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Challenges and Opportunities in Biomedical Engineering

Challenges and Opportunities in Biomedical Engineering

Robertson, J. L., Issa, A. S., Gómez, M., Sullivan, K. E., & Senger, R. S. (2023)


Background: Many systemic and urinary tract diseases alter renal structure and function, including changing the composition of urine. While routine urinalysis (physical properties, sediment evaluation, urine chemistry analytes) is useful in screening, it has limitations on separating disease processes, structural changes, and functional abnormalities. Likewise, while many individual ‘biomarkers’ have been used to screen for disease, they have not met with widespread clinical adoption. The recent COVID19 Pandemic and the recognition of post-acute sequelae SARS-CoV-2 infection (PASC) have highlighted the need for rapid, scalable, economical, and accurate screening tools for managing disease.

Aims: Validate a Raman spectroscopy-based screening technology for urine analysis that could be used for recognition and quantification of systemic and renal effects of acute and PASC COVID19 disease.

Methods: One hundred ten (110) urine specimens were obtained from consented adults diagnosed with COVID19 disease by RT-PCR and/or proximate (household) contact With RT-PCR-confirmed COVID19 disease. Samples were analyzed using Raman chemometric urinalysis, a technology that detects hundreds of discrete chemicals in urine and applies computational comparison-machine learning to detect COVID19-associated molecular patterns (‘fingerprints’).

Results: When compared with the urine multimolecular ‘fingerprints’ of healthy individuals and patients with known systemic diseases (diabetes mellitus, lupus) that alter renal structure and function, patients with acute and PASC COVID19 had unique ‘fingerprints’ indicative of alterations in renal function (i.e. – infection altered urine composition). Differences in disease severity (mild to severe) were reflected by different ‘fingerprints’ in urine. Roughly 20% of hospitalized patients developed a degree of renal dysfunction (decrements in eGFR) that were correlated with distinct changes in urine fingerprints.

Conclusion: Raman chemometric urinalysis may be a useful tool in management of patients with COVID19 disease, particularly in detecting patients with evolving renal dysfunction for whom there should be attention to medication use and renal health restoration/preservation.

Inbar, O., Inbar, O., Reuveny, R., Segel, M. J., Greenspan, H., & Scheinowitz, M. (2023)


Background: There is no agreement on the best strategy for interpreting/ analyzing cardiopulmonary exercise test (CPET) results.

Aims: This study aims to evaluate the feasibility of using computer-aided algorithms to evaluate CPET data to identify the exercise limitation/ intolerance level.

Methods: This study used 206 retrospective CPET files from the Pulmonary Institute and the Cardiology Rehabilitation Center at the Sheba Medical Center and 50 from the exercise physiology laboratory at the Washington-Hill College, both in Israel. Eighty patients with confirmed primary cardiovascular-related exercise limitation, seventy-six with ventilatory-related exercise limitation, and fifty healthy (none or very mild exercise restraints) subjects comprised the pool of examined CPET data. Support Vector Machine (SVM) Learning was performed on 150 (50 in each group) of the 206 CPETs, while model validation was performed on the remaining 56 CPET files. By applying the K-means clustering method, distribution analysis was used to compare the SVM interpretive module’s performance to that of senior cardiologists, pulmonologists, and expert exercise physiologists.

Results: Overall, the proposed interpretive model has a predictive power of between 78% and 100%, as shown by its ability to correctly classify the degree of exercise limitation.

Conclusions: The proposed machine-learning CPET interpretive module was highly sensitive and specific in identifying patients with mild, moderate, or severe cardiovascular- or ventilatory-related exercise limitations/ intolerance. Comparable modules may be applied to additional (kinds of exercise limitations) and larger populations, making this tool powerful and clinically applicable.

Boylan, J., Byers, E., & Kelly, D. F. (2023)


Malignant brain tumors are aggressive and difficult to treat. Glioblastoma is the most common and lethal form of primary brain tumor, often found in patients with no genetic predisposition. The median life expectancy for individuals diagnosed with this condition is 6 months to 2 years and there is no known cure. New paradigms in cancer biology implicate a small subset of tumor cells in initiating and sustaining these incurable brain tumors. Here, we discuss the heterogenous nature of glioblastoma and theories behind its capacity for therapy resistance and recurrence. Within the cancer landscape, cancer stem cells are thought to be both tumor initiators and major contributors to tumor heterogeneity and therapy evasion and such cells have been identified in glioblastoma. At the cellular level, disruptions in the delicate balance between differentiation and self-renewal spur transformation and support tumor growth. While rapidly dividing cells are more sensitive to elimination by traditional treatments, glioblastoma stem cells evade these measures through slow division and reversible exit from the cell cycle. At the molecular level, glioblastoma tumor cells exploit several signaling pathways to evade conventional therapies through improved DNA repair mechanisms and a flexible state of senescence. We examine these common evasion techniques while discussing potential molecular approaches to better target these deadly tumors. Equally important, the presented information encourages the idea of augmenting conventional treatments with novel glioblastoma stem cell-directed therapies, as eliminating these harmful progenitors holds great potential to modulate tumor recurrence.

