Dense fibrillar collagen-based hydrogels as functional osteoid-mimicking scaffolds

ABSTRACT There is an increasing need to generate novel materials for the treatment and augmentation of bone defects, affecting millions of people worldwide. Fibrillar type I collagen is the most abundant tissue matrix protein in bone, providing its key native scaffolding material. However, while in vitro reconstituted collagen hydrogels of physically entangled, nano-fibred meshes, have long served as three-dimensional cultures, their highly-hydrated nature impacts their physiological relevance. In an effort to create biomimetic collagen gels, approaches have been undertaken to generate osteoid-like environments with increased collagen concentrations, controlled fibrillar orientation, defined micro-architectures, and tailored mechanical properties. This review describes the state-of-the-art on collagen densification techniques, exploring their advantages, limitations and future perspectives for applications as bone grafts. Ultimately, by successfully mimicking the organic milieu of bone through acellular or cell-mediated mineralisation of the designed osteoid-like structure, functional collagen scaffolds with potential applications in bone tissue engineering can be realised. Abbreviations: 3D: three-dimensional; BG: bioactive glass; CFD: collagen fibrillar density; CHA: carbonated-hydroxyapatite; Col1: Type I collagen; ECM: extracellular matrix; GAE: gel aspiration-ejection; HHC: highly hydrated collagen; MSC: mesenchymal stem cell; NCPs: non-collagenous proteins; PC: plastic compression; PILP: polymer-induced liquid precursor; SBF: simulated body fluid