Biomedical Engineering

This work presents an energy-efficient electrocorticography (ECoG) array architecture for fully-implantable brain machine interface systems. A novel dual-mode analog signal processing method is introduced that extracts neural features from high-γ band (80-160 Hz) at the early stages of signal acquisition. Initially, brain activity across the full-spectrum is momentarily observed to compute the feature weights in the digital back-end during full-band mode operation. Subsequently, these weights are fed back to the front-end and the system reverts to base-band mode to perform feature extraction. This approach utilizes a distinct optimized signal pathway based on power envelope extraction, resulting in 1.72× power reduction in the analog blocks and up to 50× potential power savings for digitization and processing (implemented off-chip in this work). A prototype incorporating a 32-channel ultra-low power signal acquisition front-end is fabricated in 180nm CMOS process with 0.8V supply. This chip consumes 1.05 µW (0.205 µW for feature extraction only) power and occupies 0.245 mm 2 die area per channel. The chip measurement shows better than 76.5-dB common-mode rejection ratio (CMRR), 4.09 noise efficiency factor (NEF), and 10.04 power efficiency factor (PEF). In-vivo human tests have been carried out with electroencephalography and ECoG signals to validate the performance and dual-mode operation in comparison to commercial acquisition systems.

Objective. Electrocorticogram (ECoG)-based brain-computer interfaces (BCIs) are a promising platform for the restoration of motor and sensory functions to those with neurological deficits. Such bi-directional BCI operation necessitates simultaneous ECoG recording and stimulation, which is challenging given the presence of strong stimulation artifacts. This problem is exacerbated if the BCI's analog front-end operates in an ultra-low power regime, which is a basic requirement for fully implantable medical devices. In this study, we developed a novel method for the suppression of stimulation artifacts before they reach the analog front-end. Approach. Using elementary biophysical considerations, we devised an artifact suppression method that employs a weak auxiliary stimulation delivered between the primary stimulator and the recording grid. The exact location and amplitude of this auxiliary stimulating dipole were then found through a constrained optimization procedure. The performance of our method was tested in both simulations and phantom brain tissue experiments. Main results. The solution found through the optimization procedure matched the optimal canceling dipole in both simulations and experiments. Artifact suppression as large as 28.7 dB and 22.9 dB were achieved in simulations and brain phantom experiments, respectively. Significance. We developed a simple constrained optimization-based method for finding the parameters of an auxiliary stimulating dipole that yields optimal artifact suppression. Our method suppresses stimulation artifacts before they reach the analog front-end and may prevent the front-end amplifiers from saturation. Additionally, it can be used along with other artifact mitigation techniques to further reduce stimulation artifacts.

Objective. State-of-the-art invasive brain-machine interfaces (BMIs) have shown significant promise, but rely on external electronics and wired connections between the brain and these external components. This configuration presents health risks and limits practical use. These limitations can be addressed by designing a fully implantable BMI similar to existing FDA-approved implantable devices. Here, a prototype BMI system whose size and power consumption are comparable to those of fully implantable medical devices was designed and implemented, and its performance was tested at the benchtop and bedside. Approach. A prototype of a fully implantable BMI system was designed and implemented as a miniaturized embedded system. This benchtop analogue was tested in its ability to acquire signals, train a decoder, perform online decoding, wirelessly control external devices, and operate independently on battery. Furthermore, performance metrics such as power consumption were benchmarked. Mai...

Two brain signal acquisition (BSA) front-ends incorporating two CMOS ultra-low power low noise amplifier arrays and serializers operating in MOSFET weak inversion region are presented. To boost the amplifier's gain for a given current budget, cross-coupled-pair active load topology is used in the first stages of these two amplifiers. These two BSA frontends are fabricated in 130 nm and 180nm CMOS processes, occupying 5.45 mm 2 and 0.352 mm 2 of die areas, respectively (excluding pad rings). The CMOS 130 nm amplifier array is comprised of 64 elements, where each amplifier element consumes 0.216 μW from 0.4 V supply, has input-referred voltage noise (IRNoise) of 2.19 μV RM S corresponding to a power efficiency factor (PEF) of 11.7 and occupies 0.044 mm 2 of die area. The CMOS 180 nm amplifier array employs 4 elements, where each element consumes 0.69 μW from 0.6 V supply with IRNoise of 2.3 μVRMS (corresponding to a PEF of 19.3) and 0.051 mm 2 of die area. Non-invasive electroencephalographic (EEG) and invasive electrocorticographic (ECoG) signals were recorded real-time directly on able-bodied human subjects, showing feasibility of using these analog front-ends (AFEs) for future fully implantable brain signal acquisition and brain computer interface systems. Index Terms -CMOS, Electrocorticography (ECoG), Electroencephalogram (EEG), ultra-low power (ULP), noise efficiency factor (NEF), power efficiency factor (PEF), operational transconductance amplifier (OTA), instrumentation amplifier (InAmp), analog front-end (AFE), weak inversion (WI) region.

