Transforming Nanofibers into Woven Nanotextiles for Vascular

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Biological and Medical Applications of Materials and Interfaces

Transforming nanofibers to woven nanotextiles for vascular application John Joseph, Aarya G Krishnan, Aleena M Cherian, Balasubramoniam K Rajagopalan, Rajesh Jose, Praveen Varma, Vijayakumar Maniyal, Sivanarayanan Balakrishnan, Shantikumar V Nair, and Deepthy Menon ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b05096 • Publication Date (Web): 24 May 2018 Downloaded from http://pubs.acs.org on May 24, 2018

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ACS Applied Materials & Interfaces

Transforming nanofibers to woven nanotextiles for vascular application †

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John Joseph , Aarya G. Krishnan , Aleena M Cherian , Balasubramoniam Rajagopalan , #

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Rajesh Jose , Praveen Varma , Vijayakumar Maniyal , Sivanarayanan Balakrishnan , Shantikumar V. Nair

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*, Deepthy Menon†*

Centre for Nanosciences & Molecular Medicine

Department of Cardiovascular and Thoracic Surgery

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Department of Cardiology

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Central Animal Facility

Amrita Institute of Medical Sciences & Research Centre Amrita Vishwa Vidyapeetham, Kochi, Kerala – 682041. India. KEYWORDS woven nanotextiles, electrospun yarns, vascular grafts, bundled nanofibers, tubular implants, soft tissue scaffolds

ACS Paragon Plus Environment

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ABSTRACT

This study investigated the unique properties, fabrication technique and vascular applications of woven nanotextiles made from low strength nanoyarns, which are bundles of thousands of nanofibers. An innovative robotic system was developed to meticulously interweave nanoyarns in longitudinal and transverse directions, resulting in a flexible, but strong woven product. This is the only technique for producing seamless nanotextiles in tubular form from nanofibers. The porosity and mechanical properties of nanotextiles could be substantially tuned by altering the number of nanoyarns per unit area. Investigations into the physical and biological properties of the woven nanotextile revealed remarkable and fundamental differences from its non-woven nanofibrous form and conventional textiles. This enhancement in the material property was attributed to the multitude of hierarchically arranged nanofibers in the woven nanotextiles. This patterned woven nanotextile architecture lead to a superhydrophilic behavior in an otherwise hydrophobic material, which in turn contributed to enhanced protein adsorption and consequent cell attachment and spreading. Short term in vivo testing was performed which proved that the nanotextile conduit was robust, suturable, kink-proof and non-thrombogenic, and could act as an efficient embolizer when deployed into an artery.


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1. Introduction The global market for conventional woven textiles is ~1.2 trillion USD with applications in diverse range of products from automobile to aerospace and consumer goods, with 8% for medical devices1,2. The advent of woven nanotextiles, defined as woven textiles developed from nanoyarns, which are twisted bundles of thousands of nanofibers, could unfold new frontiers in the coming decade with properties significantly different from conventional textiles. Nanotextiles appear realizable with the development of electrospinning as a very scalable process to create polymeric nanofibers3; however, nanofibers by themselves are not weavable due to their very low load-bearing capability. Recently our group developed an innovative scalable process to electrospin nanofibers and combine them into yarns in the same process line continuously, yielding strong and resilient nanoyarns4. The strength of these nanoyarns could be controlled by the number of nanofibers in the yarns and the twist angle of the nanofiber bundles. A scalable process for nanoyarns has opened the possibility for developing woven nanotextiles. Fundamental property differences between nanofiber-based textiles and the conventional textilebased products were anticipated owing to its increased surface area that would therefore provide a strong advantage in any surface area-based application, such as filters5–8, catalysts9–11, bioactive scaffolds12–15 ,sensors16–18, solar cells19,20, batteries21–24, among others25. The production of non-woven textiles by the deposition of electrospun nanofibers on a planar or rotating substrate has been used to yield a nanofibrous mat26 or tubular conduit27, the mechanical properties of which are relatively poor. Recently, monofilaments (microfibers of diameter 50-200 µm) were used as the load bearing component in a plain weaving process to create a 2D textile containing monofilaments in one direction and nanofibers in the perpendicular direction28,29. Such a textile has load bearing capability only in the monofilament direction and


