Nanofiber based transformative approaches for tendon regenerative engineering: past, present and future

Abstract

Tendon injuries present a major clinical challenge due to the tissue’s limited regenerative capacity, poor vascularization, and tendency toward fibrotic healing that compromises mechanical function. Surgical and conservative treatments often fail to restore native tendon architecture, leading to high rates of retear, adhesion, and long-term functional impairment. In recent years, tissue engineering strategies have gained increasing attention, with nanofiber-based matrices emerging as promising platforms for functional tendon regeneration. Owing to their structural similarity to native extracellular matrix (ECM), nanofiber scaffolds enable precise control over fiber alignment, porosity, and mechanical properties, which are critical for guiding tenogenic cell behavior and matrix organization.

This review summarizes recent advances in nanofiber fabrication techniques, including electrospinning and hybrid nanomanufacturing approaches, and discusses strategies for tailoring scaffold properties through biophysiochemical cues, biological factor delivery, cell incorporation, and nanoparticle functionalization. Special emphasis is placed on multifunctional nanofiber systems that modulate inflammation, promote tenogenic differentiation, enhance tendon – bone interface healing, and minimize scar formation and postoperative adhesion. Finally, current challenges and future directions toward scalable manufacturing, reproducibility, and clinical translation are discussed. Collectively, nanofiber-based matrices represent a versatile and powerful approach for advancing tendon tissue engineering and achieving durable functional repair. Search: PubMed, Google Scholar, through March 2026.

1. Introduction

Musculoskeletal disorders remain a significant clinical and socioeconomic burden owing to an aging global population, leading to chronic pain and disability in the adult population. Among the components of the musculoskeletal system, tendons play a crucial role by connecting muscles to bones, transmitting contractile forces to generate movement, and providing mechanical stability and energy buffering during physical activity [1,2]. Structurally, tendons are hierarchically organized dense connective tissues with low cellularity and poor vascularization. Tendon is biochemically comprised of 70% water and 30% collagens. The collagenous content of the tendon is primarily composed of type I collagen (approximately 95%), along with smaller amounts of elastin, proteoglycans, and glycoproteins, forming an extracellular matrix (ECM) that provides both structural support and critical biochemical cues for tissue homeostasis and mechanotransduction [3,4]. The cellular component consists mainly of tenocytes and tendon progenitor or stem cells (90–95%), while chondrocytes, synovial cells, and vascular cells comprise the remainder [2].

An important aspect of the tendon injuries, especially in rotator cuff, is defected enthesis. The enthesis is a specialized, structurally complex interface that connects tendon to bone and is essential for maintaining shoulder joint integrity. Fibrocartilaginous entheses, found at the rotator cuff and Achilles tendon, display a non-uniform distribution of fibrocartilage, with thicker layers in deeper regions where mechanical stress is greatest. Enthesis is evolutionarily adapted to dissipate peak forces, enabling efficient stress transfer and preventing tendon tears while maintaining tissue homeostasis. Due to its structural heterogeneity and complexity, enthesis has a limited capacity for regeneration and typically heals with biomechanically inferior scar tissue, making effective repair a significant clinical challenge [5,6].

In this review, we present a roadmap for tendon tissue engineering using nanofibers, linking clinical challenges and current treatment limitations to engineering solutions. We outline key nanofiber fabrication methods and discuss tailoring strategies, including the incorporation of nanoparticles, cells, biological factors and biophysical and biochemical cues for enhanced regeneration. A rigorous scientific approach requires understanding the underlying mechanisms; therefore, we also describe how nanofibers orchestrate tendon regeneration and repair. As the healing process consists of inflammation, proliferation, and remodeling phases, we explain how nanofiber-based scaffolds can enhance each stage through regulation, promotion of regeneration, and prevention of scar formation. Finally, we emphasize emerging integrated approaches and discuss the key challenges in translating these strategies into clinical applications.

