Nanotechnologies for Medical Devices: Potentialities and Risks - ACS

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Nanotechnologies for medical devices: potentialities and risks Arnaud Pallotta, Igor Clarot, Jonathan Sobocinski, Elias Fattal, and Ariane Boudier ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00612 • Publication Date (Web): 21 Dec 2018 Downloaded from http://pubs.acs.org on December 24, 2018

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ACS Applied Bio Materials

Nanotechnologies for medical devices: potentialities and risks

Arnaud PALLOTTA1, Igor CLAROT1, Jonathan SOBOCINSKI2, Elias FATTAL3, Ariane BOUDIER*1

1Université

de Lorraine, CITHEFOR, F-54000 Nancy, France

2Université

de Lille, CHU Lille, INSERM U1008, Lille, France

3Institut

Galien Paris-Sud, Univ. Paris-Sud, CNRS, Université Paris-Saclay,

Châtenay-Malabry, France Phone +33 372 747 349 [email protected]

1 ACS Paragon Plus Environment

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Abstract Many novel medical devices (implantable or not) include nanomaterials through either surface-coating by nanoparticles or by direct nanostructuration of the surface. In this review we have identified several medical devices currently on the market in various health domains (wound healing, prevention or treatment of infectious diseases, cardio-vascular diseases, organ or joint replacement, and finally medical devices associated to nanomedicines). The very peculiar physicochemical characterization of the nanostructured medical devices is described. Keys to understand their possible interaction with the organism (positive or negative via toxicity) are given. Finally, as a conclusion, we discuss the specific quality control as well as the regulatory issues arising from the lack of regulation for approving nanomaterial combining medical devices.

Key-words: nanostructuration of surface; nano-objects; nanoparticles; pharmacokinetics; quality control; regulatory issues.

Highlights:    

Nanotechnologies to create tunable objects through surface/material modifications Medical devices are good candidates for nanotechnology applications Devices containing nanotechnology requires advanced characterization Toxicity and biological behaviors of such devices have to be controlled


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Table of content 1. Introduction ................................................................................................................4 2. Nanostructured devices and their evolution .............................................................11 2.1. Marketed nanostructured devices ......................................................................11 2.1.1. Non implantable medical devices...............................................................14 2.1.2. Implantable medical devices ......................................................................14 2.2. Nanostructured medical devices at early stages ................................................15 3. Nanomaterials physicochemical characterization ....................................................15 4. Nanostructured devices and their interaction with the organism .............................16 4.1. Biocompatibility tests........................................................................................16 4.2. Importance of surface effects ............................................................................16 4.3. Consideration on beneficial aspects and possible toxicity ................................17 4.3.1. Interaction with proteins.............................................................................17 4.3.1.1. Kinetic considerations .........................................................................17 4.3.1.2. Consequences of this phenomenon .....................................................18 4.3.2. Pharmacokinetic aspects of potential degradation products.......................18 Conclusion and outlook................................................................................................21 References ....................................................................................................................23



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1. Introduction It is estimated today at two million the number of different medical devices (MD) on the world market, categorized into more than 22 000 groups of generic devices 1 (see Figure 1 for the definition and classification of MD). They are classified in a wide range of references from the simplest (bandage, wheelchair…) to the most hyphenated that can be sterile and/or implantable such as needles, surgery cements, bone implants, etc. Up to now, innovative research in the field, including product already on the market, has been devoted to the development of more personalized and less invasive MD or more performant devices able to release in situ relevant drug(s) overtime after implantation.2-4


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A medical device is “A device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:  Recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,  Intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or  Intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”

“This definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. If the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug.” “Medical implants are devices or tissues that are placed inside or on the surface of the body. Many implants are prosthetics, intended to replace missing body parts. Other implants deliver medication, monitor body functions, or provide support to organs and tissues.” Some implants are made from skin,5 bone 6 or other body tissues.7 Others are made from metal, plastic, ceramic or other materials. Implants can be placed permanently or they can be removed once they are no longer needed. For example, stents or hip implants are intended to be permanent. But chemotherapy ports or screws to repair broken bones can be removed when they no longer needed.”

Figure 1. Definition of a medical device according to the Food and Drug Administration. Extracted form www.fda.gov (MD: Medical Device, IMD: Implantable Medical Device). Selected examples of MD and IMD are presented with their associated risks according to classification (from I, the lowest to III, the highest) Nanotechnologies are nowadays more and more included into the development of MD. In 2014, around 230 products were registered under the prefix “nano-”: 165 drugs and 65 MD.8 As illustrated in Figure 2A, there is a growing interest in this technology from both academic research groups as well as healthcare companies. Nanomaterials have been introduced in either non-implantable or implantable MD (IMD) (Figure 2B). The functionalization of 5 ACS Paragon Plus Environment


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medical devices that includes nanoparticles or nanocrystals may enclose precoating of the device surface with a matrix to improve surface grafting of those latter, or where nanoparticles or nanocrystals can be directly included in the surface it-self (Figure 2B).

