Nanostructures or nanomaterials have unique physical and/or chemical properties that are distinctly different from their bulk materials. They present exciting opportunities for design-ing materials with manipulated structure and properties on the nanometer scale. Smart nano-structures or nanomaterials often respond to various external stimuli such as volume, poros-ity, viscosity, stress, temperature, moisture, pH, ionic strength/strain, light, electric or magnetic fields, affinity interaction and changes in the chemical and/or physical properties. In medi-cine, they can be used to monitor, diagnose, repair and treat human biological systems and improve human health [1,2].
This article is a review of biomedical applica-tions of smart nanostructures. However, it is not intended to be comprehensive or to include all of the potential uses. In particular, the topic of smart drug delivery is not covered in this article since reviews on this topic have been published extensively in recent years [3–6].
Smart nanostructures & nanomaterialsVarious nanostructures or nanomaterials sensi-tive to environmental or biological parameters have been reported. Usually they are made of metals, metal oxides, quantum dots (QDs), silica, carbon nanotubes, C
60, hydrogel, block
copolymer, molecular imprinted polymer (MIP) and dendrimer [7–9].
Nanometer-sized metallic structures, such as platinum, gold and silver nanoparticles, exhibit unique optical properties. They have often been used as spectrophotometric reagents. The exci-tation of the surface plasmon by light on their
surface, and the resulting color transition, are very sensitive to the change of this boundary, such as the adsorption of molecules to the metal surface, since the surface electromagnetic waves propagate on the boundary of the metal and the external medium (e.g., air or water). This phe-nomenon is the basis for colorimetric measur-ment of adsorption of molecules onto the surface of metal nanoparticles. Wang et al. reports a col-orimetric assay of acetylcholinesterase (AChE), where AChE catalyzes the hydrolysis of acetyl-thiocholine into thiocholine to induce the aggre-gation of gold nanoparticles. This results in the red-shift of the plasmon absorption due to inter-particle plasmon interactions [10]. This method may extend to screening of AChE inhibitors and relevant drug discovery.
Iron oxide magnetic nanocrystals commonly consist of magnetic elements, such as iron, nickel and cobalt and their chemical compounds. Due to their nanometer-scale size, biocompatibility and ability to be manipulated under an external magnetic field, iron oxide magnetic nanocrystals have been used widely in biological detection and separation, site-specific drug delivery and imaging [11,12]. Recently, an interesting research utilizing magnetic nanoparticles to remotely control ion channels, neurons and even ani-mal behavior was reported by Huang et al. in Nature Nanotechnology [13]. The system works by exposing superparamagnetic ferrite nanopar-ticles targeted to specific proteins on the plasma membrane of cells to a radio-frequency magnetic field that heats them up. The induced tempera-ture increase is highly localized. In the study, when the temperature reached 34°C, tempera-ture-sensitive cation channels in neurons were
Smart nanostructures are sensitive to various environmental or biological parameters. They offer great potential for numerous biomedical applications such as monitoring, diagnoses, repair and treatment of human biological systems. The present work introduces smart nanostructures for biomedical applications. In addition to drug delivery, which has been extensively reported and reviewed, increasing interest has been observed in using smart nanostructures to develop various novel techniques of sensing, imaging, tissue engineering, biofabrication, nanodevices and nanorobots for the improvement of healthcare.
KEYWORDS: nanodevices n nanomedicine n nanorobots n smart nanomaterials n smart nanostructures
Jingjing He1, Xiaoxue Qi1, Yuqing Miao†1,2,
Hai‑Long Wu2, Nongyue He3
& Jun‑Jie Zhu4
1Laboratory of Biomimetic Electrochemistry & Biosensors, Institute of Physical Chemistry, Zhejiang Normal University, Jinhua 321004, China 2State Key Laboratory of Chemo/Biosensing & Chemometrics, Hunan University, Changsha 410082, PR China 3State Key Laboratory of Bioelectronics (Chien-Shiung Wu Laboratory), Southeast University, Nanjing 210096, China 4MOE Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry & Chemical Engineering, Nanjing University, Nanjing 210093, PR China †Author for correspondence:Tel.: +86 579 8228 3109 Fax: +86 579 8228 3109 [email protected]
remotely activated and action potentials resulted accordingly. This approach can be adapted to stimulate other cell types and could lead to novel therapeutics by remotely manipulating cells in site-specific tissues.
