Elsevier

Acta Biomaterialia

Volume 61, 1 October 2017, Pages 1-20
Acta Biomaterialia

Review article
Carbon nanotube, graphene and boron nitride nanotube reinforced bioactive ceramics for bone repair

https://doi.org/10.1016/j.actbio.2017.05.020Get rights and content

Abstract

The high brittleness and low strength of bioactive ceramics have severely restricted their application in bone repair despite the fact that they have been regarded as one of the most promising biomaterials. In the last few years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have gained increasing attention owing to their favorable biocompatibility, large surface specific area and super mechanical properties. These qualities make LDNs potential nanofillers in reinforcing bioactive ceramics. In this review, the types, characteristics and applications of the commonly used LDNs in ceramic composites are summarized. In addition, the fabrication methods for LDNs/ceramic composites, such as hot pressing, spark plasma sintering and selective laser sintering, are systematically reviewed and compared. Emphases are placed on how to obtain the uniform dispersion of LDNs in a ceramic matrix and maintain the structural stability of LDNs during the high-temperature fabrication process of ceramics. The reinforcing mechanisms of LDNs in ceramic composites are then discussed in-depth. The in vitro and in vivo studies of LDNs/ceramic in bone repair are also summarized and discussed. Finally, new developments and potential applications of LDNs/ceramic composites are further discussed with reference to experimental and theoretical studies.

Statement of Significance

Despite bioactive ceramics having been regarded as promising biomaterials, their high brittleness and low strength severely restrict their application in bone scaffolds. In recent years, low-dimensional nanomaterials (LDNs), including carbon nanotubes, graphene and boron nitride nanotubes, have shown great potential in reinforcing bioactive ceramics owing to their unique structures and properties. However, so far it has been difficult to maintain the structural stability of LDNs during fabrication of LDNs/ceramic composites, due to the lengthy, high-temperature process involved. This review presents a comprehensive overview of the developments and applications of LDNs in bioactive ceramics. The newly-developed fabrication methods for LDNs/ceramic composites, the reinforcing mechanisms and the in vitro and in vivo performance of LDNs are also summarized and discussed in detail.

Introduction

Tens of millions of people around the world become victims of serious diseases and accidents every year, resulting in an urgent and increasing demand for biomaterials for the diagnosis, treatment and rehabilitation of tissues and organs [1]. In the USA, ∼8 million surgeries per year are performed for these patients, but many patients lose their lives or become disabled. Each year, over 100,000 people die while waiting for organ transplants [2]. In 2016, the global market of biomaterials reached 70.90 billion dollars and is expected to reach up to 149.17 billion dollars by 2021 at a compound annual growth rate of 16.0% [3]. Especially in recent years, the occurrence of bone defects have grown rapidly due to various diseases, sport injuries, work-related injuries, traffic accidents, natural disasters, etc. As a result, bone grafting has become the second most frequently performed type of tissue transplant following blood transfusion [4]. Approximately 2.2 million patients receive bone grafting each year worldwide [5]. However, many patients have to receive amputation surgery due to the lack of appropriate bone substitutes [6], which inevitably causes a significant negative life impact.

In the past decades, considerable efforts have been devoted to developing artificial bone for bone repair, aiming to achieve the functional reconstruction or even bone regeneration of the defect site. On the basis of biocompatibility, 1st generation bioinert materials [7], including biomedical metallic materials (such as stainless steel, titanium and its alloys, and cobalt-based alloys), bioinert ceramic materials (such as medical carbon, alumina and zirconia), and organic polymer materials (such as silicone rubber and high molecular weight polyethylene), have been developed [8], [9]. These 1st generation materials are emphasized on a match of mechanical properties between the materials and defect sites, but have a universal disadvantage: they are bioinert, i.e., they can only passively adapt to the body's physiological environment, instead of forming a biological bond with tissue or promoting the repair of bone defects [7], [8], [9], [10]. Moreover, as permanent implant materials, they can hardly decompose or biodegrade in vivo [11]. As a result, a secondary surgery is necessary to remove the implant when it has malfunctioned [12].

Later, the research on artificial bone materials shifted to bioactive or biodegradable materials, i.e. the 2nd generation materials, including bioactive ceramic materials (such as hydroxyapatite, calcium phosphate and bioactive glass) and biodegradable polymer materials (such as poly (lactic acid), poly (glycolic acid) and poly (lactic-co-glycolic acid)) [13]. Compared with the 1st generation materials, bioactive materials can form strong chemical bonds with the body tissue [14], while biodegradable materials can continuously degrade by hydrolysis or enzymolysis along with tissue growth and be completely replaced by new bone tissue eventually, with no obvious interface between the implanted site and body tissues [15]. However, the 1st and 2nd generation materials for artificial bone can only serve as functional substitutes, instead of inducing bone repair and regeneration. Moreover, they are unable to respond to physiological change or biochemical stimulation [16].