1.1. Tendon injury and its clinical limitations

Despite their essential mechanical and biological functions, tendons are highly susceptible to injury due to repetitive loading, trauma, and age-related degeneration. The rotator cuff, Achilles, and patellar are the most frequently injured tendons [7]. Trauma, overuse, aging, inflammation, and genetic predisposition and etc. may lead to these tendon injuries [8]. Tendon injuries are broadly categorized as acute, such as tears or ruptures from sudden external forces, or chronic, which arise from prolonged overuse, mechanical stress, or degenerative changes [9]. Tendon injuries are one of the most common musculoskeletal disorders, affecting millions worldwide and resulting in significant pain, disability, and economic burden [10]. More than 4.8 million people seek hospital care for shoulder pain each year, largely due to rotator cuff pathologies, making rotator cuff repair one of the most common orthopedic procedures, with over 300,000 surgeries performed annually in the United States [11]. Further, ~2 million sports-related Achilles tendon injuries occur worldwide each year, with more than 250,000 cases requiring surgical intervention [12]. These injuries frequently lead to pain, swelling, impaired motion, and significant functional loss, imposing an estimated annual healthcare cost worldwide.

Tendon healing is comprised of inflammatory, proliferative, and remodeling phases, but it rarely restores native architecture, resulting in a high risk of reinjury/retear [13]. Tendon healing is a slow and inefficient process due to the tissue’s intrinsic avascularity and limited cellularity. Although natural repair processes may occur, fibrotic scar tissue forms rather than the native tendon, this results in inferior mechanical strength and a high risk of retear and adhesion formation [4,13]. Different approaches have been established for treating tendon injuries which will be presented in the next section, however, there is still a need for a comprehensive treatment plan that can mitigate all the challenges mentioned above.

Depending on the severity of the injury as well as age, occupation and medical background of the patient, different clinical treatment options might be suggested by the physician. Non-surgical management of tendon injuries initially emphasizes rest and immobilization, followed by controlled rehabilitation exercises to prevent secondary complications. Adjunct physical therapies, such as ultrasound, low-level laser therapy, and extracorporeal shockwave therapy, may aid healing by reducing inflammation and stimulating collagen synthesis [4,14]. While NSAIDs (Nonsteroidal Anti-inflammatory Drugs) and corticosteroids are commonly used for pain relief, their effects on tendon regeneration are limited and may be associated with adverse outcomes, including tendon weakening and rupture [15].

Reparative and regenerative strategies can be an alternative or a combination therapy for better functional results, these include biological grafts (auto-, allo-, and xenografts), synthetic prostheses, and tissue engineering approaches. Autografts are hindered by donor-site morbidity, while allografts and xenografts have risks of immune rejection and limited availability, whereas synthetic grafts often suffer from poor long-term durability [16–18]. In contrast, tissue engineering integrates cells, scaffolds, and bioactive cues to promote functional tendon regeneration, offering a promising platform to overcome current limitations through advances in scaffold design, stem cell therapies, mechanical stimulation, and immune modulation [4,14].

2. Regenerative engineering approaches for tendon healing: the past and present

Due to these challenges, advanced strategies promoting both structural repair and functional regeneration of injured tendons are needed. With recent advances in tendon biology and healing mechanisms, biomaterials and biomanufacturing technologies, tissue engineering and regenerative engineering has emerged as a promising approach for tendon repair [18,19]. The development of biomimetic scaffolds has a significant potential in guiding cell behavior, enhancing extracellular matrix deposition, and facilitating tendon-like tissue regeneration [4,11,20,21]. Hence, tendon regenerative engineering has become a vibrant research frontier aimed at achieving effective and functional tendon reconstruction. A variety of scaffolds have been used to address tendon reconstruction as well as enthesis regeneration. Since enthesis has a gradient structure, scaffolds that can mimic this transition from bone to tendon structure have been favored by scientists [5]. Also, tendons possess a hierarchical structure composed of aligned collagen fibrils (20 nm) organized into larger fiber bundles (up to 3 mm). To replicate this architecture, nanofibers can be engineered to mimic the ultrastructure and mechanical properties of native tendon, facilitating host-cell mediated healing and gradual remodeling [11,22,23]. Consequently, nanofiber-based scaffolds have emerged as promising alternatives for achieving biomimetic, functional, and integrative tendon repair [20,22]. However achieving the optimized system needs a synergic effect of different approaches and modifications and no single approach can fulfill the vast requirements of tendon tissue engineering.