In comparison with organic dyes and fluores-cent proteins, QDs exhibit advantages in signal brightness, photostability, multicolor-light emis-sion and size-tunable fluorescence properties, making them extremely useful for biolabeling and biosensing [14,15]. Apart from the exhibited color of gold nanoparticles, and the absorbance peak at approximately 500 nm due to the sur-face plasmon of the nanosized metal surface, a different optical feature of QDs is their emitted fluorescence, which is far more sensitive than the color of gold nanoparticles. Fluorescence quenching induced by gold nanoparticles, H
2O
2 or other quenchers may provide a versatile
method to develop QD-based bioana lysis. Since oxidases generate H
2O
2 as a product, QDs can be
used as a fluorescent reporter for the activities of oxidases and for the detection of their substrates. Gill et al. has introduced an optical method to analyze H
2O
2 with high sensitivity by the lumi-
nescence quenching of CdSe/ZnS QDs [16]. This utility is exemplified for the ana lysis of glucose in the presence of glucose oxidase. In addition, they apply QDs to monitor the inhibition of AChE. AChE hydrolyzes acetylcholine to choline and, subsequently, choline oxidase oxidizes choline to betaine while generating H
2O
2. In the presence
of an inhibitor, the hydrolysis of acetycholine by AChE is inhibited, and the final concentration of produced H
2O
2 decreases.
Hydrogels are 3D high-molecular-weight net-works composed of a polymer backbone, water and a crosslinking agent [17]. They can be designed to be stimuli sensitive, exhibiting a phase transition in response to change in environmental param-eters such as pH, ionic strength, temperature and electric currents. Polymer brushes, nanoparticles and other nanostructures of hydrogels are of great interest in drug delivery, cell encapsulation and tissue engineering [18]. A novel biomimetic gel with a self-oscillating function was reported by Yoshida et al. [19]. The self-oscillating polymer is composed of a poly(N-isopropylacrylamide) (PNIPAAm) network in which the catalyst ruthe-nium tris (2,2 -́bipyridine) for the Belousov–Zhabotinsky (BZ) reaction is covalently immobi-lized. The BZ reaction is well-known for temporal and spatiotemporal oscillating phenomena. Here, the periodical redox changes of ruthenium tris (2,2 -́bipyridine) are concerted to the mechani-cal changes of gels and generate an spontaneous
cyclic swelling–deswelling oscillation without any on–off switching of external stimuli. The self-oscillating polymer gel may be useful in medicine since one of characteristic behaviors in living systems are the spontaneous changes that can occur with temporal periodicity such as heartbeat, brain waves, pulsatile secretion of hormone, cell cycle, biorhythm, and so forth. The nanoconveyers with the spontaneous propa-gation of chemical waves were also developed by the same group, by grafting the self-oscillating polymers an with N-succinimidyl group or array-ing the gel beads on an aminosilane-coupled glass plate [20]. Nanoscale oscillation was observed in an aqueous solution containing the BZ substrates. The amplitude was approximately 10–15 nm, and the period was approximately 70 s.
