terials with at least one dimension in the nanoscale)

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1 CONTRIBUTED ORIGINAL ARTICLE INTEGRATING nanotechnology into MEDICINE: Past, PRESENT, AND FUTURE Thomas J. Webster, Northeastern University, Boston An acute shortage of organs is one of the most urgent challenges facing the healthcare sector, due to disease, trauma, congenital defects, and most importantly, age-related maladies. Synthetic materials used in today s medical device applications are typically composed of millimeter- or micron-sized particles, grains, and/or fibers. Although human cells are on the micron scale, their individual components, e.g., proteins, are composed of nanometer features. As a result of this size structure, the study of nanotechnology (or the use of ma- terials with at least one dimension in the nanoscale) in medicine has increased tremendously over the past several decades[1,2]. Only nanomaterials can mimic the nanostructured features found in natural tissues. Nanotechnology has enabled the creation of materials that can exactly match the dimensions of natural materials to improve tissue growth. Moreover, nanomaterials can possess unique surface energy (without changing chemistry) to control the initial protein adsorption that cells depend on to function (Fig. 1). Fig. 1 Schematic of how nanostructured surface features can be created on implant surfaces to control surface energy to influence the adsorption and bioactivity of proteins known to change cellular behavior. 28 SVC BULLETIN I SPRING 2017

2 Nanotechnology has enabled the creation of materials that can exactly match the dimensions of natural materials to improve tissue growth. TECHNOLOGY SVC BULLETIN I SPRING

3 CONTRIBUTED ORIGINAL ARTICLE INTEGRATING NANOTECHNOLOGY INTO MEDICINE Nanotechnology Applications in Medicine Two main areas where nanotechnology is being incorporated into medicine include: (a) the use of nanoparticles, and (b) the inclusion of nanostructured surface features. While research on the use of nanoparticles in medicine has significantly enhanced our knowledge of immune system recognition (or rather the lack thereof), targeted drug delivery, biofilm penetration, and so much more, it is clear that using nanoparticles adds an extra risk of toxicity, unintended biodistribution, and biopersistence, requiring additional caution[3,4]. In contrast, it can be argued that regulatory concerns should be much lower for the design, fabrication, and use of nanostructured implant surfaces that do not change in chemistry but do change in nanoscale topography[1,2]. Numerous examples of significantly improved biological functions (such as bone growth, vascular growth, and bacteriostatic surfaces) exist with regard to traditional materials created with a nanoscale surface to achieve quick regulatory approval[3 11]. For example, titanium alloys with nanoscale surface features created by anodization, severe plastic deformation, electron beam evaporation, and other deposition processes all represent a form of nanotexturing that can improve bone formation without introducing new chemistries into the body that are not currently approved by the Food and Drug Administration (Fig. 2)[5,6]. Other studies have demonstrated that ceramics such as hydroxyapatite when coated on titanium or other implant surfaces using electrophoretic deposition can create nanoscale surface features, which not only increase bone cell functions, but also decrease bacteria attachment and growth, all without using antibiotics (Fig. 3)[10]. Silicon nitride has also been shown in vivo to completely eliminate bacteria growth and improve bone growth when possessing nanoscale surface features in a rat calvaria infection model for three months (Fig. 4)[8]. In fact, some researchers actually proposed a mathematical equation that can predict the size of a nanoscale surface feature one should create on an implant to change surface energy that can control initial protein adsorption and bioactivity events to increase tissue growth and/or decrease infection[9]. Future of Nanotechnology in Medicine Clearly, while the aforementioned studies provide significant promise for the immediate regulatory approval of today s medical devices that improve biological performance, all of these approaches are in reaction to a patient s health problem, and this cannot be the future of medicine. World population growth is increasing at an alarming rate, yet our medical treatments are still too reactionary and not tailored to each individual s needs. Far too often, today s medical approach leads to a prescription that only treats disease symptoms and not the source of the problem. For example, patients receive medical treatment, for the most part, only when medical practitioners react to their pain and suffering from broken bones, infections, etc. Other elements of modern society do not work LOW MAGNIFICATION (10K) LOW MAGNIFICATION (10K) NANOTUBULAR PIN HIGH MAGNIFICATION (100K) GROOVED VALLEY RAISED PEAK HIGH MAGNIFICATION (100K) ANODIZATION Fig. 2 Bone pins anodized to possess nanoscale tubes (i.e., nanotubes) have been shown to increase bone growth and decrease bacteria functions without using pharmaceutical agents or antibiotics. 30 SVC BULLETIN I SPRING 2017

4 Fig. 3 Increased bone growth and decreased bacteria functions have been measured on Ti treated with a nanoscale hydroxyapatite coating as depicted on the right side micrograph, compared to a micron scale hydroxyapatite coating on the middle micrograph and plain titanium on the left micrograph. The nanoscale hydroxyapatite coating (right) was produced by electrophoretic deposition, while the micron scale hydroxyapatite coating (middle) was created via plasma spray deposition, a technique used to improve orthopedic implant osseointegration[10]. Scale bars = 1 micron. Fig. 4 Increased bone growth and decreased bacteria functions have been measured on a nanotextured silicon nitride surface (left) compared to smooth silicon nitride surface (right). The rat calvaria infection model was used to simulate bacterial growth for three months[8]. SVC BULLETIN I SPRING

