Advanced bioactive materials and strategies for tendon repair and function restoration

Abstract

Tendon injury is one of the most common clinical challenges in musculoskeletal disorders. Effective tendon repair is crucial for restoring patients' motor function and improving their quality of life. Recent advances in bioactive material-mediated tendon regeneration have shown great therapeutic potential and clinical relevance. However, systematic reviews that comprehensively integrate these developments are still scarce. Firstly, this article presents the selection of bioactive components, mainly including cell-based therapeutic strategies and nanodrug delivery strategies. Secondly, bioactive materials delivery system using tissue-engineered scaffolds is discussed in detail. In this section, we discuss the efficacy of scaffolds in tendon repair through different scaffold preparation methods and synthetic raw materials. Furthermore, the application of hydrogel systems such as enhanced hydrogels, bioadhesive hydrogels and multifunctional hydrogels in tendon repair strategies is systematically and comprehensively presented. Finally, based on a detailed review of the field, current challenges in the field were proposed and potential research directions in the field were identified, including potential research directions in smart bioactive materials and personalized treatment strategies.

The translational potential of this article

This review synthesizes tendon regeneration strategies—from molecular mechanisms to tissue-level integration—including bioactive component selection and delivery systems using tissue-engineered scaffolds. It identifies translational barriers and proposes new strategies in tendon-specific safety validation, scalable manufacturing uniformity and cost-effectiveness versus conventional therapies. These insights will refine clinical strategies for tendon injuries and advance targeted bioactive biomaterials for localized regeneration.

Graphical abstract

1. Introduction

Tendons play a pivotal role as essential tissues responsible for transmitting mechanical forces from muscles to bones and enduring substantial tensile loads. Tendon tissue, with its distinct and highly dense fiber bundles of collagen structure and relatively low density of cells, has inherent characteristics that combined with the difficulty of manipulating the complex nanostructure of the interwoven tendinous fibers, result in a limited capacity to regenerate after tendon injuries [1]. Tendon and ligament injuries are the most common injuries requiring clinical treatment. An estimated 17 million individuals per year in the USA seek medical treatment for these types of injuries [2]. For minor tendon and ligament injuries (such as common sprains and strains), surgical treatment may be unnecessary because the injury may be resolved by the tissues’ innate healing potential instead of degenerating into chronic conditions [3]. However, the degeneration and repair processes show a notable delay. In many instances, the self-repair process can only provide quality scar tissues that are inferior to natural tendon tissue [4]. For severe tendon injuries, surgeries, including suturing and autologous or allogeneic tendon grafts, are commonly required. However, owing to the length of the ligament defect, surgery usually does not affect the extracapsular ligaments during reconnection/reattachment repair. For instance, 63 % and 73 % of large and extensive tendon sheath tears, respectively, fail to heal after surgical treatment [5]. As such, achieving improved tendon healing after injury has long been the primary focus in the development of regenerative medicine.

Bioactive materials are widely used for tendon regeneration. With their favorable bioactivity and structural mechanical characteristics comparable to human natural tendons, bioactive materials can specifically interact with tendons and induce tendon regeneration and repair [6]. The delivery of bioactive agents such as cellular components and nanomedicines, as well as the application of tissue-engineered scaffolds, have emerged as promising therapeutic strategies for augmenting tendon regeneration and functional restoration. These approaches can offer an appropriate growth environment for tendon cells and accelerate the regeneration and repair of tendon tissue through the regulation of cell behavior, triggering cell proliferation and differentiation. Recent studies have yielded notable advancements in the development of bioactive materials and strategies for tendon regeneration and repair. Biomaterials based on cellular or nanomedicine delivery have received extensive attention, and cell therapy has been suggested as a strategy with promising application prospects for tendon regeneration and repair. In cell therapy, tendon tissue is regenerated and repaired by transplanting/recruiting cells with tendon-regeneration capabilities (for example, tendon stem/progenitor cells (TSPCs), mesenchymal stem cells (MSCs), and tendon cells to the injured area). Some strategies protect the migratory and collagen-synthesizing abilities of TSPCs by inhibiting M1 macrophage polarization. Simultaneously, they stabilize the M2 macrophage phenotype [7]. Moreover, nanodelivery systems for tendon regeneration, such as extracellular vesicles (EVs), nanoparticles, and nanodrugs, have been proven to be beneficial for tendon healing. EVs promote intercellular communication by delivering mRNA, microRNA, proteins, and organelle-associated cargo into recipient cells. Because of this remarkable function, EVs have been proposed as outstanding candidates for therapeutic approaches in tissue regeneration and repair [8]. Moreover, nanoparticles such as cationic nanoclusters and polydopamine nanoparticles can form nanodelivery systems in combination with EVs and nanodrugs. Ultimately, the drug can be accurately delivered to specific cells to achieve specific targeting [9].

Bioactive delivery systems using tissue-engineered scaffolds have received extensive attention. Scaffold materials typically possess good mechanical properties, biocompatibility, and degradability, providing a stable support and growth environment for tendon cells. By controlling the microstructure and surface properties of the scaffold, its interactions with cells can be further improved to enhance cell adhesion, proliferation, and differentiation [10,11]. Various repair strategies exist, including electrospinning and three-dimensional (3D) printing. Electrospun nanofibers can be fabricated with controlled fiber sizes and large surface-to-volume ratios, imitating the biological fibers of the extracellular matrix (ECM) to facilitate cell proliferation and differentiation and thereby enhance tissue repair [12]. Various hydrogel biomaterials have been used, including collagen, gelatin, silk, hyaluronic acid, alginate, and chitosan [13].

This review synthesizes the recent advances in bioactive materials and surgical strategies for tendon repair and rehabilitation. Literature was systematically sourced from PubMed, Web of Science, and Scopus (2015–2025) using core terms (“tendon repair/regeneration”) AND (“biomaterial/scaffold/stem cell/exosome/hydrogel”). Included peer-reviewed English studies on novel tendon therapies, excluding irrelevant topics, low-evidence reports, and non-mammalian models; seminal works were prioritized to minimize bias. As illustrated in Scheme 1, we analyzed bioactive components specifically engineered for therapeutic delivery systems firstly. Subsequently, we comprehensively reviewed the current scaffold-based delivery platforms, with a particular focus on their synthetic precursors and manufacturing techniques. Additionally, the emerging applications of hydrogels in scaffold delivery systems are critically examined. We further evaluated the strengths and limitations of the current research through a comparative analysis of existing methodologies. Finally, prospective research directions were proposed to address unresolved challenges in tendon regeneration.

Scheme 1.

Schematic diagram of advanced bioactive materials and strategies for tendon repair and function restoration.

2. Bioactive constituent selection

Innovative biomaterials for tendon repair increasingly integrate cell-based therapies and nanodrug systems to enhance regeneration. Cell-based strategies target the in situ activation of TSPCs, MSCs, and immune cells, which collectively drive structural restoration, microenvironment modulation, and inflammatory resolution through mechanisms such as differentiation and extracellular matrix remodeling [14]. Concurrently, nano-drug delivery systems amplify therapeutic efficacy by enabling spatiotemporally controlled release of bioactive payloads: polymeric or lipid-based carriers facilitate localized delivery of pharmacologic agents for anti-inflammatory or antifibrotic effects, while engineered nanoparticles and natural extracellular vesicles transport nucleic acid therapeutics—such as regulatory microRNAs, silencing RNAs, and messenger RNAs—to enable precise genetic interventions [15]. Hybrid biomaterial designs further synchronize these approaches by combining scaffold architectures with cell-derived vesicles and nanoparticle-loaded signaling mediators, thereby coordinating cellular recruitment, immune balance, and matrix reorganization [16,17]. Through the synergistic integration of cell activation pathways and nano-enabled precision targeting, these advanced systems collectively address both structural repair and pathological remodeling barriers across tendon healing phases, offering clinically viable solutions for functional recovery.

2.1. Cell-based therapy strategies for tendon tissue repair

Current cell-based therapeutic paradigms for tendon regeneration can be categorized into three principal types: TSPCs, MSCs, and immune cells [18]. The classification of cell therapies for tendon repair depends on the fundamental functional divergences among the three types of cells. TSPCs demonstrate lineage-committed stemness, driving structural regeneration through tenocyte-specific differentiation and biosynthesis of core tendon matrix components, such as collagen I/III and tenomodulin [19]. MSCs, conversely, harness multipotent differentiation potential and secretion of paracrine factors such as vascular endothelial growth factor (VEGF) and transforming growth factor-β (TGF-β) to orchestrate regenerative microenvironments by stimulating angiogenesis and mitigating fibrotic cascades—their efficacy is critically dependent on host immune modulation [20]. Terminally differentiated immune subsets (e.g., Tregs and M2 macrophages) resolve inflammatory processes through the phenotypic polarization and the release of anti-inflammatory mediators (e.g., interleukin-10 (IL-10)), thereby establishing temporal niches conducive to progenitor cell engraftment [21]. Therapeutically, TSPC survival requires MSC-derived trophic support. MSCs recruit immune effectors for coordinated debris clearance, and immune cells calibrate their metabolic homeostasis to enable synergistic MSC/TSPC integration. These three cell types cooperatively promote tendon repair through three distinct yet interdependent mechanisms: TSPCs execute structural reconstruction, MSCs primarily modulate the microenvironment, and immune cells implement localized immunomodulatio, collectively addressing the therapeutic demands across distinct healing phases (see Table 1). It is noteworthy that a systematic review incorporating 11 clinical studies demonstrated the efficacy of cell therapy in effectively improving the architecture of injured tendons [22]. Although cell-based therapeutic approaches show substantial promise for tendon tissue regeneration and injury treatment, several critical challenges remain unresolved. Current limitations include substantial acute cell mortality, insufficient cell retention at target sites, unpredictable off-target tissue formation, and other factors that collectively compromise clinical efficacy [23]. The successful translation of cell-based tendon-repair strategies into clinical practice depends on their ability to address these fundamental obstacles.

Table 1.

Comparison of TSPCs, MSCs and immune cells in tendon repair.