3. Nanofiber platforms in the present era of tendon tissue engineering

Among different nanostructures, nanofibers are one of the most interesting materials owing to their continuous nanoscale long fibers. They are most similar to native tendons while providing mechanical properties and analogous structure [21,24–27]. Since the first work by Laurencin and his colleagues [28], electrospinning remains the most widely used due to its ability to control fiber alignment, diameter, and composition [29–32]. Although there are other nanofiber fabrication methods such as wet spinning, microfluidics, and melt spinning that are less used [5,29].

Recent studies in the last five years demonstrate the regenerative potential of nanofiber scaffolds for tendon repair. Most of these recent studies have focused on combination of electrospinning with either biologic factors, decellularized tissue or other fabrication methods with the aim of better mimicking the tendon structure.

To better incorporate biological cues into nanofiber-based tendon scaffolds, decellularized amniotic membrane (dAM) has been combined with electrospun polycaprolactone (PCL) and gelatin (Gel) nanofibers to improve mechanical stability while slowing degradation (Figure 1(A)). This hybrid scaffold supported enhanced cell proliferation and favorable immunomodulatory effects, highlighting its promise for tendon repair using tendon-derived stem cells [33]. relying on decellularized tissue, a multilayered, nanofiber-reinforced three-dimensional scaffold was further developed to address the more complex demands of tendon – bone interface regeneration. This construct consisted of an acellular tendon core, a middle polyurethane/type I collagen yarn layer fabricated by conjugated electrospinning, and an outer electrospun PLLA (poly (L-lactic acid))/bioactive glass nanofiber membrane, thereby integrating tissue-derived structural support with region-specific nanofibrous cues for tendon and bone healing; the overall scaffold architecture is summarized in Figure 1(B) [34]. In vivo histological and biomechanical analyses demonstrated good biocompatibility together with improved tendon – bone integration and functional healing, underscoring the promise of multilayered nanofiber scaffolds for orthopedic and interface tissue engineering. However, despite their strong regenerative potential, approaches relying on amniotic membrane or tendon-derived tissues may face practical limitations related to limited supply, donor variability, and batch-to-batch inconsistency.

Figure 1.

Some of the recent studies on novel nanofiber-based scaffolds. (A) Gross appearance and SEM images of dAM (decellularized Amnion), PCL (polycaprolactone), Gel (Gelatin), PCL-dAM and Gel-dAM. Scale bar: 5 mm (dried form), 5 mm (after hydration), 10 μm (surface morphology) Adapted from [33] with permission. Copyright 2026, Elsevier. (B) Schematic illustration of the fabrication process of multi-layer nanofiber-reinforced three-dimensional scaffold for acellular tendon complex. With the SEM (Scanning Electron Microscopy) image and fluorescence micrograph of PLLA (Poly L-Lactic Acid)/BG (Bioactive Glass) nanofiber membrane (bone section). The SEM image and with fluorescence micrograph of PU (Poly Urethan)/Col 1 (Collagen 1) yarn (tendon part) Adapted from [34] with permission. Copyright 2024, Elsevier. (C) Schematic hierarchical structures of the human Achilles tendon and synthetic P/CY-ANF (Poly-Vinyl Alcohol/Cyano-p-aramid Nanofibers) hydrogel fibers. Photograph of hydrogel fibers lifting weights of 5 kg (scale bar: 2 cm) next to a hydrogel fabric produced by knitting. Adapted from [35] with permission. Copyright 2025, American Chemical Society. (D) Fabrication process of the hierarchical helical scaffold. Large-scale fluorescence image of cell culture on the helical scaffold. Longitudinal sectional images of H&E staining and transverse sectional images of Masson’s trichrome staining of implantation region Adapted from [3] with permission. Copyright 2022 Elsevier.

Extending nanofiber design beyond biochemical reinforcement, Wang et al. developed a bioinspired hierarchical helical nanofiber yarn scaffold by sequential electrospinning of PCL/PU (Poly Urethan) bilayers, followed by folding, twisting, and overtwisting to generate a highly stretchable construct that recapitulates the ability of native tendon to buffer local cellular strain during stretching. With high cell viability, progressive cell infiltration, collagen deposition, and tissue remodeling after implantation, this platform highlights the potential of mechanically adaptive nanofiber scaffolds to support dynamic tendon repair without prolonged immobilization (Figure 1(D) [3]. A related strategy focused on reproducing the hierarchical and anisotropic organization of tendon through textile-inspired scaffold construction. Cai et al. developed a high-strength nano-micro fibrous woven scaffold by integrating electrospun PLLA or silk fibroin (SF)/PLLA nanofiber yarns with PLLA microfiber yarns in a plain-weave architecture, generating a tendon-like anisotropic structure with improved mechanical performance. The SF/PLLA-containing scaffold further enhanced tenocyte proliferation and elongation and showed higher expression of tendon markers, including TNMD (Tenomodulin) and COL1 (Collagen 1), supporting its potential as a biomimetic platform for tendon repair and regeneration [36].

