Stimuli-Responsive Polyurethane Materials for Biomedical Applications

Turkchem 30 Jul 2017 76 12 dk okuma

TURKCHEM

Stimulus-responsive (shape memory) polymers are defined as smart materials that remember their original shape and have the ability to respond to any external stimulus such as heat, light, magnetic field, pH and different chemicals. Generally, the shape memory polymeric structure imparted with stimulus-responsive properties changes shape in the presence of a chemical, mechanical, magnetic or electrical external effect and returns to its original shape upon removal of this effect. One of the first applications in this field was presented following the development of poly(norbornene) structure in 1984[1]. Materials with stimulus-responsive properties have been used in various applications in the biomaterial field (Figure 1). Over time, research on polyurethane structures in stimulus-responsive formulations has accelerated in this area. In 1988, Mitsubishi Chemical obtained a polyurethane material exhibiting shape memory properties and it was observed that this product had varying transition temperature across a wide temperature range[2]. Stimulus-responsive polyurethane structures are mostly obtained at the end of a single-step process in which diisocyanate (hard segment) and polyol (soft segment) monomers are added simultaneously with cross-linking agents. The morphology change of hard and soft segments of polyurethane materials showing shape memory effect during synthesis provides the polymer with the ability to exhibit different mechanical behavior. Indeed, the presence of these regions is the most important factor in the polyurethane material exhibiting stimulus-responsive properties. In this context, the hard segment is responsible for preserving the permanent shape of the polymer through secondary interactions such as dipole-dipole interactions and hydrogen bond structures, while the soft segment is responsible for the shape memory effect observed as a result of the applied effect[2]. Additionally, stimulus-responsive properties vary depending on the molecular weight of the soft region, the ratio between soft and hard regions, the type and amount of chain extender[4-5]. These polyurethane structures imparted with stimulus-responsive properties can easily be triggered with external stimuli such as heating, light, magnetic field, water and electricity to change shape. In this context, shape memory polyurethane structures can be obtained as polymers that store multiple properties obtainable through the use of different stimuli in their memory. Today, the wide range of raw materials offered by stimulus-responsive polyurethane materials has made these materials sought-after in many fields. In particular, the high resistance exhibited against solvents, ease of shaping, the wide temperature range it possesses at transition temperature and potential biocompatibility have increased the popularity of polyurethane among shape memory polymers[6]. Today, shape memory polyurethanes (SMPUs) are used widely in the healthcare field, primarily in stents, vascular grafts, blood filters, catheters, heart valves, cardiac support devices and artificial heart chambers. Additionally, shape memory polyurethanes, which are preferred in many fields, have potential applications in aerospace, construction, transportation, furniture, packaging and other sectors.

Biomedical Applications of Stimulus-Responsive Polyurethanes

The tunable functionality of stimulus-responsive polymers enables application in many fields and makes them an attractive proposal for biomedical applications. It is quite important to consider the design requirements of shape memory polymers with potential use as biomedical devices. From this perspective, the ability to prepare shape memory polyurethane structures in different molecular designs is the reason for their preference in the biomedical field.

