Recent Advances in Shape Memory Soft Materials for Biomedical

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Recent Advances in Shape Memory Soft Materials for Biomedical Applications Benjamin Qi Yu Chan, Zhi Wei Kenny Low, Sylvester Jun Wen Heng, Siew Yin Chan, Cally Owh, and Xian Jun Loh ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b01295 • Publication Date (Web): 28 Mar 2016 Downloaded from http://pubs.acs.org on March 31, 2016

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ACS Applied Materials & Interfaces

Recent Advances in Shape Memory Soft Materials for Biomedical Applications Benjamin Qi Yu Chan1,2, Zhi Wei Kenny Low1,2, Sylvester Jun Wen Heng1,2, Siew Yin Chan1,3, Cally Owh1, Xian Jun Loh1,2,4* 1

Institute of Materials Research and Engineering (IMRE), 2 Fusionopolis Way, #08-03 Innovis, Singapore 138634, Singapore

2

3

4

Department of Materials Science and Engineering, National University of Singapore, 9 Engineering Drive 1, Singapore 117576, Singapore

School of Science, Monash University Malaysia, 47500 Bandar Sunway, Selangor Darul Ehsan, Malaysia

Singapore Eye Research Institute, 11 Third Hospital Avenue, Singapore 168751, Singapore *E-mail: [email protected]

Abstract Shape-memory polymers (SMPs) are smart and adaptive materials able to recover their shape through an external stimulus. This functionality, combined with the good biocompatibility of polymers, has garnered much interest for biomedical applications. In this review, we discuss the design considerations critical to the successful integration of SMPs for use in vivo. We also highlight recent work on 3 classes of SMPs: shape memory polymers and blends, shape memory polymer composites (SMPCs) and shape memory hydrogels. These developments open the possibility of incorporating SMPs into device design, which can lead to vast technological improvements in the biomedical field.

Keywords Smart materials; stimuli-responsive materials; shape memory polymers; shape memory polymer blends; shape memory polymer composites; shape memory hydrogels; biomedical applications;

1 ACS Paragon Plus Environment


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Content 1.

Introduction ..................................................................................................................................... 3

2.

Design Considerations of SMPs for Biomedical Applications ....................................................... 5

3.

2.1.

Biocompatibility ..................................................................................................................... 5

2.2.

Mechanical Properties ............................................................................................................. 7

2.3.

Biodegradability ...................................................................................................................... 8

2.4.

Sterilisability ........................................................................................................................... 9

SMPs for Biomedical Applications............................................................................................... 10 3.1.

3.1.1.

SMP homopolymers and copolymers ........................................................................... 13

3.1.2.

SMP Blends .................................................................................................................. 16

3.2.

SMP Composites (SMPCs) ................................................................................................... 20

3.2.1.

Reinforcements ............................................................................................................. 20

3.2.2.

Athermal stimuli-triggered SMEs ................................................................................. 26

3.2.3.

Others ............................................................................................................................ 32

3.3.

4.

Shape Memory Polymers and Blends ................................................................................... 13

Shape Memory Hydrogels .................................................................................................... 38

3.3.1.

Water-triggered SME .................................................................................................... 39

3.3.2.

SME triggered in aqueous environments ...................................................................... 40

Conclusion and Future Prospects .................................................................................................. 43

Acknowledgments................................................................................................................................. 46 References ............................................................................................................................................. 47


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1.

Introduction Stimuli-responsive systems can be found in a myriad of examples in nature. The Mimosa

pudica, displays thigmonastic responses in which the compound leaves of the plant fold up when touched. Another example is the Dionaea muscipula, or Venus flytrap, which has a leaf-shutting mechanism triggered when hairs on the leaf surface are touched by insects in rapid succession1 (Figure 1, I). Such examples provide inspiration for the design of synthetic smart materials (Figure 1, II) in which the stimuli-responsiveness of these materials may be used favourably in various applications. Within the wide range of stimuli-responsive materials, much focus has been placed on the study and synthesis of soft stimuli-responsive polymeric materials due to its versatility, enhanced biocompatibility and potential biodegradability as compared to other classes of materials like metals and ceramics. In particular, stimuli-responsive polymers such as shape memory polymers (SMPs) utilising varying stimuli for potential medical applications have been of widespread interest in recent years.

Figure 1: (I) Leaf shutting mechanism of the Venus flytrap – an example of a stimuliresponsive system found in nature – and (II) Illustration of the shape memory effect in synthetic SMPs inspired by nature. Images adapted from [1] with permission.



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Shape memory polymers (SMPs) are smart, adaptive soft materials with the ability to recover either permanent or programmed temporary shapes when exposed to an external stimulus2-4, such as temperature5-8, light9-11, magnetic fields12-15, electrical currents16-19 etc. SMPs are not confined to pure polymeric systems, but also polymer blends20-21 and composites (SMPCs)22-23 and polymer networks such as hydrogels24-26. Shape memory soft materials are lightweight, cheap and capable of larger recoverable strains than shape memory alloys. These properties make SMPs suitable for actuators27, sensors28, microfluidic systems29, biomedical applications30 such as vascular grafts and cardiovascular stents31-33, as well as applications in aerospace technology34-36, textiles37 and consumer care products38. The idea of shape memory effect in polymers has been applied in commercial products as early as 1960s in the form of heat-shrinkable polyethylene tubes used as wire wraps for the purpose of electrical insulation39. Over the past three decades, reports of SMPs activated by different stimuli and exhibiting a variety of features have been increasingly published. Therefore, there is a need for a categorical review highlighting the recent advances in this area. This paper aims to present a brief review on the considerations in designing a SMP suitable for biomedical applications, as well as recent reports of soft polymeric materials exhibiting shape memory effect – in particular SMPs blends, SMP composites (SMPC)s and shape memory hydrogels – and their applications in biomedical applications, particularly in the past three years. For further details on the working mechanism of the shape memory effect in polymeric soft materials not covered herein, readers are referred to comprehensive reviews previously published40-44.


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2.

Design Considerations of SMPs for Biomedical Applications SMPs offer interesting combinations of functionalities and tuneable properties, and have

thus emerged as an increasingly attractive proposition for biomedical applications. As such, it is important to consider design requirements of SMPs with regards to their potential utilisation as biomedical devices. A brief overview on design considerations such as biocompatibility, mechanical properties matching, biodegradability and sterilisability will be covered in this section. 2.1.

Biocompatibility One of the most important design considerations of any material for potential biomedical

applications is biocompatibility, which is the ability of the material to perform in vivo with an appropriate host response. SMPs designed for biomedical applications in mind are thus expected to be non-cytotoxic as a basic requirement. In vitro cytotoxicity studies by means of cell viability assays and cell membrane integrity assays are widely used tests as initial evaluation of the biocompatibility. Cell viability assays like MTT and MTS assays45 are based on the reduction of tetrazolium compound into a coloured, insoluble formazan product and are commonly used tests. In addition, cell membrane integrity evaluation by means of lactate dehydrogenase (LDH) assays46 and trypan blue tests47-48 are also well established protocols. These cell membrane integrity assays work on the principle that cytotoxic compounds compromise and rupture cell membranes. This allows cell dyes like trypan blue to stain dead cells for an observable evaluation of cell viability by cell counting using a hemocytometer. LDH assay, on the other hand, works on the principle that lactate dehydrogenase (LDH) enzymes which are present within living cells are released upon rupture of living cell membranes. LDH reduces pyruvate to lactate and causes a coupling oxidation reaction of reduced Nicotinamide adenine dinucleotide (NADH) to the oxidised NAD+ form (Figure 2). NAD+ has a much lower absorbance of 340nm radiation as compared 5 ACS Paragon Plus Environment


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to NADH, allowing the presence of LDH (and thus cell viability) to be quantifiable by a spectrophotometer.

