Biomineralization: Medical Aspects of Solubility

Book info: Biomineralization: Medical Aspects of Solubility (Hardcover, 302 pages) – Wiley, 2006. Language: English.

This title takes an interdisciplinary approach to the central role of solubility in pathological biomineralisation, ranging from traditional thermodynamics and kinetics to unusual concepts such as the PILP process. The scientific background and expertise of the contributors, ranges accordingly from solubility modelling and database development, renal stone and bone implant research, Mössbauer spectroscopy and structural chemistry to biochemistry and crystallisation. The chapters all have a quantitative, physico-chemical component rather than giving purely phenomenological descriptions. The contributors deal with aspects and concepts that have not previously been common in the study of pathological biomineralisation processes. About the Author Dr E. Königsberger and Dr L. Königsberger (Editors), Department of Chemistry, Division of Science and Engineering, Murdoch University, South Street, Murdoch, WA 6150, Australia Excerpt. © Reprinted by permission. All rights reserved. BiomineralizationMedical Aspects of SolubilityJohn Wiley & SonsCopyright © 2006 John Wiley & Sons, Ltd
All right reserved.
ISBN: 978-0-470-09209-5

Chapter OneSolubility Phenomena Related to Normal and Pathological Biomineralization Processes

Erich Knigsberger and LanChi Knigsberger

School of Chemical and Mathematical Sciences, Division of Science and Engineering, Murdoch University, Murdoch, Perth, WA 6150, Australia

1.1 INTRODUCTION

Biomineralization, which refers to the complex processes by which organisms form minerals, is frequently associated with a high degree of regulation on different hierarchical levels. 'Biologically controlled' mineralization, in which extra-, inter- and intracellular activities direct the nucleation, growth and morphology of minerals that form 'normal' biomaterials such as bone and teeth, is fundamentally different from 'biologically induced' mineralization, which occurs as a result of interactions between biological activity (affecting e.g. the pH and composition of secretion products) and the environment. Since there is little control of the biological system over the type and habit of minerals deposited, these vary as greatly as the environments in which they form and are often poorly defined, heterogeneous and porous. Biologically induced mineralization is commonly associated with various bacterial activities and with epicellular mineralization in marine environments, occasionally leading to the complete encrustation of organisms, that sink subsequently and form sediments. However, its characteristic features are also typical for uncontrolled 'pathological' crystallization resulting in painful or even life threatening conditions such as calculi formation (renal, biliary, pancreatic or sublingual), development of gout or arteriosclerosis, tissue calcification associated with cancer, etc.

In any event, solubility phenomena, i.e. dissolution and precipitation reactions, are fundamental to all biologically controlled or induced mineralization. Solubility phenomena in multicomponent electrolyte solutions also control numerous other 'real-life' natural or industrial processes. These include interactions in the hydrogeological cycle such as hydrothermal mineral formation, weathering and aerosol formation. The recent growth in biogeochemistry stresses the interrelations between biological and abiotic mineralization in the understanding of the past and future evolution of the Earth. Solubility phenomena are furthermore relevant to procedures for preparing, separating and purifying chemicals and (biomimetic) materials industrially or in the laboratory. The study of solubility phenomena also serves to elucidate the mechanisms of unwanted precipitation and develop methods for its prevention, both industrially (scaling) and biologically (pathological mineralization), thus highlighting important analogies between two apparently distinct areas.

The kinetics of dissolution and precipitation has frequently been studied for both biological and industrial systems. The rate equations used to interpret such kinetic data are commonly defined in terms of under- and supersaturation respectively, which requires accurate solubility data for the solid substances at the pertinent conditions. However, in some studies, such as in a fundamental investigation of calcite growth kinetics, equilibrium solubilities have been derived from the very same rate data they ought to rationalize, which might lead to a correlation between these solubility values and the parameters of the rate model so obtained. It is thus imperative to employ the most accurate solubility data that are available from independent solubility studies, as reviewed for calcite.

For the calculation of biomineral solubilities in complex biological fluids, a suitable model for aqueous activity coefficients together with stability constants of the various complex species formed in the solution as well as the solubility constants of the solid phases are required. Therefore it is important to obtain reliable information about these constants from accurate physicochemical measurements. These methods, together with techniques to measure the kinetics of precipitation and dissolution, will be briefly outlined in the following section.

1.2 EXPERIMENTAL METHODS

1.2.1 SOLUBILITY MEASUREMENTS

The majority of normal and pathological biominerals formed in humans are sparingly soluble electrolytes with basic anions (i.e. anions that can be protonated), such as phosphates, carbonates, oxalates, urates, etc. Their solubility thus depends (often strongly) on pH and is in general decreasing as the pH increases. A notable exception is uric acid, whose solubility increases with pH.

