Heating/Solvent Responsive Shape‐Memory Polymers for Implant Biomedical Devices in Minimally Invasive Surgery: Current Status and Challenge

This review is about the fundamentals and practical issues in applying both heating and solvent responsive shape memory polymers (SMPs) for implant biomedical devices via minimally invasive surgery. After revealing the general requirements in the design of biomedical devices based on SMPs and the fundamentals for the shape‐memory effect in SMPs, the underlying mechanisms, characterization methods, and several representative biomedical applications, including vascular stents, tissue scaffolds, occlusion devices, drug delivery systems, and the current R&D status of them, are discussed. The new opportunities arising from emerging technologies, such as 3D printing, and new materials, such as vitrimer, are also highlighted. Finally, the major challenge that limits the practical clinical applications of SMPs at present is addressed.     

Revealing Triple‐Shape Memory Effect by Polymer Bilayers

Bilayer polymers that consist of two epoxy dual‐shape memory polymers of well‐separated glass transition temperatures have been synthesized. These bilayer epoxy samples exhibit a triple‐shape memory effect (TSME) with shape fixities tailorable by changing the ratio between the two layers. The triple‐shape fixities of the bilayer epoxy polymers can be explained by the balance of stress between the two layers. Based on this work, it is believed that the following three molecular design criterions should be considered in designing triple‐shape memory polymers with optimum TSME: 1) well‐separated thermal transitions, 2) a strong interface, and 3) an appropriate balance of moduli and relative ratios between the layers (or microphases).

     

4D Bioprinting: Technological Advances in Biofabrication

The development of the three‐dimensional (3D) printer has resulted in significant advances in a number of fields, including rapid prototyping and biomedical devices. For 3D structures, the inclusion of dynamic responses to stimuli is added to develop the concept of four‐dimensional (4D) printing. Typically, 4D printing is useful for biofabrication by reproducing a stimulus‐responsive dynamic environment corresponding to physiological activities. Such a dynamic environment can be precisely designed with an understanding of shape‐morphing effects (SMEs), which enables mimicking the functionality or intricate geometry of tissues. Here, 4D bioprinting is investigated for clinical use, for example, in drug delivery systems, tissue engineering, and surgery in vivo. This review presents the concept of 4D bioprinting and smart materials defined by SMEs and stimulus‐responsive mechanisms. Then, biomedical smart materials and applications are discussed along with future perspectives.     

D-Sorbitol Physical Properties Effects on Filaments Used by 3D Printing Process for Personalized Medicine

Fused filament fabrication (FFF) is a process used to manufacture oral forms adapted to the needs of patients. Polyethylene oxide (PEO) filaments were produced by hot melt extrusion (HME) to obtain a filament suitable for the production of amiodarone hydrochloride oral forms by FFF 3D printing. In order to produce personalized oral forms adapted to the patient characteristics, filaments used by FFF must be controlled in terms of mass homogeneity along filament. This work highlights the relation between filament mass homogeneity and its diameter. This is why the impact of filler excipients physical properties was studied. It has been showed that the particle’s size distribution of the filler can modify the filament diameter variability which has had an impact on the mass of oral forms produced by FFF. Through this work it was shown that D-Sorbitol from Carlo Erba allows to obtain a diameter variability of less than 2% due to its unique particle’s size distribution. Using the filament produced by HME and an innovating calibration method based on the filament length, it has been possible to carry out three dosages of 125 mg, 750 mg and 1000 mg by 3D printing with acceptable mass uniformity.     

Chemical Cross‐linking of Polypropylenes Towards New Shape Memory Polymers

In this work, syndiotactic polypropylene (sPP) as well as isotactic polypropylene (iPP) are cross‐linked to gain a shape memory effect. Both prepared PP networks exhibit maximum strains of 700%, stored strains of up to 680%, and recoveries of nearly 100%. While x‐iPP is stable for many cycles, x‐sPP ruptures after the first shape‐memory cycle. It is shown by wide‐angle X‐ray scattering (WAXS) experiments that cross‐linked iPP exhibits homoepitaxy in the temporary, stretched shape but in contrast to previous reports it contains a higher amount of daughter than mother crystals.