Figure 2. Overview of the marketed nanostructured medical devices: (A) infatuation of the community extracted from Web of Sciences websites with keywords nanoparticles, nanotechnologies, nanomaterials combined with medical device (academic publications in solid line; patents in dash line) and (B) classical medical devices (MD) and implanted medical devices (IMD) and their microscopic organization.


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A quick overview of the marketed devices (Table 1) indicates that inorganic particles or nanostructured materials are the most studied. They are mainly nanotechnologies based on silver, zirconium, steel, magnesium, silicium, titanium, hydroxyapatite or its derivatives, iron and iridium. These innovative designs are developed to achieve (non-exhaustive list):    

Lighter but mechanically reinforced materials (by the inclusion of carbon nanotubes) 9 Materials able to mimic biological systems to increase the material biocompatibility 10-13 Bio-resorbable materials 14,15 Materials with an intrinsic pharmacological activity 16 or able to release an active drug.17


ACS Applied Bio Materials 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46

Organ

Skin

Medical device

Name of the marketed device

Nanotechnology

Bandage

Acticoat®

Silcryst™

Antimicrobial textile

Mipan® Magic Silver Nano

Silver NP

Suture needle

Sandvik Bioline 1RK91™

Steel nanocrystals

1-10 nm

AB SANDVIK MATERIALS TECHNOLOGY (Sweden)

Retinal implant

Argus™

Nano-electronic component

N.A.

SECOND SIGHT MEDICAL PRODUCTS (USA)

Characteristics Silver Nanocrystals (range from 1 to 100 nm) CAS Number: 744022-4 Particle size < 100 nm PVP stabilized - 33.7 mV 18

Retinal implant

N.A.

Silicium nanowires + iridium oxide nanolayer

Surgical mask

NanoMask®

Magnesium oxide and titanium dioxide NP

1 nanowire: 1 μm diameter and 9 μm height Iridium oxide layer: 30 nm 19 Positively and negatively charged NP

Surgical mask filtering influenza virus

NanoFenseTM

Silver NP

N.A.

Adhesive system

Adper™ Scotchbond™ SE

Silanized zirconium NP

Dental restoration composite

Aerosil 200®

Silicium NP

Eye

Mouth

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Tooth

5 nm spherical particles under colloid form Particle size 7 nm. Aggregates size 200 – 300 nm.

Name of the company (Country) SMITH & NEPHEW (United Kingdom)

HYOSUNG (Corea)

NANOVISION BIOSCIENCES / SAN DIEGO UNIVERCITY NANO MASK, INC (USA) APPLIED NANOSCIENCES

3M ESPE (USA) EVONIK


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Bone

Bone/joint

Dental restoration composite Photopolymerisable dental restoration composite Photopolymerisable dental restoration composite Dental restoration product based on synthetic resin

Ketac™ N100 Filtek™ Supreme Grandio®

Nano-ionomer Silicium NP Nano ceramic-hybrid composites

N.A. N.A. N.A.

Optiglaze

Silicium NP

N.A.

Kappalux Nano

Silicium and zirconium oxide NP

Metallic dental implant

NanoImplant®

Titanium NP

Product for injectable bone filling

Nanogel®

Hydroxyapatite NP

Particles size: 10 – 100 nm Particles size: 100 – 300 nm Particles size: 100 – 200 nm Nanofiber size: 100 nm length and 5 nm width Surface area/mass : 106 m2/g 20

3M ESPE (USA) 3M ESPE (USA) VOCO (Germany) GC CORPORATION (Japan) PRODUITS DENTAIRES PIERRE ROLLAND (France) TIMPLANT (Czech republic) TEKNIMED (France) AAP BIOMATIERALS (Germany) / MEDTRONIC (France)

NanostimTM / Ostim®

Hydroxyapatite nanofibers

PerOssal®

Hydroxyapatite NP

N.A.

AAP BIOMATERIALS (Germany)

FortrOss®

Hydroxyapatite NP (NanOss®) combined to osteoconductive EMatrix

N.A.

PIONEER SURGICAL TECHNOLOGY (USA)

Vitoss® Scaffold

Calcium phosphate NP

Puretex®

Nanostructured titanium surface

N.A.

Orthopedic or joint prosthesis

Nanos™ Symax™

Microporous coating (Bonit®) with hydroxyapatite nanocrystals ( made by DOT (Allemagne))

N.A.

