Stimuli-Responsive Materials for Biomedical Applications

Reaction to specific stimuli accurately is a fundamental procedure within living structures. Centered on this, stimuli-sensitive materials gained noticeable implications in the field of biomedicine owing to flexible besides intriguing designs along diverse functioning. These materials have the ability of irreversible or reversible variations in physical or chemical characteristics in reaction to minor alterations in the inner or external environment. Over the last few years, stimuli-sensitive materials are extensively engaged in the diagnosis, treatment, and sensors. These responsive materials form a basis to construct smart systems, which perform required biomedicinal roles after getting particular stimuli. Subject to the type of internal or external stimuli, stimuli-sensitive materials could be categorized into numerous groups. This chapter outlines several stimuli-sensitive materials with their recent progress in biomedical applications. In last foremost obstructions to clinical future translation regarding such materials have also been summarized.

Among the different stimuli, electrical stimuli are mainly attractive according to the precise signals that can be produced simply, and repeatedly without requiring large, complex instruments, as well as electrical devices. Electro-responsive materials are a type of smart materials with the capability to change their physical and mechanical properties in response to external electric fields. According to their exclusive properties, they can be applied in smart constructions, such as artificial organs, flexible cells, as well as biosensors, or smart drug delivery systems. They can be classified based on the types of polymers, metal and metal oxide materials, carbon-based materials, or metal-organic frameworks (MOFs), which we will discuss in this chapter.

Over the past few years, magnetic-responsive materials are extensively researched on grounds of their prospective applications in different areas. Such responsive materials are being progressively exploited as functional materials with the capability of modifying their physical properties and responding to an externally applied magnetic field. Much work has been done to synthesize magnetic materials with novel hybrid features utilizing numerous constituents. Typically, magnetic-responsive materials possibly are developed with diverse shapes, sizes, and morphologies. They react to magnetic field externally applied differently according to their natures and configurations. These materials are estimated to display stimulating magnetic behavior with an extensive range of applications, for instance in bioimaging, drug delivery, hyperthermia, tissue engineering, and bioseparation. From this perspective, this chapter presents a survey of recent literature about properties, and preparation methods, along with various important applications regarding stimuli-responsive magnetic materials.

Thermoresponsive materials change their structural properties or exhibit conformational changes in response to temperature changes. They have stimulated researchers’ attention in the biomedical field, taking into consideration that specific infections show temperature changes. For example, temperature-responsive polymers have a typical trademark highlight in the presence of a hydrophobic group: propyl, methyl, and ethyl groups. When warmed or cooled over a critical transition point, inside a small temperature range, a break of hydrophobic and intra/intermolecular electrostatic interactions takes place, and the impact is a phase transition in the volume. This chapter describes the types of preparation, structural properties, mechanism of action of thermoresponsive materials, and their various applications in biomedical.

Light is one of the safe external stimuli that can be externally applied to alter chemical/biochemical behavior offering significant potential in photopharmacology. Since it is easy to use light, achieving precise drug delivery is possible. Light could be used to switch bacterial activity in cells including inhibition and release. Interestingly, the biochemical functions can be controlled both spatially as well as temporally using externally administered light. Light can also be used to regenerate the materials a number of times depending on the reversible nature of the material. This chapter is focused on light responsive materials including azobenzenes and spiropyrans. Materials can be tailored by modifying the basic delivery system with light responsive chemical structures such as spiropyrans and azobenzene moieties in their architecture. Such type of responsive materials could be augmented for use in medical devices, drug transport and delivery etc. Several new technologies involving light activated drug carriers such as nanoimpellers, nanovalves based drug delivery are elucidated with recent examples. Materials or surface modified with light responsive tools can offer controlled response due to existence of two different forms (such as spiropyran-merocyanine or cis-trans) which can facilitate either retention or release of the drugs.

Mechanical loads, such as compressive, tensile, and shear forces, are the most well-known and traditional stimuli affecting the world continuously. Force, pressure, or deformation are all mechanical stimuli frequently present in biological systems. With body motions, most biological tissues constantly encounter numerous kinds of mechanical stimulation. The mechanical characteristics of the surrounding medium have shown to influence stem cell development. Mechano-responsive materials can quickly change their physiochemical characteristics in response to mechanical force or deformation. They are used to create artificial muscles, photo-mobile materials, soft actuators inspired by living things, inorganic-organic hybrid materials, multi-responsive composite materials, and strain sensor materials. The introduction of mechanical stimuli, material characteristics regarding these kinds of stimuli, constitutive behavior of materials, different types of responses, and uses of mechanically sensitive materials are described in this chapter.