     

Stress‐Induced Stabilization of Crystals in Shape Memory Natural Rubber

In contrast to all known shape memory polymers, the melting temperature of crystals in shape memory natural rubber (SMNR) can be greatly manipulated by the application of external mechanical stress. As shown previously, stress perpendicular to the prior programming direction decreases the melting temperature by up to 40 K. In this study, we investigated the influence of mechanical stress parallel to prior stretching direction during programming on the stability of the elongation‐stabilizing crystals. It was found that parallel stress stabilizes the crystals, which is indicated by linear increase of the trigger temperature by up to 17 K. The crystal melting temperature can be increased up to 126.5 °C under constrained conditions as shown by X‐ray diffraction measurements.     

Shape memory polybenzoxazines based on a siloxane‐containing diphenol

A siloxane‐containing diphenol is synthesized from 1,1,3,3‐tetramethyldisiloxane and o‐allylphenol, followed by the Mannich condensation with aniline, methylamine, and formaldehyde yielding two siloxane‐containing benzoxazines. The onset polymerization temperature of aniline‐based benzoxazine is higher than that of the methylamine counterpart. The dynamic mechanical properties of the polybenzoxazines depend on the structure of the starting primary amines. Both polybenzoxazines exhibit one‐way dual‐shape memory behavior in response to changes in temperature, and they show excellent shape fixity ratios in bending, tension, and tensile stress–strain tests, high shape recovery ratios in bending and tension tests, but relatively low shape recovery ratios in tensile stress–strain test. The network chain segments including the alkylsiloxane units serve as a thermal control switch based on the glass transition temperatures (39 and 53 °C) for the polybenzoxazines. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 1255–1266     

Ink‐Jet Printing of Luminescent Ruthenium‐ and Iridium‐Containing Polymers for Applications in Light‐Emitting Devices

Summary: Defined films of luminescent ruthenium(II ) polypyridyl‐poly(methyl methacrylate) (PMMA) and iridium(III ) polypyridyl‐polystyrene (PS) copolymers could be prepared by ink‐jet printing. The copolymers were deposited on photoresist‐patterned glass substrates. Films as thin as 120 nm could be printed with a roughness of 1 to 2%. In addition, the film thickness could be varied in a controlled way through the number of droplets deposited per unit area. The topography of the ink‐jet printed films was analyzed utilizing an optical profilometer. The absorbance and emission spectra were measured using fast parallel UV‐vis and fluorescence plate reader.

Photo of the solutions of luminescent ruthenium (left) and iridium (right) containing polymers in a glass microtiter plate (top). The subsequently prepared films using ink‐jet dispensing techniques are shown below.     

Resilient Amorphous Networks Prepared by Photo‐Crosslinking High‐Molecular‐Weight D,L‐Lactide and Trimethylene Carbonate Macromers: Mechanical Properties and Shape‐Memory Behavior

Tough networks are prepared by photo‐crosslinking high‐molecular‐weight DLLA and TMC macromers. These amorphous networks exhibit tunable thermal and mechanical properties and have excellent shape‐memory features. Variation of the monomer ratio allows adjustment of T_g between approximately ?13 and +51 °C. The elastic moduli at room temperature can be varied between 4.5 and 2730 MPa. The crosslinks allow the networks to return to their original shape after deformation. 60:40 DLLA:TMC networks have T_g values between room temperature and body temperature, with mechanical properties at body temperature close to soft tissues. Several medical devices are prepared from these networks.

     

Chitosan and Whey Protein Bio-Inks for 3D and 4D Printing Applications with Particular Focus on Food Industry

The application of chitosan (CS) and whey protein (WP) alone or in combination in 3D/4D printing has been well considered in previous studies. Although several excellent reviews on additive manufacturing discussed the properties and biomedical applications of CS and WP, there is a lack of a systemic review about CS and WP bio-inks for 3D/4D printing applications. Easily modified bio-ink with optimal printability is a key for additive manufacturing. CS, WP, and WP–CS complex hydrogel possess great potential in making bio-ink that can be broadly used for future 3D/4D printing, because CS is a functional polysaccharide with good biodegradability, biocompatibility, non-immunogenicity, and non-carcinogenicity, while CS–WP complex hydrogel has better printability and drug-delivery effectivity than WP hydrogel. The review summarizes the current advances of bio-ink preparation employing CS and/or WP to satisfy the requirements of 3D/4D printing and post-treatment of materials. The applications of CS/WP bio-ink mainly focus on 3D food printing with a few applications in cosmetics. The review also highlights the trends of CS/WP bio-inks as potential candidates in 4D printing. Some promising strategies for developing novel bio-inks based on CS and/or WP are introduced, aiming to provide new insights into the value-added development and commercial CS and WP utilization.     

