Vascular grafts (VGs) are medical devices intended to replace the function of a blood vessel. Available VGs in the market present low patency rates for small diameter applications setting the VG failure. This event arises from the inadequate response of the cells interacting with the biomaterial in the context of operative conditions generating chronic inflammation and a lack of regenerative signals where stenosis or aneurysms can occur. Tissue Engineered Vascular grafts (TEVGs) aim to induce the regeneration of the native vessel to overcome these limitations. Besides the biochemical stimuli, the biomaterial and the particular micro and macrostructure of the graft will determine the specific behavior under pulsatile pressure. The TEVG must support blood flow withstanding the exerted pressure, allowing the proper compliance required for the biomechanical stimulation needed for regeneration. Although the international standards outline the specific requirements to evaluate vascular grafts, the challenge remains in choosing the proper biomaterial and manufacturing TEVGs with good quality features to perform satisfactorily. In this review, we aim to recognize the best strategies to reach suitable mechanical properties in cell-free TEVGs according to the reported success of different approaches in clinical trials and pre-clinical trials. Cardiovascular diseases (CVDs) are a group of conditions affecting the heart and blood vessels. According to the World Health Organization, CVDs are currently the leading cause of death worldwide, representing 32% of all global deaths . Accordi®) and Polyethylene terephthalate (PET—known as Dacron®). Although their performance is suitable in straight blood vessels and large diameters, they are inefficient in replacing small diameter vessels (>6 mm diameter) and under non-unidirectional or non-fully developed flows, as seen in their decreased patency rates below 32% after two years [®—CryoLife) [®—LeMaitre) [® II—LeMaitre) [Currently, surgical approaches for vascular reconstruction focus on using autologous or synthetic vascular grafts (VGs) to recover the blood flow. Autologous grafts such as the great saphenous vein (GSV) and Internal Mamary Artery (IMA) can maintain long-term patency due to their regenerative properties (86% up to five years). However, GSV has limited availability and represents additional risks due to possible post-surgical complications with morbidity rates up to 50% . FurtherryoLife) , xenograeMaitre) , or xenoeMaitre) . NevertheMaitre) .These bio-based VGs are part of Tissue-engineered vascular grafts (TEVGs); these scaffolds are intended to guide the tissue regeneration of the vascular wall and are considered as a strategy to get closer to the biological response of native blood vessels. Under physiological conditions, native arteries have a complex, multilayered structure with different ECM compositions and microstructures to contribute to the required compliance precisely responding to pulsatile pressure. Components in each layer will determine the total vessel elastic, viscous, and inertial properties that provide the critical biomechanical signals required to regulate cell adhesion, growth, and differentiation .Although there is promising research on TEVGs, several barriers are still to be overcome. In this sense, the rational design of TEVGs must consider the self-defeating cellular response to biomaterial surfaces and structures under the hemodynamic operative conditions leading to graft patency loss. Accordingly, the inflammatory process after implantation of a TEVG is required for the vascular wall regeneration and depends on the ECM composition and mechanical properties regarding the presence of bioactive molecules and their micro/macrostructure . For insThe failure of TEVGs depends on the alteration of the complex interactions between the biomaterials, cells, and hemodynamic conditions in the blood flow. Namely, the most reported failure of TEVGs is related to the development of intimal hyperplasia, in which smooth muscle cells over-proliferate, and also atherogenesis, in which foreign body responses promote graft calcification . HoweverHerein, we aim to recognize the best strategies to reach suitable mechanical properties in TEVGs according to the success of different approaches in clinical and pre-clinical trials. Furthermore, we aim to identify the latest trends in cell-free TEVGs development regarding the manufacturing methods and biomaterials in the context of ideal mechanical properties.An integrative review of the literature on tissue-engineered vascular grafts was conducted and reported according to the elements described in the PRISMA guidelines. To this end, an electronic search was performed in the following databases: MEDLINE, SCOPUS, Web of Knowledge, and ClinicalTrials.gov. The indexing terms for the search strategy were in MeSH terminology. These terms included “Tissue engineering”, “Vascular graft”, “Biodegradable” and “Regenerative” from the last five years (2017–2022). A total of 4592 records were identified, with 2476 removed before the screening, as they were considered duplicated records or ineligible by automation tools.For the selection process, an initial title review was performed; if the title indicated that the study might be relevant, abstracts were reviewed, or they were otherwise excluded. Finally, identified eligible studies were read on a full-text basis. Inclusion and exclusion criteria were applied to the list of articles obtained; those that did not meet these criteria were eliminated, and the documents corresponding to the remaining articles were reviewed. Thereof, five registries in Clinicaltrials.gov were included for TEVGs, 43 records were included for TEVGs on pre-clinical models , and 46 The inclusion criteria for the screening and choice were covered by TEVGs on clinical trials registered on clinicaltrials.gov, with pre-clinical testing on in vivo models and data related to in vitro studies found in different databases, reporting at least two mechanical properties according to the requirements of the ISO 7198:2016 and from the last five years; otherwise, manuscripts were excluded. Additional exclusion criteria considered TEVGs with pre-seeded cells, articles in languages different from English or Spanish, or if the retrieved information was incomplete, did not correspond to the scope of the review, or was unavailable for retrieval for any reason. A total of 2160 records were screened, 1745 were removed, and classification was performed considering three categories: TEVGs on clinical trials, TEVGs on pre-clinical models, and TEVGs with in vitro data.Subsequently, data collection and extraction were performed regarding the mechanical properties reported in the TEVGs analyzed from the clinical trials, pre-clinical models, or in vitro models and the relationship with patency and regeneration potential. Reviewers had independent access and the data were fed as the literature review process was carried out. The data were classified according to the study type and organized according to title, authors, DOI or CT registry number, and year of publication, including manufacturing techniques, materials, and any functionalization used for developing the TEVG. Detailed information about the study, animal model, and physicochemical and biological characterization was incorporated, considering the regenerative potential through the endothelialization success and inflammatory response.As the manuscripts reporting mechanical properties were included, we compared available biodegradable TEVGs to native blood vessels (GSV and IMA) as the least defining suitable mechanical properties to be fulfilled to the TEVGs. Then, all summarized data were analyzed using descriptive analysis, reporting central tendency measures for quantitative variables and frequencies for qualitative variables. Finally, all the information was tabulated. This article’s relevant data are in tables or graphics presented in this review.The vascular system is comprised of blood vessels that can be classified into arteries, capillaries, and veins, with differences according to their size and physiological function. Blood rich in oxygen and nutrients is transported from the heart to different tissues in the body by a network of capillaries, branching from the arteries. The capillaries then transport the blood containing carbon dioxide and other metabolic wastes from the tissues to the venules and veins to remove and re-oxygenate the blood in the lungs.Besides their physiological differences, blood vessels have a complex vascular wall in terms of composition and structure, which gives them a wide variety of mechanical properties according to the different hemodynamic conditions to which the blood vessel can be exposed. However, these properties are potentially affected by pathologies that change the vascular wall, such as atherosclerosis or aneurysms, representing the world’s leading causes of death . CurrentAt the macrostructural level, the vascular wall of blood vessels presents a multilayered structure composed of 70% water and 30% collagen, elastin, proteoglycans, and vascular cells . The vasNevertheless, the wall thickness and its components may vary according to the type of blood vessel. Due to the aim of this study, we will focus on small arteries with diameters ranging between 1–6 mm and a wall thickness between 125–800 µm [The mechanical analyses of blood vessels are of utmost importance to understand their properties under different hemodynamic conditions and to guide the rational design and production of TEVGs capable of withstanding physiological stresses and pressures. The blood vessel wall presents a complex structure and composition, allowing responses to different strengths and pressures caused by blood flow. Due to the anisotropic behavior of blood vessels, they support a significant load in the circumferential direction due to the collagen components in this direction, while allowing compliance given the elastin fibers. Therefore, at high pressures in the blood vessels, the elastin fibers will allow expansion, and collagen fibers will be stiffer to permit the change in diameter but prevent damage or rupture when the pressure increases. Moreover, the compliance of the blood vessels is a property that allows us to measure the storage of blood that the artery can support and release to the vascular network in order to reach regions of lower pressure in a pulsatile flow through its stretching due to the elastin fibers . Currently, for the substitution of small diameter vessels (<6 mm), autografts from