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Undergraduate education in biomedical engineering (BME) and bioengineering (BioE) has been in place for more than 50 years. It has been important in shaping the field as a whole. The early undergraduate programs developed shortly after BME graduate programs, as universities sought to capitalize on the interest of students and the practical advantages of having BME departments that could control their own resources and curriculum. Unlike other engineering fields, BME did not rely initially on a market for graduates in industry, although BME graduates subsequently have found many opportunities. BME undergraduate programs exploded in the 2000s with funding from the Whitaker Foundation and resources from other agencies such as the National Institute of Biomedical Imaging and Bioengineering. The number of programs appears to be reaching a plateau, with 118 accredited programs in the United States at present. We show that there is a core of material that most undergraduates are expected to know, which is different from the knowledge base of other engineers not only in terms of biology, but in the breadth of engineering. We also review the role of important organizations and conferences in the growth of BME, special features of BME education, first placements of BME graduates, and a few challenges to address in the future.

This paper provides a synopsis of discussions related to biomedical engineering core curricula that occurred at the Fourth BME Education Summit held at Case Western Reserve University in Cleveland, Ohio in May 2019. This summit was organized by the Council of Chairs of Bioengineering and Biomedical Engineering, and participants included over 300 faculty members from 100+ accredited undergraduate programs. This discussion focused on six key questions: QI: Is there a core curriculum, and if so, what are its components? QII: How does our purported core curriculum prepare students for careers, particularly in industry? QIII: How does design distinguish BME/BIOE graduates from other engineers? QIV: What is the state of engineering analysis and systems-level modeling in BME/BIOE curricula? QV: What is the role of data science in BME/BIOE undergraduate education? QVI: What core experimental skills are required for BME/BIOE undergrads? s. Indeed, BME/BIOI core curricula exists and has matured to emphasize interdisciplinary topics such as physiology, instrumentation, mechanics, computer programming, and mathematical modeling. Departments demonstrate their own identities by highlighting discipline-specific sub-specialties. In addition to technical competence, Industry partners most highly value our students' capacity for problem solving and communication. As such, BME/BIOE curricula includes open-ended projects that address unmet patient and clinician needs as primary methods to prepare graduates for careers in industry. Culminating senior design experiences distinguish BME/BIOE graduates through their development of client-centered engineering solutions to healthcare problems. Finally, the overall BME/BIOE curriculum is not stagnant-it is clear that data science will become an ever-important element of our students' training and that new methods to enhance student engagement will be of pedagogical importance as we embark on the next decade.

Objective There are currently no definitive disease-modifying therapies for traumatic brain injury (TBI). In this study, we present a strong therapeutic candidate for TBI, immunomodulatory nanoparticles (IMPs), which ablate a specific subset of hematogenous monocytes (hMos). We hypothesized that prevention of infiltration of these cells into brain acutely after TBI would attenuate secondary damage and preserve anatomic and neurologic function. Methods IMPs, composed of US Food and Drug Administration-approved 500nm carboxylated-poly(lactic-co-glycolic) acid, were infused intravenously into wild-type C57BL/6 mice following 2 different models of experimental TBI, controlled cortical impact (CCI), and closed head injury (CHI). Results IMP administration resulted in remarkable preservation of both tissue and neurological function in both CCI and CHI TBI models in mice. After acute treatment, there was a reduction in the number of immune cells infiltrating into the brain, mitigation of the inflammatory status of the infiltrating cells, improved electrophysiologic visual function, improved long-term motor behavior, reduced edema formation as assessed by magnetic resonance imaging, and reduced lesion volumes on anatomic examination. Interpretation Our findings suggest that IMPs are a clinically translatable acute intervention for TBI with a well-defined mechanism of action and beneficial anatomic and physiologic preservation and recovery. Ann Neurol 2020;87:442-455.

Retinal neurons spend most of their energy to support the transmembrane movement of ions. Light-induced electrical activity is associated with a redistribution of ions, which affects the energy demand and results in a change in metabolism. Light-induced metabolic changes are expected to be different in distal and proximal retina due to differences in the light responses of different retinal cells. Extracellular K

The electroretinogram (ERG) has been employed for years to collect information about retinal function and pathology. The usefulness of this noninvasive test depends on our understanding of the cell sources that generate the ERG. Important contributors to the ERG are glial Müller cells (MCs), which are capable of generating substantial transretinal potentials in response to light-induced changes in extracellular K+ concentration ([K+]o). For instance, the MCs generate the slow PIII (sPIII) component of the ERG as a reaction to a photoreceptor-induced [K+]o decrease in the subretinal space. Similarly, an increase of [K+]o related to activity of postreceptor retinal neurons also produces transretinal glial currents, which can potentially influence the amplitude and shape of the b-wave, one of the most frequently analyzed ERG components. Although it is well documented that the majority of the b-wave originates from On-bipolar cells, some contribution from MCs was suggested many years ago and has never been experimentally rejected. In this work, detailed information about light-evoked [K+]o changes in the isolated mouse retina was collected and then analyzed with a relatively simple linear electrical model of MCs. The results demonstrate that the cornea-positive potential generated by MCs is too small to contribute noticeably to the b-wave. The analysis also explains why MCs produce the large cornea-negative sPIII subcomponent of the ERG, but no substantial cornea-positive potential.

