cell-instructive pectin hydrogels using cell-degradable peptide crosslinkers and integrin-specific adhesive ligands. Pectin, a structural polysaccharide, has been explored by our group for the design of biofunctional hydrogels owing the lack of endogenous biochemical cues and in vivo biodegradabilit

Cell-instructive hydrogels are attractive for skin repair and regeneration, serving as interactive matrices to promote cell adhesion, cell-driven remodeling and de novo deposition of extracellular matrix components. This paper describes the synthesis and photocrosslinking of cell-instructive pectin hydrogels using cell-degradable peptide crosslinkers and integrin-specific adhesive ligands. Protease-degradable hydrogels obtained by photoinitiated thiol-norbornene click chemistry are rapidly formed in the presence of dermal fibroblasts, exhibit tunable properties and are capable of modulating the behavior of embedded cells, including the cell spreading, hydrogel contraction and secretion of matrix metalloproteases. Keratinocytes seeded on top of fibroblast-loaded hydrogels are able to adhere and form a compact and dense layer of epidermis, mimicking the architecture of the native skin. Thiol-ene photocrosslinkable pectin hydrogels support the in vitro formation of full-thickness skin and are thus a highly promising platform for skin tissue engineering applications, including wound healing and in vitro testing models. Professor W. R. Wagner Editor-in-Chief, Acta Biomaterialia Manchester, July 21, 2017 Dear Editor-in-Chief of Acta Biomaterialia Professor W. R. Wagner We are submitting our original manuscript entitled “Cell-instructive pectin hydrogels crosslinked via thiol-norbornene photo-click chemistry for skin tissue engineering”, for consideration by Acta Biomaterialia. The design of advanced hydrogels capable of providing an instructive environment able to support and direct cell functions is fundamental for several tissue engineering applications. However, the majority of cell-instructive hydrogels currently available are based on synthetic polymers due to the improved control over biochemical and biophysical properties. This manuscript describes, for the first time, the synthesis and photocrosslinking of cell-instructive pectin hydrogels using cell-degradable peptide crosslinkers and integrin-specific adhesive ligands. Pectin, a structural polysaccharide, has been explored by our group for the design of biofunctional hydrogels owing the lack of endogenous biochemical cues and in vivo biodegradability. A fast and robust chemical modification strategy was developed for the norbornene-functionalization of pectin, allowing the rapid formation of hydrogels through UV photoinitiated thiol-ene click chemistry. Hydrogels were formed in the presence of dermal fibroblasts, supporting the cell viability, adhesion and spreading. The hydrogel system reported herein also enables to independently tailor the biophysical and biochemical properties of the hydrogel microenvironment, providing a modular approach for the design of cellinstructive hydrogels capable of supporting the in vitro skin formation. We believe this topic is timely and the materials reported here is original and innovative making a significant contribution to the field. Acta Biomaterialia is the adequate journal to publish this manuscript since our focus is on the innovative materials developed and their characterization for tissue engineering applications. Yours sincerely, Professor Paulo Jorge Bártolo Chair of Advanced Manufacturing Processes Head of the Manufacturing Group Director of the Manchester Biomanufacturing Centre School of Mechanical, Aerospace and Civil Engineering, University of Manchester, UK Manchester Institute of Biotechnology, University of Manchester, UK Cover Letter