On the impurities content in nanodiamonds evolve for

       On increasing the development ofnanomaterials for applications, their toxicology becomes of ever-increasing important. In addition, thetraditional factors govern the toxicological profileof bulk materials, moving from micro to the nano-scale adds more dimensions: Apartfrom elemental composition, potential toxicity of nanomaterials may depend ontheir size, shape, and dispersion state. Traditional purificationtechniques depict to produce highly pure large crystals or particles of bulk materials often fail for nanomaterials. Inaddition, when the surface to volume ratio becomes larger, the contribution ofany contaminants that usually reside on the surface of particles becomes more noticable.Therefore, control of purity and dispersion are no less important thansynthetic efforts pointed to develop the nanomedicine platforms and bringingthem to applications133.

Themajority of impurities in detonation nanodiamond (DND) arisefrom the material of the blast chamber, charge suspension device, and initiator(usually Pb, Cu or Ag azide).Carried out in a steel blast chamber, the explosion formed the ND-containingdetonation soot and originate metallic contaminations along with non-diamondcarbon. Hence, for most of its applications particullarly, in biology and medicine, DNDsshould be purified post-synthesis. A lots oftechniques has been proposed to purify NDs. Some of them could be used for NDsof different origins, whether it is detonation DNDor high-temperature high-pressure ND (HPHTND)6,65. A liquidphase oxidative treatment (with mineral acids, e.g. sulfuric,nitric, and perchloric acids or mixtures there of)seperate almost all graphitic and metal impurities.

Nevertheless, somenon-carbon functional groups, e.g., sulfonic, are found as a result of liquidoxidation. In contrast, gas phase oxidation techniques produce only oxygen-richcarbon functional groups on the nanodiamonds  surface, although these methods neededadditional treatment in dilute acids toremove metal impurities .

Microwave-assisted liquid oxidation requires a lower temperature as compared to traditional liquidoxidation, although the complete removal of metals is attain when EDTAcomplexes are used. The nanodiamonds show no innate toxicity but may show toxicity that depends on the tailorablesurface properties of the material, intensify the need for testing all surfacemodified nanodiamonds for their toxicity/biocompatibility.Thus, it is critical to examine the impurities content in nanodiamonds evolvefor applications, although many researchers tacitly rely upon almost completeremoval of metal and non-diamond carbon contaminations after air and liquidoxidation or liquid oxidation alone24,134. Thetechniques for identifying the nanodiamonds purity and content of contaminantsinclude inductively-coupled plasma mass-spectrometry and elemental analysis,SEM/TEM, XRD, XPS, and Raman spectroscopy1,2,4,135,136.        In most of cases, one method is not enough(for example, many manufacturers give the C:N:O content butno phase composition of carbon, which is necessary to assess the content ofdiamond and non-diamond phases in the material),and complete characterization needs a combination of several techniques. Thenotoriously strong aggregation of DNDs strictly limits their potential in many applications, involvingpolymer-and metal-matrix compounds, as well as different applications. Sincethe developing studies of nanodiamonds toxicity, various screenings have been execute to produce comprehensive toxicological profilesof nanodiamonds (table 2).These studies pointed to recognize the type of toxicity and the unexpressedmechanisms.

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A general conclusion, which can be drawn from multiple toxicitystudies is that nanodiamonds derivatives from various origin and sizes do not ruinthe fundamental functions of cells, organs, and organisms in a acceptable rangeof concentrations. At the same time,there are various reports of nanodiamonds toxicity, which may be associated tothe use of poorly purified nanodiamonds. Table  5 outline the purificationprotocols of nanodiamonds and the detailed contents of impurities (whenprovided) along with toxicological outcomes. In most cases wheresignificant level of toxicity was describe, nanodiamonds have beenused as-received. In those studies where nanodiamonds has been purified (forexample, air or ozone oxidized and acid treatment to dissolve metals or liquid oxidized)no remarkable toxicity was noticed. We suppose that if metallic and other impuritieswere fully removed, the nanodiamond would be shown low or no toxicity in allstudies134,137,138. Forexample, only slight apoptosis of HaCaT cells effect the membrane permeability changes, caspase activation, andrelease of intracellular lactatedehydrogenase,was noticed as a result of exposure to non-purifiedas-received ND at 100 ?g ml?1concentration139.