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limited surface area in comparison to a nanotextile made solely from nanofibers. However, no prior reports on woven tubular textiles are available, perhaps owing to the high force requirements on electrospun yarns to form closed constructs. In this work, a woven nanotextile conduit was developed using a modified textile technology approach that was able to overcome the above limitations, and could be an industrially scalable technology. The current synthetic medical textiles for larger and medium diameter vascular implants (greater than 5 mm) are PTFE and Dacron. However, these materials are hydrophobic, and for smaller diameter implants, thrombus formation and occlusion are serious problems preventing their application at these diameters30. Superhydrophilic materials are generally considered ideal for blood contacting applications31. Additionally, kink-resistance and flexibility are essential for vascular implants, all of which are properties not provided by the non-woven nanofibrous textiles. This work explored the potential of using the small diameter woven nanotextile conduits as vascular grafts and as an arterial embolizer, another important application in oncology to cut off blood supply to tumors. This study of woven nanotextile properties and its applications in medicine is expected to open up a new area of nanotextiles for innovative applications in many fields. 2. Materials and Method 2.1 Fabrication of nanoyarns 2.1.1 PCL-collagen 20% w/v of Poly(caprolactone) (PCL) (Mw = 45 kDa, Polysciences Inc., USA) and Collagen (Himedia laboratories Pvt. Ltd., India) were dissolved in 1,1,1,2- Tetrafluoroethane (75:25). Electrospinning of the above solution was carried using a modified collector as reported earlier3. Briefly, dual spinnerets were maintained at positive and negative potentials (11.5 kV) (Gamma


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High Voltage, USA) with a constant flow rate of 0.5 mL/hr (KD Scientific, USA) and a fixed uptake rate of yarns at 27 cm/min. 2.1.2 PLLA 14 % w/v of Poly-L-lactic acid (PLLA) (Mw = 100−140 kDa, Goodfellow, U.K.) was dissolved in Chloroform and acetone in the ratio 3:1 (HPLC grade, Merck, India). Dual spinnerets were maintained at positive and negative potentials (12 kV) with a constant flowrate of 2.5 ml/hr and a fixed uptake rate of yarns at 15 cm/min. 2.2 Fabrication of woven conduits As a first step, yarns were bundled by plying, ie twisting of two or more yarns. Here, longitudinal and circumferential yarns were made by bundling 12 and 4 individual nanoyarns respectively. This was achieved by using variable speed motors so as to achieve a final twist of ~ 2 turns per meter. Small diameter conduits were developed using a custom designed weaving setup, which consisted of two identical discs each containing equidistant rods that aids in the shuttling of longitudinal yarns loaded in the bobbin. During weaving, the circumferential yarns unwind from the bobbin at a pre-requisite tension (as shown in figure 2) and intercepts one or more longitudinal yarns and interweaves them one at a time. Interception and interweaving of yarns is a result of drum rotation and shuttling of the longitudinal yarn. The diameter of the central rod determines the inner diameter of the woven tube. The final product formed on the weaving rod was continuously drawn out at a constant rate. Porosity of the graft was adjusted by changing the material packing density i.e., by changing the number of longitudinal yarns. Morphological analysis of the yarns and conduits was carried out using scanning electron microscopy (JEOL, JSM- 6490LA, Japan).


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2.3 Mechanical characterization of woven conduits (based on ISO 7198) 2.3.1 Determination of Suture Retention Strength Suture retention strength is the force required to pull out a suture from the wall of prosthesis. The woven graft was cut longitudinally, and a suture was inserted 2 mm from the open end. The suture was pulled at a rate of 50 mm·min-1 in a universal testing system with 250 N load cell (H5KL, Tinius Olsen, USA). 2.3.2 Determination of Integral Leak Test Integral leak test is determined by measuring the amount of water that is leaking through the graft wall per unit area at a given time. One end of the graft was connected to the pressure transducer of a pressure-volume controller (STDDPC, GDS, UK), while the other end was closed using bulldog clamps. The graft was pressurized at 16 kPa (120 mm Hg) and the amount of water leakage through the graft wall was measured. 2.3.3 Water entry pressure The pressure at which water enters through the graft is determined as the water entry pressure. It was determined by closing one end of the graft with a bulldog clamp and connecting its other one end to the pressure transducer as above. Pressure was gradually increased until water seeps through the wall of the graft. 2.3.4 Determination of Kink Radius Kink radius is the lowest critical radius at which a graft can form a curved loop without forming any kink. The smaller the kink radius, the more the flexibility. It was determined by using cylindrical mandrels of various diameters [1 to 30 mm]. Initially the graft was pressurized at 120 mm Hg and was looped around a rotating mandrel. The lowest radius at which the graft begins to kink is determined as kink radius.


