BIOcompatible Medical IMplants Elaborated from nitrided TItanium-based Superelastic alloys – BIOMIMETIS

In accordance with the initial program, tasks 1.1, 2.1, 2.2 and 3.1 have been delivered (or close to be) in time. From now, the work will be more specifically focused on the following tasks :
Task 1.2. Fabrication of stent and staple prototypes (P1. INSA-ISCR and P3. AMF)
1.2.1. Preparing the superelastic wires for the fabrication of stent and staple prototypes
1.2.2. Fabrication of the stent and staple prototypes
1.2.3. Nitridation treatment of the stent and staple prototypes
1.2.4. Fabrication of additional (optimized) nitrided stent and staple prototypes
Task 2.3. Fatigue tests on stent and staple dispositives (P1. INSA-ISCR and P3. AMF)
2.3.1. Fatigue tests carried out on the uncoated and nitrided stent prototypes
2.3.2; Fatigue test carried out on the uncoated and nitrided staples prototypes
Task 3.2. The evaluation of biological behaviour of endothelial cells (P2. UB-DBBM)
3.2.1. Analysis of cell adhesion and cytoskeletal organization. Assessment of cell viability and proliferation of HUVECs and EPCs. Estimation of surface-dependent apoptosis of adherent HUVECs and EPCs.
3.2.2. Evaluation of endothelial cell functionality in terms of nitric oxide (NO) production, endothelial nitric oxide synthase (eNOS) and von Willebrand factor (vWf) expression. Assessment of inflammatory reactions elicited by tested materials

New titanium-based alloy (Ti-23Nb-0.7Ta-2Zr-O, Ti-23Nb-0.7Ta-2Zr-0.5N, Ti-24Nb-0.5O and Ti-24Nb-0.5N compositions) were synthesized by melting and then characterized in order to evaluate their potential for biomedical applications.

It is expected that the new Ti-based alloys will show excellent biocompatibility, low corrosion resistance in SBF and desirable mechanical properties combining the bulk superelastic property and the hard and wear resistant surface. These properties are particularly appreciated for various medical devices and, particularly, for targeted biomedical applications such as cardiovascular stents and orthopaedic bone staples.

1. Potentiality of the «Gum Metal« titanium-based alloy for biomedical applications, D.M. Gordin, R. Ion, C. Vasilescu, S.I. Drob, A. Cimpean, T. Gloriant, Mater. Sci. Eng. C (2014) 44, 362-370
2. In vitro bio-functional performances of the novel superelastic beta-type Ti-23Nb-0.7Ta-2Zr-0.5N alloy, R. Ion, D.M. Gordin, V. Mitran, P. Osiceanu, S. Dinescu, T. Gloriant, A. Cimpean, Mater. Sci. Eng. C (2014) 35, 411-419
3. Corrosion Behaviour of Nitrogen-Implantation Ti-Ta-Nb Alloy in Physiological Solutions Simulating Real Conditions from Human Body, S. I. Drob, C. Vasilescu, P. Drob, E. Vasilescu, D.M. Gordin, T. Gloriant, JOM (2015) 67-4, 818-829
4. Superelastic Multifunctional “gum metal” titanium-based alloy: its long-term electrochemical behavior and macrophage response, S. I. Drob, C. Vasilescu, J. M. Calderon Moreno, P. Osiceanu, P. Neacsu, A. Cimpean, D. M. Gordin, T. Gloriant, submitted to Acta Biomaterialia
5. Biological behavior and enhanced anti-corrosive performance of the nitrided superelastic Ti-23Nb-0.7Ta-2Zr-0.5N alloy, V. Mitran, C. Vasilescu, S. I. Drob, P. Osiceanu, J. M. Calderon-Moreno, M.C.Tabirca, D. M. Gordin, T. Gloriant, A. Cimpean, submitted to BioMed Research International.

Organs like bone and vessels have a limited capacity for self-repair, and after injury or disease the regenerative power of adult tissue is often not sufficient, leading to non-functional scaring. Despite the vast development and clinical use experienced by the metal implants during the last decades these are far from optimal.
The objective of the present BIOMIMETIS project is to design and characterize new highly biocompatible titanium -based alloys for implantable devices in human body. In order to overcome the limited lifespan of the currently used biomedical alloys the proposed project envisages gas-nitriding treatments of recently developed Ni-free superelastic alloys (Gum-metal Ti-23Nb-0.7Ta-2Zr-O, Ti-24Nb-0.5O and Ti-24Nb-0.5N alloy compositions) which will harden the surface and improve further the biocompatibility.
The 3 partners involved in the frame of this project (2 academic laboratories and 1 industrial SME) composed of metallurgists, physico-chemists, biologists and mechanical engineers possess scientific competences and complementary skills in the domain of biomaterials in general and particularly in: (i) the design of superelastic Ti alloys and nitriding treatments, (ii) the physico-chemical and mechanical characterisations, (iii) the biocorrosion resistance evaluation, (iv) the biological validation of biomaterials and (v) the fabrication of biomedical devices.
Through a scientific and engineering program organised in 3 complementary tasks, the designed Ni-free nitrided superelastic titanium-based alloys will be deeply characterized to evaluate their functionalities for targeted biomedical applications. The fabrication of bone staple and endovascular stent prototypes by the industrial partner is envisaged as proof of concept in this proposal.
Thus, comparative microstructural and mechanical characterization of coated and un-coated superelastic titanium alloys, electrochemical characterization of the coated alloys’ surfaces before and after soaking in simulated body fluid (SBF) will be evaluated. Also, an evaluation of the fatigue behaviour of biomedical dispositives will be carried out. On the other hand, an important objective of our studies will be to evaluate the biocompatibility and to which extent the behavior of osteoprogenitor and mature endothelial and endothelial progenitor cells derived from umbilical cord blood is influenced by bulk material properties and surface characteristics. For the comparative purposes, the commercial nitinol, which is widely used in the biomedical sector, will be considered as a reference biomaterial. Furthermore, these studies will be preceded by cytotoxicity tests according to ISO 10993-5 standards. The osteoblast response will be assessed in terms of cellular survival, cell attachment, spreading and morphology and promotion of osteogenic differentiation. Endothelial cell behaviour will be approached by addresing cell adhesion representing a critical phenomenon for early endothelialization of the biomaterials, cell spreading and morphology, cell viability and proliferation, cell death, nitric oxide production and expression of endothelial differentiation markers. Because endothelial inflammation is a critical early event in vascular pathology, expression of inflammatory markers following cell-biomaterial contact will be assessed.
It is expected that the new Ti-based alloys will show excellent biocompatibility, low corrosion resistance in SBF and desirable mechanical properties combining the bulk superelastic property and the hard and wear resistant surface. These properties are particularly appreciated for various medical devices and, particularly, for targeted biomedical applications such as cardiovascular stents and orthopaedic bone staples. Furthermore, our expectations are that positive osteoblast response, a better endothelialization and a reduced inflammatory response will be obtained on the corresponding TiN-coated surfaces.