Advances in biomimetic collagen mineralisation and future approaches to bone tissue engineering

Abstract

With an ageing world population and ~20% of adults in Europe being affected by bone diseases, there is an urgent need to develop advanced regenerative approaches and biomaterials capable to facilitate tissue regeneration while providing an adequate microenvironment for cells to thrive. As the main components of bone are collagen and apatite mineral, scientists in the tissue engineering field have attempted in combining these materials by using different biomimetic approaches to favour bone repair. Still, an ideal bone analogue capable of mimicking the distinct properties (i.e., mechanical properties, degradation rate, porosity, etc.) of cancellous bone is to be developed. This review seeks to sum up the current understanding of bone tissue mineralisation and structure while providing a critical outlook on the existing biomimetic strategies of mineralising collagen for bone tissue engineering applications, highlighting where gaps in knowledge exist.

Keywords: apatite; biomimetic; bone tissue engineering; collagen; mineralisation.

FIGURE 1

Diagram of collagen arrangement; (a) portion of collagen molecule; (b) 2D molecular organization within fibril; (c) 3D fibril with gap and overlap spaces aligned; (d) 3D fibre, with gap and overlap spaces aligned

FIGURE 2

TEM scans showing three distinct bone patterns which are reprojections of one another when viewed at different angles; (a, d) Filamentous motif; (b, e) Lacy motif; (c, f) Rosette motif (Modified with permission—Copyright © 2018, Reznikov et al., The American Association for the Advancement of Science)

FIGURE 3

Comparison of old versus new theories on hydroxyapatite morphology within bone: (a, b) ‘Deck of cards’ mineral arrangement, with parallel plates occupying the intrafibrillar spaces; (c) slightly twisted plates in the intrafibrillar spaces with acicular crystals (red) projecting from them; (d) 2D illustration of the relationship between acicular crystals and fibrils

FIGURE 4

3D XRD electron density map of collagen structure. (a) Intermolecular voids within collagen structure, with gap/overlap zones labelled; (b–e) cross‐section slices along the collagen fibril at position i–iv, respectively, highlighted by white arrows in (a). (b) Typical structures of the overlap region. (c–e) 2–3 nm wide channels in gap region with varying cross‐section shapes. A unit cell is highlighted by a yellow parallelogram (Modified with permission—Copyright © 2020, YiFei Xu et al., Nature Communications)

FIGURE 5

Osteoblast functions: (a) osteoblast; (b) intake of calcium ions towards the ER; (c) agglomerated calcium sent to the mitochondria for assembly with phosphate ions; (d) matrix vesicles containing ACP are secreted; (e) assembly of tropocollagen from procollagen; (f) transport from the ER to the Golgi complex; (g) exocytosis through cell membrane; (h) alternative exocytotic mechanism

FIGURE 6

Comparison of collagen mineralisation methods: (a, b) surface mineralisation, with large cluster formation in solution and minimal substrate infiltration; (c, d) PILP method, with size‐limited mineral precursors in solution and deep substrate penetration through the surface; (e, f) hydroxyapatite/Collagen coprecipitation, showing nucleation on tropocollagen molecules before crosslinking, resulting in homogeneous collagen mineralisation

FIGURE 7

Illustration of potential improvement of existing in vitro biomineralisation methods towards creating biomineralized collagen matrices as bone tissue analogues: addressing existing knowledge gaps on biomineralisation processes and regulating mineralisation in vitro for improved in vivo tissue regeneration