Background: The effect of the geometry of extracellular
matrices on bone morphogenetic protein (BMP)-induced osteogenesis
has not been systematically studied. Geometry is crucially important
for the scaffold in bone and joint tissue engineering. The purpose
of this study was to elucidate principles of geometry of matrices
in designing new scaffolds and matrices for use in reconstruction
of bone and joints.
Methods: More than ten biomaterials with different
geometries, including a unique device of honeycomb-shaped hydroxyapatite,
were combined with BMPs of recombinant (rhBMP-2) or natural bovine
origin (S300 BMP cocktail) and implanted subcutaneously into 4-week-old
Wistar-King rats. The implanted pellets were removed at 1-4 weeks
and analyzed for bone and cartilage formation by histological and
Results: BMP-induced bone and cartilage induction
was highly dependent on the geometric properties of the carrier.
Some carriers such as porous particles or blocks of hydroxyapatite
induced osteogenesis directly, without detectable chondrogenesis, whereas
other carriers such as fibrous glass membrane induced cartilage
exclusively. Still other carriers induced mostly cartilage followed
by bone formation. Solid particles of hydroxyapatite and fibrous
glass membrane with too tight a meshwork did not induce bone or
cartilage. The optimal pore size for bone-forming efficacy
in porous blocks of hydroxyapatite was a diameter of 300-400 lm. In
straight tunnel structures with various diameters in honeycomb-shaped
hydroxyapatite, tunnels with smaller diameters (90-120 mm) induced
cartilage followed by bone formation, whereas those with larger
diameters (350 mm) induced bone formation directly within the tunnels.
Conclusions: BMP carriers were classified into three
types: bone-inducing, cartilage-inducing, and cartilage-bone-inducing.
From the analysis of causative factors inducing osteogenesis and
chondrogenesis in the BMP system, we concluded that the geometry of
the carrier is crucially important and vasculature-inducing
geometry should be considered in designing effective scaffolds
for bone formation. We propose a classification of geometry of the
artificial extracellular matrices that is useful for designing a
scaffold for tissue engineering of bone and related tissues.
Clinical Relevance: Conventional requisites of the
BMP carriers for clinical use have mainly concerned the affinities
of carriers with cells and biomolecules and their mechanical strength.
The vasculature-inducing geometry of carriers adds
a new criterion in designing systems for effective bone and joint
reconstruction. The geometries of porous structures—their
sizes, continuity, and straightness as verified by hydroxyapatite
in this study—will be applicable for other biomaterials
for clinical reconstruction therapy.