GSV and IMA are used due to their excellent compliance and compatibility with the native vessels, remaining as the gold standard . For thiAs shown in The global vascular graft market is increasing due to the prevalence of cardiovascular diseases related to low levels of physical activity and a sedentary lifestyle. It is expected to reach 3.3 billion by 2026 at a CAGR of 6.4%. Polytetrafluoroethylene (PTFE or Teflon) based vascular grafts are currently the most used. PTFE as a raw material reached 710.3 million USD in 2018, and it is expected to present the fastest CARG over the forecast period due to the graft advantages related to low delamination, minimal blood loss, and excellent mechanical properties . PTFE vascular grafts are the nonwoven type. They were developed in 1972, with their first use as a venous prosthesis in a swine model, where they have since been used for more than 30 years. As PTFE-based VG has been the most successful type for small diameter applications; we have considered it a reference for superior mechanical properties.PTFE is a thermoplastic and crystalline fluorocarbon polymer like polyethylene; fluoride atoms have substituted hydrogen atoms. These Fluorinated carbons have a high affinity for avoiding reactions with other molecules, for which the PTFE is inert, biocompatible, and avoids thrombogenesis. Implantable PTFE devices were commonly manufactured from a single film of PTFE and subsequently stretched to produce a microporous structure from the non-porous film; the degree of porosity depends on the stretch. PTFE VGs nowadays are produced by extrusion and sintering in a porous tube with fibrils and nodules of controllable sizes. Therefore, the final PTFE VG comprises a fibrous structure defined by interconnected interspaced nodes . Since pDespite the wide use of PTFE-based vascular grafts, PTFE is a non-biodegradable biomaterial with low compliance and moderate stiffness. Due to this factor, PTFE VGs have been evolving through different modifications to improve the handling properties and mechanical properties. To improve mechanical properties, especially for lower limb bypass, reconstructions above or below the knee, extra-anatomic procedures, and vascular access grafts, PTFE VGs include internal or external support in the form of rings or spirals offering kink and compression resistance . On the As shown in Even though plenty of development has been reached over the last 50 years in the field of synthetic materials for the design of vascular grafts and favorable results have been obtained for aortic and wide arteries replacement, there have not been any satisfactory results in small caliber grafts due to thrombus formations and poor patency rates . Neverth®, with a mean patency rate of 73% over 18 months. Another example can be the Humacyte graft, with a patency rate of 83% at three months and 60% after six months [As stated above, patency loss is a severe complication of small diameter grafts. In this sense, PTFE VGs have been reported to present patency rates of 75% at one year, which will decrease to 44% at five years. This behavior is non-comparable to the saphenous vein with a reported patency rate of 91% at one year, decreasing to 76% at five years, superior to PTFE in all stages. On the other hand, some types of TEVGs show reasonable patency rates. One example is Artegraftx months . TherefoThe leading cause of failure of VG and TEVGs is patency loss where blood flow becomes compromised and can occur through different mechanisms. The most common mechanism is related to thrombogenesis when the surface of the biomaterial lacks the required hemocompatibility . FurtherHowever, the most common cause of failure related to the mechanical properties of the VG or TEVG includes intimal hyperplasia, in which the overproliferation of smooth muscle cells thickens the tunica intima in the blood vessel, causing the contraction of the construct and the loss of patency . On the Intimal hyperplasia has been reported to present in 10–30% of failure causes of VGs. This high failure rate has been correlated with the compliance mismatch between the VG and the native vessel. In this sense, it has also been reported that the patency loss is directly proportional to the compliance mismatch . The lowThe flow stability is key to maintaining the graft patency. The flow regime, velocity profile, and cyclical deformation caused by the pulsatile flow create determinant wall shear stresses (WSS), which are mechanical signals in the cells interacting and repopulating the TEVG . From th2 ranging between 0.3 to 1.24 N/m2 [2, medium compliance VGs display similar shear stresses with an average of 1.04 N/m2, and high compliance grafts present higher WSS with an average of 3.6 N/m2 [Regarding the compliance mismatch effect on WSS, normal WSS reported on small diameter vessels—such as the coronary artery—is 0.68 N/m.24 N/m2 . It has 3.6 N/m2 . Based o2 to 1.73 N/m2, whereas GSVs grafts below 0.71 N/m2 are predictors for the VG failure [2, contrasted with those occluded with a WSS 2.56 N/m2 [Accordingly, TEVGs for different applications must consider the compliance values and the physiological shear stress in which the TEVG will be anastomosed. For instance, GSV has an average compliance value of 4.4%/100 mmHg, and it has been reported that implanted GSV grafts for coronary artery bypass present a range of 1.22 N/m failure . Recent .56 N/m2 . Althoug2, leading to a patency rate between 75–90% at one year and 50% at 15 years [Although GSV has a different structure from arteries, the vein adapts to the arterial environment due to the different hemodynamic conditions and increased oxygen tension . The mos15 years .When developing TEVGs, it is essential to induce the regeneration of the vascular wall within the anastomosis; not only will the bioactive chemical properties of the graft induce this process, but biomechanical signals are required. Aside from the microstructure allowing the cell infiltration and proliferation, the wall shear stress will generate different responses in the cells interacting with the biomaterial in the hemodynamic context. Therefore, physiological WSS will lead to the regeneration of the vascular wall, whereas the low WSS induced by the lack of compliance will have a detrimental effect on the gene expression of immune cells, smooth muscle cells, and endothelial cells. For instance, for regeneration to occur, the inflammatory response must be modulated towards the differentiation of Macrophages to the M2 type, recognized by the cytokine secretion to induce extracellular matrix deposition. Low WSS has been correlated to the maintenance of the M1 phenotype leading to chronic inflammatory responses.On the other hand, smooth muscle cells must begin their differentiation towards a contractile phenotype rather than a synthetic phenotype. The synthetic phenotype related to low WSS has been associated with lower blood pressure responses affecting the construct’s overall compliance. Finally, endothelial cells should differentiate towards a functional phenotype able to release nitric oxide (NO) as a regulator of the vascular wall tone. Low WSS has been shown to induce senescence on endothelial cells without proliferation capacity and limited release of NO. 2O2 as a signaling molecule for endothelial cell proliferation [According to the data registered in feration . WithoutOn the other hand, low WSS on endothelial cells also increases the expression of MCP-1 (Monocyte Chemoattractant Protein-1), which is a chemoattractant for proinflammatory monocytes. At the same time, the expression of VCAM-1 (Vascular cell adhesion protein-1), ICAM-1 (Intercellular Adhesion Molecule-1), and EDN-1 (Endothelin-1) increases, which are adhesive molecules for monocytes, and PDGF (platelet-derived growth factor) also increases, promoting thrombus formation. Regarding smooth muscle cells, a low WSS decreases the expression of a-SMA (smooth muscle actin), SM22 (Transgelin), SMTN (Smothelin), and CNN ; all are genes related to the contractile function of smooth muscle cells required to respond to contractile and dilating signals from endothelial cells . FurtherFinally, macrophage modulation due to low WSS has been shown to reduce the expression of M2 phenotype-related genes such as CD206 (macrophage mannose receptor 1), IL-10 (Interleukin 10), which blocks the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) proinflammatory pathway, and TGF-B1. Furthermore, genes related to increased inflammation are reported to be activated, such as the signaling pathway related to NF-κB activation, MCP-1, and Selectin as chemotactic for new inflammatory cells, as well as present an increase in MMP9, related to the degradation of the scaffold ,57. Due to the significant differences between vascular grafts and native arteries in their mechanical properties and behavior under implantation conditions, several requirements have been studied to develop mechanical characterizations of these new grafts. The requirements to evaluate vascular grafts are outlined in International Standards ANSI/AAMI VP20: 1994  , ISO 719Test guidelines for international standards are defined for all vascular grafts: synthetic, biological, and coated . AccordiDue to the anisotropic properties associated with vascular grafts, strength tests should be performed, including more than one axis. Therefore, longitudinal, and circumferential tensile strength tests are performed to determine whether the axial and radial yield and/or breakpoint are reached, respectively. Stress vs. strain plots must be made to include and analyze the data. In addition, suture retention strength tests should be developed to determine the force required to pull a suture from the vascular graft to simulate clinical techniques . The suture is usually placed 2 mm from the edge and tested in various directions to determine the strength that the prosthesis withstands before mechanical failure.Moreover, a burst strength test is performed to determine the pressure rate change until sample bursting occurs. This method allows to report the diameter of the sample when it is pressurized directly with fluid or gas. A repeated puncture test with a dialysis needle (16G) should be performed to measure the strength that supports the prosthesis through a force test such as pressurized burst strength or circumferential tensile strength .It is necessary to perform tests to determine the thickness of the wall and the relaxed and pressurized internal diameter to observe changes in diameter under different hemodynamic conditions. Furthermore, the vascular graft