Degradable piezoelectric biomaterials for medical applications

2.1. Degradable piezoelectric small-molecule crystals

Many natural biological small-molecule crystals exhibit piezoelectricity due to the intrinsic lack of symmetry within their molecular structures. Amino acids are crucial to various physiological functions as the building blocks of proteins. Among the 20 natural amino acids, 17 display piezoelectric properties at ambient temperature.^[38] This piezoelectric effect in amino acids is attributed to stress-induced polarization, where dipole moments orient from the carboxyl group toward the amino group. Specifically, glycine and dl-alanine exhibit piezoelectric characteristics akin to those observed in quartz crystals.^[39]

Glycine primarily exists in 3 polycrystalline forms: α, β, and γ, each with distinct piezoelectric properties (Figure 2A).^[40] The α-glycine molecules are organized in an antiparallel conformation, neutralizing dipole moments and resulting in the absence of piezoelectricity. This form is classified within the P_21/c space group. In contrast, β-glycine and γ-glycine exhibit piezoelectric characteristics and are categorized under the P₂₁ and P₃₂ space groups, respectively.^[37] Notably, β-glycine possessed an exceptionally high shear piezoelectric coefficient d₁₆ with a predicted value of 195 pm V⁻¹ and a measured value of 178 pm V⁻¹.^[41] This pronounced effect was attributed to the supramolecular stacking of glycine molecules enhancing the alignment of electric dipoles along specific directions.^[38] Nonetheless, it is important to note that β-glycine is metastable, tending to spontaneously transition to the stable α and γ phases upon exposure to air.^[42] While shear piezoelectricity is a notable feature in piezoelectric biomaterials, the longitudinal piezoelectric coefficient generally has greater significance and practical applicability. γ-Glycine, with its helically oriented dipole along the axis, exhibited superior longitudinal piezoelectric coefficients d₃₃ of 9.93 pm V⁻¹, underscoring its potential utility.^[41] In addition, dl-alanine crystallizes in an orthorhombic symmetry to form a racemic mixture exhibiting significant piezoelectricity, with a d₃₃ (9.1 pm V⁻¹) comparable to γ-glycine (Figure 2B).^[43]

Peptides comprised of at least 2 amino acids connected via peptide bonds have captured significant interest due to their potent piezoelectricity and the variety of their self-assembly structures.^[44,45] FF peptide, in particular, is the most representative piezoelectric peptide (Figure 2C). FF monomers self-assemble into various micro-nanostructures, driven by intermolecular forces, including hydrogen bonds, electrostatic interactions, solvent-mediated forces, and π–π stacking.^[46,47] FF peptide nanotubes exhibited substantial shear piezoelectricity d₁₅ (60 ± 10 pm V⁻¹), but the d₃₃ of FF nanostructures ranged between 9.9 and 17.9 pm V⁻¹.^[34,36,48] The coassembly of macromolecular groups and FF peptides is an effective strategy to enhance piezoelectric properties. The designed tert-butyloxycarbonyl (Boc)-β,β-diphenyl-Ala-OH (Dip)-Dip showed exceptional d_33,eff (73.1 ± 13.1 pm V⁻¹).^[49]

Despite biological small-molecule crystals possessing high piezoelectricity and biocompatibility, their intrinsic rigidity and brittleness limit compatibility with the flexible modulus of tissues. Integrating piezoelectric small-molecule crystals with flexible substrates has emerged as an effective strategy to confer flexibility. In this approach, flexible polymers serve as substrates and significantly influence crystal growth through their functional groups, playing a pivotal role in enhancing piezoelectricity and modulating the flexibility of small-molecule crystals.^[50,51]

2.2. Degradable piezoelectric polymers

In addition to degradable biological small-molecule crystals mentioned above, a variety of degradable polymers not only demonstrate excellent piezoelectricity but also possess inherent flexibility. These polymers are typically semicrystalline and exhibit inherent piezoelectric properties due to well-organized structures with low symmetry. Chemical compositions do not solely determine their piezoelectric attributes; the 3-dimensional structural configurations are also essential for piezoelectricity.

