Combing electrospinning, layer-by-layer deposition and tetrazine ligation, the inverse-electron-demand Diels-Alder cycloaddition between s-tetrazines (Tz) and trans-cyclooctenes (TCO), we are developing a new type of fibrous patches capable of modulating cellular programs and the extracellular environment to suppress fibrogenesis and to regenerate the normal functions of soft connective tissues. Fibrous scaffolds with an average fiber diameter of 5 mm were produced by electrospinning of hydrophobic poly(e-caprolactone) (PCL). Antifibrotic drugs (model ROCK inhibitors) can be included in the spinning solution to afford drug-loaded fibers. Brief Immersion of the PCL scaffolds in an alkaline solution led to the introduction of surface carboxylates, through which tetrazine group was immobilized via an amide bond. Separately, tetrazine or TCO- modified hyaluronic acid (HA-Tz and HA-TCO), as well as TCO-tagged cell adhesive peptide (RGD-TCO), were synthesized and characterization. Dipping tetrazine-functionalized PCL scaffolds in HA-TCO and HA-Tz baths in an alternating fashion resulted in the rapid build-up of a thick HA coating (1.7-2.0 mm) around individual fibers. Inclusion of RGD-TCO in the last HA-TCO bath led to the instantaneous conjugation of integrin-binding motifs to the fiber. Primary porcine vocal fold fibroblasts (PVFFs) were introduced to the drug-releasing core-shell scaffold and the culture was maintained for up to 14 days. Compare to the control PCL fibers, the core-shell fibers significantly suppressed the myofibroblast differentiation, as evidenced by positive a-smooth muscle actin (SMA) staining and the presence of mature stress fibers. Our results suggest that priming scar tissues with a fibrous patch that is soft and compliant, at the same time, releasing antifibrotic therapies in a controlled manner, will effectively suppress the fibrogenesis.

Tetrazine ligation-mediated layer-by-layer deposition for the development of antifibrotic patches

256th National Meeting (2018)

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