Figure 2: Redox reaction of Pyruvate and NADH to Lactate and NAD+ due to the presence of lactate dehydrogenase (LDH) enzymes.

Apart from general biocompatibility, SMPs designed for tissue and blood-facing applications must further consider hemocompatibility issues49. For example, a self-expanding SMP endovascular stent must be evaluated for its propensity to cause thrombotic occlusions. With this consideration in mind, care must be taken in the selection of components when designing the SMP, such as selection of blood-inert components or oligomers for the synthesis of SMPs to be used in blood-facing applications. Govindarajan et al. also proposed that since the shape memory effect in SMPs is not a surface property, it is possible to perform surface modification techniques such as surface roughening, patterning, chemical modification (PVD, CVD, self-assembled monolayers) and thin coatings to decrease the chance of thrombotic events50.


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2.2.

Mechanical Properties

In the biomedical context, shape memory polymers, which possess an extensive range of mechanical and physical properties, allow for the better catering of adaptive materials to the requirements of human tissue. In particular, shape memory polymers have shown great potential in matching the physical properties of soft biological tissue, allowing for the expansion of the biomedical applicability of smart materials to beyond the previously explored aspects of hard biological tissue, an area well served by shape memory alloys51. The matching of the physical properties of biomedical materials to those of biological tissue is particularly crucial in the design of prototypes with the intended purpose of replacing or augmenting natural tissue function. Natural biological tissue is subjected to a variety of physiological conditions within the body that include, but are not limited to, compressive stresses during weight loading, tension during the pumping of the heart, and shear stresses from the movement of blood. It is thus imperative that the shape memory polymers employed have properties that are capable of coping with such forces involved without the loss of function. For example, stiffness and strength are required of the materials used in the production of scaffolds for bone tissue engineering as the scaffold will have to temporarily take on the function of natural bone tissue52. The consideration of other properties, such as rigidity or flexibility, to minimize damage caused to the surrounding tissue is also important. At the same time, these materials have to possess the optimal characteristics that allow for them to serve their intended functions. The catheter is one example of a biomedical device that requires a balance between these two qualities. Stiff catheters are desired due to the ease of manipulation outside the human body. However, soft catheters will ensure easier manoeuvring within the body, and, given the smaller disparity between their rigidity and that of the arterial walls, cause fewer arterial injuries53.



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Given the wide range of mechanical properties desired in the various biomedical applications, it is conceivable that shape memory polymers, which possess highly tuneable and versatile properties, can find a place of prominence in this arena. 2.3.

Biodegradability

Although biodegradation has been associated with a wide range of definitions that depend on the field in question, it has been used in the biomedical field to describe degradation processes through hydrolytic and oxidation reactions54. Biodegradability is an important consideration in the design of a shape memory polymer that is highly dependent on the intended permanence of the final product. Materials used in permanent biomedical products have to be non-biodegradable in order to resist degradation by the body and ensure that an extended period of functional use can be achieved. On the other hand, for products that are only required to serve a temporary function, the property of biodegradability will allow for a transient existence that eliminates the need for surgical removal after their functional term. Apart from the general property of biodegradability itself, the rate at which biodegradation will occur should also be tailored to best serve the purpose of the product. The field of tissue engineering, for example, sees great potential in materials with controllable degradation rates in scaffold construction as this could allow for the synchronization between scaffold degradation and natural tissue growth and replacement55. Adjusting the rate of biodegradation can also confer greater control in other shape memory polymer applications such as in drug delivery systems56-58. Shape memory polymers with adjustable biodegradation qualities have been devised, where their degradation rates could be tuned through the variation in their compositions59.


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2.4.

Sterilisability

As sterilisation before clinical use is compulsory for all medical devices, the sterilisability of shape memory polymers developed for biomedical uses must be considered. Sterilisation of the SMP must be conducted without compromising its quality. In this regard, the mode of shape memory effect activation must be considered along with conventional considerations such as thermal and chemical stability. Methods of sterilisation listed by the US Food and Drug Administration (FDA) guide include exposure to ethylene oxide (EtO), irradiation, as well as exposure to steam60. Each of the processes have their advantages and disadvantages that render it difficult for them to cater to all shape memory polymers. The conventional method of steam sterilisation, while simple, makes use of a high temperature range and cannot be applied on thermal shape memory polymers due to its potential to alter their morphological structures60-61. However, ‘cold’ sterilisation techniques developed to circumvent this not only still operate at relatively high temperatures of 30 to 60 oC61, but are still plagued by a myriad of issues. For example, lower-temperature irradiation-type sterilisation techniques are unsuitable for biodegradable polymers, which are highly prone to deterioration through chain scission, which can be induced by irradiation. Another technique that makes use of low temperature plasma has resulted in surface modification through plasma etching62 and cytotoxic effects61 in some studies, and even ethylene oxide sterilisation, which is currently considered the gold standard, cannot be applied on some water-activated shape memory polymers due to the high humidity levels involved during the sterilisation process60. Given the limitations of the currently available sterilisation methods, it is crucial to consider in the design and development of shape memory polymers its potential to be appropriately sterilised for clinical use.



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3.

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SMPs for Biomedical Applications Shape memory homopolymers and copolymers that are most commonly reported are

triggered by thermal stimuli. Thermo-responsive SMPs utilise the inherent thermal transitions of the SMP (or its components) to achieve the shape memory effect. Such thermal transitions are either melting (Tm) or glass transition (Tg) temperatures. As the melting transition occurs over a much smaller temperature range as compared to a glass transition, Tm is favoured more as a shape transition temperature. A typical programming cycle involves the introduction of strain at or above the thermal transition, followed by cooling to below the thermal transition to “lock” the SMP in the programmed deformed shape. This temporary shape is maintained due to the restriction of molecular chain motion by either the formation of crystalline domains (with a Tm transition) or a sudden drop in free volume (with a Tg transition). Subsequent exposure to a thermal stimulus above the transition temperature increases chain mobility and triggers the entropy elasticity-driven shape recovery process. Many other types of stimulus can also be used to induce the shape recovery process by incorporating nanoparticles or reinforcements to form SMP composites to improve thermal conductivity or provide heat in the form of inductive or resistive heating as well as photo-thermal effects. Shape memory behaviour in hydrogels, on the other hand, tend to involve the breaking and forming of physical netpoints when triggered by various stimuli. Both SMP composites and SMP hydrogels will be covered in later sections of this chapter. A list of SMPs covered in this review is categorised by stimulus type and summarised in Table 1. The SMPs are further categorised into various biomedical applications and summarised in Table 2.


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Table 1: Summary of shape memory polymers (SMPs) triggered by various stimuli. Stimulus

Homo/copolymers

Blends

Temperature

[63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73]

[20], [74], [75], [76], [77], [78]

Composites [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92]

Electrical currents

[99], [100], [101], [102], [103], [104]

Magnetic field

[105], [106], [107], [108]

[26], [93], [94], [95], [96], [97], [98]

[22], [109]

Light

Water

Gels

[85], [110], [111], [112], [113]

[114], [115], [116] [24], [117]

pH

[118], [119], [120], [121], [122]

Ionic concentration

[25]

Others

[123]

(Microwavetriggered)

(UVtriggered)

[124]

(Redox reactionstriggered)

[125]

(Ultrasoundtriggered)



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Table 2: Summary of various biomedical applications of shape memory polymers (SMPs). Applications

Homo/copolymers

Actuators Stents

[32], [66], [67]

Tissue Engineering

[68], [69], [71], [72]

Patent ductus arteriosus occlusion device

[73]

Blends

Composites

[27]

[78]

Gels

[83] [120], [121]

External applications (wound healing)

[122]

Intravascular thrombus removal

[126]


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3.1.

