Construction of Bio-Piezoelectric Platforms: From Structures and Synthesis to Applications

and piezoelectric performance. Bio-piezoelectric materials have attracted interdisciplinary research interest due to recent insights on the impact of piezoelectricity on biological systems and their versatile biomedical applications. This review therefore introduces the development of bio-piezoe-lectric platforms from a broad perspective and highlights their design and engineering strategies. State-of-the-art biomedical applications in both biosensing and disease treatment will be systematically outlined. The relationships between the properties, structure, and biomedical performance of the biopiezoelectric materials are examined to provide a deep understanding of the working mechanisms in a physiological environment. Finally, the development trends and challenges are discussed, with the aim to provide new insights for the design and construction of future bio-piezoelectric materials.

DOI: 10.1002/adma.202008452 electricity." [1] As the name suggests, the piezoelectric effect is characterized by a linear transformation between mecha nical and electrical variables. [2] In general, piezoelectric materials can gene rate charges on two opposing surfaces in response to a mechanical strain, such as stretching, com pression, or bending. From the perspective of crystallography, the piezoelectric effect is ascribed to the asymmetry of crystal structures or molecular chains. When ions with different charges are asymmetrically arranged in piezoelectric crystals, electric dipole moments are formed. Ferroelectric materials represent a subclass of piezo electric materials piezoelectric materials where their electric dipole moments are uniformly oriented in specific regions, leading to the formation of domain struc tures. Since the electric domains are randomly distributed in crystals, the polari zation would be mutually counterbalanced and the overall polarization intensity of the material is zero. A unique aspect of ferroelectric materials is that upon exposure to a large external electric field, the domain orientation can be aligned in a single direction to achieve an overall material polarization to enhance the piezoelectric response. [3] When piezoelectric materials are subjected to an external stress, the distance between positive and negative charge centers is changed, resulting in material polarization along the stress direction. [3,4] In this case, the surface free charges are partially released to generate piezoelectricity, which is termed the direct piezoelectric effect. Likewise, under the action of an external electric field, piezoelectric materials can produce a geo metric deformation proportional to the external electric field, which is termed the converse piezoelectric effect. Representa tive piezoelectric materials include nonferroelectric materials such as quartz and zinc oxide (ZnO), [5] and ferroelectric mate rials such as barium titanate (BaTiO 3 ), [6] lead zirconate titanate (Pb[Zr x Ti 1−x ]O 3 , PZT), [7] lithium niobate (LiNbO 3 ), [8] potassium sodium niobate (K 0.5 Na 0.5 NbO 3 , KNN), [9] polyvinylidene fluo ride (PVDF) and its copolymers. [10] Interestingly, some animal tissues, such as collagen [11] and hydroxyapatite, [12] have also been found to be piezoelectric, which is a result of the asym metrical structure of biological molecules, such as amino acids, that leads to the formation of a dipole.
Since their discovery, piezoelectric materials have been widely applied in sensing, actuation, energy conversion, [4,13] and more recently catalysis. [14] In recent years, with the

Introduction
The piezoelectric effect was first discovered and demonstrated in 1880 by Curie brothers, citing the Greek word for "pressure

Structures and Materials
To meet the critical requirements of biomedical applications, piezoelectric materials should possess high electromechanical coupling and good biocompatibility. There may also be a need to be sensitive to stimuli, be able respond to physiological behavior and offer high mechanical flexibility and strength. [23] From the perspective of their chemical structure, current piezo electric materials for biopiezoelectric platforms can be broadly classified into four categories: i) biopiezoelectric ceramics, ii) biopiezoelectric polymers, iii) biomolecular piezoelectric mate rials, and iv) biopiezoelectric nanomaterials.

Bio-Piezoelectric Ceramics
Polycrystalline ferroelectric ceramics possess randomly oriented domains, where each domain presents a disordered polariza tion vector. To provide the ceramics with a macroscopic piezo electric effect, it is necessary to polarize them by applying a strong electric field above its coercive field, thereby allowing the polarization vectors to rearrange along the direction of electric field. In general, piezoelectric properties of ceramics are closely associated with their crystal structures, as discussed below.
A number of ferroelectric materials exhibit the perovskite crystal structure, which belongs to a cubic crystal system. The general chemical formula of a perovskite is ABO 3 , [24] where A represents a lanthanide or alkali earth metal, and B refers to a transition metal. Both O and A, with their large ionic radii, are in a cubic close packed configuration, while B has a smaller ionic radius to fill the central void of the octahedron. As a typical perovskite type biopiezoelectric material, PZT has been commonly used in sensing, catalysis, and energy harvesting due to their high piezoelectric activity, high electro mechanical coupling and low manufacturing cost. Since PZT contains lead (Pb), it is potentially toxic to living organisms [3] and its application in biological systems is seriously restricted. To overcome this limitation, a number of leadfree ferroelectric materials with a perovskite structure have been developed. [25] In particular, BaTiO 3 features an improved biocompatibility, good electromechanical coupling, [26] and has been proven to be a promising candidate for a variety of biomedical applications. [27] Structural analysis reveals that BaTiO 3 is a noncentrosym metric tetragonal crystal and when subjected to an external mechanical stress, the BaTiO 3 crystal exhibits a strong electrical polarity due to the shift of Ti 4+ within the tetragonal unit cell; as seen in Figure 2a. In addition to BaTiO 3 , other leadfree ferro electric ceramics with the perovskite structure have been devel oped, including BiFeO 3 , LiNbO 3 , KNN, alkali niobate (K, Na, Li) NbO 3, and alkaline bismuth titanate (K, Na) 0.5 Bi 0.5 TiO 3 . [25,28] A second common piezoelectric crystal structure is wurtzite that belongs to a hexagonal crystal system with a tetrahe dral coordination ABtype composition. In this type of crystal structure, the A atoms are in hexagonal closepacked arrange ment with B atoms occupying the tetrahedral void. Many non ferroelectric biopiezoelectric materials possess the wurtzite crystal structure, such as ZnO, AlN, GaN, InN, CdS, and CdSe. [29] Since their polarization direction cannot be changed by a poling field, these materials are used in single crystal or highly textured form along specific crystallographic directions. In the ZnO crystal structure, the Zn 2+ and O 2− are stacked layer by layer along the caxis with their anion and cationic charge centers coinciding with each other. [2] When subjected to an external force, the positive and negative charge centers separate from each other to generate a piezoelectric potential, as shown in Figure 2b. In addition, ZnO also exhibits a high electron mobility, good transparency, and strong photoelectric properties. When combined with its piezoelectric properties, ZnO can be used in a variety of optical imaging systems, [30] energy collection devices, [31] or piezoelectric sensors. [32] More over, the excellent biocompatibility of ZnO makes it attractive candidate in biological imaging probes and tissue engineering scaffolds. [30,33] Similarly, wurtzitebased AlN is another popular biopiezoelectric material for biomedical applications due to its low toxicity. The wide bandgap and strong electromechanical coupling capability of AlN also allow it to be widely applied in sensors and resonator devices. [3,34] Despite their outstanding piezoelectric properties, most biopiezoelectric ceramics suffer from some inherent shortcom ings, such as the need for high temperature processing, high rigidity, and brittleness. As a result, biopiezoelectric ceramics exhibit a poor mechanical tolerance to defects and externally applied strains. Most biopiezoelectric sensors and transducers, such as wearable biosensors or implantable devices, often place high demands on the flexibility of the materials. As a result, the low fracture toughness of biopiezoelectric ceramic materials makes them susceptible to fracture when subject to mechanical loads or flexure, which restricts their biomedical applications.
In order to counteract this deficiency, biopiezoelectric ceramics have been assembled into ultrathin films to reduce the defect size and improve mechanical flexibility. [35]