Orthopedic or teeth prosthesis

NanoTite™

Calcium phosphate nanocrystals deposited on a surface

Nanocristal size: 20 – 100 nm 22

BIOMET 3i

External knee prosthesis

Rheo Knee

Iron NP

Particles size: 100 –

OSSUR (Iceland)

Product for injectable bone filling Nanostructured metallic orthopedic implant

Particle size: 100 nm 21

ORTHOVITA (USA) SYBRON IMPLANT SOLUTIONS (USA) SMITH&NEPHEW (United Kingdom) STRYKER (France)



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1000 nm

Vessel

Abdomen

Surgical device delivering data on custom orthopedic knee implantation

Mako

Nanosensors

Stent coating

Debiostent™

Nanoporous silicon membrane

Naked coronary stent

Catania™

Polyzene®-F

Drug-eluting stent

VestaSync™

Nanoporous hydroxyapatite coating

Vascular graft

UCL-NanoBio™

Polymer nanocages

Catheter for anesthesia

ON-Q® SilverSoaker™

Ventral Hernia Mesh

NovaMesh™

Coating including silver NP ( SilvaGard™ made by ACRYMED (USA)) Electrospun nanofibers integrated into a tissue

N.A. Pores size: 1 – 250 nm Membrane thickness: 50 nm – 250 µm 23 Coating thickness: 40 – 50 nm Coating thickness: 100 nm Cage size: 200-500 nm Cage height: 100 – 200 nm 24

ORTHOSENSOR (USA) DEBIOTECH (Switzerland) CELONOVA BIOSCIENCES (Canada) MIV THERAPEUTICS (Canada) Royal Free Hospital of London (United Kingdom)

Particles size: 10 nm

I-FLOW CORP. (USA)

N.A.

NICAST (Israel)

N.A. : Non Applicable PVP: Poly(Vinyl) Pyrrolidone Table 1: List of the marketed devices which is either nanostructured or which includes nanotechnologies. The medical indication of the device is indicated. The size of the nanotechnology is indicated when the information is available.


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The usefulness of devices including nanotechnologies may not impede the current debate on nanoparticle toxicity especially when they are inorganic,25 which raises questions about the benefit/risk balance. This review deals with MD (implantable or not) including nanoparticles or which are nanostructured and will emphasize on the advantages and drawbacks of these nanomaterials. The last report 26 was published a few years ago with no update since then. Our review will not focus on colloidal nanoparticles used as drugs or drug candidates (in cancer for example) which have already been extensively described in the literature.27-32 In the same way, even if the inclusion of nanoparticles into the development of diagnostic devices was crucial (gene bio-array or lab-on-a-chip characterized by a nearly molecular precision,33 nanostructured surfaces or miniaturized valves 34 or nanosensors 35), this is not the topic of the present paper. Herein, after an overview of the devices already on the market or under clinical trials, the physicochemical characterization of the materials will be described. Then, the biocompatibility in relation to the surface phenomena that are closely linked to the nanoscale will be detailed. Next, we will describe the possible toxicity induced by the nanoparticles entrapped into a nanostructured material or a nanomaterial. As a conclusion, the article will give outlooks on the requirement of a pharmaceutical quality control and on regulatory issues. Thus, the existing obstacles to develop new nanostructured MD or include nanoparticles into MD will be deeply discussed. 2. Nanostructured devices and their evolution The different categories of nanostructuration developed and used in medical devices can be divided into 3 technologies: deposition and embedment of inorganic nanoparticles (silver, diamond, clay, ceramic, hydroxyapatite …), use of nanofibers or polymers to create tunable matrixes with a nanoscale thickness and finally the use of nanoporous materials. 2.1. Marketed nanostructured devices Nanotechnologies either as nanoparticles entrapped into a MD or as a nanostructured material are used in a wide range of clinical applications (Tables 1 and 2, and Figure 2B). Included into MD (implantable or not), they are applied in wound healing, prevention and treatment of infectious diseases, cardio-vascular diseases, organ or joint replacement and finally medical devices associated to nanomedicines.