Self-assembly has been extensively explored to functionalize the material surface, and build nanostructures or nanomaterials. It can be defined as the spontaneous organiza-tion of molecular units into ordered structures by noncovalent or weak interactions such as van der Waals, capillary, p–p or hydrogen bonds. The folding of polypeptide chains into proteins, and nucleic acids into their functional forms, are typical examples of self-assembled biological structures. Some artificial nanostructures formed by self-assembly include ordered monolayers or multilayers, liposomes or vesicles, nanoparticles, nanotubes and nanofibers, spaning a wide range of nano- and meso-scopic structures, with differ-ent chemical compositions, shapes and function-alities. Compared with polymer hydrogels with typically very slow responses, Sun et al. devel-oped self-assembled homopolymer nanopar-ticles that rapidly and reversibly respond to the external stimuli of pH and temperature [21]. The nanoparticles or aggregates immediately formed when sulfonated aromatic poly (ether ether ketone) solution and polyallylamine solu-tion were mixed with a designed molar ratio at pH between two critical points. During the decrease of pH from 7 to 1, the average diam-eter of nanoparticles systematically decreased from 450 to 275 nm. Upon increasing the solu-tion pH, the average diameter of nanoparticles quickly returned to the original value, indicating a reversible process. When solution pH is beyond the critical range, nanoparticles immediately disassociate. Similarly, the self-assembled homo-polymer nanoparticles also rapidly and reversibly respond to environmental temperature.
Self-assembled nanostructures from block copolymers have frequently been reported [22–24]. Block copolymers consist of two or more
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covalently bonded blocks with different physical and chemical properties. They are able to gener-ate a variety of microdomain morphologies such as vesicle, lamellae, hexagonally packed cylin-ders, body-centered cubic spheres and gyroids, by self-assembly with the help of intermolecular forces [25]. Polymerization of block copolymers with shell-crosslinking or core-crosslinking was described to prepare the smart nanostructures with high stability and unique functions [26,27]. To mimic the feature in nature, formulation of materials responding to multiple stimuli in a predictable manner would be of great inter-est. Klaikherd et al. described a triple stimuli sensitive block copolymer assembly by incorpo-rating a temperature-sensitive functionality on one block of an amphiphilic block copolymer, acid-sensitive functionalities on the other block, and connecting the two with a redox sensitive disulfide linker [28]. It resulted in a supramo-lecular assembly that can respond to changes in temperature, pH and redox potential.
Various nanostructures or nanomaterials have been explored for biomedical applica-tions. However, most of them have no inde-pendent recognition ability. MIPs are tailor-made biomimetic receptors. They are often used for functionalizing the surface of of materials (including nanomaterials). MIPs are prepared by polymerization in the presence of molecular templates that are extracted after-wards, thus leaving complementary nanosized cavities behind. These polymers show a certain ‘molecular memory’ with high binding capac-ity and selectivity towards the target (template) molecule in artificially synthesized nanosized cavities. They can be used for sensing or separa-tion [29]. Usually, biological recognition com-ponents are hard to produce in large quantities. In addition, they are expensive and inherently unstable. However, MIPs, as artificial or plas-tic antibodies, can be readily mass produced. They are also highly stable and inexpensive. Zhu et al. described novel magnetic MIPs for aspirin recognition and controlled release [30]. The obtained spherical magnetic MIPs could be separated quickly by an external magnetic field. They exhibited high adsorption capacity and selectivity to aspirin. Imprinting sites onto a biomaterial could be a smart way to attract molecules favorable to tissue formation and instruct the body to heal itself.
Micro- and nano-technologies were used to develop various nanostructures and nano-materials. They also offer new opportunities towards the development of smaller medical
devices or systems. A variety of technologies including photolithography, thermal emboss-ing, step-and-f lash lithography and UV embossing have been developed to fabricate smart micro-/nano-sized patterns or devices for drug and gene delivery, tissue engineering, biosensors and diagnostic systems such as a high-throughput assay system for protein or DNA [31–34].
Sensing & imagingVarious smart sensing and imaging nano-structures were developed to collect biological, chemical or mechanical information related to health, which improves the currently available d iagnostic applications in biomedicine [35].
