Glycosaminoglycans (GAGs) govern important functional characteristics of the extracellular matrix (ECM) in living tissues. Accordingly, incorporation of GAGs into biomaterials opens up new routes for the presentation of signaling molecules in ways that allow for exploring mechanistic aspects of tumor formation and progression under defined constraints, as well as for individualized anticancer drug screening.
In an attempt to systematically explore the related options, we have introduced a rational design strategy for biology-inspired hydrogels based on multi-armed poly(ethylene glycol), GAGs and peptides (1,2,3). The theoretically predicted decoupling of biochemical and mechanical gel properties was confirmed experimentally and applied for implementing GAG-based biofunctionalization schemes to afford cell adhesiveness and morphogen presentation.
GAG-based, three dimensional (3D) culture models were used to study breast and prostate tumour vascularization in vitro. With this approach, multiple cell types were shown to be less sensitive to chemotherapy when compared with two dimensional (2D) cultures, and displayed comparative tumour regression to that displayed in vivo (5,6). Matrix metalloproteinase-sensitive GAG-based hydrogels functionalized with adhesion ligands and pro-angiogenic factors were furthermore shown to be instrumental for the ex vivo analysis of acute myeloid leukemia development and response to treatment (7).
Beyond that, immunotherapeutic organoids were developed by housing human mesenchymal stromal cells (MSCs), gene-modified for the secretion of an anti-CD33-anti-CD3 bispecific antibody (bsAb), in macroporous GAG-based cryogel scaffolds. The constructs were demonstrated to serve as a transplantable and low invasive therapeutic machinery for the treatment of acute myeloid leukemia in a mouse model (8).