water content, decreased viscoelasticity
Spatial Distribution	Predominantly peripheral, uniform thickness (20–30 ​μm under ALC)	Centrally concentrated, forms mechanical discontinuity gradient at nucleus-cortex interface
Age-Related Changes (Annual hardening rate)	+0.08 ​MPa/decade after 30 ​yrs	+0.12 MPa/decade after 30 ​yrs
Structural Basis	Regular hexagonal fiber cells Dependent on F-actin and gap junction proteins	Fiber cell dehydration/densification Increased protein crosslinking (disulfide bonds, AGEs)
Pathological effects (cataract)	Stress concentration leading to fiber breakage and water cleft formation	Increased hardness causing enhanced light scattering and reduced transparency

Beyond cataractogenesis, several studies have underscored the critical role of lens biomechanics in presbyopia. Van de Sompel et al. established an early quantitative framework linking age-related biomechanical remodeling to the progressive decline in accommodative amplitude.⁴⁴ More recently, Schumacher et al., using OCT-based in vivo elastography, demonstrated a marked reduction in nuclear strain after the age of 50, providing direct imaging evidence that regional stiffening is a primary mechanism of presbyopia.⁴⁵ Krueger et al. emphasized that accommodative function depends not only on ciliary muscle dynamics but is also fundamentally modulated by the biomechanical properties of the lens, offering an integrative perspective on how age-related stiffening compromises accommodation.⁴⁶

Lens biomechanics also have profound optical consequences. Cheng et al. demonstrated that age-related biomechanical remodeling of the lens is not only central to cataractogenesis and presbyopia but also directly degrades the optical performance of the lens.⁴⁰ Wang et al. advanced this understanding by developing a finite element-based biomechanical model that explored how changes in the mechanical properties of the lens affect its optical performance. This study highlighted the influence of lens deformation on refractive power and examined the crucial interactions between optical and mechanical properties.⁴⁷ Rao et al. further reinforced that higher-order aberrations and intraocular scatter are strongly modulated by biomechanical changes, establishing the mechanistic link between lens stiffness and visual quality.⁴⁸ Collectively, these studies underscore that biomechanical aging of the crystalline lens drives visual decline through both structural and optical pathways.

3.3. Lens capsule and biomechanics

The lens capsule, the thickest basement membrane in humans, exhibits remarkable elastic properties. Ultrastructural studies using electron microscopy reveal a cross-linked network of collagen fibers. This unique microarchitecture imparts viscoelastic characteristics, including substantial extensibility and anisotropic mechanical behavior,^49,50 providing the structural basis for lens biomechanical regulation.

The lens capsule displays marked spatial heterogeneity, with the anterior capsule (4–30 ​μm) and equatorial region (>25 ​μm) significantly thicker than the posterior capsule (2–9 ​μm), reflecting distinct graded material properties.^51,52 This thickness distribution, combined with region-specific variations in mechanical modulus, optimally distributes stress during lens deformation, maintaining central stability while minimizing peripheral warping. This characteristic has been consistently confirmed by various studies employing diverse methods to measure the lens capsule thickness.^51,52

Age-related biomechanical changes are a key focus in capsular research. Krag et al. documented a progressive increase in capsular thickness at an annual rate of 1.2%, which levels off after age 75.⁵³ Avetisov and colleagues found that the stiffness of the outer surface of the capsule increases with age, while the inner surface exhibits a decreasing trend, showing an opposing pattern. However, regardless of age, the stiffness of the inner surface remains significantly greater than that of the outer surface.^37,38 Halfter et al. confirmed this finding through comparative AFM nanomechanical analysis of the corneal Descemet's membrane and anterior lens capsule.⁵⁴ Studies suggest that this age-related stiffening may result from an increase collagen in cross-linking and enhanced accumulation of products from non-enzymatic glycation reactions.⁵⁵ Paradoxically, this stiffening is accompanied by reduced ultimate elongation and fracture toughness, reflecting the characteristic "stiffer but less compliant" mechanical phenotype of aging.