Bio-Piezoelectric Polymers
Due to their asymmetrical molecular structure and orientation, some flexible polymers exhibit ferroelectricity and piezoelec tricity by stretching, which results in an electrical polarization via molecular dipole reorientation in the bulk polymer. [3,36] Biopiezoelectric polymers are attractive biopiezoelectric mate rials due to their excellent mechanical flexibility, light weight nature, low dielectric constant, and ease of processing at low temperatures. [37] The electromechanical coupling efficiency and optical transparency of the biopiezoelectric polymers can be finely tailored through the processing parameters. [18a] More importantly, most biopiezoelectric polymers are biocompatible with minimal toxicity, [38] and biopiezoelectric polymers such as polyβhydroxybutyrate and poly3hydroxybutyrate3hydroxy valerate are even biodegradable in the human body. These advantages make biopiezoelectric polymers promising can didates for the creation of miniature, implantable and flexible electronic devices. In recent years, the development of func tional bioimplants in sensing and actuation has stimulated a demand for biopiezoelectric polymer materials. [1] PVDF is one of the most common biopiezoelectric polymers composed of CH 2 CF 2  monomers. Its molecular dipoles are generated from the difference in electronegativity between hydrogen and fluorine atoms. [37] In general, PVDF exhibits five forms of crystalline phase (α, β, γ, δ, ε), among which the α and β phases are the most common, as shown in Figure 2c. [3,39] The αphase of PVDF consists of dipoles in a reverse parallel order, thereby showing little piezoelectricity. In contrast, the dipoles in the βphase are arranged in parallel, providing a high dipole moment per unit cell and superior piezoelectric properties. [40] To further improve the performance of PVDF material, a variety of PVDF copolymers have been developed, such as polyvinylidene fluoride trifluoro ethylene [P(VDFTrFE)], see Figure 2c. [41] Compared with PVDF, the P(VDFTrFE) copolymer exhibits superior crystallinity, higher flexibility, higher residual polarization and electromechanical coupling factor, making it more applicable for flexible biosensors or tissue engineering scaffolds. [10,42] Moreover, the high strength of the CF bonds allows the P(VDFTrFE) copolymer to stabilize and preserve its piezoelectricity when exposed to biological environments, or elec tromagnetic radiation in the form of ultraviolet light and gamma rays, that is often used for sterilization. [10] In addition to PVDF and its copolymers, the piezoelectric effect has been found in other polymers, such as polyllactic acid, [43] polyacrylonitrile, [44] polyβhydroxybutyrate, [45] poly vinyl chloride, [46] and oddnumbered nylon (e.g., nylon11). [47] If we consider nylon11 as an example, the arrangement of polyamide molecules in adjacent nylon11 chains during crys tallization results in multiplehydrogen bonding and dipole orientation. In this regard, nylon11 exhibits a high melting point and comparable piezoelectricity to PVDF. [48] Furthermore, as a typical biopiezoelectric polymer, nylon11 exhibits excellent mechanical flexibility, good fatigue resistance, and piezoelectric performance without the need for polarization using high electric fields. [49] These advantages make nylon11 based biopiezoelectric polymers attractive candidates as piezoelectric fibers for electronic textiles and biopiezoelectric platforms.
It is worth noting that most biopiezoelectric polymers usu ally exhibit relatively low piezoelectric charge coefficients (d ij ) compared to the inorganic biopiezoelectric materials described above, leading to lower levels of charge generation. [50] To improve piezoelectric performance, biopiezoelectric polymers have been integrated with inorganic biopiezoelectric materials to con struct biopiezoelectric composites. Compared with individual piezoelectric components, biopiezoelectric composites can overcome the temperature limitation of biopiezoelectric poly mers and the inherent brittleness of inorganic biopiezoelectric materials while providing ease of manufacturing for largearea applications. [51] For example, biopiezoelectric poly mers have been successfully combined with biopiezoelectric ceramics, achieving synergistically enhanced piezoelectricity, biocompatibility, and mechanical flexibility. [51,52] Therefore, biopiezoelectric composites provide a compelling alterna tive to conventional piezoelectric materials for biomedical applications. [53]

Biomolecular Piezoelectric Materials
The piezoelectric effect is also found in many biomolecules (e.g., amino acids, peptides, and proteins) and biological tissues (bones, ligaments, tendons, skins, and hairs), [12b] collectively termed biomolecular piezoelectric materials. These materials are attractive for the biomedical field as a result of their high biocompatibility, stable piezoelectric coefficients, and dielectric properties. [12b,54] When subjected to mechanical stimuli, biomo lecular piezoelectric materials generate surface charge polari zation or electric field, both of which have been demonstrated with appropriate physiological functions, such as tissue growth, wound healing, and regeneration. [55] As a basic unit of biomolecules, amino acids are composed of carboxyl group (COOH), amino group (NH 2 ) and variable side chains, all of which are attached to a central carbon atom. The difference between various amino acids depends on the structure of their side chains. Taking glycine as an example, under different crystallization conditions, glycine forms three kinds of crystal structures, namely α, β, and γ ( Figure 2d). [56] The αglycine crystal exhibits crystallographic symmetry and therefore lacks piezoelectricity, while both the βglycine and γglycine have noncentrosymmetric crystal structures and exhibit ferroelectric properties. [12b,57] Recent studies reveal that the piezoelectric charge coefficient of βglycine, a measure of the charge per unit force or strain per unit electric field, can reach approximately 10 pm V −1 , which is comparable to traditional organic piezoelectric materials. [12b,57b] With amino acids as the basic unit, peptides and proteins are constructed with a variety of structures and functions. The amino acid sequence and spatial configuration ultimately determine the biological function of peptides and proteins, thus providing structuredependent piezoelectric properties. [12b] For example, diphenylalanine is a dipeptide composed of two phenylalanine, which can further selfassemble into nanostructures, such as nanotubes and hydrogels. [58] The self assembled diphenylalanine nanotube, with its noncentrosym metric hexagonal structure, exhibits piezoelectricity; this can be seen in Figure 2e. [59] Likewise, piezoelectricity is also found in proteins, especially in collagen, due to their asymmetric spatial structures. Collagen is a triple helix structure formed by three twisted polypeptide chains, with abundant polar and charged groups in the backbone, see Figure 2f. [60] When subjected to an external mechanical stress, the dipole moments of these amino acid residues in collagen reorient along the longitudinal direc tion, thereby leading to a change in polarization and a piezo electric response. [12b,60b,61] In addition to abovementioned biomolecules, specific biological tissues, such as ligaments and tendons, also exhibit the piezoelectric effect due to the presence of piezoelectric protein molecules. Likewise, the piezoelectric effect has been found in some plant tissues. [62] For example, lignocellulosic molecules, which are present in many plants also exhibit a piezoelectric response, which is the origin of the piezoelectric effect in wood. [63] In this regard, nanoscale cellulose molecules can be used to manufacture lightweight films and nanoscale paper, which have potential to be a future biopiezoelectric material for biosensors, actuators, and other biocompatible devices. [64]

Bio-Piezoelectric Nanomaterials
Advances in nanotechnology have opened new paradigms for the development of biopiezoelectric nanomaterials. In general, biopiezoelectric nanomaterials provide merits for biomedical applications in comparison to their bulk counterparts. The ultrasmall size of biopiezoelectric nanomaterials allows them to efficiently traverse a variety of physiological barriers, such as blood vessels or cell membranes. Moreover, for piezocatalysis based biomedical applications, piezoelectric nanocatalysts often exhibit superior catalytic efficiency over bulk catalysts, since their smaller dimensions provides them with enhanced electron transfer rate and stronger interactions with any sub strate. In addition, the high surface area of biopiezoelectric nanomaterials enables them to serve as multifunctional drug nanocarriers for drug delivery and disease therapy. Therefore, biopiezoelectric nanomaterials with both piezoelectric proper ties and nanosize effects exhibit significant potential for a wide range of biomedical applications. In general, according to their dimension (D), biopiezoelectric nanomaterials can be divided into three groups: 0D, 1D and 2D.
0D biopiezoelectric nanomaterials generally refer to nano particles, nanoclusters, and quantum dots. [21,65] The charac teristics of 0D biopiezoelectric nanomaterials include large surface area, excellent piezoelectric properties and being intrin sically single domain. [66] Moreover, some 0D biopiezoelectric nanomaterials, such as BaTiO 3 nanoparticles, [27c] exhibit a high biocompatibility and fast metabolic rates to meet the critical requirements of the biomedical field. [26] In addition, 0D biopiezoelectric nanomaterials can integrate with other biopiezoelectric materials, such as polymer films, to achieve improved piezoelectric properties. The advantages of 0D biopiezoelectric nanomaterials allow them to be employed in a number of versatile biomedical applications, such as bioca talysis [67] and disease treatment. [27a,c] 1D biopiezoelectric nanomaterials are often used in the form of nanowires, nanobelts, nanotubes, nanorods, and nanofibers. Compared with 0D biopiezoelectric nanomaterials, 1D bio piezoelectric nanomaterials exhibit a higher charge transfer efficiency due to their wirelike morphology. [68] In addition, they can overcome the shortcomings of agglomeration that exists for many 0D biopiezoelectric nanomaterials. [32,69] As a result, 1D biopiezoelectric nanomaterials exhibit good processability, exceptional piezoelectric effects, high sensitivity, and good flex ibility. Many 1D biopiezoelectric nanomaterials, such as PVDF [32] and ZnO nanowires, have been successfully used as electro mechanical conversion components in piezoelectric biosensing or energy harvesting devices. [70] If we consider PVDF nanowires as an example, their excellent mechanical flexibility enables them to withstand a high degree of strain and achieve a long operational lifetime. [32] In particular, 1D biopiezoelectric nano materials can be easily integrated into piezoelectric nanowire arrays to achieve enhanced piezoelectric performance. It is worth highlighting that most 1D biopiezoelectric nanomate rials possess good biocompatibility, allowing them to be widely used in biosensors, [3] smart textiles, [20] and electronic skins. [22] When thinned down to a nanometer thickness to create a 2D geometry, piezoelectric materials and even conventional non piezoelectric materials, can lose their centrosymmetry in one direction and exhibit an enhanced level of piezoelectricity. [66,71] The obtained 2D biopiezoelectric nanomaterials are planar structures with versatile morphology; this includes 2D forms such as nanoplatelets, nanoplates, nanosheets, or nanoflowers. Representative 2D biopiezoelectric nanomaterials include black phosphorus, [72] boron nitride, [73] carbon nitride, [74] mono layer transition metal dichalcogenide. [75] As a typical inplane biopiezoelectric material, a monolayer MoS 2 is constructed from a Mo plane that is sandwiched between two S planes, thereby forming a triangular prism structure with Mo atoms in the center, as seen in Figure 2g. [75,76] When subjected to an external stress, the Mo 4+ and S 2− are displaced to produce an electric dipole and polarization charges on the surface of the material, thereby providing the material with piezoelectricity. [77] In addition, MoS 2 nanosheets have been extensively studied in biomedicine as a result of its photosensitivity, thermo sensitive properties, good redox activity, and extraordinary biocompatibility. [78] All the above properties endow MoS 2 nanosheets with significant potential in biosensing and bioelec tronic applications. [77,79]

