Preparation of spherical monodisperse ferrimagnetic iron-oxide microparticles between 1 and 5 μm diameter

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Abstract

The production of spherical monodisperse iron-oxide microparticles in the size range between 0.8 and 5 μm is described. The particles can be ferrimagnetic (Fe3O4) or non-magnetic (α-Fe2O3). The particles were radiolabeled with 99mTc or 111In, and the leakage of the radiolabel within 24 h was 0.1% in the human lung. The particles can be used to study the motility and the integrity of living cells.

Introduction

Ferrimagnetic iron-oxide microparticles have been typically used for recording materials [1], but these particles are also very useful as tracers for investigating the behavior of air-borne matter in the human and animal respiratory tract [2], [3], [4], and the mechanical properties of living cells [4], [5]. Iron oxide is chemically stable and is not toxic and non-carcinogenic [6]; therefore, it allows clearance studies in the human lungs over time-periods up to 1 year. The maximum working-place concentration of respirable iron-oxide dust is 4 and 1.5 mg/m3 for dust penetrating into the alveolar region of the lungs [7]. Welders are exposed to relatively high concentrations of particulate iron oxide, where burdens up to several thousand milligrams could be detected [8], [9]. This material is deposited and recovered in the lungs over months and years.

Ferromagnetic and ferrimagnetic particles can be detected in the human body by magnetopneumographic (MPG) methods [4], [10]. Ferrimagnetic particles were also used for measurements of macrophage functions and cellular integrity (visco-elasticity) in vivo and in vitro [4], [5]. External magnetic twisting forces allow to study mechanisms that are required for the motility of animal cells [11]. Ligands can be coupled to the magnetite particles in order to attach them to specific cell membrane receptors, such as integrins [12], [13]. Radiolabeled particles are most applicable for studying short-time mucocilliary clearance in human and animal lungs. All these studies require spherical monodisperse test particles.

Iron-oxide particles in the micrometer size range can be produced by either a crystallization process [14] or by nebulization of a colloidal solution [15]. Particles obtained by crystallization are smaller than 2 μm. During crystallization the particles tend to form aggregates, which cannot be redispersed. In inhalation studies, the aggregates show different behavior from single particles and deposit in different sites in the lungs. For this reason the technique of nebulization of an aqueous solution was preferred, because it allows a direct voluntary inhalation. Two systems are available, the vibrating orifice and the spinning top, which can both form monodisperse droplets in the micrometer size range. Under normal conditions the nebulization technique yields spherical particles. The primary particles are porous, but they can be sintered in a furnace, yielding particles with high chemical stability. A further advantage of the nebulization technique is that colloids of different compositions can be mixed. This allows labeling the iron-oxide particles with colloids of radiotracers 99mTc, 111In or 198Au. The spinning top nebulization technique is easy to control and can be run over several hours unlike the vibrating orifice, since the orifice tends to clog due to impurities. The composition of iron oxide can be changed from α-Fe2O3 (hematite, red) to ferrimagnetic Fe3O4 (magnetite, black) and back to ferrimagnetic γ-Fe2O3 (maghemite, brown) by using specific carrier gas compositions and temperatures [1], [16], [17].

Section snippets

Chemical preparation

The preparation of iron-oxide particles requires several experimental steps: first, a non-magnetic α-Fe2O3 colloid was produced by hydrolysis of FeCl3 [18]. Four millilitres of a 32 wt% FeCl3 solution were prepared in deionized water. This solution was added slowly (over 20 min) to 250 ml of boiling deionized water while stirring, and an insoluble Fe(OH)3 colloid was formed spontaneously. In order to remove the chloride ions, the solution was repeatedly washed by dialysis. A chloride-free

Performance of the aerosol generator and particle shape properties

A driving pressure of 0.7 bars and a liquid supply of 30 ml/h are the optimal running conditions for obtaining the lowest particle size variance and the highest output yield [15]. The particles were found to be compact spheres with a rough surface, indicating a porous structure. Fig. 3a shows the aerodynamic diameter of the α-Fe2O3 particles, collected from the STAG, and of Fe3O4 particles, collected after reduction in the 800°C furnace. The concentration and reduction steps do not change the

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