Legally marketed comparator devices (LMCD) are required by many regulatory bodies in as a control for thrombogenicity testing when evaluating new devices. It is assumed by both the medical device manufacturing industry and regulatory bodies that these LMCD’s have good clinical history and should perform with no to minimal thrombus accumulation and thereby serve as valid negative controls for the assay. APS regularly performs these assays for many medical device manufacturers, all of whom select a predicate comparator device (required by FDA to be an LMCD), for both the in vivo Non-Anticoagulated Venous Implant (NAVI) assay as well as a custom in vitro blood loop AVI. In this retrospective analysis, we have compiled thrombogenicity scores of control/predicate devices (limited to assays which used LMCD’s), both the discrete score from the classification standard scoring scheme and the continuous values obtained from the percent surface area associated with thrombus. We have compared results from 37 NAVI studies and 22 in vitro blood loop studies. These compiled results show ∼25% of LMCDs score ≥ 3 (> 50% of the surface covered in thrombus) in the NAVI model while < 5% of LMCDs score ≥ 3 (> 50% thrombus) in the Blood-Loop assay. In addition, the median score and mean % thrombus for LMCD in the blood loop assay is substantially lower than the median and mean scores for LMCD in the NAVI assay. This retrospective assessment highlights a high proportion of false-positive scores for LMCD in a large number of NAVI assays.

The degree to which deep brain stimulation (DBS) therapy can effectively treat various brain disorders depends on how well one can selectively stimulate one or more axonal pathways within the brain. There is rapidly growing clinical interest in DBS lead implant designs with electrode arrangements that can better target axonal pathways of interest, especially in cases where the optimal target is immediately adjacent to a pathway that when stimulated will elicit adverse side effects. Numerical modeling has demonstrated that DBS leads with four radially segmented electrodes provide the best balance of directional targeting capability while minimizing the overall number of electrode contacts [1]. Here, we present a novel 4×4 DBS lead (16-channel electrode array) with the same form factor and materials as current 4 or 8-channel FDA-approved DBS leads. Electrode impedance spectroscopy was performed for three of these 4×4 DBS leads showing reliable electrode impedances before and after implantation within the brain.

Patients are frequently prescribed a medication that must be administered either by a nasal spray, an inhaler, or a self-injection device. These devices are classified as combination devices by the Food and Drug Administration (FDA) and the Medical Device Regulations (MDR). However, there has been an issue of who and how do these patients get trained. It has long been the stance of the pharmaceutical companies they will not provide training because they provide an Information for Use (IFU) and/or a demo on their website. The issues with either of these means is that neither the FDA, nor the MDR permit them as mitigation for use errors. And, in human factors testing there are considerable numbers of use errors when patients attempt to use the devices.

In 1964, Dr. Barrows first introduced the standardized patients, who are individuals trained to imitate the pathological symptoms of the real patients, and involved them in teaching and clinical skills assessment for healthcare education. In recent decades, the application of the virtual patient has been rapidly grown and has been widely used in clinical or educational practice among residents, surgeons, or other medical professionals because the virtual patient is cost-effective and time-efficient [1]. The Food and Drug Administration (FDA) collaborated with the Foundation of Research on Information Technologies in Society (IT’IS Foundation, Zürich, Switzerland) to produce a virtual family, which is a set of anatomical computer-aided design (CAD) models of adults and children [2, 3], and those CAD models are used in electromagnetic, thermal, and computer fluid dynamics simulations. However, the meaning of virtual patients or models has varied across the recent years and more and more researchers tried to categorize the terminology of virtual patients. In general, virtual patients can be classified into seven major types including: case presentation, interactive patient scenarios, virtual patient game, high fidelity software simulation, human standardized patients, high fidelity manikins, and virtual standardized patients [4]. The virtual patients discussed in this study can be classified as interactive patient scenarios, whose application includes clinical reasoning, surgical planning, and disease diagnosis.

For more than 27 years, implanted vagus nerve stimulation (VNS) devices, with electric current outputs in the 1 to 3.5 mA range, have been developed for many health care applications, including epilepsy and heart disease [1]. Mechanical compression approaches for VNS were administered under surgical conditions, using forceps, in the 1800’s [2]. Outcomes such as Electrocardiogram (ECG) data, blood pressure (BP), and heart rate (HR) were evaluated. Also, non-invasive (NI) mechanical compression of the vagus nerve for various nervous system disorders using hand, thumb, finger and belt pressure was popular in the 1800’s [3]. Cyberonics (now LivaNova) received the first FDA clearance for a surgically implanted electrical VNS device to treat refractory epilepsy in 1997.

