Smart Scaffolds: The Future of Bioceramic
Guy Daculsi
Abstract
The commercial offer for bioceramic bone substitutes is very large, however, the prerequisites for applications in bone reconstruction and tissue engineering, are most often absent. The main criteria being: on the one hand physico-chemical features providing surgeons with an injectable and/ or shapeable biomaterial; on the second hand the multi-scale bioactivity leading to osteoconduction and osteoinduction properties. In order to obtain greater suitability according to the nature of the bone defect to be treated, new bone regeneration technologies, ''smart scaf- folds'' must be developed and optimize to support suitable Ortho Biology.
The related degenerative osteo-articular pathology involved by the aging population is a major societal issue. The autologous bone grafts are commonly used by clinicians in both dental and maxillofacial surgery, orthopaedic, trauma and spinal surgery. However the collection of autologous graft requires a second surgical site, and the volume of graft used is limited and of variable quality.
A new goal is to develop a bone regenerative medicine approach, where cell suspensions and/or osteoinductive agents are implanted in association with suitable advanced scaffolds to trigger endogenous regenerative processes of bone and not only to directly repair injured tissues. To successfully design a tissue repair strategy centred on the activation of endogenous regenerative mechanisms for the repair of a tissue deficit, some prerequisites should be considered. First of all, a 3-D micro-environment enhancing cell adhesion, proliferation and differentiation. Secondly, an adequate scaffold for diffusible growth factors and modulators of cell maturation/differentiation promoting endogenous stem/progenitor cell recruitment, thus facilitating tissue regeneration.
The feasibility was demonstrated in bone tissue engineering to produce a hybrid material from an autologous bone marrow associated with synthetic matrices. All data indicated the necessity to use some specific scaffolds able to support these new and promising surgical technologies. The main goal was to develop a high potential synthetic bone substitute (''smart scaffold'') which will not only promote osteoconduction but also osteopromotion i.e. the ability to enhance of osteoinduction. This property was confirmed by the combination with human Mesenchymal Stem Cells (hMSC) suspension with ''smart osteogenic scaffold'' MBCP Technology in clinical trials from the European program (REBORNE 7th PCRD, www.reborne.org) (Fig. 1).
The smart bioceramic scaffolds will address the above pre- requisites for repair and regeneration of bone. The interest of such technology is to provide to the surgeons:
1. A resorbable medical device with versatile handling properties (solid bioceramics, or injectable to mouldable),
2. Optimized presentation for combination with osteogenic suspensions,
3. A delivery system for growth factors or biomimetic peptides of bone morphogenic proteins.
This smart scaffold technology platform is considered by the scientific experts, the clinical community, as part of the ''Smart Biomaterials Diamond Concept'' [1]:
- Restore volume
- Stabilize
- Regenerate bone
Recently several publications demonstrate osteoinductive or osteostimulative or osteogenic property for some micro macro structured calcium phosphate Bioceramics [2-6]. The key point is the nano-microscale level. The micropores are involved in the early events of body fluids diffusion and physico-chemical interaction between pro- teins, biological ions of body fluids and implant crystal surfaces. These interactions are considered osteoinductive or at least promoter of the mineralization.
Osteoinduction is the acceleration of new bone forma- tion by chemical means. This term means that primitive, undifferentiated and pluripotent cells are somehow stimulated to develop into the bone-forming cell lineage. One proposed definition is the process by which osteogenesis is induced. In complement, osteoinduction can be also define by active osteoinduction (as growth factors BMP activity), or passive osteoinduction (or osteopromotion) if the scaffolds was able, by its nano, micro and macrostructure, to induce/promote the osteogenic cell differentiation. Thus the development of a ''smart scaffold'' to support new surgical approach for regenerative medicine is a challenge.
The specificity of the scaffold was an original and unique nano-microstructure and macrostructure involving in contact with biological fluids, bone marrow, hMSC, a dynamic process, including physico-chemical processes, crystal/ proteins interactions, cells and tissue colonization, bone remodelling and finally contributing to ingrowth at the expense of the bioceramics. The processes of dissolution of CaP and biological precipitation occurring into the micropores occur simultaneously with osteoid and bone formation after implantation in bony sites and non-bony sites. Due to the specific interface formed by the biological precipitation, the newly formed mineralized surface acts as an intelligent matrix for undifferentiated cells, specifics spreading and differentiation in osteogenic cells lines due to the high Ca and P ions environment content [7]. This must be associated to the niche concept required for developing the best scaffold.
The bioceramics granules can also be combined with hydrogel for ''injectable-mouldable bioceramics''. The hydrogel will be considered only as a carrier, giving rheological properties for the bioceramics granules handling [8].
The main criteria being on the one hand physico-chemical features providing surgeons with an injectable and/or mouldable biomaterial; on the second hand the multi-scale bioactivity leading to osteoconduction and osteoinduction properties. In order to obtain greater suitability according to the nature of the bone defect to be treated, a so called bioceramic ''smart scaffold'', using latest innovating syn- thesis process and knowledge to the forefront of the bone tissue engineering field, should indeed incorporate below characteristics [9]:
Multiple ways of biomaterials absorption by surrounding host tissues:
1. Chemical dissolution process [10]
2. Lacunar resorption by osteoclasts thanks to biomimetic mineral phase [11, 12]
3. Macrophagic phagocytosis of bioceramics fragments [13]
Multi-scale 3D porosity:
- Intragranular macro porosities acting as osteoconductive niches for cell adhesion, proliferation and differentiation [14]
- Intragranular microporosities for volume interconnection networks, improved specific surface area for bioactive molecules adsorption and higher dissolution rate [15, 16]
- Intergranular 3D space available to body fluids circulation for a bioactive environment favourable to cell colonization, cell signalling, protein adsorption, and ionic exchanges [17]. The combination of this triple porosity involves a very low density bioceramic with higher osteointegration capability.
Bioactive properties:
1. Ions release for bone metabolism (calcium, phosphate) [18]
2. Apatitic re-precipitation and nucleation process from bioceramics crystals dissolution [19, 20]
3. Body fluids interaction with biomolecules adsorption for cell adhesion, growth factors osteoinduction, integration in bone regeneration cycle etc. [21, 22]
- Biomimetic: bone-like crystallography, microstructure and chemistry [23]
- Osteoconduction and osteoinduction potential [24]
- Biocompatibility (non-immunogenic, non-cytotoxic...) [25, 26]
In conclusion, the future of bioceramic scaffolds supports the role of microporous and macroporous CaP bioceramics in osteoinduction. De novo bone regeneration can be achieved, with potential ''superiority'' to autograft. Although micropores and CaP absorption, in addition to the niche concept, appear to be key requisite features for efficient smart scaffolds during bone regeneration, the cascade of biological events leading to MSC differentiation and osteogenesis remains unclear.
Acknowledgments
The research leading to these results has received funding from the European Union's 7th Framework Programme under Grant Agreement No. FP7-HEALTH-2009-241879 (REBORNE).
Received: 17 July 2014 / Accepted: 24 February 2015 (c) Springer Science+Business Media New York 2015
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