Advances in biomaterials for preventing tissue adhesion

Journal of Controlled Release 261 (2017) 318–336

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Journal of Controlled Release journal homepage: www.elsevier.com/locate/jconrel

Review article

Advances in biomaterials for preventing tissue adhesion a,b

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T a

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Wei Wu , Ruoyu Cheng , José das Neves , Jincheng Tang , Junyuan Xiao , Qing Ni , Xinnong Liub, Guoqing Pana, Dechun Lia, Wenguo Cuia,⁎, Bruno Sarmentoc,d,e,⁎ a Department of General Surgery, The First Affiliated Hospital of Soochow University, Orthopedic Institute, Soochow University, 188 Shizi St, Suzhou, Jiangsu 215006, PR China b Department of General Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, 365 Hanjiang Middle Road, Yangzhou, Jiangsu 225000, PR China c i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-393 Porto, Portugal d INEB − Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal e CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal

A R T I C L E I N F O

A B S T R A C T

Keywords: Anti-adhesion Biomimetic scaffold Electrospun fibers Biomaterials

Adhesion is one of the most common postsurgical complications, occurring simultaneously as the damaged tissue heals. Accompanied by symptoms such as inflammation, pain and even dyskinesia in particular circumstances, tissue adhesion has substantially compromised the quality of life of patients. Instead of passive treatment, which involves high cost and prolonged hospital stay, active intervention to prevent the adhesion from happening has been accepted as the optimized strategy against this complication. Herein, this paper will cover not only the mechanism of adhesion forming, but also the biomaterials and medicines used in its prevention. Apart from acting as a direct barrier, biomaterials also show promising anti-adhesive bioactivity though their intrinsic physical and chemical are still not completely unveiled. Considering the diversity of human tissue organization, it is imperative that various biomaterials in combination with specific medicine could be tuned to fit the microenvironment of targeted tissues. With the illustration of different adhesion mechanism and solutions, we hope this review can become a beacon and further inspires the development of anti-adhesion biomedicines.

1. Introduction Adhesion is caused by the interweaving of fibrin from extensive interstitial fluid leakage, being the result from various conditions such as surgical incision, trauma and other pathological situations [1]. When granular tissue rich in capillarity gradually replaces necrotic tissue, a fibrinous network forms in situ, which can ultimately causes fibrinous adhesion and subsequent dysfunction of the tissue. Briefly, a colloidal matrix of fibrin forms within three hours after injury, marking the starting point of granulation tissue infiltration. Fibroblasts [2] and macrophages [3] recruited to local damaged tissue, together with the fibrin matrix, form granulation tissue in one to three days. Subsequent increase in fibroblast and macrophage numbers in day four helps forming the fibrinous network. Approximately two weeks after injury, fibrous adhesion takes shape in situ, along with the disappearance of most cells in the network. Strategies for preventing adhesion usually proceed from either the management of damaged tissues or the application of biomaterials. Tissue-based methods involve cutting off adhesion forming processes, specifically by alleviating the inflammation and exudation of focal

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tissues, restraining the deposition and clotting of fibrin and protection of wound surface from friction. As one of the main cell types responsible for of the production of fibrin and initiating tissue overgrowth, fibroblasts are also the target of anti-adhesion treatment. Suppression of these cells has also been widely explored in preclinical trials. As for biomaterial-based methods, anti-adhesion is usually achieved by taking advantage of the physical and chemical properties materials. In another words, biomaterials act as physical barriers or bioactive agents able to suppress the formation of adhesion. This article will start with a systematic review of different types of problems related with tissue adhesion that are common during clinical work, along with their corresponding mechanisms. Prevention of adhesion with various biological scaffolds, membranes and drugs will then be summarized and critically appraised in order to look towards the future development of anti-adhesion biomaterials. 2. Adhesion disease In clinical practice, fibrous adhesion typically involves tissues such as tendon [4], dural sac [5], intestinal [6], peritoneum [7], pericardium

Corresponding authors. E-mail addresses: [email protected] (W. Cui), [email protected] (B. Sarmento).

http://dx.doi.org/10.1016/j.jconrel.2017.06.020 Received 7 May 2017; Received in revised form 19 June 2017; Accepted 20 June 2017 Available online 23 June 2017 0168-3659/ © 2017 Elsevier B.V. All rights reserved.

Journal of Controlled Release 261 (2017) 318–336

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scar tissue may prevent the formation of adhesion. Thus, a series of studies on this “barrier” was conducted in order to reduce the postsurgical damage of nerve root due to adhesion. Basically, epidural adhesion comes from epidural scar tissue, in which fibroblast plays a pivotal role during its formation. A number of minor reasons such as inflammation and hematoma are considered to promote adhesion by affecting fibroblast are summarized in the following. Hematoma and inflammation resulting from trauma, infection and foreign matter play important roles during the formation of epidural scar. Inflammatory mediators such as prostaglandin, leukotriene, interleukin-1 (IL-1) involved in the activation and chemotaxis of fibroblasts, promote the generation of scar tissue and subsequent adhesion. Dural hematoma can also act as mediator of scar tissue as it can be infiltrated by fibroblasts and ultimately result in the spread of adhesion into the spinal canal. Furthermore, growth factors such as transforming growth factor beta (TGF-beta), platelet derived growth factor and fibroblast growth factor released from hematoma promotes the proliferation and differentiation of fibroblasts. Therefore, inhibiting the formation of hematoma or accelerating hematoma degradation plays an important role in the prevention of epidural adhesion. Illustration of epidural adhesion is shown in Fig. 1.

and uterine. Besides normal symptoms such as pain, dyskinesia and paralysis, adhesion in specific organs such as the uterine cavity and oviducts can result in organ-specific symptoms such as menoxenia and reproductive dysfunction. Incidence of life-threatening illnesses such as ileus and cardiac failure can also be traced to adhesion in corresponding tissues. Therefore, the issue of adhesion is a major cause of severe pain and heavy economic burden globally, which prompted the development of anti-adhesion biomaterials and medicines. 2.1. Tendon adhesion Considered to be closely associated with its healing mechanism, adhesion of tendons accounts for most problems in the motor system such as articular dyskinesia and periarthritis. Both endogenous and exogenous factors contribute to the healing of tendons. In the process of endogenous tendon healing, the stimulation of bioactive factors contained in synovia promotes proliferation and surface or internal migration of tenocytes. Exogenous healing depends on exogenous fibroblasts proliferating in the granulation tissue that grows into the defect of the damaged tendon. This mechanism tends to result in scarring during healing, which subsequently develops into fibrous adhesion and ultimately affects the contraction of the tendon [8]. An imbalance of endogenous and exogenous healing, attributed to the various locations and degree of damage to the tendon, is recognized to be responsible for adhesion. Improper postsurgical movement of the damaged tendon is also thought to be associated with enhanced exogenous healing and corresponding adhesion. During this type of healing process, an increased number of fibroblasts in the local microenvironment is observed as the result of migration from peripheral tissue to the margin of the tendon defect. This leads to vast deposition of fibrin, which causes adhesion between the tendon and peripheral tissue. Apart from that, focal inflammation contributing to increased exudation can also aggravate fibrin leakage in defect site. As the mechanism of tendon adhesion is widely reported, several findings at the molecular level can be seen as key events. Derby et al. found a gene with increased expression at the healing site of a tendon wound and the matrix of scar tissue where inflammatory cells were infiltrating. Named as Reactive gene-1 [9], the expression product of this gene can enhance exogenous healing and aggravate adhesion. A protein named Smad3 whose overexpression can result in more severe adhesion was reported by Loiselle et al. [10] and Katzel et al. [11]. It is hypothesized that suppressing the expression of this protein can decrease the focal deposition of collagen, hence alleviating scar formation. Also, the presence of matrix metalloproteinase 9, derived from bone marrow, at healing site is reported to promote adhesion, although a specific mechanism is still under debate. Illustration of tendon adhesion is shown in Fig. 1.

2.3. Pericardial adhesion Proceeding with the leaps of medical technology at the end of the 20th century, sophisticated techniques involved in cardiac surgery became commonplace in clinical practice. Such interventions include aortocoronary bypass surgery and valve replacement surgery, which used to be considered impossible. However, these procedures were accompanied by degeneration of implants and other complications. The rate of secondary surgery thus rose over time, which meant a larger number of cardiac surgeries and greater odds for potential vascular and pericardial injury, both of which can elicit adhesion of pericardium. Also, hematoma due to intra- or post-surgical bleeding can promote scar tissue generation. As evidenced by in vivo preclinical studies, damaging of interstitial tissue due to injury, infection, ischemia and hemorrhage is considered as a necessary condition for adhesion to occur [15]. As a good example of pericardial adhesion (Fig. 1), the process after pericarditis encompasses four steps. Firstly, exudation after inflammation leads to deposition of fibrin monomer within 24 h. Secondly, following the detachment of injured mesothelial cells and fibrin deposition, cellulose deposits on interstitial tissue in the following two days. Thirdly, in the up-coming week, with the infiltration of the neovascule and lymphatic tubes, fibrin in the lesion site degrades, followed by a deposition of collagen. Finally, local adhesion forms approximately two weeks after acute onset [16]. The cause of pericardial adhesion can be primarily considered as the intra-operative peeling-off of pericardial mesothelial cells and subsequent adhesion of fibrin, platelets and inflammatory cells at the site. Over-produced fibrin and fibroblast can also break the local balance and cause deposition of scar-inducing substances.