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2.3.5 Determination of longitudinal tensile strength Longitudinal tensile strength was determined by pulling grafts of 50 mm length secured between the pneumatic grips in a universal testing machine. Test was carried out at crosshead speed of 50 mm·min-1 until failure occurred using a 250 N load cell (H5KL, Tinius Olsen, USA). 2.3.6 Determination of circumferential tensile strength Circumferential tensile strength was determined by pulling two identical split bars placed in the luminal side of the graft (length 50 mm) at a crosshead speed of 50 mm·min-1. The maximum force required to tear the walls of the graft divided by its total length yielded the circumferential strength of the graft. 2.3.7 Radial stiffness It is the circumferential force required to crimp the graft. It was determined by making a circumferential loop around the graft using a silk suture. Using the universal testing machine, the ends of the loop were pulled until complete collapse of the graft occurred. 2.4 Platelet activation study The platelet activation study was conducted in nanotextiles using platelet rich plasma (PRP). Whole blood was centrifuged to collect PRP, which was diluted (1:10) with sterile PBS. The diluted PRP was incubated with the nanotextile for 30 min at 37oC. The platelet activity was compared to positive (50µM Adenosine diphosphate, Sigma, USA) and negative control (PBS) respectively. The resultant PRP was treated with PerCP-Cy5 labeled CD62P (BD Bioscience, USA) and FITC labeled CD42b (BD Bioscience, USA) antibodies for 15 mins. The platelet activation was determined using flow cytometry (FACS Aria II, USA).


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2.5 In vivo studies All animal studies were conducted on New Zealand white rabbits (male, 3-3.5 Kg) according to the protocol approved by Institutional Animal Ethical Committee, Amrita Institute of Medical Sciences, India (IAEC/2014/3/8). 2.5.1 Measurement of inner diameter of femoral artery and blood flow velocity Rabbits were anesthetized with an intramuscular injection of a mixture of 20 mg/kg ketamine hydrochloride

and

2

mg/kg

of

xylazine.

Continuous

hemodynamic

and

surface

electrocardiographic monitoring was maintained throughout the procedure. The inner diameter of the femoral artery was determined by 2D doppler (MySono U6, Samsung, Korea). Blood flow through the implanted graft was determined both qualitatively and quantitatively by using the color doppler. 2.5.2 Angiogram of arterial implant Rabbits were anesthetized with an intramuscular injection of a mixture of 50 mg/kg ketamine hydrochloride

and

5

mg/kg

of

xylazine.

Continuous

hemodynamic

and

surface

electrocardiographic monitoring was maintained throughout the procedure. An incision was made above the right carotid artery and the vessel was dissected free, punctured with 21G cannula and a 0.14 guide wire was introduced into the carotid artery. A 4F introducer sheath was inserted into the vessel, guided over the guide wire. Intravenous heparin (1000 U/kg) was administered immediately via introducer sheath. Distal aortic and iliac vessel anatomy was delineated by contrast angiography (Omnipaque, 300mg/ml, GE USA).by using a C-arm (OEC 9800 Plus Mobile C-arm, GE, USA).


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2.5.3 Embolization procedure The utility of small diameter conduits (0.5 mm inner diameter) was tested for embolization experiments in rabbits. The arterial access was obtained as described earlier and the preembolization angiogram was carried out to assess the vessel size and its anatomy. The carotid artery was cannulated with 3 mm sheath, through which the embolization device was deployed in the femoral artery and the sheath was withdrawn subsequently. Successful graft deployment was verified by angiography. After 1 hour of deployment, one more angiogram was taken to confirm the embolization of femoral artery. The right carotid artery was ligated and the incision above the carotid artery was closed in layers. 2.5.4 Vascular graft implantation Rabbits were anesthetized with an intramuscular injection of a mixture of 20 mg/kg ketamine hydrochloride and 2 mg/kg of xylazine and monitored continuously. Anesthesia was maintained with 1.5-2 % isofluorane in oxygen- air mix using ventilator and anesthesia system (Carestation 600 Series, GE, USA). Temperature was monitored using a rectal probe. Controlled hypothermia (32-34°C) was induced by infusing supplemented ringer lactate solution (4°C) through marginal ear vein using 21G cannula. Abdominal aorta (4cm long) was exposed just above the iliac bifurcation. The woven nanotextile conduits were implanted both as interposition as well as bypass grafts via end-to-end and side-to-side anastomosis respectively, using polypropylene 8-0 sutures (Surgipro Pvt. Ltd., Singapore). The abdominal incision was closed using 3-0 Vicryl (Polygalactin 910, Ethicon, Inc.) sutures. The animal was allowed to recover by re-warming to 37°C.


