Showing papers in "Biomedical Microdevices in 2018"
TL;DR: Critical aspects of 3D printing for preoperative planning and surgical training are reviewed, starting with an overview of the process-flow and3D printing techniques, followed by their applications spanning across multiple organ systems in the human body.
Abstract: Surgeons typically rely on their past training and experiences as well as visual aids from medical imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) for the planning of surgical processes. Often, due to the anatomical complexity of the surgery site, two dimensional or virtual images are not sufficient to successfully convey the structural details. For such scenarios, a 3D printed model of the patient's anatomy enables personalized preoperative planning. This paper reviews critical aspects of 3D printing for preoperative planning and surgical training, starting with an overview of the process-flow and 3D printing techniques, followed by their applications spanning across multiple organ systems in the human body. State of the art in these technologies are described along with a discussion of current limitations and future opportunities.
123 citations
TL;DR: In-vivo human tests showed the possibility to correctly and dynamically track glycaemia over time, with approximately 10 min delay with respect to capillary blood control values, in line with the expected physiological lag time.
Abstract: Continuous glucose monitoring (CGM) has the potential to greatly improve diabetes management. The aim of this work is to show a proof-of-concept CGM device which performs minimally invasive and minimally delayed in-situ glucose sensing in the dermal interstitial fluid, combining the advantages of microneedle-based and commercially available CGM systems. The device is based on the integration of an ultra-miniaturized electrochemical sensing probe in the lumen of a single hollow microneedle, separately realized using standard silicon microfabrication methods. By placing the sensing electrodes inside the lumen facing an opening towards the dermal space, real-time measurement purely can be performed relying on molecular diffusion over a short distance. Furthermore, the device relies only on passive capillary lumen filling without the need for complex fluid extraction mechanisms. Importantly, the transdermal portion of the device is 50 times smaller than that of commercial products. This allows access to the dermis and simultaneously reduces tissue trauma, along with being virtually painless during insertion. The three-electrode enzymatic sensor alone was previously proven to have satisfactory sensitivity (1.5 nA/mM), linearity (up to 14 mM), selectivity, and long-term stability (up to 4 days) in-vitro. In this work we combine this sensor technology with microneedles for reliable insertion in forearm skin. In-vivo human tests showed the possibility to correctly and dynamically track glycaemia over time, with approximately 10 min delay with respect to capillary blood control values, in line with the expected physiological lag time. The proposed device can thus reduce discomfort and potentially enable less invasive real-time CGM in diabetic patients.
104 citations
TL;DR: Results are promising since they show the capability of the presented protocol to obtain printable fibrillar collagen at pH 7 and the potential of the printing technique for building low-cost biocompatible 3D structures which maintained the fibrillsar collagen structure after incubation in culture media without using additional strategies as crosslinking.
Abstract: Collagen is widely used in tissue engineering because it can be extracted in large quantities, and has excellent biocompatibility, good biodegradability, and weak antigenicity. In the present study, we isolated printable collagen from bovine Achilles tendon and examined the purity of the isolated collagen using sodium dodecyl sulfate polyacrylamide gel electrophoresis. The bands obtained corresponded to α1, α2 and β chains with little contamination from other small proteins. Furthermore, rheological measurements of collagen dispersions (60 mg per ml of PBS) at pH 7 revealed values of viscosity of 35.62 ± 1.42 Pa s at shear rate of 10 s − 1 and a shear thinning behavior. Collagen gels and solutions can be used for building scaffolds by three-dimensional (3D) printing. After designing and fabricating a low-cost 3D printer we assayed the collagen printing and obtaining 3D printed scaffolds of collagen at pH 7. The porosity of the scaffold was 90.22% ± 0.88% and the swelling ratio was 1437% ± 146%. The microstructure of the scaffolds was studied using scanning electron microscopy, and a porous mesh of fibrillar collagen was observed. In addition, the 3D printed collagen scaffold was not cytotoxic with cell viability higher than 70% using Vero and NIH 3 T3 cells. In vitro evaluation using both cells lines demonstrated that the collagen scaffolds had the ability to support cell attachment and proliferation. Also a fibrillar collagen mesh was observed after two weeks of culture at 37 °C. Overall, these results are promising since they show the capability of the presented protocol to obtain printable fibrillar collagen at pH 7 and the potential of the printing technique for building low-cost biocompatible 3D plotted structures which maintained the fibrillar collagen structure after incubation in culture media without using additional strategies as crosslinking.
89 citations
TL;DR: The results demonstrate the feasibility of the proposed RVIR to operate a catheter and guidewire accurately, detect the resistance forces, and complete complex surgical operations in a cooperative manner.
Abstract: Remote-controlled vascular interventional robots (RVIRs) are being developed to increase the overall accuracy of surgical operations and reduce the occupational risks of intervening physicians, such as radiation exposure and chronic neck/back pain. Several RVIRs have been used to operate catheters or guidewires accurately. However, a lack of cooperation between the catheters and guidewires results in the surgeon being unable to complete complex surgery by propelling the catheter/guidewire to the target position. Furthermore, it is a significant challenge to operate the catheter/guidewire accurately and detect their proximal force without damaging their surfaces. In this study, we introduce a novel method that allows catheters and guidewires to be operated simultaneously in complex surgery. Our method accurately captures force measurements and enables precisely controlled catheter and guidewire operation. A prototype is validated through various experiments. The results demonstrate the feasibility of the proposed RVIR to operate a catheter and guidewire accurately, detect the resistance forces, and complete complex surgical operations in a cooperative manner.
