BME 2.0: Engineering the Future of Medicine.

If the 20th century was the age of mapping and controlling the external world, the 21st century is the biomedical age of mapping and controlling the biological internal world. The biomedical age is bringing new technological breakthroughs for sensing and controlling human biomolecules, cells, tissues, and organs, which underpin new frontiers in the biomedical discovery, data, biomanufacturing, and translational sciences. This article reviews what we believe will be the next wave of biomedical engineering (BME) education in support of the biomedical age, what we have termed BME 2.0. BME 2.0 was announced on October 12 2017 at BMES 49 (https://www.bme.jhu.edu/news-events/news/miller-opens-2017-bmes-annual-meeting-with-vision-for-new-bme-era/). We present several principles upon which we believe the BME 2.0 curriculum should be constructed, and from these principles, we describe what view as the foundations that form the next generations of curricula in support of the BME enterprise. The core principles of BME 2.0 education are (a) educate students bilingually, from day 1, in the languages of modern molecular biology and the analytical modeling of complex biological systems; (b) prepare every student to be a biomedical data scientist; (c) build a unique BME community for discovery and innovation via a vertically integrated and convergent learning environment spanning the university and hospital systems; (d) champion an educational culture of inclusive excellence; and (e) codify in the curriculum ongoing discoveries at the frontiers of the discipline, thus ensuring BME 2.0 as a launchpad for training the future leaders of the biotechnology marketplaces. We envision that the BME 2.0 education is the path for providing every student with the training to lead in this new era of engineering the future of medicine in the 21st century.

Erratum to "BME 2.0: Engineering the Future of Medicine".

[This corrects the article DOI: 10.34133/bmef.0001.].

Smart Devices Are Poised to Revolutionize the Usefulness of Respiratory Sounds.

The association between breathing sounds and respiratory health or disease has been exceptionally useful in the practice of medicine since the advent of the stethoscope. Remote patient monitoring technology and artificial intelligence offer the potential to develop practical means of assessing respiratory function or dysfunction through continuous assessment of breathing sounds when patients are at home, at work, or even asleep. Automated reports such as cough counts or the percentage of the breathing cycles containing wheezes can be delivered to a practitioner via secure electronic means or returned to the clinical office at the first opportunity. This has not previously been possible. The four respiratory sounds that most lend themselves to this technology are wheezes, to detect breakthrough asthma at night and even occupational asthma when a patient is at work; snoring as an indicator of OSA or adequacy of CPAP settings; cough in which long-term recording can objectively assess treatment adequacy; and crackles, which, although subtle and often overlooked, can contain important clinical information when appearing in a home recording. In recent years, a flurry of publications in the engineering literature described construction, usage, and testing outcomes of such devices. Little of this has appeared in the medical literature. The potential value of this technology for pulmonary medicine is compelling. We expect that these tiny, smart devices soon will allow us to address clinical questions that occur away from the clinic.

Navigating the Regulatory Pathway for Medical Devices-a Conversation with the FDA, Clinicians, Researchers, and Industry Experts.

Successful translation of new and innovative medical products from concept to clinical use is a complex endeavor that requires understanding and overcoming a variety of challenges. In particular, regulatory pathways and processes are often unfamiliar to academic researchers and start-ups, and even larger companies. Growing evidence suggests that the successful translation of ideas to products requires collaboration and cooperation between clinicians, researchers, industry, and regulators. A multi-stakeholder group developed this review to enhance regulatory knowledge and thereby improve translational success for medical devices. Communication between and among stakeholders is identified as a critical factor. Current regulatory programs and processes to facilitate communication and translation of innovative devices are described and discussed. Case studies are used to highlight the importance of flexibility when considering evidence requirements. We provide a review of emerging strategies, opportunities, and best practices to increase the regulatory knowledge base and facilitate medical device translation by all stakeholders. Clinicians, regulators, industry, and researchers require regulatory knowledge and collaboration for successful translation of innovative medical devices.

Motion Artifact Reduction In Photoplethysmography For Reliable Signal Selection.