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3. Results and discussion 3.1. Fabrication of tubular woven nanotextiles By the process reported earlier by our group4, electrospun biodegradable fibers were processed into nanoyarns based on FDA approved biopolymers, viz., poly-L-Lactic acid (PLLA) (diameter:780 ± 236 nm) and poly-caprolactone (PCL) (diameter: 183 ± 14 nm). Each yarn consisted of several hundred thousand nanofibers twisted into a single thread, called a nanoyarn, of ~70-200 microns. The nanoyarns thus possess the property of hierarchy, the nanofibers comprising the yarn, and the yarns comprising the nanotextile, with progressive increase in scale. While the nanoscale can provide for enhanced biological interactions, the higher scales can impart improved mechanical strength and component integrity. We describe here the design and development of a robotic system (Figure 1a) for fabricating tightly packed woven nanofabrics, by interweaving mutually perpendicular longitudinal and circumferential nanoyarns in a stepwise manner. This strategy resulted in an overall reduction in the tension requirements of yarns, enabling weaving of low strength materials into nanotextiles, resulting in a tubular product that met the stringent demands of a vascular graft or an arterial embolization device.


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Figure 1. Fabrication of nanotextiles a) Schematic of the automated weaving system (Nanoweaver) that produces continuous woven fabric (blue-circumferential yarn, blacklongitudinal yarn). The fabric is formed on the rod placed at the center of the two large rotating discs. Inset: Photograph of the robotic system. Optical and SEM micrographs of b & e) the smallest woven fabric (0.5 mm) (inside a capillary tube), inset shows its lateral view, c & f) a 4 mm flexible woven conduit, inset shows the cross-sectional view of the inner surface, d & g) architectures formed due to inadequate tension on yarns during weaving A tubular weaving process is described which controls the tightness of weaving, nanoyarn alignment and mechanical properties of the tubular nanotextile. The final tubular product formed consisted of multiple longitudinal yarns held in position by one circumferential yarn. Conduits of different diameters (from 0.5 to 4 mm) (Figure1b and 1c whose cross-sectional SEM images are shown in Figure 1e and 1f) were fabricated by changing the diameter of the weaving rod, with corresponding changes in the number of longitudinal yarns (N) interlaced per circumferential yarn based on Equation 1 =

πD (1)

(where D = diameter of the required tubular fabric, d = diameter of longitudinal yarn). A minimal tension was always maintained on both circumferential and longitudinal yarns for proper interlocking, which otherwise lead to an open web-like structure (Figure 1 d & g) or a loosely woven structure (Figure S2, Supporting Information). By changing the number of longitudinal yarns, the packing density of the tubular conduit was altered as shown in Figure S3a, S3b, and S3c, Supporting Information, yielding high, medium and low-packed 3D woven structures. We further demonstrate the applicability of this weaving methodology to develop


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nanotextiles using low-strength mono and hybrid materials (PLLA and PCL: Collagen 75:25 respectively) as shown in Figures 2 a – h. To meet the force requirements during weaving, the yarns were packed into bundles as shown in Figure 2i. Complex multiscale conduits were also developed which has the potential to be used for other biomedical applications (Figures 2j-l).

