Biocompatibility of a polymer based on Off-Stoichiometry Thiol-Enes + Epoxy (OSTE+) for neural implants

BackgroundThe flexibility of implantable neural probes has increased during the last 10 years, starting with stiff materials such as silicone to more flexible materials like polyimide. We have developed a novel polymer based on Off-Stoichiometry Thiol-Enes + Epoxy (OSTE+, consisting of a thiol, two allyls, an epoxy resin and two initiators), which is up to 100 times more flexible than polyimide. Since a flexible neural probe should be more biocompatible than a stiff probe, an OSTE+ probe should be more biocompatible than one composed of a more rigid material. We have investigated the toxicity of OSTE+ as well as of OSTE+ that had been incubated in water for a week (OSTE+H2O) using MTT assays with mouse L929 fibroblasts. We found that OSTE+ showed cytotoxicity, but OSTE+H2O did not. Extracts were analyzed using LC-MS and GC-MS in order to identify leaked chemicals.ResultsMost constituents were found in extracts of OSTE+, whereas only initiators were found in OSTE+H2O extracts. The detected levels of each chemical found in the LC-MS and the GC-MS analysis were below the toxicity level when compared to MTT assays of all the individual chemicals, except for one of the initiators that had an IC50 value close to the detected levels.ConclusionOur notion is that the toxicity of OSTE+ was caused by one of the initiators, by impurities in the constituents or by synergistic effects of low doses of leaked chemicals. However, our conclusion is that if OSTE+ is incubated for one week in water, OSTE+ is not cytotoxic and suitable for further in vivo studies.

[1]  Vikramaditya G. Yadav,et al.  Cell and protein compatibility of parylene-C surfaces. , 2007, Langmuir : the ACS journal of surfaces and colloids.

[2]  T. Mosmann.  Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[3]  R. Molloy,et al.  Cytotoxicity study of homopolymers and copolymers of 2-hydroxyethyl methacrylate and some alkyl acrylates for potential use as temporary skin substitutes , 2003, Journal of materials science. Materials in medicine.

[4]  Justin C. Williams,et al.  Flexible polyimide-based intracortical electrode arrays with bioactive capability , 2001, IEEE Transactions on Biomedical Engineering.

[5]  B A Wester,et al.  Development and characterization of in vivo flexible electrodes compatible with large tissue displacements , 2009, Journal of neural engineering.

[6]  J. Stein,et al.  Thalamic field potentials during deep brain stimulation of periventricular gray in chronic pain , 2002, Pain.

[7]  Chuanqing Zhou,et al.  In vitro and in vivo evaluation of a photosensitive polyimide thin-film microelectrode array suitable for epiretinal stimulation , 2013, Journal of NeuroEngineering and Rehabilitation.

[8]  Abel L. Thangawng,et al.  An ultra-thin PDMS membrane as a bio/micro–nano interface: fabrication and characterization , 2007, Biomedical microdevices.

[9]  Andrew B Schwartz,et al.  Cortical neural prosthetics. , 2004, Annual review of neuroscience.

[10]  V. G. Berezkin,et al.  The essence of chromatography , 2002 .

[11]  C. Heidelberger,et al.  Mutagenicity to mammalian cells of epoxides and other derivatives of polycyclic hydrocarbons. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Giuliano Iurilli,et al.  Flexible, all-polymer microelectrode arrays for the capture of cardiac and neuronal signals. , 2011, Biomaterials.

[13]  T. Alan Hatton,et al.  Modeling of Oxygen-Inhibited Free Radical Photopolymerization in a PDMS Microfluidic Device , 2008 .

[14]  David J. Anderson,et al.  Novel multi-sided, microelectrode arrays for implantable neural applications , 2011, Biomedical microdevices.

[15]  Babak Ziaie,et al.  A hybrid PDMS-Parylene subdural multi-electrode array , 2013, Biomedical microdevices.

[16]  P. Renaud,et al.  Demonstration of cortical recording using novel flexible polymer neural probes , 2008 .

[17]  David C. Martin,et al.  A finite-element model of the mechanical effects of implantable microelectrodes in the cerebral cortex , 2005, Journal of neural engineering.

[18]  Jiping He,et al.  Polyimide-based intracortical neural implant with improved structural stiffness , 2004 .

[19]  Seung Woo Lee,et al.  In vitro biocompatibility of various polymer-based microelectrode arrays for retinal prosthesis. , 2012, Investigative ophthalmology & visual science.

[20]  Stanislav Herwik,et al.  Brain-computer interfaces: an overview of the hardware to record neural signals from the cortex. , 2009, Progress in brain research.

[21]  Jan Maes,et al.  Evaluation of 14 Organic Solvents and Carriers for Screening Applications in Zebrafish Embryos and Larvae , 2012, PloS one.

[22]  J. Obeso,et al.  Bilateral deep brain stimulation in Parkinson's disease: a multicentre study with 4 years follow-up. , 2005, Brain : a journal of neurology.

[23]  L. Wallman,et al.  A polymer based electrode array for recordings in the cerebellum , 2011, 2011 5th International IEEE/EMBS Conference on Neural Engineering.

[24]  L. Wallman,et al.  A polymer neural probe with tunable flexibility , 2013, 2013 6th International IEEE/EMBS Conference on Neural Engineering (NER).

[25]  Thomas Stieglitz,et al.  In vitro evaluation of the long-term stability of polyimide as a material for neural implants. , 2010, Biomaterials.

[26]  Kristinn B. Gylfason,et al.  Biocompatibility of OSTE polymers studied by cell growth experiments , 2013 .

[27]  J. Schouenborg,et al.  \(\boldsymbol {\mu } \) -Foil Polymer Electrode Array for Intracortical Neural Recordings , 2014 .

[28]  Marcus Granmo,et al.  ${\mbi{\mu }}$-Foil Polymer Electrode Array for Intracortical Neural Recordings , 2014, IEEE Journal of Translational Engineering in Health and Medicine.

[29]  R. Kodzius,et al.  Characterization of solid UV cross-linked PEGDA for biological applications , 2013, 2013 IEEE 26th International Conference on Micro Electro Mechanical Systems (MEMS).

[30]  P. Losi,et al.  Silicone based polyurethane materials: a promising biocompatible elastomeric formulation for cardiovascular applications , 2006, Journal of materials science. Materials in medicine.

[31]  Wouter van der Wijngaart,et al.  Beyond PDMS: off-stoichiometry thiol-ene (OSTE) based soft lithography for rapid prototyping of microfluidic devices. , 2011, Lab on a chip.

[32]  K D Wise,et al.  Microfabrication techniques for integrated sensors and microsystems. , 1991, Science.

[33]  D. Rodriguez-Amaya,et al.  A scheme for obtaining standards and HPLC quantification of leafy vegetable carotenoids , 2002 .

[34]  Y. Temel,et al.  High frequency stimulation of the subthalamic nucleus improves speed of locomotion but impairs forelimb movement in Parkinsonian rats , 2007, Neuroscience.