Abstract
Macroporous single phase hydroxyapatite (HA) and biphasic HA/β-tricalcium phosphate with 33% post-sinter hydroxyapatite (HA/β-TCP) were combined with 25 or 125 μg recombinant human transforming growth factor-β3 (hTGF-β3) to engineer a super activated bioreactor implanted in orthotopic calvarial and heterotopic rectus abdominis muscle sites and harvested on day 30 and 90. Coral-derived calcium carbonate fully converted (100%) and partially converted to 5 and 13% hydroxyapatite/calcium carbonate (5 and 13% HA/CC) pre-loaded with 125 and 250 μg hTGF-β3, and 1:5 and 5:1 binary applications of hTGF-β3: hOP-1 by weight, were implanted in the rectus abdominis and harvested on day 20 and 30, respectively, to monitor spatial/temporal morphogenesis by high doses of hTGF-β3. Bone formation was assessed on decalcified paraffin-embedded sections by measuring the fractional volume of newly formed bone. On day 30 and 90, single phase HA implants showed greater amounts of bone when compared to biphasic specimens; 5 and 13% HA/CC pre-loaded with 125 and 250 μg hTGF-β3 showed substantial induction of bone formation; 250 μg hTGF-β3 induced as yet unreported massive induction of bone formation as early as 20 days prominently outside the profile of the macroporous constructs. The induction of bone formation is controlled by the implanted ratio of the recombinant morphogens, i.e., the 1:5 hTGF-β3:hOP-1 ratio by weight was greater than the inverse ratio. The unprecedented tissue induction by single doses of 250 μg hTGF-β3 resulting in rapid bone morphogenesis of vast mineralized ossicles with multiple trabeculations surfaced by contiguous secreting osteoblasts is the novel molecular and morphological frontier for the induction of bone formation in clinical contexts.
Highlights
Nature relies on common but limited conserved molecular mechanisms tailored to provide the emergence of specialized tissues and organs
We describe the induction of bone formation by a variety of macroporous calcium phosphate-based constructs implanted in heterotopic intramuscular rectus abdominis and orthotopic calvarial sites of P. ursinus to engineer a super activated bone bioreactor by the human transforming growth factor-β3 (hTGF-β3) isoform for the rapid induction of bone formation in pre-clinical and clinical contexts
We further report that the ratio by weight of the binary application of hTGF-β3 and human osteogenic protein-1 (hOP-1) is a critical parameter that controls the synergistic induction of bone formation
Summary
Nature relies on common but limited conserved molecular mechanisms tailored to provide the emergence of specialized tissues and organs. The molecular cloning of the BMPs/OPs (Wozney et al, 1988; Özkaynak et al, 1990) and the results obtained in numerous pre-clinical studies in mammalian species including non-human primates (Reddi, 2000; Ripamonti, 2004, 2006a) have prematurely convinced molecular biologists, tissue engineers, and skeletal reconstructionists alike to believe that a single recombinant human bone morphogenetic protein would result in clinically acceptable tissue induction and morphogenesis (Friedlaender et al, 2001; Govender et al, 2002). Clinical trials of craniofacial and orthopedic applications such as mandibular reconstruction and sinus-lift operations have indicated that supra physiological doses of a single recombinant human protein are needed to induce often unacceptable tissue induction whilst incurring significant costs without equivalence to autogenous bone grafts (Ripamonti et al, 2006, 2007a, 2009a; Garrison et al, 2007; Mussano et al, 2007)
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