Conventional brain-computer interfaces (BCIs) are often expensive, complex to operate, and lack portability, which confines their use to laboratory settings. Portable, inexpensive BCIs can mitigate these problems, but it remains unclear whether their low-cost design compromises their performance. Therefore, we developed a portable, low-cost BCI and compared its performance to that of a conventional BCI. The BCI was assembled by integrating a custom electroencephalogram (EEG) amplifier with an open-source microcontroller and a touchscreen. The function of the amplifier was first validated against a commercial bioamplifier, followed by a head-to-head comparison between the custom BCI (using 4 EEG channels) and a conventional 32-channel BCI. Specifically, 5 able-bodied subjects were cued to alternate between hand opening/closing and remaining motionless while the BCI decoded their movement state in real-time and provided visual feedback through a light emitting diode. Subjects repeated...

Remote microactuators are of great interest in biology and medicine as minimally-invasive tools for cellular stimulation. Remote actuation can be achieved by active magnetostrictive transducers which are capable of changing shape in response to external magnetic fields thereby creating controlled displacements. Among the magnetostrictive materials, Galfenol, the multifaceted iron-based smart material, offers high magnetostriction with robust mechanical properties. In order to explore these capabilities for biomedical applications, it is necessary to study the feasibility of material miniaturization in standard fabrication processes as well as evaluate the biocompatibility. Here we develop a technology to fabricate, release, and suspend Galfenol-based microparticles, without affecting the integrity of the material. The morphology, composition and magnetic properties of the material itself are characterized. The direct cytotoxicity of Galfenol is evaluated in vitro using human macroph...

The adequacy of the model is evaluated by R-squared . Two-night recordings of the 45 subjects and segmented two-night recordings of 13 subjects, who are selected among the 45 subjects, are utilized for the validation of the second hypothesis. Training and evaluation of the trained classifier is performed using Leave-One-Out Cross-Validation (LOOCV) . The classification performance is evaluated using the area under the Precision-Recall curve, which is a metric more suitable than the area under the ROC curve in the case where class-imbalance problem exists. Partial data and ground-truths of the test subject/cycle are used for the construction of personalized classifier. The performance of the personalized classifier is compared to that of a subject-independent classifier. Chapter 2 gives an overview of the sleep physiology. It also summarizes the past work on unobtrusive sleep staging. The classification framework is introduced in detail as well. Furthermore, the result of an early investigation on deep sleep classification is explained in this chapter. In the end of Chapter 2, the two hypotheses that need to be validated are presented. Chapter 3 describes the methods and procedures of the validation of the two hypotheses. The description of the experiment setup and dataset employed in this research are also introduced. The result of validations and detailed discussion are presented in Chapter 4. Chapter 5 and Chapter 6 describe the conclusions and future work respectively.

