Anisotropic Shape-Memory Alginate Scaffolds Functionalized with Either Type I or Type II Collagen for Cartilage Tissue Engineering. Almeida Henrique V,Sathy Binulal N,Dudurych Ivan,Buckley Conor T,O'Brien Fergal J,Kelly Daniel J Tissue engineering. Part A Regenerating articular cartilage and fibrocartilaginous tissue such as the meniscus is still a challenge in orthopedic medicine. While a range of different scaffolds have been developed for joint repair, none have facilitated the development of a tissue that mimics the complexity of soft tissues such as articular cartilage. Furthermore, many of these scaffolds are not designed to function in mechanically challenging joint environments. The overall goal of this study was to develop a porous, biomimetic, shape-memory alginate scaffold for directing cartilage regeneration. To this end, a scaffold was designed with architectural cues to guide cellular and neo-tissue alignment, which was additionally functionalized with a range of extracellular matrix cues to direct stem cell differentiation toward the chondrogenic lineage. Shape-memory properties were introduced by covalent cross-linking alginate using carbodiimide chemistry, while the architecture of the scaffold was modified using a directional freezing technique. Introducing such an aligned pore structure was found to improve the mechanical properties of the scaffold, and promoted higher levels of sulfated glycosaminoglycans (sGAG) and collagen deposition compared to an isotropic (nonaligned) pore geometry when seeded with adult human stem cells. Functionalization with collagen improved stem cell recruitment into the scaffold and facilitated more homogenous cartilage tissue deposition throughout the construct. Incorporating type II collagen into the scaffolds led to greater cell proliferation, higher sGAG and collagen accumulation, and the development of a stiffer tissue compared to scaffolds functionalized with type I collagen. The results of this study demonstrate how both scaffold architecture and composition can be tailored in a shape-memory alginate scaffold to direct stem cell differentiation and support the development of complex cartilaginous tissues. 10.1089/ten.TEA.2016.0055
    The use of a shape-memory poly(epsilon-caprolactone)dimethacrylate network as a tissue engineering scaffold. Neuss Sabine,Blomenkamp Iris,Stainforth Rebekah,Boltersdorf Dagmar,Jansen Marc,Butz Nick,Perez-Bouza Alberto,Knüchel Ruth Biomaterials Shape-memory polymers produced from many natural or synthetic raw polymers are able to undergo a shape transformation after exposure to a specific external stimulus. This feature enables their use in minimal-invasive surgery with a small, compact starting material switching over to a more voluminous structure in the body. The use of biomaterials in modern medicine calls for compatibility tests with cell types, encountering the biomaterial during a short-term or long-term in vivo application. We analysed the cell behaviour of L929 mouse fibroblasts, human mesenchymal stem cells, human mesothelial cells and rat mesothelial cells on a biodegradable shape-memory polymer network to assess its suitability for medical applications. Further, we investigated the differentiation capacity of mesenchymal stem cells into osteoblasts and adipocytes on the polymer and we analysed the influence of the shape-memory effect on adherent cells. The polymer was cytocompatible for all tested cell types, supporting cell viability and proliferation. The differentiation capacity of mesenchymal stem cells was supported by the polymer and shape-memory effect activation did not affect the majority of adherent cells. 10.1016/j.biomaterials.2008.12.027
    Shape-memory collagen scaffold for enhanced cartilage regeneration: native collagen versus denatured collagen. Jiang L-B,Su D-H,Liu P,Ma Y-Q,Shao Z-Z,Dong J Osteoarthritis and cartilage OBJECTIVE:Nowadays, it is still questionable whether denatured collagen (DCol) can replace the native collagen (Col) as a bioactive protein in cartilage engineering. We sought to study the advantages of Col with a triple-helical structure in the collagen-based composite materials for cartilage engineering. METHODS:We presented new three-dimensional (3D) Col and DCol scaffolds with shape memory properties. The effects of Col and DCol scaffolds on rabbit chondrocytes' proliferation, adhesion, differentiation and interaction with matrix were investigated. Tissue compatibility was performed in a subcutaneous Sprague Dawley (SD) rat model. The repair ability of different scaffolds with chondrocytes for full-thickness articular cartilage defects in knee joints of New Zealand white rabbits were investigated. RESULTS:The results indicated that the Col scaffolds (with concentration 1.6wt% and 0.8wt%, respectively) promoted the proliferation, adhesion and redifferentiation of chondrocytes, as well as chondrocyte-matrix interaction, to a greater degree than the DCol scaffolds. In the animal experiment, the Col scaffolds filled in the defect hole significantly maintained chondrocytes function, promoted cartilage and subchondral bone regeneration, compared with the DCol scaffolds, and the scaffolds loaded with chondrocytes were better than the cell-free scaffolds, especially in the case of the Col scaffolds (1.6 wt%). CONCLUSIONS:Taken together, these insights suggest that the better proliferation, adhesion and redifferentiation of chondrocytes in Col scaffolds with the triple-helical structure may contribute to the greater cartilage repair ability. Col scaffolds may be more appropriate for repairing cartilage defects than DCol scaffolds, and DCol cannot as an alternative when using collagen-based materials for cartilage engineering applications. 10.1016/j.joca.2018.06.004
