Why Polyurethanes Have Been Used in the Manufacture and Design of Cardiovascular Devices: A Systematic Review

We conducted a systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to ascertain why polyurethanes (PUs) have been used in the manufacture and design of cardiovascular devices. A complete database search was performed with PubMed, Scopus, and Web of Science as the information sources. The search period ranged from 1 January 2005 to 31 December 2019. We recovered 1552 articles in the first stage. After the duplicate selection and extraction procedures, a total of 21 papers were included in the analysis. We concluded that polyurethanes are being applied in medical devices because they have the capability to tolerate contractile forces that originate during the cardiac cycle without undergoing plastic deformation or failure, and the capability to imitate the behaviors of different tissues. Studies have reported that polyurethanes cause severe problems when applied in blood-contacting devices that are implanted for long periods. However, the chemical compositions and surface characteristics of polyurethanes can be modified to improve their mechanical properties, blood compatibility, and endothelial cell adhesion, and to reduce their protein adhesion. These modifications enable the use of polyurethanes in the manufacture and design of cardiovascular devices.


Introduction
In the treatment of different cardiovascular pathologies, it is generally necessary to replace the compromised structures and tissues. For decades, biomaterials for cardiovascular applications have been studied and developed to improve their biocompatibility with the human body when implanted, as well as their capability to mimic the behavior of living tissues. Polyurethanes (PUs) are a class of polymers that are used in the preparation of medical devices owing to their biocompatibility, degradability, and non-toxicity [1].
It has been established that PUs are produced by the condensation reaction of an isocyanate and a material with a hydroxyl functionality produced by using either a single type of monomer (homopolymers) or two types of monomers (copolymers). Copolymers are of the following types: random, alternating, segmented, block, and graft [1]. With regard to medical applications, PUs could be used in peritoneal dialysis, neurological leads, and infusion pumps. In addition, PUs could be used as pacemaker leads, vascular grafts, pacemaker lead insulation, probes, wound dressings, feeding tube, cannulas, catheters, or cardiovascular catheters [1].
Microbial colonization is likely to occur on material surfaces in some the PU applications mentioned above. This results in severe and generally life-threatening complications such as infections [1].
The two elements format strategy was used for defining the research question. "Cardiovascular devices" and "polyurethane" were the key elements for P (population/phenomena) and O (outcomes), respectively. The research question was formulated as, "Why have PUs been used in the manufacture and design of cardiovascular devices?" This question follows the characteristics of a good research question: the feasible, interesting, novel, ethical, and relevant (FINER) criteria [5].

Eligibility Criteria
For this review, we selected the studies based on the type of article: journal articles and studies concerning the use of PUs in the manufacture and design of cardiovascular devices. We selected books, case reports, case series, conference, not-indexed documents, editorials, letters, manualx, miscellaneous (misc) documents, patents, proceedings, review articles, tech reports, theses, and dissertations as the exclusion criteria.

Information Sources, Search Strategy, and Study Selection
A complete database search was performed by two authors (K.N.-G. and M.F.V.) in November 2019. We used PubMed, Scopus, and Web of Science as the information sources for this review. The search parameters of the study selection were the year, publication state, and language. The search period ranged from 1 January 2005 to 31 December 2019, the publication state was "published", and the language was limited to English.
The references were managed with Rayyan Qatar Computing Research Institute (QCRI) [6] to (1) eliminate duplicates and (2) exclude articles with insufficient information (both in the title and in the abstract); articles with keywords such as electrospun, electrospinning or electrospinning technique, drugs, blood vessels, blood contacting, urea, poly(etherurethane urea) (PEUU), poly(carbonate urethane) (PCU), polyhedral oligomeric silesquioxanes (POSS) or simulations; and articles with insufficient information on the use of PU as a material for constructing cardiovascular devices. Specifically, The searches in PubMed, Scopus, and Web of Science yielded 861, 343, and 348 articles, respectively. In total, 647 articles were excluded after being managed with Rayyan QCRI [6]; 40 fulltext articles were assessed for eligibility. The searches in PubMed, Scopus, and Web of Science yielded 861, 343, and 348 articles, respectively. In total, 647 articles were excluded after being managed with Rayyan QCRI [6]; 40 full-text articles were assessed for eligibility.
After a full-text revision, 19 articles were excluded owing to the following reasons: 9 did not contain information on PU characterization and 10 presented PU syntheses using the electrospun or electrospinning technique. A total of 21 papers were included in the analysis.