3.4. Lens zonule and biomechanics

Zonular fibers, while primarily serving as the main suspensory structure of the crystalline lens, are essential for lens stability and biomechanical regulation. Increasing evidence shows that changes in their biomechanical properties contribute to cataract formation. Advances in research now recognize zonular biomechanics as an active factor that influences stress distribution within the lens, affecting its transparency and metabolic balance.²²

Zonular fibers are composed mainly of microfibrils rich in fibrillin, whose molecular integrity defines their tensile strength and elasticity. Genetic mutations such as FBN1 defects weaken these fibers, compromising lens stability and leading to asymmetric stress and capsular folds, which disrupt cortical fiber arrangement and impair optical properties, promoting cataract formation.⁵⁶ Furthermore, based on studies in the Chinese population, Zhang et al. introduced the concept of "balance tension" in the ciliary zonule, showing that uneven zonular tension can cause lens displacement and morphological changes.⁵⁷ These alterations affect the optical properties of the lens, disrupt stress distribution, and promote degeneration and opacification. This suggests that cataract development results not only from metabolic or age-related degeneration but also from changes in the biomechanical environment of the zonule.

In recent years, imaging and computational modeling studies have revealed the potential contribution of zonular insertion angles and force vector distribution to cataract development. Finite element models demonstrate that both the angle of insertion and the magnitude of tension within individual fiber bundles significantly influence lens curvature and its ability to deform. When the zonular insertion angle is abnormal, the deformation pathway of the lens becomes restricted, causing the capsule and cortical regions to be subjected to sustained non-physiological loading, providing a biomechanical basis for cataract formation.⁵⁸ Moreover, increasing attention has been directed toward the synergistic interaction between the ciliary zonule and the vitreous interface. Scarfone et al. reported that this interaction plays a critical role in maintaining capsular stability during and after surgery.⁵⁹ Disruption of this balance can lead to postoperative capsular contraction and wrinkling of the capsule, further predisposing to secondary complications following cataract surgery.

4. Cataract associated with lens biomechanical properties

The biomechanical properties of the crystalline lens undergo significant age-related changes that are closely linked to cataract formation and progression. Detailed data are presented in Table 3. Studies show that lens stiffness and elasticity are regulated by multiple factors at the tissue, cellular, and molecular levels.⁹ At the tissue level, the integrity of the lens capsule is crucial for maintaining mechanical properties, with its elasticity decreasing with age.⁹ Choi et al. demonstrated through AFM that the Young’ s modulus of the anterior lens capsule in cataract patients was significantly higher than in controls, highlighting a strong correlation between capsular stiffening and cataractogenesis.¹⁰ This reduced capsular elasticity disrupts the dynamic relationship between the lens and capsule, leading to diminished accommodative ability and abnormal protein accumulation.²⁶ At the cellular level, age-related alterations occur in the interlocking structure of lens fiber cells and their suture patterns. Cheng et al. observed that while young mouse lenses exhibit regularly arranged hexagonal fiber cells, this organization becomes progressively disordered after 12 months, with abnormal compression bands appearing in the cortical region by 24 months. These structural changes directly contribute to light scattering and cortical cataract formation.⁴⁰ At the molecular level, Cheng identified disulfide bond formation and protein cross-linking as key drivers of lens stiffening.⁹ The accumulation of advanced glycation end-products (AGEs) is another critical mechanism, increasing matrix stiffness through covalent collagen cross-linking.⁴⁰ These molecular changes ultimately lead to nuclear sclerosis and loss of accommodative ability. Quantitative studies confirm a significant age-dependent increase in lens Young's modulus.

Table 3.

Age-dependent variations in lens Young's modulus and cataract development.

