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Injectable Glycosaminoglycan-Based Cryogels from Well-Defined Microscale Templates for Local Growth Factor Delivery.

ABSTRACT: Glycosaminoglycan-based hydrogels hold great potential for applications in tissue engineering and regenerative medicine. By mimicking the natural extracellular matrix processes of growth factor binding and release, such hydrogels can be used as a sustained delivery device for growth factors. Since neural networks commonly follow well-defined, high-aspect-ratio paths through the central and peripheral nervous system, we sought to create a fiber-like, elongated growth factor delivery system. Cryogels, with networks formed at subzero temperatures, are well-suited for the creation of high-aspect-ratio biomaterials, because they have a macroporous structure making them mechanically robust (for ease of handling) yet soft and highly compressible (for interfacing with brain tissue). Unlike hydrogels, cryogels can be synthesized in advance of their use, stored with ease, and rehydrated quickly to their original shape. Herein, we use solvent-assisted microcontact molding to form sacrificial templates, in which we produced highly porous cryogel microscale scaffolds with a well-defined elongated shape via the photopolymerization of poly(ethylene glycol) diacrylate and maleimide-functionalized heparin. Dissolution of the template yielded cryogels that could load nerve growth factor (NGF) and release it over a period of 2 weeks, causing neurite outgrowth in PC12 cell cultures. This microscale template-assisted synthesis technique allows tight control over the cryogel scaffold dimensions for high reproducibility and ease of injection through fine gauge needles.

SUBMITTER: Newland B

PROVIDER: S-EPMC8033563 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sustained, localized protein delivery can enhance the safety and activity of protein drugs in diverse disease settings. While hydrogel systems are widely studied as vehicles for protein delivery, they often suffer from rapid release of encapsulated cargo, leading to a narrow duration of therapy, and protein cargo can be denatured by incompatibility with the hydrogel crosslinking chemistry. In this work, we describe injectable nanocomposite hydrogels that are capable of sustained, bioactive, release of a variety of encapsulated proteins. Injectable and porous cryogels were formed by bio-orthogonal crosslinking of alginate using tetrazine-norbornene coupling. To provide sustained release from these hydrogels, protein cargo was pre-adsorbed to charged Laponite nanoparticles that were incorporated within the walls of the cryogels. The presence of Laponite particles substantially hindered the release of a number of proteins that otherwise showed burst release from these hydrogels. By modifying the Laponite content within the hydrogels, the kinetics of protein release could be precisely tuned. This versatile strategy to control protein release simplifies the design of hydrogel drug delivery systems.Statement of significanceHere we present an injectable nanocomposite hydrogel for simple and versatile controlled release of therapeutic proteins. Protein release from hydrogels often requires first entrapping the protein in particles and embedding these particles within the hydrogel to allow controlled protein release. This pre-encapsulation process can be cumbersome, can damage the protein's activity, and must be optimized for each protein of interest. The strategy presented in this work simply premixes the protein with charged nanoparticles that bind strongly with the protein. These protein-laden particles are then placed within a hydrogel and slowly release the protein into the surrounding environment. Using this method, tunable release from an injectable hydrogel can be achieved for a variety of proteins. This strategy greatly simplifies the design of hydrogel systems for therapeutic protein release applications.

Project description:To minimize premature release of drugs from their carriers during circulation in the blood stream, we have recently developed reversible disulfide cross-linked micelles (DCMs) that can be triggered to release drug at the tumor site or in cancer cells. We designed and synthesized thiolated linear-dendritic polymers (telodendrimers) by introducing cysteines to the dendritic oligo-lysine backbone of our previously reported telodendrimers comprised of linear polyethylene glycol (PEG) and a dendritic cluster of cholic acids. Reversibly cross-linked micelles were then prepared by the oxidization of thiol groups to disulfide bond in the core of micelles after the self-assembly of thiolated telodendrimers. The DCMs were spherical with a uniform size of 28 nm, and were able to load paclitaxel (PTX) in the core with superior loading capacity up to 35.5% (w/w, drug/micelle). Cross-linking of the micelles within the core reduced their apparent critical micelle concentration and greatly enhanced their stability in non-reductive physiological conditions as well as severe micelle-disrupting conditions. The release of PTX from the DCMs was significantly slower than that from non-cross-linked micelles (NCMs), but can be gradually facilitated by increasing the concentration of reducing agent (glutathione) to an intracellular reductive level. The DCMs demonstrated a longer in vivo blood circulation time, less hemolytic activities, and superior toxicity profiles in nude mice, when compared to NCMs. DCMs were found to be able to preferentially accumulate at the tumor site in nude mice bearing SKOV-3 ovarian cancer xenograft. We also demonstrated that the disulfide cross-linked micellar formulation of PTX (PTX-DCMs) was more efficacious than both free drug and the non-cross-linked formulation of PTX at equivalent doses of PTX in the ovarian cancer xenograft mouse model. The anti-tumor effect of PTX-DCMs can be further enhanced by triggering the release of PTX on-demand by the administration of the FDA approved reducing agent, N-acetylcysteine, after PTX-DCMs have reached the tumor site.

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Injectable Glycosaminoglycan-Based Cryogels from Well-Defined Microscale Templates for Local Growth Factor Delivery.

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