2.2. Epidural adhesion Key, Ford et al. [12] seminal work on the Anterior Source theory about the mechanism of epidural adhesion in 1948 set intraoperative damage of intervertebral disc as the reason for postsurgical adhesion of dural sac. Yet in 1974, the Posterior Source theory from LaRocca et al. [13] stated that it is the laminectomy membrane formed due to the damage of dorsal musculus sacrospinalis that results in adhesion by means of fibroblast infiltration. Recognized by most researchers as the doctrine to follow, Posterior Source theory has guided anti-adhesion clinical work and preclinical studies for decades. With the validation of a wide range of research work, Songer et al. [14] found that not only damage to the intervertebral disc and posterior longitudinal ligament but also a wounded erector spinae can become the source of scar tissue, and subsequent adhesion can produce a tractive force on the nerve root beside the dural sac. Since then, a three-dimensional theory of adhesion forming mechanisms has gradually come into shape. Inspired by the principle of this theory, a biomedical barrier between the dural sac and

2.4. Intrauterine adhesion First reported by Fritsch in 1894, intrauterine adhesion (IUA) refers to adhesion between the uterine muscle wall or cervical canal resulting from injury to the uterine cavity or cervical canal due to various factors [17]. A detailed depiction of IUA and a large quantity of cases have long been reported by Asheman et al. and, thus, symptoms caused by IUA are also known as Asheman Syndrome [18]. As the conclusions from a retrospective study of 2981 cases from more than 90 studies of Asheman Syndrome by Schenker and Margalioth indicates, IUA can result mainly from: (i) iatrogenic injury during pregnancy such as postpartum curettage, pregnancy termination and cesarean section; and (ii) non-pregnancy injury of the uterus such as curettage, uterus tumor rejection, cervical biopsy or polyp resection, placement of IUD and 319

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Tendon adhesion (a)

Pericardial adhesion

Abdominal adhesion

Epidural adhesion Intrauterine adhesion

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(k) (i) (g)

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Fig. 1. Illustration of tissue adhesion: (a–c) Tendon adhesion; (d–f) Pericardial adhesion; (g–h) Abdominal adhesion; (i–j) Epidural adhesion; and (k–n) Intrauterine adhesion [#]. #: a–n: http://gushuini.com.cn/product/detail.php?id=1; g: http://www.cmt.com.cn/; i: http://blog.sina.com.cn/s/blog_672c64830100wmc3.html; k–m: http://www.jiangjiama.com/ wenzhang/2015/1118/680777.html.

proteins and cytokines in the blood, abdominal hematoma can be the concomitant factor along with the above factors that results in severe abdominal adhesion. While congenital factors are rarely involved in peritoneal adhesion, the aforementioned factors are mainly responsible for adhesion [20]. As the serous with largest covering area and complex distribution in vivo, the peritoneum possesses self-healing and defensive functions, which are however involved in the mechanism of peritoneal adhesion. Both mesothelial cells and fibroblasts from peritoneum tissue is capable of secreting fibrin to heal and strengthen the serous. Under physiological conditions, deposition and degradation of fibrin regulates homeostasis which is yet fragile against pathological factors such as inflammation, mechanical damage and ischemia. With such stimulation, fibrinogen can be over-produced via proliferating fibroblasts [21,22]. On the other end of the balance, however, the bioactivity of major prodegradation factor t-PA is significantly suppressed in the aforementioned conditions. This neutrophil- and macrophage-derived active factor is responsible for the activation of plasmin and subsequent degradation of fibrin through the breakdown and liquefaction of fibrin backbone. Due to the pathological microenvironment brought by inflammation and ischemia, t-PA could be inactivated via various chemical or physical stimuli such as fluctuant pH and pathological enzymatic clearance [23]. Hence, under such circumstances, fewer bioactive plasmin is not enough to degrade over-produced fibrin. Taken together, excessive fibrin deposits and interweaves into networks on the peritoneum, ultimately leading to adhesion.

irradiation. While acute intrauterine infection and genital tuberculosis can significantly increase the risk for IUA, the role of chronic and subacute endometritis related to IUA is still under debate. Genetic defects such as congenital uterine malformation can also be the source of adhesion. So far, TGF-beta 1 is believed to be the major factor responsible for promoting activity of fibroblast in forming of intrauterine adhesion through specific binding with its receptor on fibroblast membrane. Additionally, with matrix metalloproteinases-9 (MMP-9) in the extracellular matrix (ECM), homeostasis between deposition and degradation of ECM could be easily disrupted in various pathological states when MMP-9 is abnormally expressed. Similar effects were also reported on insulin-like growth factors-1 (IGF-1) acting as the promoter of ECM deposition. Known as the key enzyme in fibrinolytic system, tissue plasminogen activator (tPA) could activate fibrinase into fibrinogen to take part in adjustment of fibrinolytic activity, thus also significantly affecting metabolism of fibrin in adhesion forming process. Illustration of intrauterine adhesion is depicted in Fig. 1. 2.5. Peritoneal adhesion Defined as the adhesion between surfaces of the peritoneum of posttrauma or post-surgery scar tissue, peritoneal adhesion has been not only the most common complications after abdominal surgery, but also the most common pathology of intestinal resistance. Due to the prevalence of surgical techniques such as electrocoagulation, ultrasound or laser resection, peritoneum is more likely to suffer from dense scaring, thus its tendency to form adhesion postsurgically. Apart from these techniques, not so tissue-friendly allogenic tissue left behind in the abdominal cavity after surgery can also be the source of scar tissue. Besides, immune reaction and radioactive material also tend to elicit tissue damaging and promote adhesion [19]. Due to the abundant

3. Biomaterials in the prevention of adhesion As the further development of scar tissue derived from tissue damage, infection and hematoma, adhesion between originally independent tissues, as a consequence of scar tissue derived from tissue 320

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Table 1 Natural materials tested for preventing adhesion. Material

Structural formula

Advantages

Disadvantages

References

Hyaluromic acid and derivatives

Non-immunogenic Anti-inflammatory Lubricating

Short resident time

[21–27]

Chitosan and derivatives

Hemostasis Anti-inflammatory

Low yield

[28–34]

Trehalose

Protectant Resist desiccation Anti-inflammatory

Expensive

[35]

Pullulan

Strong adhesiveness Biodegradable

Complex process

[36]

Phospholipid

Reduce surface Tension Lubrication Anti-inflammatory

Prone to oxidation Easily metabolized

[37–38]

Gelatin

Soft Hemostasis Breathability

Prone to friction

[39–40]

3.1. Hyaluronic acid and derivatives

damage, infection and hematoma has been a significant cause of concern due to its threat towards quality of life and associated economic burden. Hence effective control over local inflammation and protection of damaged tissue has become pivotal to prevent adhesion. Aiming to repair or substitute human tissues, high-tech biomaterials underwent significant progress in the last few decades. With the integration of specific drugs into the material, manufactured scaffolds or membranes possess both the physical and chemical elements to aid against adhesion, making them inherently superior over drug therapy alone. Predominant bioactivity promoting proliferation and differentiation of local cells, and tunable degradation rate matching tissue regeneration, along with proper biocompatibility and appropriate mechanical properties, may turn biomaterials suitable for anti-adhesion applications. Apart from metallic and inorganic materials such as bioactive ceramics and hydroxyapatite, organic molecules, mostly polymers, account for a large share of used biomaterials. Both natural materials such as collagen, silk fibroin, fibrin, chitosan (Table 1) and synthetic polymers, such as polylactic acid, ployurethane and polyvinyl alcohol (Table 2) can be engineered in order to yield different biological, mechanical and even controlled drug-release properties. Therefore, various materials hold great potential for preventing tissue adhesion.