Photoplethysmography (PPG) is a non-invasive and economical technique to extract vital signs of the human body. Although it has been widely used in consumer and research grade wrist devices to track a user's physiology, the PPG signal is very sensitive to motion which can corrupt the signal's quality. Existing Motion Artifact (MA) reduction techniques have been developed and evaluated using either synthetic noisy signals or signals collected during high-intensity activities - both of which are difficult to generalize for real-life scenarios. Therefore, it is valuable to collect realistic PPG signals while performing Activities of Daily Living (ADL) to develop practical signal denoising and analysis methods. In this work, we propose an automatic pseudo clean PPG generation process for reliable PPG signal selection. For each noisy PPG segment, the corresponding pseudo clean PPG reduces the MAs and contains rich temporal details depicting cardiac features. Our experimental results show that 71% of the pseudo clean PPG collected from ADL can be considered as high quality segment where the derived MAE of heart rate and respiration rate are 1.46 BPM and 3.93 BrPM, respectively. Therefore, our proposed method can determine the reliability of the raw noisy PPG by considering quality of the corresponding pseudo clean PPG signal.

Erratum: Advancing medical technology innovation and clinical translation via a model of industry-enabled technical and educational support: Indiana Clinical and Translational Sciences Institute's Medical Technology Advance Program - ERRATUM.

[This corrects the article DOI: 10.1017/cts.2021.1.].

Advancing medical technology innovation and clinical translation via a model of industry-enabled technical and educational support: Indiana Clinical and Translational Sciences Institute's Medical Technology Advance Program.

The success rate for translation of newly engineered medical technologies into clinical practice is low. Traversing the "translational valleys of death" requires a high level of knowledge of the complex landscape of technical, ethical, regulatory, and commercialization challenges along a multi-agency path of approvals. The Indiana Clinical and Translational Sciences Institute developed a program targeted at increasing that success rate through comprehensive training, education, and resourcing. The Medical Technology Advance Program (MTAP) provides technical, educational, and consultative assistance to investigators that leverages partnerships with experts in the health products industry to speed progress toward clinical implementation. The training, resourcing, and guidance are integrated through the entire journey of medical technology translation. Investigators are supported through a set of courses that cover bioethics, ethical engineering, preclinical and clinical study design, regulatory submissions, entrepreneurship, and commercialization. In addition to the integrated technical and educational resources, program experts provide direct consultation for planning each phase along the life cycle of translation. Since 2008, nearly 200 investigators have gained assistance from MTAP resulting in over 100 publications and patents. This support via medicine-engineering-industry partnership provides a unique and novel opportunity to expedite new medical technologies into clinical and product implementation.

Toward Automation of the Supine Pressor Test for Preeclampsia.

Preeclampsia leads to increased risk of morbidity and mortality for both mother and fetus. Most previous studies have largely neglected mechanical compression of the left renal vein by the gravid uterus as a potential mechanism. In this study, we first used a murine model to investigate the pathophysiology of left renal vein constriction. The results indicate that prolonged renal vein stenosis after 14 days can cause renal necrosis and an increase in blood pressure (BP) of roughly 30 mmHg. The second part of this study aimed to automate a diagnostic tool, known as the supine pressor test (SPT), to enable pregnant women to assess their preeclampsia development risk. A positive SPT has been previously defined as an increase of at least 20 mmHg in diastolic BP when switching between left lateral recumbent and supine positions. The results from this study established a baseline BP increase between the two body positions in nonpregnant women and demonstrated the feasibility of an autonomous SPT in pregnant women. Our results demonstrate that there is a baseline increase in BP of roughly 10-14 mmHg and that pregnant women can autonomously perform the SPT. Overall, this work in both rodents and humans suggests that (1) stenosis of the left renal vein in mice leads to elevation in BP and acute renal failure, (2) nonpregnant women experience a baseline increase in BP when they shift from left lateral recumbent to supine position, and (3) the SPT can be automated and used autonomously.

Real-time estimation of aerodynamic features for ambulatory voice biofeedback.

The development of ambulatory voice monitoring devices has the potential to improve the diagnosis and treatment of voice disorders. In this proof-of-concept study, real-time biofeedback is incorporated into a smartphone-based platform that records and processes neck surface acceleration. The focus is on utilizing aerodynamic measures of vocal function as a basis for biofeedback. This is done using regressed Z-scores to compare recorded values to normative estimates based on sound pressure level and fundamental frequency. Initial results from the analysis of different voice qualities suggest that accelerometer-based estimates of aerodynamic parameters can be used for real-time ambulatory biofeedback.

