Smart biophysical cue-based strategies and materials for intervertebral disc degeneration therapy

Abstract

Low back pain (LBP) is the leading cause of non-fatal disability globally, significantly affecting quality of life and imposing an immense socioeconomic burden. Intervertebral disc degeneration (IVDD) is a major cause of LBP. Although advances in biomaterials and drug delivery have provided new therapeutic options, their efficacy remains limited by invasive delivery approaches and the spatiotemporal dynamic changes in the microenvironment during treatment. In recent years, smart biophysical cue-based strategies—represented by electrical, magnetic, photo, ultrasonic, and mechanical cues—have offered breakthrough noninvasive or minimally invasive approaches for IVDD intervention. Such cues can act directly or indirectly on disc tissues, modulating oxidative stress signaling pathways, optimizing the inflammatory microenvironment, and influencing cellular behavior and extracellular matrix metabolism, thereby delaying or even reversing the degenerative process. These modalities possess highly controllable and precise regulatory potential for tissue repair and can synergize with intelligent biomaterials, drug delivery systems, and other therapeutic strategies to achieve multi-dimensional and multi-targeted regulation. Current research in this field has largely concentrated on isolated biophysical cues or individual material systems, resulting in fragmented advances and a lack of systematic cross-comparison, which limits their translational relevance for precise clinical intervention. This review goes beyond single-cue perspectives to provide a comprehensive and comparative integration of multiple biophysical cue-based strategies and materials within the IVDD field, systematically elucidating their mechanisms of action and developmental trajectories. Moreover, from an interdisciplinary perspective, this review provides new theoretical foundations and directions for precision therapy in IVDD.

Graphical abstract

Highlights

• •A comprehensive overview of biophysical cue-based strategies for IVDD therapy.
• •Biophysical cues enable noninvasive or minimally invasive IVDD therapeutic approaches.
• •Biophysical cues synergize with smart materials to enable precise and durable tissue repair.
• •Convergence of medicine and engineering fosters innovative disc regeneration strategies.
• •Biophysical cue-based therapies offer scalable, patient-friendly pathways toward clinical translation.

LBP	Low back pain	IVDD	Intervertebral disc degeneration
IVD	Intervertebral disc	NP	Nucleus pulposus
AF	Annulus fibrosus	CEP	Cartilaginous endplate
ECM	Extracellular matrix	NPC	Nucleus pulposus cell
GAG	Glycosaminoglycan	AFC	Annulus fibrosus cell
NF-κB	nuclear factor kappa-B	MAPK	Mitogen-activated protein kinase
TNF-α	Tumor necrosis factor-α	IL	Interleukin
MMP	Matrix metalloproteinase	ADAMTS	A disintegrin and metalloproteinase with thrombospondin motifs
ROS	Reactive oxygen species	Nrf2	Nuclear factor erythroid 2-related factor 2
PI3K	Phosphoinositide 3-kinase	Akt	Protein kinase B
SIRT	Sirtuin	SASP	Senescence-associated secretory phenotype
mTOR	Mechanistic target of rapamycin	cGAS	Cyclic GMP-AMP synthase
STING	Stimulator of interferon genes	FOXO	Forkhead box O1a
Piezo	Piezo-type mechanosensitive ion channel component	HSP	Heat shock protein
ES	Electrical stimulation	LCCS	Low-current continuous stimulation
CC	Capacitively coupled	BMP	Bone morphogenetic protein
PSCI	Peripheral sensory-computer interface	R waves	Regenerative waves
CGRP	Calcitonin gene-related peptide	Cav	Calcium voltage-gated channels
CaMK1	Ca2+-dependent protein kinase I	CDK	Cyclin-dependent kinase
NKN	Sodium potassium niobate	PVDF	Polyvinylidene fluoride
PLLA	Poly-L-lactic acid	PCL	Polycaprolactone
BMSC	Bone marrow–derived mesenchymal stem cell	GelMA	Gelatin methacryloyl
ICP	Inherently conductive polymer	PPy	Polypyrrole
PANi	Polyaniline	TRAM1	Translocation associated membrane protein 1
TREX1	Three-prime repair exonuclease 1	EV	Extracellular vesicle
MN	Microneedle	TENG	Triboelectric nanogenerator
TENS	Transcutaneous electrical nerve stimulation	EA	Electroacupuncture
AQP	Aquaporin	cAMP	Cyclic adenosine monophosphate
PKA	Protein kinase A	MF	Magnetic field
SMF	Static magnetic field	PEMF	Pulsed electromagnetic field
Bcl2	B-cell lymphoma-2	Bax	Bcl-2-associated X protein
MSC	Mesenchymal stem cell	Kif5b	Kinesin family member 5b
PEI	Polyethylenimine	IONP	Iron oxide nanoparticle
MNP	Magnetic nanoparticle	NPSC	Nucleus pulposus stem cell
PBM	Photobiomodulation	ATP	Adenosine triphosphate
DLT	Diode laser therapy	PTT	Photothermal therapy
PDA	Polydopamine	NIR	Near-infrared
PTA	Photothermal agent	TGF-β	Transforming growth factor-β
C. acnes	Cutibacterium acnes	GSNO	S-nitrosoglutathione
UV	Ultraviolet	HILT	High-intensity laser therapy
VAS	Visual analogue scale	BP	Body pain
ODI	Oswestry Disability Index	GH	General health
VT	Vitality	SF	Social function
PF	Physical function	ROM	Range of motion
NPADS	Neck pain and disability scale	US	Ultrasound
HIFU	High-intensity focused ultrasound	LIPUS	Low-intensity pulsed ultrasound
TCPP	Tetrakis (4-carboxyphenyl) porphyrin	PVA	Polyvinyl alcohol
HOMO	Highest occupied molecular orbital	LUMO	Lowest unoccupied molecular orbital
YAP	Yes-associated protein	TAZ	Transcriptional coactivator with PDZ-binding motif
K2P	Two-pore-domain potassium	TRPV4	Transient receptor potential vanilloid 4
CTS	Cyclic tensile strain	WBV	Whole-body vibration
ACAN	Aggrecan	COL2A1	Collagen type II alpha 1 chain
SOX9	SRY-box transcription factor 9	LMHFV	Low-magnitude high-frequency vibration
E2	17β-oestradiol	LMMS	Low-magnitude mechanical signals
RVE	Resistive vibration exercise	AI	Artificial intelligence
CaM	Calmodulin

1. Introduction

A global epidemiological study has identified low back pain (LBP) as the leading non-fatal condition impairing quality of life and imposing the greatest socioeconomic burden worldwide [1]. Among its etiologies, intervertebral disc degeneration (IVDD) represents a major contributor. With the rapid progression of population ageing, the prevalence of IVDD-associated LBP continues to rise, posing a substantial public health and economic challenge to both patients and society [2].

The intervertebral disc (IVD) is a spinal joint composed of the nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous endplates (CEPs) [3]. The NP, located at the center of the IVD, is a highly hydrated, gel-like structure that functions as a cushion to absorb axial loads [4]. The AF, which comprises layers of inter-lamellar shearing fibers, surrounds the NP and resists its radial expansion [5]. The CEPs are hyaline cartilage structures that secure the IVDs to the adjacent vertebral bodies, serving as critical conduits for nutrient transport and metabolic exchange between the disc and the vertebral vasculature [6]. Under various stressors, the IVD undergoes aging and progressive structural deterioration, ultimately leading to vertebral instability, spinal canal stenosis, and segmental deformity, which manifest clinically as LBP and functional impairment [7].

As an early-stage therapeutic approach, conservative management provides only limited intervention in disease progression through anti-inflammatory, analgesic, neurotrophic, and antispasmodic effects. Surgical strategies such as discectomy and spinal fusion remain essentially palliative, as they fail to restore the disc's native biomechanics and mobility, and may even increase mechanical stress on adjacent segments [8]. Recent advances in biomaterials science have opened new avenues for IVDD therapy, including the delivery of therapeutic agents and bioactive molecules, as well as the implantation of static scaffolds. These innovative approaches aim to slow the degenerative process, preserve disc homeostasis and microenvironmental stability, and ultimately achieve complete tissue regeneration [9]. However, the pathological microenvironment of the degenerating disc is highly dynamic, posing a major challenge to the adaptability of traditional biological therapies. Furthermore, as the largest avascular tissue in the human body, the IVD is isolated by endplate barriers that hinder the diffusion of systemically administered drugs. Most current biomaterial-based delivery systems therefore rely on intradiscal injection, a procedure that may compromise the structural integrity of the AF and promote aberrant neurovascular ingrowth [10]. In recent years, the convergence of medicine and engineering has brought transformative insights into IVDD treatment. Biophysical cues refer to externally applied physical signals that modulate cellular behavior and tissue function through controlled energy inputs. Such cues encompass electrical, magnetic, photo, ultrasonic, and mechanical signals, which have been shown to promote disc regeneration. The key advantage of biophysical cue-mediated regulation lies in its drug-independent mode of action: it acts directly on IVD tissues, modulating their structure and function or synergizing with implanted biomaterials to achieve precise biological regulation and tissue repair. Moreover, these noninvasive or minimally invasive biophysical approaches offer dynamic controllability, with external stimulation systems theoretically adjustable in real time according to microenvironmental feedback—ushering in a paradigm shift from passive repair to active modulation [11]. Biophysical cue-based systems can also be integrated with intelligent drug carriers, enabling stimulus-responsive drug release that enhances pharmacological stability and targeting specificity while minimizing systemic side effects [12]. In addition, biophysical cue-based strategies can synergize with pharmacological, surgical, and biomaterial-based treatments, achieving multi-target, multi-pathway regulation for enhanced therapeutic efficacy. The interdisciplinary convergence of materials science and rehabilitation medicine has further catalyzed the development of next-generation biofunctional systems featuring noninvasive or minimally invasive operation, active modulation, and precise targeting. These innovations not only reduce or even eliminate the risk of mechanical damage associated with conventional implants but also provide a theoretical foundation for functional disc regeneration.

Current research in this field has largely focused on isolated biophysical cues or individual material systems, leading to fragmented advances and limited cross-comparison among different physical modalities, which in turn constrains their translational relevance for precise clinical intervention. This review adopts a novel integrative perspective, systematically consolidating research on multiple biophysical cue-based strategies and materials for IVDD intervention and covering the full spectrum from fundamental mechanistic studies to early clinical translation. A key innovation of this review lies in emphasizing the critical role of interdisciplinary integration—linking medicine, biomedical engineering, and materials science—in driving the clinical translation of biophysical cue-mediated technologies. Furthermore, we highlight the emerging prospects of intelligent and miniaturized biophysical cue-responsive systems for personalized IVDD therapy (Fig. 1). By synthesizing current evidence and projecting future directions, this review aims to provide both theoretical guidance and technological reference to advance precision interventions using biophysical cue-based strategies and materials in IVDD.

Fig. 1.

Frontier progress in biophysical cue-based strategies for IVDD therapy.

2. Physiology and pathophysiology of IVDD

The IVD, a fibrocartilaginous tissue connecting adjacent vertebral bodies, plays a pivotal role in the spinal functional unit by transmitting mechanical loads and maintaining mobility [13]. The NP primarily comprises two cell types: notochordal cells of embryonic origin and mature nucleus pulposus cells (NPCs). Notochordal cells gradually decline after birth and are largely replaced by NPCs, which are primarily responsible for synthesizing the main ECM components of the NP, including proteoglycans, predominantly type II collagen, and hyaluronic acid. The glycosaminoglycan (GAG) chains of proteoglycans bear negatively charged sulfate and carboxyl groups, which attract cations and generate osmotic pressure within the matrix [14]. The high osmotic pressure generated by proteoglycans, together with the irregular collagen network, endows the NP with a water content of 70–90% [15]. This high hydration, in combination with the distinctive collagen arrangement, confers elasticity to the NP, allowing it to evenly distribute axial loads and assist in balancing mechanical stress on the disc [7]. The AF consists of annulus fibrosus cells (AFCs) embedded within a dense ECM predominantly composed of type I collagen. Along the radial axis of AF, from the outer to the inner regions, increasing water content is associated with a progressive increase in type II collagen and a concomitant decrease in type I collagen, together with a transition in angle-ply fiber orientation from 65° to 30–45° [16]. Such an alternating lamellar layup of collagen fibers is central to the anisotropic mechanical performance of the AF and plays a key role in resisting hydrostatic pressure from the NP [3,17]. The CEP is a layer of hyaline cartilage located on the superior and inferior surfaces of the IVD. It serves as a structural barrier preventing the disc from bulging into the adjacent vertebral bodies and provides essential mechanical anchorage for the NP and AF [18]. In addition, a capillary network originating from the vertebral marrow cavity extends to the interface between the bony endplate and the CEP, making the CEP a critical pathway for nutrient transport to the otherwise avascular IVD [19].