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Study name Medical device Status

Official title

Purpose

nanoparticles ClinicalTrials.gov Identifier: Effect of Antibacterial Nanoparticles, Incorporated in root canal sealer material and in provisional restoration

IABN Clinical Study: the Antibacterial Effect of Insoluble Antibacterial Nanoparticles (IABN) Incorporated in Dental Materials for Root Canal Treatment NCT01167985

Clinical Study: the Effect of Addition of Insoluble Antibacterial Nanoparticles(IABN) in Resin Base Provisional Cement NCT00502606

Effect of Antibacterial Nanoparticles, Incorporated in cement, on S. mutans in the margins of provisional restorations

Dental restoration Polyethyleneimine nanoparticles

Unknown

Effect of Antibacterial Nanoparticles

Clinical Evaluation of Esthetic Restorations Placed in Primary Molars With Composite Resin Enriched With Insoluble Anti Bacterial NanoParticles (IABN) NCT00389714 Clinical Study of Antibacterial Nanoparticles Incorporated in Composite Restorations NCT00299598 Altrazeal Range of Motion Study Comparing

Alkylated polyethylenimine nanoparticles Hydrogel bandage

Completed Terminated due to a lack of

Resin composites withholding antibacterial properties useful in preventing recurrent caries

Difference in joint range of motion of a new flexible hydrogel nanoparticle wound dressing compared to typical


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With Typical Carboxymethyl (ROM) NCT01062191

enrollment Nanoflex® NP Electronic nose (E-nose)

SNOOPY2 Exhaled Breath Olfactory Signature of Pulmonary Arterial Hypertension NCT02782026

Gold-nanoparticles coated with organic ligands Denture teeth

Currently recruiting

Wear Characteristics of Denture Teeth Terminated

sodium carboxymethylcellulose dressing Aquacel AG for treatment of partial thickness burns Evaluate the diagnostic performance of a novel electronic nose (E-nose) for the detection of Pulmonary Arterial Hypertension (PAH)

To evaluate the wear characteristics of new resin denture teeth (nano particles - hybrid composite) made by an injection technique

NCT01188226 Nano hybrid composite

Table 2. List of the nanostructured devices currently under clinical trial evaluation. Extracted from https://clinicaltrials.gov/ (keywords: nanoparticles, nanotechnologies and nanomaterials)



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2.1.1. Non-implantable medical devices Nanostructuration is already used in needles, bandages, catheters, scalpels and diagnostic devices (Table 1 and Figure 2B). Since antiquity, silver, as a nitrate salt or under its colloidal form, has been introduced in bandages for its antimicrobial properties with broad spectrum activity. If the mechanisms of anti-infectious action remain unclear, hypotheses rely on a synergistic action of both nanoparticles (through catalytic and Fenton-like reactions) and silver ions. They result from the dissolution/corrosion of nano-objects due to a contact between extracellular water and patient exudates.36-38 The colloidal form allows a prolonged and enhanced effect compared to salt.39,40 This strategy is used both in surgical masks to prevent infections and in the coating of catheters to prevent nosocomial infections.41 Further work on catheters tries to include a polymeric matrix made of clay or ceramic nanoparticles or even carbon nanotubes in order to reinforce the conventional material and to improve the mechanical and physical properties.42 Scalpels are also nanostructured by a diamond nanometric coating allowing a more precise and tinier incision and a less invasive surgery thanks to a low friction coefficient.43 The developed coating also decreases tissue adhesion on the scalpel surface and ease its penetration. 2.1.2. Implantable medical devices Among IMD, the ones containing NP currently developed are synthetic grafts, stents, implants for various organs as well as artificial organs (Table 1 and Figure 2B). Synthetic grafts are mainly applied to vessel replacement to develop in silico organs. In this way, nanofibers are created for example by electrospinning.44,45 These nanofibers are tunable in terms of shape (by the support and template), density and fiber size (as a function of the polymer used) and are therefore able to create extracellular matrices very similar to the biological environment. Arterial occlusion that could lead to myocardial infarction, cerebro-vascular accident or limb amputation can be treated by angioplasty usually followed by the implantation of a stent. These medical devices are generally composed by a metallic (stainless steel, titanium, chromium/cobalt or nickel/titanium alloys) or a polymeric (polylactic acid) scaffold. These bare stents are exposed to early intra-stent restenosis implying reintervention or symptoms recurrence. Some of them can release drugs such as immunosuppressive or antiproliferative agents to decrease that pathophysiological phenomena but expose to other adverse event such as acute late thrombosis. Others leads are under development by example, nanometric coatings made of nanoporous ceramic or polymers are tested to modify stent surface. The Polyzene-F® (a polyphosphazene derivative) is a stent nanocoating with satisfying hemocompatibility, fast and complete vessel healing thanks to an antiplatelet effect at the site of implantation.46,47 After clinical evaluation, the benefit/risk balance of such coating was superior compared to devices with other strategies such as novel metallic alloy or biodegradable stents.48 Apart from the vascular domain, a wide range of implants are on the market to be applied to bones, joints, teeth, and eyes. These implants are placed for a long time (10 to 15 years 12) and the chosen metallic alloys are characterized by good mechanical properties and resistance versus corrosion. Implant surface nanostructuration as well as the nano-object nature (e.g. hydroxyapatite or calcium phosphate for bone) was shown to enhance cell adhesion and differentiation improving long-term biocompatibility.49 14 ACS Paragon Plus Environment

