The complex tissue‐specific physiology that is orchestrated from the nano‐ to the macroscale, in conjugation with the dynamic biophysical/biochemical stimuli underlying biological processes, has inspired the design of sophisticated hydrogels and nanoparticle systems exhibiting stimuli‐responsive features. Recently, hydrogels and nanoparticles have been combined in advanced nanocomposite hybrid platforms expanding their range of biomedical applications. The ease and flexibility of attaining modular nanocomposite hydrogel constructs by selecting different classes of nanomaterials/hydrogels, or tuning nanoparticle‐hydrogel physicochemical interactions widely expands the range of attainable properties to levels beyond those of traditional platforms. This review showcases the intrinsic ability of hybrid constructs to react to external or internal/physiological stimuli in the scope of developing sophisticated and intelligent systems with application‐oriented features. Moreover, nanoparticle‐hydrogel platforms are overviewed in the context of encoding stimuli‐responsive cascades that recapitulate signaling interplays present in native biosystems. Collectively, recent breakthroughs in the design of stimuli‐responsive nanocomposite hydrogels improve their potential for operating as advanced systems in different biomedical applications that benefit from tailored single or multi‐responsiveness.

Bottom‐up tissue engineering is a promising approach for designing modular biomimetic structures that aim to recapitulate the intricate hierarchy and biofunctionality of native human tissues. In recent years, this field has seen exciting progress driven by an increasing knowledge of biological systems and their rational deconstruction into key core components. Relevant advances in the bottom‐up assembly of unitary living blocks toward the creation of higher order bioarchitectures based on multicellular‐rich structures or multicomponent cell–biomaterial synergies are described. An up‐to‐date critical overview of long‐term existing and rapidly emerging technologies for integrative bottom‐up tissue engineering is provided, including discussion of their practical challenges and required advances. It is envisioned that a combination of cell–biomaterial constructs with bioadaptable features and biospecific 3D designs will contribute to the development of more robust and functional humanized tissues for therapies and disease models, as well as tools for fundamental biological studies.

The development of stimuli-responsive nanomedicines with tunable cargo release is gathering an increased applicability in bone regeneration and precision biomedicine. Yet, the formulation of nanocarriers that explore skeletal-specific stimuli remains remarkably challenging to materialize due to several endogenous and disease-specific barriers that must be considered during particle design stages. Such anatomo-physiological constrains ultimately hinder nanocarriers bioavailability in target bone tissues and impact the overall therapeutic outcome. This review aims to showcase and critically discuss the hurdles encountered upon responsive nanocarriers delivery in the context of skeletal diseases or tissue regeneration scenarios. Such focus is complemented with an in-depth and up-to-date analysis of advances in the development of stimuli-responsive, bone-focused delivery systems. In a holistic perspective, a deeper knowledge of human osteology combined with advances in materials functionalization via simple precision-chemistry is envisioned to incite the manufacture of stimuli-triggered nanomedicines with more realistic potential for clinical translation.

The use of natural compounds for treating chronic bone diseases holds remarkable potential. Among these therapeutics, naringin, a flavanone glycoside, represents one of the most promising candidates owing to its multifaceted effect on bone tissues. This review provides an up-to-date overview on naringin applications in the treatment of bone disorders, such as osteoporosis and osteoarthritis, and further highlights its potential for stem cell pro-osteogenic differentiation therapies. A critical perspective on naringin clinical translation is also provided. The topic is discussed in light of recently developed biomaterial-based approaches that potentiate its bioavailability and bioactivity. Overall, the reported pro-osteogenic, antiresorptive and antiadipogenic properties establish this flavanone as an exciting candidate for application in bone tissue engineering and regenerative medicine.

The development of nanocomposite hydrogels that take advantage of hierarchic building blocks is gaining increased attention due to their added functionality and numerous biomedical applications. Gathering on the unique properties of these platforms, herein we report the synthesis of bioactive nanocomposite hydrogels comprising naringin-loaded salmon-derived lecithin nanosized liposomal building blocks and gelatin methacryloyl (GelMA) macro-sized hydrogels for their embedding. This platform takes advantage of liposomes’ significant drug loading capacity and their role in hydrogel network reinforcement, as well as of the injectability and light-mediated crosslinking of bioderived gelatin-based biomaterials. First, the physicochemical properties, as well as the encapsulation efficiency, release profile, and cytotoxicity of naringin-loaded nanoliposomes (LipoN) were characterized. Then, the effect of embedding LipoN in the GelMA matrix were characterized by studying the release behavior, swelling ratio, and hydrophilic character, as well as the rheological and mechanical properties of GelMA and GelMA-LipoN functionalized hydrogels. Finally, the dispersion of nanoliposomes encapsulating a model fluorescent probe in the GelMA matrix was visualized. The formulation of naringin-loaded liposomes via an optimized procedure yielded nanosized (114 nm) negatively charged particles with a high encapsulation efficiency (~99%). Naringin-loaded nanoliposomes administration to human adipose-derived stem cells confirmed their suitable cytocompatibility. Moreover, in addition to significantly extending the release of naringin from the hydrogel, the nanoliposomes inclusion in the GelMA matrix significantly increased its elastic and compressive moduli and decreased its swelling ratio, while showing an excellent dispersion in the hydrogel network. Overall, salmon-derived nanoliposomes enabled the inclusion and controlled release of pro-osteogenic bioactive molecules, as well as improved the hydrogel matrix properties, which suggests that these soft nanoparticles can play an important role in bioengineering bioactive nanocomposites for bone tissue engineering in the foreseeable future.