discontinuity should be reported when the lumen diameter decreases during kinking and the radius of curvature that impedes normal flow through the graft. Another way to evaluate conditions that approach the preclinical environment is by measuring diameter change simulated under cardiac cycle conditions to determine the radial dynamic compliance. In addition, the rate of water leakage through the prosthesis wall should be characterized to avoid leakage at the time of implantation .The ideal graft must have comparable mechanical properties to those of the native vessels that will be anastomosed. For instance, it has been shown that the gold standard for the repair of peripheral vessels is the GSV, whereas in other applications such as in Coronary Artery Bypass Graft Surgery (CABG), the gold standard corresponds to the IMA. This is implemented to reduce the level of mechanical decoupling and levels of failure that can lead to stenosis or aneurysms and, therefore, long-term permeability loss. The most important factors involve mechanical strength and compliance concerning the viscoelasticity of the scaffold. Likewise, the grafts must have sufficient mechanical strength and compliance to withstand the changes in blood pressure. At the same time, they should adjust correctly to the adjacent vessels when completing the suture procedure, enabling the correct velocity profiles and continuity in the pressure waves. In the following sections, the current trends in TEVGs design, biomaterials, and manufacturing techniques are reviewed according to the TEVGs that have been reached, including clinical trials, pre-clinical studies on animal models, and techniques that have been tested on in vitro conditions during the last five years. After analyzing the current trends in TEVGs, five clinical trials were identified regarding TEGVs for human use in different contexts. The main mechanical properties of each vascular graft compared to GSV and IMA grafts are summarized in The most recent TEVG that has entered to clinical trial phase is a Polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane (POSS-PCU) small-diameter vascular graft, fabricated through extrusion and phase inversion method using sodium bicarbonate as a porogen. This TEVG is currently being tested as arteriovenous fistulas for hemodialysis; the study began in 2021 and is expected to reach completion in April of 2025. This TEVG has a small diameter (<5 mm) with a mean wall thickness of 0.94 mm that is placed in adult female patients undergoing hemodialysis and in need of new arteriovenous access but without any viable access for dialysis. This study has an inclusion criteria of patients on oral contraceptives or with an intrauterine device, aiming to demonstrate patency in patients with increased risk of thrombosis. It is expected to measure patency rates at 18 months by Doppler ultrasonography (d-US) and compare it to the patency of the PTFE grafts. They also will measure the occurrence of any Serious Adverse Event (SAE) related to the implantation of the POSS-PCU TEVG. For the initial characterization of the POSS-PCU vascular graft, they used Delfino’s strain energy potential to capture the viscoelastic properties of the materials. Later, they conducted different experimental and computational experiments to show shear stress within the graft wall in the context of increased uniaxial strength. They concluded that besides the overall resistance of the graft, the stiffness and long-term viscoelastic properties could be improved with better manufacturing techniques; detailed mechanical properties of this TEVG can be found in the A Human Acellular Vessel (HAV) from Humacyte is a graft also developed for patients with need of hemodialysis access but who are not candidates for a fistula. This TEVG is created in vitro through the culture of human smooth muscle cells and fibroblast cultured over a biodegradable polymer. Further decellularization process creates a structure that retains the extracellular matrix protein and provides corresponding mechanical properties. Animal models were performed in baboons as arteriovenous grafts with 80% patency at six months. This vascular graft has been included in different clinical trials. One of the most relevant, made in 2016 as a phase 2 trial in 40 elected patients, demonstrated primary patency rates of 63% (95% CI 47–72) at six months and 28% (95% CI 17–40) at 12 months. Conversely, secondary assisted patency rates at six and 12 months were 97% (95% CI 85–98) and 89% (95% CI 74–93), respectively. Secondary patency rates in extensive multicenter cohort studies with PTFE were 55–66% at one year, making HAV a suitable option. In the group of patients, they also measured serious adverse events (SAEs) that occurred 155 times in 33 patients, leading to increased reintervention rates. SAEs mainly included patency loss, infection, and one case of steal syndrome. HAV provides an exciting conclusion, as they have better secondary patency rates than PTFE-based VGs, leading to a well-tolerated TEVG with no signs of aneurysm formation or degradation with low immunogenicity. For which it has been included in different clinical trials from 2015 to 2020. Research-ers found that Artegraft® has primary, primary-assisted, and secondary patency rates of immunogenicity. However, HAV has the lower reported tensile strengths  along all TEVGs in clinical trial phases (1400 and 1200 KPa) and low dynamic compliance compared to human allografts (1.5 vs. 4.4 and 5.22%/100 mmHg), leading to increased stiffness and a poor vascular physiology resemblance; complete data can be found in the Likewise, the TRUE vascular graft is also a decellularized arteriovenous TEVG designed by neonatal human dermal fibroblasts seeded in a bovine fibrin gel. A baboon pre-clinical model was performed on 10 subjects to determine its safety in terms of occurrence of adverse events and to find patency rates. They found patency rates at 3 and 6 months of 83% (5 of 6) and 60% (3 of 5), respectively, with evidence of recellularization of smooth muscle cells and endothelium formation. This TEVG is currently being tested as an arteriovenous graft for hemodialysis access on 10 participants beginning in May of 2021 and it is expected to finish in June of 2022. The mechanical properties of this kind of graft can be seen in the ®, a decellularized bovine carotid artery used for arteriovenous fistula generation. These TEVG have been included in different clinical trials from 2015 to 2020. Researchers found that Artegraft® has primary, primary-assisted, and secondary patency rates of 73.3%, 67%, and 89%, respectively. SAE was present in one immunocompromised patient that presented a resistant infection, leading to the early removal of Artegaft® at two months. A relevant finding is that anastomotic venous stenosis occurred in some grafts and was the most common indication of graft removal. Artegraft® demonstrated similar tensile strength properties compared to PTFE VGs. However, its low dynamic compliance [Another kind of TEVG for hemodialysis accesses is Artegraft® are bovine pericardial xenografts used as a strategy for vascular graft infections due to their regenerative properties; these series of clinical trials began in 2019. A prospective study of six patients with infected aortoiliac segments treated with BioIntegral Surgical No-React ® demonstrated that four out of the six patients are still alive with complete patency demonstrated by d-US. Unfortunately, two died from acute myocardial infarction, and the other due to sepsis secondary to the vascular infection. Although this graft has a remarkably increased longitudinal tensile strength compared to GSVs and IMA , it conferred to most patients (4 out of 6) a proper control of the infection with reasonable long-term patency rates.BioIntegral Surgical No-React According to the reported data, a mean value was extracted from the mechanical properties of the current vascular grafts undergoing on clinical trials and were compared to the mechanical properties of the GSV, as shown in n = 26; 46.46%) of the studies reported the use of Poly ε-caprolactone (PCL), mostly manufactured through electrospinning  and more frequently tested on murine animal models (rats). PCL has been shown to be biocompatible, and the constructs exhibit slow degradation rates of about 1–2 years [After the analysis of the recruited data, a total of 43 studies fulfilled inclusion criteria for TEVGs that have reached pre-clinical animal models ,106,107.–2 years ,105,107.–2 years . HoweverTo overcome these limitations, various authors have chosen to use a variation of PCL such as poly (L-lactide-co-ε-caprolactone) or PLCL with a softer and more elastic nature. Compared to PCL, PLCL-based TEVGs present higher compliance values close to 8%/mmHg . It has n = 6; 10.71%). PUs has been considered as a good base biomaterial due to its relatively high tensile and flexural strength [Polyurethane-Based TEVGs (PUs) are the second most reported TEVGs , which can be correlated to the advantages of maintaining the structure and mechanical properties of native tissues. Moreover, these biomaterials have a relatively low immune response from the patient, cause minor damage to other bioactive components, and usually do not use chemical reagents to reduce adverse reactions in the body [The third most common biomaterial for TEVGs fabrication corresponds to decellularized arteries , and PLGA (poly(lactic-co-glycolic acid)) are the most used, together with natural biomaterials such as collagen and gelatin ,155,156.Based on these biomaterials, there has been a significant trend of various manufacturing methods, in which the electrospinning method is one of the most used. This methodology is based on the formation of nanofibers through the application of electricity to the material. This process is usually used due to its versatility in adjusting different parameters such as porosity, size, thickness, and density of the graft. About 37% of the articles mentioned used the electrospinning method in manufacturing ,154,155.n = 37) was evidenced, thus indicating that most of the grafts resist high longitudinal forces [n = 17) [However, different authors carry out mechanical and cell viability tests to prove the possible behavior of the grafts in a patient. Due to the mechanical tests, a trend has been found regarding the tests carried out, of which the longitudinal tensile strength tests are most often reported. This measurement helps to determine the vascular graft resistance against longitudinal tensile forces. Along with the revised manuscripts, an