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Nanoparticles has allowed innovations for the design of artificial organs: heart, kidney, and retina. The first totally artificial heart (Carmat Company) was implanted in 2013. Up to now, ten patients have benefited from this innovative heart. In this technology, the internal surfaces which are in contact with the bloodstream are coated by synthetic or biological hydrophobic biomaterials (near valves in order to avoid any coagulation cascade activation and blood cell adhesion) or nanoporous surfaces (at the interface of veins and arteries) in addition to other miniaturized captors for the adaptation of the heart to physical activity. It is important to point out that problems encountered after this artificial heart implantation (power failure, bacterial infections … resulting in patient death) were not directly related to the presence of nanomaterials inside this device Artificial kidneys have also been developed. They are composed of thousands of nanoporous structures able to selectively adsorb toxins.50 The principle relies on a combination between an ultrafiltration membrane and a bioreactor made of human kidney tubule cells to reproduce the metabolic, endocrine and immunological functions of the organ. Cells are cultivated on a nanoporous silicon film 51,52 in order to mimic renal activity, avoiding the deposition of protein and limiting a loss of blood proteins. Three artificial retinas using nano-electrodes able to transmit information recorded by a camera to the optical nerve are currently being marketed or under evaluation. These implants (3 × 3 mm) are composed by up to 1500 miniaturized electrodes. Recently, some papers described new strategies to develop artificial retinas.53,54 2.2. Nanostructured medical devices at early stages Numerous marketed MD that include NP or which are nanostructured are already available and an intensive research still focuses on this topic. Some authors study implantable active MD at the nanometric size: e.g. ultra-sensitive captor,55 molecular computers.56 The components are described as biocompatibles and bioresorbables.57 To achieved such a result, authors described the use of several polymer scaffolds in association with silk nanofibers (< 150 nm) that were biocompatibles. They presented and important half-life in the body.57 According to the studies, these nanorobots could, in a future, be able to specifically find the cell that generated the disease and erase it, thus preserving the patient from the disease process. Translating to the nanoscopic scale can widen the range towards new surgery perspectives by the development of nano-electromechanic systems assisted by a computer. These technologies could supply biological exploration tests although comprising device implantation via mini-invasive surgeries (“nano-manipulation”) controlled by the surgeon.58 3. Nanomaterials physicochemical characterization Physicochemical characterization of nanomaterials is essential to define the material and to predict the behavior inside an organism. Only knowing the nanoparticle size or chemical composition is needed but not sufficient to understand, apprehend or anticipate behavior of the material over time. Nowadays, a thorough overview of the literature highlights the measurement of 8 fundamental physicochemical parameters which are considered as relevant for the biological evaluation. These parameters include the size and the size distribution, the shape, the possible aggregation and agglomeration, the specific surface, the composition, the surface charge and the surface chemistry. Physical parameters (size and size distribution, shape, aggregation/agglomeration linked to a thermodynamical instability and specific surface) are usually measured by microscopic (transmission/scanning electron microscopies, atomic force microscopy) and/or spectroscopic (light scattering) techniques and physisorption (Brunauer, Emmett and Teller (BET) method). These characteristics greatly impact the potential stability and reactivity of the surface. Chemical parameters (composition, surface 15 ACS Paragon Plus Environment


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charge and surface chemistry) are explored by various complementary techniques (e.g. spectroscopies (Xray diffraction, NMR, IR etc… 59), thermal analysis, and spectrometries (Mass Spectrometry, elemental analysis… 59,60 and electrophoresis 60,61). Some methodologies combine both the study of physical and chemical parameters such as capillary electrophoresis,60,61 liquid chromatography 62 coupled to Mass Spectrometry, UV-Vis. or fluorescence detections. The chemical composition should quantify active substances (if relevant) as well as impurities (see dedicated paragraph) which are called “related substances” when we refer to pharmaceutical products. While the levels are well-defined for a drug by Pharmacopoeias, it is not the case for nanomaterials at the moment as no monographs exist. However, it seems to be of main importance when nanomaterials are combined to MD since the impurities can come from degradation products, synthesis intermediates, solvents, catalyzers. Surface chemistry and surface charge are key points since they govern the direct interactions between a nanomaterial and its biological environment through catalytic properties, molecule adsorption/desorption 63,64 or diffusion,65 and finally condition the expected therapeutic relevancy. 4. Nanostructured devices and their interaction with the organism It is obvious that nanostructured devices develop an important contact surface interacting with the organism. This can bring either beneficial events or toxicological issues. 4.1. Biocompatibility tests Biocompatibility is defined by ISO 10-993 as the ability of a material to perform an appropriate host response in a specific situation.66 Biocompatibility is therefore different from inertness since it suggests a beneficial interaction, as examples: the depot of a hydroxyapatite film on the implant surface improves its affinity towards osteoblasts 67 and the implant microstructuration of titanium surface modifies its interaction with blood proteins and favors cell adhesion.68 The tests usually performed for this are described below. They are organized into:   

