Nanomedicine, Volume IIA: Biocompatibility

© 2003 Robert A. Freitas Jr. All Rights Reserved.

Robert A. Freitas Jr., Nanomedicine, Volume IIA: Biocompatibility, Landes Bioscience, Georgetown, TX, 2003 Chemical Stability of Alumina and Sapphire

It is generally accepted that alumina ceramics such as BionitR [1025] and single-crystal sapphire [1031, 1035] have excellent biological inertness and chemical stability. Atomically ultrasmooth sapphire surfaces are stable in air and water for months [899]. Exposed to water, the polished single-crystal alpha-alumina (0001) surface elicits a hydration reaction, with a water vapor pressure of ~1 torr sufficient to fully hydroxylate the surface [1751]. Alumina is corrosion-resistant because it exists in the highest oxidation state that aluminum metal can possess. Thus this material has the potential for microstructural control of the interface (with tissue) without formation of toxic corrosion products [956].

However, it is also known that alpha-alumina is very slightly soluble in highly acidic or alkaline aqueous environments (Section This solubility has been measured experimentally using in vivo intratracheal and biopersistence studies of high-alumina rock wool fibers [4811]. While inert particles such as carbon can reside uneventfully in phagolysosomes for long periods of time, sapphire particles could release ions into the relatively acidic intra-organelle environment. Since aluminum ions are generally considered toxic [1079-1083, 5388], and since aluminum-containing bone cements have on rare occasion caused death from neurotoxicity [4770], it is of interest to determine whether or not these ions can leach into the body from alumina implants or sapphire nanorobots. Early studies in the 1970s found no movement of known contaminants into the surrounding tissue from sintered alumina implants inserted into the iliac crests (hip bones) and mandibles of rabbits [782]. During the 1980s and 1990s, small increases in blood aluminum concentrations were demonstrated in smelter workers [960]. However, this potential exposure level is several orders of magnitude less than for bodily uptake of more soluble aluminum compounds used as food additives [961], as antacid medication [960], or from food packaging materials and cooking utensils [966]. In 1990, Lewandowska-Szumiel and Komender [988] investigated aluminum release from an alumina bioceramic during standardized biocompatibility testing in an animal experiment. Alumina implants introduced into rat femurs and guinea-pig mandibles and then removed 6-8 months later were found to be well tolerated, and no changes in the surfaces of the removed implants were observed under SEM examination. The researchers decided to compare the aluminum content of the femurs of experimental and control rats using atomic absorption spectroscopy, and discovered that the level of aluminum was higher in the bones of the experimental animals.

In 1991, Arvidson et al [1031] investigated the corrosion resistance of single-crystal sapphire implants with respect to the release of aluminum ions, and found no ions in the test solutions. The next year, Christel [973] reported that alumina exhibited greater bioinertness than all other implant materials currently available for joint replacement, and that no lymphocyte or plasma-cell infiltration into joint implants is observed “because of the absence of soluble component release.”

Then in 1992, Wang et al at the Shanghai Institute of Traumatology and Orthopedics [1041] bored a hole, 6 mm in diameter and 2 mm deep, on each iliac crest of 30 rabbits, then implanted 2 pieces of alumina into the hole on one side, leaving the opposite side as a control. Calcium, phosphorus and aluminum contents of iliac bone on both sides were determined by Inductively Coupled Plasma-Atomic Emission Spectrometry at 10, 20, 40, 60 and 90 days after operation. The aluminum content of the implanted side was higher than that of the control and the difference was statistically significant in the 10-, 40- and 60-day groups, demonstrating that the implant released aluminum into the bone. Calcium and phosphorus also were significantly lower on the implanted side than on the control side in the 10- and 20-day groups. Wang concluded that aluminum released from the implant in the early stage might be interfering with the local calcium and phosphorus metabolism and delaying the mineralization of the bone [1041].

Another study in 1994 by Toni et al at the Orthopaedic Clinic, University of Bologna, Italy [1022] examined the behavior of human bone tissue adjacent to the alumina coating in eight cementless hip prosthetic stems that appeared radiologically stable and were explanted because of pain. Histologic evaluation demonstrated the presence of a consistent layer of decalcified bone tissue in continuity with and parallel to the prosthetic interface, a demineralization phenomenon which the authors attributed to a high local concentration of aluminum ions with metabolic bone disease [1022]. This is histologically comparable to the osteomalacic osteodystrophy described in dialysis patients [5363-5366].

Can medical nanorobots with primarily sapphire exteriors avoid solvation in the aqueous biological environment? A therapeutic population of 1012 nanorobots present in one human blood volume implies ~5400 micron3 per nanorobot (~0.1% nanocrit for 1.75-micron wide cubic devices). Taking equilibrium solubility of alumina as 10-7 - 10-5 M at normal blood pH (Section, we should expect an equilibrium aluminum ion concentration of 100-10,000 ions/micron3. However, the human bloodstream concentration of aluminum ranges from 1-88 x 10-8 gm/cm3 (Appendix B), or roughly 200-20,000 ions/micron3, fairly close to the 0.1% Nct equilibrium solvation concentration. There is also evidence that atomically-precise ultrasmooth sapphire surfaces [899] are somewhat hydrophobic (Section, which might help to reduce the solvation problem. A comprehensive investigation would inquire first whether there is a clinically significant amount of sapphire leaching, and if so, what are the precise limits of toxicity and the minimum thresholds for biological effects? Further research is needed to resolve these issues.


Last updated on 30 April 2004