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RAPIDOS Report Summary

Project ID: 604517
Funded under: FP7-NMP
Country: Netherlands

Periodic Report Summary 2 - RAPIDOS (Rapid Prototyping of Custom-Made Bone-Forming Tissue Engineering Constructs.)

Project Context and Objectives:
Road traffic injuries kill nearly 1.3 million people annually while 50 million sustain non-fatal injuries. If current trends continue, road crashes are predicted to rise from 9th leading cause of death to 5th by 2030. Worldwide, the number of bone grafts used in surgical procedures has been estimated at over 24 million in 2010. Indeed, bone is the most often transplanted tissue after blood and the need for bone graft substitute materials is enormous. About one third represents the European market, while the total Asian markets (China and India) for bone graft substitutes and other biomaterials increased by 53.2% from 2009 to 2010. The bone graft sales are forecasted to reach a total of $3.3 billion worldwide in 2017. Therefore, the global increase of needs for bone graft substitutes and emergence of large healthcare providers in Asia support the necessities for better bone repair solutions based on biomaterial scaffolds.
Among pertinent non-healing bone fractures occurring in road traffic accidents, the region of the head is a major target for development of precise custom-made bone constructs. In cranio-maxillofacial surgery, large blow-out orbital floor fractures have still mitigated outcomes and improved scaffold solutions are needed. The reconstruction of large bone defects in proximal femur or proximal tibia is also an enormous challenge for biomaterial devices due to the requirements for both complex shape and partial load bearing ability, but also due to the risk of incidence of steroid-associated osteonecrosis or infection which may exceed 30% for large open fractures. The technical issues for the engineering of scaffold for bone tissue engineering therapies are: (i) fabrication of biomaterial scaffolds for anatomical fit of complex three-dimensional large bone defect, (ii) fabrication of biomaterials with adequate mechanical and structural stability/degradation kinetics and (iii) fabrication of biomaterials with optimised macro-architecture for improved mass transport and perfusion for delivery of biological effectors.
Advanced solid free form fabrication also called rapid prototyping (RP) could provide the necessary control to create such innovative medical devices. For example, stereolithography offers the high resolution that is necessary to create controlled architecture and anatomically fitting device while low temperature rapid prototyping is a unique technique in its ability to incorporate into the scaffolds temperature sensitive active compounds.
Thus, the goal of this European and Chinese consortium is to apply RP technologies to create custom-made tissue engineered biomaterial constructs by integrating 1) imaging and information technologies, 2) biomaterials and process engineering, and 3) biological and biomedical engineering for novel and truly translational bone repair solutions. The main objective of this project is to apply precise and rapid prototyping technologies for custom-made bone tissue engineering with optimised macro-architecture, osteoinduction via the inclusion of calcium phosphate and a Chinese medicine phytomolecule (icaritin), and bactericidal properties.

Project Results:
Since the beginning of the RAPIDOS project, the partners have developed a clinical CT imaging process technology workflow for development of anatomically relevant and precise custom-made macro-structured designed scaffolds. The goal of this workflow is to allow the surgeons to design and self-assess patient specific implants taking into account the constraints of the biomaterial and fabrication process.
The optimisation of composite formulations; poly(trimethylcarbonate) (PTMC)/calcium phosphate and poly(lactic-co-glycolic)/tricalcium phosphate/magnesium (PLGA/TCP/Mg) respectively, for stereolithography and low temperature rapid manufacturing has been performed and already implant scaffolds were fabricated by both stereolithography and low temperature rapid prototyping. Biodegradable polymeric nanofibers and microspheres loaded with icaritin, a Chinese medicine phytomolecule as potential drug delivery vehicle have been prepared and incorporated into the photo-polymerisable resin formulation for stereolithography. In vitro studies have shown the osteopromotive effect of the hydroxyapatite nanoparticles loaded into PTMC scaffolds. In vivo studies in rabbit calvarial defects showed the enhance bone ingrowth in Calcium phosphate nanoparticles loaded PTMC Stereolithography scaffolds in comparison to PTMC scaffolds. The osteopromotive effect of icaritin in PLGA/TCP/Mg scaffolds was assessed too in vivo and in vitro. Quaternised chitosan and magnesium were shown to decrease biofilm formation onto the surface of PLGA/TCP/Mg scaffolds in vitro and in vivo without being detrimental to mesenchymal stem cells osteogenic differentiation.
To date, the RAPIDOS project activities have led to 20 peer-review manuscripts and the filling of 2 patents. Three workshops were organised and attended by European and Chinese partners. Finally, the RAPIDOS results have contributed to the creation of one Spin-off company for production of new biomaterials.

Potential Impact:
The RAPIDOS Project expected results are:
1) Establishment of an imaging process, morphing patient specific implant shape and optimized internal macro-structure;
2) Development of precise and rapid prototyping technologies and advance biomaterials incorporating optimised macro-architecture and biological effectors;
3) Validation and optimization of architecture design and bioactivity of scaffolds for bone Tissue Engineering in vitro and in vivo;
4) Consolidation of EU-China biomaterials research through close collaboration between partners.

The RAPIDOS Project potential impact
Already, the project as led to development in imaging captures and process technologies workflow for development of anatomically relevant and precise custom-made macro-structured designed scaffolds. Innovative biomaterials and fabrication of structures using two rapid-prototyping technologies have been created and optimised. Hydroxyapatite nanoparticles have been incorporated for improved biocompatibility, osteopromotion of the scaffolds. Anti-infection strategies have been successfully assessed in vitro and in vivo. In addition, significant advance in the assessment of use of magnesium and Chinese medicine phytomolecule component (e.g. icaritin) derived from osteogenic Chinese medicine was achieved.

In term of economic and development impact, we expect that the simultaneous approach of the RAPIDOS consortium will give rise to multiple innovations to be exploited:
1) High value inventions based upon the materials, process technologies and tools defined in the scientific plan.
2) Improve European competitiveness and research visibility to international surgeons' network and Chinese partners.
3) Additional patents and competitive positioning of industrial Partner on the technologies and models developed.
4) Improved knowledge and competitiveness of Europe on Biomaterials and Tissue Engineering development.
5) Decrease healthcare cost by decreasing re-operation rate due to bone none-union in critical size defect and improving patient specific surgery.

The RAPIDOS results have contributed to creation of intellectual property (2 patents filling) and the creation of one Spin-off company for production of new biomaterials positioning the partners in a competitive position for the translation into the clinic.

Finally, in a wider societal application, the RAPIDOS project may improve therapeutic for population suffering from bone none-healing and faster recovery through advanced custom-made implant patient specific therapy and improvement of life quality through improved recovery.

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