Primary tests: in vitro assays of cytotoxicity, genotoxicity, and hemolysis and in vivo assays of cancerogenicity, reproduction, and systemic toxicity; Secondary tests: mucosal or cutaneous irritation test, sensitization, and implantation; Clinical trials.

Besides, some specific tests (as a function of MD/IMD use, expandability of stents, porosity of condoms…) are performed according to the MD classification (extracted from FDA/EMA and corresponded to the associate risk towards patient (I, IIa, IIb and III, Figure 1)). 4.2. Importance of surface effects Biocompatibility depends not only on the nature of the material but also on its interaction with the organism i.e. at the material/tissue interface: its superficial composition and organization (roughness, pores, mesh …) are key factors influencing it. Due to their specific properties (chemical, physical, magnetic, electric, optic, mechanic…), nanotechnology can improve or at least modify the MD properties. However, the main cause of interaction with the organism is based on the ratio between surface and volume. As an example, if one considers a microcrystal of iron (1 µm of diameter) less than 1% of its atoms are localized at the surface; on the contrary, 90% of the atoms are present at the surface of a nanocrystal (1 nm of diameter).69 Consequently, the specific surface (external surface over mass ratio) 16 ACS Paragon Plus Environment

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which is the exchange surface is a lot more important at the nano-scale compared to the micro-one. 4.3. Consideration on beneficial aspects and possible toxicity 4.3.1. Interaction with proteins It is of common knowledge that nanoparticles or nanomaterials exposed to a biological environment are rapidly covered with a layer of organic compounds. The most described elements in the literature are proteins but one should keep in mind that other elements can interact with nanomaterials, such as natural organic matter (NOM),70 lipids 71 or other cells compounds.72 However in order to keep it “simple” we decided to focus only on protein adsorption as described in the next sections. 4.3.1.1. Kinetic considerations When a nanomaterial is exposed to a biological environment, it is covered very rapidly by a protein layer in a dynamic equilibrium creating a corona. The affinity of a protein towards a material surface highly depends on its state, bulk or nanometric, in relation to its structuration, specific surface, surface reactivity. Moreover, the “material/protein” complex evolves depending on the time. The phenomenon, called the Vroman’s effect,73 explains a biphasic kinetic: firstly the proteins present at a high concentration adsorb and are secondly progressively replaced by other proteins characterized both by a higher affinity and a lower concentration (Figure 3). Albumin (circa 40 g/L) is usually the first interacting element before other such as fibrinogen (circa 2-3 g/L), complement protein (C3 (1.6 g/L 74), C4, and C5), immunoglobulins (IgA 2.5 g/L, IgG 11.0 g/L, IgM 1.3 g/L 75). Protein adsorption tends to increase with a positive surface charge (this is explained by the isoelectric point value of blood proteins which confers to them a global negative charge at the physiological pH) and with a hydrophobic surface.76 Even though surface properties of a material are of main importance in this phenomenon, its composition may influence protein adsorption. Indeed, when core/corona nanoparticles are included in a material, a re-organization may be described and the core components may migrate at the surface, implying a modification of the reactivity.77 On the contrary, protein adsorption can be limited by a direct grafting of polymers such as N,N-dimethylacrylamide (PDMA),78 polyethylene oxide (PEO) nanobrushes or even using poly(lactic-co-glycolic) acid (PLGA) grafted by PEO.79



