Injectable supramolecular polymer–nanoparticle hydrogels enhance human mesenchymal stem cell delivery

Abstract

Stem cell therapies have emerged as promising treatments for injuries and diseases in regenerative medicine. Yet, delivering stem cells therapeutically can be complicated by invasive administration techniques, heterogeneity in the injection media, and/or poor cell retention at the injection site. Despite these issues, traditional administration protocols using bolus injections in a saline solution or surgical implants of cellladen hydrogels have highlighted the promise of cell administration as a treatment strategy. To address these limitations, we have designed an injectable polymernanoparticle (PNP) hydrogel platform exploiting multivalent, noncovalent interactions between modified biopolymers and biodegradable nanoparticles for encapsulation and delivery of human mesenchymal stem cells (hMSCs). hMSC-based therapies have shown promise due to their broad differentiation capacities and production of therapeutic paracrine signaling molecules. In this work, the fundamental hydrogel mechanical properties that enhance hMSC delivery processes are elucidated using basic in vitro models. Further, in vivo studies in immunocompetent mice reveal that PNP hydrogels enhance hMSC retention at the injection site and retain administered hMSCs locally for upwards of 2 weeks. Through both in vitro and in vivo experiments, we demonstrate a novel scalable, synthetic, and biodegradable hydrogel system that overcomes current limitations and enables effective cell delivery. K E Y W O R D Scell delivery, human mesenchymal stem cell, hydrogel, injectable

Injectable Hydrogels for Sustained Codelivery of Subunit Vaccines Enhance Humoral Immunity

“…These values describe both gels’ abilities to remain solid-like under low stresses (i.e., before and after injection), therefore maintaining a solid gel structure after injection and preventing flow from the injection site, which facilitates the creation of a local inflammatory niche. 50 …”

“… 29 , 47 , 48 In addition, PNP hydrogels are easily administered due to their shear-thinning and self-healing properties. 46 , 49 , 50 The fabrication process, which is easily scaled and therefore highly translatable, involves straightforward mixing of the polymer, NPs, and an aqueous solution of cargo. 47 , 51 This combination of unique properties makes PNP hydrogels ideal candidates for use as a vaccine delivery platform.…”

Structural considerations for physical hydrogels based on polymer–nanoparticle interactions

“…Recently we developed a PNP hydrogel platform and demonstrated its injectability, two-stage release of therapeutic cargo, enhanced cell viability after injection, and efficacy in preventing post-surgical adhesions. 21,22,27,28 In these applications, the underpinning functionality is made possible by the intricate combination of viscoelasticity, flow properties, yield stress, and microstructure characteristic of PNP hydrogels. 21,22,27,28 These hydrogels are formed as nanoparticles are added to hydroxypropylmethylcellulose (HPMC) solutions, and the robustness of gelation can be tuned by attaching different hydrophobic pendant groups onto the HPMC chains.…”

“…21,22,27,28 In these applications, the underpinning functionality is made possible by the intricate combination of viscoelasticity, flow properties, yield stress, and microstructure characteristic of PNP hydrogels. 21,22,27,28 These hydrogels are formed as nanoparticles are added to hydroxypropylmethylcellulose (HPMC) solutions, and the robustness of gelation can be tuned by attaching different hydrophobic pendant groups onto the HPMC chains. This tunability creates a useful handle to modulate bulk properties crucial for each application, such as modulus, relative elasticity, and flow behaviour.…”

“…For example, when engineering materials for drug delivery, microstructure design is critical for controlling solute diffusivity and release kinetics, while control over viscoelasticity is important for creating an injectable material that remains cohesive under physiological stresses. [27][28][29] 2. Experimental section…”