Hyaluronic acid (HA) is a non-specific hydrophilic polysaccharide with a linear structure. It exists in synovial fluid and ECM of tissues such as cartilage and skin. With a monomer composed of a D-glucuronic acid and an N-acetylglucosamine, bioactivity of HA vary according to its molecular weight (MW). HA with a MW larger than 2 × 106 Da possesses anti-inflammatory properties and superior viscoelasticity, while HA with 1–2 × 106 Da tends to be moisturizing and lubricating and suitable for controlled drug release-HA with MW smaller than 8 × 104 Da was found to be effective in anti-tumor, immunomodulation, and tissue regeneration of bone and vessels. HA with MW larger than 1 × 106 Da is applied in the field of anti-adhesion biomaterials due to its outstanding performance as a physical barrier. Briefly, HA with large MW could take up larger space which also means better barrier effect. Inversely, low MW HA lacks enough size to oppose adhesion. HA matrices can provide a three-dimensional microstructure for cell adhesion and proliferation. The inherently disordered network structure of HA can also separate adjacent wound surfaces, thus reducing friction. Moreover, intrinsic negative charge of HA has an inhibitory effect on both proliferation and migration of fibroblasts, which

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Table 2 Synthetic polymer tested for preventing adhesion. Polymers

Structural formula

Advantages

Disadvantages

References

ePTFE

Flexibility Biodegradable

May cause adhesion

[41–42]

PLGA

Controllable degradation

Inflammation

[46–47] [57,63]

promoting physiological tissue regeneration instead of scar tissue, thus potentially acting as an anti-adhesion biomaterial. In addition, the effects of chitosan on hemostasis reduce adhesion. Significant suppression over proliferation of fibroblasts was reported by Parida et al. [31] according to cell morphology on material and increased cells in quiescence, and is considered as the mechanism behind the anti-adhesion property of chitosan. Lauder et al. [32] reported the application of succinylated chitosan hydrogel together with dextran against peritoneal adhesion. Preventive effects were also reported on rat postsurgical intra-articular adhesion model by Wang et al. [33], presumably due to the suppression of fibroblast proliferation and collagen deposition. Fang et al. [34] reported on a thermosensitive hydrogel made of chitosan presenting a sol-gel transition able to maintain gel state at physiological temperature. Such injectable semisolid material provided an anti-adhesion barrier with flexible shapes, hemostasis and anti-bacterial property. When tested by Zhang et al. [35] after laminectomy, a chitosan membrane showed significant preventive effects in tissues surrounding the membrane. Similar results with even better tissue affinity were obtained through composition of chitosan and dextran. Carboxymethylated chitosan showed similar molecular structure of hyaluronic acid and was reported to produce adhesion with lower density after application through pericardial perfusion by Daroz et al. [36]. Clinical use of chitosan is no more confined to the material itself, instead, expanding towards different forms through various processing technologies such as the preparation of chitosan microspheres and various functionalization methods.

are considered the culprit of adhesion. On the other hand, while directly acting as a placeholder, HA also reduces local bleeding, resulting in fewer fibrin deposition. Thus, both the biological and physical properties of HA endow it with promising features useful for application in anti-adhesion treatment. Hayashi et al. [24] found that a biodegradable HA/hydroxymethylcellulose composite membrane applied intraoperatively could significantly reduce the risk of intestinal resistant after gastrectomy, which frequently results from postoperative intestinal and peritoneal adhesion. Similar results were obtained using a membrane made of HA and 1,4-butanediol diglycidyl ether by Ji et al. [25]. Seprafilm, a degradable biological membrane, was proved to effectively suppress adhesion only at the area that the membrane covers, as reported by Sheldon et al. [26]. Data from these researchers also emphasized the safety of the material. The membrane applied in the form of sprays was also reported to effectively reduce adhesion without affecting the healing of normal tissue, bringing more convenience to clinical practice. When combined with gellan gum and xanthan gum, an HA membrane successfully prevented adhesion in a rat tendon adhesion model [27]. When compared with Seprafilm, the membrane had no negative effect on the mechanical properties of the repaired tendon, and endured for longer period in vivo, thus providing a sustained barrier for suppressing adhesion. As reported by Wang et al. [28], a HA hydrogel could significantly lower the risk of postsurgical epidural adhesion and subsequent lower back pain when deployed after laminectomy. Based on the model of the New Zealand white rabbit, Liu et al. [29] also reported smaller chance of epidural adhesion in the early phase after surgery, yet long-term outcome failed to prove the same efficacy. Apart from compositions of HA with or without other polymers, derivatives of HA such as Carbylan-SX were also tested in preclinical trials. As an example, Connors et al. [30] reported the superiority of Carbylan-SX over the commercially-available Seprafilm in the rabbit pericardial adhesion model. Due to its biocompatibility and biodegradability, HA has gained popularity in clinical practice. However, this is not the ideal biomaterial as HA alone can barely satisfy all needs. Problems such as insufficient endurance in vivo still trouble its further application. Hence, functionalization and composition of HA is desired for future trials and clinical translation.

3.3. Trehalose The molecular structure of trehalose endows it with unique physicochemical properties, as the monomers are connected through glycosidic bonds. Hence, the rigid structure and clamshell shape of trehalose makes it a suitable substitute for the water molecule in phospholipid bilayer to protect the integrity of cells, as demonstrated on artificial phospholipid bilayer. Therefore, application of trehalose is supposed to protect mesothelial cells from damage and prevent adhesion. Based on observed injury and dryness related to wear between tissues after hysterectomy, Fujino et al. used 7% aqueous solution of trehalose to prevent intrauterine adhesion due to its anti-dryness and anti-inflammatory effect. The preventive effects of trehalose on mesothelial cells from damage related with dryness in vitro was also verified by Atsushi et al. [37]. Through the evaluation of different amounts of trehalose, the optimized concentration of 3% was found to reduce adhesion between the intestinal wall and surrounding tissues in a rabbit adhesion model. Hence, aqueous solution of trehalose holds great potential, and is an emerging strategy when employed in combination with physical barriers.

3.2. Chitosan and derivatives Chitosan is a glucosamine resulting from the partial deacetylation of chitin, the main component of exoskeleton of crustacean. It possesses considerable biocompatibility and bioactivity and its degradation rate is tunable according to the degree of deacetylation (DD). Inherent selectivity in promoting the proliferation of epithelial and endothelial cell while suppressing that of fibroblasts make chitosan suitable for

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3.4. Pullulan

3.7. Expanded polytetrafluoroethylene (ePTFE)

Produced via fermentation of Spodoptera littoralis, pullulan is a polysaccharide possessing a molecular structure similar to dextran and xanthan gum. With trisaccharide repeating units connected by α-1,4glycosidic bonds and further polymerized via α-1,6-glycosidic bonds, pullulan holds great stretchability and water-solubility. When dissolved in water, pullulan displays strong tissue adhesive properties, endowing this polysaccharide with long-term in vivo residence, thus achieving the basic requirement of a physical barrier. Furthermore, the biodegradability of pullulan eliminates the need for a secondary surgery to remove the barrier when its job is done, bringing convenience to both patients and surgeons. Sumi et al. [38] functionalized pullulan polysaccharide through 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) reactions. Injectable pullulan polysaccharide hydrogel was obtained via reaction between functionalized polysaccharide and horseradish peroxidase. Tough anti-adhesion properties in vivo were shown for this hydrogel and corresponding in vitro cell experiments also confirmed significant suppression of fibroblast proliferation.

Expanded polytetrafluoroethylene (ePTFE) is an emergent medical polymer produced from polytetrafluoroethylene via special treatment such as stretching process. Greater elasticity and flexibility of ePTFE enable it to bend at will, while microfiber composition provides ePTFE with mesh structure and micropores. Also, good biocompatibility and resistance to aging of ePTFE indicates that this polymer may be a potential candidate for preventing adhesion. Anisotropic structure of ePTFE with one porous surface allowing for fibrous tissue ingrowth and one smooth surface acting as contact surface with wounds is reported to reduce the traction force on nerve root in epidural adhesion. Smooth and non-adhesive dural sac in patient epidural adhesion model supplied with ePTFE membrane was reported by Kawaguchi et al. [43]. These researchers proved the efficacy of the material in cardiac surgery. In particular, an ePTFE membrane was applied as the substitute for pericardium, serving as a physical barrier to prevent heart and aorta from contacting with bone structure and reducing friction during breathing movement. Yet contradictory conclusions were reported by Backer et al. [44]. This last group reported that there were no significant differences between tissue adhesion with or without ePTFE. However, when mixed with poly lactic acid (PLA), promising anti-adhesion effect were again apparent, with similar results reported by Naito et al., bringing hope for further use of ePTFE. Overall, literature about ePTFE seems to provide ambiguous information on this polymer. Possible immune rejection and potential to provide scaffolds for adhesion growth puts ePTFE in an undefined situation. Therefore, further exploration of ePTFE is still needed.

3.5. Phospholipids Phospholipids are the main component of biological membranes and the natural components in the abdominal cavity. These molecules are amphiphilic, consisting of a hydrophilic end containing nitrogen or phosphorus and a hydrophobic hydrocarbon chain. Able to be dissociated from peritoneal effusion, phosphatidylcholine is found to effectively reduce the surface tension and hydrophobicity of the membrane. Lubrication performance of phosphatidylcholine is also outstanding through complete phosphatidylcholine coverage of the peritoneum, producing a liquid barrier that separates surfaces from each other, thus reducing adhesion. Kyriakos et al. [39] proved that phospholipids have the ability to significantly suppress adhesion, relief inflammation and restrict mesothelial cell from fibrosis after intraperitoneal administration. Pulmonary surfactant is a multi-component complex secreted by type II alveolar epithelial cells containing phospholipid and specific protein, and primarily functions as a stabilization element of alveoli. Inspired by the physical function of this complex, Yavuz et al. [40] applied pulmonary surfactant to prevent adhesion and found a fibrin dissolution effect elicited by the complex, proving its anti-adhesion property.

