Diabetic retinopathy (DR) is one of the most prevalent complications of DM. The progression of DR is associated with chronic DM status, hyperglycemia, hypertension, dyslipidemia, higher body mass index, and smoking (32). Recent studies demonstrated the potential association between glaucoma and DR, as they share several common risk factors (e.g., blood pressure, obesity, serum total cholesterol, etc.) and pathophysiological features (e.g., impairment of vascular supply, and neuroretina degeneration, etc.) (33, 34). We previously confirmed that the body mass index (BMI) is positively correlated with CSFP (35), and the latest meta-analysis demonstrated that obesity (BMI > 30 kg/m²) was a risk factor for non-proliferative DR. Collectively, we speculated that the high BMI induces the elevation of CSFP, which may lead to the dysfunction of capillary reflux and the upregulation of retinal venous pressure. Retinal venous pressure is reported to be increased in both DR and glaucoma (36). The elevated retinal venous pressure causes hypoxia and tissue edema, resulting in potential pathologic changes including microaneurysm and cotton wool spots at the early stage of DR. Moreover, the increased retinal venous pressure may trigger mechanosensitive channels such as TRPV4 in endothelial cells. TRPV4 activation is linked to higher BRB permeability, and the genetic ablation of TRPV4 could efficiently alleviate retinal edema and BRB compromise in diabetic mice (37, 38). Thus, targeting mechanosensitive channels like TRPV4 could be a promising therapeutic strategy for the treatment of DR.

Intriguingly, the possible association between DM and keratoconus (KC) was also reported. McKay et al. (39) proposed a similar collagen crosslinking mechanism in the development of both diseases, they hypothesized that DM is associated with increased ACEs that led to inter- and intramolecular crosslinking, thus increasing the corneal rigidity. On the contrary, KC is characterized by decreased mechanical stiffness and secondary corneal ectasia. Hence, excessive crosslinking in DM may protect against KC development, but further studies are required to verify this hypothesis.

The cornea is the outermost transparent tissue of the eye, its biomechanical properties, such as strength and stiffness, are determined by its five composing layers, namely epithelium, bowman's layer, stroma, Descemet's membrane, and the endothelium. The imbalance of biomechanical homeostasis cross cornea contributes to the occurrence of corneal diseases such as KC. KC is a progressive corneal ectasia condition featured as a cone-shaped cornea with local thinning corneal stroma. Top risk factors of KC include family history, eye rubbing, eczema, asthma and allergy (40). Associated with disorganization and undulation of tissue structure, the alteration in ocular biomechanics plays an essential role in the pathogenesis of KC. Bettahar et al. (41) reported that eye rubbing is a considerable contributing factor in corneal degeneration of KC patients. Rubbing action triggers several mechanical insults, including IOP spikes, altered shear stress, and high hydrostatic tissue pressure. For instance, vigorous rubbing can skyrocket the IOP to more than 10 times of a normal resting IOP, generating more dramatic pressure strain on the cornea (7). Mechano-transducers like YAP in stromal cells and β-catenin in epithelial cells are associated with the regulation of substrate stiffness and protease production in KC (42, 43). A comprehensive understanding of the mechanobiology of corneal diseases may pave the way for new avenues for therapeutic approaches.

Glaucoma is an irreversible visual impairment disease with substantial changes in ocular biomechanical properties. The main risk factors for glaucoma include aging, elevated IOP, family history of glaucoma, and high myopia (44). The biomechanical disturbance is indispensable in the pathogenesis of glaucoma. Moreover, the glaucomatous biomechanical stress is generated by several ocular tissues (e.g., TM, iris, peripapillary sclera, and ONH), which exert direct or indirect biomechanical roles in various subtypes of glaucoma. Here, we mainly discuss the biomechanical features of glaucoma in predominant clinical subtypes including primary congenital glaucoma (PCG), primary angle-closure glaucoma (PACG), malignant glaucoma and primary open-angle glaucoma (POAG).

