Background: In a series of studies in the primate Papio
ursinus, we have examined the capacity of bone morphogenetic
proteins (BMPs/OPs) delivered in a variety of biomaterial
carrier systems to elicit bone formation in heterotopic and orthotopic
sites. In this review, we compare the osteoinductive effects of
different biomaterial delivery systems that have or have not been
pretreated with BMPs/OPs. In particular, we focus on the
geometric induction of bone formation by sintered porous hydroxyapatite
(SPHA) discs with concavities on their planar surfaces, which elicit
bone formation without exogenously applied BMPs/OPs.
Methods: Heterotopic bone formation was examined
by bilaterally implanting 100-mg pellets of a collagenous carrier
containing BMPs/OPs in the rectus abdominis muscle
of the adult baboon. Orthotopic bone formation was examined by implanting
1 g of a collagenous carrier containing BMPs/OPs into two
full-thickness critical-sized 25-mm-diameter defects on each side
of the calvaria of adult baboons. The BMPs/OPs whose effects
were examined included recombinant human osteogenic protein-1 (rhOP-1), recombinant
human transforming growth factor-ß1 (rhTGF-ß1),
rhTGF-ß2, and porcine platelet derived transforming
growth factor-ß1 (pTGF-ß1). Tissue from
the rectus abdominis muscle was harvested 30 or
90 days after implantation. Tissue from the orthotopic calvarial
model was examined at 1, 3, 6, 9, and 12 months after implantation.
To demonstrate the effect of surface geometry on bone induction,
hydroxyapatite powders were sintered to form solid discs with a
series of concavities on the planar surfaces of the SPHA discs.
The discs were either pretreated with exogenous rhOP-1 or not treated
with exogenous OP-1. They were then implanted heterotopically or
orthotopically into calvarial defects. Bone formation was evaluated
histologically in undecalcified sections stained with Goldner’s
trichrome stain or 0.1% toluidine blue.
Results: Naturally derived BMPs/OPs or
rhOP-1 in a collagenous carrier elicit heterotopic bone formation and
the complete healing of 25-mm-diameter critical-sized defects by
day 90 following implantation. Binary applications of TGF-ß1
together with rhOP-1 in the collagen carrier induced massive endochondral
ossicles in heterotopic sites and bone formation in calvarial defects.
pTGF-ß1, rhTGF-ß1, and rhTGF-ß2
are powerful inducers of heterotopic endochondral bone formation
but elicit limited bone formation in calvarial defects. SPHA discs
pretreated with rhOP-1 elicited extensive bone formation in both
heterotopic and orthotopic sites. However, SPHA without
rhOP-1 also elicited bone formation in heterotopic and orthotopic
sites and complete healing of the calvarial defects.
Conclusion: We have prepared SPHA discs with concavities
on their planar surfaces that induce bone formation in heterotopic
or orthotopic critical-sized calvarial defects without exogenously
applied BMPs/OPs. This biomaterial induces bone
formation by intrinsic osteoinductivity regulated by the geometry
of the substratum. The incorporation of specific biological activities
into biomaterials by manipulating the geometry of the substratum,
defined as geometric induction of bone formation, may
make it possible to engineer morphogenetic responses for therapeutic
osteogenesis in clinical contexts.
Clinical Relevance: We have implemented a clinical
trial using naturally derived BMPs/OPs extracted and purified from
bovine bone matrices and implanted in craniofacial defects in humans.
In addition, the discovery that specific geometric and surface characteristics of
sintered hydroxyapatites can induce intrinsic osteoinductivity in
primates paves the way for formulation and therapeutic application
of porous substrata designed to obtain predictable intrinsic
osteoinductivity in clinical contexts.