We have been performing arthroscopic rotator cuff repair since 1991. Short-term results have been previously presented and have been encouraging. Presented here are long-term results (minimum of 8 years postoperative) in a consecutive series of 64 patients who underwent 64 arthroscopic rotator cuff repairs. Three patients had died and 6 could not be located, leaving 55 patients who were reevaluated. We were able to personally interview and examine 48 patients; 7 patients were interviewed by telephone. The average age of these patients was 68 years. The repair technique used in these patients was predominantly our older technique utilizing No. 1 PDS and push-in anchors. Most of the tears were nonretracted crescent shaped tears and were repaired directly end to bone. We have traditionally evaluated our patients using the Modified UCLA (MUCLA) scoring system (45 points maximum). This group of patients was also evaluated using this scoring system. Eight year postoperative American Shoulder and Elbow Society and Constant scores were also determined for this group. For MUCLA scoring, we were able to compare the preoperative scores with the results of our previously published evaluation at 2-3 years and our current evaluation at 8 years. The average preoperative MUCLA score was 17, the 2-3 year score was 41, and the 8 year score was also 41. Excellent results were achieved in 68% at 2-3 years and in 75% at 8 years. Good results were obtained in 25% at 2-3 years and 10% at 8 years. Fair results were obtained in 2% of both 2-3 year and 8 year follow-up groups. Poor results were recorded in 5% at 2-3 years and 13% at 8 years. American Shoulder and Elbow Society Scores at 8 years were as follows: 90.8 average overall score (range 40-100), Average pain score was 0.9. Average ADL score was 27.3. Average strength score was 4.8 (abduction) and 4.9 (IR and ER). Constant Scores at 8 years were as follows: 91.3 average overall score (range 68-100). Average pain score was 13. Average total ADL score was 18.8. Average ROM score was 36.1. Average strength score was 12.3. Average strength score when compared to the unaffected side (operated side score ϫ 25/unaffected side score) was 22.4. We used this comparison value to determine the overall average score. Overall, the results of arthroscopic rotator cuff repair are very good and have shown to be durable at 8 year follow-up. These results compare well to the long-term results of open repairs. It must be noted, however, that these are the results of the repair of only the smaller tears that were undertaken at the time. Currently we are using stronger sutures with higher pull-out strength anchors and are repairing much larger tears. The short-term results of these repairs are also good but their long-term durability must still be determined.

To analyze the effect of intramedullary reaming on fracture healing, we investigated whether or not cortical reamings contain viable bone cells. There are several tissue components contained in medullary reamings including blood, bone marrow and cortical bone. This study is focused on the cortical reamings, which are produced during reaming of the medullary cavity. They may stimulate fracture healing but it is still unclear if they contain vital bone cells. We tested the hypothesis that these cortical reamings are a source of viable bone cells and compared cell cultures with cultivated cells from iliac crest biopsies. Responses of protein content and ALP activity to vitD stimulation in the cells were considered as properties of viability. Ten in tact living sheep femora were fully reamed and the cortical reamings were cultivated in a standard manner and compared with cultivated cells from ipsilateral iliac crest biopsies from the same animals. Cells started to grow from the reamings as well as the iliac crest within 2-5 days, and covered the entire culture flask within 9-13 days. Protein content and ALP activity in cells from both reamings and iliac crest were significantly responsive to vitD stimulation. Cortical reamings from intramedullary nailing have osteoblastic potential and contain living bone cells similar to bone cells from the iliac crest. These findings may further explain the superior healing of fractures, treated with reamed nailing.

Hydroxyapatite is a synthetic bone graft, which is used for the treatment of bone defects and nonunions. However, it is a rather inert material with no or little intrinsic osteoinductive activity. Recombinant human osteogenic protein‐1 (rhOP‐1) is a very potent biological agent, that enhances osteogenesis during bone repair. Bone marrow contains mesenchymal stem cells, which are capable of new bone formation. Biosynthetic bone grafts were created by the addition of rhOP‐1 or bone marrow to granular porous hydroxyapatite. The performance of these grafts was tested in a sheep model and compared to the results of autograft, which is clinically the standard treatment of bone defects and nonunions. A 3 cm segmental bone defect was made in the tibia and fixed with an interlocking intramedullary nail. There were five treatment groups: no implant (n = 6), autograft (n = 8), hydroxyapatite alone (n = 8), hydroxyapatite loaded with rhOP‐1 (n = 8), and hydroxyapatite loaded with autologous bon...

Study Design: Retrospective study and review of literature. Objectives: Study of demographic data concerning spinal fractures caused by horse riding, classification of fractures according to the AO and Load Sharing classifications, evaluation of mid-term radiological results and long-term functional results. Methods: A review of medical reports and radiological examinations of patients presented to our hospital with horse riding-related spine fractures over a 13-year period; long-term functional follow-up is performed using the Roland Morris Disability Questionnaire (RMDQ-24). Results: Thirty-six spine fractures were found in 32 patients. Male to female ratio is 1:7. Average age is 33.7 years (8-58 years). The majority of the fractures (78%) are seen at the thoracolumbar junction Th11-L2. All but two patients have AO type A fractures. The average Load Sharing Classification score is Keywords Sports medicine AE Spinal fractures AE Horses AE Review

Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.

