Chapter 1: Introduction

Over many centuries the scientific community has developed manifold strategies to protect and prolong the quality of human life. Nevertheless, there remain many unresolved healthcare challenges facing mankind. Cardiovascular diseases, chronic respiratory diseases, viral and bacterial infections, cancer, and diabetes are responsible for many deaths each year.¹  Cancer caused 9.6 million deaths worldwide in 2018,²  and malaria claimed 409 000 deaths in the year 2019.³  Pandemics such as COVID-19 still cause immense damage to human health and wellbeing. At the time of writing, more than 2.5 million people have lost their lives to COVID-19, and many more have lost their livelihoods as COVID has devastated economies around the world. The effects of disease are not confined to adults and the elderly, but also affect children. For example, more than one third of all deaths in low-income countries are among children younger than 15 years. These deaths are due primarily to respiratory infections, diarrheal diseases, malaria, AIDS, and birth complications.

There are a range of types of intervention which can be used to reduce the burden of disease. One is vaccination, in which the body's immune system is ‘trained’ to recognise and respond to a pathogenic species before an infection (so-called prophylaxis). If a patient is already suffering from a disease (infectious or otherwise), then therapy is required to ameliorate their symptoms and control and/or halt the progression of disease. For the latter, we administer a drug, an entity capable of triggering a pharmacological response in the body. Although this is conceptually simple, delivering the correct dose to the affected part of the body at the right time is hugely challenging. The manufacture of effective medicines is thus still an area attracting significant global research interest. Our ability to effectively treat disease is greatly enhanced by diagnostic and imaging technologies, which allow physicians to determine exactly what is wrong with the patient. Ideally diagnosis would be conducted in a non-invasive manner, but this is not always possible at present. Increasingly, researchers are exploring so-called theranostics, formulations which combine a diagnostic or imaging agent and a drug. These can enable the progression of a patient's disease to be followed at the same time as it is treated, helping to optimise the dosage regimen and ensure effective outcomes without adverse side effects.

Around one third to one half of the world had essential health services coverage in 2017. However, health services are often lacking in low- and middle-income countries.⁴  This encourages the development of low cost and long shelf-life interventions which can be provided in low-resource environments. There is also a great need to develop materials that are able to deliver a therapeutic payload in a precisely targeted fashion, to avoid off-target side effects. Inorganic materials have the potential to help overcome both these issues. However, developing biocompatible and biodegradable inorganic materials is a challenge which remains to be addressed in many cases. The introduction of a foreign object into the human body could lead to unpredictable side effects and/or toxicity. In addition, the immune system may be hostile towards unfamiliar materials and could initiate a defence mechanism leading to side effects or the rejection of the construct. Alternatively, long-term exposure to a drug might result in resistance and a lack of therapeutic efficacy. The key requirements and challenges of a therapeutic intervention are presented in Figure 1.1.

Inorganic materials provide a diversity of tools to engineer solutions to current challenges in biomedicine. While biocompatibility can be a problem, inorganic materials are widespread in nature and many are endogenous to the human body: for instance, calcium-based materials are found in bones and teeth. This offers a wealth of opportunities to develop multifunctional and safe therapeutic interventions. Inorganic materials have been proven to have potential for therapeutics, diagnostics, and drug delivery. For example, inorganic nanoparticles are key to signal generation in techniques like magnetic resonance imaging⁵  and positron emission tomography.⁶  Therapeutic strategies using, for example, gold- or iron-based materials have been successfully explored as advanced formulations to treat cancer.⁷  Inorganic drug delivery systems have also been established to target pathological tissues, for tissue restoration, wound healing, and vaccination. Underpinning all of these innovations are some key families of inorganic materials, and we introduce these briefly in the following sections.

A number of noble metals have been explored in biomedicine, mainly as pure metal nanoparticles. Gold-based materials, especially colloidal gold nanoparticles, are simple to prepare, and have easily manipulated surface chemistry and high stability. These, together with their surface plasmon resonance properties and biocompatibility, have led to a wide range of potential applications.^8,9  Gold nanoparticles show varied properties depending on their morphology and size, and can be fabricated with a range of shapes including spheres,¹⁰  rods,¹¹  and star-shaped particles (Figure 1.2).¹²  They have been studied as diagnostic tools,¹³  vaccine delivery systems,¹⁴  drug carriers,¹⁵  theranostic systems,¹⁶  and photothermal therapeutics.¹⁷ 

Silver nanoparticles have been similarly widely explored, and are particularly known for their antibacterial properties. This means they can be used, for instance, to solve problems of infections with scaffolds and implants.^18,19  Silver-based biomaterials have also shown promise in wound healing and reducing inflammation and scars.²⁰ 

Nanosized particles of magnetic elements, such as iron, nickel, cobalt, and their oxides, show superparamagnetism and high magnetic flux density, which endows them with applications in magnetic resonance imaging (MRI), targeted drug delivery, and theranostics.^21,22  Other applications include bone repair²³  and phototherapy.²⁴ 