Characteristics and Results of Included Studies
The following data were tabulated from the included articles: author, year of publication, geographic setting, PU type or chemical composition, type of study (in vitro or in vivo) or type of cells, field of application, and main results ( Table 1).
This study had limitations. We only used three databases (PubMed, Scopus, and Web of Science) and only articles in English were screened. The systematic review included articles that represent a small fraction of the literature on synthesis techniques for application in cardiovascular devices. A method of encasing cardiovascular stents with an expandable PU coating was developed to provide a smooth homogeneous inner wall that allows for a confluent growth of endothelial cells. The PU film covered the metal wire stent structure, thereby minimizing biocorrosion of the metal (stainless steel or nitinol) and providing a homogeneous surface. The stent structure covered with a film of less than 25 µm could display sufficient corrosion resistance and flexibility without producing excess stress in the structure. In this work, PEM of CS/DS (CS as a positively charged agent, and DS as a negatively-charged and an antiadhesive agent) were deposited onto the aminolyzed TPU film surface by the LBL self-assembly technique. The authors note that the deposition of over four bilayers with DS, as the outermost layer could improve the hydrophilicity of the TPU film, suppress the protein adsorption and platelet adhesion, and prolong the blood coagulation time.
Stachelek et al. [9] 2006 USA Tecothane™/cholesterol (Chol) In vitro, in vivo. Sheep blood outgrowth endothelial cells (BOECs) Heart valve PU-Chol has been presented as an option for BOECs for applications such as PU heart valve leaflet implants. This work indicated that PU-Chol has significantly better BOEC adhesion properties than unmodified PU under simulated and in vivo heart valve shear force conditions.
This work showed that the covalent modification of PUs such as Tecothane by using DBP conferred biodegradation resistance in vivo and that this biodegradation is dependent on the DBP dose. It is important to note that the modification with DBP could be effective in trapping oxygen radicals that are released from adherent MDMs that interact with PUs. In this work, authors observed that shape memory materials have been proposed for cardiovascular stents owing to their self-expansion capability. This capability is important for polymeric stent deployment at temperatures near the body temperature. To work on this capability, the investigators used crystallinity-induced shape memory effect to incorporate elastic memory in a stent. They used PU/PCL blends as materials for shape memory stents. The PU/PCL blend compositions and crystallization conditions were modified. The PU/PCL (70/30) blend showed remarkable biocompatibility, which was indicated by the adhesion and proliferation of bone marrow mesenchymal stem cells compared with the other blends. Furthermore, this blend is a potential material for use in stent implantx.

Vascular tissue engineering applications
In this study, the authors used double porogen (PEG-salt) to optimize the pore interconnectivity and to increase the porosity in the PU without compromising on the scaffold mechanical integrity. The materials were tested under dynamic mechanical stretching to mimic the biomechanical conditions. The use of PEG-salt porogens was effective in improving the pore interconnectivity through the production of micropores in the range of 1 to −5 µm, and in increasing the total scaffold porosity by enabling the addition of more salt within the monomer-porogen mixture.
Ashton et al. [ In this work, the authors modified the PU chemical composition and used clay as a filler. They described that these modifications enable the determination of an appropriate formulation for biostable cardiovascular devices. Among the chemical compositions, the authors used a nonaromatic diisocyanate (HDI). This enables the development of mechanical properties close to those of the native mitralic tissue and prevents the production of highly toxic aromatic diamines. The authors indicated that a higher percentage of PTMO in the soft segment improved the mechanical performances of PUs. That is, it increased the Young's modulus, the stress at break, and the maximum strain. The Young's modulus values at 37 • C were included in the required range (6 MPa in the circumferential (parallel to the annulus) direction and 2 MPa in the longitudinal (perpendicular to the annulus) direction) for annuloplastic applications. In this study, the freeze-drying technique was used to fabricate 3-D interconnected porous scaffolds using a non-toxic, waterborne, biodegradable PU emulsion. The goal was to prepare scaffolds with appropriate pore diameter, pore diameter distribution, and porosity for use in soft tissue engineering. The authors observed that the relatively smaller pore diameter, narrower pore diameter distribution, and lower porosity were more advantageous for the scaffold endothelialization.
In vitro. Rat heart cell line (H9C2 cardiomyoblasts) Heart patches for myocardial function restoration and cardiac tissue regeneration after an MI The authors used TIPS technique to prepare scaffolds with an analogous structure of the striated myocardial tissue for myocardial applications. The authors noted that the material was similar to the streaked muscle tissue because of the presence of the anisotropic microstructure. Thereby, the so called "structural biomimicry" was achieved, which is a requirement for the application of biomaterials in TE. The different pore sizes can promote different processes: large pores favor cell colonization, cell migration, and nutrient supply; meanwhile, small pores can promote vascularization.