Modeling the effects of a posterior glottal opening on vocal fold dynamics with implications for vocal hyperfunction.

Despite the frequent observation of a persistent opening in the posterior cartilaginous glottis in normal and pathological phonation, its influence on the self-sustained oscillations of the vocal folds is not well understood. The effects of a posterior gap on the vocal fold tissue dynamics and resulting acoustics were numerically investigated using a specially designed flow solver and a reduced-order model of human phonation. The inclusion of posterior gap areas of 0.03-0.1 cm(2) reduced the energy transfer from the fluid to the vocal folds by more than 42%-80% and the radiated sound pressure level by 6-14 dB, respectively. The model was used to simulate vocal hyperfucntion, i.e., patterns of vocal misuse/abuse associated with many of the most common voice disorders. In this first approximation, vocal hyperfunction was modeled by introducing a compensatory increase in lung air pressure to regain the vocal loudness level that was produced prior to introducing a large glottal gap. This resulted in a significant increase in maximum flow declination rate and amplitude of unsteady flow, thereby mimicking clinical studies. The amplitude of unsteady flow was found to be linearly correlated with collision forces, thus being an indicative measure of vocal hyperfunction.

Response to "Comments on 'A theoretical model of the pressure distributions arising from asymmetric intraglottal flows applied to a two-mass model of the vocal folds'" [J. Acoust. Soc. Am. 130, 389-403 (2011)].

Hirschberg [J. Acoust. Soc. Am. 134, 9-12 (2013)] presents a commentary and criticisms of the viscous flow model presented by Erath et al. [J. Acoust. Soc. Am. 130, 389-403 (2011)] that solves for the asymmetric pressure loading on the vocal fold walls. This pressure loading arises from asymmetric flow attachment to one vocal fold wall when the glottal channel forms a divergent configuration. Hirschberg proposes an alternative model for the asymmetric loading based upon inviscid flow curvature at the glottal inlet. In this manuscript further evidence is provided in support of the model of Erath et al. and the underlying assumptions, and demonstrates that the primary criticisms presented by Hirschberg are unwarranted. The model presented by Hirschberg is compared with the model from the original paper by Erath et al., and it is shown that each model describes different and complementary aspects of divergent glottal flows.

Subglottal Impedance-Based Inverse Filtering of Voiced Sounds Using Neck Surface Acceleration.

A model-based inverse filtering scheme is proposed for an accurate, non-invasive estimation of the aerodynamic source of voiced sounds at the glottis. The approach, referred to as subglottal impedance-based inverse filtering (IBIF), takes as input the signal from a lightweight accelerometer placed on the skin over the extrathoracic trachea and yields estimates of glottal airflow and its time derivative, offering important advantages over traditional methods that deal with the supraglottal vocal tract. The proposed scheme is based on mechano-acoustic impedance representations from a physiologically-based transmission line model and a lumped skin surface representation. A subject-specific calibration protocol is used to account for individual adjustments of subglottal impedance parameters and mechanical properties of the skin. Preliminary results for sustained vowels with various voice qualities show that the subglottal IBIF scheme yields comparable estimates with respect to current aerodynamics-based methods of clinical vocal assessment. A mean absolute error of less than 10% was observed for two glottal airflow measures -maximum flow declination rate and amplitude of the modulation component- that have been associated with the pathophysiology of some common voice disorders caused by faulty and/or abusive patterns of vocal behavior (i.e., vocal hyperfunction). The proposed method further advances the ambulatory assessment of vocal function based on the neck acceleration signal, that previously have been limited to the estimation of phonation duration, loudness, and pitch. Subglottal IBIF is also suitable for other ambulatory applications in speech communication, in which further evaluation is underway.

A theoretical model of the pressure field arising from asymmetric intraglottal flows applied to a two-mass model of the vocal folds.

