Hung Cao

Power Approaches for Implantable Medical Devices

Implantable medical devices have been implemented to provide treatment and to assess in vivo physiological information in humans as well as animal models for medical diagnosis and prognosis, therapeutic applications and biological science studies. The advances of micro/nanotechnology dovetailed with novel biomaterials have further enhanced biocompatibility, sensitivity, longevity and reliability in newly-emerged low-cost and compact devices. Close-loop systems with both sensing and treatment functions have also been developed to provide point-of-care and personalized medicine. Nevertheless, one of the remaining challenges is whether power can be supplied sufficiently and continuously for the operation of the entire system. This issue is becoming more and more critical to the increasing need of power for wireless communication in implanted devices towards the future healthcare infrastructure, namely mobile health (m-Health). In this review paper, methodologies to transfer and harvest energy in implantable medical devices are introduced and discussed to highlight the uses and significances of various potential power sources.

An Integrated μLED Optrode for Optogenetic Stimulation and Electrical Recording

In this letter, we developed an integrated neural probe prototype for optogenetic stimulation by microscale light-emitting diode (μLED) and simultaneous recording of neural activities with microelectrodes on a single-polyimide platform. Optogenetics stimulates in vivo neural circuits with high-cellular specificity achieved by genetic targeting and precise temporal resolution by interaction of light-gated ion channels with optical beam. In our newly developed optrode probe, during optogenetic stimulation of neurons, continuous sensing of neuronal activities in vicinity of the activation site can provide feedback to stimulation or examine local responses in signal pathways. In the device, focusing the light from the μLED was achieved with an integrated photo-polymerized lens. The efficacy of the optrode for cortical stimulation and recording was tested on mice visual cortex neurons expressing channelrhodopsin-2. Stimulation intensity and frequency-dependent spiking activities of visual cortex were recorded. Our device has shown advantages over fiber-coupled laser-based optrode in terms of closed-loop integration, single-implant compactness and lower electrical power requirements, which would be clinically applicable for future prosthetic applications in personalized medicine.

An Implantable, Batteryless, and Wireless Capsule With Integrated Impedance and pH Sensors for Gastroesophageal Reflux Monitoring

In this study, a device for gastroesophageal reflux disease (GERD) monitoring has been prototyped. The system consists of an implantable, batteryless and wireless transponder with integrated impedance and pH sensors; and a wearable, external reader that wirelessly powers up the transponder and interprets the transponded radio-frequency signals. The transponder implant with the total size of 0.4 cm ×0.8 cm ×3.8 cm harvests radio frequency energy to operate dual-sensor and load-modulation circuitry. The external reader can store the data in a memory card and/or send it to a base station wirelessly, which is optional in the case of multiple-patient monitoring in a hospital or conducting large-scale freely behaving animal experiments. Tests were carried out to verify the signal transduction reliability in different situations for antenna locations and orientation. In vitro, experiments were conducted in a mannequin model by positioning the sensor capsule inside the wall of a tube mimicking the esophagus. Different liquids with known pH values were flushed through the tube creating reflux episodes and wireless signals were recorded. Live pigs under anesthesia were used for the animal models with the transponder implant attached on the esophageal wall. The reflux episodes were created while the sensor data were recorded wirelessly. The data were compared with those recorded independently by a clinically used wireless pH sensor capsule placed next to our implant transponder. The results showed that our transponder detected every episode in both acid and non-acid nature, while the commercial pH sensor missed events that had similar, repeated pH values, and failed to detect pH values higher than 10. Our batteryless transponder does not require a battery thus allowing longer diagnosis and prognosis periods to monitor drug efficacy, as well as providing accurate assessment of GERD symptoms.

Moving Domain Computational Fluid Dynamics to Interface with an Embryonic Model of Cardiac Morphogenesis