	Tissue type	Sample	Measurement	Young's ​modulus ​(kPa)	Reference
Age-related	Lens	human	OCE	12.28 ​± ​0.87 (18–32 years) 18.59 ​± ​1.45 (60–75 years)	26
	capsule	human	OCE	6.33 ​± ​0.36 (18–32 years) 13.33 ​± ​0.74 (60–75 years)	26
	Lens	Rabbit	OCE	7.74 ​± ​1.56 (2–3 months) 15.15 ​± ​4.52 (over 6 months)	41
	Lens	mouse	AFM	10.4 ​± ​4.2 (10 weeks) 23.2 ​± ​9.5 (38 weeks)	8
	Lens	Rabbit	ARF-USE	5.82 ​± ​1.75 (60 days) 16.07 ​± ​4.05 (150 days)	74
Cataract	Lens	porcine	SD-OCT	11.3 ​± ​3.4 (control) 21.8 ​± ​7.8 (cataract)	60
	Lens	porcine	OCE	5.62 ​± ​1.24 (control) 11.40 ​± ​2.68 (cataract)	61

These biomechanical alterations were closely linked to nuclear volume expansion and compression of cortical fiber cells. Further supporting this relationship, Cheng and coworkers found that 30-month-old mouse lenses exhibited only 50% of the axial and equatorial compressive strain observed in 2-month-old lenses, accompanied by a significant increase in nuclear volume. These changes collectively contribute to accommodative decline and cataract formation.⁴⁰ Beyond natural aging, experimental models provide additional insights. Cold cataract models further demonstrate the dynamic relationship between lens opacity and stiffness—Young's modulus increased from 11.3 ​kPa in the normal state to 21.8 ​kPa during opacification, returning to baseline upon reversal, suggesting protein aggregation (e.g., γ-crystallin precipitation) directly regulates mechanical properties.⁶⁰ Similarly, Chen et al.⁶¹ and Li et al.⁶² also confirmed the increase in the Young's modulus of the lens by using cold-induced cataract models.

In summary, age-related lens biomechanical changes primarily manifest as nuclear sclerosis and loss of capsular elasticity, promoting cataract formation through distinct mechanisms: nuclear sclerosis driven by protein cross-linking and nuclear volume expansion leads to presbyopia and nuclear cataracts, while capsular and cortical fiber cell disorganization causes cortical cataracts.

4.1. Nuclear cataract

The hallmark biomechanical feature of nuclear cataract is a significant increase in the elastic modulus of the lens nucleus. Studies in animal models demonstrate this phenomenon clearly. In a sodium selenite-induced rat model of nuclear cataract, it was found that as cataracts progressed, the hardness of the nucleus gradually increased, with the nuclear region exhibiting a significantly greater increase than the cortex. Moreover, stiffness showed a strong correlation with hardness in both regions of the lens.⁶³. This suggests that protein cross-linking and water loss in the nucleus are the primary drivers of hardening. Consistent with this, cold-induced cataract models in porcine lenses, demonstrate a near-doubling of Young's modulus, from 11.3 ​kPa to 21.8 ​kPa, reinforcing the positive correlation between lens stiffness and opacification.⁶⁰ This mechanical change is closely associated with the aggregation of nuclear proteins (e.g., α- and β-crystallin) into insoluble complexes, where intermolecular cross-linking leads to structural densification.^64,65 Notably, the elevation in nuclear stiffness correlates with increased light scattering and reduced transparency. Czygan et al. conducted a combined mechanical-optical analysis and found that nuclear transmittance negatively correlates with destructive force, while nuclear coloration (reflecting chromophore accumulation) positively correlates with stiffness. These observations indicate that protein aggregation not only enhances mechanical rigidity but also promotes light scattering through the formation of high-molecular-weight complexes.⁶⁵ The "transport barrier hypothesis" proposed by McGinty further explains the underlying mechanism: age-related barriers at the nuclear-cortical interface hinder the entry of antioxidants (e.g., glutathione) into the nucleus, leading to oxidative damage, protein cross-linking, and the generation of tryptophan derivatives, ultimately contributing to both nuclear hardening and opacification.⁶⁴