	TSPCs	MSCs	Immune cells
Stemness	High (specific tendon differentiation ability)	Medium (Multi-lineage differentiation potential)	Low (Mainly involved in immune regulation)
Major sources	Tendon tissue	Bone marrow, fat, umbilical cord	Blood and lymphoid tissues
Mechanism	Tenogenic differentiation (SCX/Tnmd upregulation via YAP/TAZ mechanotransduction [24]) ; Immunomodulation (M2 polarization via TSG-6/PGE2 [25]; NETs suppression by IL-10 [26]); ECM synthesis (collagen I/III, fibronectin deposition; Tenascin-C-mediated niche maintenance) [27]; Mitochondrial rescue (tunneling nanotube-mediated ATP transfer; PINK1/Parkin mitophagy) [11]; Anti-fibrotic/anti-angiogenic action (TSP-1/Endostatin blockade [28]; miR-29a-mediated TGF-β suppression [29]).	Tenogenic differentiation (induced by TGF-β, CTGF, load-dependent mechanotransduction) [30]; Paracrine signaling (secretion of growth factors like IGF-1, PDGF, bFGF) [31]; Immunomodulation (M2 macrophage polarization via TSG-6/PGE2, T-cell suppression) [32]; ECM remodeling (collagen I/III synthesis, fibronectin deposition, reduced MMP activity) [33].	Inflammatory resolution (phagocytosis of debris and secretion of anti-inflammatory factors) [21]; Tissue repair and regeneration (secretion of growth factors like TGF-β) [34]; Microenvironment modulation (Regulating the activity and function of tendon cells, and influencing the synthesis and remodeling of collagen) [35]; Interaction with stem cells (Regulating the differentiation and proliferation of MSCs and TSPCs) [21].
Therapeutic interdependencies	Dependent on MSC-secreted paracrine factors	Modulating immune cell recruitment for targeted clearance of injury foci	Establishing a critical therapeutic window for TSPC/MSC-mediated tendon regeneration
Main secretory factor	Growth factors (such as TGF-β, BMP) [36]	Cytokines, chemokines [37]	Cytokines (such as IL-10, TNF-α) [38]

Abbreviation: TSPCs, tendon stem/progenitor cells; MSCs, mesenchymal stem cells; SCX, scleraxis bHLH transcription factor; Tnmd, tenomodulin; YAP, yes-associated protein; TAZ, tafazzin; TSG-6, tumor necrosis factor-stimulated gene-6; PGE₂, phenyl glycidyl ether; NETs, netosis; IL-10, interleukin-10; ECM, extracellular matrix; TSP-1, thrombospondin-1; BMP, bone morphogenetic protein; TGF-β, transforming growth factor-β; CTGF, connective tissue growth factor; IGF-1, insulin-like growth factor 1; MMP, matrix metalloproteinase; TNF-α, tumor necrosis factor-α

2.1.1. TSPC-based strategies

TSPCs exhibit fundamental stem cell characteristics including clonogenicity, self-renewal capacity, and multipotency [39]. While TSPCs demonstrate robust proliferation and differentiation capabilities during neonatal stages, enabling functional tendon regeneration, their regenerative potential is substantially diminished in mature tendons, which are characterized by hypocellularity and insufficient nutrient and oxygen supply [40]. Current limitations in understanding the specific regulatory factors governing postnatal tendon development have hindered successful long-term TSPC culture and functional tendon regeneration, emphasizing the critical importance of elucidating developmental mechanisms for advancing tissue-engineering strategies [41].

Wang et al. conducted a comprehensive transcriptional analysis of tendon development and identified periostin (Postn) as a crucial ECM protein that regulates TSPC function and tendon regeneration. Using a rat Achilles tendon defect model, they demonstrated that recombinant periostin (rPOSTN)-incorporated scaffolds enhanced endogenous TSPC recruitment and facilitated native-like hierarchical collagen organization, allowing restoration of mechanical properties and functional recovery (Fig. 1a) [42]. Building on the finding that bone marrow MSC-derived exosomes (BMSCs-exos) enhance TSPC functionality, Yu et al. developed an exosome-embedded fibrin hydrogel system for patellar tendon repair. This delivery platform achieved controlled exosome release with sustained retention and successful TSPC uptake [43]. Mao et al. used a combination of gelatin methacrylate (GelMA) hydrogels and tendon-derived stem cells (TDSCs) to address chronic tendon micro-injury repair. The GelMA microenvironment promoted TDSC adhesion, proliferation, and early tenogenic differentiation while stimulating ECM production through RAS/ERK signaling activation [44]. Through near-field electrospinning techniques, Ye et al. engineered microfiber scaffolds with tunable elastic moduli to investigate the mechanical regulation of tendon stem cells (TSCs). Scaffolds with a moderate modulus (1429 MPa) demonstrated optimal performance in upregulating tendon-specific markers (Col I, Tnmd, SCX, and TNCF) [45]. A novel TSPC delivery system was developed using DNA hydrogel encapsulation (TSPC-Gel), which provides an artificial ECM microenvironment that supports cellular proliferation while protecting against shear forces. This approach notably enhanced TSPC retention within tendon tissues [14]. Comparative studies evaluating human periodontal ligament stem cells (hPDLSCs) on biomimetic silk scaffolds have revealed that aligned microstructures promote cell proliferation and orientation more effectively than random scaffolds during in situ tendon regeneration [46]. A bioinspired bimodal micro-nanofiber scaffold was designed to mimic the native tendon architecture by combining microscale fiber organization with nanoscale fibrillar features. This dual-scale topography enhanced TSPC elongation and tenogenic differentiation in comparison with the findings in single-scale controls (Fig. 1b) [47].

Fig. 1.

Cell-based strategies for tendon tissue repair. a) Schematic representation illustrating three-dimensional spheroid differentiation processes. Adapted with permission [42]. Copyright 2021, Wang et al. b) Mechanistic illustration detailing the fabrication methodology and characterization of aligned fibrous scaffold systems. Adapted with permission [47]. Copyright 2022, Yin et al. c) Structural remodeling of RSF during mechanical training. Reproduced with permission [49]. Copyritght 2023, Dong et al. d) Schemata of the decellularization-based modification strategy for bioactive xenografts promoting tendon repair. Reproduced with permission [7]. Copyritght 2023, Jin et al. e) Schematic illustration of the preparation procedure of the HA-ADH@PA/Fe hydrogel patch and its regulating macrophages to promote tendon repair. Reproduced with permission [56]. Copyritght 2024, Yao et al.

2.1.2. MSC-based strategies

Human-derived MSCs demonstrate remarkable therapeutic potential, which can be attributed to their accessibility, reduced immunogenicity, and capacity for tenogenic differentiation [48]. Researchers have engineered a fibrous artificial tendon (FAT) using a biomimetic approach inspired by natural silk protein fibrillation. Their findings demonstrated that FAT's highly aligned nanofibrillar architecture enhanced tendon-specific gene expression while supporting native Achilles tendon structure and function (Fig. 1c) [49]. Investigation of human hair follicle (hHF)-derived MSCs revealed their efficacy in rabbit Achilles tendon repair. Molecular analysis identified the following mechanism of action: enhanced collagen fiber regeneration through dual regulation of tenascin C (TNC) upregulation and matrix metalloproteinase (MMP)-9 downregulation [50]. Donderwinkel et al. developed an advanced hydrogel culture system combining methacrylated poly(D,L-lactic acid-ethylene glycol-D,l-lactic acid) (P(LA-EG-LA)) with GelMA for encapsulation of human bone marrow-derived MSCs (hBMSCs). Their systematic evaluation explored the synergistic effects of mechanical stimulation—both static and intermittent cyclic uniaxial strain—alongside TGF-β3 supplementation on hBMSC tenogenic differentiation [51]. Timmer et al. investigated human mesenchymal stem cell (hMSC) behavior in thiolated gelatin (Gel-SH) hydrogel environments and examined their responses to chondrogenic stimuli and paracrine signaling from MSC-populated bone and tendon scaffold regions [52]. Ren's team developed polyethylene glycol-packed CeONPs (PEG-CeONPs) for integration with human umbilical cord mesenchymal stem cells (hUCMSCs) to combat oxidative stress. Transplantation of these PEG-CeONP-loaded hUCMSCs reduced reactive oxygen species (ROS) levels at tendon injury sites while promoting healing [53]. Researchers engineered an advanced delivery system utilizing ultrasound-controlled growth factor release from liposomal nanohybrid cerasomes combined with polydopamine-modified 3D-printed PCL scaffolds loaded with BMSCs for infraspinatus tendon repair in a rabbit model [54].

2.1.3. Immune cell-based strategies

Immune cells have a substantial effect on inflammatory responses and tissue repair in tendinopathy. Thus, efficient scavenging of local ROS and inflammation, modulation of macrophage polarization, and prevention of postoperative infection may disrupt the harmful cycle and accelerate the transition of tendon healing from the inflammatory phase to the repair and remodeling phases [55].

Jin et al. engineered a rosiglitazone-loaded decellularized ECM (R-dECM) derived from human tissue. This construct protected TDSC migration and collagen synthesis through selective inhibition of M1 macrophage polarization (Fig. 1d) [7]. Scientists have engineered an advanced hydrogel network employing dual crosslinking mechanisms: metal–ligand coordination between Fe³⁺ ions and catechol moieties of protocatechuic aldehyde (PA) coupled with dynamic imine formation between HA-ADH amine groups and PA aldehydes. The resulting PCL@HA-ADH@PA/Fe construct demonstrated dual therapeutic benefits in tendon repair, simultaneously promoting tissue regeneration while minimizing adhesion formation through orchestrated regulation of macrophage phenotypes and inflammatory cascades at both local and systemic levels (Fig. 1e) [56]. Investigation of PCL-hyaluronic acid (HA) electrospun scaffolds with varying fiber dimensions and orientations revealed their immunological profiles through Toll-like receptor (TLR) reporter cell analysis. The results demonstrated no activation of the TLR2/1 and TLR2/6 pathways by these constructs [57]. Xu et al. introduced a novel therapeutic approach using bioactive glass (BG)-enhanced MSC-EVs. These modified vesicles (EVBs) exhibited upregulation of therapeutic miRNAs, particularly miR-199b-3p and miR-125a-5p, which are crucial for M2 macrophages(Mø)-mediated angiogenesis, demonstrating enhanced angiogenic potential in comparison with conventional MSC-EVs (EVNs) [58]. Wei et al. developed an electrospun polycaprolactone scaffold that was modified for Wnt3a protein delivery. In vivo studies demonstrated the ability of the scaffold to enhance early macrophage recruitment and increase M2 Mø populations during tendon healing [59]. Xu et al. further explored an injectable BG/sodium alginate (SA) hydrogel system for postsurgical tendon repair. The construct accelerated tenogenesis without heterotopic ossification, which was attributable to enhanced angiogenesis and rapid M1-to-M2 Mø phenotype transition within seven days post-surgery [[60], [61], [62], [63], [64]].

When evaluating tendon regeneration strategies, TSPCs, MSCs, and immune cells exhibit fundamentally divergent therapeutic paradigms that necessitate rigorous comparative assessment: TSPCs demonstrate superior tissue-specific differentiation potential and functional tenogenic commitment, yet their clinical translation is significantly hampered by limited proliferative capacity in aged or degenerated tendons and inherent phenotypic instability during in vitro expansion, creating substantial scalability barriers. Conversely, MSCs offer practical advantages through established isolation protocols from accessible tissue sources and robust proliferative potential, but their utility is counterbalanced by unpredictable tenogenic differentiation kinetics requiring precise biochemical and biophysical cues to mitigate risks of ectopic tissue formation and inconsistent regenerative outcomes. Meanwhile, immune cells—particularly macrophage-mediated strategies—provide unique immunomodulatory leverage critical for orchestrating inflammation-to-regeneration phase transitions through polarization dynamics, though their therapeutic window remains exceptionally narrow with risks of unintended immunosuppression or fibrosis amplification if spatiotemporal control mechanisms prove inadequate. Crucially, this tripartite comparison reveals a clinical readiness hierarchy: MSC-based approaches currently dominate translational pipelines due to standardized manufacturing frameworks and extensive safety documentation, whereas TSPC technologies lag due to unresolved expansion challenges and phenotypic drift concerns, and immune cell therapies remain predominantly preclinical pending validation of long-term safety profiles and targeted delivery systems. This analysis underscores that while each cell type occupies a distinct therapeutic niche, all share critical dependencies on advanced biomaterial platforms to overcome cell-specific limitations—through enhanced retention strategies, microenvironmental cue orchestration during phase transitions, and synergistic mechanisms that amplify regenerative potential while neutralizing inherent risks.

