Injectable PTHF-based thermogelling polyurethane implants for long-term intraocular application

Abstract

Background Hydrogels show great potential to be used for intraocular applications due to their high-water content and similarity to the native vitreous. Injectable thermosensitive hydrogels through a small-bore needle can be used as a delivery system for drugs or a tamponading substitute to treat posterior eye diseases with clear clinical potential. However, none of the currently available thermosensitive hydrogels can provide intraocular support for up to 3 months or more. Method In this study, an injectable polytetrahydrofuran (PTHF)-based thermosensitive hydrogel was synthesized by polyurethane reaction. We examined the injectability, rheological properties, microstructure, cytotoxicity, and in vivo compatibility and stability of the hydrogels in rabbit eyes. Results We found that the PTHF block type and PTHF component ratio could modulate thermogelation properties of the polyurethane polymers. The PTHF-based hydrogel implants retained normal retinal structure and function. Incorporating bioinert PTHF generated highly biocompatible and more stable thermogels in the vitreous cavity, with gel networks and the presence of polymer still observed after 3 months when other thermogels would have been completely cleared. Moreover, despite lacking hydrolytically cleavable linkages, the polymers could be most naturally removed from the native vitreous by bio-erosion without additional surgical interventions. Conclusion Our findings suggest the potential of incorporating hydrophobic bioinert blocks to enhance the in vivo stability of supramolecularly associated hydrogels for long-term intraocular applications. Graphical Abstract

Optimization of an Injectable Hydrogel Depot System for the Controlled Release of Retinal-Targeted Hybrid Nanoparticles

“…While this is true, especially in such a small model, such as in a mouse, advanced methodologies for higher-order animals (i.e., rabbits) have already started to overcome this issue by performing a small vitrectomy before gel injection to reduce the overall pressure. This work showed that such a procedure in the rabbit retina did not lead to inflammation or other damage, opening the possibility for more detailed studies going forward [ 79 ].…”

MOF–Thermogel Composites for Differentiated and Sustained Dual Drug Delivery

“…With the influence of MOFs on model Pluronic F127 thermogels established, we investigated the effects of MOF addition on gelation of EPC thermogels (Figure 1). Although Pluronic F127 has been widely studied in drug delivery applications, it still possesses several limitations such as fast erosion rate, high gelation concentration, 59 and low biodegradability. 60 This is due to the low molecular weight and insufficient hydrophobicity of commercial Pluronics, which preclude strong micelle aggregation.…”

Recent advances in thermogels for the management of diabetic ocular complications

“…71 Zhang et al subsequently modified EPC by substituting PCL with poly(tetrahydrofuran carbonate) diol (PTHF) to obtain a thermogel (termed as EPT). 72 PTHF was used because it is structurally similar to PEG and PPG and it is a material that has been previously used for long-term biomedical appli-…”

“…This was demonstrated when it was found that EPC degrades completely and becomes undetectable in the vitreous at 3 months post-implantation while about 30% of EPT would still be observable for the same duration. Release kinetic studies performed in vitro with Bovine Serum Albumin (BSA) as a model drug showed that EPT had a consistent protein release profile and was able to release 50% of the loaded amount over 28 days in vitro, which indicates its ability for extended protein release 72 and the potential for long-term anti-VEGFs delivery for the treatment of DR. Another multiblock polyurethane thermogel was fabricated by Park and co-workers consisting of Poly-(N-Boc-serinol) as the hydrophobic block and PEG as the hydrophilic block for the delivery of the anti-VEGF agent, bevacizumab. 73 This biodegradable PEG-poly-(serinol hexamethylene urethane) (ESHU) thermoresponsive hydrogel could be injected at 15 wt% polymer in PBS solution or a solution of bevacizumab in its sol state and undergo a rapid sol-gel phase transition at 37 °C.…”

“…This was demonstrated when it was found that EPC degrades completely and becomes undetectable in the vitreous at 3 months post-implantation while about 30% of EPT would still be observable for the same duration. Release kinetic studies performed in vitro with Bovine Serum Albumin (BSA) as a model drug showed that EPT had a consistent protein release profile and was able to release 50% of the loaded amount over 28 days in vitro , which indicates its ability for extended protein release 72 and the potential for long-term anti-VEGFs delivery for the treatment of DR.…”