Synthesis and Modification Strategies
To perform targeted biomedical functions, biopiezoelectric materials are usually manufactured into two types of platforms, namely thin films and nanoplatforms. Biopiezoelectric films with high flexibility can be applied to skin, muscle, and other tissue surfaces for biosensing or disease treatment. More importantly, the large surface area of a biopiezoelectric film provides abundant bonding sites for electronic devices (e.g., capacitors, inductors, and resistors) that allows the develop ment of miniaturized or portable biomedical devices. The main synthetic methods of forming biopiezoelectric films include magnetron sputtering, pulsed laser deposition, and solution casting. Biopiezoelectric nanoplatforms exhibit many unique advantages, [77] such as extremely small size, high biocompat ibility, large specific surface area, and excellent piezoelectric performance, which greatly expand their application prospects in biomedicine. With the increase of research effort on the synthesis and modification methods, biopiezoelectric nano platforms for the field of biomedicine have become a topic of intense research interest. [2] To prepare biopiezoelectric nano platforms, versatile strategies have been developed in recent years, including mechanical exfoliation, chemical exfoliation, vapor phase deposition, hydrothermal, and solgel method.

Bio-Piezoelectric Thin Films
With the emergence of microelectricmechanical systems in biomedicine applications, biopiezoelectric thin films have become an ideal platform for the efficient integration of multiple components at small scales. Biopiezoelectric thin films exhibit good mechanical flexibility, easy production, low cost, and high stability. [80] Moreover, biopiezoelectric thin films can be readily combined with semiconductor materials, thus realizing a sensitive response to micromechanical pressures. [17,80] To date, a range of approaches such as magnetron sputtering, pulsed laser deposition, and solution casting have been investigated to prepare highquality biopiezoelectric thin films.
Magnetron sputtering is a relatively mature method for thin film preparation, which can be used to prepare films of various substrates including metals, semiconductors, ceramics, and polymers. [81] It possesses the merits of fast film formation, high film density, and good film formation consistency. [81a] During magnetron sputtering, electrons are accelerated by an electric field between a target and substrate, and are simultaneously bound by a magnetic field. As a result, electrons are able to collide with gas molecules, thereby increasing the ionization rate of plasma. [82] Under the action of a highvoltage electric field, the plasma collides with the target to release target atoms, which subsequently travel to the substrate and form a thin film, as seen in Figure 3a. [25c,81] Magnetron sputtering can produce thin films with tailored piezoelectricity and conductivity via controlling deposition conditions, such as gas flow rate, substrate temperature, deposition rate, sputtering gas pressure, and annealing conditions. Using polyethylene terephthalate (PET) as a substrate, Costa et al. deposited a series of ZnO biopiezoelectric thin films through varying the oxygen flux during a direct current magnetron sputtering process. [82a] The obtained ZnO thin film was well adhered to the PET substrate with a uniform film structure and good mechanical strength. At the same time, the surface deposition of ZnO thin film increased the surface energy and hydrophobicity of the PET substrate surface. As a result, the ZnO thin film prepared under an oxygen flux possessed a high piezoelectric coefficient and good adhesion to the substrate. [82a] Pulsed laser deposition (PLD) is another method to produce biopiezoelectric thin films at low temperature with a clean interface. Highenergy laser pulses are focused on the target surface in an ultrahigh vacuum system. The target materials are then rapidly vaporized and deposited on the substrate as a thin film, as seen in Figure 3b. [25c,d,83] The use of noncontact laser heating effectively avoids sample contamination to provide films of high quality. In this regard, PLD technology has been widely utilized for preparing biomedical microdevices. [83] Scarisoreanu et al. used the PLD method to grow highquality leadfree biopiezoelectric thin films of (1x)Ba(Ti 0.8 Zr 0.2 )TiO 3 x(Ba 0.7 Ca 0.3 )TiO 3 , x = 0.45 (BCZT 45) on a Pt/Si substrate, and then deposit it on a Kapton polyimide polymer substrate. [84] The obtained film not only exhibited high piezoelectric per formance, but it also demonstrated excellent biocompatibility and flexibility due to the use of compliant Kapton substrates. In vitro studies revealed that BCZT 45 coatings on a Kapton polymer substrates can promote the adhesion and osteogenic differentiation of stem cells, demonstrating their application prospects for bone repair. Nevertheless, the need for relatively expensive equipment and the complicated nature of the PLD process can restrict its largescale application.
Solution casting is a simple and commonly used process for thin film preparation. In this process, a powder sample is combined with a suitable dispersant to form a uniformly dis persed slurry, and a thin film is prepared on a casting machine ( Figure 3c). [85] Due to the simplicity of the equipment and an ability to achieve a continuous and automated operation with a high production yield, the solution casting method has been widely employed for the preparation of biopiezoelectric films. Hosseini et al. synthesized a freestanding biopiezoelectric film from glycine and chitosan via the solution casting process. [86] For this film, βglycine crystals were crystallographically oriented within a chitosan matrix, providing the film with high biocompatibility and flexibility, which can be processed into biopiezoelectric pressure sensors for wearable devices.
As a whole, biopiezoelectric thin films as biomedical platforms present unique advantages, including high mechanical flexibility, lightweight nature, and excellent sensitivity to surface micro pressure. However, the 2D nature of micrometer thinfilms limits their broader biomedical applications, especially for those that require 3D structures (e.g., scaffolds). Moreover, the small micrometer sizes restrict their biomedical performance, such as the inability to induce or stimulate cells at the nanoscale.

Bio-Piezoelectric Nanoplatforms
Despite the great potential of biopiezoelectric nanoplatforms in biomedicine, it remains a significant challenge to prepare high quality biopiezoelectric nanoplatforms with welldefined morphologies (e.g., nanoparticles, nanofibers, nanowires, and nanoplatelet) and controlled crystalline phases (e.g., cubic, quadrangle, and polyphase). A variety of methods have been developed to fabricate highquality biopiezoelectric nano platforms, such as solvothermal, hydrothermal, electrostatic spinning, and mechanical exfoliation.
Solvothermal and hydrothermal synthesis are efficient methods for the controlled synthesis of biopiezoelectric nanoplatforms with a variety of morphologies. During their preparation, chemical reactions are undertaken in a sealed autoclave at high temperature, thereby producing high quality nano crystals via onepot reactions, as shown in Figure 3d. [87] Wang et al. prepared ferroelectric tetragonal BaTiO 3 nano particles with an average size of 130 nm through hydrothermal reactions between Ti(C 4 H 9 O) 4 and Ba(OH) 2 .
[27c] The BaTiO 3 nano particles provided high piezoelectric activity for the generation of radicals (·OH or ·O 2 − ) during the application of ultrasonic vibrations to facilitate the cleaning of teeth. The hydro thermal method with its simple operation, low cost, low reaction temperature, and wide applicability for producing various mor phologies, sizes, and dimensions can also produce hierarchical nanostructures with specific geometry. [87] Ha et al. reported on the formation of ZnO nanowiredecorated polydimethylsiloxane micropillar arrays via a hydrothermal process, where the ZnO nanowires were grown on polydimethylsiloxane micropillars with a high aspect ratio and precisely controlled dimensions. [88] The obtained ZnO nanowire array demonstrated a high degree of bending, ultrafast response, and low thermal expansion, and could be fabricated as a flexible electronic skin.
Electrostatic spinning is a common method for nanofiber preparation. [1] In brief, the polymer solution is continuously sprayed from a jet, and stretched under a high electric field to form electrospinning nanofibers on a receiving device, as shown in Figure 3e. [89] The formed fiber membranes exhibit good elasticity and high tolerance to applied strains. [1] Specifi cally, the use of a high electric field promotes material polariza tion during the spinning process, providing the nanofibers with excellent piezoelectric properties. [18a] Bairagi and Ali developed KNN/ZnO incorporated PVDF nanocomposites via electrospin ning. [90] During the electrospinning process, the PVDF polymer underwent mechanical stretching and in situ poling, which transformed the nonpolar αphase into a highly polar βphase to enhance its piezoelectric properties. Biopiezoelectric nanofiber networks can be prepared with a similar morphology to natural tissue by regulating the composition of the precursor solution and electrospinning parameters, such as flow rate, voltage, concentration, and the distance between needle tip and receiver. For example, Jacob et al. prepared biopiezoelectric nanofiber scaffolds from poly3hydroxybutyrate3hydroxy valerate and BaTiO 3 nanoparticles, where both the morphology and pore size were similar to natural cartilage by optimizing the spinning parameters. [91] The addition of BaTiO 3 nano particles not only enhanced the mechanical properties and piezo electric coefficients of the poly3hydroxybutyrate3hydroxy valerate, but also prolonged its degradation time. Accordingly, the obtained scaffolds exhibited excellent mechanical proper ties and piezoelectric coefficients, which were comparable to natural cartilage.
Monolayer nanomaterials can be exfoliated from their bulk counterparts under certain mechanical forces, which breaks the weak van der Waals' force between layers. This method is termed mechanical exfoliation, and is also known as the "Scotch tape method." [77] As a physical separation process, the exfoliation process is simple and rapid for the preparation of biopiezoelectric nanomaterials. However, mechanical exfo liation also possesses several inherent shortcomings, such as inhomogeneity of products, low efficiency of the stripping operation, and poor control of nanomaterial morphology. Recently, liquid exfoliation has been developed as an exten sion of mechanical exfoliation. In this case, the weak van der Waals interactions between adjacent layers of bulk crystals are broken by ultrasonic treatment in an appropriate solvent or surfactant, see Figure 3f. [77,92] The solvent molecules can pre vent the restacking and aggregation of the lamellar products by forming a protecting layer on their surface. [93] For example, Wu et al. exfoliated monolayer MoS 2 nanosheets from a bulk MoS 2 powder in Nmethyl2pyrrolidone by ultrasonicassisted liquidphase exfoliated method. [94] Our group has prepared free standing black phosphorus nanosheets via liquid exfoliation of black phosphorus crystals in Nmethyl2pyrrolidone solvent. [95]