average of 94,300 KPa  .n = 13), suture retention resistance with an average result of 7.34 N (n = 11), and finally dynamic compliance with a mean result of 327.28 mmHg (n = 6). This can be evidenced in Likewise, some articles have also included other relevant tests to comply with international standards. Another of the most important tests is circumferential traction resistance, with an average result of 9210 KPa , suture resistance strength (7860 ± 1600 KPa) compared to saphenous vein grafts (2405 and 3200 KPa), and internal mammary artery (4300 and 1300 KPa), respectively. These results show that TPU is a highly rigid material that does not resemble vascular physiology. However, when used as part of a mixture of other materials, TPU can provide the rigidity necessary for more flexible materials rather than being used alone. Regardless of there being no information regarding dynamic compliance, three out of five TPU-based TEGVs had endothelization. All TEGVs were manufactured by electrospinning ,141,154.Finally, PLGA-based TEGVs had intermediate mechanical properties. Its circumferential tensile strength (8350 KPa) and suture resistance strength (1950 ± 1670 KPa) was higher than the internal mammary artery properties (4100 and 1350 KPa), but lower than the saphenous vein graft (9760 and 3200 KPa), respectively. Its longitudinal tensile strength (5008 ± 3468 KPa) was higher than the saphenous vein graft (2450 KPa) and the internal mammary artery (4300 KPa), but its dynamic compliance (3.41%/100 mmHg) was lower than both vessels (4.4 and 5.22%/100 mmHg). In addition, endothelization was found in two out of four PLGA-based TEGVs and the principal manufacturing technique was electrospinning. These results conclude that PLGA is a rigid material that, as with TPU, can give rigidity to a TEVG, but more flexible materials need to be used to offer compliance to the vascular graft ,141,154.All these data are summarized in Despite the advances made in TEVGs development, the pursuit of the optimal mechanical properties that approximate those of native arteries is still ongoing. Multiple factors are essential to achieve suitable surgical and mechanical properties, including the proper selection of biomaterials, manufacturing techniques, and surface functionalizations. For instance, new biomaterials have been developed to increase patency rates and avoid complications such as pulmonary thromboembolism . In thesThe article published by Bai et al. showed structured scaffolds with biodegradable polyester-polydepsipeptid and silk fibroin (PCL-PIBMD/SF). The manufacturing process was on a sandwich-like composite delivering plasmid complexes aiming to induce endothelialization and was manufactured through layer-by-layer electrospinning and electrospraying techniques. The scaffold was tested with human umbilical vein endothelial cell cultures (HUVECs). The average diameter of nanofibers decreased from 573.8 nm to 285.1 nm, with SF content increasing from 0 to 90%. The mechanical properties found were suitable for vascular scaffolds when the weight ratio of SF was 10%, as the found tensile strength and elongation were 7050.34 kPa and 210 ± 21%. A porosity of 27.5 ± 7.4% with a weight ratio of 90/10 was reported. The HUVECs coverage ratio on day three was 66 ± 3%. This scaffold showed mechanical properties that suggest promising application for TEVGs and also demonstrated the promotion of cell proliferation, adhesion, spreading, and migration .Adding to the research, the study published by Xie et al. designed a tissue-engineered vascular scaffold with portulaca flavonoid (PTF) via electrospinning and was integrated with PCL. It was tested on a culture of human vascular smooth muscle cells (HVSMCs). The scaffold exhibited biomimetic net-like fiber structures, an elastic modulus of 2–20 MPa, the ultimate tensile stress of 2000 kPa, and a fracture strain of 60% in the transverse direction. In addition, it showed that compared to the PCL scaffold, the integration of bioactive PTF had better hydrophilicity and degradability. In addition, inhibition of abnormal intimal hyperplasia was observed .Moreover, one of the most critical factors in understanding the clinical use of each native artery/vein is the clinical practice guidelines that continue to support using native arteries or veins. However, we have observed that native arteries/veins are used for the clinical condition and the patient’s requirements, whereas even for the same pathology, different vessels with very different mechanical properties are used. In pathologies involving small vessels, the evidence supports the individualized and specific use of different types of native vessels. The clearest example is the variability between myocardial revascularization per se and infrainguinal revascularization.The ACC/AHA/SCAI Coronary Revascularization Guidelines published in 2021 recommend using the radial artery in isolated Coronary Artery Bypass Grafting (CABG) and the left mammary artery in multiple bypasses over the saphenous vein. The evidence shows that using the left mammary artery prolongs the survival of the patient who only requires isolated CABG in a significantly stenosed non–Left Anterior Descending (LAD) vessel. In addition, the case of the radial artery has shown that in the medium and long term, it has higher patency rates and better clinical results at ten years of undergoing CABG to bypass the LAD .On the other hand, the Society for Vascular Surgery practice guidelines for the atherosclerotic occlusive disease of the lower extremities recommends infrainguinal bypass using the saphenous vein .Depending on the patient’s need and underlying pathology, this variability in mechanical property requirements also applies to vascular grafts. Thus, evaluating the different mechanical properties in each clinical indication is necessary since it is possible to hypothesize that not only a single small vascular graft with specific mechanical properties will be required.n = 25; 58.14%); this is because it offers the ability to fine-tune mechanical properties during the fabrication processes while also offering precise control over the composition, dimension, and alignment of the fiber of the material [Currently, there is a great diversity of manufacturing techniques for small diameter TEVGs. Several biomaterials have the plasticity required for application on different manufacturing techniques. Most studies reported the use of electrospinning as the primary method of fabrication  tend to polarize into the immunomodulatory and tissue remodeling (M2) phenotype, while thinner-fiber grafts (2–3 μm) express a pro-inflammatory (M1) phenotype . In thisn = 3; 6.98%) [Another relatively common technique typically used for the manufacture of TEVGs is Freeze tawing  ,164,165;; 6.98%) . RegardiAnother topic related to the physicochemical properties of TEVGs and its mechanical properties are the surfaces of the designed scaffolds. Depending on these properties, biomechanical stimuli–the same as the effect of WSS–might have an impact on cell adhesion and regeneration, or even might promote bacterial colonization. For instance, some micropatterns as well as stiffer surfaces promote cell adhesion and migration, and these data have been widely reported. Nevertheless, one of the least studied topics on TEVGs is how to prevent vascular infections, which is one of the most detrimental complications. Due to the increase in antimicrobial resistance and infection of different types of implants, multiple strategies have been studied to prevent bacterial colonization and biofilm formation. One of the most efficient strategies is a colonization-resistant surface by coating the surface with the inclusion of superhydrophobic, uncharged, or highly hydrophilic molecules that do not allow bacterial adhesion. For example, polyethylene glycol and zwitterionic polymers have been shown to inhibit bacterial adhesion because they generate a stearic repulsion and movement phenomenon. Hydrophilic molecules such as heparin have also been used to inhibit bacterial adhesion. Superhydrophobic structures with specific topographies have shown efficiency in decreasing adhesion ,167,168.Although less studied, microparticles and nanoparticles with antimicrobial peptides are also used for functionalization, with a wide range of inhibitory effects against bacteria, fungi, parasites, and viruses. Other alternatives include coatings with silver, aluminum, cobalt, zinc, and copper, given that the ions destabilize the bacterial membrane. The same principle applies to Cationic polymers such as chitosan and polyethyleneimine (PEI). Other strategies include local mechanisms of controlled release of antibiotics such as gentamicin, amoxicillin, and vancomycin, among others. For this purpose, multiple transport media such as alginate nanoparticles, hydrogels loaded with these molecules, and even mixing biomaterials with these antibiotics have been employed ,172,173.A 2003 meta-analysis found that autologous vein repairs at any site have a better prognosis and better long-term outcomes regarding graft patency than PTFE grafts in peripheral vessels. In addition, evidence regarding the use of other materials such as bovine pericardium in abdominal aortic repairs, and rifampicin-embedded or silver-embedded prostheses has come to be considered. However, reinfection rates are often higher than 10%. So far, the only regenerative vascular graft for application in aortic aneurysm repair and large-diameter peripheral vessel repair is Omniflow II from the commercial house LeMaitré. Omniflow II is a biosynthetic vascular graft composed of a polyester mesh as an endoskeleton covered by cross-linked ovine collagen. Its simple fabrication is based on the immune response to foreign body and fibrous tissue formation on the polyester mesh implanted in the animal after a few months. Collagen-based biosynthetic vascular grafts have demonstrated graft patency rates approaching 70–80% at one year, with favorable rates (57–64%) in below-knee reconstructions. Infection rates are meager, being lower than prosthetic grafts due to better healing patterns linked to their collagen structure, better integration with host tissue, and evidence of capillary growth or micro vascularization of the graft. In the diabetic population–who are at higher risk of infection–low incidences of reinfection have been found, ranging from 2.8 to 4.8%–much lower than in other types of materials. In this regard, the evidence associated with collagen biosynthetic grafts tends to be very promising. However, their use has only been described in