Lignin‐Based Fluorescent Polymers: From Aggregation‐Induced Emission Mechanism to Intelligent Bone Regeneration

ABSTRACT

Lignin's intrinsic fluorescence and bioactivities (antioxidant, antibacterial, photoprotective) arise directly from its polyphenolic macromolecular architecture. This review critically integrates lignin‐based fluorescent polymers for intelligent bone regeneration, bridging lignin photophysics and tissue engineering. We dissect the macromolecular origins of lignin's biological modalities and its aggregation‐induced emission (AIE) behavior, where clustering of phenylpropanoid units transforms concentration quenching into a luminescent design advantage. Synthetic strategies that employ lignin as macromonomers, initiators, and crosslinkers to fabricate fluorescent polymers with tunable optics and preserved bioactivity are surveyed. We highlight two emerging applications: non‐invasive, real‐time tracing of scaffold degradation via intrinsic fluorescence, and integrated theranostics that synergize antibacterial defense, oxidative stress modulation, and pro‐osteogenic induction within a single macromolecular system. Critically, we identify five translational bottlenecks—heterogeneity‐driven photophysical variability, insufficient quantum yield, long‐term chromophore biosafety, multifunctionality‑processability trade‐offs, and batch‑to‑batch fluorescence inconsistency—and propose chemical and processing strategies to overcome them. By merging lignin macromolecular chemistry, fluorescence photophysics, and bone biology, we position lignin‐based fluorescent polymers as a distinct bioactive class where therapeutic function is programmed into the polymer backbone, offering a promising paradigm for macromolecular design.

Lignin, an abundant aromatic biopolymer from the pulp and paper industry, is valorized as a renewable macromolecular scaffold for engineering fluorescent polymers via green synthetic strategies. These sustainable materials integrate real‐time degradation monitoring with antibacterial, antioxidant, and osteogenic functions, enabling multifunctional theranostic platforms for intelligent bone regeneration. This review establishes design principles for lignin‐based fluorescent systems, advancing the transition toward environmentally compatible regenerative medicine.

1. Introduction

The landscape of bone tissue engineering has undergone a profound evolution, transitioning from the implementation of bio‐inert scaffolds to the deployment of bioactive matrices, and culminating in the emergence of intelligent biomaterial systems. Although traditional metal and ceramic implants exhibited the capacity to afford requisite mechanical support, they were

Inherently deficient in bioactivity and tissue integration, frequently triggering immune rejection and compromising the kinetics of healing [1, 2]. Concurrently, a parallel and equally critical evolution has occurred in polymer science, where the demand for “smart” materials has shifted focus from passive biocompatibility toward the rational design of macromolecular architectures that encode therapeutic and responsive functions directly into the polymer backbone. This convergence of macromolecular engineering and regenerative medicine has established a new materials design paradigm. With the burgeoning integration of materials science and regenerative medicine, intelligent bone repair materials are currently anticipated to possess sophisticated functionalities: beyond ensuring favorable biocompatibility and mechanical integrity, they should also actively orchestrate vascularization and osteogenic differentiation, permit longitudinal monitoring of the healing progression, and demonstrate responsive sensitivity to the microenvironment to achieve precision treatment. However, existing intelligent materials continue to be hampered by persistent challenges such as functional singularity, cumbersome fabrication methodologies, high costs, and the limited availability of real‐time feedback mechanisms. Moreover, from a sustainability perspective, the reliance on non‐renewable resources and environmentally taxing synthesis routes for many conventional biomaterials poses additional concerns, underscoring the urgent need for green and sustainable alternatives in regenerative medicine.

Lignin, a highly heterogeneous aromatic biopolymer, constitutes a pivotal structural constituent of the lignocellulosic matrix [3], As the second most abundant aromatic biopolymer on Earth and a major by‐product of the global pulp and paper industry, an estimated 50–70 million tons of lignin are generated annually, yet the vast majority is burned as low‐value fuel [4, 5]. However, beyond the well‐recognized imperative of its valorization within a green chemistry framework, lignin presents a promising and increasingly recognized opportunity for polymer science: its complex polyphenolic macromolecular architecture intrinsically encodes a suite of functionalities that are typically achieved in synthetic polymers only through elaborate post‐polymerization modification. Specifically, its heterogeneous topology—forming a three‐dimensional network through a diverse array of ether and carbon‐carbon linkages connecting G, S, and H‐type phenylpropane units, supplemented by abundant of active functional groups such as hydroxyl, methoxy, and quinone moieties [6, 7], endows it with favorable antioxidant and antibacterial activity, UV shielding, and endogenous fluorescence [8, 9, 10]. These are not externally added features but are inherent properties directly arising from its aromatic skeleton and functional group architecture. This unique convergence of intrinsic bioactivity and photophysical behavior within a single, renewable macromolecular scaffold positions lignin as a versatile platform for constructing fluorescent functional polymers, circumventing the need for hazardous reagents and maximizing atom economy in materials synthesis through a macromolecular engineering approach.

Recently, a growing body of research has revealed that lignin exhibits intrinsic Aggregation‐Induced Emission (AIE) characteristics—a photophysical phenomenon that fundamentally distinguishes it from conventional luminescent materials that suffer from aggregation‐caused quenching (ACQ) [11]. The AIE behavior of lignin, which arises from the restriction of intramolecular motion and the interplay of through‐space interactions, offers a unique opportunity to transform this natural polymer into a robust fluorescent platform without the need for external fluorophore conjugation. However, despite the growing interest in lignin‐based AIE systems, a comprehensive review that systematically bridges the gap between the fundamental AIE mechanisms of lignin, macromolecular engineering strategies, and their specific applications in intelligent bone regeneration remains conspicuously absent. Therefore, this review specifically focuses on the mechanisms of lignin‐based AIE, polymer design strategies, and their emerging roles in scaffold degradation tracking and imaging‐guided bone defect repair, aiming to establish a macromolecular design framework for next‐generation bone repair materials.

To achieve these goals, this review will commence by dissecting the macromolecular structure and properties of lignin, explicating the mechanistic origins of its aggregation‐induced emission (AIE) behavior and its tunability from a polymer physics perspective. It will then systematically categorize the prevailing synthetic strategies that repurpose lignin as a macromolecular building block (as macromonomers, initiators, and crosslinkers) for constructing functional fluorescent polymers. Finally, it will critically evaluate the application prospects of these lignin‐based fluorescent platforms in intelligent bone regeneration systems, with a particular emphasis on scaffold degradation tracking, microenvironmental sensing, and imaging‐guided bone defect repair. The ultimate goal is to establish a theoretical nexus between lignin macromolecular chemistry and translational tissue engineering, thereby providing a macromolecular design paradigm for the development of next‐generation bone repair materials.

2. Lignin: A Unique Natural Polymer Platform

2.1. Structure of Lignin

Lignin is a complex three‐dimensional amorphous polymer. From a polymer physics standpoint, its structural complexity primarily originates from the inherent variability of its constituent structural units (phenylpropane derivatives), their inter‐unit linkage patterns, and the diversity of peripheral functional groups, all of which collectively govern its thermal, mechanical, and photophysical behavior.

2.1.1. Monomer Composition

Lignin is primarily composed of three canonical phenylpropane units: guaiacyl (G), syringyl (S), and p‐hydroxyphenyl (H) (Figure 1) [12]. The chemical architecture, botanical provenance, and relative abundance of these units critically dictate the physicochemical performance of lignin (Table 1) [11].

FIGURE 1.

A representative lignin polymer structure and its fundamental structural units. Reproduced with permission [12]. Copyright 2020 Wiley‐VCH Verlag GmbH & Co. KGaA.

TABLE 1.

Structural characteristics of lignin from different plant sources.

Feedstock Type	Structural Features	Reaction Conditions	Main Products	Reference
Hardwood Lignin (e.g., Birch, Beech, Poplar)	High S‐unit	Catalytic pyrolysis at 600°C	Syringol, 4‐Propyl syringol	[13, 14]
Softwood Lignin (e.g., Spruce, Pine)	90%–95%G ‐units	Catalytic pyrolysis at 600°C	Guaiacol, Cresol	[13, 14]
Herbaceous Lignin (e.g., sugarcane, Corn)	G, S, and H units	Catalytic pyrolysis at 500°C	4‐vinylphenol, Ferulate	[15]

The guaiacyl (G) unit, derived from coniferyl alcohol [16], is the predominant motif of softwood lignin (e.g., pine, spruce), accounting for 90%–95% [17]. Due to its high propensity to form carbon‐carbon bonds such as 5‐5' and β‐5' linkages [3], G‐rich lignin exhibits substantial structural rigidity and hydrophobicity, contributing to the exceptional mechanical strength and biological recalcitrance of softwoods. In contrast, the S unit, derived from sinapyl alcohol, constitutes the backbone of hardwood lignin (e.g., birch, poplar) together with G units [18]. The steric hindrance from its two methoxy groups favors the formation of flexible β‐O‐4 ether linkages, making S‐rich lignin more soluble and processable, which facilitates its fractionation during pulping. The H unit, derived from p‐coumaryl alcohol and lacking methoxy substitution, is more abundant in herbaceous plants (e.g., wheat straw) [19, 20]. Its “expose” benzene ring structure markedly amplifies reactivity during thermochemical or alkali‐mediated modifications. In summary, the stochastic distribution of G, S, and H units constitutes the essence of lignin's structural heterogeneity. This polydispersity fundamentally determines its macromolecular behavior: A high G content augments mechanical tenacity and antioxidant capacity, whereas a high S content improves flexibility and processability. This structure‐property relationship offers opportunities to tailor material properties through strategic feedstock selection and fractionation.

2.1.2. Linkage Patterns and Functional Groups

In lignin macromolecules, the structural units are connected via β‐O‐4 ether bonds and carbon‐carbon bonds (e.g., 5‐5', β‐5', β‐β') [21, 22]. The β‐O‐4 ether bond is the most abundant (accounting for approximately 50%–60%) and the most easily cleavable linkage, formed between the β‐carbon of one monomer's side chain and the phenolic oxygen on another monomer's benzene ring. Consequently, it is the primary target for chemical, biological, and industrial degradation processes (such as pulping) [21]. Conversely, carbon‐carbon bonds constitute the rigid, stable core of the lignin structure; their higher bond energy makes them difficult to cleave, significantly enhancing the thermal stability and mechanical strength of lignin [23].

The lignin molecular framework is also rich in active functional groups, primarily including phenolic hydroxyl, aliphatic hydroxyl, carboxyl, and carbonyl groups, along with benzene ring conjugated systems [24]. These functional groups not only constitute the chemical basis for lignin's inherent bioactivities (e.g., antioxidant, antibacterial, and metal chelating properties) [25], but also serve as active sites for targeted chemical modification and functionalization, enabling its use as a customizable precursor for high‐performance materials.

2.2. Inherent Biological Modalities

Lignin is not merely a structural polymer; its abundant polyphenolic structure and active functional groups also confer a range of unique biological functions, including antioxidant, antibacterial, and photoprotective activities. These intrinsic bioactivities—encoded within the macromolecular architecture itself—lay an important foundation for its application in fields such as biomedicine.

2.2.1. Antioxidant Potency Exploiting

Based on its polyphenolic structure, lignin can function directly as an antioxidant or act synergistically with synthetic antioxidants, demonstrating application potential in fields such as food, pharmaceuticals, and cosmetics [25, 26, 27]. The core of its antioxidant activity lies in the phenolic hydroxyl groups acting as hydrogen donors, effectively terminating free radical chain reactions. Highly reactive free radicals like reactive oxygen species (ROS) can be oxidized by lignin into inert or less reactive forms, thereby achieving scavenging. The antioxidant performance of lignin is primarily influenced by factors such as phenolic hydroxyl content, molecular weight, and S/G ratio. Typically, lignin fractions with higher phenolic hydroxyl content and lower molecular weight tend to exhibit comparable antioxidant performance. Similarly, Yuan et al. [26], in a study on the sodium bicarbonate fractionation of alkali‐extracted lignin‐carbohydrate complexes from corn stalks, found that the obtained water‐soluble, low molecular weight fraction F3‐1 possessed the highest total polyphenol content (34.73 wt.%) and the potent ABTS radical scavenging capacity. Li et al. [28] discovered that laccase enzymatic treatment could modulate lignin's molecular weight and phenolic hydroxyl content. Among these, hydrolyzed lignin HL‐L1.0 had the highest phenolic hydroxyl content (1.96 mmol/g) and a lower molecular weight (1500 Da), demonstrating the strongest antioxidant activity, superior to commercial antioxidants BHT and BHA. Enzymatic treatment enhanced the proportion of phenolic hydroxyl groups and reduced molecular weight through demethylation and depolymerization, thereby strengthening its hydrogen donor capacity and the stability of free radical intermediates. The dimethoxy groups on the benzene ring of syringyl (S) units are electron‐donating groups, which increase the electron cloud density of the phenolic oxygen atom, promote O─H bond cleavage, and thus enhance radical scavenging capacity. Consequently, lignin with a high S/G ratio typically exhibits stronger antioxidant activity. For example, Li et al. [29] systematically compared and found that hardwood lignin with a high S/G ratio (1.63) and high phenolic hydroxyl content (3.35 mmol g^{− 1}) had a significantly higher radical scavenging rate (75%) than grass lignin (49%) and softwood lignin (53%) (Figure 2e–c). Zhong et al. [30] significantly increased the phenolic hydroxyl content (3.68 mmol/g) and reduced the molecular weight (Mw = 1536 g/mol) of lignin through alkali‐catalyzed organosolv pretreatment. The resulting lignin exhibited activity superior to the commercial antioxidant BHT in DPPH and ABTS radical scavenging assays, confirming a significant positive correlation between phenolic hydroxyl content and antioxidant activity. At the nanoscale, the morphology of lignin also modulates its antioxidant performance. Xu et al. [31] developed a green and effective method to prepare highly antioxidant lignin nanoparticles (LNPs) using a glycerol potassium deep eutectic solvent (PG‐DES) treatment combined with laccase oxidation. The significantly improved antioxidant activity benefited from a 170.8% increase in phenolic hydroxyl content and a reduced average particle size (59.0 nm). Pavaneli et al.’s [32] study on preparing nanoparticles from industrial hardwood lignin showed that lignin nanoparticles (LNPs) obtained via the nanoprecipitation method, with particle sizes of about 75–106 nm, exhibited excellent antioxidant activity in ABTS radical scavenging assays due to their high specific surface area and surface‐enriched phenolic hydroxyl groups.