The applications of nanoparticles in diagnos-tics are almost unlimited because they enable the selective capture of a wide range of medically important analytes, including bacteria, biomark-ers and individual molecules, such as proteins and DNA [36–38]. Accurate targeting and quan-tification at the level of single cells and single molecules is a demanding task for medical detec-tion and diagnoses [6]. Agrawal et al. reported a method for single-molecule detection based on dual-color imaging and automated colocaliza-tion of nanoparticle probes at nanometer preci-sion [39]. As shown in Figure 1, by using green and red nanoparticles to simultaneously recognize two binding sites on a single target, individual biomolecules such as nucleic acids are detected and identified without target amplification or probe/target separation. Unbound particles are distributed randomly and do not show spatial correlation when spread and imaged on a solid surface. This method is potentially important for the ultrasensitive detection of disease bio-markers and intact infectious agents such as viruses and bacteria.
In recent years, the smart nanostructures of polydiacetylene (PDA) have been exploited for diverse biosensing applications. PDA is a conju-gated polymer that undergoes rapid colorimet-ric (blue-red) and fluorescence transformations, which are induced by external structural per-turbations [40]. Amphiphilic diacetylenic mol-ecules and biological receptors can be mixed with lipids to form various ordered biomimetic structures of vesicles, liposomes, monolayers, bilayers and others by self-assembly. The ordered nanostructures can be stabilized by polymer-ization with UV irradiation into a blue-colored poly diacetylene. The binding of target mol-ecules induces a distortion of the conjugation plane of polydiacetylene, leading a blue–red
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1132
color transition. These smart nanostructures have been constructed to develop various novel techniques for peptide (Figure 2), toxin, bacte-ria, virus and other analytes [41–43]. Even living mammalian cells have been labeled with PDA to evaluate pesticide cytotoxicity [44]. Within a short time after the addition of membrane-inter-acting tested compounds to the labeled cells, the PDA patches emit high fluorescence, which can be monitored by conventional spectroscopy and microscopy apparatus. The chromatic technol-ogy is capable of distinguishing between toxic effects associated with membrane interactions versus intracellular mechanism. One advantage of these biochromic conjugated polymer sensors is that their molecular recognition and signal
transduction functionalities are resident in a single functional unit, making them amenable to c onvenient microfabrication and use [45].
Quantum dots exhibit unique physical, chemical and optical properties. They are now emerging as a preferred candidate for imag-ing and optical detection since the organic fluorophores such as fluorescein isothiocyanate (FITC) and rhodamine, which are traditionally used in clinical diagnosis, are not photostable and have low intensity [46,47]. They are resistant to photo-bleaching and photo, chemical and metabolic degradation, exhibit high quantum yield and enable the simultaneous identification of multiple markers by the signal of fluorescent light [6,48]. QDs with different size or composi-tion emit different color light owing to quantum confinement, for which they are often used in multicolor optical coding for biological assays or medical imaging [49]. Theoretically, the use of ten intensity levels and six colors could code one million nucleic acid or protein sequences [50]. This spectral coding technology is expected to open new opportunities in gene expression studies, high-throughput screening and medical diagnostics. Proteases play a great role in cancer development and promotion by regulating the activities of growth factors/cytokines and sig-naling receptors. Altered expression of particu-lar proteases is a common biomarker of cancer, atherosclerosis, and many other diseases. Chang et al. developed a smart nanostructure that does not emit light in its original state but lights up very brightly in the presence of proteases [51]. As shown in Figure 3, the design involves tethering a gold nanoparticle (AuNP) to the QD to inhibit luminescence. The tether is a peptide sequence specific for a protease of interest, which holds the gold close enough to prevent the QD dot from giving off its energy. These QD–peptide–AuNPs imaging probes are activated once the tether peptide is cleaved by a specific protease resulting in the release of AuNPs. Energy trans-fer no longer occurs between the AuNPs and the QD, allowing strong radiative emission by the QD. The new probes could be used to alert doctors to tumors and other disease sites [51].
