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The materials designed and chosen for pH-responsive carriers also depend on the characteristics of the target drugs. For an instance, to deliver the drugs that are degradable in an acid environment i. Those polymers become less soluble in an acidic environment, which is helpful to prevent the drug from gastric degradation, while when they arrive at alkaline intestine table 1 , the polymers are easy to dissolve and release the encapsulated drug [ 43 ].

For non-viral gene delivery, cationic polymers are promising because they can easily form complexes with the negatively charged nucleotides via electrostatic interaction. With the aim of using the physiological pH gradients i. For the temperature-responsive drug carrier, the phase transition temperature is the key performance indicator, and it must match a set of conditions for a specific application.


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The phase transition temperature needs to be between room temperature and body temperature for inherent temperature sensitivity towards the physiological conditions. LCST polymers form hydrogen bonds with surrounding water, and the hydrogen bonding weakens with increasing temperature, which result in the expelling of water and aggregation of the partially dehydrated polymer chains. The balance between polymer-polymer interactions and polymer-solvent interactions affects the phase transition temperature, i. For the most-investigated temperature responsive polymer, PNIPAM, the copolymerization of polar or ionic monomers increased the transition temperature [ 48 ], and the copolymerization of hydrophobic monomers shifted the transition temperature to lower temperatures [ 49 ].

Besides the chemical structure, the solutes, especially salts in the surrounding solution, may also affect the transition temperature. The salts that increase the hydrophobic interaction decrease the transition temperature and vice versa [ 50 ]. As mentioned in section 1. To achieve this, one strategy is to use the aggregates of nanoparticles assembled through non-covalent bonding between the nanoparticles, and the aggregates can be disassembled by the high shear stress near the stenosis area figure 7. Since the hemodynamic force that moves the particles along the flow is proportional to the square of the particle size, the disassembled nanoparticles adhere more efficiently to the surrounding vascular wall than the micro-sized aggregates, and the unaffected nanoparticle aggregates are pulled away by the blood flow [ 51 ].

Another strategy for shear-stress response is microcapsules, microvesicles, and liposomes that deform and increase the permeability to release the loaded drug when subjected to high shear-stress [ 52 , 53 ]. Figure 7. Schematic illustration of the responses of nanoparticle aggregates, deformed microcapsules or microvesicles, nanoparticle-RBC complexes and supermolecular self-assembled hydrogels when subjected to increased shear stress.

With the adhesion of nanoparticles on the surfaces of red blood cells RBCs , the nanoparticle-RBC complexes can also achieve shear-stress response because the nanoparticles would fall off the RBC's membrane surface to release drugs under the condition of high shear stress at the vascular stenosis site [ 54 , 55 ]. The combination of nanoparticles and RBCs fully uses the advantages of nanoparticles and RBCs such as high efficiency of drug loading and a long period of circulation to accomplish shear stress response.

However, the specific interactions between nanoparticles and RBCs remains unclear, which makes it difficult to precisely regulate the interactions. As a result, it is difficult to effectively regulate the binding strength and shear response behavior of nanoparticles and RBCs. Therefore, further investigations on these interactions by preparing model nanoparticles with controllable structure and surface properties are required. Supramolecular self-assembled hydrogels with macroscopic reversible properties or self-healing functions can also be used to design shear stress-responsive drug delivery system.

The supramolecular systems usually rely on non-covalent cross-linking, self-assembly interactions and subject-guest interactions. Those self-assembled hydrogels can release more drugs when shear stress is applied to break the supramolecular interactions figure 7 [ 56 , 57 ]. Based on the nature of the redox stimuli, redox-responsive polymeric systems can be further divided into reduction-responsive systems and oxidation-responsive systems. For the reduction-responsive system, it commonly contains disulfide and diselenide linkages which will be broken with a significant increases in the level of surrounding reducing agents such as GSH.

Common methods to incorporate disulfide linkage in the system includes direct formation of disulfide linkage and crosslinking by a disulfide-containing crosslinker figure 8.

Polymers of biological and biomedical significance

Disulfide can be introduced in the polymer as the end group by living or controlled polymerization e. On the other hand, the polymeric micelles that contain drugs can also be crosslinked by disulfide-containing crosslinkers using bis 2,2'-hydroxyethyl disulfide, dithiodipropionic acid and their derivatives to prevent drug leakage, and after the micelles reach the target, the disulfide linkers break to release the drugs [ 59 ].

Figure 8.

Illustration of the common strategies to introduce disulfide bonds in the polymeric systems. Nevertheless, introduction of the diselenide linkage in the polymeric system is not as easy as that of the disulfide linkage, and further investigations on the efficient synthetic methods are still required [ 60 ].