2.2. Nanodrugs

The application of nanodrugs in tendon repair has recently become a research hotspot in the fields of biomedical engineering and regenerative medicine [65]. Due to their unique physicochemical properties and precise delivery capabilities, nanodrugs show notable advantages in addressing key issues such as inflammation regulation, cell regeneration, and mechanical strength restoration in tendon repair [66]. Notably, the term “nanodrug” as defined in this context encompasses two distinct carrier systems: engineered therapeutic nanoparticles and biologically derived EVs (specifically exosomes). While synthetically fabricated nanoparticles exhibit tailorable pharmacokinetic profiles and enable the encapsulation of diagnostic/therapeutic payloads for targeted tendon repair, exosomes, as endogenous nanoscale entities, leverage their cell-secreted biological components (e.g., native phospholipid bilayers and endogenous signaling molecules) to demonstrate inherent biocompatibility advantages. In the following sections, we introduce the application of nanomedicines in tendon repair in two parts.

2.2.1. Exosomes

Exosomes, nanoscale vesicles (30–150 nm) secreted by most cell types, have emerged as promising therapeutic carriers. These vesicles transport diverse biological cargoes, including proteins, lipids, DNA, mRNA, and non-coding RNA, which are capable of modifying the recipient cell characteristics. Their crucial role in intercellular communication has demonstrated therapeutic potential in various tissues, including myocardial ischemia/reperfusion injury [67], kidney injury [68], bone defects [69], and osteoarthritis [70].

Song et al. characterized the therapeutic potential of TSC-derived exosomes in tendon healing, with a particular focus on microRNA regulation. Their findings demonstrated accelerated repair through the miR-144-3p-mediated enhancement of tenocyte function via ARID1A pathway modulation [71]. Parallel investigations revealed the ability of TSC-Exos to enhance BMSC activity across multiple parameters, including proliferation and migration. The mechanism involved elevated miR-21a-5p activity that regulated the programmed cell death protein 4 (PDCD4), ultimately activating PDCD4/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) cascade [72]. Zhang et al. characterized TSC-Exo interactions with tenocytes and demonstrated concentration-dependent cellular uptake and subsequent activation of the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase 1/2 (ERK1/2) signaling pathways, leading to enhanced proliferation and migration (Fig. 2a and b) [73]. Zhang et al. engineered an innovative topical therapy by combining TSC-sEVs with a GelMA hydrogel. The in vivo application involved UV-crosslinked TSC-sEV/GelMA hydrogel coverage of the damaged Achilles tendon tissue. The controlled-release properties of the system enabled sustained therapeutic effects, resulting in enhanced tendon regeneration through improved tendon expression, controlled ossification, and superior mechanical properties [74]. Research utilizing aged chronic rotator cuff tear rat models has shown that healthy tendon stem cell-derived exosomes (h-TSC-Exos) effectively modulate the tendon-bone interface microenvironment, promoting an anti-inflammatory state during the acute postoperative phase. This environmental modification enhanced tendon-bone healing outcomes through rejuvenation of tendon stem/progenitor cells (Fig. 2c) [75]. In addition to TSC-derived exosomes, PLT-derived exosomes have also been proven to improve tendon function during tendon repair. Innovations in exosome engineering have led to the development of PLT-Exo-Yap1, in which platelet-derived vesicles are electroporated with the Yap1 protein to enhance TSC properties. This modification results in sustained stemness and the maintenance of functionality during extended culture periods [76]. Lin et al. investigated the combined therapeutic potential of fibrin gels and platelet-rich plasma-derived exosomes (PRP-Exos) for rotator cuff tear (RCT) repair, including the optimization of implantation methods. In vitro studies revealed that PRP-Exos have a notable influence on the phenotypic modulation of TSPCs [77].

Fig. 2.

Exosomes, Nanoparticles, and Nanodelivery systems for tendon repair. a) The establishing of Achilles tendon injury model. b) Characterization of TSC-Exos. Reproduced with permission [73]. Copyritght 2020, Zhang et al. c) A comprehensive mechanistic diagram illustrating the pathways through which healthy tendon stem cell-derived exosomes facilitate tendon-bone healing in aged chronic rotator cuff tears. Adapted with permission [75]. Copyright 2024, Zhang et al. d) Detailed methodology depicting the isolation process of SHED-Exo bio-nanoparticles and characterization of their anti-aging signaling mechanisms, coupled with the design and synthesis protocol for GM@PDA&SHED-Exo micro-nano composite engineered for aged tendon regeneration. Adapted with permission [66]. Copyright 2023, Jin et al. e) Mechanistic illustration detailing CR-sEVs/MN's role in enhancing rotator cuff tendon-bone integration. Adapted with permission [79]. Copyright 2024, Song et al. f) Schematic illustration of the therapeutic energy-supporting enzyme-mimic nanoscaffold for tendon regeneration. Adapted with permission [11]. Copyright 2022, Wang et al. g) Schematic representation of macrophage-targeted mRNA editing strategies for peritendinous adhesion (PA) therapy. Adapted with permission [9]. Copyright 2024, Wang et al.

Exosomes from healthy donor cells have been shown to improve the function of recipient cells. Researchers developed an injectable hydrogel system (H-Exos-gel) incorporating human umbilical vein endothelial cell (HUVEC)-derived exosomes (HUVECs-Exos). The hydrogel was created to enhance tendon repair. Histological and behavioral examinations of the Achilles tendon after 2 and 4 weeks indicated that H-Exos-gel augmented the Achilles tendon mechanical strength, modulated the inflammatory response, and supported tendon regeneration and functional recovery [78]. In a study on aging, exosomes derived from the stem cells of human exfoliated deciduous teeth (SHED-Exos) were shown to contain abundant anti-aging signals. Mechanistically, SHED-Exos modulated histone methylation and inhibited nuclear factor-κB (NF-κB) to reverse the aging of tendon stem/progenitor cells (AT-SCs). Local delivery of SHED-Exos-loaded microspheres conferred anti-aging phenotypes, including a reduced number of senescent cells and decreased ectopic bone formation, thereby enhancing endogenous tendon regeneration and repair capacity in aged rats (Fig. 2d) [66]. Finally, in a study on the circadian rhythm of adipose-derived stem cells, the yield and anti-inflammatory capacity of small EVs (sEVs) were enhanced. Circadian rhythm-regulated sEVs (CR-sEVs) delivered platelet factor 4 to Mø, activating the cyclic adenosine monophosphate (cAMP) signaling pathway and inhibiting M1 polarization. A triphasic microneedle (MN) scaffold was designed for local delivery of CR-sEVs at the tendon-to-bone junction by incorporating a tendon-derived decellularized ECM at the base to facilitate tendon repair (Fig. 2e) [79].

In conclusion, these studies indicate that EVs can activate multiple intracellular signaling pathways to improve skeletal muscle function and promote tendon regeneration.

2.2.2. Nanoparticles

Nanoparticles offer substantial advantages in the treatment of tendon injuries, mainly because of their precise drug-delivery ability, long-acting sustained-release characteristics, and multiple functions in promoting tissue regeneration [80]. First, nanoparticles can achieve active targeting through surface modification, precisely delivering anti-inflammatory drugs or growth factors to tendon injury sites with low vascular density, overcoming the problem of low efficiency in traditional systemic drug delivery and significantly increasing local drug concentration [81]. Second, nanocarriers can achieve controllable sustained release of drugs and avoid tissue damage caused by frequent injections [82]. Meanwhile, nanoparticles can serve as gene vectors to deliver siRNA or carry miRNAs to promote collagen synthesis and regulate the microenvironment of tendon regeneration at the molecular level [83]. Finally, the biocompatible materials of nanoparticles can reduce the risk of immune rejection, and their small size characteristics can help penetrate the dense tendon matrix and improve penetration efficiency [16]. These characteristics together promote the transition of nanoparticles from basic research to clinical practice in the field of tendon repair.

The primary obstacle hindering the widespread adoption of tendon repair systems is the lack of suitable and effective delivery methods. Innovative approaches, such as cell-targeted nanoclusters and hydrogel/nanoparticle-based sustained-release systems, have been recently developed to address tendon injuries. Nanomaterials and exosomes exhibit biological activity and can serve as drug carriers, while hydrogels possess tissue-adhesive properties [9]. Consequently, these integrated nanodelivery systems have the potential to facilitate slow drug release during tendon healing, thereby enhancing tendon repair [84].

Zhou et al. demonstrated the efficacy of polydopamine (PDA) nanoparticles (NPs) in reducing tendon adhesion through photothermal-mediated inhibition of myocyte fibrosis in rat models, indicating novel thermal approaches to prevent postsurgical adhesions [85]. Another study evaluated verapamil-loaded polydopamine nanoparticles (VP-PDA NPs) in Achilles tendon repair, showing significantly reduced adhesion scores in comparison with the control groups at both six weeks (3.175 ± 0.08) and four weeks (3.35 ± 0.25) [86].

Yang et al. engineered nanoparticle complexes for targeted silencing of TGF-β1 and/or PD-L1, optimizing the post-injury immune environment and minimizing adhesion formation in flexor tendons [38]. Complementary research has utilized microfluidic technology to develop lipid nanoparticles (LNPs) simultaneously carrying SMAD3 siRNA and collagen I mRNA, demonstrating dual antifibrotic and regenerative capabilities in human tenocyte models [87]. Advanced development of lipid-polymer hybrid nanoparticles (LPNs) co-loaded with budesonide and serpine1 siRNA resulted in significant anti-inflammatory and antifibrotic effects in both murine and human macrophage systems [16]. MicroRNA29a has emerged as a key therapeutic target for regulating immune responses and matrix remodeling. Researchers have developed microfluidic-engineered MicroRNA29a-loaded lipid nanoparticles incorporated within PELA-shelled core–shell nanofibers for localized delivery to injured tendons [88]. Innovations in scaffold design have led to the development of a smart system that integrates ceria nanozymes (CeNPs) within nanofiber bundle scaffolds (NBS@CeO). This construct enhanced mitochondrial function and microenvironment remodeling, promoting endogenous regeneration while improving mechanical properties (Fig. 2f) [11,89]. Macrophage-targeting cationic polymers have also been screened to facilitate the delivery of the Cas13 ribonucleic–protein complex (Cas13 RNP) into macrophages. This approach effectively reduced the emergence of SPP1-producing macrophages, leading to diminished fibroblast activation and mitigated peritendinous adhesion (Fig. 2g) [9]. Li et al. engineered a hydrogel-nanoparticle delivery system to overcome the pharmacokinetic limitations (poor absorption and short half-life) of metformin. In vivo evaluation demonstrated the efficacy of the system in reducing adhesion and enhancing the gliding function in repaired flexor tendons [83]. Research on nanoparticle-functionalized sutures carrying growth factors has revealed notable improvements in tendon repair. Animal studies in both chicken and rat models showed that sutures releasing basic fibroblast growth factor (bFGF) and VEGF-A substantially enhanced the ultimate strength of the repaired tendon in comparison with conventional sutures [90]. Leveraging like-charge repulsion principles, researchers have developed dual-layered, positively charged micro-nano fibrous membranes using electrospinning technology. This innovative design enabled the directional delivery of siRNA-loaded cationic nanocarriers specifically to the tendon–paratenon interface, optimizing targeted gene therapy approaches [91]. Innovations in drug delivery led to the development of a novel dual-barb poly-gamma-glutamic acid (γ-PGA) microneedle system loaded with TSPC-derived nanovesicles containing WP1066 (MN-WP1066-NVs). The specialized barb architecture enhanced skin adhesion, facilitating sustained WP1066-NV release and promoting TSPC self-renewal, migration, and stem cell characteristics [92]. Advanced development of biocompatible PCL-PEG nanoparticles for sustained rapamycin delivery has demonstrated superior outcomes in the treatment of delayed rotator cuff repair with fatty infiltration. Weekly intra-articular administration of RAPA/PCL-PEG NPs showed enhanced efficacy in reducing fatty infiltration, preserving muscle mass, and improving both mechanical properties and gait in comparison with daily rapamycin injections [93].