Figure 2. Hierarchical multiscale nanotextiles. SEM micrographs of conduits fabricated using yarns constituted of well-oriented fibers. a-d) PCL-collagen. e – h) PLLA. i) Cross-sectional view showing hierarchical bundling of fibers j) Conduits with step change in diameter, inset shows its optical image k,l) Hierarchical concentric and multi-channeled structures. Red arrows indicate individual conduits of same or different diameter The concept of weaving tubular fabrics and the force requirements are further clarified in Figure S4, Supporting Information. During weaving, the circumferential yarn intercepts one or more longitudinal yarns (Figure S4 a-c, Supporting Information) and interweaves them one at a


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time. It can be noted that there is a proportional increase in the number of intercepting yarns and a corresponding demand on the circumferential yarn in terms of its tension, with increasing conduit diameter. Based on this, an empirical relation [Equation S1, Supporting Information] was deduced to determine the minimum force requirement of yarns for uninterrupted weaving. As shown in the tabulation (Figure S4, Supporting Information), a corresponding increase in the number of longitudinal/intercepting yarns was required to account for the tight packing. The process design optimization based on this strength requirement is critical here because the fibers have one-tenth to one-half the strength of cotton fibers [Figure S1, Supporting Information] and hence cannot be woven by a conventional process. 3.2. Physical properties of woven nanotextiles 3.2.1 Wettability of woven nanotextiles We first present data on the enhanced wettability of nanotextiles in comparison to other nonhierarchical forms such as the non-woven nanofibrous PLLA mat (wherein nanofibers are in random directions- denoted as ES), a film of the same material, and conventional medical textile (silk) (Figures 3a-d). Water contact angle measurements revealed remarkable changes in the hydrophobic nature of PLLA when woven as tightly packed aligned nanotextiles. Water drops spread almost instantaneously on the nanotextile having aligned PLLA yarns, with apparent contact angle close to zero (Figure 3d). In contrast, the droplet did not spread at all on the same PLLA material in thin film form (Figure 3a), or when nanofibers are randomly oriented as in an electrospun PLLA mat (Figure 3b), or even on textiles made from conventional silk microyarns (Figure 3c), indicating that slight hydrophobicity can transform to strong hydrophilicity in aligned nanotextiles. In a solid film, the spreading of a droplet is dictated by the contact angle, which is governed by how the surface tension is balanced against the droplet-material and


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material-air surface energies32. If the material-air surface energy is greater than the materialdroplet interfacial energy, the material is hydrophilic, and is hydrophobic when the opposite is true. When the two energies are equal, the droplet takes on a semicircular profile on the material surface, as illustrated by the well-known equation

=

− (2)

where, − is the difference between the material-air and material-droplet interfacial energies and T is the surface tension of the droplet, being the contact angle. The same principle applies also in conventional textile material surfaces. We observed Equation 2 to break down in aligned nanotextiles, wherein spreading is complemented by substantial capillary “wicking” action between the nanoyarns via channels. When the liquid can “wet” the material, that is, when − is positive, the residual force on the meniscus drags the liquid front along the capillary channel. If there are a very large number of such channels, then the droplet will spread along the channel direction, reducing the effective contact angle far below what is predicted by Equation 2. This is what was observed in Figure 3d wherein the large number of nanoscale channels both within and between the nanoyarns essentially “wicked” the liquid along the nanotextile in the direction of yarn alignment. No such wetting was observed in conventional textiles (Figure 3c), or on nanofibrous mats with random fiber orientation (Figure 3b), wherein nanochannels are absent, or are not continuous in one direction, implying that hydrophobic (nonwetting) surfaces ( ≥ 90°) cannot exhibit “wicking” action. This was further reinforced when the wicking of a water-based dye was observed to be maximum for individual nanoyarns having aligned nanofibers, in contrast to yarns with twisted nanofibers, multi or monofilament fibers (Figures 3e-3i). Increasing twist angle is equivalent to closing nanochannels along the nanoyarn, thereby decreasing the wettability (Figure 3j). During