Due to the inherent piezoelectricity of amino acids, numerous proteins have demonstrated piezoelectric responses, such as collagen, silk proteins, viruses, and poly(γ-benzyl-l-glutamate) (PBLG).^[52] Collagen has been the subject of extensive study for its piezoelectric properties since the discovery of the piezoelectric effect in bone (Figure 3A).^[53,54] The prevailing theory suggests that the piezoelectric effect in collagen results from the accumulation of dipole moments along the peptide chain and the hydrogen bonding interactions within the supramolecular structure.^[55] The highest measured d₁₄ in collagen was 12 pm V⁻¹.^[56] Compared to collagen, silk exhibits a higher d₃₃ (Figure 3B). An electrospun-induced, highly oriented, electrically polarized silk film achieved a d₃₃ of 38 pm V⁻¹.^[57] The M13 phage has also attracted considerable attention due to its considerable d₃₃ (13.2 pm V⁻¹) and scalability.^[58] However, concerns regarding its biosafety have curtailed its further application in vivo.

Polysaccharides are large biomolecules found extensively in animals and plants. They consist of numerous monosaccharides linked by glycosidic bonds. Cellulose and chitin, as representatives of polysaccharides, possess hierarchical fiber structures with low symmetry, demonstrating notable piezoelectric properties.^[34] Cellulose possesses alternating highly ordered crystalline and amorphous regions, stabilized by hydrogen bonds and van der Waals forces (Figure 3C). The source of cellulose’s piezoelectricity lies in the orderly dipoles formed by the strong hydrogen bonds between the oxygen and hydrogen atoms within each unit cell. Theoretical calculations indicated that the piezoelectric coefficient of cellulose ranged from 4.3 to 36.4 pm V⁻¹.^[35] The arrangement of cellulose crystals would be effectively achieved through mechanical stretching and electric field polarization to enhance its piezoelectric properties. Ultrathin-oriented cellulose nanocrystal (CNC) films prepared using assisted shear force and electric field exhibited a high d₂₅ of 210 pm V⁻¹.^[59] Direct current-assisted confinement cell technology further stabilized the vertical alignment of CNC rods, ensuring that all dipole moments are oriented perpendicular to the film surface, thereby yielding a more practical d₃₃ of 19.3 ± 2.9 pm V⁻¹.^[60] Similarly, chitin and its deacetylated derivative chitosan, with structures akin to cellulose, demonstrated reported maximum d₃₃ of 9.49 and 18.4 pm V⁻¹, respectively.^[61,62]

Laboratory-synthesized polymers significantly expand the diversity and versatility of piezoelectric materials. Adjusting the polymer chain orientations to create dipoles can induce piezoelectricity in synthetic polymers. Modifying groups susceptible to hydrolysis or oxidative degradation can also regulate their degradability.^[35] PLLA is a commonly used degradable synthetic piezoelectric polymer. Due to its helical chain structure, PLLA has shear piezoelectricity parallel to the z-axis. Its d₁₄ ranged from 9 to 19 pm V⁻¹.^[35,63] Its piezoelectricity depends on the crystallinity and dipole arrangement of the C=O bond of PLLA (Figure 3D).^[64] The thermal annealing process can control the crystallinity of PLLA, and external electric field and mechanical stretching can align the dipoles parallel to each other and perpendicular to the molecular chain direction, thus increasing its shear piezoelectric properties.^[32,65]

2.3. Degradability of piezoelectric biomaterials

Since amino acids and peptides are water soluble and degrade into alkaline molecules in an aqueous environment, they can be reabsorbed as nutrients in vivo.^[66,67] Polymers are made up of the copolymerization of many small chemical units. Their relatively complex degradation process necessitates breaking long chains into smaller molecules. This process is usually sluggish under natural conditions, but it can be accelerated with the assistance of enzymes, fungi, and other catalysts. For instance, silk and collagen necessitate enzyme catalysis under physiological conditions to degrade into amino acids the human body can absorb.^[67] Cellulose cannot be directly degraded and absorbed in the human body and can only be broken down into carbon dioxide and water by microorganisms and fungal enzymes.^[68,69] Chitin can be hydrolyzed by lysozyme in the human body.^[70] Similarly, PLLA degrades slowly in aqueous solutions, but microorganisms can speed up its degradation into carbon dioxide and water.^[71] Since these piezoelectric polymers are semicrystalline, their degradation in aqueous solutions occurs in 2 stages. First, water penetrates the amorphous region, breaking the polymer chains with the aid of a catalyst. Then, degradation spreads from the amorphous region to the crystalline region until complete decomposition into small molecular compounds occurs.