These biomechanical alterations in nuclear cataract have significant clinical implications. For instance, ultrastructural studies of the anterior capsule reveal that, although capsular thickness does not differ between intumescent and nuclear cataracts, the latter exhibits disorganized basal membrane fiber bundles and lamellar disruptions, which may increase the risk of intraoperative capsular tears.⁶⁶ Additionally, Scheimpflug densitometry demonstrates a strong correlation between nuclear density and higher-order aberrations (HOA), suggesting that mechanical-optical parameters could serve as early diagnostic markers.⁶⁷ However, studies in dystrophin-deficient models show the opposite trend—lens stiffness decreases significantly (Young's modulus reduced by 16%–20%) and exhibits an inverse correlation with age.⁶⁸ This suggests that different etiologies may lead to heterogeneous biomechanical behaviors in nuclear cataracts, highlighting the need for further investigation into the role of specific protein complexes in modulating the mechanical-optical relationship.

4.2. Cortical cataract

The biomechanical behavior of cortical cataracts is primarily characterized by mechanical instability at the capsule-cortex interface, a pathological process that ultimately leads to lens fiber breakage and the formation of characteristic wedge-shaped opacities. From a biomechanical perspective, this instability exhibits distinct spatial specificity. FEM reveals that mechanical stress during lens accommodation is distributed non-uniformly, with significant concentration in the anterior and posterior equatorial cortical regions. Notably, this stress concentration zone closely corresponds with the clinically observed predilection site for cortical opacities,⁶⁹ providing crucial biomechanical insights into the pathogenesis of cortical cataracts. In vitro accommodation simulation experiments further validate this mechanical mechanism. Studies demonstrate that aged cortical cataract lenses exhibit significant structural vulnerability at the nucleus-cortex interface (approximately 520 ​μm depth), where mechanical rupture frequently occurs. In contrast, younger lenses maintain structural integrity under identical conditions due to superior nucleus-cortex mechanical compatibility.⁷⁰ This age-dependent behavioral difference stems from dynamic changes in the internal stiffness gradient of the lens: while young lenses exhibit relatively higher cortical stiffness than nuclear stiffness, the nucleus undergoes accelerated hardening after age 50, eventually creating a significant mechanical discontinuity. This reversed stiffness gradient generates localized shear stress during accommodation, serving as a key mechanical trigger for cortical cataract formation.⁷¹

At the molecular level, cortical cataract development involves intricate mechanotransduction pathways. Emerging evidence highlights that mechanical stress directly induces cortical fiber damage through PIEZO1-mediated calcium signaling and cellular senescence pathways. In vitro studies applying a 6% tensile strain to human LECs confirm significant upregulation of PIEZO1, which subsequently activates multiple downstream pathways, including SMAD, NF-κB, and p38MAPK. These pathways ultimately drive the abnormal accumulation of senescence markers,⁶⁹ mechanistically linking mechanical stress with cellular aging in cataractogenesis. Equally important to lens biomechanics is the maintenance of intercellular junction stability. Research using Arvcf knockout mouse models reveals that disruption of adherens junctions (AJs), particularly through disintegration of the N-cadherin complex, leads to disordered fiber interlocking, abnormal lens hardening, and compromised stress relaxation, ultimately progressing to typical cortical cataracts.⁷²

These molecular and cellular alterations collectively produce two major pathological consequences: First, sustained mechanical stress causes deep cortical fibers to develop characteristic folding, undulating deformations, and "water cleft" formations, with fracture termini often sealed by membranous structures amidst surrounding fiber disarray.⁷¹ Second, stress-induced fiber damage promotes crystallin misfolding and abnormal aggregation, increasing light scattering, which clinically manifest as sectoral or wedge-shaped opacities. Importantly, these structural changes often exhibit regional distribution patterns, likely reflecting the inherent heterogeneity of intra-lenticular stress distribution.