QDs have been demonstrated as excellent flu-orescent probes. However, they suffer from the intrinsic limitations of optical imaging systems such as low penetration depth and large back-ground fluorescence [52]. Magnetic nanocrystals are now emerging in biomedical applications with new opportunities. Magnetic resonance imaging (MRI) is an ideal technique for imag-ing soft tissue to detect disease early [53]. MRI
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often includes the administration of chemical contrast agents to enhance signal intensity. Some recent prototype MRI contrast agents have been designed to respond to cellular processes or cel-lular markers, such as pH, dissolved oxygen, enzymes, metal ions, or an area of interest. In fact, pH is an ideal parameter for detecting early-stage cancer since the pH of the cancerous tissue is significantly lower than that of healthy tissue. Hartman et al. reported a high-performance MRI contrast agent with superparamagnetic Gd3+-ion clusters confined within ultrashort single-walled carbon nanotube capsules [53]. As ultrasensitive ‘smart’ probes, they exhibit a dra-matic response to pH with a 40-fold increase in efficacy compared with those in current clinical use. The smart nanostructures might be excel-lent candidates for the early detection of cancer where the extracellular pH of tumors drops to pH 7 or below.
Nanoporous silicon is also a promising mate-rial for optical biosensing via changes in the optoelectronic and photoluminescence prop-erties of the material. Kilian et al. reported a smart tissue culture using nanostructured pho-tonic crystals to monitor the activity of pro-tease secreted from liver cells in situ [54]. The protease-responsive polypeptide biopolymers were incorporated within the nanostructure of photonic crystals. In the presence of proteases, the polypeptides are cleaved and the biopolymers removed from the pores, which yields a blue shift in the photonic crystal reflectivity and therefore provides a label-free method of detecting prote-ase activity. The development of new techniques for monitoring enzyme secretion in tissue cul-ture is important for fundamental research, bioengineering, toxicology and drug discovery.
Tissue engineering & biofabricationTissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of biologi-cal substitutes that restore, maintain or improve the function of tissue or a whole organ [55–57]. A more inclusive term, biofabrication, has been introduced to bridge the life, physical and engi-neering sciences with various applications in tissue science and engineering, disease patho-geneses, and drug pharmacokinetic studies, bio-chips, biosensors and so on [58]. Biofabrication is defined as the production of complex living and nonliving biological products from raw materials such as living cells, molecules, extra-cellular matrices and biomaterial. It is increas-ingly important to rationally control molecular
and cellular interactions at material surfaces for a range of fields including drug and gene delivery, tissue engineering, biosensors and diagnostic systems. Surface characteristics of substrate material such as topography, chem-istry and surface physics affect cell/biomaterial interactions greatly. Special research interest has been directed to the smart systems that can be reversibly switched between interacting and noninteracting states. Cole et al. reviewed the
recent literature on switchable coatings respond-ing to stimuli such as light, temperature, electric potential, pH and ionic strength to control pro-tein adsorption/desorption and cell attachment/detachment for the development of various smart biointerfaces [59].
The combination of smart materials and nan-otechnology contributes greatly to the develop-ment of tissue engineering and biofabrication. PNIPAAm is a type of polymer hydrogel with stimuli sensitivity, attracting considerable atten-tion as a smart gel for use in biomedical and tissue engineering. It exhibits significant hydro-philic/hydrophobic property changes with tem-perature changes. Below the phase transition temperature of approximately 30–35°C, the polymer is hydrophilic and it swells in water.
Above the transition temperature, the polymer surface becomes more hydrophobic. Therefore, it could be used to activate a surface to grab or release proteins and cells. A simple process for nanopatterned cell culture substrates has been reported using an electron beam lithog-raphy system to locally polymerize and directly graft N-isopropylacrylamide onto hydrophilic polyacrylamide-grafted glass surfaces where the fabricated thermoresponsive polymers could be used to develop functional cell recovery systems for in vitro tissue reconstructions [60]. By chang-ing the irradiated area, a minimal stripe pattern with a 200 nm line-width could be fabricated. At temperatures above the lower critical solu-tion temperature, the cells adhered and spread with an orientation along the pattern direction. Below the lower critical solution temperature, they detached with shrinkage and folded along the pattern direction. The harvested cell sheets maintain their function, so that they can be transferred for stratification with other cell sheets in vitro and for direct transplant in vivo. This patterned cell recovery technique may be use-ful for the construction of functional cell sheets with efficient shrinkage/relaxation in a specific direction and spheroidal 3D cell structures for tissue engineering and bioreactors.