Purpose This study evaluated the macular microvascular changes in eyes with proliferative diabetic retinopathy (PDR) following panretinal photocoagulation (PRP). Design Using optical coherence tomographic angiography (OCTA), we prospectively studied 10 eyes of 10 subjects with high-risk PDR immediately before, at 1 month, and at 3-6 months following PRP, using a 3- × 3-mm OCTA scan at each visit. Methods The following parameters were calculated for the superficial (SCP), middle (MCP), and deep capillary plexuses (DCP): parafoveal vessel density (VD), adjusted flow index (AFI), and percent area of nonperfusion (PAN). Parafoveal SCP vessel-length density (VLD) was also evaluated. We performed univariate and multivariable statistics, adjusting for age and signal strength. To model the hemodynamic effect of PRP, we also present a mathematical model based on electrical circuits. Results We found no significant difference for the vascular density parameters following PRP, except for decreased density at the MCP at the latest timepoint in the adjusted multivariable model. PAN, a metric of nonperfusion adjusted for noise, and AFI, a surrogate metric of blood flow, showed significant increases at all capillary levels in the adjusted model. Our mathematical model explained how PRP would increase macular blood flow. Conclusions Using OCTA, we found an overall increase in the flow metrics of all capillary layers in the macula following PRP, unrelated to macular edema or thickening, in line with the mathematical model. Our results suggest an overall redistribution of blood flow to the posterior pole following PRP, adding a new dimension to our understanding of the complex biologic effects of PRP in PDR. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Purpose The purpose of this study was to determine whether the ability of the rat retina to control its pH is affected by diabetes. Methods Double-barreled H+-selective microelectrodes were used to measure extracellular [H+] in the dark-adapted retina of intact control and diabetic Long-Evans rats 1 to 6 months after intraperitoneal injection of vehicle or streptozotocin, respectively. Two manipulations-increasing of blood glucose and intravenous injection of the carbonic anhydrase blocker dorzolamide (DZM)-were used to examine their effects on retinal pH regulation. Results An increase of retinal acidity was correlated with the diabetes-related increase in blood glucose, but only between 1 and 3 months of diabetes, not earlier or later. Adding intravenous glucose had no noticeable effect on the retinal acidity of control animals. In contrast, similar injections of glucose in diabetic rats significantly increased the acidity of the retina. Again, the largest increase of retinal acidity due to artificially elevated blood glucose was observed at 1 to 3 months of diabetes. Suppression of carbonic anhydrase by DZM dramatically increased the retinal acidity in both control and diabetic retinas to a similar degree. However, in controls, the strongest effect of DZM was recorded within 10 minutes after the injection, but in diabetics, the effect tended to increase with time and after 2 hours could be two to three times larger than at the beginning. Conclusions During development of diabetes in rats, the control over retinal pH is partly compromised so that conditions that perturb retinal pH lead to larger and/or more sustained changes than in control animals.

The electroretinogram (ERG) has been employed for years to collect information about retinal function and pathology. The usefulness of this noninvasive test depends on our understanding of the cell sources that generate the ERG. Important contributors to the ERG are glial Müller cells (MCs), which are capable of generating substantial transretinal potentials in response to light-induced changes in extracellular K+ concentration ([K+]o). For instance, the MCs generate the slow PIII (sPIII) component of the ERG as a reaction to a photoreceptor-induced [K+]o decrease in the subretinal space. Similarly, an increase of [K+]o related to activity of postreceptor retinal neurons also produces transretinal glial currents, which can potentially influence the amplitude and shape of the b-wave, one of the most frequently analyzed ERG components. Although it is well documented that the majority of the b-wave originates from On-bipolar cells, some contribution from MCs was suggested many years ago and has never been experimentally rejected. In this work, detailed information about light-evoked [K+]o changes in the isolated mouse retina was collected and then analyzed with a relatively simple linear electrical model of MCs. The results demonstrate that the cornea-positive potential generated by MCs is too small to contribute noticeably to the b-wave. The analysis also explains why MCs produce the large cornea-negative sPIII subcomponent of the ERG, but no substantial cornea-positive potential.

Ketamine/xylazine anesthesia has been used primarily for short term procedures in animals, but two prior reports used intravenous ketamine/xylazine for experiments taking many hours. However, there is a discrepancy about the appropriate dose, which is resolved here. Adult Long-Evans rats were used for recording from the retina. Doses of Ketamine/xylazine were adjusted to minimize anesthetic in terminal experiments lasting 10 h. An allometric relation was fitted to the resulting data on doses as a function of body weight, and compared to prior work. The allometric relationship between the continuously infused specific dose and weight was: dose = 9.13 (weight)−1.213 (r2 = 0.73), where dose is in mg-kg−1-hr−1 and rat weight is in kg. The dose of xylazine was 3.3% of the ketamine dose. No attempt was made to explore different relative doses of xylazine and ketamine. Prior work is consistent with this relationship, showing that the earlier discrepancy resulted from using rats of different sizes. Ketamine at the doses used here still depressed the electroretinogram relative to historical controls using urethane. We conclude that intravenous ketamine dosing in rats should not use the same mg-kg−1-hr−1 dose for all rats, but take into account the strong allometric relationship between dose and rat weight. There is an advantage in using smaller doses in order to prevent unnecessary depression of neural responses., Biological sciences; Neuroscience; Physiology; Ophthalmology; Laboratory medicine; Rat; Anesthesia; Ketamine; Xylazine; Electroretinogram; ERG; Retina

Inhaled general anesthetics are used commonly in adults and children, and a growing body of literature from animals and humans suggests that exposure to anesthesia at an early age can impact brain development. While the origin of these effects is not well understood, it is known that anesthesia can disrupt oxygen regulation in the brain, which is critically important for maintaining healthy brain function. Here we investigated how anesthesia affected brain tissue oxygen regulation in neonatal rabbits by comparing brain tissue oxygen and single unit activity in the awake and anesthetized states. We tested two common general anesthetics, isoflurane and sevoflurane, delivered in both air and 80% oxygen. Our findings show that general anesthetics can greatly increase brain tissue PO(2) in neonates, especially when combined with supplemental oxygen. Although isoflurane and sevoflurane belong to the same class of anesthetics, notable differences were observed in their effects upon neuronal activity and spontaneous respiration. Our findings point to the need to consider the potential effects of hyperoxia when supplemental oxygen is utilized, particularly in children and neonates.

Purpose In the dark, photoreceptor outer segments contain high levels of cyclic guanosine 3'-5' monophosphate (cGMP), which binds to ion channels, holding them open and allowing an influx of cations. Ion pumping activity, which balances cation influx, uses considerable amounts of adenosine triphosphate (ATP) and oxygen. Light reduces cation influx and thereby lowers metabolic demand. Blood vessels are compromised in the diabetic retina and may not be able to meet the higher metabolic demand in darkness. Emixustat is a visual cycle modulator (VCM) that reduces chromophore levels and, therefore, may mimic light conditions. We evaluated the effect of emixustat on oxygen consumption and cation influx in dark conditions. Methods Cation influx was measured in rats using Mn2+-magnetic resonance imaging (MEMRI). Retinal oxygen profiles were recorded to evaluate oxygen consumption. In the MEMRI protocol, animals were treated with either emixustat or vehicle. In the oxygen protocol, animals were untreated or treated with emixustat. Results In vehicle-treated animals, cation channel activity increased in the dark. Emixustat treatment reduced cation channel activity; activity was comparable to vehicle-treated controls in light conditions. In vehicle-treated animals, minimum retinal oxygen tension decreased as the retina recovered from a photobleach, indicating that more oxygen was being consumed. Emixustat treatment prevented the decrease in oxygen pressure after photobleach. Conclusions Emixustat reduced the cation influx and retinal oxygen consumption associated with dark conditions. VCMs are a promising potential treatment for ischemic retinal neovascularization, such as that in diabetic retinopathy.