The management of unstable traumatic thoracolumbar fractures without neurological deficits remains controversial. The objective of this study was to compare the effectiveness of operative and conservative treatment of unstable traumatic thoracolumbar fractures. PubMed was used to search for articles published from January 1992 to January 2003 using a variety of keywords. References were checked to identify additional studies. Inclusion criteria were: (1) traumatic lumbar, thoracic or thoracolumbar fractures, (2) unstable fractures without neurological deficits, (3) a comparison between operative and conservative treatment, (4) at least ten patients were included in the study. Seventeen studies were identified; four prospective and 13 retrospective studies. Sample sizes in 15 studies were relatively small (18-100 patients); two studies had larger sample sizes. Comparison among different studies was difficult due to insufficient description of interventions, different outcome measures, and different length of follow-up periods. The current literature does not provide a reliable answer to whether operative or conservative treatment is more effective for unstable traumatic thoracolumbar fractures. High quality randomised controlled trials are direly needed. Keywords Traumatic thoracolumbar fractures AE Management AE Operative AE Non-operative treatment

In this paper, a novel combination method of electrospinning and rapid prototyping (RP) fused deposition modeling (FDM) is proposed for the fabrication of a tissue engineering heart valve (TEHV) scaffold. The scaffold preparation consisted of two steps: tri-leaflet scaffold fabrication and heart valve ring fabrication. With the purpose of mimicking the anisotropic mechanical properties of the natural heart valve leaflet, electrospun thermoplastic polyurethane (ES-TPU) was introduced as the tri-leaflet scaffold material. ES-TPU scaffolds can be fabricated to have a well-aligned fiber network, which is important for applications involving mechanically anisotropic soft tissues. We developed ES-TPU scaffolds as heart valve leaflet materials under variable speed conditions and measured fiber alignment by fast Fourier transform (FFT). By using FFT to assign relative alignment values to an electrospun matrix, it is possible to systematically evaluate how different processing variables affect the structure and material properties of a scaffold. TPU was suspended at certain concentrations and electrospun from 1,1,1,3,3,3-hexafluoro-2-propanol onto rotating mandrels (200-3000 rpm). The scaffold morphological property and mechanical anisotropic property are discussed in the paper as a function of fiber diameter and mandrel RPM. The induction of varying degrees of anisotropy imparted distinctive material properties to the electrospun scaffolds. A dynamic optimum design of the heart valve ring graft was constructed by FDM. Fabrication of a 3D heart valve ring was constructed using proengineer based on optimum hemodynamic analysis and was converted to an STL file format. The model was then created from PCL which was sewed and glued with electrospun nanofibrous leaflets. This proposed method was proven as a promising fabrication process in fabricating a specially designed graft with the correct physical and mechanical properties.

We present, for the first time, an analysis of the error signatures captured during pulsed laser microprobe testing of high-speed digital SiGe logic circuits. 127-bit shift registers, configured using various circuit level latch hardening schemes and incorporated into the circuit for radiation effects self test serve as the primary test vehicle. Our results indicate significant variations in the observed upset rate as a function of strike location and latch architecture. Error information gathered on the sensitive transistor nodes within the latches and characteristic upset durations agree well with recently reported heavy-ion microprobe data. These results support the growing credibility in using pulsed laser testing as a lower-cost alternative to heavy-ion microprobe analysis of sensitive device and circuit nodes, as well as demonstrate the efficiency of the autonomous detection and error approach for high speed bit-error rate testing. Implications for SEU hardening in SiGe are addressed and circuit-level and device-level Radiation Hardening By Design recommendations are made. Index Terms-Built-in self-test, circuit level hardening, highspeed bit-error rate testing, pulsed laser testing, silicon-germanium (SiGe), single-event effects (SEU). I. INTRODUCTION S ILICON-GERMANIUM HBT technology continues to make in-roads into the extreme environment electronics market. Recently reported results on the most aggressively scaled SiGe technologies include excellent low temperature performance [1] and inherent tolerance to multi-Mrad (SiO ) levels of ionizing dose [2]. These attributes, coupled with its seamless integration with best-of-breed CMOS to form SiGe Manuscript received August 25, 2006.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

We have applied wide-field digital interferometry (WFDI) to examine the morphology and dynamics of live red blood cells (RBCs) from individuals who suffer from sickle cell anemia (SCA), a genetic disorder that affects the structure and mechanical properties of RBCs. WFDI is a noncontact, label-free optical microscopy approach that can yield quantitative thickness profiles of RBCs and measurements of their membrane fluctuations at the nanometer scale reflecting their stiffness. We find that RBCs from individuals with SCA are significantly stiffer than those from a healthy control. Moreover, we show that the technique is sensitive enough to distinguish classes of RBCs in SCA, including sickle RBCs with apparently normal morphology, compared to the stiffer crescent-shaped sickle RBCs. We expect that this approach will be useful for diagnosis of SCA and for determining efficacy of therapeutic agents.