In conclusion, nanodrugs can not only serve as carriers to load bioactive components to promote the repair of tendon injuries but also perform the functions of nano-enzymes, eliminating ROS at the injury site and promoting cell proliferation.

3. Bioactive-material delivery systems using tissue-engineered scaffolds

Tissue-engineered scaffolds have shown potential for use in tendon repair [12]. Preclinical studies have suggested that scaffolds featuring well-designed structures and materials can facilitate tenocytes and coordinate the microenvironment in a complex manner to allow tendon regeneration. Various biophysical cues have been included to mimic the structures of natural tendons. For example, aligned arrangements [94], porous structures [95], and groove designs [96] have been introduced to regulate the interactions between cells and scaffolds. These features facilitate cell adhesion, growth, and tendon-specific lineage differentiation [97,98]. Furthermore, structured behavior is effective in regulating the polarization of macrophages toward the M2 phenotype in vivo, which, in turn, alleviates the activation of inflammation induced by tendon injury [99]. In addition, scaffolds produced from the ECM possess tunable degradation rates and excellent mechanical properties that allow them to provide mechanical support for repair processes in the early stages to achieve successful tendon regeneration.

In addition, hydrogels, as an important component of scaffold systems, have received extensive attention, mainly because of their excellent bionic properties and multifunctionality. Researchers have successfully employed various hydrogel biomaterials, including collagen [100], gelatin [101], silk [46], hyaluronic acid [102], alginate [103], and chitosan [13], in both in vitro and in vivo models to promote tendon and ligament regeneration. The porous and highly water-content structure of hydrogels is similar to that of natural ECM, which can provide a suitable environment for cell adhesion, migration, and proliferation [104]. By regulating the crosslinking density or material composition, the degradation rate of mechanical properties can be flexibly adjusted to match the repair requirements of tendons [105]. Hydrogels can also load drugs, growth factors, or cells to achieve precise sustained release or cell protection [106]. 3D printing technology further expands these applications and can be used to customize scaffolds with complex anatomical structures. In addition, some hydrogels (such as hyaluronid-based hydrogels) have anti-inflammatory and immunomodulatory functions that can reduce scar formation [107]. Despite challenges such as insufficient vascularization, hydrogels, as important components of scaffold-delivery systems, offers substantial potential in the field of tendon repair.

3.1. Common scaffolds used in delivery systems for bioactive materials

Scaffolds serve as critical structural and functional platforms in advanced biodelivery systems, enabling precise spatiotemporal control over the release of therapeutic agents while replicating the native tissue microarchitecture. The three-dimensional porous networks in scaffolds can provide mechanical support for cell adhesion, proliferation, and differentiation, while simultaneously acting as reservoirs for bioactive cargo (e.g., growth factors, siRNA, and exosomes) [108]. The tunable porosity and interconnectivity of these scaffolds can also facilitate nutrient and waste diffusion and neovascularization, whereas their surface chemistry and degradation kinetics can be engineered to synchronize with tissue-regeneration timelines. Furthermore, scaffolds protect labile therapeutics from premature degradation and mitigate off-target effects through localized delivery, thereby substantially enhancing their therapeutic efficacy. Currently, the most common pivotal fabrication techniques are electrospinning, 3D printing, and fiber braiding. Electrospinning produces nanofibrous scaffolds that mimic the native ECM, thereby enhancing cell adhesion and nutrient diffusion. 3D printing, particularly extrusion-based printing or stereolithography, enables precise control over the scaffold architecture, which is ideal for complex tissue constructs. Notably, braiding creates anisotropic scaffolds that mimic ligaments/tendons by controlling fiber alignment and porosity. This approach enables tunable mechanics and interconnected macropores for cell infiltration while maintaining structural integrity under cyclic stress, thereby guiding oriented tissue regeneration. Typically, researchers use electrospinning, 3D printing, and fiber-braiding technology to fabricate tissue-engineering scaffolds from different materials such as PLGA, poly (l-lactic acid) (PLLA), and polycarbonate polylactide (PCL) to meet the requirements of tendon repair [93,100,104]. These technologies and materials address the diverse needs of regenerative medicine by balancing mechanical stability, biodegradability, and biocompatibility. In this section, we first discuss the common preparation techniques for tissue-engineering scaffolds and then introduce the common raw materials for tissue-engineering scaffolds.

3.1.1. Common methods for preparing scaffolds

The scaffold, which is an important component of the delivery system, varies greatly in performance depending on the preparation method. Electrospinning generates nanofibrous scaffolds with high surface-to-volume ratios that optimally retain bioactives and emulate native ECM topography, thereby enhancing cellular interactions and the sustained molecular release essential for soft tissue regeneration [105]. Conversely, 3D printing enables precise spatial control over the scaffold macroarchitecture through layer-by-layer deposition, allowing anatomical customization, embedded vascular networks, and programmable multi-material gradients critical for complex tissue interfaces and spatiotemporal therapeutic programming [109]. In contrast, fiber-braiding techniques produce mechanically robust anisotropic constructs through interlaced microfibers, delivering directional tensile strength, strain tolerance, and interconnected macropores that collectively guide cell alignment and withstand cyclic loading and thereby uniquely addressing functional regeneration in load-bearing tissues, where structural integrity supersedes nanotopographical cues [110]. Collectively, these methodologies offer complementary solutions spanning nano-to-macro design hierarchies. Electrospinning dominates bioactive delivery in thin-section applications. 3D printing excels in anatomical biomimicry with multifactorial control; and braiding provides unmatched mechanical functionality for dynamic physiological environments. Together, these approaches have allowed the development of scaffold-delivery platforms to meet diverse clinical requirements.

3.1.1.1. Electrospinning for preparing scaffolds

Electrospinning is a versatile and cost-effective method for fabrication of polymer nanofibers and nanocomposites. This method enables the production of nanofibrous membranes with exceptional attributes, including an ultrahigh surface-to-volume ratio, tunable porosity, and biomimetic architecture that closely resembles the natural extracellular matrix [111]. These unique structural advantages have propelled the adoption of this technique across interdisciplinary domains spanning regenerative medicine, advanced filtration systems, sustainable packaging solutions, and energy-harvesting technologies [112]. In biomedical contexts, electrospun membranes show notable clinical potential due to their submicron-scale interstitial spacing (0.2–5 μm), which effectively creates a physical barrier against fibroblast infiltration while maintaining tissue compartmentalization. This selective permeability mechanism is particularly valuable in tendon-repair applications, where such membranes can serve as bioactive interfaces to optimize surgical suturing protocols and prevent postoperative adhesions [10].

Xu et al. pioneered a novel nanofibrous barrier by utilizing trifluid side-by-side electrospinning to create nanofibers with an eccentric Janus-like structure, incorporating three functional components: beeswax (BW), quercetin, and ketoprofen. This innovative structure enhanced mechanical properties while enabling sustained drug release, with in vitro and in vivo studies demonstrating significant anti-adhesion efficacy (Fig. 3a) [113]. Miescher et al. produced a bilayered tube combining electrospun hyaluronic acid/polyethylene oxide (HA/PEO) biodegradable and non-biodegradable DegraPol® (DP) components. Testing in rabbit Achilles tendon laceration models revealed superior anti-adhesive properties in comparison with pure DP tubes [114]. Liang et al. developed an advanced scaffold system utilizing carbon-fiber-mediated electrospinning, in which conductive single-bundle carbon fibers were encased in nanofiber membranes. In studies using rabbit Achilles tendon defects, their system demonstrated enhanced collagen-secreted fiber formation in these conductive scaffolds in comparison with nonconductive polyethylene glycol terephthalate alternatives (Fig. 3b) [115]. Cai et al. combined advanced electrospun nanofiber yarn generation with traditional textile manufacturing to create innovative nano-micro fibrous woven scaffolds. These constructs demonstrated a tendon-like anisotropic architecture and high-strength mechanical properties suitable for large-scale tendon injury treatment [116]. Li and colleagues developed a novel hybrid nanofibrous composite through sequential electrospinning of poly(l-lactide-co-ε-caprolactone) (PLCL) and gelatin (Ge) nanofibers onto a polyethylene terephthalate (PET) fiber substrate, enhancing both biocompatibility and biodurability [117]. Miescher et al. explored adhesion prevention through two innovative implant materials: an electrospun random fiber mesh combining HA with poly(ethylene oxide) (PEO), and silver nanoparticle-modified electrospun DegraPol (DP-Ag) designed to reduce bacterial adhesion. Their findings confirmed reduced biofilm formation on the silver nanoparticle-treated DP surfaces [118]. In other studies, researchers engineered a unidirectional Janus membrane through sequential electrospinning, combining randomly oriented polycaprolactone fibers containing tannic acid/Fe³⁺ particles for adhesion prevention with aligned gelatin fibers promoting tissue repair [119,120].

Fig. 3.

Scaffolds based on electrospinning, 3D printing, and various advanced materials. a) A diagram of the tri-fluid side-by-side electrospinning and the resultant tri-section Janus nanofibers. Adapted with permission [113]. Copyright 2024, Xu et al. b) Comprehensive illustration detailing CPS preparation protocol and applications. Adapted with permission [115]. Copyright 2024, Yu et al. c) Detailed representation of biomimetic multicellular scaffold fabrication process and its application in tendon-bone interface reconstruction. Adapted with permission [98]. Copyright 2023, Du et al. d) Process illustration depicting fabrication and implementation of 3D-printed hydrogel particles incorporating PRP-laden TDSCs in rat tendinopathy model. Adapted with permission [123]. Copyritght 2023, Li et al. e) High-throughput molecular screening platform evaluating small molecule efficacy in maintaining TSPC phenotype and proliferation capacity. Adapted with permission [124]. Copyright 2021, Zhang et al.

3.1.1.2. 3D printing for preparing scaffolds

3D bioprinting is a recent platform in precision medicine that offers great promise in reconstructing anatomically complex biological tissues [107]. 3D printing is a layered technique capable of creating biomimetic architectures with high resolution (micron-scale in all three axes: 50–200 μm resolution) with nanoscale control of topological form features and cellular microenvironments by using special bioinks (most often based on cell-encapsulation hydrogel [e.g., GelMA, alginate]) or hydrophilic biodegradable thermoplastics [e.g., PCL, PLGA] that can deposit multiple biological units simultaneously by computer-aided extrusion, inkjet, or laser-based printing processes [98]. Thus, 3D printing-based microfabrication techniques allow the fabrication of complex tissue constructs. Such construct design allows for more complex forms exhibiting multi-transition heterogeneity through the spatial organization of multi-component bioinks in way which is beyond feasibility by conventional approaches.