The pH has a significant role in the proper physiological functions of organs, tissue, cells, or sub-cellular organism. The deviation from the characteristic pH indicates some perturbation of their vital role in healthy conditions. It thereby leads to unwanted issues or diseases in the body, such as abnormal growth of cells leading to the tumor with an intrinsic acidic micro-environment that vastly differs from the normal physiological pH. Therefore, the detection of pH could be used as an alarm for disease diagnosis of organs or tissues. Researchers further focused on the therapy of the disease as the basis of the changed pH stimuli. Therefore, the ‘pH-alarm’ brought enormous attention to the synthesis, characterization, and therapeutic applications of pH-responsive materials in the biomedical field. In particular, Polymer exhibited considerable potential in drug delivery by introducing the pH stimuli for changing morphology, or assembly-disassembly and on-demand delivery of drugs at the alarming pH environment. Herein, we mainly focus on the different aspects of pH-sensitive polymer-based systems and their biomedical applications, like cancer, tuberculosis, inflammation, etc. These pH-responsive polymers provide satisfactory results in biomedical applications and could enter preclinical or clinical trials after proper evaluation.

Reactive oxygen species (ROS), mainly including hydrogen peroxide (H₂O₂), singlet oxygen (¹O₂), superoxide anion radical (O₂ ^•–), and hydroxyl radical (•OH), are the reduction products of oxygen. The mitochondria produce internal ROS, which are vital for cellular communication and metabolism. Excessive ROS amounts are connected to various diseases, such as cancer, atherosclerosis, diabetes, infection, inflammation, and aging, which encourages scientists to create ROS-responsive technologies to treat these diseases. In an environment with excessive amounts of ROS, ROS-responsive biomaterials undergo changes in physical properties (especially solubility) and changes in chemical bonds. Nanomaterials that respond to reactive oxygen species (ROS) have emerged as effective biomaterials; in particular, dendrimers, nanogels, and polymeric micelles have been extensively studied as efficient transporters for medicines, genes, and antigens. This chapter describes the types of ROS-responsive compounds, their structural properties, their mechanism of action, and their various biomedical applications.

Currently, various methods have been used to deliver anticancer drugs that have shown incomplete performance for their therapeutic potential. The biodistribution of drugs in the body is recognized as a fundamental challenge that reduces targeted and accurate cargo delivery to the pathological situation and blocks disease progression. Direct drug delivery to cancer tissue/cells can be a strategy to solve this problem due to the appropriate dose rate and with high efficiency and much fewer side effects than common methods, as well as increased stability of the drug in the physiological condition. Upregulation or downregulation can modulate the expression of heterogeneous enzymes such as proteases, glycosidases, and lipases to become pathologies of cancer, neurodegeneration, and inflammation. Therefore, enzymes appear as a heterogeneous stimulus in targeted drug and gene delivery systems due to the mild catalyze reaction conditions, spatiotemporal, and lack of harm. Enzyme-responsive platforms rely on enzymatic degradation of bond cleavage of oligopeptide substrate, the extracellular matrix, and stable functional groups into biomaterials. This chapter describes the types of enzyme-responsive biomaterials, their mechanism of action, and their various biomedical applications.

Sugar-sensitive materials can mimic normal endogenous insulin production as a response to the presence of glucose by limiting diabetic disorders and delivering the bioactive agent in a driven way. Glucose-responsive systems are precisely engineered to produce insulin and are based on enzymatic oxidation of glucose by glucose oxidase (GOx) or binding of glucose with components such as lectin and phenylboronic acid. The response to the environmental glucose change is a volume transition of the glucose-responsive matrix or reservoir, and in this manner, the conformational changes is driven by body’s glucose level. This chapter describes the types of preparation, structural properties, mechanism of action of glucose-responsive materials, and their applications in smart insulin delivery systems.

Single-responsive biomaterials have been of great importance for three decades in biomedical applications and cancer therapy in particular. However, the need for improvement in their efficiency and therapeutic results can still be felt. Evolved from these nanocarriers, multi-responsive ones have gained immense attention recently because of their multifunctionality—targetability, hyperthermia, ROS generation, smart and controlled drug release, and imaging. Due to complex structure of cancerous tumors, these nanomaterials are more applied in this field with more promising outcomes under a term called combined therapy. Multi-responsive nanocarriers are divided into three main groups: endogenous or internal, exogenous or external, and the integration of both. This chapter focuses on nanomaterials responsive to more than one stimulus in cancer therapy. The internal (pH, enzyme, GSH, etc.), external (light, ultrasound, magnetism, etc.), and combination of both are covered separately.