Recent Insights Into the Biomedical Applications of Shape‐memory Polymers

Shape‐memory polymers (SMP) are versatile stimuli‐responsive materials that can switch, upon stimulation, from a temporary to a permanent shape. This advanced functionality makes SMP suitable and promising materials for diverse technological applications, including the fabrication of smart biomedical devices. In this paper, advances in the design of SMP are discussed, with emphasis on materials investigated for medical applications. Future directions necessary to bring SMP closer to their clinical application are also highlighted.

     

Shape Memory Hydrogel based on a Hydrophobically‐Modified Polyacrylamide (HMPAM)/α‐CD Mixture via a Host‐Guest Approach

A novel thermally sensitive shape memory (SM) hydrogel is prepared by block copoly­merization of a cationic surfactant monomer, dimethylhexadecyl[2‐(dimethylamino)ethylmethacrylate]ammoniumbromide (C₁₆DMAEMA), and acrylamide (AM) in the presence of α‐cyclodextrin (α‐CD) using N,N’‐methylenebisacrylamide (MBA) as a crosslinker. XRD, solid state ¹³C NMR, and DSC measurements show that the crystalline domains, induced by the hydrogen bonds between α‐CDs threaded on the hydrophobic units of the polymer chains through the host‐guest approach, can reversibly melt and crystallize at different temperatures. Rheological measurements show that both the elastic modulus G’ and viscous modulus G’’ drastically change due to the formation and dissolution of the crystalline domains. These thermo‐sensitive crystalline domains serve as reversible physical crosslinks, endowing the hydrogel with excellent SM properties. Cyclic experiments show that the hydrogel can recover to almost 100% of the deformation in each cycle and can be reused several times.

     

New Strategy to Access Dual‐Stimuli‐Responsive Triple‐Shape‐Memory Effect in a Non‐overlapping Pattern

Multistimuli‐responsive shape‐memory polymers are highly desirable in various applications, and numerous modes have been developed in recent years. However, most of them need to reprogram before they are ready to respond to another stimulus while one is triggered. Here, a new strategy is developed to achieve dual‐stimuli‐responsive triple‐shape memory with non‐overlapping effect in one programming cycle. Here, a series of poly(l ‐lactide)‐poly(tetramethylene oxide) glycol copolymers (PLA‐PTMEG‐A) is prepared by selected dangling photoresponsive anthracene moieties on the crystalline PTMEG backbone. The architectures of the copolymers are well‐controlled in order to keep a good balance between the crystallinity of the soft segment and the mobility of the anthracene moieties. Thus, PLA‐PTMEG‐A's can respond to heat and light with non‐overlapping effect. The thermally‐induced shape‐memory effect (TSME) is realized by the crystallization–melting transition of PTMEG soft segments, while the light‐induced shape‐memory effect (LSME) is achieved by the reversible photodimerization of anthracene groups. In view of the non‐overlapping effect of TSME and LSME in the copolymers, a triple‐shape‐memory effect triggered by dual‐stimuli is realized in one programming and recovery cycle.

     

Cell‐Laden Hydrogels for Multikingdom 3D Printing

Living materials are created through the embedding of live, whole cells into a matrix that can house and sustain the viability of the encapsulated cells. Through the immobilization of these cells, their bioactivity can be harnessed for applications such as bioreactors for the production of high‐value chemicals. While the interest in living materials is growing, many existing materials lack robust structure and are difficult to pattern. Furthermore, many living materials employ only one type of microorganism, or microbial consortia with little control over the arrangement of the various cell types. In this work, a Pluronic F127‐based hydrogel system is characterized for the encapsulation of algae, yeast, and bacteria to create living materials. This hydrogel system is also demonstrated to be an excellent material for additive manufacturing in the form of direct write 3D‐printing to spatially arrange the cells within a single printed construct. These living materials allow for the development of incredibly complex, immobilized consortia, and the results detailed herein further enhance the understanding of how cells behave within living material matrices. The utilization of these materials allows for interesting applications of multikingdom microbial cultures in immobilized bioreactor or biosensing technologies.     

