Tendon Adhesion and Novel Solutions

Abstract

Tendon adhesion refers to the development of fibrotic tissue accumulation between injured tendon and the surrounding tissue, which usually happens as complications after surgical intervention for tendinopathies or traumatic rupture of tendon, resulting in undesired outcomes in the aspects of mechanical properties and functionality. Researches and understanding of tendon adhesion indicate that the process is related to the dominance of extrinsic tendon healing, with important factors such as inflammatory response, cell transference, certain growth factors, mistakenly stimulated signaling pathways and infection, and overdriving tendon remodeling. Taken the advantage of advanced material science and biochemistry, novel biomimetic materials have gradually emerged and been revealed to obtain satisfying antiadhesion capabilities. Taken the advantage of advanced material science and biochemistry, novel strategies, including hydrogels, nanoparticles, nanofibrous membranes, and substitutions for tendon and peritendinous apparatus, have gradually emerged and been revealed to obtain satisfying anti-adhesion capability solely or as drug delivery platforms. Although most of these results are currently limited in vitro or in animal models, future modification of these biosynthetic materials will help gain better mechanical properties and biocompatibility for clinical application. The establishment of next-generation delivery platforms against tendon adhesion requires the crosstalk among multiple fields.

1. Introduction

Tendons are dense connective tissue extending from muscles, which travel across joints to transmit force and produce motion. Although tendons possess remarkable tensile strength that can tolerate large force generated from muscle contraction, they are susceptible to damages caused by chronic overuse tendinopathies and traumatic rupture [1, 2]. It is noted that lacerated tendons cannot undergo spontaneous healing and surgical procedures are often required [3, 4, 5]. Conventional reconstruction techniques, including suturing, grafting, and synthetic prothesis replacement, however, are unfortunately associated with postoperative adhesion formation between surrounding tissue and the injured site, which results in undesired outcomes in the aspects of mechanical properties and range of motions.

With a better understanding of peritendinous adhesion, it is widely accepted that the process is related to the dominance of extrinsic tendon healing. To illustrate, the early inflammatory response and external fibroblast invasion are mainly responsible for the promoted tendon adhesion [6, 7, 8, 9]. Intrinsic factors of tendons, including low cellularity and metabolic activity, along with limited blood supply, also lead to a slow rate of tendon healing and remodeling, which increases tendency of re-rupture and hampering outcomes [10, 11].

Diverse strategies have been applied to overcome this clinical challenge. When anti-inflammatory drugs, antiadhesion growth factors, and certain genes that inhibit peritendinous adhesion have shown satisfactory outcomes in experimental studies, solely using these degradable molecules still face many limitations including swift inactivity, uncontrolled release, and toxicity before clinical translation. Besides, although physical barriers such as silk, silica gel and gold foil promote tendon gliding when wrapping around the injured site, with little biodegradability, these materials may inhibit intrinsic healing and cause body rejection, eventually leading to tendon necrosis and reoperation [12, 13]. Hence, current researchers have shifted their attention towards combinatory approaches, combatting tendon adhesion through loading different pharmaceutics and biologics into three-dimensional scaffolds, which were fabricated via various techniques including cryo-drying, solvent casting, gas foaming, braiding, and tissue engineering [14]. These scaffolds enable critical functions such as cell adhesion, proliferation, differentiation, and response to extracellular signals, while important issues still need to be discussed and improved. The scaffold should generally allow sufficient vascularization and interchange of nutrients and wastes, which is essential for tendon healing, while abnormal immune reactions should not be risen by the artificial scaffold [15, 16]. Additionally, adequate mechanical strength of the scaffold is also of vital importance to support tendon repair, mechanical load and gliding [17]. Besides, cargoes of the scaffolds should have promising effects on preventing peritendinous adhesion through alleviating inflammatory response, restricting unusual fibrogenesis, accelerating intrinsic healing, and promoting lubrication [18, 19]. In recent years, biosynthetic materials, including hydrogels, nanoparticles, nanofibrous membranes have gained wide attention for tendon adhesion prevention and have shown marvelous effects ex and in vivo [14, 20, 21]. At the same time, the advancement of biological materials and their derivations such as amnion, pericardium, and tendon sheath also shed light on strategies of tendon reconstruction and adhesion prevention [22, 23, 24, 25, 26, 27]. However, low accessibility of the resources, low productivity of the advanced biochemical products, and unknown biocompatibility to human body curbed their application to clinical usage [14, 20].

This chapter provides a comprehensive discussion of the current understanding of the mechanisms through which tendon adhesion is supposed to form, and identifies the pearls and pitfalls of the advanced biomaterials in preventing tendon adhesion.

2. Tendon structure and mechanisms of peritendinous adhesion

2.1 Tendon structure and composition

Tendon is composed of water (55–70% of whole tendon) and collagen (60–85% of dry weight) [28]. Type I collagen is the primary collagen in tendon, which accounts for 90% and the rest are type III, V and XI [29, 30]. Tendon also contains glycoproteins, cells and so on [31, 32].

Tendon is arranged orderly in a hierarchical manner which includes six levels: collagen molecule, pentafibril, collagen fibril, collagen fiber, fascicle and whole tendon. The basic unit of tendon is collagen molecule, five of which are bound together to form pentafibrils (also called microfibrils). Pentafibrils pack together to form collagen fibrils [33, 34].

In tendon, collagen fibrils are the unit of collagen fibers that aggregate to form fascicle with diameters ranging from 50 to 300 μm. A connective tissue, interfascicular matrix (IFM), is bound around the fascicles which is also the elemental structure of tendon. Moreover, the tendon is covered by the epitenon which is connected with IFM.

2.2 Tendon regeneration and repair

Tendon healing is a long period including three phases: inflammatory (days 1 to 7), fibroblastic (days 3 to 14), and remodeling (beyond day 10). Once tendon is injured, both external and internal cells are recruited and proliferated surrounding the injury site such as macrophage outside and tenocytes inside. After 3 days, the collagen is deposited to form extracellular matrix at the injury site, especially collagen type III. Then collagen type III is turned to be type I during the remodeling phase to heal the wounded tendon. However, the biomechanical strength of the healed tendon cannot reach as good as the one of the uninjured (Figure 1) [12, 35].

Figure 1.

(A) Peritendinous adhesion formation due to the unbalance between the intrinsic and extrinsic tendon healing, where antiadhesion materials are placed and function locally. (B) the key cellular and matrix changes and duration of three tendon injury repair phases (inflammation, reparation, and remodeling).