Macroscopically, IVDD manifests as CEP calcification, NP dehydration, and AF rupture, ultimately leading to a reduction in disc height. Microscopically, IVDD involves a dynamic, multidimensional process encompassing inflammatory cascades, oxidative stress injury, cellular senescence, cell death, and ECM metabolic imbalance [20]. Inflammation plays a pivotal role throughout all stages of IVDD progression. It can be triggered by both extrinsic and intrinsic factors: external mechanical loading may cause micro-injuries that disrupt the immune-privileged status of the IVD, whereas intrinsic cues such as ECM degradation fragments and microcrystals act as endogenous inflammatory mediators, amplifying cytokine release and immune activation [21]. At the molecular level, these processes are predominantly driven by activation of canonical inflammatory pathways such as nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling, accompanied by increased expression of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 [22]. Sustained inflammation enhances the synthesis and activity of ECM-degrading enzymes, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), leading to reduced osmotic pressure, loss of hydration, structural disruption of the AF, and deterioration of biomechanical properties. Notably, these changes in turn exacerbate inflammation and immune cell infiltration, forming a self-perpetuating vicious cycle [23]. During IVDD, local oxidative stress is markedly intensified. Although IVD cells adapt to a hypoxic niche, they still maintain oxygen-dependent metabolism and continuously generate reactive oxygen species (ROS) through conventional pathways [24]. Furthermore, impaired cellular recycling capacity and various stress stimuli lead to mitochondrial dysfunction, disrupting mitochondrial dynamics and quality control systems, thereby increasing ROS production [25]. Excessive ROS surpasses the antioxidant capacity of cells, resulting in membrane disruption, altered permeability, and cytotoxicity that drive cellular senescence and death [26]. Accumulating evidence indicates that activation of endogenous antioxidative signaling pathways, such as nuclear factor erythroid 2-related factor 2 (Nrf2), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), and members of the sirtuin (SIRT) protein family, can effectively mitigate oxidative stress and thereby slow the progression of IVDD [[27], [28], [29]]. Cellular senescence is characterized by irreversible cell-cycle withdrawal, macromolecular damage, metabolic imbalance, and the acquisition of a senescence-associated secretory phenotype (SASP) [30]. Multiple senescence-associated signaling pathways, including p53 and mechanistic target of rapamycin (mTOR) signaling, NF-κB-mediated inflammatory signaling, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING)-dependent DNA damage response signaling, forkhead box O1a (FOXO)-related stress response pathways, and piezo-type mechanosensitive ion channel component (Piezo) 1 signaling, have been implicated in the regulation of cellular senescence during IVDD [31,32]. Cells exhibiting SASP secrete large quantities of proinflammatory cytokines, chemokines, growth factors, and MMPs, thereby aggravating the inflammatory microenvironment and accelerating the senescence process [33]. These processes directly or indirectly lead to cell loss or death, resulting in irreversible depletion of disc cells and severe ECM destruction, which together contribute to the progressive loss of IVD structure and function. To date, biophysical cue-based strategies have been reported to intervene in IVDD through several distinct yet complementary mechanisms. First, certain biophysical cues can directly modulate the disc microenvironment by exerting anti-inflammatory effects and promoting disc cell survival and ECM regeneration, through stimulus-responsive cellular components that mediate the transduction of biophysical inputs into biochemical signals, with integrins as a representative example. Second, advanced biomaterial platforms enable the interconversion of distinct biophysical cues, for example, transforming light inputs into localized photothermal stimulation that activates intracellular heat shock protein (HSP) responses, thereby enhancing cellular tolerance to hostile microenvironmental conditions such as inflammation. Third, integrating biophysical cues with controlled drug delivery allows modulation of pathological microenvironmental features, including oxidative stress and cellular senescence, as well as other pathological mechanisms that remain insufficiently elucidated in the context of direct physical stimulation. Because drug release is directly coupled to well-defined biophysical triggers, these systems allow the timing and duration of drug release to be precisely controlled, facilitating prolonged drug retention and sustained therapeutic efficacy. Importantly, such stimulus-responsive systems can display an on-off mode of drug release, thereby confining therapeutic action to defined activation windows and minimizing off-target effects. Through these mechanisms, biophysical cue-based approaches actively reshape the degenerative trajectory of the IVD and offer promising avenues for IVDD treatment.

3. Biophysical cue-based strategies and materials

Over the past two decades, groundbreaking advances have driven tissue engineering from a paradigm dominated by single biochemical stimulation toward a new stage of multimodal synergistic regulation. By integrating diverse biochemical cues such as growth factors, hormones, extracellular vesicles, drugs, and material structures, researchers have achieved remarkable progress in therapeutic intervention of IVDD. However, the role of biophysical cue-based strategies within this framework remains insufficiently explored. Incorporating physical factors such as electrical, magnetic, photo, ultrasonic, and mechanical cues into IVDD treatment strategies may offer a novel regulatory dimension for tissue repair and open up promising therapeutic avenues (Table 1).

Table 1.

Summary of the therapeutic mechanisms of different biophysical cue-based strategies for IVDD therapy.

Biophysical cues	Stimulus Form	Types	Type/parameters	Mechanism	Refs.
Electrical cues	Direct stimulation	Biphasic signals	Current: 10 μA Voltage: ±750 mV Frequency: 200 Hz	Reduce the protein production of IL-6 and IL-8 in NPCs	[34]
			Current: 5, 10, 20, and 100 μA Voltage: ±300 mV Frequency: 200 Hz	Improve inflamed NPCs' morphological phenotype and kinetic properties	[35]
		Electrical pulses	Voltage: 1.1 V Frequency: 0.003 Hz Duty cycle: 96%	Increase the matrix regeneration while reducing inflammation and pain markers	[36]
		Sinusoidal signals	Voltage: 260 mVpp Frequency: 60 kHz Field strength: 17.33 mV/cm	Upregulate the production of the IVD-matrix macromolecules aggrecan, collagen II, and sGAG by a mechanism involving BMPs	[37]
		Regeneration wave	Peak voltage: 5 V Frequency: 0–20 Hz	Improve the inflammatory microenvironment, potentially inhibiting degeneration and fostering regeneration	[38]
		Ultrasonic current	Amplitude:0.1 μA/cm2	Activate the Ca2+-CaMK1-CDK1/2 signaling axis, thereby advancing the cell cycle and promoting NPC regeneration	[39]
	Piezoelectricity	Short-circuit current output	Peak current: ∼50 nA	Improve the migration and adhesion of BMSCs, and ultimately recruiting them around the scaffold	[40]
		Sinusoidal electrical signal output	–	Activate Piezo1 channels, rapidly increasing intracellular free Ca2+ concentrations to enhance BMSC survival after delivery	[41]
		Short-circuit current signals	Voltage: 0.2 V	Change the pathogenic PI3K-Akt/NF-κB axis, shifting metabolism from inflammatory catabolism to anabolic regeneration in NPCs	[42]
		Ultrasonic current	Current density: ∼2.4 mA/cm2	Activate the AMPK-FOXO1a signaling pathway and enhance impaired mitochondrial clearance of NPCs	[43]
	Electro-responsive	Triboelectric energy	Open-circuit voltage: ∼255 V Transferred charge: ∼80 nC short-circuit current: increase from ∼3 to ∼16 μA	Drove the loss of electrostatic attraction between anionic EVs and the PPy layer in the reductive state to release therapeutic EVs	[44]
Magnetic cues	Direct stimulation	PEMF	Duty cycle: 25% Pulse frequency: 3850 Hz Burst frequency: 15 Hz Rate of change maximum: 10 T/s	Reduce the expression of proinflammatory factors and matrix degradation enzymes	[45]
				Inhibit IL-6 transcription induced by IL-1α	[46]
			Burst width: 5 ms; Pulse width: 0.2 ms; Pulse wait: 0.02 ms; Burst wait: 60 ms; Pulse rise and fall times: 0.3 μs, 2.0 μs Frequency: 15 Hz	Promote the SIRT1-autophagic network to enhance ECM synthesis in NPCs	[47]
			Intensity: 5 mT Frequency: 10–100 Hz Pulse width: 0.05 s/0.005 s	Regulate the expression of apoptotic proteins	[48]
		SMF	Strength: 0–80 mT	Enhances microvesicles secretion by augmenting Kif5b-mediated mitochondrial transport	[49]
	Magneto-responsive	Controllable dynamic MF	Strength: 400 mT Frequency: 0.1 Hz and 0.5 Hz	Induces micro/nano-scale forces via superparamagnetic iron oxide nanoparticles	[50]
Photo cues	Direct stimulation	PBM	Wavelength: 630 nm Doses: 16 and 64 J/cm2	Inhibit the levels of MMP-1 mRNA and protein in NPCs	[[51], [52]]
			Wavelength: 525 nm Doses: 16 and 32 J/cm2	Reduce the secretion of MMP-1 protein in NPCs
			Wavelength: 630 nm Doses: 32 J/cm2	Elevate the secretion of the TIMP-1 protein in NPCs
		PBM	Wavelengths: 645, 525, and 465 nm Doses: 16, 32, and 64 J/cm2	Suppress MMP-3 protein production(Except for PBM at 645 nm with 16 J/cm2)and IL-8 and BDNF mRNA expression
			Wavelength: 465 nm Doses: 32 and 64 J/cm2	Suppress levels of VEGF mRNA and protein in AFCs
		Diode laser therapy	Wavelength: 970 nm Radiation power: 2W	Attenuate IL-1β-induced ECM degradation in NP tissues by suppressing the p38 MAPK pathway	[53]
	Photothermal effect	NIR	Wavelength: 808 nm Power density: 2.0 W/cm2	Resist inflammatory damage by activating the TGF-β/Smad signaling pathway in NPCs	[54]
			Wavelength: 808 nm	Increase the level of cytoprotective HSPs in AFCs	[55]
			Wavelength: 808 nm Power density: 1.0 W/cm2		[56]
			Wavelength: 1064 nm Power density: 1.5 W/cm2	Suppress inflammation and restore ECM homeostasis in AF tissue	[57]
	Photo-Responsive	Red Light	Wavelength: 630 nm Power density: 30 mW/cm2	Activate coumarin-based NO donors via photoredox catalysis, allowing for controlled NO release	[58]
		NIR	Wavelength: 808 nm Power density: 1.0 W/cm2	Photothermal stimulation-induced controlled NO release via thermosensitive GSNO	[56]
Ultrasonic cues	Direct stimulation	LIPUS	Frequency: 1.5 MHz Pulse width: 200 μs Repetition rate: 1.0 kHz	Upregulate of DNA synthesis at 7.5 and 15 m W/cm2 on both NPCs and AFCs. Upregulate proteoglycan synthesis at high intensities ranging from 30 to 120 mW/cm2 on both NPCs and AFCs	[59]
			Frequency: 1.5 MHz Pulse width: 200 μs Repetition rate: 1.0 kHz Temporal average intensity: 30 mW/cm2	Stimulate proteoglycan synthesis and collagen synthesis in IVD cells	[60]
				Promotes the ECM synthesis of degenerative NPCs through activation of FAK/PI3K/Akt pathway	[61]
	Ultrasound-responsive	Ultrasound	–	Induce ATI2341 release from a temperature-sensitive hydrogel via ultrasound heating	[62]
			Frequency: 1 MHz Duty cycle: 50% Intensity: 1.5 W/cm2 Exposure Duration:​ 60 s	Induce resveratrol release from a nanobubble by inertial cavitation	[63]
			Intensity: 2.0 W/cm2 Exposure Duration:​ 60 s	Destruct the plasmid DNA-loaded microbubbles and lead to transient holes in NPC surface, allowing efficient transfer of plasmid DNA into the cytoplasm	[64]
			Intensity: 1.2 W/cm2	Trigger ultrasonic current, which in turn induces Ca2+ influx	[39]
			Intensity: 2.0 W/cm2 Frequency: 1.0 MHz Duty cycle: 50%	Induce piezoelectric responses in pyrrole/BaTiO3 nanoparticles, leading to controlled release of electrostatically adsorbed TGF-β	[43]
Mechanical cues	Traction	Adjustable longitudinal cyclic stretching	Frequency: 0.5 Hz Cyclic tensile strain: 5% Exposure Duration: 24 h	Rescue the inflammatory responses and enhanced AFC proliferation, migration and ECM synthesis by suppressing Cav1-mediated integrin β1 and NF-κB signaling pathways	[65]
		In situ traction	Exposure Duration: 4 weeks	Promote the synthesis of proteoglycans and reconstruction of the bony endplate microstructure, while avoiding the formation of osteophytes	[66]
		Traction	Force: 22 N Exposure Duration: 2 and 4 weeks	Improve IVD height, GAG synthesis, and increase the number of endplate pores	[67]
		Rotational traction	Pulling force: 1 Kg, once daily Rotation: ±2°, once daily Duration of combined loading: 30 min per day Constant load: 3 Kg	Lower the creep displacement, enhance the fatigue resistance, increase the tensile strength and protect the IVD structure	[68]
	Vibration	Combination of 17β-oestradiol and LMHFV	Frequency: 45 Hz Peak-to-peak acceleration: 0.3 g	Present a protective effect against cell loss and decrease IL-6 production	[69]
		Axial vibration	Amplitude: >0.4 g Exposure Duration: 10 min	Upregulate the expression of ECM genes	[70]
		Low-intensity mechanical vibrations	Frequency: 90 Hz Peak acceleration: 0.2 g	Preserve both the disc morphology and sGAG content	[71]
		Micro/nano‐scale forces	–	Promote NPSC proliferation and differentiation toward NP-like cells	[50]
	Physically priming	Cyclic compression	Strain: 10% Frequency: 0.1 Hz (5 s strain and 5 s load rejection)	Increased sGAG synthesis in 3D AFC matrix constructs	[72]
		Hydrostatic pressure	Magnitude: 5 MPa Frequency: 0,5 Hz	Enhanced ECM elaboration and organization by outer annulus-seeded constructs	[73]
		Tension	strain: 20 ± 3%	Increase cellular and matrix alignment and scaffold elastic modulus	[74]
		Cyclic compression	Strain: 10% Frequency: 1 Hz	Enhanced expression of chondrogenic markers in NP of engineered IVD	[75]
		Exercise-mimetic stimulation	–	Increase endogenous irisin cargo through the AMPK- PGC-1α pathway and enhance exosomal production via Ca2+ influx	[76]
	Physical properties of biomaterials	GelMA microsphere modified with fibronectin	Elastic modulus: 2 Kpa ligand density: 2 μg/mL	Support the NP-like differentiation of NPSCs by translocating YAP	[77]
		High-aspect-ratio anisotropic rod-shaped Microgel	Long axis: 400 μm Height and width: 100 μm	Enhancing NPC adhesion, proliferation, and antiapoptotic ability Trigger YAP/TAZ activation, which enhances nuclear membrane stability, reduces DNA damage, downregulates cGAS-STING, and inhibits NPC senescence	[78]

