Bioinspired approaches to toughen calcium phosphate-based ceramics for bone repair.

Highlights

• Bone has a multi-level hierarchical organisation which is key for its outstanding properties.

• Calcium phosphate (CaP) ceramics are promising for achieving the mechanical and biological requirements for bone implants.

• However, the CaP ceramics produced today remain intrinsically brittle.

• Bioinspired CaP ceramics and composites could be toughened through multi-level hierarchical microstructures.

• Recent advances in ceramic processing may pave the way for a new generation of medical implants.

Abstract

To respond to the increasing need for bone repair strategies, various types of biomaterials have been developed. Among those, calcium phosphate (CaP) ceramics are promising since they possess a chemical composition similar to that of bones. To be suitable for implants, CaP ceramics need to fulfill a number of biological and mechanical requirements. Fatigue resistance and toughness are two key mechanical properties that are still challenging to obtain in CaP ceramics. This paper thus reviews and discusses current progress in the processing of CaP ceramics with bioinspired microstructures for load-bearing applications. First, methods to obtain CaP ceramics with bioinspired structure at individual lengthscales, namely nano-, micro-, and macroscale are discussed. Then, approaches to attain synergistic contribution of all lengthscales through complex and biomimetic hierarchical structures are reviewed. The processing methods and their design capabilities are presented and the mechanical properties of the materials they can produce are analyzed. Their limitations and challenges are finally discussed to suggest new directions for the fabrication of biomimetic bone implants with satisfactory properties. The paper could help biomedical researchers, materials scientists and engineers join forces to create the next generation of bone implants.

Introduction

Bone autografts are the gold standard for bone repair (Wang and Yeung, 2017). With the ageing population, changes in diet, the global rise in diabetes and other health problems have been weakening our skeleton, leading to an increasing prevalence of dramatic bone injuries (Pressley et al., 2012; Bikbov et al., 2018; Amin et al., 2015) or amputations (Narres et al., 2017). Many strategies have thus been developed to help patients recover their limbs usage. These strategies include allogenic grafts, tissue engineering approaches, and implantation of bioinert and bioactive materials. Allogenic grafts have limited supply and have a potential risk of inflammation and disease transmission. Tissue engineering (TE) approaches are time-consuming since cells are stimulated to re-mineralize bone in response to the signals sent by an implanted porous material. Allographs and TE approaches are thus non-ideal solutions for the repair of load-bearing bones and the joints associated whereby a quick recovery of the structural functions is required (Perez et al., 2018). As an alternative, bioinert implants made from cement, ceramics or metals are currently clinically used. However, in practice, those implants tend to fail after 10–15 years due to unmatching mechanical properties and stress-shielding (Le Ferrand and Athanasiou, 2020). In addition, insufficient integration to the surrounding tissues can lead to micromotion, particle debris and inflammation (Teoh, 2000). Bioactive implants, in turn, stimulate an appropriate biological response from the body. Implant materials made of calcium phosphate, in particular, can provide satisfactory osteoconduction and osseointegration but are often limited in their mechanical performance (Jeong et al., 2019). This paper will be discussing this last type of artificial implants.

The main mineral component of bone is calcium phosphate (CaP). Bioactive implants thus contain calcium in the form of glass (Jones, 2013), calcium-based cements (Niu et al., 2014) and calcium phosphate ceramics, composites and coatings. Among the various CaP ceramics, hydroxyapatite (HA), tricalcium phosphate (TCP), and a mixture of both, biphasic calcium phosphate (BCP), have been the most studied and the most promising candidates for bone repair (Champion, 2013). Indeed, these CaP ceramics fulfill several important criteria required for their use as load-bearing clinical implants such as the femoral stem of hip joint replacements or screws for dental implants. These criteria are (Le Ferrand and Athanasiou, 2020):

• To present bone-matching “static” mechanical properties, such as stiffness, hardness and strength.

• To promote osseointegration, osteoinduction and remodelling processes.

• To have a similar weight as the original bone defect.

• To be shaped according to the defect.

• To be available quickly and without limitation of material.

• To present “dynamic” bone-like mechanical properties, such as fatigue cycle resistance, stable crack propagation, and toughness.

However, this last criterion (vi), namely toughness and fatigue resistance, is still particularly challenging to obtain in bioactive ceramics due to their inherent brittleness (Fig. 1). The comparison of the mechanical properties of most common bioceramics with those of cancellous (porous or trabecular) and cortical (dense or compact) bones, indicates that although the Young's modulus and flexural strength of CaP ceramics are generally satisfactory (Fig. 1A and B), their toughness and resistance to fatigue are still mediocre (Fig. 1C). Since synthetic materials do not self-repair like biomaterials do, damage-tolerant properties with flexural fracture toughness are very important properties to pursue. It is therefore critical to pursue research to engineer biomaterials with such mechanical properties.

Toughening mechanisms in natural load-bearing bones have been studied extensively (Piekarski, 1970; Launey et al., 2010; Ritchie et al., 2009; Zimmermann et al., 2010). Healthy long bones display high toughness in their transverse direction. This is illustrated by a rising resistance curve, or R-curve, where the stress intensity factor $K_{jc}$ increases with the crack length (Fig. 2A) (Launey et al., 2010). Indeed, hydrated bones loaded transversely do not break in a catastrophic brittle manner. Instead, extrinsic toughening mechanisms such as microcracking, fiber pull-out, crack deflections and crack twisting are observed in the cortical part (Fig. 2B–D) (Launey et al., 2010; Nalla et al., 2003). These mechanisms are intimately related to the intricate hierarchical organisation of bones, spanning across 12 lengthscales (Fig. 2E) (Reznikov et al., 2018).

Developing strategies to toughen structural materials has been the focus of many comprehensive reviews. In the context of CaP materials, there has been many reviews tackling the mechanics of CaP composites (Wagoner Johnson and Herschler, 2011), their capability to stimulate cell proliferation, differentiation and bone tissue regeneration (Gao et al., 2014), and the additive manufacturing of ceramic scaffolds (Du et al., 2018). This paper aims at complementing the existing literature by providing an overview of CaP ceramics manufacturing processes that allow multiscale structural control to better reproduce bone architecture and properties. Indeed, bioinspired approaches have been studied for many years and have led to promising results in other materials (Fratzl et al., 2013). First, we present processing methods of CaP ceramics with structural control at individual lengthscales, namely at the nanoscale with the control of crystallographic phases and their transformation, at the microscale with the formation of intended micropores, and at the macroscale with the design of complex shapes. For each lengthscale, the methods are described along with their structural design capabilities and their impacts on the mechanical and biological properties. Then, multiscale bioinspired approaches explored to increase the mechanical performance of those materials are reviewed. Those approaches comprise the use of reinforcing particles, and the construction of hierarchical features inspired by bones and other biomaterials. Finally, the challenges and limitations in the fabrication of CaP ceramics for bone repair are discussed. Future research directions are suggested based on the recent advances in processing of toughened ceramics. The fabrication techniques and resulting properties presented in this review highlight the need for collaborations between material scientists, mechanical engineers, chemists, biologists and clinicians. The results reviewed here could constitute a common basic knowledge and understanding across the disciplines and suggest ideas for future research towards improved bone implant materials.