Reliable techniques to measure solubilities of sparingly soluble electrolytes with basic anions were reviewed recently. The recommended method consists of equilibrating the solid phase and the solution in thermostatted, all glass, percolation type solubility cells equipped with glass and reference electrodes. The pH variation method (i.e. the systematic variation of the initial [H.sup.+] concentration from run to run) was used. Constant ionic strength media were employed throughout to keep the activity coefficients of the reacting species essentially constant. Thus, hydrogen ion concentrations (rather than activities) were measured potentiometrically and hereafter p[H], defined as p[H] = -log {[[H.sup.+]]/mol [dm.sup.-3]} will frequently be used instead of pH. The metal ion and organic anion concentrations were determined by standard analytical methods, such as AAS and UV spectrophotometry respectively.

1.2.2 SOLUTION CALORIMETRY

The direct measurement of enthalpies of solution of solid phases provides important information on thermodynamic consistency by comparison with the enthalpy values derived from the temperature dependence of solubility constants. For instance, isoperibolic solution calorimeters were employed to measure the dissolution enthalpies of the calcium oxalate hydrates, uric acid anhydrate and dihydrate and xanthine. In the first case, a thermodynamic cycle was employed to obtain the dissolution enthalpy at ionic strength zero. In the other two studies, the ionic strengths were adjusted to the values employed at the solubility measurements and TRIS buffer solutions of appropriate pH were used to increase the solubility and to ensure a defined final state of predominantly hydrogenurate and hydrogenxanthinate respectively. In all cases, it was found that temperature-dependent solubility constants and calorimetrically measured enthalpies of solution were thermodynamically consistent.

Solution calorimetry has proved very useful for studying the energetics of iron oxide/oxyhydroxide and other nanoparticles. Measurements have been performed either near room temperature (with an acid as the solvent) or at 700 to 800C in an oxide melt. Both nano- and bulk materials of the same composition were reacted under the same conditions. The enthalpy difference between the two measurements is related to the difference in the surface energies of bulk and nanomaterial. Such differences are not only useful for the evaluation of the relationship between particle size and solubility, they may also serve to stabilize, in the nanoregime, polymorphs that are not stable in the bulk.

1.2.3 KINETIC MEASUREMENTS

Studies of the dissolution and crystallization kinetics of solids first require the preparation of metastable under- and supersaturated solutions, followed by appropriate measurement of the respective reaction rates. One of the earliest experimental approaches was that of 'free drift' in which the rates are obtained by measuring concentration changes as function of time. To keep the thermodynamic driving forces (i.e. the activities of the reacting ions) constant, the 'constant composition' (CC) method pioneered by Nancollas is widely used nowadays for the determination of dissolution and growth kinetics. This technique can also mimic biomineralization processes during which constant ionic concentrations are regulated by homeostasis. To simulate, in addition, the slow crystallization rates commonly prevailing in vivo, the CC method has been combined with a double-diffusion (DD) technique. This 'CCDD method' has been applied to simulated body fluids resulting in the growth of carbonate apatites very similar to biological specimens.

As there are close relationships among the observed solubilities, the kinetics of dissolution and crystallization, and the interfacial tensions between the solid phases and their solutions, the accurate measurement of the latter has received considerable attention.

1.3 THERMODYNAMIC MODELING OF BIOLOGICAL SYSTEMS

1.3.1 INTRODUCTION

D.R. Williams was one of the first who proposed and systematically pursued the idea that chemical equilibria in biological systems can be studied by the very same, well established experimental and computational methods that have been used in solution chemistry for a long time. Once the formation constants of all (or at least the most important) metal-ligand complexes have been characterised in vitro either experimentally (e.g. by potentiometric titration) or by appropriate estimation methods, the so-called speciation (i.e. the distribution of the metal among its low molecular weight complexes) can be calculated. This can e.g. be achieved by solving a system of equations derived from the law of mass action using suitable mass balance equations as a constraint. It is then assumed that the speciation established in this way reflects the metal-ligand distribution in the biological system in vivo, which in turn permits conclusions to be made about metal toxicity and bioavailability, metabolism, mobilization and immobilization, transport, deposition, etc. It has to be understood, however, that due to the complexity of some biological fluids containing a large number of N-, O- and S-ligands, the species distribution of a metal in vivo among the low-molecular-weight ligands such as amino and organic acids is never completely known. Nevertheless, this approach has proved successful for many applications, some of which are outlined below while others, related to bioinorganic chemistry, have been reviewed recently.

1.3.2 CHEMICAL SPECIATION, BLOOD PLASMA MODELS AND CHELATION THERAPY

Among the most prominent applications of (quasi)equilibrium calculations for biological systems are computer simulations of metal ion distributions amongst the low molecular weight ligands in blood plasma. These 'blood plasma models' were pioneered by Perrin and were further developed in various laboratories, as reviewed by May. The term quasiequilibrium indicates that the system of metal ions and organic ligands does not attain a stable thermodynamic equilibrium state, which would imply, for instance, that the ligands decompose when conditions are oxidizing. One of the most sophisticated computer codes for this kind of simulations is the JESS (Joint Expert Speciation System) package of computer programs, which contains an extensive thermodynamic database. JESS can handle equilibrium calculations involving thousands of species and is also able to take redox equilibria and kinetic constraints into account.

