Advances in Electrical Materials for Bone and Cartilage Regeneration: Developments, Challenges, and Perspectives

Abstract

Severe bone and cartilage defects caused by trauma are challenging to treat, often resulting in poor outcomes. An endogenous electric field (EnEF) is crucial for bone regeneration, making electrical materials a promising therapy. This review provides a comprehensive overview of the role of bioelectric signals in bone and cartilage cells, alongside recent advancements in electrical biomaterials, with particular emphasis on nanogenerators, piezoelectric materials, triboelectric scaffolds, and zwitterionic hydrogels. It further investigates the impact of these electrical biomaterials on bone and cartilage regeneration, as well as the applications of both endogenous and exogenous electrical stimulation (ES) and the mechanisms underlying ES-induced cellular and molecular responses. Finally, the review underscores future directions for ES systems in tissue engineering, emphasizing the critical importance of integrating structural integrity, mechanical properties, and electrical signal delivery into intelligent implantable scaffolds.

Keywords: electrical biomaterials; electrical stimulation; endogenous electric fields; nanogenerators; piezoelectric materials.

Figure 1

Principles and applications of electrical biomaterials. Electrical biomaterials can be divided into four main categories: nanogenerators, piezoelectric biomaterials, triboelectric scaffolds, and zwitterionic hydrogels. 1. Nanogenerators: Nanogenerators convert small mechanical movements into electrical energy, leveraging the piezoelectric or triboelectric effect. In neurological applications, nanogenerators could potentially harvest bio‐mechanical energy to power implants or wearable devices, which can monitor brain activity, stimulate nerve cells, or facilitate nerve repair. These could also play a role in pacemakers or other implantable devices that harvest energy from body movements. 2. Piezoelectric Biomaterials: Piezoelectric materials generate an electric charge in response to applied mechanical stress. In biomedical applications, piezoelectric biomaterials are useful for wound healing, tissue engineering, and regenerative medicine, where mechanical stimuli are converted into electrical signals to encourage cellular response. 3. Triboelectric Scaffolds: Triboelectric scaffolds leverage the triboelectric effect, where two materials generate charge when rubbed together. These scaffolds are especially promising for bone and cartilage regeneration, as mechanical movements during joint activity can generate electric stimulation, which promotes cell growth and tissue repair. 4. Zwitterionic Hydrogels: Zwitterionic hydrogels are hydrogels that carry both positive and negative charges. They are highly flexible, biocompatible, and resistant to protein fouling, making them ideal for wearable devices or flexible electronics. They are commonly used in bioelectronics and soft robotics, as they can maintain function while enduring repetitive motion. The hydrogel's conductive properties enable it to act as a sensor or actuator in applications like wearable sports equipment or medical monitoring devices. Each of these categories represents a unique way in which mechanical energy or environmental stimuli are converted into electrical energy to influence biological processes or power devices. The concept of electrical biomaterials holds promise in applications ranging from neural interfaces to regenerative medicine and wearable health devices.

Figure 2

a) Direct and converse piezoelectric effect. Reproduced with permission.^{[ 30 ]} Copyright 2018, Wiley‐VCH. b) “d ₃₁” mode means that the force direction is perpendicular to poling voltage direction. In contrast, the force direction is parallel to poling voltage direction in “d ₃₃” mode. Reproduced with permission.^{[ 29 ]} Copyright 2021, Wiley‐VCH. c) ZnO fiber‐zinc ore structural model, piezoelectric potential in compression and tensile mode. Reproduced with permission.^{[ 32 ]} Copyright 2022, Wiley‐VCH. Theoretical models for d) dielectric‐to‐dielectric contact‐mode TENG and e) conductor‐to‐dielectric contact‐mode TENG.^{[ 49 ]} Theoretical models for f) dielectric‐to‐dielectric sliding‐mode TENG and g) conductor‐to‐dielectric sliding‐mode TENG. Reproduced with permission.^{[ 48 ]} Copyright 2013, Wiley‐VCH. h) Piezoelectric nanogenerator (PENG), based on ZnO nanosheets (NSs), interacts with living cells to induce a local electric field that self‐stimulates and modulates cell activity. Reproduced with permission.^{[ 53 ]} Copyright 2017, Wiley‐VCH. i) A bioadhesive triboelectric nanogenerator (BA‐TENG) for instant and robust wound sealing and ultrasound‐driven accelerated wound healing. Reproduced with permission.^{[ 54 ]} Copyright 2023, Wiley‐VCH.