Researchers developed an innovative approach incorporating TGF-β1 gene-silencing miRNA-based RNAi plasmid into a 3D-printed tendon scaffold. This construct demonstrated dual functionality by enhancing tendon regeneration while preventing adhesion formation and ultimately improving functional recovery [108]. Breakthroughs in biomaterial engineering have led to the development of a biomimetic ink system that integrates tissue-specific cells with Mo-containing silicate (MS) bioceramics. The ionic microenvironment generated by MS bioceramics enables the 3D-printed constructs to simultaneously promote tenogenic and osteogenic differentiation in vitro while supporting integrated tendon-bone interface regeneration in vivo (Fig. 3c) [98]. Chae et al. engineered an advanced therapeutic platform combining 3D cell printing with tissue-specific bioinks to achieve gradual physiological transitions for tendon-bone interface (TBI) regeneration. Their innovative approach involved spatial arrangement of cell-laden tendons and bone-specific bioinks in a gradient pattern, replicating the complex architecture of the native fibrocartilaginous interface [121]. Further advancements in tissue engineering utilized polydopamine (PDA) to immobilize bFGF on 3D electrohydrodynamic-printed PCL scaffolds. This modification demonstrated synergistic enhancement of tenogenic marker expression at 14 days in tendon stem/progenitor cells (TSPCs), with evidence suggesting that tenogenic differentiation occurred through activation of the TGF-β signaling pathway [122]. Investigators employed projection-based 3D bioprinting to generate injectable GelMA microparticles incorporating TDSCs and PRP (PRP-TDSC-GM). Their findings revealed that PRP-TDSC-GM enhanced tendon differentiation in TDSCs while attenuating inflammatory responses through downregulation of the PI3K-AKT pathway, ultimately facilitating structural and functional tendon restoration in vivo (Fig. 3d) [123]. Advances in research have led to the development of a small-molecule cocktail that targets distinct stages of tendon development, including proliferation, tenogenesis initiation, and maturation. This approach notably enhances tendon-specific gene and protein expression in TSPCs. The integration of this small-molecule strategy with 3D printing technology has demonstrated superior efficacy in supporting tendon repair and regeneration (Fig. 3e) [124]. Zhang et al. engineered an efficient protocol for synthesizing a visible-light-crosslinkable PHT prepolymer resin within 30 min at ambient temperature. This innovation has enabled the production of 3D-printable constructs exhibiting tendon-mimetic mechanical properties while serving as delivery vehicles for tenogenic factors [125]. Additionally, researchers have developed an innovative microfluidic piggyback platform that facilitates precise control of collagen fiber formation and alignment on culture dish surfaces. A comparative analysis revealed that tenocytes cultured on these aligned fibrillar substrates demonstrated enhanced expression of tenogenic markers at both the transcriptional and translational levels, surpassing the outcomes observed with conventional tissue culture plastic or non-fibrillar collagen coating methods [126].

3.1.1.3. Fiber braiding for preparing scaffolds

In comparison with other methods for preparing scaffolds, fiber braiding involves the precise interlacing of continuous polymeric or composite filaments (e.g., PCL, PLGA, or silk fibroin) in helical patterns, enabling controlled modulation of scaffold architecture at multiple hierarchical levels [127]. This technique excels in emulating the uniaxial tensile strength and strain-stiffening behavior of the tendon through strategic manipulation of the braiding angles, fiber diameter, and yarn count, which directly govern the stress distribution and collagen-mimetic alignment. Crucially, braided scaffolds exhibit strain-dependent fiber reorientation that mirrors the native tendon's response to physiological loading, whereas the interconnected porosity facilitates nutrient diffusion and tenocyte infiltration. Comparative studies have demonstrated that braided constructs achieve elastic moduli closer to the native tendon than isotropic electrospun meshes, with dynamic mechanical analysis confirming superior fatigue resistance under cyclic loading [128]. Furthermore, hybrid approaches that integrate braiding with surface functionalization (e.g., RGD peptide grafting) or core-sheath designs enhance the bioactivity without compromising the structural integrity [128]. The scalability of the technique for producing continuous patient-specific grafts in a computer-controlled manner makes it a pivotal strategy for overcoming the current limitations in load-bearing soft tissue regeneration, warranting its inclusion as a cornerstone methodology in scaffold design paradigms [129]. Nowotny et al.’ produced braided chitosan scaffolds via wet spinning, and these scaffolds showed superior ultimate stress with larger yarns and supported robust hMSC proliferation, exceeding the controls for tendon-derived cells, thereby enabling functional tendon analog design (Fig. 4a–c) [130]. In another study, silkworm gut fiber braids demonstrated a linearly adjustable breaking force and tendon/ligament-matching elastic modulus when hydrated, while supporting excellent hMSC/fibroblast adhesion and proliferation in vitro, making them promising scaffolds for future in vivo tendon/ligament repair (Fig. 4d) [110]. In addition, Cai et al. found that fiber-braided nano-micro nm SF/PLLA scaffolds enhanced tenocyte growth/M2 macrophage polarization and enabled biomechanical functional tendon regeneration without biological additives, offering clinically ready solutions (Fig. 4e) [116]. Yuan et al. also found that a novel fiber-braiding technology could create modular 3D nanofiber scaffolds with tunable mechanics and biocompatibility, demonstrating enhanced soft tissue regeneration (Fig. 4f) [131].

Fig. 4.

Scaffolds based on fiber braiding. a) Diamond pattern structure. b) Light microscopic image (scale bar 1 mm). c) Scaffold 16–300 and scaffold 16–600. Adapted with permission [130]. Copyright 2016, Nowotny et al. d) SEM image of individual SGFs and a braid made with these fibers. Adapted with permission [110]. Copyritght 2019, Pagán et al. e) Illustration of fabrication of nano-micro fibrous woven textile scaffold and its application for Achilles tendon repair and regeneration. Adapted with permission [116]. Copyright 2023, Cai et al. f) The diagram outlines the sequential manufacturing steps for producing an orthogonally woven 3D nanofiber scaffold. Adapted with permission [131]. Copyright 2024, Yuan et al.

3.1.2. Common materials for tissue-engineering scaffolds

Current tendon tissue engineering leverages synthetic, decellularized, and composite scaffolds to address biomechanical reinforcement, immunomodulation, and microenvironmental regulation [59,132,133]. Innovations focus on optimizing biodegradation kinetics, enhancing electromechanical signaling, and integrating anti-adhesive functionalities through advanced fabrication techniques like electrospinning and biomimetic design. While significant progress has been made in achieving biomimetic mechanical properties, sustained bioactive delivery, and macrophage polarization, critical challenges remain in replicating native tendon hierarchical complexity across multi-tissue interfaces. Future research must prioritize scalable manufacturing for clinical translation, elucidate long-term host–material interactions to prevent fibrotic encapsulation, and develop dynamic scaffolds capable of adapting to physiological loading regimes to fully restore tendon functionality.

3.1.2.1. Synthetic polymer scaffolds

At present, synthetic polymer scaffolds are widely used in tendon repair. As illustrated in Table 2, PCL, PLGA, and PLLA scaffolds exhibit distinct regenerative profiles: PCL demonstrates exceptional capacity for long-term electrical microenvironment restoration through piezoelectric composites, supporting sustained bioactive molecule delivery while maintaining biomimetic mechanical compliance [108]. PLGA offers versatile degradation kinetics ideal for acute clinical scenarios, with its Janus architectures and micro-engineered designs enabling simultaneous anti-adhesion functionality and prolonged antimicrobial/therapeutic agent release to address urgent repair needs [95]. In contrast, PLLA leverages inherent piezoelectricity and electroconductive enhancements to replicate critical interface biomechanics, particularly for bone-tendon junctions, while its core–shell carrier systems facilitate sophisticated sequential molecule release aligned with cellular recruitment phases [116]. Collectively, PCL excels in electro-sensitive tissue remodeling, PLGA dominates rapid-intervention applications requiring multifunctional barriers, and PLLA provides specialized solutions for mechanically demanding interfaces, establishing a complementary materials spectrum spanning immediate repair to chronic tissue maturation.

Table 2.

Comparison of PCL, PLGA and PLLA.

Feature	PCL	PLGA	PLLA
Source/Approval	Synthetic/Widely studied	Synthetic/FDA-approved	Synthetic/FDA-approved
Core Advantage	Long-term stability, toughness, processability	Tunable degradation/drug release, versatility	Piezoelectricity, Good mechanical strength
Typical Degradation	Slow (>12 months)	Tunable (weeks-months by LA:GA ratio)	Moderate-Slow (months-years)
Mechanical Properties	Flexible, ductile, tough	Tunable (Stiffer with higher LA)	Stiff, high tensile strength
Key Challenges	Hydrophobic, lack of bioactivity	Acidic degradation byproducts	Relatively brittle
Common Functionalization/Loading Strategies	Surface modification (e.g., PDA, plasma treatment) [134], growth factor conjugation [135], drug/nanoparticle incorporation [136]	Direct drug incorporation (electrospinning, blending) [137], surface coatings (e.g., Janus) [138], composite formation [139]	Piezoelectric element integration (ZnO, BTO) [140], conductive filler addition (e.g., GnP) [141], bioactive molecule loading [142]

∗Abbreviation: PCL, polycaprolactone; PLGA, polylactic acid; PLLA, poly (L-lactic acid); PDA, polydopamine; FDA, food and drug administration.

3.1.2.1.1. Scaffolds based on PCL

PCL nanofiber scaffolds represent a cutting-edge class of synthetic biomaterials that combine biodegradability and biomimetic properties. These constructs exhibit optimal biocompatibility, controlled degradation kinetics, and adaptable mechanical properties that can be precisely tuned for specific therapeutic applications [[11], [12], [13], [14]]. Their proven ability to provide both biological signaling cues and structural reinforcement has accelerated their adoption in clinical practice [143].

Wang et al. engineered an innovative fiber system by incorporating dopamine (PDA)-modified piezoelectric tetragonal-SrTiO₃ (T-SrTiO₃) into electrospun PCL fibers, and designated the system as T-SrTiO₃@PCL. This system was developed to restore the native electrical microenvironment of the tendon, thereby facilitating repair (Fig. 5a) [144]. In another study, Wei et al. fabricated a biodegradable tendon-repair scaffold using PCL through electrospinning. Researchers engineered a framework designed to deliver the Wnt3a protein, functioning as an implantable construct to augment tendon regeneration in a rat Achilles tendon injury model (Fig. 5b) [59]. In a parallel study, Shalumon et al. interwove individual PCL filaments to generate a multi-yarn (MY) architectural scaffold. The construct underwent oxygen plasma surface modification, followed by heparin conjugation. By exploiting the biological affinity between heparin and fibroblast growth factor 2 (FGF2), the authors successfully immobilized FGF2 onto the modified construct, yielding a bioactive scaffold (MY-FGF2) specifically engineered for extensor digitorum tendon (EDT) regeneration (Fig. 5c) [10]. In a separate investigation, naproxen sodium-containing nanofibers were integrated into polylactic acid microfilaments by electrospinning to generate a dual-layered core-spun yarn (DY). Both in vitro and in vivo evaluations demonstrated that the controlled release of naproxen sodium within the constructs effectively suppressed excessive foreign fibroblast proliferation, enhanced macrophage polarization, mitigated inflammatory responses, and promoted tendon tissue regeneration [145]. Additionally, investigators have documented the development and fabrication of an innovative system incorporating nitric oxide-loaded metal–organic frameworks (MOFs) encapsulated within PCL/gelatin (Gel)-aligned coaxial scaffolds (NMPGA) for tendon reconstruction [129,146].