and 0,4 mm for the glenoid width. For glenoidal measurements, both methods were similar. For humeral measurements, the MPR-method demonstrated a higher inter-and intraobserver reliability than the 3DRmethod. Conclusions: The newly described MPR-method for the assessment of the glenoid track and HSI is at least as accurate as the published 3DR-method, with a better intra-and interobserver reliability. Since MPR are also easier to obtain, this method could be recommended for on/off track evaluation in daily practice.

was significantly lower compared with contralateral side (p < 0.001). Posterior deltoid activity was no detectable. Range of motion at 2 years of follow-up decreased in terms of forward flexion (p = 0.045), abduction (p = 0.03) and external rotation (p < 0.001). Conclusions Our study demonstrates that even if the patients remain pain-free, progressive deterioration of the deltoid activity is unavoidable and may lead to poor functional outcomes overtime. Shoulder • Osteoarthritis • Reverse shoulder prostheses • Deltoid muscle • Electromyography * A. Pellegrini

Background Implant registries have proved valuable in assessing the outcomes of arthroplasty procedures. Moreover, by identifying lesser quality implants they have indirectly improved the quality of care. The registry of prosthetic shoulder implants was established in 2008. Methods It records information on all types of primary and revision arthroplasty procedures involving the glenohumeral joint, including reverse and total arthroplasty, hemiarthroplasty, resurfacing, removal, and any other surgical procedures that are required to manage these patients. The collected data include patient demographics, weight, height, operated side, cuff status, and diagnosis/reason for revision surgery, information on previous surgical procedures involving either shoulder, comorbidities, antibiotic and thromboembolic prophylaxis, blood transfusions, surgical approach, cuff repair procedures performed during arthroplasty, bone grafts, drains, and perioperative complications, and data about the prosthetic components implanted, including the fixation method. Results Procedures were performed on 3754 shoulders. They included 2226 RSA, 320 TSA, 730 HA, 233 resurfacing procedures, 245 revisions, and 77 "other" procedures. The survival curves of the implants are greater than 90%, and no differences were found among prosthesis from different manufacturers. The diagnosis that prompted to arthroplasty was: osteoarthritis in 60.9% of cases and fractures, bone necrosis, sequelae of fracture and rotator cuff tear arthropathy for the rest of implants. Discussion and conclusion This study describes the epidemiological data and mid-term implant outcomes of the shoulder arthroplasty procedures performed in our region, from 2008 to 2014, and compares them with published data from national registries of similar size. Level of evidence III.

Background: Arthroscopic repair of anterior dislocation of the shoulder can faii. We hypothesized that patients who are at higher risk for redislocation following repair could be recognized preoperatively on the basis of their clinical history. The purpose of the present study was to identify the risk factors for recurrence in a community-based population of patients with traumatic unidirectional instability that was treated with a single arthroscopic technique. Methods: From January 2000 to December 2003, 625 patients with anterior unidirectional instability were managed with an arthroscopic Bankart technique, and 385 met the criteria for inclusion in the study. Demographic data were collected, and clinical follow-up was performed at three, six, twelve, twenty-four, and thirty-six months. Results: At thirty-six months, thirty-one patients (8.1%) had experienced a redislocation: the rate was 13.3% among patients who were twenty-two years of age and younger and 6.3% among older patients. Age at the time of the first dislocation, male sex, and the time from the first dislocation until surgery were significant risk factors for recurrence (p < 0.05 for all). Conclusions: Patients who are more likely to have a redislocation following arthroscopic repair of an anterior shoulder dislocation can be identified preoperatively on the basis of sex, age, and the time from the first dislocation to surgery.