87 citations
TL;DR: A novel method is introduced that provides higher operation efficiency than a previous prototype and allows for complete robot sterilization and preliminarily demonstrated that the proposed RVIR has good safety and reliability and can be used in clinical surgeries.
Abstract: Remote-controlled vascular interventional robots (RVIRs) are being developed to increase the accuracy of surgical operations and reduce the number of occupational risks sustained by intervening physicians, such as radiation exposure and chronic neck/back pain. However, complex control of the RVIRs improves the doctor's operation difficulty and reduces the operation efficiency. Furthermore, incomplete sterilization of the RVIRs will increase the risk of infection, or even cause medical accidents. In this study, we introduced a novel method that provides higher operation efficiency than a previous prototype and allows for complete robot sterilization. A prototype was fabricated and validated through laboratory setting experiments and an in-human experiment. The results illustrated that the proposed RVIR has better performance compared with the previous prototype, and preliminarily demonstrated that the proposed RVIR has good safety and reliability and can be used in clinical surgeries.
77 citations
TL;DR: Experimental results demonstrated that the proposed method can measure the proximal force of catheter/guidewire accurately and assist surgeons to distinguish the change of proximalforce more easily and is suitable for use in actual surgical operations.
Abstract: Minimally invasive vascular interventional surgery is widely used and remote-controlled vascular interventional surgery robots (RVIRs) are being developed to reduce the occupational risk of the intervening physician in minimally invasive vascular interventional surgeries. Skilled surgeon performs surgeries mainly depending on the detection of collisions. Inaccurate force feedback will be difficult for surgeons to perform surgeries or even results in medical accidents. In addition, the surgeon cannot quickly and easily distinguish whether the proximal force exceeds the safety threshold of blood vessels or not, and thus it results in damage to the blood vessels. In this paper, we present a novel method comprising compensatory force measurement and multimodal force feedback (MFF). Calibration experiments and performance evaluation experiments were carried out. Experimental results demonstrated that the proposed method can measure the proximal force of catheter/guidewire accurately and assist surgeons to distinguish the change of proximal force more easily. This novel method is suitable for use in actual surgical operations.
70 citations
TL;DR: A novel slave manipulator is proposed to realize on-line sensing of guidewire torsional operating torque and axial operation force during robotic assisted operations and can provide the foundation for enabling accurate haptic feedback to the surgeon to improve surgical safety.
Abstract: Vascular interventional surgery has its advantages compared to traditional operation. Master-slave robotic technology can further improve the operation accuracy, efficiency and safety of this complicated and high risk surgery. However, on-line acquisition of operating force information of catheter and guidewire remains to be a significant obstacle on the path to enhancing robotic surgery safety. Thus, a novel slave manipulator is proposed in this paper to realize on-line sensing of guidewire torsional operating torque and axial operation force during robotic assisted operations. A strain sensor is specially designed to detect the small scale torsional operation torque with low rotational frequency. Additionally, the axial operating force is detected via a load cell, which is incorporated into a sliding mechanism to eliminate the influence of friction. For validation, calibration and performance evaluation experiments are conducted. The results indicate that the proposed operation torque and force detection device is effective. Thus, it can provide the foundation for enabling accurate haptic feedback to the surgeon to improve surgical safety.
68 citations
TL;DR: ZnO nanoparticles synthesized using the Chelidonium majus extract demonstrate high efficiency in treatment of human non-small cell lung cancer A549 and were excellent antimicrobial agents.
Abstract: The basic goal of this study was to synthesize zinc oxide nanoparticles using the Chelidonium majus extract and asses their cytotoxic and antimicrobial properties. The synthesized ZnO NPs were characterized by UV-Vis, Scanning Electron Microscopy (SEM) with EDS profile, Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), Transmission Electron Microscopy (TEM) and Atomic Force Microscopy (AFM). The aforementioned methods confirmed that the size of synthesized ZnO nanoparticles was at the range of 10 nm. The antimicrobial activity of ZnO nanoparticles synthesized using the Ch. majus extract was tested against standard strains of bacteria (Staphylococcus aureus NCTC 4163, Pseudomonas aeruginosa NCTC 6749, Escherichia coli ATCC 25922), yeast (Candida albicans ATCC 10231), filamentous fungi (molds: Aspergillus niger ATCC 16404, dermatophytes: Trichophyton rubrum ATCC 28188), clinical strains of bacteria (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus) and yeast (Candida albicans). The study showed that zinc oxide nanoparticles were excellent antimicrobial agents. What is more, biologically synthesized ZnO nanoparticles demonstrate high efficiency in treatment of human non-small cell lung cancer A549.