FIGURE 2.

Radical scavenging rate of lignins from different sources (a)Total phenolic hydroxyl (TPC), half‐maximal inhibitory concentration (IC₅₀), (b) and TEAC content of lignins from different sources (c). Reproduced with permission [29]. Copyright 2025 American Chemical Society. (d) Schematic diagram illustrating the positive regulatory effect of LCC on bone metabolism via ROS scavenging. Reproduced with permission [34]. Copyright 2021 Elsevier. (e) Schematic diagram demonstrating the antibacterial mechanism of LNPs. Reproduced with permission [38]. Copyright 2023 Elsevier.

During the bone repair process, inflammation induced by implants can lead to local ROS overload, subsequently impairing osteoblasts, exacerbating inflammation, and hindering bone healing [33, 34]. It is noteworthy that oxidative stress is particularly prominent in specific bone pathophysiological processes, such as osteoporosis and osteoarthritis. In osteoporosis (e.g., postmenopausal osteoporosis), the redox imbalance caused by aging and estrogen deficiency promotes osteoclast differentiation and activity while inhibiting osteoblast function, thereby exacerbating bone resorption and bone loss. In this context, the ROS scavenging capacity of lignin holds significant importance. Research indicates that lignin‐rich lignin‐carbohydrate complexes (LCC‐A) isolated from wheat straw exhibit excellent ROS scavenging capacity (89.8%), significantly higher than that of LCC‐B (57.8%). Both in vitro and in vivo experiments have demonstrated their effectiveness in promoting osteogenesis, inhibiting osteoclast activity, and improving bone metabolism [34] (Figure 2d). Zheng et al. [35] fractionated wheat straw kraft lignin (KL‐A) into three fractions with different molecular weights. Among them, the KL‐C fraction, characterized by moderate molecular weight and functional group content, demonstrated the optimal performance in inhibiting chondrocyte apoptosis in the SW1353 chondrocyte cell line, suggesting its potential as an optimal lignin for treating OA. Furthermore, Visan et al. [36] integrated lignin into bone implant coatings (e.g., polyaniline‐grafted lignin coatings), which not only provided an antioxidant barrier but also enhanced osseointegration and prevented infection. Such coatings are expected to reduce the risk of peri‐implant osteolysis by scavenging excessive ROS induced by wear debris. In summary, incorporating the natural antioxidant lignin into bone repair materials can effectively address post‐implantation oxidative stress, offering an innovative strategy for constructing an antioxidant bone repair microenvironment. In the context of bone regeneration, the ROS scavenging capacity of lignin is critical for preventing oxidative stress‐induced osteoblast apoptosis and mitigating inflammatory responses in the defect microenvironment.

2.2.2. Antibacterial Properties

Lignin exhibits intrinsic antibacterial efficacy, predominantly ascribed to its polyphenolic architecture. The underlying bactericidal mechanism is orchestrated through a synergistic multifactorial modality. The hydrophobic aromatic domains within lignin macromolecules can intercalate into the bacterial cell membrane [37], compromising membrane integrity and inducing heightened permeability. This disruption precipitates the leakage of intracellular electrolytes and metabolites, ultimately culminating in bacterial stasis or lysis [38] (Figure 2e). Exemplifying this, Liu et al. [39] isolated high‐purity lignin from diverse biomass sources (birch wood chips, wheat straw, and oat hulls), all of which demonstrated profound inhibitory potency against Staphylococcus aureus while concurrently reducing the viable population of Escherichia coli. Xu et al. [40] derived a low molecular weight lignin fraction (M_w = 1890 g/mol) via fractionation within a γ‐valerolactone/water system. Attributed to its enriched phenolic hydroxyl content (2.80 mmol/g), this fraction yielded an inhibition zone of 17.09 mm against S. aureus, representing a 13.0% enhancement relative to pristine lignin (Figure 3a,b). Gao et al. [41] fabricated nano‐lignin (40–300 nm) via acetone fractionation, which attained a 100% inhibition rate against both E. coli and S. aureus. The bactericidal mechanisms encompassed cell wall disruption (evidenced by elevated alkaline phosphatase leakage of 0.12 U/mL) and cellular internalization to perturb protein synthesis. Zhang et al. [42] synthesized hydrothermally modified lignin microspheres (HTLNS‐180) at 180°C, endowing them with a hierarchical porous structure.

FIGURE 3.

(a) Antibacterial activity of lignin samples against Escherichia coli and Staphylococcus aureus, and (b) mechanisms of the antibacterial action of lignin samples. Reproduced with permission [40]. Copyright 2021 Elsevier. (c–e) Inhibition rates of lignin fractions obtained from different acetone/water ratios (20%–100%) against Staphylococcus aureus and Escherichia coli. Reproduced with permission [41]. Copyright 2023 Elsevier. (f) Schematic diagram of a high‐strength, UV‐resistant composite film based on Fe^{3 +}‐coordinated lignin/PVA. Reproduced with permission [54]. Copyright 2024 John Wiley and Sons.

These microspheres demonstrated inhibition rates of 51.0% and 54.3% against S. aureus and E. coli, respectively, mechanistically corroborated by nucleic acid leakage and heightened membrane permeability.

Furthermore, lignin possesses the capability to generate trace amounts of reactive oxygen species (ROS) via redox reactions, which directly compromise intracellular macromolecules (e.g., proteins and nucleic acids) and derail normal metabolic processes, thereby exerting bactericidal effects. This seemingly contradictory role, relative to the aforementioned function of lignin as a potent ROS scavenger, can be reconciled by the unique microenvironmental conditions that govern its redox behavior. At sites of bacterial infection or inflammation, altered pH, the presence of transition metal ions (e.g., Fe^{3 +}), and the specific nanostructure of lignin can collectively facilitate electron transfer to oxygen, generating localized, bactericidal levels of ROS while avoiding systemic oxidative damage in healthy tissues. This adaptive switch enables on‐demand antimicrobial action through controlled, localized ROS production. For instance, Morena et al. [43] engineered phenolated lignin nanoparticles (PheLigNPs, 217 ± 54 nm) boasting an augmented phenolic hydroxyl content (296.4 vs 212.5 mg GAE/g). These nanoparticles lowered the minimum inhibitory concentration (MIC) against S. aureus to 1.25 mg mL^{− 1}, driven by mechanisms involving membrane potential depolarization and oxidative stress induction via ROS generation.

Moreover, lignin can impede bacterial proliferation through the chelation‐mediated sequestration of essential metal ions (e.g., iron, zinc). Investigations indicate that lignin‐mediated iron chelation diminishes iron bioavailability and modulates the microbial community structure, evidenced by a reduction in E. coli‐related taxa such as Proteobacteria [44]. Liu et al. [45] developed Fe^{3 +}‐chelated lignin‐based PVA composites (PVA/PLig‐Fe) that achieved substantial inhibition rates (>99.9%) against both E. coli and S. aureus. The chelation of Fe^{3 +} not only imparted flame‐retardancy and UV‐shielding properties to the composite but also conferred potent antibacterial activity by sequestering iron, effectively depriving bacteria of essential Fe^{3 +} nutrients, as illustrated in Figure 4.

FIGURE 4.

(a) PVA and PVA composites after flame exposure, (b) residual char images, (c) LOI values, (d,e) antibacterial efficiency of PVA, PVA/PLig, and PVA/PLig‐Fe. Reproduced with permission [45]. Copyright 2025 Elsevier.

In the context of bone repair, implant‐associated infection remains a prominent etiology underlying delayed healing and implant failure. The most formidable clinical challenge in such infections is not the planktonic bacteria themselves, but the biofilm formed after bacterial adhesion and colonization on the implant surface, which is notoriously difficult for antibiotics to penetrate. The intrinsic, non‐antibiotic bactericidal modality of lignin, which mitigates the risk of resistance emergence, holds immense translational prospects. For example, Puertas–Segura et al. [46] constructed a coating on urinary catheter surfaces via an enzyme‐assisted layer‑by‑layer self‑assembly technique, incorporating aminated lignin(AmL) nanoparticles with catechol‑functionalized chitosan and hyaluronic acid. The resulting coating effectively inhibited biofilm formation by Staphylococcus aureus and Escherichia coli for 7 days under simulated human hydrodynamic conditions, with an inhibition rate exceeding 60%, and no cytotoxicity was observed.

In this context, the innate antioxidant capacity of lignin can still contribute to controlling the inflammatory microenvironment, while its ROS‐generating capacity provides an infection‐triggered defense. This dual, microenvironment‐dependent redox modulation makes lignin a highly adaptable functional component for bone repair materials. These studies indicate that introducing lignin into bone repair materials—such as bone cement, artificial periosteum, and titanium‑based coatings—can endow the materials with sustained antibacterial capability, reduce the risk of infection, and improve the success rate of bone repair. Furthermore, when combined with the intrinsic fluorescence tracking capabilities discussed in subsequent sections, these antimicrobial and anti‐inflammatory properties position lignin‐based composites as multifunctional smart scaffolds capable of simultaneously preventing infection, modulating the local microenvironment, and enabling non‐invasive monitoring of bone healing progression.

2.2.3. Photoprotective Function

While Ultraviolet (UV) radiation constitutes a pivotal source for vitamin D synthesis in the human body, excessive exposure precipitates deleterious effects on biological tissues and disrupts the molecular integrity of materials, culminating in performance degradation [47, 48]. Lignin exhibits exceptional photoprotective efficacy, inherently derived from its conjugated aromatic architecture [49]. The mechanism underpinning its UV absorption stems from the electronic excitation within the aromatic ring system [50]. Upon exposure to UV irradiation, lignin functions as a natural shield by absorbing harmful ultraviolet quanta and dissipating the dissipating the energy as heat or non‐radiative decay, thereby providing robust protection.

CONTEMPORARY INVESTIGATIONS INTO lignin in the field of UV protection PREDOMINANTLY center on augmenting the photo‐oxidative resistance of plastics [51], amplifying the efficacy of sunscreen formulations, and bolstering the photostability of pesticides [52]. For instance, Zhang et al. [53] engineered a composite film incorporating pectin and lignin nanoparticles (LNPs), which demonstrated near‐total blockade of UVB (320–275 nm) and UVC (275–200 nm) wavelengths, alongside significant attenuation of UVA (400–320 nm) radiation. Concurrently, the integration of LNPs potentiated the film's antioxidant capacity by 6.33‐fold and bolstered its antibacterial properties, rendering it highly viable for food preservation and packaging applications. In a parallel study, Zhang et al. [54] fabricated a mechanically robust, UV‐resistant composite film by chelating Fe^{3 +} with lignin and PVA, achieving a 100% UV shielding efficiency (Figure 3f), thereby catering to scenarios requiring rigorous UV protection. Furthermore, Zhou et al. [55] synthesized AL‐PDA, a photostable and biocompatible hybrid, by grafting dopamine (DA) onto alkali lignin (AL) via radical addition reactions. Subsequent emulsification and cross‐linking yielded nanocapsules that effectively impeded the dermal penetration of UV filters, achieving a Sun Protection Factor (SPF) of 195.33 while maintaining stability under UV irradiation for over 8 h at a 10 wt.% loading, highlighting its promise in cosmetic applications. Chen et al. [56] integrated lignin‐based carbon quantum dots (L‐CQDs) with lignin‐containing cellulose nanofibrils (LCNF). By regulating the lignin content in LCNF and the structure of L‐CQDs, highly transparent films that efficiently block UV and high‐energy blue‐violet light were obtained. The films exhibit good thermal stability, mechanical properties, and hydrophobicity, providing a design basis for all‐lignocellulose‐based photoprotective materials. Despite the formidable potential lignin demonstrates in UV protection, its practical utility is constrained by its intrinsic dark coloration [57], arising primarily from its complex aromatic constitution and condensation reactions induced during extraction. This chromophore‐rich profile presents a stark contrast to commercial polymers or emulsions, which are predominantly colorless or white. Consequently, this chromatic attribute represents a significant bottleneck impeding the substitution of commercial UV absorbers with lignin derivatives. Therefore, the development of novel isolation and modification protocols that strike an equilibrium between chromatic amelioration and the retention of UV absorption capacity constitutes a critical trajectory for advancing its commercial translation.

2.3. Physicochemical Properties of Lignin

Having delineated lignin's inherent biological functions, we now turn to its fundamental physicochemical properties that directly govern its behavior as a macromolecular building block. These properties—thermal stability, amphiphilicity, and fluorescence—are not merely supplementary characteristics but rather the very basis upon which lignin‐based functional polymers are designed and engineered.

2.3.1. Thermal Stability and Rigidity

Lignin is sequestered within the plant secondary cell wall, intercalated between cellulose and hemicellulose, where it plays a pivotal role in conferring structural rigidity and mechanical strength to the stem. From a polymer physics perspective, its competitive thermal stability and rigidity primarily emanate from its distinctive aromatic backbone and the intricate intermolecular crosslinked network [58]. The thermodynamic stability of the benzene ring combined with the high bond dissociation energy of intramolecular linkages renders lignin refractory to decomposition upon heating. This attribute endows it with a relatively elevated glass transition temperature (Tg, ranging from 90°C to 145°C) and thermal decomposition temperature (Td, typically 250°C–500°C), with specific values contingent upon its botanical origin, structural heterogeneity, and extraction methodology [59, 60].

This thermal robustness and rigidity profoundly influence its processability in polymer blends—a key consideration in macromolecular engineering. During melt blending with thermoplastic matrices such as polyhydroxybutyrate (PHB) and polylactic acid (PLA) [61, 62], lignin preserves its structural integrity at elevated processing temperatures, circumventing excessive degradation [63]. Concurrently, its rigid aromatic skeleton functions as a reinforcing phase, augmenting the mechanical modulus of the composite blend [64, 65].

2.3.2. Amphiphilicity and Self‐Assembly

Lignin represents an inherently amphiphilic biopolymer. Its phenylpropane backbone constitutes the hydrophobic domain, whereas oxygenated functional groups such as hydroxyl and methoxy moieties impart hydrophilicity. This duality empowers lignin to undergo spontaneous self‐assembly in solvent systems via non‐covalent interactions, including hydrogen bonding and π–π stacking, yielding [66, 67] structurally ordered lignin nanoparticles (LNPs) that drastically augment the density of interfacial interaction sites [68]. The morphological architecture of these assemblies is critically modulated by molecular parameters (e.g., the hydrophilic‐to‐hydrophobic ratio) and solvent properties [69]. From a macromolecular engineering standpoint, this self‐assembly capability not only broadens the horizon of lignin applications in polymer composites, drug delivery vehicles, and tissue engineering but also unveils novel avenues for its high‐value utilization as a building block for nanostructured materials [70].

