Functionalization of endovascular devices with superparamagnetic iron oxide nanoparticles for interventional cardiovascular magnetic resonance imaging.

Presently, cardiovascular interventions such as stent deployment and balloon angioplasty are performed under x-ray guidance. However, x-ray fluoroscopy has poor soft tissue contrast and is limited by imaging in a single plane, resulting in imprecise navigation of endovascular instruments. Moreover, x-ray fluoroscopy exposes patients to ionizing radiation and iodinated contrast agents. Magnetic resonance imaging (MRI) is a safe and enabling modality for cardiovascular interventions. Interventional cardiovascular MR (iCMR) is a promising approach that is in stark contrast with x-ray fluoroscopy, offering high-resolution anatomic and physiologic information and imaging in multiple planes for enhanced navigational accuracy of catheter-based devices, all in an environment free of radiation and its deleterious effects. While iCMR has immense potential, its translation into the clinical arena is hindered by the limited availability of MRI-visible catheters, wire guides, angioplasty balloons, and stents. Herein, we aimed to create application-specific, devices suitable for iCMR, and demonstrate the potential of iCMR by performing cardiovascular catheterization procedures using these devices. Tools, including catheters, wire guides, stents, and angioplasty balloons, for endovascular interventions were functionalized with a polymer coating consisting of poly(lactide-co-glycolide) (PLGA) and superparamagnetic iron oxide (SPIO) nanoparticles, followed by endovascular deployment in the pig. Findings from this study highlight the ability to image and properly navigate SPIO-functionalized devices, enabling interventions such as successful stent deployment under MRI guidance. This study demonstrates proof-of-concept for rapid prototyping of iCMR-specific endovascular interventional devices that can take advantage of the capabilities of iCMR.

DNA Thioaptamer with Homing Specificity to Lymphoma Bone Marrow Involvement.

Selective drug accumulation in the malignant tissue is a prerequisite for effective cancer treatment. However, most drug molecules and their formulated particles are blocked en route to the destiny tissue due to the existence of multiple biological and physical barriers including the tumor microvessel endothelium. Since the endothelial cells on the surface of the microvessel wall can be modulated by inflammatory cytokines and chemokines secreted by the tumor or stromal cells, an effective drug delivery approach is to enhance interaction between the drug particles and the unique spectrum of surface proteins on the tumor endothelium. In this study, we performed in vivo screening for thioaptamers that bind to the bone marrow endothelium with specificity in a murine model of lymphoma with bone marrow involvement (BMI). The R1 thioaptamer was isolated based on its high homing potency to bones with BMI, and 40-60% less efficiency in accumulation to healthy bones. In cell culture, R1 binds to human umbilical vein endothelial cells (HUVEC) with a high affinity ( Kd ≈ 3 nM), and the binding affinity can be further enhanced when cells were treated with a mixture of lymphoma cell and bone marrow cell conditioned media. Cellular uptake of R1 is through clathrin-mediated endocytosis. Conjugating R1 on to the surface of liposomal doxorubicin nanoparticles resulted in 2-3-fold increase in drug accumulation in lymphoma BMI. Taking together, we have successfully identified a thioaptamer that preferentially binds to the endothelium of lymphoma BMI. It can serve as an affinity moiety for targeted delivery of drug particles to the disease organ.

A Liposome Encapsulated Ruthenium Polypyridine Complex as a Theranostic Platform for Triple-Negative Breast Cancer.

Ruthenium coordination complexes have the potential to serve as novel theranostic agents for cancer. However, a major limitation in their clinical implementation is effective tumor accumulation. In this study, we have developed a liposome-based theranostic nanodelivery system for [Ru(phen)2dppz](ClO4)2 (Lipo-Ru). This ruthenium polypyridine complex emits a strong fluorescent signal when incorporated in the hydrophobic lipid bilayer of the delivery vehicle or in the DNA helix, enabling visualization of the therapeutic agent in tumor tissues. Incubation of MDA-MB-231 breast cancer cells with Lipo-Ru induced double-strand DNA breaks and triggers apoptosis. In a mouse model of triple-negative breast cancer, treatment with Lipo-Ru dramatically reduced tumor growth. Biodistribution studies of Lipo-Ru revealed that more than 20% of the injected dose accumulated in the tumor. These results suggest that Lipo-Ru could serve as a promising theranostic platform for cancer.