Shape Memory Polymers and Blends

3.1.1. SMP homopolymers and copolymers SMP homopolymers have been consistently reported and characterised for their properties over the years. Just recently, Collins et al. expanded on the long list of homopolymers displaying shape memory effect in their detailed investigation of the shape memory properties of amorphous thermoplastic poly(para-phenylene) (PPP)63. The study investigated on temperature and time effects of the shape programming of PPP on its shape recovery characteristics. However, SMP copolymer systems are of interest, particularly for biomedical applications, due to their versatility brought about by the possibility to mix and match desired properties of different moieties by copolymerisation. Linear block copolymer SMP systems make use of phase segregation between hard segments and switching segments with the thermal transition of the switching segments controlling the shape memory effect of the copolymer. In such SMPs, polyurethane and poly(urea urethane) copolymers are the most widely explored in this group, with the urethane and urea functional groups serving as the hard segments due to strong intermolecular interactions, with polymer moieties serving as the switching segment. Polyurea and polyurethane-based SMPs are highly tailorable, and can be synthesised by reacting a wide range of diamine or dihydroxy-terminated oligomers with diisocyanates. Earlier, Wang et al. synthesised a triple-shape memory polyurethane comprising poly(εcaprolactone) (PCL), methylene diphenyl diisocyanate (MDI) and N,N-bis-(2-hydroxyethyl) cinnamamide which displayed good biocompatibility assessed by the Alamar blue assay on osteoblast cells64. In a similar but more recent work, Zhou’s group reported a star-shaped polyurethane synthesised with multiple-arm PCL coupled with MDI and chain extended using 1,4-butylene glycol (BDO). The polyurethane copolymer synthesised with six-arm PCL



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displayed an impressive triple-shape memory65. In vitro cytotoxicity tests using the Alamar blue assay showed excellent osteoblast viability. The triple-shape memory polyurethanes reported by Wang et al. and Zhou’s group displayed excellent biocompatibility, making them suitable materials for biomedical applications. Earlier PCL-containing copolymers reported includes work by Yang et al.66 and Garle et al.67, with proposed applications as stents and treatment of endovascular problems. In general, SMPs can be categorised into two main groups: thermoplastic physically crosslinked systems, and chemically crosslinked thermoset networks. Xie et al. recently reported on a chemically crosslinked electroactive SMP comprising six-armed poly(lactic acid) (PLA) and aniline trimer (AT)68. The biodegradable PLA/AT thermoset were proven to be electroactive and displayed excellent mechanical and shape memory properties. Additionally, immunofluorescence, enzyme activity and relative gene expression tests confirmed the superior osteogenic differentiation capabilities of the copolymer, making it a candidate material for bone tissue engineering applications. Physically crosslinked SMP systems can be processed (and re-processed) using heat or solvents by overcoming the physical interactions, allowing for the SMP to be remoulded after synthesis. As such, physically crosslinked SMP systems can be fabricated into many forms to suit various applications. A few of the most notable forms include SMP foams, as well as micro and nanofibers which bear much potential in biomedical applications. Electrospinning is one processing technique that is of growing popularity due to the increasing interest in nanostructured materials for biomedical applications. Kai et al. explored the many potential applications of electrospun nanofibers, which include tissue engineering69, drug delivery and biosensors127. Chen et al. earlier attempted to produce an electrospun SMP film with reversible fibrous structure using triethoxysilane end-capped poly(urea urethane)


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copolymer, which is further crosslinked after electrospinning. The group found that the SMP film, which had a stable fibrous structure, showed a faster shape recovery response compared to bulk polymer samples70. The work serves as a platform to further improve surface and shape memory properties that expands the potential capabilities of SMPs as biomedical materials. Zhang’s laboratory explored the potential of electrospinning nanofibers of a biodegradable shape memory copolymer of D,L-lactide copolymerised with trimethylene carbonate71. The product was a biomimetic scaffold with shape memory effect afforded by the synergistic combination of the properties of nanofibers and SMPs. The scaffold produced displayed excellent shape fixity and recovery, and showed good osteoblast proliferation (Figure 3), demonstrating its potential as a scaffold for bone regeneration using minimally invasive medical procedures.



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Figure 3: (I) SEM micrographs and (II) Fluorescence staining images of electrospun poly(D,L-lactide-co-trimethylene carbonate) nanofibers showing good osteoblast attachment and proliferation. Images adapted from [71] with permission.

Apart from nanofibers, porous SMP structures like SMP foams may also find potential in biomedical applications. Erndt-Marino et al. investigated PCL-diacrylate SMP foams coated with polydopamine (PD) and found that the coated SMP foams promoted the expression of osteogenic proteins of human mesenchymal stem cells (MSCs)72. This indicates PD-coated SMP foams promote human MSC differentiation into osteoblasts. Such foams may find potential applications as self-expanding scaffolds for bone regeneration. Wierzbicki et al. designed a prototype device using SMP for the occlusion of patent ductus arteriosus73, a death-threatening congenital deficiency in which the aorta and pulmonary artery of a baby remains connected after birth. The SMP device displayed favourable characteristics such as lower force required for device removal, as well as improved ability of the device to fully expand instead of applying pressure to blood vessel walls (as compared to commercially available devices).

3.1.2. SMP Blends SMPs are also often blended with other polymers for the purpose of modifying morphology and tuning shape memory behaviour. Chatterjee et al. demonstrated that the blending of an ethylene octane copolymer (EOC) with ethylene propylene diene terpolymer (EPDM) displayed superior physical and mechanical behaviour due to the compatibility brought about by structural similarities between the blend components20. The authors also


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reported significant increase in shape recovery ratio with increasing EPDM content. It was noted however that the shape recovery of the thermos-responsive blend was highly dependent of the heating method, with the blends displaying a distinctly lower recovery ratio when heated by air convection (Figure 4).

Figure 4: Shape recovery ratio of EOC:EPDM blends heated by hot water (pink) and hot air (yellow). Images adapted from [20] with permission.

Zhang et al. recently reported on the blending of poly(L-lactide) (PLLA) with poly(ethylene vinyl acetate) (PEVA), which was previously investigated for its shape memory effect128. They found that the blending of PLLA into PEVA enhanced the shape fixity and reduced the temperature dependence of fixity on the fixing temperature, as well as increased the shape recovery ratio of the polymer blend above a critical temperature74. The incorporation of PLLA in the polymer blend may also serve to improve the biocompatibility and biodegradability of the SMP blend for potential biomedical applications.



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Chen and his colleagues recently reported their findings on bio-based SMP based on poly(lactic acid) (PLA) blended with natural rubber (NR)75 and epoxidised natural rubber (ENR)76 followed by vulcanisation to obtain blend networks. These blends displayed continuous rubber networks embedded within the PLA phase instead of phase segregated rubber particles in other rubber blend systems. The group found that their blends presented much more superior shape recovery ratios as compared to the PLA homo-polymer (Figure 5), made possible by the continuous rubber phase providing a strong driving force for shape recovery. The use of biodegradable PLA resin obtained from renewable sources also makes the PLA:NR and PLA:ENR blends interesting potential options for biomedical materials.

