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Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients. Here, we introduce a fully bladder-implantable platform that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. We demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 d postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 wk compared with traditional UDS. These results suggest that our system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.
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Vejiga Urinaria , Infecciones Urinarias , Animales , Humanos , Vejiga Urinaria/cirugía , Urodinámica/fisiología , Prótesis e Implantes , CistectomíaRESUMEN
The synthesis of PVA hydrogels (PVA-Hy) requires a highly basic environment (e.g., an aqueous solution of sodium hydroxide, NaOH, 14% w/w, 4.2 M), but the rapid crosslinking of PVA due to high pH makes it challenging to perform layer-by-layer three-dimensional (3D) printing of PVA-Hy. This work demonstrated 3D printing of PVA-Hy in moderate alkaline conditions (e.g., NaOH, 1% w/w, 0.3 M) assisted by aqueous two-phase system (ATPS). Salting out of PVA to form ATPS allowed temporal shape retention of a 3D-printed PVA structure while it was physically crosslinked in moderate alkaline conditions. Crucially, the layer-to-layer adhesion of PVA was facilitated by delayed crosslinking of PVA that required additional reaction time and overlapping between the layers. To verify this principle, we studied the feasibility of direct ink write (DIW) 3D printing of PVA inks (5-25% w/w, µ = 0.1-20 Pa s, and MW = 22 000 and 74 800) in aqueous embedding media offering three distinct chemical environments: (1) salts for salting out (e.g., Na2SO4), (2) alkali hydroxides for physical crosslinking (e.g., NaOH), and (3) a mixture of salt and alkali hydroxide. Our study suggested the feasibility of 3D-printed PVA-Hy using the mixture of salt and alkali hydroxide, demonstrating a unique concept of embedded 3D printing enabled by ATPS for temporary stabilization of the printed structures to facilitate 3D fabrication.
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Flexible and stretchable antennas are important for wireless communication using wearable and implantable devices to address mechanical mismatch at the tissue-device interface. Emerging technologies of liquid-metal-based stretchable electronics are promising approaches to improve the flexibility and stretchability of conventional metal-based antennas. However, existing methods to encapsulate liquid metals require monolithically thick (at least 100 µm) substrates, and the resulting devices are limited in deformability and tissue-adhesiveness. To overcome this limitation, fabrication of microchannels by direct ink writing on a 7 µm-thick elastomeric substrate is demonstrated, to obtain liquid metal microfluidic antennas with unprecedented deformability. The fabricated wireless light-emitting device is powered by a standard near-field-communication system (13.56 MHz, 1 W) and retained a consistent operation under deformations including stretching (>200% uniaxial strain), twisting (180° twist), and bending (3.0 mm radius of curvature) while maintaining a high quality factor (q > 20). Suture-free conformal adhesion of the polydopamine-coated device to ex vivo animal tissues under mechanical deformations is also demonstrated. This technology offers a new capability for the design and fabrication of wireless biomedical devices requiring conformable tissue-device integration toward minimally invasive, imperceptible medical treatments.
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Adhesivos Tisulares , Dispositivos Electrónicos Vestibles , Metales , Prótesis e Implantes , Tecnología InalámbricaRESUMEN
This study demonstrates a method to mount electronic components using gallium-based liquid metals (LMs) with reduced contact resistivity between the LM and a copper (Cu) electrode. Gallium-based LMs have low volume resistivity and low melting points, and they are used as electronic components such as interconnects and sensors of stretchable electronic devices. However, the high contact resistivity of the oxide layer on the surface of the Ga-based LMs becomes a problem when the Ga-based LMs are used in contact with rigid electronic components. To overcome this problem, we studied herein the effect of the oxide layer on contact resistivity via the contact methods of the Ga-based LM (galinstan) and the Cu film. Through the placement of galinstan after the placement of the Cu film and application of vacuum to reduce the effect of the oxide layer, the contact resistivity was reduced to 0.59 × 10-7 Ωm2, which was 90% lower than that in the case where the Cu film was placed on galinstan on which the oxide layer grew (5.7 × 10-7 Ωm2) (day 1). Additionally, it was found that the contact resistivity decreased in the same order (10-8 Ωm2) over time regardless of the methods in which galinstan was applied (day 103). Furthermore, alloy formation on the Cu film surface was confirmed via elemental analysis. Finally, the mounting method using galinstan was demonstrated, which enabled the change in contact resistance to be maintained as low as 7.2% during 100% stretching deformation repeated 100 times (day 1 and day 130). Our results show that low and stable contact resistance with a high stretch tolerance can be achieved via the mounting method using galinstan based on our contact methods. This mounting method, therefore, expands the range of materials suitable for use as substrates and provides new opportunities for the development of stretchable electronics.
