Clay nanoparticles for regenerative medicine and biomaterial design: A review of clay bioactivity

Abstract

Clay nanoparticles, composites and hydrogels are emerging as a new class of biomaterial with exciting potential for tissue engineering and regenerative medicine applications. Clay particles have been extensively explored in polymeric nanocomposites for self-assembly and enhanced mechanical properties as well as for their potential as drug delivery modifiers. In recent years, a cluster of studies have explored cellular interactions with clay nanoparticles alone or in combination with polymeric matrices. These pioneering studies have suggested new and unforeseen utility for certain clays as bioactive additives able to enhance cellular functions including adhesion, proliferation and differentiation, most notably for osteogenesis. This review examines the recent literature describing the potential effects of clay-based nanomaterials on cell function and examines the potential role of key clay physicochemical properties in influencing such interactions and their exciting possibilities for regenerative medicine.

Introduction

Recent studies have shed new light on the potential of clay nanoparticles and composites for biomaterial design and regenerative medicine [[1], [2], [3]]. Clay nanoparticles are biocompatible at doses significantly higher than most other nanomaterials [4,5] and their degradation products are non-toxic, absorbable and of relevance to osteogenic cell function [[6], [7], [8]]. Furthermore, several studies have convincingly demonstrated direct, beneficial, concentration-dependent effects of clay nanoparticles on cellular adhesion, proliferation and differentiation [[4], [5], [6],[9], [10], [11], [12]]. These new observations combined with the well-established utility of clay nanoparticles to impart attractive mechanical or rheological properties to polymeric hydrogels and scaffolds [[9], [10], [11], [12], [13], [14]], and the opportunities afforded by their classic use as drug delivery modifiers [15,16], suggest the striking potential of clays for the creation and development of new bioactive scaffolds.

Clay minerals, also called sheet-silicates or phyllosilicates, are a family of inorganic layered nanomaterials classically defined as “minerals which impart plasticity to clay and which harden upon drying or firing” [17]. Based on archaeological and written records, clays have played an important role in medicine from the dawn of mankind, ranging from oral ingestion for therapeutic purposes (geophagy) to wound healing and haemorrhage inhibition [18,19]. Clays are still widely applied as active ingredients in pharmaceutical formulations, typically administered either orally as antacids, gastrointestinal protectors, and anti-diarrheic or topically as dermatological protectors and anti-inflammatories [20]. Clays also play an important role in pharmaceutical preparations as excipients functioning as disintegrants, diluents and binders, emulsifying, thickening and anticaking agents, flavour correctors and delivery modifiers of active agents [21,22].

Extensive research has been undertaken to investigate the role of clay minerals in drug/gene delivery and in the development of polymer-clay nanocomposites (PCNs). This interest is due to the high retention capacities, swelling and rheological properties of clays and their affinity for interaction with biopolymers (either through exfoliation or intercalation). For instance, clay minerals can act as transport vehicles/carriers for the efficient delivery of therapeutic molecules (drugs and genes) by modifying the rate and/or time of release, increasing the stability of the drug or improving the dissolution profile of a drug [23]. Furthermore, the incorporation of a small percentage of clay nanoplatelets (dispersed phase) into a polymeric network (continuous phase) can improve the polymer's mechanical properties, swelling capacity, film-forming capability, rheological properties and bioadhesion without losing the inherent processability of the matrix [24].

The interest in clay nanoparticles for drug/gene delivery, polymer clay nanocomposites and, more recently, regenerative medicine is due to their unique physicochemical properties including particle size and shape, specific surface area, density of charge and structural and exchanged cations. These properties are dependent on the clay mineral type and crystal structure. Understanding how these clay structural/compositional parameters influence stem cell function will be important for exploring the fundamental mechanisms underlying clay bioactivity, and in the ability to exploit these properties in the development of 3D matrices, niche environments or delivery scaffolds for regenerative medicine.

In this review, we will introduce key aspects of clay chemistry with a specific focus on biomaterial design for regenerative medicine. We highlight recent advances in the development of clay-based biomaterials and discuss the evidence for the biocompatibility of clays. Finally, we explore the various mechanisms of clay bioactivity including modulation of cell adhesion, protein localisation, and biomineralisation as well as the possibility of clay nanoparticles to directly affect the osteogenic differentiation of skeletal populations.