    Shape Memory Silk Protein Sponges for Minimally Invasive Tissue Regeneration. Brown Joseph E,Moreau Jodie E,Berman Alison M,McSherry Heather J,Coburn Jeannine M,Schmidt Daniel F,Kaplan David L Advanced healthcare materials Porous silk protein scaffolds are designed to display shape memory characteristics and volumetric recovery following compression. Two strategies are utilized to realize shape recovery: addition of hygroscopic plasticizers like glycerol, and tyrosine modifications with hydrophilic sulfonic acid chemistries. Silk sponges are evaluated for recovery following 80% compressive strain, total porosity, pore size distribution, secondary structure development, in vivo volume retention, cell infiltration, and inflammatory responses. Glycerol-modified sponges recover up to 98.3% of their original dimensions following compression, while sulfonic acid/glycerol modified sponges swell in water up to 71 times their compressed volume, well in excess of their original size. Longer silk extraction times (lower silk molecular weights) and higher glycerol concentrations yielded greater flexibility and shape fidelity, with no loss in modulus following compression. Sponges are over 95% porous, with secondary structure analysis indicating glycerol-induced β-sheet physical crosslinking. Tyrosine modifications with sulfonic acid interfere with β-sheet formation. Glycerol-modified sponges exhibit improved rates of cellular infiltration at subcutaneous implant sites with minimal immune response in mice. They also degrade more rapidly than unmodified sponges, a result posited to be cell-mediated. Overall, this work suggests that silk sponges may be useful for minimally invasive deployment in soft tissue augmentation procedures. 10.1002/adhm.201600762
    Strong electroactive biodegradable shape memory polymer networks based on star-shaped polylactide and aniline trimer for bone tissue engineering. Xie Meihua,Wang Ling,Ge Juan,Guo Baolin,Ma Peter X ACS applied materials & interfaces Preparation of functional shape memory polymer (SMP) for tissue engineering remains a challenge. Here the synthesis of strong electroactive shape memory polymer (ESMP) networks based on star-shaped polylactide (PLA) and aniline trimer (AT) is reported. Six-armed PLAs with various chain lengths were chemically cross-linked to synthesize SMP. After addition of an electroactive AT segment into the SMP, ESMP was obtained. The polymers were characterized by (1)H NMR, GPC, FT-IR, CV, DSC, DMA, tensile test, and degradation test. The SMP and ESMP exhibited strong mechanical properties (modulus higher than GPa) and excellent shape memory performance: short recovery time (several seconds), high recovery ratio (over 94%), and high fixity ratio (almost 100%). Moreover, cyclic voltammetry test confirmed the electroactivity of the ESMP. The ESMP significantly enhanced the proliferation of C2C12 cells compared to SMP and linear PLA (control). In addition, the ESMP greatly improved the osteogenic differentiation of C2C12 myoblast cells compared to PH10 and PLA in terms of ALP enzyme activity, immunofluorescence staining, and relative gene expression by quantitative real-time polymerase chain reaction (qRT-PCR). These intelligent SMPs and electroactive SMP with strong mechanical properties, tunable degradability, good electroactivity, biocompatibility, and enhanced osteogenic differentiation of C2C12 cells show great potential for bone regeneration. 10.1021/acsami.5b00191
    Elastic poly(ε-caprolactone)-polydimethylsiloxane copolymer fibers with shape memory effect for bone tissue engineering. Kai Dan,Prabhakaran Molamma P,Chan Benjamin Qi Yu,Liow Sing Shy,Ramakrishna Seeram,Xu Fujian,Loh Xian Jun Biomedical materials (Bristol, England) A porous shape memory scaffold with biomimetic architecture is highly promising for bone tissue engineering applications. In this study, a series of new shape memory polyurethanes consisting of organic poly(ε-caprolactone) (PCL) segments and inorganic polydimethylsiloxane (PDMS) segments in different ratios (9 : 1, 8 : 2 and 7 : 3) was synthesised. These PCL-PDMS copolymers were further engineered into porous fibrous scaffolds by electrospinning. With different ratios of PCL: PDMS, the fibers showed various fiber diameters, thermal behaviour and mechanical properties. Even after being processed into fibrous structures, these PCL-PDMS copolymers maintained their shape memory properties, and all the fibers exhibited excellent shape recovery ratios of  >90% and shape fixity ratios of  >92% after 7 thermo-mechanical cycles. Biological assay results corroborated that the fibrous PCL-PDMS scaffolds were biocompatible by promoting osteoblast proliferation, functionally enhanced biomineralization-relevant alkaline phosphatase expression and mineral deposition. Our study demonstrated that the PCL-PDMS fibers with excellent shape memory properties are promising substrates as bioengineered grafts for bone regeneration. 10.1088/1748-6041/11/1/015007
    Fabrication and characterization of shape memory polyurethane porous scaffold for bone tissue engineering. Yu Juhong,Xia Hong,Teramoto Akira,Ni Qing-Qing Journal of biomedical materials research. Part A Tissue engineering is a promising alternative for treating bone defects. However, improvements in scaffold design are needed to precisely match the irregular boundaries of bone defects as well as facilitate clinical application. In this study, a shape memory polyurethane scaffold was fabricated using a salt-leaching-phase inverse technique. Different sizes of salts were used to obtain scaffolds with different pore sizes. Scanning electron microscope, X-ray photoelectron spectroscopy, and X-ray micro-computed tomography analysis confirmed that three-dimensional porous polyurethane scaffolds were obtained. The mechanical properties and biocompatibility of the scaffolds were analyzed by compression testing, thermal mechanical analysis, and cell experiments with osteosarcoma MG-63 cells. The results revealed that the scaffolds had good mechanical properties and shape memory properties for bone repair, and also had the ability to promote cell proliferation. Thus, this scaffold design has good prospects for application to bone tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1132-1137, 2017. 10.1002/jbm.a.36009
    Fabrication of a Bioactive, PCL-based "Self-fitting" Shape Memory Polymer Scaffold. Nail Lindsay N,Zhang Dawei,Reinhard Jessica L,Grunlan Melissa A Journal of visualized experiments : JoVE Tissue engineering has been explored as an alternative strategy for the treatment of critical-sized cranio-maxillofacial (CMF) bone defects. Essential to the success of this approach is a scaffold that is able to conformally fit within an irregular defect while also having the requisite biodegradability, pore interconnectivity and bioactivity. By nature of their shape recovery and fixity properties, shape memory polymer (SMP) scaffolds could achieve defect "self-fitting." In this way, following exposure to warm saline (~60 ºC), the SMP scaffold would become malleable, permitting it to be hand-pressed into an irregular defect. Subsequent cooling (~37 ºC) would return the scaffold to its relatively rigid state within the defect. To meet these requirements, this protocol describes the preparation of SMP scaffolds prepared via the photochemical cure of biodegradable polycaprolactone diacrylate (PCL-DA) using a solvent-casting particulate-leaching (SCPL) method. A fused salt template is utilized to achieve pore interconnectivity. To realize bioactivity, a polydopamine coating is applied to the surface of the scaffold pore walls. Characterization of self-fitting and shape memory behaviors, pore interconnectivity and in vitro bioactivity are also described. 10.3791/52981