Poly(N-isopropylacrylamide) are usually pre-pared either by using an organic cross-linker or by irradiation with UV or an electron beam. However, these chemically cross-linked hydro-gels have very limited applicability owing to their poor mechanical properties. Haraguchi et al. developed a new type of physically cross-linked hydrogel, a polymer/clay nanocompos-ite hydrogel [61]. They exhibit distinguished mechanical properties as well as excellent opti-cal and swelling/deswelling properties, superior to the chemically crosslinked hydrogels. It was found that human hepatoma cells, human der-mal fibroblasts and human umbilical vein endo-thelial cells could be cultured to be confluent on the surfaces of the polymer/clay nanocomposite hydrogel. The cultured cells on the surfaces of hydrogels could be detached and harvested in the form of sheets of cells without trypsin treat-ment, but by just decreasing the temperature to 20°C.
Nanostructures have also been employed to develop smart applications for tissue regenera-tion or degradation and self-healing/repair [62,63]. Rajangam et al. reported interesting nanostruc-tures with strong angiogenic capacity to promote growth of blood vessels [62]. The self-assembled cylindrical nanofibers were formed in a few
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seconds by simply mixing two liquids. One liq-uid is an aqueous solution of the peptide amphi-phile designed with the sequence LRKKLGKA and a strong binding affinity for heparin. The second liquid is an aqueous solution of heparin with angiogenic growth factors, and has been linked to protection from protease degradation and boosting blood vessel formation, respectively. The nanofibers were found to measure 6–7.5 nm and further aggregated to create fiber bundles 50–100 nm in diameter. The nanostructure is a more rigid scaffold than ordinary polymers, which could help orient the proper domains of growth factors for receptor binding. The self-assembled nanostructures could be delivered eas-ily as liquids to the tissues of interest. Preliminary experiments using the angiogenic matrix in rabbit skin ischemic wound and mouse heart infarct models have shown promising results.
The report of Jun et al. demonstrates a new strategy for the regeneration of dental tissues using cell-responsive peptide-amphiphile nano-fiber networks containing degradation and adhe-sion moieties [63]. The peptide structure consists of three functional regions: GTAGLIGQ with matrix metalloproteinase-2 (produced by dental pulp cells)-specific cleavage sites; a glutamic acid to assist in calcium binding and water solubil-ity; and RGDS, a cell adhesion sequence. The addition of Ca2+ ions results in nanostructured cylindrical micelles. At sufficiently high concen-tration these fibers undergo physical crosslink-ing to form the gelled macrostructure. The gels
are broken up by matrix metalloproteinase-2 and cause the nanostructure network to become degraded and more permissive, enabling dental pulp cell adhesion and migration through the matrix and eventual remodeling of the matrix.
Smart nanodevices & nanorobotsNanotechnology holds promise to develop implantable sensing and/or treatment devices to collect information for diagnosing disease and administering treatment in vivo. Early diag-nosis and treatment mean a higher chance of r ecovering health.
Smart nanodevices or nanorobots could be injected into the body to search and destroy disease-causing cells and repair damaged ones. Cavalcanti et al. presented a nanobioelectronics-based nanorobot architecture for diabetes using computational nanotechnology for medical device prototyping [64]. As shown in Figure 4, the software simulator of nanorobot control design provides a 3D workspace comprising of a blood vessel, red blood cells and nanorobots. The nano-robots flow with the red blood cells through the bloodstream, detecting the glucose levels. Once the glucose achieves critical levels, the nanorobot emits an alarm through the cell phone, remind-ing the patient to take medications. All observed blood glucose levels can also be transferred to the cell phone, which records the historical informa-tion for later clinical analyses. A cell phone is a handheld wireless t ransmitter to communicate with nanorobots.