2.3 Factors affecting tendon adhesion

2.3.1 Inflammation

An acute inflammatory response to tendon rupture site is initiated lasting for 3 to 7 days [7, 8, 36]. In the initiation stage after tendon injury, the gene expression of pro-inflammatory cytokines significantly ascends attributed to recruitment of neutrophils, macrophages, and monocytes [37, 38, 39]. The inflammatory storm response to defect site after tendon injury is extensively considered as contribution to tendon adhesion formation and confusing matrix degradation, both of which are attributed to substantial up-regulation of inflammatory factors simulated by activated fibroblasts and matrix degradation [40, 41]. Besides, inflammation-mediated increased exudation and aggravation of fibrin leakage also lead to promotion of tendon adhesion formation. Therefore, spatially and temporally further understanding and adjustment to inflammatory response to tendon adhesion during the whole process of tendon healing will be far more crucial in inhibition of tendon adhesion formation.

2.3.2 Cell transference

Tendon healing includes the effect of both internal and external cells [42]. During the phase of inflammation, external cells play an important role in the adult tendon [43]. Neutrophils are recruited into the injury site in the first 24 h. Few minutes later, monocytes and macrophages reach, and macrophages become the dominant cell population instead of neutrophils after 24 h. Macrophages can be categorized into two main types: classically activated (M1) or alternatively activated (M2). Generally, M1 refers to the function of proinflammation, while M2 is considered an element of antiinflammatory response [44]. There are also other cell populations contacted with the phase of initial tendon injury such as T cells and mast cells [45, 46].

When it comes to the proliferative phase, the obvious character is the deposit of collagen type III in the injury site released by cells, especially fibroblasts. To begin with, it is the epitenon cells that proliferate. Both canine and murine models can be seen that the layer of epitenon become thicker in the early phase of proliferation [6, 47]. Epitenon cells can release more fibronectin than tendon itself, especially in the scar of injury site [9]. Nearly 2 days after injury, fibroblasts were recruited and proliferate rapidly, while the origin of fibroblasts remains unclear. Recently, researchers have identified a few different populations of resident tendon stem/progenitor cells involved in tendon healing, including cells from tendon fascicles, epitenon, and perivascular cells [48, 49, 50, 51, 52, 53].

After 10 days, there are fewer cells in the scar which is called the remodeling phase. Generally, the scar is finally replaced by organ-specific cell populations such as bones. However, scar in the tendon is partly replaced. The decrease of scleraxis basic helix–loop–helix transcription factor positive tendon cells may attribute to this phenomenon [54]. Moreover, the external cells such as inflammatory cells and myofibroblasts also play an essential role, but the explicit mechanism remains to discover [55, 56].

2.3.3 Growth factors

Generally, it is considered that GFs mainly work on proliferation phase overlapping the inflammation phase [7]. GFs, including transforming growth factor-beta (TGF-β), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), bone morphogenetic proteins-12, -13, and -14 (BMPs) also known as growth and differentiation factors-5, -6, and -7 (GDFs) respectively and insulin-like growth factor-1 (IGF-1) has been extensively authenticated their existence during different phases of tendon healing and regeneration process, and their significant roles have been widely studied [21, 57, 58, 59, 60]. TGF-β1 is an isoform of TGF-β with multifunction, which is widely demonstrated as main cytokine for tendon adhesion formation [61, 62]. VEGF, bFGF, and PDGF have been demonstrated to promote tendon healing by intensifying mesenchymal stem cells (MSCs) proliferation and differentiation to tenogenic lineages, increasing vascularization and ascending biomechanical strength after tendon regeneration [63, 64, 65, 66]. BMPs have been shown great induction force to tenogenic differentiation of MSCs as well as necessity to the regeneration of tenocytes, especially BMP-14 has been utilized to initiate tenogenic lineage of adipose-derived stem cells (ASCs), and it is widely demonstrated its high efficiency of pro-differentiation when associated with ASCs [67, 68, 69, 70, 71, 72]. However, BMP-14 has also been reported its an additional benefit of tendon adhesion resistance during tendon healing [58, 73]. Furthermore, whether the final production of BMPs activation is tenogenic or osteogenic lineage relies not only on the isoform of BMPs but also the type of biomechanical stimulation [74, 75]. IGF-1 has been proved to stimulate regeneration and tenogenic lineage differentiation of ASCs, however, the recent question regarding the practical usage of IGF-1 in tendon healing is whether IGF-1 acts independently or cooperates under the guideline of growth factors for single use of IGF-1 presented abominable outcomes in tendinopathic human patellar tendon [76, 77, 78, 79]. Therefore, in-depth understanding of the multifarious roles of GFs not only by themselves but also in synergy with others will help us better understand tendon adhesion formation and anchor efficient therapeutic targets.

2.3.4 Signaling pathways

Inflammation, cell recruitment, and growth factors provide new insights of mechanism of tendon adhesion formation, and these factors may produce marked effects under the specific guidelines of signaling transduction process concatenating above three. After tendon injury, the tendon biomechanical changes including but not limited to loss of collagen fiber tension, primary cilium deformation and nuclear deformation initiate the pathology reaction by accumulation of specific molecular messengers such as ions or cytokines [80]. Inflammation is the primary pathology reaction raised up by a certain signaling pathway. The nuclear factor-kappa B (NF-κB) signaling pathway is involved at the initial stage of inflammation during the tendon healing. It is located in the cytoplasm and enters the nucleus after activation playing a role of transcription factor. In the early stage of tendon injury, accumulated cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β and -6 (ILs) act on the surface of tendon cells by Toll-like receptor, which activates NF-κB and then up regulates the expression of the above inflammatory factors to form positive feedback, amplifying inflammatory effect [81, 82]. Abraham et al. have found that inhibition of NF-κB signaling pathway by blocking I-kappaB kinase beta could mitigate tendinopathy development [83].