    Self-fitting shape memory polymer foam inducing bone regeneration: A rabbit femoral defect study. Xie Ruiqi,Hu Jinlian,Hoffmann Oskar,Zhang Yuanchi,Ng Frankie,Qin Tingwu,Guo Xia Biochimica et biophysica acta. General subjects Although tissue engineering has been attracted greatly for healing of critical-sized bone defects, great efforts for improvement are still being made in scaffold design. In particular, bone regeneration would be enhanced if a scaffold precisely matches the contour of bone defects, especially if it could be implanted into the human body conveniently and safely. In this study, polyurethane/hydroxyapatite-based shape memory polymer (SMP) foam was fabricated as a scaffold substrate to facilitate bone regeneration. The minimally invasive delivery and the self-fitting behavior of the SMP foam were systematically evaluated to demonstrate its feasibility in the treatment of bone defects in vivo. Results showed that the SMP foam could be conveniently implanted into bone defects with a compact shape. Subsequently, it self-matched the boundary of bone defects upon shape-recovery activation in vivo. Micro-computed tomography determined that bone ingrowth initiated at the periphery of the SMP foam with a constant decrease towards the inside. Successful vascularization and bone remodeling were also demonstrated by histological analysis. Thus, our results indicate that the SMP foam demonstrated great potential for bone regeneration. 10.1016/j.bbagen.2018.01.013
    Four-Dimensional Printing Hierarchy Scaffolds with Highly Biocompatible Smart Polymers for Tissue Engineering Applications. Miao Shida,Zhu Wei,Castro Nathan J,Leng Jinsong,Zhang Lijie Grace Tissue engineering. Part C, Methods The objective of this study was to four-dimensional (4D) print novel biomimetic gradient tissue scaffolds with highly biocompatible naturally derived smart polymers. The term "4D printing" refers to the inherent smart shape transformation of fabricated constructs when implanted minimally invasively for seamless and dynamic integration. For this purpose, a series of novel shape memory polymers with excellent biocompatibility and tunable shape changing effects were synthesized and cured in the presence of three-dimensional printed sacrificial molds, which were subsequently dissolved to create controllable and graded porosity within the scaffold. Surface morphology, thermal, mechanical, and biocompatible properties as well as shape memory effects of the synthesized smart polymers and resultant porous scaffolds were characterized. Fourier transform infrared spectroscopy and gel content analysis confirmed the formation of chemical crosslinking by reacting polycaprolactone triol and castor oil with multi-isocyanate groups. Differential scanning calorimetry revealed an adjustable glass transition temperature in a range from -8°C to 35°C. Uniaxial compression testing indicated that the obtained polymers, possessing a highly crosslinked interpenetrating polymeric networks, have similar compressive modulus to polycaprolactone. Shape memory tests revealed that the smart polymers display finely tunable recovery speed and exhibit greater than 92% shape fixing at -18°C or 0°C and full shape recovery at physiological temperature. Scanning electron microscopy analysis of fabricated scaffolds revealed a graded microporous structure, which mimics the nonuniform distribution of porosity found within natural tissues. With polycaprolactone serving as a control, human bone marrow-derived mesenchymal stem cell adhesion, proliferation, and differentiation greatly increased on our novel smart polymers. The current work will significantly advance the future design and development of novel and functional biomedical scaffolds with advanced 4D printing technology and highly biocompatible smart biomaterials. 10.1089/ten.tec.2015.0542
    Towards 4D printed scaffolds for tissue engineering: exploiting 3D shape memory polymers to deliver time-controlled stimulus on cultured cells. Hendrikson Wilhelmus J,Rouwkema Jeroen,Clementi Federico,van Blitterswijk Clemens A,Farè Silvia,Moroni Lorenzo Biofabrication Tissue engineering needs innovative solutions to better fit the requirements of a minimally invasive approach, providing at the same time instructive cues to cells. The use of shape memory polyurethane has been investigated by producing 4D scaffolds via additive manufacturing technology. Scaffolds with two different pore network configurations (0/90° and 0/45°) were characterized by dynamic-mechanical analysis. The thermo-mechanical analysis showed a T at about 32 °C (T = T ), indicating no influence of the fabrication process on the transition temperature. In addition, shape recovery tests showed a good recovery of the permanent shape for both scaffold configurations. When cells were seeded onto the scaffolds in the temporary shape and the permanent shape was recovered, cells were significantly more elongated after shape recovery. Thus, the mechanical stimulus imparted by shape recovery is able to influence the shape of cells and nuclei. The obtained results indicate that a single mechanical stimulus is sufficient to initiate changes in the morphology of adherent cells. 10.1088/1758-5090/aa8114
    Dynamic topographical control of mesenchymal stem cells by culture on responsive poly(ε-caprolactone) surfaces. Le Duy M,Kulangara Karina,Adler Andrew F,Leong Kam W,Ashby Valerie Sheares Advanced materials (Deerfield Beach, Fla.) 10.1002/adma.201100821
    Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. Liu Xian,Zhao Kun,Gong Tao,Song Jian,Bao Chongyun,Luo En,Weng Jie,Zhou Shaobing Biomacromolecules Implantation of a porous scaffold with a large volume into the body in a convenient and safe manner is still a challenging task in the repair of bone defects. In this study, we present a porous smart nanocomposite scaffold with a combination of shape memory function and controlled delivery of growth factors. The shape memory function enables the scaffold with a large volume to be deformed into its temporal architecture with a small volume using hot-compression and can subsequently recover its original shape upon exposure to body temperature after it is implanted in the body. The scaffold consists of chemically cross-linked poly(ε-caprolactone) (c-PCL) and hydroxyapatite nanoparticles. The highly interconnected pores of the scaffold were obtained using the sugar leaching method. The shape memory porous scaffold loaded with bone morphogenetic protein-2 (BMP-2) was also fabricated by coating the calcium alginate layer and BMP-2 on the surface of the pore wall. Under both in vitro and in vivo environmental conditions, the porous scaffold displays good shape memory recovery from the compressed shape with deformed pores of 33 μm in diameter to recover its porous shape with original pores of 160 μm in diameter. In vitro cytotoxicity based on the MTT test revealed that the scaffold exhibited good cytocompatibility. The in vivo micro-CT and histomorphometry results demonstrated that the porous scaffold could promote new bone generation in the rabbit mandibular bone defect. Thus, our results indicated that this shape memory porous scaffold demonstrated great potential for application in bone regenerative medicine. 10.1021/bm401911p
    Electrospun biomimetic fibrous scaffold from shape memory polymer of PDLLA-co-TMC for bone tissue engineering. Bao Min,Lou Xiangxin,Zhou Qihui,Dong Wen,Yuan Huihua,Zhang Yanzhong ACS applied materials & interfaces Multifunctional fibrous scaffolds, which combine the capabilities of biomimicry to the native tissue architecture and shape memory effect (SME), are highly promising for the realization of functional tissue-engineered products with minimally invasive surgical implantation possibility. In this study, fibrous scaffolds of biodegradable poly(d,l-lactide-co-trimethylene carbonate) (denoted as PDLLA-co-TMC, or PLMC) with shape memory properties were fabricated by electrospinning. Morphology, thermal and mechanical properties as well as SME of the resultant fibrous structure were characterized using different techniques. And rat calvarial osteoblasts were cultured on the fibrous PLMC scaffolds to assess their suitability for bone tissue engineering. It is found that by varying the monomer ratio of DLLA:TMC from 5:5 to 9:1, fineness of the resultant PLMC fibers was attenuated from ca. 1500 down to 680 nm. This also allowed for readily modulating the glass transition temperature Tg (i.e., the switching temperature for actuating shape recovery) of the fibrous PLMC to fall between 19.2 and 44.2 °C, a temperature range relevant for biomedical applications in the human body. The PLMC fibers exhibited excellent shape memory properties with shape recovery ratios of Rr > 94% and shape fixity ratios of Rf > 98%, and macroscopically demonstrated a fast shape recovery (∼10 s at 39 °C) in the pre-deformed configurations. Biological assay results corroborated that the fibrous PLMC scaffolds were cytocompatible by supporting osteoblast adhesion and proliferation, and functionally promoted biomineralization-relevant alkaline phosphatase expression and mineral deposition. We envision the wide applicability of using the SME-capable biomimetic scaffolds for achieving enhanced efficacy in repairing various bone defects (e.g., as implants for healing bone screw holes or as barrier membranes for guided bone regeneration). 10.1021/am405101k
    A bioactive "self-fitting" shape memory polymer scaffold with potential to treat cranio-maxillo facial bone defects. Zhang Dawei,George Olivia J,Petersen Keri M,Jimenez-Vergara Andrea C,Hahn Mariah S,Grunlan Melissa A Acta biomaterialia While tissue engineering is a promising alternative for treating critical-sized cranio-maxillofacial bone defects, improvements in scaffold design are needed. In particular, scaffolds that can precisely match the irregular boundaries of bone defects as well as exhibit an interconnected pore morphology and bioactivity would enhance tissue regeneration. In this study, a shape memory polymer (SMP) scaffold was developed exhibiting an open porous structure and the capacity to conformally "self-fit" into irregular defects. The SMP scaffold was prepared via photocrosslinking of poly(ε-caprolactone) (PCL) diacrylate using a SCPL method, which included a fused salt template. A bioactive polydopamine coating was applied to coat the pore walls. Following exposure to warm saline at T>T(trans) (T(trans)=T(m) of PCL), the scaffold became malleable and could be pressed into an irregular model defect. Cooling caused the scaffold to lock in its temporary shape within the defect. The polydopamine coating did not alter the physical properties of the scaffold. However, polydopamine-coated scaffolds exhibited superior bioactivity (i.e. formation of hydroxyapatite in vitro), osteoblast adhesion, proliferation, osteogenic gene expression and extracellular matrix deposition. 10.1016/j.actbio.2014.07.020
    Erratum: Borderud SP, Li Y, Burkhalter JE, Sheffer CE and Ostroff JS. Electronic cigarette use among patients with cancer: Characteristics of electronic cigarette users and their smoking cessation outcomes. Cancer. doi: 10.1002/ cncr.28811. Cancer The authors discovered some errors regarding reference group labels in Table 2. The corrected table is attached. The authors regret these errors. 10.1002/cncr.29118