2.3.3. Intrinsic Fluorescence Characteristics

Lignin is distinguished as an intrinsically luminescent material [71]. As a photophysically active biopolymer, it harbors endogenous luminophores within its aromatic structure capable of emitting blue‐green fluorescence under ultraviolet excitation, typically manifesting a broad emission spectrum within the 350–650 nm range [72, 73]. This fluorescence characteristic is predominantly ascribed to specific structural motifs such as coniferyl alcohol, stilbene, and phenylcoumarone embedded within its macromolecular framework [74]. Critically, the photophysical behavior of lignin is not merely a passive property but is intimately tied to its aggregation state—a phenomenon known as aggregation‐induced emission (AIE), wherein the clustering of phenylpropanoid units restricts intramolecular motion and enhances radiative decay, transforming a conventional concentration‐quenching limitation into a design advantage for luminescent polymer systems. Currently, this macromolecular fluorescence behavior has garnered significant traction, with lignin serving as a fluorescent probe in domains such as metal ion sensing [75], bioimaging [76], and pH monitoring [77], thereby opening new frontiers for its value‐added exploitation.

In synthesis, lignin is a structurally complex yet functionally versatile natural aromatic polymer that defies conventional classification. Its inherent bioactivities (e.g., antioxidant, antibacterial) are not supplementary surface functions but are encoded within its macromolecular backbone, poised to meet the requirements of smart biomaterials for microenvironment modulation; its profusion of functional groups and amphiphilic nature facilitate precise polymer engineering and nanomanufacturing; and its AIE‐governed fluorescence offers a built‐in reporter function for real‐time material monitoring. These properties collectively transcend the conventional perception of lignin as merely a “green raw material,” repositioning it as a highly tunable macromolecular platform capable of responsively addressing intricate biological demands through rational design at the polymer level.

3. Photophysical Basis of Lignin Fluorescence Characteristics

3.1. Molecular Origin of Fluorescence

Understanding the fluorescence behavior of lignin at the molecular level is not merely an academic pursuit in polymer photophysics; it is the essential prerequisite for engineering emissive scaffolds capable of providing real‐time feedback during bone healing. A precise grasp of which chromophoric moieties contribute to emission, and how they interact within the macromolecular network, directly dictates the rational design of lignin‐based fluorescent probes for non‐invasive tracking of scaffold degradation and tissue regeneration.

3.1.1. Chromophores

The fluorescence of native lignin and its chemically modified derivatives originates from intrinsic chromophoric moieties within the macromolecular network. In contrast, the emission of lignin‐derived carbon quantum dots (L‐CQDs) and lignin nanoparticles (LNPs) is largely governed by surface defect states and quantum confinement effects, which are fundamentally different mechanisms. This section focuses on the molecular origin of fluorescence in native lignin and its derivatives. Structurally, lignin constitutes a hyper‐branched three‐dimensional network derived from the radical polymerization of diverse phenylpropane precursors. From a macromolecular photophysics standpoint, its supramolecular architecture can be viewed as a sophisticated multi‐fluorophore system in which heterogeneous phenylpropane aggregates function as coupled emissive units (Figure 5a) [71]. Given the inherent variability in the taxonomy, stoichiometry, and spatial distribution of chromophores across lignin variants of distinct botanical origins, their fluorescence profiles exhibit pronounced diversity. Despite the relatively limited extent of extended molecular conjugation, lignin demonstrates potent broad‐spectrum ultraviolet absorption capabilities spanning the 250–400 nm regime [78]. The labyrinthine structural complexity and conformational polydispersity of lignin currently preclude the definitive cataloging of its entire chromophoric repertoire [79]. Compounding this challenge, intricate charge and energy transfer cascades transpire between electronic energy levels within the densely packed macromolecular matrix [71], thereby exacerbating the complexity of elucidating its fluorescence mechanisms. Nevertheless, specific chromophoric moieties possessing significant UV absorptivity have been identified, encompassing quinones, catechols, stilbenes, chalcones, phenol‐conjugated carbonyls, and metal complexes, among others [80, 81].

FIGURE 5.

(a) Corresponding mechanistic model diagram of lignin fluorescence. Reproduced with permission [71]. Copyright 2020 Elsevier, and (b) Schematic diagram of cellulase enzymatic lignin nanoparticle (CEL‐NP) preparation. Reproduced with permission [82]. Copyright 2018 American Chemical Society.

3.2. Aggregation‐Induced Emission (Aie) Phenomenon

3.2.1. Evidence and Mechanisms

Contemporary investigations have unveiled that lignin exhibits Aggregation‐Induced Emission (AIE) attributes—a photophysical phenomenon of fundamental importance in polymer science, wherein the aggregation of macromolecules or chromophore‐containing segments restricts intramolecular motions, enhancing radiative decay and transforming a conventional concentration‐quenching limitation into a deliberate design advantage for luminescent polymer systems. The proliferation of aromatic rings and conjugated architectures within lignin constitutes the structural foundation underpinning the AIE phenomenon. Xue et al. [73] furnished the seminal direct evidence of AIE behavior in alkali lignin (AL) and lignosulfonate (LS) within mixed solvent systems: as the proportion of poor solvent escalated, molecular aggregation was potentiated, culminating in marked fluorescence enhancement. The AIE of lignin is predominantly ascribed to the restriction of intramolecular motion (RIM) mechanism, encompassing restricted intramolecular rotation (RIR) and restricted intramolecular vibration (RIV). For instance, Ma et al. [82] engineered cellulase‐enzymatic lignin nanospheres (CEL‐NPs) where the impediment of intramolecular rotation mediated by J‐type stacking of benzene rings amplified fluorescence emission (Figure 5b). π–π interactions, a hallmark of aromatic polymer physics, also exert a pivotal influence during the aggregation process. Exemplifying this, Niu et al. [83] induced lignin aggregation via π‐π interactions to synthesize lignin‐based carbon quantum dots (LCQDs) possessing dual single‐ and two‐photon fluorescence emission capabilities. Furthermore, rational molecular design from a synthetic polymer chemistry perspective can further augment its AIE performance. Notably, Guo et al. [84] synthesized carbazole derivatives endowed with AIE properties by catalytically transforming the β‐O‐4 structural units in lignin. Ji et al. [85] utilizing lignin phenolic β‐O‐4 models as precursors, synthesized functionalized carbazole derivatives exhibiting both twisted intramolecular charge transfer (TICT) and AIE effects, thereby propelling the application of lignin in luminescent materials.

Although the AIE mechanism provides an important theoretical framework for understanding lignin fluorescence, the photophysical mechanisms underlying lignin aggregates remain controversial in the academic community and have not yet been fully elucidated. Recent studies suggest that the clusteroluminescence (CL) mechanism—whereby non‐conjugated, non‐aromatic luminophores generate visible light emission through through‐space interactions (TSI) [86, 87]—may serve as an important complementary theory for explaining the fluorescence of lignin and its derivatives. In fact, the pioneering study by Xue et al. [73] already recognized this complexity; they pointed out that lignin “does not exhibit blue emission based on its limited conjugated structure”, and therefore proposed that carbonyl cluster aggregates and the RIR effect jointly contribute to the AIE activity. This interpretation essentially aligns with the clusteroluminescence mechanism, indicating that both RIR and TSI likely coexist and synergistically contribute to the photophysical behavior of lignin aggregates. A comprehensive consideration of these mechanisms is necessary for a more accurate understanding and rational design of lignin‐based luminescent materials.

3.2.2. Performance Comparison

Archetypal AIE molecules encompass tetraphenylethylene (TPE), distyrylbenzenes (DSA), hexaphenylsiloxane (HPS), 1,8‐naphthalimide, 2,4,6‐triphenylpyridine, and tetraphenylpyrazine (TPP), among others [88, 89]. Governed by the RIR mechanism, these synthetic AIE luminogens exhibit intensified fluorescence emission in high‐concentration solutions or the solid state and are frequently integrated into polymer backbones through polymerization or modification to fabricate AIE‐active materials [90]. As compared in Table 2, synthetic AIEgens possess distinct advantages in quantum yield, color purity, and tunable emission. However, these benefits often come at the cost of complex synthesis and potential cytotoxicity.

TABLE 2.

Comparison of AIE performance between synthetic AIEgens and lignin‐based systems.

Parameter	Synthetic AIEgens (e.g., TPE, HPS)	Lignin‐based Systems
Fluorescence Quantum Yield (QY)	High intensity (governed by RIR mechanism)	Inferior to synthetic analogs due to heterogeneous structure
Emission Characteristics	Narrow emission bands	Broad emission spectra
Color Purity	High color purity	Lower color purity
Biocompatibility	Potential cytotoxicity concerns	Excellent biocompatibility, suitable for bioimaging
Cost & Sustainability	Often expensive, multi‐step organic synthesis	Cost‐effective, ubiquitously available, renewable
Mechanism	Predominantly RIR mechanism	RIR mechanism (combined with clusteroluminescence)

In juxtaposition, lignin‐based AIE, as an intrinsic property of a natural macromolecule, presents distinct merits regarding cost efficiency, biocompatibility, and ecological sustainability, making it suitable for biomedical domains such as bioimaging [91]. However, its inherent heterogeneous structure leads to lower quantum yields and broader emission spectra. Nevertheless, from a macromolecular engineering perspective, these limitations define the specific design parameters for subsequent chemical modification, which are expected to further potentiate its fluorescence properties. From a translational perspective, the lower quantum yields of lignin‐based AIE systems should not be viewed primarily as a limitation. Instead, they define specific design parameters for application in intelligent bone regeneration: where bright, high‐purity emission is required for deep‐tissue imaging, synthetic modifications or nanoscale engineering can be applied; and where moderate, broader emission is acceptable, lignin's inherent biocompatibility and cost‐effectiveness make it an ideal candidate for tracking superficial scaffold degradation and monitoring the local healing microenvironment.

3.3. Fluorescence Regulation Strategies

The modulation of lignin's fluorescence properties is not an end in itself, but a deliberate macromolecular engineering strategy aimed at tailoring its photophysical behavior to meet the specific demands of bone regeneration applications. To enable effective scaffold degradation tracking, microenvironmental sensing, and imaging‐guided repair, the emission wavelength, quantum yield, and stimulus‐responsiveness of lignin must be precisely controlled. This section systematically discusses the two primary approaches for achieving such regulation: nano‐structuring and chemical modification.

Lignin, as a naturally abundant aromatic polymer, exhibits inherent fluorescence properties stemming from its complex phenylpropane unit structure. Nevertheless, its pristine utility in fluorescent materials is severely circumscribed by intrinsic limitations, including low molecular conjugation, suboptimal fluorescence quantum yield, monochromatic emission, and structural heterogeneity. Crucially, these fluorescence characteristics can be effectively tailored through two macromolecular engineering approaches: precision nano‐structuring to control aggregation state, and chemical modification to alter the electronic structure of the polymer backbone.

3.3.1. Modulation via Nano‐Structuring

Unlike native lignin, the fluorescence behavior of lignin nanoparticles (LNPs) and lignin‐derived carbon quantum dots (L‐CQDs) can be effectively modulated through nano‐structuring strategies. This section focuses on the optical regulation of these nanoscale systems. Lignin fluorescence is highly responsive to its aggregation state—a direct manifestation of the structure‐property relationship in emissive polymers. Nano‐structuring strategies (e.g., synthesis of quantum dots, nanoparticle fabrication, and nanocomposite construction) represent pivotal approaches for fine‐tuning its optical properties. Lignin nanoparticles (LNPs) and lignin‐based carbon quantum dots (L‐CQDs), capitalizing on merits such as low cytotoxicity, tunable fluorescence, and facile surface functionalization, have garnered significant attention in diverse arenas including bioimaging [92], sensing [93], drug delivery [94], and tissue engineering [95].

The transformation of lignin into nanoparticles (LNPs) serves as a fundamental strategy for amplifying lignin fluorescence. The mechanism underpinning this enhancement is fundamentally a polymer aggregation effect: rapid spatial confinement of molecules within the nanoscale impedes the π‐π stacking of aromatic rings, thereby mitigating Aggregation‐Caused Quenching (ACQ). Prevalent fabrication methodologies encompass solvent exchange, self‐assembly, antisolvent precipitation, and interfacial crosslinking [96, 97]. Concurrently, the precise modulation of reaction parameters (e.g., concentration, solvent ratio) enables the synthesis of LNPs with monodisperse particle sizes [98]. The resultant nanoparticles feature highly reactive functional groups and promising dispersibility, laying a robust foundation for subsequent functionalization.

Carbon quantum dots (CQDs) constitute a class of zero‐dimensional fluorescent nanomaterials with dimensions typically falling below 10 nm [99]. Owing to their exceptional water solubility, low toxicity, modifiability, and photostability, they find extensive utility in ion detection, fluorescent labeling, drug delivery, bioimaging, and photoelectrocatalysis [100, 101]. Synthetic paradigms for CQDs are conventionally delineated into two categories: top‐down and bottom‐up [102]. L‐CQDs, derived from lignin as a carbon precursor, synergize the biocompatibility of lignin with the optical virtues of carbon dots. Given the amorphous macromolecular nature of lignin, “bottom‐up” approaches (e.g., hydrothermal/solvothermal carbonization, pyrolysis) are predominantly adopted [103, 104]. Their size distribution, surface chemistry, and fluorescence attributes can be finely tuned by adjusting reaction conditions or introducing heteroatoms (e.g., N, S) for surface passivation. For instance, Chen et al. [105] synthesized L‐CQDs with an emission wavelength of 430 nm via an H₂O₂‐mediated hydrothermal oxidation method. Sun et al. [106] valorized corncob lignin to fabricate pH‐responsive carbon dots achieving a quantum yield of 43.9%, which exhibited superb colloidal stability in aqueous media. Furthermore, this material demonstrated outstanding fluorescence emission properties with a lifetime exceeding 10 ns, underscoring its potential value in biosensing and environmental monitoring.