4.3. Posterior subcapsular cataracts

PSC is an important subtype with distinct biomechanical characteristics. Although direct studies from a stress distribution perspective are lacking, evidence suggests that PSC development is closely linked to the biomechanical environment at the posterior capsule–cortex interface. Stress concentration and local stiffness disparities in this region can trigger abnormal proliferation and migration of LECs, leading to epithelial–mesenchymal transition (EMT), Wedl cell formation, and subsequent matrix remodeling.⁷³ Unlike nuclear cataracts driven mainly by age-related nuclear sclerosis, PSC emphasizes the role of localized biomechanical imbalance at the posterior pole, with mechanisms also distinct from cortical cataracts. Major risk factors—including aging, diabetes, and ionizing radiation—induce oxidative stress and disrupt ionic homeostasis, resulting in LEC dysfunction.⁷³ With disease progression, chronic inflammation and premature aging processes further contribute to the development of PSC's characteristic opacities. Thus, localized mechanical stress abnormalities and impaired cell–matrix interactions are considered key drivers of PSC pathogenesis.

5. Clinical applications of lens biomechanical properties

5.1. Clinical diagnosis

Accurate assessment of lens biomechanical properties is crucial for the early diagnosis of cataracts, predicting disease progression, and optimizing surgical strategies.²⁶ In recent years, various non-invasive imaging techniques have been employed for quantitative analysis of lens mechanical properties, including ultrasound elastography (USE), Brillouin microscopy, and OCE. These high-resolution, high-sensitivity techniques offer clinicians robust tools for measuring biomechanical parameters.

Acoustic radiation force-based ultrasound elastography (ARF-USE) shows promising clinical applications. This technique quantitatively evaluates lens stiffness by measuring shear wave velocity, offering advantages such as deep tissue penetration and operational simplicity. In a rabbit model, Xinyu Zhang and coworkers reported a marked age-dependent increase in shear wave velocity, accompanied by a near-tripling of Young's modulus.⁷⁴ These results validate shear wave velocity as a reliable biomarker for lens stiffness. Further refining clinical utility, Chuprov and coworkers developed a preoperative grading system based on ultrasound density (δ), categorizing lens hardness as high (δ ​≤0.2), moderate (0.3≤ δ ​≤0.5), or low (δ ​≥0.6),⁷⁵ thereby enhancing preoperative assessment accuracy and guiding surgical planning.

Brillouin microscopy offers unique advantages for evaluating lens biomechanics, providing micrometer-scale resolution—far surpassing the millimeter-level precision of ultrasound elastography—and enabling detailed mapping of microstructural mechanical heterogeneity. Pioneered by Scarcelli et al., this technique allows in vivo 3D imaging of lens elastic modulus in live mice,⁷⁶ overcoming constraints of traditional ex vivo methodologies. With non-contact operation, rapid acquisition speed (millisecond-scale measurements), high repeatability, infrared laser illumination, and low-power design, this technique holds strong clinical potential for early diagnosis of biomechanical abnormalities in cataracts and evaluation of drug effects on lens elasticity.

In addition, OCE has garnered attention due to its micrometer-scale spatial resolution. By integrating the high-resolution imaging capabilities of OCT with the mechanical sensitivity of elastography, OCE enables precise detection of localized elastic changes in the lens.⁷⁷ A major breakthrough was achieved by Yulei Chen et al. with the development of a non-contact air-pulse OCE system, which, for the first time, enabled in situ measurement of lens elasticity within intact eyes.⁶¹ This innovative system not only quantifies dynamic stiffness variations during cataractogenesis with high precision but also demonstrates superior sensitivity in detecting early nuclear cataracts compared to conventional visual grading systems. Furthermore, by providing objective biomechanical data, this technology facilitates personalized phacoemulsification parameter selection, marking a critical step toward precision medicine in cataract surgery.