Figure 5: (I) Shape fixity ratio of various compositions of PLA:ENR blends as compared to that of pure PLA. (II) Shape recovery ratio of various compositions of PLA:ENR blends as compared to that of pure PLA. Images adapted from [75-76] with permission.

Kang et al. developed a two-way SMP blend by building a core and shell composite from an SMP and an elastomer, respectively. The SMP used was synthesised from MDI, PCL and BD in varying ratios, while the elastomer used was poly(styrene-butadiene-styrene) (SBS). It was reported to have achieved reversible strains of about 10%77. 18 ACS Paragon Plus Environment

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Using an alternative method, Wu et al. synthesised another two-way SMP blend with a “switch-spring” composition by introducing an elastomer network to replace the external tension required in the previously mentioned approach. He developed an interpenetrating network (IPN) of crystalline PCL and elastomeric poly(tetramethylene ether) glycol (PTMEG). The crystalline PCL network was first crosslinked on exposure to ultraviolet (UV) light (Figure 6, a1) then stretched and fixed in a strained state (Figure 6, a2). Following this, the elastomeric network was then crosslinked with heat and allowed to cool before releasing the applied stress from the previous step (Figure 6, a3). Here, on heating beyond the switching temperature defined by the Tm of PCL crystallites, the crystalline PCL network melts into an amorphous phase and begins to shrink (as it was stretched in the synthesis process), compressing the elastomer network and increasing its stored energy (Figure 6, b1). On cooling the material back to room temperature, the stored energy in the elastomeric network is released, helping to orientate the PCL chains during the crystallisation process, resulting in an elongated material (Figure 6, b2)78.

Figure 6: “Switch-spring” model of a SMP blend comprising poly(ε-caprolactone) (PCL) and poly(tetramethylene ether) glycol (PTMEG). Image adapted from [78] with permission.



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3.2.

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SMP Composites (SMPCs) Shape-memory polymers (SMPs) can often be reinforced with fibrous or particulate

fillers to improve their mechanical properties or imbue them with special functions. This is effective in nullifying some of the notable shortcomings of SMPs, for instance, low mechanical strength (e.g. low strength or low Young’s modulus) or problems of uniform stimulation (e.g. inability to heat material uniformly or problems associated with direct heating). The former classifies the use of fillers as reinforcements, and can lead to improvements in the strength, stiffness and recovery force of the SMPs. Carbon and metallic particles, carbon nanotubes (CNTs), carbon nanofibers (CNFs) and glass fibres are but a few notable candidates of such fillers. On the other hand, fillers may also be used to bestow on SMPs with alternate ways of triggering shape recovery and multiple shape-memory effects. SMPs may be augmented with electroactive shape memory effect (SME) by introducing conductive fillers like carbon black or CNTs. Magnetic-active SMP composites (SMPCs) may be created by introducing magnetic particles into the SMP network. It should also be noted that fillers often serve dualpurposes, and they can influence the SME of SMPCs in multiple ways. 3.2.1. Reinforcements 3.2.1.1.

Reinforcement with CNTs and carbon nanofibers (CNFs)

The introduction of CNTs improves the shape recovery stress100, compressive performance129, tensile strength130 and thermal and electrical conductivity131 of SMP systems. When the CNT-loaded SMPC is deformed, some strain energy is stored in the CNTs, which is released during recovery. The improvement to recovery stress is thus attributed to the degree to which the CNTs deform during programming. Because of their exceptional strength 20 ACS Paragon Plus Environment

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and Young’s modulus, their incorporation into SMPCs contribute to increasing improvements to the Young’s modulus, yield stress and tensile stress of the SMPCs with increasing loading132 (Figure 7). CNTs are electrically and thermally conductive, and hence serve to improve the electrical and thermal conductivities of the SMPCs, with the only difference between the two being the absence of a percolation threshold for thermal conductivity131 (Figure 8). The dispersion of the CNTs influence their effectiveness in transferring applied loads, and are critical to their overall effect on the mechanical properties of the SMPC131. Current methods employed to incorporate CNTs into the SMP systems include in situ polymerisation133, ultrasonication134-135, a combination of ultrasonic and three-roll mill mixing136, chemical functionalisation137 and mechanical melt mixing100.

Figure 7: Vapour growth carbon fibres (VGCFs) of different weight fraction were dispersed throughout SMP matrix compared to bulk SMP (0.0% VCGF). (I) Association between Young’s modulus and VGCF weight fraction, (II) Association between yield stress and VGCF weight fraction, and (III) Stress–strain curves (tensile tests) for SMP and SMP with different VCGF weight fraction at temperatures (a) 25 °C, (b) 45 °C, and (c) 65 °C. Images adapted from [132] with permission. 21 ACS Paragon Plus Environment


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Figure 8: (I) Electrical conductivity, and (II) thermal conductivity of SMPCs with different degree of CNT dispersion by composition. Images adapted from [131] with permission.

A recent work by Lu and Huang99 obtained improved behaviour of CNT loaded SMPCs through the synergistic effect of self-assembled carboxylic acid-functionalised CNTs and CNFs. CNT reinforced SMPCs have been around for some time, and recent studies focusing on shape memory polyurethanes (SMPUs) reinforced with CNTs include works by Fonseca et al.100, Bai et al.79, Tijing et al.138, Yu et al.123, Du et al.101 and Li et al.129. Such CNT strengthened polyurethanes may find potential applications in small load-bearing biomedical devices such as tracheal and laryngeal stents to provide mechanical support for the prevention of trachea and larynx collapse. These devices may be collapsed for easy insertion and expanded using the shape memory effect when affixed in the desired location. 3.2.1.2.

Reinforcement with organoclay

The incorporation of small amounts of exfoliated clay into SMPCs can improve mechanical properties139 and shape recovery stress140. The effect on mechanical properties depends on the balance between the disruption of the soft segments caused by clay


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incorporation and the content of clay. Organoclay may also be incorporated into SMPCs to act as a filler and physical crosslinker141. Barwood et al. found that shape memory recovery times were improved significantly with the incorporation of benzyl tallow dimethylammonium-exchanged bentonite (BTDB) into an acrylate based thermo-responsive SMP80 (Figure 9). Haghayegh and Sadeghi found that a good dispersion of nanoclay allowed for improved shape memory properties in a polycaprolactone-diol (PCL-diol) and 1,4-butanediol SMPU because of more effective hydrogen bonding between the hydroxyl groups in the modified nanoclay and the hard segments of the SMP network81. Interesting concepts of shape memory starch-clay bionanocomposites with production methods that may be up-scaled have also been conceived82.

Figure 9: Improved recovery times by incorporating benzyl tallow dimethylammoniumexchanged

bentonite

(BTDB)

into

poly(t-butyl

acrylate)-co-poly(ethylene

glycol)

dimethacrylate shape memory nanocomposite. Image adapted from [80] with permission.