To augment the fluorescence intensity of L‐CQDs, numerous investigations have opted to incorporate heteroatoms such as N, P, S, or metal ions during the synthesis process to optimize their optical performance [107]. Yang et al. [108] through Mg and N co‐doping, engineered CQDs boasting a quantum yield of 46.38%. Notably, upon pH variation from 12.0 to 5.4, the Mg, N‐CQDs displayed a bathochromic fluorescence shift from blue to green (Figure 6a). Zhu et al. [102], by modulating acid additives containing N and S, synthesized carbon dots with a quantum yield of 30.5% (Figure 6b). Their red‐shifted emission is ascribed to the elevated degree of graphitization and narrowed bandgap resulting from doping (Figure 6c). Zhu et al. [109] proposed a facile two‐step method to synthesize CQDs from biomass lignin using the mild additive o‐aminobenzenesulfonic acid. These CQDs outperformed the majority of biomass waste‐derived carbon quantum dots, featuring an average diameter of 4.86 nm, a quantum yield reaching 23.68% (Figure 6d), and a maximum green emission at 476 nm. To further elevate performance from a polymer precursor design perspective, Zhao et al. [107] devised a two‐step strategy: initially, the catalytic depolymerization of lignin yielded low molecular weight precursors, followed by the fabrication of L‐CQDs without exogenous doping. Their fluorescence intensity was significantly potentiated, and they were successfully deployed for tumor cell labeling and in vivo imaging.

FIGURE 6.

(a) Photographs of Mg, N‐CQDs solutions under UV light at different pH values. Reproduced with permission [108]. Copyright 2021 Elsevier. (b) Method for synthesizing lignin‐derived CQDs using four different acid additives containing N or S, (c) Illustrations of Eg, HOMO, LUMO and the possible structures of the four CQDs. Reproduced with permission [102]. Copyright 2021 American Chemical Society. (d) Relative QYs and images of CQDs synthesized with varying amounts (0.1‐1.1 g) of o‐aminobenzenesulfonic acid additive under sunlight and UV light (365 nm) irradiation. Reproduced with permission [109]. Copyright 2021 Elsevier.

3.3.2. Chemical Modulation

Functional group modification constitutes a pivotal strategy for the chemical regulation of lignin fluorescence at the macromolecular level. The underlying mechanistic principle entails the rational modulation of electron cloud density, energy level gradients, and intra‐/intermolecular interactions within luminescent clusters. This is achieved via the strategic introduction of electron‐donating/electron‐withdrawing moieties, heteroatom doping, and the manipulation of aggregated state architectures, all while preserving or fortifying the aromatic conjugated backbone. Consequently, this facilitates the targeted augmentation of fluorescence intensity, tuning of emission wavelengths, and maximization of quantum yields. It should be noted that the chemical modification strategies discussed in this section are primarily focused on native lignin and its macromolecular derivatives. The metal‐ion‐induced fluorescence quenching of carbon quantum dots (CQDs) and graphene quantum dots (GQDs) involves distinct mechanisms such as surface coordination and electron transfer, which will be discussed in the context of composite systems later in this review.

While pristine lignin exhibits subdued fluorescence attributed to its limited conjugated structure, the covalent incorporation of heteroatomic groups into the lignin macromolecule can remarkably potentiate its photoluminescence (PL) properties. Amination stands out as an efficacious methodology. Research has elucidated that pretreatment of lignin with ethylenediamine (EDA) not only streamlines component extraction but also effectuates concurrent chemical modification [110]. Shi et al. [111] leveraged EDA pretreatment to implant nitrogen atoms during extraction, unveiling a significant positive correlation between nitrogen content and fluorescence intensity, with the aqueous luminescence intensity of the isolated lignin being amplified by 6.6‐fold. The introduction of N‐containing groups (e.g., ‐NH₂, ‐CONH‐) can contract the HOMO‐LUMO bandgap, inducing a bathochromic shift in emission while bolstering clusteroluminescence (CL) efficiency—a phenomenon intimately linked to the through‐space conjugation of heteroatom‐containing polymer segments. The aggregation of these groups fosters electronic (n→π ^*) transitions and promotes intermolecular and/or intramolecular electron delocalization. Furthermore, aminated lignin(AmL) reinforces the spatial interaction between N and O, stabilizing the structure against non‐radiative rotation and averting self‐quenching. Owing to the proliferation of basic groups, its fluorescence behavior manifests responsive sensitivity toward pH variations. This amination and amidation approach opens a novel avenue for broadening lignin‘s utility in organic fluorescent materials. In a parallel study, Li et al. [112] extracted lignin from agricultural waste via EDA. The resultant aminated lignin (AmL) possessed a nitrogen content of 14.33% and exhibited Aggregation‐Induced Emission (AIE) characteristics; its PL intensity surpassed that of alkali lignin (AL) by 4.88 times, positively correlating with pretreatment temperature (Figure 7a). The EDA pretreatment process is schematically depicted in Figure 7b. Additionally, this AmL functioned as a fluorescent probe for Fe^{3 +} detection, expanding the functional applications of lignin‐derived materials. Building upon this, Yang et al. [113] synthesized lignin nanoparticles modified with EDA and vitamin B1 (LEVs) via a hydrothermal method. Their fluorescence performance escalated with increasing vitamin B1 content, ascribed primarily to surface passivation by amide groups and N, S heteroatom co‐doping.

FIGURE 7.

(a) Fluorescence intensity of AL, (b) EDA pretreatment process. Reproduced with permission [112]. Copyright 2026 Elsevier. (c) PL response of LCQDs in the presence of different metal ions (100 µm) (F₀ and F₁ are the fluorescence intensities in the absence and presence of metal ions, respectively), (d) PL emission spectra of LCQDs treated with different Fe^{3 +} concentrations, which were 0, 1, 5, 10, 15, 20, 25, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, and 650 µm (from top to bottom). The inset shows the relationship between the F₀/F₁ value and the Fe^{3 +} concentration. Reproduced with permission [115]. Copyright 2019 Elsevier.

Metal ion coordination also exerts a profound, dualistic influence (amplification or quenching) on lignin fluorescence, a behavior that can be rationalized through the lens of polymer‐metal complex photophysics. Lignin, replete with hydroxyl and carboxyl groups, not only facilitates coordination with metal ions to engender ligand‐metal charge transfer (LMCT) and d‐d transitions—substantially augmenting visible light capture capacity—but also functions as a surfactant to regulate the nucleation and growth of metal oxides, yielding uniformly distributed nanoparticles that compensate for infrared absorption deficiencies. Liu et al. [114] utilized alkali lignin (AL) and Cu²⁺ under alkaline conditions to fabricate MLC. The absorption spectrum displayed a bathochromic shift attributed to the oxidative conversion of phenolic structures to quinone structures by Cu²⁺, which potentiated photothermal properties, resulting in markedly improved light absorption and conversion performance. Conversely, metal ions may induce fluorescence quenching. Gao et al. [115] proposed a facile and economical hydrothermal method to synthesize L‐CQDs featuring selective fluorescence response toward Fe^{3 +} (Figure 7c), possessing unique optical attributes suitable for bioanalytical applications. As shown in Figure 7d, the PL intensity of these L‐CQDs diminished progressively with increasing Fe^{3 +} content, demonstrating pronounced quenching due to the formation of non‐emissive complexes (L‐CQDs/Fe^{3 +}). Zhu et al. [116] synthesized high‐caliber alkali lignin(AL)‐derived graphene quantum dots (GQDs). These nitrogen‐doped GQDs exhibited robust fluorescence stability across broad pH ranges (3–10), extended periods (1‐12 h), and ionic strengths, with a quantum yield peaking at 28%. The constructed fluorescent sensor achieved a detection limit of 1.49 µmol/L for Fe^{3 +}, with quenching originating from the formation of GQD‐Fe^{3 +} complexes.

4. Design and Synthesis of Lignin‐Based Polymers

Having established the photophysical foundation, we now address the core question of polymer science: how can lignin's unique macromolecular structure be systematically exploited to construct fluorescent polymers with tailored architectures and functions? This section surveys the strategies that repurpose lignin as a macromolecular building block—as macromonomers, macromolecular initiators, and crosslinkers—highlighting the design principles that bridge lignin chemistry with advanced polymer synthesis.

4.1. Lignin as a Macromolecular Building Block

As the preeminent natural aromatic polymer in the biosphere, lignin features an intricate three‐dimensional network replete with reactive sites, notably phenolic and aliphatic hydroxyl groups. From the perspective of macromolecular engineering, it represents a unique, renewable scaffold that, through strategic chemical modification, can be converted into macromolecular monomers or functionalized initiators bearing polymerizable moieties, thereby establishing a robust platform for the development of bio‐based functional polymer materials with precisely controlled architectures.

4.1.1. Macromonomers

The hydroxyl and ancillary functional groups of lignin can be chemically derivatized to incorporate polymerizable units such as epoxy or vinyl groups, facilitating its direct integration into step‐growth or chain polymerization paradigms as a true macromonomer. For instance, Salanti et al. [117] executed the selective epoxidation of phenolic hydroxyl groups within industrial kraft lignin, subsequently coupling them with CO₂ to yield cyclic carbonate macromonomers. These were then subjected to ring‐opening addition reactions with amines to construct poly(hydroxyurethane) networks under mild conditions. Yan et al. [118] systematically elucidated that upon transforming lignin hydroxyls into end groups amenable to controlled polymerization, techniques such as Atom Transfer Radical Polymerization (ATRP) and Reversible Addition‐Fragmentation Chain Transfer (RAFT) can be deployed to achieve precision engineering over the polymer chain architecture (e.g., grafting density, chain length), exemplifying the power of modern macromolecular chemistry applied to a natural substrate.

Synergizing lignin with biodegradable polymers (e.g., polylactic acid, PLA) can effectively broaden material functionalities through copolymerization. Boarino et al. [119] grafted lactide onto lignin nanoparticles via ring‐opening polymerization to fabricate PLA‐g‐LNPs (Figure 8a). This composite achieved homogeneous dispersion within the PLA matrix, significantly augmenting the film's UV shielding and antioxidant performance. Dutta et al. [120] initially synthesized epoxidized lignin (EL) using epichlorohydrin, followed by the synthesis of Lig‐PLA copolymers through lactide grafting polymerization. Notably, when the lactide content exceeded 50 wt.%, the resultant films exhibited high flexibility (Figure 8b–g), corroborating the efficacy of this method in producing flexible films with high lignin loading.

FIGURE 8.

(a) Synthesis of lignin nanoparticles and their grafting with polylactic acid (PLA) via ring‐opening polymerization of lactide. Reproduced with permission [119]. Copyright 2022 Alice Boarino et al. (b‐g) Photographs of lignin‐polylactic acid copolymer films prepared at EL:LA weight ratios of 1:0.75, 1:1, 1:2, 1:3, 1:4, and 1:5, respectively. Reproduced with permission [120]. Copyright 2023 Springer Nature. (h) Phenolation process for lignin graft copolymers. Reproduced with permission [127]. Copyright 2024 Elsevier.

Furthermore, lignin, functioning as a polyol, is widely exploited in systems such as phenolic resins, epoxy resins, and polyurethanes [121, 122, 123]. Xue et al. [124] partially substituted polycarbonate diol (PCDL) with modified alkali lignin (AL) and reacted it with isophorone diisocyanate (IPDI) to synthesize lignin‐based polyurethane (LPU) films. At an NCO/OH ratio of 1.8, the film exhibited optimal mechanical properties, thermal stability, and UV blocking efficacy. Da Silva Costa et al. [125] engineered lignin‐based epoxy resins endowed with flame‐retardant and UV‐shielding functions by integrating phosphorylation and glycidylation modifications.

4.1.2. Macromolecular Initiators

The intrinsic structural motifs within lignin, such as phenoxy groups and aromatic carbonyls, confer photosensitive properties that are highly valuable for polymer synthesis. Through chemical modification, lignin can be repurposed as a macromolecular initiator for use in controlled polymerization systems (ATRP, RAFT, ROP) [126], enabling the precision design of polymer chain architectures while simultaneously anchoring functionality to the initiating core. Singh et al. [127] pioneered the introduction of bromine atoms onto lignin via esterification, producing a macromolecular ATRP initiator (L‐Br). This successfully triggered the graft polymerization of 4‐acetoxystyrene, amplifying the density of reactive sites by over tenfold (Figure 8h). Qi et al.120 utilized de‐alkali lignin (DAL) as a backbone to construct a polymerizable macromolecular photoinitiator, DAL‐11ene‐amine, by covalently tethering photosensitive units and co‐initiators—a design that showcases how the initiator itself can become a functional block of the final polymer. This initiator exhibited high initiation efficiency and low migration under 405 nm irradiation, and the cured film possessed full‐spectrum UV shielding capability. Liu et al. [128] further advanced this concept by preparing a water‐soluble macromolecular photoinitiator, L‐PEG‐2959, which underwent self‐assembly into ∼75 nm core–shell nanoparticles in aqueous phase, with lignin as the core and PEG‐2959 as the shell. It combined good initiation activity with low migration characteristics. When applied in a gelatin‐GMA system, it elevated the Young's modulus of the gel by nearly tenfold while maintaining >78% cell viability.

In the realm of controlled radical polymerization, lignin‐based macroinitiators offer a direct route to well‐defined graft copolymers. Bhadane et al. [129] systematically investigated the influence of lignin source on the synthesis of lignin‐grafted poly(n‐butyl acrylate) copolymers via SARA ATRP. Using macroinitiators derived from birch, spruce, and wheat straw lignin, the study revealed that esterification efficiency varied significantly with lignin origin. Spruce lignin exhibited the highest conversion (97.2%) in macroinitiator formation, attributed to its higher proportion of less sterically hindered guaiacyl units. Birch lignin showed moderate efficiency (83.2%), while wheat straw lignin displayed the lowest conversion (74.7%) due to its structural complexity and higher carboxylic acid content. These differences directly influenced subsequent copolymerization, with spruce‐ and birch‐based systems yielding well‐defined graft copolymers suitable for adhesive applications, whereas wheat straw lignin resulted in inefficient polymerization and poor product recovery. The resulting BLNBA4 had an Mn of 42 kDa with a moderate molecular weight distribution. It met the Dahlquist criterion for pressure‐sensitive adhesives in the range of 50–300 kPa, demonstrating favorable viscoelastic properties. Wu et al. [130] leveraged ARGET ATRP technology to co‐graft lauryl methacrylate (LMA) and isobornyl methacrylate (IBOMA) onto a lignin backbone, constructing an all‐biomass macromolecular initiator, OL‐Br. By modulating the IBOMA/LMA/OL‐Br molar ratio, the glass transition temperature and molecular weight of the grafted chains could be precisely tuned. The resulting OL0.24‐g‐P(IBOMA300‐co‐LMA) exhibited a tensile strength of 6.66 MPa and an elongation at break of 232%. Capitalizing on the presence of lignin, a fully biomass‐based elastomer was prepared featuring robust mechanical properties, UV absorption, and multi‐substrate adhesion performance (Figure 9a).