Figure 2. Polyurethane structure and polyurethane films

One of the most important design factors for any material in biomedical applications is that the material demonstrates biocompatibility, which is the ability to create a minimal inflammatory response in the area where the material is applied. In this context, the high blood compatibility contained in polyurethane materials clearly demonstrates that it is an ideal material for biomedical applications. Another important design factor to be considered in obtaining shape memory polymers is the biodegradability level of the final product designed. While biological degradation of materials used as permanent biomedical products is not desired, it is desired that temporary biomedical products that eliminate the need for surgical removal after their functional period degrade and be eliminated from the body. In this context, the wide range of raw materials offered by shape memory polyurethane structures enables the development of materials with the desired level of biodegradation rate. In addition, the transition temperature being close to the human body and possessing the desired level of mechanical strength in polyurethane materials that show shape memory properties are among the important reasons for their preference in biomedical applications. Polyurethane material imparted with stimulus-responsive properties has a wide range of applications particularly in the manufacture of smart medical devices, tissue scaffolds and various implants. In addition, it is known to be highly effective in drug delivery systems. One of the most important shape memory polyurethane applications encountered recently is the design of drug-eluting stents. Endovascular stents applied in surgical operations today are made of metal materials and cause thrombotic occlusion. For this reason, the inclusion of a drug-loaded polyurethane material imparted with stimulus-responsive properties in stent applications would be an alternative solution to many problems. In this context, the self-opening ability of materials with stimulus-responsive properties caught the attention of Ajili and colleagues and led them to prepare shape-memory-based polyurethane stents. In their study, Ajili and colleagues prepared polyurethane/polycaprolactone (PU/PCL) polymers containing polycaprolactone in four different ratios of 20%, 30%, 40% and 50% and examined their shape memory behavior. Additionally, the in vitro biocompatibility of the PU/PCL (70/30) blend, which showed the best biomedical application potential in the body temperature range, was evaluated with human bone marrow mesenchymal stem cells. Cell adhesion, morphology and mitochondrial functions on the PU/PCL (70/30) polymer surface were analyzed. As a result, it was predicted that the prepared copolymer could find application in medical uses as a stent implant (Figure 3) [7]. Shape memory polyurethane materials have research toward the use of soft catheters. Through research conducted by Hayashi and colleagues for various medical applications, it was determined that stimulus-responsive polyurethane materials also have the flexibility that can be used in the human body [8]. This suggests that flexible polyurethane materials could be used in catheter manufacturing. The negative characteristics of rigid catheters and the easier applicability of soft (flexible) catheters have led to polyurethane-based catheters being frequently used in surgical applications. Furthermore, the lower thrombogenic effect of shape memory polyurethane materials has enabled their widespread use in the manufacture of products and devices related to hematology [9-11]. Another application field of polyurethane materials imparted with stimulus-responsive properties is the design of materials effective in self-stretching wound closure. In this context, the transition temperature of polyurethane-based suture materials exhibiting shape memory properties having a value close to the human body enables their use in wound closure. In the wound closure process, an external force applied to the material imparted with stimulus-responsive properties enables the suture material to take its permanent shape in the wound area, performing wound closure. During the process following the wound healing stages, this stimulus-responsive polyurethane structure biologically degrades and separates from the applied area [12-14]. Another study conducted for biomedical applications is the investigation of the usability of polyurethane-based shape memory polymer foams as an intravascular occlusion agent in aneurysm treatments. In this context, it is known that DiAPLEX foams, which are a commercial application of stimulus-responsive polyurethanes, were investigated as an aneurysm occlusion material [15]. Additionally, Metcalfe and colleagues examined the effectiveness of polyurethane foams known as CHEM (Cold Hibernated Elastic Memory) in foam model aneurysms. At the end of the study, polyurethane foams were observed to show positive results in in vitro biocompatibility tests and it was reported that new devices for endovascular interventions could be designed using CHEM's unique physical properties [16]. One of the most important applications using shape memory polyurethane structures is artificial heart valves. Heart valves can present major problems due to infection, aging, valve calcification and rheumatic fever. These problems develop as valve insufficiency, valve wear, stenosis, calcification, thickening and valve anomaly and may require surgical intervention. In some advanced cases, the valve must be removed and an implant placed in its place. Polyurethane artificial heart valves are frequently used in this field. Polyurethanes are particularly advantageous in terms of blood compatibility and wear resistance. In this field, shape memory structures are preferred to facilitate the placement of artificial heart valves on the heart surface. These structures are applied by placing them with their secondary shapes in place of the worn heart valve removed by surgical operation. Here, the polymer takes its primary shape with body heat and holds firmly in place. As a result, the shape memory polymer used facilitates the attachment of the implant and prevents leaks. In addition, various studies on shape memory polyurethanes have contributed to the literature with a considerable number of studies having significant scientific impact for particularly biomedical applications. Many