The document discusses current issues with implantable devices, such as poor tissue adhesion, bio-compatibility, and the risk of infection, proposing nanowire assemblies as a solution to enhance tissue growth, reduce complications, and improve anchoring. Specifically, titanium dioxide (TiO2) nanowires can replace traditional mechanical anchoring, providing anti-bacterial properties and better integration with tissue. This novel approach is applicable to devices like pain management implants and endovascular stent-grafts, aiming to increase reliability and lower surgery-related costs.

1. Nanowires Assemblies and Implantable Devices “ Current Problems with Implantable devices” Tissue does not adhere to device surface (Interfaces to peripheral nerves & muscles) Bio compatibility requires surgery for removal Device does not stay anchored to surrounding Infection at the implant site. Fluid Leakage & tissue tear. Solution Growth of Nanowires assemblies on the surface of Bio-compatible implanted material replaces mechanical anchoring, is bio compatible, promotes tissue growth, reduces fluid leakage and tissue tearing and prevents infection. When Used with Implants: TiO 2 Nanowires: Size of Nanowires Scaffold match to artery surface & Tissue Nanowires geometry : tissue growth (rough surface for many cells to grab ) Relative surface finish limits leakage at interface Nanowires are Anti-bacterial (photo- catalytic in UV) Relative size prevents bacteria from binding Nanowires Scaffolds can be used for drug delivery Replace mechanical anchoring

2. Using Nanowires scaffolds for Implantable Devices OUTLINE Traditional Devices that can benefit from use of Nanowires - Bion : (Pain management, Spinal cord stimulator, Drug delivery system) - Stent : (Endovascular Stent-Graft); EVSG  Properties of TiO 2 (useful for implants) - Bio-compatibility (Corrosion, disinfection) - Mechanical ( toughness, resistant to bend and shear) - Anti-bacterial (UV % Drug delivery) - Geometry (Promotes tissue growth, Less leakage)  Growth of Nanowires on TiO2 - Low Cost Fabrication Process - Application extends to many implants currently used. Conclusion References

3. Problem Description - Growth of tissue on the surface of implants is difficult - Anchoring: Device is dislocated from target site - Bio-compatibility ( corrosion, disinfection) Heat dissipation ( during re charging of implants) can be implemented Leakage & tissue tear High failure rate/cost (30% require repeat surgery) Lack of adhesion to surface of implants ( Implants are frequently removed ) . Bion Implant: Existing Mechanism for anchoring in tissue Is inadequate and results in high cost of surgery for removal. Surface is un-smooth and tissue binding is a problem Catheters that are threaded through the blood vessels. Anchored with hooks & wires .Leakage Infection Multiple surgery The way it is today ! Mechanical Anchoring Inadequate

4. Devices that can benefit from use of Nanowires BION: Pain management One or more implants are injected through a 12-gauge hypodermic insertion tool into muscles or adjacent to motor nerves, where they provided the means to activate the muscles ( electric shock) in any desired pattern, intensity & frequency.[1]. It receives power and signals from an external radiofrequency transmission coil. Problems: 1. Dislocation in tissue due to improper anchoring or Patient movement ( Currently the device is anchored to tissue by mechanical forks) 2. Corrosion leads to malfunction ( many materials are used) 3. Tissue does not adhere to device surface 4. Overgrown tissue around device Self assembled nano wires (scaffolds) can solve anchoring Biocompatibility and tissue binding simultaneously Bion Implant is used in many applications that can use Nanowires Nanowires Scaffolds has applications across platforms & addresses existing problems -Hooks have been replaced by Nanowires scaffolds -Pockets for anti-bacterial solutions -Promote tissue binding -Redistributes dissipation during charging

5. Endovascular Stent-Graft (EVSG): Artery Repair Tube comprised of fabric (graft) supported by a metal mesh (stent). Typically used for treatment of abdominal aortic aneurysms (AAA). A catheter guides a radial compressed stent/graft through the artery and is expanded upon reaching the aneurysm (a weak spot in artery) thereby creating a new path for the blood flow. Are there any complications? Leaking of blood around the graft (“Endoleaks”) Infection Movement of the graft away from the desired location (“migration”) Graft fracturing ( lack of toughness) Blockage of the blood flow through the graft (buildup, overgrown tissue, collapse) 5. Clotting Devices that can benefit from use of Nanowires Stent graft passed up over catheter wire and expanded to 'line' the AAA Catheter wire inserted into AAA through right groin artery Abdominal Aortic Aneurysm (AAA)