Using adaptive optics scanning laser ophthalmoscopy (AOSLO), we measured retinal blood velocity and flow in healthy control eyes and eyes of diabetic patients with or without retinopathy. This cross-sectional study included 39 eyes of 30 patients with diabetes (DM) with mild non-proliferative diabetic retinopathy (NPDR) or without retinopathy (DM no DR) and 21 eyes of 17 healthy age-matched controls. Participants were imaged with a commercial optical coherence tomography angiography (OCTA) device (RTVue-XR Avanti) and AOSLO device (Apaeros Retinal Imaging System, Boston Micromachines). We analyzed AOSLO-based retinal blood velocity and flow, and OCTA-based vessel density of the superficial (SCP), deep retinal capillary plexus (DCP), and full retina. Retinal blood velocity was significantly higher in eyes with DM no DR and lower in NPDR across all vessel diameters compared to controls. Retinal blood flow was significantly higher in DM no DR and lower in NPDR in vessel diameters up to 60 &mu, m compared to controls. When comparing flow outliers (low-flow DM no DR eyes and high-flow NPDR eyes), we found they had a significantly different retinal vessel density compared to the remaining eyes in the respective groups. Retinal blood velocity and flow is increased in eyes with DM no DR, while these parameters are decreased in eyes with mild NPDR compared to healthy age-matched controls. The similarity of OCTA vessel density among outliers in the two diabetic groups suggests an initial increase followed by progressive decline in blood flow and OCTA vessel density with progression to clinical retinopathy, which warrants further investigation.

Double-barreled H(+)-selective microelectrodes were used to measure local extracellular concentration of H(+) ([H(+)]o) in the retina of dark-adapted anesthetized Long-Evans rats. The microelectrode advanced in steps of 30 μm throughout the retina from the vitreal surface to retinal pigment epithelium and then to the choroid, recording changes in [H(+)]o evoked by light stimulation. Recordings were performed in diabetic rats 1-3 months after intraperitoneal injection of streptozotocin and the results were compared with data obtained in age-matched control animals. Brief light stimulation (2.5 s) evoked changes of [H(+)]o with amplitudes of a few nM. Throughout the retina, there was a transient initial acidification for ∼200 ms followed by steady alkalinization, although amplitudes and kinetics of these components were slightly variable in different retinal layers. No significant difference was found when the light-induced [H(+)]o changes recorded in various retinal layers of early diabetic rats were compared with the [H(+)]o changes from corresponding layers of control animals. Also, when H(+)-selective microelectrodes were located in the retinal pigment epithelium (RPE) layer, an increase in H(+) was recorded, whose time course and amplitude were similar in control and diabetic rats. However, a striking difference between light-induced [H(+)]o changes in controls and diabetics was observed in the choriocapillaris, in the thin layer (10-20 μm) distal to the basal membrane of the RPE. In control rats, choroidal [H(+)]o decreased in a few cases, but much more often practically did not change. In contrast, diabetic rats demonstrated either an increase (in half of the cases) or no change in choroidal [H(+)]o. The data suggest that the active participation of the choroidal blood supply in stabilization of [H(+)]o could be partially compromised already at early stages of diabetes in rats. Interestingly, it appeared that the acid removal by the choroidal circulation was compromised most after 1 month of diabetes and tended to improve later.

PURPOSE: Changes in retinal pH may contribute to a variety of eye diseases. To study the effect of acidosis alone, we induced systemic metabolic acidosis and hypothesized that the retina would respond with altered expression of genes involved in acid/base regulation. METHODS: Systemic metabolic acidosis was induced in Long-Evans rats for up to two weeks by adding NH(4)Cl to the drinking water. After two weeks, venous pH was 7.25±0.08 (SD) and [HCO(3)(−)] was 21.4±4.6 mM in acidotic animals; pH was 7.41±0.03 and [HCO(3)(−)] was 30.5±1.0 mM in controls. Retinal mRNAs were quantified by qRT-PCR. Protein was quantified with Western blots and localized by confocal microscopy. Retinal [H+](o) was measured in vivo with pH microelectrodes in animals subject to metabolic acidosis and in controls. RESULTS: NH(4)Cl in drinking water or given IV was effective in acidifying the retina. Cariporide, a blocker of Na(+)/H(+) exchange, further acidified the retina. Metabolic acidosis for two weeks led to increases of 40 to 100% in mRNA for carbonic anhydrase isoforms II (CA-II) and XIV (CA-XIV) and acid sensing ion channels 1 and 4 (ASIC1 and ASIC4) (all p

Today’s science, technology, engineering, and mathematics (STEM) graduate students and postdoctoral fellows are tomorrow’s new faculty members; but these junior academicians often receive limited pedagogical training. We describe four iterations of an entry-level program with a low time commitment, Mentored Discussions of Teaching (MDT). The program is designed to introduce participants to pedagogical issues and literature in STEM disciplines and foster related discussions. It consists of group meetings, classroom observations, and discussions with faculty members. Program components were generally highly rated and valuable, even for those with prior teaching experience. We have found that this program is also an effective way to engage faculty members in the teaching aspects of students’ professional development.

In diabetic retinopathy, neovascularization is hypothesized to develop due to hypoxia in the retina. However, evidence for retinal hypoxia is limited, and the progressive changes in oxygenation are unknown. The objective of this study was to determine if retinal hypoxia occurs early in the development of diabetes. Intraretinal oxygen (PO2) profiles were recorded with oxygen-sensitive microelectrodes in control and diabetic Long-Evans rats at 4 and 12 weeks after induction of diabetes. Diabetes did not affect oxygen consumption in the photoreceptors in either dark or light adaptation. Oxygenation of the inner retina was not affected after 4 weeks of diabetes, although vascular endothelial growth factor levels increased. At 12 weeks, average inner retinal PO2, normalized to choriocapillaris PO2, was higher in diabetic rats than in age-matched controls, which was opposite to what was expected. Thus retinal hypoxia is not a condition of early diabetes in rat retina. Increased inner retinal PO2 may occur because oxygen consumption decreases in the inner retina.

