A Biocompatible Therapeutic Catheter‐Deliverable Hydrogel for In Situ Tissue Engineering

Abstract

Hydrogels have emerged as a diverse class of biomaterials offering a broad range of biomedical applications. Specifically, injectable hydrogels are advantageous for minimally invasive delivery of various therapeutics and have great potential to treat a number of diseases. However, most current injectable hydrogels are limited by difficult and time‐consuming fabrication techniques and are unable to be delivered through long, narrow catheters, preventing extensive clinical translation. Here, the development of an easily‐scaled, catheter‐injectable hydrogel utilizing a polymer–nanoparticle crosslinking mechanism is reported, which exhibits notable shear‐thinning and self‐healing behavior. Gelation of the hydrogel occurs immediately upon mixing the biochemically modified hyaluronic acid polymer with biodegradable nanoparticles and can be easily injected through a high‐gauge syringe due to the dynamic nature of the strong, yet reversible crosslinks. Furthermore, the ability to deliver this novel hydrogel through a long, narrow, physiologically‐relevant catheter affixed with a 28‐G needle is highlighted, with hydrogel mechanics unchanged after delivery. Due to the composition of the gel, it is demonstrated that therapeutics can be differentially released with distinct elution profiles, allowing precise control over drug delivery. Finally, the cell‐signaling and biocompatibility properties of this innovative hydrogel are demonstrated, revealing its wide range of therapeutic applications.

Automated and Continuous Production of Polymeric Nanoparticles

“…An emerging application of polymeric NPs is as building blocks for the assembly of PNP hydrogels (Appel et al, 2015a,b;Guzzi et al, 2019;Lopez Hernandez et al, 2019;Stapleton et al, 2019;Steele et al, 2019). PNP hydrogels form spontaneously upon simple mixing of an appropriately paired polymer, e.g., hydroxypropylmethylcellulose (HPMC) or C12-functionalized hyaluonic acid, and a concentrated solution of core-shell NPs under aqueous conditions.…”

“…PNP hydrogels form spontaneously upon simple mixing of an appropriately paired polymer, e.g., hydroxypropylmethylcellulose (HPMC) or C12-functionalized hyaluonic acid, and a concentrated solution of core-shell NPs under aqueous conditions. PNP hydrogels are shear-thinning and self-healing owing to the reversible interactions between the polymers and NPs, and have been used for site specific delivery of therapeutics following injection in vivo (Appel et al, 2015b;Fenton et al, 2019;Steele et al, 2019). The clinical potential of these materials is significant; however, biomedical PNP gels are currently limited in the scale of their production.…”

A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model

“…All of these methods, however, employ systemic or otherwise untargeted delivery, leading to a potentially suboptimal therapeutic concentration of NRG in the heart. Our team has endeavored to circumvent these obstacles by utilizing engineered hydrogels (HG) to permit targeted and sustained one-time delivery of therapeutic agents directly to the myocardium [28][29][30]. Within the hydrogel, a therapeutic agent may be protected from degradation to increase its half-life, kept from diffusing away from the target site to maintain a greater effective concentration, and gradually released to prolong the duration of exposure beyond a bolus dose.…”

In situ Enabling Approaches for Tissue Regeneration: Current Challenges and New Developments

“…Recently, several injectable hydrogels have emerged as a potential candidates for cardiac tissue regeneration due to improved patient compliance and facile administration via minimal invasive mode that treats complex infarction (Radhakrishnan et al, 2014). For instances, in a work of Steele et al (2019) a catheter−injectable hyaluronic acid hydrogel is proposed utilizing a polymer-nanoparticle crosslinking mechanism. Due to the notable shear−thinning the hydrogel can be easily injected through a long, narrow, physiologically−relevant catheter and needle with hydrogel mechanics unchanged after delivery.…”