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Reinforcement with other particles

Another method to reinforce SMPs involves the introduction of other particles into the network. Some examples include silicon carbide (SiC), silicon dioxide (SiO2), alumina (Al2O3), or tungsten (W) nanoparticles. As with other fillers used as reinforcements, the use of particles that can bond with the polymer chains in the SMP network chemically would promote better SME, and improve the mechanical properties of the composite. An added benefit of faster shape memory response can also be had if the embedded particles improve the thermal conductivity of the SMP system. Earlier, Guo et al. reported on a SMP composite made of raw bio-based materials comprising poly(propylene sebacate) (PPS) and incorporating boehmite (BM) nanoplatelets as a follow-up to their earlier paper on PPS as a SMP for potential biomedical applications83. They found that the SMPC transition temperature may be brought close to body temperature by manipulating BM nanoplatelet content and extent of curing. The PPS-BM composites were also found to have improved mechanical properties, excellent shape memory properties and biocompatibility, as well as faster degradation compared to PPS SMP reported by the group earlier (Figure 10). The BM-embedded SMPC may find potential applications in high strength transient implants.


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Figure 10: Mass loss of PPS-BM composites of various compositions as compared to pure PPS, indicating a higher degradation rate for the BM-embedded SMPC. Image adapted from [83] with permission.

Hasan et al. synthesised SMP foams embedded with SiO2 nanoparticles, which reportedly improved the mechanical and thermal properties of the foams. The introduction of these nanoparticles also aided in the SME, showing 77% volume recovery at 0.5% loading of SiO284. The group also embedded the SMP foams with Al2O3 and W nanoparticles, reporting higher tensile strength, toughness, and better thermal stability at low levels of loading. At higher concentrations, the nanoparticles tended to form aggregates, interfering with the interactions between polymers, resulting in a reduction in mechanical properties. More recently, Liu et al. presented a thermo-responsive and water-responsive SMPC synthesised by crosslinking cellulose nanocrystals (CNCs) with polycaprolactone (PCL) and poly(ethylene glycol) (PEG) with shape memory transition temperature that was close to human body temperature85. The presence of CNC improved the mechanical properties of the



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SMPC. The PCL and PEG-containing nanocomposite also showed good biocompatibility evaluated by Alamar blue assays on osteoblast cells, indicating its potential as a biomaterial. Typically, SMPs have inadequate physical strength for most applications. With reinforcements to improve their mechanical integrity and recovery stress, it opens up numerous potential applications for SMPs. For instance, these stronger counterparts can be utilised in the making of custom-fitted orthopaedic braces or splints. Polymers generally have poor mechanical properties as compared to their metallic and ceramic counterparts35, 132, 142-145. With reinforcements to improve their mechanical integrity and recovery stress, it opens up numerous potential applications for SMPs. Another useful aspect of SMPs in general is that with the SME, they enable minimally invasive surgeries. 3.2.2. Athermal stimuli-triggered SMEs 3.2.2.1.

Electro-active SME

The usage of electricity or the passing of a voltage to achieve shape recovery is evidenced in conducting PU multi-walled carbon nanotube (MWNT) composites, where MWNTs were used to confer electrical conductivity to the SMPs. In this case, the temperature of the sample could be raised locally via Joule heating that occurs through the application of a voltage to trigger the SME, rather than through external heating146. Other than MWNTs, carbon nanofibers (CNF), carbon black (CB), and graphene can also be used for resistive heating to enable electro-active SME102. As mentioned before, it also has to be noted that the addition of these fillers will also alter the mechanical properties of the SMP system. Furthermore, impregnating the SMP system with conductive particles serves to improve the thermal conductivity of the material, and hence reduces recovery times. Of particular interest is the electroactive SMPs based on aniline trimer (AT), as the electroactive segment, and star-shaped polylactide (PLA) synthesised by Xie et al., developed 26 ACS Paragon Plus Environment

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for bone regeneration and bone tissue engineering. It has exceptional biocompatibility, aiding in the osteogenic differentiation of myoblast cells, and it also boasts shape fixity and recovery ratios of up to 100% and 94%, respectively68. Another example of recent work in electroactive SME is by Mahapatra et al., where the group filled a poly(ε-caprolactone)-based hyperbranched polyurethane with MWNTs. They reported improvements to mechanical properties, shape recovery ratios of above 98%, and fast recovery times103. Kim et al. also synthesised an electroactive SMP by using thermally reduced graphenes (TRG) as fillers in a SMPU network. They reportedly achieved up to 97% shape recovery ratio104. 3.2.2.2.

Magnetic field triggered SME

Another method of activating shape memory involves the use of magnetic fields. By incorporating surface-modified superparamagnetic nanoparticles into the SMP matrix, shape actuation can be activated by remote magnetic stimulus (Figure 11). As the SMP composite is subjected to high frequency magnetic fields, the incorporated nanoparticles transform electromagnetic energy to heat energy via a relaxation process, raising its temperature, resulting in shape recovery12. This presents a crucial advantage in biomedical applications as magnetic fields can fully penetrate the human body without attenuation. Two vital parameters that might influence the efficiency of magnetic-active SME are the size and the volume fraction of the magnetic particles147.



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Figure 11: Magnetic field triggered SMP made by the incorporation of surface-modified superparamagnetic nanoparticles. Image adapted from [12] with permission.

One example of a magnetic-active SMPC uses iron oxide (Fe3O4) nanoparticle-coated MWNT as fillers in a chemically crosslinked poly(ε-caprolactone) matrix105, whilst another simply utilised the ferromagnetic Fe3O4 particles dispersed into an SMPU matrix to achieve the magnetic-active SME106. Fe3O4 particles are found to be suitable for in vivo use and have been widely studied for applications such as magnetic resonance imaging (MRI) contrast agents and hyperthermia procedures for cancer treatment148-149. In the former work, the electrospun composite fibres by Gong et al. showed good biocompatibility and the cytotoxicity analyses yielded positive results, promising potential biomedical applications. The magnetic-active SME mentioned above is triggered due to the heat generated from hysteresis loss when the material is subject to an alternating magnetic field. Zhang et al. incorporated Fe3O4 into nonwoven Nafion nanofibers, and this SMPC exhibited quick and controlled recovery without significant increase of the surface temperature of the material107. In other recent work by Razzaq et al., the magnetic-active SME was achieved by using magnetite nanoparticles in poly(ω-pentadecalactone) networks108. They reported shape fixity and recovery ratios of up to 95 and 97% respectively. However, it is noteworthy that the poly(ω-pentadecalactone)-magnetite composite reaches high temperatures for actuation, which might limit its use in biomedical applications. Additionally, further biocompatibility


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studies need to be performed for this composite to provide better evaluation on the suitability of such composites as biomedical devices. As with electro-active SMPCs, magnetic-active SMPCs introduce the concept of “remote actuation”. This is particularly useful as magnetic fields are frequently employed in the biomedical field, and magnetic nanoparticles are known to degrade harmlessly in the human body12. This technology can also be utilised to allow medical professionals to do mechanical adjustments in the patient’s body remotely. It could also be used in remote-activated drug delivery systems. Another potential application is the remote-inflation of an intragastric implant to curb a patient’s appetite150. 3.2.2.3.

