Special Issue on ‘Advances in Hydrogel Scaffolding of Stem Cells’

We are currently in the midst of an exciting phase in the field of biomedical engineering, where the convergence of material chemistry and cell biology is opening up new avenues for understanding human physiological systems and advancing stem-cell-based approaches to mitigate tissue degeneration and organ failure. This multidisciplinary synergy is driving innovation in both in vitro modeling and in vivo tissue repair. In the realm of in vitro modeling, cell encapsulation within synthetic matrices has provided valuable insights into stem cell maturation, therapeutic release, and the modeling of tumor microenvironments.

Hydrogels are polymeric matrices predominantly composed of water and offer distinct advantages by enabling the development of biomimetic environments with tunable chemistry, architecture, and mechanical properties. Their versatile properties are crucial for the successful design of both in vitro models and in vivo tissue repair strategies. Specially, to harness the full potential of stem cell therapies, it is essential to have a comprehensive understanding of the stem cell microenvironment and the ability to systematically tailor hydrogel properties. This includes not only the chemical modification of hydrogels to enhance cell adhesion but also the optimization of hydrogel rheological properties to facilitate the smooth injection of stem cells. The rational design of biomimetic hydrogels also necessitates a deep consideration of immune modulation, reactivity, and biocompatibility. On the other hand, different classes of hydrogels have been developed with sustained release properties for use as anti-cancer or anti-inflammatory drug-eluting constructs. Over the past decade, breakthroughs in 3D and 4D bioprinting have taken us further by allowing the creation of mini-organs, functional tissues and drug-eluting constructs with diverse architectures and compositions. These developments in hydrogel scaffolding are pushing the boundaries in replicating human physiological systems and developing ways to improve the bioavailability of therapeutic biomolecules or drugs in ways never before achievable. In practical terms, these improvements can take various forms. For instance, researchers are exploring novel chemical modifications of hydrogels to create 3D micro-architectures that promote cell adhesion and interaction, as well as to release drugs smoothly from the matrices.

In this Special Issue on ‘Advances in Hydrogel Scaffolding of Stem Cells’ in Processes, we focused on recent advancements in the development of hydrogels for cell therapy, as well as the application of hydrogels for in vitro modeling or cell physiological studies. This issue features a comprehensive review from Kandilogiannakis et al. [1], wherein they have discussed the extensive repertoire of natural and synthetic hydrogels that have been harnessed for the encapsulation of stem cells in depth. They aimed to provide a thorough examination of these materials, both individually and in combination, shedding light on the myriad advantages they bring to the realm of cell therapy through the innovative approach of functional cell encapsulation. Their discussion encompasses not only the intrinsic qualities of these hydrogels but also their potential synergistic effects when used in combination. They have covered both synthetic and natural hydrogels that are in clinical and pre-clinical use and stressed the continual development of gel matrices that can improve the viability of encapsulated cells, providing a longer biodegradation and minimal host immune reactions to the implanted hydrogels. In the review by Hassan et al. [2], the authors provide a concise summary of the most recent breakthroughs in 3D bio-scaffolds versus the conventional 2D cultures, which are strategically designed to replicate the complex microenvironment of cancer stem cells (CSCs) and to meet their specific chemical and biological requirements. Their discussion not only delves into the essential characteristics of these biomaterials but also explores their potential impacts on both tumor cells and the surrounding microenvironment. They focused extensively on the critical factors that govern the CSC microenvironment and have laid the foundation for future investigations in this field by offering practical insights, particularly in the realm of drug screening. The review article by Kantawong et al. [3] discusses the possibility of the transdifferentiation of fibroblasts into the neuronal cell type on stimuli-responsive 3D hydrogels. Fibroblasts are found throughout the body and are frequently employed in research due to their accessibility through a safe and non-invasive skin biopsy procedure. Moreover, they are readily cultivated in laboratory settings. Consequently, the ability to generate human induced pluripotent stem cells (iPSCs) from fibroblasts is highly advantageous. In this regard, hydrogels could certainly be a promising candidate for the transdifferentiation of human fibroblasts to neurons by providing a conducive extracellular matrix that can provide growth cues to support cell maturation in controlled conditions. For instance, they report several cases in which changes in substratum (3D matrix) mechanics, electrical stimulation, growth or differentiation factors, and their synergistic combination has resulted in the transdifferentiation of encapsulated fibroblasts towards neuronal lineages. Such methods can result in the development of functional hydrogels prepared from patients’ own stem cells ready for use in neural therapies.

Our feature also features three insightful research articles on the development and application of 3D hydrogel constructs. In the first research article by Sharma et al. [4], the authors conducted an evaluation of the physical and mechanical characteristics of bioprinted structures produced using an innovative microsphere-laden bioink. Their assessment involved the determination of elastic moduli in both bioprinted constructs with microspheres and those without, employing a modified Hertz model. They reported the storage and loss modulus, viscosity, swelling rates, biodegradation, porosity, and rheology (shear rates) of the modified constructs. They concluded that the inclusion of microspheres in the bioink resulted in improved mechanical strength, reduced degradation rates, and elevated elastic modulus in the bioprinted tissues, indicating a high level of suitability for neural tissue engineering. In the second research article by Korkmaz-Bayram et al. [5], the authors studied the gene expression of mouse hippocampal stem cells in a galactose-based hydrogel. They cultured both directly extracted fresh hippocampus cells (ex vivo) and the primary cells (in vitro) in galactose-based GalC7 gels and assessed the Sox8, Sox9, Sox10, Dcx, and Neurod1 gene expression levels. They showed that the GalC7 gel supported enhanced expression of Dcx and Neurod1, the marker of neurogenesis, and neuronal differentiation, respectively, in comparison to the regular neurosphere-based culture conditions. Overall, their study indicates that GalC7 hydrogel offers unique conditions for inducing the differentiation and maturation of neural progenitor cells compared to other polymeric supports. In the third research article by Fiorini et al. [6], the authors characterized a novel method of producing polyethylene oxide (PEO) hydrogels by exploiting hydroxy–tyrosol (HT). Hydroxy–tyrosol is olive leaf extract, and the molecule could be used to tune the cross-linking of the formed gel since it acts as a free radical scavenger, which can either prevent or limit gamma-ray-induced cross-linking. The authors studied the effects of the changes caused by introducing HT in the gel matrix in various concentrations (ratios). They propose an innovative use of high-temperature free radical scavenging activity to mitigate the cross-linking reactions caused by irradiation, which can aid in the development of hydrogels characterized by improved viscosity and injectability and can be further assessed for clinical applications.

In summary, the fusion of material chemistry and stem cell biology is propelling the field of biomedical engineering to new heights. The ability to create biomimetic environments, optimize material properties, and address immune reactivity challenges is at the forefront of designing safe and efficient stem cell therapies. Furthermore, many more future works involving detailed studies of the immune system’s response to implanted materials, cells and drugs are critical to further advance cell- and drug-based therapies. Strategies for immune modulation and suppression are becoming integral parts of the design process to enhance the biocompatibility of these materials and improve their long-term effectiveness. As these technologies continue to advance, we can anticipate groundbreaking developments in both our understanding of human physiology and our capacity to develop innovative treatments for various diseases and conditions.