IL: Interleukin; NPCs: Nucleus pulposus cells; IVD: Intervertebral disc; sGAG: Sulfated glycosaminoglycans; BMPs: Bone morphogenetic proteins; BMSCs: Bone marrow mesenchymal stem cells; Piezo1: Piezo type mechanosensitive ion channel component 1; EVs: Extracellular vesicles; PPy: Polypyrrole; PEMF: Pulsed electromagnetic field; SIRT1: Sirtuin1; SMF: Static magnetic field; Kif5b: Kinesin family member 5B; MF: Magnetic field; NPSC: Nucleus pulposus stem cell; MMP: Matrix metalloproteinase; PBM: Photobiomodulation; TIMP-1: Tissue inhibitor of metalloproteinases 1; BDNF: Brain-derived neurotrophic factor; VEGF: Vascular endothelial growth factor; AFCs: Annulus fibrosus cells; ECM: Extracellular matrix; NP: Nucleus pulposus; MAPK: Mitogen-activated protein kinase; NIR: Near-infrared radiation; TGF-β: Transforming growth factor-β; HSP: Heat Shock Protein; GSNO: S-nitrosoglutathione; LIPUS: low-intensity pulsed ultrasound; FAK: Focal adhesion kinase; PI3K: Phosphatidylinositol-3-kinase; Akt: Protein kinase B; CAMK1: Calcium/calmodulin dependent protein kinase I; CDK: Cyclin-dependent kinase; Cav1: Caveolin-1; NF-κB: Nuclear factor kappa-B; GAG: glycosaminoglycan; LMHFV: Low-magnitude, high-frequency vibration; AMPK: AMP-activated protein kinase; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator-1 alph; YAP: Yes-associated protein; TAZ: Transcriptional coactivator with PDZ-binding motif; cGAS: Cyclic GMP-AMP synthase; STING: Stimulator of interferon genes; –: data not available or not reported.

3.1. Electrical cue-based strategies and materials for IVDD therapy

The exploration of electrotherapy can be traced back to around 43–48 AD, when the Roman physician Scribonius Largus applied torpedo fish to the limbs and scalp of patients to relieve headaches through electric currents [79]. However, it was not until the 18th century, with the advancing understanding of electricity and electrophysiology, that electrical stimulation (ES) gradually found applications across various medical fields. Compared with conventional pharmacological approaches that primarily rely on diffusion, ES acts more directly on target tissues, enabling efficient energy transmission. Moreover, when integrated with material-based platforms, it can deliver long-term and stable signaling, thereby establishing a physiologically relevant electrical microenvironment within the tissue milieu.

3.1.1. Positive effects of direct ES

Beyond their classical roles in nerve impulse transmission and muscle contraction, electrical cues play a critical regulatory role in cellular processes. Through mechanisms such as alteration of membrane potential, polarized redistribution of membrane receptors, and modulation of voltage-gated ion channel activity, electrical cues regulate downstream signaling pathways, including Ca²⁺/calmodulin (CaM), MAPK, Wnt/β-catenin, and integrin-mediated signaling, thereby modulating protein synthesis and influencing cell migration, fate and behavior [42,[80], [81], [82], [83], [84], [85]]. With ongoing research, ES has achieved substantial advances in multiple fields—including cartilage repair, skin wound healing, spinal cord functional recovery, and muscle hypertrophy—owing to its minimally invasive nature, tunability, and precise targeting [[86], [87], [88]]. In contrast, the application of ES in the IVD field has lagged behind, with relatively slow research progress. Kim et al. developed a microfluidic platform capable of applying low-current continuous stimulation (LCCS) to NPCs [35]. In this setup, NPCs were treated with IL-1β to induce inflammation and degeneration, and the therapeutic effects of different ES intensities (5, 10, 20, 50, and 100 μA) were evaluated. Using immunofluorescence and computational imaging analysis, the authors found that ES at 5, 10, 20, and 100 μA restored the morphological phenotype and improved the kinetic properties of inflammatory human NPCs. In a subsequent study, Kim et al. developed a microfluidic platform integrated with an ES array to investigate the regulatory effects of ES on macrophage-induced inflammatory responses in NPCs (Fig. 2a) [34]. The results showed that under co-culture conditions, a 10 μA ES significantly reduced IL-6 and IL-8 production in human NPCs, whereas a 20 μA ES promoted the secretion of these cytokines in macrophages. These findings suggest that under inflammatory conditions, ES of an appropriate intensity could suppress the production of proinflammatory cytokines in NPCs, thereby alleviating neuropathic pain and reducing immune cell chemotaxis. Kanan et al. created an in vitro degeneration model by puncturing porcine IVDs [36]. DisCure electrodes were implanted to deliver ES, and the discs were cultured under mechanical loading for 21 days before being evaluated. Gross morphological assessment and histological staining indicated that ES promoted collagen fiber reattachment and healing, thereby preventing NP extrusion from the AF. Gene expression analysis further revealed that, compared with unstimulated IVDs, ES not only reduced the expression of proinflammatory cytokines and pain-related markers but also increased the expression of anti-inflammatory factors and ECM markers. In another study, researchers applied capacitively coupled (CC) stimulation to NPCs cultured in alginate beads. They found that CC stimulation activated the endogenous bone morphogenetic protein (BMP)-4 and BMP-7. As a result, it significantly upregulated key ECM components, including sulfated GAG, aggrecan (ACAN), and type II collagen [37]. Wang et al. developed a peripheral sensory-computer interface (PSCI) based on a two-dimensional MoS₂ transistor array for IVDD [38]. The PSCI captures neural signals via cuff electrodes wrapped around the dorsal root ganglion and isolates specific bioelectrical signals associated with IVD regeneration (R band). When a deficiency in R band power is detected, percutaneously implanted electrodes deliver pre-programmed regenerative waves (R waves) directly to the degenerated discs (Fig. 2b). After 28 days of ES stimulation, genes related to ECM synthesis and the repair marker calcitonin gene-related peptide (CGRP) in mouse IVDs were significantly upregulated, accompanied by improved histological scores. This approach not only surpasses conventional ES therapy but also establishes a precedent for applying advanced bioelectronic technologies in in vivo models. Although ES has shown promising therapeutic potential in the treatment of IVDD, the underlying cellular and molecular mechanisms by which ES regulates IVD cells remain incompletely understood. Recently, Zhang et al. developed a sonosensitive particle system that generated free electrons under ultrasound irradiation, thereby producing an electric current within a conductive hydrogel [39]. This ES modulated the membrane potential of degenerative NPCs, triggering the opening of calcium voltage-gated channels (Ca_V). The ensuing Ca²⁺ influx activated Ca²⁺-dependent protein kinase I (CaMK1), which subsequently activated cyclin-dependent kinase (CDK) 1 and 2, driving cell-cycle progression and ultimately promoting NPC regeneration (Fig. 2c). These findings highlight the presence and functional relevance of electro-sensing elements in IVD cells and provide mechanistic insights that support the rational application of ES-based therapies for IVDD.

Fig. 2.

The role of electrical cues in the treatment of IVDD. a) Schematic presentation of microfluidic electroceuticals platform [34]. Copyright 2022, MDPI, Basel, Switzerland. b) Schematic representation of the Peripheral Sensory-Computer Interface (PSCI) system [38]. Copyright 2024, Elsevier B.V. c) The intracellular molecular mechanism by which current facilitates the cell cycle progression in NPCs [39]. Copyright 2025, American Association for the Advancement of Science. d) The fabrication process and biological effects of the self-powered sandwich-structured scaffold with dual-electroactivity for repairing the damaged IVD [40]. Copyright 2025, The Royal Society of Chemistry. e) Piezoelectric injectable hydrogel delivers bone marrow-derived mesenchymal stem cells (BMSCs) by generating ES in response to mechanical stress [41]. Copyright 2025, Elsevier B.V. f) Triboelectric-responsive microneedles (MNs) using the electrochemical characteristics of polypyrrole (PPy) [44]. Copyright 2024, Springer Nature.

3.1.2. Piezoelectric materials

Since the discovery in 1880 by Pierre and Jacques Curie that applying pressure to certain crystals generates electrical properties, the piezoelectric effect has garnered widespread attention and found applications across various fields [89]. Subsequent studies revealed that biological tissues themselves exhibit piezoelectric properties. For example, in the field of sports medicine, bone tissue generates electrical signals through its collagen fibers under mechanical stress, influencing bone remodeling [90]. Studies have shown that the piezoelectricity of the bovine caudal IVD can locally generate a longitudinal voltage of 0.38 to 1.5 nV [91]. In recent years, piezoelectric materials have rapidly emerged. Through the electric dipole moment of their non‐symmetric crystal structures, these materials become polarized along the direction of applied stress, thereby releasing electrical charges [92]. Based on this property, piezoelectric materials have been used as tissue engineering scaffolds to achieve in vivo ES without an external power supply, providing both mechanical support and stable ES for IVD repair [93]. Piezoelectric biomaterials can be broadly classified according to their chemical composition into inorganic and organic categories. Representative inorganic piezoelectric materials include BaTiO₃, sodium potassium niobate (NKN), ZnO, LiNbO₃, and MgSiO₃, which are generally characterized by relatively high piezoelectric coefficients [94]. In contrast, organic piezoelectric materials such as polyvinylidene fluoride (PVDF), poly-L-lactic acid (PLLA), collagen, and polysaccharides exhibit notable advantages in biocompatibility and mechanical flexibility [95]. Wang et al. incorporated graphene into a polycaprolactone (PCL) matrix to form electro-osmotic networks, resulting in an electroconductive scaffold (G10) [40]. Subsequently, PVDF fibrous membranes doped with tetragonal BaTiO₃ were electrospun onto both the upper and lower surfaces of G10, yielding a nanostructured scaffold with combined piezoelectric and dielectric activities. The obtained sandwich-structured scaffold effectively restored the electrophysiological microenvironment of the IVD and harvested mechanical energy at defect sites of injured IVDs to generate ES, thereby promoting the regeneration process. In vivo implantation of the dual-electroactive scaffolds in rats significantly reduced cell loss, preserved disc structural integrity, and accelerated the repair of IVD defects (Fig. 2d). Xiang et al. developed an injectable hydrogel incorporating BaTiO₃ nanoparticles and loaded it with bone marrow–derived mesenchymal stem cells (BMSCs) [41]. Under mechanical loading, the ES generated by the hydrogel activated Piezo1 channels, increasing intracellular Ca²⁺ levels and triggering endogenous repair mechanisms, thereby enhancing BMSC survival after delivery. Meanwhile, the voltage generated by continuous mechanical loading activated the MAPK and Wnt signaling pathways, promoting BMSC proliferation and differentiation into NPCs (Fig. 2e). In a rat model of IVDD, this piezoelectric hydrogel maintained a higher disc height index and MRI water signal intensity, while histological analyses revealed significantly increased expression of type II collagen and ACAM. Liu et al. combined human genetic evidence with histological validation of degenerated IVDs to identify aberrant activation of the PI3K-Akt signaling pathway as a key node in lumbar disc herniation [42]. On this basis, they integrated the piezoelectric properties of diphenylalanine crystals with the structural advantages of gelatin methacryloyl (GelMA) to construct a piezoelectric scaffold with hierarchical porosity and high cellular and nutrient permeability. In vitro, mechanical deformation of the scaffold generated bioelectrical signals that suppressed PI3K-Akt signaling, leading to marked anti-inflammatory and anti-oxidative effects and improved mitochondrial function. In a rat IVDD model, the scaffold promoted restoration of NP structure and biochemistry, reestablished fixed charge density associated with disc electrochemical homeostasis, and recovered disc biomechanical function. Similarly, Wu et al. demonstrated that piezoelectric stimulation generated by their engineered pyrrole/BaTiO₃ nanoparticles activated the AMPK-FOXO1a signaling pathway and promoted FOXO1a nuclear translocation [43]. The intranuclear increase of FOXO1a effectively enhanced mitophagy, improved mitochondrial quality control, and ultimately delayed senescence in NPCs. Meanwhile, the co-loaded tannic acid facilitated ROS scavenging and synergized with piezoelectric stimulation to enhance FOXO1a transcriptional activity via upregulation of SIRT1.

