A Selective, Hydrogel‐Based Prodrug Delivery System Efficiently Activates a Suicide Gene to Remove Undifferentiated Human Stem Cells Within Neural Grafts

Abstract

The directed differentiation of human pluripotent stem cells (hPSCs) into defined populations has advanced regenerative medicine, especially for Parkinson's disease where clinical trials are underway. Despite this, tumorigenic risks associated with incompletely patterned and/or quiescent proliferative cells within grafts remain. Addressing this, donor stem cells carrying the suicide gene, thymidine kinase (activated by the prodrug ganciclovir, GCV), are employed to enable the programmed ablation of proliferative cells within neural grafts. However, coinciding the short half‐life of GCV with the short S‐phase of neural progenitors is a key challenge. To overcome this, a smart hydrogel delivery matrix is fabricatedto prolong GCV presentation. Following matrix embedment, GCV retains its functionality, demonstrated by ablation of hPSCs and proliferating neural progenitors in vitro. A prolonged GCV release is measured by mass spectrometry following the injection of a GCV‐functionalized hydrogel into mouse brains. Compared to suboptimal, daily systemic GCV injections, the intracerebral delivery of the functionalized hydrogel, as a “one‐off treatment”, reduce proliferative cells in both hPSC‐derived teratomas and neural grafts, without affecting the graft's functional unit (i.e., neurons). It is demonstrated that a functionalized biomaterial can enhance prodrug delivery and address safety concerns associated with the use of hPSCs for brain repair.

Neuronal Replenishment via Hydrogel-Rationed Delivery of Reprogramming Factors

“…This measure is important for nutrient diffusion and should be considered in terms of the distance between structures and should not be confused with micropore size, which is seen via TEM . It is well-known that the AAV is a small nonenveloped virus with a size of 24–26 nm. , When the payload size is larger than the mesh size of the hydrogel, the payload is physically constrained as it becomes incorporated inside the network during shear thinning and entrapped upon gelation . In this case, the release of the immobilized drug/payload can happen through diffusion, network degradation, swelling, or deformation of the network .…”

Green Electrospun Nanofibers for Biomedicine and Biotechnology

“…At infection sites, bacteria metabolize conjugates, activating drugs in sustained bursts. Conductive mixed-ligand hydrogels localize drug-resistant bacteria and anodes, killing cells through reactive oxygen species while releasing drugs [192][193][194][195][196][197][198]. Such living materials bypass many drug resistance challenges by coupling enzymatic activation with synergistic therapies.…”