Functionalization of oligo(poly(ethylene glycol)fumarate) hydrogels with finely dispersed calcium phosphate nanocrystals for bone-substituting purposes

Biodegradable polymers that can be processed into injectable hydrogel matrices are promising candidates for bone-substituting purposes. Furthermore, by incorporating degradable calcium phosphate (CaP) particles and growth factors into these hydrogel matrices, a bone construct can be designed which stimulates the formation of new bone by the surrounding tissue, thereby compensating for the loss of structural integrity of the degrading synthetic bone-substitute. Generally, a major challenge in synthesis of nanoceramic-reinforced polymers is the achievement of a fine dispersion of nanoparticles throughout the polymer, since the unique properties of nanocomposites are lost when nanoparticles aggregate. In the current study, composite hydrogels consisting of oligo(poly(ethylene glycol)fumarate) (OPF) matrices and CaP dispersions of varying crystallinity were successfully developed using physical or chemical preparation strategies. Physical mixing of dried, micrometer-sized CaP powders resulted into formation of irreproducible composites with a highly heterogeneous dispersion of large and agglomerated CaP microparticles throughout the OPF matrix. On the contrary, reproducible and homogeneous hydrogels were fabricated using a chemical mixing strategy, whereby CaP crystals were formed in the presence of dissolved OPF macromers. This co-precipitation technique resulted into a much higher degree of dispersion of the CaP crystals, which can enable higher CaP contents in organic matrices such as OPF. By using these CaP suspensions instead of dried powders, the nanosized structure of separated CaP crystals was preserved, resulting into a higher reactivity of the CaP phase, as indicated by a reduced swelling behavior of these hydrogels. This effect was most likely caused by a physicochemical interaction between Ca²⁺ and unreacted COOH end-groups, thereby leading to increased physical cross-linking of the composite hydrogels.