Native human tissues are supported by a viscoelastic extracellular matrix (ECM) that can adapt its intricate network to dynamic mechanical stimuli. To recapitulate the unique ECM biofunctionality, hydrogel design is shifting from typical covalent crosslinks toward covalently adaptable networks. To pursue such properties, herein hybrid polysaccharide-polypeptide networks are designed based on dynamic covalent assembly inspired by natural ECM crosslinking processes. This is achieved through the synthesis of an amine-reactive oxidized-laminarin biopolymer that can readily crosslink with gelatin (oxLAM-Gelatin) and simultaneously allow cell encapsulation. Interestingly, the rational design of oxLAM-Gelatin hydrogels with varying aldehyde-to-amine ratios enables a refined control over crosslinking kinetics, viscoelastic properties, and degradability profile. The mechanochemical features of these hydrogels post-crosslinking offer an alternative route for imprinting any intended nano-or microtopography in ECM-mimetic matrices bearing inherent cell-adhesive motifs. Different patterns are easily paved in oxLAM-Gelatin under physiological conditions and complex topographical configurations are retained along time. Human adipose-derived mesenchymal stem cells contacting mechanically sculpted oxLAM-Gelatin hydrogels sense the underlying surface nanotopography and align parallel to the anisotropic nanoridge/nanogroove intercalating array. These findings demonstrate that covalently adaptable features in ECM-mimetic networks can be leveraged to combine surface topography and cell-adhesive motifs as they appear in natural matrices.

The design of dynamically crosslinked hydrogel bioinks for three-dimensional (3D) bioprinting is emerging as a valuable strategy to advance the fabrication of mechanically tuneable cell-laden constructs for 3D in vitro disease modelling and tissue engineering applications. Herein, a dynamic bioink comprising boronic acid-functionalised laminarin and alginate is explored for bioprinting 3D constructs under physiologically relevant conditions. The formulated bioink takes advantage of a double crosslinked network that combines covalent but reversible boronate ester bonds and ionic gelation via divalent cations. Moreover, it exhibits suitable rheological properties and improved mechanical features owing to its modular crosslinking chemistry, yielding stable constructs with user-programmable architecture. We explored such dynamic bioink as a supporting matrix for different cell classes, namely osteoblast precursors, fibroblasts and breast cancer cells. The resulting cell-laden bioprinted hydrogels display a homogeneous cell distribution post-printing and exceptional cell viability (>90%) that can be maintained for prolonged time periods in culture (14 days) for all cell lines. This simple and chemically versatile approach is envisaged to accelerate the development of multifunctional bioinks and contribute towards the fabrication of biomimetic 3D scaffolds with applicability in a wide range of predictive or exploratory biomedical platforms.

Naringin is a naturally occurring flavanone with recognized neuroprotective, cardioprotective, anti-inflammatory, and antiosteoporotic properties. Herein, the delivery of Naringin-loaded methoxy-poly(ethylene glycol)-maleimide-thiol-poly(l-lactide) (mPEGMSPLA) diblock polymeric micelles to human adipose-derived stem cells (hASCs) with the aim to augment its pro-osteogenic effect in these cells is reported for the first time. The synthesis of the diblock copolymer is performed via Michael-type addition reaction between hydrophilic methoxy-poly(ethylene glycol)-maleimide (mPEGMAL) and hydrophobic thiol-poly(l-lactide) (PLASH) and confirmed by H NMR and attenuated total reflectance Fourier transformed infrared (ATR-FTIR) spectroscopy. The resulting mPEGMSPLA copolymer self-assembles into monodispersed polymeric micelles (≈84.4 ± 2 nm) and presents a high Naringin encapsulation efficiency (87.8 ± 4%), with a sustained release profile at physiological pH. Alongside, in vitro data reveal that upon internalization into hASC 2D cultures, Naringin nanomicellar formulations attain a higher pro-osteogenic effect than that of free drug. Notably, these bioactive carriers also induce superior osteopontin expression and increase matrix mineralization in these cells over free drug administration. Overall, such findings support for the first time the use of polymeric nanomicelles for Naringin delivery into hASCs as a valid approach for modulating stem cell osteogenic differentiation.