Peristaltic contraction of the embryonic heart tube produces time- and spatial-varying wall shear stress (WSS) and pressure gradients (∇P) across the atrioventricular (AV) canal. Zebrafish (Danio rerio) are a genetically tractable system to investigate cardiac morphogenesis. The use of Tg(fli1a:EGFP)y1 transgenic embryos allowed for delineation and two-dimensional reconstruction of the endocardium. This time-varying wall motion was then prescribed in a two-dimensional moving domain computational fluid dynamics (CFD) model, providing new insights into spatial and temporal variations in WSS and ∇P during cardiac development. The CFD simulations were validated with particle image velocimetry (PIV) across the atrioventricular (AV) canal, revealing an increase in both velocities and heart rates, but a decrease in the duration of atrial systole from early to later stages. At 20-30 hours post fertilization (hpf), simulation results revealed bidirectional WSS across the AV canal in the heart tube in response to peristaltic motion of the wall. At 40-50 hpf, the tube structure undergoes cardiac looping, accompanied by a nearly 3-fold increase in WSS magnitude. At 110-120 hpf, distinct AV valve, atrium, ventricle, and bulbus arteriosus form, accompanied by incremental increases in both WSS magnitude and ∇P, but a decrease in bi-directional flow. Laminar flow develops across the AV canal at 20-30 hpf, and persists at 110-120 hpf. Reynolds numbers at the AV canal increase from 0.07±0.03 at 20-30 hpf to 0.23±0.07 at 110-120 hpf (p< 0.05, n=6), whereas Womersley numbers remain relatively unchanged from 0.11 to 0.13. Our moving domain simulations highlights hemodynamic changes in relation to cardiac morphogenesis; thereby, providing a 2-D quantitative approach to complement imaging analysis.

Fabrication and characterization of biomimetic multichanneled crosslinked‐urethane‐doped polyester tissue engineered nerve guides

Biomimetic scaffolds that replicate the native architecture and mechanical properties of target tissues have been recently shown to be a very promising strategy to guide cellular growth and facilitate tissue regeneration. In this study, porous, soft, and elastic crosslinked urethane-doped polyester (CUPE) tissue engineered nerve guides were fabricated with multiple longitudinally oriented channels and an external non-porous sheath to mimic the native endoneurial microtubular and epineurium structure, respectively. The fabrication technique described herein is highly adaptable and allows for fine control over the resulting nerve guide architecture in terms of channel number, channel diameter, porosity, and mechanical properties. Biomimetic multichanneled CUPE guides were fabricated with various channel numbers and displayed an ultimate peak stress of 1.38 ± 0.22 MPa with a corresponding elongation at break of 122.76 ± 42.17%, which were comparable to that of native nerve tissue. The CUPE nerve guides were also evaluated in vivo for the repair of a 1 cm rat sciatic nerve defect. Although histological evaluations revealed collapse of the inner structure from CUPE TENGs, the CUPE nerve guides displayed fiber populations and densities comparable with nerve autograft controls after 8 weeks of implantation. These studies are the first report of a CUPE-based biomimetic multichanneled nerve guide and warrant future studies towards optimization of the channel geometry for use in neural tissue engineering.

Shear Stress–Activated Wnt-Angiopoietin-2 Signaling Recapitulates Vascular Repair in Zebrafish Embryos

Objective— Fluid shear stress intimately regulates vasculogenesis and endothelial homeostasis. The canonical Wnt/&bgr;-catenin signaling pathways play an important role in differentiation and proliferation. In this study, we investigated whether shear stress activated angiopoietin-2 (Ang-2) via the canonical Wnt signaling pathway with an implication in vascular endothelial repair. Approach and Results— Oscillatory shear stress upregulated both TOPflash Wnt reporter activities and the expression of Ang-2 mRNA and protein in human aortic endothelial cells accompanied by an increase in nuclear &bgr;-catenin intensity. Oscillatory shear stress–induced Ang-2 and Axin-2 mRNA expression was downregulated in the presence of a Wnt inhibitor, IWR-1, but was upregulated in the presence of a Wnt agonist, LiCl. Ang-2 expression was further downregulated in response to a Wnt signaling inhibitor, DKK-1, but was upregulated by Wnt agonist Wnt3a. Both DKK-1 and Ang-2 siRNA inhibited endothelial cell migration and tube formation, which were rescued by human recombinant Ang-2. Both Ang-2 and Axin-2 mRNA downregulation was recapitulated in the heat-shock–inducible transgenic Tg(hsp70l:dkk1-GFP) zebrafish embryos at 72 hours post fertilization. Ang-2 morpholino injection of Tg (kdrl:GFP) fish impaired subintestinal vessel formation at 72 hours post fertilization, which was rescued by zebrafish Ang-2 mRNA coinjection. Inhibition of Wnt signaling with IWR-1 also downregulated Ang-2 and Axin-2 expression and impaired vascular repair after tail amputation, which was rescued by zebrafish Ang-2 mRNA injection. Conclusions— Shear stress activated Ang-2 via canonical Wnt signaling in vascular endothelial cells, and Wnt-Ang-2 signaling is recapitulated in zebrafish embryos with a translational implication in vascular development and repair.