Fig. 5.

Scaffolds based on synthetic polymers. a) Synthesis protocol and therapeutic mechanisms of SrTiO3@PCL fiber systems. Adapted with permission [144]. Copyright 2024, Wang et al. b) Visualization of Achilles tendon defect model alongside novel Wnt3a-functionalized biomaterial scaffold design. Adapted with permission [59]. Copyright 2023, Wei et al. c) Ultrastructural and optical characterization of PCL fiber-reinforced suture systems through scanning electron microscopy. Adapted with permission [10]. Copyright 2022, Shalumon et al. d) Engineering approach for dual-functional Janus membrane patch, designed to simultaneously suppress exogenous healing while promoting endogenous regeneration. Adapted with permission [138]. Copyright 2024, Xie et al. e) Mechanistic illustration depicting exercise-mediated mechanoelectrical signal generation by the RPB/OPZ scaffold and its role in enhancing tendon-bone integration. Adapted with permission [153]. Copyright 2024, Zhang et al. f) Technical route diagram of aligned Arg/HA/PLLA macrofibers for tendon regeneration. Adapted with permission [154]. Copyright 2023, Xuan et al. g) Comprehensive visualization of the GnP matrix fabrication methodology. Adapted with permission [155]. Copyright 2022, Shemshaki et al.

3.1.2.1.2. Scaffolds based on PLGA

PLGA is a multifunctional co-polyester approved by the Food and Drug Administration (FDA). It has attracted notable attention for numerous clinical applications, including suture anchors, fracture fixation, orthopedic implants, drug delivery, and tendon/ligament reconstruction [99].

Using electrospinning technology, Weng et al. generated simvastatin-loaded PLGA nanofibrous matrices and demonstrated their therapeutic potential and durability for tendon regeneration [147]. Investigators also engineered an innovative Janus patch that simultaneously enhances endogenous healing and prevents exogenous tissue formation, thereby optimizing tendon-repair outcomes. Laboratory evaluations revealed the remarkable efficacy of the patch in reducing cell adhesion and motion friction by 92.41 % and 79.89 %, respectively. Animal studies demonstrated its capacity to suppress tendon adhesion through modulation of the TGF-β/Smad signaling cascade while promoting tendon maturation (Fig. 5d) [138]. Xu et al. developed a biomimetic surgical suture (SS) characterized by helical and hierarchical micro/nanoarchitectures utilizing nano- and micro-PLGA filaments (ny). This construct was subsequently crosslinked with a transient chemotactic (TC) physiological fibrin network layer (TC-nySS) [148].

For Achilles tendon rupture treatment, researchers engineered a comprehensive scaffold system that integrates additively manufactured PCL tubular supports with electrospun collagen/drug-infused PLGA nanofibrous matrices. Mechanical analysis revealed the superior performance of the diamond-pored PCL supports. The drug-enriched PLGA nanofibers exhibited sustained antimicrobial agent release, maintaining therapeutic levels of vancomycin and ceftazidime for 40 days while providing extended lidocaine delivery beyond 10 days under laboratory conditions [149]. Another study focused on the development of doxycycline-incorporated biodegradable PLGA nanofibers through electrospinning. The experimental findings demonstrated sustained doxycycline release, maintaining therapeutic concentrations for more than 40 days after surgery. Additionally, animals receiving doxycycline-loaded nanofiber implants exhibited enhanced mobility and superior tendon strength after surgical intervention [150].

3.1.2.1.3. Scaffolds based on PLLA

PLLA, an FDA-approved polymer, has gained prominence in the development of piezoelectric tissue scaffolds for multiple applications, including bone, cartilage, and neural regeneration [151]. Chen et al. demonstrated the efficacy of growth/differentiation factor 5 (GDF-5)-activated adipose-derived stem cell (ASC) sheets in tendon engineering. Molecular profiling through PCR and western blot analysis revealed enhanced expression of key tenogenic markers, including Col I and III, tenomodulin (TNMD), biglycan, and tenascin C, in GDF-5-treated sheets compared to controls. The integration of these bioactive sheets with P(LLA-CL)/silk fibroin nanoyarn matrices yielded sophisticated tendon constructs [152]. A breakthrough in interface engineering produced a novel Janus nanofibrous system that combined piezoelectric functionality with a natural collagen-mimetic architecture. This advanced platform utilizes dual-component electrospinning to merge PLLA/ZnO and PLLA/BTO layers, with precise fiber alignment achieved through controlled roller dynamics. The resulting scaffolds exhibited biomechanical properties that closely matched the native TBI requirements, particularly in terms of tensile strength and suture retention (Fig. 5e) [153]. In their investigation, Xuan et al. employed stable emulsion jet electrospinning to generate aligned ultrafine PLLA fibers incorporating dual bioactive components: l-arginine (Arg) and low-molecular-weight HA. The resultant Arg/HA/PLLA microfibrous construct exhibited a distinctive core–shell architecture, enabling the controlled sequential release of Arg and HA based on their charge characteristics. This advanced scaffold exhibited enhanced hydrophilic properties, resulting in improved cellular migration, spreading, and proliferation dynamics (Fig. 5f) [154]. Shemshaki focused on developing an electroconductive matrix through the strategic integration of graphene nanoplatelets (GnPs) within aligned poly (L-lactide acid) (PLLA) nanofibers. The authors reported that this GnP-containing matrix significantly enhanced myotube formation, mainly owing to elevated levels of calcium ions in the cells. The long-term biocompatibility of the GnP matrix, along with its role in addressing problems, such as muscle degeneration, promises to promote the healing and regeneration of muscle-related connective tissues (Fig. 5g) [155].

3.1.2.2. Decellularized ECM scaffolds

Native tendon-derived components within the decellularized tendon matrix (DTM) have demonstrated remarkable efficacy in promoting tenogenic differentiation and enhancing tendon regeneration [62]. ML et al. demonstrated in a systematic review of 13 studies of 432 patients that decellularised extracellular matrix scaffolds could effectively promote the recovery of tendon injury [156]. ne group of researchers developed an innovative anti-adhesion membrane that utilizes a homologous ECM as the primary component. Experimental evaluation in rabbit Achilles tendon models revealed the dual functionality of this DTM construct in preventing adhesion formation while simultaneously enhancing tissue-regeneration quality, highlighting its therapeutic potential [61]. Innovations in biomaterial design also led to the development of “BioTenoForce," a sophisticated tendon substitute integrating tendon ECM's biological complexity with a mechanically robust polyurethane elastomer. This composite structure mimics native tendon characteristics while supporting sustained shoulder mobility (Fig. 6a) [62]. To advance tissue-engineering strategies, researchers engineered an in situ MnO₂-modified decellularized construct specifically designed to optimize the regenerative microenvironment for enhanced tendon healing (Fig. 6b) [63].Yin et al. investigated the structural significance of DTM's aligned architecture in tissue regeneration. Their findings emphasized the critical importance of maintaining DTM's native aligned configuration of the DTM for optimal stem cell tenogenic differentiation and tissue repair outcomes, establishing this as a crucial consideration in DTM applications [64]. Engineering advances have also led to the development of a composite construct, designated as a PET matrix patch (PM), which is fabricated by immersing plain-woven PET in a decellularized matrix gel followed by freeze-drying. Characterization studies revealed that PM had exceptional cytocompatibility and robust mechanical properties, demonstrating failure load resistance up to 480N [157]. Further innovations in scaffold design have resulted in the integration of a decellularized bovine tendon sheet (DBTS) with a TDSC ECM, creating a biomechanically and biochemically optimized construct (tECM-DBTS) designed to provide an enhanced microenvironment for tendon regeneration. Studies have also revealed that tECM-DBTS creates an optimal biomimetic environment conducive to endogenous stem cell recruitment and in situ tendon regeneration [158]. Innovative research produced a mussel-inspired artificial tendon utilizing double-cross-linked chitosan modification, where the decellularized construct functioned as a biomimetic platform to enhance tendon repair, cell migration, and adhesion (Fig. 6c–e) [159]. Yun et al. engineered a composite scaffold combining demineralized bone matrix (DBM) with fibrocartilage extracellular matrix (FCECM), characterized its physiochemical attributes, and demonstrated its efficacy in TBI restoration in rabbit models [160]. In parallel, Zhao et al. developed a functionalized scaffold (DTS-TA) by modifying decellularized tendon slices (DTSs) with tannic acid (TA) and incorporating anti-inflammatory and antioxidant properties. Experimental validation using both laboratory and animal studies demonstrated the effectiveness of DTS-TA in modulating inflammation through enhanced M2/M1 macrophage ratios, elevated IL-4 levels, reduced IL-6 and IL-1β secretion, and ROS neutralization [132].

Fig. 6.

Scaffolds based on decellularized extracellular matrix. a) Dual analysis of BioTenoForce and TenoForce scaffolds showing hASC viability through Live/Dead assay alongside tenogenic differentiation via fluorescent marker visualization. Adapted with permission [62]. Copyright 2024, Huang et al. b) Comprehensive characterization of porcine-derived decellularized tendon fabrication process and properties. Adapted with permission [63]. Copyright 2024, Lun et al. c) Detailed illustration depicting muscle-derived artificial tendon preparation methodology and its applications in functional tendon reconstruction. d) Multifaceted characterization of mussel-derived artificial tendon including tensile strength evaluation, FTIR spectral analysis, and SEM ultrastructural imaging. e) Histological and immunohistochemical analysis of regenerated tendon tissue through H&E, Masson's trichrome, Sirius red, and IHC staining. Adapted with permission [159]. Copyright 2023, Wang et al.

An investigation into thermal processing revealed its influence on DCB osteoinductivity by comparing the effects of heat and H₂O₂ treatments on BMP-2 inactivation. Both methodologies successfully eliminated BMP-2 and osteocalcin while maintaining cytocompatibility and reducing TDSC osteogenic differentiation in DCB-H and DCB-HO preparations [161]. Advanced scaffold engineering has led to the development of a novel three-dimensional nanofiber-reinforced construct for acellular tendon complexes; this construct features a trilayer architecture: an acellular tendon core, an intermediate PU/Col I yarn layer, and an outer PLLA/bioactive glass nanofiber membrane, with each layer serving distinct yet complementary functions [162]. Further research explored tECM fractionation through enzymatic digestion (utilizing pepsin, hyaluronidase, and chondroitinase) and gelation-based separation into collagen matrix-enriched (CM) and non-collagenous matrix-enriched (NCM) components. These findings suggest that non-collagenous tECM proteins, rather than collagen components, likely serve as key biochemical mediators of tECM's pro-tenogenic activity [163].

