Biomaterials for Musculoskeletal Regeneration

In this introductory chapter, the clinical perspective highlighting the relevance of biomaterials towards human healthcare is discussed. The major driving force behind the development of new generation of biomaterials is the implant failure, longer healing time post-surgical implantation or leading to clinically unacceptable host response. These issues are emphasized after defining a few concepts of biomaterials science. It is envisaged that the brief discussion in this chapter will set the platform for the readers to realise the significant thrust to develop implantable biomaterials with better host response for musculoskeletal applications.

The research on bulk hydroxyapatite (HA)-based composites is driven by the need to develop biomaterials with better mechanical properties without compromising biocompatibility properties. Despite several years of research, the mechanical properties of the HA-based composites still need to be enhanced to match the properties of natural cortical bone. In this regard, the scope of the present chapter is limited to discuss the processing and the mechanical as well as biocompatibility properties in the context of bone tissue engineering applications of a model system i.e. HA–Ti. It will be discussed as how hydroxyapatite-titanium (HA–Ti) based bulk composites can be processed to have better fracture toughness and strength together with uncompromised biocompatibility. On the materials fabrication aspect, the recent results are discussed to demonstrate that advanced manufacturing technique like, spark plasma sintering can be adopted as an advanced processing route to restrict the sintering reactions, while enhancing the mechanical properties. Various toughening mechanisms are discussed with an emphasis to synergize multiple toughening mechanisms, which requires careful tailoring of microstructure. The in vitro cytocompatibilty, as well as in vivo biocompatibility results are also reviewed.

This chapter will present some of the unique processing approaches to develop porous scaffolds with porosity scaling in the range of either 1–50 μm or in the range of 100–300 μm. In the first part of this chapter, the results will be summarized to illustrate how hydroxyapatite scaffolds with micro/mesoscale porosity in the range of 1–50 μm can be produced using the polymer blend method using PMMA (poly methyl methacrylate) as porogenous template. The cytocompatibility assessment using human osteoblast cells (Saos2) confirm that the adopted processing approach to produce porous hydroxyapatite scaffolds can stimulate significant cell adhesion and osteoblast differentiation. In the second part of this chapter, the efficacy of polymer sponge replication method to prepare the macroporous hydroxyapatite scaffolds with interconnected oval shaped pores of 100–300 µm with pore wall thickness of ~50 µm will be demonstrated. The enhanced cellular functionality and the ability to support osteoblast differentiation for porous scaffolds in comparison to dense HA has been explained in terms of higher protein absorption on porous scaffold. The last part of the chapter will present the results on the protein adsorption and release kinetics as well as in vitro biodegradability of cryogenically cured hydroxyapatite-gelatin based micro/macroporous scaffolds (CHAMPS). The adsorption and release of bovine serum albumin (BSA) protein exhibits steady state behavior over the incubation period up to 10 days. The extensive micro-computed tomography (micro-CT) analysis establishes cancellous bone-like highly interconnected and complex porous architecture of CHAMPS scaffold. Importantly, excellent adsorption (up to 50 %) and release (up to 60 % of adsorbed protein) of BSA has been uniquely attributed to the inherent porous microstructure of the CHAMPS scaffold.

The most important property of bone cement or a bone substitute in load bearing orthopaedic implants is good integration with host bone with reduced bone resorption and increased bone regeneration at the implant interface. Long term implantation of metal-based joint replacements often results in corrosion and particle release, initiating chronic inflammation leading onto osteoporosis of host bone. An alternative solution is the coating of metal implants with hydroxyapatite (HA) or bioglass or the use of bulk bioglass or HA-based composites. One of the desired properties for any new biomaterial composition is its long term stability in a suitable animal model and such property cannot be appropriately assessed by performing short term implantation studies. While hydroxyapatite or bioglass coated metallic biomaterials are being investigated for in vivo biocompatibility properties, such study is not extensively being pursued for bulk glass ceramics. In view of their inherent brittle nature, the implant stability as well as impact of long term release of metallic ions on bone regeneration have been a major concern. In the above perspective, the present study reports the in vivo biocompatibility and bone healing of the strontium (Sr)-stabilized bulk glass ceramics with the nominal composition of 4.5SiO₂–3Al₂O₃–1.5P₂O₅–3SrO–2SrF₂ during short term implantation of up to 12 weeks in rabbit animal model followed by long term implantation for 26 weeks in cylindrical bone defects in rabbit model. The progression of healing and bone regeneration was qualitatively and quantitatively assessed using fluorescence microscopy, histological analysis and micro-computed tomography. The overall assessment of the present study establishes that the investigated glass-ceramic is biocompatible in vivo with regards to local effects after short term implantation in rabbit animal model. Excellent healing was observed, which is comparable to that seen in response to a commercially available implant of HA-based bioglass.