Photo-triggered SME

For light actuation, two methods have been investigated. The first of which involves the usage of a laser to heat the polymer151, causing it to actuate based on the method described earlier for thermo-responsive SMPs. Lu et al. developed a photo-active SMP by incorporating boron nitride and CNT, which reportedly have a synergistic effect, into an epoxy-based SMP22. The CNTs served to improve the thermal conductivity of the material and its infra-red light absorption, whilst the nitrides transferred the aided in the heat transfer to the SMP matrix, resulting in faster shape memory recovery. Shou et al. also developed near-infrared (NIR) light-responsive SMPs by incorporating gold nanorods (AuNRs) into a poly(εcaprolactone) matrix109, where exposure to NIR light induced the embedded AuNRs to be heated, triggering the SME. The second method, as reported by Lendlein and colleagues, involves the introduction of cinnamic groups, which can be actuated by ultraviolet light illumination. Here, irradiation with ultraviolet (UV) light greater than a certain specific wavelength causes the formation of crosslinks, “fixing” the temporary shape. Upon irradiation with UV light of smaller 29 ACS Paragon Plus Environment


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wavelength, these photosensitive crosslinks that were newly formed are cleaved, causing the material to return to its original permanent shape10 (Figure 12). This principle can be applied to other systems containing light-sensitive polymer groups like azobenzene152-153.

Figure 12: (I) Photo-induced shape memory polymer film and (II) molecular mechanism of photo-induced shape memory effect at various states: (a) permanent shape, (b) spiral temporary shape, and (c) recovered shape by irradiation with UV light. Images adapted from [10] with permission.

Light-actuated SMPCs can be applied to smart surgical suturing, to avoid directly heating biological tissue. Intravascular laser-activated therapeutic devices have also been developed, as in the application where a thrombus in the brain’s arterial network is mechanically removed126.


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3.2.2.4.

Water-triggered SME

Most of what has been mentioned involves actuation via some form of heating, and this is inextricably tied to a local increase in temperature, which might result in varying degrees of thermal tissue damage154. An interesting way to circumvent this problem would be to use water – which is always present in the bloodstream, as a means of triggering this shape recovery effect, after initial discoveries of the effect that water molecules had on lowering the glass transition temperature (Tg)155. By focusing on manipulating Tg, a notable consequence is that actuation can now occur within a larger range of temperatures. In the simplest setup, the water-sensitive SMP would comprise hydrophobic and hydrophilic segments, as the hard and soft segments respectively. When the water-sensitive SMP is immersed in water, the water molecules penetrate the matrix and interact with the hydrophilic segments, acting as a plasticiser to improve the mobility of the polymer chains of the soft segment156. This results in the observed fall in Tg, and if the temperature of the surroundings are above this new Tg, actuation can occur. Alternatively, water-sensitive SMPs can also be made by incorporating a hydrophilic or water-swellable component in conjunction with a hydrophobic component. Upon immersion, water molecules will interact with the water-swellable components, causing them to swell, destroying the crystalline structure. In this state, the SMP becomes compliant, and can be deformed significantly. To fix the temporary shape, the crystalline structure has to be restored by drying the sample157. This second method apparently accelerates the shape recovery process, cutting down recovery times significantly. This was demonstrated by Wu et al. in a recent work by incorporating poly(methacrylic acid)-grafted clay into thermoplastic urethane (PMAA-g-clay-TPU), which could achieve shape fixity and recovery ratios of 82% and 91%, respectively110. Here, water diffuses through the hydrophilic PMAA-g-clay phase, which acts as the switching segment for the SMPC. The fast water absorption and the mechanical adaptiveness of the clay allows for 31 ACS Paragon Plus Environment


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quick water-active SME. In other work, Wu et al. combined poly(glycerol sebacate urethane) (PGSU) with a 23.2 vol% loading of cellulose nanocrystals (CNCs) to obtain an SMPC with shape fixity and recovery ratios of 98% and 99%, respectively111. In this SMPC, the wateractive SME can be attributed to the formation of the continuous CNC network in the polymer matrix. Another work by Wu et al. incorporated hydrophilic poly(vinyl alcohol) (PVA) submicron particles into a TPU matrix, where a 15 vol.% loading of the PVA particles exhibited the best shape memory performance with 97% shape recovery and shape fixity ratios112. Recently, Liu et al. developed a water-responsive poly(D,L-lactide)-microcrystalline cellulose composite113. This particular SMPC functioned based on water acting as a plasticiser to reduce the Tg of the material, and its good cytocompatibility and biodegradation behaviour holds promising applications in the biomedical field. Water-active SMPCs are particularly attractive for use in endovascular applications. Thermal actuation of SMPs entail local heating, which might lead to the damage of nearby tissue154. This can be effectively avoided by using water-actuated SMPCs, as water is abundant in the bloodstream. 3.2.3. Others 3.2.3.1.

Multiple-shape memory composites (MSMPCs)

In order for SMPs to exhibit multiple-shape memory effects, the transition temperatures (Ts) of the associated thermal transitions have to be distinct or well separated (Figure 13). This may be achieved by using blends of different polymers, polymerisation of multiple polymer network systems or introducing fillers with a distinct switching transition.


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Figure 13: Storage modulus changes in a triple-shape SMP with well separated thermal transitions – (A) temporary shape (T > Tg,1,Tg,2); (B) intermediate shape (Tg,1 > T > Tg,2); and (C) permanent shape (T < Tg,1,Tg,2) – based on dual polymer network by thiol monomers (mercaptoacetate and mercaptopropionate) and vinyls (vinyl sulfone and acrylate). Images adapted from [86] with permission.

The two most prominent methods of programming triple-SMPCs are two-step programming procedures (2SPP) like 2SPP-I and 2SPP-II. 2SPP-I involves firstly heating the triple-SMPC to a temperature that is beyond both thermal transitions (Ts,low and Ts,high), followed by deformation into the first temporary shape A. The SMPC will then be cooled to a temperature between Ts,low and Ts,high while maintaining the applied stress. Cooling below Ts,high fixes the temporary shape A by “freezing” the switching domains associated with the higher thermal transition. While maintaining this intermediate temperature, a second temporary shape B can be programmed in a similar manner, where the applied stress is maintained as the polymer is cooled to a lower temperature, Tlow (below both Ts,low and Ts,high). 2SPP-II, on the other hand, involves firstly heating beyond both Ts,low and Ts,high, and fixing the shape by cooling the polymer to Tlow. After which, the polymer is reheated to an



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intermediate temperature between Ts,low and Ts,high, where shape B is programmed and fixed by maintaining and then cooling the polymer back to Tlow4. Recently, Chatani et al. synthesised a triple-SMPC from the in situ polymerisation of mercaptoacetate (MA), mercaptopropionate (MP), vinyl sulfone and acrylate. Here, two polymer networks were formed at distinct times, with the MA-vinyl sulfone network forming before the MP-acrylate network86. These networks had different and distinct Tss, which was vital for triple-SME to be possible. Dong et al. also synthesised a triple-SMPC from a common CNT/epoxy nanocomposite by utilising self-made epoxy-graft-polyoxyethylene octyl phenyl ether (EP-g-TX100) as an emulsifier87. The EP-g-TX100 network served as the second reversible phase in this new SMPC system, enabling the triple-SME. In 2014, Nejad et al. synthesised a triple-SMPC foam by curing a mixture of PCL and a composite derived from diglycidyl ether of bisphenol-A (DGEBA) and neopentyl glycol diglycidyl ether monomers with poly(propylene glycol) bis(2-aminopropyl ether) (Jeffamine® D230) added as a crosslinker88. This mixture eventually separated into PCL-rich and epoxy-rich phases, granting the system triple-SME. The development of MSMP composites opens the possibility of multiple shape transitions for biomedical applications. This might allow for more precise actuation and adjustment of complex shapes and their transitions4. 3.2.3.2.

Self-healing SMPCs

The shape memory effect in SMPs can be utilised to aid in the self-healing or selfregeneration of SMP materials in a process termed as shape memory assisted self-healing (SMASH)89-90, or close-then-heal (CTH) self-healing91-92,

158

. These describe the same

process, which generally begins with shape memory actuation to firstly close a crack,


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following which some components of the SMP system are melted to rebond the crack (Figure 14).