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the bundling of nanoyarns, it is the twist of the fibers that controls the number of channels and its spacing as evident from the SEM images of yarns obtained at different twist angles [Figure S5, Supporting Information]. Aligned yarns were comprised of channels with a wide range of channel width between 600-6000 nm [Figure S6, Supporting Information]. However, there was a significant reduction in the number of channels, resulting in the closure of smaller channels below ~2000 nm when the twist angle was increased to ~ 30o as in the case of highly twisted yarns [Figure S5c, Table S7, Supporting Information]. Twisting of yarns also resulted in the compaction of fibers leading to the reduction in yarn diameter (inset of Figure S5, Supporting Information) thereby reducing its wettability. Additionally, wettability of nanotextiles of different packing fabricated using aligned yarns, was found to be time-dependent. Hence, the contact angle would also be time-dependent, as observed in Figure 3k, with tightly packed nanotextiles (high interweaving denotes as HI) showing instantaneous wetting in comparison to textiles having lower packing density (medium and low interweaving denoted as MI and LI respectively). Videos S1 and S2 in Supporting Information reveal significant spreading of the dye for various material packing, with no seeping through the textile. Amongst various forms of yarns, PLLA aligned nanofibrous yarns (Figure 3g) showed maximum wettability. Thus, nanotextiles formed by tightly packed aligned PLLA nanoyarns transformed an inherently hydrophobic polymer into a hydrophilic product. This unique behavior can be attributed solely to the capillary action-driven wetting in nanotextiles.


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Figure 3. Physical properties of nanotextiles: Optical image of water droplets on a) PLLA bulk film b) PLLA non-woven fibrous mat c) silk textile and d) PLLA nanotextile, inset shows corresponding image of a droplet of dye. e) Wicking of dye on f) Twisted PLLA yarn g) Aligned PLLA yarn h) Micro-filamentous silk yarn i) Monofilament PLLA yarn and their corresponding SEM micrographs clearly depicting the closure, presence, lesser number and absence of channels respectively. j) Delta change in contact angle with time for various types of yarns. PLLA aligned nanofiber showing a higher degree of wettability compared to other forms. Statistical significance in delta contact angle of PLLA (aligned nanofibers) were comparison with other groups. k) Time dependent variations in contact angle on PLLA conduits of varying material packing (HI, MI, LI) with reference to non-woven PLLA fibers (ES). Spread of serum proteins through two different fibrous forms of PLLA. SEM micrographs of l) HI (inset high magnification showing uniform dissemination) m) ES (inset high magnification showing the boundary of the protein clump and non woven nanotextile). Mean values in different groups


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were tested for statistical significance using one-way ANOVA with Tukey’s post-hoc multiple comparison. P-value of each comparison is depicted in the plot and was considered statistically significant at P < 0.05. Error bars represent standard deviation. ***P < 0.001. HI, MI and LI denotes high, medium and low material packing of woven nanotextiles respectively 3.2.2 Protein and cell interaction Capillary-driven wetting can substantially change protein-fabric interaction as well, which is fundamental to biological interactions of nanotextiles. Proteins are the first to interact with any foreign material in a human body, and the nature, type and amount of proteins that bind to nanotextiles will dictate its interaction with the human body33. A uniform dissemination of total serum proteins was noted over the nanotextiles in comparison to the relatively hydrophobic nonwoven mat (Figures 3l, 3m). This protein spreading is capillary-driven, being drawn along nanochannels by the serum, with subsequent trapping of protein molecules, perhaps within the channels. In contrast, the type and concentration of proteins on a solid film would be governed by the protein-surface binding energy. Hence, on nanotextiles, it is expected that protein size and conformation will play a more significant role in capillary-driven wetting rather than protein binding energy with the material. Concurrently, we found that nanotextiles promoted excellent endothelial proliferation and spreading within 48 hours [Figure S8, Supporting Information]. This endothelialization can be attributed to the rapid uptake of serum proteins on fibres through capillary action, followed by protein-aided cellular attachment. This behavior is invaluable for vascular graft applications. 3.2.3. Mechanical properties of woven nanotextiles Yet another feature vital for vascular applications of nanotextiles is its mechanical characteristics. For tightly packed tubes (HI), the suture retention strength, circumferential


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strength, tensile strength and radial stiffness were all significantly higher than for non-woven tubes (ES) (Figures 4a-d). Specifically, for nanotextiles to be used as vascular grafts, an important property is its suture retention strength, which was much higher for the woven nanotextile tubes (Figure 4a). Moreover, HI conduits which possessed optimal circumferential and longitudinal tensile strengths (Figures 4b, 4c) and radial stiffness (Figure 4d), performed best in its integral leak test, which qualifies the ability of the graft to contain blood flow [Figure S9, Supporting Information]. Notably, the woven nanotextile provided a uniform mechanical strength along both longitudinal and transverse directions, unlike monofilament reinforced nanofabrics28,29. It is also important to note that the nanotextile HI conduit did not rupture even at pressures exceeding 11000 mmHg, while PTFE (medical textile) ruptured at ~3000 mmHg. 3.2.4. Kink-resistance One important requirement of tubular implants is its ability to resist kinking. The woven grafts had a much smaller tendency to kink, with an average kink radius of 6 mm, compared to >30 mm for the non-woven graft (Figures 4e,f). The resistance to kinking is imparted by the bilateral orientation of nanoyarns which is absent in the non-woven conduit (ES). This property implies the capability of the woven graft to bend without kinking, thereby facilitating normal blood flow and eventually patency. Thus, the mechanical properties of woven nanotextiles could be tailored to design implants with the requisite characteristics.