Blood-contacting medical devices
The authors applied the PLAL technique to generate TPU-noble metal nanocomposites with different concentrations of Pt or Au nanoparticles between 0 and 1 wt%. The presence of metal nanocomposites in TPU improved the biocompatibility and cell adhesion. The authors relate this effect to the hydrophilic and negatively-charged surface. Results showed that ECFCs seeded onto the nanocomposites remained in a nonthrombogenic and noninflammatory state. Thereby, the material can potentially decrease the number of reoperations and deaths in the field of cardiovascular medicine.

Cardiac tissue engineering
The authors worked on materials for TE. They studied the low conductivity of the patch in cardiac TE because this characteristic could limit the patch's capability to couple transplanted cells electrically to the local host myocardium. This study recommends the use of oligoaniline as an electroactive conductive polymer. These materials were non-toxic, supported cell proliferation and attachment, and combined with antioxidant properties.  The authors aimed to study the toxicity development in cardiovascular implants. The materials synthesized included hydrophilic PEG side-chains attached to the HS. The authors noted that these chains increase the hydrophilicity of the macromolecules and modify the hydrogen bonds among the HS, both of which favor hydrolytic degradation. The results did not show any maternal and fetal toxicity. The use of this material in cardiovascular applications was proposed based on this observation.

L-929 cells Biomedical applications
The authors used three methods (solution mixing, melt processing, and in situ methods) to synthesize conductive composites of a siloxane PU and graphene for potential use in biomedical applications. The results showed that the solution mixing method yielded composites with the highest electrical conductivity and that it is suitable for preparing composites with better mechanical properties. The authors also noted that the materials were not cytotoxic to living cells in vitro and are potentially useful in biomedical applications.

Biomedical applications related to soft and cardiovascular tissues
The authors aimed to study materials for potential biomedical applications. They synthesized PU from castor oil, PCL, and IPDI, using CS as the additive. The results showed that the presence of CS in materials enhances the ultimate tensile strength and does not affect the strain at fracture in PUs with 5% w/w of PCL and CS in the range of 0-2% w/w. The authors noted that PUs had mechanical properties similar to those of the aorta and skin.

Cardiovascular stents
The goal of this work was to synthesize materials for rapid self-expandable stents for possible endoscopic surgeries. The authors used a one-pot single step technique to obtain a carbon dot-silver nanohybrid. The results showed that it was possible to obtain a material with self-expandable and shape memory behaviors, as well as enhanced thermal and mechanical properties.
Cortella et al. [2] 2017 Brazil-Germany CO/MDI In vitro. iHUVEC Cardiovascular devices In this work, the authors recommended the use of the DLA technique for producing patterned topographies in the micrometer range. The results show that the topographical patterns produced by the DLA technique on cellular processes may contribute to the development and maintenance of a functional endothelium on target surfaces by the functionalization of their blood-contacting surfaces. The authors recommended PU modification with PEG for blood-contacting applications. They observed that the PU modification reduced non-specific protein adsorption and promoted endothelial cell attachment and proliferation. They also emphasized that the PU surfaces modified with PEG and gelatin enhanced the hydrophilicity. This yielded enhanced biocompatibility and hemocompatibility.
However, studies reported that PUs show severe problems [22] when applied in blood-contacting devices, such as the biodegradation that occurs during long-term implantation [29] by the adhesion of inflammatory cells [27], surface-induced thrombosis [2,22], and protein fouling [22] (which are known to participate in PU biodegradation); and the absence of endothelialization [2].

PCL
We have identified PCL as a bioresorbable and biocompatible polymer with good mechanical properties [12,16]. PU/PCL blends (copolymer and homopolymer) are well known for their low degradability, cell adhesion, and proliferation, which indicate good biocompatibility. They have been used as materials with elastic memory to achieve self-expansion within the range of the body temperature. Silvestri et al. illustrated that the shape recovery of PU/PCL blends is related to the elastic strain generated during deformation owing to the elasticity of the PU as a matrix phase in these blends [16]. Specifically, PU/PCL blends and PCL/PEG/PCL tri-blocks with different aliphatic and amino-acid-based chain extenders did not present toxicity. The authors recommend the use of the blend for tissue engineering (TE) applications, considering that their mechanical behavior and cell response depend on their chemical composition [12].

