An introduction to injectable hydrogels

Abstract

Injectable hydrogels have emerged as intelligent and versatile materials that have been proven to possess huge potential for many biomedical applications including drug delivery, tissue engineering, and regenerative medicine. Hydrogels are a class of polymers with highly hydrated 3D networks that have microenvironmental properties such as oxygen/nutrient permeability that are similar to the native extracellular matrix. In addition to possessing the typical advantages of conventional hydrogels, injectable hydrogels offer extra unique features, enabling minimally invasive injectability and durability for irregularly shaped sites, and the possibility of processing these materials via, e.g., additive manufacturing techniques. As such, there has been a growing interest in using injectable hydrogels as scaffolds/carriers for therapeutic agents, including but not limited to drugs, cells, proteins, and bioactive molecules, targeted to treat chronic diseases including cancer, but also to facilitate the repair and regeneration of damaged organs/tissues. In this themed collection of Journal of Materials Chemistry B and Biomaterials Science, we include outstanding contributions covering recent developments in this rapidly evolving field of injectable hydrogels including emerging chemistries, synthesis pathways, fabrication methods, cell–material interaction, in vitro, ex vivo and in vivo performances, and subsequent targeted applications (drug delivery, tissue engineering and regenerative medicine) of injectable hydrogels.

Julieta I. Paez

Julieta Paez is an associate professor in the Department of Developmental Bioengineering at the University of Twente (UT). She obtained her PhD in Chemistry at the Universidad Nacional de Córdoba in Argentina. Afterwards, she did postdoctoral work at the Freie Universiteit in Berlin and at the Max Planck Institute for Polymer Research in Mainz, Germany. After becoming project leader at the INM—Leibniz Institute for New Materials in Saarbrücken, she joined the UT in 2021. She develops chemical tools to empower soft biomaterials. Her research focus includes hydrogels for engineering cell microenvironments and bioadhesive materials for soft tissue repair.

Khoon S. Lim

Khoon Lim is an Australian Research Council Future Fellow and an associate professor in the School of Medical Sciences at the University of Sydney, Australia. He currently leads the Light Activated Biomaterials research group, where his research focuses on developing functional hydrogels for biofabrication, and delivery of bioactive molecules for tissue regeneration. He is the current President of the Australasian Society for Biomaterials and Tissue Engineering, and also serves on the Board of Directors of the International Society for Biofabrication. He is also an editorial board member of 6 journals, including Biomaterials Science.

In this collection, Selvam et al. provided an interesting perspective on the adaptation of click chemistry in developing injectable organo-hydrogels in revolutionizing pharmaceutical research and development (https://doi.org/10.1039/D3TB01674A). The pathway towards clinical advancements of such injectable hydrogels is clearly articulated, building on current clinical progress of injectable organo-hydrogels in the market, targeted for a range of biomedical applications. Throughout the various examples, hyaluronic acid (HA) is showcased as one of the most widely used biomaterials as the main polymer backbone in designing intelligent injectable hydrogels, mainly due to its native extracellular matrix mimicry (structural and mechanical properties). It is however noted that any bench-to-bedside translation is heavily reliant on regulatory boards such as the Food and Drug Administration (FDA) and the European Medical Agency (EMA), where regulatory requirements should be considered during the injectable hydrogel design process. Furthermore, Morel et al. reported on using other chemical modification processes beyond click chemistry to further improve functionality of injectable HA hydrogels (https://doi.org/10.1039/D3TB02108D). In their study, thermoresponsive polyoxazoline was grafted onto HA, resulting in injectable hydrogels that undergo a reversible sol–gel transition at 25 °C. These hydrogels demonstrated enhanced robustness, thermal stability, and resistance to enzymatic degradation, showing great potential in therapeutic drug delivery applications.

In terms of applications, Xie et al. focussed on designing injectable hydrogels as long-lasting dermal fillers (https://doi.org/10.1039/D3BM01488F). Silk fibroin was used as their biomaterial of interest, fabricated into hydrogels which were then mechanically fragmented into microparticles. Interestingly, these silk microparticles had to be dispersed in HA solution prior to subcutaneous injection in a rat model. Subsequent functional evaluation showed lasting filler performance after 2 months, with good tissue infiltration and blood vessel in-growth. These results are highly promising, demonstrating that the injectable silk dermal fillers can be used to increase soft tissue volume in a minimally invasive procedure, further implying quick recovery, cost effectiveness and long-lasting aesthetic improvement. On the other hand, Han et al. explored the use of injectable hydrogels as bioinks for cutting-edge 3D bioprinting technologies (https://doi.org/10.1039/D3BM02111D). Injectable materials that exhibit a shear-thinning behaviour have been widely adopted as bioinks for extrusion-based bioprinting modalities. In this case, the authors were interested in decellularized extracellular matrix (dECM) due to its tissue-specific nature but were also challenged with its unsuitable inherent rheological properties. Therefore, they specifically developed gelatinized-dECM (GeldECM) through heat-induced denaturation of dECM, which was then used as a rheological modifier to improve injectability of dECM bioinks. Through mixing dECM and GeldECM, they proposed a triple crosslinking process – physical entanglement, photo-oxidation of di-tyrosine bonds, and thermal crosslinking of collagen fibrils, which enabled microextrusion of cm-scale, tough and resilient tissue constructs. This study showed the feasibility of gelatinized-dECM as a strategy to impart injectability into native dECM, further paving the way for development of tissue-specific bioinks. In another study, Piglionico et al. developed fibrinogen–blood injectable hydrogels as scaffolds for dental pulp regeneration (https://doi.org/10.1039/D3BM00515A). Biologics contained in blood favored the tissue regeneration, while a high concentration of fibrinogen in the formulation enabled tuning of the mechanical and degradability properties of the matrices. These hydrogels supported survival and proliferation of dental pulp cells as well as demonstrated angiogenic potential, as tested in an ex vivo rat aortic ring assay. These results are promising to support the revascularization of newly formed tissue and pave the way for the use of these materials in regenerative endodontic treatment.

The articles highlighted here are only a selected few out of a collection of exciting contributions from leading researchers working on injectable hydrogels. We hope this themed collection will inspire the community to explore and harness the exciting and versatile features of injectable hydrogels, to further generate significant impact in the multiple fields of application demonstrated in the articles included in this themed collection. We would also like to thank the editorial staff at the Royal Society of Chemistry, editorial staff, for their assistance throughout commissioning this themed collection.

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