Injectable biodegradable copolymer hydrogels, which exhibit a sol–gel phase transition in response to external stimuli, such as temperature changes or both pH and temperature (pH/temperature) alterations, have found a number of uses in biomedical and pharmaceutical applications, such as drug delivery, cell growth, and tissue engineering. These hydrogels can be used in simple pharmaceutical formulations that can be prepared by mixing the hydrogel with drugs, proteins, or cells. Such formulations are administered in a straightforward manner, through site‐specific control of release behavior, and the hydrogels are compatible with biological systems. This review will provide a summary of recent progress in biodegradable temperature‐sensitive polymers including polyesters, polyphosphazenes, polypeptides, and chitosan, and pH/temperature‐sensitive polymers such as sulfamethazine‐, poly(β‐amino ester)‐, poly(amino urethane)‐, and poly(amidoamine)‐based polymers. The advantages of pH/temperature‐sensitive polymers over simple temperature‐sensitive polymers are also discussed. A perspective on the future of injectable biodegradable hydrogels is offered.magnified image

In the past two decades, physical polymeric hydrogels have been extensively explored for biomedical applications, such as drug delivery and tissue engineering. These hydrogels exhibit a sol–gel phase transition in response to external stimuli, such as pH, temperature, glucose, electric field, magnetic field, ionic strength, or their combination. Hydrogel precursors can be mixed with bioactive molecules or cells and then simply injected into the body at specific sites. Substantial progress has been made in the development of novel hydrogels and applications. In this Perspective, we report recent progress in physically cross-linked hydrogels responding to pH and/or temperature and their pharmaceutical and tissue engineering applications. The outlook for the future, including remaining challenges of injectable hydrogels, is also discussed.

To date, RNA interfering molecules have been used to differentiate stem cells on two-dimensional (2D) substrates that do not mimic three-dimensional (3D) microenvironments in the body. Here, in situ forming poly(ethylene glycol) (PEG) hydrogels were engineered for controlled, localized and sustained delivery of RNA interfering molecules to differentiate stem cells encapsulated within the 3D polymer network. RNA interfering molecules were released from the hydrogels in a sustained and controlled manner over the course of 3-6 weeks, and exhibited high bioactivity. Importantly, it was demonstrated that the delivery of siRNA and/or miRNA from the hydrogel constructs enhanced the osteogenic differentiation of encapsulated stem cells. Prolonged delivery of siRNA and/or miRNA from this polymeric scaffold permitted extended regulation of cell behavior, unlike traditional siRNA experiments performed in vitro. This approach presents a powerful new methodology for controlling cell fate, and is promising for multiple applications in tissue engineering and regenerative medicine.

Polymer hydrogels have been widely explored as therapeutic delivery matrices because of their ability to present sustained, localized and controlled release of bioactive factors. Bioactive factor delivery from injectable biopolymer hydrogels provides a versatile approach to treat a wide variety of diseases, to direct cell function and to enhance tissue regeneration. The innovative development and modification of both natural-(e.g., alginate (ALG), chitosan, hyaluronic acid (HA), gelatin, heparin (HEP), etc.) and synthetic-(e.g., polyesters, polyethyleneimine (PEI), etc.) based polymers has resulted in a variety of approaches to design drug delivery hydrogel systems from which loaded therapeutics are released. This review presents the state-of-the-art in a wide range of hydrogels that are formed though self-assembly of polymers and peptides, chemical crosslinking, ionic crosslinking and biomolecule recognition. Hydrogel design for bioactive factor delivery is the focus of the first section. The second section then thoroughly discusses release strategies of payloads from hydrogels for therapeutic medicine, such as physical incorporation, covalent tethering, affinity interactions, on demand release and/or use of hybrid polymer scaffolds, with an emphasis on the last 5 years.

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The growing socioeconomic burden of musculoskeletal injuries and limitations of current therapies have motivated tissue engineering approaches to generate functional tissues to aid in defect healing. A readily implantable scaffold‐free system comprised of human bone marrow‐derived mesenchymal stem cells embedded with bioactive microparticles capable of controlled delivery of transforming growth factor‐beta 1 (TGF‐β1) and bone morphogenetic protein‐2 (BMP‐2) was engineered to guide endochondral bone formation. The microparticles were formulated to release TGF‐β1 early to induce cartilage formation and BMP‐2 in a more sustained manner to promote remodeling into bone. Cell constructs containing microparticles, empty or loaded with one or both growth factors, were implanted into rat critical‐sized calvarial defects. Micro‐computed tomography and histological analyses after 4 weeks showed that microparticle‐incorporated constructs with or without growth factor promoted greater bone formation compared to sham controls, with the greatest degree of healing with bony bridging resulting from constructs loaded with BMP‐2 and TGF‐β1. Importantly, bone volume fraction increased significantly from 4 to 8 weeks in defects treated with both growth factors. Immunohistochemistry revealed the presence of types I, II, and X collagen, suggesting defect healing via endochondral ossification in all experimental groups. The presence of vascularized red bone marrow provided strong evidence for the ability of these constructs to stimulate angiogenesis. This system has great translational potential as a readily implantable combination therapy that can initiate and accelerate endochondral ossification in vivo. Importantly, construct implantation does not require prior lengthy in vitro culture for chondrogenic cell priming with growth factors that is necessary for current scaffold‐free combination therapies. Stem Cells Translational Medicine 2017;6:1644–1659

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Delivery of RNAi molecules may be a valuable strategy to guide cell behavior for tissue engineering applications, but to date there have been no reports of a biomaterial system capable of both encapsulation of cells and controlled delivery of incorporated RNA. Here, we present PEG hydrogels that form in situ via Michael type reaction, and that permit encapsulation of hMSCs and the concomitant controlled delivery of siNoggin and/or miRNA-20a. These RNAs were chosen to suppress noggin, a BMP-2 antagonist, and/or PPAR-γ, a negative regulator of BMP-2-mediated osteogenesis, and therefore promote osteogenic differentiation of hMSCs and subsequent bone repair in critical-sized rat calvarial defects. Simultaneous delivery of hMSCs and miRNA-20a enhanced repair of these defects compared to hydrogels containing hMSCs without siRNA or with negative control siRNA. This in situ forming PEG hydrogel system offers an exciting platform for healing critical-sized bone defects by localized, controlled delivery of RNAi molecules to encapsulated hMSCs and surrounding cells.