With the rapid developments of molecular biology, cell biology, and manufacturing science, researchers have begun to use the relevant principles of engineering and life science to construct in vitro artificial substitutes with biological functions for bone repair and regeneration, resulting in a new discipline named tissue engineering [17]. In 1995, G M Crane from Rice University comprehensively expounded the definition, research focus and future development of bone tissue engineering [18]. The basic methods are as follows (Fig. 1): firstly, an artificial bone scaffold that matches with the defect site is fabricated with biodegradable materials, and then a three-dimensional compound of cells and scaffold is established; secondly, the compound not only provides necessary sites for nutrition access, gas exchange, waste discharge and growth metabolism of cells, but also induces cell proliferation and differentiation, as well as the synthesis and assembly of an extracellular matrix, meanwhile the bone scaffold is gradually degraded and absorbed; after the complete degradation of bone scaffold, the morphology, structure and function of the bone defect can be eventually repaired and reconstructed [18]. It can be seen that bone tissue engineering combines the two independent concepts of bioactivity and degradation, and could stimulate and regulate the specific responses of cells at the molecular level, thereby inducing new bone formation [19]. It enables the transformation of bone repair from simple mechanical fixation and is a functional alternative to regenerate and reconstruct living bone tissue, i.e. from temporary functional repair to permanent repair and regeneration [20].

Section snippets

Bioactive ceramic bone scaffolds

As one of the three elements of bone tissue engineering, bone scaffold plays an important role in bone repair. An ideal bone scaffold should firstly provide structural support for the defect site, and then create a microenvironment for cell adhesion, proliferation and function exertion by simulating the microscopic pore structure and chemical properties of natural bone [21]. Furthermore, the scaffold should be able to induce osteogenic differentiation and new bone formation with the assistance

Low-dimensional nanomaterials (LDNs)

According to the Griffith theory of fracture [98], ceramic fracture originates from the micro-cracks inside ceramics, instead of atomic bond breaking. In ceramics, the micro-cracks constantly propagate and interconnect with each other under stress until brittle fracture occurs. This makes the actual strengths of ceramics generally 2–3 orders of magnitude lower than their theoretical values [99]. Although the brittleness of bioactive ceramics is determined by the crystal structure, some scholars

Fabrication of LDNs/ceramic composite bone scaffolds

In order to explore the potential of LDNs in reinforcing bioactive ceramics, increasing efforts are being devoted to fabricating LDNs/ceramic composite scaffolds for bone tissue engineering applications. The first research priority is how to minimize or even avoid the structural damage of LDNs during the fabrication of ceramic bone scaffolds [154]. Bioactive ceramics are usually fabricated by sintering where the powder or compacts are heated to a temperature slightly below the melting point of

Dispersion and reinforcing mechanisms of LDNs

As nano-sized second phases, the dispersion state and interfacial characteristics of LDNs within the matrix are widely regarded as the two critical factors for reinforcing effects [188], [190], [191], [192]. At a low content, LDNs can be uniformly dispersed and form good interface bonding with the ceramic matrix, especially for graphene, where the wrinkled surface could lead to effective mechanical interlocking with the matrix [193], [194]. When a crack propagates to the vicinity of LDNs, the

In vitro and in vivo performance of LDNs/ceramic composites

Apart from the mechanical properties of the LDNs/ceramic composites, another major concern in bone tissue engineering applications could be their biological properties (such as cytocompatibility, bone formation, and so on) in vitro and in vivo. In vitro cytocompatibility of LDNs/ceramic composites has been performed using human osteoblast cells [132], [151], [171], [181], neuronal cells [206], pre-osteoblast cells [207], [208], fibroblast cells [209], [210] and mesenchymal stem cells (MSCs)

Summary and future direction

The fabrication of ideal bone scaffolds has persisted as a challenge in the field of biofabrication. Bioactive ceramics are widely recognized as promising biomaterials owing to their similar chemical compositions to natural bone and the capability to form synostosis with bone tissue. To date, intensive studies have been carried out to explore the capacity of bioactive ceramics for bone repair. Inspiring biological performance, high brittleness and low strength especially at load bearing sites

Acknowledgements

This work was supported by the following funds: (1) The Natural Science Foundation of China (51575537, 81572577); (2) Overseas, Hong Kong & Macao Scholars Collaborated Researching Fund of National Natural Science Foundation of China. (81428018); (3) Hunan Provincial Natural Science Foundation of China (14JJ1006, 2016JJ1027); (4) The Project of Innovation-driven Plan of Central South University (2015CXS008, 2016CX023); (5) The Open-End Fund for the Valuable and Precision Instruments of Central

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