The TGF-β signaling pathway is widely studied in the pathological process of tendon adhesion formation. Smads proteins 2 and 3 (SMAD2/3) are molecules acting as a transcription factor of TGF-β as well as a signal transducer in the TGF-β pathway [84, 85]. The activated TGF-β acts on the fibroblasts and then phosphorylates the Smad2/3 protein in the cytoplasm to regulate the expression of target genes promoting fibroblasts proliferation and differentiation into myofibroblasts, so as to promote collagen secretion [86, 87, 88, 89]. Down-regulate expression of TGF-β may significantly inhibit tendon adhesion formation. Wu el al. designed a three-dimensional tendon scaffold loading with TGF-β small interfering RNA (siRNA) plasmid and proved its satisfactory efficiency on prevention of tendon adhesion formation as well as promotion of tendon function repair [90]. Interestingly, after activated TGF-β binding to its receptor, extracellular signal-regulated kinase 1 and 2 (ERK1/2) which belongs to mitogen-activated protein kinases (MAPKs) pathways are also phosphorylated simultaneously to act on the binding sites of SMAD2/3, indirectly enhancing TGF-β/SMAD2/3 signaling pathway to promote exogenous fibroblast proliferation and collagen synthesis [86, 91, 92]. It indicated that the TGF-β signaling pathway could work in conjunction with other pathways like the MAPK pathway or BMP pathway [93].

Matrix metalloproteinase (MMP) is a protease family with metal ions as cofactors. TGF-β can induce the expression of plasminogen activator inhibitor-1 (PAL-1) in tenocytes to accelerate the degradation of plasmin and its mediated MMP-2, leading to excessive deposition of extracellular matrix (ECM) and type I collagen [94, 95, 96]. Lu et al. [97] confirmed that MMP comes from bone marrow cells that migrate to the injury site significantly enhance regeneration of tendon as well as tendon adhesion formation. Cai et al. [98] constructed a macrophage reactive siMMP hydrogel for high efficient synergistic prevention of tendon adhesion formation.

Besides, cyclooxygenase-2 (COX-2)/prostaglandin E (PGE)/prostaglandin type 4 receptor (EP4) signal transduction pathway also promote the tendon adhesion formation. It is found that the content of COX2 increases during tendon healing process, which can catalyze the decomposition of arachidonic acid into PGE acting on EP4 located in cell membrane to contribute to synthesis and accumulation of ECM [99, 100, 101]. Therefore, inhibition of COX2/PGE/EP4 signaling pathway may reduce the formation of tendon adhesion. However, some researches have demonstrated that the inhibition of COX-2 by high-dose utilization of non-steroidal anti-inflammatory drugs (NSAIDs) can increase the apoptosis of tenocytes recruited to defect sites, which is not conducive to tendon healing [102, 103, 104]. Furthermore, systemic application of EP4 inhibitor can increase the infiltration of macrophages and the secretion of type 1 collagen aggravating the degree of tendon adhesion [105]. In conclusion, the role of COX-2/PGE/EP4 signaling pathway in tendon adhesion formation is complex indicating more requirements for further studies on mechanism and more cautious usage of NSAIDs.

Altogether, it should be noted that tendon adhesion is a complex pathology process under the guidelines of multiple signaling pathways that interact with each other participating with various cytokines, growth factors and cells. Although studies on single regulation or recently synergistic regulation of signaling pathways have shown satisfactory outcomes in tendon adhesion prevention and tendon healing promotion, fully understanding on how exactly these signaling transduction pathways interact is on great demand.

2.3.5 Infections

Infection is mostly caused by a significant degree of contamination during the initial tendon injury [2, 7, 106]. The infection rate and severity depend on where the injury happens and how it is caused [107, 108]. And a review paper in 2018 reported the most common bacterial populations causing tendon adhesion formation even some devastating effects like gangrenosis. Therefore, it should be highly noted that infection which can mediate tendon adhesion formation should be completely forbidden, and recent study shows that it is capable to integrate an antimicrobial biomaterial. Shalumon et al. [109] constructed a multifunctional electrospun nanofiber membrane to perform excellent anti-infection effect as well as prolonged prevention of inflammation and tendon adhesion formation.

3. Tranditional strategies against tendon adhesion

Surgical intervention is usually unavoidable because lacerated tendon cannot repair by themselves and may retract and have remarkable defects after injury. Meanwhile, simultaneous injuries of adjacent skin, nerves, vessels, and bones also require surgical repair.

3.1 Intraoperative repair methods and tendon adhesion

Modified Kessler suture technique remains globally accepted method for flexor tendon repair with reliable mechanical strength and less peritendinous adhesion [3]. However, even if different modifications for tendon suture have been studied for decades, peritendinous adhesion often occurs and reoperation is still required due to undesired scar tissue formation [4, 110]. When it comes to tendon defect reconstruction, adhesion mechanism of autologous tenograft is believed to involve both intrinsic tenocyte necrosis and extrinsic fibrogenetic and inflammatory cell invasion, while mild peritendinous adhesion was observed in decellularized tendon allograft transplantation since the intrinsic mechanism was forbidden [106, 111]. Rather than adhesion formation, xenograft transplantation for tendon reconstruction may raise another important issue, high postoperative infection rate [112].

Physical barriers made of non-degradable materials including silica gel and gold foil have been previously applied intraoperatively to reduce peritendinous adhesion by wrapping the injured site [113]. However, these barriers are outdated and clinical application are eliminating since their non-degradability and non-permiability may prevent substance exchange and eventual tendon necrosis [24].

3.2 Pharmaceutic intervention

The use of anti-inflammatory drugs against tendon adhesion dates back to the 1980s when NSAIDs were simply injected to the injured area to reduce expression of pro-inflammatory factors that might promote scar tissue formation [114]. However, detrimental side effects of these drugs on cardiovascular and genitourinary systems sometimes occur when they are excessively used [115]. The effect of local steroid administration has been documented by several earlier studies as a dose-related decreased fibrogenesis, collagenesis, adhesion and tensile strength of the repaired tendon [116]. However, a recent animal study has also reported increased risk of peritendinous adhesion [117]. In the contrast, the controlled release of steroid by entrapping them with synthetic polymers showed promising antiadhesion and antiinflammatory effects in recent years [118]. To date, there is no consensus on whether steroid application should be a standard therapy for tendon adhesion.

4. Advanced materials against tendon adhesion

4.1 Basic characteristics

Taking advantage of advanced knowledge of materials, several polymeric or biogenetic materials have been studied and exploited as alternatives for conventional tendon restore strategies [12, 20, 119, 120]. Except for antiadhesion functionality, a few characteristics should be acquired for such materials, which include biodegradability, biocompatibility, accessibility with proper architecture, and reliable mechanical properties [21].

Polymer implantation materials are not supposed to permanently stay in human body, indicating that these synthetic materials should be biodegradable to avoid certain side effects, such as rejection reaction. The degradation should not interfere with the mechanical properties of the materials until safe gliding can be performed by the injured tendon, and the by-product should not be toxic and can be eventually eliminated by the human body [121]. The degradability of these polymers has been proven to be related with molar mass, crystallinity, and mechanical loading [122, 123, 124]. On the other hand, biogenetic materials against tendon adhesion, such as amnion, autograft membranes and allograft tendon sheath and pericardium, as well as their derivations, once show ability to replace natural tendon sheath, should otherwise tolerate biodegradation in order to perform as eternal sheath instead.

Biocompatibility is described as nontoxic, noncarcinogenic, nonthrombogenic, nonimmunogenic characteristics, and proper response to the host of implantation materials [125]. For acceptable biocompatibility of polymeric materials, in vitro cell seeding test should announce a cell viability over 70% [126]. The structural architecture of the implantation materials should manipulate the process of antiadhesion by allowing exchange of information and material, including growth factors, drugs, hormones and degradation by-products. Also, sufficient porosity is required in order to promote neovascularization [127, 128, 129]. Synthetic strategies determine not only the processability of the material but also the mechanical properties. Thus, it is of importance that the processing technique should be easy and cost-efficient for clinical application, and mechanical strength of the construct should be able to tolerate certain impact, e.g. tensile tests, to identify its biomechanical stability [130].

4.2 Synthetic materials against tendon adhesion

4.2.1 Hydrogel

Hydrogels represent a bunch of polymers crosslinking hydrophobic groups and hydrophilic residues with large water content, high porosity and similarity to extracellular environment. The hydrophobic outer layer stands for a physical barrier to isolate exogenous inflammatory response and inhibit fibroblast and macrophage migration during tendon repair, while the hydrophilic inner layer mimics the inner side of tendon sheath to direct and lubricate tendon gliding [131]. Topographic structure of hydrogel allows for carrying certain therapeutic agents to promote tendon healing and inhibit tendon adhesion. By controlling raw material concentration and crosslinking levels, appropriate hydrogel can be obtained with desired mechanical properties and degradation rate (Figure 2) [119, 131].

Figure 2.

Basic design considerations of therapeutic platforms for prevention of peritendinous adhesion including fabrication technologies, scaffold materials, therapeutic structures, and drug-loading.

Hyaluronic acid (HA) is a kind of hydrophilic polysaccharide component of natural synovial fluid. With negative charge, its antiadhesion ability was confirmed by inhibiting fibroblast proliferation and migration [18]. Besides, HA exhibits an essential source of nutrition and lubrication for tendon gliding and repair, with strong potential in eliminating harmful inflammatory factors [132]. Hundreds of injectable hydrogel-based materials have been developed with the participation of HA in order to prevent peritendinous adhesion, among which Seprafilm, consisting of carboxymethylcellulose and HA, and xanthan gum/gellan gum/hyaluronan hydrogel showed both biocompatibility and antiadhesion efficacy in vitro and in vivo [133, 134]. Phospholipid-based hydrogels possess considerable biocompatibility in antiadhesion application as they do not induce foreign body reaction or cause protein conformational changes [135, 136]. Controllable degradation rate of such hydrogels can be achieved by altering the rate of coordinating compound [136]. Injectable hydrogels show great potential in inhibiting tendon adhesion because of its convenient, cost-effective, and minimally invasive manner in postsurgery rehabilitation, and the potential can be amplified when cross-linked with functional molecules. By integrating thermo-responsive material with chitosan and HA, liquid hydrogel will transfer to gel state and suit the tendon defect once body temperature is reached, and then chitosan plays its cytostatic role locally by suppressing fibroblast growth and infiltration [137, 138]. Solely applying chemosynthetic hydrogel remains less satisfactory due to nonspecific blocking adhesion as physical barrier. Therefore, developing drug-delivery platform with formulated hydrogel becomes an alternative method for inhibiting peritendinous adhesion. Cyclooxygenase-engineered miRNA plasmid-loaded polymer nanoparticles has been designed to be encapsulated into HA hydrogel to extend plasmid release against oxidative stress and adheasion formation during tendon repair [139]. Besides, appropriate 5-fluorouracil loading of hydrogel was proved to suppress fibroblast proliferation and migration. Despite the fact that these agent-hydrogel crosslinking materials have shown remarkable ability in the aspect of antiadhesion, a lack of proper mechanical properties still challenges their application in mimicking natural tendon sheath tissue, which promotes proliferation and tenogenic differentiation of stem cells by possessing suitable tensile loading and elasticity [17, 140].

4.2.2 Nanoparticles

Another important therapeutic agent delivery vehicle system is various nanoparticles (NPs). Compared with large molecules, NPs have shown better delivery efficacy and biocompatibility in delivering growth factors, genes and drugs by easier internalization of cells [141]. Quicker escaping from endosomes of the NPs also eliminates cargo biodegradation and thus prolongs bioactive cargo release [142].

Multiple growth factors have shown essential roles during tendon repair, as VEGF enhances neovascularization and accelerates healing process, PDGF promotes tendon gliding, and bFGF induces the differentiation of MSCs towards tenogenic linkage [143, 144]. NPs have been reported to serve as nonviral vectors for growth factors genes delivery, such as bFGF and VEGF, to induce overexpression in tenocytes of lacerated tendon, and downstream macromorphological effects, including enhanced tendon mechanical strength and tendon gliding, were observed in vivo, indicating satisfactory antiadhesion function of the transfected genes [66]. Although the NPs system has been proved to restrain adhesion by loading TGF-β miRNA plasmid for weeks, and simplify the procedure by minimally invasive injection, the absence of rigid mechanical strength of these particles forbids them from acting as physical barriers to separate ruptured tendon from surrounding tissue and migrating inflammatory cells [24]. Similar obstacle was also faced by antiadhesion nanoparticle-coated suture, as no proper timberland could separate the extrinsic healing and cell invasion [145]. New insights of employing self-healing HA hydrogel with NPs entrapping antiadhesion molecules may be reliable solutions to avoid unexpected artificial physical barrier rupture during tendon gliding. Cai et al. [98] reported successful inhibition of fibroblast proliferation and peritendinous adhesion in murine model with self-healing HA hydrogel loading Smad3-siRNA nanoparticles.

4.2.3 Nanofibrous membranes

Nanofibrous membranes (NFMs) have been approved as both reliable antiadhesion barriers and effective carriers of pharmaceutical agents due to their functional characteristics in the aspects of systematically and locally delivering medication, stem cells, components of ECM and genes, and being as physical goalkeepers inhibiting adhesion related to external tendon healing [127, 128, 129, 146, 147].

Among multiple methods to produce such NFMs, electrospinning remains one of the most popular ones for the fabrication of different nanofibers with diverse biomedical applications. Manufactured with this convenient and robust technique, the electrospun scaffolds share similar characteristics with natural ECM including topography and high porosity, and their mechanical properties can be easily modulated by altering the fiber alignment and diameter, and by manipulating the viscosity and volatility of the solution, applied voltage, flow rate of each polymer, along with the distance between the capillary and the collectors.

The electrospun NFMs should defend their payload against rapid degradation and permit release of the drugs or molecules in desired patterns for their antiadhesion applications. By controlling the material composition, drug-encapsulation technology and the architecture of the NFMs, this delivery system has been modified in order to optimizing its pharmacodynamics.

A variety of techniques, including surface modification, blending, coaxial and emulsion electrospinning, have been employed in order to encapsulate pharmaceutic agents into these nanofibers [148]. By physically and chemically altering the surface of the nanofibers with biomolecules, the surface modification technique is usually applied for vulnerable agents such as nucleic acids, proteins, growth factors and polysaccharides, which possess swift biodegradation rate and may lose their functionality during the process of electrospinning [149, 150, 151, 152, 153, 154]. The rest three techniques were then established to accomplish gradual release of the therapeutic molecules. The blending technique requires the drugs or molecules to be dissolved in a polymeric solution before electrospinning, in which process the compatibility of the polymer and the solvend depends on the wettability to provide appropriate drug solubility and distribution [148, 150]. Coaxial electrospinning refers to the modification of traditional electrospinning process by concentrically locating the therapeutic cargoes during nanofiber fabrication, which will protect the biomolecules from environmental risks and attenuate drug degradation thus extending release period [155, 156]. Another effective method to prolong the drug release period is emulsion electrospinning, through which the organic solvent evaporates faster than the aqueous phase in which dissolves the molecular cargoes, leading to central migration of the biomolecules [157, 158, 159, 160]. Besides, sequential electrospinning technique has been widely utilized to produce multi-layered NFMs which combine hydrophilicity or hydrophobia as well as mechanical strength and permeability of each layer of polymer, lubricate the tendons wrapped inside, and protect the longevity of the delivered molecules in order to release them during desired periods [161, 162, 163, 164].

A wide spectrum of electrospun NFMs with diverse properties has been employed as flexible delivery platforms for pharmaceutic agents as well as nanoparticles to inhibit peritendinous adhesion. Despite alleviating tendon adhesion, the rapid clearance of NSAIDs and side effects on tendon repair limit their application for tendon healing and adhesion prevention. By loading ibuprofen (IBU) to poly (l-lactic acid)- polyethylene glycol (PELA) NFMs, Liu et al. [128] revealed that the delivery system could decrease peritendinous adhesion and kinetics of drug release was proved to be mostly dependent on its diffusion and polymer matrix degradation. Besides, more effective blocking of cell adhesion/proliferation and inflammation could be achieved by incorporating low content of polyethylene glycol (PEG) with PELA nanofibers [128]. To reduce postsurgical peritendinous adhesion with long-lasting release of NSAIDs, modified mesoporous silica (MMS) nanoparticles loading IBU was prepared and encapsulated within poly (l-lactic acid) (PLLA) nanofibers with emulsion electrospinning technique [165, 166, 167]. This IBU-MMS-PLLA drug delivery scaffold sustained release of drug by entrapping IBU within the porous MMS particles and its antiadhesion and antiinflammation functionality was observed even 8 weeks postoperatively. HA represents a widely used agent in preventing postsurgical adhesion and permitting tendon gliding due to its features of synovial fluid. By coating poly (ε-caprolactone) (PCL) with HA from the inner side, a bi-layer PCL/HA-PCL NFM has been reported to mimic tendon sheath as the outer layer PCL reduced cell adhesion/invasion and pro-inflammatory cytokine penetration, while the inner layer of HA lubricated the tendon and promoted gliding and healing [146]. Chitosan is another well-known polymer that can enhance the mechanical strength of NFMs when hybridized with other polymers, such as PCL, but the effect of chitosan-based NFMs against peritendinous adhesion remains controversial [147]. Although the hydrophilic nature of chitosan may partially reduce surface adhesion, other factors, including electric charge and roughness of the NFM also influences fibroblast attachment and recent studies have confirmed that PCL/chitosan NFMs had little impact on decreasing peritendinous adhesion [19, 168, 169, 170, 171]. Meanwhile, the efficacy of loading certain particles to HA and then merging the HA-particle cargo to NFMs has also been well studied in terms of antiadhesion. Although mitomycin (MMC)-induced fibroblast apoptosis can inhibit collagen synthesis and is supposed to reduce tendon adhesion, misguided use of MMC may result in local and systematic toxicity [172]. By wrapping MMC in HA hydrogel and encapsulating the composite particle in PLLA nanofibers, notably controlled release of MMC was achieved and inhibition of tendon adhesion was observed in vivo [159]. Postsurgical infection also presents and important risk factor for peritendinous adhesion due to inflammation cascade and fibroblast infiltration [109]. Since silver (Ag) and its derived nanoparticles have shown strong antibacterial properties, NFMs with cored HA and Ag nanoparticles embedded in PCL shell have been investigated to possess adhesion prevention functionality [173]. Controlled release of the cored HA could promote tendon gliding and reduce fibroblast attachment, while the Ag nanoparticle-loaded NFM sheath with thinner diameter showed better capability of preventing fibroblast attachment in vitro and inhibiting peritendinous adhesion in vivo [174].

Incorporating biologics, including stem cells and growth factors, with NFMs scaffolds has recently gained significant attention in the field of tendon repair and antiadhesion [175]. Researchers have also attempted to load growth factors into nanofibers to exploit their antiinflammation and antiadhesion bioactivities, but the growth factors degrade easily when exposed to in vivo conditions and may be damaged during electrospinning preparation [65, 143]. Thus, similar to the afore-mentioned drug-nanoparticle-nanofiber delivery system, fabricating NFMs carrying growth factor-loaded nanoparticles may result in satisfying application of growth factors to prevent peritendinous adhesion. For instance, bFGF-loaded dextran glassy nanoparticles (DGNs) have been reported to contain higher proportion, less burst release and better-preserved bioactivity of bFGF when pre-formulated and encapsulated with PLLA nanofibers using the emulsion electrospinning technique, compared with bFGF-loaded PLLA, and in vivo investigations revealed that the bFGF-DGNs-PLLA NFM scaffold not only promoted tendon healing but also mediated collagen remodeling in ECM and reduced tendon adhesion [176]. However, few attempts were taken to eliminate tendon adhesion by delivering stem cells with NFM scaffold. Liao et al. [177] found no significant reduction in tendon adhesion, despite the delivery of MSCs with minimal burst release using bi-layered HA/copolyermized l-lactide and ε-caprolactone NFMs, indicating a plenty of scope and opportunities for this approach.

Given the fact that inhibiting crucial cellular signaling pathways would reduce formation of adhesion, NFMs loading exogenous genetic materials have been developed to alter expression of certain genes related to peritendinous adhesion [178]. Small interfering RNA downregulating expression of ERK2 and SMAD2/3 has been shown to prevent fibroblast proliferation as well as abnormal collagen accumulation [179]. To employ such functionality, a pyridinedicarboxaldehyde-polyethylenimine (PDA)-mediated exogenous ERK2-siRNA delivery system based on PLLA/hyaluronan (P/H) nanofiber scaffold has been developed in order to gradually inhibit ERK2 bioactivity and reduce peritendinous adhesion [178]. In vivo model demonstrated that ERK2-siRNA-PDA-P/H delivery system could reduce type III collagen density through down-regulating ERK2 and SMAD3 gene expression, thus inhibiting tendon adhesion (Table 1).

Researchers	Type of material	Source of material	Molecule loading	Manufacture	Mechanical strength	Cell line	In vitro results	Animal model	In vivo results	Publication year	Publication title
Liu et al.	biomimetic bilayer sheath membrane	PCL, HA	HA	combination of sequential and microgel electrospinning technologies	bilayer of; PCL-HA0%:2.13 ± 0.25 MPa; PCL-HA4%:1.91 ± 0.21 MPa; PCLHA8%:1.77 ± 0.18 MPa; PCL-HA12%:1.55 ± 0.21 MPa	multipotent C3H10T1/2cells	More cells adhered to and were better distributed on the surface of the inner HA-loaded PCL layer and the tissue culture plate surfaces	flexor tendon of Leghorn chickens	The average scores of adhesions and tendon healing in the biomimetic bilayer sheath membrane group were lower than the other groups	2012	Biomimetic sheath membrane via electrospinning for antiadhesion of the repaired tendon
Liu et al.	Electrospun fibrous membranes	PELA	Ibuprofen	electrospinning	Maximum tensile strength (MPa) PELA-0% 3.72 ± 0.32, PELA-2% 3.42 ± 0.36, PELA-6% 3.13 ± 0.38, PELA-10% 2.89 ± 0.31	L929 mouse fibroblast	Fewer cells adhered to the ibuprofen-loaded PELA fibers	flexor digitorum profundus tendons of Leghorn chickens	No peritendinous adhesions were detected in most tendons treated with the ibuprofen-loaded PELA fibrous membrane	2013	Prevention of Peritendinous Adhesions with Electrospun Ibuprofen-Loaded Poly(L-Lactic Acid)-Polyethylene Glycol Fibrous Membranes
Liu et al.	Electrospun fibrous membranes	PLLA	dextran glassy nanoparticles (DGNs) loaded with bFGF	electrospinning	Tensile strength(MPA) PLLA 4.38 ± 0.33, bFGF PLLA 4.38 ± 0.33 and bFGF/DGNs-PLLA fibrous membranes 3.54 ± 0.25	multipotent C3H10T½ (C3) cells	The PLLA membrane showed an anti-adhesion effect, more cells adhered to and were better distributed on the surface of the bFGF/DGNs-PLLA membrane	Achilles tendon of male SD rats	In the bFGF/DGNs-PLLA group, A significantly increased tendon thickness was observed, tendon healing and vascular prominence and angiogenesis were significantly better, and an increase in breaking force was detected but still lower than control group.	2013	Tendon healing and anti-adhesion properties of electrospun fibrous membranes containing bFGF loaded nanoparticles
Kuo et al.	Hydrogel	xanthan gum/gellan gum/hyaluronan; hydrogel	/	Blending	/	/	/	Achilles tendon of SD rats	Help reduce the incidence of postoperative tendon adhesion, and enable tendon healing and preserve the mechanical strength as effectively as Seprafilm.	2014	Evaluation of the ability of xanthan gum gellan gum hyaluronan hydrogel membranes to prevent the adhesion of postrepaired tendons
Chen et al.	nanofibrous membrane	chitosan-grafted PCL	/	electrospinning	Ultimate tensile strength (MPa) PCL1.4 ± 0.1, PCL-g-CS 2.2 ± 0.5	Human foreskin fibroblast (Hs68) cells	The inhibition of cell migration by PCL-g-CS NFMs was evident, and the CS layer on the PCL-g-CS NFM can prevent more nonspecific cell adhesion.	flexor digitorum profundus of New Zealand white rabbits	In the tendons treated with the PCL-g-CS NFM, no adhesion was observed, There was a statistical improvement in the DIP joint flexion angle, PIP joint flexion angle and sliding excursion. And tendons treated with PCL-g-CS NFM required the least pull-out force and showed the lowest degree of stiffness.	2014	Prevention of peritendinous adhesions with electrospun chitosan-grafted polycaprolactone nanofibrous membranes
Chen et al.	nanofibrous membrane	HA, PCL, PEO	Ag	electrospinning		human foreskin fibroblasts (Hs68)	Compared to other NFMs, the lowest number of cells and the least cell spreading were found on the PCL/HA + Ag NFMs.	flexor tendon of New Zealand white rabbits	The surface of the repaired tendon was smooth, and no adhesion was observed between the repaired tendon and the peritendinous tissue. No adhesions were observed between the repaired tendon and the surrounding tissue in the HA/PCL + Ag NFM treatment; group	2015	Dual functional core-sheath electrospun hyaluronic acid/polycaprolactone nanofibrous membranes embedded with silver nanoparticles for prevention of peritendinous adhesion
Tang et al.	Nanoparticle	PEI-modified PLGA	AAV2-TGF-β1-miRNA	solvent evaporation	/	Rabbit tenocytes	significantly improved the expression of the gene of type I collagen	flexor digitorum profundus tendons of chickens	Gene therapy through AAV2 vectors is efficient to deliver growth factor genes to the healing tendon and reduce adhesion formations, but reduces in tendon healing strength	2016	Gene therapy strategies to improve strength and quality of flexor tendon healing
Liu et al.	Electrospun nanofibers menbrane	PLA	Ibuprofen	Blending	/	RAW264.7 macrophages	Less RAW264.7 adhered to the surface of IBU/PLA-M than to the surface of PLA-M.	flexor digitorum profundus tendons of Leghorn chickens	Although granuloma formation was investigated in the IBU/PLA-M group, a clear space around the tendon could usually be observed. The number of α-SMA positive vessels in the IBU/PLA-M group is significantly lower than that in the PLA-M group.	2017	Macrophage infiltration of electrospun polyester fibers
Zhou et al.	Hydrogel	thiol-modified hyaluronic acid/PEG-diacrylate	COX-1 and COX-2 miRNA plasmids	Blending	The elastic modulus, yield strength, and elongation to yield for hydrogel are 0.121 ± 0.01 MPa, 0.014 ± 0.003 MPa, and 3.50% ± 0.5%, respectively.			flexor digitorum profundus tendons of white Leghorn chickens	This hydrogel could effectively reduce the expression of COX-1 and COX-2 proteins in the tendons and subcutaneous tissues.	2018	Localized delivery of miRNAs targets cyclooxygenases and reduces flexor tendon adhesions
Chen et al.	Micro-hydrogel-generated asymmetric scaffold	chitosan	tendon stem/progenitor cells	Self-deposition technique	641.61 ± 12.43 MPa	tendon stem/progenitor cells sided onto the scaffold	displayed higher levels of tenogenic specific genes expression and protein production.	Achilles tendon of SD rats	synergistic effect; on tendon regeneration and yielded better-aligned collagen fibers with elongated, spindle-shaped; cells.	2018	An asymmetric chitosan scaffold for tendon tissue engineering
Jayasree et al	Electrospun menbrane	PCL-Collagen-bFGF	PCL, collagen bFGF nanofiber	electrospinning	89.4 ± 5.3 MPa	Rabbit tenocyte	Upon dynamic stimulation, mPCL-nCol-bFGF-DS scaffolds showed significantly higher expression of tenascin C, collagen I, biglycan, and fibronectin.	Achilles tendon of New Zealand white rabbits	The alignment of collagen was highly in comparison to native tendon which showed perfectly aligned fiber morphology, whereas, by 12 weeks, the implants showed more aligned nature of collagen fibers which was further confirmed by MT staining.	2019	Bioengineered Braided Micro-Nano (Multiscale) Fibrous Scaffolds for Tendon Reconstruction
Park et al.	film	cross-linked electrospun cartilage acellular matrix (CAM)	CAM, PLGA	cross-linking	25.06 ± 1.4 N	L929 mouse fibroblast cells	Cell migration; from serum-free medium area towards serum containing medium area was inhibited in the CX-CAM film group	Achilles tendon of New Zealand White rabbits	The degree of adhesion in histology was highest in the repair group, followed by Seprafilm, CX-CAM; film, and sham group.	2020	Cross-linked cartilage acellular matrix film decreases postsurgical peritendinous adhesions
Song et al.	Electrospun menbrane	PCL	mechano-growth factor	Electrospinning	/	RAW264.7 mouse macrophages	Antiinflammatory macrophage phenotype polarization	Achilles tendon of SD rats	Almost no adhesion can be detected in the MGF-modified group with a sheath space formed between tendon and scaffold.	2021	Surface modification of electrospun fibers with mechano-growth factor for mitigating the foreign-body reaction
Chen et al.	Core-sheath nanofiber membrane	PLA, HA,	Ag/Tn/Tk	Blending and core-shell	/	NIH/3 T3 mouse embryonic fibroblasts	A synergistic effect was found by combining Ag NPs with HA as Tn+, with Ag NPs embedded in the thin sheath and the highest amount of released HA, which demonstrated the least staining of vinculin by inhibiting cell adhesion as well as suppressing cell spreading.	flexor digitorum profundus tendons of New Zealand White rabbits	The Tn + group showed a nearly complete lack of adhesion and demonstrated the most regular collagen arrangement.	2021	Functional Hyaluronic Acid-Polylactic Acid/Silver Nanoparticles Core-Sheath Nanofiber Membranes for Prevention of PostOperative Tendon Adhesion

Table 1.

Recent research on biomaterials for the prevention of peritendinous adhesion.

Source: [128, 139, 146, 173, 174, 176, 180, 181, 182, 183, 184, 185]

4.3 Biomimetic materials against tendon adhesion

4.3.1 Amnion and its deviations

Human amniotic membrane (HAM) tissue is inexpensive, easily stored, of minimal antigenicity and with low immunogenic rejection, and has shown advanced potential in preventing postsurgical adhesion [186]. Recent findings also revealed its reinforcement on mechanical strength after combined with modified Kessler suture in flexor tendon repair, probably due to the expression of multiple growth factors that promotes tenocyte proliferation [187, 188]. The decellularized HAM can physically inhibit cell infiltration and preserve tendon gliding through “tunnel effect”, and biochemically suppress ILs-induced immunologic cascade to alleviate systematic inflammatory response and local abnormal collagen synthesis [189, 190, 191, 192, 193].

Typical strategy to apply HAM and other films to the injured site of tendon generally depends on wrapping and suture. However, excessive suture burden may also result in consequent fibrogenesis and adhesion, stimulated by the suture as foreign body. To reduce such complications, several modification techniques has been employed for HAM modification. Photochemical tissue bonding (PTB) technique requires photo-active substance, e.g. Rose Bengal (RB), to conglutinate tissues through illumination [194]. Ding et al. [27] found that by immersing decellularized HAM in 0.1% (w/v) RB, attaching HAM to repaired chicken tendon became suture-less and significantly reduced inflammatory cell chemotaxis and better joint performance were observed. Wrapping freeze-dried HAM around the sutured site of lacerated tendon may also result in moderate peritendinous adhesion because of the uncontrolled expression and emission of TGF-β, which promotes exogenous fibroblast migration and collagen synthesis through ERK/SMAD pathway [24]. Coating PCL on both surfaces of the HAM by electrospinning technique has been identified in a rabbit model to reduce such adhesion by (1) prevent outer fibroblast and inflammatory infiltration, (2) gradual release of multiple growth factors, e.g. PDGF, VEGF, and TGF-β from the intermediate HAM layer, and (3) maintaining tendon gliding inside the membrane, thanks to the appropriate porous network of the PCL NFMs [195].

HAM and its deviations have been gradually utilized in preventing peritendinous adhesion during clinical practice. Compared with synthesized polymer membrane and control group, HAM has been reported to significantly attenuated complication rate of erythema, exudate and rupture in repaired Zone II human flexor tendons, but there was no difference in ultimate interphalangeal joint range of motion [196]. In addition, local administration of HAM wrapping around injured human flexor tendon was observed to reduce serum level of IL-6 and TGF-β1, indicating a systematic antiinflammation effect during tendon repair, thus preventing tendon adhesion [190]. On the other hand, effect of HAM allograft against tendon adhesion, tenolysis and joint complications after application in flexor tendon repair was questioned by Leppänen et al. [197] since half of the 10 patients enrolled developed these complications.

4.3.2 Tendon and sheath graft and reconstruction

Two-stage flexor tendon defect reconstruction remains gold standard [198]. The technique requires first-stage silicone rod insertion for tendon pseudo-sheath formation for at least 3 months and second-stage rod removal with tendon grafting. Functional results of this technique are not always predictable, which also depend a lot on patient’s compliance with prolonged duration of rehabilitation and time off work [106]. By employing tubular polyurethane nanocomposite graft surrounding autologous tenograft, single-staged flexor tendon reconstruction in sheep hind extremity model revealed mild histological adhesion and satisfactory tendon gliding [199]. In addition to artificial synovial graft, the in vivo experimental study of artificial tendon substitution assembled with platelet gel-collagen-polydioxanone has also shed light on promising Achilles tendon healing and adhesion prevention [26, 200]. It is believed that abundant PDGF level in such platelet gel may alter fibro-adiogenic progenitors from fibrotic differentiation towards tendon stem cells, thus relatively alleviate scar tissue formation [201].

Two-stage extensor tendon reconstruction is not a preferable approach in reported literature because of the absence of fibroosseous sheath guiding both extrinsic and intrinsic musculotendinous movement [202]. However, one-stage extensor tendon reconstruction may be accompanied with subsequent adhesion in cases with multiple soft tissue defect, severe contamination, and bone defect or fracture which requires long-term immobilization [203, 204]. In those cases, first-stage artificial tendon substitutions insertion, including silicone rods, can be an alternative method to maintain tendon route and form pseudo-synovial tunnel, to inhibit inflammation and infection, and thus to prevent adhesion formation for second-stage tendon grafting [205]. The use of such synthetic silicone rods has declined over years due to many complications, such as pyogenic tenosynovitis and high failure rate [206, 207].

Extra synovial tendon autografts are currently wide-accepted donor for tendon defect reconstruction. These tendons, such as palmaris longus, however, lack natural synovial cells mounted on loose connective tissue in tendons possessing sheaths, such as flexor digitorum superficialis. It has been observed in canine model that extra synovial tendon autograft underwent quicker cell death and ECM remodeling, and more excessive peritendinous adhesion, compared with intra synovial tendon autograft [208]. Explanation for such differences may lie in the different initial expression spectrum of these two kinds of tendons, and in their different response to the extracellular environment of the recipient site [209]. Rabbit model revealed that after 28 days of autograft transplantation using extra or intrasynovial tendon, donor segment showed different proteomic features in the expression of certain proteins, including heat shock protein 47, tenascin, periostin, etc., indicating the relationship among environmental stimuli around recipient site, oxidative stress, cell homeostasis and consequent peritendinous adhesion [23].

The availability of tendon allograft offers reconstruction options for patients without adequate tendon autograft reservation. Early studies have demonstrated triumphs in clinical flexor tendon reconstruction using fresh tendon allograft with composite sheath and volar plates, which, however, arouse concerns, including the harvesting and storing technique, transmission of diseases, and ethical issues [210]. Since programmed sterilization, decellularization and lyophilization have been shown to have little influence on biomechanical properties of composite tendon allograft, diverse modifications of such allograft have been studied to minimize postsurgery peritendinous adhesion [211, 212]. These modifications include synthetic polymer loading, tonogenic stem cell repopulation, and antiadhesion genes delivery, all of which were shown to reduce tendon graft gliding resistance in animal models [213, 214, 215]. Although safe and effective clinical use of lyophilized and sterilized tendon allograft has been reported in upper extremity reconstruction, no biologically modified acellular tendon allograft has been implanted in humans to date in the aim of preventing tenograft adhesion [216].

4.3.3 Pericardium as tendon sheath substitution

Due to the difficulties in tendon sheath suture with conventional surgical techniques, tendon sheath engineering has drawn wide attention in order to support tendon gliding and prevent peritendinous adhesion, apart from chemosynthetic materials. Typical biogenetic tendon sheath usually requires a scaffold, either from decellularized membraneous allograft or xenograft, or simple scaffold synthesized with collagen or lipoprotein, and techniques reseeding certain cells onto the membraneous scaffold. Bioengineered tendon sheath with collagen scaffold and harvested synoviocyte has been reported to inhibit Achilles tendon adhesion formation in rabbit model [217]. Porcine pericardium has also been applied as bioengineered tendon sheath scaffold since the pericardium functions similar as tendon sheath to lubricate heart beating, based on which decellularized bovine pericardium tendon xenograft and allograft have achieved successful adhesion prevention outcomes in chicken and donkey models [22]. Although Megerle et al. [25] did not test the tendon gliding resistance in vivo, their repopulationed human synoviocyte and adipose-derived stem cell on decellularized porcine pericardium showed shifted expression of downregulated collagen and upregulated hyaluronan synthase, suggesting potential antiadhesion mechanism during human cell line transplantation [218].

5. Conclusion

Taken together, the successful exploration and application of advanced antiadhesion materials highly depend on the collaboration among experts with diverse backgrounds, including engineering, biology, chemistry, surgeons, and sociologists. Intensive understanding of the pathophysiological procedure of tendon adhesion in combination with advanced material fabrication technologies will do a great favor to establishing next-generation of therapeutic platforms against tendon adhesion.