64 citations
TL;DR: A novel catheter operating system based on tissue protection to prevent vessel puncture caused by collision and the results show that the further collision damage can be effectively prevented by the CPM, which implies the realization of relative safe catheterization.
Abstract: The robot-assisted catheter system can increase operating distance thus preventing the exposure radiation of the surgeon to X-ray for endovascular catheterization. However, few designs have considered the collision protection between the catheter tip and the vessel wall. This paper presents a novel catheter operating system based on tissue protection to prevent vessel puncture caused by collision. The integrated haptic interface not only allows the operator to feel the real force feedback, but also combines with the newly proposed collision protection mechanism (CPM) to mitigate the collision trauma. The CPM can release the catheter quickly when the measured force exceeds a certain threshold, so as to avoid the vessel puncture. A significant advantage is that the proposed mechanism can adjust the protection threshold in real time by the current according to the actual characteristics of the blood vessel. To verify the effectiveness of the tissue protection by the system, the evaluation experiments in vitro were carried out. The results show that the further collision damage can be effectively prevented by the CPM, which implies the realization of relative safe catheterization. This research provides some insights into the functional improvements of safe and reliable robot-assisted catheter systems.
60 citations
TL;DR: The results demonstrate that the proposed robot-assisted catheter operating system (RCOS) has the ability to enable decreasing the contact forces between the catheter and vasculature.
Abstract: In this paper, a novel robot-assisted catheter operating system (RCOS) has been proposed as a method to reduce physical stress and X-ray exposure time to physicians during endovascular procedures. The unique design of this system allows the physician to apply conventional bedside catheterization skills (advance, retreat and rotate) to an input catheter, which is placed at the master side to control another patient catheter placed at the slave side. For this purpose, a magnetorheological (MR) fluids-based master haptic interface has been developed to measure the axial and radial motions of an input catheter, as well as to provide the haptic feedback to the physician during the operation. In order to achieve a quick response of the haptic force in the master haptic interface, a hall sensor-based closed-loop control strategy is employed. In slave side, a catheter manipulator is presented to deliver the patient catheter, according to position commands received from the master haptic interface. The contact forces between the patient catheter and blood vessel system can be measured by designed force sensor unit of catheter manipulator. Four levels of haptic force are provided to make the operator aware of the resistance encountered by the patient catheter during the insertion procedure. The catheter manipulator was evaluated for precision positioning. The time lag from the sensed motion to replicated motion is tested. To verify the efficacy of the proposed haptic feedback method, the evaluation experiments in vitro are carried out. The results demonstrate that the proposed system has the ability to enable decreasing the contact forces between the catheter and vasculature.
53 citations
TL;DR: A novel portable exoskeleton device which could provide support for rehabilitation patients with variable actuated stiffness in the elbow joint which has five passive degrees of freedom to guarantee the user’s natural joint range of motion and intra-subject variability, as well as an integrated variable stiffness actuator (VSA).
Abstract: Robot-assisted movement training by means of exoskeleton devices has been proven to be an effective method for post-stroke patients to recover their motor function. However, in order to be used in home-based rehabilitation, the kinematic structure of a wearable exoskeleton device should provide portability and make allowances for the natural joint range of motion for the user. Additionally, the actuated stiffness of the target joint is desired to be adjustable in accordance with the specific impairment level of the patient's upper limb. In this paper, we present a novel portable exoskeleton device which could provide support for rehabilitation patients with variable actuated stiffness in the elbow joint. It has five passive degrees of freedom to guarantee the user's natural joint range of motion and intra-subject variability, as well as an integrated variable stiffness actuator (VSA) which can adjust the joint stiffness independently by moving the pivot position. An elbow power-assist trial with different actuated joint stiffnesses was tested on a healthy subject to evaluate the functionality of the proposed device. By regulating the joint stiffness, the proposed device could provide variable power assistance for the wearer's elbow movements.
TL;DR: Results establish a foundation for the use of Two-Photon Polymerization lithography as a means to fabricate microneedles to perforate the RWM and other similar membranes.
Abstract: The cochlea, or inner ear, is a space fully enclosed within the temporal bone of the skull, except for two membrane-covered portals connecting it to the middle ear space. One of these portals is the round window, which is covered by the Round Window Membrane (RWM). A longstanding clinical goal is to reliably and precisely deliver therapeutics into the cochlea to treat a plethora of auditory and vestibular disorders. Standard of care for several difficult-to-treat diseases calls for injection of a therapeutic substance through the tympanic membrane into the middle ear space, after which a portion of the substance diffuses across the RWM into the cochlea. The efficacy of this technique is limited by an inconsistent rate of molecular transport across the RWM. A solution to this problem involves the introduction of one or more microscopic perforations through the RWM to enhance the rate and reliability of diffusive transport. This paper reports the use of direct 3D printing via Two-Photon Polymerization (2PP) lithography to fabricate ultra-sharp polymer microneedles specifically designed to perforate the RWM. The microneedle has tip radius of 500 nm and shank radius of 50 μ m, and perforates the guinea pig RWM with a mean force of 1.19 mN. The resulting perforations performed in vitro are lens-shaped with major axis equal to the microneedle shank diameter and minor axis about 25% of the major axis, with mean area 1670 μ m2. The major axis is aligned with the direction of the connective fibers within the RWM. The fibers were separated along their axes without ripping or tearing of the RWM suggesting the main failure mechanism to be fiber-to-fiber decohesion. The small perforation area along with fiber-to-fiber decohesion are promising indicators that the perforations would heal readily following in vivo experiments. These results establish a foundation for the use of Two-Photon Polymerization lithography as a means to fabricate microneedles to perforate the RWM and other similar membranes.
