Ocular Biocompatibility and Structural Integrity of Micro- and Nanostructured Poly(caprolactone) Films

Abstract

The identification of biomaterials that are well tolerated in the eye is important for the development of new ocular drug delivery devices and implants, and the application of micro- and nanoengineered devices to biomedical treatments is predicated on the long-term preservation within the target organ or tissue of the very small functional design elements. This study assesses the ocular tolerance and durability of micro- and nanostructured biopolymer thin films injected or implanted into the rabbit eye. Structured poly(caprolactone) (PCL) thin films were placed in adult rabbit eyes for survival studies, with serial ophthalmic examinations over 6 months. Morphologic abnormalities and device/tissue reactions were evaluated by histologic studies, and scanning electron microscopy (SEM) of films was used to determine the structural integrity. Structured PCL thin films (20- to 40-μm thick) were constructed to design specifications with 50-μm linear microgrooves or arrays of nanopores with ~30-nm diameters. After up to 9 months of ocular residency, SEM on devices retrieved from the eye showed preservation of micro- and nanostructural features. In ocular safety evaluations carried out over 6 months, serial examinations in 18 implanted eyes showed no evidence of chronic inflammation, cataractogenesis, or retinal toxicity. Postoperative ocular inflammation was seen in 67% of eyes for 1 week, and persistent corneal edema occurred in 1 eye. Histology revealed no ocular inflammation or morphologic abnormalities of ocular tissues. Thin-film/tissue responses such as cellular reaction, fibrosis, or surface biodeposits were not seen. Micro- and nanostructured PCL thin films exhibited acceptable ocular tolerance and maintained the structural integrity of design features while residing in the eye. Thin-film micro- and nanostructured PCL appears to be a feasible biomaterial for intraocular therapeutic applications.

In vivo and in vitro sustained release of ranibizumab from a nanoporous thin-film device

“…Nanostructured PCL films have a history of biocompatibility when implanted in the vitreous [33]. Implantation of ranibizumab-loaded devices showed no significant increase in IOP over the 12 weeks of our study, along with no change in device location or signs of implant rejection.…”

“…Examination of devices after extraction shows that device perimeter seals continue to retain osmotic pressure and there is no visible large-scale fibrous encapsulation by proteins or cells. This is expected given the eye’s immune privileged nature and previous work with PCL in the eye demonstrating a lack of an inflammatory response [33]. High magnification SEMs of the device surfaces reveal a nanoporous surface with a mix of open and obstructed pores, possibly blocked by aggregates of ranibizumab formed in the highly concentrated interior of the device.…”

“…PCL is a biodegradable polymer that has the property of maintaining physical structure throughout the majority of its degradation: this enables nanostructure-controlled release rates to last for the duration of the drug payload. In addition, nanostructured PCL films have shown biocompatibility in the eye, and their flexibility as thin films allow them to be furled in an injection device [33,34]. …”

In Vitro and In Vivo Sustained Zero-Order Delivery of Rapamycin (Sirolimus) From a Biodegradable Intraocular Device

“…18 Polycaprolactone is a polyester with a favorable intraocular biocompatibility profile that can be fabricated into thin films with thicknesses in the range of 10 to 40 lm. [18][19][20] Additionally, PCL thin films can be patterned with nanofeatures or microfeatures by solvent-casting to modify diffusion behavior through the thin films. 21 Control of the nano-and microstructure of a PCL thin film allows tuning of drug diffusion behavior across the film.…”

“…Previous in vivo studies on the safety of these PCL thin films has shown them to be well tolerated in the posterior chamber of rabbit eyes over 6 months, in addition to showing minimal changes in morphology from degradation. 19 Based on previous in vivo studies it is estimated that PCL will remain intact for approximately 3 years before losing mechanical integrity. 20,22,23 We investigated a drug delivery device for rapamycin that demonstrates zero-order release behavior up to 14 weeks in vitro.…”