Neuronal activity is associated with transmembrane ionic redistribution, which can lead to an osmotic imbalance. Accordingly, activity-dependent changes of the membrane potential are sometimes accompanied by changes in intracellular and/or extracellular volume. Experimental data that include distributions of ions and volume during neuronal activity are rare and rather inconsistent partly due to the technical difficulty of performing such measurements. However, progress in understanding the interrelations among ions, voltage and volume has been achieved recently by computational modelling, particularly “charge-difference” modelling. In this work a charge-difference computational model was used for further understanding of the specific roles for cations and anions. Our simulations show that without anion conductances the transmembrane movements of cations are always osmotically balanced, regardless of the stoichiometry of the pump or the ratio of Na+ and K+ conductances. Yet any changes in cation conductance or pump activity are associated with changes of the membrane potential, even when a hypothetically electroneutral pump is used in calculations and K+ and Na+ conductances are equal. On the other hand, when a Cl- conductance is present, the only way to keep the Cl-equilibrium potential in accordance with the changed membrane potential is to adjust cell volume. Importantly, this voltage-evoked Cl--dependent volume change does not affect intracellular cation concentrations or the amount of energy that is necessary to support the system. Taking other factors into consideration (i.e. the presence of internal impermeant poly-anions, the activity of cation-Cl- cotransporters, and the buildup of intra- and extracellular osmolytes, both charged and electroneutral) adds complexity, but does not change the main principles., Author summary We have developed software that calculates membrane potential and cell volume that result from redistribution of principal ions (K+, Na+, and Cl-) during normal cellular activity and experimental manipulations. Calculations in the model are done by an iterative charge-difference method that makes few assumptions about governing equations. Most of the features that were considered to be important for volume and voltage regulation were incorporated in the model, including the unique capability to perform calculations with different values of transmembrane water permeability. We have used the program to reexamine interactions between ionic fluxes, membrane potential, and cell volume and found that there was a previously unappreciated difference in the way that the distribution of cations and anions affect the cell. Na+ and K+, which are distributed unevenly across the membrane by the Na+/K+-ATPase, are primarily responsible for the membrane potential, but, contrary to popular belief, do not directly participate in volume regulation. On the other hand, the Cl- conductance determines the extent of volume changes, because Cl- has to follow the changes of membrane potential, which inevitably leads to changes in cell volume. The software is available to download and use for other investigations.

We hypothesized that the retina of diabetic animals would be unusually acidic due to increased glycolytic metabolism. Acidosis in tumors and isolated retina has been shown to lead to increased VEGF. To test the hypothesis we have measured the transretinal distribution of extracellular H(+) concentration (H(+)-profiles) in retinae of control and diabetic dark-adapted intact Long-Evans rats with ion-selective electrodes. Diabetes was induced by intraperitoneal injection of streptozotocin. Intact rat retinae are normally more acidic than blood with a peak of [H(+)]o in the outer nuclear layer (ONL) that averages 30 nM higher than H(+) in the choroid. Profiles in diabetic animals were similar in shape, but diabetic retinae began to be considerably more acidic after 5 weeks of diabetes. In retinae of 1-3 month diabetics the difference between the ONL and choroid was almost twice as great as in controls. At later times, up to 6 months, some diabetics still demonstrated abnormally high levels of [H(+)]o, but others were even less acidic than controls, so that the average level of acidosis was not different. Greater variability in H(+)-profiles (both between animals and between profiles recorded in one animal) distinguished the diabetic retinae from controls. Within animals, this variability was not random, but exhibited regions of higher and lower H(+). We conclude that retinal acidosis begins to develop at an early stage of diabetes (1-3 months) in rats. However, it does not progress, and the acidity of diabetic rat retina was diminished at later stages (3-6 months). Also the diabetes-induced acidosis has a strongly expressed local character. As result, the diabetic retinas show much wider variability in [H(+)] distribution than controls. pH influences metabolic and neural processes, and these results suggest that local acidosis could play a role in the pathogenesis of diabetic retinopathy.

The lack of capability to quantify oxygen metabolism noninvasively impedes both fundamental investigation and clinical diagnosis of a wide spectrum of diseases including all the major blinding diseases such as age-related macular degeneration, diabetic retinopathy, and glaucoma. Using visible light optical coherence tomography (vis-OCT), we demonstrated accurate and robust measurement of retinal oxygen metabolic rate (rMRO2) noninvasively in rat eyes. The rMRO2 was calculated by concurrent measurement of blood flow and blood oxygen saturation (sO2). Blood flow was calculated by the principle of Doppler optical coherence tomography, where the phase shift between two closely spaced A-lines measures the axial velocity. The distinct optical absorption spectra of oxy- and deoxy-hemoglobin provided the contrast for sO2 measurement, combined with the spectroscopic analysis of vis-OCT signal within the blood vessels. We continuously monitored the regulatory response of oxygen consumption to a progressive hypoxic challenge. We found that both oxygen delivery, and rMRO2 increased from the highly regulated retinal circulation (RC) under hypoxia, by 0.28±0.08 μL/min (p

In many tissues, PO2 fluctuates spontaneously with amplitudes of a few mmHg. Here we further characterized these oscillations. PO2 recordings were made from the whisker barrel cortex of six rabbits with acutely or chronically placed polarographic electrodes. Measurements were made while rabbits were awake and while anesthetized with isoflurane, during air breathing, and during 100% oxygen inspiration. In awake rabbits, 90% of the power was between 0 and 20 cycles per minute (cpm), not uniformly distributed over this range, but with a peak frequently near 10 cpm. This was much slower than heart or respiratory rhythms and is similar to the frequency content observed in other tissues. During hyperoxia, total power was higher than during air-breathing, and the dominant frequencies tended to shift toward lower values (0-10 cpm). These observations suggest that at least the lower frequency fluctuations represent efforts by the circulation to regulate local PO2. There were no consistent changes in total power during 0.5 or 1.5% isoflurane anesthesia, but the power shifted to lower frequencies. Thus, both hyperoxia and anesthesia cause characteristic, but distinct, changes in spontaneous fluctuations. These PO2 fluctuations may be caused by vasomotion, but other factors cannot be ruled out.