TL;DR: A novel real-time master–slave interventional surgical robotic system with a closed-loop force feedback that allows a surgeon to sense the true force during remote operation, provide adequate haptic feedback, and improve control accuracy in robot-assisted catheterization is developed.
Abstract: In robot-assisted catheterization, haptic feedback is important, but is currently lacking. In addition, conventional interventional surgical robotic systems typically employ a master–slave architecture with an open-loop force feedback, which results in inaccurate control. We develop herein a novel real-time master–slave (RTMS) interventional surgical robotic system with a closed-loop force feedback that allows a surgeon to sense the true force during remote operation, provide adequate haptic feedback, and improve control accuracy in robot-assisted catheterization. As part of this system, we also design a unique master control handle that measures the true force felt by a surgeon, providing the basis for the closed-loop control of the entire system. We use theoretical and empirical methods to demonstrate that the proposed RTMS system provides a surgeon (using the master control handle) with a more accurate and realistic force sensation, which subsequently improves the precision of the master–slave manipulation. The experimental results show a substantial increase in the control accuracy of the force feedback and an increase in operational efficiency during surgery.
TL;DR: A novel open microfluidic chip design that encompasses a freely variable number of nodes interconnected by axon-permissible tunnels, enabling structuring of multi-nodal neural networks in vitro, thus providing a versatile, highly relevant platform for the study of neural network dynamics applicable to developmental and regenerative neuroscience.
Abstract: Neural network formation is a complex process involving axon outgrowth and guidance. Axon guidance is facilitated by structural and molecular cues from the surrounding microenvironment. Micro-fabrication techniques can be employed to produce microfluidic chips with a highly controlled microenvironment for neural cells enabling longitudinal studies of complex processes associated with network formation. In this work, we demonstrate a novel open microfluidic chip design that encompasses a freely variable number of nodes interconnected by axon-permissible tunnels, enabling structuring of multi-nodal neural networks in vitro. The chip employs a partially open design to allow high level of control and reproducibility of cell seeding, while reducing shear stress on the cells. We show that by culturing dorsal root ganglion cells (DRGs) in our microfluidic chip, we were able to structure a neural network in vitro. These neurons were compartmentalized within six nodes interconnected through axon growth tunnels. Furthermore, we demonstrate the additional benefit of open top design by establishing a 3D neural culture in matrigel and a neuronal aggregate 3D culture within the chips. In conclusion, our results demonstrate a novel microfluidic chip design applicable to structuring complex neural networks in vitro, thus providing a versatile, highly relevant platform for the study of neural network dynamics applicable to developmental and regenerative neuroscience.
TL;DR: A rapid, sensitive molecular diagnostic that integrates patient swab sample lysis, nucleic acid extraction, thermophilic helicase-dependent amplification, an internal amplification control, and visual lateral flow detection within an 80 min run time is reported on.
Abstract: Globally, the microbe Neisseria gonorrhoeae (NG) causes 106 million newly documented sexually transmitted infections each year. Once appropriately diagnosed, NG infections can be readily treated with antibiotics, but high-risk patients often do not return to the clinic for treatment if results are not provided at the point of care. A rapid, sensitive molecular diagnostic would help increase NG treatment and reduce the prevalence of this sexually transmitted disease. Here, we report on the design and development of a rapid, highly sensitive, paperfluidic device for point-of-care diagnosis of NG. The device integrates patient swab sample lysis, nucleic acid extraction, thermophilic helicase-dependent amplification (tHDA), an internal amplification control (NGIC), and visual lateral flow detection within an 80 min run time. Limits of NG detection for the NG/NGIC multiplex tHDA assay were determined within the device, and clinical performance was validated retroactively against qPCR-quantified patient samples in a proof-of-concept study. This paperfluidic diagnostic has a clinically relevant limit of detection of 500 NG cells per device with analytical sensitivity down to 10 NG cells per device. In triplicate testing of 40 total urethral and vaginal swab samples, the device had 95% overall sensitivity and 100% specificity, approaching current laboratory-based molecular NG diagnostics. This diagnostic platform could increase access to accurate NG diagnoses to those most in need.
TL;DR: 3D bioprinted a gelatin hydrogel microchannel construct to promote and preserve the contractile phenotype of vascular smooth muscle cells (vSMCs), which is crucial for vasoresponsiveness.
