New developments in polymer-controlled, bioinspired calcium phosphate mineralization from aqueous solution

Abstract

The polymer-controlled and bioinspired precipitation of inorganic minerals from aqueous solution at near-ambient or physiological conditions avoiding high temperatures or organic solvents is a key research area in materials science. Polymer-controlled mineralization has been studied as a model for biomineralization and for the synthesis of (bioinspired and biocompatible) hybrid materials for a virtually unlimited number of applications. Calcium phosphate mineralization is of particular interest for bone and dental repair. Numerous studies have therefore addressed the mineralization of calcium phosphate using a wide variety of low- and high-molecular-weight additives. In spite of the growing interest and increasing number of experimental and theoretical data, the mechanisms of polymer-controlled calcium phosphate mineralization are not entirely clear to date, although the field has made significant progress in the last years. A set of elegant experiments and calculations has shed light on some details of mineral formation, but it is currently not possible to preprogram a mineralization reaction to yield a desired product for a specific application. The current article therefore summarizes and discusses the influence of (macro)molecular entities such as polymers, peptides, proteins and gels on biomimetic calcium phosphate mineralization from aqueous solution. It focuses on strategies to tune the kinetics, morphologies, final dimensions and crystal phases of calcium phosphate, as well as on mechanistic considerations.

Introduction

Calcium phosphates are important materials in biology and biomaterials science. They have therefore been studied extensively [1], [2], [3]. In the form of substituted hydroxyapatite (HAP), calcium phosphate is the most common mineral in vertebrate tissues. It confers mechanical stability to bones and teeth, and is therefore a key component in human health. As a result, calcium phosphate powders, coatings, composites and ceramics have attracted interest from the academic and commercial sides [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Calcium phosphate has also been used as a stable, biocompatible, non-toxic and cheap inorganic material for nanoparticulate ingredients in cosmetics, organic/inorganic hybrid particles for drug delivery and microcontainers for pharmaceutical applications [18], [19], [20], [21], [22], [23], [24].

Biomimetic mineral formation avoids harsh conditions, such as high temperatures. It therefore, for example, enables the synthesis of calcium phosphate composites containing unstable calcium phosphate phases. Such materials may be interesting for drug delivery, bone or dental repair, or RNA delivery [25], [26], [27]. These synthetic approaches, however, rely on the control of multiple interactions between precursor ions, polymeric additives and all precipitating phases. If one intends to tailor a specific mineralization process or calcium phosphate/polymer combination for a specific application, these interactions need to be understood and quantified. Moreover, the thermodynamics and kinetics of precursor association, nucleation and crystal growth need to be known and controlled. This is a complex endeavor because, in both nature and technology, numerous parameters, such as pH, temperature, salt and polymer concentration, polymer molecular weight, polymer architecture or the presence of further compounds, affect nucleation and growth at different points in time and space [28]. Quantifying polymer-controlled mineralization is therefore a multi-time scale and multi-length scale problem, which in many cases makes the investigation of individual mineralization steps challenging. The situation is further complicated by the large number of different calcium phosphate phases (see Table 1).

The chances of understanding biomimetic mineralization will increase once sufficiently large datasets on the effects of polymers on nucleation and growth are available from the literature. However, it is important to realize that the understanding of, for example, calcium carbonate mineralization is also helpful to understand calcium phosphate mineralization. Calcium phosphate mineralization should therefore not be viewed as an isolated problem of a small community of biomimetics researchers; rather, it should be seen as a point in case centered around a very important biomineral and we therefore recommend the extensive literature on calcium carbonate [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39] as support for the development of a quantitative understanding of polymer-controlled calcium phosphate mineralization.

Because of the scientific and commercial interest, the recent past has seen a surge in original publications and reviews on calcium phosphate. Calcium phosphate ceramics (mostly for implantation) have been reviewed by Dorozhkin [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. Similarly, the mineralization of collagen and gelatin with calcium phosphate has also been studied in detail [40], [41], [42], [43], [44], [45]. We will therefore refer to these subjects only when deemed relevant to the broader scope of the article. Similarly, we will not extensively discuss the role of low-molecular-weight additives [36]. Finally, we will not discuss the electrospinning of polymers with prefabricated calcium phosphate, although this is an interesting and useful field in itself [46], [47], [48]. Rather, the idea of this review is to provide an overview of true biomimetic calcium phosphate mineralization from aqueous solution. In particular, we are interested in concepts that go beyond trial-and-error approaches for the design of calcium phosphate hybrid materials. As a result, we will also briefly touch upon nucleation and growth mechanisms.

This review will thus focus on the use of (co)polymers for calcium phosphate precipitation under roughly physiological conditions. As there is already a comprehensive review summarizing the state of the field as at 2007 [49], we will focus more on developments published since then. Where necessary, we will also include information on new developments in amino acid and peptide-mediated mineralization as a means to better understand the role of proteins in bioinspired mineralization. Besides water-soluble templates, we will also discuss insoluble scaffolds, like polymer films, hydrogels, fibers, fiber mats, and nano- and microcontainers.

While writing the current article, we noticed a shift in the focus of the published subjects from synthetically, chemically and structurally rather simple polymeric additives, such as water-soluble homo- and diblock copolymers, towards scaffolds with more complex architectures. For example, double-hydrophilic block copolymers (DHBCs) are efficient growth modifiers for inorganic minerals. In particular, poly(ethylene oxide)s with a second block consisting of poly(carboxylates) have been studied as growth-regulating agents [49], [50], [51], [52], [53], [54], [55], [56], [57], [58]. In spite of this, the role of DHBCs is still not fully resolved, despite the number of publications on the topic decreasing recently [59], [60], [61]. This indicates that other aspects, such as application-oriented questions, have become more important.

Prior to delving into the subject of polymer-controlled calcium phosphate mineralization, we will briefly discuss the calcium phosphate phases [62], [63] and a few key points of nucleation and growth in biomimetic processes.