3.8. Other synthetic polymers Apart from their facile synthesis and functionalization when compared to natural competitors, superior biocompatibility, good chemical stability, and tunable mechanical property of different synthetic polymers also makes them suitable as physical barriers in wound dressing preventing adhesion. Polymers such as PLA [45–47], poly(lactic-coglycolic acid) (PLGA) [48,49], polyvinyl alcohol (PVA) [50] and polycaprolactone (PCL) [51] have gained increasing potential for application in clinical practice in coming years. 3.9. General considerations for selecting biomaterials Both natural and synthetic materials hold their respective merits and demerits as candidates for preventing adhesion. Although natural materials typically possess a wide range of sources, superior biocompatibility and biodegradability, their clinical application is hampered by their inferior mechanical properties, poorer output stability and difficulty in allowing further functionalization. On the other hand, synthetic materials possess good chemical stability and mechanical properties and, most importantly, the incomparable potential for further modification and functionalization. Yet their poorer biocompatibility may lead to possible onset of inflammation in vivo. Hence combining the advantages of the two major kinds of biomaterials seems to be a good option for developing anti-adhesion biomaterials. In general, choice of material(s) should be based on the specific needs for designated situations of tissue adhesion.

3.6. Gelatin Gelatin, the degradation product of collagen and the main protein of animal tissue origin, is widely applied in our daily life, from food industry to medical devices. Sponges derived from gelatin possess not only good mechanical properties but also excellent biocompatibility. Strong adhesive effect towards wound surface, hemostasis effect, and selective promotion and suppression to different cells favor gelatin as an anti-adhesive material. Tian et al. [41] tended to prevent epidural adhesions after surgery with dexamethasone-soaked gelatin sponges and found effective reduction on adhesion occurrence, while similar results were obtained on a rabbit epidural adhesion model with endorhachis healing in 2 to 12 week post operation. Recently, modification of gelatin has been proposed as the modified molecule may possess better water retaining structure, softer mechanical property and tunable degradation rate. Also abundant active groups such as amino and carboxyl endow gelatin with greater opportunities for modification. Si et al. [42] used gelatinchitosan crosslinked films to prevent adhesion and found that gelatinchitosan crosslinked films were promising systems for effective hemostasis and prevention of adhesion of scar tissue.

4. Specific medicinal structures for preventing adhesion Biomaterials play an important role in preventing tissue adhesion but a single material often cannot satisfy every aspect of clinical needs [52]. Only by engineering a single material or composite with different micro- or nanometer structure and further functionalization [53], can specific requirements be met for preventing adhesion. Different general structures based on biomaterials can be categorized as: electrospun fiber membranes [54], hydrogels [55], microspheres [56] and absorbable biofilms [57]. 323

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Liu et al. [64] packed fibroblast growth factor (bFGF) into dextran nano-glass in order to ensure its biological activity and long-acting release. bFGF-loaded PLA fiber membranes were prepared by means of emulsion electrospinning. Fiber diameters were 0.86 ± 0.24, 0.81 ± 0.22 and 0.77 ± 0.21 mm for electrospun PLLA, bFGF-PLLA and bFGF/DGNs-PLLA fiber membranes, respectively. The prepared electrospun fiber membranes could effectively prevent tendon adhesion due to their physical barrier effect and, when present, bFGF activity. Indeed, this last growth factor could not only promote the migration of endothelial cells and the proliferation of smooth muscle cell, but also inhibit the migration of smooth muscle cells, resulting in the promotion of new angiogenesis and repair of the scaring endothelial cell. In their experiment, the adhesion and proliferation of C3 cells on the surface of tissue culture plates, electrospun PLLA membrane, bFGF-PLLA membrane and bFGF/DGNs-PLLA fiber membranes were compared after one and four days. Related literature shows that when simple drugs-material blending fiber membrane is used as a drug carrier, initial burst release is substantial, which shortens the effective drug availability. When drugs are loaded on membranes there may also occur a decrease in activity due to the effect of the electric field used during preparation. The core-shell structure of electrospun fiber membranes obtained through the emulsion electrospinning technique, micro sol electrostatic spinning method and micro gel can solve the above shortcomings, thus effectively reducing biological macromolecular inactivation and initial burst release. In addition, the loading of water-soluble drugs and uniform distribution of the drug in the fiber membranes can be achieved, as depicted in Fig. 2. Zhao et al. [65] proposed that tendon adhesion caused by exogenous healing could be inhibited by adjusting the gene of apoptosis of exogenous fibroblasts and collagen synthesis. HA-PLA fiber membranes loaded with mitomycin C were prepared by means of micro sol electrospinning, allowing not only the sustained release of mitomycin C for 40 days in vitro, but also the inhibition of fibroblast proliferation and attachment, and induce cell apoptosis in vitro. Zhao et al. [66] loaded bFGF into PLGA fiber membranes by emulsion electrospinning technique. They found that bFGF had the ability to sustain the release of bioactive molecules for three weeks in vitro, which could be potentially beneficial for promoting the reconstruction of tendon-bone. Single-layer electrospun fiber membranes are unsuitable for simulating the complex structure of biological tissues. Researchers attempted to prevent adhesion and promote the effect of tissue repair, so as to simulate normal biological tissue, by constructing multi-layered electrospun fiber membranes or combining electrospun fiber membranes with other materials. For example, Li et al. [67] built a kind of double bionic tendon sheath that could release celecoxib and prevent tissue adhesion. Bionic sheath from the outer layer of poly(L-lactic acid)–PEG (PELA)–HA was used for the sustained release of the nonsteroidal anti-inflammatory drug celecoxib to attenuate inflammatory response, while the inner layer of HA- PELA was used for providing lubrication and promoting healing of tendon. Deepthi et al. [68] constructed a thin layer by merging collagen-chitosan hydrogel with a PLA electrospun fiber membrane to mimic the native tendon structure, and protein adsorption was suppressed by means of alginate coating to prevent adhesion. Kakinoki et al. [69] constructed PLA-based fibers with three layers to enhance nerve regeneration and prevent adhesion to surrounding tissue. The inner layer of 25% elastin-laminin simulated protein for promotion of neurite growth, and the middle layer of PLA gave the pipe of mechanical properties while the outermost layer of 10% PEG prevented adhesion with surrounding tissue. Wang et al. [70] constructed a multi-layer scaffold for promoting epidural restoration by electrospinning technology, with the inner PLA fiber in direct contact with the brain tissue to reduce adhesion formation, the middle layer of PCL-PLA used as waterproof sealing and the outermost layer, which contains plenty of collagen, capable of enhancing the attachment and proliferation of cells. The composite scaffold could effectively enhance the repair of dura mater and reduce the adhesion to brain tissue.

4.1. Electrospun fiber membranes Electrostatic spinning technology is a method which uses jet polymer under static electricity to spin fibers. Firstly, thousands or even tens of thousands of volts are applied to a polymer solution under high voltage static electricity produced by the action of electric field forces, causing charged polymer droplets to be accelerated in a capillary Taylor cone vortex. The polymer droplets overcome surface tension to form a jet trickle when the electric field force is large enough. The solvent evaporates in the trickle jet process, and the trickle falls in the receiving device by curing, thus forming a similar nonwoven fabric of fiber film. Electrospun fibers, whose diameter may be less than that of a cell, can simulate the structure and biological functions of natural ECM. Most tissues and organs are similar with nanofibers in form and structure, which lays the groundwork for electrospinning fibers to be used in tissue engineering. Some materials have good biological compatibility and biodegradable properties, and can be applied as active molecule carriers in the human body and degrade at proper rates. In addition, electrospun fibers, which have interesting properties such as large specific surface area and porosity, can be a physical barrier to prevent adhesion without affecting the normal functions of tissues. Compared with gels, the time it takes for electrospun fibers to degrade is much longer, which makes these suitable as a long-lasting material for adhesion prevention. Furthermore, electrospun fiber membranes can be easily functionalized, thus attracting the attention of many researchers engaged in the development of prevention strategies for adhesion. Functionalized electrospun fiber membranes can be prepared by different technologies including blend electrospinning, co-solvent electrostatic spinning, micro sol electrostatic spinning, emulsion electrospinning, coaxial electrospinning and multilayer electrospinning. Blend electrospinning is a technique where solutions of drugs and carrier polymers are directly mixed in a first step, and after which electrostatic spinning procedure is conducted to get drug-loaded fiber membranes. It is practical method for preparing composite drug-loaded polymeric nanofibers. Chitosan–PLGA–poly(ethylene oxide) (PEO) electrospun fiber membranes were prepared by Ko et al. [58]. These researchers achieved good results when using the membranes for preventing the intestinal adhesion in rats. Andrychowski et al. [59] prepared PCL electrospun fiber membranes that could prevent the excessive healing in the process of spinal cord regrowth and the formation of adhesions. Lee et al. [60] manufactured drug-loaded PLGA blend fiber membranes by mixing it with gallic catechin-3-O-gallic acid ester (EGCG), a polyphenol derived from green tea with anti-oxidant, antiinflammatory and anti-fibrosis activity. These fiber membranes have are presumably able of controlling antibacterial growth and preventing postoperative adhesion formation. Excessive fibroblast proliferation and over-synthesis of collagen upon surgical intervention make tenosynovitis adhesion of tendon sheaths a serious problem. ERK1/2 and SMAD2/3 play a vital role in this procedure. Hence, Jiang et al. [61] put forward the hypothesis to terminate the expression of ERK1/2 and SMAD2/3 which affect oxidative phosphorylation to prevent adhesion formation by celecoxib acting on exogenous fibroblast. The authors mixed celecoxib with double block copolymer of polyethylene glycol (PEG)-PLA, electrospun it and used obtained membranes for rabbit tendon repairing. Curiously, the polymer itself was found to be capable of preventing the formation of adhesions and provided a new direction for the future development of barrier materials. Liu et al. [62] constructed PLA electrospun fiber membranes with silver nanoparticles to endow the system with antibacterial activity. These membranes were used for both its antibacterial and antiaging effects to repair tendon sheath. Hu et al. [63] blended mesoporous silica microspheres carrying ibuprofen into PLA electrospun fiber membranes, which laid a solid foundation for the composite system to provide long-term prevention of tendon sheath adhesion, because of the role of PLA and mesoporous silica in sustaining the release of ibuprofen. 324