Quantum dots (QDs) are semiconductor nanomaterials that can absorb broad-spectrum light and emit signals of a specific wavelength (Figure 1.2).²⁵  They are hence potentially potent materials for biomedicine, but their applications in this regard have faced obstacles due to high toxicity, low stability, and difficulty in surface modification.²⁶  However, recent developments have begun to overcome these limitations and QDs have thus been proposed to have potential for both imaging and theranostics.^27–30 

Carbon-based materials have attracted attention in the biomedical field by dint of their durability, high rate of biological distribution, and electrical and optical properties.³¹  Materials explored include graphene, graphene oxide, carbon nanotubes, fullerenes, and others (Figure 1.2).³²  Graphene is a hydrophilic 2D single carbon layer derived from graphite.³³  Through oxidation, graphene oxide can be generated.³⁴  Graphene and graphene oxide have been explored in drug delivery,^35,36  biosensing and gene delivery,³⁷  and cancer therapy.³⁸ 

Carbon nanotubes are hollow structures comprising carbon atoms in the form of a single-walled tube or multiple-walled cylinders. Their structure allows thermal and electrical conductivity as well as giving high mechanical strength.^39,40  Carbon nanotubes show high surface area, allow facile surface functionalisation, and have high stability. All of these characteristics render them potentially useful as drug delivery systems^41,42  and biosensors.^43,44  They also have osteogenic activity, allowing their application in bone implants.⁴⁵  However, it should be noted that toxicity is a matter of concern, especially for graphene and its oxide.^46,47 

Layered double hydroxides (LDHs) represents a class of layered materials held together by electrostatic attractions. They have the general formula [M_1−x²⁺ M′_x³⁺(OH)₂]^x+A_x/nⁿ⁻·zH₂O, where M denotes divalent cations (e.g. Mg²⁺, Co²⁺, Mn²⁺), M′ trivalent metal ions (e.g. Fe³⁺, Al³⁺), and Aⁿ⁻ charge-balancing anions such as NO₃⁻, Cl⁻, and CO₃²⁻ (Figure 1.2).^48,49  LDHs’ –OH groups provide a pH-responsive system that can degrade in an acidic medium to release a drug cargo. The positive charge of the LDH surface enhances the particles’ interaction with biological membranes, and hence facilitates intracellular delivery.^50,51  LDHs have been explored in various biomedical applications, including cancer therapy, gene delivery, diagnosis, implants, and scaffolds.⁴⁹ 

Transition metal dichalcogenides (TMDCs) are described by the formula MX₂. Transition metal atoms from groups 4–6 in the periodic table (M = Ti, Zr, Hf, etc.) are coordinated by chalcogen elements (X = S, Se, or Te) to form two-dimensional layered materials (Figure 1.2).^52,53  A wide range of TMDC formulations can be obtained through variation of the composition.⁵³  TMDCs show several promising properties, including a generally high surface area-to-volume ratio, particularly when the particles are nanosized. This allows a high drug loading to be achieved. In addition, the optical properties of TMDCs facilitate their application in photo-responsive therapy and optical biosensors.⁵⁴  They can be used to convert near-infrared light to heat, and thus for photothermal treatments and photoacoustic imaging.^55,56  TMDCs constructed from elements of high atomic number can be used as a contrast agent for computed tomography.⁵⁷  They have hence attracted significant attention for gene and drug delivery, bioimaging, and other applications in biomedicine.^56–59  However, the in vivo safety of TMDCs is still a matter of concern, and to date only MoS₂, WS₂, and WSe₂ have been tested in vitro and in vivo for their toxicological effects.^60–62 

Silica (Si–O–Si) framework materials can be readily formed via condensation reactions, and a range of templates can be used to generate systems with a variety of particle shapes, sizes and porosities (see Figure 1.2).^63–65  The high surface area of silica-based materials, their easily tuneable pore size, biocompatibility, high stability and dispersibility, osteostimulative properties, and easily functionalised surfaces facilitate a wide range of biomedical applications.^66,67  For instance, they have been used as drug delivery systems,⁶⁸  gene delivery systems,⁶⁹  scaffolds for bone tissue engineering,⁶⁷  multifunctional theranostics⁷⁰  and formulations able to respond to changes in pH⁷¹  or temperature,⁷²  to ultrasound,⁷³  or other stimuli.⁷⁴ 

Metal–organic frameworks (MOFs) are composed of metal centres connected by organic bridging ligands (Figure 1.2). This renders them a hugely versatile family of materials. An enormously diverse range of ligands and metals can be used to construct the framework, resulting in tuneable porosity and the potential for surface optimisation and functionalisation.⁷⁵  MOFs can be loaded with a drug cargo, and particles prepared with tuneable size, biocompatibility, and biodegradability.⁷⁶  MOFs have thus been explored in cancer therapy⁷⁷  and multimodal bioimaging,⁷⁸  inter alia.

The remainder of this volume will consider in detail the potential of inorganic materials in biomedicine. Chapter 2 will discuss inorganic material based drug delivery systems, while Chapter 3 is focused on imaging. Chapter 4 considers diagnostic and theranostic applications of inorganics, and Chapter 5 elucidates the use of inorganics for hard tissue regeneration. Finally, Chapter 6 explores the use of inorganics in vaccine formulations.