Cell transplantation via direct cell injection at the target site is a minimally invasive and clinically preferred strategy for treating various injuries and degenerative diseases. The therapeutic success of the functional recovery critically hinges on the survival and subsequent maintenance of the transplanted cells. We previously designed a recombinant protein polymer system that forms a mixing-induced two-component hydrogel (MITCH), which is shear-thinning and cell-protective during syringe injection. However, MITCH was completely resorbed in vivo within two weeks and had a shear modulus of ~10 Pa, which may be too compliant for many therapeutic applications. To address these limitations, we designed an injectable hydrogel that undergoes two different physical crosslinking mechanisms. The first crosslinking step occurs ex vivo through peptide-based molecular recognition to encapsulate cells within a physical hydrogel, while the second crosslinking step occurs in situ through a thermal phase transition to form a reinforcing network. Specifically, the molecular recognition takes place between a star-shaped peptide-polyethylene glycol (PEG) copolymer binding to an engineered recombinant protein, while the thermal phase transition is rendered via a thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) segment tethered to the PEG. At room temperature, the MITCH-PEG-PNIPAM physical hydrogel is shear-thinning and self-healing to facilitate gentle cell encapsulation and transplantation by syringe injection. At body temperature, the hydrogel forms a secondary network resulting in a 10-fold increase in shear modulus Human adipose-derived stromal cells (hASCs) exposed to hand-injection through a 28-gauge syringe needle were significantly protected from disruptive mechanical forces when encapsulated within the hydrogel compared to injection of cells in saline alone (93 � 4% vs. 69 � 5% cell viability, respectively). These results suggest that in situ formation of a reinforcing network within an already existing hydrogel can enhance mechanical properties, potentially improving long-term cell protection, and providing support towards functional tissue regeneration.

Injectable hydrogels with in situ double network formation for cell transplantation

248th National Meeting (2014)

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