PCG is characterized by the abnormal anatomical structure of the TM and anterior chamber angle, thus resulting in aqueous outflow resistance and IOP elevation in infancy (45). With the progression of the disease, the affected eye may display a larger cornea or eyeball size than normal individuals, which is named “hydrophthalmos” or “buphthalmos.” Of note, these two terms involve different etiologies and clinical features. Hydrophthalmos mainly refers to the enlargement of the cornea, with or without the whole eyeball expansion. Here, we speculate that the vitreous biomechanics might be involved in the formation of hydrophthalmos. The vitreous cavity is full of intact, dense and regularly structured vitreous gel without vitreous liquefaction in infancy (46), which acts as a favorable mechanical buffer to counteract the anterior pressure derived from the elevated IOP. The posterior segment of the eye tissues is less susceptible to mechanical stimuli than the cornea, thus the primary ocular deformation occurs in the cornea. However, with the constant IOP elevation and chronic damage to the eye tissues, the biomechanical buffering role of the vitreous cannot fully offset the excessive pressure impacted on the still-elastic young eye, eventually forming “buphthalmos” featured by sclera distension and eyeball enlargement (47).

The relative pupillary block between the iris and lens is the common mechanism of PACG. The pathogenic structural changes include lens antedisplacement, plateau iris configuration and iris bombe, sequentially inducing the pupillary block accompanied by the obstruction of aqueous humor. These changes raise the pressure difference between the posterior chamber and anterior chamber, contributing to the angle closure and IOP elevation (48). Severe acute angle-closure glaucoma can lead to morphological changes of lens, known as the glaucomatous fleck, which is an irregular grayish-white spot in the anterior lens capsule at the pupillary area. It might relate to nutritional disorders, or direct contact between the iris and the anterior lens capsule under a high IOP attack (49).

Malignant glaucoma is featured with the progressive elevation of IOP and resistance to therapeutics. It is also termed as ciliary block glaucoma, vitreous displacement glaucoma, aqueous humor misdirection syndrome, or vitreociliary block glaucoma. Although the underlying etiology of malignant glaucoma is not well-elucidated, some widely-accepted theories indicate that it may result from the anterior displacement of irido-crystalline diaphragm elicited by the swelling, hypertrophy, or anterior displacement of the ciliary body, or by the laxity of zonular (50). The increasing pressure difference in these compartments blocks the normal forward passage of aqueous humor and traps the refluxed aqueous flow in the vitreous cavity. The excessive pressure difference between vitreous cavity and anterior chamber escalates the anterior displacement of irido-crystalline diaphragm, accompanied by a flattened anterior chamber (51). Recent research proposed potential risk factors such as choroidal expansion and anterior vitreous abnormalities in malignant glaucoma, subsequent confirmation still needs to be performed (52).

The prominent role of TLCPD, established by IOP and CSFP across the ONH, is well-acknowledged in the POAG etiology. Our previous studies identified that patients with normal-tension glaucoma had significantly lower CSFP and a higher TLCPD when compared with the normal subjects (53). The increased TLCPD may contribute to the LC deformation involving astrocyte migration, axonal bundle disorganization and extracellular matrix alternation (54, 55). Specifically, the individual role of these two forming ingredients is not equivalent, IOP-driven biomechanical effects display a more dominant role than CSFP (56). Multiple mechanosensitive channels such as Piezo, TRPV4, and TREK-1 are proven to have biomechanical effects in glaucoma on an experimental basis. The chemical inhibition or genetic ablation of these channels significantly ameliorates pathological phenotypes of optic nerve degeneration caused by IOP elevation, indicating the potential therapeutic roles of targeting mechanosensitive channels in glaucoma (57).