Current lens biomechanical assessment technologies have established a multi-scale, multi-modal framework. Future research priorities include standardizing cataract biomechanics, developing dynamic in vivo monitoring techniques, and clarifying the link between biomechanical properties and clinical outcomes. As these technologies evolve, biomechanical assessment is expected to become routine in cataract diagnosis and treatment, supporting precision medicine.

5.2. Surgical strategy optimization

The biomechanical properties of the lens capsule play a pivotal role in postoperative IOL stability. FEA studies reveal that von Mises stress is significantly higher in the equatorial region of the capsular bag compared to the capsulorhexis edge, demonstrating a markedly asymmetric distribution pattern.^78,79 This stress asymmetry directly influences postoperative capsular contraction patterns, potentially resulting in IOL tilt or decentration. Therefore, preoperative quantitative assessment of capsular biomechanics using advanced imaging techniques such as OCE or USE is recommended for providing objective data for personalized surgical planning.

The morphology, centration, size, and position of the anterior capsulotomy are critical determinants of intraocular lens (IOL) stability.^78,80 Femtosecond laser capsulotomy (FLC) not only provides precise control of capsulotomy diameter (5.0–5.5 ​mm) and geometric symmetry, thereby reducing decentered or irregular capsulotomies, but more importantly, it optimizes anterior capsular stress distribution. This biomechanical improvement helps to regulate capsular contraction dynamics and ultimately reduces postoperative IOL tilt and decentration. From a biomechanical perspective, a symmetric and smooth-edged capsulotomy minimizes local stress concentrations, lowers the risk of capsular tear, and ensures more uniform stress transmission across the capsule. Both finite element analysis and clinical evidence support this effect. For example, the LenSx system has been shown to improve stress distribution uniformity by approximately 37%, significantly decreasing the likelihood of capsular rupture.⁸¹ In contrast, irregular or thermally affected edges may disrupt the collagen fiber network, creating localized high-stress zones and raising the risk of anterior capsule tears.⁸² Therefore, the significance of FLC lies not only in its geometric precision but also in its capacity to reshape capsular contraction dynamics and anterior capsule stress transmission, thereby ensuring long-term IOL stability. This reframes FLC as more than a technical refinement—it is a biomechanically informed surgical optimization strategy.

The use of vital dyes in cataract surgery not only enhances intraoperative visualization but also exerts significant biomechanical effects on the anterior capsule through photochemical mechanisms. Multiple experimental studies have shown that dye staining reduces capsular elasticity while increasing stiffness, thereby altering stress transmission patterns. For example, Simsek et al. demonstrated via nanoindentation that trypan blue and related dyes decrease elasticity while increasing stiffness.⁸³ Similarly, Dick et al. reported lower rupture stress in stained capsules compared to controls, along with an elevated viscous modulus.⁸⁴ In porcine models, Wollensak further showed that trypan blue under illumination induced collagen crosslinking, increasing stress at 25% strain by 70% and elastic stiffness by 47%.⁸⁵ These biomechanical alterations indicate that the choice and application of dyes directly modulate the capsular stress environment. Excessive stiffening may generate localized stress concentrations, predisposing to irregular capsulotomies or anterior capsule tears; conversely, excessive loss of elasticity may reduce the capsule's ability to stabilize the IOL, leading to tilt or decentration. Although some clinical studies (e.g., Jaber et al., Sándor et al.) have suggested that commonly used concentrations do not significantly compromise capsulorhexis safety,^86,87 the findings emphasize that dye-related biomechanical effects are strongly dependent on concentration, illumination conditions, and baseline capsular properties. From a biomechanical standpoint, the rationale for dye selection should extend beyond visualization to encompass the optimization of the capsular stress field. For example, in elderly patients or those with thin capsules, lower dye concentrations and reduced illumination times may minimize excessive stiffening⁸⁴; in patients with pseudoexfoliation or inherently stiffer capsules, dyes with minimal impact on elasticity may be preferable.¹²