From a different but complementary materials-engineering perspective, recent work has focused on creating tendon-mimetic fibrous constructs without relying on biologically sourced tissues. A rapid and scalable strategy was reported in which cyano-p-aramid nanofibers were integrated with poly (vinyl alcohol) (PVA) through continuous dry-jet wet spinning to generate ultrastrong, water-rich hydrogel fibers [35]. In this system, the anisotropic nanofiber network enabled gelation within approximately 1 min, allowing continuous fabrication of long hydrogel fibers without additional cross-linking steps, while also achieving high water content and tensile strength up to 17.9 MPa; the overall concept and representative mechanical performance are highlighted in Figure 1(c). These hydrogel fibers could be further assembled into textile-like constructs and also exhibited strain-sensing capability, illustrating how nanofiber-reinforced hydrogel systems may expand the design space for artificial fibrous tissues and tendon-related applications.

Beyond scaffold composition alone, other studies have combined bioactive cargo delivery or hierarchical yarn assembly with electrospinning to more closely recapitulate the structural and biochemical environment of native tendon. Chen et al. developed core – sheath electrospun nanofibers with a PCL sheath for mechanical support and a hyaluronic acid (HA)/platelet-rich plasma (PRP) core for sustained growth factor delivery. The aligned fiber architecture promoted unidirectional tenocyte growth, and the combined effects of PRP incorporation and fiber alignment significantly enhanced cell proliferation together with the expression of tendon-related genes and proteins [37]. Similarly, Yang et al. fabricated three-dimensional aligned PCL nanofiber yarns by dry – wet electrospinning to mimic the hierarchical organization of collagen fibers and fascicles in native tendon [38]. These yarn-based scaffolds supported cell alignment and elongation in vitro, with fibers of approximately 50 μm diameter most effectively promoting tenogenic differentiation, and bundled nanofiber yarns further improved tendon regeneration in vivo by enhancing organized neocollagen deposition and alignment. Together, these studies illustrate how advances in nanofiber scaffold design are moving from simple structural mimicry toward integrated platforms that combine anisotropic architecture, mechanical competence, biological functionality, and translational manufacturability. To better understand the field, we have categorized the methods of fabrication, modification, and mechanism of effect in the following sections.

3.1. Nanofiber fabrication for tendon regeneration

3.1.1. Electrospinning

In the electrospinning process, the polymer-based solution ejects from a feed pump into an electric field applied between the feed pump and the collector to fabricate and stretch the nanofiber. Different varieties of electrospinning with differing parameters have been developed over the years fulfilling the need for a more controllable and tailorable fabrication method for tendon tissue engineering (Figure 2) [28,39,40]. These methods include: blend electrospinning [41–46], emulsion electrospinning [47,48], co-axial electrospinning [49–55], Triaxial Electrospinning [56], side-by-side electrospinning [57–61]. We can also combine it with other techniques: using electrospun scaffolds as the building block for different textile fabrication methods such as yarns [36,62–67], strips [68], composite layers [69–72]. We can also mix electrospinning with 3D printing by using short fibers in the 3D printing ink [73–76], or modifying the surface of the 3D printed scaffold [77] or alternating between 3D printing and electrospinning to have a layered construct [78–86]. Other methods have also been used in combination with electrospinning such as lyophilization [87–99], gas foaming [100–108].

Figure 2.