Data base improvements, e.g. due to the measurement of new complex formation constants that were not known before, have changed likely species distributions in blood plasma dramatically. For instance, older models have indicated that Fe(III) and Cu(II) complexes predominate, while modern computer simulations which include redox equilibria suggest that these two metals complexed by low molecular weight ligands are overwhelmingly present in blood plasma as Fe(II) and Cu(I) species.

Due to the binding of metals to proteins, blood plasma models are unable to provide absolute species concentrations in vivo, however, they can give valuable information on the competitiveness of low molecular weight ligands for metal ions in solution, which is expressed as relative (percentage) species distribution. Thus, trends in such species distributions can be established when the homeostatically regulated metal or ligand concentrations become imbalanced. Disruptions of normal metal homeostasis may lead to conditions such as thalassemia or Wilson's disease (Cu and Fe overload respectively, leading to the depositions of corresponding solids) or to Alzheimer's disease, with an associated deposition of solids in the brain, including an alleged [Cu.sup.2+] induced aggregation of -amyloid (A plaques) and nanoscale magnetic biominerals such as magnetite and maghemite. These deposits result in Fe and Cu redox cycling, i.e. a metalloenzyme like activity, leading to oxidative stress by continuous [H.sub.2][O.sub.2] generation which probably accelerates the degeneration of brain tissue.

Metal overload in humans can be treated by administering chelating agents that help to excrete the excess metal. Effective drugs for chelation therapy have often been identified by computer simulations. For instance, the treatment of Wilson's disease requires life long administration of an appropriate Cu chelator such as D-penicillamine, which was introduced half a century ago and is still regarded as one of the most effective drugs, although alternatives have been recommended. However, the study mentioned above, which used a newly determined set of formation constants for Cu(I) thioamino acid complexes, arrived at the conclusion that the mechanism of copper removal by penicillamine in vivo is unlikely to depend on complexation alone, in contrast to earlier simulations that apparently confirmed its therapeutic action. Other Cu chelators have been shown to dissolve A plaques in vitro and in post-mortem brain tissue. Recently, it has been suggested that D-penicillamine carried by nanoparticles (which had been found to be able to cross the blood-brain barrier) has the potential to prevent the A accumulation in the brain observed in Alzheimer's disease. The development of agents that can selectively prevent transition metals from binding to the A peptide without perturbing the action of other metal containing biomolecules in the brain and therapies that focus on intervening in the roles of metal ions in oxidative stress are currently of high priority.

1.3.3 METAL SOLUBILITY AND TOXICITY

As many metals are biotransformed in humans to a limited extent, it is often the speciation before entering the body that determines toxicity, as is, for instance, the case for Ni, As or Hg compounds. While some metals are completely inert biologically (e.g. Ta), solubility may be a criterion for the toxicological assessment of others (nontoxic, sparingly soluble BaS[O.sub.4] vs toxic, soluble Ba[Cl.sub.2] as opposed to slightly toxic, soluble and hence easily excretable Ni[Cl.sub.2] vs carcinogenic, sparingly soluble [Ni.sub.3][S.sub.2] which becomes phagocytosed in particulate form and consequently leads to very high intercellular Ni concentrations). Moreover, it is often important to distinguish between organic and inorganic species of the metal, such as mercury. Hg(II) undergoes bioalkylation in the environment and the resulting, highly toxic C[H.sub.3][Hg.sup.+] ion accumulates in fish and shellfish and is not metabolized further in the human body. On the other hand, nontoxic arsenosugars may also be ingested from seafood and form a significant fraction of the total blood As in humans. However, exposure to toxic inorganic As is indicated by the occurrence of mono- and dimethylarsenates in blood, which are the major As metabolites in humans.

For other substances, speciation may change dramatically in the body, e.g. upon the passage from the stomach (pH [approximately equal to] 1-2) to the intestine and subsequent absorption into the blood (pH [approximately equal to] 7.4). Under the latter conditions, metals like Fe or Al form very slightly soluble hydroxides, however, Al absorption (and hence toxicity) can be greatly increased, due to complexation, by coingestion with citrate or tartrate, both of which are commonly found in fruits and in industrial foods and drinks. It has also been reported that ulcer patients (with associated excess acid production in the stomach) had increased serum and urine Al levels on an Al hydroxide absorption test, which indicates a dependence of gastrointestinal Al hydroxide absorption on gastric pH and hence implies a potential risk of prolonged administration of antacids containing Al.

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