Fonseca et. al. Enzymatic, physicochemical and biological properties of MMP-sensitive alginate hydro

Biofunctional derivatives namely through the

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Unformatted text preview: onal derivatives, namely through the incorporation of cell-signalling moieties. INEB – Instituto de Engenharia Biom´dica, Universidade do Porto, Rua do Campo e Alegre 823, 4150-180 Porto, Portugal. E-mail: ccbarrias@ineb.up.pt; Fax: +351226094567; Tel: +351-226074982 a b ´ Departamento de Engenharia Metalurgica e Materiais, Faculdade de Engenharia da Universidade do Porto (FEUP), Porto, Portugal c ~ Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de Sao ~ Paulo, Rua Trˆs de Maio 100, 04044-020 Sao Paulo, Brazil e d Instituto de Ciˆncias Biom´dicas Abel Salazar (ICBAS), Universidade do Porto, Porto, e e Portugal This journal is ª The Royal Society of Chemistry 2013 3D The incorporation of ECM-like peptides on the polymer backbone is among the strategies most used to promote cell interactions with hydrogels.10,11 Since the rst modication of alginate with tethered motifs containing the cell-adhesive peptide sequence Arg-Gly-Asp (RGD),12 several authors explored the behaviour of various cell types cultured on or within RGDalginate hydrogels, in vitro and in vivo.5,13–15 The co-incorporation of proteolytically cleavable peptides into hydrogels to promote cell-mediated degradation, a strategy originally proposed for the modication of PEG,16 may empower the future applications of alginate matrices as biomaterials. Recently, we reported the functionalization of alginate with the peptide sequence GGYGPVGYLIGGK, which contains a matrix metalloproteinase (MMP)-sensitive substrate (underlined; the arrow represents the cleavage site).17 The designed sequence bears a free amine at each end, the terminal a-amino and Lys 3amino groups, providing two reactive sites for the carbodiimide peptide graing into alginate carboxyl groups.17 This doubleend graing strategy was intended to afford a low degree of PVGLIG-mediated crosslinking of the polymer chains, which thus remained water-soluble and could still be converted into hydrogels using an in situ ionic crosslinking approach as envisaged. This crosslinking process is reversible upon addition of a chelating agent, allowing cell recovery without the need for Soft Matter, 2013, 9, 3283–3292 | 3283 View Article Online Downloaded by State University of New York at Buffalo on 16/04/2013 03:56:51. Published on 08 February 2013 on http://pubs.rsc.org | doi:10.1039/C3SM27560D Soft Matter any mechanical or enzymatic treatments, which represents an additional advantage of these hydrogels as 3D culture matrices. The PVGLIG motif, originally deduced from a combinatorial peptide library of MMP–substrates,18 was rst proposed by Chau et al. as a labile linker for MMP-activated delivery of chemotherapeutics,19 and later on used to functionalize self-assembling peptide hydrogels.20 It was shown to be cleavable by MMP-2 and MMP-9, but no other MMPs were tested.19 Since MMPs generally share many common features in their consensus cleavage motifs,18 a more detailed analysis of GGYGPVGYLIGGK se...
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