Nanofiber fabrication strategies for tendon tissue engineering. Schematic overview of conventional and hybrid nanofiber manufacturing approaches used to engineer tendon-mimetic scaffolds. Traditional electrospinning techniques include blend electrospinning, coaxial/triaxial electrospinning for core – shell architectures, side-by-side electrospinning for anisotropic fiber composition, and wet electrospinning for three-dimensional fiber deposition. Advanced assembly strategies such as nanofiber yarn formation and textile-based architecture enable hierarchical organization and improved mechanical performance. Hybrid fabrication approaches combining electrospinning with three-dimensional printing or lyophilization further expands structural complexity and functional tunability. Together, these methods highlight the versatility of nanofiber fabrication techniques for designing biomimetic scaffolds tailored to tendon regeneration. Created in ChatGPT based on GPT-5.3 and edited in PowerPoint.

Following the growth in electrospinning, there are now industry sized machines with different sizes and up to 5000 nozzles for high throughput fabrication. Automation, monitoring, and use of robotic arms make the process reproducible and hence, appropriate for commercialization of electrospun products (Linarinanotech [109], Nanoscience [110], Matregenix [111], Vivolta [112]).

3.1.2. Nano 3D printing

Recent advances in 3D printing have made it possible to achieve nano-scale precision. In the 2PP nanolithography technique, a femtosecond or picosecond laser is used. The polymerization is started by two-photon absorption (TPA) triggered by a focused laser pulse, which provides a nonlinear energy distribution centered at the laser’s focal point applied to the photosensitive materials [113], forming the polymerized 3D micro/nanostructure [114,115]. There are currently lithography-based 3D printers using ultra-short laser pulses with the ability to print down to 150 nm commercially available (Pi [116]).

3.2. Tailoring nanofiber matrices for enhanced tendon regeneration

Electrospun nanofiber scaffolds have emerged as promising platforms for tendon and ligament repair due to their structural similarity to native ECM and capacity for biochemical and biophysical modification [117]. Recent strategies focus on integrating biophysiochemical modifications, biological factors, cells, and nanoparticles into these scaffolds to enhance their regenerative potential (Figure 3) [2,4].

Figure 3.

Strategies for tailoring nanofiber matrices to enhance tendon regeneration. Electrospun nanofiber scaffolds serve as versatile platforms that can be engineered through biophysical, biochemical, biological, cellular, and nanomaterial-based modifications. By integrating aligned architecture, mechanical tuning, growth factor delivery, stem cell incorporation, and functional nanoparticles, nanofiber matrices can direct tenogenic differentiation, regulate inflammation, promote organized extracellular matrix deposition, and improve functional tendon healing. Created in ChatGPT based on GPT-5.3 and edited in Powerpoint.

3.2.1. Biophysiochemical factors

There are various biophysiochemical parameters affecting the performance of a scaffold. We can harness the biochemical cues by using composites as blends [41,42,44,46], surface adsorption [118,119], surface encapsulation [120–123], or covalent conjugation [124–127] or biophysical cues by altering the pore size [31,38,128], fiber orientation [37,119,129–134], mechanical properties [117,135,136], hydrophilicity [137–140], or electroconductivity [119,134,141,142]. It is reported that mechanical stimulation is one of the most important physical cues affecting cell proliferation, gene expression, ECM formation, collagen fiber alignment, and tissue remodeling in tendons and ligaments [143]. Appropriate mechanical stimuli can enhance the metabolism, structural and mechanical properties of tendons by increasing the collagen type I production of fibroblasts and the cross-sectional area and tensile strength of the tendons [4,144]. Cyclic uniaxial mechanical stretch, similar to the mechanical environment in tendon tissues in vivo, can increase ECM production and organize collagen fibril alignment [145]. Cyclic mechanical longitudinal strain can stimulate proliferation and apoptosis, in contrast to extended stress duration. A constant stress duration can inhibit cell proliferation and apoptosis [146].

3.2.2. Biological factors

Different biological factors such as growth factors and PRP have been used to improve scaffold function [37,147]. Platelet-rich plasma (PRP) is a plasma fraction enriched in platelets, produced by centrifugation of whole blood to remove red blood cells. It contains multiple bioactive growth factors, which are known to support and enhance tendon repair processes [4]. Growth factors are a group of cytokines that are involved in the process of cell growth, proliferation and differentiation [4,148–150]. One of the growth factors that has been shown to promote tendon regeneration is connective tissue growth factor (CTGF) [151,152], a downstream mediator of transforming growth factor-β (TGF-β) involved in the process of tendon development and repair, however this crosstalk mechanism is still unclear [153]. TGF-β has an important effect on the healing process by producing and organizing collagen fibers [4]. Moreover, it has been shown that Insulin growth factor 1 (IGF-I) promotes tendon healing by stimulating fibroblast proliferation and migration and increasing collagen and proteoglycan production [127,154]. Basic fibroblast growth factor (bFGF) has shown strong potential to enhance cell differentiation, migration, and tendon/ligament healing [155–157].

