Divide, combine and conquer : on the effect of individual properties of biomaterials for bone regeneration

Abstract

The increase of life expectancy in the developed countries has resulted in a growing demand for replacement of damaged and degraded bone. To overcome the limitations of autologous bone grafts, research efforts have focused for decades on developing synthetic substitutes that can be produced in large quantities, are readily available and relatively inexpensive. Among various synthetic bone graft substitutes, calcium phosphate (CaP)-based ones have been extensively used in bone repair and regeneration because of their close resemblance with natural bone mineral. CaP bone graft substitutes are biocompatible, osteogenic and osteoconductive, and some have shown osteoinductive properties, which are believed to be a prerequisite for reaching the same bone regenerative potential as natural bone grafts. Nevertheless, none of the CaP-based bone graft substitutes developed has yet reached the status of a full alternative to natural bone grafts. Bone graft substitutes are traditionally developed with the aim to find a material with the highest bone regenerative potential, using a somewhat trial-anderror approach. In an iterative process of, often small, modifications to a single material property and, often simplified, biological evaluations, large numbers of biomaterials are developed with similar performance. However, in most functional biomaterials properties are interlinked, making it very difficult to control and modify a single material parameter without affecting the others, and to describe the exact relationship between this material property and a biological response. The strategy developed in this thesis was to step away from the conventional, processing-driven biomaterials development to a design-driven one, whereby combining and converging of materials and technologies is a logical step. The overall aim was twofold: (1) to explore strategies to isolate individual properties of complex biomaterials in order to investigate their independent effects on a biological response and based on this knowledge (2) to recombine individual properties into new, improved functional biomaterials. Using this approach, the chemical and structural properties of CaP materials were investigated and exploited throughout this thesis by designing innovative implants in CaP-based composites (Chapter 2), investigating the independent effect of calcium and phosphate ions (Chapter 3), studying the effect of CaP crystal topography and decoupling this effect from that of the CaP chemistry (Chapter 4), and finally by recombining the desired chemical and structural properties into improved functional materials (Chapters 4 and 5). This exploratory journey aspired to identify tools and techniques that can be used to change the way bone graft substitute materials are designed and developed. The final aim is thereby to deliver fundamental answers regarding the effect of specific material properties on the biological system, while developing innovative and improved materials.