For nanodevices or nanorobots to perform tasks they have to be powered, which is often inspired by the biological system. Owing to the force of its rotational motion being com-patible, the genetically engineered protein F
1–adenosine triphosphatase (F
1-ATPase, the
F1 portion of ATPase) has been suggested to
be an attractive choice for powering nanoma-chinery or nanorobots to function in biological systems [65]. A nanodevice was constructed by d-free F
oF
1-ATPase within chromatophores and
actin filaments through biotinlipid-streptavidin-biotin-(AC
5)
2Sulfo-OSu system [66]. One actin
filament linking with many chromatophores functions as the nanodevice body and many d-free F
oF
1-ATPase as the nanodevice motors.
The results show that the nanodevice was driven by proton-motive force in the cooperating d-free F
oF
1-ATPase. The cooperation of F
oF
1-ATPase
will have wide application in the design of smart nanodevices for the in vitro investigation of cel-lular metabolism and the diagnosis of diseases. Kinesin, myosin and ATPase are important motor proteins. Even the flagellum of bacteria and sperm could be directly employed to power nanorobots [67].
Conclusion & future perspectiveAt present, nanotechnology and material sci-ence are experiencing a rapid growth period with major advances arriving quickly. It is expected that medicine will be an important beneficiary of their development for years to come through the continuous collaboration and efforts of research-ers from different fields, including chemistry, physics, biology, medicine, materials science and engineering. The study of smart nanostructures or nanomaterials promises new ways to diag-nose disease, treat disease and improve health, providing exciting opportunities for scientists to promote the development of modern biomedical science and engineering.
The successful clinical application of smart nanostructures or nanomaterials requires important considerations of stability, selectiv-ity, sensitivity, reproducibility, and spatial and temporal resolution. In particular, sufficient
evidence about toxicity and biocompatibil-ity has to be provided if they are to be used in vivo.
During the past years, there have been numer-ous reports of various smart nanostructures with sensitivity to a single stimulus. However, in nature, the living activity of organisms is often a result of their integrated responses to many environmental factors. Therefore, construction of new smart nanostructures that can respond to multiple stimuli would be of great interest in the future.
Nature offers many examples of smart, adaptive and multifunctional materials, inspiring us to fab-ricate similar structures or materials. Biomimicry represents a great technical challenge and it has opened doors to develop innovative smart n anostructures for diverse medical applications.
A combination of micro- and nano-electro-mechanical systems and other nanofabrication techniques has the promise to develop smart micro- or nano-devices for analytical sens-ing, drug delivery and disease treatment. They include a smart microchip implanted under the skin to continuously monitor key body param-eters, or a smart nanorobot that is capable of navigating through the body for early detection and treatment of disorders. The construction of nanoscale devices or robots that are able to perform specific tasks in medicine, which is a long-term goal of nanomedicine and provides great opportunities for scientists from different academic backgrounds, is still in its infancy.
Financial & competing interests disclosureThe authors greatly appreciate the support received from the National Natural Science Foundation of China (No. 20975093), Zhejiang Provincial Natural Science Foundation of China (No. R4100049) and Foundation of the State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, China (No. 200909). The authors have no other relevant affiliations or financial involvement with any organi-zation or entity with a financial interest in or financial con-flict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Executive summary
Smart nanostructures & nanomaterials � Self-assembly has been explored to functionalize the material surface, and build nanostructures or nanomaterials.
Tissue engineering & biofabrication � Smart nanostructures have been employed for tissue regeneration or degradation and self-healing/repair.
Smart nanodevices & nanorobots � Great attention has been paid to develop implantable smart nanodevices and nanorobots to collect information in vivo for diagnosing
disease and administering treatment.
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