On theother hand, purified nanodiamond in same concentrationdid not affect basal cellular toxicity of A549 cells140. Anotherreason for induced cell death may be associated to unreasonably highnanodiamonds concentrations used in the tests. For example, an increased levelof apoptosis has been noticed in both normal and cancer cells at 200–1000?g ml?1nanodiamonds.

At the same time, the nanodiamonds concentrations below than 50 ?gml?1no apparent toxicity was observed141. Nanodiamondsdid not persuade any cytotoxicity and inflammation in concentrations up to 50 ?gml?1,as shown through examination of gene expression mechanisms, cell morphology,immunotoxicity, and apoptosis142 .Analysis of other effects (size, shape, and origin of nanodiamonds)have shown that the concentration played the most important role in nanodiamondsinduced toxicity and inflammation143.         The immunotoxicity, that results in anincreased secretion of chemokines and cytokines, has been estimate for nanodiamondsderivatives with many cell types. After exposure to ND-COOH, themesenchymalstem cells did not change the secretion of cytokines, chemokines, and growthfactors144. Celloxidative stress is another indicator of cellular toxicity.

The oxidativestress produce by nanodiamonds derivatives is cell specific.For example, no signs of oxidative stress have been observed in neuroblastomacells, macrophages, keratinocytes, and PC-12 cells . On the other hand,lymphocytes and endothelialcells have shown nanodiamonds induced oxidativestress that can be partially associated to the use of as-received non-purifiednanodiamonds145. A conceptof adsorption, distribution, metabolism, and elimination (ADME)is broadly used to analyse carbon nanomaterials bioavailability, tissuedistribution, metabolism, and excretion from the body . NDs labeled with 188Re,125I, and 18F radionuclides have been used in biosafetyexplorative studies on mice and rats.

Alike to other nanomaterials, exposureroutes to nanodiamonds can impact toxicity146. Twostudies of pulmonary delivery of nanodiamonds report counter results that showthe both toxic and non-toxic properties of nanodiamonds in lungs and otherorgans, together with cardiovascular system. This controversy can be detectback to a dose-dependent nature of the noticed effects or to differences inpurity of nanodiamonds used. In another example, the controversial nanodiamondstoxicity towards blood could be described by impurities and poor purification,since the researchers reported rupture of the membranes of white and red bloodcells using non-purified as-received nanodiamonds101. On theother hand, no signs of hematological toxicity were observed with acid purifiedBASD detonation nanodiamonds.

Substantial attention has been paid to the developmental toxicity of nanodiamonds. Classictest systems using embryos of Xenopus laevis, andDanio rerio (zebrafish) to determine teratogenic andembryogenic potential of nanodiamonds have been reported147. Xenopusembryos turned out to be sensitive to nanodiamonds surface functionalization,which sometimes resulted in a low survival rate due to developmentalabnormalities. Dose-dependent toxicity of nanodiamonds was reported for the zebrafish model143. Particleaggregation and inability of sub-vertebrate species to cleanse nanodiamondsfrom their body at higher nanodiamonds concentrations can donate to thereported nanodiamonds toxicity in these cases148.

The fateof nanodiamonds carbon in other organisms, and particularly, in animals raisesquestions. Unlike metal nano-particles, nanodiamonds cannot be digested ordissolved in the human body78. Toconclude, nanodiamonds is undoubtedly a perspective nanomaterial with less concerns regarding its toxicity as comparedto other carbon materials, as well as CTAB-coated gold nanoparticles, semiconductor quantum dots, etc.

Some contradictions in the experimental resultsnoticed for nanodiamonds can be descibed by the impurities content, and thus aproper purification of as-received nanodiamondsis utterly important. The level of impurities as well as surface chemistry of nanodiamondsmust be taken into account during analysing the nanodiamonds toxicological profile.In particular, heavy metals, graphitic and amorphous carbon, ceramic and otherpotentially harmful impurities have to be removed14.