3.2.3. Cell-loaded scaffolds

Variety of cells has been used to enhance the scaffold function, such as tendon stem/progenitor cells [38,158,159]. Given the limited number and low regenerative activity of native tendon stem cells, scaffolds seeded with mesenchymal stem cells (MSCs) offer a potent alternative [160–162]. MSCs provide self-renewal capacity, multilineage differentiation, and paracrine signaling that support tendon healing and matrix remodeling [4,163]. Pluripotent stem cells, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), possess extensive proliferative and multilineage differentiation potential, making them attractive candidates for tendon regeneration [164,165]. The clinical application of ESCs is limited by ethical concerns and the risk of teratoma or ectopic tissue formation. iPSCs circumvent ethical issues associated with ESCs, yet they share similar safety challenges, particularly the risk of teratoma formation, and unwanted genetic modification depending on the inducing pluripotency method. Strategies aimed at eliminating undifferentiated iPSCs prior to implantation have been proposed to enhance biosafety, positioning both ESCs and iPSCs as promising but currently constrained cell sources for tendon tissue engineering [4,166].

3.2.4. Nanoparticle-enhanced scaffolds

Nanoparticle incorporation can further improve scaffold functionality. Silica nanoparticles enhance wettability, stiffness, and degradation kinetics, fostering ECM formation, while hydroxyapatite (HAp) nanoparticles promote porous structure formation and osteogenic compatibility [167]. Silver nanoparticles (AgNPs) impart antibacterial properties, minimizing post-surgical inflammation and adhesion [168]. Similarly, zinc oxide (ZnO) nanoparticles enhance antibacterial activity and stimulate cellular proliferation and differentiation, supporting osteogenic, chondrogenic, and tenogenic outcomes [169]. Additionally, controlled drug-release systems – such as mitomycin C-loaded electrospun fibers – can modulate fibroblast activity and reduce scar formation [170]. Using Graphene Nanoparticles (GNP)is also another improvement to achieve electrical conductivity for better repair and function of the tendon and muscle in rotator cuff injuries [119].

Together, these tailored nanofiber matrices – engineered through biophysiochemical, biological, cellular, and nanomaterial integration – represent a synergistic approach to replicate the complexity of native tendon tissue and promote functional regeneration. However, implementing each approach solely won’t address the tendon degeneration fully, and a multifunctional nanofiber encompassing multiple of these modifications can eventually lead to tissue regeneration.

3.3. Multifunctional nanofibers orchestrating repair

3.3.1. Regulation of inflammation

Inflammation is an early hallmark of tendon degeneration and can hinder healing through crosstalk between immune cells and fibroblasts [171]. Electrospun nanofiber scaffolds can modulate this response through their structural and biochemical features. Highly aligned PCL scaffolds enhance tenogenic gene expression (e.g., collagen I, collagen III, and tendon ECM regulators) while downregulating inflammatory and degradative mediators, compared with randomly oriented fibers [172]. Mechanical loading on aligned scaffolds further promotes macrophage polarization toward an anti-inflammatory M2 phenotype, facilitating tissue repair [173]. Moreover, hybrid scaffolds – such as SF/PLLA composites – demonstrate reduced CD68 expression and attenuated inflammation, supporting the concept of “immune-regulatory” biomaterials [174]. To suppress post-surgical adhesion and inflammation, core – shell electrospun fibers incorporating Ag nanoparticles (AgNPs) and ibuprofen have been developed. These systems release antibacterial and anti-inflammatory agents locally, decreasing macrophage infiltration and fibroblast adhesion while reducing infection and pain [168].

3.3.2. Promotion of proliferation and regeneration

Three-dimensional (3D) electrospun architectures provide enhanced porosity and spatial organization for cell infiltration and tenogenic differentiation [2]. These scaffolds promote the expression of tendon markers such as Col I [175] and TNMD [176]. Advanced designs, like metal – organic framework (MOF)-based electrospun membranes, release metal ions that stimulate osteogenesis and angiogenesis, enabling simultaneous tendon – bone interface regeneration [46]. Similarly, 3D porous PCL scaffolds combined with CTGF promote mesenchymal stem cell differentiation into ligament/tendon lineages, accelerating functional matrix deposition [177].