Oxidation-responsive systems primarily respond to ROS, the byproducts from aerobic metabolism. Sulfur-based materials represent a type of oxidation-responsive material. Poly propylene sulfide PPS can be oxidized by ROS to form sulfoxide to achieve hydrophobic-hydrophilic transition [ 61 ]. The major limitation of the sulfur-containing materials is the relative high stability of the sulfur, and the response to ROS may not be so sensitive.

Incorporation of selenium, which is more reactive than sulfur in the polymers, raises the sensitivity of the response to ROS [ 62 ]. Ferrocene-containing polymers are another major class of the oxidation-responsive polymers due to its oxidation sensitivity, and ferrocene can be incorporated in the backbone, side chain and terminal group of the polymers [ 6 , 63 ].

To extend the applications, emerging motifs such as boronic ester groups, tetrathiafulvalene, and oligoproline have also been investigated for the construction of novel oxidation-responsive polymers [ 64 , 65 ].

003-Biological Polymers

The synthesis of enzyme-responsive polymers for biomedical applications should follow some basic rules. Specific conditions e. Besides the presence of the substrate or substrate-mimic unit for the targeted enzyme to react, the actions of the targeted enzymes need to induce a change in the polymers' properties for the specific functions.

The enzyme's action and the final material's response can be carried out simultaneously or in a step-by-step way. For example, the DNA nanoparticles were prepared using peptides as the crosslinker, and degradation of the peptide by proteases immediately destructs the nanoparticles [ 66 ]. Enzymes control bond formation and cleavage, substrate oxidation and reduction, and isomerization reactions in the living organisms, and the first two types of the reactions have been used in designing enzyme-responsive materials figure 6.

Many natural and artificial polymers have been explored as the matrix materials for the construction of enzyme-responsive systems, such as chitosan, dextran, alginate, polyacrylamide, polyethylene glycol and poly butyl methacrylate. The detailed information is provided in the review papers [ 8 , 26 , 68 ].

With the progress of the investigations on the stimuli-responsive system, it has been found that the system with single responsiveness may not achieve the desired goals due to the complexity of the real physiological microenvironment. For example, drug-delivery efficiency is reduced by a hierarchy of barriers such as blood brain barrier, mononuclear phagocyte system, cell internalization and endosome escape existing in organs, tissues, and cells. Thus, polymeric systems with multi-stimuli responsiveness have been designed for biomedical applications.

It is easy to provide pH responsiveness by introducing ionizable groups in the polymer, and thus the current multi-stimuli responsive systems are commonly constructed via adding a responsiveness property to a pH-responsive system, including pH-reduction responsive, pH-diol responsive, pH-light responsive, and pH-temperature responsive systems [ 69 ].

Such multi-responsive systems can be obtained in the forms of particles, films or hydrogels. The multi-stimuli responsive films are commonly prepared via the layer-by-layer LBL assembling or by using polymer brushes. LBL assembling involves alternatively depositing different polymers on a substrate, and the deposited polymers can be assembled into the LBL coating via various interactions such as electrostatic interactions, host-guest interactions, hydrogen bonding and coordination bonding [ 70 ]. For the polymer brush strategy, the initiator is anchored to the substrate and the polymer brushes with different functions are then formed via the surface-initiated living polymerization [ 71 ].

Hydrogels are crosslinked hydrophilic polymer networks with large amounts of water absorbed in the network, which can not only encapsulate cells and bioactive cytokines but also be highly permeable for oxygen and nutrients. Multi-stimuli responsive hydrogels can be easily obtained by crosslinking the polymers with different responsiveness properties, and the hydrogels are programmed to swell, shrink, or dissociate in response to various stimuli [ 72 , 73 ].

In another example, PNIPAM and positively charged poly diallyldimethylammonium chloride were used to prepare a temperature and pH-responsive hydrogel, which is assembled on a layer of gold-coated polydimethylsiloxane [ 75 ]. The changes in solution temperature and pH induce the modulation of the hydrogel solvation state, which subsequently results in a unique bidirectional bending behavior.

The bilayers could be used as temperature- and pH-induced grippers for the controlled delivery of small molecules, which is useful for various biomedical applications. Most bio-responsive systems focus on controlled drug release, especially for cancer treatment. Although the recent progress in chemotherapy leads to the appearance of various new drugs for cancer treatment and remarkably improves the prognosis and quality of life for the patients, a major challenge remains the lack of sensitivity of the drugs towards neoplastic cells [ 76 ].

The possible fatal systemic adverse effect and the presence of multidrug resistance for the anticancer drug compromise the therapeutic effect [ 77 ]. Further development of the chemotherapy requires sufficient drug release at the tumor site and the prevention of endosomal entrapment of the drug-carriers, and the construction of appropriate stimulus-responsive systems has exhibited great promise on these aspects. This is based on the fact that the microenvironment of tumor tissues can provide multiple endogenous stimuli.