5 CONTRIBUTED ORIGINAL ARTICLE INTEGRATING NANOTECHNOLOGY INTO MEDICINE Analyzer instrument Computer Radio frequency signal e.g., Nanostructure polypyrrole film immobilized antibiotics coating e.g., Multi-walled carbon nanotubes grown out of nanotubular titanium electrode measuring bone growth/loss, infection, and inflammation Fig. 5 A hip implant sensor that measures, via resistance, the type of cells that attach to the implant[11]. The sensor is composed of multiwalled carbon nanotubes grown out of anodized nanotubular titanium. The hip implant sensor can also communicate biological events surrounding the implant to a handheld device or computer in real time. Through the use of a biodegradable conductive implant coating, the sensor can release biomolecules to fight infection, reverse inflammation, and grow bone through external electrical activation. this way. Think, for example, do we only fix a bridge when it collapses, killing all of those on it? Our medicine needs to become more predictive and proactive, anticipating patient needs and fixing them before they become problematic or life threatening. Moreover, it is now well established that while most of us have similar components to our immune system (the same cells, same molecular pathways, etc.), parts of our immune system are quite different from one another. We all have different life experiences and have exposed our bodies to different chemicals. A one-size-fits-all medical approach where one patient may be cured by the same treatment that could kill another patient is highly problematic. Modern medicine needs to become more personalized and less generalized. Nanomedicine is offering potential solutions in these fu- ture directions of medicine as well. Specifically, researchers are creating hip implants that can respond to an individual s immune system and detect in real time what type of cells are growing next to an implant (Fig. 5)[11]. Such hip implant sensors can communicate via wireless radio frequency technology to a clinician to relay if too many bacteria are present or not enough bone growth has occurred. Moreover, these same sensors can be externally activated to release biomolecules to reverse adverse biological events in real time before a problem occurs. While much more work can be done, these sensors represent predictive, rather than reactionary, medicine. Lastly, many research groups are creating synthetic immune cells that can be used to kill unwanted bacteria in the body (Fig. 6). In this manner, modern society is moving closer to personalized medicine using nanotechnology. Summary In summary, the world of nanotechnology coatings and processes is very bright, not only due to new materials that can significantly improve the ones we are implanting today (without changing their chemistry), but also by developing new sensors and immune cells that allow for more predictive personalized medicine. It is exciting to see what the future holds for the integration of nanomaterials into medicine. References 1. H. Liu and T.J. Webster, Nanomedicine for Implants: A Review of Studies and Necessary Experimental Tools, Biomaterials, 28(2), pp , L. Zhang and T.J. Webster, Nanotechnology and Nanomaterials: Promises for Improved Tissue Regeneration, NanoToday, 4(1), pp , Fig.6 An image of drug-resistant E. coli being attacked by synthetic immune cells. Scale bar = 1 micron. 32 SVC BULLETIN I SPRING 2017

6 3. E. Taylor and T.J. Webster, Reducing Infections through Nanotechnology and Nanoparticles, International Journal of Nanomedicine, 6, pp , J.T. Seil and T.J. Webster, Antimicrobial Applications of Nanotechnology: Methods and Literature, International Journal of Nanomedicine, 7, pp , S. Puckett, E. Taylor, T. Raimondo, and T.J. Webster, The Relationship Between the Nanostructure of Titanium Surfaces and Bacterial Attachment, Biomaterials, 31(4), pp , B. Ercan, E. Taylor, E. Alpaslan, and T.J. Webster, Diameter of Titanium Nanotubes Influences Anti-bacterial Efficacy, Nanotechnology, 22(29), pp , L. Liu, B. Ercan, L. Sun, and T.J. Webster, Understanding the Role of Polymer Surface Nanoscale Topography on Inhibiting Bacteria Adhesion and Growth, ACS Biomaterials-Science & Engineering, 2(1), pp , T.J. Webster, A.A. Patel, and M.N. Rahaman, Anti-infective and Osteointegration Properties of Silicon Nitride, Poly (Ether Ether Ketone), and Titanium Implants, Acta Biomaterialia, 8(12), pp , D. Khang, S.Y. Kim, P. Liu-Synder, G.T.R. Palmore, S.M. Durbin, and T.J. Webster, Enhanced Fibronectin Adsorption on Carbon Nanotubes/ Poly (Carbonate) Urethane: Independent Role of Surface Nano Roughness and Associated Surface Energy, Biomaterials, 28(32), pp , D. Mathew, G. Bhardwaj, Q. Wang, and T.J. Webster, Decreased Staphylococcus Aureus and Increased Osteoblast Density on Nanostructured Electrophoretic-deposited Hydroxyapatite on Titanium Without the Use of Pharmaceuticals, International Journal of Nanomedicine, 9, pp , S. Sirinrath, R. Pareta, and T.J. Webster, Electrically Controlled Drug Release from Nanostructured Polypyrrole Coated on Titanium, Nanotechnology, 22(8), pp , About the Author: Thomas J. Webster Thomas J. Webster is the director of the Nanomedicine Laboratories and has completed extensive studies on the use of nanophase materials in medicine. He was appointed department chair of Chemical Engineering at Northeastern University in He is the founding editor-in-chief of the International Journal of Nanomedicine. Webster has received numerous honors including: Fellow of both the American Institute for Medical and Biological Engineering and the Biomedical Engineering Society, recipient of the International Materials Research Chinese Academy of Science Lee-Hsun Lecture Award, and member of the International College of Fellows. He was recently elected president of the U.S. Society for Biomaterials. Webster has appeared on BBC, NBC, ABC, Fox News, the Weather Channel and many other news outlets talking about science. For more information, SVC QUALITY CRYSTALS Sensor Heads And Feedthroughs Rate/Thickness Monitors Electron Beam Gun Parts Ion Source Parts Quality Crystals, Gold, Stress Relieving Alloy, Liquid Plating Crystals Ionization Gauge Tubes Thermocouple And Convection Gauges Crucible Liners Krytox Fluids And Greases 704 Silicone And Hydrocarbon Fluids...Savings, Quality, and Stock Delivery tel fax SVC BULLETIN I SPRING