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Figure 4. Various mechanical properties of conduits with three different material packing a)-e). Tested in comparison with ES (non-woven fibers) and PTFE (commercial standard) denoted as dotted red line. Inset in e) depicts optical images of flexibility of HI with respect to MI and ES f) HI of different diameter showed differences in its kink radius i) 0.5mm ii)1.5mm iii) 4mm iv) PTFE. Mean values in different groups were tested for statistical significance using one-way


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ANOVA with Tukey post-hoc multiple comparison tests. Error bars represent standard deviation. P-value of each comparison is depicted in the plot and was considered statistically significant at P < 0.05. HI, MI and LI denotes high, medium and low material packing of woven nanotextiles respectively. 3.3. In vivo vascular applications 3.3.1 Embolization device The mechanically compliant nanotextile conduits were further evaluated for its applicability in vivo. A novel application of woven conduits was its use as an embolization (vascular occlusion) device in small diameter arteries, required during chemoembolization. To demonstrate this, conduits of similar arterial dimensions (determined by ultrasound imaging Figure S10, Supporting Information) were fabricated (Figures 1b & e), with high maneuverability, flexibility (Figure 5a), low radial stiffness and kink proof nature as shown in Figure 4f(i). Radio-opacity was imparted to the conduit by tagging with platinum (Figure 5b). The trackability and traceability was demonstrated in the vascular system of rabbits by deploying the conduit through the carotid to femoral artery via abdominal aorta, as schematically shown in Figure 5c and Video S3, Supporting Information. Vascular occlusion was evident from the histology and angiograms shown in Figure 5d and Figure 5e-5g respectively, wherein an immediate obstruction of the distal portion of femoral artery was visualized [Video S4, Supporting Information]. This was achieved due to the low radial stiffness of the conduit, which in turn resulted in its collapse due to the inward radial force exerted by the femoral artery (Figure 5d). Hemocompatibility of the nanotextiles was confirmed by the platelet activation study using flow cytometry as shown in Figure 6a-c. The woven nanotextile did not induce any activation of platelets, proving that the blood flow was hampered due to mechanical occlusion of the artery. This alternative novel


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approach of embolization has advantages over the existing embolization method using microparticles and gels34, which has a high risk of particle aggregation, catheter occlusion, nontarget embolization, etc35,36. Additionally, the possibility of drug loading within the fibrous yarns37 would bestow the conduit with multifunctional characteristics in terms of imaging, drug loading and embolization. Importantly, the above embolization procedure using nanotextiles was performed according to current clinical protocols and hence holds good potential for translation.

Figure 5. Nanotextile as embolization device a) Optical image of highly flexible small diameter embolization device showing absence of kink. b) X-ray image of radio-opaque embolization device inside a catheter, Yellow arrows represent platinum tag attached to both ends of woven conduit. c) Schematic of embolization procedure in rabbit femoral artery using woven conduit, inset shows the optical image of the device deployed at the target site (inside femoral artery).