3.1.2.3. Scaffolds based on various materials

Drawing inspiration from the natural architecture of bamboo, Zhang et al. developed an innovative tape suture that incorporated hollow and porous structural elements through a combined triaxial braiding and melting process. Performance evaluation of this suture against the clinical standard USP No.2 PET suture demonstrated significant improvements; the novel tape suture achieved 36 % reduction in mass while decreasing the cut-through tendon distance by 61 % [164].

Chen et al. engineered a sophisticated bilayer membrane system to encapsulate surgical sites after tendon suturing, addressing the dual challenges of adhesion prevention and healing promotion. The membrane architecture featured a strategically designed bilayer configuration: an outer layer composed of carboxymethyl cellulose crosslinked with 1,4-butanediol diglycidyl ether (CX), complemented by an inner layer incorporating Bletilla striata polysaccharides within the crosslinked network (CXB) [165]. Wang et al. pioneered the development of biomimetic scaffolds using QHM (Q: Quadrol, H: Hexamethylene diisocyanate; M: Methacrylic anhydride) polyurethane with tendon-like mechanical properties through ultraviolet-controlled crosslinking. These constructs were functionalized with growth and differentiation factor-7 (GDF-7) and demonstrated robust tenogenic properties. In rat rotator cuff injury models, the QHM polymer facilitated in situ tendon-like tissue formation while successfully preventing heterotopic ossification [166]. Scientists engineered an innovative piezoelectric platform utilizing aligned nanofibers constructed from ferroelectric poly(vinylidene fluoride-co-trifluoroethylene) designed to investigate cellular response mechanisms in tendon regeneration. Their findings confirmed that motion-driven electromechanical stimulation through a piezo-bioelectric device modulated ion channel activity in vitro and regulated key regenerative signaling pathways [167]. Innovations in scaffold design have led to the development of a multilayer-induced scaffold (IS@DN) that combines gradient-degradable layers (DLs) with nanoguided layers (NLs). Progressive exposure to NLs facilitates continuous cellular and collagen fiber alignment. Macroscopic evaluation demonstrated the efficacy of the scaffold in rat Achilles tendon regeneration, achieving a native tissue failure load of 91.37 % [168].

Gwon et al. engineered a tissue-engineered tendon nanoconstruct (TNC) specifically designed for rotator cuff regeneration. This advanced construct enhanced healing across the TBI in chronic RCT models by optimizing cell proliferation, differentiation, protein expression, and growth factor secretion [133]. Zhang et al. developed an innovative split-hollowed magnesium alloy anchor system for rotator cuff repair in a rabbit model. Their design effectively addressed degradation-related failures common to traditional eyelet structures, thereby providing enhanced suture stability [169]. Wang et al. developed an advanced suture anchor-tendon hybrid graft (SATHG) integrating enthesis-inspired design principles across both digital and physical platforms. This system, constructed from QHM photocrosslinkable polyurethane, achieved exceptional biomechanical properties, including peak load capacity of 132.9 N, failure displacement of 1.78 mm, structural stiffness of 135.4 N/mm, and a work-to-failure measurement of 422.1 × 10⁻³ J [170].

A group of scientists have also created a sophisticated trilayer scaffold based on tissue-inducing principles: the first layer consists of PLGA and nano-hydroxyapatite incorporating BMP2-gelatinmp for bone simulation (BP); the second utilized SA and type I collagen with TGF-β3 for cartilage mimicry (CP); and the third featured precisely oriented l-poly-lactic-acid fibers replicating tendon architecture (TP). This hierarchical system demonstrated remarkable healing acceleration in rat Achilles models, which was driven by enhanced cellular differentiation pathways [171]. Heidari et al. developed sophisticated hybrid biocomposites by integrating poly(p-dioxanone) (PDO), poly(lactide-co-caprolactone) (LCL), and silk to create high-performance tendon grafts. In vivo evaluation revealed the ability of these constructs to downregulate pro-inflammatory cytokine expression at six weeks after implantation [172]. Drawing inspiration from natural exoskeletal structures, Han et al. engineered an innovative biomaterial (CS-FS) by modifying natural fish scales (FS) with calcium silicate nanoparticles (CS NPs) to enhance tendon-bone healing. This biomimetic “Bouligand” microstructure enabled exceptional mechanical properties, achieving tensile strength of 125.05 MPa and toughness of 14.16 MJ/m3 and surpassing natural tendon performance by 1.93 and 2.72 times respectively. These superior mechanical characteristics make the scaffold particularly suitable for rotator cuff tendon reconstruction applications [89,116].

3.2. Hydrogel repair systems for tendon tissue

Hydrogels have emerged as indispensable components in drug-delivery systems because of their exceptional biomimetic properties, including high water content resembling that of native ECM, tunable mechanical properties through modulation of crosslinking density, and the capacity for sustained release of bioactive payloads [163]. The porous architecture of hydrogels enables efficient nutrient diffusion, while providing structural support for cell proliferation and migration [107]. Smart hydrogels with stimuli-responsive behavior (e.g., pH-, temperature-, or enzyme-triggered degradation) further allow spatiotemporal control over therapeutic agent delivery, which is particularly critical for coordinating tissue-regeneration phases [105]. The integration of functional motifs (e.g., RGD peptides and conductive polymers) enhances cell–material interactions and electrical signal transduction, making hydrogels versatile platforms for addressing complex regenerative challenges in load-bearing tissues and dynamic physiological environments [173]. Currently, common hydrogels are classified into three types: reinforced, bioadhesive, and multifunctional hydrogels.

Enhanced hydrogels are defined by structural reinforcement strategies (e.g., Janus architectures, macroporous networks, and nanocomposite integration) that overcome the mechanical deficiencies of conventional hydrogels [38,174]. In contrast, bioadhesive hydrogels prioritize interfacial molecular engineering (catechol, Schiff base, or dynamic crosslinking) for robust tissue adhesion, as demonstrated by dopamine-grafted HA hydrogels that sustained >40 kPa of adhesion to wet tendons under cyclic loading [175]. Multifunctional hydrogels integrate ≥3 concurrent therapeutic modalities (e.g., mechanical support + bioactive delivery + environmental responsiveness), illustrated by multifunctional electrospun hydrogel patch (MEHP) Janus systems delivering curcumin (antioxidant), IL-4 (immunomodulator), and Ag NPs (antibacterial agent) while maintaining adhesion [176,177]. Although the three types of hydrogels show functional overlaps, their classification hinges on the primary objective: enhanced types focus on bulk properties; bioadhesive types focus on interfacial performance; and multifunctional systems emphasize synergistic deployment of bioactive payloads within a unified matrix.

3.2.1. Reinforced hydrogels

Traditional hydrogel applications in tendon repair face substantial limitations, primarily owing to insufficient mechanical strength and adhesion properties. These deficiencies render them unsuitable for maintaining structural integrity under complex mechanical loads, resulting in potential displacement or structural failure during motion-induced deformation [178]. This highlights the critical need to develop enhanced hydrogel systems with superior mechanical resilience and durability.

Jiang et al. developed an innovative Janus-structured hydrogel patch (JAHP@bFGF) featuring a dual-layer design to enhance tendon regeneration. This construct combines an external PVA/SA/Na3Cit hydrogel layer that provides mechanical stability, protein resistance, and low-friction characteristics with an internal TCSB@bFGF microgel layer that responds dynamically to microenvironmental changes. The internal layer enables precise bFGF delivery and promotes cellular proliferation and migration, while providing antimicrobial protection. This system demonstrated significant improvements in tendon-healing outcomes and repair quality in models of extensive tendon injury (Fig. 7a) [174]. In another study, researchers engineered a sophisticated macroporous hydrogel (MHA-sEV) that integrated SA and HA with ASC EVs (sEVs). This construct featured aligned structural architecture and immunomodulatory properties and achieved biomechanical strength twice that of the control materials, indicating its potential for reducing postsurgical retear incidence (Fig. 7b) [103]. Inspired by the anatomical and pathophysiological mechanisms underlying tendon adhesion, a dual-layer Janus patch has been designed. This patch features an inner layer composed of an MEHP that interfaces with the operated tendon and an outer layer composed of a PLLA fibrous layer that is in contact with the surrounding tissue. The inner MEHP exhibited superior mechanical performance, adhesion strength, and outstanding antioxidant, anti-inflammatory, and antibacterial properties. The enhanced adhesion properties of the construct created an optimized microenvironment that supported tendon regeneration (Fig. 7c) [106]. Researchers have developed an innovative fiber-reinforced hydrogel (FRH) as a synthetic tendon graft that replicates the hierarchical architecture of native tendons. The design incorporated ultrahigh molecular weight polyethylene (UHMWPE) fibers into either a polyvinyl alcohol/gelatin hydrogel (FRH-PG) or a composite system combining polyvinyl alcohol/gelatin with strontium-hardystonite (Sr-Ca₂ZnSi₂O₇, Sr-HT) (FRH-PGS). Both variants demonstrated tensile strengths between 77.0 and 81.8 MPa, comparable to the reported values for human Achilles tendons [179]. Zhang et al. demonstrated that a gastrodin-loaded submucosal (SIS) hydrogel effectively restored the mechanical properties of the Achilles tendon. The system enhanced ECM remodeling and collagen organization through improved protein synthesis translocation, while simultaneously reducing inflammatory responses via NF-κB pathway inhibition and decreasing inflammatory cell infiltration [180].

Fig. 7.

Hydrogel Systems in Tendon Repair a) Schematic representation of the JAHP@bFGF patch and its preparation process. Adapted with permission [174]. Copyright 2024, Jiang et al. b) MHA-sEVs therapeutic impact on bone-tendon junction restoration in osteoporotic rotator cuff models. Adapted with permission [103]. Copyright 2023, Song et al. c) Engineering approach for novel Janus patch construction. d) Schematic illustration of the Janus patch. Adapted with permission. Copyright 2023, Zhang et al. e) Preparation process for siRNA@DHP-PB patch. Adapted with permission [185]. Copyright 2025, Jiang et al. f) Schematic diagram of CP@SiO2 treatment for tendon injury. Adapted with permission [97]. Copyright 2024, Wan et al.

3.2.2. Bioadhesive hydrogels

Bioadhesive hydrogels have emerged as promising alternatives to conventional sutures and staples for tendon repair, owing to their biological tissue-like properties and capacity to form robust biointerfaces [181]. Recent innovations in hydrogel technology have accelerated the development of functional bioadhesive systems with enhanced tissue-regeneration capabilities [182].

Zhang et al. engineered a specialized bioadhesive hydrogel featuring controlled nanoscale phase separation for anterior cruciate ligament (ACL) treatment. When combined with sutures, this system creates a flexible yet rigid bio-interface with tendon tissues, inhibiting fibroblast migration and excessive connective tissue formation to optimize tendon healing [183]. Innovations in biomaterial sourcing led to the development of SSAD hydrogels derived from the skin secretions of the Chinese giant salamander (Andrias davidianus). This unique double-layer construct demonstrated robust adhesion properties and successfully bridged Achilles tendon ruptures in rat models without the need for sutures [184]. Researchers have also developed a high-strength, shape-conforming hydrogel (PH/GMs@bFGF&PDA) inspired by mussel adhesion mechanisms. This system integrates polyvinyl alcohol (PVA) and phenylboronic acid-functionalized hyaluronic acid (BA-HA) with polydopamine- and bFGF-loaded gelatin microspheres (GMs@bFGF). This construct's adaptive shape-conforming properties enable precise fitting to tendon injury sites, while its substantial adhesion strength (101.46 ± 10.88 kPa) ensures stable wound contact throughout the healing process [102].