    Self-deploying shape memory polymer scaffolds for grafting and stabilizing complex bone defects: A mouse femoral segmental defect study. Baker Richard M,Tseng Ling-Fang,Iannolo Maria T,Oest Megan E,Henderson James H Biomaterials Treatment of complex bone defects places a significant burden on the US health care system. Current strategies for treatment include grafting and stabilization using internal metal plates/screws, intramedullary rods, or external fixators. Here, we introduce the use of shape memory polymer (SMP) materials for grafting and adjunct stabilization of segmental defects. Self-deploying SMP grafts and SMP sleeves capable of expanding and contracting, respectively, under intraoperative conditions were developed and evaluated in a mouse segmental defect model in vivo. Integration between grafts/sleeves and native bone was assessed using x-ray radiography, microcomputed tomography, and torsional mechanical testing. We found that SMP grafts were able to integrate with the native bone after 12 weeks, maintain defect stability, and provide torsional mechanical properties comparable to an allograft alone treatment; however no gross de novo bone formation was observed. SMP sleeves did not inhibit bony bridging at the margins, and limbs treated with a sleeve/allograft combination had torsional mechanical properties comparable to limbs treated with an allograft alone. In vitro torsional and bending tests suggest sleeves may provide additional torsional stability to defects. Incorporation of shape memory into synthetic bone graft substitutes and adjunct stabilization devices is anticipated to enhance functionality of synthetic materials employed in both applications. 10.1016/j.biomaterials.2015.10.064
    Shape memory polymer network with thermally distinct elasticity and plasticity. Zhao Qian,Zou Weike,Luo Yingwu,Xie Tao Science advances Stimuli-responsive materials with sophisticated yet controllable shape-changing behaviors are highly desirable for real-world device applications. Among various shape-changing materials, the elastic nature of shape memory polymers allows fixation of temporary shapes that can recover on demand, whereas polymers with exchangeable bonds can undergo permanent shape change via plasticity. We integrate the elasticity and plasticity into a single polymer network. Rational molecular design allows these two opposite behaviors to be realized at different temperature ranges without any overlap. By exploring the cumulative nature of the plasticity, we demonstrate easy manipulation of highly complex shapes that is otherwise extremely challenging. The dynamic shape-changing behavior paves a new way for fabricating geometrically complex multifunctional devices. 10.1126/sciadv.1501297
    Spatiotemporal control of cardiac anisotropy using dynamic nanotopographic cues. Mengsteab Paulos Y,Uto Koichiro,Smith Alec S T,Frankel Sam,Fisher Elliot,Nawas Zeid,Macadangdang Jesse,Ebara Mitsuhiro,Kim Deok-Ho Biomaterials Coordinated extracellular matrix spatiotemporal reorganization helps regulate cellular differentiation, maturation, and function in vivo, and is therefore vital for the correct formation, maintenance, and healing of complex anatomic structures. In order to evaluate the potential for cultured cells to respond to dynamic changes in their in vitro microenvironment, as they do in vivo, the collective behavior of primary cardiac muscle cells cultured on nanofabricated substrates with controllable anisotropic topographies was studied. A thermally induced shape memory polymer (SMP) was employed to assess the effects of a 90° transition in substrate pattern orientation on the contractile direction and structural organization of cardiomyocyte sheets. Cardiomyocyte sheets cultured on SMPs exhibited anisotropic contractions before shape transition. 48 h after heat-induced shape transition, the direction of cardiomyocyte contraction reoriented significantly and exhibited a bimodal distribution, with peaks at ∼45 and -45° (P < 0.001). Immunocytochemical analysis highlighted the significant structural changes that the cells underwent in response to the shift in underlying topography. The presented results demonstrate that initial anisotropic nanotopographic cues do not permanently determine the organizational fate or contractile properties of cardiomyocytes in culture. Given the importance of surface cues in regulating primary and stem cell development, investigation of such tunable nanotopographies may have important implications for advancing cellular maturation and performance in vitro, as well as improving our understanding of cellular development in response to dynamic biophysical cues. 10.1016/j.biomaterials.2016.01.062
    Recent Advances in Shape Memory Soft Materials for Biomedical Applications. Chan Benjamin Qi Yu,Low Zhi Wei Kenny,Heng Sylvester Jun Wen,Chan Siew Yin,Owh Cally,Loh Xian Jun ACS applied materials & interfaces 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 three classes of SMPs: shape memory polymers and blends, shape memory polymer composites, 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. 10.1021/acsami.6b01295
    Osteogenic Capacity of Human Adipose-Derived Stem Cells is Preserved Following Triggering of Shape Memory Scaffolds. Tseng Ling-Fang,Wang Jing,Baker Richard M,Wang Guirong,Mather Patrick T,Henderson James H Tissue engineering. Part A Recent advances in shape memory polymers have enabled the study of programmable, shape-changing, cytocompatible tissue engineering scaffolds. For treatment of bone defects, scaffolds with shape memory functionality have been studied for their potential for minimally invasive delivery, conformal fitting to defect margins, and defect stabilization. However, the extent to which the osteogenic differentiation capacity of stem cells resident in shape memory scaffolds is preserved following programmed shape change has not yet been determined. As a result, the feasibility of shape memory polymer scaffolds being employed in stem cell-based treatment strategies remains unclear. To test the hypothesis that stem cell osteogenic differentiation can be preserved during and following triggering of programmed architectural changes in shape memory polymer scaffolds, human adipose-derived stem cells were seeded in shape memory polymer foam scaffolds or in shape memory polymer fibrous scaffolds programmed to expand or contract, respectively, when warmed to body temperature. Osteogenic differentiation in shape-changing and control scaffolds was compared using mineral deposition, protein production, and gene expression assays. For both shape-changing and control scaffolds, qualitatively and quantitatively comparable amounts of mineral deposition were observed; comparable levels of alkaline phosphatase activity were measured; and no significant differences in the expression of genetic markers of osteogenesis were detected. These findings support the feasibility of employing shape memory in scaffolds for stem cell-based therapies for bone repair. 10.1089/ten.TEA.2016.0095