3.3.3. Prevention of scar formation and adhesion

Scar tissue formation compromises tendon elasticity and increases retear risk [2,178]. Scar formation is believed to arise from macrophage-derived TGF-β1 during the inflammatory phase, which promotes fibroblast recruitment [179]. Elevated TGF-β at injured entheses enhances type I and III collagen deposition while suppressing chondrogenic differentiation [6,180], Functional electrospun scaffolds, such as PLGA-based hedging immune strategy using a microfibrous membrane (Him-MFM), modulate macrophage polarization and suppress pro-fibrotic myofibroblast activity (α-SMA expression), thereby minimizing scar formation. Enhanced secretion of interleukin-33 (IL-33) activates regenerative Th2 signaling, fostering a pro-healing environment [181]. Additionally, scaffolds with aligned fiber topography guide fibroblast orientation without triggering fibrotic activation, promoting smoother repair surfaces and reducing postoperative adhesion [182].

Overall, multifunctional electrospun nanofiber systems, through their immunomodulatory, proliferative, and anti-fibrotic capabilities, represent an integrated platform to orchestrate inflammation resolution, cellular proliferation, and scar-free tendon regeneration.

4. Challenges and future perspectives

Nanofiber-based matrices hold significant promises for advancing tendon tissue engineering due to their ability to closely mimic the native ECM architecture. Future developments are expected to focus on improving the biological functionality, mechanical performance, and clinical translatability of these scaffolds. One key direction is the design of hierarchically organized and anisotropic nanofiber constructs that more accurately recapitulate the multiscale structure of tendon, from collagen fibrils to fascicles. However, the challenges of using nanofibers should not be dismissed. One of the main limitations is dense fiber packing that impedes cell migration and tissue integration. Another important factor is that the successful regeneration is dependent on in situ homogenous integration of the scaffold on both ends tendon-to-tendon and bone-to-bone [5], also for a more translatable system, technical issues during surgery, such as the ability of the scaffold to be sutured and especially the suture pull out should be considered [5,6]. Other non-nanofiber scaffolds have also been used in tendon tissue engineering that can address some challenges [4,183,184]. For example, textile technology can ensure mechanical stability and saturability but lacks the porosity while gas foaming provides porosity but lacks the biomimetic properties [150]. Freeze-drying technique has been long used for its tailored porosity and the ability to fabricate aligned scaffold; however, the poor mechanical properties has hindered its use in tendon tissue engineering [185,186]. Another novel method is electrohydrodynamic jet printing (E-jetting) which has arisen from electrospinning and 3D printing. It fabricated controlled 3D structure with microporosities providing surface attachment as well as mechanical stability [187]. A promising future direction is the integration of these approaches, combining the favorable porosity of microfibers, suturability and mechanical stability with the biomimetic cues provided by nanofibers. Continued advances in electrospinning and additive manufacturing are expected to enable precise control over fiber alignment, diameter, and spatial patterning, facilitating more physiologically relevant load transfer and improved cell migration.

Another important future avenue is the incorporation of bioactive and dynamic features into nanofiber matrices. Smart scaffolds capable of targeted delivery of growth factors, cytokines, or gene-regulatory cues, either through surface functionalization or controlled release systems, may enhance tenogenic differentiation while minimizing fibrosis and ectopic adipogenesis. In parallel, integrating mechanosensitive and responsive materials that adapt to mechanical loading could promote tendon-specific cell behavior and improve matrix remodeling under physiological strain. Combining nanofibers with stem cells, tendon-derived progenitor cells, or immunomodulatory strategies targeting macrophage polarization and FAP (Fibroadipogenic Progenitor) behavior may further improve regenerative outcomes. It is important to consider challenges associated with cell/stem cell applications such as disease transmission, unwanted differentiation, availability, shelf-life, and high cost.

