Zirconia microbead-assisted ball milling and BASD are now mainly used for the formation of single-digit dentonated nanodiamonds for research, in particular, for adsorption and delivery of insoluble anti-cancer therapeutics. Both techniques needs the use of ?30 ?m ZrO2 microbeads. In BASD, for example, the dense ZrO2 microbeads, propelled by the energy of cavitation, collide and crush nanodiamonds  aggregates trapped in-between (figure 5). BASD yields the stable single-digit ND   col-loids  upto 10 wt% concentration with up to 80% yield relative to the initial ND mass. However, BASD, as well as ZrO2 microbead-assisted ball milling have some disadvantages, such as a high cost (ZrO2 microbeads are expensive, special mills have to be designed for the process, separation of microbeads from NDs is also costly) and difficult to remove ZrO2 debris (harsh acid or base treatment is required to dissolve ZrO2, which have negatively impacts on production safety and contributes to the cost of the purified ND). On the other hand, if ZrO2 is not removed completely, then the presence of this contaminant in uncontrolled quantities may negatively effect the prospects of clinical approval for ND enabled theranostic platforms73. Thus, ZrO2 and similar ceramic contaminants may pose a serious obstacle on the way to low-cost and safe ND therapeutics.

On the contrary, water-soluble dry media-assisted attritor milling and SAUD utilize inexpensive, non-toxic, and non-contaminating crystalline milling media such as sodium chloride or sucrose. Upon completion of the deg-gregation process, the milling media can be easily washed out with water, providing a remarkable advantage over a process containing insoluble ceramic beads. However, during the dry media-assisted attritor milling, parts of the mill contaminate nanodiamonds with Fe, Ni, and other components of steel, so it required an extra purification step. Moreover, significantly reducing the aggregate size from micrometer scale down to 50–30 nm, dry media-assisted attritor milling does not yield truly single-digit nanodiamonds unless the dispersion pH is adjusted to ?11 upon completion of milling83,84.

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SAUD uses ultrasonic power transport by a standard lab horn sonicator into suspensions of different water-soluble crystalline media (e.g., sodium chloride, potassium chloride, sodium acetate, etc) to yield single-digit nanodiamonds colloids without any pH adjustments (figure 5).      Since no ZrO2 is used, SAUD completely eliminates zirconia or any other difficult-to-remove impurities in nanodiamonds85. The mechanical action of salt crystals in SAUD is combined with formation of a corresponding salt of Na+, K+, etc with COO? groups of nanodiamonds, thus improving the stability of single-digit nanodiamonds colloid. In another approach, hydrogen annealing of nanodiamonds at 800 °C–850 °C gives rise to deaggregated hydrogen and –OH-terminated nanodiamonds. These hydrogenated nanodiamonds show high colloidal stability in water due to their high positive zetapotential86,87.


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