3D Printing of Aniline Tetramer‐Grafted‐Polyethylenimine and Pluronic F127 Composites for Electroactive Scaffolds

Electroactive hydrogel scaffolds are fabricated by the 3D‐printing technique using composites of 30% Pluronic F127 and aniline tetramer‐grafted‐polyethylenimine (AT‐PEI) copolymers with various contents from 2.5% to 10%. The synthesized AT‐PEI copolymers can self‐assemble into nanoparticles with the diameter of ≈50 nm and display excellent electroactivity due to AT conjugation. The copolymers are then homogeneously distributed into 30% Pluronic F127 solution by virtue of the thermosensitivity of F127, denoted as F/AT‐PEI composites. Macroscopic photographs of latticed scaffolds elucidate their excellent printability of F/AT‐PEI hydrogels for the 3D‐printing technique. The conductivities of the printed F/AT‐PEI scaffolds are all higher than 2.0 × 10⁻³ S cm⁻¹, which are significantly improved compared with that of F127 scaffold with only 0.94 × 10⁻³ S cm⁻¹. Thus, the F/AT‐PEI scaffolds can be considered as candidates for application in electrical stimulation of tissue regeneration such as repair of muscle and cardiac nerve tissue.

     

Biodegradable Multiblock Copolymers Based on Oligodepsipeptides with Shape‐Memory Properties

Thermoplastic phase‐segregated multiblock copolymers with polydepsipeptides and PCL segments were prepared via coupling of diol and PCL‐diol using an aliphatic diisocyanate. The obtained multiblock copolymers showed good elastic properties and a shape memory. Almost complete fixation of the mechanical deformation, resulting in quantitative recovery of the permanent shape with a switching temperature around body temperature, was observed. In hydrolytic degradation experiments, a quick decrease of the molecular weight without induction period was observed, and the material changed from elastic to brittle in 21 d. These materials promise a high potential for biomedical applications such as smart implants or medical devices.

     

3D Printing of Silk Protein Structures by Aqueous Solvent‐Directed Molecular Assembly

Hierarchical molecular assembly is a fundamental strategy for manufacturing protein structures in nature. However, to translate this natural strategy into advanced digital manufacturing like three‐dimensional (3D) printing remains a technical challenge. This work presents a 3D printing technique with silk fibroin to address this challenge, by rationally designing an aqueous salt bath capable of directing the hierarchical assembly of the protein molecules. This technique, conducted under aqueous and ambient conditions, results in 3D proteinaceous architectures characterized by intrinsic biocompatibility/biodegradability and robust mechanical features. The versatility of this method is shown in a diversity of 3D shapes and a range of functional components integrated into the 3D prints. The manufacturing capability is exemplified by the single‐step construction of perfusable microfluidic chips which eliminates the use of supporting or sacrificial materials. The 3D shaping capability of the protein material can benefit a multitude of biomedical devices, from drug delivery to surgical implants to tissue scaffolds. This work also provides insights into the recapitulation of solvent‐directed hierarchical molecular assembly for artificial manufacturing.     

Low‐Voltage All‐Polymer Field‐Effect Transistor Fabricated Using an Inkjet Printing Technique

Summary: An all‐polymer field‐effect transistor (FET) fabricated using an inkjet printing technique is presented in this paper. Poly(3,4‐ethylenedioxythiophene) works as the source/drain/gate electrode material because of its good conductivity. Polypyrrole acts as the semiconducting layer. Poly(vinyl pyrrolidone) K60, an insulating polymer with a dielectric constant of 60, operates as the dielectric layer. All the polymers are diluted with deionized water, and can be printed with a piezoelectric inkjet printing system. The device functions at a depletion mode with low operation voltage. It has a field‐effect mobility of 0.1 cm² · V⁻¹ · s⁻¹, an on/off ratio of 2.9 × 10³, and a subthreshold slope of 2.81 V · decade⁻¹.

Schematic of the all‐polymer FET synthesized here.