case reports and very small cohorts, especially in repairs associated with the abdominal aorta, which is why more evidence is needed. For this reason, a regenerative vascular graft that reduces reoperation rates and ensures laminar flow through the anastomoses will guarantee long-term graft patency and limb salvage ,174,175.Various biodegradable biomaterials with bacteriostatic/bactericidal activity have been developed. For this purpose, electrospinning–an additive manufacturing technique for the controlled deposition of nanofibers–has been one of the most widely used techniques. Using antibacterial agents such as tetracycline, chlorhexidine, triclosan, and even eugenol loaded on fibers obtained by electrospinning biodegradable polymers as a wound dressing in tissue engineering has been reported. In 2018, Zhenguang, L et al. designed membranes by electrospinning polycaprolactone (PCL) and gelatin incorporating eugenol and adhesive peptides for endothelial cells as a method for fabricating a regenerative vascular graft with bactericidal properties. Its inhibitory antimicrobial activity against S.aureus was 78% and against E.coli was 74%, which was attributed to the ability to destabilize the cell membrane ,177,178.As for bacteriostatic/bactericidal vascular grafts, none are currently on the market with this indication, and the literature reports few approaches. However, one of the most common is the fabrication of vascular grafts with hydrogels or polymers, including chitosan. Due to their bacteriostatic properties, they have helped stop the microbial activity. In addition, some of these TEVGs include other molecules such as silver and even heparin, which, although their general purpose is not to contribute to antimicrobial activity, do have this function.This literature review aimed to identify the different trends in the use of materials to develop readily available TEVGs without pre-seeded cells. We show that PCL is currently one of the most used polymers in both in vivo and in vitro studies. However, lack of compliance with PCL-based TEVG has been identified as one of the main limitations of its long-term implementation in clinical trials. Other polymers such as TPU, PU, and PLGA show relevant properties to offer the required circumferential and longitudinal tensile strength for TEVGs applications. However, their use should be carefully implemented, including other materials to offer the required flexibility required for improved compliance and to provide the biomechanical properties suitable for TEVGS applications.On the other hand, electrospinning is currently the most used manufacturing method, offering standardization and industrialization of the TEVGs. Furthermore, it is easy to use for various polymers while providing proper microstructure and macrostructure. Nonetheless, more studies are still required in manufacturing to reach an ideal fiber thickness and porosity for the grafts since cell migration can be affected while maintaining the long-term graft mechanical properties. Strategies such as decellularized blood vessels offer a suitable alternative for TEVGs since their mechanical properties are very similar to the native tissues and are successful in the regeneration process. However, standardization and industrialization are more complex and will require multiple steps to be commercialized. Personalized medicine marks the future of health sciences, and the use of vascular grafts from tissue engineering allows us not only to create alternatives for each of the vascular pathologies but also to offer quality and durable elements that meet each patient’s requirements concerning their vascular physiology and rheology. Finally, the biomaterials and manufacture methods should ensure the compliance of the anastomosed artery or blood vessel, considering that the increase in the compliance mismatch is directly correlated to the long-term patency loss due to the low wall shear stresses generated by the flow pattern disturbances along the blood vessel and the vascular graft. Therefore, the main objective of a TEVG to provide the required biomechanical signals for regeneration is to reach proper compliance.


This article sketches out two distinct attitudes towards textuality in international law, namely international hermeneutics and international poetics. It argues that these two attitudes towards textuality espouse very different types of dualism of thought. This difference bears major implications on how the international lawyer approaches international legal texts. In exposing these two attitudes towards textuality and the distinct types of dualism they reveal, this article makes a plea for a greater embrace of international poetics by international lawyers, and thus for a complete remoulding of international lawyers’ dualist patterns of thought. The aspirational and hopeful attitude towards textuality is labelled international poetics.This article sketches out two distinct attitudes towards textuality in international law. One of them is actual whilst the other is aspirational. One is at a dead end and yet casually perpetuated by international lawyers. The other is the only hope that international lawyers—and especially international legal scholars—have left to take the textuality of which they are in charge seriously. The actual and ill-fated attitude towards textuality is called here Notwithstanding their dramatic differences, international hermeneutics and international poetics have in common a resort to dualist patterns of thoughts. In fact, as it is argued here, both of them are manifestations of the strong dualism that has informed international lawyers’ engagements with textuality since the advent of modern international law. And yet, as this article will show, albeit articulated around dualist patterns of thoughts, these two attitudes towards textuality espouse a very different type of dualism. In exposing these two attitudes towards textuality and the distinct types of dualism they reveal, this article makes a plea for a greater embrace of international poetics by international lawyers, and thus for a complete remoulding of international lawyers’ dualist patterns of thought.The article is structured as follows. The second section considers the omnipresence of dualist patterns of thought in international legal thought, which the two attitudes towards textuality examined here are manifestations of. The third section describes the actual hermeneutic attitude towards textuality, namely international hermeneutics, and elucidates the type of dualism it is built on. Section 4 introduces the aspirational attitude towards textuality, namely international poetics, and sheds light on the dualism around which it is articulated. The last section makes a plea for a greater embrace of international poetics and the dualist patterns of thought it puts in place, simultaneously showing that this may not be as revolutionary as it sounds, for the type of dualism at the heart of international poetics may already be at work in international legal thought and practice.Postulating binaries and articulating one’s claims in dualist terms, like this article does, is a common pattern of thought. In the West, dualism of thought is usually traced back to Descartes, who allegedly put forward the first articulated form of dualism.For sure, this article, by postulating two attitudes towards textuality in international law, belongs to and continues this long philosophical dualist tradition. It must be made clear that such ancestry is nothing sensational, for the entirety of the international legal literature, at least in the English language, is built on dualist patterns of thought that bear some important kinship with the philosophical tradition that has just been described here. In fact, it seems possible to claim that dualism of thought has shaped and orderedThe two attitudes towards textuality that are examined in the following sections, namely international hermeneutics and international poetics, are similarly exhibiting a strong kinship with dualism. For reasons that are discussed in the next section, it is probably international hermeneutics that epitomises most explicitly the use of dualist patterns of thoughts.It must be preliminarily stressed that the exposition by this article of two distinct attitudes towards textuality as well as of the two types of dualism that inform them is not entirely novel. Literary theory and 20th-century philosophy have long distinguished between two attitudes towards textuality. For instance, Barthes claimed that there are two ways in which one can engage with a piece of literary work: one that seeks to map and catalogue all its distinct meanings and one that seeks to pick just one meaning.A final terminological and definitional remark is in order. The distinction between hermeneutics and poetics is itself borrowed from critical literary theory.linear dualism (section 3B).This section describes an attitude towards textuality that is deemed dominant in international legal thought and practice and that is called here international hermeneutics (section 3A).opinio juris’, ‘jus cogens’, ‘force majeure’), aphorism  or text  of international law always stands for a thing, an idea, a norm, a practice, a behaviour, an institution, a discourse, etc. To put it differently, for international hermeneutics, the words, idioms, aphorisms and texts of international law—that is, what is called here the forms of the international legal discoursemean, thereby necessitating that the international lawyer constantly seeks to elucidate and extract what such forms mean.From the perspective of international hermeneutics—as is broadly understood here, any word , idiom  the meaning they carry and deliver; it also makes the forms of the international legal discourse secondary theretoThe dualism that comes with the distinction between form and meaning at the heart of international hermeneutics is also strongly differential. In fact, in international hermeneutics as is understood here, the pre-existing meaning carried and delivered by the forms of the international legal discourse is supposedly retrieved through a system of differences between forms themselves.Lastly, the dualism that informs international hermeneutics thanks to its articulation around the distinction between form and meaning can similarly be said to be The type of dualism at the heart of international hermeneutics, as it has just been described, brings about a very specific type of attitude towards international law texts. It is submitted here that, taken together, the existential, hierarchical and