Additive manufacturing of intraocular lenses and their functionalisation for ophthalmic drug delivery

Cataract is the leading cause of blindness worldwide. The only treatment currently available for this disease is surgery. This procedure consists of the removal of the cataractous lens fibres by phacoemulsification and the subsequent implantation of an artificial intraocular lens (IOL) in the resulting capsular bag. While this method results in a good restoration of vision, a high rate of recurrence of cataract is caused by the development of posterior capsule opacification (PCO). This syndrome occurs as a consequence of the wound-healing response elicited in the eye after cataract surgery, which results in the transdifferentiation and migration of lens cells to the posterior capsule. These cells deposit aberrant extracellular matrix proteins which cause the contraction and wrinkling of the capsular bag, hence causing a significant loss of vision. Whilst PCO can be treated by performing a laser capsulotomy, this technique is associated with numerous complications such as the damage to the IOL and retinal detachment. Hence, it would be highly desirable to prevent PCO in order to ensure the eradication of cataract while avoiding these issues. This is of particular importance in the context of an ageing population that is leading to an increase in the incidence of this disease. Numerous approaches can be taken in order to reduce the incidence of PCO. These include the creation of IOLs with materials and designs that modulate the cellular responses which lead to this disease and the administration of therapeutic agents which target the signalling pathways involved in this pathology. However, the high costs and limited accessibility of the techniques currently employed in the manufacture of IOLs do not facilitate the development of novel implants with improved bioactivity. Thus, the development of alternative methods of production would be highly beneficial for the achievement of this objective. Within this context, the present thesis aimed at demonstrating the suitability of additive manufacturing technologies for the production of functional IOLs. The technique of choice for these experiments was stereolithography. Thus, novel photopolymerisable formulations were developed which allowed the production of IOLs by employing this technique. The process was optimised in order to obtain the highest resolution possible, hence allowing the production of implants with a high fidelity with respect to the commercial IOL used as a model. Furthermore, novel prototypes that presented structural elements which aided in the prevention of PCO were fabricated with this technique. The evaluation of the resulting lenses indicated that these implants possessed the optical and mechanical properties required for an IOL to be biofunctional. Moreover, these implants were biocompatible and implantable in a human capsular bag, as demonstrated by performing implantability tests employing a human model ex vivo. Once the IOLs were printed and characterised, their surface was functionalised in order to allow the attachment of a drug delivery system which would release Axitinib® into the capsular bag in order to prevent the development of PCO. This was achieved by generating polymer brushes on the surface of the lenses in such a way that covalent interactions could be created between these molecules and a delivery system composed of 4-arm PEG-maleimide. The rationale behind the choice of this polymer is the possibility of conjugating the maleimide groups to MMP2-cleavable peptide crosslinkers in order to create an enzyme-responsive system which would release the therapeutic agent during the onset of PCO