Figure 3

a) Crystal structures of cubic, wurtzite, hexagonal, and rhombohedral BN. Reproduced with permission.^{[ 62 ]} Copyright 2017, Wiley‐VCH. b) The anchoring of single‐atom tungsten (W) can cause significant lattice distortions in h‐BN lattice plane, thus introducing a strikingly enhanced piezoelectric response, approximately 12‐fold that of the parent h‐BN nanosheets. Reproduced with permission.^{[ 68 ]} Copyright 2022, Elsevier. c) Adopting stacking strategy, the corresponding d ₃₃ piezoelectric coefficient of α‐In₂Se₃ increases from 0.34 (monolayer) to 5.6 pm V⁻¹ (bulk) without any odd–even effect. Reproduced with permission.^{[ 70 ]} Copyright 2018, American Chemical Society. d) A label‐free microfabricated thickness shear mode electroacoustic device based on a ZnO piezoelectric film for the assay of cardiac biomarkers. Reproduced with permission.^{[ 80 ]} Copyright 2020, Elsevier. e) and f): Piezoelectric materials as sonodynamic sensitizers to eliminate cancer cells with reactive oxygen species (ROS). Reproduced with permission.^{[ 82 ]} Copyright 2020, American Chemical Society.

Figure 4

The applications of piezoelectric materials and nanogenerators for bone regeneration. a) BTO/P(VDF‐TrFE) film exhibited a favorable bone healing in rat calvarial models. Reproduced with permission.^{[ 163 ]} Copyright 2016, American Chemical Society. b) Histological outcomes and Micro‐CT image of bone healing calvarial models with CS, HA‐CS and HA‐MS‐CS implant show more newly developed bone tissues compared with HA‐CS and CS scaffold in vivo.^{[ 159 ]} Copyright 2017, American Chemical Society. c) WH NPs and PWH‐750 NPs exhibit different osteogenic differentiation potential with or without LIPUS treatment.^{[ 152 ]} Copyright 2021, Elsevier. d) Biomimetic piezoelectric scaffolds promote nerve and vascular regeneration via continuously releasing Mg²⁺ to enhance bone regeneration.^{[ 157 ]} Copyright 2023, KeAi Communications Co.

Figure 5

The applications of zwitterionic hydrogel and triboelectric scaffold for bone regeneration. a) Self‐powered electrical stimulator promotes adhesion and proliferation of osteoblasts.^{[ 172 ]} Copyright 2019, Elsevier. b) Self‐powered electrical stimulator promotes osteogenesis of MC3T3‐E1 cells.^{[ 172 ]} Copyright 2019, Elsevier. c) Hybrid tribo/piezoelectric nanogenerator for repairing bone defects through self‐powered electrical stimulation.^{[ 12 ]} Copyright 2024, AAAS. d) An implantable poly zwitterionic hydrogel scaffold (PDMAPS) was synthesized using methacrylated sulfobetaine (DMAPS) and acrylated gelatin (GelMA) as the matrix. Using polyanionic fiber (PAC) and polydimethyldiallylammonium chloride (PDAC) as control, the repairing effect of PDMAPS hydrogel scaffold on rat femoral defect was observed.^{[ 179 ]} Copyright 2023, Wiley‐VCH.

Figure 6

The applications of electroactive biological materials for cartilage regeneration. a) Macrophotography, electromechanical response, cyclic compression, and scanning electron microscopy (SEM) images of piezoelectric 3D scaffolds fabricated with 0.7PHBV.^{[ 187 ]} Copyright 2024, Cell. b) Piezo PLLA hydrogels produce better articular cartilage regeneration compared with sham and non‐piezo PLLA hydrogels by H&E, Safranin O/fast green, and collagen II staining.^{[ 190 ]} Copyright 2023, Springer Nature. c) Triboelectric scaffolds (TESs) promote cartilage regeneration compared with Poly (glycerol sebacate) (PGS).^{[ 10 ]} Copyright 2024, Wiley‐VCH. d) Piezoelectric scaffold promotes ADSC chondrogenesis under, and exercise‐induced piezoelectric stimulation enhances bone and cartilage regeneration.^{[ 5 ]} Copyright 2024, AAAS.

Figure 7

Exploration of electric stimulation‐induced molecular and cell responses. a) Electrical stimulation accelerates proliferation and differentiation of osteoblasts, promotes vascularization, and improves macrophage phagocytosis in the process of bone healing.^{[ 199 ]} Copyright 2024, Wiley‐VCH. b∼c) Scratch test exhibits the migration of stem cell by treated with control, Piezo, and collagen hydrogel (Scale bars: 500 µm).^{[ 190 ]} Copyright 2023, Springer Nature. d) Bright‐field images and fluorescence images of GelMA and GelMA‐Pani by digital projection micro‐GelMA‐Pani produced by stereolithography.^{[ 216 ]} Copyright 2016, Elsevier. e) GO functional enrichment analysis including cellular component, biological process, and molecular function.^{[ 12 ]} Copyright 2024, AAAS. f) The gene expression patterns in cells after electric stimulations.^{[ 12 ]} g) Schematic of the battery‐free Bd‐eS for patients performing active and the possible mechanism for bone and cartilage repair. Copyright 2024, AAAS.^{[ 12 ]}

Figure 8

Illustration shows the ECM of bone and cartilage repair as well as the underlying mechanisms.