Abstract: Three dimensional (3D) bioprinting has been proposed as a method for fabricating tissue engineered small diameter vascular prostheses. This technique not only involves constructing the structural features to obtain a desired pattern but the morphology of the pattern may also be used to influence the behavior of seeded cells. Herein, we 3D bioprinted a gelatin hydrogel microchannel construct to promote and preserve the contractile phenotype of vascular smooth muscle cells (vSMCs), which is crucial for vasoresponsiveness. The microchanneled surface of a gelatin hydrogel facilitated vSMC attachment and an elongated alignment along the microchannel direction. The cells displayed distinct F-actin anisotropy in the direction of the channel. The vSMC contractile phenotype was confirmed by the positive detection of contractile marker gene proteins (α-smooth muscle actin (α-SMA) and smooth muscle-myosin heavy chain (SM-MHC)). Having demonstrated the effectiveness of the hydrogel channels bioprinted on a film, the bioprinting was applied radially to the surface of a 3D tubular construct by integrating a rotating mandrel into the 3D bioprinter. The hydrogel microchannels printed on the 3D tubular vascular construct also orientated the vSMCs and strongly promoted the contractile phenotype. Together, our study demonstrated that microchannels bioprinted using a transglutaminase crosslinked gelatin hydrogel, could successfully promote and preserve vSMC contractile phenotype. Furthermore, the hydrogel bioink could be retained on the surface of a rotating polymer tube to print radial cell guiding channels onto a vascular graft construct.
TL;DR: The utility of the graphene oxide (GO) coated μPADs coupled with smartphone-based colorimetric detection for the direct quantification of glucose concentrations in a portable, and repeatable manner is demonstrated.
Abstract: Rapid, disposable, point-of-care (POC) oral fluid testing has gained considerable attention in recent years as saliva contains biomarker and components of the serum proteome that offer important information on both oral and systemic disease. Microfluidic paper-based analytical devices (μPADs) coupled with smartphone reflectance sensing systems have long been considered to be an effective POC tool for the diagnostics of biomarkers in oral fluid. However, the existing portable systems are limited by the poor color distribution in the detection area as well as not being universally applicable. Therefore, using the properties of nanomaterials to our advantage, we present a simple, universally applicable approach that features graphene oxide (GO) coated μPADs coupled with smartphone-based colorimetric detection for the direct quantification of glucose. An integrated portable system is used to implement the approach. Owing to the enhanced reagents absorptivity, reactive efficiency and homogeneity of color distribution from the deposition of GO, the glucose assay performance was improved. Also, by using a self-developed app, the glucose concentrations in physiological range can be automatically quantified. Finally, the approach is universally applicable as the modification of μPADs with GO can be achieved without the use of any linker, binder or retention aid, which avoids possible enzyme cross contamination. The system was first calibrated by standard glucose buffer solutions, and the limit of detection as well as the linear dynamic range were found to be 0.02 mM and 0~1 mM, respectively, which are appropriate for analyzing glucose concentrations in a clinically relevant range. Finally, the system was used for quantifying glucose concentrations in artificial saliva and the results obtained using our portable system showed reasonable agreement with the actual use concentrations. Thus, the utility of the system in sensitively quantifying glucose concentrations in a portable, and repeatable manner is demonstrated.
TL;DR: This review paper is a preliminary attempt to summarize the state-of-the-art concerning diagnostic microbeads; including microsphere composition, synthesis, encoding technology, detection systems, and applications.
Abstract: In recent years, there has been growing interest in optically-encoded or tagged functionalized microbeads as a solid support platform to capture proteins or nucleotides which may serve as biomarkers of various diseases. Multiplexing technologies (suspension array or planar array) based on optically encoded microspheres have made possible the observation of relatively minor changes in biomarkers related to specific diseases. The ability to identify these changes at an early stage may allow the diagnosis of serious diseases (e.g. cancer) at a time-point when curative treatment may still be possible. As the overall accuracy of current diagnostic methods for some diseases is often disappointing, multiplexed assays based on optically encoded microbeads could play an important role to detect biomarkers of diseases in a non-invasive and accurate manner. However, detection systems based on functionalized encoded microbeads are still an emerging technology, and more research needs to be done in the future. This review paper is a preliminary attempt to summarize the state-of-the-art concerning diagnostic microbeads; including microsphere composition, synthesis, encoding technology, detection systems, and applications.
TL;DR: The characterization of a chip-on-tip endoscope, consisting out of a soft robotic pneumatic bending microactuator equipped with a 1.1 × 1.1 mm2 CMOS camera, and the feasibility of using this system in a surgical environment is shown.
Abstract: In the ever advancing field of minimally invasive surgery, flexible instruments with local degrees of freedom are needed to navigate through the intricate topologies of the human body. Although cable or concentric tube driven solutions have proven their merits in this field, they are inadequate for realizing small bending radii and suffer from friction, which is detrimental when automation is envisioned. Soft robotic actuators with locally actuated degrees of freedom are foreseen to fill in this void, where elastic inflatable actuators are very promising due to their S3-principle, being Small, Soft and Safe. This paper reports on the characterization of a chip-on-tip endoscope, consisting out of a soft robotic pneumatic bending microactuator equipped with a 1.1 × 1.1 mm2 CMOS camera. As such, the total diameter of the endoscope measures 1.66 mm. To show the feasibility of using this system in a surgical environment, a preliminary test on an eye mock-up is conducted.