6. Current Technique in EVSG Technology: Endovascular stent-grafts retrofitted with hooks and/or barbs to prevent migration is not reliable. Existing Problems: - Leakage due to progressive artery dilation - Barb & Hook dislocation - Tear of Arterial wall EVSG models & force results, smooth, weak hooks and barbs, strong hooks and barbs (left to right) Devices that can benefit from use of Nanowires

7. Fabrication of TiO 2 Nanowires scaffolds Fabrication : Low cost; Mass Production Hydrothermal reaction of alkali with the Ti metal without using any seeds, templates, TiO2 powder, or stabilizers. The Nanowires root firmly inside the Ti substrate and grow on top to eventually self-assemble into macro porous scaffolds. 10 mL of 1.0 mol/L NaOH solution. Afterward, Heated at 160-250 °C for 2-10 h. ( Control Size, Diameter, Density) Ti substrates, covered by the titanate Nanowires scaffolds, were finally collected, rinsed with deionized water, and dried in air. The Nanowires can grow via a newly revealed upward downward co-growth route, and the scaffold was formed via a self-assembly of the Nanowires . Thus-formed scaffolds may mimic the nature’s extra cellular matrix and exhibit a good cellular compatibility, mechanical toughness, on-site drug release function, and structural robustness.

8. TiO 2 Nanowires Provide Antibacterial Effect Photo-catalytic in UV light: Strong oxidative potential of positive holes oxidize water molecules and organic materials denatures bacteria-> less chance of infection & rejection of device Anatase exhibits higher photo-catalytic effect over other forms of TiO2 (such as rutile) Expose implant to UV before implantation Can also apply UV light after implantation as means to fight/prevent infection Oxidation Mechanism (Three bond Technical News)

9. Surface Roughness of TiO2 Scaffold Improves Biocompatibility and Reduce Leakage There is a race between bacteria and cells If bacteria bind 1st-> infection If cells bind 1st -> success Increased Roughness yields faster attachment of macrophages (cells) to surface and increases the probability of cell binding Macrophages engulf foreign particles Rough surface provides many more places for cell to “grab” on to Macrophages produce cytokines that control wound healing, cell recruitment and proliferation Cell binding reduces leakage at interface SEM images of unstimulated macrophages cultured on mechanically polished (above) and sand-blasted & acid etched (below) Ti surfaces. 500x magnification (Refai) Macrophage (of mouse) stretching its “arms” to engulf to potential pathogens (Wikipedia) Experiments with TiO2 surface roughness shows enhanced cell growth and size construability Mechanically polished Ti Sand-blasted & acid etched Ti

10. Nanowires/ Nanotubes : Sustained Drug Release Grow Nanotubes on Nanowires Could grow Nanotubes ~120nm inner diameter on the Nanowires by anodic oxidation via NH4F/H2SO4 solution at 20v. Device must be able to withstand 300 ºC Load tubes with antibiotics or growth factors before implantation. Growth factors can decrease healing time Less time available for shifting -> higher chance of success Vary tube length, diameter and wall thickness to control the sustained release of specific drugs in vivo (Ketul Popat). Scaffold of Ti Nanotubes (Wenjun Dong) Nanowires on scaffold (Wenjun Dong) Nanotubes (Zhengrong Tian) TiO 2 Nanowire/tube Scaffolds (on the surface of implants) can be loaded simultaneously anesthetics and drug delivery

11. Optimal Scale for Nanostructures Trend demonstrates that smaller pattern/roughness increases cell proliferation Suggest Scaffold: holes ~50 µm Nanowires: diameter ~5 µm Nanotubes: diameter ~120nm TiO2 structures at these scales should provide faster cell growth Faster tissue growth anchors the device in body more quickly! Increased rat endothelial cell (RAEC) after 4 hour culture on different scale patterned Ti (Jing Lu). RAEC proliferation after 5 th day of culture on Ti patterns of (A) 750 nm (B) 2um (C) 5um (D) 75um (E) 100um (F) random nanostructures Ti surfaces (Jing Lu). This trend suggests that: Organized, ordered arrays increase cell proliferation Scale from .75-100um results not crucial factor in cell proliferation Nanowires scaffold geometry can match to tissue or artery surface roughness

