Biomaterials can be endowed with biologically instructive properties by changing basic parameters such as elasticity and surface texture. However, translation from in vitro proof of concept to clinical application is largely missing. Porous calcium phosphate ceramics are used to treat small bone defects but in general do not induce stem cell differentiation, which is essential for regenerating large bone defects. Here, we prepared calcium phosphate ceramics with varying physicochemical and structural characteristics. Microporosity correlated to their propensity to stimulate osteogenic differentiation of stem cells in vitro and bone induction in vivo. Implantation in a large bone defect in sheep unequivocally demonstrated that osteoinductive ceramics are equally efficient in bone repair as autologous bone grafts. Our results provide proof of concept for the clinical application of “smart” biomaterials.

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In the past thirty years, a number of biomaterials have shown the ability to induce bone formation when implanted at heterotopic sites, an ability known as osteoinduction. Such biomaterials -osteoinductive biomaterials -hold great potential for the development of new therapies in bone regeneration. Although a variety of well characterised osteoinductive biomaterials have so far been reported in the literature, scientists still lack fundamental understanding of the biological mechanism underlying the phenomenon by which they induce bone formation. This is further complicated by the observations that larger animal models are required for research, since limited, if any, bone induction by biomaterials is observed in smaller animals, including particularly rodents. Besides interspecies variation, variations among individuals of the same species have been observed. Furthermore, comparing different studies and drawing general conclusions is challenging, as these usually differ not only in the physico-chemical and structural properties of the biomaterials, but also in animal model, implantation site and duration of the study. Despite these limitations, the knowledge of material properties relevant for osteoinduction to occur has tremendously increased in the past decades. Here we review the properties of osteoinductive biomaterials, in the light of the model and the conditions under which they were tested. Furthermore, we give an insight into the biological processes governing osteoinduction by biomaterials and our view on the future perspectives in this research fi eld.

The need for bone tissue regeneration is continuously expanding due to the improvement of life quality and the consequent increase in life expectancy. Although natural bone grafts have shown excellent clinical successes, their use is associated with some important drawbacks, limited availability being one of the most important. Cell- and growth-factor based tissue engineering provides a promising alternative to natural bone grafts; however, the performance of tissue-engineered constructs often depends on the used carrier. An important challenge in the field of bone regeneration is the development of synthetic bone graft substitutes that are "intelligent" in that they are able to instruct the in vivo environment to form bone. A group of potentially "intelligent" bone graft substitutes are osteoinductive biomaterials. In this paper, background on the phenomenon of osteoinduction and an overview of synthetic biomaterials with osteoinductive potential are given. Furthermore, we elaborate on physicochemical properties of biomaterials that are of influence on their osteoinductive potential. Finally, we discuss the relevance of osteoinductivity of biomaterials in the repair of clinically relevant bone defects.

The combination of the high mechanical strength of metals with the osteoconductive properties of calcium phosphates make hydroxyapatite coatings on titanium implants widely used in orthopedic surgery. However, the most popular coating method, plasma spraying, exhibits some important drawbacks: the inability to cover porous implants and to incorporate biologically active agents, delamination, and particle release. The aim of this study was to elaborate a dense, strong, and thick calcium-phosphate coating on titanium and poroustantalum implants using a two-step biomimetic procedure. In the first step, the implants were soaked in a solution that was 5 times more concentrated than regular simulated body fluid (SBF-A solution). A thin but uniform amorphous calciumphosphate coating was deposited on the metal. Then, the implants were immersed in the SBF-B solution, which had a similar composition as the SBF-A solution, but with decreased contents of crystal growth inhibitors (i.e., Mg 2؉ and HCO 3 ؊ ). This resulted in the fast precipitation of a 30 m thick crystalline calcium-phosphate coating. The pH of the SBF-B solution and the thickness of the crystalline coating layer were studied as a function of time. The Fourier transform infrared spectra and X-ray diffraction patterns showed that this new coating closely resembles bone mineral. Our biomimetic coating should facilitate rapid bone formation around the implant, reducing therewith the patient's recovery time after surgery.

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The organ-on-a-chip (OoC) is an intriguing scientific and technological development in which biology is coupled with microtechnology 1,2 to mimic key aspects of human physiology. The chip takes the form of a microfluidic device containing networks of hair-fine microchannels for guiding and manipulating minute volumes (picolitres up to millilitres) of solution [3][4][5] . The organ is a more relatable term that refers to the miniature tissues grown and residing in the microfluidic chips, which can recapitulate one or more tissue-specific functions. Although they are much simpler than native tissues and organs, scientists have discovered that these systems can often serve as effective mimics of human physiology and disease. OoCs comprise advanced in vitro technology that enables experimentation with biological cells and tissues outside the body. This is achieved by containing them inside vessels conditioned to sustain a reasonable semblance of the in vivo environment, from a biochemical and physical point of view. Working on the microscale lends a unique opportunity to attain a higher level of control over the microenvironment that ensures tissue life support, as well as a means to directly observe cell and tissue behaviour.The OoC is a relatively recent addition to the toolbox of model biological systems available to life science researchers to probe aspects of human pathophysiology and disease. These systems cover a spectrum of physiological relevance, with 2D cell cultures the least relevant, followed in increasing order by 3D cell cultures, organoids and OoCs. Unsurprisingly, the use of model organisms such as mice and Drosophila physiologically exceeds engineered tissue approaches 6,7 . While biological complexity increases with physiological relevance in model organisms, this unfortunately leads to increased experimental difficulty. In vivo physiological processes are, in many ways, the least accessible to direct investigation in mice, humans and other mammals, despite significant advances in in vivo imaging. However, 2D and 3D cell cultures, such as spheroids and stem cell-derived organoids, sacrifice some aspects of in vivo relevance to facilitate experimentation. The OoC may be regarded as a bridging technology, offering the ability to work with complex cell cultures, while providing better engineered microenvironments to maximize the model.Following on from early concepts, including animal-on-a-chip 8 , body-on-a-chip 9 and breathing lung-on-a-chip 10 , research in the OoC and microphysiological systems fields has grown exponentially; evidenced by numerous excellent reviews published recently 1,2,11 . Recognition of OoC technology now extends far beyond university laboratories, driven by a need to better understand the human physiology underlying health and disease, and to find new approaches to improve the human condition. The World Economic Forum, for instance, selected the OoC as one of the top ten emerging technologies in 2016 (ref. 12