Modification and Engineering Methods
To meet the critical requirements of biomedical applications, ideal biopiezoelectric platforms should possess not only excel lent piezoelectric performance, but they should also exhibit suitable surface properties that are tailored to their applica tion; these can include hydrophilicity, roughness, and porosity. Moreover, biopiezoelectric platforms are expected to be bio compatible and biodegradable to ensure biosafety and should exhibit sufficient mechanical properties to provide longterm flexibly and durability. However, many piezoelectric materials cannot fulfill all of the abovementioned requirements. In this regard, surface modification and engineering of piezoelectric materials have become particularly important to achieve the desired biomedical performance and combination of proper ties. (Figure 3g).
To improve piezoelectric properties of biopiezoelectric polymers, the integration of nanofillers such as BaTiO 3 , ZnO, metal nanoparticles, graphene oxide, and carbon nano tubes into a polymer matrix has been demonstrated to be an effective method. [20] For example, the addition of nanofillers into PVDF generates an electrostatic interaction with the surrounding PVDF chains and influences the chain orienta tions, thereby improving the overall piezoelectric response of the composites. [18a,41] Similarly, Deng et al. improved the piezoelectric performance of PVDF film by wrapping ZnO nanospheres into PVDF electrospinning nanofibers. [96] The ZnO nanospheres not only enhanced the local electric field during the electrospinning process to increase the fraction of βphase PVDF crystals, but also provided a synergistic effect with PVDF nanofibers to promote the piezoelectric performance of the composites. In addition, the piezoelectric properties of the composites could be readily controlled by adjusting the weight ratio between the ZnO nanospheres and PVDF polymer. To improve piezoelectric performance of inorganic biopiezoelectric materials, the crystal grain size can be tuned to adjust the piezoelectric properties. For example, BaTiO 3 ceramics possess good piezoelectric performance (maximum value of 519 pC N -1 ) and high dielectric constant (maximum of 6079) when their grain size is ≈1 µm. [97] Moreover, the piezoelectric properties of biopiezoelectric nanomaterials can be adjusted by altering their morphology since surface area changes the long and shortrange ordering of dipoles. [98] Shirazi et al. improved the piezoelectric coefficient of BaTiO 3 nanofibers by decreasing the fiber diam eter. [98] In addition, since the mechanical properties are highly related to geometry, [99] the creation of welldefined and optimized morphologies can have a positive effect on overall piezoelectric response. For example, Zhang et al. prepared a piezoelectric energy generator based on PZT microcubes and P(VDFTrFE) by a solution casting method. [100] Since the cubeshaped particles possessed pronounced stress concentrators at the particle corners and edges, they exhibited superior piezoelectric activity compared to a generator based on spherical PZT particles.
Chemical vapor deposition (CVD) is a conventional method to prepare biopiezoelectric nanomaterials with high purity, good crystallinity, facile controllability, and tunable thickness. Based on these merits, CVD has been widely employed to synthesize monolayer transition metal dichalcogenide, [66,101] such as MoS 2 monolayers. [102] However, a large number of intrinsic point defects, such as sulfur (S) vacancies, can be formed during the CVD process, which limits the piezoelectric properties of a monolayer transition metal dichalcogenide. To overcome this shortcoming, Han et al. prepared a Svacancy passivated MoS 2 nanosheet based on CVD growth through a S treatment. [102c] Since S vacancies on the MoS 2 surface tend to covalently bond with the S functional group, the S atom can form a chemical bond with the S vacancy by capturing free electron, thus passivating the S vacancy. Compared with untreated MoS 2 , the S vacancy passivated MoS 2 nanosheets present significantly enhanced piezoelectric performance, which is considered to be a potential power source for wearable electronic devices.
The surface structure of biopiezoelectric materials is a crucial parameter for biomedical applications. For instance, in tissue regeneration, the wettability of the material surface can regulate cell adhesion and cell spreading. The presence of a suitable level of porosity supports blood circulation and the movement of biologically active substances. The surface roughness of the material can also promote cell adhesion, proliferation, and differentiation. [103] For example, Qian et al. prepared a ZnOloaded polycaprolactone (PCL) piezoelectric nano generator scaffold by 3D injectable multilayer biofabri cation technology. [104] The distribution of ZnO nanoparticles increased the surface roughness of the scaffold and induced a polarization of its surface, which was beneficial to both cell adhesion and proliferation. The high hydrophobicity of the piezoelectric PVDF polymer hinders cell attachment and expansion, thereby limiting its application in the field of tissue engineering. Kitsara et al. prepared PVDF nanofiber scaffolds with a superhydrophilic surface through a plasma treatment, which stimulated the adhesion and diffusion of osteoblasts without the need for an external power supply. [105] Post treatment with an oxygen plasma altered the surface chemical composition of the PVDF scaffold, which led to longterm and stable hydrophilicity.
Biocompatibility and biosafety are the primary factors that determine the successful application of a biopiezoelectric material in biomedicine. As an example, PZT possesses a high piezoelectric charge constant and excellent electromechanical properties, making it attractive for constructing biological microelectronic devices. [100,106] However, the toxicity of PZT as a result of the presence of lead (Pb) reduces its biocompatibility when used in conjunction with living cells. Therefore, effort has been devoted to improving the biocompatibility of PZT via surface modification and engineering. The use of coatings to provide biocompatible layers is currently a widely employed strategy to improve the biocompatibility and biosafety of PZT. [107] Sakai et al. treated the PZT surface with titanium to enhance its biocompatibility. [108] Recently, Kim et al. encapsu lated Mn doped (1x)Pb(Mg 1/3 Nb 2/3 )O 3 (x)Pb(Zr,Ti)O 3 film with biocompatible passivation epoxy to minimize the overall cyto toxicity and inflammatory reactions. [109] In contrast, developing new piezoelectric materials with both high piezoelectric activity and biocompatibility is another effective strategy to overcome the toxicity issue of PZT. For example, Yuan et al. [15a] devel oped a biocompatible piezoelectric nanogenerator using (1x) Ba(Zr 0.2 Ti 0.8 )O 3 x(Ba 0.7 Ca 0.3 )TiO 3 (BZTBCT) nanowires. BZT BCT was measured with a comparable piezoelectric coefficient (≈620 pC N 1 ) to that of many conventional PZTs (200-710 pC N 1 ), [15a,110] but with superior biocompatibility and biosafety.
Biodegradability is another important requirement for bio piezoelectric platforms. For biopiezoelectric filmbased implants, their degradation rates should be sufficiently slow to ensure stable and longterm performance. For biopiezoelectric nanoplatforms, their biodegradability and excretion are examined to avoid the accumulation of material in the body which can have a potentially adverse effect on tissues. To control material biodegradability, Huang et al. deposited an ultrathin atomic layer film of alumina to tune the degradation rate of electronic devices in water. [111] The biodegradation rate of the electronic device was linearly dependent on the thickness of the alumina coating layer, thus allowing precise control over the lifetime of implantable devices.

Biomedical Applications of Bio-Piezoelectric Platforms
The electromechanical conversion characteristics of biopiezoelec tric platforms enable them to convert external stimuli (ultrasonic waves, pressure, motion) into electrical energy, which not only overcomes the limitation of battery life but can efficiently sense any environmental changes for realtime biosensing. Moreover, biopiezoelectric platforms that use polarized materials with an internal electrical field can regulate a variety of physiological behav iors of cells, such as growth, migration, differentiation, and apop tosis, thereby exhibiting therapeutic effects on diseases. Overall, the biomedical applications of biopiezoelectric platforms can be divided into two major groups: biosensing and disease treatment.