3.1.3. Electro-responsive materials

ES can also function as a physical on–off switch, enabling precise therapeutic control and minimizing side effects. Inherently conductive polymers (ICPs) constitute a class of smart electro-responsive materials whose redox states can be reversibly switched under an applied electrical potential, enabling controllable modulation of drug release profiles. Among them, polypyrrole (PPy) is the most widely used ICP owing to its well-established biocompatibility and high electrical conductivity, making it particularly suitable for electrically controlled and precisely triggered release systems in biomedical applications [96]. Polyaniline (PANi) represents another extensively investigated ICP that can exist in multiple oxidation states, among which the emeraldine form is the most stable and electrically conductive [97]. Zhang et al. demonstrated that excessive mechanical loading disrupts the translocation associated membrane protein 1 (TRAM1)-three-prime repair exonuclease 1 (TREX1) protein complex in NPCs, leading to the translocation of the DNA exonuclease TREX1 from the endoplasmic reticulum to the nucleus [44]. This translocation causes genomic DNA damage and accelerates NPC senescence. To counteract this process, extracellular vesicles (EVs) engineered to carry TRAM1 were constructed to restore the TRAM1-TREX1 complex within the IVD. To achieve controlled release, the researchers developed a self-powered microneedle (MN) system based on a triboelectric nanogenerator (TENG): body movements drive relative motion between different friction layers in the TENG, generating an electrical signal. This signal reduces the PPy coating on the MNs from its oxidized state to a zero-valence state, abolishing its electrostatic adsorption and thereby precisely releasing the negatively charged engineered EVs on the MN surface (Fig. 2f). This system was shown to effectively suppress cellular senescence and inflammation during IVDD progression, offering an innovative strategy for precise treatment of IVDD.

3.1.4. Clinical applications of ES in IVD-related diseases

Ratajczak et al. compared the therapeutic efficacy of diadynamic current therapy and transcutaneous electrical nerve stimulation (TENS) in patients with discogenic low back discopathy [98]. Compared with baseline, both interventions significantly reduced pain intensity and improved performance in functional fitness tests, indicating comparable clinical benefits of these electrotherapeutic modalities. Wang et al. investigated the clinical efficacy of ES therapy for sciatica caused by lumbar disc herniation [99]. They enrolled 100 patients with lumbar disc herniation-induced sciatica and randomly assigned them to a control group, which received conventional therapies such as traction, and an experimental group, which received ES using a functional ES therapy instrument. The results showed that the experimental group exhibited significantly higher total cure-remarkable-effectiveness rate and greater reductions in pain scores compared with the control group. In addition, peripheral ROS levels decreased in both groups after treatment, with the experimental group showing significantly lower ROS levels than the control group. These findings indicate that ES is not only an effective physical therapy for pain relief but may also exert therapeutic effects by modulating oxidative stress.

Additionally, electroacupuncture (EA), which combines traditional acupuncture with modern ES, has a long history of use in back pain management. Wang et al. demonstrated that EA alleviates IVDD by restoring the expression of aquaporin (AQP) 1 and AQP3 via the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway [100]. However, clinical studies investigating EA for IVDD-related pain remain limited. Future research should employ large-scale, multicenter randomized controlled trials to further elucidate the molecular mechanisms and therapeutic standards of EA in treating disc degeneration, thereby promoting its clinical translation and standardized application.

Although ES has shown potential in treating IVDD by modulating the inflammatory microenvironment, promoting ECM regeneration, and alleviating pain, its clinical application still faces multiple challenges. The lack of disease models that simulate human mechanical loading, such as 3D multicellular interaction platforms, limits mechanistic insights and the precise optimization of treatment protocols. Future studies should integrate single-cell sequencing and organ-on-a-chip technologies to map metabolic reprogramming in IVD cell subpopulations under ES, thereby elucidating dynamic regulatory networks linking electrical signals, gene expression, and matrix synthesis. Recent randomized controlled trials comparing TENS with exercise for lumbar disc herniation suggest that TENS may have limited effects on pain relief and functional improvement compared with exercise alone [101,102]. This may be due to the minimal current delivered through the skin, resulting in negligible effects on deeper disc tissue. In addition, penetrating electrodes pose risks of infection and potential interference with cardiac pacemakers, which severely hampers clinical translation and widespread adoption. Therefore, developing more targeted, tolerable, and noninvasive ES technologies remains a key challenge. With advances in lightweight batteries and self-powered devices, ES systems are becoming increasingly portable, physiologically compatible, and suitable for long-term implantation. These technological improvements not only enhance the feasibility and patient compliance of ES therapy but also open new possibilities for treating deep-tissue conditions such as disc degeneration [103,104]. Nevertheless, achieving long-term electrical stability, precisely controllable biodegradability, and genuinely intelligent, adaptive bioelectronic feedback remains a central challenge for next-generation implantable ES systems and represents a key frontier for future research.

3.2. Magnetic cue-based strategies and materials for IVDD therapy

Electric and magnetic fields (MFs) are two manifestations of electromagnetic phenomena. While distinct, they are closely interconnected and together form the foundation of electromagnetism. Unlike direct ES, which relies on electrodes to deliver localized currents, MFs can induce biological effects in a contact-free and noninvasive manner, enabling deeper tissue reach and improved patient tolerability. MFs have been found not only to serve as cues for orientation in certain organisms but also to possess notable advantages for tissue repair, including non-invasiveness, strong penetration, and high biocompatibility [[105], [106], [107]]. These attributes have fueled the emerging field of magnetobiology, an interdisciplinary discipline that focuses on the effects of MFs on organisms, cells, and biomolecules, and holds significant potential for advancing unexplored areas of research. Depending on their origin and temporal characteristics, MFs can be categorized into static magnetic fields (SMFs) and dynamic MFs. Among these, SMFs and pulsed electromagnetic fields (PEMFs) are the most widely used in both basic and clinical studies [108,109]. SMFs, in which the intensity and direction remain constant over time, represent the most fundamental form of MFs and serve as the basis for other types of electromagnetic fields [110].

3.2.1. Positive effects of direct MFs

MFs can be transduced into biologically perceivable signals through intracellular magnetically induced proteins and various magnetic materials, thereby exerting diverse cellular effects, such as magnetocaloric, magnetochemical and magnetostrictive effect [111]. At the cellular level, MFs have been shown to interact with membrane ion channels, promote the polarized translocation of intracellular organelles, and modulate integrin clustering, providing a basis for subsequent regulation of cell behavior [112,113]. Miller et al. investigated the effects of PEMF on gene expression in IVD cells under inflammatory conditions and found that PEMF treatment reduced the early expression of proinflammatory cytokines and ECM-degrading enzymes, although this effect diminished after seven days [45]. The therapeutic benefit of PEMF appeared to be limited to the suppression of early inflammatory signaling. The authors further speculated that the observed effects might be associated with accelerated activation of CaM and its downstream NO signaling pathway. Similarly, Tang et al. reported that PEMF exposure suppressed IL-6 transcription induced by the proinflammatory cytokine IL-1α, further supporting the notion that PEMF exerts its therapeutic effects through modulation of inflammatory signaling [46]. Zheng et al. demonstrated that PEMF activated a SIRT1-dependent autophagic network in NPCs, which enhanced ECM synthesis and successfully alleviated IVDD in a rat model (Fig. 3a) [47]. Kermani et al. demonstrated that PEMFs, at both high and low frequencies, significantly reduced the B-cell lymphoma protein 2 (Bcl2)-associated X protein (Bax)/Bcl2 ratio in degenerated rat IVDs [48]. These findings suggest that modulation of apoptotic proteins may represent one of the mechanisms by which PEMFs delay IVDD.

Fig. 3.

The role of magnetic cues in the treatment of IVDD. a) The PEMF exposure system and output waveform [47]. Copyright 2022, Frontiers Media S.A. b) SMF enhance the secretion of microvesicles by mesenchymal stem cells (MSCs) [49]. Copyright 2024, Springer Nature. c) Schematic illustration of fabrication of superparamagnetic hydrogel and its role in enhancing in situ IVD regeneration [50]. Copyright 2024, Wiley-VCH GmbH.

Increasing evidence indicates that EVs derived from mesenchymal stem cells (MSCs), including microvesicles and exosomes, can be internalized by NPCs to modulate the microenvironment and cellular phenotype, thereby promoting tissue regeneration and repair [114]. Shi et al. employed RNA-seq analysis and found that exposure to a SMF upregulated the microtubule-based transport protein kinesin family member 5b (Kif5b) and enhanced its interaction with Rab22a, ultimately promoting the secretion of microvesicles from MSCs [49]. These microvesicles were encapsulated within a photocrosslinkable GelMA hydrogel, which significantly delayed IVDD in vivo (Fig. 3b). Interestingly, MFs not only play a role in promoting EV secretion but also show potential for facilitating the transfection of biomolecules into EVs. Wang et al. developed an innovative gene therapy strategy based on magnetofection technology [115]. Polyethylenimine (PEI)-modified iron oxide nanoparticles (IONPs) were employed as non-viral vectors. Under the synergistic action of an electromagnetic field, this system efficiently delivered miR-21 into BMSCs and human umbilical vein endothelial cells by activating the p38 MAPK signaling pathway. When the miR-21-transfected cells were seeded onto 3D-printed scaffolds and implanted into a rat spinal fusion model, the treatment effectively promoted new bone formation and achieved successful vertebral fusion. In the future, this magnetofection strategy may also be applicable to IVD cells.

3.2.2. Magneto-responsive materials

Beyond directly regulating cellular behavior, MFs have been incorporated into smart materials to create various responsive therapeutic platforms, further expanding their potential in IVD repair. Many researchers have focused on embedding magnetic nanoparticles (MNPs) into hydrogels, enabling these hydrogels to efficiently convert magnetic energy into motion and force under an applied MF, thereby serving as potential artificial micro-/nanomotors for targeted therapy [107]. For biomedical applications, MNPs are typically selected from materials with high saturation magnetization, such as pure metals and ferrites. However, due to the high toxicity and susceptibility to oxidation of pure metals, iron oxides with excellent stability and biocompatibility are preferred [116]. Xue et al. utilized superparamagnetic IONPs to construct a magneto‐responsive cellular hydrogel (Mag-gel) [50]. The aptamer DB67 in Mag-gel exhibits specific binding affinity for endogenous nucleus pulposus stem cells (NPSCs) and recruits them to sites of IVD injury. Under a MF, the implanted Mag-gel responds and applies tunable micro-/nano-scale forces to the recruited NPSCs, remodeling their cytoskeleton and activating calcium channels, thereby promoting NPSC proliferation and precise differentiation (Fig. 3c).

3.2.3. Clinical applications of MFs in IVD-related diseases

Clinical studies applying MFs to the IVD are still limited, and most researchers have focused on alleviating pain and restoring functional outcomes rather than directly assessing improvements in IVDD. In a double-blind randomized controlled trial involving patients with cervical disc herniation, the experimental group received TENS, hot pack (HP) therapy, and real PEMF, while the control group received the same TENS and HP treatments but with a sham PEMF exposure without current flow. Both groups showed general improvements in pain, functional disability, anxiety, depression, and quality of life after 3 weeks of treatment. However, during the 12-week follow-up, the PEMF group demonstrated significant advantages, exhibiting greater improvements in pain and sleep quality compared with the control group [117]. In another randomized controlled trial, patients with lumbar disc herniation–induced radicular pain were assigned to receive either PEMF or a placebo treatment to evaluate PEMF's efficacy as a conservative therapy for LBP with radiculopathy. PEMF was found to significantly reduce pain, improve daily function, and alleviate lower limb nerve compression symptoms while enhancing neural function [118].

Magnetic cues have attracted increasing attention owing to their high tissue penetration depth and relatively low energy attenuation [111]. However, the clinical translation of MF therapies still faces multiple challenges. First, most existing clinical studies involve small sample sizes and substantial interindividual variability, limiting the generalizability and statistical robustness of their findings. Second, in vitro experiments fail to fully recapitulate the complex in vivo microenvironment, thereby weakening the clinical relevance of the conclusions. From a technical standpoint, the parameters of PEMFs, such as waveform and intensity, remain highly variable. It is therefore essential to determine the optimal settings that promote anabolism, suppress catabolism, and improve the inflammatory microenvironment. Moreover, both SMFs and PEMFs typically exhibit relatively broad radiation ranges, making precise spatial targeting difficult. This lack of selectivity may lead to undesired off-target effects and restrict their use in patients with implanted electronic devices, such as pacemakers. Consequently, the development of miniaturized MF generators with spatially confined and precisely controllable radiation range would be highly advantageous [119]. With respect to magnetic biomaterials, further investigation is required to systematically evaluate cellular biosafety, as well as to design next-generation magnetic nanomaterials with enhanced biocompatibility and programmable biodegradability. Despite these challenges, MF therapy holds promise as a forward-looking strategy that may overcome the limitations of many conventional approaches.

3.3. Photo cues-based strategies and materials for IVDD therapy

Light, as a noninvasive physical factor in the life sciences, has demonstrated unique advantages in medicine. Advances in technology have transformed light from a simple observational tool into a precise and versatile modality with profound implications for targeted therapy [120]. Distinct from electrical or magnetic cues, light represents a fundamentally distinct class of biophysical cues, enabling contact-free and highly localized regulation that may be difficult to achieve with electrical or magnetic cues. From dermatological disorders such as psoriasis to neurodegenerative diseases like Alzheimer's disease and ophthalmic conditions including dry eye disease, phototherapy has become a standardized clinical practice. Owing to its ease of operation and controllable side effects, it has emerged as an attractive alternative to conventional pharmacological and surgical treatments [[121], [122], [123]]. In the following section, we discuss the applications of photo cues in IVDD.