An ionic/thermal-responsive agar/alginate wet-spun microfiber-shaped hydrogel combined with grooved/wrinkled surface patterns and multi-functions.

A dual stimuli-responsive wet-spun microfiber-shaped hydrogel is prepared by injecting a hot blend of two stimuli biopolymers alginate (i.e., ionic-responsive) and agar (i.e., temperature-responsive) into a pre-cooling and metal cation containing coagulation bath. Experimental results indicate the fiber microstructure could be manipulated by the extrusion rate and cooling temperature, achieving an anisotropic shrinkage characteristic and novel grooved/wrinkled surface patterns. Importantly, the integration of metal cations (e.g., Ca2+and/or Zn2+) was confirmed to significantly improve the hydrogel mechanical properties (i.e., double networks) and enhanced blue fluorescent intensity as a typical metal-polymer complexation formed within the agar gel matrix. Moreover, the functionality-independent double networks enabled typical pH-shape memory and sustainable antibacterial properties have also been demonstrated. Therefore, combing the facile fabricating approach and multifunctionality, this study would advance the development of stimuli-responsive hydrogel microfiber for complex biomedical systems.

Study on injectable silver-incorporated calcium phosphate composite with enhanced antibacterial and biomechanical properties for fighting bone cement-associated infections.

Although commonly used in orthopedic surgery, bone cements often face a high risk of post-operative infection. Developing bone cement with antibacterial capability is an effective path for eliminating implant-associated infections. Herein, the potential of silver ions (Ag+) and silver nanoparticles (AgNPs) in modifying CPC for long-term antibacterial property was investigated. Ag+ ions or AgNPs of various concentrations were incorporated in starch-modified calcium phosphate bone cement (CPB) to obtain Ag+-containing (Ag+@CPB) and AgNPs-containing (AgNP@CPB) bone cements. The results showed that all silver-containing CPBs had setting times of about 25-40 min, compressive strengths of greater than 22 MPa, high cytocompatibility but inhibitory effect on Staphylococcus aureus growth. After soaking for 1 week, the mechanical properties and the cytocompatibility of all cements revealed no significant changes, but only CPB with a relatively high content of Ag+ (H-Ag+@CPB) maintained good antibacterial capability over the tested time period. In addition, all the cements showed high injectability and interdigitating capability in cancellous bone and demonstrated augmentation effect on the cannulated pedicle screws fixation in the Sawbones model. In summary, the sustainable antibacterial capability and enhanced biomechanical properties demonstrated that Ag+ ions were more suitable for the fabrication of antibacterial CPC compared to AgNPs. Also, the H-Ag+@CPB, with good injectability, high cytocompatibility, good interdigitating and biomechanical property in cancellous bone, and sustainable antibacterial effects, bears great potential for the treatments of bone infections or implant-associated infections.

Degradable silk-based soft actuators with magnetic responsiveness.

Soft actuators with stimuli-responsiveness have great potential in biomedical applications such as drug delivery and minimally invasive surgery. In this study, protein-based soft actuators with magnetic actuation are fabricated using naturally occurring silk proteins and synthesized Fe3O4 magnetic nanoparticles (NPs). Briefly, magnetic silk films are first prepared by solution casting of a mixture containing silk proteins, synthesized Fe3O4 NPs, and glycerol. The molecular structures of the magnetic silk films are characterized by FTIR spectroscopy, which show that the ß-sheet content in the films is about 20%. The mechanical tests show that the magnetic silk films can be stretched to over 200% under wet conditions and Young's modulus is estimated to be 4.89 ± 0.69 MPa, matching the stiffness of soft tissues. Furthermore, the enzymatic degradability, good biocompatibility, and in vivo X-ray visibility of the films are demonstrated by the in vitro enzymatic degradation test, in vivo biocompatibility test, and micro-CT imaging, respectively. Degradable silk-based soft actuators with magnetic responsiveness are successfully prepared by thermal forming or plastic molding of the magnetic silk films. The fabricated soft actuators can be actuated and move with precise locomotive gaits in solutions using a magnet. In addition, the retention of the soft actuators and localized drug delivery in gastrointestinal tracts by attaching a magnet to the abdominal skin are demonstrated using model systems. The degradable silk-based soft actuators provide many opportunities for improving current therapeutic strategies in biomedicine.

Supertough and highly stretchable silk protein-based films with controlled biodegradability.