12. SUMMARY Properties of TiO 2 Nanowires assemblies can increase the reliability of biomedical implant devices beyond traditional practices. Growth of Nanowires TiO 2 on Ti implant surface is demonstrated to improve patients’ health, and reduce expensive post-surgery costs. The nano-retrofitted “Bion” and “EVSG” devices are novel approaches that address many inadequacies of current technology. Bion & nano: Replaced mechanical anchoring, enhance tissue growth, reduce effects of corrosion, Reduced infection Stent & Nano: Reduced leakage, Replaced mechanical anchoring, enhance tissue growth, reduce effects of corrosion, reduced infection Increase reliability, Lower cost, Improve Patients’ health. Size of Nanowires Scaffold match to artery surface & Tissue Nanowires geometry : tissue growth (rough surface for many cells to grab ) Relative surface finish limits leakage at interface Nanowires are Anti-bacterial (photo-catalytic in UV) Relative size prevents bacteria from binding Nanowires Scaffolds can be used for drug delivery Replace mechanical anchoring

13. Stent and Nanowires Scaffold Perform FEA to determine vascular migrating forces - Experimental Approach: Construct scaled model of abdominal aortic aneurysm using a visco-elastic material (i.e. amorphous polymer – natural rubber, PDMS) and simulate adhesion of “TiO2 EVSG” via theoretical approximations Commercially available Particle Image Velocimetry (i.e. LaVision) PIV setup PIV of Poiseuille Flow/Idealized health aorta

14. Framework for Proposed Endovascular Solution Relevant Analysis: PIV numerical results for comparison with healthy artery analytical solution - Womersley method Pressure distribution to determine necessary anchoring force of novel “TiO 2 Endovascular Stent-graft” “ Healing time” – time for significant biological/mechanical adhesion to occur between stent-graft and artery wall - Stent migration typically occurs > 12 months post-procedure - Reported cell growth on TiO 2 scaffolds is 42 days Adhesion forces between stent-graft and artery wall, post-”healing time” realization Comparison between results of previous solution of more invasive (hooks and barbs) approach and common smooth EVSGs AAA flow field

15. References [1] “The BION devices: Inject able interfaces with peripheral nerves and muscles” GERALD E. LOEB, M.D., FRANCES J. R. RICHMOND, PH.D., AND LUCINDA L. BAKER, P.T., PH.D. Neurosurg Focus 20 (5):E2, 2006 [2] “ Mechanics of Bio-Materials: NEUROLOGICAL IMPLANTED STIMULATORS FOR CEREBELLAR, NEUROMUSCULAR, SPINAL CORD, PERIPHERAL NERVE FOR PAIN RELIEF, TEN, INTRACEREBRAL / SUBCORTICAL” ;Applications of Engineering Mechanics in Medicine, GED -- University of Puerto Rico Mayaguez; May 2005 [3] “Enhanced Functions of Vascular Cells on Nanostructured Ti for Improved Stent Applications” Saba Choudhary, Karen M. Haberstroh, Thomas J. Webster. Tissue Engineering. July 1, 2007, 13(7): 1421-1430. doi:10.1089/ten.2006.0376. [4] “Multifunctional Nanowires Bioscaffolds on Titanium”, Wenjun Dong,† Tierui Zhang,† Joshua Epstein Chem. Mater. 2007, 19, 4454-4459 [5] “Nanotextured implant materials: blending in, not fighting back”, Brown University, April 9, 2007 [6] “Improved endothelial cell adhesion and proliferation on patterned titanium surfaces with rationally designed, micrometer to nanometer features”, Jing Lu, et al. July 8, 2008 [ 7] “Titania Nanotubes: A Novel Platform for Drug-Eluting Coatings for Medical Implants?” Ketul C. Popat, et al. Small 2007, 3, No.11, 1878-1881. Doi:10.1002/sml.2000700412 [8] “Effect of titanium surface topography on macrophage activation and secretion of proin-flammatory cytokines and chemokines,” Ali Refai, et al. 7 June 2004 in Wiley Inter-Science. DOI: 10.1002/jbm.a.30075 [9] “Large Oriented Arrays and Continuous Films of TiO2-Based Nanotubes,” Zhengrong R. Tian, et al. JACS Communications. June 27, 2003. [ 10] “Titanium-Oxide Photo-catalyst,” Three bond Technical News. Tokyo, Japan: January 1, 2004. [11] “Evolution of Wall Shear Stress during Progressive enlargement of symmetric abdominal aortic aneurysm,” J. Fluid Mech. (2006), vol. 560, pp. 19–51. [12] “Endovascular AAA Exclusion: Will Stents With Hooks and Barbs Prevent Stent-Graft Migration?,” Journal of Endovascular Surgery: (1998) Vol. 5, No. 4, pp. 310–317.