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Fig. 2. (I) bFGF/DGNs-loaded PLLA fibrous membrane was fabricated by electrospinning for promotion of tendon healing and simultaneous adhesion prevention. (II) SEM images of electrospun PLLA (A), bFGF-PLLA (B) and bFGF/DGNs-PLLA (C) fibers. TEM images of electrospun PLLA (D), bFGF-PLLA (E) and bFGF/DGNs-PLLA (F) fibers. (III) Daily release of bFGF from the electrospun bFGF-PLLA (red circles) and bFGF/DGNs-PLLA (black squares) fibers [64]. Adapted with permission. Copyright 2013 Elsevier.

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Fig. 3. (I) Biomimetic bilayer sheath membrane was fabricated by sequential electrospinning to mimic the synovial layer and the fibrotic layer. (II) SEM observations showing crosssectional and surface morphological features of PCL fibers and HA/PCL fibers with different sheath membranes thicknesses. (III) Masson's trichrome staining of untreated repair site, histologic evaluation and histologic quality of tendon adhesions [72]. Adapted with permission. Copyright 2012 American Chemical Society.

technologies for anti-adhesion of repaired tendon. Fiber diameters were 3.66 ± 0.57 μm for the outer PCL layer, while the inner PCL layer with different amounts of HA, namely 0% (PCL-HA0%), 4% (PCL-HA4%), 8% (PCL-HA8%) and 12% (PCLHA12%). In the case of the previous, fiber diameters were 3.89 ± 0.59, 3.42 ± 0.62, 2.99 ± 0.54 and 2.86 ± 0.71 μm, respectively. Thickness of the fabricated scaffold was around 200 μm. In this work, the adhesion and proliferation of C3H10T1/2 cells on the surface of the tissue culture plate was prevented (Fig. 3). Xu et al. [73] produced a biomimetic designed micro/nanoscaled

Arnalpastor et al. [71] deposited HA on the surface of pre-prepared PLA electrospun fiber membranes to obtain a HA/PLA laminated film. The film had an adhesive surface and a non-adhesive surface, and the two interfaces were well-bonded together. PLA fiber membranes could promote cell adhesion and proliferation and thus it could be used as a good carrier for cells. Furthermore, the HA surface played a role in preventing cell adhesion due to its intrinsic negative charge. Liu et al. [72] constructed a biomimetic bilayer sheath consisting of PCL-HA fibers as the inner layer, while fiber the outer layer was produced with PCL by a combination of sequential and microgel electrospinning 325

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Fig. 4. (I) Schematic illustration of the fabrication process of hierarchical micro/nanofibrous scaffolds, and using the scaffolds with special function to repair dural defect and prevent epidural scar. (II) The morphology of micro/nanofibrous scaffolds. (III) MRI images of epidural adhesion in the laminectomy sites treated with different scaffold. (IV) Masson's trichrome of laminectomy site at A) 8 and B) 24 weeks [73]. Adapted with permission. Copyright 2017 John Wiley and Sons.

scaffold with integrated hierarchical dual fibrillar components in order to repair dura mater and prevent the formation of epidural scars. The method of production involved collagen molecule self-assembly, electrospinning, and biological interface crosslinking strategies. The fabricated biomimetic scaffolds displayed micro/nanofibers stacked with hierarchical architecture and featured good mechanical properties and biocompatibility. Moreover, fibers had a profound effect on attachment, proliferation, and differentiation of fibroblasts, as shown in Fig. 4. While potentially playing an important role in preventing tissue adhesion single-layer electrospun fiber membranes have been gradually losing their ability to meet the needs of clinical practice. Conversely, multi-layer electrospun fiber membranes have been increasingly studied and developed. Compared with single-layer electrospun fiber membranes, multilayered systems can actually allow producing materials bearing different functions and properties on the same carrier to meet clinical needs, preferably simulating biological tissue, and providing a new direction for the development of biological materials.

4.2. Hydrogels Hydrogels are a kind of high water content polymer materials with a three-dimensional network structure. They can be manufactured by adding part of the hydrophobic groups and hydrophilic residues in cross-linked structures formed by water-soluble polymer. In this type of systems, hydrophilic residues combine with hydrogen, which is wrapped inside the network structure and the hydrophobic groups swell when encountering water. Meanwhile, hydrogels have the ability to regulate cellular differentiation by self-controlling their mechanical properties [74]. Hydrogels can perfectly cover both complicated and minor wounds. Besides, hydrogel properties can be tuned by adjusting concentration and crosslinking levels to obtain appropriate mechanical properties and optimized degradation rates. Furthermore, hydrogels can protect injured tissues from the immune system without affecting the access to oxygen and nutrients. Also, it is possible and convenient to use sprayed or injected hydrogels in laparoscopic surgery. Because of

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Intestine Fig. 5. (a) Schematic of the coverage of an abdominal tissue surface with a phenolic hydroxyl modified HA (HA-Ph) hydrogel. (b) Scheme for HA-Ph hydrogel formation via glucose oxidase and horseradish peroxide catalyzed reactions by consuming glucose in body fluids. (c) Image of a pinched HA-Ph hydrogel formed by pouring a solution. (d) Abdominal sidewalls of mice treated with solution containing at (I and II) 1 week and (III) 1 month after treatment. (e) Hematoxylin and eosin-stained sections of the abdominal sidewalls of mice treated with solution at (I and II) 1 week and (III) 1 month after treatment [76]. Adapted with permission. Copyright 2015 Elsevier.

the effects on the cardiac function. Sakai et al. [76] constructed an antiadhesion system consisting of phenolic hydroxyl modified HA hydrogel, for which the cross-linking reaction was triggered by contact with body fluids, as shown in Fig. 5. Hydrogel contains glucose oxidase and horseradish peroxidase, and cross-linking reaction took place on the conditions that two catalytic reactions occur through contact of the two types of enzyme with body fluids. Thus, the hydrogel could be triggered to the gel state in situ through the contact with body fluids. In vivo results showed that no abdominal adhesion appeared after one week of surgery when using hydrogel as a defensive adhesion measure to the animal. Ito et al. [77] synthesized injectable hydrogels, which were composed of a HA modified by hydrazide and a cellulose derivative modified by aldehyde (CMC-Na, hydroxypropyl cellulose, methyl cellulose). The gelling reaction formed by this method can be completed within one minute and has a higher shear modulus than the HA hydrogel. The results of animal experiments showed that when using this material as anti-adhesive, no peritoneal adhesions were found in mice within 3 weeks. In the rabbit model of intestinal lateral wall injury caused by adhesion, the area of adhesion obviously decreased in all animals treated with cellulose derivatives hydrogel. Seprafilm® is composed of hyaluronic acid and carboxymethylcellulose, which is transformed into

their high water content, similarly to the ECM, hydrogels have favorable biocompatibility. Therefore, hydrogels can be used not only as anti-adhesion shields, but also as wound dressing and materials for tissue engineering. Hydrogels can be classified into natural and synthetic polymer hydrogels according to composition. Natural polymer hydrogels have caught increasing attention due to their greater range of source materials, lower price, favorable biocompatibility and environmental sensitivity. 4.2.1. Natural polymer hydrogels Guardix-SL® is a mixture of sodium hyaluronate and sodium carboxymethyl cellulose (CMC-Na), which was proven to significantly reduce postoperative adhesion. Guardix-SG® is a type of temperature sensitive mixture that contains poloxamer, alginate and calcium chloride and is used as a physical barrier to prevent adhesion. The material maintains viscous liquid state at 21 °C but, when the temperature rises to 37 °C, it undergoes sol-gel transition and forms a gel. Hong et al. [75] used Guardix-SL® and Guardix-SG® to prevent adhesion in cardiac surgery. It was found that both materials could reduce the formation of post-surgery adhesion, although the effect of Guardix-SG® was better than Guardix-SL®. However, Guardix-SG® has the potential to reduce the ejection score, so further experiments are needed to verify 327