Naturally derived protein-based biopolymers are considered potential biomaterials in biomedical applications and eco-friendly materials for replacing current petroleum-based polymers due to their good biocompatibility, low environmental impact, and tunable degradability. However, current strategies for fabricating protein-based materials with superior properties and tailored functionality in a scalable manner are still lacking. Here, we demonstrate an aqueous-based scalable approach for fabricating silk protein-based films through controlled molecular self-assembly (CMS) of silk proteins with plasticizers and salt ions. The films fabricated using this method can achieve a toughness of up to 64±5 MJ/m3 with a stretchability of up to 574±31%. We also demonstrate the tunable enzymatic degradability, low in vitro cytotoxicity, and good in vivo biocompatibility of the films. Furthermore, the films can be patterned with predesigned complex structures through laser cutting and functionalized with bioactive components. The functional silk protein-based films show great potential in various applications, including flexible electronics, bioelectronics, tissue engineering, and bioplastic packaging. STATEMENT OF SIGNIFICANCE: Inspired by the naturally optimized multi-scale self-assembly of silk proteins in natural silks, we develop an aqueous-based approach for scalable production of superior protein-based films through controlled molecular self-assembly (CMS) of silk proteins with glycerol and calcium ions. The prepared silk films present outstanding mechanical properties, controlled enzymatic biodegradability, low in vitro cytotoxicity, and good in vivo biocompatibility. Notably, the films fabricated using this method can achieve a high toughness of 64±5 MJ/m3 with a stretchability of 594±31%. The approach introduced in this work provides a facile route toward making silk-based materials with superior properties. It also paves new avenues for developing functional protein-based materials with precisely controlled structures and properties for various applications.

Dytiscus lapponicus-Inspired Structure with High Adhesion in Dry and Underwater Environments.

The epidermal adhesive structure of many animals generates reliable adhesion on their engaged surfaces. However, current bio-inspired adhesion structures are difficult to function well in dry and underwater environments simultaneously. Interestingly, the male Dytiscus lapponicus attaches firmly to the rough shell of the female D. lapponicus in both dry and underwater conditions owing to the adhesive setae of its forelegs, and to the best of our knowledge, designing adhesive structures on multienvironments has never been reported. Here, a D. lapponicus-inspired adhesion structure (DIAS) is proposed and fabricated using double-exposure-fill molding technology accompanied with the material curing shrinkage, in which different structural features could be achieved by varying curing shrinkage ratios, elastic moduli, and back exposure time. The DIAS offered high, reversible, and repeatable strength in dry and underwater conditions with values of 205 and 133 kPa, respectively. By comparing the adhesion properties of different shapes via testing experiments and numerical analysis, a structural feature with an inclination of 15° was found to be optimal. Finally, the potential application of the DIAS in flexible electronic smart skin-attachable devices was demonstrated on a pig skin, paving the way for further bio-inspired adhesive designs for both dry and wet scenarios.

Oxidase-like Nanozyme-Mediated Altering of the Aspect Ratio of Gold Nanorods for Breaking through H2O2-Supported Multicolor Colorimetric Assay: Application in the Detection of Acetylcholinesterase Activity and Its Inhibitors.

A convenient, fast, and colorful colorimetric platform with high resolution for acetylcholinesterase (AChE) activity and its inhibitors detection based on the regulation of oxidase-like nanozyme-mediated etching of gold nanorods (AuNRs) has been proposed in this work. MnO2 nanosheets are selected as the nanozyme. Their excellent oxidase-like activity enables the etching process to proceed smoothly without the usage of unstable H2O2. When AChE is present, it catalytically hydrolyzes acetylthiocholine (ATCh) to thiocholine (TCh). With high reducing ability, TCh induces the decomposition of MnO2 nanosheets, causing them to lose their oxidase-like activity. Thus, the etching of AuNRs is hampered. Consequently, with the increasing concentration of AChE, an apparent change in the AuNRs solution color is observed. The proposed platform achieves high-sensitivity detection of AChE (limit of detection = 0.18 mU/mL). Furthermore, the proposed platform also has been demonstrated its applicability for its inhibitors detection. Benefiting from the advantages of convenient and high resolution of visual readout, the proposed platform holds great potential for the detection of AChE and its inhibitors in clinical diagnosis.

Switchable Adhesion for Nonflat Surfaces Mimicking Geckos' Adhesive Structures and Toe Muscles.