FIGURE 9.

(a) Demonstration of the adhesive properties of OL0.24‐g‐P(IBOMA300‐co‐LMA) adhering to various solid materials. Reproduced with permission [130]. Copyright 2023 Elsevier. (b) Schematic structure of the prepared L‐BF, (c) Schematic of the structure and fabrication of HEG prepared via one‐pot UV‐initiated polymerization and its application in underwater sensing and communication. Reproduced with permission [132]. Copyright 2024 John Wiley and Sons. (d) Synthesis mechanism of plant‐derived protein adhesives and (e) their mildew‐proof mechanism. Reproduced with permission [138]. Copyright 2024 Elsevier. (f) Cell viability values (%) estimated via MTT assay after incubation with samples containing different concentrations of lignin at 37°C for 24 h. Reproduced with permission [142]. Copyright 2020 Elsevier.

Furthermore, Liu et al. [131] deployed a photo‐initiated RAFT strategy to introduce dithioester chain transfer units onto lignin, constructing a self‐initiating macromolecular CTA—a concept that merges the roles of initiator and control agent in a single macromolecule. This system enables sequence‐controlled monomer polymerization obviating the need for external initiators. The resulting DL‐P(MMA‐AA) can self‐assemble into 174 nm nanoparticles in water, demonstrating potential as a Pickering emulsion stabilizer. Harnessing lignin's inherent light absorption properties, this approach allows for the one‐step preparation of amphiphilic graft copolymers with tunable structures, significantly simplifying the traditional RAFT process. Luo et al. [132] grafted benzoylformate groups onto lignin. Exploiting its UV‐cleavage characteristic to initiate polymerization, they prepared a zero‐migration, underwater high‐adhesion conductive gel, expanding lignin's potential application in the field of flexible electronics (Figure 9b,c).

In summary, lignin has been successfully implemented as a macromolecular initiator in various controlled polymerization systems. Through rational structural design, it not only effectively circumvents impediments such as lignin's inherent low reactivity and poor compatibility but also mitigates residual small‐molecule initiators. Simultaneously, it endows materials with multiple functionalities, such as UV shielding, biocompatibility, and adhesion, offering an efficacious strategy for developing high‐performance sustainable polymers—a prime example of how a biogenic macromolecule can be elevated to the status of a versatile tool in polymer chemistry.

4.1.3. Crosslinker

Lignin, emerging as a sustainable surrogate for petroleum‐based crosslinkers, has been extensively deployed in polymer systems encompassing polyurethanes, hydrogels, and composites [133, 134, 135, 136, 137]. Its three‐dimensional network architecture is replete with reactive moieties, notably phenolic and benzylic hydroxyl groups. Through strategic chemical modification, it can be engineered into a multifunctional crosslinker that establishes covalent networks with monomers during polymerization, effectively potentiating the material's mechanical properties, thermal stability, and dimensional integrity—a classic strategy in polymer network engineering.

Investigations substantiate that lignin can be chemically derivatized (e.g., via amination, esterification, or graft copolymerization) to introduce reactive functional groups, facilitating the formation of covalent crosslinked networks with polymer backbones. Exemplifying this strategy, Wang et al. [138] transformed lignin into lignin amine (LA); its subsequent grafting with polyurethane (PU) prepolymers yielded a PU‐LA crosslinker. This system orchestrates multiple networks with protein chains through Schiff base reactions and hydrogen bonding, augmenting the wet shear strength of plant protein adhesives by 188% and imparting well‐suited mildew resistance (Figure 9d, e). In a parallel vein, Gu et al. [139] synthesized aminated lignin (AmL) via the Mannich reaction and subsequently fabricated AmL@QPTPT crosslinked membranes with quaternized poly(aryl 53piperidinium) (QPTPT) through the Menshutkin reaction. This architecture not only bolstered the mechanical strength of the membrane but also effectively mitigated its oxidative degradation in Fenton's reagent. The phenolic hydroxyl groups of lignin can also engage in free radical polymerization, enabling its use as a reactive crosslinking comonomer. Dou et al. [140] incorporated methacrylated lignin (LMA) as a bio‐based macromolecular crosslinker into a PVA/AMPS system, successfully constructing a three‐dimensional crosslinked hydrogel nanofiber membrane for lithium‐ion battery separators.

In the architecture of dynamic crosslinking systems, lignin can function as a multifunctional component, introducing reversibility and responsiveness into the polymer network. Du et al. [141] integrated hydroxylated lignin into a polyurethane system based on the Diels‐Alder (DA) reaction (PUDA‐L), constructing a reversible network endowed with self‐healing properties, robust mechanical strength, and thermal stability. Xu et al. [142] utilized alkali lignin (AL) as a dual‐function component (crosslinker and filler), copolymerizing it with polycarbonate diol (PCDL) and polydimethylsiloxane (PDMS) to fabricate semi‐interpenetrating network elastomers (IPU). In this system, a fraction of the AL participates in crosslinking, while the remainder disperses as nanoparticles serving as rigid reinforcement.

Cytotoxicity assays confirmed favorable biocompatibility (Figure 9f), validating the premise for the efficient, low‐dosage utilization of lignin.

In synthesis, the functionalization of lignin as a crosslinker is contingent upon rational structural modification and functional group design. Critically, the intrinsic aromatic structure of lignin confers inherent fluorescence properties upon the crosslinked networks. From a polymer science perspective, this opens a compelling avenue for intelligent bone regeneration: the fluorescence intensity and emission wavelength of lignin‐based crosslinked networks can be modulated by the degree of crosslinking and the local polymer chain mobility. Therefore, future investigations could harness this intrinsic fluorescence for non‐destructive, real‐time characterization of crosslinking density, scaffold degradation uniformity, and in vivo aging monitoring. This would transform lignin‐based crosslinkers from mere structural reinforcements into smart, self‐reporting components for bone tissue engineering scaffolds. It is important to note that while many of the above studies were developed for applications such as drug delivery or flexible electronics, the underlying macromolecular design principles—particularly the control over crosslinking density and stimuli‐responsiveness—are directly transferable to bone tissue engineering scaffolds. However, their specific efficacy in promoting osteogenesis, supporting vascularization, and degrading in a bone‐defect microenvironment must be validated in dedicated bone‐related models.

4.2. Achieving Tailored Responsiveness Through Chemical Functionalization

Beyond serving as a passive structural component, lignin can be chemically engineered at the macromolecular level to impart tailored responsiveness—targeting capability, environmental sensitivity, and signal amplification—to the resulting polymers. This section examines the chemical strategies that transform lignin's functional group landscape into programmable macromolecular behavior.

4.2.1. Targeted Modification

Targeted modification is predominantly realized via the covalent grafting of molecules possessing specific recognition motifs onto the lignin macromolecular backbone. By conjugating specific recognition ligands such as RGD peptides, bone‐targeting peptides, or bisphosphonates, lignin‐based polymers can be endowed with active targeting functionality toward specific tissues (e.g., bone tissue)—a strategy that parallels the ligand‐functionalized synthetic polymer therapeutics.

RGD peptides can specifically bind to cell surface integrin receptors and are ubiquitously employed for biomaterial functionalization [143, 144]. Figueiredo et al. [145] conjugated iRGD peptides to the surface of carboxylated lignin nanoparticles (LNPs) via EDC/NHS chemistry, constructing an LNPs‐iRGD system—a demonstration of how standard bioconjugation chemistry can be applied to a lignin macromolecular platform. This system exhibited good biocompatibility across multiple cancer cell lines and, driven by an integrin‐mediated mechanism, demonstrated enhanced cellular uptake efficiency in both 2D and 3D models compared to unmodified LNPs, establishing a foundation for active targeting nano‐delivery systems.

Bisphosphonates (e.g., alendronate, ALEN) constitute a class of compounds that exhibit robust binding affinity to calcium ions in bone tissue, manifesting strong avidity for hydroxyapatite (HAP) on bone surfaces [146]. ALEN is a prototypical therapeutic agent for treating osteoporosis, capable of augmenting osteoblast activity and stimulating osteoblast proliferation, and can serve as a bone‐targeting ligand [147]. Yingjun et al. [148] co‐hybridized ALEN with a lignin derivative (LS) to modify nano‐hydroxyapatite (n‐HA), which was then utilized as a filler in poly(lactide‐co‐glycolide) (PLGA). The lignin derivative, through its functional groups binding with Ca^{2 +}, synergistically facilitated apatite deposition on the composite surface (Figure 10a), significantly ameliorating the dispersion of n‐HA in the matrix and its osteogenic activity, culminating in a 24% augmentation in the material's mechanical properties—a result that underscores how interfacial chemistry enabled by lignin can dictate the macroscopic performance of hybrid polymer systems. However, this study did not encompass validation through in vitro osteogenic activity or in vivo experiments.

FIGURE 10.

(a) SEM images of the composite after 8 weeks of degradation. Reproduced with permission [148]. Copyright 2023 Elsevier. (b) Synthesis route of the LG‐M(N‐DOX)‐PEG copolymer and schematic diagram of its self‐assembly into nanoparticles, and (c) schematic diagram of the dual pH‐responsive LG‐M(N‐DOX)‐PEG NPs. Reproduced with permission [149]. Copyright 2022 American Chemical Society. Swelling capacity of the LNIH hydrogel at (d) 25°C and (e) 42°C under different pH values. Reproduced with permission [154]. Copyright 2018 American Chemical Society.

4.2.2. Design of Intelligent Responsiveness

By imparting lignin‐based polymers with responsiveness to pH, temperature, redox conditions, and other stimuli through judicious macromolecular design, smart materials tailored for tissue engineering, controlled drug release, and other fields can be constructed. The key design principle is the installation of stimuli‐labile linkages or responsive polymer segments onto the lignin scaffold.

pH responsiveness is conventionally attained via the introduction of labile linkages such as hydrazone or acetal bonds to tether active components onto the lignin skeleton, enabling pH‐triggered cleavage or conformational change in the resulting macromolecular conjugates. Drug delivery carriers often exploit this pH‐responsive property of lignin‐based polymers (Table 3). Yang et al. [149] fabricated pH‐responsive lignin‐based nanoparticles, LG‐M(N‐DOX)‐PEG, via a three‐step reaction (Figure 10b). The loaded doxorubicin (DOX) could be rapidly liberated within the acidic tumor microenvironment (pH 6.5) through the cleavage of the hydrazone bond (Figure 10c).

TABLE 3.

pH‐Responsive Lignin‐Based Polymers for Drug Delivery Applications.

Carrier	Dosage Form	Stimulus Type	Loaded Drug Type	EE (%)	Biological evaluation model	Reference
LG‐M(N‐DOX)‐PEG	NPs	pH	DOX	—	In vitro cytotoxicity: 4T1 breast cancer cells and NIH‐3T3 mouse embryonic cells. In vivo: 4T1 breast cancer tumor‐bearing mouse model via subcutaneous inoculation on the right back for anti‐tumor assessment.	[149]
SLQD‐Doxo	NPs	pH	DOX	81	In vitro cytotoxicity: MCF‐7 breast cancer cells.	[150]
AAL‐g‐PMAA	Nanomicelle	pH	IBU	84	In Vitro Cell Experiments: Human colon cancer cell line HT‐29 cells, human bone marrow stromal cell line hBMSC cells, and mouse embryonic fibroblast cell line NIH‐3T3 cells.	[151]
Lig/Chi	NPs	pH	DTX CCM	90	In Vitro: HeLa cells toxicity analysis.	[152]
CLNPs‐PEG‐PHIS‐CPP	NPs	pH	BZL	50 ± 10	In Vitro:Human umbilical vein cell line (EA.hy926), human mammary carcinoma cell lines (MDA‐MB‐231 and MCF‐7), human prostate cancer cell line (PC3‐MM2) and human colorectal adenocarcinoma cell line (Caco‐2).	[158]
AmL‐His	NPs	pH	HCPT	15	In vitro cytotoxicity: Human breast cells (MCF‐7 cells). In vivo: BALB/c mice anti‐tumor model inoculated of 4T1 by subcutaneous injection.	[159]
Chi/Lig/Sm	NPs	pH	CUR	40	—	[160]

Liaqat et al. [150] condensed sitagliptin with lignin and loaded it with ZnSe quantum dots and DOX, creating an SLQD‐Doxo nanosystem with a maximum drug encapsulation efficiency of 81.75%. At pH 6.5, protonation of lignin destabilized non‐covalent interactions, triggering burst drug release, and orchestrating synergistic chemotherapy, photodynamic, and immunomodulatory effects. Cheng et al. [151] engineered an amphiphilic lignin copolymer, AAL‐g‐PMAA, which could self‐assemble into pH‐sensitive micelles—a macromolecular architecture wherein the pH‐responsive PMAA segments undergo conformational switching. It achieved sustained release of ibuprofen (81.81%) in simulated intestinal fluid (pH 7.4), while remaining stable (retaining over 84.36%) in gastric fluid (pH 1.5). Chai et al. [152] prepared lignin/chitosan nanoparticles (Lig/Chi NPs) with an effective drug loading rate of 90%. Leveraging the synergy between the surface cationic layer and lignin, the final cumulative release reached 50% in a tumor acidic environment (pH 5.4), far surpassing that of the free drug (27%).

Temperature responsiveness can be conferred by grafting thermosensitive polymers such as poly(N‐isopropylacrylamide) (PNIPAM) onto the lignin backbone, creating macromolecular hybrids that undergo coil‐to‐globule transitions at a defined lower critical solution temperature (LCST) [153]. Jin et al. [154] synthesized lignin‐based hydrogels through the copolymerization of NIPAM, itaconic acid, and sodium lignosulfonate functionalized with methacrylate, endowing them with dual temperature and pH responsiveness. Their swelling kinetics were modulated by lignin content: as the lignin content increased (from 3.7% to 14.3%), the swelling capacity decreased (from 31.6 to 19.1 g/g), and the phase transition temperature approximated body temperature (Figure 10d, e), demonstrating potential utility for drug release applications. Diaz–Baca et al. [155] fabricated KLS materials by crosslinking kraft lignin with starch using epichlorohydrin, which exhibited temperature‐dependent solubility and gelation behavior, showing promise for applications in smart hydrogels and packaging films.

