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In the past decade, stimuli-responsive hydrogels are increasingly studied as biomaterials for tissue engineering and regenerative medicine purposes. Smart hydrogels can not only replicate the physicochemical properties of the extracellular matrix but also mimic dynamic processes that are crucial for the regulation of cell behavior. Dynamic changes can be influenced by the hydrogel itself (isotropic vs anisotropic) or guided by applying localized triggers. The resulting swelling-shrinking, shape-morphing, as well as patterns have been shown to influence cell function in a spatiotemporally controlled manner. Furthermore, the use of stimuli-responsive hydrogels as bioinks in 4D bioprinting is very promising as they allow the biofabrication of complex microstructures. This perspective discusses recent cutting-edge advances as well as current challenges in the field of smart biomaterials for tissue engineering. Additionally, emerging trends and potential future directions are addressed.

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Ovarian cancer is one of the most lethal gynecological cancers in the world. In recent years, nucleic acid (NA)-based formulations have been shown to be promising treatments for ovarian cancer, including tumor nodules. However, gene therapy is not that far advanced in clinical reality due to unfavorable physicochemical properties of the NAs, such as high molecular weight, poor cellular uptake, rapid degradation by nucleases, etc. One of the strategies used to overcome these drawbacks is the complexation of anionic NAs via electrostatic interactions with cationic polymers, resulting in the formation of so-called polyplexes. In this work, the role of the size of pDNA and siRNA polyplexes on their penetration into ovarian-cancer-based tumor spheroids was investigated. For this, a methoxypoly(ethylene glycol) poly(2-(dimethylamino)ethyl methacrylate) (mPEG-pDMAEMA) diblock copolymer was synthesized as a polymeric carrier for NA binding and condensation with either plasmid DNA (pDNA) or short interfering RNA (siRNA). When prepared in HEPES buffer (10 mM, pH 7.4) at a nitrogen/phosphate (N/P) charge ratio of 5 and pDNA polyplexes were formed with a size of 162 ± 11 nm, while siRNA-based polyplexes displayed a size of 25 ± 2 nm. The polyplexes had a slightly positive zeta potential of +7-8 mV in the same buffer. SiRNA and pDNA polyplexes were tracked in vitro into tumor spheroids, resembling in vivo avascular ovarian tumor nodules. For this purpose, reproducible spheroids were obtained by coculturing ovarian carcinoma cells with primary mouse embryonic fibroblasts in different ratios (5:2, 1:1, and 2:5). Penetration studies revealed that after 24 h of incubation, siRNA polyplexes were able to penetrate deeper into the homospheroids (composed of only cancer cells) and heterospheroids (cancer cells cocultured with fibroblasts) compared to pDNA polyplexes which were mainly located in the rim. The penetration of the polyplexes was slowed when increasing the fraction of fibroblasts present in the spheroids. Furthermore, in the presence of serum siRNA polyplexes encoding for luciferase showed a high cellular uptake in 2D cells resulting in ∼50% silencing of luciferase expression. Taken together, these findings show that self-assembled small siRNA polyplexes have good potential as a platform to test ovarian tumor nodulus penetration..

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Type 1 diabetes mellitus is an auto-immune disease causing the T-cell mediated destruction of insulin-producing ß-cells, resulting in chronic hyperglycemia. Current treatments such as insulin replacement therapy or the transplantation of pancreas or pancreatic islets present major disadvantages such as the constant need of drugs, as well as a shortage of donor organs. In this review, we discuss a sustainable solution to overcome these limitations combining the use of ß-cells, derived from stem cells, and their encapsulation within a protective matrix. This article provides an exhaustive overview of currently investigated stem cell sources including embryonic, mesenchymal as well as induced pluripotent stem cells in combination with various up to date encapsulation methods allowing the formation of immuno-protective devices. In order to identify current limitations of this interdisciplinary therapeutic approach and to find sustainable solutions, it is essential to consider key aspects from all involved domains. This includes biological parameters such as the stem cell origin but also the different aspects of the encapsulation process, the used materials and their physico-chemical properties such as elasticity, porosity and permeability cut-off as well as the best implantation sites allowing efficient and self-autonomous control of glycemia by the transplanted encapsulated cells.

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Designing new materials to encapsulate living therapeutic cells for the treatment of the diseases caused by protein or hormone deficiencies is a great challenge. The desired materials need to be biocompatible towards both entrapped cells and host organisms, have long-term in vivo stability after implantation, allow the diffusion of nutrients and metabolites, and ensure perfect immune-isolation. The current work investigates the in vivo biocompatibility and stability of alginate@TiO2 hybrid microcapsules and the immune-isolation of entrapped HepG2 cells, to assess their potential for cell therapy. A comparison was made with alginate-silica hybrid microcapsules (ASA). These two hybrid microcapsules are implanted subcutaneously in female Wistar rats. The inflammatory responses of the rats are monitored by the histological examination of the implants and the surrounding tissues, to indicate their in vivo biocompatibility towards the hosts. The in vivo stability of the microcapsules is evaluated by the recovery rate of the intact microcapsules after implantation. The immune-isolation of the entrapped cells is assessed by their morphology, membrane integrity and intracellular enzymatic activity. The results show high viability of the entrapped cells and insignificant inflammation of the hosts, suggesting the excellent biocompatibility of alginate@TiO2 and ASA microcapsules towards both host organisms and entrapped cells. Compared to the ASA microcapsules, more intact alginate@TiO2 hybrid microcapsules are recovered 2-day and 2-month post-implantation and more cells remain alive, proving their better in vivo biocompability, stability, and immune-isolation. The present study demonstrates that the alginate@TiO2 hybrid microcapsule is a highly promising implantation material for cell therapy.

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The number of patients suffering from diseases linked with hormone deficiency (e.g., type 1 diabetes mellitus) has significantly increased in recent years. As organ transplantation presents its limits, the design of novel robust devices for cell encapsulation is of great interest. The current study reports the design of a novel hybrid alginate microcapsule reinforced by titania via a biocompatible synthesis from an aqueous stable titania precursor (TiBALDH) and a cationic polyamine (PDDAC) under mild conditions. The biocompatibility of this one-pot synthesis was confirmed by evaluation of the cytotoxicity of the precursor, additive, product, and by-product. The morphology, structure, and properties of the obtained hybrid microcapsule were characterized in detail. The microcapsule displayed mesoporous, which was a key parameter to allow the diffusion of nutrients and metabolites and to avoid the entry of immune defenders. The hybrid microcapsule also showed enhanced mechanical stability compared to the pure alginate microcapsule, making it an ideal candidate as a cell reservoir. HepG2 model cells encapsulated in the hybrid microcapsules remained intact for 43 days as highlighted by fluorescent viability probes, their oxygen consumption, and their albumin secretion. The study provides a significant progress in the conception of the robust and biocompatible reservoirs of animal cells for cell therapy.

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