Hydrogels provide a regenerative medicine platform with their ability to create an environment that supports transplanted or endogenous infiltrating cells and enables these cells to restore or replace the function of tissues lost to disease or trauma. Furthermore, these systems have been employed as delivery vehicles for therapeutic genes, which can direct and/or enhance the function of the transplanted or endogenous cells. Herein, we review recent advances in the development of hydrogels for cell and non-viral gene delivery through understanding the design parameters, including both physical and biological components, on promoting transgene expression, cell engraftment, and ultimately cell function. Furthermore, this review identifies emerging opportunities for combining cell and gene delivery approaches to overcome challenges to the field.

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Tissues derived from human pluripotent stem cell (hPSC) often represent early developmental time points. Yet, when transplanted into immunocompromised mice, these hPSC-derived tissues further mature, which has been enhanced with biomaterial scaffolds, gaining tissue structure and cell types similar to the native adult lung. Our goal was to define the physico-chemical biomaterial properties, including the polymer type, degradation, and pore interconnectivity of the scaffolds. Transplantation of human lung organoids (HLOs) on microporous poly(lactide-co-glycolide) (PLG) scaffolds or polycaprolactone (PCL) produced organoids that formed tube-like structures that resembled both the structure and cellular diversity of an adult lung airway. Microporous scaffolds formed from poly(ethylene glycol) (PEG) hydrogel scaffolds inhibit maturation and the HLOs remain as lung progenitors. The structures formed from cells that occupy multiple pores within the scaffold, and pore interconnectivity and polymer degradation contributed to the maturation. Finally, the overall size of the generated airway structure and the total size of the tissue was influenced by the material degradation rate. Collectively, these biomaterial platforms provide a set of tools to promote maturation of the tissues and to control the size and structure of the organoids.

The formation of 10 to 40 μm Composite Gel MicroParticles (CGMPs) comprising ~100 nm drug containing nanoparticles (NPs) in a poly(ethylene glycol)(PEG) gel matrix is described. The CGMP particles enable targeting to the lung by filtration from the venous circulation. UV radical polymerization and Michael addition polymerization reactions are compared as approaches to form the PEG matrix. A fluorescent dye in the solid core of the NP was used to investigate the effect of reaction chemistry on the integrity of encapsulated species. When formed via UV radical polymerization, the fluorescence signal from the NPs indicated degradation of the encapsulated species by radical attack. The degradation decreased fluorescence by 90% over 15 minutes of UV exposure. When formed via Michael addition polymerization, the fluorescence was maintained. Emulsion processing using controlled shear stress enabled control of droplet size with narrow polydispersities. To allow for emulsion processing, the gelation rate was delayed by adjusting the solution pH. At a pH= 5.4 the gelation occurred at 3.5 hours. The modulus of the gels was tuned over the range of 5 to 50 kPa by changing the polymer concentration between 20 and 70 vol %. NPs aggregation during polymerization, driven by depletion forces, was controlled by the reaction kinetics. The ester bonds in the gel network enabled CGMP degradation. The gel modulus decreased by 50% over 27 days, followed by complete gel degradation after 55 days. This permits ultimate clearance of the CGMPs from the lungs. The demonstration of uniform delivery of 15.8 ± 2.6 μm CGMPs to the lungs of mice, with no deposition in other organs, is shown, and indicates the ability to target therapeutics to the lung while avoiding off-target toxic exposure.