Lignin can also synergistically modulate chondrogenesis by establishing a defined window of intracellular oxidative stress within the microenvironment—a function directly arising from its redox‐active macromolecular structure. Pei et al. [156] synthesized lignin dehydrogenation polymers (DHPs) using arabinogalactan (DHP‐A) and xylose (DHP‐X) precursors via a bi‐enzymatic method. DHP‐A, abundant in phenolic hydroxyl groups, possessed potent ROS scavenging capability. The hydrogel prepared by crosslinking it with hyaluronic acid could regulate intracellular ROS levels through a “pre‐oxidation” paradigm, promoting the differentiation of bone marrow mesenchymal stem cells into chondrocytes, inhibiting hypertrophy, and supporting hyaline cartilage regeneration (Figure 11). This study was the first to elucidate the role of lignin in promoting hyaline cartilage regeneration through a biphasic fluctuation (initial rise followed by a decrease) in ROS, providing a rationale for designing ROS‐responsive lignin‐based smart materials. Cunningham et al. [157] covalently tethered stilbazolium dyes to lignin via phenol hydroxyl alkylation‐click reactions, producing self‐assembled fluorescent nanoparticles—an exemplary macromolecular engineering strategy that introduces synthetic chromophores while preserving the lignin scaffold. Among them, the borate ester derivative L‐BMB⁺ could be oxidized by H₂O₂ to the phenolic form L‐BMH⁺, resulting in an 87% fluorescence enhancement, facilitating oxidative stress imaging at the live‐cell level and offering a novel concept for lignin‐based degradable fluorescent probes.

FIGURE 11.

(a) Schematic diagram illustrating how DHP promotes the multi‐differentiation of BMSCs into cartilage by regulating oxidative stress in vitro, (b) Schematic diagram of DHP‐HA hydrogel repairing rat cartilage defects through the modulation of oxidative stress, and (c) photographic comparison of defects in the five groups at 4 weeks post‐operation. Reproduced with permission [156]. Copyright 2023 Springer Nature.

Collectively, these intelligent responsiveness strategies (pH, temperature, redox) are not merely chemical curiosities; they are powerful tools for translating lignin‐based polymers into smart bone scaffolds. For instance, pH‐responsive lignin polymers can be designed to detect local acidosis at the site of bone inflammation or infection, while ROS‐responsive systems can report on the oxidative stress levels in the bone defect microenvironment. When coupled with lignin's intrinsic fluorescence, these responsive systems offer a dual modality: they can both sense pathophysiological cues and provide optical readouts, enabling real‐time, non‐invasive monitoring of the bone healing progression. This represents a critical step toward imaging‐guided bone regeneration.

4.2.3. Fluorescence Signal Amplification

The intrinsic broad‐spectrum fluorescence emission profile of lignin substantially augments its utility as a donor fluorophore capable of pairing with diverse acceptor moieties. From a polymer photophysics standpoint, the strategic architecture of Förster Resonance Energy Transfer (FRET) or Aggregation‐Induced Emission (AIE) systems represents a potent methodology for amplifying the fluorescence signal intensity of lignin‐based polymers through precisely engineered inter‐chromophore interactions. The efficacious construction of a FRET pair is predicated upon the judicious selection of donor and acceptor fluorophores. Crucially, the emission spectrum of the donor must exhibit substantial spectral overlap with the absorption spectrum of the acceptor, while maintaining an inter‐chromophoric distance confined within the Förster radius (typically 1–10 nm).

The strategic architecture of Förster Resonance Energy Transfer (FRET) or Aggregation‐Induced Emission (AIE) systems represents a potent methodology for amplifying the fluorescence signal intensity of lignin‐based polymers. The efficacious construction of a FRET pair is predicated upon the judicious selection of donor and acceptor fluorophores. Crucially, the emission spectrum of the donor must exhibit substantial spectral overlap with the absorption spectrum of the acceptor, while maintaining an inter‐chromophoric distance confined within the Förster radius (typically 1–10 nm).

Spirolactam rhodamine B (SRhB) stands as an archetypal fluorescent probe, extensively deployed in the design of intensity‐based and ratiometric sensors. Xue et al. [161] engineered a water‐soluble ratiometric fluorescent pH probe, L‐SRhB, via the chemical grafting of SRhB onto a lignosulfonate (LS) backbone—a macromolecular design wherein LS serves as both a polymeric scaffold and an energy donor in the FRET pair. This probe demonstrates rapid kinetic responsiveness within the pH range of 4.60–6.20, rendering it highly suitable for monitoring acidic organelles. Furthermore, it exhibits distinctive selective staining capabilities in cancer cell imaging (Figure 12a). To streamline the synthetic protocol and bolster practical utility, the same research group orchestrated the non‐covalent assembly of SRhB with LS via electrostatic interactions, constructing an SRhB/LS composite system. In acidic microenvironments, this system undergoes FRET driven by the intramolecular energy transfer cascade inherent to LS (Figure 12b) [72], thereby achieving precise ratiometric pH detection. Beyond its role in FRET, lignin intrinsically possesses AIE attributes—a macromolecular photophysical phenomenon described in Section 3.2. The physical blending or covalent copolymerization of lignin with AIE‐active small molecules can yield composite materials featuring potentiated AIE effects. Guo et al. [83] synthesized bio‐based carbazole derivatives endowed with AIE properties via a vanadium‐catalyzed one‐pot reaction between lignin β‐O‐4 fragments and 3‐alkenylated indoles, attaining a fluorescence quantum yield of 13.7%. These compounds adopt an Acceptor‐Donor‐Acceptor (A‐D‐A) configuration, manifesting luminescent behavior stemming from the synergistic interplay between Twisted Intramolecular Charge Transfer (TICT) and AIE mechanisms (Figure 12c). Furthermore, their solid‐state emission characteristics are critically modulated by molecular conformation and crystalline packing modes. Varying substituents can fine‐tune the HOMO‐LUMO distribution and energy gap, inducing a bathochromic shift in emission wavelength and enabling precise chromatic tuning. This strategy furnishes a novel paradigm for the high‐value valorization of lignin through rational macromolecular design of advanced bio‐based AIE materials.

FIGURE 12.

(a) Cancer cell images treated with L‐SRhB (A) and FL‐SRhB (B). Reproduced with permission [161]. Copyright 2016 American Chemical Society. (b) Schematic diagram of the multi‐path energy transfer in the SRhB/LS system. Reproduced with permission [72]. Copyright 2019 American Chemical Society. (c) Construction of carbazole‐based bio‐AIEgen from lignin β‐O‐4 with γ‐OH. Reproduced with permission [83]. Copyright 2023 Springer Nature.

This strategy furnishes a novel paradigm for the high‐value valorization of lignin through rational macromolecular design of advanced bio‐based AIE materials. Importantly, from the perspective of bone tissue engineering, these FRET and AIE‐amplified lignin systems hold immense potential for imaging‐guided bone regeneration. By incorporating stimuli‐responsive FRET probes, lignin‐based scaffolds can be engineered to provide ratiometric fluorescence readouts of local pH, enzyme activity, or metal ion concentrations within the bone defect. This capability enables clinicians and researchers to track scaffold degradation, monitor the onset of infection, and assess tissue regeneration in real time, thereby facilitating precision medicine in bone repair.

4.3. Nano‐ and Macro‐Engineering of Lignin Hybrid Materials

Unlike the previous sections focusing on individual lignin‐based components, this section discusses lignin‐containing composite scaffolds and hybrid materials, where the fluorescence behavior is often a combination of the embedded lignin and the polymer matrix environment. Moving from molecular‐level functionalization to hierarchical structural construction, this section examines how lignin‐based polymers can be engineered across multiple length scales—from nanocomposites to macroscopic scaffolds—to achieve the structural and functional complexity required for biomedical applications. The unifying theme is the deliberate control over polymer‐inorganic interfaces and processing‐structure‐property relationships.

4.3.1. Nanocomposites

The strategic hybridization of lignin with inorganic nanoparticles (notably upconversion nanoparticles and nano‐hydroxyapatite) constitutes a pivotal paradigm for fabricating high‐performance hybrid materials, wherein lignin's multifunctional macromolecular structure mediates the organic–inorganic interface.

Hydroxyapatite (HA), as the predominant inorganic constituent of bone tissue, exhibits exemplary biocompatibility and osteoconductivity. Lignin, replete with phenolic and aliphatic hydroxyl groups, demonstrates potent Ca^{2 +} chelation capacity, thereby fostering biomineralization and the oriented crystallization of HA—a function that directly arises from its macromolecular architecture functioning as a polymeric template for inorganic phase nucleation. Wang et al. [162] fabricated lignin/polycaprolactone nanofibers via electrospinning, which facilitated HA deposition in simulated body fluid. The resultant elastic modulus approximated that of cancellous bone, and the scaffolds significantly augmented osteoblast adhesion, spreading, and proliferation, corroborating their optimal osteoconductivity. Nugroho et al. [163] engineered a composite of lignin‐based polyurethane with HA, revealing that HA modulated the material's porosity and hydrophilicity, enhanced surface roughness, facilitated the sustained release of therapeutic agents such as quercetin, and concurrently mitigated cytotoxicity, underscoring its promising utility in tissue regeneration scaffolds (specifically bone scaffolds).

To ameliorate the dispersion and interfacial adhesion of nano‐HA (n‐HA) within poly(lactide‐co‐glycolide) (PLGA) matrices, investigations have leveraged lignin derivatives for surface modification—a strategy grounded in the macromolecular surfactant‐like behavior of amphiphilic lignin. Exemplifying this, Yingjun et al. [148] co‐hybridized n‐HA with sodium lignosulfonate and alendronate. Exploiting the competitive coordination between sulfonate and phosphonate moieties, this approach refined crystallite size and inhibited particle agglomeration, yielding a 24.43% augmentation in the tensile strength of the PLGA composite and fostering the deposition of bone‐like apatite. Tang et al. [164] subjected n‐HA to synergistic modification using carboxymethyl β‐cyclodextrin and lignin, bolstering the mechanical properties, degradation controllability, and bioactivity of the PLGA composite via a dual hydrogen bond‐coordination network, thereby accelerating bone‐like apatite formation and cell proliferation. Furthermore, Kandil et al. [165] incorporated lignin into a chitosan/HA system, determining that a 25 wt.% loading optimized the scaffold's mechanical properties and degradation kinetics. Its phenolic hydroxyl groups facilitated calcium ion adsorption and bone‐like apatite deposition while concurrently enhancing cell adhesion and proliferation.

Upconversion nanoparticles (UCNPs) possess the capability to emit higher‐energy photons under near‐infrared (NIR) excitation, affording distinct advantages including deep‐tissue penetration and minimized background fluorescence. The integration of lignin‐based polymer matrices with UCNPs is a sophisticated macromolecular engineering challenge that hinges on controlling the polymer‐inorganic interface for efficient energy transfer. Lignin‐based polymer nanoparticles, owing to their natural aromatic backbone and surface‐accessible functional groups (hydroxyl and ether bonds), can assemble into core–shell microspheres with chitosan via electrostatic co‐assembly, furnishing a stabilized microenvironment for encapsulating rare‐earth luminescent nanoparticles. Quezada et al. [160] embedded Sm₂O₃ nanoparticles into a lignin‐chitosan matrix for deployment as drug carriers. The π‐conjugated structure of lignin amplifies energy transfer via the antenna effect, while its phenolic hydroxyl groups, through coordination with Sm^{3 +}, attenuate non‐radiative relaxation, thereby enhancing the fluorescence quantum yield. With increasing Sm₂O₃ content, the ‐OH signal in FTIR diminished while amine bands sharpened (Figure 13a), signifying the preferential binding of particles to lignin and their subsequent encapsulation by chitosan to form uniformly dispersed luminescent centers. These composite particles exhibited stable fluorescence intensity across the pH range of 3–7 and demonstrated sustained curcumin release kinetics, facilitating theranostics and highlighting application potential in bioimaging and in vitro assays, particularly for oral delivery microcarriers.

FIGURE 13.

(a) FTIR spectra of Chi/Lig/Sm composites with different incorporation concentrations of Sm₂O₃ nanoparticles. Reproduced with permission [160]. Copyright 2025 Copyright 2025 Gilda Quezada et al. Lignin‐promoted chondrogenic differentiation: (b‐d) Compared to the control without GGH‐Lignin(gellan gum with an alkali lignin), the presence of lignin improved the upregulation of chondrogenic genes in a dose‐dependent manner, with GG_HLLign0.4 (GG_HLLign0.4 refers to gellan gum with an alkali lignin content of 0.4% (w/v), where H/L denotes high/low acyl content gellan gum) showing significant effects vs. 0.1 and 0.2 (p < 0.05, indicated by § and #, respectively), (e) Histology confirmed the formation of cartilage‐like ECM: Alcian Blue staining showed the presence of mucopolysaccharides (light blue, nuclei in black), Sirius Red staining revealed the deposition of collagen fibers (red) within the cytoplasm (yellow), and Safranin O confirmed the appearance of mucins (red, nuclei in black). Reproduced with permission [168]. Copyright 2022 Elsevier.

Sun et al. [166] loaded Gd^{3 +}‐doped CeVO₄ UCNPs onto modified attapulgite, subsequently coupling them with sodium lignosulfonate (SLS) to harness upconversion fluorescence for optimizing light energy utilization and driving the oxidative cleavage of lignin into value‐added chemicals such as vanillin. The maximal SLS conversion rate reached 73.2%, with a vanillin yield of 4.5 mg/g SLS. This study constituted the first confirmation that the upconversion luminescence‐lignin interface can effectively catalyze photochemical reactions, establishing the theoretical and experimental infrastructure for the subsequent development of lignin‐upconversion nanocomposites tailored for drug delivery, bioimaging, or photothermal‐photodynamic synergistic platforms—an emerging paradigm at the nexus of polymer photophysics and nanomedicine.

4.3.2. Macrostructure Fabrication

Recent strides in tissue engineering and regenerative medicine have propelled 3D bioprinting technologies to the forefront of strategies for repairing or regenerating damaged tissues and organs, with bioinks constituting a pivotal determinant of success [167]. Lignin, capitalizing on its amorphous macromolecular topology and inherent bioactivities (notably antioxidant and antibacterial efficacy), has garnered substantial interest as a renewable macromolecular feedstock for fabricating high‐performance 3D printed constructs [168].