Highly uniform silicon nanopore membranes were developed for applications in implantable bioartificial organs. A robust, readily scalable, non-fouling surface coating is required to enhance silicon nanopore membrane hemocompatibility. However, the coating must be ultrathin to keep the nanopores from occluding. Recently, zwitterionic brush polymers have demonstrated significantly lower fouling under biological conditions. In this study, we explore ultrathin zwitterionic poly(sulfobetaine methacrylate) (pSBMA) surface coating at sub-5 nm thickness. Membrane hydraulic permeability was measured before and after surface modification of silicon nanopore membranes, and pores were found to be patent and in agreement with coating thickness measurements. Coating stability was analyzed under biological shear as well as under blood flow in vitro and in vivo. Following exposure to shear over 24 h, coatings were characterized via X-ray photoelectron spectroscopy, goniometry, and ellipsometry, and found to survive biological shear. In vitro blood experiments with fresh human blood as well as in vivo 7-day and 26-day implants in a porcine model demonstrate minimal platelet adhesion and activation with pSBMA surface modification compared to unmodified silicon exposed to fresh human blood in vitro. These results demonstrate that ultrathin pSBMA surface modification is a viable choice for application in blood contacting implants with critical nanoscale features.

While extracorporeal membrane oxygenation (ECMO) is a valuable therapy for patients with lung or heart failure, clinical use of ECMO remains limited due to hemocompatibility concerns with pro-coagulatory hollow fiber membrane geometries. Previously, we demonstrated the feasibility of silicon nanopore (SNM) and micropore (SμM) membranes for transport between two liquidphase compartments in blood-contacting devices. Herein, we investigate various pore sizes of SNM and SμM membranesalone or with a polydimethylsiloxane (PDMS) protective coatingfor parameters that determine suitability for gas exchange. We characterized the bubble or rupture point of these membranes to determine sweep gas pressures at which gas emboli would form. The smallest pore size SNM and the SμM with PDMS coating could be pressurized in excess of 260 cmHg without rupture, which is comparable to hollow fiber sweep gas pressures. Oxygen flux for the SμM with and without PDMS was insignificantly different at 0.0306 ± 0.0028 and 0.0297 ± 0.0012 mL/min, respectively, while SNM flux was significantly lower at 0.0149 ± 0.0040 mL/min. However, the area-normalized mass transfer coefficient of the SNM was 338 ± 54 mL O 2 m -2 min -1 cmHg -1an order of magnitude higher than that of the SμM with and without PDMS (57.3 ± 5.5 and 55.6 ± 2.2 mL O 2 m -2 min -1 cmHg -1 ). Ultimately, we conclude that SμM-PDMS may make effective membranes for ECMO, since they are both mechanically robust and capable of high oxygen flux.

Goal-Our objective is to provide a framework for extracting signals of interest from the wearable seismocardiogram (SCG) measured during walking at normal (subject's preferred pace) and moderately-fast (1.34 -1.45 m/s) speeds. Methods-We demonstrate, using empirical mode decomposition (EMD) and feature tracking algorithms, that the pre-ejection period (PEP) can be accurately estimated from a wearable patch that simultaneously measures electrocardiogram (ECG) and sternal acceleration signals. We also The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Over 300,000 Americans are dependent on hemodialysis as treatment for renal failure, and kidney transplantation is limited by scarcity of donor organs. This shortage has prompted research into tissue engineering of renal replacement therapy. Existing bioartificial kidneys are large and their use labor intensive, but they have shown improved survival compared to conventional therapy in preclinical studies and an US Food and Drug Administration-approved phase 2 clinical trial. This hybrid technology will require miniaturization of hemofilters, cell culture substrates, sensors, and integration of control electronics. Using the same harvesting and isolation techniques used in preparing bioartificial kidneys for clinical use, we characterized human renal tubule cell growth on a variety of silicon and related thin-film material substrates commonly used in the construction of microelectromechanical systems (MEMS), as well as novel silicon nanopore membranes (SNMs). Human cortical tubular epithelial cells (HCTC) were seeded onto samples of single-crystal silicon, polycrystalline silicon, silicon dioxide, silicon nitride, SU-8 photoresist, SNMs, and polyester tissue culture inserts, and grown to confluence. The cells formed confluent monolayers with tight junctions and central cilia. Transepithelial resistances were similar between SNMs and polyester membranes. The differentiated growth of human tubular epithelial cells on MEMS materials strongly suggests that miniaturization of the existing bioartificial kidney will be feasible, paving the way for widespread application of this novel technology.