There has been an emerging interest in high intensity focused ultrasound (HIFU) for therapeutic applications. By means of its thermal or mechanical effects, HIFU is able to serve as a direct tool for tissue ablation, or an indirect moderating medium to manipulate microbubbles or perform heating (hyperthermia) for the purpose of targeted drug delivery. The development and testing of HIFU based phased arrays is favorable as their elements allow for individual phasing to steer and focus the beam. While FDA has already approved tissue ablation by HIFU for the treatment of uterine fibroids (2004) and pain from bone metastases (2012), development continues on other possible applications that are less forgiving of incomplete treatment, such as thermal necrosis of malignant masses. Ideally, each element, of such an array must have its own fully programmable electrical driving channel, which allows the control of delay, phase, and amplitude of the output from each element. To enable full control, each channel needs a waveform generator, an amplification device, and an impedance matching circuit between driver and acoustic element. Similar projects utilizing this approach to drive therapeutic arrays include a 512-channel therapy system which was built at the University of Michigan using low cost Field-Programmable Gate Arrays (FPGA) microcontroller and highly efficient MOSFET switching amplifiers [1]. However, this system lacks the ability to drive both, continuous wave (CW) and transient short duty-cycle high power pulses. This paper presents a hybrid system, which is able to perform CW and transient short duty-cycle high power excitation. In the following we will describe the design, programming, fabrication, and evaluation of this radiofrequency (RF) driver system as used in our laboratory for a 1.5 MHz center frequency, 298-element array (Imasonic SA, Besancon, France) [2], FPGA-controlled amplifier boards and matching circuitry. Advantages of our design include: 1. Inexpensive components (<$15/channel); 2. Ability to program/drive individual output channels independently; 3. Sufficient time and amplitude resolution for various acoustic pattern design; 4. Capability of hybrid switching between low power CW and short duty cycle, high instantaneous power.

The purpose of this test method is to assist in the determination of the thrombogenic potential of medical materials exposed to human whole blood. By evaluating surface-induced activation, platelet adherence to a material, and platelet and leukocyte depletion from blood, a material’s potential for thrombus formation can be assessed. If a significant decrease in platelets and/or leukocytes is observed in whole blood when compared to a blank control, the tested material has the potential to induce an in-vivo thrombogenic response. The present standard for the testing of platelet and leukocyte response to cardiovascular materials, ASTM F2888-13, Standard Test Method for Platelet Leukocyte Count - An In-Vitro Measure for Hemocompatibility Assessment of Cardiovascular Materials [1], mandates the use of several reference materials in the presence of blood anticoagulated with sodium citrate. This study was designed to address the relevance of the assay method when using a potent anticoagulant, 3.2% sodium citrate, to evaluate the thrombogenic potential of medical devices. Current studies on this question are under investigation at the FDA also with the intent of improving the standard methods for this assay by evaluating blood anticoagulated with 2–3 IU/mL of heparin [2]. For this study, the effects of several biomaterials were evaluated when exposed to blood anticoagulated with sodium citrate and, concurrently, an even lower dose of heparin at 1 IU/mL also used by our laboratory in a new circulating in vitro assay for thrombogenicity [3]. We believe this test method allows for a sensitive assay that can more accurately predict potential thrombogenic outcomes of cardiovascular materials, while maintaining appropriate responses in both positive and negative control materials.

Thrombogenicity testing is often a requirement for regulatory approval of many types of blood-contacting medical devices [1, 2]. This study describes the continuing improvement in design and characterization of a minimally-heparinized in vitro blood-loop assay which utilizes freshly drawn ovine blood. These modifications were made after studies using this in vitro model were submitted to the FDA in lieu of the in vivo nonanticoagulated venous implant (NAVI) thrombogenicity test. After extensive discussions with FDA reviewers, several modifications which further characterize and improve the assay have been included: 1). Improved temperature control of the blood before and during the incubation period, 2). Improved uniformity and reproducibility of loop geometry, specifically the length of working space for device deployment and a fixed curvature for the radius of the return segment of the loop, 3). Additional measurement of blood parameters prior to and during the incubation period, complete blood counts and activated clotting time (ACT), 4). More rigorous management of ACT, 5). Measurement of non-adherent thrombus formation in the blood, 6).Incorporation of a legally marketed predicate comparator device in all the assays, and 7).Physical characterization of the positive controls. This validated method with enhanced characterization and more reproducible methods allows for a more robust and reliable assay. These results continue to support the premise that this in vitro blood loop assay may eventually supplant the NAVI model for routine hemocompatibility testing for catheter-like blood contacting medical devices.

Personal protective equipment (PPE) such as respirators will form the first line of defense in the event of a public health emergency including an airborne pandemic or a bio-terror attack. The two major pathways by which virus-carrying aerosols can reach the human lungs through these PPEs are: a) the intrinsic penetration through porous layers of the PPE and b) the leakage through gaps between the PPE and a person’s face [1, 2]. The contribution from the second pathway can be significantly reduced using fit-testing i.e. by choosing the appropriately sized respirator for a specific face. Unfortunately, in case of an emergency, it would not be possible to fit-test the entire US population. In this scenario, excessive leakage can occur through the gaps. [1]. Hence, it is critical to identify the potential anatomical leak sites (gaps) and quantify the amount of aerosol leakage through surgical respirators for the average US population. At the behest of Office of Counterterrorism and Emerging Threats, the Center for Devices and Radiological Health, US Food and Drug Administration (FDA), has been developing a comprehensive risk assessment model for determining the risk to different populations in case of an “off-label” use of such PPEs, i.e. for public emergency scenarios for which these FDA cleared respirators were not intended to be used. In order to develop the risk assessment model, establishing a correlation between the respirator gaps and aerosol leakage between the face and the respirator is critical. A previous study [3] identified the gaps of N95 surgical respirators for a large population and quantified the aerosol leak using computational fluid dynamics. However, the gap surface area, which is a key parameter required for establishing the gap-aerosol leak correlation, has not been quantified before. In this study, gaps were identified and the gap surface areas were quantified for multiple head-respirator combinations under realistic conditions using imaging coupled with computer-aided design and modeling.