of these studies focus on copolymer systems that provide the ability to mix and match the desired properties of different monomers. In their study, Wang and colleagues synthesized a three-dimensional shape memory polyurethane containing polycaprolactone (PCL), methylene diphenyl diisocyanate (MDI) and N, N-bis(2-hydroxyethyl) cinnamide. The binding and proliferation effect of the obtained formulation on osteoblast cells was examined using the Alamar Blue test and it was reported that a polyurethane structure exhibiting high biocompatibility was obtained. As a result of the study based on the synthesis of three-dimensional shape memory polyurethanes, the material obtained was stated to be suitable for biomedical applications [17]. Yang and colleagues, in a similar but more recent study, synthesized a star-shaped polyurethane by combining multi-armed polycaprolactone with methylene diphenyl diisocyanate and using 1,4-butylene glycol (BDO) as a chain extender. Within the scope of the study, the thermal properties of the synthesized polymers were examined using differential scanning calorimetry (DSC) and dynamic mechanical analysis (DMA) equipment. The results show that as the hard segment content increases, both the melting temperature (Tm) and transition temperature (Ttrans) of the stimulus-responsive polyurethane material decrease. Additionally, analysis results performed using X-ray diffraction (XRD) showed that the increased number of arms increased the crystallinity of the polyurethane material. This result revealed that the six-armed polyurethane material had the best shape fixity and wide melting temperature range. Furthermore, the Alamar Blue cytotoxicity test performed on osteoblast cells indicates that the polyurethane material exhibits high biocompatibility. As a result, Yang and colleagues' prepared stimulus-responsive polymer was stated to be potentially usable as a new smart material in the biomaterial field [18]. In their study, Mo and colleagues synthesized a series of shape memory polyurethanes from liquefied 4,4'-diphenylmethane diisocyanate (L-MDI), 1,4-butanediol (BDO) and polyethylene glycol (PEG) using the cast polymerization method. The effect of the synthesized polymers on structure, morphology, properties and biocompatibility depending on hard segment content was investigated. It was determined that the polyurethane system consisting of PEG6000/L-MDI/BDO comprised a semi-crystalline soft phase and an amorphous hard phase. In cyclic tensile testing where shape memory properties were determined, the best shape fixity was observed in materials where the hard segment ratio was less than 35%. Furthermore, because macrophage cells play a role in embryogenesis, wound repair, clearance of apoptotic cells and tissue regeneration, a cell counting kit applied to macrophage cells evaluated the biocompatibility of stimulus-responsive polyurethane materials. The data obtained showed that polyurethane materials with hard segment content less than 35% could be suitable materials for the biomedical field in terms of both shaping properties and biocompatibility [19]. Recent studies aimed at obtaining shape memory polyurethanes have focused on the addition of filler materials known to significantly improve shape effect properties. Studies show that nanocomposite structuring improves the compression performance, tensile strength and thermal and electrical conductivity of shape memory polymers. In this context, numerous studies on carbon nanotube-reinforced shape memory polyurethane composites have been added to the literature. It has been predicted that polyurethanes reinforced with carbon nanotubes have the potential to be used as small load-bearing biomedical devices that could be used particularly in the prevention of tracheal and laryngeal collapse. In addition, it is known that these devices can be narrowed using the shape memory effect in their placement in the desired location and subsequently expanded [20]. Furthermore, various studies on stimulus-responsive polyurethane materials have recently targeted polyurethane materials synthesized with the use of vegetable oils as a renewable source due to their contribution to biocompatibility and are investigating their usability in biomedical applications. One of these is the polyurethane films prepared without the use of catalyst and solvent, which is defined by Bonfil and colleagues and contains polyethylene glycol (PEG), castor oil (CO), hexamethylene diisocyanate (HDI) and 1,4-butanediol (BDO). Within the scope of the study, in determining the shape memory properties of the prepared polyurethane materials, the soft region length, hard region content and cooling rate during the programming phase were determined. Subsequently, biocompatibility properties were measured using the MTT test in fibroblast NIH/3T3 cell line. As a result, the obtained polyurethane-based materials were stated to be usable in medical applications[21]. Calvo-Correas and colleagues synthesized a stimulus-responsive bio-based cross-linked polyurethane material in their study. The polymer, whose structural characterization and shape memory properties were examined, showed that stimulus-responsive effectiveness varied depending on cross-link density. In addition, cytotoxicity test results conducted using L-929 fibroblast cells showed that it was biocompatible at a level that could be used in biomedical applications[22].

Conclusion

Shape memory polyurethane materials have been the subject of extensive research in recent years, whether for different applications or biomedical applications. In particular, due to the superior properties contained in polyurethane materials, stimulus-responsive biomedical materials with increasing functionality can be designed. Additionally, shape memory materials made with polyurethane-based composites have come to the fore with recent studies. In this context, the preparation of shape memory materials containing polyurethanes is a candidate to be one of the important research areas of the future. Dr. Merve Gökşin Karaaslan / Master's Student / Department of Chemistry / Faculty of Arts and Sciences / İnönü Üniversitesi Melike Kantarcıoğlu / Department of Chemistry / Faculty of Arts and Sciences / İnönü Üniversitesi Assoc. Prof. Dr. Süleyman Köytepe / Department of Chemistry / Faculty of Arts and Sciences / İnönü Üniversitesi Prof. Dr. Burhan Ateş / Department of Chemistry / Faculty of Arts and Sciences / İnönü Üniversitesi