TL;DR: The results demonstrated that the newly-fabricated high-sensitive OxyChip is capable of providing long-term measurements of oxygen concentration in a reliable and repeated manner under clinical conditions.
Abstract: Tissue oxygenation is a critical parameter in various pathophysiological situations including cardiovascular disease and cancer. Hypoxia can significantly influence the prognosis of solid malignancies and the efficacy of their treatment by radiation or chemotherapy. Electron paramagnetic resonance (EPR) oximetry is a reliable method for repeatedly assessing and monitoring oxygen levels in tissues. Lithium octa-n-butoxynaphthalocyanine (LiNc-BuO) has been developed as a probe for biological EPR oximetry, especially for clinical use. However, clinical applicability of LiNc-BuO crystals is hampered by potential limitations associated with biocompatibility, biodegradation, or migration of individual bare crystals in tissue. To overcome these limitations, we have embedded LiNc-BuO crystals in polydimethylsiloxane (PDMS), an oxygen-permeable biocompatible polymer and developed an implantable/retrievable form of chip, called OxyChip. The chip was optimized for maximum spin density (40% w/w of LiNc-BuO in PDMS) and fabricated in a form suitable for implantation using an 18-G syringe needle. In vitro evaluation of the OxyChip showed that it is robust and highly oxygen sensitive. The dependence of its EPR linewidth to oxygen was linear and highly reproducible. In vivo efficacy of the OxyChip was evaluated by implanting it in rat femoris muscle and following its response to tissue oxygenation for up to 12 months. The results revealed preservation of the integrity (size and shape) and calibration (oxygen sensitivity) of the OxyChip throughout the implantation period. Further, no inflammatory or adverse reaction around the implantation area was observed thereby establishing its biocompatibility and safety. Overall, the results demonstrated that the newly-fabricated high-sensitive OxyChip is capable of providing long-term measurements of oxygen concentration in a reliable and repeated manner under clinical conditions.
TL;DR: The designed microneedle electrodes are much more efficient than the conventional electrodes for superficial transcutaneous nerve stimulation purposes and will lead to less harmful Faradaic current passing through the tissue during stimulation in different frequencies.
Abstract: Electrophysiological devices are connected to the body through electrodes. In some applications, such as nerve stimulation, it is needed to minimally pierce the skin and reach the underneath layers to bypass the impedance of the first layer called stratum corneum. In this study, we have designed and fabricated surface microneedle electrodes for applications such as electrical peripheral nerve stimulation. We used molybdenum for microneedle fabrication, which is a biocompatible metal; it was used for the conductive layer of the needle array. To evaluate the performance of the fabricated electrodes, they were compared with the conventional surface electrodes in nerve conduction velocity experiment. The recorded signals showed a much lower contact resistance and higher bandwidth in low frequencies for the fabricated microneedle electrodes compared to those of the conventional electrodes. These results indicate the electrode-tissue interface capacitance and charge transfer resistance have been increased in our designed electrodes, while the contact resistance decreased. These changes will lead to less harmful Faradaic current passing through the tissue during stimulation in different frequencies. We also compared the designed microneedle electrodes with conventional ones by a 3-dimensional finite element simulation. The results demonstrated that the current density in the deep layers of the skin and the directivity toward a target nerve for microneedle electrodes were much more than those for the conventional ones. Therefore, the designed electrodes are much more efficient than the conventional electrodes for superficial transcutaneous nerve stimulation purposes.
TL;DR: In vitro fabrication of hydrogel microstructures by two photon laser lithography for single cell immobilization and excitation is investigated, demonstrating the illumination of cells by on-the-fly fabricatedHydrogel waveguide networks connected to an external light source, thereby exciting a fluorescence signal in a single immobilized cell.
Abstract: We investigate in vitro fabrication of hydrogel microstructures by two photon laser lithography for single cell immobilization and excitation. Fluorescent yeast cells are embedded in water containing the hydrogel precursor mixtures and cross-linking is used to selectively immobilize a particular cell. Cell viability within the hydrogel precursor is estimated using a life/dead assay and elastic and stiff hydrogel structures are fabricated, immobilizing cells in a microfluidic environment. Additionally, we demonstrate the illumination of cells by on-the-fly fabricated hydrogel waveguide networks connected to an external light source, thereby exciting a fluorescence signal in a single immobilized cell.
TL;DR: This study proposes a spring type medical microrobot that can be manipulated by an electromagnetic actuation (EMA) system and respond to an external stimulus (NIR) and verified its feasibility with regard to targeting and drug delivery.