For example, the tumor tissues have mild acidity, high GSH concentration and elevated level of hyaluronidase [ 15 ], and thus the pH-, redox- and enzyme-responsive drug carriers or their combination to further improve the drug release performance have been widely investigated. A novel illustration is the human serum albumin HSA -coated MnO 2 nanoparticles as the intelligent carrier of cis-platinum.

The MnO 2 reacts with the endogenous H 2 O 2 at the tumor site to in situ produce O 2 to overcome the drug resistance induced by local hypoxia, and simultaneously, the nanoparticles are able to degrade in an acidic environment to release cis-platinum [ 78 ]. In another design, the poly 2- dimethylamino ethyl methacrylate PDMAEMA was used to prepare a nanogel, and the hydrophilic rhodamine B was covalently linked to the PDMAEMA through disulfide bonding with the hydrophobic coumarin physically entrapped in the nanogel.

This system is multistimuli-responsive, i. In recent decades, there has been a tremendous increase in developing bio-responsive drug carriers for control release, and further improvement of release efficiency results in the dual and multiple-responsive systems that can deliver more than one drugs for programmed site-specific drug delivery. The various designs of the bio-responsive delivery system aim to overcome the key challenges in drug delivery: drug loading, stability in physiological environment, tumor-targetability, efficient uptake by cancer cells, and programmed intracellular drug release.

Although there is much excellent research, most of it focuses on one point of the challenges and remains at the early stage of concept-proof [ 80 ]. To translate the research into clinical practices, the problems associated with most of the current bio-responsive drug delivery systems must be solved such as low capacity of drug loading, biodegradability, the ability to retain circulation and enrich in the targeted tissues e.

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In addition, further investigations should be conducted on the microcosmic in vivo performance of the bio-responsive systems and the effect of systemic physiological factors on drug release [ 80 ]. The development of biomedical research significantly expands the understanding of the human body and the mechanisms of the physiological activities and diseases.

Therefore, besides disease treatment, another important goal is diagnostics where bio-responsive materials have also exhibited great promise to detect low levels of biochemicals, proteins and genes which serve as specific markers of diseases. Those markers are conventionally measured on various expensive chromatography systems such as high-performance liquid chromatography and gas chromatography-mass spectrometry, but with the stimuli-responsive systems, simple, fast, sensitive and low-cost detection strategies can be developed.

Thus, such IONs have been used as a T2 contrast agent for the diagnosis of liver diseases. However, they are insensitive for the diagnosis of small hepatocellular carcinomas SHC , and the successful diagnosis is critically important to increase the median five-year survival rate for the patients [ 81 ]. When the ION was functionalized with i-Motif DNAs that can transform from single-stranded state to intercalated quadruple-helical structure in an acid environment, the decrease in pH would disperse the aggregates of the functionalized IONs.

Another interesting example is the pH-responsive surfaces composed of nanoparticles with a coating of amino group-containing silane. An acidic environment results in the protonation of the amino groups, which makes the surfaces very hydrophilic, while an alkali condition changes the surfaces into a very hydrophobic state. With this surface, the level of glucose in the saliva and urine can be accurately measured in one second by recording the contact angle of the liquid sample, based on the produced gluconic acid after the addition of glucose oxidase in the sample [ 83 ].

This non-invasive, low-cost, rapid glucose detection method is beneficial to overcome the limitations of the traditional invasive diagnosis of diabetes such as pain and infection risk.

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Although the current investigations have shown the promise and success of the stimuli-responsive system in preclinical tests for diagnostic applications, most of the constructed system cannot meet the requirements for clinical practices. This is due to a great diversity of compounds in the real samples harvested from the patients of various conditions e. Besides detecting the level of the biochemicals, their local distribution in the human body and continuous monitoring which are difficult to achieve may be also needed.

Thus, the stimuli-responsive diagnostic systems remain in the early stage, and further investigations are needed for the commercialization in clinical management of diseases. The research on tissue engineering and regenerative biomedicine aim at replacing the necrotic or pathological tissues, and the general requirements of the corresponding materials including biodegradability, proper physical properties, bioactive ligands and the ability to control suitable cellular behaviors. For the synthetic scaffold which is relative low cost and has predefined properties, it is important to mimic the matrix metalloproteinases MMP -mediated cellular invasion which regulates the balance between scaffold degradation and cell ingrowth.

Incorporation of the integrin-binding sites and the substrates of MMP in hydrogels can provide the enhanced cell adhesion and controllable biodegradability.