The design parameters of IOLs are decisive for postoperative stability. From a biomechanical perspective, IOLs do not merely occupy space within the capsular bag; rather, their optic and haptic structures interact dynamically with the capsule, modulating stress distribution and contraction patterns. Clinical and experimental evidence has demonstrated that plate-haptic designs (e.g., Model C) provide superior biomechanical stability compared to conventional C-loop haptics. With an approximately 32% increase in compressive force and an 80% reduction in decentration,⁸⁸ the plate-haptics’ enlarged contact area and optimized geometry promote more uniform force transmission across the capsule. This improved biomechanical equilibrium minimizes postoperative IOL tilt and displacement. In high myopia patients requiring low-power IOLs (≤20 D), the thinner optic and larger residual capsular space result in insufficient IOL–capsule contact, preventing the formation of an effective "capsular bend". From a biomechanical standpoint, this leads to uneven stress transmission at the optic edge, thereby facilitating LEC migration and PCO.⁸⁹ To address this issue, IOLs with optimized optic geometry or specialized surface materials can enhance capsular adhesion, promote stress anchoring at the optic edge, and biomechanically suppress LEC proliferation. Further supporting evidence comes from in vitro studies. Wormstone's model demonstrated that the CT LUCIA 611PY IOL maintains stable haptic spacing over time and effectively suppresses asymmetric capsular contraction.⁹⁰ This highlights that the ultimate value of IOL design lies not only in initial positioning but in sustaining long-term biomechanical homeostasis of the capsular bag. In essence, well-designed IOLs optimize stress distribution and contraction dynamics, thereby ensuring postoperative stability and capsular clarity.

Capsular tension rings (CTR) are essential in cataract surgery, especially for patients with weakened zonules. While they provide crucial support, there is no consensus on their exact indications. CTRs are commonly used in cases with zonular weakness, traumatic cataracts, or risk of posterior capsule rupture, as they stabilize the capsular bag and aid in proper IOL positioning.^91,92 However, their use in cases with mild capsular weakness or no significant zonular laxity remains debated.⁹³ Cataract surgery significantly alters the stress distribution within the capsular bag, with native anterior capsular stress (67 ​kPa) decreasing to 16–48 ​kPa.⁹⁴ These stress changes can lead to LEC fibrosis and PCO. CTR implantation helps maintain a more uniform stress distribution postoperatively, reducing circumferential stress by 76% to 16 ​kPa and radial stress to nearly zero.⁹⁴ Additionally, CTRs inhibit the transformation of LECs into myofibroblasts, reduce abnormal collagen deposition,⁹⁵ and compensate for asymmetric zonular forces in patients with zonular laxity, thus mitigating the risk of IOL decentration.⁵⁷ Recent findings by Ameku et al. confirm CTRs reduce fibrotic thickening along the visual axis by 40% and peak stress by 60%,⁹⁶ particularly benefiting patients with zonular laxity or oversized capsular bags (>10 ​mm diameter). Despite their clear advantages, CTRs are not free from complications. Mispositioning or excessive tension may lead to abnormal capsular stress distribution, resulting in capsular deformation, IOL decentration, or refractive errors. In addition, CTR implantation has been associated with increased anterior chamber depth, particularly in eyes receiving plate-haptic IOLs, which may necessitate postoperative refractive target adjustment.⁹⁷ Moreover, some reports suggest that CTRs can induce shallow anterior chamber or angle narrowing, thereby raising the risk of angle-closure glaucoma in predisposed patients.98, 99, 100 Careful preoperative evaluation of anterior chamber depth and angle configuration, combined with intraoperative attention to proper CTR placement, is therefore essential.

In summary, a biomechanical perspective provides an essential framework for refining cataract surgical strategies. Femtosecond laser capsulotomy improves capsular geometry and stress distribution, vital dyes influence capsular elasticity, and the design of intraocular lenses together with capsular tension ring implantation contribute to the mechanical stability of the capsule–IOL complex. These biomechanically informed approaches not only enhance postoperative IOL centration and refractive predictability but also support the maintenance of long-term visual quality.