Biosensing
The concept of a biosensor was first proposed by Professor Leland C. Clark Jr in 1962. [112] Over the past decade, biosensors have gone through rapid development with the trend of being miniature, wearable, portable, and appropriate for potential commercialization. [113] Conventional capacitor and inductorbased biosensors involve the detection of a change in dielectric properties according to the characteristic bonding of the electrode surface. [114] However, due to the need for an external power supply, the practical applications of such biosensors can be restricted by their large volume, low structural flexibility, short battery life, and poor biocompatibility. [115] Nevertheless, bio piezoelectric biosensors have attracted research interest because of their ease of operation, flexible structure, biocompatibility, low detection limit, high sensitivity, and accuracy. [3,115c,116] More importantly, these sensors are capable of noncontact sensing and selfpowered supply under certain conditions, which opens a new era for biosensors. [117]

Monitoring of Physical Health
To realize realtime health monitoring, traditional implantable medical electronics (IMEs) are driven by an external power supply (e.g., batteries) which often have a poor structural flexibility. [114] Batteries have to be surgically replaced when expired, leading to an increased infection risk to patients. [23c,114] Due to the development of biopiezoelectric materials, a variety of miniature and intelligent biopiezoelectric biosensors have been developed for detecting a variety of physiological signals. In contrast to traditional IMEs, biopiezoelectric biosensors are able to harvest mechanical energy from body motion and convert it into electricity to achieve selfpowered operation and a degree of autonomy, thus avoiding the problem of short battery life in traditional IMEs. [17,19] In addition, polymerbased piezo electric biosensors with extraordinary flexibility are responsive to small levels of deformation and forces, and are suitable to sensitively monitor physiological signals in the body. [118] Recently, wearable and attachable health monitoring plat forms have been proposed that are based on flexible electronic devices, as seen in Figure 4a. [119] This form of physiological signal monitoring platform is portable and easily attached to skin or tissues, thus circumventing the need for painful surgery for implantation. Chen et al. constructed a selfpowered biosensor based on a biopiezoelectric nanowire array with a vertical arrangement and a preferential polarization orienta tion for monitoring vital signs. [32] A voltage was applied to an electrode pair that was composed of a nanoporous aluminum oxide template and a conductive substrate coated with P(VDF TrFE) biopiezoelectric film. The electrical growth and polari zation of the P(VDFTrFE) nanowires were carried out in the nanopores. The confinement effect of the nanometer template promoted the alignment of polymer dipoles along the vertical direction of the nanowires, as shown in Figure 4b. The applica tion of external mechanical forces led to the nanowires to pro duce detectable piezoelectric signals. The biosensor exhibited a high sensitivity and flexibility, which was suitable for detecting subtle pressure changes from human activities, including human respiration and pulse rate; this is shown in Figure 4c,d. In addition, Liu et al. created a wearable selfpowered biosensor based on a flexible PVDF nanogenerator, which was used to monitor human respiration and healthcare in real time. [120] The PVDF membrane, prepared by electrospinning, was used as the biopiezoelectric layer because of its high piezoelectric voltage constant. During breathing, the flexible PVDF membrane on the wearable device was compressed or stretched to produce contin uous electrical signals for monitoring respiration in real time. Compared with organic biopiezoelectric materials, inorganic biopiezoelectric materials, such as BaTiO 3 and PZT, usually exhibit superior piezoelectric properties, [121] thereby producing a higher piezoelectric output for selfpowered biosensors. As a result, Park et al. designed a selfpowered flexible piezoelectric biosensor based on a PZT thin film for realtime arterial pulse monitoring, see Figure 4e. [122] The piezoelectric PZT thin film was transferred onto an ultrathin plastic substrate, and then conformally attached to a human wrist using a biocompatible liquid bandage spray. The biosensor exhibited high mechanical flexibility and could be stably deformed in response to blood vessel movements, and the generated electrical signals could be transmitted wirelessly to a smartphone for realtime monitoring of an arterial pulse. The biosensor showed not only an accurate piezoelectric response (Figure 4f), but also exhibited an excel lent mechanical stability after 5000 cycles (Figure 4g).
Wearable electronic textiles based on the piezoelectric effect have attracted attention due to their lightweight nature and high flexibility. Such textiles can also be used in selfpowered wireless sensors to monitor human health. [123] Unlike biosen sors driven by solar or thermal energy, wearable electronic textiles can harvest energy from human movement. [20] Since human activities often rely on mechanical motion, harvesting energy from body motion in daily activities is of significant interest for wearable electronic devices. [20] Zhu et al. devel oped a selfpowered and selffunctional sock for sensing and monitoring physiological signals such as gait and contact force, see Figure 4h. [124] The system incorporated a poly(3,4ethylen edioxythiophene) polystyrene sulfonate (PEDOT:PSS) coated fabric triboelectric nanogenerator and a PZT piezoelectric chip, as seen in Figure 4i. The sock transmitted the characteristic waveforms as the wearer walked, providing an easy approach to recognize walking patterns for healthcare applications, in particular for gait monitoring of patients with Parkinson's dis ease, as shown in Figure 4j. Mao et al. developed a selfpowered piezoelectricbiosensing textile based on tetrapodshaped ZnO (TZnO) nanowires for physiological monitoring of individual sports. [125] The TZnO nanowires were firmly anchored on the textiles using a PVDF binder to harvest the mechanical energy from motion and output electrical signals. These fabrics could be worn on different areas of the skin to monitor a variety of physiological states. Such piezoelectric biosensors are suitable for continuous monitoring and sensing, and ultimately stimu late the development of selfpowered wearable devices.

Disease Diagnosis
Biosensors integrating recognition and signal transduction have been widely used in the quantitative or semiquantitative analysis of biologically relevant analytes, see Figure 5a. [126] The biosensing process is generally based on changes at an interface after the combination, or reaction, between analytes and recog nition elements on the transducer surface. [127] In this strategy, www.advancedsciencenews.com

(11 of 28)
© 2021 The Authors. Advanced Materials published by Wiley-VCH GmbH oscillating piezoelectric resonators as signal transducers are coated with recognition molecules, such as antibodies or enzymes. The changes in the fundamental frequency of the piezoelectric resonators are recorded to provide quantitative or semiquantitative analysis of target molecules. [128] Currently, highquality quartz crystals are widely used as piezoelectric transducers, whereas their high cost and moderate sensitivity limit their application in piezoelectric sensors. [129] Su et al. developed a biosensor using a PZT ceramic resonator as a transducer in order to detect cancer biomarkers for the prelimi nary diagnosis of cancer, as shown in Figure 5b,c. [106] The pros tatespecific antigen (PSA) antibody or αfetoprotein antibody was modified on the surface of the resonator. The relative frequency of the resonator was changed by the antibodyantigen interaction, thereby realizing quantitative detection of PSA and αfetoprotein in serum. Compared with traditional quartz crystals, the ceramic resonator was more sensitive and cost effective, see Figure 5d, providing the possibility for creating sensor arrays for multiplex detection in the future.
In addition to cancer, piezoelectric biosensors have been also employed to detect biomarkers of many other diseases. Pohanka et al. developed a piezoelectric immunosensor for detection of inflammatory marker Creactive protein in blood, providing reference for distinguishing bacterial and viral infections. [130] Liu et al. constructed a biosensor based on a ZnO biopiezoelectric film for detecting a biomarker (cardiac troponin I, cTnI) of acute myocardial infarction, Figure 5e. [131] The formation of micronthick biopiezoelectric films allowed the resonator to operate at high frequency, up to several thou sand megahertz, thus achieving a detection limit as low as a single molecule.
Beyond biomarker detections, piezoelectric needle sensors have been developed to diagnose pathological tissues based on their mechanical heterogeneity and density, see Figure 5f. [132] When a piezoelectric needle is inserted into a tissue, the elec tric current signal is converted into an electrical signal by a piezoelectric sensor to directly examine pathological changes in tissue. Such a labelfree strategy simplifies the screening methods for the diagnosis of malignant thyroid nodules, solid tumors, and other diseases.
In most cases, disease diagnosis with biosensors usually involves painful and invasive sampling procedures, such as the drawing of blood or cerebrospinal fluid collection. As a result, a noninvasive and convenient method is preferable for disease diagnosis at the early stage or continuous testing. [133] Fu et al. developed a selfpowered breath analyzer based on a polyaniline/polyvinylidene fluoride (PANI/PVDF) piezoelectric gassensing array, see Figure 5g. [134] The PVDF film in the device converted the energy associated with exhalation into an electrical signal to achieve a selfpowered supply, and five PANI electrodes with different dopants were employed as the gas sensing material. Each sensing unit has a favorable selectivity to a particular gas marker, which leads to the change of the output electrical signals of the corresponding unit; as shown in Figure 5h. [135] The biosensor presented constant response/ recovery circles under different gas flow rates (Figure 5i). Such a piezoelectric biosensor possesses application prospects for the early diagnosis of a variety of diseases, such as airway inflam mation, asthma, liver cirrhosis, and diabetes.