3.3.1. Positive effects of direct light stimulation

Photobiomodulation (PBM) refers to the use of optical devices to regulate biological activity through non-thermal mechanisms. PBM relies on the absorption of photons by photoacceptor molecules (primarily cytochrome oxidase), leading to the activation of various signaling pathways as well as alterations in intracellular levels of adenosine triphosphate (ATP), NO, and ROS, which in turn directly or indirectly promote gene expression [[124], [125], [126]]. Therefore, PBM, as an inexpensive and noninvasive approach, holds great promise in various fields—including tissue regeneration, neural stimulation, and inflammation suppression. Hwang et al. used macrophage-conditioned medium to culture human NPCs, upregulating ECM enzymes and successfully inducing a degenerative response in these cells [51]. PBM was able, in a dose- and wavelength-dependent manner, to selectively modulate the gene expression and protein secretion of ECM enzymes—particularly MMP-1—in this degenerative NPC model without causing cytotoxicity. In a separate study by the same group, PBM was shown to selectively inhibit the production of inflammatory mediators, ECM enzymes, and neurotrophins in degenerated human AFCs, also in a dose- and wavelength-dependent manner [52]. Zhang et al., in a rabbit IVDD model, applied 970-nm diode laser therapy (DLT), which upregulated collagen II and ACAN while suppressing the expression of inflammatory cytokines [53]. Western blot analysis revealed that inhibition of the p38 MAPK signaling pathway played a critical role in the DLT-mediated improvements observed during IVDD progression (Fig. 4a).

Fig. 4.

The role of photo cues in the treatment of IVDD. a) Schematic diagram of the potential protective effects of 970-nm diode laser in IVDD [53]. Copyright 2023, Springer Nature. b) Restoration of IVDD by HA-NCSN/Cu hydrogel through antioxidant and photothermal therapy [54]. Copyright 2024, Wiley-VCH GmbH. c) Schematic illustration of high-strength smart MNs enabling minimally invasive AF penetration and NIR-controlled drug release and photothermal therapy [55]. Copyright 2023, Wiley-VCH GmbH. d) Red light-mediated NO release for the treatment of IVDD and modic changes and the local delivery of NO can exert antibacterial, anti-inflammatory, and anti-osteoclastogenesis Effects [58]. Copyright 2022, American Chemical Society.

3.3.2. Photothermal materials

Nanoparticle-mediated photothermal therapy (PTT) is a minimally invasive approach with high spatiotemporal control and precise targeting, showing great promise in tumor therapy and tissue repair [127]. Studies have shown that mild thermal stimulation generated when the oscillation of electrons on nanoparticle surfaces resonates with incident light can enhance cellular function, alleviate tissue hypoxia, and promote tissue regeneration [128,129]. Certain inorganic materials, including carbon-based nanomaterials, metal nanoparticles and their compounds, and metal oxides, as well as organic materials such as porphyrins, polypyrroles, and polydopamine (PDA), exhibit efficient responses to near-infrared (NIR) irradiation with strong light absorption and high photothermal conversion efficiencies, and have therefore been widely utilized as photothermal agents (PTAs) [130,131]. Bu et al. grafted thiourea groups onto hyaluronic acid, effectively chelating Cu²⁺ to form a dynamic hydrogel (HA-NCSN/Cu) [54]. In this structure, the thiourea groups not only directly scavenge ROS to alleviate the inflammatory stress of NPCs but also, due to their strong reducing nature, rapidly reduce a portion of Cu²⁺ to Cu⁺. This reduction causes the hydrogel to darken during the gelation process, endowing it with photothermal properties. Under 808 nm NIR irradiation, the photothermal effect activates the transforming growth factor-β (TGF-β)/Smad signaling pathway, promoting ECM synthesis and inhibiting ECM degradation. They validated this one-stone-two-birds strategy in vitro, successfully achieving the restoration of the structure and function of the damaged IVD (Fig. 4b). Similarly, Meng et al. also combined anti-inflammatory and photothermal therapies [55]. They developed a PDA/GelMA composite MN system anchored to the AF. Diclofenac sodium, serving as the extracellular anti-inflammatory agent, was loaded into the MNs, while PDA nanoparticles also had ROS-scavenging properties. Upon NIR external stimulation, the photothermal effect significantly increased the transcription of HSP genes in AFCs, thereby enhancing cellular self-protection and resistance to the harsh microenvironment. Notably, the introduction of the photothermal effect allowed for the remote release of diclofenac from the MNs in response to NIR over long distances (Fig. 4c). Chen et al. developed a photothermal hydrogel system containing Mn₃O₄ nanoparticles, which could adhere to AF defects [57]. The Mn₃O₄ nanoparticles not only possess triple antioxidant enzyme activities (SOD/CAT/GPx) but also induce a mild photothermal effect under NIR irradiation, suppressing inflammation and restoring ECM homeostasis.

3.3.3. Photo-responsive materials

The magic of light extends beyond this—it also serves as a switch for cargo release and material synthesis, playing a crucial role in various material systems with significant implications for advanced biomedical applications, including those for IVDD. Coupling photothermal effects with thermoresponsive materials offers a simple and feasible stimulus-responsive strategy. Meanwhile, incorporating photosensitive moieties into hydrogels or nanocarriers allows the design of a wide range of smart systems, with commonly used groups including o-nitrobenzyl, coumarin-4-ylmethyl, azobenzene, and spiropyran. However, it should be noted that many of these photosensitive moieties, particularly o-nitrobenzyl and coumarin-4-ylmethyl groups, predominantly respond to UV or visible light, which suffers from limited tissue penetration and thus restricts their applicability in deep tissues such as the IVD [[132], [133], [134]]. Consequently, strategies that shift or extend photo-responsiveness into the near-infrared or red-light window are critical for improving translational feasibility. Cutibacterium acnes (C. acnes) infection is considered a pathogenic factor in both IVDD and Modic changes, but the avascular nature of IVDD makes it difficult for orally administered antibiotics to penetrate and effectively clear the infection. Tao et al. designed and synthesized micellar nanoparticles containing a palladium (II) meso-tetraphenyl-tetraphenylporphyrin photocatalyst and coumarin-based NO donors [58]. Leveraging photoredox catalysis, this system successfully modulated the photo-responsiveness of coumarin-based donors, enabling efficient NO release under red-light irradiation. The locally delivered NO exerts a synergistic triple action—antibacterial, anti-inflammatory, and antiosteoclastogenesis effectively treating C. acnes-induced IVDD and Modic changes (Fig. 4d). Xie et al. integrated the PTA polyaniline with the NO donor S-nitrosoglutathione (GSNO) to construct an AF-targeted microneedle platform that combines photothermal capability with photo-responsive NO release [56]. Under mild photothermal conditions, this platform induced HSP expression in AFCs, while simultaneously exploiting the thermosensitive nature of GSNO to achieve controlled NO release. This dual-mode therapeutic strategy effectively attenuated inflammation in AFCs, promoted ECM remodeling, and facilitated tissue repair. In recent years, photo-crosslinked hydrogels have recently attracted considerable interest in the treatment of IVDD, thanks to their capacity to gel in situ and be easily delivered via injection [135]. Kumar et al. developed a novel light-curable injectable synthetic hydrogel using polyamidoamine-grafted polyhydroxyethyl methacrylate co-N-(3-aminopropyl) methacrylamide and the photoinitiator Irgacure 2959 [136]. The researchers mixed human MSCs with the polymer solution and optimized ultraviolet (UV) exposure to achieve safe and efficient photo-crosslinking, providing encapsulated MSCs with a hypoxic condition to drive their differentiation into NPCs. This design not only supports MSC encapsulation and differentiation but also offers an injectable, biodegradable engineered solution for IVD regeneration.

In addition to material-mediated photo-responsive strategies, optogenetics, which enables genetically encoded, light-controlled regulation of specific cellular signaling pathways with high spatiotemporal precision, represents a conceptually attractive light-based approach [137]. To the best of our knowledge, optogenetic strategies have not yet been directly applied to IVDD therapy, but they may provide a promising conceptual framework for future photo-regulated interventions in disc regeneration research.

3.3.4. Clinical applications of light stimulation in IVD-related diseases

Unlike the studies mentioned above, which use mild light stimulation to promote the physiological function and morphological characteristics of IVD cells, clinical research tends to focus more on the effects of high-intensity light stimulation for pain relief and improvement in functional recovery. Boyraz et al. compared the efficacy of high-intensity laser therapy (HILT), ultrasound therapy, and a combination of medication and exercise therapy in patients with lumbar disc herniation [138]. The results showed significant improvements in pain-related scores [visual analogue scale (VAS), body pain (BP), Oswestry Disability Index (ODI)], general health (GH), vitality (VT), and social function (SF) following HILT treatment. Further significant improvements in ODI, physical function (PF), BP, GH, and VT were observed at the third month after therapy compared with values at the end of treatment. Collagenase chemonucleolysis is a targeted enzymatic therapy that specifically hydrolyzes type II collagen fibers, thereby reducing the volume of herniated NP tissue and alleviating nerve compression. Song et al. evaluated whether combining HILT with collagenase chemonucleolysis could accelerate early postoperative recovery in patients with lumbar disc herniation, compensating for the delayed onset of collagenase treatment [139]. Their results showed that at one week and one month postoperatively, the combined therapy produced superior outcomes in VAS scores, excellent/good rates, ODI scores, and SF-36 quality-of-life measures compared to the control group, although these benefits gradually diminished over time. These findings suggest that HILT can enhance early pain relief and functional recovery following collagenase chemonucleolysis, addressing unmet needs in postoperative care. Yilmaz et al. compared HILT with a combination of ultrasound treatment and TENS therapy for cervical disc herniation-related pain, cervical range of motion (ROM), and functional outcomes [140]. They found that HILT combined with exercise therapy improved ROM, VAS scores, and neck pain and disability scale (NPADS) scores compared to baseline, demonstrating the potential clinical utility of HILT in disc-related disorders.

Although phototherapy shows promising potential in treating IVDD, its clinical translation still faces several challenges. First, conventional light sources have limited tissue penetration, making it difficult to effectively target deep regions of the IVD, while light scattering in biological tissues leads to uneven energy distribution and restricts precise targeting. High-intensity irradiation may also induce local temperature rises, posing potential risks of thermal damage. Moreover, systematic comparisons of different energy levels and irradiation durations are still lacking. A randomized clinical study by Ay et al. reported no significant differences between laser and placebo laser treatments in pain severity or functional capacity in patients with acute or chronic LBP caused by lumbar disc herniation, highlighting the controversial and inconsistent clinical evidence despite encouraging experimental findings [141]. In the future, systematic investigations across different light wavelengths, irradiation intensities, and exposure durations will be essential to clarify therapeutic windows and enable phototherapy to progress from symptomatic relief toward precise interventions that promote structural regeneration of the IVD.

3.4. Ultrasonic cues-based strategies for IVDD therapy

Given the inherent limitations of phototherapy in tissue penetration and deep targeting, there is a growing interest in alternative noninvasive physical modalities capable of delivering energy more effectively to deep IVD regions without inducing excessive thermal damage. In this context, ultrasound (US) has emerged as a particularly attractive candidate. US technology has long been widely utilized in medical imaging and diagnosis, and its non-invasive nature, perceived safety, targeting ability, strong penetration, and ease of use have gradually highlighted its significant therapeutic potential [142]. In recent years, the application of US technology has expanded beyond its role as a diagnostic tool to encompass a variety of therapeutic applications. For instance, high-intensity focused ultrasound (HIFU) enables non-invasive tumor ablation, while low-intensity pulsed ultrasound (LIPUS) promotes tissue repair. Moreover, US has demonstrated great promise in cutting-edge fields such as material construction, drug delivery, and gene therapy, steadily evolving into a multifunctional therapeutic platform. These advancements position US technology as a pivotal tool in the realm of medical treatments. Adams et al. demonstrated that spatially precise delivery of LIPUS to deep lumbar IVDs is clinically feasible [143]. Using 3D anatomical models and simulation-based analysis, LIPUS was accurately focused on AF and NP regions with minimal off-target exposure and negligible thermal elevation. These findings support the translational potential of noninvasive and controllable US therapy for IVDD.

3.4.1. Positive effects of direct US stimulation

US can serve as a direct external stimulus, inducing both thermal and non-thermal effects, such as cavitation, microstreaming, and radiation force to achieve therapeutic outcomes [[144], [145], [146]]. Iwashina et al. applied LIPUS using the Sonic Accelerated Fracture Healing System to stimulate alginate 3D-cultured rabbit IVD cells, systematically reporting the dual-promoting effects of LIPUS on the proliferation of NPCs and AFCs, as well as the synthesis of proteoglycans [59]. In a contemporaneous study, Miyamoto et al. verified the regulatory effects of LIPUS on the ECM metabolism of NP and inner/outer AF cells in cattle [60]. They found that LIPUS significantly enhanced proteoglycan and collagen synthesis in bovine IVD cells​. Zhang et al. revealed that the mechanical stimulation induced by LIPUS upregulated or aggregated integrins in the cell membrane, subsequently activating the FAK/PI3K/Akt/Sox9 pathway, which significantly promoted ECM synthesis and inhibited degradation in degenerated human NPCs, providing a molecular basis for non-invasive treatment of IVD (Fig. 5a) [61].

Fig. 5.

The role of ultrasonic cues in the treatment of IVDD. a) The signaling pathway activated by LIPUS [61]. Copyright 2016, Wolters Kluwer Health, Inc. b) US-mediated improvement of IVDD by Gelatin-Agarose-Laccase (GAL) hydrogel and the underlying mechanism [62]. Copyright 2024, Elsevier B.V. c) Schema of the microbubble-enhanced US gene transfer to the IVD in vivo [64]. Copyright 2006, Lippincott Williams & Wilkins, Inc. d) The mechanism by which US-induced TCPP@PPy sonosensitive particles generate free electrons [39]. Copyright 2025, American Association for the Advancement of Science. e) Schematic illustration of US-induced piezoelectric activation in pyrrole/BaTiO₃ nanoparticles and the consequent controlled release of electrostatically adsorbed TGF-β [43]. Copyright 2025, Elsevier Ltd.