CO
A variation of the PU chemical composition with a CO/aliphatic diisocyanates blend is recommended in the included articles. Arévalo et al. used CO as the polyol because of its composition (ricinoleic acid), which presents a structure that enables the synthesis of cross-linked urethanes. Furthermore, it is a renewable source and has low toxicity. The CO/aliphatic diisocyanates (isophorone diisocyanate, IPDI) blend can be used to synthesize biomedical PUs because they do not promote the generation of carcinogenic products, such as the aromatic diamines, in in vivo conditions [20].

Nanomaterial Carbon Dot-Silver Nitrate
Meanwhile, Dura et al. developed a material incorporating a biocompatible nanomaterial carbon dot-silver nitrate (CD-Ag) in a smart polymer matrix for potential use as a stent. The study indicated that they attained a faster self-expansion of the material (in less than a minute), which prevented the migration of the device during in vivo deployment. The authors propose the use of both silver nitrate owing to its potent antibacterial activity, which prevents biofilm formation; and carbon dots owing to their highly polar peripheral groups, which enhance the mechanical properties of the nanocomposite [15].

PU Modification in Terms of Surface Functionalization
Ten studies described how the biomaterials interact with blood. Implantation begins with the blood-foreign material interaction [22,34].
At this stage, the plasma proteins are adsorbed onto the material surfaces, which occurs within a few seconds. This adsorption causes the adhesion of platelets, white blood cells, and a few red blood cells onto the plasma protein layer [34]. Yu et al. revealed that the aggregated platelets on the surface release materials such as adenosine diphosphate (ADP), which results in the formation of thrombin, an insoluble fibrin network, or thrombus [14,22]. Raut et al. explained that the thrombus may obstruct the blood flow and cause device failure. In addition, clots may be released into the systemic blood circulation from the devices that do not fail, resulting in an embolism [14]. Furthermore, Liu et al. highlighted that after the implantation, monocytes may be activated after adhesion to the biomaterials and release cytotoxic mediators, such as cytokines and reactive oxygen species (ROS) [34]. Monocytes have been recognized for their essential role in mediating inflammatory responses [37]. Du et al. described how thrombi that form inside a catheter lumen make the catheter unsuitable for biomedical uses, such as withdrawal of blood, delivery of fluids, or medication. Thrombi, which form outside the catheter, could permanently damage the vessel integrity, resulting in pain and swelling [42].