The design and development of glass ceramic materials provide us the unique opportunity to study the microstructure development with changes in either base glass composition or heat treatment conditions and thereby developing an understanding of processing-microstructure-property (mechanical/biological) relationship. Among various brittle materials, the mica based glass ceramics with crystalline ceramic embedded in a glass matrix are of greater scientific interest, because of their machinability. Considering the potential of these materials as dental implants, this chapter summaries the published results on K₂O–B₂O₃–Al₂O₃–SiO₂–MgO–F glass ceramics to demonstrate the microstructure dependent mechanical, tribological and cytocompatibility properties. Among the high hardness of around 8 GPa together with 3-point flexural strength and elastic modulus of 80 MPa and 69 GPa, respectively were obtained in glass ceramics with maximum amount of crystals. While analyzing influence of environment on the friction and wear behavior systematic decrease in wear rate with test duration was recorded with a minimum wear rate of 10⁻⁵ mm³/Nm after 100,000 fretting cycles in artificial saliva. The in vitro results illustrate how small variation in fluorine and boron in base glass composition influences significantly the cytocompatibility and antimicrobial bactericidal property, as evaluated using a range of biochemical assays. Overall, the mechanical, tribological property, in vitro cytocompatibility study, when taken together clearly reveals that microstructure and base glass composition play an important role in enhancing the cellular functionality and antimicrobial property.

In this chapter, the published research results of author’s own group are summarized to establish the HDPE–HA–Al₂O₃ based hybrid composites with enhanced mechanical properties and good biocompatibility properties. The processing related concerns in injection molding route are discussed in reference to addition. The tensile and flexural fracture properties are analyzed. The cytocompatibility with osteoblast-like cells and in vitro mineralization are also discussed. More importantly, the osseointegration in rabbit model is qualitatively and quantitatively analyzed.

In some of the preceding chapters, the processing and biocompatibility property are discussed with a focus on ‘lab-scale’ research of designing new biomaterials. The translation of bench to bedside requires the fabrication of biomedical device prototype based on the lab-scale tested biomaterials. While addressing this aspect, this chapter and ZrO₂—toughened Al₂O₃ reports design and development of the compression molded high density polyethylene (HDPE)-based biocompatible acetabular socket with 20 wt% hydroxyapatite (HA) and 20 wt% alumina (Al₂O₃) ceramic fillers for the total hip joint replacement applications. This new implant material can be used either for non-cemented socket or as a liner for a metal back porous coated cup. This is more relevant as the total hip joint replacement (THR) arthroplasty has reduced pain clinically and tremendously improved the quality of life for millions. In the context of a growing need to develop patient-specific biomedical devices, this chapter describes some physical properties and more importantly 3D microstructural characterization using micro-computed tomography.

In the past decade, cartilage tissue engineering research envisaged on the development of engineered constructs to repair cartilage defects, which could be inflicted due to degenerative disease or traumatic injury. However, despite significant efforts, development of load bearing functional cartilage remains elusive. 3D bioprinting offers a fascinating approach to replicate the complex anatomical cartilaginous tissue architecture by precise delivery of encapsulated cells and morphogens at pre-determined location. Silk fibroin protein can be used for cartilage 3D bioprinting, as it possesses unique features such as shear thinning behaviour, self-supporting filamentous extrusion, instant cytocompatible sol-to-gel transition and tailorable mechanical strength. But systematic optimization of chemistry and rheology of bioink, topographical, physico-chemical and biomechanical functionality of printed cartilage constructs should be done to achieve this target. In this chapter we tried to summarize how chondrogenic differentiation is supported in 3D printed construct and signaling mechanisms minimizing hypertrophic differentiation of progenitor cells towards development of phenotypically stable engineered cartilage constructs.