The key to its utility lies in its capacity to modulate the rheological behavior of bioinks—a direct consequence of its macromolecular structure and intermolecular interactions. Exemplifying this utility, Bonifacio et al. [168] integrated lignin into a gellan gum matrix, employing magnesium ion crosslinking to formulate a printable cartilage ink that demonstrated characteristic shear‐thinning behavior.

A modest lignin loading of 0.4% conferred potent antioxidant activity (achieving a DPPH scavenging efficiency equivalent to 83% of ascorbic acid), suppressed the proliferation of Staphylococcus aureus, and concurrently upregulated the expression of chondrogenic‐related genes (e.g., COL2A1, ACAN, SOX9) in bone marrow mesenchymal stem cells (BMSCs), effectively realizing the multifunctional integration of antibacterial, antioxidant, and chondroinductive properties (Figure 13b‐e). Silva‐Barroso et al. [169] incorporated Kraft lignin into a tricalcium phosphate/sodium alginate slurry and fabricated bone scaffolds utilizing a 3D plotter—a demonstration of how lignin's macromolecular properties can be harnessed to tune the processability of ceramic‐polymer hybrid inks. At a lignin incorporation ratio of 1:2, the mechanical strength of the scaffold was augmented by 15%, while preserving favorable wettability, osteogenic activity, and biomineralization capacity, thereby offering a sustainable therapeutic solution for bone defect repair. Notably, the ultimate compressive strength (Cs) of the lignin‐modified scaffold reaches approximately 21 MPa, which lies well within the range of values observed in natural trabecular bone (typically 1–30 MPa). This indicates that the scaffold can adequately meet the mechanical requirements for trabecular bone regeneration in non‐ or low‐load‐bearing defects. Decante et al. [170] engineered a printable and stretchable GelAL hydrogel via the one‐step blending of alkali lignin (AL) and gelatin. The reversible electrostatic complexation established between the phenolic hydroxyl groups of lignin and the basic residues of gelatin—a supramolecular interaction governed by the macromolecular characteristics of both components—enhanced the hydrogel's elongation at break to 659%, and its rheological profile (shear‐thinning) satisfied the stringent requisites for extrusion‐based bioprinting. Moreover, the degradation kinetics could be finely modulated by adjusting crosslinking temperature or post‐processing techniques such as lyophilization, rendering it highly applicable for soft tissue engineering and drug delivery vehicles.

In synthesis, capitalizing on its rigid phenylpropane backbone, polyphenolic reactivity, and sustainable provenance, lignin has emerged as an ideal bioink component for 3D printing bone, cartilage, and dermal scaffolds. This paradigm opens novel avenues for the high‐performance utilization of natural polymers and the value‐added valorization of industrial lignin through macromolecular processing technologies.

In the domain of electrospinning—another macromolecular processing technique of central importance to tissue engineering—the strategic blending of lignin with polymers such as polycaprolactone (PCL) and polylactic acid (PLA) facilitates the fabrication of nanofibrous scaffolds, whose surface properties (e.g., hydrophilicity/hydrophobicity, roughness) exert a direct influence on cellular behavior. The incorporation of lignin can profoundly modulate the morphology and physicochemical performance of electrospun fibers through its effects on solution viscosity, conductivity, and phase separation behavior. Polymers like poly(3‐hydroxybutyrate) (PHB) and PCL are ubiquitously deployed as substrates to derive lignin‐based hydrogels or nanofibers for orthopedic applications. The primordial event in cell‐scaffold interaction is the cell adhesion process, which is governed by intensive physicochemical interplay at the cell‐biomaterial interface. These interactions are predominantly dictated by surface characteristics such as wettability, roughness, and topographical cues [173].

Mohammadalipour et al. [171] incorporated 6 wt.% lignin and 3 wt.% cellulose nanofibers (CNF) into a PHB matrix to engineer an electrospun nanocomposite scaffold (PLC)—a ternary polymer system wherein lignin and CNF synergistically modulate fiber architecture. This scaffold exhibited attenuated fiber diameter, augmented surface roughness, and an accelerated degradation rate, while significantly potentiating osteogenic gene expression (ALP and OPN expression escalated by 7.9‐ and 12.1‐fold, respectively) in MG63 cells (Figure 14a–d). Haider et al. [172] fabricated core–shell structured lignin nanoparticles (LNPs)‐loaded PCL nanofibers (LgNP/PCL). The material surface induced bone‐like apatite formation and markedly promoted calcium nodule deposition in MC3T3‐E1 cells (with a 2.3‐fold increase in area). The addition of LNPs ameliorated the surface wettability and swelling properties of the inherently hydrophobic PCL polymer (Figure 14e–g)—a direct manifestation of how a hydrophilic macromolecular additive can reconfigure the surface energetics of an electrospun fiber. Crucially, the incorporation of LNPs endowed the nanofibers with effective antioxidant activity and facilitated the biodegradation process. It was corroborated that nano‐lignin exhibited bifunctional efficacy (mineralization and antioxidation) on the fiber surface, accelerating degradation while continuously liberating reactive oxygen species (ROS) scavenging signals, thereby circumventing sterile inflammation precipitated by the accumulation of acidic degradation byproducts from PCL. However, a marginal impact on crystallinity and mechanical properties was noted.

FIGURE 14.

AFM morphology of different scaffolds and fibers: (a) PHB, (b) PC, (c) PL, and (d) PLC. Reproduced with permission [171]. Copyright 2023 Elsevier. (e)Water contact angle, and (f) swelling behavior of PCLNM and LgNP/PCLNM, (g) digital images of PCLNM and LgNP/PCLNM after immersion in PBS at different time intervals. Reproduced with permission [172]. Copyright 2023 Elsevier.

Further exploring the structure‐property relationships in lignin‐containing electrospun systems, Kai et al. [174] determined that lignin could reinforce the mechanical properties of poly(3‐hydroxybutyrate) (PHB) composites, exhibiting tunable antioxidant activity and exemplary biocompatibility both in vitro and in vivo, ultimately fostering cartilage regeneration. Liang et al. [175] engineered lignin‐PLA copolymer nanofibrous scaffolds, which shielded bone marrow mesenchymal stem cells from oxidative stress and stimulated chondrogenic differentiation, demonstrating therapeutic potential for osteoarthritis treatment. Additionally, Jiang et al. [176] developed a PCL/lignin nanofibrous membrane functioning as an artificial periosteum, which displayed favorable hydrophilicity and mechanical properties, synergizing the dual functions of osteogenesis promotion and potent antibacterial activity. Liu et al. [177] further advanced this architecture by growing ZIF‐8 in situ on the surface of PCL/lignin fibers—an elegant integration of a metal–organic framework (MOF) with a biopolymer matrix. Leveraging the synergistic interplay between lignin and the MOF, the composite material exhibited excellent wettability, controllable degradation, and osteogenic differentiation capabilities, achieving the holistic integration of antibacterial, antioxidant, and osteogenic functions. Table 4 summarizes the applications of lignin‐based electrospun materials in bone tissue engineering.

TABLE 4.

Applications of Lignin‐Based Electrospun Polymer Nanofiber Composites in Tissue Engineering.

Polymer Matrix	Lignin Form/Amount	Lignin Type	Key Properties	Biological Effects/ Applications	Biological evaluation model	Reference
PHB	Lignin‐PHB Copolymer	Alkali lignin	Improves material brittleness, enhances mechanical properties; imparts tunable antioxidant activity.	Good biocompatibility, promotes cartilage regeneration and neutralizes free radicals in the bone matrix.	In Vitro: NIH/ 3T3 fibroblasts in vitro biocompatibility assay. In Vivo: PHB/lignin‐PHB fibers (5 mm diameter with 0.3 mm thickness) were subcutaneously implanted into the backs of female Sprague−Dawley (SD) rats.	Kai et al. [174]
PHB/CNF	6 wt.% Lignin + 3 wt.% CNF	—	Suppresses PHB banded structure, reduces fiber diameter (1400 nm → 450 nm); increases surface roughness (Ra) by 19%; accelerates degradation (PBS weight loss 20%→40%); increases tensile toughness threefold.	Significantly enhances osteogenic gene expression (ALP and OPN expression in MG63 cells increased by 7.9 and 12.1 times, respectively); improves hydrophilicity, mechanical properties, and stiffness, promoting osteogenesis.	In Vitro: MG63 cell morphology assessment.	Mohammadalipour et al. [171]
PLA	Lignin‐PLA Copolymer	Alkali lignin	Forms nanofibrous scaffold structure with good mechanical and viscoelastic properties and antioxidant activity; exhibits good biocompatibility.	Protects bone marrow mesenchymal stem cells (BMSCs) from oxidative stress and promotes chondrogenic differentiation; implantation in vivo for 6 weeks promotes cartilage regeneration and defect repair.	In Vitro: Morphology and proliferation of BMSCs. In Vivo: Regeneration model of cartilage defect repair in the SD rat femoral patellar groove.	Liang et al. [175]
PLA	ZnO@LNP	Alkali lignin	Increases PLA stiffness and tensile strength; stem cells respond to the film's mechanical properties by coordinating F‐actin‐Filamin A interactions.	Suitable for culturing adult bone marrow mesenchymal stem cells and adipose‐derived stem cells; nanocomposite PLA films are applicable for biomedical uses.	In Vitro: Viability assay of hBM‐MSCs and hASCs.	Luzi et al. [178]
PCL	Blended	Kraft lignin	Guides cell filopodia extension and improves fiber morphology; exhibits good cell viability and osteoconductivity.	Effectively promotes osteoblast adhesion and proliferation; the combination of lignin with hydroxyapatite (HA) can promote osseointegration.	In Vitro: The MC3T3‐E1 (subclone 4) cell line derived from mouse osteoblasts was tested to confirm biocompatibility.	Wang et al. [162]
PCL	Core–shell Lignin Nanoparticles (LNPs) loaded	Alkali lignin	Improves surface wettability and swelling of PCL; imparts excellent antioxidant activity and accelerates degradation; slight reduction in crystallinity, mechanical and thermal properties.	Induces apatite mineralization (Ca/P = 1.67); increases calcium nodule area in MC3T3‐E1 cells by 2.3 times; exhibits antibacterial efficacy against Staphylococcus aureus; provides sustained ROS scavenging.	In Vitro: Viability and proliferation assay of the MC3T3‐E1 osteoblastic cells.	Haider et al. [172]
PCL	Blended	—	Achieves good hydrophilicity and mechanical properties; exhibits good osteogenic and antibacterial performance.	Possesses dual functionality of promoting osteogenesis and providing potent antibacterial activity, suitable for artificial periosteum.	In Vitro cell morphology, growth, viability and osteogenic activity: BMSCs derived from 6 to 8 weeks old SD rats. Anti‐bacterial assays: Gram‐positive S. aureus and gram‐negative Escherichia coli. In vivo: Bilateral calvarial bone defect model in male SD rats (1 cm incision).	Jiang et al. [176]
PCL/ZIF‐8	Lignin blended + ZIF‐8 in situ growth	—	Achieves good wettability and acceptable degradation rate.	Synergy between lignin and ZIF‐8 integrates antibacterial, antioxidant, and osteogenic‐promoting multifunctionality, suitable for bone defect treatment.	In Vitro evaluation of osteogenic activity: rBMSCs. Anti‐bacterial assays: Staphylococcus aureus (S. aureus atcc2592) and Escherichia coli (E. coli atcc29213).	Liu et al. [177]

While the above studies highlight the successful integration of lignin into 3D‐printed and electrospun scaffolds, a critical opportunity remains largely unexplored: the combination of these macro‐engineering techniques with ligni's intrinsic fluorescence. By carefully controlling the dispersion state of lignin within the polymer matrix during 3D printing or electrospinning, the fluorescence emission of the resulting scaffold can be tuned to provide real‐time feedback on scaffold degradation. For instance, a decrease in fluorescence intensity could correlate with the loss of lignin from the matrix, serving as a non‐destructive indicator of in vivo degradation kinetics. Furthermore, the integration of stimuli‐responsive fluorescent lignin probes into these macro‐scaffolds would enable spatiotemporal mapping of the bone healing microenvironment, bridging the gap between the structural support function of the scaffold and the imaging‐guided monitoring function of the fluorescent polymer. This convergence of hierarchical structural engineering and photophysical functionality represents the future frontier of intelligent bone regeneration.

5. Application Potential of Lignin‐Based Fluorescent Polymers in Intelligent Bone Regeneration

The macromolecular design strategies and photophysical principles delineated in preceding sections converge in the application of lignin‐based fluorescent polymers to intelligent bone regeneration. Here, the unique combination of intrinsic fluorescence, biodegradability, and bioactivity—all encoded within a single renewable macromolecular scaffold enables functionalities that are difficult to achieve with conventional synthetic polymers.

5.1. Degradation Kinetics Tracing

Real‐time, non‐invasive monitoring of scaffold degradation is a cornerstone of intelligent bone regeneration. Unlike conventional methods that rely on post‐mortem histological analysis or indirect radiological imaging, lignin‐based fluorescent polymers offer a unique advantage: the fluorescence signal is intrinsically coupled to the polymer matrix integrity. As the scaffold degrades in vivo, the gradual loss of the fluorescent moiety—and the accompanying changes in the local microenvironment—can be directly visualized and quantified, providing a dynamic optical readout of the bone healing process. This section highlights key studies demonstrating this paradigm.

In the realm of bone tissue engineering, the degradation profile of scaffolding biomaterials exerts a deterministic influence on the efficacy of de novo bone formation and defect reparation. Conventional monitoring modalities predominantly rely on invasive histological sampling or surrogate radiographic inference, rendering longitudinal, dynamic, and precise observation formidable. Lignin‐based fluorescent polymers, by virtue of their macromolecularly integrated fluorophores, present a paradigm‐shifting approach for the in situ and real‐time optical tracing of material degradation kinetics—a concept rooted in the direct coupling of polymer matrix erosion to fluorescence signal modulation.