Heart failure is the number one cause of death in the United States and a significant burden to the healthcare system. One of the primary complications of heart failure is fluid overload, for which current treatments are limited. Medical therapy is first-line; however, rates of diuretic insensitivity This article is protected by copyright. All rights reserved. are high, medications are not easily titrated, and they do not address the underlying physiologic derangement that leads to hypervolemia. Removal of isotonic fluid via hemofiltration and peritoneal dialysis is an understudied but promising therapy that enables decongestion without maladaptive stimulation of fluid retention pathways. Published studies report conflicting data on long-term outcomes of ultrafiltration but reach consensus on greater and more durable volume reduction with ultrafiltration than conventional medical therapy. These studies are noteworthy for their neglect to standardize both patient selection and fluid removal protocol, which likely contribute to outcome variation. Novel technology in preclinical testing includes implantable ultrafiltration, which has potential to treat volume overload while minimizing the adverse effects associated with conventional hemofiltration. We performed a literature review of English-language studies on hemoand peritoneal filtration for management of fluid overload in congestive heart failure. Also included is a discussion of the pathophysiology of congestive heart failure and first-line management as well as emerging technologies for ultrafiltration.

A major challenge in developing blood-contacting medical devices is mitigating thrombogenicity of an intravascular device. Thrombi may interfere with device function or embolize from the device to occlude distant vascular beds with catastrophic consequences. Chemical interactions between plasma proteins and bioengineered surface occur at the nanometer scale; however, continuum models of blood predict local shear stresses that lead to platelet activation or aggregation and thrombosis. Here, an iterative approach to blood flow path design incorporating in silico, in vitro, and in vivo experiments predicted the occurrence and location of thrombi in an implantable hemofilter. Low wall shear stress (WSS) regions identified by computational fluid dynamics (CFD) predicted clot formation in vivo. Revised designs based on CFD demonstrated superior performance, illustrating the importance of a multi-pronged approach for a successful design process.

End-stage renal disease afflicts *750,000 Americans and claims >100,000 lives annually in the United States. Kidney transplantation is associated with longest survival and least cost but is limited by scarcity of donor organs. The balance of patients are treated with dialysis, a cumbersome, morbid, and expensive procedure. Each hemodialysis treatment consumes in excess of 160 liters of water and anchors the patient to a machine for 12-15 h per week. Cultured tubule cells can reduce the obligate fluid requirements of a bioengineered artificial kidney by concentrating wastes and reabsorbing filtered salt and water. Primary tubule epithelial cells rapidly dedifferentiate in culture and form a flattened epithelium lacking the brush border essential to apicobasal transport. We hypothesized that substrate mechanical properties have a strong influence on differentiation in primary cell culture. We cultured primary renal tubule cells on polyacrylamide hydrogels of varying elasticity and measured expression of key transporter proteins essential to renal tubule cell function. Primary tubule cells cultured on soft substrates for extended periods showed increased expression of key transporters characteristic of differentiated proximal tubule cells. These data support the hypothesis that scaffold elasticity is a critical factor in cell culture, and, unexpectedly, that prolonged culture of primary cells was essential to observing this difference.

Reliable models of renal failure in large animals are critical to the successful translation of the next generation of renal replacement therapies (RRT) into humans. While models exist for the induction of renal failure, none are optimized for the implantation of devices to the retroperitoneal vasculature. We successfully piloted an embolization-to-implantation protocol enabling the first implant of a silicon nanopore membrane hemodialyzer (SNMHD) in a swine renal failure model. Renal arterial embolization is a non-invasive approach to near-total nephrectomy that preserves retroperitoneal anatomy for device implants. Silicon nanopore membranes (SNM) are efficient blood-compatible membranes that enable novel approaches to RRT. Yucatan minipigs underwent staged bilateral renal arterial embolization to induce renal failure, managed by intermittent hemodialysis. A small-scale arteriovenous SNMHD prototype was implanted into the retroperitoneum. Dialysate catheters were tunneled external...

The definitive treatment for end-stage renal disease is kidney transplantation, which remains limited by organ availability and post-transplant complications. Alternatively, an implantable bioartificial kidney could address both problems while enhancing the quality and length of patient life. An implantable bioartificial kidney requires a bioreactor containing renal cells to replicate key native cell functions, such as water and solute reabsorption, and metabolic and endocrinologic functions. Here, we report a proof-of-concept implantable bioreactor containing silicon nanopore membranes to offer a level of immunoprotection to human renal epithelial cells. After implantation into pigs without systemic anticoagulation or immunosuppression therapy for 7 days, we show that cells maintain &gt;90% viability and functionality, with normal or elevated transporter gene expression and vitamin D activation. Despite implantation into a xenograft model, we find that cells exhibit minimal damage,...