After a long-term spaceflight, some astronauts were bothered by visual changes associated with ocular conditions, which were termed spaceflight-associated neuro-ocular syndrome (SANS) (58). The occurrence of SANS is primarily attributed to the chronic exposure of the astronauts to the unique microgravity environment during long-term spaceflight. Other associated risk factors include radiation exposure, inflated ambient CO₂ concentrations, high salt diets, intense resistance exercise, nutritional disturbance, and genetic variations in the one-carbon metabolism pathway (59, 60). Due to the prolonged microgravity exposure, SANS is generally characterized as fluid redistribution in the optic nerve sheath (ONS) and cerebrospinal fluid cavity (61). The cephalad fluid shifts occurring with weightlessness elevate the biomechanical strain transmitted to the ONH, as evidenced by progressive papilloedema and globe-flattening (62). To better distinguish the pathologies, a terrestrial analog called 6-degree head-down tilt bed rest (HDTBR) was established. After 30 days of examination, similar ocular changes of SANS were also identified in the HDTBR model with elevated ICP (63). Moreover, the alterations of TLCPD are also suspicious in the development of optic disc edema with increased ONS pressure protruding the LC anteriorly (64). Several countermeasures have been proposed to rebalance the biomechanical homeostasis at the site of ONH in SANS cases. A lower body negative pressure apparatus has been used to combat the cephalad fluid shift and showed a significant reduction of ICP in HDTBR testing (65). To rebuild the positive and posteriorly-directed pressure gradient, a swim goggles compression experiment was adopted to increase IOP and restore the normal TLCPD (64). These discoveries highlight the malignant impacts of imbalanced TLCPD induced by idiopathic intracranial hypertension, underscoring the fundamental role of biomechanical homeostasis in ocular health.

Retinal vein occlusion (RVO) is a constellation of hypertensive retinopathies associated with multiple risk factors like aging, systemic hypertension, cardiovascular disorders, hyperlipidemia, diabetes, glaucoma, and thrombophilic mutations (e.g., antithrombin, protein C or protein S) (66, 67). The physical obstruction of the retinal venous system is generally induced by thrombosis, deformation of the vein wall, and external biomechanical compression secondary to glaucoma (68). Mechanically, it is postulated that the elevated IOP compresses the LC and optic disc, thereby leading to the stretching and weakening of the vessel wall, which further predisposes the retinal vein to occlusion (69). An excessive dropout of parapapillary choroidal microvasculature is also observed in RVO patients (70). Meanwhile, the direct biomechanical insult of IOP obstructs the retinal vein drainage and induces venous stasis, consequently exacerbating the intimal proliferation in the vein (71). Substantial evidence is required to further elucidate the underlying biomechanical changes in RVO etiology.

As the most common refractive condition, myopia often starts in childhood and is manifested as short- or near-sightedness. Emerging evidence has supported the role of nature (genetics and inheritance) and nurture (environment and lifestyle) in the onset of myopia (72). Specifically, the major risk factors include higher education levels, prolonged near-work time, reduced outdoor activities, and inherited genetic predispositions (e.g., MYP1 family, ZNF644, SCO2, BSG, APLP2, etc.) (72–74). The biological deformation of myopia is typically characterized by an elongated posterior scleral shell. Severe scleral thinning in high myopia can lead to the biomechanical deformation of the posterior scleral wall, manifested as posterior staphyloma. It has been validated in several animal studies that the sclera thins during experimental myopia, suggesting the distinct role of scleral remodeling in the pathological axial elongation (75, 76). Scleral remodeling is a process of micro-deformation in a volume-conserving pattern, which results in the rearrangement of existing tissue materials. In highly myopic eyes, this mechanical adaption to the scleral tension is even greater than an equivalent IOP attack in the aspect of globe enlargement and posterior thinning of the eye wall (77). Besides, David et al. (78) have studied the impact of vitreous torsional oscillation stress on the retina secondary to regular ocular motion. They found that the high myopia eye is hypersensitive to this chronic mechanical torsional stress, speculating it as the underlying cause of rupture-induced retinal detachment occurred in pathological myopia.