    Shape-memory surfaces for cell mechanobiology. Ebara Mitsuhiro Science and technology of advanced materials Shape-memory polymers (SMPs) are a new class of smart materials, which have the capability to change from a temporary shape 'A' to a memorized permanent shape 'B' upon application of an external stimulus. In recent years, SMPs have attracted much attention from basic and fundamental research to industrial and practical applications due to the cheap and efficient alternative to well-known metallic shape-memory alloys. Since the shape-memory effect in SMPs is not related to a specific material property of single polymers, the control of nanoarchitecture of polymer networks is particularly important for the smart functions of SMPs. Such nanoarchitectonic approaches have enabled us to further create shape-memory surfaces (SMSs) with tunable surface topography at nano scale. The present review aims to bring together the exciting design of SMSs and the ever-expanding range of their uses as tools to control cell functions. The goal for these endeavors is to mimic the surrounding mechanical cues of extracellular environments which have been considered as critical parameters in cell fate determination. The untapped potential of SMSs makes them one of the most exciting interfaces of materials science and cell mechanobiology. 10.1088/1468-6996/16/1/014804
    Three-Dimensional Printing of Shape Memory Composites with Epoxy-Acrylate Hybrid Photopolymer. Yu Ran,Yang Xin,Zhang Ying,Zhao Xiaojuan,Wu Xiao,Zhao Tingting,Zhao Yulei,Huang Wei ACS applied materials & interfaces Four-dimensional printing, a new process to fabricate active materials through three-dimensional (3D) printing developed by MIT's Self-Assembly Lab in 2014, has attracted more and more research and development interests recently. In this paper, a type of epoxy-acrylate hybrid photopolymer was synthesized and applied to fabricate shape memory polymers through a stereolithography 3D printing technique. The glass-to-rubbery modulus ratio of the printed sample determined by dynamic mechanical analysis is as high as 600, indicating that it may possess good shape memory properties. Fold-deploy and shape memory cycle tests were applied to evaluate its shape memory performance. The shape fixity ratio and the shape recovery ratio in ten cycles of fold-deploy tests are about 99 and 100%, respectively. The shape recovery process takes less than 20 s, indicating its rapid shape recovery rate. The shape fixity ratio and shape recovery ratio during 18 consecutive shape memory cycles are 97.44 ± 0.08 and 100.02 ± 0.05%, respectively, showing that the printed sample has high shape fixity ratio, shape recovery ratio, and excellent cycling stability. A tensile test at 62 °C demonstrates that the printed samples combine a relatively large break strain of 38% with a large recovery stress of 4.7 MPa. Besides, mechanical and thermal stability tests prove that the printed sample has good thermal stability and mechanical properties, including high strength and good toughness. 10.1021/acsami.6b13531
    The effect of hydroxyapatite nanoparticles on mechanical behavior and biological performance of porous shape memory polyurethane scaffolds. Yu Juhong,Xia Hong,Teramoto Akira,Ni Qing-Qing Journal of biomedical materials research. Part A The scaffold which provides space for cell growth, proliferation, and differentiation, is a key factor in bone tissue engineering. However, improvements in scaffold design are needed to precisely match the irregular boundaries of bone defects as well as facilitate clinical application. In this study, controllable three-dimensional (3D) porous shape memory polyurethane/nano-hydroxyapatite (SMPU/nHAP) composite scaffold was successfully fabricated for bone defect reparation. Detailed studies were performed to evaluate its structure, apparent density, porosity, and mechanical properties, emphasizing the contribution of nHAP particles on shape recovery behaviors and biological performance in vitro. The effect of nHAP particles in porous SMPU/nHAP composite scaffold was found to enhance the compression resistance by 37%, shorten the compression recovery time by 41%, reduce the tensile resistance by 78%, reach the shape recovery ratio of 99%, and promote the cell proliferation by 13% after 7 days of culture. These results revealed that the 3D structure and aperture of as-prepared scaffold were controllable. And in minimally invasive surgery and bone repair surgery, this porous composite scaffold could significantly reduce the operative time and promote the bone cell growth. Therefore, this porous SMPU/nHAP composite scaffold design has potential applications for the bone tissue engineering. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 244-254, 2018. 10.1002/jbm.a.36214
    Biodegradable Shape Memory Polymers in Medicine. Peterson Gregory I,Dobrynin Andrey V,Becker Matthew L Advanced healthcare materials Shape memory materials have emerged as an important class of materials in medicine due to their ability to change shape in response to a specific stimulus, enabling the simplification of medical procedures, use of minimally invasive techniques, and access to new treatment modalities. Shape memory polymers, in particular, are well suited for such applications given their excellent shape memory performance, tunable materials properties, minimal toxicity, and potential for biodegradation and resorption. This review provides an overview of biodegradable shape memory polymers that have been used in medical applications. The majority of biodegradable shape memory polymers are based on thermally responsive polyesters or polymers that contain hydrolyzable ester linkages. These materials have been targeted for use in applications pertaining to embolization, drug delivery, stents, tissue engineering, and wound closure. The development of biodegradable shape memory polymers with unique properties or responsiveness to novel stimuli has the potential to facilitate the optimization and development of new medical applications. 10.1002/adhm.201700694