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SprayGel [82] is a brand of adhesive barrier consisting of two kinds of polyethylene glycol polymer. Both PEGs are liquid when not mixed; upon contact, the polymers quickly cross-link in situ, forming a bioabsorbent hydrogel. SprayGel was proven safe and effective in preventing adhesion formation in patients with ileostomy. A gel consisting of poly-ethylene oxide (PEO) and CMC-Na (POC gel), with calcium chloride as stabilizer, is commonly used for laparoscopic examination. The gel as been shown rather effective in such event in humans and rabbits, and can also effectively reduce the degeneration of epidural fibrosis and nervous lesion after lumbar surgery. The gel can be used to reduce postoperative adhesion after hysteroscopic surgery. In addition, Sardo et al. [83] found that after hysteroscopy, the use of POC gel could significantly improve the uterine endometrial patency in subsequent hysteroscopy. Wu et al. [84] prepared a new thermosensitive hydrogel through open-loop polymerization of PCL and PEG. The triblock copolymer, PCL-PEG-PCL, was able to be dissolved at 55 °C and form polymer micelles; however, at 37 °C, the micelle solution formed a hydrogel. The hydrogel can be gradually degraded into a viscous liquid after 7–9 days of peritoneal retention, and completely resorbed within 12 days. Animal experiments showed that it the system was safe and effective when used in postoperative defensive adhesion. In another work, Gong et al. [85] synthesized a new thermosensitive hydrogel based on PEG-PCLPEG. This copolymer was able to change from solution to gel state at 37 °C. When used to cover wounds, the hydrogel gradually degraded within seven days, transforming into a viscous liquid, which could be fully absorbed by the biological tissue within 12 days. Because of the prevention of fibrin adhesion and fibroblast invasion, as well as promotion of the regeneration of mesothelial cells, the hydrogel may have a role in preventing abdominal adhesion. Zhang et al. [86] synthesized a new polycaprolactone monoacrylate (PCLA)-PEG-PCLA biodegradable thermosensitive hydrogel as a biological barrier to prevent postoperative adhesion, as detailed in Fig. 6. Bae et al. [87] synthesized PVA/gelatin gel, and applied it to the prevention of postoperative

a hydrophilic gel after implantation for 24 h, protecting trauma tissues within 7 days. Huang et al. [78] studied the effect of anti-adhesion and immunological reactions. It was found that Seprafilm® could effectively prevent adhesion between liver and diaphragm. Through short-term and long-term observations, it was found that Seprafilm® as a foreign body could cause localized inflammatory reactions because of cell infiltration in the main tissues. Therefore, patients with weaker immunity need to be cautious when using such materials. Wei et al. [79] prepared a thermosensitive hydrogel which takes butyl chitosan as raw material, and found that the hydrogel could effectively prevent the formation of adhesion. Chan et al. [80] synthesized chitosan/dextran hydrogels, which had anti-inflammatory and anti-fibrosis activity, and may be used as biodegradable physical barriers to prevent formation of postoperative adhesion. 4.2.2. Synthetic polymer hydrogel Synthetic polymers such as polyethylene, PEG polyacrylic acid and some derivatives have been used to create synthetic polymer hydrogels by cross-linking. In particular, some have been developed for preventing the occurrence of adhesion, taking advantage of their adjustable mechanical properties and ability to be chemically modified. For example, Ishiyama et al. [81] mixed polymethyl methacrylate and amphiphilic polybutyl methacrylate, both water-soluble polymers, with trivalent iron ions thus obtaining a hydrogel that is able to undergo in situ cross-linking. The hydrogel featured a honeycomb type of structure and pore diameter in the nanometer scale. The hydrogel did not affect the penetration of both cellular factors and growth factors while resisting to the cell invasion. Moreover, the degradation rate of hydrogels could be controlled by regulating the concentration of the trivalent iron ions. The authors studied the effects of the hydrogel on the prevention of tendon sheath adhesion and the promotion of tendon healing in two separate animal models. It was found that this type of hydrogel could prevent the formation of tissue adhesion without affecting tendon healing.

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Fig. 6. (I) (A)Chemical structure, Photographs of the polymer solution Schematic diagram and of PCLA-PEG-PCLA hydrogel. (II)Microscopic images of MC-3T3 cells cultured with different indicated chemicals in medium to evaluate cytotoxicity. (III) Optical micrographs of HE-straining slices for the injured site 30 days after surgery [86]. Adapted with permission. Copyright 2011 Elsevier.

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data have shown that REPEL-CV is safe and reliable to prevent severe adhesion after cardiac surgery [94]. CardioWrap® [95] is a biodegradable film composed of PLA (70% L-lactide and 30% D,L-lactide), which can be completely degraded and absorbed within 6 months. Animal experiments showed that the film can effectively reduce the formation of adhesion as compared with the control group.

abdominal adhesion in rats. They found that PVA/gelatin (10/90) could significantly reduce adhesion level and play a role in preventing adhesion. Yang et al. [88] synthesized biodegradable thermosensitive PEG-PCL-PEG, and showed that a hydrogel formed with the previous could be converted from solution into gel at 37 °C in 20 s. The gel could further prevent the formation of fibrin and the invasion of fibrous cells, thereby preventing adhesion in the rabbit experiment. Compared with electrospun fiber membranes, hydrogels have faster degradation rates, provide more perfect coating for complex and tiny wound, and are easier to administrate, for example, as a spray. Hydrogels can be flexibly modified according to the required absorbing features. Moreover, their degree of cross-linking and concentration can be adjusted in line with the need for slower or faster degradation rates. Therefore, it is expected that these and novel hydrogels can be further developed and applied to adhesion prevention.

4.4. Microspheres Particulate systems in the micrometer range have been attracting the attention of multiple researchers for many decades, in particular in the biomedical field. Microspheres composed of various materials can be useful as versatile carrier systems. These can improve the stability of associated drugs and allow their controlled release, as well as accommodate live cells. When considering the prevention of adhesion, microspheres have been mostly developed as carriers for prolonging the release of active molecules. In recent years, increasing attention has been focused on the TGFbeta family because of its crucial role in the formation of adhesions and scar after tendon injury. It has been shown that the formation of scar tissue during healing can be effectively reduced in the presence of TGFbeta 1 and TGF-beta 2 antibodies or by increasing the amounts of TGFbeta 3. Zhou et al. [96] encapsulated a microRNA plasmid that can silence the expression of the TGF-beta 1 gene into PLGA microspheres, in order to reduce the formation of scaring and adhesion, as detailed in Fig. 8. In another study, Jiang et al. [97] loaded TGF-beta 3 with chitosan in order to construct a tissue engineered scaffold capable of sustaining the release of this cytokine. Then, an engineered synovial tissue sheath was prepared, which could sustain the release of TGF-beta 3, alongside incorporating synovial cells. The release of TGF-beta 3 from microspheres for seven days reached a total of 46.2% of the initial loading. Synovial cells featured adequate growth inside the scaffold and the engineered synovial sheath was able to effectively reduce the occurrence of adhesion after tendon healing. De Clercq et al. [98] prepared gelatin microspheres with controlled degradation rate by varying the cross-linker (genipin) concentration and crosslinking time. In vitro experiments indicated that the gelatin microspheres have favorable biocompatibility and degradability. Furthermore, peritoneal adhesions in a surgical mouse model were significantly decreased after treatment with microspheres. The prevention of adhesion was presumably achieved by the physical barrier effect of microspheres and could possibly be increased by future incorporation of adequate active molecules.

4.3. Films Absorbable thin films obtained from different polymeric or macromolecular materials may play a role in the prevention of adhesion, being used as physical barriers. These can be classified based on the nature of the materials used as natural or synthetic films. 4.3.1. Natural films Natural materials are typically regarded as having present good compatibility with biological tissues and may be obtained from a wide range of sources. Many researchers have used films based on these last for adhesion prevention. For instance, Van'T et al. [89] used type I bovine collagen membranes to prevent abdominal adhesions. Also, Bel et al. [90] used 18 sheep to perform sternotomy and 3000 min period of cardiopulmonary bypass. Sheep were divided into three groups: pericardium left open, placement of an expanded polytetrafluoroethylene membrane taken as a non-absorbable substitute comparator and placement of the absorbable Cova™ CARD membrane. Four months later, the animals underwent a new sternotomy and were macroscopically assessed for the degree of material resorption and the intensity of formed adhesions. The bioengineered membrane was absorbed and replaced by a loosely adherent tissue leading to the best adhesion score. CorMatrix® [91] is a thin sheet composed of cell matrix, which is clinically used in repairing both intracardiac and pericardium deficiencies caused from congenital heart defects. It can be used as a biological scaffold to promote the migration and proliferation of autologous tissue. Notably, of all the patients who have been treated with CorMatrix®, only one underwent a new surgery. In the study by Andrea et al. [91], it was observed that cysts were similar to that of the normal pericardium and the morphology of adhesion was mainly membranous, under which no angiogenesis was found. Cova™ CARD [92] is a biological engineered film composed of purified porcine tendon collagen type I. Animal experiments showed that the film can be biodegraded within 4 months; compared to the control group, the film group had a lower adhesion score, loose adhesion to pericardium and no inflammation. In addition, fibrosis could be controlled down to minimum levels without influencing the repairmen of the cortex in the pericardial surface. Nonetheless, the clinical application cannot be achieved. Lee et al. [93] develop a gellan gum-based film which could be photocrosslinked as an anti-adhesion barrier for medical applications, as shown in Fig. 7.

