Synthetic materials that are capable of autonomous healing upon damage are being developed at a rapid pace because of their many potential applications. Despite these advancements, achieving self-healing in permanently cross-linked hydrogels has remained elusive because of the presence of water and irreversible cross-links. Here, we demonstrate that permanently cross-linked hydrogels can be engineered to exhibit self-healing in an aqueous environment. We achieve this feature by arming the hydrogel network with flexible-pendant side chains carrying an optimal balance of hydrophilic and hydrophobic moieties that allows the side chains to mediate hydrogen bonds across the hydrogel interfaces with minimal steric hindrance and hydrophobic collapse. The self-healing reported here is rapid, occurring within seconds of the insertion of a crack into the hydrogel or juxtaposition of two separate hydrogel pieces. The healing is reversible and can be switched on and off via changes in pH, allowing external control over the healing process. Moreover, the hydrogels can sustain multiple cycles of healing and separation without compromising their mechanical properties and healing kinetics. Beyond revealing how secondary interactions could be harnessed to introduce new functions to chemically cross-linked polymeric systems, we also demonstrate various potential applications of such easy-to-synthesize, smart, self-healing hydrogels.

Significance: A mechanistic understanding of how calcium phosphate (CaP) minerals contribute to osteogenic commitment of stem cells and bone tissue formation is a necessary requirement for developing efficient CaP-based synthetic matrices to treat bone defects. This study unravels a previously unknown mechanism, phosphate-ATP-adenosine metabolic signaling, by which the CaP-rich mineral environment in bone tissues promotes osteogenic differentiation of human mesenchymal stem cells. In addition to a mechanical perspective on how biomaterials can influence stem cell differentiation through metabolic pathways, this discovery opens up new avenues for treating critical bone defects and bone metabolic disorders.

This review discusses the principles underlying stimuli-responsive behavior of hydrogels and how these properties contribute to their biomimetic functions and applications.

Nanocomposite hydrogels with enhanced mechanical properties could have tremendous biomedical applications. Here we describe synthesis and characterizations of biocompatible poly(ethylene glycol) diacrylate (PEGDA)/Laponite nanocomposite (NC) hydrogels that can support both two- and three-dimensional (2D and 3D) cell cultures. The PEGDA/Laponite NC hydrogels with enhanced mechanical properties were developed by harnessing the ability of PEGDA oligomers to simultaneously form chemically crosslinked networks while interacting with Laponite nanoparticles through secondary interactions. Incorporation of Laponite nanoparticles significantly enhanced both the compressive and tensile properties of PEGDA hydrogels, which were dependent on both the molecular weight of PEG, and concentrations of Laponite nanoparticles. Unlike PEGDA hydrogels, PEGDA-NC hydrogels supported cell adhesion and their subsequent spreading in a 2D culture. In addition to supporting the 2D cell growth, the PEGDA NC hydrogels supported 3D cell encapsulation similar to that of widely used PEGDA hydrogel systems. Such nanocomposite hydrogels with enhanced mechanical properties could have potential applications as 3D scaffolds for tissue engineering. Additionally, the ability of PEGDA NC hydrogels to support 3D culture of encapsulated cells makes them an ideal injectable system with minimally invasive strategies for in vivo applications.

Engineered skeletal muscle tissues can be used for in vitro studies that require physiologically relevant models of native tissues. Herein, we describe the development of a three-dimensional (3D) skeletal muscle tissue that recapitulates the architectural and structural complexities of muscle within a microfluidic device. Using a 3D photo-patterning approach, we spatially confined a cell-laden gelatin network around two bio-inert hydrogel pillars, which induce uniaxial alignment of the cells and serve as anchoring sites for the encapsulated cells and muscle tissues as they form and mature. We have characterized the tissue morphology and strain profile during differentiation of the cells and skeletal muscle tissue formation by using a combination of fluorescence microscopy and computational tools. The time-dependent strain profile suggests the existence of individual cells within the gelatin matrix, which differentiated to form a multinucleated skeletal muscle tissue bundle as a function of culture time. We have also developed a method to calculate the passive tension generated by the engineered muscle tissue bundles suspended between two pillars. Finally, as a proof-of-concept we have examined the applicability of the skeletal muscle-on-chip system as a screening platform and in vitro muscle injury model. We studied the dose-dependent effect of cardiotoxin on the engineered muscle tissue architecture and its subsequent effect on the passive tension. This simple yet effective tool can be appealing for studies that necessitate the analysis of skeletal muscle structure and function, including preclinical drug discovery and development.