Figure 14: Self-healing exhibited in an SMPC produced by electrospinning poly(vinyl acetate) (PVAc) and Poly(ε-caprolactone) (PCL). (I) Sample damaged by notching with a blade and bending to propagate crack. (II) Sample after allowing it to heal at 75 °C for 10 min. Images adapted from [89] with permission.

Nejad et al. demonstrated this self-healing effect by creating an interwoven polymeric network of PCL and poly(vinyl acetate) (PVA) by dual-electrospinning. These systems not only possessed self-healing capabilities, but also exhibited both dual and triple-SME (in dry and wet states, respectively)89. Earlier on, Luo and Mather also developed a shape memory assisted self-healing coating based on a similar principle, where they distributed PCL fibres randomly within a shape memory epoxy matrix90. Li and Zhang also constructed an SMPC from strain hardened polyurethane fibres (synthesised from poly(butylene adipate) (PBA), 4’4-diphenylmethane diisocyanate (MDI), and 1,4-butanediol (BDO)) coated with acrylic conformal coating followed by epoxy coating. The coating improved the shape fixity of the SMP system, and the material showed good healing properties, which were repeatable91. In an earlier work, Nji and Li synthesised an SMPC by dispersing small amounts of copolyester 35 ACS Paragon Plus Environment


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in a Veriflex polystyrene SMP matrix92. Here, the shape recovery of the SMP is utilised to close the cracks, following which healing is achieved by the molten thermoplastic particles, as described in the CTH scheme. In their earlier work, they reported healing efficiencies of up to 65% with 6 vol% loading of copolyester in a PS SMP matrix158. With self-healing SMPCs, we may lengthen the lifespan of surgical implants by repairing them with exposure to stimuli, rather than replacing them constantly. This may be useful in applications where SMPs are used as parts of implanted biomedical devices, or bio-actuators.


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3.2.3.3.

Two-way shape memory polymer composites (2W-SMPCs)

The guiding principle for two-way shape memory (2W-SM) is the constant stress applied by an external structure or an interpenetrating polymer network onto the SMP component in the composite. The SMPs/SMP fibres are typically deformed at a temperature beyond Ts and allowed to cool at constant strain before an overlying material is set or cured. This second component of the SMPC exerts a constant strain on the SMP to fix the composite in its primary shape. Upon heating beyond Ts, the SMPC can contract to a new secondary shape, and upon cooling, it will once again return to its primary shape (Figure 15).

Figure 15: Two-way shape memory mechanism. Image adapted from [77] with permission.

A suggested application of 2W-SMPCs in the biomedical field is their usage as artificial tendons or muscles78. Also, should the constituents of the SMPC be non-biodegradable, retrieval surgery might have to be carried out. In this case, the ability for the SMPC to be reshrunk to its original smaller dimensions (prior to implantation) might be useful.



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3.3.

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Shape Memory Hydrogels

Hydrogels are hydrophilic polymer networks with high water content and good biocompatibility159. Their soft and wet nature make them very similar to human tissue160, and are thus suitable candidates for biomedical applications such as drug delivery161, tissue engineering162 and artificial skin163. However high water content levels negatively affect the mechanical properties of hydrogels, making them weak and brittle164-165. This can hinder the ability of shape memory in hydrogels as a minimum level of mechanical robustness is usually required in order to withstand physical deformation during the shape-change process. The mediocre mechanical properties of hydrogels are widely recognised as a barrier to the potential use of hydrogels for many applications, and extensive work has been done to improve hydrogel mechanical properties164-167. Tough hydrogels have been designed, which show remarkable improvements in their tensile strengths (2-8MPa) while retaining high levels of elongation of up to 700%93, 114, 168. Shape memory behaviour and mechanical properties in hydrogels are also closely related due to their dependence on the type and degree of crosslinking within the hydrogel network. Similar to blends and composites, shape recoverability and fixity require inter-chain interactions to be broken and formed easily, while mechanical strength is directly related to the concentration and collective strength of the various forms of crosslinks. It is thus important to consider the implications of both features in the design of shape memory hydrogels. The high water content levels in hydrogels enable them to shrink or swell to large degrees through a loss or gain in water respectively159-160. This has given rise to shape-memory materials capable of undergoing large degrees of deformation between the temporary and permanent states94 (Figure 16, I). Water flows in or out of the polymer network via diffusion,


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and the kinetics of this process are dependent on factors such as network porosity in the various states of deformation. Shape transitions have thus been reported to occur in a wide range from a few seconds26 to several hours119 (Figure 16, II and III). This significantly affects the types of applications shape memory hydrogels can be incorporated in. Shape memory response in hydrogels is thus mostly triggered in the presence of water, either through the introduction of water to the system114-116, or a change in the aqueous environment of the material such as temperature26, 94-98, pH117, 169, ion concentration118-121 or a redox reaction124. Other types of SME triggers have also observed in hydrogels, such as UV irradiation25 and ultrasound125.

Figure 16: (I) A shape memory hydrogel of length 26.3mm being stretched to a length of 45.2mm, 170% of its original length, for its temporary shape. The kinetics of shape transitions of shape memory hydrogels can range from (II) seconds to (III) hours. Images adapted from [26, 94, 119] with permission.

3.3.1. Water-triggered SME Water-triggered shape memory hydrogels hold their temporary shapes through a procedure involving a considerable reduction in water content. The water loss is caused through evaporative loss by taking the gel out of water and can be enhanced by heating the gel115. As this happens, polymer chains in the network are brought closer and this can result in new inter-chain interactions, which can hold the strained polymer network in its temporary shape.



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Cui et al. have designed an extremely strong polyethylene glycol (PEG)-based hydrogel with supramolecular crosslinks capable of such a water-triggered response. Hydrogel strips are extended and left in air to dry, causing PEG chains in the network to crystallise and hold the gel network in its deformed state, and the authors report a shape fixity value of close to 100%. The permanent shape is then recovered by placing the gel back into water, which causes the dissolution of the PEG crystallites and thus recovery of the strain in the material114.

3.3.2. SME triggered in aqueous environments Most other stimuli take place within an aqueous environment, in the presence of specific changes in the environment, such as solution pH. Such systems can be potentially useful for biomedical applications if they are designed to be responsive towards physiological conditions. Thermally-responsive hydrogels result from the thermal sensitivity of physical crosslinking. The temporary shapes are usually programmed by placing the hydrogels in a heated environment to cause the dissociation of weaker physical crosslinks. This causes the material to soften, and a deformation is then applied. A cooling process follows after, which re-forms the previously broken physical interactions and holds the deformation in place. Yasin et al. reported a hydrogel system which forms physical interactions through a αcyclodextrin (α-CD) inclusion complex. Cyclodextrin inclusion complexes have been previously shown to be able to form temperature-sensitive aggregates which result in supramolecular hydrogels170-172. In this system, the hydrogel is held together by covalent crosslinkers, and reinforced with the α-CD inclusion complexes, which gives rise to the thermally responsive shape memory behaviour95. The shape recovery for temperaturesensitive systems tends to take place in less than 1 minute. However the shape recovery