4.5. General considerations for selecting a specific medicinal structure From the various anti-adhesion medicinal structures discussed above, electrospun fiber membranes, hydrogels and films appear to possess many advantageous features for their clinical use. Specifically, electrospun fiber membranes can act as long-term anti-adhesion materials due to their slow degradation rate, thus providing an enduring barrier. Yet, concerns related with immune rejection in different degrees may impair their use as a result from long-term in vivo residence. Conversely, hydrogels are regarded as versatile as these systems can fit different tissue surfaces due to their easily adjustable shape. On the downside, fast degradation of hydrogels unables long-term prevention of adhesion. Films possess similar properties to hydrogels. Despite their current wide application in clinical practice, available off-the-shelf films with a single function could hardly handle commonly complex situations and lesions. As one of the most popular carriers for controlled drug release over recent years, microspheres are designed to maintain the bioactivity of encapsulated drug(s) and release them in a sustained manner. While the simple use of plain microspheres as a physical barrier seems unfeasible, increasing efforts have been focused on the combination of the above discussed medicinal structures and drugloaded microspheres. Such strategy can combine advantages of the different systems, while offseting their respective weaknesses. For

4.3.2. Synthetic films Films composed of synthetic polymers can be specifically designed in order to biodegrade in vivo. Such systems may have favorable and tunable mechanical properties and their application in preventing adhesion has gradually attracted the attention of researchers. For example, REPEL-CV barrier [94] is a kind of biodegradable transparent film, which is made up of 52% PLA and 47% PEG. This film can be completely absorbed and degraded within 28 days. Animal and clinical 329

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Fig. 7. (a) The photocrosslinking mechanism of gellan gum. (b) Repair of the injured sites between the cecum and the peritoneal wall in the operated rats 3 and 7 days after surgery: (a and b) adhesion formation (control group) and (c and d) treated with gellan gum-cin film without adhesion formation, and histological observation of the wound site in the operated rats 3 and 7 days after surgery [93]. Adapted with permission. Copyright 2012 Elsevier.

Fig. 8. (A) Schematic diagram of the synthesis process of nanoparticle/plasmid complexes. (B) (a) Structures of flexor tendons (Zone 2, areas) and major pulley (2C) in the area between the proximal interphalangeal and distal interphalangeal joints in chicken toes; (b) Lacerated tendon cross-sectional surface injected with various agents at a depth of 0.5 cm through a microinjection needle [96]. Adapted with permission. Copyright 2017 Elsevier.

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example, incorporation of microspheres into electrospun fiber membranes may produce an anti-adhesion film acting both as a physical barrier and a drug-releasing platform. Such approach may shed new light on the direction of developing anti-adhesion products.

5.4. Rosuvastatin Rosuvastatin is a novel type of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. Compared with other types of statins, rosuvastatin has stronger affinity for HMG-CoA reductase and also the longest half-life of its class. In addition, this drug can prevent the formation of fibrosis by inhibiting TGF-beta 1. As an example, Gürer et al. [105] found that fibrosis of the rat dural sac after vertebral plate resection could be prevented by local injection of rosuvastatin.

5. Incorporation of drugs to prevent adhesion As mentioned above for specific cases, molecules possessing antiadhesion activity may be conveniently associated to biomaterials and specific medicinal structures in order to obtain potentially advanced products. Main drugs used for preventing adhesion are summarized in Table 3, while the next sub-sections provide additional details on their features.

5.5. Methotrexate Methotrexate is an immunosuppressive drug with various applications including in cancer and autoimmune diseases. Among other mechanisms, this antimetabolite is able to stop cell division by inhibiting DNA and RNA synthesis due to upstream hampering of tetrahydrofolate synthesis. In the case of adhesion prevention, cell apoptosis by activation of the endoplasmic reticulum stress response seems an important action of the drug. For example, Chen et al. [106] used methotrexate to activate an endoplasmic reticulum stress reaction, which induces apoptosis of fibroblasts, thus preventing postoperative adhesion.

5.1. Mitomycin C Mitomycin C is a cell cycle non-specific drug, which can cause damage to the structure and function of the DNA double strand. As far as its use in preventing adhesion, Su et al. [99] divided 70 rats into five groups injected with either normal saline or mitomycin C at different concentrations (0.1, 0.3, 0.5 and 0.7 mg/mL). After four weeks, the saline group evidenced severe adhesion, while the mitomycin C-treated animals presented mild or no adhesion across the epidural scar tissue area. Anti-adhesion effects were concentration dependent and was animals treated with 0.5 and 0.7 mg/mL showed fewer epidural adhesion. In another study, Sun et al. [100] found that mitomycin C could induce apoptosis of fibroblasts by regulating RhoE targeted by miR-200b and miR-200b so as to reduce extradural fibroblasts. Orhan et al. [101] also used mitomycin C to reduce the proliferation of fibroblasts in order to prevent adhesion after cardiac surgery.

5.6. Indomethacin Indomethacin is a non-steroidal anti-inflammatory drug acting on cyclooxygenase. Alizzi et al. [107] demonstrated the ability of indomethacin to counterattack postoperative adhesion in a swine model. 5.7. Acetylsalicylic acid Acetylsalicylic acid, commonly known as aspirin, is another nonsteroidal anti-inflammatory drug with antipyretic and analgesic effects. Low doses of aspirin has a reduced role in pulsatile and resistance indices at all levels of uterine arterial blood flow and increased role for uterine blood supply. Besides, it can also improve the thickness of the endometrium, which has a positive effect on the morphological restoration of uterine cavity [108].

5.2. 10-Hydroxycamptothecine (10-HCPT) 10-HCPT belongs is a tryptophan-terpene alkaloid anticancer drugs that acts on DNA topoisomerase I and inhibits DNA replication, transcription, and mitosis. Sun et al. [102] divided 72 rats undergoing laminectomy into four groups treated with different concentrations of 10HCPT (saline only, 0.1, 0.05 and 0.01 mg/mL). After four weeks, analysis of epidural scaring and the degree of adhesion showed that the scar area and the number of fibroblasts in the 0.1 mg/mL group were significantly lower than that of 0.05 mg/mL, 0.01 mg/mL and saline group. In a further study, Yang et al. [103] prepared liposomes loaded with 10-HCPT and used it in a laminectomy rabbit model for postoperative adhesion prevention. Researchers found that drug loaded liposomes allowed sustained release of 10-HCPT that resulted in of the prevention of postoperative adhesion formation.

5.8. Pirfenidone Pirfenidone is a novel small molecule that has potent anti-inflammatory, anti-fibrosis and anti-oxidant effects. Pirfenidone acts by reducing inflammatory cytokines such as tumor necrosis factor (TNF)alpha, monocyte chemotactic factor-1, interleukin-1beta and interleukin-6; down-regulating profibrotic growth factor, including TGFbeta; and reducing lipid peroxidation and oxidative stress. Bayhan et al. [109] demonstrated its excellent effectiveness towards preventing postoperative peritoneal adhesion on a rat model.

5.3. Polysaccharide hemostatic agent

5.9. Rosemary acid

Polysaccharide hemostatic agent possesses excellent efficacy without causing tissue reaction or inflammation and while promoting healing. Moreover, other characteristics such as biodegradability, low cost, ease of use and compatibility with radiographic imaging are also claimed as interesting. The polysaccharide hemostatic agent is obtained by the purification of plant polysaccharides and is available as microporous spherical particles (40–150 μm). The particles can rapidly take up water from red blood cells, platelets, and hemoglobin, leading to the formation of a gel matrix that causes hemostasis. Additionally, the surface of the newly formed gel matrix triggers a chain reaction on blood coagulation, which causes platelet activation and fibrin precipitation, resulting in the formation of a blood clot that further restricts bleeding. Within about two days, the clot can be completely degraded by endogenous alpha-amylase. Tural et al. [104] found that the prevention of epidural fibrosis could be achieved by using polysaccharide hemostatic agent after lumbar vertebral arch resection and decompression surgery in rats.

Rosemary acid is a natural phenol antioxidant existing in many species of the Lamiaceae family. Various pharmacological activities are claimed for this compound, including anti-viral, anti-bacterial, antiinflammatory and anti-oxidant effects. Lee et al. [110] showed that polygalacturonic acid-based membranes cross-linked with hyaluronic acid and containing rosemary acid presented promising anti-inflammatory activity and adhesion resistance. The use of rosemary acid was linked to a preventive effect on the formation of tissue adhesion. 5.10. Estrogen Estrogen is a female hormone mainly produced by the ovaries and placenta, and, to a small extent, by the adrenal cortex. Bozkurt et al. [111] reported that estrogen promoted endometrial hyperplasia. When combined with estrogen receptors, the hormone changes into a 331

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Table 3 Main drugs used for preventing adhesion in clinical practice. Drugs

Structural formula

Mechanism of action

References

Mitomycin C

Reduction of fibroblast proliferation

[94–96]

10-Hydroxy camptothecin

Inhibition of DNA replication, transcription and mitosis

[97–98]

Polysaccharide hemostatic agent

Hemostasis

[99]

Rosuvastatin

Inhibition of TGF-beta 1

[100]

Methotrexate

Induction of fibroblast apoptosis

[101]

Indometacin

Anti-inflammatory

[102]

Acetylsalicylic acid

Anti-inflammatory

[103]

Pirfenidone

Anti-fibrosis, anti-oxidation, anti-inflammatory

[104]

Rosmarinic acid

Antibacterial, anti-inflammatory

[105]

(continued on next page)

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Table 3 (continued) Drugs

Structural formula

Mechanism of action

References

Estrogen

Regulation of intrauterine adhesion with MMPs, IGF-1, TGF

[106]

Gonadotropin-releasing hormonealpha

Inhibiting the secretion of gonadotropin

[107]

IGF-1: insulin-like growth factor 1; MMPs: matrix metalloproteinases; TGF: transforming growth factor; TGF-beta 1: transforming growth factor beta 1.

