Cell‐adhesive thermogelling PNIPAAm/hyaluronic acid cell delivery hydrogels for potential application as minimally invasive retinal therapeutics

Abstract

Copolymers of N-isopropylacrylamide (NIPAAm) and acrylic acid N-hydroxysuccinimide (NAS) were synthesized via free radical polymerization and conjugated with amine-functionalized hyaluronic acid (HA) and cell adhesive RGDS peptides. These novel copolymers were designed to facilitate noninvasive delivery of a liquid suspension of cells into the delicate subretinal space for treatment of retinal degenerative diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. The various synthesized copolymers all displayed subphysiological phase transition temperatures, thereby allowing temperature-induced scaffold formation and subsequent entrapment of transplanted cells within an adhesive support matrix. Successful grafting of HA and RGDS peptides were confirmed with Fourier Transform Infrared (FTIR) spectroscopy and quantified with (1)H Nuclear Magnetic Resonance (NMR) spectroscopy. All copolymers demonstrated excellent compatibility with retinal pigment epithelial (RPE) cells in culture and minimal host response was observed following subcutaneous implantation into hairless SKH1-E mice (strain code 447).

Polymer Brushes with Precise Architectures for Molecular Biorecognition

“…Below the LCST, the PNIPAM chains adopt a random coil conformation (brush conformation and hydrophilic state), however, above the LCST the polymer chains exhibit a collapsed globular conformation (hydrophobic state). PNIPAM polymer brushes have been applied as supports for culturing and harvesting of cells enabling effective detachment of the intact cell sheets upon only small temperature variations [72][73][74][75]. Further developments on these surfaces are based on the immobilization of biospecific cues, such as collagen [76] and RGD-peptide sequence [71], on the PNIPAMm-grafted surfaces, which improve cell adhesion and proliferation above the LCST without destroying the cell detachment properties at lower temperatures ( Fig.…”

Bimodal in vivo imaging provides early assessment of stem-cell-based photoreceptor engraftment

“…25,[28][29][30][31] However, the performance of these materials cannot be assessed in vivo using standard imaging techniques. A recent (2014) study, implanting a monolayer of RPE attached to a ridged polyester scaffold, utilized a similar approach to our bimodal imaging to help address this very limitation.…”

Approaches to Cell Delivery: Substrates and Scaffolds for Cell Therapy

“…RPE cells demonstrated excellent viability when cultured with the scaffolds. Mazumder et al [69] synthe- sized copolymers based on N-isopropylacrylamide (NIPAAm), acrylic acid N-hydroxysuccinimide conjugated with amine functionalized hyaluronic acid and cell-adhesive RGDS peptides for minimally invasive cell delivery to the posterior segment of the eye to combat retinal degenerative diseases [69]. The NIPAAM-based copolymers demonstrated excellent compatibility with RPE cells in culture, and minimal host response was observed following subcutaneous implantation [69].…”

“…Mazumder et al [69] synthe- sized copolymers based on N-isopropylacrylamide (NIPAAm), acrylic acid N-hydroxysuccinimide conjugated with amine functionalized hyaluronic acid and cell-adhesive RGDS peptides for minimally invasive cell delivery to the posterior segment of the eye to combat retinal degenerative diseases [69]. The NIPAAM-based copolymers demonstrated excellent compatibility with RPE cells in culture, and minimal host response was observed following subcutaneous implantation [69]. Tezcaner and Hicks [70] incorporated interphotoreceptor matrix (IPM) isolated from porcine eye and basic fibroblast growth factor (bFGF) into a multilayered polyelectrolyte film [70].…”