Bio-responsive smart polymers and biomedical applications - IOPscience

In another study, four-armed PEG with arginylglycylaspartic acid RGD peptide units was crosslinked by MMP-sensitive crosslinkers to form microparticles, and a porous and injectable scaffold was formed by annealing those microparticles with each other. Such an enzyme-responsive scaffold is beneficial for maintainoing the balance between the rates of the scaffold biodegradation and tissue regeneration, and the rapid cutaneous-tissue regeneration was found within five days [ 86 ]. Besides the molecular design, spatiotemporal control of the hydrogel's physical and chemical properties is also important, and photochemical strategies including photoconjugation and photocleavation are useful tools for dynamic tuning [ 87 ].

Besides scaffolds, another important application of the bio-responsive materials is to construct intelligent surfaces or coatings on medical devices. For example, to prevent the implant-related infections, nanotubes were formed on the surfaces of titanium implants and antibiotics were loaded in the nanotubes. The nanotubes were then capped with 1,4-bis imidazolylmethyl benzene BIB using metal ions as the coordination linkage between the titanium and BIB. When bacteria attach on the titanium implant, the acidic metabolism products break the coordination linkage, resulting in the release of the loaded antibiotics to kill the bacteria.

The loaded antibiotics ceased to release when the attached bacteria are completely killed [ 88 ]. However, compared with bio-responsive scaffolds, there is much less research on the bio-responsive coating. In past decades, there has been an explosive growth in the research on bio-responsive polymers which have exhibited the significant influence in materials science, molecular pharmaceutics and nanobiotechnology. The variation in pH, temperature, stress, redox, enzyme and ATP can trigger various responses in the materials such as swelling, shrinkage, assembly, disassembly, degradation, sol-gel transition and crosslinking, and the stimulus-responsive systems exhibit many promising applications.

The stimuli-responsive functions are achieved through proper molecular design including introduction of protonated groups, polar side chains, reducing groups and enzyme substrate units as well as supramolecular self-assembly. Most of the stimulus-responsive systems are designed for controlled drug delivery to achieve programmed release and overcome the shortcomings associated with systemic administration of drugs, and the increasing attention is gained on the development of novel materials for diagnostics and tissue engineering.

Besides the system that can only respond to a single stimulus, dual or multiple stimuli-triggered bio-responsive systems have also been developed to further improve the responsive efficiency. The construction of bio-responsive systems depends on several integrated steps such as the design of the responsive forms, determination of the biological stimuli, and incorporation of the responsive units. The prepared system should exhibit a desired responsive performance with high sensitivity and selectivity, and as a material for biomedical applications, the system should also have satisfied stability and biocompatibility.

Taking drug delivery as an example, the drug carriers are designed to stabilize in the circulatory system and interact with the microenvironment of the target tissues. Good biocompatibility is required to avoid the possible systematic toxicity and immunogenicity, and it is important to control the timing for sufficient interaction between the carrier and the target tissues.

Sometimes, it would be useful to incorporate dual or multi-stimuli or step-by-step function for the precise spatiotemporal control of drug delivery. Despite the rapid growth in the research on bio-responsive biopolymers, it remains very difficult to get the products commercialized or even into the stage of clinical trials. Practical commercialization usually requires the potential of scale-up production and strong evidence to illustrate the clinical safety and efficiency.

Thus, the key polymers in the bio-responsive system should have a simple molecular structure or can be synthesized by routine strategies. Unfortunately, this aspect has restricted the commercial potential of most published investigations due to their 'overdesigned' characteristics with the sophisticated structures and complex responsive mechanisms. Further exploration on the discovery of simple polymers or facile synthetic routes with defined responses is needed. Clear demonstration of the safety and efficiency of the bio-responsive systems requires the full understanding of the in vivo behavior of the materials.

It should be noted that the biological environment and the level of the target cues are different between the animal model and human body or even among the individual patients. It is urgently needed to develop fundamental biochemical and physiological research and for the evaluation of the influence of the variation in the biological situations and discovery of novel in situ imaging techniques for analyzing the interaction between the bio-responsive system and the target tissues.

The information on the various biological cues should also be intensively gathered and analyzed in detail. In addition, the development of bioinspired or biomimetic systems to mimic the natural bio-responsive phenomena in the human body is promising. Another promising strategy to overcome the limitation of the inconsistent parameters of the endogenous stimuli is the use of exogenous stimuli that can be manually controlled such as light, ultrasound and magnetic field.

Provides comprehensive coverage of recent advances in polymers as materials of significance in biological and biomedical research. Addresses synthesis, surface activation, and characterization of biomaterials. Examines biological effects related to specific physical chemical factors. Explores synthetic bioactive chain molecules and polymers for controlled transport of active agents. An introductory section contains reviews of fast-growing research areas which provide concise introductory notes to succeeding parts of the book. Convert currency. Add to Basket. Book Description American Chemical Society, Condition: New.

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