    Three-dimensional piezoelectric fibrous scaffolds selectively promote mesenchymal stem cell differentiation. Damaraju Sita M,Shen Yueyang,Elele Ezinwa,Khusid Boris,Eshghinejad Ahmad,Li Jiangyu,Jaffe Michael,Arinzeh Treena Livingston Biomaterials The discovery of electric fields in biological tissues has led to efforts in developing technologies utilizing electrical stimulation for therapeutic applications. Native tissues, such as cartilage and bone, exhibit piezoelectric behavior, wherein electrical activity can be generated due to mechanical deformation. Yet, the use of piezoelectric materials have largely been unexplored as a potential strategy in tissue engineering, wherein a piezoelectric biomaterial acts as a scaffold to promote cell behavior and the formation of large tissues. Here we show, for the first time, that piezoelectric materials can be fabricated into flexible, three-dimensional fibrous scaffolds and can be used to stimulate human mesenchymal stem cell differentiation and corresponding extracellular matrix/tissue formation in physiological loading conditions. Piezoelectric scaffolds that exhibit low voltage output, or streaming potential, promoted chondrogenic differentiation and piezoelectric scaffolds with a high voltage output promoted osteogenic differentiation. Electromechanical stimulus promoted greater differentiation than mechanical loading alone. Results demonstrate the additive effect of electromechanical stimulus on stem cell differentiation, which is an important design consideration for tissue engineering scaffolds. Piezoelectric, smart materials are attractive as scaffolds for regenerative medicine strategies due to their inherent electrical properties without the need for external power sources for electrical stimulation. 10.1016/j.biomaterials.2017.09.024
    Healability Demonstrates Enhanced Shape-Recovery of Graphene-Oxide-Reinforced Shape-Memory Polymeric Films. Xiang Zilong,Zhang Ling,Yuan Tao,Li Yixuan,Sun Junqi ACS applied materials & interfaces The fabrication of shape-memory polymers or films that can simultaneously heal the mechanical damage and the fatigued shape-memory function remains challenging. In this study, mechanically robust healable shape-memory polymeric films that can heal the mechanical damage and the fatigued shape-memory function in the presence of water are fabricated by layer-by-layer assembly of branched poly(ethylenimine) (bPEI)-graphene oxide (GO) complexes with poly(acrylic acid) (PAA), followed by the release of the (PAA/bPEI-GO)*n films from the underlying substrates. The free-standing (PAA/bPEI-GO)*35 films made of bPEI-GO complexes with a mass ratio of 0.02 between GO nanosheets and bPEI are mechanically robust with a Young's modulus of 19.8 ± 2.1 GPa and a hardness of 0.92 ± 0.15 GPa and exhibit excellent humidity-induced healing and shape-memory functions. Benefiting from the highly efficient healing function, the (PAA/bPEI-GO)*35 films can heal cuts penetrating thorough the entire film and achieve an ∼100% shape-recovery ratio for a long-term shape-memory application. Meanwhile, the shape-memory function of the mechanically damaged (PAA/bPEI-GO)*35 films can be finely restored after being healed in water. The shape-memory functions of the (PAA/bPEI-GO)*35 films and their healing capacity originate from the reversibility of electrostatic and hydrogen-bonding interactions induced by water between PAA and bPEI-GO complexes. 10.1021/acsami.7b14588
    Shape memory polymers and their composites in biomedical applications. Zhao Wei,Liu Liwu,Zhang Fenghua,Leng Jinsong,Liu Yanju Materials science & engineering. C, Materials for biological applications As a kind of intelligent material, shape memory polymer (SMP) can respond to outside stimuli and possesses good properties including shape memory effect, deformability and biological compatibility, etc. SMPs have been introduced for medical applications such as tissue engineering, biological sutures, stents and bladder sensors. Due to the shape memory effect, the medical devices based on SMP can be implanted into body through minimally invasive surgery in contraction or folded state and recovered to their requisite original shapes at target position. In this paper, a review of SMPs utilized in biomedical applications and their actuation methods are listed. Various biomedical applications and potential applications based on the beneficial properties of SMP are also summarized. 10.1016/j.msec.2018.12.054
    Nickel-titanium arched shape-memory alloy connector combined with bone grafting in the treatment of scaphoid nonunion. Zhou Pan-Yu,Jiang Li-Qiang,Xia De-Meng,Wu Jiang-Hong,Ye Yuan,Xu Shuo-Gui European journal of medical research PURPOSE:To summarize the techniques and clinical effectiveness in treating scaphoid nonunion with nickel-titanium (Ni-Ti) arched shape-memory alloy connector in combination with autologous iliac bone grafts. METHODS:This study retrospectively analyzed 18 scaphoid nonunion cases treated with arched connectors with autologous iliac bone grafts. Based on scaphoid nonunion, 2 cases were classified as type II (fibrous union), 4 cases as type III (mild sclerotic union), 6 cases as type IV (moderate resorption and sclerosis), 5 cases as type V (severe bone resorption and sclerosis), and 1 case as type VI (pseudarthrosis formation). At the first 4, 8 and 12 weeks after the surgery, wrist anteroposterior, lateral X-ray were obtained, respectively, to evaluate bone healing. Patients who had not yet reached the standard of healing at 12 weeks after surgery would continue to receive additional appointments for follow-up visits, such as 14 weeks, 16 weeks, 18 weeks after surgery, until their imaging studies had achieved satisfactory bone healing. Clinical effectiveness was evaluated comprehensively, based on bone union time, Mayo wrist score, and visual analog pain score. RESULTS:All 18 patients achieved satisfactory reduction and fixation with a mean union time of 4.2 months. Preoperative Mayo wrist score averaged 57.4 and average final postoperative follow-up was 91.4. On the other hand, mean preoperative VAS score was 6.8, and final postoperative follow-up average was 1.6. Mayo wrist score of the overall treatment effectiveness was excellent (90-100) in 12 cases, good (80-90) in 5 cases, and acceptable (60-80) in 1 case with zero poor (below 60) cases observed. Statistical analysis suggested that a statistically significant improvement in fracture healing, wrist function recovery and visual analog pain after surgery when compared to the scores of the patients before surgery. CONCLUSION:Using Ni-Ti arched shape-memory alloy connector in combination with autologous bone grafting provided a new modality to treat scaphoid nonunions in a less traumatic, convenient to operate and satisfactory manner in treatment outcomes, and thus is worthy of further application. 10.1186/s40001-019-0380-y