Ren et al. [179] engineered a fluorescent polylactic acid (PLA)/poly(propylene carbonate) polyurethane (PPCU) composite integrated with lignin‐based carbon quantum dots (CQDs), possessing robust and tunable emission characteristics, thereby establishing a framework for non‐invasive, real‐time degradation monitoring. Upon 365 nm UV excitation, this composite manifests intense green fluorescence (Figure 15a), with a maximum emission peak at 516 nm that exhibits high spectral stability independent of excitation wavelength variations. From a polymer physics perspective, the incorporation of PPCU not only augments the material‘s toughness (yielding an 8‐fold increase in elongation at break) but also effectively mitigates the self‐quenching of CQDs induced by π–π stacking, contributing to their homogeneous dispersion and sustained fluorescence activity within the polymer matrix—a critical requirement for reliable optical reporting. Concomitant with the gradual degradation of the PLA matrix, distinct variations in the CQD fluorescence signal emerge, facilitating the quantitative correlation of material degradation rates and absorption processes via in vivo and in vitro fluorescence imaging. Moreover, this material exhibits high mechanical properties and shape memory functionality (shape fixity ∼99%, recovery rate ∼92%). Its melt rheological behavior, amenable to 3D/4D printing (Figure 15b,c), further demonstrates how macromolecular processability can be harnessed to fabricate porous bone scaffolds that concurrently afford mechanical support, morphological adaptability, and built‐in optical feedback regarding the degradation process.

FIGURE 15.

(a) TEM image of CQDs (inset: diameter distribution and fluorescence image of CQDs under 365 nm UV light), (b) shape memory process of a 3D printed sample, (c) 4D printing spring design and shape memory process under 365 nm UV light. Reproduced with permission [179]. Copyright 2024 Elsevier. (d) Preparation of LEV via hydrothermal synthesis, (e) fluorescence phenomenon of PVA/LEV2 composite hydrogel under UV lamp irradiation. Reproduced with permission [113]. Copyright 2024 American Chemical Society.

In a parallel investigation, Crouvisier–Urion et al. [180], utilizing two‐photon microscopy, unveiled that lignin distributes as micron‐scale aggregates within chitosan‐based composite films. Critically, its fluorescence signal displays non‐linear correlations with concentration and structural reorganization, signifying acute sensitivity to microstructural perturbations within the polymer blend. This fluorescent behavior is profoundly modulated by hydration levels, implying that material degradation precipitated by physiological fluid infiltration and cellular metabolism within the bone microenvironment could be indicated in real‐time via the attenuation or spatial redistribution of the lignin fluorescence signal.

In synthesis, lignin‐based fluorescent polymers synergize macromolecular fluorescence with biodegradable matrices, furnishing a direct and dynamic non‐invasive monitoring strategy for elucidating the degradation kinetics of bone repair materials. The correlation established between fluorescence signal evolution and material degradation progress demonstrates a generalizable design principle: by covalently or physically integrating luminophores into a degradable polymer network, the degradation‐osteogenesis coupling within intelligent bone regeneration systems can be optically monitored and potentially regulated.

5.2. Integrated Diagnostic and Therapeutic Platform

Lignin exhibits intrinsic antibacterial efficacy, orchestrated via multimodal mechanisms encompassing membrane disruption, ROS‐mediated oxidative damage, and metal ion chelation—functions that arise directly from its polyphenolic macromolecular architecture. The convergence of these bactericidal attributes with the luminescent capabilities of lignin‐derived materials creates the foundation for single‐component, macromolecular theranostic platforms wherein diagnostic and therapeutic functions are co‐integrated at the molecular level.

Yang et al. [113] engineered fluorescently enhanced, antibacterial LEV nanohybrids by grafting vitamin B1 and ethylenediamine onto lignin nanoparticles via a hydrothermal protocol (Figure 15d). From a macromolecular engineering standpoint, the surface passivation mediated by ethylenediamine, coupled with nitrogen and sulfur heteroatom doping, modulates the energy band structure of the lignin‐based material, inducing a bathochromic shift and substantial amplification of fluorescence emission—an exemplary case of how covalent chemical modification can systematically tune the photophysical output of a biopolymer scaffold. LEV manifests a maximum emission peak at 600 nm under 540 nm excitation, demonstrating robust fluorescence stability and excitation wavelength dependence, attributes that render it an ideal imaging probe. Simultaneously, LEV achieves sterilization rates exceeding 99.9% against Escherichia coli and Staphylococcus aureus, with its antibacterial potency ascribed to mechanisms including ROS bursts, membrane depolarization, and phenolic hydroxyl proton permeation [113]. This convergence of optical performance and antibacterial activity empowers LEV to realize simultaneous real‐time imaging and antibacterial therapy within a single macromolecular construct, offering a holistic solution for infection monitoring and intervention in intelligent bone regeneration. Building upon this, the hydrogel fabricated by compounding LEV with polyvinyl alcohol (PVA) not only exhibited augmented mechanical properties but also sustained antioxidant and antibacterial functions (maintaining ∼50% DPPH scavenging rate within 24 h and >99% bacterial inhibition). This PVA/LEV hydrogel retains distinctive blue‐green fluorescence under UV irradiation (Figure 15e), underscoring its imaging utility within complex biological microenvironments. Collectively, these findings establish a macromolecular materials foundation for developing integrated antibacterial‐imaging theranostic platforms, demonstrating that lignin‐based polymers can transcend the conventional paradigm of separate diagnostic and therapeutic agents, instead embodying both functionalities within a single, renewable polymer architecture. This convergence of imaging and therapeutic functions directly supports the paradigm of imaging‐guided bone regeneration, wherein the same lignin‐based scaffold serves as both a therapeutic agent and a non‐invasive reporter of tissue repair status. Critically, it is essential to distinguish between studies that have been validated in bone‐related biological contexts and those that have only been demonstrated in general diagnostic or drug delivery settings. For example, the LEV system [113] demonstrates promising antibacterial and imaging capabilities, but its potential for bone regeneration requires further validation using osteoblast cell lines, animal bone‐defect models, and specific osteogenic markers (e.g., ALP, RUNX2, OCN). In contrast, several lignin‐based composite scaffolds have already been evaluated in in vivo bone defect models, with quantitative data on mechanical properties, degradation kinetics, and fluorescence tracking capabilities. The following discussion focuses primarily on those studies that have demonstrated direct relevance to bone repair.

6. Conclusion and Perspectives

Lignin, distinguished by its structural heterogeneity, aromatic macromolecular backbone, and myriad inherent biological functions, constitutes a unique renewable polymer platform for architecting intelligent bone regeneration systems. From a polymer science perspective, this review has systematically elucidated the structure–activity relationships governing lignin's chemical constitution, fluorescence behavior, and bioactivities, establishing that its optical properties can be effectively tuned through physical nano‐structuring and chemical modification strategies—both of which operate through well‐defined macromolecular mechanisms. Furthermore, we have delineated diverse design pathways for valorizing this abundant industrial by‐product as macromolecular monomers, initiators, or crosslinkers in the synthesis of fluorescent polymers, demonstrating how controlled polymerization and polymer‐analogous reactions can transform a heterogeneous biopolymer into precisely engineered functional materials. These sustainable materials not only possess intrinsic biological functions—such as osteoinduction, antibacterial efficacy, and antioxidant potency—but also enable non‐invasive, longitudinal monitoring of implant degradation and bone healing processes through luminescent feedback, holding promise as core components for sophisticated theranostic platforms. Ultimately, this convergence establishes a closed‐loop paradigm for bone repair: the fluorescent signal reports on the scaffold's degradation status in real time, which in turn guides the timing and intensity of therapeutic interventions, thereby enabling a highly responsive and personalized approach to bone regeneration.

Notwithstanding these advances, the translation of lignin‐based fluorescent polymers from laboratory prototypes to clinical reality confronts several formidable bottlenecks that demand solutions grounded in macromolecular science and polymer engineering:

1. Heterogeneity‐Induced Performance Variability. The chemical constitution of lignin is intrinsically contingent upon botanical provenance, extraction protocols, and subsequent treatments, precipitating substantial batch‐to‐batch discrepancies in molecular weight, functional group topography, and crosslinking density. This inherent variability directly impacts fluorescence performance, degradation kinetics, and bioactivity, posing impediments to material standardization, reproducible fabrication, and quality control. From a polymer chemistry standpoint, addressing this bottleneck requires the development of bio‐engineered lignin cultivars for generating structurally homogeneous macromolecular feedstocks, the deployment of advanced fractionation technologies for precision separation according to molecular weight and functionality, and the integration of machine learning to establish robust “structure–property–function” prediction models. Such data‐driven approaches would enable the rational macromolecular design and improved control of material performance, transforming lignin from a variable natural product into a reliable polymer precursor.

2. Augmentation of Optical Efficacy and Biological Applicability. The endogenous fluorescence intensity of lignin is typically subdued, and its emission wavelength often resides in the visible region, limiting tissue penetration depth and increasing susceptibility to biological background interference. Furthermore, its fluorescence performance often undergoes irreversible quenching in response to microenvironmental fluctuations, restricting the reliability of long‐term dynamic monitoring. To overcome these photophysical limitations through macromolecular engineering, future research could prioritize chemical modifications that extend the conjugated system or introduce donor‐acceptor motifs to shift emission toward the Near‐Infrared‐II (NIR‐II) window, thereby enhancing penetration depth and signal‐to‐noise ratios. Additionally, design strategies that exploit aggregation‐induced emission (AIE) and other aggregation‐state‐dependent photophysical phenomena at the polymer level can bolster fluorescence stability and environmental responsiveness without relying on toxic synthetic fluorophores.

3. Biological Complexity and Longitudinal Safety Profiles. Bone repair involves a multifaceted symphony of physiological activities including inflammation, angiogenesis, and osteogenic differentiation. For lignin‐based macromolecular scaffolds, a critical determinant of their in vivo safety and functionality is their biodegradation profile. Within the physiological environment, the primary degradation products are expected to be low‐molecular‐weight phenolic oligomers and monomeric aromatic aldehydes or acids (e.g., vanillin, syringaldehyde, and their respective derivatives), originating from the enzymatic or hydrolytic cleavage of the polymer backbone. Subsequent metabolic processing of these fragments likely involves hepatic phase I (e.g., cytochrome P450‐mediated hydroxylation) and phase II (e.g., glucuronidation and sulfation) biotransformation reactions, facilitating their eventual clearance via renal excretion or biliary elimination. The degradation products, metabolic pathways, and potential immunogenicity of these lignin‐based macromolecular constructs within the dynamic in vivo environment warrant systematic interrogation. Currently, there is a paucity of long‐term toxicological and immunological evaluation data compliant with Good Laboratory Practice (GLP) standards. Rigorous studies are imperative to clarify the biological effects of both the intact polymers and their metabolic fragments at cellular, tissue, and systemic levels, and to explore surface modification or copolymerization strategies that modulate their interaction with the immune system while preserving the inherent bioactivities of the lignin scaffold.

4. Synergistic Integration and Intelligent Responsiveness. The orchestration of multifaceted functionalities—encompassing fluorescence tracing, antibacterial activity, antioxidant capacity, osteogenic promotion, and vascularization—into a single macromolecular system, while achieving temporal control and spatial localization, represents a formidable polymer design challenge. Moreover, the response modes of existing materials are predominantly passive. Future macromolecular architectures must transition toward incorporating sophisticated feedback mechanisms—such as enzyme‐cleavable linkages, mechano‐responsive motifs, or electro‐active segments—directly into the polymer backbone or network, thereby achieving on‐demand therapeutic action and moving toward the paradigm of “intelligent” repair through responsive polymer design.

5. Translational Engineering and Scale‐up Bottlenecks. The translation from bench‐top prototypes to clinical products mandates the resolution of challenges including the stable, large‐scale supply of lignin raw materials with consistent macromolecular characteristics, the sustainability and economic viability of polymer synthesis and processing, the impact of sterilization protocols on polymer structure and performance, and engineering aspects such as mechanical properties and long‐term stability. Simultaneously, the establishment of evaluation standards and regulatory frameworks tailored for such novel natural‐derived macromolecular therapeutics is essential to facilitate their responsible commercialization and widespread adoption in regenerative medicine.

6. Toward Imaging‐Guided Clinical Translation. The successful clinical translation of lignin‐based fluorescent scaffolds ultimately depends on the development of reliable, portable, and cost‐effective imaging systems capable of translating optical signals into actionable clinical data. Future research must focus on engineering lignin‐based scaffolds with emission wavelengths optimized for tissue penetration (e.g., NIR‐II window) to enable deep‐tissue imaging. Concurrently, the integration of these fluorescent scaffolds with smartphone‐based or wearable optical readers could significantly lower the barrier to clinical adoption, enabling point‐of‐care monitoring of bone healing progression outside of specialized hospital settings.

7. Establishing a Rigorous Evaluation Framework for Bone Repair. To accelerate the clinical translation of lignin‐based fluorescent polymers, future studies must adopt a standardized evaluation framework that includes: (i) osteoblast and osteoclast cell models; (ii) in vivo animal bone‐defect models (e.g., calvarial, femoral, or tibial defects); (iii) quantitative analysis of osteogenic markers (e.g., ALP, RUNX2, OCN); (iv) antibacterial and antioxidant assays; (v) vascularization assessment; (vi) mechanical properties and degradation behavior; and (vii) real‐time fluorescence tracking of scaffold degradation and tissue ingrowth. Only when these criteria are systematically addressed can lignin‐based fluorescent scaffolds be reliably considered as intelligent bone regeneration platforms.

To address these multifaceted challenges, intensive interdisciplinary collaboration at the nexus of polymer science, chemical engineering, biology, and clinical medicine is imperative. Systematic work—from rational macromolecular design and precision polymer synthesis to stringent in vitro evaluation, animal models, and eventual clinical validation—must be undertaken with a polymer‐centric perspective that treats lignin not as a waste by‐product but as a programmable macromolecular platform. Only through such integrative approaches can the advantages of lignin as a renewable, intrinsically functional, and optically active polymer be fully harnessed, promoting its practical application in bone regeneration engineering and paving the way for bio‐based smart materials in the 21st century.

Author Contributions

F.S. contributed to Writing – original draft, Investigation, Methodology. S. T., Y.W., and X. F. contributed to Writing – review & editing, Data curation, Investigation, Methodology. L. J. contributed to Supervision, Investigation, Writing – review & editing, Funding acquisition.

Declaration of Generative AI and AI‐Assisted Technologies in the Writing Process

During the preparation of this work, the author(s) used Deepseek for grammatical correction. After using these tools, the author(s) reviewed and edited the content as needed and take full responsibility for the final content of the publication.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.