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Metronomic photodynamic therapy (mPDT) is a form of PDT that induces cancer cell death by intermittent continuous irradiation with a relatively weak power of light for a long duration (several days). We previously developed a wirelessly powered, fully implantable LED device and reported a significant anti-tumor effect of mPDT. Considering application in clinical practice, the method used for repeated administrations of photosensitizers required for mPDT should not have a high patient burden such as the burden of transvenous administration. Therefore, in this study, we selected 5-aminolevulinic acid (ALA), which can be administered orally, as a photosensitizer, and we studied the antitumor effects of mPDT. In mice with intradermal tumors that were orally administered ALA (200 mg/kg daily for 5 days), the tumor in each mouse was simultaneously irradiated (8 h/day for 5 days) using a wirelessly powered implantable green LED device (532 nm, 0.05 mW). Tumor growth in the mPDT-treated mice was suppressed by about half compared to that in untreated mice. The results showed that mPDT using the wirelessly powered implantable LED device exerted an antitumor effect even with the use of orally administered ALA, and this treatment scheme can reduce the burden of photosensitizer administration for a patient.
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Implantes Experimentales , Ácidos Levulínicos/administración & dosificación , Fotoquimioterapia , Administración Metronómica , Administración Oral , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Fluorescencia , Calor , Ratones Endogámicos BALB C , Neoplasias/patología , Protoporfirinas/farmacología , Factores de Tiempo , Tecnología Inalámbrica , Ácido AminolevulínicoRESUMEN
Syringe-injectable biomaterials and medical devices are important as minimally invasive implants for diagnosis, therapy, and regenerative medicine. Free-standing polymeric nanosheets with a thickness less than 1 µm and a flexural rigidity less than 10-2 nN m are a promising platform of syringe-injectable, implantable devices that provide conformable and long-term stable adhesion to the target biological tissues for in situ delivery of therapeutic materials. Here, we developed free-standing ultrathin films (<1 µm thick) based on polyurethane-based shape-memory polymer (SMP) and magnetic nanoparticles (MNP), termed MNP-SMP nanosheets. With the temperature-mediated shape-memory effect of SMP, we overcome the limitation in the manipulation of the conventional polymer nanosheets. In particular, we demonstrated the following four capabilities using the 710 nm thick MNP-SMP nanosheet with the glass transition temperature (Tg) of 25 °C: (1) syringe-injectability through the medical needles, (2) self-expandability after ejection, (3) conformability and removability on the biological surfaces, and (4) guidability in an external magnetic field. The MNP-SMP nanosheets were readily interfaced with an additional layer of poly(lactic-co-glycolic acid) (PLGA) to extend their functionality as a carrier of molecular and cellular drugs. The MNP-SMP nanosheets will contribute to the development of advanced syringe-injectable medical devices as a platform to deliver drugs, sensors, cells, and engineered tissues to the specific site or lesion in the body for minimally invasive diagnosis and therapy.
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Metronomic (that is, low-dose and long-term) photodynamic therapy (mPDT) for treating internal lesions requires the stable fixation of optical devices to internal tissue surfaces to enable continuous, local light delivery. Surgical suturing-the standard choice for device fixation-can be unsuitable in the presence of surrounding major nerves and blood vessels, as well as for organs or tissues that are fragile, change their shape or actively move. Here, we show that an implantable and wirelessly powered mPDT device consisting of near-field-communication-based light-emitting-diode chips and bioadhesive and stretchable polydopamine-modified poly(dimethylsiloxane) nanosheets can be stably fixed onto the inner surface of animal tissue. When implanted subcutaneously in mice with intradermally transplanted tumours, the device led to significant antitumour effects by irradiating for 10 d at approximately 1,000-fold lower intensity than conventional PDT approaches. The mPDT device might facilitate treatment strategies for hard-to-detect microtumours and deeply located lesions that are hard to reach with standard phototherapy.