5.3. Drug/material development

Recent advances in biomechanics and molecular biology have provided groundbreaking insights into the molecular regulation of lens biomechanics, opening new avenues for pharmacological interventions in cataract treatment. SPARC, a key regulatory protein of HSPGs, plays a critical role in maintaining the structure and function of the lens capsule. Studies have shown that SPARC deficiency leads to disorganized collagen IV deposition and increased capsule permeability, ultimately causing fiber cell edema and lens opacification.¹⁰¹ This discovery not only elucidates a novel mechanism in age-related cataract formation but also highlights the therapeutic potential of targeting SPARC-ECM interactions for cataract prevention.

Moreover, significant progress has been made in understanding mechanical stress-related pathways. Chen et al. employed innovative 3D FEM coupled with RNA sequencing to demonstrate that mechanical stress activates calcium signaling and inflammatory cascades via PIEZO1 channels, promoting HLEC senescence.⁶⁹ This finding not only explains the molecular basis of age-related lens hardening but also provides a rationale for developing PIEZO1 inhibitors. In parallel, Martin et al. revealed that Arvcf protein-mediated adhesion junction stability is critical in cortical cataract pathogenesis.⁷² Collectively, these studies suggest that dysregulation of mechanical stress perception and signaling systems is an important driver of cataract development.

From a translational medicine perspective, recent research has established novel therapeutic paradigms for cataract pharmacotherapy by targeting lens biomechanical properties. Particularly promising is the development of biocompatible polymeric materials mimicking youthful lens mechanics,¹⁰² which may eventually serve as surgical alternatives. This approach has been explored primarily through lens refilling techniques, in which the cataractous or presbyopic lens contents are removed and replaced with injectable polymers. Experimental and preclinical studies have shown that materials such as silicone-based polymers, PEG-derived hydrogels, and hyaluronic acid derivatives can partially restore accommodation, although issues such as polymer leakage and posterior capsule opacification remain major obstacles.¹⁰³ More recently, hydrogel-based intraocular lens materials exhibited excellent optical clarity, mechanical tunability, and biocompatibility, further underscoring their potential for accommodative lens refilling.¹⁰⁴ While these innovations could complement traditional antioxidant approaches to enable precision prevention, clinical translation faces challenges including drug delivery methods, target specificity, and long-term safety.

6. Conclusions

The age-related degeneration of the biomechanical properties of the lens is a core pathophysiological mechanism in the development and progression of cataracts. This dynamic process involves multi-level structural and functional changes, ranging from molecular to tissue scales, ultimately leading to a decline in lens transparency and a loss of accommodation ability. In recent years, with advances in biomechanical research techniques, we have gained a deeper understanding of the relationship between the mechanical properties and optical function of the lens. This has provided a new theoretical foundation and intervention approach for the diagnosis and treatment of cataracts. Looking ahead, it is essential to integrate multidisciplinary techniques, establish a standardized evaluation system for biomechanical parameters, and continue to deepen research into the underlying mechanisms and material innovations. This will help translate biomechanical research into accessible clinical diagnostic tools and treatment strategies, driving cataract diagnosis and treatment into a new era of precision, personalization, and minimally invasive techniques.

Study approval

Not Applicable.

Author contributions

The authors confirm contribution to the paper as follows: YZ: Data curation, Project administration, Resources, Writing ​– ​original draft., WY: Formal analysis, Validation, Writing ​– ​original draft., JG: Formal analysis, Validation, Writing ​– ​original draft. SC: Formal analysis, Validation, Writing ​– ​original draft. ZP: Formal analysis, Validation, Writing ​– ​original draft. YY: Project administration, Supervision. All authors reviewed the results and approved the final version of the manuscript.

Funding

This study has been supported by the National Natural Science Foundation of China (No.82371036) and Key research and development program of Zhejiang Province (No.2025C02156).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.