3.4.2. US-responsive materials

The capacity of US to precisely regulate cellular responses underscores its versatility as a programmable stimulus, in which parameters such as intensity and frequency can be engineered to act as controllable “switches” that trigger material responses for spatiotemporal drug or biofactor release. In general, US-induced drug release from delivery carriers is primarily mediated by two mechanisms: thermal effects and cavitation associated with nano- or microbubbles. Inertial cavitation, characterized by the violent collapse of bubbles, generates intense shear stresses and shock waves that promote rapid drug release but may simultaneously disrupt cellular structures and induce ROS generation; this mechanism is therefore more commonly exploited in tumor therapy. In contrast, stable cavitation occurs when the frequency of applied US closely matches the oscillation frequency of the bubbles, resulting in relatively mild oscillations without catastrophic collapse, rendering it more suitable for regenerative and tissue-repair applications [147]. Lu et al. designed and fabricated a temperature-sensitive injectable hydrogel based on gelatin and agarose, which was loaded with laccase and a CXCR4 agonist (ATI2341) [62]. Laccase consumes oxygen to effectively activate HIF-1α, thereby suppressing apoptosis of NPCs and maintaining ECM homeostasis, while ATI2341 can be released in response to the thermal stimuli generated by US to recruit stem cells toward the NP region. In vivo experiments in rats demonstrated that the combined application of this hydrogel and US stimulation effectively alleviated IVDD (Fig. 5b). Shen et al. developed a US-responsive system for IVDD therapy by loading resveratrol (RES) into PLGA nanobubbles conjugated with CDH2 antibodies [63]. Under low-intensity US stimulation, cavitation effect induced the rupture of nanobubbles, triggering the release of encapsulated RES. The released RES activated the SIRT1 signaling pathway, thereby suppressing apoptosis and promoting ECM synthesis in NPCs. Similarly, Nishida et al. designed a microbubble-enhanced US gene transfer technique [64]. In brief, they mixed the microbubbles with plasmid DNA and injected the resulting complexes into the rat caudal IVDs. Subsequent US exposure at the disc surface caused the microbubbles to collapse and generated transient pores on the cell membrane, enabling efficient intracellular delivery of plasmid DNA. This US-mediated gene transfer technique markedly enhanced the in vivo transfection efficiency of NPCs, offering several advantages for IVD gene delivery, including low immunogenicity and high biosafety (Fig. 5c). Beyond thermal effects and cavitation, US can be converted into bioelectrical cues via engineered material systems, providing an alternative mechanism for US-responsive regulation. As discussed above, US-induced ES has shown promise in regulating IVD cell behavior. Here, we focus on the material design strategies underlying the generation of US-induced ES. Zhang et al. reported that tetrakis (4-carboxyphenyl) porphyrin (TCPP) exhibits excellent aqueous solubility, biocompatibility, high photothermal conversion efficiency, and remarkable sonosensitivity [39]. Based on these properties, they encapsulated TCPP within PPy to form sonosensitive particles (TCPP@PPy), which were further integrated with conductive PPy/polyvinyl alcohol (PVA) polymers and the ROS-sensitive cross-linker TSPBA to construct a sonosensitive conductive hydrogel (TCPP@PPy-PPy/PVA). Under US irradiation, electrons within the TCPP@PPy are more readily excited from the highest occupied molecular orbital (HOMO), overcome the bandgap, and transition into the lowest unoccupied molecular orbital (LUMO). Concurrently, the conductive PPy functions as an electron trap, facilitating free electron transfer and thereby generating an ultrasonic current. This ES activates the Ca²⁺-CaMK1-CDK1/2 signaling cascade to promote cell cycle progression and tissue regeneration, while TSPBA enhances ROS clearance to suppress ferroptosis (Fig. 5d). Customized US treatment using this system successfully alleviated IVDD in a goat model, demonstrating the clinical translational potential of this noninvasive therapeutic strategy. However, invasive delivery remains partially indispensable. Moreover, the intrinsic periodic oscillatory nature of US endows it with unique compatibility with piezoelectric materials, thereby enabling highly efficient and precisely controllable ES. As discussed in the section on piezoelectric materials, the work by Wu et al. provides a representative example of this US-piezoelectric response strategy [43]. In their study, TGF-β was stably anchored onto the surface of pyrrole/BaTiO₃ nanoparticles via electrostatic adsorption. Upon US stimulation, TGF-β was released in a controllable manner, thereby effectively modulating ECM imbalance (Fig. 5e).

3.4.3. Clinical applications of US stimulation in IVD-related diseases

US has long been employed in physical therapy and is considered a safe and effective modality in the clinical management of various musculoskeletal disorders. In the randomized controlled trial by Boyraz et al., in addition to evaluating the efficacy of HILT, the study also revealed that patients who received US treatment for lumbar discopathy showed significant post-treatment improvements in pain-related scores, functional parameters, and mental health indicators compared with their baseline values [138]. Long-term (3-month) follow-up revealed that the US group maintained more sustained improvements in the ODI score as well as in PF, BP, GH, and MH parameters. These findings suggest that US can serve as an effective physical therapy option for lumbar disc herniation, particularly for patients seeking long-lasting therapeutic benefits. In another study mentioned earlier, Yilmaz et al. reported that US + TENS + exercise and HILT + exercise achieved comparable therapeutic outcomes, both significantly relieving cervical disc herniation-related pain and improving cervical mobility and function immediately after treatment [140]. However, the absence of a standalone US group and the short follow-up duration limited the evaluation of the independent and long-term effects of US therapy.

Nevertheless, it should be noted that US exposure may be accompanied by thermal effects depending on acoustic parameters, exposure duration, and tissue properties, which, if not carefully controlled, could increase the risk of localized overheating or inflammatory responses. Moreover, inertial cavitation induced by high-intensity US may disrupt cellular membranes and ECM integrity, leading to localized tissue damage and, in extreme cases, affecting nearby neural structures such as spinal nerves [148]. Consequently, achieving an optimal balance between sufficient tissue penetration and the minimization of side effects remains an urgent and unresolved challenge. The continued development and integration of these technologies are paving the way for more effective and minimally invasive therapies for IVDD.

3.5. Mechanical cues-based strategies for IVDD therapy

Unlike other biophysical cues that act primarily as external modulatory signals, mechanical biophysical cues are intrinsically and inseparably coupled to the IVD, a load-bearing organ. Mechanical signals are therefore not merely therapeutic interventions but fundamental determinants of disc homeostasis and degeneration. Existing studies have reported that aberrant mechanical loading may activate Piezo1, thereby promoting inflammation, oxidative stress, and senescence in IVD cells [149,150]. Excessive cyclic tensile strain can even disrupt the circadian rhythm of NPCs and accelerate the degradation of the ECM [151]. However, a growing body of evidence suggests that mechanical stimulation is not entirely detrimental. In fact, mechanical stress, in concert with biological factors, collectively influences the physiological homeostasis of IVD cells, the anabolic metabolism of the ECM, and the morphological structure of the disc. Disruption of this balance may lead to pathological conditions such as AF fissures, NP dehydration, and endplate sclerosis [152].

3.5.1. Positive effects of direct mechanical stimulation

Integrins, Piezo channels, yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), two-pore-domain potassium (K2P) channels and transient receptor potential vanilloid 4 (TRPV4) are widely recognized as critical effectors of cellular mechanotransduction and have been extensively investigated in recent years [[153], [154], [155], [156]]. Through these mechanosensitive pathways, physiological-level and moderate mechanical stimulation have been proposed to enhance cellular activity and serve as a therapeutic approach for tissue repair and regeneration [157]. Zhang et al. applied a loaded cell culture system to provide AFCs with tunable cyclic tensile strain (CTS) [65]. They found that moderate CTS (5%) attenuated inflammatory responses and promoted AFC proliferation, migration, and ECM synthesis by inhibiting Cav1-mediated integrin β1 and NF-κB signaling pathways, whereas excessive CTS (12%) exerted the opposite detrimental effects. Guo et al. proposed that a stable biomechanical environment may facilitate regeneration or repair of degenerated IVDs [66]. Using Kirschner-wires and external fixation devices, they applied in situ traction and excessive traction to rat degenerated IVDs induced by mechanical compression (Fig. 6a). Histological staining and imaging analyses revealed that in situ traction, which restored physiological disc height, significantly promoted disc height recovery, proteoglycan synthesis, and the microstructural reconstruction of bony endplates, while avoiding osteophyte formation (excessive traction induced osteophytes). Another related study indicated that early-stage traction (2–4 weeks) on degenerated discs significantly improved disc height, GAG synthesis, and endplate porosity and morphology, but excessive traction at later stages (6–8 weeks) led to further reduction in endplate pores [67]. These findings may help optimize the therapeutic intensity and duration of traction devices in the clinical treatment of disc degeneration and provide insights into the underlying mechanobiological effects. In a recent study, Han et al. cultured rabbit functional spinal units in vitro and divided them into five groups to receive different mechanical loads: control, pressure, traction, rotation, and rotational traction (Fig. 6b) [68]. The results showed that the rotational traction group exhibited the most favorable biomechanical responses, including the lowest creep displacement, enhanced fatigue resistance, and increased tensile strength, whereas the rotation-only group caused the most severe cellular damage and tissue degeneration. These findings suggest that rotational traction may help delay IVDD, providing a theoretical basis for noninvasive clinical interventions, while also highlighting that patients and high-risk individuals should avoid excessive rotational movements in daily life. Beyond macroscopic tensile stresses, sophisticated material design offers powerful tools for uncovering the biological effects of subtle, cell-scale mechanical stimuli. As discussed in the section on magneto-responsive materials, Xue et al. demonstrated that magneto-mechanical stimulation generated by Mag-gel activated YAP signaling and promoted its nuclear-cytoplasmic translocation, thereby facilitating cytoskeletal remodeling in NPSCs [50]. This stimulation also triggered the activation of mechanosensitive Ca²⁺ channels. These events enhanced the proliferation and guided the directed differentiation of DB67-recruited NPSCs. More broadly, this work highlights the potential of intelligently designed biomaterials to integrate chemical and physical cues, thereby offering a conceptual framework for synergistic regulation of stem cell fate.

Fig. 6.

The role of mechanical cues in the treatment of IVDD. a) Schematic of the animal traction model and experimental groups [66]. Copyright 2020, Elsevier Inc. b) Process of cultivation of functional spinal unit and tests of results [68]. Copyright 2025, Elsevier B.V. c) The vibration culture system. The IVD lies inside a polycarbonate culture chamber (right), immersed in DMEM culture medium (arrow) [70]. Copyright 2010, Lippincott Williams & Wilkins, Inc. d) Schematic illustration depicting the preparation of exercise-mimetic exosomes (EMEs) and their therapeutic mechanism for IVDD [76]. Copyright 2025, Wiley-VCH GmbH. e) Mechanical training directs cell differentiation via mechanotransduction [77]. Copyright 2023, Wiley‐VCH GmbH. f) Mechanisms of mechanotransduction and crosstalk with cytoskeletal and nuclear mechanics [78]. Copyright 2025, American Chemical Society.

3.5.2. Positive effects of vibration

Vibration is a form of mechanical stimulation characterized by oscillatory motion [158]. In the medical field, whole-body vibration (WBV), in which subjects are placed on specially designed platforms generating sinusoidal vibrations, has been widely applied for the treatment of musculoskeletal disorders (such as osteoporosis and chronic LBP) and for health promotion (including muscle strengthening and limb balance) [[159], [160], [161]]. However, numerous studies have indicated that vibration can have deleterious effects on human joints and may contribute to disc degeneration and herniation [152,162]. Gene expression analyses from existing studies have shown that prolonged WBV can induce the expression of IL-1β in IVD tissues, accompanied by upregulation of MMP3, MMP13, and ADAMTS5. Interestingly, ECM-related genes such as ACAN, collagen type II alpha 1 (COL2A1), and SRY-box transcription factor 9 (SOX9) have also been reported to increase in expression in response to WBV [163,164]. Widmayer et al. similarly highlighted the dual effects of vibration and investigated whether combining estrogen, which has a positive effect on IVD cell proliferation, with low-magnitude high-frequency vibration (LMHFV) could synergistically influence cellular anabolic metabolism in bovine IVD organ cultures [69]. Their results showed that 17β-oestradiol (E2) alone significantly increased the production of IL-6 and MMP-3, which are involved in IVD matrix catabolism, whereas LMHFV alone led to a reduction in cell number and an increase in IL-6. Compared with either E2 or LMHFV treatment alone, the combination of E2 and LMHFV reversed cell loss and reduced both IL-6 and MMP-3 production. This study provides insights into the individual and combined effects of estrogen and LMHFV on IVDD and offers valuable guidance for exploring vibration-based therapies for IVDD of postmenopausal women. Given that the effects of mechanical cues on IVD health appear to be highly parameter-dependent, a key question arises: among amplitude, frequency, and duration, which vibration parameter has the greatest impact on the disc? Desmoulin et al. exposed bovine tail IVDs to axial vibrations with varying parameters and found that amplitude had the most substantial and wide-ranging effects [70]. Increasing amplitude enhanced the expression of key matrix-related genes such as Collagen II, Decorin, and Biglycan (Fig. 6c). These findings provide a solid theoretical and experimental foundation for the development of precision vibration therapy in IVDD. In another study, Holguin et al. simulated IVD unloading or weightlessness using a hindlimb unloading model, which rapidly induced IVDD characterized by reduced disc height and sulfated GAG content [71]. In the experimental group, rats were allowed to stand upright for 15 min daily on a platform delivering vibration at a peak acceleration of 0.2 g. The results demonstrated that 90 Hz vibration significantly restored disc height and improved sulfated GAG content, thereby protecting the disc from unloading-induced degeneration. This study provides a promising strategy for maintaining disc health in conditions such as space missions or prolonged bed rest. Importantly, mechanical stimulation at the cellular scale in the form of subtle micro-vibrations should also be considered. Evidence from Mag-gel systems indicates that nanoscale vibrations induced under US stimulation are sufficient to modulate NPSC adhesion and differentiation, potentially by promoting YAP translocation and activating mechanosensitive Ca²⁺ ion channels [50]. These observations indicate that IVDD may be amenable to therapeutic strategies based on low-amplitude, minimally perceptible vibrational cues, highlighting the potential of microvibration-based mechanical interventions as a gentle and cell-sensitive approach for disc regeneration.