Heart failure (HF) is a serious condition in which the heart cannot pump sufficient blood to sustain the metabolic needs of the body. A common indication of failure is a low ejection fraction, or the volumetric proportion of blood ejected when the ventricle contracts. In end-stage HF, support from a ventricular assist device (VAD) can assume some or all of the heart’s pumping work, improving the ejection fraction and restoring normal circulation. VAD therapy options for end-stage right heart failure (RHF) are limited, with only a few FDA-approved devices available for mechanical circulatory support [1]. These devices are based on continuous flow impellers; and despite anticoagulation therapy, use of currently available VADs is associated with thrombogenic risk since the blood must contact artificial non-biologic surfaces. An implantable VAD for RHF based on soft robotic pulsatile assistance has previously been proposed [2]. This device is comprised of a contractile element that is anchored to the ventricular septum and the right ventricle (RV) free wall. The device is programmed to contract in synchrony with the native heart beat and assist in approximating the septum and free wall together in order to augment blood ejection (Fig. 1). Potential advantages of this approach include reduced risk of thrombosis, since there is no blood flow through the lumen of the device, and the possibility for minimally invasive deployment of the device under ultrasound guidance. A key component in this VAD concept is the anchoring mechanism that couples the contractile actuator to the ventricular septum. In this work, we report design, fabrication and testing of a new septal anchor design. We exploit the emerging technology of pop-up MEMS [3] in order to fabricate a collapsible anchoring mechanism. Origami-inspired engineering and pop-up MEMS manufacturing techniques have previously been used for developing disposable and low-cost medical tools and devices [4]. The pop-up anchor can be deployed into the left ventricle (LV) via a standard delivery sheath. We validate the load bearing ability of the anchor and demonstrate deployment in an ex vivo simulation.

Particle Image Velocimetry (PIV) is currently the most widely used and well-established tool for non-invasive flow field velocity measurements, and a valuable method for validating computational fluid dynamics (CFD) models of medical devices. One of the critical steps in the CFD validation process is quantification of the experimental uncertainties. This work utilizes a new uncertainty estimation methodology developed by Charonko et al. 1 for quantifying the PIV cross-correlation uncertainties. Uncertainties from experimental sources, including image magnification and acquisition timing, were propagated using Taylor series expansion for PIV data within the FDA benchmark Nozzle model 2 .

Patients may be exposed to potentially carcinogenic color additives released from polymers used to manufacture medical devices; therefore, the need exists to adequately assess the safety of these compounds. The US FDA Center for Devices and Radiological Health (CDRH) recently issued draft guidance that, when final, will include FDA’s recommendations for the safety evaluation of color additives and other potentially toxic chemical entities that may be released from device materials. Specifically, the draft guidance outlines an approach that calls for evaluating the potential for the color additive to be released from the device in concert with available toxicity information about the additive to determine what types of toxicity information, if any, are necessary. However, when toxicity data are not available from the literature for the compounds of interest, a scientific rationale can sometimes be provided for omission of these tests. Although the FDA has issued draft guidance on this topic, the Agency continues to explore alternative approaches to understand when additional toxicity testing is needed to assure the safety of medical devices that contain color additives. An emerging approach that may be useful for determining the need for further testing of compounds released from device materials is Quantitative Structure Activity Relationship (QSAR) modeling. In this paper, we have shown how three publically available QSAR models (OpenTox/Lazar, Toxtree, and the OECD Toolbox) are able to successfully predict the carcinogenic potential of a set of color additives with a wide range of structures. As a result, this computational modeling approach may serve as a useful tool for determining the need to conduct carcinogenicity testing of color additives intended for use in medical devices.

Ischemic stroke affects nearly 690,000 patients a year in the United States and is the leading cause of long-term disability and the third leading cause of death [1, 2]. Acute ischemic stroke occurs when a clot becomes lodged in a cerebral vessel, cutting off blood supply to areas of the brain. There are two treatment options for acute ischemic stroke: tissue plasminogen activator (beneficial within the first 4 hours of stroke onset), and mechanical removal (beneficial from 4 to 8 hours after stroke onset). The two FDA approved clot removal devices (MERCI and Penumbra) for ischemic stroke are capable of achieving revascularization rates between 48% and 80% [3, 4].

The Charite III artificial disc replacement was approved for use in the United States in October of 2004 by the FDA. Another similarly designed lumbar disc replacement called the ProDisc II was also approved by the FDA a year later in January of 2006. The purpose of this study was to retrospectively review 29 patients with either the Charite III or the Prodisc II disc replacement surgery and complications.