Invited Review PaperBioinspired approaches to toughen calcium phosphate-based ceramics for bone repair.
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):
- (i)
To present bone-matching “static” mechanical properties, such as stiffness, hardness and strength.
- (ii)
To promote osseointegration, osteoinduction and remodelling processes.
- (iii)
To have a similar weight as the original bone defect.
- (iv)
To be shaped according to the defect.
- (v)
To be available quickly and without limitation of material.
- (vi)
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 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.
Section snippets
Bioinspired approaches at individual lengthscales
In the following we review the bioinspired approaches and resulting mechanical properties used to engineer CaP ceramics with structural control at the nano-, micro-, and macroscale. At the nanoscale, crystallographic phases and grain sizes are key for satisfying static mechanical (requirement (i)) and biological properties (requirement (ii)). At the microscale, the porosity plays an important role for the osseointegration (requirement (ii)) and lightweightness (requirement (iii)). At the
Reinforced microstructures in CaP ceramics and highly mineralized composites
As a first approach, reinforcing dense CaP ceramics with nanofibers, nanoplatelets, or nanoparticles has been explored (Fig. 6). Generally, the use of nanoelements in a microstructure increases the toughness via extrinsic toughening mechanisms such as crack bridging, crack deflection and twisting, and reinforcement pull-out, similarly to what is observed in cortical bones (Fig. 2B–D).
HA ceramics have been reinforced with nanoparticles that have some intrinsic toughness, like ZrO2 (Drdlik et
Limitations, challenges, and suggestions
Despite the large amount of research produced to fabricate materials for bone implants, further research is still needed to develop manufacturing methods that would improve their toughness and biological response. There are indeed multiple challenges to face to overcome the current limitations in mechanical properties and biological response of today's implants, namely poor specific strength and toughness, Young's modulus mismatch, and lack of integration with the surrounding tissues. However,
Conclusion
We have reviewed the fabrication methods and strategies to fabricate CaP ceramics for bone repair (Fig. 10). CaP ceramics and their composites can be processed using traditional ceramic methods to tune the mineral phases and grain sizes to present stiffness and bioactivity, microporosity can be added via a range of strategies comprising foaming and freezing methods to yield light materials, and macroscopic shapes and scalable designs can be realized by 3D printing. The CaP ceramics resulting
CRediT authorship contribution statement
Peifang Dee: Data curation, Writing - original draft. Ha Young You: Data curation, Writing - original draft. Swee-Hin Teoh: Writing - review & editing. Hortense Le Ferrand: Conceptualization, Supervision, Writing - review & editing.
Declaration of Competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors acknowledge financial support from the National Research Foundation, Singapore (Fellowship NRFF12-2020-0002).
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