In many tissues, PO2 fluctuates spontaneously with amplitudes of a few mmHg. Here we further characterized these oscillations. PO2 recordings were made from the whisker barrel cortex of six rabbits with acutely or chronically placed polarographic electrodes. Measurements were made while rabbits were awake and while anesthetized with isoflurane, during air breathing, and during 100 % oxygen inspiration. In awake rabbits, 90 % of the power was between 0 and 20 cycles per minute (cpm), not uniformly distributed over this range, but with a peak frequently near 10 cpm. This was much slower than heart or respiratory rhythms and is similar to the frequency content observed in other tissues. During hyperoxia, total power was higher than during air-breathing, and the dominant frequencies tended to shift toward lower values (0–10 cpm). These observations suggest that at least the lower frequency fluctuations represent efforts by the circulation to regulate local PO2. There were no consistent changes in total power during 0.5 or 1.5 % isoflurane anesthesia, but the power shifted to lower frequencies. Thus, both hyperoxia and anesthesia cause characteristic, but distinct, changes in spontaneous fluctuations. These PO2 fluctuations may be caused by vasomotion, but other factors cannot be ruled out.

Purpose: Transient changes in intraretinal oxygen tension (PO 2 ) in response to light stimuli were studied in order to understand the dynamics of light-evoked changes in photoreceptor oxidative metabolism. Methods: PO 2 changes during illumination were recorded by double-barreled microelectrodes in the outer part of the perifoveal retina in five macaques (Rhesus and Cynomolgus) and were fitted to a single exponential equation to obtain the time constant (τ) and maximum PO 2 change. Results: At the onset of light, PO 2 increased at all illuminations in all animals. The magnitude of the light-evoked PO 2 change increased with increasing illumination over 3–4 log units but decreased in all animals at the maximum illumination. The median time constant of the PO 2 change (τ ) was 26 sec and was not correlated with illumination. The time constant for the return to darkness was similar for illuminations below rod saturation. Since O 2 diffusion is fast over the short distance from the choroid to the inner segments, τ reflects the time course of the underlying change in oxidative metabolism. Conclusions: Previous results suggested that two competing processes influence the change in photoreceptor oxidative metabolism with light, Na + /K + pumping and cyclic guanosine monophosphate (cGMP) turnover. Because a single exponential fitted the PO 2 data, it appears that these processes have time constants that differ by no more than a few seconds in primate. In monkeys, τ is longer than previously reported values for cat and rat. Longer time constants are related to larger photoreceptor volume, possibly because metabolic rate is controlled by intracellular Na + , and a change in intracellular Na + after the onset of illumination occurs more slowly in larger photoreceptors. The “metabolic threshold” illumination that reduced oxygen consumption by about 10% is approximately the same as the illumination that closes 10% of the light-dependent cation channels that are open in the dark. keyw ORDS: Non-human primate; Monkey; Retinal metabolism; Photoreceptor; Retina; Oxygen; Macaque

This paper discusses an effort to enhance the learning and affective experience of students in a laboratory module in metabolism through the use of the “How People Learn” framework, which is grounded in educational theory and research. The laboratory, which was a component of a systems physiology course in biomedical engineering, was modified such that some students had educational experiences informed by How People Learn principles while other students encountered a more traditional laboratory. Students were compared on a number of dimensions including knowledge acquisition, ability to use information to solve problems, transfer, and perceptions of their course experience. Several differences were observed between groups, with students in the “How People Learn” group out-performing controls on measures that required a deeper ability to use the material, but not differing in basic acquisition of information. Implications for the development of similar laboratories are discussed.

This work assessed the relative effects of inspiring carbogen (95% O(2)/5% CO2) and 100% O2 on intraretinal PO2 and oxygen consumption in the cat retina. Oxygen microelectrodes were used to measure the distribution of oxygen in the central retina of dark-adapted anesthetized cats during normoxia, 100% O2 breathing, and carbogen breathing. Profiles of oxygen tension (PO2) as a function of retinal depth were recorded. Changes in PO2 caused by the transient administration of carbogen and 100% oxygen were also measured at selected retinal depths. Average PO2 values at the choroid, at the boundary between the inner and outer retina, and across the inner retina were significantly higher during inspiration of carbogen than 100% O2. There were no significant differences among conditions in outer retinal oxygen consumption. During the transient gas administration, average changes in PO2 generally increased with depth. At the end of gas administration, the decay of PO2 within the retina occurred quickly, meaning that short-term gas administration may have little therapeutic value.

Fluorescein angiography (FA) is the current clinical imaging standard for vascular related retinal diseases such as macular degeneration and diabetic retinopathy. However, FA is considered invasive and can provide only two-dimensional imaging. In comparison, optical coherence tomography angiography (OCTA) is noninvasive and can generate three-dimensional imaging; investigations of OCTA already demonstrated great promise in retinal vascular imaging. Yet, to further develop and apply OCTA, strengths and weaknesses between OCTA and FA need to be thoroughly compared. To avoid complications in image registration, an ideal comparison requires co-registered and simultaneous imaging by both FA and OCTA. In this Letter, we developed a system with integrated laser-scanning ophthalmoscope FA (SLO-FA) and OCTA, and conducted simultaneous dual-modality retinal vascular imaging in rodents. In imaging healthy rodent eyes, OCTA can resolve retinal capillaries better than SLO-FA does, particularly deep capillaries. In imaging rodent eyes with laser-induced choroidal neovascularization (CNV), OCTA can identify CNV that eludes SLO-FA detection.

Adequate function of the retina is dependent on proper oxygen supply. In humans, the inner retina is oxygenated via the retinal circulation. We present a method to calculate total retinal oxygen extraction based on measurement of total retinal blood flow using dual-beam bidirectional Doppler optical coherence tomography and measurement of oxygen saturation by spectrophotometry. These measurements were done on 8 healthy subjects while breathing ambient room air and 100% oxygen. Total retinal blood flow was 44.3 ± 9.0 μl/min during baseline and decreased to 18.7 ± 4.2 μl/min during 100% oxygen breathing (P

This study investigated the changes in pH during retinal artery occlusion by means of extracellular H+ concentration ([H+]o) measurements in the retina under both air and 100% O2 ventilation. Occlusion was produced in intact anesthetised cats by pressing with a probe onto a retinal artery. [H+]o profiles were recorded across the retina with pH sensitive microelectrodes. The average inner retinal [H+]o increased during occlusion, resulting in an acidification of as much as 0.10 pH units, even under 100% O2 ventilation. The inner retinal H+ profile magnitude decreased during occlusion due to impaired clearance. The average outer retinal H+ profile magnitude also increased even though outer retinal H+ production did not increase during occlusion. This might be due to H+ diffusion from the inner retina to the outer retina, which is opposite to the flux in the normal retina. After reperfusion, [H+]o returned to its preocclusion value. In conclusion, arterial occlusion leads to acidification of the retina. Enhanced oxygenation during occlusion did not decrease this acidification. This may explain why increasing PO2 in the retina by enhanced O2 breathing improves retinal function during and after occlusion, but does not totally reverse the effect of occlusion.