Extremely preterm infants have poor clinical outcomes due to lung immaturity. An artificial placenta could provide extracorporeal gas exchange, allowing normal lung growth outside of the uterus, thus improving outcomes. However, current devices in development use hollow-fiber membrane oxygenators, which have a high rate of bleeding and clotting complications. Here, we present a novel style of oxygenator composed of a stacked array of rigid and flat silicon semi-permeable membranes. Using computational fluid dynamic (CFD) modeling, we demonstrated favorable hemocompatibility properties, including laminar blood flow, low pressure drop, and minimal cumulative shear stress. We then constructed and tested prototype devices on the benchtop and in an extracorporeal pig model. At 20 mL/min of blood flow, the oxygenators exhibited an average oxygen flux of 0.081 ± 0.020 mL (mean ± standard error) and a pressure drop of 2.25 ± 0.25 mmHg. This study demonstrates the feasibility of a building a...

Recent developments in sensor technology and computational analysis methods enable new strategies to measure and interpret lung acoustic signals that originate internally, such as breathing or vocal sounds, or are externally introduced, such as in chest percussion or airway insonification. A better understanding of these sounds has resulted in new instrumentation that allows for highly accurate as well as portable options for measurement in the hospital, in the clinic, and even at home. This review outlines instrumentation for acoustic stimulation and measurement of the lungs. We first review the fundamentals of acoustic lung signals and the pathophysiology of the diseases that these signals are used to detect. Then, we focus on different methods of measuring and creating signals that have been used in recent research for pulmonary disease diagnosis. These new methods, combined with signal processing and modeling techniques, lead to a reduction in noise, and allow improved feature extraction and signal classification. We conclude by presenting the results of human subject studies taking advantage of both the instrumentation and signal processing tools to accurately diagnose common lung diseases. This paper emphasizes the active areas of research within modern lung acoustics, and encourages the standardization of future work in this field.

Lung transplantation has become an increasingly important modality for the treatment of severe lung disease. From its inception, the procedure has been refined so that it now represents the standard of care for end stage respiratory failure. The widespread adoption of this treatment option, however, has brought into sharp relief the current organ donor shortage. In tandem with the explosion in lung transplant procedures, a number of support modalities have seen an expanded role. Perhaps one of the most versatile tools in the armamentarium of the pulmonary transplant surgeon is extracorporeal membrane oxygenation (ECMO). This powerful tool is being increasingly implemented in all stages of lung transplantationfrom supporting the failing native organ as a bridging tool to transplantation, to stabilizing the patient intra-operatively during the transplant procedure, to rescuing the patient with severe primary graft dysfunction immediately post-transplant. A number of advanced techniques for the application of ECMO in order to optimize the pulmonary transplant procedure are gaining traction-and with ECMO's expanded role in lung transplantation, so also has come a new set of technical and ethical challenges that must also be overcome.

While extracorporeal membrane oxygenation (ECMO) is a valuable therapy for patients with lung or heart failure, clinical use of ECMO remains limited due to hemocompatibility concerns with pro-coagulatory hollow fiber membrane geometries. Previously, we demonstrated the feasibility of silicon nanopore (SNM) and micropore (SμM) membranes for transport between two liquidphase compartments in blood-contacting devices. Herein, we investigate various pore sizes of SNM and SμM membranesalone or with a polydimethylsiloxane (PDMS) protective coatingfor parameters that determine suitability for gas exchange. We characterized the bubble or rupture point of these membranes to determine sweep gas pressures at which gas emboli would form. The smallest pore size SNM and the SμM with PDMS coating could be pressurized in excess of 260 cmHg without rupture, which is comparable to hollow fiber sweep gas pressures. Oxygen flux for the SμM with and without PDMS was insignificantly different at 0.0306 ± 0.0028 and 0.0297 ± 0.0012 mL/min, respectively, while SNM flux was significantly lower at 0.0149 ± 0.0040 mL/min. However, the area-normalized mass transfer coefficient of the SNM was 338 ± 54 mL O 2 m -2 min -1 cmHg -1an order of magnitude higher than that of the SμM with and without PDMS (57.3 ± 5.5 and 55.6 ± 2.2 mL O 2 m -2 min -1 cmHg -1 ). Ultimately, we conclude that SμM-PDMS may make effective membranes for ECMO, since they are both mechanically robust and capable of high oxygen flux.