    Shape-dependent regulation of differentiation lineages of bone marrow-derived cells under cyclic stretch. Maeda Eijiro,Atsumi Yoshinori,Ishiguro Mai,Nagayama Kazuaki,Matsumoto Takeo Journal of biomechanics Multipotent stem cells are considered as a key material in regenerative medicine, and the understanding of the heterogeneity in the differentiation potentials of bone marrow-derived cells is important in the successful regenerative tissue repair. Therefore, the present study has been performed to investigate how the differentiation of post-harvest, native bone marrow-derived cells is regulated by cyclic stretch in vitro. Bone marrow-derived cells were obtained from mouse femur of both hind limbs and categorized into the following five categories: amebocytes, round cells, spindle cells, stellate cells and others. The cells were seeded on a silicone-made stretch chamber, and subjected to cyclic stretch with an amplitude of 10% at a frequency of 1 Hz for 7 days for cell shape analysis and for 3 days for the analysis of the expression of marker proteins of osteogenic (osteocalcin), vascular smooth muscle (α-smooth muscle actin and smooth muscle myosin heavy chain) and neurogenic (neurofilament) differentiation. When disregarding the differences in the cell shapes, there was an overall trend that the application of 10% cyclic stretch inhibited osteogenic and neurogenic differentiation, but enhanced smooth muscle differentiation. Close examinations revealed that round cells were influenced the most by cyclic stretch (significant up- or down-regulation in all the four marker protein expressions) while amebocytes and spindle cells were only influenced by cyclic stretch for vascular smooth muscle and/or neurogenic differentiation. As far as the authors know, this is the first study reporting the shape-related differences in the fate decision criteria for mechanical strain in bone marrow-derived cells. 10.1016/j.jbiomech.2019.109371
    Four-dimensional bioprinting: Current developments and applications in bone tissue engineering. Wan Zhuqing,Zhang Ping,Liu Yunsong,Lv Longwei,Zhou Yongsheng Acta biomaterialia Four-dimensional (4D) bioprinting, in which the concept of time is integrated with three-dimensional (3D) bioprinting as the fourth dimension, has currently emerged as the next-generation solution of tissue engineering as it presents the possibility of constructing complex, functional structures. 4D bioprinting can be used to fabricate dynamic 3D-patterned biological architectures that will change their shapes under various stimuli by employing stimuli-responsive materials. The functional transformation and maturation of printed cell-laden constructs over time are also regarded as 4D bioprinting, providing unprecedented potential for bone tissue engineering. The shape memory properties of printed structures cater to the need for personalized bone defect repair and the functional maturation procedures promote the osteogenic differentiation of stem cells. In this review, we introduce the application of different stimuli-responsive biomaterials in tissue engineering and a series of 4D bioprinting strategies based on functional transformation of printed structures. Furthermore, we discuss the application of 4D bioprinting in bone tissue engineering, as well as the current challenges and future perspectives. STATEMENTS OF SIGNIFICANCE: In this review, we have demonstrated the 4D bioprinting technologies, which integrate the concept of time within the traditional 3D bioprinting technology as the fourth dimension and facilitate the fabrications of complex, functional biological architectures. These 4D bioprinting structures could go through shape or functional transformation over time via using different stimuli-responsive biomaterials and a series of 4D bioprinting strategies. Moreover, by summarizing potential applications of 4D bioprinting in the field of bone tissue engineering, these emerging technologies could fulfill unaddressed medical requirements. The further discussions about future challenges and perspectives will give us more inspirations about widespread applications of this emerging technology for tissue engineering in biomedical field. 10.1016/j.actbio.2019.10.038
    [F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer. Jouberton Elodie,Schmitt Sébastien,Chautard Emmanuel,Maisonial-Besset Aurélie,Roy Marie,Radosevic-Robin Nina,Chezal Jean-Michel,Miot-Noirault Elisabeth,Bouvet Yann,Cachin Florent EJNMMI research PURPOSE:Pathological complete response to the neoadjuvant therapy (NAT) for triple negative breast cancer (TNBC) is predictive of prolonged patient survival. Methods for early evaluation of NAT efficiency are still needed, in order to rapidly adjust the therapeutic strategy in case of initial non-response. One option for this is molecular imaging of apoptosis induced by chemotherapy. Therefore, we investigated the capacity of [F]ML-10 PET imaging, an apoptosis radiotracer, to detect tumor cell apoptosis and early predict the therapeutic response of human TNBC. RESULTS:Initially, the induction of apoptosis by different therapies was quantified. We confirmed, in vitro, that paclitaxel or epirubicin, the fundamental cytotoxic drugs for breast cancer, induce apoptosis in TNBC cell lines. Exposure of TNBC models MDA-MB-231 and MDA-MB-468 to these drugs induced a significant increase (p < 0.01) of the apoptotic hallmarks: DNA fragmentation, membrane phospholipid scrambling, and PARP activation. Secondarily, apoptotic fraction was compared to the intracellular accumulation of the radiotracer. [F]ML-10 accumulated in the apoptotic cells after 72 h of treatment by paclitaxel in vitro; this accumulation positively correlated with the apoptotic fraction. In vivo, [F]ML-10 was rapidly cleared from the nontarget organs and mainly eliminated by the kidneys. Comparison of the in vivo [F]FDG, [F]FMISO, and [F]ML-10 uptakes revealed that the tumor accumulation of [F]ML-10 was directly related to the tumor hypoxia level. Finally, after the in vivo treatment of TNBC murine xenografts by paclitaxel, apoptosis was well induced, as demonstrated by the cleaved caspase-3 levels; however, no significant increase of [F]ML-10 accumulation in the tumors was observed, either on day 3 or day 6 after the end of the treatment. CONCLUSIONS:These results highlighted that PET imaging using [F]ML-10 allows the visualization of apoptotic cells in TNBC models. Nevertheless, the increase of the chemotherapy-induced apoptotic response when using paclitaxel could not be assessed using this radiotracer in our mouse model. 10.1186/s13550-019-0587-5