3.5.3. Mechanical cue-mediated physical priming in IVD tissue engineering

Of course, mechanical stimulation does not necessarily have to act directly on the degenerated IVD itself. Traditionally, disc-relevant cell phenotypes and matrix formation have been guided primarily through biochemical cues, such as defined growth factors and morphogens [165,166]. Encouragingly, emerging studies suggest that mechanical signals can also serve as powerful regulators of disc cell behavior and tissue development, particularly in the context of IVD tissue engineering. Gokorsch et al. used a custom bioreactor to apply cyclic mechanical strain to 3D AF cell-matrix constructs, which significantly enhanced GAG synthesis [72]. Reza and Nicoll investigated the effects of dynamic hydrostatic pressure on outer and inner AFCs seeded on fibrous poly(glycolic acid)-poly(L-lactic acid) scaffolds [73]. Under the mechanical stimulus, both outer and inner annulus-seeded constructs showed more uniform type II collagen deposition compared with unloaded controls, with the most pronounced enhancement observed in outer annulus-seeded constructs, which was accompanied by improved ECM elaboration and organization. Turner et al. demonstrated that AFCs cultured on oriented nanofibrous polyurethane scaffolds are mechanosensitive to tensile loading: while cells on relaxed scaffolds exhibited higher proliferation and ECM synthesis, monotonic tensile strain promoted greater cellular and matrix alignment and resulted in a significantly higher scaffold elastic modulus [74]. Tsai et al. developed an IVD implant composed of scaffolds with distinct structural features designed to support cell colonization—an AF scaffold made of aligned PLLA/PCL nanofibers, a NP scaffold mimicking a hydrated environment, and osseous endplate scaffolds constructed from nanofibrous mats with random fiber orientation [75]. Their findings showed that MSCs co-cultured with IVD cells in appropriate ratios within the implant could differentiate into AF-like or NP-like cells under the influence of intercellular interactions and/or paracrine signaling. Moreover, when the IVD construct was subjected to cyclic compressive loading (10% strain, 1 Hz) in a perfusion bioreactor, the expression of cartilage-related genes was suppressed in the AF scaffold but enhanced in the NP scaffolds. Interestingly, in the osseous endplate scaffold, the expression of bone-related markers was markedly downregulated, whereas the cartilage-related marker collagen II was upregulated during the culture process. These studies elucidated how the integration of scaffold design, cell-cell interactions, and mechanobiological cues can synergistically guide tissue-specific differentiation, providing valuable insights for the future development of IVD tissue engineering. However, not all studies report beneficial effects of mechanical cues on tissue engineered IVDs. For example, Fotticchia et al. demonstrated that axial cyclic compression applied to an engineered IVD-like construct was mechanically transformed into amplified circumferential tensile stresses within the AF region [167]. Such stress amplification markedly compromised AFC viability, particularly at higher displacement amplitudes, highlighting that adverse cellular outcomes may arise when macroscopic compressive loading is converted into excessive local tensile stress through structural constraints. Besides, physiological loading of the IVD is more complex than simple compression or hydrostatic pressure, and different modes of mechanical loading may also influence IVD cell behavior, warranting further investigation. Notably, mechanical cues have been explored not only as potential modulators of lineage commitment, but also as regulatory inputs that reshape cellular secretory profiles and paracrine functions after differentiation. Zhao et al. proposed an innovative exercise-mimetic exosome (EME) therapy for the treatment of IVDD [76]. In their study, human induced pluripotent stem cells were stepwise differentiated into myotubes (iMyotubes), which were then subjected to cyclic mechanical stretching to simulate muscle contraction. After optimizing the mechanical stimulation parameters, not only was the exosome yield from iMyotubes significantly increased, but these exosomes were also markedly enriched with irisin—a key exercise-inducible component. These EMEs were shown to target two critical pathological processes of IVDD simultaneously: in degenerated NPCs, they restored ECM metabolic homeostasis and inhibited the NF-κB signaling pathway; in macrophages, they suppressed degeneration-induced M1 polarization and reduced inflammatory infiltration (Fig. 6d).

3.5.4. Mechanical cues derived from the physical properties of biomaterials

The physical properties of biomaterials, including stiffness, viscoelasticity, size, geometric architecture, and load-bearing capacity, critically influence cell adhesion, proliferation, differentiation, and degenerative phenotype. Notably, recent research has revealed that mechanical cues encoded by the physical properties of biomaterials (rather than direct external mechanical loading) can serve as a novel regulatory approach for IVDD therapy. Such mechanical signals are transmitted via ligand-integrin interactions, generating cytoskeletal tension that regulates nuclear pore expansion and transcriptional activator translocation (e.g., YAP), thereby modulating cellular behavior [168,169]. Chen et al. developed fibronectin-modified GelMA microspheres (Fn-GelMA) with independently tunable elastic moduli (1–10 kPa) and ligand densities (2 and 10 μg mL⁻¹), and systematically investigated the morphology and differentiation behavior of NPSCs cultured on microspheres presenting distinct mechanical cues [77]. Their results demonstrated that the combination of a soft matrix (2 kPa) and low ligand density (2 μg mL⁻¹) supported NPSC differentiation toward a NP-like phenotype through regulating YAP subcellular localization. Furthermore, by loading platelet-derived growth factor BB into Fn-GelMA microspheres, the system effectively induced endogenous stem cell migration and guided lineage commitment via mechanical conditioning, achieving superior NP repair capacity in both in vitro and in vivo models (Fig. 6e). Li et al. employed physical extrusion to fabricate GelMA microgels with distinct geometries, including rod-shaped Microgel (MicroRod) and MicroSphere, and systematically compared their effects on NPCs [78]. Compared with isotropic MicroSphere, the anisotropic MicroRod, owing to its long-axis polarity and closer resemblance to the physiological ellipsoidal structure of the IVD, significantly enhanced NPC adhesion, proliferation, and resistance to apoptosis through the integrin–FAK-PI3K-AKT signaling pathway. Moreover, MicroRod promoted YAP/TAZ activation, leading to enhanced nuclear membrane stability and attenuation of cGAS-STING signaling, ultimately contributing to delayed NPC senescence (Fig. 6f). Together, these results suggest that geometry-mediated mechanical cues encoded within biomaterials may enable localized and patient-tolerant mechanomodulation, thereby providing a promising translational pathway beyond conventional macroscopic mechanical interventions.

It is worth mentioning that after deployed in IVD, the biomaterials work under dynamic physiological loadings. The physical properties of biomaterials simultaneously determine the mechanical cues of material-contact cells, the mechanical environment of adjacent tissues, and the mechanical functions of whole IVD organ under loading. Therefore, the physical properties of biomaterials should be well designed to handle the dynamic physiological loadings for promoting tissue repair. For example, a glycerol cross-linked PVA gel (GPG) with shear-thinning injectability and NP-like viscoelasticity was designed for IVDD treatment [170]. GPG could withstand cyclic deformation with high energy dissipation. In vitro study revealed that GPG could preserve NPC vitality and function against pathological mechanical environment. While in vivo studies confirmed the efficacy of GPG in maintaining NP integrity, disc height, and hydration in puncture models, as well as stimulating fibrous repair in discectomy models. In the future, the influences of physical properties of biomaterials on the IVD mechanical environment at cell/tissue/organ levels should be well deciphered for a rational and personalized design of biomaterials for IVDD intervention.

3.5.5. Clinical applications of mechanical cues in IVD-related diseases

A meta-analysis has demonstrated that lumbar traction is associated with significant reductions in LBP and improvements in functional outcomes among patients with herniated IVDs in the short term [171]. Lee et al. compared the clinical effects of a newly developed lumbar lordotic curve-controlled traction with those of traditional traction in patients with herniated lumbar IVD disease [172]. Pain scores decreased significantly after traction treatment in both groups, with further improvements in functional scores and IVD morphology observed in patients receiving curve-controlled traction. Holguin et al. not only applied vibration stimulation in rats but also evaluated the effects of high-frequency, low-magnitude mechanical signals (LMMS) on lumbar IVD swelling in humans, a condition commonly induced by prolonged bed rest or spaceflight [173]. All participants underwent 90 days of strict bed rest followed by a 7-day reambulation phase, during which the LMMS group received an additional daily 10-min vibration intervention at 30 Hz with accelerations of 0.3 g or 0.5 g. Compared with the untreated group, LMMS treatment reduced disc swelling by an average of 41% and 30% at days 60 and 90, respectively. In the untreated group, prolonged bed rest led to significant disc expansion, and even after 7 days of reambulation, the disc volume remained 8% larger than baseline, whereas LMMS treatment effectively restored the disc volume to baseline levels. In addition, Belavý et al. pioneered a resistive vibration exercise (RVE) protocol to counteract the effects of prolonged bed rest or spaceflight [174]. Specifically, participants in the experimental group were positioned supine on a specially designed suspended vibrating platform that provided axial force equivalent to 1.2–1.8 times their body weight, thereby simulating gravitational loading on Earth. Compared with the control group, the RVE intervention effectively mitigated spinal lengthening, IVD area expansion, and multifidus muscle atrophy induced by prolonged bed rest. Collectively, these studies provide visionary spinal protection strategies with significant implications for the advancement of space medicine.

At present, the application of mechanical stimulation in IVDD therapy remains in its infancy. On one hand, the definition and standardization of appropriate versus excessive mechanical loading have not yet been clearly established and remain key challenges to be addressed. Taking the studies by Holguin and Belavý as representative examples, this line of research has predominantly focused on healthy volunteers or spaceflight analog models, rather than patients with bona fide IVDD. In clinical settings, IVDD patients commonly exhibit endplate calcification, AF fissures, chronic inflammation, and heightened pain sensitization, all of which substantially reduce their tolerance to mechanical stimulation. Consequently, identical vibrational or axial traction regimens may shift from being protective to potentially exacerbating tissue injury, highlighting that achieving individualized mechanical intervention strategies remains a distant and unresolved goal. On the other hand, the mechanisms by which IVD cells sense mechanical cues and how mechanical stimulation promotes the restoration of endplate porosity require further elucidation. Looking forward, accelerating the translation of biomaterial-encoded mechanical cues may enable localized and patient-tolerant therapy, thereby offering a promising pathway beyond conventional macroscopic mechanical interventions. These clinical applications of biophysical cues across different modalities are summarized in Table 2.

Table 2.

Clinical applications of biophysical cues in IVD-Related Diseases.

