Digital light processing-bioprinted poly-NAGA-GelMA-based hydrogel lenticule for precise refractive errors correction

Abstract

Refractive disorder is the most prevalent cause of visual impairment worldwide. While treatment of refractive errors can bring improvement to quality of life and socio-economic benefits, there is a need for individualization, precision, convenience, and safety with the chosen method. Herein, we propose using pre-designed refractive lenticules based on poly-NAGA-GelMA (PNG) bio-inks photo-initiated by digital light processing (DLP)-bioprinting for correcting refractive errors. DLP-bioprinting allows PNG lenticules to have individualized physical dimensions with precision achievable to 10 micron (μm). Material characteristics of PNG lenticules in tests included optical and biomechanical stability, biomimetical swelling and hydrophilic capability, nutritional and visual functionality, supporting its suitability as stromal implants. Cytocompatibility distinguished by morphology and function of corneal epithelial, stromal, and endothelial cells on PNG lenticules suggested firm adhesion, over 90% viability, phenotypic maintenance instead of excessive keratocyte-myofibroblast transformation. In-vitro immune response analyzed by illumina RNA sequencing in human peripheral blood mononuclear cells indicated that PNG lenticules activated type-2 immunity, facilitating tissue regeneration and suppressing inflammation. In-vivo performance assessed using intrastromal keratoplasty (ISK) models in New Zealand white rabbits illustrated that implantation of PNG lenticules maintained stable optical pathway, induced controlled stromal bio-integration and regeneration, avoided complications such as stromal melt, interface scarring, etc., but exerted no adverse effects on the host. Postoperative follow-up examination on intraocular pressure, corneal sensitivity, and tear production remained unaffected by surgery up to 1-month post-implantation of PNG lenticules. DLP-bioprinted PNG lenticule is a bio-safe and functionally effective stromal implants with customizable physical dimensions, providing potential therapeutic strategies in correction of refractive errors.

Biopolymeric corneal lenticules by digital light processing based bioprinting: a dynamic substitute for corneal transplant

“…In another study recombinant human collagen type I hydrogels were observed to be 91% transparent [70]. Additionally, a report on DLP-bioprinted lenticule displayed visual transparency over 85% which is comparable to the native corneal transparency of 87%, similar to the observation made in the current study [36,46].…”

“…Multilayered structures of native cornea have been fabricated using DLP. However, there is limited evidence that DLP-bioprinted refractive lenticules possess all the necessary characteristics for clinical functionality and refractive error correction [36,40,44]. Therefore, in the present study, we generated DLPbio-printed corneal lenticules composed of dual network bioinks using HA-MA and Gel-MA.…”

“…Several studies have discussed the use of Gel-MA, methacrylated hyaluronic acid (HA-MA), or their combination with other components and photocrosslinkers for designing hydrogels and scaffolds [35][36][37][38]. Gel-MA in combination with decellularized extracellular matrix (ECM), PEGDA, HA-GM, and poly-NAGA (N-Acryloyl glycineamide) have been explored for DLP bioprinting of corneal hydrogels [36,37,39,40]. Additionally, HA-MA has been utilized in combination with Gel-MA for DLP-based bioprinting for various applications including functional volumetric soft tissues, cartilage tissue engineering, and 3D hepatic models, but not for corneal regeneration [41][42][43].…”

“…Several studies have discussed the use of Gel-MA, methacrylated hyaluronic acid (HA-MA), or their combination with other components and photocrosslinkers for designing hydrogels and scaffolds [35][36][37][38]. Gel-MA in combination with decellularized extracellular matrix (ECM), PEGDA, HA-GM, and poly-NAGA (N-Acryloyl glycineamide) have been explored for DLP bioprinting of corneal hydrogels [36,37,39,40].…”

Research progress of photo-crosslink hydrogels in ophthalmology: A comprehensive review focus on the applications

“… Direction Application Materials Curative Effect Ref. 3D printing Corneal PEGDA/GelMA Excellent cytocompatibility, supporting cell adhesion, proliferation and migration, accelerating epithelial healing and matrix regeneration [ 196 ] GelMA Promoting re-epithelialization of corneal defects, cell adhesion and neuronal regeneration [ 197 ] Conjunctiva GelMA Loading delivery of CjSCs,as well as maintaining their vitality and dryness [ 198 ] Crystalline Lens PAH With good transparency and cytocompatibility, no increase in inflammatory cells in the anterior chamber angle after implantation [ 199 ] Retinal HAMA Construction of a multilayered tissue model with the same arrangement and localization as the natural retina and good cell viability of PR obtained by co-differentiation [ 200 ] Orbital Implant Ca 2 –Zn–Si–O 7 Good cell adhesion, cell viability and angiogenic effects [ 201 ] Corneal Contact Lens Poly-NAGA-GelMA Maintaining epithelial phenotype and avoiding its excessive transformation to keratinocytes-myofibroblasts; inhibiting inflammation and promoting tissue regeneration [ 202 ] Lacrimal Plug PEGDA/PEG400 Long-acting and sustained-release drug-loaded lacrimal plug with broad promise in dry eyes [ 203 ] Biosensor IP-VISIO Extremely low response of the grafted foreign body, and can accurately sense and respond to physiological sti...…”