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Neoplasias/tratamiento farmacológico , Óptica y Fotónica/instrumentación , Fotoquimioterapia , Tecnología Inalámbrica , Adhesividad , Administración Metronómica , Animales , Línea Celular Tumoral , Dimetilpolisiloxanos/química , Femenino , Indoles/química , Masculino , Ratones , Nanopartículas/química , Neoplasias/patología , Polímeros/química , Ratas , SuturasRESUMEN
Ultrathin flexible electronic devices have been attracting substantial attention for biomonitoring, display, wireless communication, and many other ubiquitous applications. In this article, organic robust redox-active polymer/carbon nanotube hybrid nanosheets with thickness of just 100 nm are reported as power sources for ultrathin devices conformable to skin. Regardless of the extreme thinness of the electrodes, a moderately large current density of 0.4 mA cm-2 is achieved due to the high output of the polymers (>10 A g-1 ). For the first time, the use of mechanically robust yet intrinsically soft electrodes and polymer nanosheet sealing leads to the fabrication of rechargeable devices with only 1-µm thickness and even with stretchable properties.
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Nanopartículas/química , Compuestos Orgánicos/química , Polímeros/química , Piel/anatomía & histología , Resinas Acrílicas/química , Óxidos N-Cíclicos/química , Electricidad , Electroquímica , Electrodos , Nanopartículas/ultraestructura , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestructuraRESUMEN
It is anticipated that flexible wearable/implantable devices for biomedical applications will be established for the development of medical diagnostics and therapeutics. However, these devices need to be compatible with the physical and mechanical properties of the living body. In this minireview, we introduce free-standing polymer ultra-thin films (referred to as "polymer nanosheets"), for which a variety of polymers can be selected as building blocks (e.g., biodegradable polymers, conductive polymers, and elastomers), as a platform for flexible biomedical devices that are mechanically compatible with the living body, and then we demonstrate the use of "printed nanofilms" by combining nanosheets and printing technologies with a variety of inks represented by drugs, conductive nanomaterials, chemical dyes, bio-mimetic polymers, and cells. Owing to the low flexural rigidity (<10-2 nN m) of the polymer nanosheets, which is within the range of living brain slices (per unit width), the flexible printed nanofilms realize bio-integrated structure and display various functions with unique inks that continually monitor or detect biological activities, such as performing surface electromyography, measuring epidermal strain, imaging tissue temperature, organizing cells, and treating lesions in wounds and tumors.
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Materiales Biocompatibles/química , Fenómenos Mecánicos , Nanoestructuras/química , Nanotecnología/métodos , Impresión Tridimensional , Humanos , Polímeros/químicaRESUMEN
Flexible materials are important for the development of neural probes in recording stable signals (spikes) in vivo. Here, we present inkjet-printed, flexible neural probes for spike recording by using polymeric thin films. The neural probes were constructed from 400 nm-thick poly(d,l-lactic acid) nanofilms, inkjet-printed lines consisting of Au and poly(3,4-ethylenedioxythiophene):polystyrenesulfonate nanoinks, and fluoropolymer layers. Microelectrodes were exposed by cutting the edge with a razor. The 6 µm-thick probes were connected to the external amplifiers by gradual increase of stiffness with thickness-dependent manner. The probe was formed into a needle shape, which recorded spikes from mouse thalamus in vivo.
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We synthesized a novel cyclooctyne-based clickable fluorescent probe with versatile properties such as high cell-membrane permeability and free diffusibility in the cell. Our probe "FC-DBCO" was conjugated to an azide-modified mannose via a Cu-free click reaction in living HeLa cells and displayed intracellular specific fluorescence imaging with low background signals.
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Química Clic , Ciclooctanos/química , Colorantes Fluorescentes/análisis , Colorantes Fluorescentes/química , Espacio Intracelular/química , Espacio Intracelular/metabolismo , Permeabilidad de la Membrana Celular , Supervivencia Celular , Cobre , Ciclooctanos/síntesis química , Difusión , Colorantes Fluorescentes/síntesis química , Células HeLa , Humanos , Microscopía Confocal , Estructura MolecularRESUMEN
The powerful strategy of "intracellular click reaction" was used to retain a chemical Ca(2+) indicator in the cytosol. Specifically, a novel clickable Ca(2+) indicator "N3-fura-2 AM" was coupled with dibenzylcyclooctyl-modified biomacromolecules via copper-free click reaction in living cells and Ca(2+) oscillation was observed for an extended period of time.