This article focuses on undergraduate biomedical engineering (BME) curriculum, particularly on how to address industrial needs and to what extent a common curriculum can and should exist. It is part review, part description of the current work of the VaNTH (Vanderbilt University; Northwestern University; University of Texas at Austin; and Health, Science and Technology at Harvard/MIT) Engineering Research Center for Bioengineering Educational Technologies, and part editorial. The editorial offers a snapshot of the continually evolving effort to integrate ideas from many sources for the improvement of curriculum in BME. These ideas and recommendations are accessible on the Web site of the VaNTH curriculum project. The term "biomedical engineering" denotes a type of engineering with a strongly medical focus. It encompasses programs that are called "bioengineering" (BE) but which have the same flavor as BME. The first BME undergraduate degrees were granted less than 40 years ago. Full agreement about the content knowledge needed for a B.S. in BME does not exist now and is not likely to exist in the near future. Our recent survey of required curriculum in accredited programs found no courses that were required by all, although courses in biomechanics and systems physiology were quite common. This lack of agreement at the course level does not mean that there is no similarity at the content level, however. Our hypothesis is that it will be possible to achieve consensus about key elements of the BME curriculum.

Most biomedical engineering (BME) programs appreciate the need to provide their students with knowledge in the field of systems physiology. One objective in teaching systems physiology to undergraduate or graduate BME students should be to provide them with enough understanding of physiology that they can acquire what further understanding they need as such a need arises later in life. An instructional goal should therefore be to provide a solid framework in physiology from which learning through self-instruction is enhanced. With the preceding reasoning in mind, a project is underway in the VaNTH (Vanderbilt University; Northwestern University; University of Texas at Austin; and Health. Science and Technology at Harvard/MIT) Engineering Research Center (ERC) to define certain key concepts in systems physiology that we feel are essential in the training of BME students. We believe that in planning a curriculum in BME it is more meaningful to define the key concepts (e.g., homeodynamics, emergent properties, etc.) that one should seek to cover in a systems physiology course or course sequence than to specify the particular systems in which one would cover these concepts. The latter might be constrained by local expertise or by other local biases. We propose that, if students are presented with the key concepts well, their ability to generalize them to new systems should be greatly eased, promoting self-learning.

Oxygen tension (PO 2 ) was measured in rabbit whisker barrel cortex using oxygen sensitive electrodes to investigate the impact of isoflurane anesthesia on oxygen autoregulation. Responses to 90 s episodes of 100% oxygen inspiration were obtained from rabbits before anesthesia, and then when the animals were anesthetized with 0.5% or 1.5% isoflurane. For each episode, ΔPO 2 (i.e., hyperoxic PO 2 minus baseline PO 2 ) was computed. Compared to the conscious state, brain ΔPO 2 increased during anesthesia with 1.5% isoflurane (0.73 MAC) by an average of 116%, whereas 0.5% isoflurane produced an insignificant average increase of 31%. The results suggest that moderate levels of isoflurane impaired autoregulation of brain tissue oxygen tension.

The present work quantifies aspects of photoreceptor structure related to mitochondria, inner segment dimensions, and optical properties, as a basis for furthering our understanding of rod and cone function. Electron-microscopic analyses were performed on the retina of one stumptail macaque (Macaca arctoides) to obtain stereological measurements of ellipsoid mitochondrial density, and sizes and shapes of outer and inner segments. In addition, the distribution of mitochondria and the optical properties of human foveal cones were examined with electron microscopy and Nomarski differential interference contrast (NDIC) imaging. Mitochondria comprised 74–85% of cone ellipsoids and 54–66% of rod ellipsoids in macaque. Ellipsoid volume increased with eccentricity by 2.4-fold for rods and more than 6-fold for cones over eccentricities to 12.75 mm, while the volume of the outer segment supported by the ellipsoid was essentially constant for both rods and cones. Per unit volume of outer segment, cones contained ten times as much mitochondria as rods. In human fovea, as in the rest of the retina, most cone mitochondria were located in the distal inner segment. In the foveal center, however, there are also mitochondria in the myoid, as well as in the outer fiber, proximal to the external limiting membrane (ELM). Analyses of the optical aperture of human foveal cones, the point at which their refractive index clearly differs from the extrareceptoral space, showed that it correlated well with the location of mitochondria, except in the foveal center, where the aperture appeared proximal to the ELM. While mitochondria have an important metabolic function, we suggest that the striking differences between rods and cones in mitochondrial content are unlikely to be determined by metabolic demand alone. The numerous cone mitochondria may enhance the waveguide properties of cones, particularly in the periphery.

Purpose To investigate inner retinal oxygen metabolic rate (IRMRO2) during early stages of type 1 diabetes in a transgenic mouse model. Methods In current study, we involved seven diabetic mice (Akita/+, TSP1-/-) and seven control mice (TSP1-/-), and applied visible-light optical coherence tomography (vis-OCT) to image functional parameters including retinal blood flow rate, oxygen saturation (sO2) and the IRMRO2 value longitudinally from 5 weeks of age to 13 weeks of age. After imaging at 13 weeks of age, we analyzed the imaging results, and examined histology of mouse retina. Results Between diabetic mice and the control group, we observed significant differences in venous sO2 from 9 weeks of age (P = 0.006), and significant increment in IRMRO2 from 11 weeks of age (P = 0.001) in diabetic mice compared with control group. We did not find significant differences in retinal blood flow rate as well as arterial sO2 during imaging between diabetic and control mice. Histologic examination of diabetic and control mice at 13 weeks of age also revealed no anatomical retinal alternations. Conclusions In diabetic retinopathy, complications in retinal oxygen metabolism may occur before changes of retinal anatomical structure.