An important concept that has been increasingly recognised in the biomedical research community is the ‘bedside-bench-bedside’ concept. Once a new biomaterial is found to exhibit a pre-clinically acceptable biocompatibility, the final and the most important stage of research is the clinical trial using ethically-approved protocols. The research on biomaterials should evolve around a specific disease model and, therefore, in vitro as well as in vivo biocompatibility assessments should involve the use of relevant cell lines or animal models, respectively. This chapter introduces the importance of clinical trials in biomaterials’ research, which has received increasing attention, but is yet at a lower intensity than those in the case of new drug designs and development. Further more, various possible avenues to conduct clinical trials are also briefly mentioned. Subsequently, this chapter discusses the concept of Randomised Control Trials (RCTs). Some illustrative examples are also provided to substantiate how clinical trials can establish the clinical efficacy of some of in vivo biocompatible implants. The various stages of the clinical trials are also highlighted. One specific example is discussed to describe the rationale for the study of design as well as the outcomes of clinical trials, particularly in the context of dental implants in prosthodontics. Subsequently, the chapter closes with the ethical issues/approval stages to be critically considered prior to conducting any clinical trials. The content and discussion in this chapter should be used only for academic purposes as the ethical approval and associated legal issues involved in clinical trials can vary from country to country. In order to illustrate some published clinical study reports in the field of bone tissue engineering applications are described for the readers to develop an understanding of how to conduct such experiments in clinical settings as well as how to evaluate the outcomes of such important studies. As a cautionary note to the readers, this chapter should neither be used to design any clinical trial study nor does this document have any legal binding.

Increasing number of clinical incidences of maxillofacial disorders has developed the quest for the fabrication of improved synthetic materials to aid in complete craniofacial restoration. Replicating the complex 3D architecture and functional dynamics of maxillofacial bone tissue is a challenging proposition which aggravates the need for a custom-made, on demand tissue replacement strategy for rendering patient specificity which could not be achieved till date. Textile technology offers versatility to develop 3D spatial structures with tailor-made mechanical properties in the order of micro- and macro meters. 3D printed structures have fascinating potential for reconstruction of maxillofacial deformations due to the ability to fabricate patient-specific, defect site-specific structural features in the order of several nanometers along with the flexibility of being tailored into any desired shape or size. These case studies highlight clinical trials to evaluate the key properties of high performance textile braided structures for preservation of dimension of alveolar ridge as well as 3D printed Hydroxyapatite Direct-write scaffolds for maxillofacial reconstruction and how tailoring their architecture could enhance patient-specificity and defect-specificity in situ.

Any attempt to pursue translational research requires adopting a truly interdisciplinary approach by integrating the ideas drawn from multiple disciplines such as Mechanical engineering, Materials Science, Biological sciences and Biomedical engineering. While emphasizing the need to develop a scalable and commercially viable strategy to fabricate biomedical implants, this chapter will discuss the concepts of Technology Readiness Levels (TRLs) and Manufacturing Readiness Levels (MRLs). In discussing various TRLs, the different aspects of property measurements or process control are emphasized. The maturation of technology can be realized once one travels across different TRLs. Two illustrative examples are provided so that one can judge how to assign various TRLs at different levels of technology development in research on bone tissue engineering.

The last one decade has witnessed a significant impetus towards patient-specific solutions of biomedical implant prototypes. The discussion in preceding chapters emphasize that multidisciplinary efforts are required to establish such patient-specific implants. Finite element (FE) modelling is used to predict the site-specific mechanical properties, which in-turn requires 3D reconstructed models of macroscopic biological entities based on CT/MRI scan data. The importance of low temperature additive manufacturing processes in fabrication of the patient-specific implants have been particularly highlighted. Also the major challenges related to the design, development and performance limiting properties of the scaffolds are discussed in this chapter. It has been emphasized that the optimization of the shape and size of the pores in the scaffolds is a challenging task in order to obtain the desired in vivo cytocompatibility property. The chapter closes with the author’s perspective on developing biomedical research programs leading to device/implant fabrication.