U. Ripamonti et al., Induction of bone formation by recombinant human osteogenic protein-1 and sintered porous hydroxyapatite in adult primates, PLAS R SURG, 107(4), 2001, pp. 977-988
A critical issue in tissue engineering and morphogenesis of bone is the dev
elopment of novel biomimetic biomaterials that are capable of optimizing th
e biological activity of recombinant human bone morphogenetic and osteogeni
c proteins, which are molecules that initiate bone formation in vivo. From
a therapeutic perspective, a carrier matrix is required for the local deliv
ery of these proteins to evoke a desired osteogenic effect. In view of the
affinity of these proteins for hydroxyapatite, which may reflect the in viv
o supramolecular assembly of bone proteins bound to both the extracellular
matrix and the mineral component of bone, we investigated the efficacy of s
ingle applications of different doses of human osteogenic protein-1 (hOP-1)
adsorbed onto sintered porous hydroxyapatites for bone induction in orthot
opic calvarial defects in 12 adult male baboons (Papio ursinus) and heterot
opically in the rectus abdominis of four additional baboons. In orthotopic
specimens, pretreatment of sintered porous hydroxyapatites with 100 mug of
hOP-1 in 500 mul of 5 mM hydrochloric acid resulted in rapid and diffuse os
teoinduction restricted within the porous spaces of the hydroxyapatite, as
evaluated by histology and histomorphometry on day 30. Hydroxyapatites trea
ted with 500 mug of hOP-1 showed a different pattern of bone formation and
distribution on day 30 as compared with the lower dose of the recombinant m
orphogen. Although bone formation was extensive with the higher dose, it wa
s found on the endocranial and pericranial aspects of the specimens, envelo
ping the implanted hydroxyapatite carrier, and the internal porous spaces w
ere occupied by a rich vascular network without any bone formation. By 90 a
nd 365 days after the implantation of both doses of hOP-1, however, there w
as remodelling and complete penetration of the newly induced bone within th
e available porous spaces. The combination of hOP-1 and hydroxyapatite also
showed extensive bone formation in heterotopic specimens harvested from th
e rectus abdominis muscle of the baboon using doses of 5, 25, and 45 mug of
hOP-1 per implant. These findings in the adult primate demonstrate extensi
ve bone formation by hOP-1 adsorbed onto sintered porous hydroxyapatites an
d suggest that predictable osteogenesis in clinical contexts for treatment
of craniofacial bone defects may be engineered using inorganic, nonimmunoge
nic, and carvable delivery systems that initiate osteogenesis with relative
ly low doses of recombinant osteogenic proteins, thus mimicking the macrost
ructure and microstructure of living bone.