3.1. Energy harvester and sensor

Piezoelectric materials are the core component of piezoelectric nanogenerators (PENGs). Specifically, degradable piezoelectric materials provide new opportunities for self-powered transient implantable bioelectronics and sensors (Figure 4). The degradable PENGs not only facilitate converting energy from human movements into power for wearable and implantable electronics but also ensure their degradation and absorption postutilization, thereby circumventing the need for secondary processing. Su et al notably enhanced the crystallinity and piezoelectric constant of self-assembled FF films by applying a 7-kV voltage. Under an exerted force of 90 N, fabricated PENG demonstrated a open-circuit voltage (Voc) of 3.4 V, an short-circuit current (Isc) of 235 nA, and a power density of 9.98 W m⁻³, surpassing several nanogenerators predicated on degradable biomaterials.^[72] The output power of PENG based on degradable piezoelectric materials is typically in the nanowatt range, which is lower than that of other energy harvesting devices, but its unique degradable properties remain highly appealing in bioelectronic devices.

In addition to energy harvesting, the sensing prioritizes signal correlation over the magnitude of energy output. Force sensors employing degradable piezoelectric materials manifest superior suitability for in vivo detection of physiological signals. Curry et al constructed an implantable pressure sensor based on PLLA. This sensor comprised a PLLA piezoelectric material, a molybdenum electrode, and a polylactic acid (PLA) packaging layer. This PLLA film pressure sensor, upon implantation within the abdominal cavity of mice, was capable of monitoring diaphragm contraction pressure.^[73] Furthermore, Yang et al developed a glycine-polyvinyl alcohol (PVA) heterostructure film characterized by a sandwich structure wherein the crystalline glycine layer self-assembles and aligns autonomously between 2 PVA films. This configuration significantly amplified its macroscopic piezoelectric properties, achieving a piezoelectric coefficient (d₃₃) of 5.3 pm V⁻¹. The PENG with glycine-PVA film was implanted under the skin of the thigh and chest areas, producing Vpp signals of >150 mV and peak-peak voltage (Vpp) of >20 mV, respectively.^[50] However, the existing literature mainly focuses on degradable pressure sensors designed for movement and respiration monitoring, with limited studies addressing the monitoring of small physiological signals such as heartbeat, pulse, and blood flow.^{[73–74–75]}

3.2. Actuator and transducer

Utilizing the inverse piezoelectric effect, intelligent medical tweezers crafted from PLLA fibers could generate vibrations by applying a voltage at a specific frequency, effectively cleaning thrombi in blood vessels.^[76] In addition, Nguyen et al adopted an electrospinning process to create highly oriented glycine-polycaprolactone (PCL) nanofibers. This composite exhibited an exceptionally effective piezoelectric coefficient (d₃₃) of 19 pm V⁻¹. The fabricated ultrasound transducer generated significant levels of ultrasound to open the blood–brain barrier, facilitating the auxiliary delivery of paclitaxel for treating mice with an orthotopic glioblastoma tumor model. The survival rate of animals receiving glycine-PCL device-based ultrasound-mediated paclitaxel treatment was nearly double that of animals receiving ultrasound treatment from a current state-of-the-art implantable ultrasound transducer.^[77] These intelligent actuators and transducers fabricated from degradable piezoelectric materials have demonstrated significant practical value in the biomedical field.

3.3. Tissue engineering scaffold

Electricity plays a crucial role in the functionality of biological tissues, with many human body components exhibiting piezoelectricity.^[53,54] Early studies on the piezoelectricity of bone revealed that it primarily stems from collagen, contributing to bone regeneration.^[78] This discovery has spurred further research into using piezoelectric materials in tissue engineering.^[79,80] Degradable piezoelectric materials, particularly, have garnered attention for their excellent biocompatibility and degradability, making them an attractive option for tissue engineering applications. These materials have been used in creating electroactive scaffolds for bone regeneration,^[81,82] nerve repair,^{[83–84–85–86]} and electroactive dressings for wound healing.^[87,88] The electricity generated by the deformation of implanted piezoelectric material regulates the physiological electrical environment of cells, causing a series of changes in cells, such as migration, proliferation, differentiation, activation of ion channels, and activation of signaling pathways, and ultimately promotes tissue repair.