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Alginate is a biomaterial that has found numerous applications in biomedical science and engineering due to its favorable properties, including biocompatibility and ease of gelation. Alginate hydrogels have been particularly attractive in wound healing, drug delivery, and tissue engineering applications to date, as these gels retain structural similarity to the extracellular matrices in tissues and can be manipulated to play several critical roles. This review will provide a comprehensive overview of general properties of alginate and its hydrogels, their biomedical applications, and suggest new perspectives for future studies with these polymers.

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Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform in which various physiochemical interactions with the encapsulated drugs control their release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel–drug interactions across the network, mesh, and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over the drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems, and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multi-faceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and ultimately to enhance stem cell integration in vivo for therapeutic benefit.Control over stem cell trafficking, survival, proliferation, and differentiation within a complex in vivo milieu is extremely challenging. In studies of animal models and humans where stem cell engraftment has been quantified after injection, only a few percent of cells remain after several days or weeks [eg.(1)]. Many clinical trials are nonetheless underway, particularly with adult bone marrow derived mesenchymal stem cells (MSC) which are being investigated as treatments for diseases of non-hematopoietic tissues -primarily myocardial infarction and peripheral ischemia (2). Although FDA approval for human testing of cells differentiated from embryonic stem cells (ESC) is a recent landmark for the field (3), two widely reported clinical cases highlight some of the technical opportunities and challenges with stem cells in soft tissue repair. One patient in Spain was successfully transplanted with a re-engineered trachea in 2008: donor trachea was first decellularized using a detergent (without denaturing the collagenous matrix), and then this scaffold was re-cellularized in a rotating bioreactor using MSC-derived cartilage-like cells (4). Long term safety and efficacy will be important to monitor and understand. Indeed, in a second case, the cerebellum of a boy with ataxia telangiectasia (AT) was injected with human fetal neural stem cells (NSC), and four years later, a glio-neuronal brain tumor of stem cell origin was found (5). Upon implantation, stem cells and their derived lineages encounter a multitude of cues that can influence cell fate. Efforts to parse the molecular mechanisms for translation from bench to clinic will increasingly benefit from a wide range of new and established technologies. Here we briefly review salient features of microenvironments, mechanics, and material systems that are being pursued to control stem cells for both basic insight and application.Correspondence: discher@seas.upenn.edu, mooneyd@seas.harvard.edu, peter.zandstra@utoronto.ca. NIH Public Access Niche interactions and in vitro designsThe niche is the in vivo microenvironment that regulates stem cell survival, self-renewal, and differentiation. Key niche components and interactions include growth factors, cell-cell contacts, and cell-mat...

Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel’s initial elastic modulus, cell-adhesion-ligand density and degradation. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.

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