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d) Histological section (Verhoeff’s Van Gieson stain) of the embolization device which is mechanically compressed by the femoral artery due to the low radial stiffness of nanotextile (4 x magnification). Blue line shows the reduced luminal area of nanotextile which reduces the blood flow e) Angiogram of patent arteries before embolization f) fluoroscopic image of device deployed within femoral artery using guide wire g) Angiogram of occluded femoral artery after deploying the conduit and retracting the guide wire 3.3.2 Vascular graft Another mechanically demanding application demonstrated here is the applicability of the highly packed (HI) superhydrophillic nanotextile tubular conduit as small diameter vascular graft. The mechanical properties of the nanotextiles, tested using ISO standards revealed superiority over commercial standards [PTFE] (Figures 4a-f). However, due to the microscopic porosity between the interlocked yarns, water entry pressure of the fabric was lower (20-30 mmHg) which was similar to the non woven form. Hence, to make the construct impervious, an additional electrospun nanofibrous layer was introduced [Figure S11, Supporting Information]. This construct was tested as interposition (Figure 6d) and aortoiliac bypass grafts (Figure 6e), adopting end-to-end and side-to-side anastomosis respectively. A preliminary safety and feasibility analysis for 48 hours revealed the graft to be free from thrombus and aneurysm, with a pulsatile blood flow, confirmed by ultrasound (Figure 6f). The graft could withstand the high arterial pressure without transmural or suture line bleeding. Histological evaluation of the implanted material showed no signs of acute inflammatory response in the initial 48 hours of implantation (Figure 6g, h). Studies on the long-term patency of the graft in large animal models is currently underway.


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Figure 6. Nanotextile as vascular graft a-c) Assessment of platelet activation using flow cytometry a) Positive control –ADP b) Negative control- PBS c) Nanotextile d) Implantation of woven conduit (diameter: 2.5 mm) as interposition graft in abdominal aorta e) implantation of conduit as bypass graft from abdominal aorta (AA) to iliac artery(IA). Blue dotted lines represent the route of blood flow from abdominal aorta to left and right iliac arteries before bypassing, and green solid line the route of blood flow after implantation of bypass graft. Yellow arrow depicts ligation of iliac artery adjacent to bifurcation. f) Color Doppler image showing blood flow


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through the implant after 48 hours of graft implantation (arrows indicate the position of the graft), Bottom panel depicts the pulsatile flow and blood velocity. g) & h) H&E staining of nanotextile after 48 hours of implantation, 10x and 40 x respectively 4. Conclusion In this work we have addressed how the challenges in fabricating tubular nanotextiles from weak fibrous yarns can be surmounted through a novel mechanism that reduces the tension demands on polymeric yarns during weaving process. By adopting this principle, flexible, tightly packed, woven nanotextile conduits were made that possessed mechanical properties superior to the clinical standards (PTFE), owing to the uniaxial alignment of yarns in both longitudinal and circumferential directions. A unique finding was the remarkable increase in wettability brought about by the multitude of nanosized channels present in nanotextiles, which was low/absent in commercial medical textiles. This enhanced wettability opened up the applicability of nanotextiles for blood contacting applications. In contrast to the non-woven form (electrospun conduit), the woven nanotextile was superior in terms of kink-resistance, mechanical properties and scalability. Small diameter woven conduits with low radial stiffness and flexibility could also successfully embolize femoral arteries. A proof of concept for small diameter vascular graft substitutes was demonstrated using suturable, non-thrombogenic conduits having low kink radius. Thus woven nanotextiles, owing to its scalable and unique properties, unfold wideranging applications for exploration in biomedical and engineering fields.


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ASSOCIATED CONTENT Supporting Information Details of tensile strength of yarns, SEM image of irregularly packed woven graft, measure of interweaves per unit area, SEM image of cell attachment and spreading, measure of water permeability for different material packing, ultrasound of femoral artery, assessment of platelet activation and measure of water permeability after nanolayer deposition are shown in this section. This material is available free of charge via the Internet at http://pubs.acs.org

AUTHOR INFORMATION Corresponding Author *Email: [email protected], [email protected] Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding Sources This study is supported by the Department of Science and Technology (DST), Government of India through the “Thematic Projects in Frontiers of Nanoscience & Technology” (SR/NM/TP15/2016G). Notes The authors declare no competing financial interest


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ACKNOWLEDGMENT Authors acknowledge the financial support from Nanomission, Department of Science and Technology and Amrita University for all infrastructure support. John Joseph acknowledges Council of Scientific and Industrial Research and Commonwealth scholarship commission for a Senior Research Fellowship (9/963(0035)2k14-EMRI) and Commonwealth scholarship award (INCN-2016-176). We thank Mr. Muraleedharan A. V and Mr. Shinu Thomas for all their valuable inputs for this work. ABBREVIATIONS PLLA, Poly-L- Lactic Acid; PCL, Poly-ε- Caprolactone; PTFE, Poly(tetrafluoroethylene) REFERENCES (1)

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Transforming Nanofibers into Woven Nanotextiles for Vascular

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