Abstract: Currently, microrobots are receiving attention because of their small size and motility, which can be applied to minimal invasive therapy. Additionally, various microrobots using hydrogel with the characteristics of biocompatibility and biodegradability are also being developed. Among them, microrobots that swell and deswell in response to temperature changes caused by external near infrared (NIR) stimuli, focused ultrasound, and an alternating magnetic field, have been receiving a great amount of interest as drug carriers for therapeutic cell delivery. In this study, we propose a spring type medical microrobot that can be manipulated by an electromagnetic actuation (EMA) system and respond to an external stimulus (NIR). Additionally, we verified its feasibility with regard to targeting and drug delivery. There exist various methods of fabricating a spring type microrobot. In this study, we adopted a simple method that entails using a perfluoroalkoxy (PFA) microtube and a syringe pump. Moreover, we also used a hydrogel mixture composed of natural alginate, N-Isopropylacrylamide (NIPAM) for temperature responsiveness, and magnetic nanoparticles (MNPs) for electromagnetic control. Then, we fabricated a spring type alginate/NIPAM hydrogel-based soft microrobot. Additionally, we encapsulated doxorubicin (DOX) for tumor therapy in the microrobot. To verify the feasibility of the proposed spring type hydrogel-based soft microrobot's targeting and drug delivery, we developed an EMA and NIR integrated system. Finally, we observed the swelling and deswelling of the soft microrobot under NIR stimulation and verified the EMA controlled targeting. Moreover, we implemented a control function to release the encapsulated anticancer drug (DOX) through the swelling and deswelling of the soft microrobot by NIR, and evaluated the feasibility of cancer cell therapy by controlling the release of the drug from the soft microrobot.
TL;DR: This work validated the compatibility of the iSIMPLE with drug delivery in a controlled way into a skin-like matrix, envisioning a whole new scenario for intradermal injections using self-contained skin patch.
Abstract: In this work, we present a new iSIMPLE concept (infusion Self-powered Imbibing Microfluidic Pump by Liquid Encapsulation), which requires no external power for activation nor liquid manipulation, it is easy to use while its fabrication method is extremely simple, inexpensive and suited for mass replication. The pump consists of a working liquid, which is - after finger activation - absorbed in a porous material (e.g. filter paper). The air expelled from the porous material increases the pressure in the downstream outlet channel and propels the outlet liquid (i.e. the sample) through the channel or ejects it. Here we investigated the influence of different filter papers on the iSIMPLE flow rates, achieving a wide range from 30 down to 0.07 μL/min. We also demonstrated the versatility of the iSIMPLE in terms of the liquid volume that can be manipulated (from 0.5 μL up to 150 μL) and the working pressure reaching 64 kPa, unprecedented high for a self-powered microfluidics pump. In addition, using a 34 G microneedle mounted on the iSIMPLE, we successfully injected liquids with different viscosities (from 0.93 up to 55.88 cP) both into an agarose matrix and a skin-like biological ex vivo substrate (i.e. chicken breast tissue). This work validated the compatibility of the iSIMPLE with drug delivery in a controlled way into a skin-like matrix, envisioning a whole new scenario for intradermal injections using self-contained skin patch. In addition, due to the extreme flexibility of the design and manufacturing, the iSIMPLE concept offers enormous opportunities for completely autonomous, portable and cost effective LOC devices.
TL;DR: The organization of 3D cancer spheroids-based biosensor, which has higher predictive value for drug discovery and personalized medicine screening, is expected to be well applied in the area of pharmacy and clinical medicine.
Abstract: To perform the drug screening, planar cultured cell models are commonly applied to test efficacy and toxicity of drugs However, planar cultured cells are different from the human 3D organs or tissues in vivo To simulate the human 3D organs or tissues, 3D spheroids are developed by culturing a small aggregate of cells which reside around the extracellular matrix and interact with other cells in liquid media Here we apply lung carcinoma cell lines to engineer the 3D lung cancer spheroid-based biosensor using the interdigitated electrodes for drug efficacy evaluation The results show 3D spheroid had higher drug resistance than the planar cell model The anticarcinogen inhibition on different 3D lung cancer spheroid models (A549, H1299, H460) can be quantitatively evaluated by electric impedance sensing Besides, we delivered combination of anticarcinogens treatments to A549 spheroids which is commonly used in clinic treatment, and found the synergistic effect of cisplatin plus etoposide had higher drug response To simultaneously test the drug efficacy and side effects on multi-organ model with circulatory system, a connected multiwell interdigitated electrode arraywas applied to culture different organoid spheroids Overall, the organization of 3D cancer spheroids-based biosensor, which has higher predictive value for drug discovery and personalized medicine screening, is expected to be well applied in the area of pharmacy and clinical medicine
TL;DR: A novel fiber attenuated total reflection (ATR) sensor with silver nanoparticles (AgNPs) on the flattened structure based on mid-infrared spectroscopy for detecting low concentration of glucose with high precision is proposed.
Abstract: This paper proposes a novel fiber attenuated total reflection (ATR) sensor with silver nanoparticles (AgNPs) on the flattened structure based on mid-infrared spectroscopy for detecting low concentration of glucose with high precision. The flattened structure was designed to add the effective optical path length to improve the sensitivity. AgNPs were then deposited on the surface of the flattened area of the fiber via chemical silver mirror reaction for further improving the sensitivity by enhancing the infrared absorption. Combining the AgNPs modified flattened fiber ATR sensor with a CO2 laser showed a strong mid-infrared glucose absorption, with an enhancement factor of 4.30. The glucose concentration could be obtained by a five-variable partial least-squares model with a root-mean-square error of 4.42 mg/dL, which satisfies clinical requirements. Moreover, the fiber-based technique provides a pretty good method to fabricate miniaturized ATR sensors that are suitable to be integrated into a microfluidic chip for continuous glucose monitoring with high sensitivity.