Finally, translation to the clinic will require scalable manufacturing, reproducibility, and long-term safety validation (Figure 4). The only nanofiber-based matrix commercially available now is SportMesh. This biodegradable matrix is made of polycaprolactone-based polyurethane urea, which degrades by hydrolysis. It is crafted from Artelon fibers using a wet spinning method [188] and holds approval from both the European conformity requirements or CE (Conformite Europeenne) and US FDA (Food and Drug Administration) for strengthening soft tissues, such as the rotator cuff, Achilles, patellar, biceps, and quadriceps. This soft tissue reinforcement effectively strengthens weakened or repaired tissue [189–191].

Figure 4.

Clinical translation and outlook of nanofiber-based tendon scaffolds. Schematic illustrating the pathway from laboratory-scale design of nanofiber matrices to clinical application in tendon repair. Advances in scalable and automated nanofiber manufacturing enable reproducible, high-throughput production of aligned and multifunctional scaffolds. These platforms can be customized through material composition, bioactive functionalization, and architectural control to address injury severity and anatomical sites. Integration with minimally invasive delivery strategies and rigorous preclinical and regulatory evaluation supports the development of off-the-shelf nanofiber-based matrices, ultimately facilitating safe clinical translation and improved functional outcomes in tendon regeneration. Created in Gemini March 2026.

Future nanofiber matrices are likely to evolve into off-the-shelf, customizable platforms that can be tailored to injury severity, anatomical site, and patient-specific needs. Integration with minimally invasive delivery methods and in vivo monitoring technologies will be critical for clinical adoption. Collectively, these advances position nanofiber matrices as a central component of next-generation tendon repair strategies, bridging the gap between biological regeneration and functional mechanical restoration.

5. Conclusion

Tendon injuries remain a major clinical challenge due to their limited intrinsic healing capacity. Conventional treatments often fail to restore native structure and mechanical performance, leading to high rates of retear and long-term functional deficits. Nanofiber-based matrices have emerged as a powerful strategy in tendon tissue engineering because they closely mimic the native extracellular matrix and allow precise control over scaffold architecture, mechanical properties, and biological cues. Advances in electrospinning and hybrid fabrication techniques have enabled the development of hierarchical, aligned, and multifunctional scaffolds that support tenogenic differentiation, organized matrix deposition, and tendon – bone interface regeneration.

Beyond structural support, modern nanofiber scaffolds are increasingly designed to actively modulate the micro-environment healing. By incorporating biophysiochemical cues, growth factors, cells, and functional nanoparticles, these systems can regulate inflammation, promote regeneration, and reduce scar formation and postoperative adhesion. Despite remaining challenges related to standardization, scalability, and long-term safety, continued interdisciplinary efforts are expected to accelerate clinical translation. Overall, nanofiber-based matrices represent a central and rapidly advancing platform with strong potential to shift tendon repair strategies from symptomatic treatment toward durable, functional regeneration.

Article highlights.

• Tendon injuries remain a major clinical challenge due to limited intrinsic healing capacity, poor vascularization, and a tendency toward fibrotic repair that compromises mechanical function.

• Conventional treatments, including surgical repair and grafting, often fail to restore native tendon structure and are associated with high rates of retear and long-term functional deficits.

• Nanofiber-based scaffolds have emerged as promising platforms for tendon tissue engineering due to their structural similarity to the native extracellular matrix and their tunable mechanical and biological properties.

• This review provides a comprehensive roadmap linking clinical challenges to engineering solutions, guiding the design and application of nanofiber-based scaffolds for tendon regeneration.

• Multiple fabrication strategies are discussed, including electrospinning, 3D-printing, and emerging hybrid techniques, enabling precise control over fiber alignment, architecture, and functionality.

• Scaffold performance can be enhanced through biophysiochemical modifications, incorporation of growth factors, cells, and nanoparticles to regulate cell behavior and promote regeneration.

• Nanofiber scaffolds play an active role in modulating all phases of tendon healing, inflammation, proliferation, and remodeling, by promoting regenerative signaling and reducing fibrosis and adhesion formation.

• Advanced multifunctional and hierarchical scaffold designs better mimic native tendon structure and support improved mechanical integrity and biological integration.

• Key challenges remain in scalability, reproducibility, and clinical translation, highlighting the need for standardized manufacturing and long-term safety validation.

• Future directions include integrated and smart nanofiber systems, as well as translational strategies to enable clinically viable, off-the-shelf tendon repair solutions.