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Figure 3. (A) Kinetic of interaction of nanostructured materials with plasmatic proteins and their affinity for protein adsorption. Three phases can be observed: highly concentrated protein with low affinity are first adsorbed (green curve) and this equilibrium is progressively modified towards protein less concentrated with better affinity for material surface (red curve). (B) Influence of the nanostructuration on protein adsorption. 4.3.1.2. Consequences of protein adsorption Protein adsorption at the surface of nanomaterials implies either negative or beneficial consequences. For example, as a function of the polymeric brush grafting density on a nanomaterial, a modulation of hemostasis is observed. Thus, a poor PDMA density of grafting implies an initiation of the coagulation cascade whereas a high density would inhibit platelet aggregation.78,80 Moreover, nanostructured materials using poly(alkylcyanoacrylate) (PACA) nanoparticles can induce a different immunologic response as a function of the geometry (brush or loop) of the polymers grafted onto the nanoparticles.81 For nanostructured materials, the quantity and the nature of adsorbed proteins are essential to modulate adhesion, migration, and cell differentiation. Yang et al., showed that a titanium nanostructured surface adsorbed fibronectin in a more specific pathway compared to albumin.82 This led to new specific surface properties. In this study, osteoblasts adhesion and in parallel osteointegration was promoted by the fibronectin coating, helping tissue reparation. 4.3.2. Pharmacokinetic aspects of potential degradation products The pharmacokinetic aspects described in this part concerns the degradation products coming from the NP included in the MD (Figure 4). The pharmacokinetic profile of colloidal nanoparticles (administered per se) will not be described and can be found elsewhere.83,84 Degradation products from these materials can be:  

Colloidal nanoparticles included or not in the matrix which entrapped them; Aggregated or agglomerated nanoparticles included or not into the matrix; 18 ACS Paragon Plus Environment

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 

Nanoparticle fragments; Metallic ions coming from the nanoparticle dissolution 36,38 or from the metallic device surface corrosion.85

Figure 4. (A)Biodistribution of nanoparticles originated for specific MD (modified from 106) and (B) corresponding potential degradation products and the questions regarding their pharmacokinetics in the body. Confirmed pharmacokinetic pathways are indicated in plain arrows and hypothesized ones in dotted arrows. Based on this, all the pharmacokinetic steps can be detailed. Absorption With the use of nanomaterial combining MD, degradations products can be absorbed by various pathways: transcutaneous route, and oral/respiratory routes. Topical medical devices such as bandages that entrapped silver nanoparticles imply an important exposure to these particles or their degradation products. Healthy skin represents an efficient physical barrier against attacks from the environment that prevents the absorption of chemical products such as silver nanoparticles.86 However, when the skin is damage, the penetration of nanoparticles from bandage may become possible and even quite important: high serum silver concentrations (under ionic state) were quantified in patients suffering from severe burns, by example with serum concentrations returning close to 0 only 3 months after the end of the treatment.86 Nanostructured dental products (such as some prostheses) and nanostructured MD applied to the upper aero-digestive ways can provide degradation products that penetrate the body through the digestive tract. As an example, a recent study proved that nanoparticle fragments deriving from dental prosthesis were absorbed by the intestine and resulted with apparition of 19 ACS Paragon Plus Environment


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side effects: fever, liver and spleen lesions, acute renal failure. All these symptoms were observed one year after the implantation of the dental prosthesis, and just disappeared as the implant was removed.87 Distribution and metabolism After circulating within the blood stream, degradation products can be opsonized by opsonins (components of the complement system such as C3, C4, and C5) and other proteins (laminin, fibronectin, C-reactive protein, type I collagen and many others) to be easily recognized by the reticuloendothelial system and phagocyted by monocytes and macrophages as this can be observed with colloidal nanoparticles.83 Those latter are then orientated to the spleen, liver and/or kidneys where they can be metabolized and/or stocked.88 They are potentially detectable in the long term in the heart, the lungs, the bone marrow and a migration into the central nervous system can also be recorded. Excretion The elimination of degradation products is not well-described. It mainly depends on the exposure pathways and on the physicochemical features of the considered fragment. The ones present in the digestive tract may be eliminated by feces. When they are present in the blood, degradation products can either be filtered by the kidney to be excreted in the urinary tract or in the biliary juice after liver metabolism.89 This last pathway is classically described for drugs but remain to be confirmed for nanoparticles or degradation products coming from nanomaterial combining MD. Toxicity The possible persistence of degradation products coming from nanostructured MD in the human body may induce acute or chronic toxicities. In any case the most important risks related to degradation and even aging tin the release in the body of nanoparticulate units with unknown effect. This is for instance particularly critical in the case of joint protheses where due to friction forces between articular surfaces, bone interaction and corrosion phenomenon, the material can release particles (ca. 1012 particles/year) with a size of ca. 50 nm.90 However, it is possible that particles characterized by a diameter of less than 50 nm can be underestimated due to the limitation imposed by the detection techniques in a biological medium. In all cases, generated fragments can be endocytosed by macrophages before being transported to the lymph nodes for excretion.91 However, if cells are phagocytosing nanoparticles that they are unable to eliminate, they can activate a response characterized by the secretion of inflammation factors such as pro-inflammatory cytokines.92 This triggers an inflammatory reaction activating the immune system, which can involve B lymphocytes or macrophages within the scope of a delayed hypersensitivity response. These responses are associated with changes in the expression of different genes including genes for inflammation, apoptosis or control of the cell cycle. They can also be responsible for DNA lesions indicating risks of genotoxicity and carcinogenicity.93 A few incidents were related to the presence of nanoparticles in MD particularly with silver nanoparticles. For instance, the antimicrobial properties of the silver nanoparticles are due not only to their inherent properties but also to their dissolution into ions (Ag+) via a corrosion phenomenon.36,38, 94-96 These agents can be absorbed by the transcutaneous route because of a damaged skin as previously explained. A hepatotoxicity, appearing one week after the beginning of the treatment, was described in a patient presenting burns and treated by silver nanoparticles containing bandage. A total regression of the symptoms was observed when the 20 ACS Paragon Plus Environment