Smart Devices and Bionic Prostheses
For smart devices and bionic prostheses, sensory feedback is highly dependent on the performance of the biosensor, which requires maximum simplification of information processing. The piezopotential of piezoelectric devices triggered by mechanical stimuli can be readily captured and analyzed, which can replace traditional sensing components. Chen et al. developed an artificial sensory synapse composed of a piezoelectric nano generator and an iongel gated transistor, see Figure 6a-c. [136] The piezoelectric properties of the piezoelectric nano generator enabled the synaptic device to be selfpowered; while the coupling effect of the piezoelectric potential converts strain information into a postsynaptic current to simulate synaptic functions. Thus, such piezotronic artificial synapses achieves selfpowered sensing and efficient signal processing of external stimuli.
Among the range of haptic feedback devices, electronic skins (eskins) have the advantages of high spatial resolution, ultrahigh sensitivity, ultrafast response speed, and excellent durability; these have therefore become a worldwide research focus. [22,137] Ha et al. proposed a bioinspired eskin composed of hierarchical ZnO nanowire arrays with an interlocked geo metry arrangement, as seen in Figure 6d. [88] The interlocked ZnO nanowires with piezoresistive (change in resistance with  [126] Copyright 2017, American Chemical Society. Schematic of b) ceramic resonator and c) dual ceramic resonators in biosensors. d) Frequency changes with PSA concentration. Reproduced with permission. [106] Copyright 2013, Elsevier. e) Biosensor for detection of cardiac biomarkers. Reproduced with permission. [131] Copyright 2020, Elsevier. f) Schematic of the piezoelectric needle sensor. Reproduced with permission. [132] Copyright 2019, Springer Nature. g) Fabrication process of the self-powered breath analyzer, and SEM images of PANI/PVDF interface. h) Response of five sensing units to 600 ppm gases, and i) relationship between responses and gas flow rates. Reproduced with permission. [134] Copyright 2018, Springer Nature. the stress) and piezoelectric sensing capabilities were respon sive to tactile stimuli due to ZnO nanowire bending and the change of internanowire contact area, see Figure 6e. The eskin could detect not only static stimuli, such as small vibrations and sound stimulation (Figure 6f), but it could also detect high frequency dynamic vibrations at up to 250 Hz, see Figure 6g. Wang et al. reported a flexible eskin biosensor based on a singleelectrode piezoelectric nanogenerator for simultaneous tactile and temperature sensing. [138] The piezoelectric nano generator was composed of an electrode array prepared by magnetron sputtering and an PVDF biopiezoelectric layer by electrospinning, see Figure 6h. The electrospinning biopiezoelectric PVDF nanofibers provide the biosensor with excellent flexibility and selfpowered capability for future appli cations as a bionic eskin.
In addition to tactile sensing, selfpowered wearable eskins for sensing taste have been developed. [139] A gustation (tasting) eskin was formed which was based on an enzymemodified ZnO nano wire array on a flexible substrate of patterned electrodes, which can operate in a liquid solution, and collect data directly in the biological environment, and acts in a similar way as a taste bud on the tongue. The coupling between the piezoelectricenzymatic reaction allows the eskin to harvest mechanical energy from the body for selfpowered sensing. Different enzymes on the hydrothermally synthesized ZnO nanowire array catalyze spe cific enzymatic reactions of tasteproducing substances, thereby generating piezoelectric signals for taste sensing.
In addition to tactile sensing, selfpowered wearable eskins for sensing taste have also been developed, see Figure 6i. [131] A gustation (tasting) eskin was formed which was based on an enzymemodified ZnO nanowire array on a flexible substrate of patterned electrodes, which can operate in a liquid solution, and collect data directly in the biological environment, and acts in a similar way as a taste bud on the tongue. The coupling between the piezoelectricenzymatic reaction allows the eskin to harvest mechanical energy of body for selfpowered sensing. Different enzymes on the hydrothermally synthesized ZnO nanowire array catalyze specific enzymatic reactions of tasteproducing substances (Figure 6j), thereby generating piezoelectric signals for taste sensing.

Disease Treatment
Bioelectricity is a cell communication and information trans portation mode generated from a variation in membrane poten tials across individual or fields of cells. It plays an important role in multiple biological processes, [140] including cell activity (e.g., migration, proliferation, differentiation, and intracellular communication), and tissue functions such as neural con duction and tissue reparation. [21] Moreover, a range of studies have indicated the significant potential of bioelectric therapy for a variety of diseases, such as cancer, tissue dysfunction, neuro degenerative disorders, and bacterial infection. Due to Figure 6. a) Biological sensory nerve system. Mechano-receptors in human skin receive mechanical stimulus and convert it into the presynaptic potentials. Presynaptic potentials are transmitted to central nervous system through neurons and synapses. b) Schematic of piezotronic graphene artificial sensory synapse and c) coupling effect of piezoelectric potential through an ion gel. Reproduced with permission. [136] Copyright 2019, Wiley-VCH. d) Schematic of piezoresistive e-skin device based on hierarchical ZnO nanowire arrays. e) Schematic of piezoelectric potential between the interlocked ZnO nanowires (state i). Applied pressure bends the bare ZnO nanowires and creates a piezoelectric potential (state ii). f) High-frequency vibration sensing capability of piezoelectric e-skins, and g) minimum detection capability of e-skins showing the detection of a small water droplet (0.58 Pa) on the e-skin. Reproduced with permission. [88] Copyright 2015, Wiley-VCH. h) Fabrication of single-electrode e-skin. Reproduced with permission. [138] Copyright 2018, American Chemical Society. their unique electromechanical conversion capabilities, bio piezoelectric materials have been demonstrated as an ideal platform for bioelectricity generation and bioelectric therapy.

Cancer Treatment
The anticancer activity of biopiezoelectric materials is predominantly mediated by the following three processes: piezoelectric stimulation, reactive oxygen species (ROS) genera tion, and controlled drug delivery.
In general, upon the application of an external stress, bio piezoelectric platforms generate piezoelectric potential that can interfere with ion channels and inhibit the proliferation of cancer cells. As a typical example, BaTiO 3 has attracted significant attention in cancer therapy due to its excellent piezoelectric properties and high biocompatibility. [141] Marino et al. fabricated an innovative biopiezoelectric nanoplatform based on BaTiO 3 nanoparticles for ultrasoundactivated anti cancer treatment. [27a] This work considered the overexpression of human epidermal growth factor type 2 receptor (HER2) in breast cancers, [142] where the biopiezoelectric BaTiO 3 nano particles were functionalized with an antiHER2 antibody to target breast cancer cells, see Figure 7a-e. Under ultrasonic stimulation, the BaTiO 3 nanoparticles generated a piezoelectric potential due to the acoustic stress [143] that inhibited the proliferation of cancer cells by interfering with K + channels and Ca 2+ homeostasis. [144] [146] Copyright 2020, American Chemical Society. i) Structure of hybrid nano-eels for drug delivery. j) Swimming behavior of the hybrid nano-eels. k) Bright field and fluorescent images of cancer cells with nano-eels in swimming model, and l) in drug release model. Reproduced with permission. [148] Copyright 2019, Wiley-VCH.
ROSbased cancer therapy has been demonstrated as a clean and safe therapeutic modality due to it being free of highly toxic chemotherapeutic drugs or ionizing radiation. Thus, significant effort has been devoted to ROSbased cancer therapy in recent years, such as photodynamic, chemodynamic, radiodynamic, and sonodynamic therapies. Piezoelectric materials as energy transducers convert mechanical energy into electricity, thereby facilitating the production of highly toxic ROS for tumor eradi cation. Among the various mechanical strains, ultrasound is the most widely used due to its ease of operation and appli cation, high tissue penetrating depth, and minimal tissue damage. In general, ultrasonic waves apply compressive/tensile stresses to piezoelectric materials and induce the generation of electric fields for the separation of free electrons and holes. The generated electrons and holes act as redoxactive sites to sub sequently react with H 2 O and O 2 in its surroundings to yield highly toxic ROS, such as hydroxyl radical (·OH) and singlet oxygen ( 1 O 2 ). [14,145] Therefore, piezoelectric sonosensitizers usually exhibit a high efficiency in terms of ROS production. Li et al. employed piezoelectric black phosphorus nanosheets as a new class of sensitizers for sonodynamic cancer therapy, see Figure 7fh. [146] Both in vitro and in vivo experiments demon strated that such a therapeutic strategy is effective in inhibiting tumor growth. Recently, Zhu et al. utilized H 2 O 2 to perform hydrophilic treatment of tetragonal BaTiO 3 nanoparticles and embedded them into an injectable hydrogel which catalyzes ROS generation under ultrasound stimulation, exhibiting a positive effect on killing tumor cells. [67b] The construction of a controlled drug delivery system has proven to an efficient way to improve drug bioavailability and minimize adverse effects. [147] Piezoelectric carriers can respond to mechanical motion and generate electric polarization, which changes the charge distribution on the carrier surface that can influence drug binding and release profiles. [148] Mushtaq et al. proposed multifunctional piezoelectric nanorobots for delivering anticancer drug doxorubicin (Dox) to cancer cells under the control of an external magnetic field, see Figure 7il. [148] A polypyrrole (Ppy) nanowire as the head of the nanorobot was decorated by nickel (Ni) rings for magnetic actuation, and a PVDFbased copolymer tail with spontaneous electric polari zation under strain was employed for drug loading. Under the manipulation of an alternating magnetic field, the magnetic head module (NiPpy) oscillated and induced an electric polari zation in the PVDF tail to release the Dox drug via electrostatic repulsion. Such a strategy avoids premature drug leakage from carriers, and accurately releases drugs at targeted locations on demand.