Quantitatively determining physiological parameters at a microscopic level in the retina furthers the understanding of the molecular pathways of blinding diseases, such as diabetic retinopathy and glaucoma. An essential parameter, which has yet to be quantified noninvasively, is the retinal oxygen metabolic rate (rMRO2). Quantifying rMRO2 is challenging because two parameters, the blood flow rate and hemoglobin oxygen saturation (sO2), must be measured together. We combined photoacoustic ophthalmoscopy (PAOM) with spectral domain-optical coherence tomography (SD-OCT) to tackle this challenge, in which PAOM measured the sO2 and SD-OCT mapped the blood flow rate. We tested the integrated system on normal wild-type rats, in which the measured rMRO2 was 297.86 ± 70.23 nl/minute. This quantitative method may shed new light on both fundamental research and clinical care in ophthalmology in the future.

Kang Derwent and Linsenmeier (2000) reported that the a- and b-waves of the cat electroretinogram (ERG) are resistant to hypoxemia, at least for PaO2 above 40 mm Hg. The a-wave may be resistant because the photoreceptor can increase glycolysis during hypoxemia. This hypothesis was tested by making the animal hypoglycemic, which should minimize the ability of the photoreceptor to switch to glycolysis. The ERG of dark-adapted anesthetized cats was recorded between an Ag/AgCl electrode in the vitreous humor and a reference electrode near the eye. Responses to bright flashes of diffuse white light were recorded at 3-min intervals during hypoxic episodes at three levels of blood glucose. The moderate hypoglycemia (50 to 70 mg/dl) had a relatively small effect on the a-wave amplitude. Furthermore, the a-wave amplitude increased transiently by 16 ± 7% within 30–40 min of the start of severe hypoglycemia (20 to 40 mg/dl), before recovering to near normal. Severe hypoglycemia alone decreased the b-wave amplitude by 15 ± 13%. Combined hypoxemia and hypoglycemia decreased the b-wave amplitude more than the a-wave amplitude. At all levels of blood glucose, b-wave decreases began at a higher PaO2 than the a-wave changes. For both the a- and b-waves, hypoxemic effects began at higher PaO2 when the animal was hypoglycemic. The increased sensitivity to hypoxemia during severe hypoglycemia suggests that a switch from oxidative to glycolytic metabolism ordinarily protects the retina from moderate hypoxemia. Because the a- and b-waves were affected to different degrees and at different PaO2s, it is unlikely that inner retinal changes are caused completely by changes in the photoreceptor.

It has often been assumed that the recovery of the a-wave from its trough is caused by the intrusion of the b-wave. This study examined the recovery following the a-wave trough using intraretinal recordings in dark-adapted intact cat retina. Adult cats were anesthetized and paralyzed. The vitreal ERG was recorded between the vitreous humor and a reference electrode near the eye. Intraretinal recordings were made by referencing a microelectrode to the vitreal electrode. Bright flashes of diffuse white light were used to elicit a- and b-waves. Intravitreal injections of 2-amino-4-phosphonobutyrate (APB), cis 2,3-piperidine dicarboxylic acid (PDA), and kynurenic acid (KYN) were used to block the responses of bipolar and horizontal cells. Intravitreal injections of UL-FS 49 or DK-AH 269 were used to block Ih, a hyperpolarization-activated potassium current. Since the microelectrode was referenced to the vitreal electrode, recordings from the inner retina showed only the oscillatory potentials and b-waves. In the inner retina, the potential was flat until the b-wave became measurable, ∼17 ms from the onset of the flash. The a-wave started to appear as the microelectrode reached the photoreceptors and its amplitude increased with depth until the microelectrode reached the choroid. The a-wave peaked at ∼8 ms in response to flashes that saturated its amplitude and then began to recover well before any inner retinal responses were apparent. After injections of APB, PDA, and KYN, vitreal and intraretinal recordings showed only the a-wave, which consisted of an increase to peak at ∼10 ms followed by a recovery to a plateau which was reached at ∼25 ms. Blockers of Ih reduced the recovery, but did not eliminate it. The a-wave peaks and partially recovers before the b-wave intrudes. Both phases survive blockers of second-order neurons which implies that the photoreceptors generate both the rising and recovery phase of the a-wave. The recovery phase may be due to a current generated by the inner segment of photoreceptors.

Tissue [Formula: see text] was measured in the primary visual cortex of anesthetized, artificially ventilated normovolemic cats to examine tissue oxygenation with respect to depth. The method utilized 1) a chamber designed to maintain cerebrospinal fluid pressure and prevent ambient[Formula: see text] from influencing the brain, 2) a microelectrode capable of recording electrical activity as well as local[Formula: see text], and 3) recordings primarily during electrode withdrawal from the cortex rather than during penetrations. Local peaks in the [Formula: see text] profiles were consistent with the presence of numerous vessels. Excluding the superficial 200 μm of the cortex, in which the ambient[Formula: see text] may have influenced tissue[Formula: see text], there was a slight decrease (4.9 Torr/mm cortex) in [Formula: see text] as a function of depth. After all depths and cats were weighted equally, the average [Formula: see text] in six cats was 12.8 Torr, with approximately one-half of the values being ≤10 Torr. The kurtosis of the [Formula: see text] histogram, with all depths and cats weighted equally, was 3.61, and the skewness was 1.70.

Tissue[Formula: see text] was measured in the primary visual cortex of anesthetized, artificially ventilated, normovolemic cats to evaluate the effect of small doses [1 g perfluorocarbon (PFC)/kg] of a PFC emulsion (1 g PFC/1.1 ml emulsion; Alliance Pharmaceutical, San Diego, CA) on brain oxygenation. The change in tissue [Formula: see text]([Formula: see text]), resulting from briefly changing the respiratory gas from room air to 100% oxygen, was measured before and after intravenous infusion of the emulsion. Before emulsion, [Formula: see text] was 51.1 ± 45.6 Torr ( n = 8 cats). Increases in [Formula: see text] of 34.0 ± 26.1 (SD) % ( n = 8) and 16.3 ± 8.4% ( n = 6) were observed after the first and second emulsion infusions, respectively. The further increase in [Formula: see text] after the third dose (7.9 ± 10.5%; n = 7) was not statistically significant. The observed increases in tissue oxygenation as a result of the PFC infusions appear to be the result of enhanced oxygen transport to the tissue.