TL;DR: The capability to rapidly activate sperm and consistently measure motility with CASA using the microfluidic device described herein will help improve the reproducibility of studies on sperm and assist development of germplasm repositories.
Abstract: A microfluidic chip is described that facilitates research and quality control analysis of zebrafish sperm which, due to its miniscule (i.e., 2–5 μl) sample volume and short duration of motility (i.e., <1 min), present a challenge for traditional manual assessment methods. A micromixer molded in polydimethylsiloxane (PDMS) bonded to a glass substrate was used to activate sperm samples by mixing with water, initiated by the user depressing a transfer pipette connected to the chip. Sample flow in the microfluidic viewing chamber was able to be halted within 1 s, allowing for rapid analysis of the sample using established computer-assisted sperm analysis (CASA) methods. Zebrafish sperm cell activation was consistent with manual hand mixing and yielded higher values of motility at earlier time points, as well as more subtle time-dependent trends in motility, than those processed by hand. Sperm activation curves, which indicate sample quality by evaluating percentage and duration of motility at various solution osmolalities, were generated with on-chip microfabricated gold floor electrodes interrogated by impedance spectroscopy. The magnitude of admittance was linearly proportional to osmolality and was not affected by the presence of sperm cells in the vicinity of the electrodes. This device represents a pivotal step in streamlining methods for consistent, rapid assessment of sperm quality for aquatic species. The capability to rapidly activate sperm and consistently measure motility with CASA using the microfluidic device described herein will help improve the reproducibility of studies on sperm and assist development of germplasm repositories.
TL;DR: The microtissue vacuum-actuated stretcher (MVAS) was shown to be capable of delivering reproducible dynamic bulk strain amplitudes up to 13%, and may further the understanding of the reciprocity shared between cells and their environment.
Abstract: Although our understanding of cellular behavior in response to extracellular biological and mechanical stimuli has greatly advanced using conventional 2D cell culture methods, these techniques lack physiological relevance. To a cell, the extracellular environment of a 2D plastic petri dish is artificially flat, extremely rigid, static and void of matrix protein. In contrast, we developed the microtissue vacuum-actuated stretcher (MVAS) to probe cellular behavior within a 3D multicellular environment composed of innate matrix protein, and in response to continuous uniaxial stretch. An array format, compatibility with live imaging and high-throughput fabrication techniques make the MVAS highly suited for biomedical research and pharmaceutical discovery. We validated our approach by characterizing the bulk microtissue strain, the microtissue strain field and single cell strain, and by assessing F-actin expression in response to chronic cyclic strain of 10%. The MVAS was shown to be capable of delivering reproducible dynamic bulk strain amplitudes up to 13%. The strain at the single cell level was found to be 10.4% less than the microtissue axial strain due to cellular rotation. Chronic cyclic strain produced a 35% increase in F-actin expression consistent with cytoskeletal reinforcement previously observed in 2D cell culture. The MVAS may further our understanding of the reciprocity shared between cells and their environment, which is critical to meaningful biomedical research and successful therapeutic approaches.
TL;DR: A promising class of drug delivery system known as micelle-like nanoparticles is introduced and their synthesis and advantages for gene therapy as well as the recent findings in in vitro, in vivo and clinical studies are explored.
Abstract: Gene therapy has emerged as an alternative in the treatment of cancer, particularly in cases of resistance to chemo and radiotherapy. Different approaches to deliver genetic material to tumor tissues have been proposed, including the use of small non-coding RNAs due to their multiple mechanisms of action. However, such promise has shown limits in in vivo application related to RNA's biological instability and stimulation of immunity, urging the development of systems able to overcome those barriers. In this review, we discuss the use of RNA interference in cancer therapy with special attention to the role of siRNA and miRNA and to the challenges of their delivery in vivo. We introduce a promising class of drug delivery system known as micelle-like nanoparticles and explore their synthesis and advantages for gene therapy as well as the recent findings in in vitro, in vivo and clinical studies.
TL;DR: A new 3D printed bioreactor system, which allows optical access to the cells throughout testing for in line monitoring, and was optimized to achieve the maximum fluid transport through the central chamber, which corresponds to optimal nutrient or drug exposure.
Abstract: Bioreactors are systems that can be used to monitor the response of tissues and cells to candidate drugs. Building on the experience developed in the creation of an osteochondral bioreactor, we have designed a new 3D printed system, which allows optical access to the cells throughout testing for in line monitoring. Because of the use of 3D printing, the fluidics could be developed in the third dimension, thus maintaining the footprint of a single well of a typical 96 well plate. This new design was optimized to achieve the maximum fluid transport through the central chamber, which corresponds to optimal nutrient or drug exposure. This optimization was achieved by altering each dimension of the bioreactor fluid path. A physical model for optimized drug exposure was then created and tested.