Gecko-inspired dry adhesion has attracted much attention for many applications such as soft grippers and wall-climbing robots, which, however, demonstrate stable adhesion on flat surfaces and small adhesion on nonflat surfaces. In practice, geckos' capability of walking upside down on both flat and nonflat surfaces comes from the combined action of adhesive structures for passive adhesion and toe muscles for stiffness modulation. Inspired by this behavior, this study proposes a hierarchal adhesive structure for high and switchable adhesion on nonflat surfaces. The three-layer adhesive consists of a mushroom-shaped structure top layer, stiffness modulation thermoplastic polyurethane (middle layer), and an electrothermal film (bottom layer) that mimics the epidermal adhesive structures, toe muscles, and electromyographic signals, respectively. Through the tunable structural stiffness controlled by adjusting the voltage, the adhesive force can be increased by 1 or 2 orders of magnitude compared to the conventional adhesive structures and further used for attachment and detachment functions. The gecko-inspired soft gripper is successfully tested as a pick-up and drop-down system for transporting a surface with different features, which has great application potential in industrial lines and daily life.

An Electrically Actuated Soft Artificial Muscle Based on a High-Performance Flexible Electrothermal Film and Liquid-Crystal Elastomer.

Liquid-crystal elastomer (LCE)-based soft robots and devices via an electrothermal effect under a low driving voltage have attracted a great deal of attention for their ability on generating larger stress, reversible deformation, and versatile actuation modes. However, electrothermal materials integrated with LCE easily induce the uncertainty of a soft actuator due to the non-uniformity on temperature distribution, inconstant resistance in the deformation process, and slow responsivity after voltage on/off. In this paper, a low-voltage-actuated soft artificial muscle based on LCE and a flexible electrothermal film is presented. At 6.5 V, a saturation temperature of 189 °C can be reached with a heating rate of 21 °C/s, which allows the soft artificial muscle quick and significant contraction and is suitable for untethered operation. Meanwhile, uniform temperature distribution and stable resistance of the flexible electrothermal film in the deformation process are obtained, leading to a work density of 9.97 kJ/m3, an actuating stress of 0.46 MPa, and controllable deformation of the soft artificial muscle. Finally, programmable low-voltage-controlled soft artificial muscles are fabricated by tailoring the flexible electrothermal film or designing structured heating pattern, including a prototype of soft finger-like gripper for transporting small objects, which clearly demonstrates the potential of low-voltage-actuated soft artificial muscles in soft robotics applications.

A Novel DNA Aptamer for Dual Targeting of Polymorphonuclear Myeloid-derived Suppressor Cells and Tumor Cells.

Aptamers have the potential to be used as targeting ligands for cancer treatment as they form unique spatial structures. Methods: In this study, a DNA aptamer (T1) that accumulates in the tumor microenvironment was identified through in vivo selection and validation in breast cancer models. The use of T1 as a targeting ligand was evaluated by conjugating the aptamer to liposomal doxorubicin. Results: T1 exhibited a high affinity for both tumor cells and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Treatment with T1 targeted doxorubicin liposomes triggered apoptosis of breast cancer cells and PMN-MDSCs. Suppression of PMN-MDSCs, which serve an immunosuppressive function, leads to increased intratumoral infiltration of cytotoxic T cells. Conclusion: The cytotoxic and immunomodulatory effects of T1-liposomes resulted in superior therapeutic efficacy compared to treatment with untargeted liposomes, highlighting the promise of T1 as a targeting ligand in cancer therapy.

Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery.

Dissolving microneedles have been employed as a safe and convenient transdermal delivery system for drugs and vaccines. To improve effective drug delivery, a multilayered pyramidal dissolving microneedle patch, composed of silk fibroin tips with the ability of robust mechanical strength, rapid dissolution and drug release supported on a flexible polyvinyl alcohol (PVA) pedestal is reported. To show the utility of this approach the ability of the fabricated microneedles to deliver insulin is demonstrated. The dissolving microneedles have sufficient mechanical strength to be inserted into abdomen skin of mice to a depth of approximately 150µm, and release their encapsulated insulin into the skin to cause a hypoglycemic effect. The fabrication of microneedles avoids high temperature which benefits storage stability at room temperature for 20d. This result indicates >99.4% of insulin remained in the microneedles. In comparison to traditional needle-based administration, the proposed multilayered pyramidal dissolving microneedle patches enable self-administration, miniaturization, pain-free administration, drug delivery and drug stability, all being important features in needle free drug delivery.