Natural hydrogels are promising scaffolds to engineer epidermis. Currently, natural hydrogels used to support epidermal regeneration are mainly collagen- or gelatin-based, which mimic the natural dermal extracellular matrix (ECM) but often suffer from insufficient and uncontrollable mechanical and degradation properties. In this study, a photocrosslinkable gelatin (i.e., gelatin methacrylamide (GelMA)) with tunable mechanical, degradation and biological properties is used to engineer the epidermis for skin tissue engineering applications. The results reveal that the mechanical and degradation properties of the developed hydrogels can be readily modified by varying the hydrogel concentration, with elastic and compressive moduli tuned from a few kPa to a few hundred kPa and the degradation times varied from a few days to several months. Additionally, hydrogels of all concentrations displayed excellent cell viability (>90%) with increasing cell adhesion and proliferation with increase in hydrogel concentrations. Furthermore, the hydrogels are found to support keratinocyte growth, differentiation and stratification into a reconstructed multi-layered epidermis with adequate barrier functions. The robust and tuneable properties of GelMA hydrogels have suggested that the keratinocyte laden hydrogels can be used as epidermal substitutes, wound dressings or substrates to construct various in vitro skin models.

Direct injection is a minimally invasive method of stem cell transplantation for numerous injuries and diseases. However, despite its promising potential, its clinical translation is diffi cult due to the low cell retention and engraftment after injection. With high versatility, high-resolution control and injectability, microfabrication of stem-cell laden biomedical hydrogels holds great potential as minimally invasive technology. Herein, a strategy of microfl uidicsassisted technology entrapping bone marrow-derived mesenchymal stem cells (BMSCs) and growth factors in photocrosslinkable gelatin (GelMA) microspheres to ultimately generate injectable osteogenic tissue constructs is presented. Additionally, it is demonstrated that the GelMA microspheres can sustain stem cell viability, support cell spreading inside the microspheres and migration from the interior to the surface as well as enhance cell proliferation. This fi nding shows that encapsulated cells have the potential to directly and actively participate in the regeneration process. Furthermore, it is found that BMSCs encapsulated in GelMA microspheres show enhanced osteogenesis in vitro and in vivo, associated with a signifi cant increase in mineralization. In short, the proposed strategy can be utilized to facilitate bone regeneration with minimum invasiveness, and can potentially be applied along with other matrices for extended applications. One potential attractive strategy for stem cell delivery that overcomes these limitations is to suspend the stem cells in hydrogels which can be injected and solidifi ed in situ . Hydrogels have a high water content, similar to tissues, which not only enables homogeneous encapsulation of cells and growth factors, but also allows for facile delivery via injection. Their readily tunable degradation properties provide further control over the release behavior of incorporated cargo material. [ 5 ] Hydrogels of synthetic origin, poly (ethylene glycol) diacrylate (PEGDA), [ 6 ] and of natural origin, such as hyaluronic acid (HA), [ 7 ] alginate, [ 8 ] collagen, [ 9 ] and gelatin [ 10 ] have been tested. However, their clinical success has frequently been impeded by insuffi cient oxygen and nutrient supply due to the large size of the bone defects, which compromises cell survival and performance, resulting in poor bone regeneration. [ 11 ] Furthermore, the bulk environment and the limited interfacial interactions between the cells and the hydrogel material restrict tissue regeneration. Therefore, development of alternate hydrogel geometries for stem cell delivery is required to further drive clinical translation of BMSC-based bone repair strategies. DOIOne such geometry is hydrogel microspheres which can encapsulate both stem cells and their growth factors; they facilitate nutrient and waste transfer and thereby maintain the viability of preseeded cells, while also preserving the scaffold's injectability. [ 12,13 ] In addition, such 3D scaffolds have large surface area which improves cell-matrix interactions. Thus the us...

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