differential dimensions of the dualism informing international hermeneutics entail a linear type of reading of international law texts.The specific mode of reading that is enabled by international hermeneutics could be illustrated as follows. Should an expert of international law and security be solicited to determine whether article 51 of the United Nations Charter  could be invoked to justify the use of force against non-state actors (eg insurgents), she will, following the attitude prescribed by international hermeneutics, start by distinguishing the text of article 51 and its content and presupposing that an original meaning was agreed upon and then inscribed in the text of article 51. Seeking to unearth that original meaning as well as the way in which this meaning has possibly evolved independently from the text of article 51 itself, the international lawyer will look at the way in which article 51 is possibly linked with other provisions of the Charter (eg article 2.4) from which the meaning article 51 could have possibly been derived. Still looking to elucidate article 51’s original meaning, the international lawyer will also look at the preparatory works of the Charter, possibly even taking the geopolitical context of the drafting of that document as a type of context that can help her determine the original meaning of article 51. Having so traced the origin and the cause of article 51, namely the original meaning that was allegedly inscribed in the text of that provision, the international lawyer will then look at the way in which this original meaning has possibly evolved since its inscription into article 51. This will entail mapping out the other meanings that have subsequently been inscribed in that text. To do so, she will, for instance, turn to the case law of some of the most authoritative judicial bodies that came to apply that provision, as well as the most authoritative scholarly commentaries of the provision. The mapping of these other and subsequent meanings will allow the international lawyer embracing the linear dualism prescribed by international hermeneutics to draw an overall semantic genealogy, one that began with the original meaning loaded into the text of article 51, deemed to be the cause and the origin of that provision, and that ends with the latest other meaning inscribed into that text. Whatever she eventually concludes as to whether article 51 applies to non-state actors, the international lawyer embracing international hermeneutics would thus have been distinguishing the meaning and the text before going on to draw lines between the former and the latter, between the original meaning and other subsequent meanings, and between these other subsequent meanings and the text of article 51.spatial dualism (section 4B).The previous section sketched out and illustrated what is deemed the dominant attitude towards textuality in international legal thought and practice, namely international hermeneutics, as well as the type of dualism of thought that permeates it. This section describes an alternative approach to textuality and a new type of dualism of thought, which is called international poetics. The section first defines international poetics as an attitude towards textuality based on the deferral of meaning by the forms of the international legal discourse (section 4A). It then sheds light on the distinct type of dualism around which international poetics is articulated, namely defer meaning to other forms without such deferral process ever being completed and meaning ever being pinned down.International poetics is premised on the idea that the forms of the international legal discourse do not carry and deliver any pre-existing meaning and that meaning cannot be the cause and origin of such forms. From the perspective of international poetics, the words, idioms, aphorisms and texts of international law—that is, the forms of the international legal discourse—do not carry and deliver any pre-existing meaning but, instead, constantly postpone meaning, thereby condemning meaning to be permanently absent from forms. When asked to signify a thing, an idea, a norm, a practice, a behaviour, an institution, a discourse, etc, the forms of the international legal discourse constantly pass on the job of signification to other forms. When these other forms to which signification is passed are, in turn, asked to signify, they will similarly point away to yet other forms. In other words, when asked to signify a thing, an idea, a norm, a practice, a behaviour, an institution, a discourse, etc, the forms of the international legal discourse permanently self-difference.Although the foregoing might run counter to the international lawyer’s most mundane attitude towards textuality, it must be stressed that the claim that forms postpone meaning by perpetually deferring the latter and thereby leaving the process of signification eternally unachieved is no novel affirmation and has long been advocated in literary theory and philosophy.To appreciate how each and every form of the international legal discourse has an identity of its own despite it carrying and delivering no pre-existing meaning, two observations are warranted about what the identity of forms cannot possibly be. First, it should be repeated that the distinct identity of each and every form of the international legal discourse is not any kind of inherent pre-existing meaning or meaning in disguise. Second, and more fundamentally, it must be emphasised that the distinct identity of the forms of the international legal discourse is not simply and mechanically constituted by the relationships of difference with other forms, for this would, once again, reintroduce a presupposition of a pre-existing meaning.outside the form concerned—that is, in its relationship of difference with other forms—but within each and every form. More specifically, according to such argument, each and every form differentiates itself from others by virtue of the otherness within itself. To take but a few examples from the international legal discourse, it is by virtue of such self-difference that ‘invalidity’ is not ‘wrongfulness’, ‘general principles of law’ are not ‘customary law’, an ‘armed attack’ is not a ‘use of force’, an ‘injured state’ is not a ‘non-injured state’, ‘responsibility’ is not ‘liability’, ‘jus cogens’ is not ‘erga omnes’, etc. Inhabited by what it is not, each and every form of the international legal discourse has an identity of its own.If not by virtue of any pre-existing meaning, of some meaning in disguise or of relationships of difference with other forms, how can a form be distinct from another form? In other words, what is the self-difference of forms if not some kind of pre-existing meaning, some meaning in disguise or the result of a system of differences? It is argued here that the difference with other forms is not trace, which is said to ‘haunt’ the form.The difference within the selfsame that informs the work of self-difference is sometimes captured through the notion of the trace of what it is not, that is, the mark of other forms that it is different from. It is the trace of other forms (which is a difference within the selfsame) that confers the identity to the form. As a result of this trace of what it is not, each and every form of the international legal discourse can be said to have a divided identity, such form being always already inhabited by other forms.Such a notion of trace—which expresses the work of self-difference, that is, the difference within the selfsame—is helpful to understand how self-difference allows the forms of the international legal discourse to have a distinct identity short of any pre-existing meaning or of a system of differences. Indeed, each form carries an other.That the identity of forms is a divided identity by virtue of the trace of other forms calls for yet another important remark. Such divided identity cannot be a binary identity and the trace of the other cannot be the trace of an opposite.It must be emphasised that international poetics does not entail that the search for the meaning of forms is simply supplanted by a search for the meaning of forms’ self-difference. Indeed, as was already indicated above, the forms’ self-difference does not constitute yet another content that can possibly be extracted, interpreted or created. Such traces of otherness within the selfsame are no surrogate for meaning. Actually, the moment traces of the other forms come within purview, they are already caught in the deferral of meaning and have vanished. In that sense, the trace of otherness within the selfsame, that is, self-difference, can never be apprehended, produced, given a content and interpreted. That does not entail that the forms of the international legal discourse are empty. On the contrary, the forms of the international legal discourse are always in a state of saturation because of the constant deferral of meaning: forms’ self-difference ensures that forms are always saturated with traces of those other forms to which meaning is deferred.Here, too, the consequences of the attitude towards textuality that has just been outlined are best illustrated by reference to the way in which interpretation can be understood and practised from the perspective of international poetics. In fact, as can probably be anticipated, international poetics bears major consequences on the understanding and practice of interpretation. If the forms of the international legal discourse, as is posited by international poetics, neither carry nor deliver meaning, there are simply no meanings to be determined or found, be that of forms themselves or of their origin, context, authors, agendas, effects, etc. Said differently, from the perspective of international hermeneutics, interpretation cannot be about determining any meaning whatsoever, for the latter is always absent.It is submitted here that international poetics, although it does not repudiate dualism altogether, seriously qualifies the linear dualism of international hermeneutics. In fact, as is shown here, international poetics rests on a different type of dualism that is called spatial dualism.International poetics’ rupture with international hermeneutics’ dualism can be summarised as follows. International poetics departs from international hermeneutics’ dualism in that it no longer elevates the distinction between form and meaning into a condition of the international legal discourse. Indeed, for international poetics, meaning is absent from the international legal discourse, which is entirely dominated by (and articulated