Development of 3D-printed Therapeutic Bandage Contact Lenses for the Treatment of Corneal Injuries
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Corneal blindness is a leading cause of irreversible visual impairment worldwide and can occur due to improper healing of the corneal tissues after induced injury or corneal surgery. The corneal epithelium has a self-healing mechanism wherein the frequent movement and differentiation of limbal stem cells residing in the limbus continuously replenish the epithelial layer. However, a key factor in promoting this natural healing process is the control of the inflammatory response within the cornea via the use of anti-inflammatory medications. These medications are usually administered via eye drops, a delivery method that is associated with very poor drug bioavailability (˂ 5%). To overcome this, frequent administration of eye drops is required, and this can often be inconvenient for patients. Currently, bandage contact lenses (BCLs) are applied after surgeries to protect the injured cornea, reduce pain and promote healing. Often, topical medications are also prescribed in conjunction with BCLs and therefore require patients to adhere to the dosage regimen in order to promote healing and prevent complications. The primary aim of this thesis is to develop a tailor-made novel 3D-printed medicated BCL for the treatment of mild, moderate and severe corneal injuries. The corneal bandage is designed to protect the injured cornea from the external environment and pathogens and act as a matrix to support the adhesion of the newly generated corneal cells, thereby promoting rapid corneal healing. Two types of therapeutics were loaded in the bandages: an anti-inflammatory corticosteroid drug, dexamethasone (DEX), used to reduce the inflammation of the injured cornea and promote self-regeneration post- surgeries or in cases of mild-moderate corneal injuries (presented in chapters 3 and 4); and the second being human corneal epithelial primary cells (HCEpC) which can be used to compensate for the loss of corneal stem cells in moderate-severe corneal injuries thereby minimising the need for corneal grafts (presented in chapters 5 and 6). In chapter 3, an all-in-one drug-eluting silicone hydrogel BCL was developed to protect the injured eye while delivering dexamethasone (DEX) as an anti-inflammatory medication over a period of 2 weeks. p(HEMA-co-TRIS-co-PDMS) lenses were prepared and the molar ratios of the co-monomers were varied to determine their effect on the release profiles of DEX and the properties of BCLs. Extended release of DEX for up to 14 days was achieved from the prepared lenses with properties comparable to commercial silicone hydrogel contact lenses. In chapter 4, Gelatine methacrylate (GelMA) BCLs were prepared by solvent casting and 3D-printing techniques. DEX was loaded within the hydrogel matrix in the presence of Polyethylene glycol diacrylate (PEGDA) as a crosslinker. It was found that the incorporation of PEGDA improved the lenses’ resistance to handling and prolonged their degradation time, reduced the EWC values and extended the release of the incorporated drug. In chapters 5 and 6, a BCL that can carry human corneal epithelial primary cells (HCEpC) for treatment of moderate-severe corneal injuries in patients with limbal stem cell deficiencies (LSCDs), GelMA hydrogel lenses were developed. In chapter 5, GelMA/PEGDA hydrogel meshes were 3D-printed, cured and dried, then the HCEpC were loaded within the meshes. The incorporation of PEGDA enhanced the mechanical properties of GelMA hydrogels, increased their degree of crosslinking and significantly reduced the in vitro degradation rates. Moreover, in vitro cell culture experiments using HCEpC showed high adhesion, proliferation and viability over a period of 1 week in all the 3D-printed meshes. In chapter 6, either hyaluronic acid (HA) or collagen were incorporated within the 8% GelMA hydrogel matrix. The effect of various hydrogel compositions on the properties of the 3D-printed meshes including shape, degree of crosslinking, ESR, biodegradability and cell viability of the printed meshes were evaluated. It was found that the incorporation of 0.5% HA within the hydrogel composition resulted in a continuous extruded filament and a good printed structure. Moreover, the incorporation of 1% collagen within the hydrogel composite obtained a smooth printed mesh and enhanced the adhesion and proliferation of the seeded cells resulting in the formation of cell sheets within the printed structure. In conclusion, the feasibility of loading therapeutics within BCLs that can be 3D-printed was confirmed. Furthermore, the good viability of HCEpC within the hydrogel lenses demonstrates the promising potential for the use of cell-loaded BCLs in the treatment of corneal injuries, and the viability of a convenient, non-invasive alternative to the currently available treatment protocols.