Tissue Regeneration
When subjected to mechanical stress as a result of body motion or cell migration, a piezoelectricbased scaffold can generate an electrical potential difference via the piezoelectric effect. In most cases, electrical stimulation can regulate voltage gated ion channels, such as calcium channels, to tune the intracellular ion level, thereby promoting cell proliferation and differentiation. [149] For example, an increased intracellular Ca 2+ concentration has been proven to activate calmodulin, calcineurin and calcineurin dephosphorylates nuclear factor, which further translocate into the nucleus to elevate the expres sion of growth factors, as shown in Figure 8a. In this regard, biopiezoelectric materials provide an effective platform for stimulating the regeneration of complex tissues, such as bone and cartilage. [149a,150] Recently, Fernandes et al. constructed a magnetoactive 3D porous scaffold for bone regeneration which was composed of a biopiezoelectric PVDF polymer and magnetostrictive CoFe 2 O 4 nanoparticles that strain with an applied magnetic field, see Figure 8b. [151] The negatively charged CoFe 2 O 4 NPs interact with the positively charged CH 2 groups of the biopiezoelectric PVDF, thereby inducing the nuclea tion of the electroactive βphase of the polymer and improving magnetoelectric coupling. [152] As a result of the magnetic properties of the CoFe 2 O 4 nanoparticles and the piezoelectric properties of the PVDF polymer, the scaffolds exhibited both magnetomechanical and magnetoelectrical effects, both of which synergistically promoted bone tissue reparation under the control of an applied magnetic field, see Figure 8c. In addi tion, the porous and hydrophilic scaffold structure was benefi cial to cell proliferation and penetration within the scaffolds.
Wound repair is also a research focus of tissue regenera tion. Current woundhealing therapies mostly involve a passive healing process, which focuses on reducing wound infection and increasing tissue rehydration at the wound site. [153] Com pared with passive treatment strategies, biopiezoelectric mate rials can transform motioninduced mechanical energy into internal electric field to actively accelerate wound healing. [21,154] Recent studies have disclosed the specific effects of electrical stimulation on wound healing within three intersecting stages: inflammation, proliferation, and remodeling. In the inflam mation stage, electrical stimulation can increase blood flow and tissue oxygenation supply to inhibit bacterial growth and minimize wound edema. In the proliferative phase, electrical stimulation accelerates wound contraction, fibroblast prolifera tion, angiogenesis, and collagen deposition. In the remodeling stage, electrical stimulation enhances maturation and remod eling of collagens, thereby accelerating wound contraction and increasing wound tensile strength, see Figure 8d. [154,155] There fore, biopiezoelectric materials as smart biomaterials generate bioelectric signals under mechanical stimulus to conduct wound repairing functions. [156] For example, Bhang et al. devel oped a hydrothermally synthesized ZnO nanorodbased piezo electric dermal patch for skin wound healing. A piezoelectric potential was generated on the piezoelectric dermal patch upon motiontriggered mechanical deformation, which subsequently induced an electric field to stimulate skin regeneration, see Figure 8eg. [153]

Neurotrauma and Neurodegenerative Treatment
A number of nervous system diseases (NSD), such as nerve trauma and neurodegenerative diseases, are a major cause of disability and mortality. [157] It has been reported that electrical stimulation upregulates brainderived neurotrophic factor (BDNF) and its highaffinity receptor tropomyosin receptor kinase B (TrkB) in neuronal cells. Via a calciumdependent mechanism, upregulated BDNF and TrkB increase the expression of regenerationassociated genes by upregulating cyclic adenosine monophosphate (cAMP) pathways, and ulti mately promote axon bursting and prevention of growth cone collapse, as shown in Figure 9a. [158] Therefore, biopiezoelectric materials are able to enhance nerve regeneration via generating electrical stimulation to injured nerves under a mechanical stimulus.
Stem cellbased therapy is a promising therapeutic modality and has been widely studied for NSD treatment. Liu et al. examined a biodegradable Spirulina platensis with Fe 3 O 4 and BaTiO 3 nanoparticles formed by electrostatic adsorption, pro viding a magnetically powered and piezoelectric nanoparticle loaded micromotor. [159] Under the control of a lowintensity rotating magnetic field, the micromotor was able to selectively target neural stem cells. Moreover, the piezoelectric properties of the BaTiO 3 nanoparticles converted ultrasonic energy into a form of electrical stimulation, and activated intracellular Ca 2+ channels and subsequent signaling cascades to induce neural stem cell differentiation, as shown in Figure 9b,c.
For peripheral nerve regeneration, nerve conduits provide mechanical support and electrical conductivity for the self reparation of defected peripheral nerves. In particular, the bio electrical conductivity of nerve conduits is a critical parameter affecting peripheral nerve viability, axon extension, and signal transmission. Since biopiezoelectric nanomaterials generate a piezoelectric potential during the application of an external mechanical load, piezoelectric strategies have been developed to provide an electrically conductive microenvironment to  [151] Copyright 2019, American Chemical Society. d) Effect of electrical stimulation on the three stages of wound healing. Reproduced with permission. [154] Copyright 2016, Wiley-VCH. e) Fabrication method of the ZnO nanorod-based piezoelectric dermal patch. f) The von Kossa staining exhibited the condensed calcium deposition (indicated by arrows) in keratinocyte cell membranes after 24 h treatment. g) Immunohistochemical staining of CD31-positivemicrovessels (green: CD31; blue: nucleus) (left) and SM α-actin positive arterioles (green: SM α-actin; blue: nucleus) (right) at the wound healing region 14 d post treatment. Reproduced with permission. [153] Copyright 2017, Wiley-VCH.
accelerate peripheral nerve reparation. Qian et al. created a bio piezoelectric ZnOloaded polycaprolactone (ZnO/PCL) com posite as a selfpowered nanogenerator scaffold for enhancing motor recovery and neural functions. [104] Under the action of an external ultrasonic stimulus, the biopiezoelectric ZnO/PCL scaffold showed proangiogenic and proneurogenic effects owing to the mechanoelectric stimulation of Schwann cells. Interest ingly, when rats implanted with the biopiezoelectric ZnO/PCL scaffold received running practice, their motor recovery was improved due to the creation of bioelectrical milieu for periph eral nerve regeneration; this is shown in Figure 9d-g.
Another therapeutic strategy for NSD is to construct implantable neuroprostheses, such as microelectrodes, which are capable of transmitting information to nerves in the form of electrons, photons, or ions. Implantable devices execute restoring or substituting functions for patients with neurolog ical deficits or disabilities. [160] Despite the promise of implant able neuroprostheses, significant challenges remain prior to  [104] Copyright 2020, Wiley-VCH. h) Schematic of key components of a device which utilizes lead-free piezoelectric composite as the core component, wavy-structure-based flexible electrodes as external contact, and a silicone elastomer as encapsulation. The device provides adjustable electrical outputs driven by ultrasound for electrical stimulation. i) Images of device to demonstrate mechanical properties. Reproduced with permission. [161] Copyright 2019, Wiley-VCH. © 2021 The Authors. Advanced Materials published by Wiley-VCH GmbH their successful clinical application. In particular, the longterm biointegration of the system requires the implant device to have a continuous power supply for stable functionality. Jiang et al. proposed a millimeterscale biopiezoelectric patch, which was capable of wirelessly selfpowering itself by converting ultrasonic energy into a piezoelectric potential for biological implants. [161] The biopiezoelectric patch generated tunable elec trical output under ultrasonic stimulation, which supplied suf ficient power for microdevices and strong current signals for retinal electrical stimulation; this is shown Figure 9h,i.