around) forms referring to other forms in their deferral of meaning. Likewise, international poetics does away with international hermeneutics’ hierarchical dualism in the sense that it foregrounds the forms, and only the forms, unmaking the primacy of meaning over forms. Finally, international poetics repudiates international hermeneutics’ differential dualism in that the identity of the forms of the international legal discourse no longer lies in a system of differences of meanings between forms but in forms’ self-difference. In undoing the existential, hierarchical and differential dualism of international hermeneutics, international poetics breaks away from any type of linear dualism and ceases to reduce international law texts to systems of lines with a beginning and an end.spaces with no centreSuch repudiation by international poetics of the linear dualism of international hermeneutics bears dramatic consequences on the attitude of the international lawyer towards international law texts. In fact, once the linear dualism of international hermeneutics is resisted, international law texts can be approached as spaces rather than lines. Free from the idea that the meaning pre-exists the form and is carried and delivered by it, international poetics particularly enables the international lawyer to appreciate that international law texts are Turning international law texts into spaces rather than lines is no minor rupture from the dualism of international hermeneutics. Indeed, such spatial understanding of textuality concretely entails a recognition of the multidimensionality of textsImportantly, however, approaching international law texts in a non-linear fashion does not amount to a complete repudiation of dualist patterns of thoughts. In fact, dualism remains very present in international poetics for a number of reasons. First, international poetics, just like international hermeneutics, still brings about a process of interrogation of international law texts, albeit not for single answers but for an appreciation of such texts’ plenitudes. This interrogative posture always carries a form of dualism, one that distinguishes between the interrogating reader and the interrogated text.oppositional. Such an observation is important because many international legal scholars who have come close to espousing an approach to textuality that corresponds to international poetics have simultaneously promoted an attitude towards textuality based on oppositional reading.an other. Construing self-difference as a binary identity, and thus understanding the trace of the other as a trace of the opposite, would presuppose a pre-existing opposite, and thus bring back the linear dualism of international hermeneutics.An observation is in order regarding the type of reading of international law texts that is enabled by the spatial dualism of international poetics: the spatial dualism that permeates international poetics cannot lead to a reading that is The work of the spatial dualism that accompanies international poetics, as it has been sketched out here, can also be illustrated by reference to article 51 of the United Nations Charter (which is famous for providing for an inherent right of self-defence). The international lawyer who is solicited to determine whether article 51 is applicable to non-state actors and who espouses the spatial dualism of international poetics will first refrain from presupposing that an original content had first been agreed upon and subsequently inscribed in article 51. She will still isolate the text from its content, but will not consider such a content to be preceding the text or to be the cause thereof. Likewise, she will come to ascribe no beginning and no end to article 51, let alone a semantic genealogy that begins with an original meaning loaded onto the text of that provision and ends with another meaning deemed more authoritative and subsequently inscribed into that text. Instead, she will construe the text of article 51 as a signifying space where content has always been and will continue to be eternally created by all those that have ever invoked article 51. As a result, the international lawyer sensitive to the spatial dualism of international poetics will see herself not as extracting or deriving a meaning from article 51, but as navigating an immense semantic space inhabited by the incalculable traces of other texts that themselves carry the incalculable traces of further texts. In doing so, she will realise that article 51 bears the traces of other texts that are both anterior and posterior to it, be it some preparatory works of the United Nations Charter or subsequent juridical or scholarly pronouncements about article 51, themselves referring to a myriad of other anterior or posterior texts, words, forms, etc outside the legal realm. Although conscious of the infinity of the semantic universe enabled by article 51 and of the absence of origin and end to anything that such provision could mean, the international lawyer amenable to international poetics will appreciate that only a slow and meticulous reading of the infinite possibilities of article 51 will simultaneously realise that the little sense she can make of the text of article 51 remains dependent on her own repertoires of available semantic possibilities, of the other texts that her reading of article 51 brings her to and even of her affects, her desires, her emotions, her loyalties, etc.It is important to highlight that, in the above-mentioned example, being caught in the deferral of meaning at work in the signifying space of the text of article 51 of the United Nations Charter does not entail that the international lawyer sensible to international poetics will be unable to answer the question whether article 51 applies to non-state actors, let alone that she will be caught in a forever reading of that text and find herself unable to answer any pressing question about what that provision dictates. On the contrary, she will be able to make a better choice, not as to which fixed meaning is allegedly attached to the text of article 51, but as to which deferral of meaning ought to be entailed by article 51—and thus which other forms article 51 ought to be referring to, a choice that will more consciously mobilise her individual ethics. The maximisation of the ethical responsibility of the international lawyer when espousing international poetics is a point to which the final section of this article returns.The previous sections have sketched out two attitudes towards textuality in international legal thought and practice, one that has been deemed dominant and called international hermeneutics and one that has been perceived as aspirational and called international poetics. In this last section, this article explicitly makes a plea for a greater embrace of international poetics and of the spatial dualism that accompanies it.It is argued here that the international lawyer would gain much from letting international poetics guide her attitude towards textuality. The point made here is that international poetics, thanks to the spatial dualism it puts in place, allows the international lawyer to be true to her texts. Indeed, rather than perpetuating a theatrical quest for an ever-absent meaning, the international lawyer that embraces international poetics enables texts to be texts, namely spaces where something is always happening.That international law texts, from the perspective of international poetics, are eternally new and constantly renewable is rather good news for those pursuing something like reform.It must be conceded that international poetics and its spatial dualism make the international lawyer a permanent nomad in a textual universe.It could also be objected that international poetics and its spatial dualism, by leading the international lawyer to an infinite and always-unfinished reading of international law texts, contradicts the core functions that law, the lawyers and their texts are called upon to perform.One could similarly take issue with the failure of international poetics to capture and appreciate the processes of material inscription and communication of international law textsInternational poetics could also be perceived as condemning the international lawyer that embraces the spatial dualism thereof to some vile pragmatism and a resignation not to seek truth from the text.A final argument can be made in favour of international poetics. It is an argument of a descriptive nature that turns international poetics into a naturalistic necessity.


Parkia platycephala (PPL) was studied. This study aimed to investigate the possible orofacial antinociceptive of PPL lectin in adult zebrafish and rodents. Acute nociception was induced by cinnamaldehyde (0.66 μg/mL), 0.1% acidified saline, glutamate (12.5 µM) or hypertonic saline (5 M NaCl) applied into the upper lip (5.0 µL) of adult wild zebrafish. Zebrafish were pretreated by intraperitoneal injection (20 µL) with vehicle (Control) or PPL  30 min before induction. The effect of PPL on zebrafish locomotor behaviour was evaluated in the open field test. Naive groups were included in all tests. In one experiment, animals were pre-treated with capsazepine to investigate the mechanism of antinociception. The involvement of central afferent C-fibres was also investigated. In another experiment, rats pre-treated with PPL or saline were submitted to the temporomandibular joint formalin test. Other groups of rats were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of mechanical sensitivity using von Frey. PPL reduced nociceptive behaviour in adult zebrafish, and this is related to the activation of the TRPV1 channels since antinociception was effectively inhibited by capsazepine and by capsaicin-induced desensitization. PPL reduced nociceptive behaviour associated with temporomandibular joint and neuropathic pain. The results confirm the potential pharmacological relevance of PPL as an inhibitor of orofacial nociception in acute and chronic pain.Lectins are a heterogeneous group of proteins that reversibly bind to simple sugars or complex carbohydrates. The plant lectin purified from the seed of  According to the International Association for the Study of Pain IASP, 2008), pain is characterised as an unpleasant sensory and emotional experience, associated with actual or potential tissue damage, or described in terms of this damage. The damage is one of the classic signs of the inflammatory process and initially results from the sensitization of nociceptors, besides being present as a symptom of many clinical disorders