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temperatures are still slightly high and take place between 60-90 °C26, 94-96, and this shows an opportunity for the development of shape memory hydrogels with stimulus temperatures close to the human body temperature of 37 °C. Other athermal stimuli such as pH or ion concentration sensitivities result in interesting shape memory behaviour within hydrogels. Hu et al. shared their findings on a DNAfunctionalised hydrogel which shows pH responsiveness through pH-induced Hoogsteen-type interactions. The gel exists as a solid in its permanent shape at pH 7, but softens into a quasiliquid state at either pH 5 or 7, depending on the type of chain functionalised onto the gel169. Such a system can be potentially useful in parts of the body such as the digestive system where environmental changes in pH are observed. For ion-triggered shape memory behaviour, Liu’s group has developed a Zn2+-responsive triple shape memory hydrogel, where different cationic concentrations can have either a strengthening or weakening of crosslinking within the hydrogel network118. Cell viability and other tests have since been conducted on shape memory hydrogels based on this mechanism to investigate their potential use as cell scaffolds120-121. In another paper, Yasin et al. reported a ferric phosphate induced shape memory hydrogel that holds its temporary shape through ionic crosslinking with Fe3+ ions119. Through the introduction of a reducing agent, erythorbic acid, Fe3+ ions are reduced to Fe2+, which cause the ionic crosslinks to dissociate and result in permanent shape recovery. This system can be potentially applied in the human body and activated through natural means, as the human body contains mechanisms capable of reducing Fe3+ ions to Fe2+ such as the reductase, duodenal cytochrome B173. In another recent work, Xu et al. showed ion-responsive hydrogels strengthened by hydrogen bonding using a facile one-pot synthesis to copolymerise 2-vinyl-4,6-diamino1,3,5-triazine (VDT), poly(ethylene glycol) diacrylate (PEGDA), and 1-vinylimidazole (VI)122. Their study concluded that the inclusion of VI and hydrogen bonding between 41 ACS Paragon Plus Environment


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diaminotriazine (DAT) moieties gave rise to significantly improved mechanical properties. The group further demonstrated that the introduction of zinc ions improved mechanical properties of the hydrogels, and the uptake and release of zinc ions allowed for the hydrogels to display shape memory effect. More importantly, the hydrogels were found to be antiinflammatory with good wound healing efficacy (Figure 17), making this hydrogel system a potential scaffold material for tissue engineering, particularly in bone tissue engineering applications due to the good mechanical properties displayed.

Figure 17: Micrographs of subcutaneous implanted hydrogels stained by hematoxylin and eosin (H&E). Histological sections of Zn2+-fixed samples (E-H) displayed a faster decrease in inflammatory response as compared to PBS-soaked samples. Image adapted from [122] with permission.


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4.

Conclusion and Future Prospects Nature-inspired design of stimuli-responsive materials has led to interesting developments

in the field of shape memory soft materials such as shape memory polymers (SMPs), shape memory polymer composites (SMPCs) and shape memory hydrogels. These polymers or hydrogels are able to recover their original state when exposed to specific stimuli such as temperature, electrical currents, magnetic fields, light, and water. Compared to shape memory alloys (SMAs), SMPs have added advantages such as lower raw material cost, lower fabrication and processing costs, tailorable properties, easier shape-programming procedures and low density. Most importantly, SMPs have higher recoverable strains as compared to SMAs which are limited to around 8% deformation, as compared to 800% in SMPs42. Despite the inherent weakness in mechanical properties of SMPs as compared to SMAs, the advantages that SMPs offer make them attractive propositions as materials for use in biomedical applications. However, there are inherent requirements to be met in the design of a SMP system for biomedical use. In order to fulfil the potential of SMPs as biomaterials, design considerations in terms of biocompatibility, mechanical properties, biodegradability, and sterilisability are important factors. Such design considerations and recent advancements in the development of the various classes of SMPs were reported in this review. SMPs are often also blended with other polymers or modified to form composites for the purpose of tuning mechanical properties, morphology and shape memory behaviour. Recent studies also reported multiple-shape SMPs which exhibit various well distinctive thermal transition temperatures, self-healing SMPs utilising SME and intermolecular hydrogen bonding to achieve their self-healing properties, as well as two-way SMPs which remembers two shapes; viz one at lower temperature and one at higher temperature. Shape memory hydrogels, on the other hand, have weak mechanical properties that may pose challenges with regards to potential biomedical applications. Concentration of crosslinks 43 ACS Paragon Plus Environment


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and the collective strength of various inter-chain interactions are important factors to be considered in the design shape memory hydrogel systems due to the interdependence between shape memory behaviour and mechanical properties. Apart from the types of stimuli mentioned above, shape memory hydrogels can also be triggered by stimuli such as pH, ion concentration, a redox-reactions or ultrasound. The research in SMP technology over the past decade has allowed SMPs to find several commercial applications in the biomedical industry. Current applications of SMPs in the biomedical field include stents for the treatment of vascular and laryngeal stenosis. The utilisation of SMPs as stents has been claimed to enhance healing after implantation174. SMPs are also ideal candidate materials for devices to be used in minimally invasive procedures, diagnostic devices or sensors, tissue scaffolds for cell growth, artificial skin, self-tightening degradable sutures, drug delivery systems, or even as materials for 3D printing of biomedical devices. The development of SMPs may impact the biomedical field and open up new possibilities for designing novel bio-devices. Previously, SMP devices suffered from major disadvantage of shape change being oneway and irreversible. With advances in SMP research and technology, two-way/reversible and multiple shape-memory systems are now achievable (see section 3.2.3). However, shape change in SMP devices are still either remotely controlled or requires a “user input” to trigger the process. This severely limits the translation of SMP technology into useful, autonomous medical devices. In the future, shape change between multiple programmed shapes could be triggered automatically by dynamic properties (e.g. molecular weight of a transient SMP device, or the presence of specific biomarkers) such that a SMP device may potentially function over a longer time period without the need for any form of supervision or manual input. Development of SMP technology in this direction would open opportunities for an even wider range of potential applications such as self-removing biodegradable stents and 44 ACS Paragon Plus Environment

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self-detaching tissue engineering scaffolds, as well as dynamic drug delivery systems. As such, we foresee that the development of multiple-shape, two-way SMPs with value-added properties like that mentioned above will become the focus of SMP research in the future. The tailoring of SMP response speeds could be another important direction in SMP research. Current literature provides examples of SMP systems with response times that range between minutes to hours. SMPs with slower response may find value in applications such as medical implants, in order to prevent post-implant shocks caused by sudden alteration of the physiological environment. On the other hand, speed is a key performance indicator for actuators, and fast-response SMPs may thus be of importance in actuating applications such as robotic systems and artificial muscles. More effort can be placed on the design of potential SMP systems with response times and switching temperatures that are tuneable after the synthesis and device manufacturing process. Advances in this direction would be greatly advantageous for the SMPs to be used in the biomedical field. Despite the increasing number of reports of SMPs for biomedical applications, smarter material designs with better functionality and performance are imperative to further push boundaries in this area. In summary, SMPs for biomedical applications must be biocompatible, durable, biodegradable and non-immunogenic to the human body in order to be applied in the biomedical field. Collaborative research between different branches of science and medicine is required to bring forth further advancements in SMP technology and the translation of research progress from bench to bedside.



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Acknowledgments B.Q.Y. Chan and Z.W.K. Low would like to acknowledge the A*STAR Graduate Scholarship from A*STAR. S.Y. Chan would like to acknowledge funding and support from Monash University Malaysia and IMRE.


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Table of Contents (TOC) Graphic


Recent Advances in Shape Memory Soft Materials for Biomedical

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