3.2.3. Multifunctional hydrogel systems

Multifunctional hydrogels are advanced biomaterial platforms engineered to concurrently deliver three or more therapeutic functionalities within an integrated matrix, distinguishing them through synergistic payload coordination rather than isolated material enhancements.

Zhang et al. addressed postoperative peritendinous adhesions by developing a dual-layer Janus patch featuring a core MEHP. The MEHP, which was fabricated by co-electrospinning of gelatin methacryloyl (GelMA) and zinc oxide (ZnO) nanoparticles followed by TA treatment, serves as the adhesive and therapeutic interface directly contacting the repaired tendon. It has five critical properties: 1) robust mechanical support, 2) strong tissue adhesion, 3) potent antioxidant activity, 4) anti-inflammatory action, and 5) broad-spectrum antibacterial properties. This multifunctional hydrogel actively created a regenerative microenvironment while mitigating early oxidative/inflammatory stress. Encased in a protective poly-l-lactic acid (PLLA) barrier, the MEHP-driven design coordinated the tendon-healing phases to reduce late-stage adhesion (Fig. 7d) [106]. In a different study, Zhang et al. introduced a multifunctional self-healing hydrogel (DHP) as the core of an anti-adhesion patch. Formed by dynamic crosslinking, the DHP hydrogel intelligently releases TGF-β1 siRNA/TAT directionally to suppress fibrosis while synergizing bidirectionally with berberine-loaded fibers: the outward siRNA blocks fibrotic signaling, while the inward berberine delivers antimicrobial/antioxidant/anti-inflammatory actions. This drug-free hydrogel platform achieved chronotherapeutic coordination of immediate anti-inflammatory and delayed anti-adhesion effects, offering a breakthrough strategy for tendon regeneration (Fig. 7e) [185]. Another study pioneered an injectable multifunctional hydrogel (CP@SiO₂) for Achilles tendon repair that was formed by in situ self-assembly of chitosan and puerarin integrated with mesoporous silica nanoparticles. The CP@SiO₂ hydrogel dually modulated the regenerative microenvironment by enhancing TDSC proliferation/differentiation and reducing inflammation through macrophage polarization. In vivo validation confirmed the improved histological structure and biomechanical function of the injured tendons. As a versatile bioactive platform, CP@SiO₂ demonstrates substantial translational potential for clinical tendon regeneration (Fig. 7f) [97].

Despite the advancements in multifunctional hydrogels, hydrogel systems exhibit critical limitations in tendon-repair applications. The primary limitation is their inadequate mechanical properties: most hydrogels possess tensile strengths of only 0.1–10 MPa, which are substantially lower than the tensile strengths of native tendons (80–100 MPa) and render the hydrogels prone to mechanical failure under physiological loads [186]. Additionally, hydrogels demonstrate poor fatigue resistance under cyclic stress, with rapid stress relaxation times (<100 s) in comparison with tendons (∼1500 s), leading to stress-shielding effects and compromised load transfer [187]. The inability of hydrogels to replicate the graded mineralized structure of the tendon-to-bone insertion site (enthesis) further impedes stable biological integration, resulting in interfacial detachment. Although anti-adhesion hydrogels may reduce scar formation, they simultaneously interfere with the necessary cell recruitment for tendon regeneration. Microhydrogels face challenges in achieving a uniform distribution within tendon tissues and maintaining structural integrity under shear forces. These intrinsic limitations in biomechanical performance and biointegration currently restrict hydrogel-based strategies to achieve clinically viable tendon repair.

4. Summary and future perspectives

This review examines the recent progress in tendon regeneration, focusing on selection of bioactive components and delivery systems based on tissue-engineered scaffolds. Cell-based therapies can effectively influence immune cells, promoting blood vessel formation, and reducing scar tissue. Nanodelivery platforms such as EVs, which are naturally occurring carriers that facilitate cell communication, similarly transport therapeutic molecules. Innovations, including enzyme-enhanced scaffolds and responsive hydrogels, have improved the functionality by allowing integration of drugs, nanoparticles, and signaling proteins. Although these advances show substantial promise, they face notable translational challenges beyond laboratory settings. Current scaffold designs still fall short of replicating natural tendon complexity, requiring better mimicry of the structural organization and mechanical behavior. Combining 3D printing techniques with natural tissue matrices offers pathways for optimizing cellular environments, whereas hydrogel systems bridge structural support with biological healing. Nevertheless, clinical implementation encounters persistent obstacles such as regulatory approval processes, manufacturing consistency across production batches, and cost-effectiveness relative to existing treatments.

Beyond the technical limitations, nanoparticle-based approaches also present critical safety considerations that require thorough resolution. The body's reaction to foreign materials raises concerns regarding immune responses, wherein certain synthetic components may trigger unintended reactions despite surface modifications. The elimination pathways remain inadequately understood, particularly in tendon tissues with a limited blood supply, and this challenge is compounded by manufacturing variations during large-scale production. Long-term safety profiles represent another significant gap since residual particles or their breakdown products can potentially cause chronic inflammation, tissue thickening, or cellular changes in the healing environment. These concerns require comprehensive immune response testing, detailed tracking of particle distribution in the body, and extended safety evaluations beyond short-term studies. Compounding these issues, manufacturing scalability faces reproducibility challenges that affect treatment reliability, and resource-intensive safety assessments intensify cost comparisons with conventional therapeutic approaches.

Overcoming these interconnected barriers requires coordinated efforts across research, regulation, and healthcare delivery. Future investigations should prioritize combined therapeutic approaches that integrate cellular treatments, growth factors, and advanced biomaterials, while developing robust safety evaluation frameworks. Regulatory progress requires harmonized guidelines to establish clinical-grade production standards and tendon-specific material testing protocols. Manufacturing improvements must emphasize consistent quality through systematic monitoring of essential characteristics. To demonstrate healthcare value and justify medical coverage, new treatments must demonstrate meaningful clinical advantages over the current standards. Computer modeling can yield valuable tools for connecting laboratory findings with clinical outcomes, potentially reducing development expenses. Successful patient translation ultimately depends on parallel advancements in three key areas: (1) tendon-specific safety evaluation accounting for physical stress during recovery, (2) reliable large-scale manufacturing ensuring uniform product quality, and (3) economically sustainable implementation models aligned with healthcare systems. Together, these advancements will enable personalized regenerative solutions that will substantially improve patient recovery outcomes and quality of life.

Credit author statement

Sidan Wang: Writing – review & editing, Writing – original draft, Project administration, Investigation, Conceptualization. Zixuan Ou: Writing – original draft, Methodology, Conceptualization. Feng Xiao: Writing – review & editing, Methodology. Xiaobo Feng: Writing – review & editing, Visualization, Software. Lei Tan: Writing – review & editing, Methodology, Investigation. Shuangshuang Cheng: Visualization, Validation, Data curation. Di Wu: Investigation, Formal analysis. Cao Yang: Visualization, Investigation. Haoqun Yao: Supervision, Resources.

Declaration of competing interest

The authors declare no competing interests.

Abbreviations

TSPCs

tendon stem/progenitor cells

MSCs

mesenchymal stem cells

EVs

extracellular vesicles

VEGF

vascular endothelial growth factor

TGF-β

transforming growth factor-β

IL-10

interleukin-10

SCX

scleraxis bHLH transcription factor

Tnmd

tenomodulin

CTGF

connective tissue growth factor

TSG-6

tumor necrosis factor-stimulated gene-6

YAP

yes-associated protein

TAZ

tafazzin

IGF-1

insulin-like growth factor 1

PDGF

platelet derived growth factor

PGE₂

phenyl glycidyl ether

MMP

matrix metalloproteinase

TSP-1

thrombospondin-1

BMP

bone morphogenetic protein

TDSC

tendon-derived stem cell

Postn

periostin

rPOSTN

recombinant periostin

BMSCs-exos

bone marrow mesenchymal stem cells-derived exosomes

GelMA

methacrylate

TSCs

tendon stem cells

hPDLSCs

human periodontal ligament stem cells

FAT

fibrous artificial tendon

hHF

human hair follicle

TNC

Tenascin-C

hUCMSCs

human umbilical cord mesenchymal stem cells

dECM

decellularized extracellular matrix

PA

protocatechuic aldehyde

TLR

Toll-like receptor

BG

bioactive glass

SA

sodium alginate

PDCD4

programmed cell death 4

AKT

protein kinase B

mTOR

mammalian target of rapamycin

PI3K

phosphoinositol 3-kinase

MAPK

mitogen-activated protein kinase

ERK1/2

extracellular signal-regulated kinase 1/2

h-TSC-Exos

healthy tendon stem cell-derived exosomes

PLT

platelets

PRP-Exos

plasma-derived exosomes

RCT

rotator cuff tear

HUVECs-Exos

human umbilical vein endothelial cell-derived exosomes

NF-κB

nuclear factor-κB

CR-sEVs

circadian rhythm-regulated sEVs

Mø

macrophages

cAMP

cyclic adenosine monophosphate

MN

microneedle

PDA NPs

polydopamine nanoparticles

VP-PDA NPs

verapamil-loaded polydopamine nanoparticles

LNPs

lipid nanoparticles

SMAD3

mothers against decapentaplegic homolog 3

LPNs

lipid-polymer hybrid nanoparticles

CeNPs

ceria nanozymes

VEGFA

vascular endothelial growth factor A

bFGF

basic fibroblast growth factor

γ-PGA

poly-gamma-glutamic acid

PCL

polycaprolactone

PEG

polyethylene glycol

ECM

extracellular matrix

PLGA

polylactic acid

PLLA

poly (L-lactic acid)

PCL

polycaprolactone

PLCL

poly(L-lactide-co-ε-caprolactone)

Gel

gelatin

PET

polyethylene terephthalate

HA

hyaluronic acid

PEO

poly(ethylene oxide)

MS

Mo-containing silicate

FDA

food and drug administration

MY

multi-yarn

FGF2

fibroblast growth factor 2

EDT

extensor digitorum tendon

DY

dual-layered core-spun yarn

MOF

metal–organic framework

SS

surgical suture

TC

transient chemotactic

HA

hyaluronic acid

Arg

arginine

Gnp

graphene nanoplatelets

DBTS

decellularized bovine tendon sheet

FCECM

fibrocartilage extracellular matrix

DTS

decellularized tendon slice

BMP-2

bone morphogenetic protein 2

NCM

non-collagenous matrix-enriched

CM

collagen matrix-enriched

GDF-7

growth and differentiation factor-7

DLs

degradable layers

NLs

nano-guided layers

TNC

tendon nano-construct

SATHG

suture anchor-tendon hybrid graft

BP

bone simulation

PDO

poly(p-dioxanone)

MEHP

multifunctional electrospun hydrogel patch

PVA

polyvinyl alcohol

TA

tannic acid

ROS

reactive oxygen species

TNF-α

tumor necrosis factor-α