A wireless strain sensor system for bladder volume monitoring

A wireless strain sensor system has been designed to monitor the bladder volume in patients suffering from urinary incontinence. An interdigitated capacitive (IDC) strain sensor was micro-machined from a 127-µm thick brass shim with a laser system, followed by an encapsulation process to package the sensor in elastic polydimethylsiloxane (PDMS). A proof-of-concept passive telemetry platform was developed to employ the sensor in vivo and a commercial wireless module was utilized for networking and data recording. The system includes a transducer implant, an external wearable unit and a base station. The implant harvests electromagnetic energy from the external unit, supplies power to operate the sensor and transduces the sensor data back. The wearable unit processes and transfers the signals to the base station connected to a computer which continuously displays and records the strain sensor data on the bladder. The sensor was calibrated and the entire system was tested with a bladder phantom model. Results were promising and demonstrated the feasibility of our passive wireless strain sensing system for urinary incontinence management.

Hemodynamics and ventricular function in a zebrafish model of injury and repair.

Myocardial infarction results in scar tissue and irreversible loss of ventricular function. Unlike humans, zebrafish has the capacity to remove scar tissue after injury. To assess ventricular function during repair, we synchronized microelectrocardiogram (μECG) signals with a high-frequency ultrasound pulsed-wave (PW) Doppler to interrogate cardiac hemodynamics. μECG signals allowed for identification of PW Doppler signals for passive (early [E]-wave velocity) and active ventricular filling (atrial [A]-wave velocity) during diastole. The A wave (9.0±1.2 cm·s(-1)) is greater than the E wave (1.1±0.4 cm·s(-1)), resulting in an E/A ratio <1 (0.12±0.05, n=6). In response to cryocauterization to the ventricular epicardium, the E-wave velocity increased, accompanied by a rise in the E/A ratio at 3 days postcryocauterization (dpc) (0.55±0.13, n=6, p<0.001 vs. sham). The E waves normalize toward the baseline, along with a reduction in the E/A ratio at 35 dpc (0.36±0.06, n=6, p<0.001 vs. sham) and 65 dpc (0.2±0.16, n=6, p<0.001 vs. sham). In zebrafish, E/A<1 at baseline is observed, suggesting the distinct two-chamber system in which the pressure gradient across the atrioventricular valve is higher compared with the ventriculobulbar valve. The initial rise and subsequent normalization of E/A ratios support recovery in the ventricular diastolic function.

Sol-Gel Iridium Oxide-Based pH Sensor Array on Flexible Polyimide Substrate

Iridium oxide pH sensing film is demonstrated with wide pH-sensing ranges, high durability, and small drifts in potentials. Using sol-gel process, a lower fabrication cost and less labor-intensive method, to deposit iridium oxide thin films for pH sensing is reported previously by our group with expected advantages. In this paper, we fabricate and test pH sensing characteristics of 4 × 4 anhydrous iridium oxide thin-film electrode arrays on flexible substrates. The sensors in arrays exhibit Nernstian potential responses in the range of 57.0-63.4 mV/pH. Stability, repeatability, and hysteresis effects of the pH sensor arrays are examined. A multichannel recording system is built to demonstrate the functionality of the pH sensor arrays in monitoring spatial and temporal pH changes across a surface.

Stretchable electrochemical impedance sensors for intravascular detection of lipid-rich lesions in New Zealand White rabbits

Flexible electronics have enabled catheter-based intravascular sensing. However, real-time interrogation of unstable plaque remains an unmet clinical challenge. Here, we demonstrate the feasibility of stretchable electrochemical impedance spectroscopy (EIS) sensors for endoluminal investigations in New Zealand White (NZW) rabbits on diet-induced hyperlipidemia. A parylene C (PAC)-based EIS sensor mounted on the surface of an inflatable silicone balloon affixed to the tip of an interrogating catheter was deployed (1) on the explants of NZW rabbit aorta for detection of lipid-rich atherosclerotic lesions, and (2) on live animals for demonstration of balloon inflation and EIS measurements. An input peak-to-peak AC voltage of 10 mV and sweeping-frequency from 300 kHz to 100 Hz were delivered to the endoluminal sites. Balloon inflation allowed EIS sensors to be in contact with endoluminal surface. In the oxidized low-density-lipoprotein (oxLDL)-rich lesions from explants of fat-fed rabbits, impedance magnitude increased significantly by 1.5-fold across the entire frequency band, and phase shifted ~5° at frequencies below 10 kHz. In the lesion-free sites of the normal diet-fed rabbits, impedance magnitude increased by 1.2-fold and phase shifted ~5° at frequencies above 30 kHz. Thus, we demonstrate the feasibility of stretchable intravascular EIS sensors for identification of lipid rich lesions, with a translational implication for detecting unstable lesions.