Antifouling Treatment
Fouling is a complex process in which material from the environment, such as macromolecules, microorganisms, or suspended particles, adhere to the surface reversibly or irrevers ibly. [162] Fouling can cause many health problems, such as bac terial growth, implant rejection, and biosensor insensitivity. [162] As a typical example, tooth stains are present in the majority of people, which negatively affects human daily life. To remove tooth stains, dentists currently employ strong oxidants, such as hydrogen peroxide, to bleach teeth and professional equip ment to polish teeth. However, these methods usually lead to serious side effects, such as tooth damage, gingival irritation, and acute pulpitis. [163] Wang et al. reported on a nondestruc tive, harmless, and convenient abrasive for teeth whitening based on hydrothermally synthesized biopiezoelectric BaTiO 3 nanoparticles. [27c] Under the ultrasonic vibration of an electric toothbrush, the polarized BaTiO 3 nanoparticles produced ROS (i.e., ·OH and ·O 2 − ) to whiten pigmented teeth with minimal damage to tooth enamel and surrounding cells, as shown in Figure 10ac.
Compared with tooth stains, biological fouling caused by bacteria is a more serious challenge. The adhesion of bacteria on a tissue surface eventually leads to biofilm formation. [164] The biofilm not only provides a microenvironment for micro organism proliferation and migration, but also protects them from ultraviolet rays and antibacterial agents, which aggravates bacterial resistance against treatment. [165] Feng et al. investi gated the antifouling properties of biopiezoelectric PVDF film from the respect of surface charge variation under mechanical stimuli. The PVDF film was resistant to bacterial adhesion and proliferation under appropriate frequency of mechanical stimuli, as shown in Figure 10d. [166] Overall, inorganic biopiezoelectric materials usually exhibit higher piezoelectric coefficients compared to biopiezoelectric polymers. [107] The performance of inorganic biopiezoelectric materials in disease treatments is related with their piezoelectric catalytic activity, which is highly dependent on particle size and crystal structure. In this regard, inorganic biopiezoelectric nanoplatforms with a nanoscale size and subjected to nanocon finement effects to improve activity have been used in biological applications such as drug transportation, cancer killing, tissue repair, and neuromodulation. However, few inorganic bio piezoelectric materials are reported with excellent dispersion stability and good biocompatibility, which make current avail able biopiezoelectric nanoplatforms relatively limited. Recent studies have revealed that some biocompatible piezoelectric bulk materials could be readily exfoliated into biopiezoelectric nanomaterials, which offers a new strategy to overcome this problem. [66,77] Furthermore, material modification and surface engineering can be employed to improve the performance of existing biopiezoelectric nanomaterials. In contrast to inor ganic piezoelectric materials, biopiezoelectric polymers provide good mechanical flexibility, high biological safety, an acoustic impedance similar to human tissue, and ease of processing; these characteristics make them attractive in the field of bio medical electronic devices. Nevertheless, biopiezoelectric poly mers commonly exhibit moderate piezoelectric properties. To overcome the shortcoming, biopiezoelectric composites, [26,167] which combine high piezoelectric performance of inorganic piezoelectric materials with flexibility of piezoelectric polymers, have been developed for biomedical applications, including health monitoring, disease diagnosis, and bionic/smart devices. Notably, micro and nanoscale multifunctional piezoelectric bio sensors have become the mainstream of bioelectronics. Such a miniatured biopiezoelectric device usually requires complex fabrication processes, which can limit its production at mass scale for commercialization. As a result, more effort should be paid to new multifunctional biopiezoelectric materials and costeffective fabrication technologies.

Summary and Outlook
As a functional biomedical material, biopiezoelectric plat forms can provide the merits of low cost, ease of preparation, and stable performance, and have become a research hotspot in the field of biomedicine. The electromechanical characteris tics of piezoelectric materials make it possible to transfer the strain from biological movements (such as muscle contraction, body movement, blood circulation, breathing, heartbeats, etc.) into electrical energy. Not only can it be used as an implantable medical device to achieve longterm and stable energy supply, but it can also be used as a realtime sensing device to monitor a variety of vital signs such as heart rate, breathing and blood pressure. Piezoelectric biosensors can also lead to the emer gence of advanced medical equipment, such as cardiac pace makers, cochlear implants, artificial retinas, neurostimulators, and electronic skins. While the applications of biopiezoelectric platforms have previously focused on bioelectronics, recent advances in biopiezoelectric nanomaterials have opened up new opportunities for creating biopiezoelectric platforms in biomedicine. Their nanoscale dimensions and ability for elec tromechanical conversion provide materials with piezoelectric catalytic activity to generate reactive oxygen species for cancer treatment and antifouling. Moreover, biopiezoelectric nano materials with high piezoelectric coefficients can efficiently respond to smallscale mechanical strains and thereby regulate biological systems. Their ability for electromechanical conver sion allows these fascinating materials to be used as a strong functional platform in a variety of biological applications, such as electronic skins, drug delivery, nerve stimulation, tissue regeneration, wound healing, and cancer treatment.
This review has described the structures and synthesis of biopiezoelectric materials, with an emphasis on their modi fication and design. We have also summarized the latest biomedical applications of biopiezoelectric materials, in terms of health monitoring, disease diagnosis, bionic/smart devices, cancer treatment, tissue regeneration, neurotrauma treatment and antifouling. These applications areas, materials, properties, and outcomes are summarized in detail in Table1.
Despite the significant application potential of piezoelectric materials in the field of biomedicine, a number of challenges in the development of biopiezoelectric platforms remain, as shown in Figure 11.
(1) Biopiezoelectric platforms should fulfill critical biomedical re quirements prior to their practical application. For applications in biosensing and implant devices, biopiezoelectric platforms are expected to possess high biocompatibility, excellent mechanical flexibility and high electromechanical conversion efficiency. For disease treatment with biopiezoelectric nano platforms, their biodegradability, immunogenicity and tissue accumulation must be also considered. Although significant effort has been paid to the development of biopiezoelectric materials, current available biopiezoelectric platforms are still limited in terms of the range of available materials and there is a need for research in the development of new piezoelectric and ferroelectric materials/composites and their surface modification. In this regard, the development of leadfree ferroelectric ceramics, polymers, and composites could be particularly important.
(2) Most studies on biopiezoelectric materials have a focus on exploring and improving material physical properties, such as morphology, transparency, flexibility, piezoelectricity, and mechanical strength. Limited attention has focused on their chemical properties as well as their synergy with piezoelec tricity. For example, many biopiezoelectric materials possess fascinating chemical properties in terms of photocatalysis and electrocatalysis, such as MoS 2 and black phosphorus. We believe more innovative biopiezoelectric platforms will emerge when material piezoelectricity is combined in synergy with their chemical properties.
(3) At present, the development of theoretical calculations and simulations (such as density functional theory, molecular dynamics, molecular structure mechanics) has greatly promoted the progress of theoretical research. Such approaches can inform materials design, which can greatly accelerate the investigation of biopiezoelectric materials. Of particular interest is the potential for the use of highthroughput (HT) [168] and machine learning methods [169] for materials discovery.
(4) Ultrasound is currently the main mechanical stimuli to induce material piezoelectricity. Nevertheless, a high dosage of ultrasound can lead to tissue damage as a result of ultra sonic cavitation effects. Therefore, it is desirable to develop additional biocompatible strategies to induce material piezo electricity. In addition, improving the piezoelectricity of exist ing biopiezoelectric platforms can also minimize the level of applied ultrasonic power to a biologically safe range.
(5) Biopiezoelectric materials offer an excellent avenue to induce multifunctionality in the bioactive platforms. For instance, pyroelectric materials as a subclass of biopiezoelectrics have also shown potential for the application in biomedicine, especially for cancer photothermal therapy. These materials possess an inherent polarization which changes as the mate rial is thermally excited, resulting in a change in the bound surface charge. This effect has been utilized to develop a pyroelectric dynamic therapy [170] that generates reactive oxygen species from pyroelectric nanomaterials during Reproduced with permission. [166] Copyright 2019, American Chemical Society.  thermal excitation by nearinfrared light. The reactive oxygen species attack the cancer cells and heat can shock proteins re sponsible for the thermotolerance of tumor cells resulting in an enhanced therapy efficacy. Since all pyroelectric materials and also piezoelectric, there is potential to use such materi als during a combined ultrasound and photothermal therapy.
(6) Many biopiezoelectric platforms which are based on electri cal stimulation to promote cell growth, differentiation and proliferation have been reported; however, the safe range of electrical signals has yet to be clearly defined. Studies have shown that an inappropriate electrical stimulation may have negative effect on cell growth and proliferation, and can even lead to cell death. [171] Therefore, the safety of piezoelectric stimulation to different cells and tissues should be thorough ly evaluated and carefully explored. In addition, piezoelectric stimulation is influenced by a variety of parameters, such as piezoelectric coefficient, material morphology, surface charge, duration of applied mechanical stress, and site of action. Based on these aspects, the electrical stimulation gen erated by piezoelectric materials is expected to be precisely controlled to achieve desired therapeutic effects.
(7) Clinical application is the ultimate goal of the biopiezoe lectric platforms. Although biopiezoelectric materials have achieved preliminary success in biomedical field, their long term toxicity, targeting ability, biosafety, and biodegradabil ity should be further assessed. To minimize the required dosage, the development of biopiezoelectric materials with high piezoelectric efficiency is highly desirable. Moreover, optimizing synthesis methods and developing new surface engineering technologies are of significance for promoting the clinical translation of biopiezoelectric platforms. While biopiezoelectric platforms are in their infancy stage, there continues to be plenty of scope and opportunities for research and development in this intriguing growing area.
With a broad interdisciplinary research effort in the pursuit of new biopiezoelectric materials and systems, it can be envi sioned that these new emerging platforms will achieve exciting biomedical applications in the future.