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Geometric induction of bone formation
- Soluble, insoluble and geometric signals sculpt the architecture of mineralized tissues

To trigger the cascade of tissue morphogenesis and endochondral bone differentiation, the soluble signals require reconstitution with an insoluble signal, or substratum [2-6]. Whilst molecular biology has elucidated many of the cellular and sub-cellular events activated by the molecular soluble signals, significantly less is known of optimal delivery systems to act as insoluble substrata [2, 9, 10, 12].

The requisite properties of the substratum are that it should be nonimmunogenic, inorganic, carvable and amenable to contouring for optimal adaptation to the various shapes of bone defects. Optimal osteogenic activity should be induced with relatively low doses of recombinant human (rh) BMPs/OPs [2, 10–12, 35]. In addition, an ideal substratum for bone tissue engineering should promote angiogenesis and mesenchymal tissue invasion to be brought in contact with rhBMPs/OPs previously adsorbed on the substratum. The processes of bone remodelling finally occur once the regenerative processes are well under way.

Significantly, the surface characteristics and geometric configurations of the delivery system are critical for bone induction to occur with and without the exogenous application of BMPs/OPs [2, 9, 10, 12, 36–45].

A major objective of our research has been to develop biomaterials that are specifically designed to optimise upregulation of specific BMPs/OPs genes upon implantation of geometrically and biologically correct matrices [10, 11, 40, 41]. After many studies in the primate Papio ursinus we have shown in collaboration with the Council for Scientific and Industrial Research (CSIR) Pretoria [40, 46], that a specific geometry of the substratum of sintered and highly crystalline hydroxyapatite drives bone formation by induction within the porous hydroxyapatite, a phenomenon which we have labelled as geometric induction of bone formation [40, 46]. We have found that the optimal morphogenetic geometry has the shape of a concavity of a specific dimension, and that the concavity is smart in the sense that it anchors specific endogenous BMPs/OPs at the interface of the hydroxyapatite with the fibrovascular tissue invading the concavities with induction of bone as a secondary response [2, 9–12, 40, 47] (Figs. 4 and 5).

To investigate intrinsic osteoinductivity imparted by surface geometry, monolithic discs of hydroxyapatite with concavities on both planar surfaces were implanted in the rectus abdominis muscle of the primate Papio ursinus. Histological analysis of the specimens harvested 30 and 90 days after implantation revealed that bone differentiation was initiated exclusively in the concavities of the substratum (Figs. 4 and 5). On day 30, BMP-3 and OP-1 (also known as BMP-7) were detected by immunolocalization at the mesenchymal tissue-hydroxyapatite interfaces within the concavities of the substratum [40]. Thus the sintered hydroxyapatite acts as a solid state matrix for adsorption and anchorage of endogenously produced BMP-3 and OP-1, and new bone formation occurs as a secondary response [2, 10, 11, 40, 47]. Importantly, porous discs of sintered hydroxypatite implanted in non-healing calvarial defects in non-human primates showed substantial bone formation, culminating in complete deposition of bone spanning the defects [40].

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