Biophysical cues	Diseases	Types	Parameters	Efficacy	Limitations	Refs
Electrical cues	Lumbar disc herniation	Diadynamic current therapy	Current intensity: ∼15 mA Duration per session: 10 min Treatment frequency: 1 time/day Treatment course: 2 weeks (with weekend breaks)	Reduce pain scores and improve functional fitness	1Infection risk associated with penetrating electrodes 2Risk of electrochemical reactions and local tissue damage at the electrode-tissue interface 3Potential interference with implanted electronic devices 4Limited tissue penetration and nonuniform distribution of electric stimuli 5Discomfort or pain leading to poor patient compliance	[98]
		TENS	Current intensity: ∼30 mA Duration per session: 30 min Frequency: 10 Hz (first 10 min), 100 Hz (subsequent 20 min) Treatment frequency: 1 time/day Treatment course: 2 weeks (with weekend breaks)
	Lumbar disc herniation	Functional electrical stimulation	Frequency: 35 Hz Pulse width: 0.28 ms Duration per session: 30 min Treatment frequency: 1 time/day Treatment course: 4 weeks	Significantly lowere PRI, PPI, and VAS scores, as well as the peripheral ROS levels		[99]
Magnetic cues	Cervical disc herniation	PEMF	Frequency: 50 Hz Intensity: 0.6 mT Duration per session: 20 min Treatment frequency: 5 days/week Treatment course: 3 weeks	Improve the VAS and Nottingham Health Profile sleep subparameter in the 12th week after treatment	1Limited spatial precision and targeting accuracy 2Undesired off-target effects because of relatively broad radiation ranges 3Potential interference with implanted electronic devices	[117]
	Discogenic lumbar radiculopathy		Frequency: 7 Hz – 4 kHz Field strength: 5 – 15 Gauss Duration per session: 20 min Treatment frequency: 1 time/day Treatment course: 3 weeks	Ameliorate nerve compression symptoms; enhance neural function; reduce VAS and modified ODI scores.		[118]
Photo cues	Lumbar disc herniation	HILT	Power: 3.8 W Wavelength: 1064 nm Duration per session: 14 min Treatment frequency: 5 sessions/week Treatment course: 2 weeks	Improve the VAS score, ODI scores, BP, GH, VT, and SF at the end of the therapy; maintain the improvements in ODI, PF, BP, GH, and VT for 3 months	1Limited tissue penetration depth 2Scattering and absorption by biological tissues reduce spatial precision 3Potential risks of thermal damage under high-intensity irradiation 4Ultraviolet irradiation may induce cellular injury and carcinogenesis	[138]
	Patients with lumbar disc herniation who underwent collagenase chemonucleolysis		Power: 15 W Dose: 10 J/cm2 Duration per session: 4–6 min Treatment frequency: 1 session/day Treatment course: 5 days	Show better outcomes in pain VAS scores, excellent/good rate, ODI scores, and SF-36 quality of life scores		[139]
	Cervical disc herniation		Power: 8 W Wavelength: 1064 nm Dose: 5 J/cm2 Duration per session: 15 min Treatment frequency: 5 sessions/week Total sessions: 20 sessions	Improve VAS, NPADS and ROM measurements		[140]
Ultrasonic cues	Lumbar disc herniation	Ultrasound therapy	Intensity: 1.5 W/cm2 Frequency: 1 or 3 MHz Duration per session: 6 min Treatment frequency: 5 sessions/week Treatment course: 2 weeks	Improve the VAS, ODI, and PF, RP, BP, GH, VT, SF, RE, and MH parameters at the end of the therapy; maintain the improvements in ODI score and PF, BP, GH, and MH parameters for 3 months	1Limited penetration and attenuation in heterogeneous tissues 2Potential risks of US-induced thermal effects 3Risk of irreversible cellular damage caused by inertial cavitation	[138]
	Cervical disc herniation		Intensity: 1.5 W/cm2 Frequency: 1 MHz Mode: 50% cut mode Duration per session: 4 min Treatment frequency: 5 sessions/week Total sessions: 20 sessions	Improve VAS, NPADS and ROM measurements		[140]
Mechanical cues	Lumbar disc herniation	Lumbar lordotic curve-controlled traction	Maximum traction power: <100 pounds/0.5 times body weight Duration per session: 15 min Total sessions: 15 sessions	Reduce pain and improve patient functional scores and disc morphology	1Limited tolerance to axial traction and vibration in IVDD patients 2Limited long-term patient compliance 3Undesired off-target effects because of elatively broad radiation ranges	[172]
	Swelling of the lumbar IVD	LMMS	Frequency: 30 Hz Peak-to-peak acceleration: 0.3 g or 0.5 g Duration per session: 10 min/day Treatment course: 90 days	Mitigate the detrimental changes in disc morphology		[173]
	Healthy male	Vibration	Frequency: 19–26 Hz Amplitude: 3.5–4 mm Axial force: 1.2–1.8 times body weight Duration per session: 5–10 min Treatment frequency: 2 sessions/day Treatment course: 8 weeks	Reduce atrophy in the lumbar multifidus muscle and reduce lengthening of the spine and sagittal disc area increases during bed-rest		[174]

TENS: Transcutaneous electrical nerve stimulation; PRI: Pain rating index; PPI: Present pain intensity; VAS: Visual analogue scale; ROS: Reactive oxygen species; PEMF: Pulsed electromagnetic field; ODI: Oswestry Disability Index; HILT: High intensity laser treatment; BP: Body pain; GH: General health; VT: Vitality; SF: Social functioning; PF: Physical function; SF-36: Short form 36; NPADS: Neck pain and disability scale; ROM: Range of motion; RP: Restricted physical roles; RE: Restricted emotional roles; MH: Mental health; IVD: Intervertebral disc; LMMS: Low-magnitude mechanical signals.

4. Discussion and conclusion

This review summarizes recent progress in biophysical cue-based strategies for the treatment of IVDD, encompassing five major modalities: electrical, magnetic, photo, ultrasonic, and mechanical cues. These advances will help inform the design of improved therapies based on the interdisciplinary integration of medicine and engineering, enabling the use of physical cues to regulate disc repair and remodeling. These approaches have garnered increasing attention due to their noninvasive nature, tunable controllability, and precise regulation of cellular functions. Several of these strategies have demonstrated favorable biosafety and promising therapeutic efficacy in in vivo studies or early-stage clinical trials, highlighting their potential in regenerative medicine, particularly as safer and more ethically acceptable alternatives to conventional cell and gene therapies.

Despite these promising prospects, the fundamental theoretical framework of external stimulation remains underdeveloped. Many studies focused primarily on improvements in cellular function and tissue morphology, while the specific mechanisms remain unclear. A key limitation lies in the lack of systematic studies investigating the dynamic proteomic and transcriptomic changes in NPCs during ES. Therefore, establishing a comprehensive regulatory network that links external stimuli to gene expression and protein modulation in IVD cells has become a critical scientific challenge in advancing physical therapies for IVDD. In addition, considerable heterogeneity exists among studies in terms of stimulation settings such as intensity, frequency, and duration, as well as in the design of physical cue platforms. For instance, in studies involving ES, some report current intensity in microamperes (μA), while others use milliamperes per square centimeter (mA/cm²) as the measurement unit [35,37]. Such inconsistencies in parameter reporting hinder cross-study comparisons, reduce reproducibility, and impede clinical translation. Standardizing parameter reporting is therefore essential. Beyond harmonizing parameter units and reporting formats, a more fundamental challenge lies in defining the optimal therapeutic window for each type of biophysical cue. Specifically, the effective intensity ranges, exposure durations, stimulation frequencies, and safety thresholds that confer maximal regenerative benefit while minimizing adverse effects remain insufficiently characterized. Moreover, the IVD is located deep within the body, and after passing through intervening tissues and bone, the actual intensity, spatial distribution, and directionality of externally applied physical stimuli at the target disc tissue remain highly uncertain. To address these uncertainties, a two-tiered approach may be employed: first, employing organoid or tissue-mimicking models that better recapitulate the 3D microenvironment of human discs can provide a controlled platform to optimize stimulation parameters and validate therapeutic potential; second, the development of implantable or minimally invasive in situ sensors can enable real-time monitoring and dynamic adjustment of biophysical stimulation in vivo, thereby improving dose accuracy, reproducibility, and translational relevance.

Clinical studies on biophysical cue-based interventions for IVDD remain relatively limited in scope. Most available studies focus on symptomatic outcomes, such as pain relief and functional improvement, but objective structural assessments of disc regeneration are far less frequently reported. In particular, imaging-based evaluations, including magnetic resonance imaging-derived measurements of disc height, hydration status, and degeneration grade, are often lacking or insufficiently standardized. This imbalance between functional endpoints and structural validation hampers the ability to determine whether biophysical stimulation induces genuine disc regeneration or merely provides transient symptomatic relief, thereby constraining the clinical interpretation and translational potential. Another major limitation is the lack of long-term follow-up data. Most studies focus on short-to mid-term outcomes, whereas clinically meaningful endpoints such as sustained maintenance of disc height, progression-free survival, or recurrence risk over 5–10 years are rarely evaluated. Without stratification by disease severity, patient age, or baseline disc integrity, it remains difficult to establish personalized treatment paradigms or to predict which patient subgroups are most likely to benefit from specific biophysical modalities. Due to small sample sizes and ethical constraints, clinical evidence supporting the use of biophysical stimulation remains limited, with additional uncertainty introduced by publication bias that favors the reporting of positive findings over negative or inconclusive results. Therefore, more well-designed, stratified and large-scale preclinical and clinical studies are urgently needed.

When evaluated from a translational perspective, different biophysical cues exhibit distinct profiles in terms of tissue penetration, safety, patient tolerability, technical complexity, and clinical feasibility. In general, penetration depth represents a primary discriminating factor for IVD applications. Mechanical stimulation, MFs, and US possess an inherent advantage in accessing deep spinal tissues, whereas electrical and photo cues are more constrained by tissue conductivity or optical attenuation and therefore often rely on invasive delivery strategies or material-assisted amplification to reach the disc space [143,175,176]. From the standpoint of spatial controllability and targeting precision, US offers a distinct advantage owing to its ability to be focused and steered with high spatial resolution, enabling localized energy deposition within deep tissues. This feature makes US particularly attractive for site-specific modulation of the IVD while minimizing off-target effects. In contrast, MFs generally exert more diffuse biological influences. Thermal risk further differentiates these modalities, as unintended heat accumulation may compromise cellular viability, exacerbate inflammatory responses, and narrow the therapeutic safety window, thereby increasing regulatory and clinical barriers to their translation. Electrical, photo, and ultrasonic cues may induce appreciable heat accumulation under specific parameter regimes, particularly when higher intensities are required to overcome tissue attenuation or when energy is coupled to responsive materials. In contrast, MFs and mechanical stimulation typically operate within non-thermal or weakly thermal windows when appropriately dosed. It is worth noting that US may also induce cavitation effects under specific conditions, which could cause mechanical damage to tissues and cells, while ultraviolet light, a type of photo cue, tends to damage cells and DNA, posing potential genotoxic risks. Regarding patient comfort and compliance, non-contact or minimally perceptible modalities such as MFs, low-intensity US, and PBM generally demonstrate superior tolerability, whereas electrical and mechanical stimulation may provoke discomfort or pain when parameters exceed individual thresholds, potentially limiting long-term adherence. These considerations become particularly relevant for chronic conditions such as IVDD, where repeated or prolonged interventions are often required. An additional layer of complexity arises from patient heterogeneity and personalized medicine considerations. Factors such as age, sex, ethnicity, and comorbidities can modulate responsiveness to biophysical cues. For example, elderly patients or those with severe chronic LBP and sciatica may exhibit reduced tolerance to mechanical stimulation. Moreover, certain modalities, including electrical and magnetic cues, may be contraindicated or require caution in patients with implanted devices such as pacemakers or other electronic implants. Device complexity, cost, and accessibility also shape clinical applicability. Electrical and mechanical stimulation platforms are comparatively simple and cost-effective, lending themselves to broader dissemination, including in resource-limited settings. In contrast, advanced US systems, electromagnetic generators, and precision optical devices may entail higher equipment costs and stricter operational requirements, which can restrict widespread clinical adoption despite promising biological efficacy. The clinical maturity of these modalities varies. TENS currently has the most established clinical utility, particularly in pain management, supported by multiple randomized controlled trials. PEMF has accumulated considerable clinical evidence for pain relief and musculoskeletal applications, although outcomes vary across indications. PBM has been widely used in rehabilitation and soft tissue repair, but results remain heterogeneous, whereas LIPUS shows potential in bone and tissue healing, but its clinical effectiveness remains limited and under debate.

In light of the respective advantages and limitations associated with different biophysical cue-based therapies, synergistic multimodal stimulation and integration with biological interventions may represent a complementary and rational strategy to maximize therapeutic efficacy while mitigating individual shortcomings. For instance, the combination of US with piezoelectric materials constitutes an advanced and emerging approach, as it effectively addresses the limited penetration depth and suboptimal patient compliance often associated with conventional ES by enabling localized, wireless, and on-demand electromechanical activation within deep tissues. Similarly, the integration of MFs with IONPs and therapeutic agents leverages the superior tissue penetration and low attenuation of magnetic cues to achieve remote, spatiotemporally controlled drug release, thereby expanding the therapeutic window and enhancing precision in deep intervertebral disc environments. Together, these representative strategies underscore a broader design principle that is expected to further enhance therapeutic specificity and controllability.

Furthermore, clinical translation still faces multiple challenges, including the bulky size of stimulation devices, suboptimal biocompatibility of implants, and limited durability and functional stability over time. These challenges are particularly pronounced for emerging material-assisted biophysical strategies, such as piezoelectric systems, photothermal platforms, and other stimulus-responsive biomaterials, which largely remain at the preclinical stage and have not yet received regulatory approval (e.g., FDA clearance). To address these translational barriers, several complementary strategies may be pursued. First, advances in microfabrication and materials science can facilitate the development of miniaturized and flexible stimulation systems, thereby improving implantability and mechanical compliance with native tissues. Second, translational pathways for material-based systems and device-material hybrids are likely to rely on the preferential use of clinically compliant or previously approved materials, together with simplification of device architectures. Finally, stable long-term performance will require the rational design of biophysical cue-based materials that maintain reproducible signal transduction under sustained mechanical loading, as well as stepwise validation emphasizing biocompatibility, long-term stability, and reproducibility under physiologically relevant conditions. Indeed, these challenges also signify that the field is currently in a critical transitional phase, bridging fundamental research and clinical application. Overcoming these barriers step by step will be essential to achieving effective translation of biophysical stimulation therapies for IVD repair and related conditions.

Future research should also focus on technological integration and intelligent development. On one hand, artificial intelligence (AI) and machine learning can be leveraged to optimize and predict physical cue parameters, enabling personalized and precision therapy. On the other hand, the development of miniaturized, implantable physical cue devices equipped with real-time monitoring and feedback regulation functions is essential, along with improvements in their biocompatibility and mechanical stability to enhance clinical feasibility. Moreover, integrating these technologies with advanced biomaterials and wearable systems holds great promise for expanding the applications of noninvasive biophysical cue-based strategies in broader therapeutic contexts.

CRediT authorship contribution statement

Shanfeng Chen: Writing – original draft, Visualization. Yiming Zhang: Writing – original draft, Conceptualization. Jinhao Gong: Data curation, Validation. Yuwen Zhang: Data curation. Zhuoya Li: Data curation, Data curation. Lianyong Wang: Data curation, Visualization. Lei Yang: Writing – review & editing, Supervision. Xigao Cheng: Writing – review & editing, Supervision. Qiang Yang: Writing – review & editing, Validation, Supervision, Funding acquisition, Conceptualization.

Ethics approval and consent to participate

The type of this article is a review and does not address ethical issues.

Declaration of competing interest

Lei Yang is an editorial board member for Bioactive Materials and was not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests.