Section 3 Biochemical Aspects

#### **Chapter 3**

### Tendon Adhesion and Novel Solutions

*Shen Liu, Qinglin Kang, Rui Zhang, Yanhao Li and Rong Bao*

#### **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.

**Keywords:** tendon adhesion, mechanism, countermeasure, advanced material, drug delivery system, future direction

#### **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 [3–5]. 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 [6–9]. 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 [22–27]. 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].

#### **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 proinflammatory cytokines significantly ascends attributed to recruitment of neutrophils, macrophages, and monocytes [37–39]. 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

#### **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).*

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 [48–53].

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 factorbeta (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, 57–60]. 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 [63–66]. 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 [67–72]. 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 [76–79]. 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 [86–89]. 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 [94–96]. 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 [99–101]. 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 [102–104]. 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 [122–124]. 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 [127–129]. 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].

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].

#### **Figure 2.**

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

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, costeffective, 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 drugdelivery platform with formulated hydrogel becomes an alternative method for inhibiting peritendinous adhesion. Cyclooxygenase-engineered miRNA plasmidloaded 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 selfhealing 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 [127–129, 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 [149–154]. 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 [157–160]. 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 [161–164].

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 [165–167]. 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 (εcaprolactone) (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, 168–171]. 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 εcaprolactone 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**).

#### **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 [189–193].

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 sutureless 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].







#### **Table 1.**

*Recent research on biomaterials for the prevention of peritendinous adhesion.*

### *Tendon Adhesion and Novel Solutions DOI: http://dx.doi.org/10.5772/intechopen.108019*

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 [213–215]. 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 adiposederived 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.

#### **Author details**

Shen Liu1,2\*, Qinglin Kang1 , Rui Zhang<sup>1</sup> , Yanhao Li1,2 and Rong Bao1,2

1 Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

2 Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China

\*Address all correspondence to: liushensjtu@126.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 4

## Insights for Treatment

#### **Chapter 4**

## Medical Implications of the Relationships among Protein Denaturation, Necrosis and Inflammation: An Intriguing Story

*Bruno Silvestrini and Mauro Silvestrini*

#### **Abstract**

This story deals with the role of protein denaturation in inflammation. The starting point was the description of the necrotizing action of inflammatory proteins, followed by the discovery of the antidenaturant action of NSAIDs (nonsteroidal antiinflammatory drugs). Hence, the idea is that the antidenaturant action accounted for the action of NSAIDs. This hypothesis was dropped following the discovery of the antiprostaglandin action of NSAIDs, which shifted the focus to the arachidonic acid cascade. It was revived by assuming that protein denaturation is a process in its own, suitable for separate medical treatment. This approach led to bendazac and bindarit, the first selective antidenaturant drugs. This experience shows that protein denaturation has two main pathological sequelae. The first concerns the so-called primary (innate) inflammation. The second sequela concerns the so-called secondary (acquired) inflammation. Natural antidenaturant agents represent a promising alternative to the synthetics bendazac and bindarit. Within this framework, tendinitis finds a separate but significant place.

**Keywords:** inflammation, protein denaturation, bendazac, bindarit, fatty acids, tendons

#### **1. Introduction**

To start with, inflammation is part of homeostasis, the fundamental process of life of preserving the milieu intérieur by reacting to changes with opposing measures [1–3]. More specifically, inflammation is "the vital response to injury", which may be related to exposure to infection, toxins, damaged cells, waste, and chemical and physical agents [4, 5]. The function of inflammation is to repair the damage that does not result from the inflammation itself, but from overactivation or deviation of the underlying physiological process. Consider the five cardinal signs of inflammation described by Celsius and Galen over 2000 years ago: heat (calor), pain (dolor), redness (rubor), swelling (tumor), and impairment (functio laesa). Without pain, for example, a person would be exposed to disease without realizing it. Similarly, impairment (functio laesa) implies

the setting aside of a function to allow recovery. A fracture would not be repaired without temporary immobilization of the broken bone. The overlap of physiological and pathological elements is the key point of the medical treatment of inflammation. Based on these introductory remarks, there are two inflammatory processes. The innate one is based on the hyperactivation of genetically innate physiological processes. Acquired inflammation is different in that it involves the immune system.

#### **2. Pathophysiological considerations**

It consists of an immune reaction adapted to each aggressive agent so as to neutralize it without damaging the surrounding tissues. This measure takes into account the genetic characteristics that distinguish each living being, as well as the chemical structure and macromolecules that the organism must take up. Acquired inflammation combines the collateral damage of innate and acquired processes. For example, deaths from SARS-CoV-2 and variants are caused not only by the virus, which penetrates and kills cells but also by the excessive immune-inflammatory reaction that impairs respiration and blood clotting.

With this in mind, the current story begins about 60 years ago with the description of the irritating and necrotizing effects on the skin of protein complexes related to both acquired and innate inflammation [6–9]. It should be noted that a similar necrotizing effect is produced by urea, a metabolite of the aforementioned complexes [10]. Subsequently, NSAIDs were found to exert an antidenaturant action at concentrations that roughly correspond to their anti-inflammatory effects [11, 12]. The resulting hypothesis was that "most strongly anti-inflammatory drugs might owe at least part of their effects on some biochemical processes to their physicochemical property of interacting with proteins." The quoted portion is from the original article [12]. Simply put, the hypothesis was that the antidenaturant effect of NSAIDs underlies their mechanism of action. Hence, the protein denaturation assay was proposed as a simple screening test for antirheumatic and antiphlogistic drugs [13, 14]. The proteincentered hypothesis had some inconsistencies. For example, the antidenaturant effect occurs at relatively higher concentrations than at anti-inflammatory concentrations [15]. In addition, antidenaturant drugs may not have anti-inflammatory effects [16].

Inconsistencies aside, the above hypothesis was abandoned following the discovery of the antiprostaglandin action of aspirin-like drugs, which shifted the focus to the arachidonic acid cascade [17]. Prostaglandins are lipid autacoids derived from arachidonic acid that have widespread physiological roles in the body, including homeostatic functions involved in the inflammatory process [18]. The arachidonic acid cascade fits like a glove with the concept that inflammation involves the hyperactivation of a physiological process. For example, NSAIDs reduce mucosal hypersecretion in the common cold, along with a reduction in the physiological secretion that protects the gastric mucosa [19]. In fact, it has been reported that half of the patients treated with NSAIDs have gastric erosions and 10–30% have gastric ulcers [20]. Therefore, the problem of overlap between physiological and pathological aspects of inflammation has remained unresolved.

Incidentally, steroidal anti-inflammatory drugs are different. Rather than showing antidenaturant and antiprostaglandin effects, they inhibit the functions of leukocytes, which participate in both innate and acquired inflammation [21]. Their mechanism of action is reminiscent of the stress "attack" reaction to dangerous and life-threatening events [22, 23]. This reaction consists of a threefold adrenal discharge *Medical Implications of the Relationships among Protein Denaturation, Necrosis… DOI: http://dx.doi.org/10.5772/intechopen.108018*

involving sympathetic catecholamines, glucocorticosteroids, and mineralcorticostseroids [24, 25]. Leukocyte functions [including the immune response] are temporarily set aside, as they are useless in acute emergencies. In essence, adrenal discharge activates the somatic and mental processes needed to cope with emergencies. During World War II, the Nazis administered an adrenal cortex extract to fighter pilots that mimicked the corresponding biological process. Steroidal anti-inflammatory drugs belong to the above stress discharge, including hydrocortisone (cortisol), which has been found to explain the remission of jaundice-induced rheumatoid arthritis [26, 27]. We will return to this phenomenon shortly.

Returning to the protein-centered inflammation hypothesis, it has been revived in different terms. The idea was that protein denaturation was a process in its own right, suitable for separate medical treatment [28, 29]. Similarly, paracetamol is an antiinflammatory drug that shows selective antinociceptive and antifebrile effects. Based on this idea, the aforementioned protein denaturation assay [13, 14] was used to select drugs, with the exception that they had to be free of the antiphlogistic and related side effects that others sought.

#### **3. Pharmacotherapeutic implications**

Bendazac, also known as bendazolic acid, is the first selective antidenaturant drug that has undergone thorough preclinical evaluation and medical use. The drug teaches something about the theoretical and practical value of this approach. First, the antidenaturant action of bendazac is against several agents, including extreme pH, heat, UV, and sunlight [10, 30–34]. It follows that bendazac is not a free radical scavenger. Rather, it binds to reactive protein sites, thus providing a protective barrier against free radicals. This binding does not result in a significant change in protein architecture and function. This suggests that the antidenaturant action depends on Van der Waals forces, which differ from covalent and ionic forces. Rather, they depend on the fluctuating polarizations of neighboring particles as a consequence of quantum dynamics.

Considering the pharmacological profile of bendazac, its most striking feature is its antinecrotic action [10]. Therefore, clinical studies have focused on dystrophic conditions [35]. More specifically, bendazac has been tested and shown to be active against inflammatory and allergic dermatoses: contact dermatitis, occupational dermatitis, seborrheic dermatitis, diaper and childhood dermatitis, constitutional eczema, erythema and localized itching, urticaria, drug allergies, and insect bites [36–42].

Thus, the preclinical and clinical experience gathered with bendazac supported the idea that protein denaturation is a process in its own right, suitable for targeted medical treatment. It is noteworthy that bendazac has been shown to be active against cataracts, which consist of physical opacification of the lens [43–46]. This suggests that a protein-denaturing agent could affect other medical conditions, such as kidney and gallstones, which are triggered by a protein-denaturing core.

Bindarit is another selective antidenaturant drug [47]. It shares a pharmacological profile with bendazac, but its study focused on adjuvant-induced arthritis in rats. It consists of the injection of Freund's adjuvant (a fine suspension of dead tubercle bacilli in liquid kerosene) into the plantar pad of rats. The adjuvant produces a primary inflammatory lesion at the injection site, followed, after about 10–15 days, by secondary lesions in areas of the body distant from the injection site [48–51]. The secondary lesions are accompanied by humoral changes consisting of denatured

GLIMBAL-like (globulin-like migrating proteins) proteins, which have been detected in patients with rheumatoid arthritis [52]. Returning to bindarit, it selectively inhibits secondary lesions and related humoral changes, whereas hydrocortisone- and aspirin-like drugs inhibit both primary and secondary lesions [47]. Subsequently, bindarit was found to prolong survival and reduce renal damage in murine autoimmune disease [53, 54]. At this point, available information suggests that: (A) protein denaturation triggers the secondary immune-inflammatory process by exposing antigens common to both denatured and native proteins; and (B) an antidenaturing drug may show a protective action against autoimmune conditions in the absence of immunosuppressive effects. The resulting medical opportunities are exciting, but nevertheless, after 20 years bindarit still remains a matter of preclinical research and working hypotheses. Why?

The answer deserves a separate comment. It goes back to 1961, the year of thalidomide when images of phocomelic infants went around the world. This tragedy sent a warning signal about the risks of the hitherto uncontrolled use of synthetic drugs. Since then, they have been subject to strict toxicological controls, which have increased safety but burdened and delayed medical use. At the same time, there has been a resurgence of interest in drugs of natural origin, such as hormones, vitamins, and vaccines. They are not necessarily safer than synthetic ones, but they have a history of how to use them safely.

*"It is important for us to identify nature's powerful, if accidental, antidotes,"* said Philip Hench on the occasion of receiving the Nobel Prize for the discovery of hydrocortisone. A small but exciting opportunity in the field of natural antidotes came with the experimental reevaluation of jaundice, the natural phenomenon that had paved the way for the treatment of rheumatoid arthritis with hydrocortisone a quarter century earlier [26, 27]. In a nutshell, it was discovered that jaundice involves an inhibition of protein denaturation, which, based on the above data and ideas, could participate in the remission of rheumatoid arthritis [55]. This phenomenon was partly attributable to the antidenaturant bilirubin and bile salts, but the effective doses and concentrations were hardly compatible with medical use. Hence, the search for more convenient compounds. Among the natural substances examined so far [56–60], candidates for medical use include fatty acids belonging to the composition of cell membranes [61]. Like bile salts and bendazac, they also prevent hemolysis of erythrocytes [62–64]. Hopefully, they will not have the same fate as bindarit.

In this story focusing on protein denaturation, tendinitis occupies a marginal but significant position. The tendon consists mainly of collagen (80%), the most abundant, ubiquitous, and versatile protein in mammals [65]. The type I collagen in the tendon gives it the strength and elasticity needed to connect muscle to bone, transmitting the mechanical forces of muscle contraction to the skeletal system. Its denaturation results in a loss of its elastoplastic function, which is irreversible. Experience with collagen deficiency disease suggests that tendinitis could also be addressed with dietary measures that promote collagen regeneration [66]. This is the message of the biological evidence, which is different but sometimes as strong as the experimental evidence.

#### **4. Conclusions**

This long and intriguing story ends up under the banner of biology. In modern science, it has been pushed aside by molecular biology, which focuses on single details that are difficult to trace back to their overall meaning. It is a kind of intellectual,

#### *Medical Implications of the Relationships among Protein Denaturation, Necrosis… DOI: http://dx.doi.org/10.5772/intechopen.108018*

rather than visual, myopia. Like the cells in which they are produced, proteins have a biological cycle: they are born, mature, age (denature) and disintegrate, giving rise to waste. Slags are normally recycled to synthesize new proteins that replace aged ones or are excreted. The problem of slag mainly affects so-called perennial cells, including lens cells and neurons that last a long time without renewing themselves and their proteins [67, 68]. This is the case with cataracts, which are caused by scoriae that blur vision. Bendazac shows that an antidenaturing agent could influence this condition by reducing the extent of protein denaturation [30]. Slag is also involved in brain proteinopathy, which is related to beta-amyloid denaturation resulting in the formation of aggregates and toxic metabolites [69, 70]. The use of high doses of aspirin, an antidenaturant, has been reported to reduce the prevalence of Alzheimer's dementia [71]. Unfortunately, NSAIDs are burdened with unavoidable side effects. Bendazac and bindarit are potentially a step forward because of their selective antidenaturant action. This article presents some additional natural compounds, which belong to the composition and apparently to the physiological modulation of the protein life cycle.

#### **Author details**

Bruno Silvestrini1 \* and Mauro Silvestrini<sup>2</sup>

1 The Noopolis Foundation, Rome, Italy

2 Department of Experimental and Clinical Medicine, Polytechnic University of Marche, Ancona, Italy

\*Address all correspondence to: brunosilvestrini25@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 5**

## Calcific Tendinitis: Limited Role of Surgery

### *John Christian Parsaoran Butarbutar*

#### **Abstract**

Calcific tendinitis is not an uncommon condition, although many patients may experience no symptoms, and calcification was found accidentally through imaging studies. Even so, in some cases, calcific tendinitis may arise with bothersome symptoms that can lead to diminished function of the affected joint. Calcific tendinitis is usually a self-limiting disease, where in its course, it may resolve on its own, may not need further interventions. In symptomatic cases, conservative treatment is the main option. More aggressive treatment such as percutaneous lavage may be needed in acute or unresponsive chronic pain. Surgical intervention may be needed to help resolve the symptoms, but it is rarely indicated.

**Keywords:** calcified tendinitis, surgery, arthroscopy, ultrasonography, lavage

#### **1. Introduction**

Calcific Tendinitis (CT) is a condition of abnormal deposition of calcium salt inside of the tendon. It is also known as calcific periarthritis, which implies that the calcification is not happening within the joint, and calcifying tendinitis, describe the transient nature of the disease [1, 2].

It may occur in many regions of the body, but it is mostly found in the shoulder region, usually the rotator cuff in which the supraspinatus tendon is most frequently affected, followed by the infraspinatus and the subscapularis. Hip girdle region is the second most affected region, including rectus femoris and gluteus Medius tendon. CT also has been reported to occur at proximal hamstring, biceps brachii, longus colli, Achilles, flexor carpi ulnaris, and many other sites [1].

Number of incidences varies between 2.7 to 22% in individuals without symptoms detected by X-Ray with bilateral incidence in about 10–20% of cases [3–5]. A study conducted by Bosworth et al. in 1941 found incidence of 2.7% out of 6061 patients have CT in which 34.7% were symptomatic [4]. A newer descriptive study reported the incidence of calcific tendinosis in the shoulder can be found in 7.8% of asymptomatic patients and 42.5% of patients with subacromial pain syndrome [6]. Both studies have shown that CT affected more women than men, in the age group of 30 to 60.

#### **2. History**

Duplay was accredited as the first to describe CT of the shoulder in 1872. He defined it as "painful periarthritis of the shoulder" [7]. Later, Painter rendered the first case report of calcific deposit about the shoulder in 1907, misinterpreting it as thickening of the walls of the bursa [8]. This was followed by other authors who proposed the accumulation of scar tissue [9], hemorrhage under pressure [10] and metamorphosis of fat deposits [11], which suggest subacromial bursa pathology.

In 1908, Codman reported the surgical removal of deposits composed chiefly of calcium, in or on the supraspinatus tendon. In his classic textbook on the shoulder (1934), he then made the following definitive statement: "The deposits do not arise in the bursa itself, but in the tendons beneath it." The critical area, a concept of there being a specific vulnerable area in the supraspinatus tendon susceptible to calcification was first proposed by Codman [12]. Other authors in agreement like Bishop and Sandstrom suggested that some kind of degeneration of the rotator cuff due to overuse or ischemia leads to calcific deposits in the tendon. The process may begin with necrosis of tenocytes along with intracellular accumulation of calcium [13, 14]. This view was then supported by Refior in a later paper, using cadaveric study [15].

In contrast, Uhthoff and Loehr think that the transient, self-healing nature of calcifying tendinitis did not fit the degenerative disease characteristic. They proposed the multiphasic disease theory, which suggests that deposition of calcium in the tissues will be followed by spontaneous resorption of the calcific deposit. They believe that the process of calcification is actively mediated by cells in a viable environment [16]. This view becomes more prevalent in recent years, with imaging studies and classifications adopting different stages of the disease.

Most of our understanding of this disease comes from observation of CT of rotator cuff of the shoulder.

#### **3. Symptoms**

CT can present in three different clinical scenarios. It can be an asymptomatic incidental finding, a condition involving chronic low-grade pain, or a very painful acute condition that affects the range of movement and function of the joint. In shoulder, pain is often aggravated by abduction of the arm above shoulder height or by lying on the affected shoulder. Point exquisite tenderness is found in the calcific region, especially in acute phase [17, 18].

#### **4. Investigation**

Calcific deposits appear as irregular punctuate, circular, linear, or plaque-like radio-dense areas that do not possess a trabecular or cortical structure. In the rotator cuff tendons, it can be localized using the anteroposterior radiographs of the shoulder in internal and external rotation and axillary lateral radiographs. The French Arthroscopic Society using the anteroposterior view of X-rays which then becomes the widely used classification defined four types of deposits. Type-A calcifications are sharply delineated, dense, and homogenous. Type B are sharply delineated and dense in appearance, with multiple fragments. Type C are heterogeneous in appearance, with

#### *Calcific Tendinitis: Limited Role of Surgery DOI: http://dx.doi.org/10.5772/intechopen.107511*

a fluffy deposit (**Figure 1**). Type D are dystrophic calcifications at the tendon insertion. The last two types are associated with the resorptive stage of the disease [19, 20].

The second useful investigation is ultrasonographic evaluation. It is sensitive to detecting the calcium deposits in soft tissue. Although in the presence of calcifications, shadows may cause false-positive and false-negative findings, ultrasonographic is still beneficial to detect the cuff tears nearby, and concomitant impingement syndrome. On ultrasound, calcification was classified as arc-shaped (an echogenic arc with clear shadowing), fragmented or punctate (at least 2 separated echogenic spots or plaques) with shadowing, fragmented or punctate without shadowing, and nodular (an echogenic nodule without shadowing) [21]. A study reported that an arc-shaped and hyperechoic deposit indicates calcification in the resting phase, whereas on-arc shaped deposit, may be fragmented, cystic or nodular indicating the resolving phase of the calcification [22]. Bianchi and Martinelo described three types of calcifications based on the percentage of calcium content found by ultrasonography. They described Type I as hyperechoic focci with well-defined acoustic shadowing due to high calcium amount, Type II as hyperechoic focci with mild acoustic shadowing due to reduced calcium amount, and Type III as focci which is isoechoic to the tendon (**Figure 2** )[23].

**Figure 1.**

*Anteroposterior (A) and internal rotation (B) view of the left shoulder showing Type C calcification according to French Arthroscopic Association classification within the supraspinatus tendon of a 41-year-old woman.*

#### **Figure 2.**

*Ultrasonographic of a 49-year-old woman showed a Type II calcific deposit in the subscapularis tendon according to Bianchi and Martinoli, who later underwent ultrasound-guided percutaneous lavage with dramatic improvement of acute pain.*

The use of magnetic resonance imaging in cases of CT has shown to be unessential as it tells no specific additional information and does not alter the treatment plan. The deposit can be found in MRI imaging as a low-intensity lesion in the T1-weighted images. High intensity may be found in T2 sequence indicating edema around the deposit which correlates to the resorptive phase of calcification. MRI also allows better evaluation of coexisting pathology when conservative treatment fails and surgery is indicated [24].

Computed tomography allowed better localization of the deposits but is rarely indicated.

In contrast to metastatic calcification, laboratory findings are usually within normal limits. Some metabolic abnormal findings may be found as a predisposing factor to CT such as type 2 diabetes and hypothyroid conditions [16].

#### **5. Pathomechanism**

There are two most accredited proposed mechanisms for CT: degenerative, which highlights similarities with degenerative lesions of the rotator cuff, and reactive, proposed by Uhthoff and Loehr, which suggests that deposition of calcium in the tissues is a cell-mediated process that is followed by spontaneous resorption [15, 16].

The degenerative calcification theory proposes that CT is a form of dystrophic calcification of the tendon that follows an ischemic, degenerative, and necrotic phase, secondary to wear and tear, overuse and microinjury all attributable to aging. In the shoulder, it is suggested that the pathogenesis of both cuff tears and calcific tendinopathy are identical. The concept of there being a specific area in the supraspinatus tendon susceptible to calcification and tearing was first proposed by Codman. This is supported by the observation that CT seldom affects people before the fourth decade [25–27], although studies on correlation between rotator cuff tear and CT showed conflicting results. Another objection is that CT can be observed, not only in the supraspinatus and subscapular tendon within the "avascular critical zone," but also in the subscapularis and teres minor tendon outside the "avascular critical zone".

In contrast, Uhthoff proposed a different mechanism, which is an active calcification followed by resorption and tendon remodeling. The reactive calcification theory involves four phases (pre-calcific, formative, resorptive, and healing). In pre-calcific phase, the fibrocartilaginous focus was developed on extracellular matrix of tendon. Matrix that will be filled with calcium in the calcific phase. In resorptive phase, macrophage and giant cell migrates surrounding the calcification site and begins phagocytosis. In the post-calcific phase, fibroblast proliferation occurs, followed by remodeling of the affected tendon. Uhthoff regards the transformation of fibrocytes into chondrocytes as the initial stage. He was not able to find any similar metaplasia in the case of rotator cuff rupture. Therefore, he concluded that CT and rupture of the rotator cuff have no common degenerative preconditions. The data shows peak at 50 years of age and fail to show that trauma and overuse as risk factor; dominant hand is not more frequent than non-dominant, and it is not more prevalent in heavy jobs. This view is also supported by a variety of imaging studies demonstrating a complete resolution of the calcium deposits. This is confirmed later by several studies [1, 28, 29]. The concept has been challenged by Refior, who was able to prove the simultaneous incidence of rotator cuff ruptures and intra-tendinous calcification in 13 of 22 cases of rotator cuff ruptures. The coexistence of CT and rotator cuff tear is not as rare as previously mentioned. A total of 28%' of patients with CT revealed rotator cuff tear with arthrography study, and five of these were confirmed at surgery [30].

It has been reported in subsequent studies that endocrine disorders (thyroxine, estrogen, insulin) and genetic factors may also be related to the development of CT and affect resolution process.

Long-term data on the natural history of CT vary greatly. Gärtner et al. reported an 85% chance of natural resolution after 3 years for type III deposits, as opposed to 33% for type I and II deposits. In his classic study, Bosworth reported that 6.4% off calcific lesions showed spontaneous resorption.

Neer proposed four types of pain on CT in shoulder. The first type is characterized by pain caused by chemical irritation as a result of the calcium deposits. The second type involves pain caused by increased local pressure within the tissue as it swells. The third type causes impingement-like pain through bursal thickening and irritation by prominent calcium deposits. The fourth type reflects pain caused by chronic stiffness of the glenohumeral joint, such as frozen shoulder [31].

#### **6. Treatment**

No treatment is indicated in incidental findings of CT without symptoms.

#### **6.1 Acute stage**

This stage represents resorption phase, characterized by acute exquisite focal tenderness with restriction of joint movement, possibly from chemical irritation of calcific deposit. This is associated with The French Arthroscopy Association radiologic type C, with fragmented or nodular appearance on ultrasonography [32]. Although anti-inflammatory drugs, analgesics, and steroid injections had been recommended, ultrasound-guided percutaneous lavage should be the main treatment option, since it has been largely successful in reducing the pain dramatically and removing calcium deposits. ESWT is not feasible because of the associated pain, and there is no indication for more invasive therapeutic measures such as surgery in this stage [33, 34].

#### *6.1.1 Percutaneous lavage of rotator cuff calcific tendinitis (barbotage)*

Patients sit whilst putting the affected forelimb behind the back in cases of supra and infraspinatus, and externally rotated in for subscapularis CT. The affected shoulder is facing the operator and the ultrasonography monitor is placed on contralateral side in line with the operator. With aseptic technique, deposits are identified using the Ultrasound linear probe, 12−17 MHz, and entry is made into the deposit, with inline technique, after anesthetizing the pathway. Procedure can be done using large bore needle 18−20G especially if the calcific lesion is hard, or regular 23G needle in cases of soft lesion, with syringe filled with lidocaine. The tip of the needle should be placed at the soft spot of calcific deposit, and the needle should be aimed upward to allow gravity to help facilitate calcific material not returning into the deposit cavity. Some amount of lidocaine is injected by pulsating technique into the lesion, and the dissolved calcium will enter syringe, passively. Repeat injections until the syringe fluid is saturated with the material. Further same procedure continued with saline until no calcific material can be extracted anymore. The puncture and aspiration can be done with 1 or 2 different needles according to preferences. Furthermore, the needle is pulled out slowly until it reaches subdeltoid bursa space, and 20–40 mg triamcinolone mixed with 2 cc lidocaine 2% and 10 cc normal saline is injected. After treatment, the patient is advised to rest his shoulder for several days and avoid abovethe-shoulder activity for approximately 3 weeks.

#### **6.2 Chronic stage**

Chronic stage of the disease may represent calcific, resorptive, and remodeling phases of the disease. Patient complained of chronic, inconsistent pain that sometimes interferes with daily living and can last for years, especially with shoulder abduction. Tenderness can be felt on the calcific deposit site. Some combined with mechanical impingement pain due to bursal thickening that is best shown with dynamic ultrasonography examination (**Figure 3**).

On newly diagnosed untreated CT with mild symptoms and of radiologic type A, conservative measures such as anti-inflammatory drugs, analgesics, and physiotherapy can be initiated with the aim of stimulating vascularization of the tendon and hence improving the conditions for resorption of the calcium deposit. Subacromial steroid injection could be offered in cases with combined impingement syndrome (**Figure 4**).

In calcification radiologic types A and B, complementary focused ESWT or UGN can be offered to disintegrate the calcium deposit. Both methods had shown clinically significant improvement in function and pain, although UGN shows superiority in calcium resorption [35–37].

#### **Figure 3.**

*(A) Clinical image and (B) ultrasonographic image showing needle positioning (red arrow) towards calcium deposit during ultrasound-guided percutaneous lavage of subscapular tendon of the patient from Figure 2, showing saturated syringe content.*

#### **Figure 4.**

*Post percutaneous lavage shows saturated saline-filled syringes (A), (B), (C) consecutively and (D) saturated lidocaine-filled syringe.*

Ultrasonography-guided needling could be repeated after 3 months if the calcific deposit remains, and symptoms persist even if it were previously possible to partially extract the calcium. Finally, steroid injections may be recommended when the calcification has become poorly defined on imaging and it is no longer possible to puncture it. The disappearance of the calcification between 3 and 12 months is also observed in one-third of patients, without any additional treatment [38].

#### *6.2.1 Surgery*

Since surgery has a significant risk of iatrogenic tendon tear, it is usually reserved for failed conservative treatment only, especially if it is combined with concomitant lesions such as intraarticular, rotator cuff tear, and impingement syndrome. It consists of open or arthroscopic removal of calcific deposit, with or without tendon

repair and decompression with excellent short and mid-term clinical outcomes. But it has shown to have slow recovery of functional scores with majority of patients needing 6 to 12 months to recover [39–42].

#### *6.2.1.1 Arthroscopy removal of calcific deposit*

Patient is positioned in either lateral decubitus or beach chair position under general anesthesia, according to the surgeon's preference. Firstly, diagnostic arthroscopy of the glenohumeral joint is performed to address any intra-articular pathology with standard posterior portal. Then, the arthroscope is moved to the subacromial space. A lateral portal is then created above the calcific deposit and bursectomy is performed around the suspected calcific deposit. The calcium deposit is located using probe or by percutaneous needling. Hypervascularization, bulging, or calcific substance might be identified from the bursal site. The overlying tendon is then carefully incised longitudinally using a No. 11 blade and the calcific deposit is then removed by using a probe and motorized shaver. Inaccurate identification of the site of the calcification may result in iatrogenic tendon tears [43]. Intraoperative ultrasound has been reported to increase accuracy of calcific location. The arthroscopic surgery should be converted to mini-open surgery in case of unsuccessful identification of calcific deposit [17].

The surgeon should avoid overzealous calcium deposit removal and should err to incomplete removal to avoid unnecessarily large defects that may be challenging to repair. The remaining tendon after excision of the calcium deposits may not hold the repair. It also may result in excessive tension during margin convergence of the cuff. Although several authors reported shoulder better function in whom complete removal had been achieved [24, 44, 45], recent studies showed that it was not important to remove all the calcific deposit. Residual calcification was resorbed within 6–12 months of the surgical treatment and there were no significant differences in outcomes between patients with and those without complete removal of calcific deposits [39, 40, 42]. The postoperative spontaneous resorption of the remnant calcification may explain the similarity in clinical outcomes between patients whose calcific deposits were completely removed and those whose were not.

Whether it is necessary to repair rotator cuff defect after calcific debridement is debatable. Although rotator cuff repair had been reported to have superior functional outcomes, it had been also related to prolonged recovery [42, 46, 47], and stiffness. Most authors still recommend repairing large defects or encompassing significant thickness of tendon cuff width [48]. That is why surgeon should aim to remove calcific deposit conservatively, using combination of shaver and probe, preserving surrounding healthy tendon as much as possible with longitudinal opening. If large defects resulted despite all efforts, repairing the tendon with side-to-side suture is preferable, which is feasible in majority of cases (**Figure 5**).

#### *6.2.2 Rehabilitation*

Since surgery on CT had been shown to have a slow recovery, it is imperative to inform patients before treatment that pain may persist for up to 6 months of the treatment.

No special rehabilitation regimen is prescribed in CT debridement without cuff repair. Several days of rest in a sling are followed by gradual passive and active ROM

**Figure 5.**

*Subacromial arthroscopic view of (A) supraspinatus calcific tendinitis bulging with hypervascularization on the surface, (B) debridement of calcific deposit, and (C) post debridement.*

as tolerated. Patients refrained from excessive load exercises for the first 6 postoperative weeks to avoid disturbance of tendon healing.