In 2011, the American Institute for Medical and Biological Engineering (AIMBE) (www.aimbe.org) celebrated its 20th anniversary by undertaking to identify major societal challenges to which medical and biological engineers can contribute solutions in the next 20 years. This report is a summary of the six major challenges that were identified. The report also discusses some specific areas within these high-level challenges that can form the basis for policy action, provides a brief rationale for pursuing those areas, and discusses roadblocks to progress. The six overarching challenges are: 1) engineering safe and sustainable water and food supply, 2) engineering personalized health care, 3) engineering solutions to injury and chronic diseases, 4) engineering global health through infectious disease prevention and therapy, 5) engineering sustainable bioenergy production, and 6) engineering the 21st century US economy. While arrived at independently by AIMBE, many of the elements overlap with similar challenges identified by other bodies. The similarities highlight the central mission of medical and biological engineers, working with other experts, which is to solve important problems central to human health and welfare.

Therapeutic isovolemic hemodilution has been reported to improve blood flow and oxygen delivery. Few reliable measurements have been made, however, showing the effect of hemodilution on tissue oxygen tension.We measured retinal oxygen tension during experimental isovolemic hemodilution in normal cats. Polarographic oxygen microelectrodes were placed in the vitreous humor within 100-200 microns of the retinal surface.Tissue oxygen tension increased initially during isovolemic hemodilution to a maximum approximately 50% above baseline at approximately two thirds of the original hematocrit level. Hemodilution beyond this point to lower hematocrits caused a steady decline in tissue oxygen tension. Cardiac output measured in one cat undergoing isovolemic hemodilution increased as hematocrit was lowered, but the cardiac erythrocyte flux actually decreased steadily.The observed increase in tissue oxygen tension with hemodilution appears to be explained by a lesser reduction in capillary than in systemic hematocrit, coupled with an increased capillary blood flow. The increase in tissue oxygen tension we observed could in part explain the clinically beneficial effects of hemodilution.

Miniaturized electrochemical biosensors for glucose were constructed, using recessed gold microelectrodes (diameter 350 to 425 μm) and ultramicroelectrodes (diameter less than 25 μm) as the base sensors. The gold was a substrate for chemically attached thiolated glucose oxidase containing adsorbed hydroquinonesulfonate, which served as a mediator of electron transfer between the electrode surface and the enzyme. The chemically modified electrodes were coated with Nafion® to reduce the effects of anionic interferences, such as ascorbic acid, and were tested in sodium phosphate buffered glucose solutions (pH 7.4) at 25°C by cyclic voltammetry and steady-state amperometry at positive potentials suitable for glucose detection. Cyclic voltammetry confirmed that the glucose oxidase and hydroquinonesulfonate were both securely immobilized at the surface of the electrodes. The amperometric t 90 response times for the ultramicroelectrodes and microelectrodes were under 20 and 100 s respectively. The current response of both electrode types was linear up to glucose concentrations of 50 mM, and the response to ascorbic acid at physiological concentrations was reduced by Nafion® by 53.3%. Key advantages of this electrode are that it is miniaturized for optimum in vivo analysis, it is unresponsive to variable oxygen tension, and its recess allows for increased response stability and faster response times.

Retinal O2 utilization was studied to identify the O2 consuming processes in the retina and the spatial distribution of those processes. Neural retina, retinal pigment epithelium and choroid were dissected from the toad eye and superfused with an oxygenated Ringer's solution. Double-barreled microelectrodes were used to measure O2 and local voltage simultaneously within the retina in both light and dark adaptation. The profile of PO2 was measured during a withdrawal of the electrode tip across the retinal pigment epithelium and through the neural retina. The PO2 decreased through the distal retina, reaching a minimum in the inner segment or outer nuclear layer, and then increased steadily through the proximal retina. From fitting PO2 profiles measured in the dark-adapted retina to a three-layer diffusion model, O2 consumption was found to be 1.0 +/- 0.4 and 0.4 +/- 0.3 ml O2 (100 g min)-1 in the outer and inner halves of the retina, respectively. Light decreased consumption in both halves of the retina. In steady illumination (500 nm) that saturated the ERG b- and c-waves, O2 utilization decreased significantly to 48% and 68% of the dark values in the outer and inner retina, respectively. When Na+ was removed from the superfusate to inhibit the photoreceptor Na+/K+ pump, O2 consumption in the outer retina decreased by about the same amount as in light, but O2 consumption in the inner retina was not significantly affected.

The purpose of this study was to investigate the oxygen distribution and consumption in the pigmented Long-Evans rat retina in vivo during dark and light adaptation, and to compare these results to previous work on cat and albino rat. Double-barreled microelectrodes recorded both intraretinal PO 2 depth profiles and the electroretinogram (ERG), which was used to identify the boundaries of the retina. Light adaptation decreased photoreceptor oxygen consumption per unit volume ( Q av ) from 3.0 ± 0.4 ml·100 g −1 min −1 (mean ± SEM) in darkness to 1.8 ± 0.2 ml·100 g −1 min −1 and increased minimum outer retinal PO 2 at the inner segments ( P min ) from 17.4 ± 3.0 to 29.9 ± 5.3 mmHg. The effects of light on outer retinal PO 2 and Q av were similar to those previously observed in cat, monkey, and albino rats; however, dark-adapted P min was higher in rat than cat. The parameters derived from fitting the oxygen diffusion model to the rat data were compared to those from cat. Oxygen consumption of the inner segments ( Q 2 ) and choroidal PO 2 ( P C ) in rat and cat were similar. P min was higher in rat than in cat for two reasons: first, rat photoreceptors have a shorter oxygen consuming region; and second, the retinal circulation supplied a greater fraction of consumed oxygen to rat photoreceptors. The average PO 2 across the inner retina ( P IR ) was not different in dark adaptation (25.4 ± 4.8 mmHg) and light adaptation (28.8 ± 5.4 mmHg) when measured from PO 2 profiles. However, with the microelectrode stationary at 9–18% retinal depth, a small consistent decrease in PO 2 occurred during illumination. Flickering light at 6 Hz decreased inner retinal PO 2 significantly more than an equivalent steady illumination, suggesting that changes in blood flow did not completely compensate for increased metabolism. This study comprehensively characterized rat retinal oxygenation in both light and dark, and determined the similarities and differences between rat and cat retinas.