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bandages were taken off.97 When these particles are associated to catheters, the antimicrobial properties were maintained but an initiation of the coagulation cascade was noticed with a possible associated risk of thrombosis.98 In parallel, the clinical trials AVERT which tested the efficiency of heart valves containing silver nanoparticles was prematurely stopped in particular because of the appearance of side effects such as thrombosis. The coating made of nano-objects was questioned even though the collected data were not significant from a statistical point of view.99,100 Conclusion and outlook As a conclusion, many nanomaterials used in MD and IMD are already available on the market and proved numerous beneficial aspects. Further works on this topic may open new perspectives in therapy or diagnostic or even in theranostic. This wide pharmaceutical domain is indeed characterized by an important dynamism in terms of innovation (Figure 2a). However, in spite of the great potential offered by the domain, it seems that there is a lack of dedicated pharmaceutical quality control and regulatory issues are not totally well addressed. In literature, even though eight criteria are usually used to describe nanomaterials combining products, it is still not sufficient to define them from a pharmaceutical point of view. It is obvious that the quality control of such product is much more complicated than the one of bulk materials. There is, indeed, a wide variety of products which are nanostructured or including nano-objects (Figure 2b) and maybe new properties have to be taken into consideration in a case-by-case approach. This suggests the development or at least the transposition of analytical methods that may provide information in a complementary manner. This really represents a new multidisciplinary challenge not only for analysts but also for scientists of other expertise domain. At this time, in the regulatory texts, there are no standard guidelines for nano-product manufacturing and their control, so they must follow the current good manufacturing practices (cGMP). Moreover, there is no monograph on any nanomaterial in the Pharmacopoeias (US or European). This situation is the same than the one observed a few years ago for raw materials coming from medicinal plants and vegetal drugs. A lot of impurities can be generated from nanomaterials combining products from which a potential toxicity may originate: impurities coming from the synthesis and the storage or even the degradation products (as cited above and illustrated into Figure 4). These elements must be defined and their amount should be normalized into assay values and corresponding calculated standard deviations. It is obvious that a better characterization and quality control of such products would lead to a better understanding of the potential interaction with biological elements as well as a possible related toxicity and the way to avoid it. Even though there is an international definition of nanomaterials given by the ISO, the regulatory Authorities of each country possess its own definition which was recently highlighted in a review.101 This induces an important lack of clarity. In parallel, the classification of a product as either a drug or an MD may be different depending on the concerned regulatory Authorities from one country to another. Altogether, these Agencies have started to discuss about nanomedicine; for example, there was a first joint workshop between the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2010.8 This may help for further normalization of regulatory issues. Moreover, as nanomaterials can easily be functionalized by drugs with high yields, one can easily imagine new devices combining three partners: a device, nano-objects or a nanostructuration and an active molecule. Some lab works 102-106 are currently developing such products showing an important axis of innovation and dynamism in the design, the 21 ACS Paragon Plus Environment


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architecture and in the adopted medical strategy. This idea can lead to a new family of combination compound. This class of medicine already combines two or three singleregulated entities: drug, biological and/or medical device (with as examples transdermal patches or drug-eluting stents 2). This definition may need to be broadened in order to include product containing drug(s), MD and nanomaterials. These hyphenated technologies might also trigger new regulatory aspects. According to the FDA definition of the MD (Figure 1) and of drug, the difference is set as “if the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually a drug”. Although this statement clearly separates MD from drug, the approval of such drug and nanomaterial combining products ought to be more defined by new regulatory issues. To go further, with the development of such products, the regulatory barriers between drug, nanomaterials and MD may progressively fade away. Acknowledgements: Authors are very grateful to Marjorie Antoni (lifelong learning division of Université de Lorraine) for helping to improve the level of English in the manuscript. Conflict of interest: none


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Nanotechnologies for Medical Devices: Potentialities and Risks - ACS

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