A theoretical flow solution is presented for predicting the pressure distribution along the vocal fold walls arising from asymmetric flow that forms during the closing phases of speech. The resultant wall jet was analyzed using boundary layer methods in a non-inertial reference frame attached to the moving wall. A solution for the near-wall velocity profiles on the flow wall was developed based on a Falkner-Skan similarity solution and it was demonstrated that the pressure distribution along the flow wall is imposed by the velocity in the inviscid core of the wall jet. The method was validated with experimental velocity data from 7.5 times life-size vocal fold models, acquired for varying flow rates and glottal divergence angles. The solution for the asymmetric pressures was incorporated into a widely used two-mass model of vocal fold oscillation with a coupled acoustical model of sound propagation. Asymmetric pressure loading was found to facilitate glottal closure, which yielded only slightly higher values of maximum flow declination rate and radiated sound, and a small decrease in the slope of the spectral tilt. While the impact on symmetrically tensioned vocal folds was small, results indicate the effect becomes more significant for asymmetrically tensioned vocal folds.

An anatomically based, time-domain acoustic model of the subglottal system for speech production.

A time-domain model of sound wave propagation in the branching airways of the subglottal system is presented. The model is formulated as an extension to an acoustic transmission-line modeling scheme originally developed for simulating the supraglottal system in the time-domain during speech production [Maeda (1982). Speech Commun. 1, 199-229; Mokhtari et al. (2008). Speech Commun. 50, 179-190]. The approach allows for predictions of time-varying acoustic pressure and volume velocity at any point along the various generations of subglottal airways from trachea to alveoli. In addition, the model can be configured so that its overall structure simulates different geometric forms, including airways that branch in a symmetric or asymmetric pattern. Three subglottal configurations, two symmetric and one asymmetric, were represented based on reported anatomical dimensions of the subglottal airways. Estimates of the acoustic input impedances of these subglottal configurations revealed resonant characteristics similar to those found in the previous studies. Simulations of voiced sound propagation into the subglottal airways, achieved by coupling the subglottal model to a two-mass vocal fold model and a supraglottal tract configured for different vowels, yielded predictions of time-domain sound pressure waveforms below the vocal folds that compare favorably to previous measurements in human subjects.

Observation and analysis of in vivo vocal fold tissue instabilities produced by nonlinear source-filter coupling: a case study.

Different source-related factors can lead to vocal fold instabilities and bifurcations referred to as voice breaks. Nonlinear coupling in phonation suggests that changes in acoustic loading can also be responsible for this unstable behavior. However, no in vivo visualization of tissue motion during these acoustically induced instabilities has been reported. Simultaneous recordings of laryngeal high-speed videoendoscopy, acoustics, aerodynamics, electroglottography, and neck skin acceleration are obtained from a participant consistently exhibiting voice breaks during pitch glide maneuvers. Results suggest that acoustically induced and source-induced instabilities can be distinguished at the tissue level. Differences in vibratory patterns are described through kymography and phonovibrography; measures of glottal area, open/speed quotient, and amplitude/phase asymmetry; and empirical orthogonal function decomposition. Acoustically induced tissue instabilities appear abruptly and exhibit irregular vocal fold motion after the bifurcation point, whereas source-induced ones show a smoother transition. These observations are also reflected in the acoustic and acceleration signals. Added aperiodicity is observed after the acoustically induced break, and harmonic changes appear prior to the bifurcation for the source-induced break. Both types of breaks appear to be subcritical bifurcations due to the presence of hysteresis and amplitude changes after the frequency jumps. These results are consistent with previous studies and the nonlinear source-filter coupling theory.

Air-borne and tissue-borne sensitivities of bioacoustic sensors used on the skin surface.

Measurements of body sounds on the skin surface have been widely used in the medical field and continue to be a topic of current research, ranging from the diagnosis of respiratory and cardiovascular diseases to the monitoring of voice dosimetry. These measurements are typically made using light-weight accelerometers and/or air-coupled microphones attached to the skin. Although normally neglected, air-borne sounds generated by the subject or other sources of background noise can easily corrupt such recordings, which is particularly critical in the recording of voiced sounds on the skin surface. In this study, the sensitivity of commonly used bioacoustic sensors to air-borne sounds was evaluated and compared with their sensitivity to tissue-borne body sounds. To delineate the sensitivity to each pathway, the sensors were first tested in vitro and then on human subjects. The results indicated that, in general, the air-borne sensitivity is sufficiently high to significantly corrupt body sound signals. In addition, the air-borne and tissue-borne sensitivities can be used to discriminate between these components. Although the study is focused on the evaluation of voiced sounds on the skin surface, an extension of the proposed methods to other bioacoustic applications is discussed.