Sugammadex, a gamma-cyclodextrin used for selectively blocking rocuronium, was also shown by Sahin et al. [114] as effective in preventing abdominal adhesion in a rat model. Hyacinth bletilla, a kind orchid used in traditional Chinese medicine, has been studied due to its effects in hemostasis. In a work by Tian et al. [115], a spray containing tuber of hyacinth bletilla, among other herbal components, was found effective in preventing intestinal adhesion after abdominal surgery in rabbits. Herbal preparations based on Salvia miltiorrhiza, a plant also used in traditional Chinese medicine may be effective in both activating blood circulation and relieving blood stasis. In addition, these preparations may also improve fibrinolytic activity and prolong both bleeding time and coagulation time, thus inhibiting platelet aggregation. Furthermore, these can be used to improve blood circulation and shorten healing time leading to tissue repair. For example, Zhang et al. [116] found that a preparation containing Salvia miltiorrhiza could effectively prevent intestinal adhesion.

dipolymer, which then can be combined with endoplasmic reticulum reactive components and activate gene transcription. Protein is obtained after transcription and translation, then transcribed into the target gene, which plays a promoter role in the endometrial and interstitial cells mitosis, so that blood vessels, endometrial basement layer and functional layer glands thicken and hyperplasia. Furthermore, together with MMPs, IGF-1, TGF and other cytokines, estrogen can regulate uterine cavity adhesion [111]. 5.11. Gonadotropin-releasing hormone alpha (GnRH-alpha) GnRH-alpha is a synthetic peptide that can be used to inhibit the secretion of gonadotropin by the pituitary gland and reduce sexual hormones secreted by the ovaries. The following has been demonstrated and suggested as reviewed by Schindler et al. [112]: (i) Hypoestrogenic conditions in rats were associated with decreased adhesion formation. This could be related to the influence on estrogendependent growth factors and growth modulators by reliable and constant inhibition of ovarian estradiol biosynthesis and secretion. However, non-competitive estrogen antagonism seems to also play a role. (ii) Treatment with GnRH-alpha reduces growth hormone release as stimulated by growth hormone-releasing hormone. (iii) Treatment with GnRH-alpha influences neoangiogenesis by affecting vascular endothelial growth factor and basic fibroblastic growth factor. (iv) GnRHalpha reduces the basal rate of coagulation processes. The frequency and extent of fibrin-generating and degrading processes are reduced. Activity of the plasminogen activating inhibitor is reduced, suggesting an improvement in fibrinolytic reactivity. (v) GnRH-alpha alters the vascular resistance and pulsatility indices, the vascular peak velocity and, possibly, the immune response. (vi) Avoidance of bleeding can reduce fibrin and therefore decrease the matrix for invasion by fibroblasts. (vii) GnRH-alpha reduces the degree of inflammation postoperatively. Adhesion prevention seems to be at its best when pre- and postoperative GnRH-alpha treatment is administered.

5.13. General considerations regarding the use of anti-adhesion drugs Major anti-adhesion mechanisms of the aforementioned drugs could be generally attributed to (i) induction of fibroblasts apoptosis, (ii) suppression of DNA replication, transcription and translation, (iii) antiinflammatory and anti-oxidant activities, (iv) hemostasis, (v) suppression of fibrous tissue-inducing growth factors and (vi) regulation of blood circulation. Despite regarded as beneficial, side effects can arise from such mechanisms. For instance, drug targeting DNA have poor cell specificity and can interrupt DNA function of normal cells, thus leading to potential risk of cancer. Another possibility is the formation of blood clots resulting from the use of polysaccharide hemostatic agent, which could conversely promote the formation of fibrous tissue. Although various drugs with adhesion-preventing effects have been proposed, specific clinical effects remain to be further studied. Apart from individual use of anti-adhesion drugs, combination therapy has drawn considerable attention over recent years, namely for enhancing therapeutic effects while minimizing side effects. Furthermore, combination of drugs with biomaterials is likely to improve the treatment of injury and prevention of adhesion at same time.

5.12. Other drugs Alongside drugs discussed above, other molecules have also been considered as potentially useful in prevention adhesion. For example, N-acetyl cysteine, is a precursor of glutathione and an antioxidant bearing sulfhydryl groups with excellent free radical scavenging. This last feature may be of relevance since the increase of reactive oxygen products during cardiac surgery plays an important role in postoperative adhesion formation. Colak et al. [113] explored the local effect of N-acetyl-cysteine in preventing postoperative pericardial adhesions in a rabbit model. These researchers found that, owing to its anti-fibrosis ability and role as a kind of physical barrier, N-acetyl cysteine could protect the serous surface from injuries during operation, thus playing an important role in preventing pericardial adhesion.

6. Conclusions and future perspectives Current approaches for preventing the occurrence of adhesion rely mainly on inhibiting of inflammation, averting wound contact with other tissues, avoiding fibrin deposition, promoting the dissolution and absorption of fibrin, and inhibiting the proliferation of fibroblasts. Biomaterials can play a variety of roles in preventing adhesion, not only by providing a physical barrier that prevents wounds from adhering to other tissues but also by, in some cases, actually inhibiting inflammation. Therefore, engineering functional biomaterials that combine biomaterials with drugs will likely be more effective in preventing the 333

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Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the projects “Institute for Research and Innovation in Health Sciences” (POCI-010145-FEDER-007274). The authors thank Jincheng Tang, Junyuan Xiao and Wasim Kapadia for editing language.

formation of adhesions. Moreover, using biomaterials with a particular structure will further improve prevention of adhesion. This review provided a comprehensive summary on several major adhesion diseases and associated pathological mechanisms in order to guide the design of biomaterials. Besides various useful materials, specific structures and scaffolds have attracted much attention, as well as the incorporation of many drugs in these last. Such holistic approach to the development of new products is likely to result in enhanced disease treatment and functional recovery. At present, most of the anti-adhesion products used in clinical practice are still quite simple but fast pace in the field will undoubtedly lead to introduction of innovative and multifunctional materials. Research on valuable biomaterials, precisely engineered structures and new drugs will likely contribute to the establishment of novel approaches in preventing adhesion. Despite many advances, the field of tissue adhesion prevention requires new tools and approaches. Important topics being currently addressed but requiring further development are detailed in the following, serving as hints for future research:

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(i). Functional biomaterials and structures made thereof need to be designed in order to match injured tissues, namely by improving structure flexibly, and to achieve the goal of preventing adhesion. For example, bionic multi-layered structures could be designed with an outside layer acting as a barrier, and another inside layer responsible for drug release. (ii). The development of structures loaded with cells, namely stem cells, could deal with adhesion from a more biologically viewpoint. For instance, structures containing stem cells could promote in situ differentiation and growth of desired cell types in order to promote healing of specific tissue, while serving as a physical barrier to adhesion. (iii). Structures containing multiple drugs loaded scaffold could fulfill combination therapy while differently controlling active payload release depending on the stage of treatment. Hence, these structures could heal the wound at earlier stages and repair the tissue at later periods. Another potential advantage of controlling drug release may be the avoidance of side effects. (iv). Restricting drugs to specific areas or sides of one structure may be helpful for more localized therapeutic action according to the needs of differently damaged or healthy tissues. For example, a multilayer film structure could be fabricated with different drugs loaded in each layer to accomplish on-demand local drug release of distinct tissues. More specifically, it could deliver pro-healing agents to the damaged tissue and anti-adhesion compounds to a potential adhesion site. (v). Finally, a structure presenting immunologic function as conferred by surface modification and/or loading of immune moieties such as antibodies could be seen as advantageous. Such structure could aid injured tissues to self-repair by regulating the immunological environment. Antibodies could not only be tethered onto the surface of a structure but also be loaded inside it. Similar to multiple drug-loaded structures, different ways of associating antibodies could lead to sequential action, as superficially immobilization could lead to fast effects, while slow release of loaded antibodies could ensure long-term effects. Acknowledgements We gratefully acknowledge financial support from the National Natural Science Foundation of China (51373112), Social Development Project of Yangzhou Key Research Program (YZ2015070), Jiangsu Provincial Special Program of Medical Science (BL2012004) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). This work was also financed by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and 334

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