Scleral permeability

The sclera is the outer white tough part of the eye, which is an important structural element, with the site of insertion of extraocular muscles. It covers 80% of the exterior surface and is white and nontransparent. It borders the transparent cornea at the pars planar. The sclera is divided into three layers episclera, stroma, and lamina fusca. Only a limited number of blood vessels, originating from arteriolar branches of the anterior ciliary vessels, are found and superficial vessels are mainly confined to the loose outer episclera. Scleral permeability approximates that of the corneal stroma and has been shown to be permeable to solutes up to 70 kDa in molecular weight [14]. 

Ambati et al. [44] measured the permeability of rabbit sclera to a series of fluorescein-labeled hydrophilic compounds and found that scleral permeability decreased with increasing molecular weight and molecular radius but was quite permeable to large molecules, such as IgG (145 kDa). Thus when targeting the retina by the topical or subconjunctival routes the sclera is not a rate-limiting barrier and the main barriers are beyond this tissue at the choroid, RPE, and ELM. 

Olsen, T.W., et al. 1995. Human scleral permeability. Effects of age, cryotherapy, transscleral diode laser, and surgical thinning. Invest Ophthalmol Vis Sci 36 1893. 

Several investigators have used a two-chamber diffusion cell apparatus to characterize in vitro scleral permeability (3-5,22-25) to radioactively—or fluores-cently—labeled compounds. 

We measured the permeability of rabbit sclera to a series of fluorescently labeled hydrophilic compounds with a wide range of molecular weights and radii. Sodium fluorescein, the smallest compound, had the highest permeability coefficient, whereas 150 kDa dextran, which had the largest molecular radius, had the lowest permeability coefficient. Our rabbit permeability data was quite similar to the reported permeability of human sclera. Bovine scleral permeability was less than that of the rabbit or human (Table 1). 

Surgical thinning of the sclera predictably increases its permeability however, neither cryotherapy nor transscleral diode laser application alters permeability (4). It also increases with increasing tissue hydration (28). Scleral permeability of small molecules increases rapidly with increasing temperature (23). This low activation energy supports the existence of an aqueous pore pathway rather than a transcellular one. This paracellular pathway presumably traverses the aqueous media of the mucopolysaccharide matrix. 

The diffusion of small molecules across the sclera has been well characterized. Various sulfonamides diffuse across rabbit sclera (40,41). In patients undergoing cataract surgery, methazolamide, a hydrophilic compound, penetrated the sclera much faster than the cornea, but ethoxzolamide, which is lipophilic, had similar diffusion across the sclera and cornea (40). Other studies also have found greater scleral permeability to hydrophilic molecules than lipophilic ones (42,43). 

Unlu N, Robinson JR. Scleral permeability to hydrocortisone and mannitol in the albino rabbit eye. J Ocul Pharmacol Ther 1998 14 273-281. 

Rudnick DE, Noonan JS, Geroski DH, Prausnitz MR, Edelhauser HF. The effect of intraocular pressure on human and rabbit scleral permeability. Invest Ophthalmol Vis Sci 1999 40 3054-3058. 

Kim JW, Lindsey JD, Wang N, Weinreb RN. Increased human scleral permeability with prostaglandin exposure. Invest Ophthalmol Vis Sci 2001 42 1514-1521. 

Shuler RK, Dioguardi PK, Henjy C, Nickerson JM, Cruysberg LPJ, Edelhauser HF. Scleral permeability of a small, single-stranded oligonucleotide. J Ocul Pharmacol Ther... 

Ophthalmic diseases are most commonly treated by topical instillation of eye drops. These formulations evidence limitations like poor stability and efficacy, reduced cor-neal/scleral permeability, systemic toxicity and lack of compUance [2]. In this sense, the development of effective therapies for visual disorders is of high priority [1], which makes the field of ocular delivery one of the most interesting and challenging areas for pharmaceutical scientists [3]. There has been significant research directed towards the development of new systems for controlled drug delivery in ophthalmology such... 

The common element of most such studies is the dissection and isolation of scleral tissue, followed by placement of the sclera between two chambers representing the episcleral surface and the uveal surface. One chamber contains the labeled compound, and the other chamber is sampled periodically after steady-state flux is attained. Some studies have used an apparatus where the chambers are constantly stirred. This may yield a higher apparent permeability by utilizing an unmixed depot on the tissue surface where static boundary layers may exist. However the impact of boundary layers on high molecular weight tracers is not expected to be significant, especially when temperature fluctuations are minimal (26,27). 

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