that affect a large portion of the population, causing damage to the quality of life ,2. Natur008, painLectins are proteins of non-immunological origin with the ability to recognize and bind to carbohydrates and glycoconjugates . The mosIn general, the biological activities described for lectins are related to the ability of these proteins to recognize carbohydrates on the surface of cell membranes and trigger an intracellular signalling that results in a biological response . Recently, our research group described the first work showing the effect of a lectin in inhibiting orofacial pain in a zebrafish model . SubsequParkia platycephala is a species found predominantly in the North and Northeast of Brazil and is popularly known as visgueiro or faveira [Parkia platycephala glucose/mannose lectin (PPL) was the first of its genus to have its amino acid sequence elucidated. The primary structure is formed by 447 amino acid residues and the three-dimensional structure is formed by three β-prism domains, and each one has a non-identical mannose binding site [Species of the genus Parkia are used in traditional medicine as an analgesic drug, especially against dental pain . Parkia  faveira . Parkia ing site ,18. PPL ing site , antinocing site .Parkia platycephala (PPL) lectin in adult zebrafish and rodents.This study aimed to investigate the possible orofacial antinociceptive of The purification of PPL was achieved by affinity chromatography on sephadex-G100 column, as previously described by Cavada et al. . The chrp < 0.05 vs Control) and this effect was prevented by the pre-treatment with capsazepine (p < 0.05–** p < 0.01 vs Control) on the nociceptive behaviour evoked by the local application of 5 M NaCl solution to the corneal surface (Capsaicin injection into the lips of adult zebrafish induced nociceptive behaviour A. PPL (0sazepine A. PPL at surface B.p < 0.001 vs control) and abolished the antinociceptive effect of PPL (0.025 mg/mL).According to p < 0.001 vs Control).Capsaicin injection into the upper lip of mice induced face rubbing A. Pre-trp < 0.01 vs Control). The injection of formalin into the temporomandibular junction induced the nociceptive behaviours of head flinching, face rubbing and chewing. As shown in Left IONX produced sustained hypersensitivity to facial mechanical stimulation that was reflected in a reduced mechanical withdrawal threshold for 21 days. The thresholds in sham-operated and naive rats did not significantly change. To investigate the effects of PPL on the mechanical withdrawal threshold in IONX rats, PPL (0.25 mg/kg) or vehicle (control) was administrated at post-operative days 1, 3, 5, 7, 10, 14 and 21. PPL reversed the reduced mechanical threshold on post-operative days 3–21 when compared with Control .Danio rerio) of both sexes (short-fin phenotype), aged 60–90 days, of a similar size (3.5 ± 0.5 cm) and weight (0.3 ± 0.2 g), were obtained from Agroquímica: Comércio de Produtos Veterinários LTDA . Groups of 50 fish were acclimatized for 24 h in a 10-L glass tank (30 × 15 × 20 cm) containing dechlorinated tap water (ProtecPlus®) and an air pump with a submerged filter, at 25 °C and pH 7.0, under near-normal circadian rhythm (14:10 h of light/dark). The fish received ad libitum feed 24 h prior to the experiments. All experimental procedure was approved by the Ethics Committee on Animal Research of the Ceará State University .Adult wild zebrafish (®) in environmentally controlled conditions , with free access to standard pellet diet  and water. The experimental protocols were approved by Animal Ethics Committee of the University of Fortaleza .Swiss mice (20–30 g) and Wistar rats (250–300 g) obtained from the Núcleo de Biologia Experimental of the University of Fortaleza were used. They were housed  for 4 h at 25 °C. The mixture was centrifuged at 10,000× g for 20 min at 4 °C. The clear supernatant (crude extract) was applied to a Sephadex G-100 column (2 × 10 cm) equilibrated with 150 mM NaCl containing. After washing of the unbound material in the equilibrium solution, the lectin was eluted with 100 mM mannose, pooled, exhaustively dialyzed against distilled water, and freeze-dried. Absorbance at 280 nm was used to estimate the protein concentration in all chromatographic fractions. The retained peak  was lyophilized and tested for purity by SDS-PAGE [a et al. . Mature SDS-PAGE .® BD) with a 30-gauge needle was used to inject the lips or for the intraperitoneal treatment.On the day of the experiment, zebrafish were randomly selected, then transferred to a wet sponge for treatment with the study lectin or controls, intraperitoneally (i.p.), after which they were placed in individual beakers (250 mL) containing 150 mL of water from the fish tank and allowed to recover. For oral treatments, a 20 μL variable pipette was used. An insulin syringe  at 0.025; 0.05 or 0.1 mg/mL [The concentrations of the noxious and antagonistic agents, as well as the time of nociceptive action analysis used, were based on our previous reports: 0.66 μg/mL cinnamaldehyde , 0.1 % an = 8/group), 30 min after pre-treatment (20 μL) with PPL (0.025 mg/mL) or vehicle . Another group (n = 8) received capsazepine  15 min before PPL. A naive group (n = 8) was included. The antinociceptive activity was observed individually during 10–20 min.Orofacial nociception was induced with capsaicin  dissolved in ethanol, PBS, and distilled water (1:1:8), injected into the lips of the animals (n = 8/group) were grouped into: Repeated treatment with interval capsaicin produces a reduction in functional response, causing desensitization of type C afferent fibres . In this(a) Control-saline .(b) Desensitized Control (DC)-capsaicin  administered at times 15, 30, 60, 120 and 240 min before saline.(c) PPL .(d) PPL -capsaicin  administered at times 15, 30, 60, 120 and 240 min before PPL.(e) Naive.Orofacial nociception was induced with glutamate, as described in n = 8/group), 30 min after pre-treatment with PPL (see 3.2) or vehicle . A naive group (n = 8) was included. The animals were then placed in a glass Petri dish (∅ 15 cm), divided into quadrants and the nociceptive response was quantified in terms of locomotor activity performed during 0–5 min.Corneal nociception was induced with hypertonic saline  injected into the right eye of the animals (n = 6/group), 30 min after pre-treatment with PPL or vehicle . A naive group (n = 6) was included. The mice were observed in related capsaicin  into the perinasal area (vibrissae) of the right cheek of the animals to the time(s) of facial rubbing behaviour with the posterior and/or anterior ipsilateral paws during the period 10–20 min, as described by Pelissier et al. [Orofacial nociception was induced by subcutaneous application o  were acclimated individually in a glass test chamber (30 × 30 × 30 cm) for 30 min to minimize stress. The animals were pre-treated  with PPL (0.25 mg/kg) or vehicle  and, 30 min later, the animals were anesthetized (i.p.) with ketamine (100 mg/kg) and xylazine (10 mg/kg), and the left temporomandibular joint was injected with 50 μL of 2 % formalin. A sham group receiving 0.9 % NaCl  and a naive group were also included (n = 6/group) [Rats (6/group) .After their recovery from anaesthesia (20 min), the animals were returned individually to the test chamber to quantify nociception as asymmetrical rubbing of the orofacial region with the ipsilateral fore- or hind-paw, and as head flinching (intermittent and reflexive shaking of the head) . The timn = 6/group): PPL  or vehicle . Naive and sham-operated animals (n = 6/group) were used as controls.Rats were anesthetized (i.p.) with ketamine (100 mg/kg) and xylazine (10 mg/kg) to expose the left infraorbital nerve (ION) at its entry into the infraorbital foramen by way of an intra-oral incision (2 mm) in the oral mucosa of the left fronto-lateral maxillary vestibulum, as previously described . The IONn = 6/group) was administered on each post-operative day. Mechanical sensitivity of the left whisker pad skin was assessed using an electronic von Frey instrument at 30 min after the PPL or vehicle treatment. The head-withdrawal threshold for mechanical stimulation of the whisker pad skin was defined as the minimum force needed to evoke an escape more than three times as a result of five stimuli. The rats were acclimated, trained and tested for facial mechanical sensitivity  1 day prior to nerve transection (baseline) and on post-operative days 1, 3, 5, 7, 10, 14 and 21, as previously described . A singlp < 0.05).The results are presented as mean ± S.E.M. of each group of animals. Normality of distribution was confirmed (Kolmogorov-Smirnov) and data were submitted for the analysis of variance (one-way ANOVA), followed by the Tukey post-hoc test, or two-way ANOVA, followed by Bonferroni’s post-hoc test. For analyses of PPL (and vehicle) effects in IONX animals, the baseline was normalized, and all values post-PPL or post-vehicle administration were expressed as percentage (%) change from baseline. The level of statistical significance was set at 5% (In our previous work, we verified that PPL produced an orofacial antinociceptive effect in adult zebrafish, and this activity is related to the interaction of PPL with glycans present in the TRPV1 receptor . In the PPL, as expected, reduced nociceptive behaviour induced by capsaicin applied to the lip. Besides this, PPL prevented nociceptive behaviour induced by hypertonic saline applied into the cornea. Since the hypertonic saline stimulus in the human cornea is related to the activation of the TRPV1 channels , this reTo investigate the modulation of TRPV1 receptors by PPL, adult zebrafish were pre-treated with the TRPV1 receptor antagonist capsazepine. This compound prevented the antinociceptive effect of PPL. Besides this, depletion of TRPV1+ C fibres by capsaicin eliminated antinociception produced by PPL. Soares et al.  demonstrTRPV1 is a glycosylated receptor composed of N-glycans rich in mannose residues. Veldhuis and collaborators  demonstrTemporomandibular disorders are musculoskeletal pain conditions characterized by pain in the temporomandibular joint and/or masticatory muscles . Here, tReceptors are up-regulated after the injury of the infraorbital nerve and to the fact that pharmacological blockade or selective ablation of trigeminal ganglia cells expressing TRPV1 results impaired the development of facial hyperalgesia ,36. UsinIn conclusion, our results indicate that PPL might to be an effective analgesic drug in acute and chronic orofacial pain states and that this effect may be due to the modulation of the TRPV1 channel.