Surface Functionalization-Modified PU to Promote EC Adhesion and Proliferation
Surface coverage with ECs prevents the material from directly contacting with blood and can be considered as a solution for preventing thrombus formation in cardiovascular implants [2]. ECs are known to provide an antithrombogenic surface by producing antithrombogenic substances [40], such as prostacyclin (PGI2), tissue plasminogen activator (t-PA), heparin-like glycosaminoglycans, and thrombomodulin [21]. The use of ECM proteins such as Coll and Fn as coatings on synthetic polymers enhances endothelialization [23].
Stachelek et al. changed the PU formulation by including cholesterol (Chol). Cholesterol-modified polyurethane (PU-Chol) increased the adhesion of blood outgrowth endothelial cells (BOECs) compared with controls. This change in the adhesion rate is important because it is known that BOECs are an outgrowth of a circulating progenitor cell. These are present in peripheral blood, and thus represent an important potential source of autologous cells for seeding investigations [9].
Heparinized surfaces are clinically used to reduce thrombogenicity [36] as potent anticoagulants that interact strongly with antithrombin (AT) to prevent the formation of fibrin clots [39]. The presence of heparin on the surface positively affects EC growth and proliferation by binding and stabilizing cell growth factors (GFs) [40]. However, a disadvantage of immobilizing heparin onto a polymer surface is that the heparin has low bioactivity [38]. Klement et al. recommended the modification of a PU with an antithrombin-heparin (ATH) covalent complex, which displays the capability for rapid direct inhibition of thrombin [39].
A PU nanocomposite (polymer matrix with embedded nanoparticles of Au-Pt) is a PU modification that has been recommended by Hess et al. to improve cell adhesion, which are functions of the concentration of nanoparticles [3].
The surface functionalization of biomedical devices could be attained by changing the material topographies to enhance the adhesion and growth of ECs [2]. Our results indicate the use of different techniques to enhance surface functionalization, such as direct laser ablation technique (DLA) [2], polymeric endoaortic paving (PEAP) [10], pulsed laser ablation in liquid (PLAL) [3], thermally induced phase separation (TIPS) [13], and freeze-drying [25].
DLA is a technique that modifies the surface topography [2]. Cortella et al. showed the functionalization of PU by DLA-created microtopography, which improved the adhesion and proliferation rate of ECs [2].
Ashton et al. recommends an alternative method to enhance conventional endoaortic therapy to reduce the risk of endoleak. PEAP is a process where a polymer is endovascularly delivered and thermoformed to coat or pave the lumen of the aorta [10]. Meanwhile, the PLAL technique for solid targets is advantageous for the synthesis of biocompatible nanomaterials, because it generates nanoparticles without the need for chemical precursors, which potentially cause cell behavior side effects. Furthermore, the technique enables in situ functionalization with biomolecules and adsorption onto microparticle surfaces [3].
Vozzi et al. recommend the use of TIPS to fabricate oriented scaffolds. This technique modified the PU porosity by modulating the polymer concentration, quenching temperature, thermal gradient, and solvent type [13]. The authors indicate that fiber alignment supports cardiomyocytes in the generation of a tissue-like structure [13]. The last technique identified by us for enhancing surface functionalization was freeze-drying. Jiang [14], fibrinolytic enzymes or proteins [14], heparin [22], CS [22], and dextran sulfate (DS) [22], as surface modification substances [14,22] in order to enhance the compatibility of PUs with the blood components.
Another PU modification technique was presented by Gu et al. through the incorporation of PEG to enhance bioactivity. PEG chains were selected as hydrophilic and flexible spacers between the biological molecules and PU backbones [24]. Hess et al. recommended a PU modification with embedded nanoparticles of Au-Pt to improve biocompatibility, which are functions of the concentrations of nanoparticles [3]. Stachelek et al. recommended the use of modified PU with DBP to provide antioxidant activity to prevent biodegradation. The microscopy results showed that DBP-modified PU confers biodegradation resistance to surface cracking with dose-dependent DBP loading [7].
A different PU modification was presented for electrically conductive polymeric materials. These materials could be used in biomedical applications, such as for biosensors, drug delivery systems, biomedical implants, and TE. Kaur et al. recommended the incorporation of conductive fillers such as graphene to enhance the electrical conductivity without changing the polymeric characteristics [18].

Conclusions
PUs have found applications in medical devices because of their properties-their capability to tolerate contractile forces that originate during the cardiac cycle without undergoing plastic deformation or failure, and their ability to imitate the behaviors of different tissues. Although studies have reported that PUs suffer from severe problems when applied in blood-contacting devices that are implanted for long periods, they can be modified in terms of both the chemical composition and surface characteristics to improve their mechanical properties (blood compatibility and EC adhesion) and reduce protein adhesion. These modifications enable the use of PUs in the manufacture and design of cardiovascular devices.
Our analysis revealed the following: 1.
For stent design, it is important that the selected material displays self-expandable and shape memory behavior, which must be maintained at temperatures similar to those encountered in the human body. In addition, this expansion must be carried out as quickly as possible to prevent the migration of the stent during surgery. Modified PUs, such as those with added PCL or carbon dot-silver nanohybrid, show high modulus and tensile strength with low elongation and biocompatibility. Furthermore, these maintain self-expandable and shape memory behaviors. All these properties permit us to propose the use of these PUs as potential materials for stent implants.

2.
Among cardiovascular devices, heart patches and heart valves require the use of materials with appropriate properties such as strength and an elastomeric mechanical behavior to tolerate the contractile cardiac tissue and support its regeneration. For the design of heart patches and heart valves, it is important to create a structure that is similar to the muscle tissue. PUs are appropriate materials for cardiac applications because their biocompatibility and elastomeric behavior enable them to resist the cyclic heart stresses without deformation or failure. The PU structure can be modified to create anisotropic microstructures that may mimic the heart tissue function of different pore sizes. This could promote cell colonization, cell migration, nutrient supply, and vascularization. 3.
In general, for blood-contacting devices, the interactions between the material and blood generate cell responses that could favor the formation of thrombi. PUs provide a surface that can be modified to reduce non-specific protein adsorption and promote endothelial cell attachment and proliferation. This can enhance the biocompatibility and hemocompatibility. This implies that the fabrication of blood-contacting devices with modified PUs could decrease the numbers of repeated operations and deaths in cardiovascular surgery [3]. Acknowledgments: Sincere thanks to Luis Eduardo Díaz-Barrera and Said Arévalo-Alquichire for their essential contributions to the article selection procedures.

Conflicts of Interest:
The authors declare no conflict of interest.