In cases with significant defects and cuff repairs, early rehabilitation should be performed to prevent secondary stiffness and shoulder abduction splint is worn for 3 to 6 weeks according to rotator cuff repair protocol [42].

#### **7. Complications**

The progression of natural course of untreated disease leads to following complications, although some may also happen postoperatively as well [19].

#### **7.1 Adhesive capsulitis**

Adhesive Capsulitis, also known as frozen shoulder can be predisposed by factors inside the shoulder (Fracture, shoulder inflammation, CT) or by extra-articular factors (type 2 diabetes, hyperthyroidism). Some researchers also agree that prolonged immobilization can be a factor predisposing adhesive capsulitis [49, 50]. In symptomatic cases of CT, the calcification may cause severe pain and therefore may induce voluntary immobility. In cases of chronic CT, pain may have subsided, but limited range of shoulder motion is almost always noted, in which adhesive capsulitis becomes the common sequela. On another hand, adhesive capsulitis may be associated with the inflammation that's happening within the surrounding structures of the shoulder, and as previously mentioned, systemic diseases such as diabetes can be a predisposing factor to both CT and adhesive capsulitis. A study done by Jacobs et al. also showed that 18% of patients who underwent arthroscopy removal of the calcification experienced adhesive capsulitis and was suggested due to irritation of shoulder capsule by the residual calcium debris [51].

#### **7.2 Greater tuberosity osteolysis**

Greater tuberosity osteolysis is one of the rare complications of CT. A study done by Porcellini et al. shows that calcium deposits that come in contact with the tuberosities have consistently caused cortical lesions. This cortical lesion that happens due to biochemical effects of bone lysis can lead to insertion of calcification into the bone, which may cause further pain [52].

#### **7.3 Ossifying tendinitis**

Ossifying tendinitis is also a rare complication of CT. Ossifying tendinitis usually happens due to trauma or surgical intervention in the Achilles tendon, gluteus maximus tendon, and distal biceps. A case series and literature review by Merolla et al. found ossifying tendinitis histologically when performed a CT arthroscopy removal. Two cases were described showing persistent shoulder pain that was previously diagnosed as CT, but when removal was done, the calcification was found to be hard. Histological examination showed bone metaplasia. It was hypothesized that ossification happened because of mesenchymal cell transformation to bone-forming cells as a result of the calcification excision previously done [53].

#### **8. Conclusion**

Although CT is a transient disease that has self-healing nature, it can result in severe acute or prolonged chronic pain. X-ray, and ultrasonography are the most essential investigation for diagnosis and treatment plans. Conservative treatment should be the main treatment in newly diagnosed CT with mild symptoms, but more aggressive treatment is frequently needed in acute phase or unresponsive chronic phase. Ultrasound-guided percutaneous needling and lavage had been shown to effectively reduce pain and remove calcific deposits. It can be repeated in the lessresponsive cases. Surgery role is limited. It should be reserved only for failed conservative treatment. Preservation of surrounding living tissue of the calcification during debridement should be a priority since residual calcification from incomplete excision can be resorbed spontaneously.

#### **Acknowledgements**

We thank Earlene Tasya Suginawan, MD for the assistance with English redaction and references that greatly improved the manuscript. We also thank Troydimas Panjaitan, MD for letting us use his arthroscopy images.

#### **Conflict of interest**

The authors declare no conflict of interest.

*Calcific Tendinitis: Limited Role of Surgery DOI: http://dx.doi.org/10.5772/intechopen.107511*

#### **Author details**

John Christian Parsaoran Butarbutar Faculty of Medicine Universitas Pelita Harapan, Department of Orthopaedic and Traumatology, Tangerang, Indonesia

\*Address all correspondence to: john.butarbutar@lecturer.uph.edu

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Nahum Rosenberg*

The biological and mechanical connection between muscles and bones is made by tendon tissue. The physiological function of tendons is to enable joint movements by transmitting the force of muscle contraction. Due to their connective tissue content, tendons have semi-elastic properties and are thus vulnerable to structural failure and inflammatory degeneration, both of which have extremely disabling effects, particularly pain and hampered joint function. This book examines the causes of mechanical and inflammatory structural pathologies of the tendons and related therapeutic approaches for managing these injuries and conditions.

Published in London, UK © 2023 IntechOpen © tonaquatic / iStock

Tendons - Trauma, Inflammation, Degeneration, and Treatment

Tendons

Trauma, Inflammation,

Degeneration, and Treatment

*Edited by Nahum Rosenberg*