Effect of body position on lung sounds in healthy young men.

BACKGROUND: The effect of body position on the generation of abnormal respiratory sounds (eg, snoring and stridor) is well recognized. Postural effects on normal lung sounds have been studied in less detail but need to be clarified if respiratory acoustic measurements are to be used effectively in clinical practice. METHODS: Lung sounds and airflow were recorded in six healthy male subjects. Two acoustic sensors were placed over corresponding sites of the right and left chest, first anteriorly and then on the back. Subjects were studied in sitting, supine, prone, and lateral decubitus positions. Lung sound intensity (LSI) was determined at flows of 0.4 to 0.6 L/s and 0.8 to 1.2 L/s within frequency bands of 150 to 300 Hz and 300 to 600 Hz. RESULTS: LSI was greater over the dependent lungs in the lateral decubitus positions. In the sitting position, LSI was greater on the left compared with the right posterior lung at the same airflow within the same frequency bands. Compared with sitting, neither the supine nor prone positions caused a significant change in LSI. CONCLUSIONS: Our study confirms previously reported asymmetries of normal lung sounds. The insignificant change of flow-specific LSI between the upright and horizontal positions in healthy subjects is encouraging for the clinical use of respiratory acoustic measurements. Further studies should address postural effects on lung sounds in patients with acute lung injury and other lung pathologies.

Sound propagation in liquid-filled arterial segments: measurements and model predictions.

The efficacy of an acoustic transmission line model (TLM) for predicting distortion that occurs with axial propagation in liquid-filled arterial segments was assessed. Water-filled segments of excised bovine aorta were excited with acoustic pulses and noise to evaluate if velocities, attenuation, and transverse resonance frequencies could be accurately predicted using the TLM. Regions of low acoustic power that were attributed to transverse wall resonance effects were evident in all vessels, but the model generally under-predicted upper frequency limit of the high loss regions. Model-predicted velocities were in fair agreement with measured velocities both in trend and values, however, the energy losses were under-predicted. These preliminary results indicate that the TLM can forecast the general distortion of longitudinal acoustic propagation in liquid-filled arterial segments, yet it requires further refinement to accurately predict dispersive characteristics.

Computer simulation tool for predicting sound propagation in air-filled tubes with acoustic impedance discontinuities.

A computer tool, based on an acoustic transmission line model, was developed for modeling and predicting sound propagation and reflections in cascaded tube segments. This subroutine considered the number of interconnected tubes, their dimensions and wall properties, as well as medium properties to create a network of cascaded transmission line model segments, from which the impulse response of the network was estimated. Acoustic propagation was examined in air-filled cascaded tube networks and model predictions were compared to measured acoustic pulse responses. The model was able to accurately predict the location and morphology of reflections. The developed code proved to be a useful design tool for applications such as the guidance of catheters through compliant air-filled biological conduits.

Influence of acoustic loading on an effective single mass model of the vocal folds.

Three-way interactions between sound waves in the subglottal and supraglottal tracts, the vibrations of the vocal folds, and laryngeal flow were investigated. Sound wave propagation was modeled using a wave reflection analog method. An effective single-degree-of-freedom model was designed to model vocal-fold vibrations. The effects of orifice geometry changes on the flow were considered by enforcing a time-varying discharge coefficient within a Bernoulli flow model. The resulting single-degree-of-freedom model allowed for energy transfer from flow to structural vibrations, an essential feature usually incorporated through the use of higher order models. The relative importance of acoustic loading and the time-varying flow resistance for fluid-structure energy transfer was established for various configurations. The results showed that acoustic loading contributed more significantly to the net energy transfer than the time-varying flow resistance, especially for less inertive supraglottal loads. The contribution of supraglottal loading was found to be more significant than that of subglottal loading. Subglottal loading was found to reduce the net energy transfer to the vocal-fold oscillation during phonation, balancing the effects of the supraglottal load.