Kulshreshtha, P., Neyaz, O., Goel, A., Barde, P., Mukherjee, D., Deepak, K. K., & Kathrotia, R. (2023)


A purple butterfly symbolizes the heightened sensitivity to even a gentle touch in fibromyalgia (FM), which is a common syndrome with persistent widespread pain and tenderness. The biopsychosocial model is currently the main framework used to appreciate different factors contributing to chronic pain in FM.  Widespread pain in fibromyalgia is effected by multiple biopsychosocial factors (cognitive ability, depression, somatization, psychological trauma, anxiety, and social deprivation/isolation), which interact and contribute to chronic persistent pain.  Interaction of influences such as gender, neuroendocrine milieu, and the hypothalamo–pituitary–adrenal axis also affect FM susceptibility and its clinical expression. Multiple neuroanatomic and neurochemical systems with many autonomic, cognitive & affective processes manifest as multisymptom illness in FM. While the etiology of FM is elusive, the associated symptoms indicate the role of autonomic dysfunction in its pathophysiology. Fatigue and widespread pain characterizing FM may be consequent to peripheral tissue ischemia caused by sympathetically mediated vasoconstriction. In light of some common denominators among FM patients, which include genetic variation, sympathetic hyper-activation, maladaptive thoughts, ineffective coping strategies, and nonrestorative sleep,  an individualized care approach can help subgroup and phenotype these patients for specific diagnosis and management. A multidisciplinary approach involving person-centered approaches to biopsychosocial concepts in FM, incorporating relaxation therapy, physical activity, and psychotherapy targeting negative emotions that amplify pain, maladaptive coping strategies, and environmental stressors, can help manage FM’s course, outcomes, and treatment.

Hocking, K. M., Huston, J., Schmeckpeper, J., Polcz, M., Case, M., Breed, M., Vaughn, L., Wervey, D., Brophy, C. M., Lindenfeld, J., & Alvis, B. D. (2022)


Introduction: A cornerstone of heart failure assessment is the right heart catheterization and the pulmonary capillary wedge pressure measurement it can provide.  Clinical and hemodynamic parameters such as weight and jugular venous distention are less invasive measures often used to diagnose, manage, and treat these patients. To date, there is little data looking at the association of these key parameters to measured pulmonary capillary wedge pressure (PCWP). This is a large, retrospective, secondary analysis of a right heart catheterization database comparing clinical and hemodynamic parameters against measured PCWP in heart failure patients.

Methods: A total of 538 subjects were included in this secondary analysis. Spearman’s Rho analysis of each clinical and hemodynamic variable was used to compare their association to the documented PCWP. Variables analyzed included weight, body mass index (BMI), jugular venous distention (JVD), creatinine, edema grade, right atrial pressure (RAP), pulmonary artery systolic pressure (PASP), systemic vascular resistance, pulmonary vascular resistance, cardiac output (thermal and Fick), systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate, oxygen saturation (SpO2), and pulmonary artery diastolic pressure (PADP).

Results: Ten out of 17 selected parameters had a statistically significant association with measured PCWP values. PADP had the strongest association (0.73, p<0.0001), followed by RAP and PASP (0.69, p<0.0001 and 0.67, p<0.0001, respectively). Other significant parameters included weight (0.2, p<0.001), BMI (0.2, p<0.001), SpO2 (-0.17, p<0.0091), JVD (0.24, p<0.005) and edema grade (0.2, p<0.0001).

Conclusion: This retrospective analysis clarifies the associations of commonly used clinical and hemodynamic parameters to the clinically used gold standard for volume assessment in heart failure patients, PCWP.

Huang, C. F., Garnett, K., Moncure, M., Dyer, K., Young, S., & Huang, R. (2023)


We analyzed videos of boxing matches and mixed-martial-arts fights. We observed an immediate and severe loss of muscle tone following a knockout. This impact-induced loss of muscle tone was typically transient, lasting seconds or less. This phenomenon involved muscles in the upper and lower limbs, and possibly axial muscles as well as the facial musculature. The observation is best described as an active person instantaneously transformed into an inanimate object, followed by a free fall in gravity accompanied by flaccidity or paralysis. Analyzing double-knockouts, we concluded that the observed impact-induced loss of muscle tone occurred within tens of milliseconds of a head hit. The speed, scope, and severity of the muscle tone loss are not consistent with a local loss-of-function mechanism. Because such loss of muscle tone closely resembles sudden attacks in cataplexy patients, we hypothesized that severe head impacts may directly involve brain centers that regulate rapid eye movement sleep. These brain centers may be part of an active mechanism to shut down the muscle tone quickly and globally. When muscle tone is low or absent, athletes are at elevated risk for further injuries in combat or contact sports. Athletes, athletic trainers, and referees in combat as well as contact sports should be vigilant and recognize signs of impact-induced loss of muscle tone in order to improve player safety and better protect these athletes.

Huang, C. F., Garnett, K., Moncure, M., Dyer, K., Young, S., & Huang, R. (2023)


Purpose: To introduce a novel technique using PANIS method (Plasma assisted noninvasive surgery) in pterygium removal surgery with conjunctival rotation flap.

Methods: Two patients (1 male, 1 Female) with grade 3 and 4 of pterygium, based on SLIT2 grading system, underwent surgery with local anesthesia, removing pterygium tissue from cornea and also all related subtenon. Then surgeon used residual conjunctiva to cover bare sclera using rotational method. Fusion of the border of conjunctival flaps from nasal to superior occurred by plasma spots. UCVA, BCVA, OSDI and patient satisfaction were evaluated before, 1 month, 6 months and 1 year after the surgery, as well as 1 day and 1 week post-operation examinations included slit-lamp and external check-up that has been done by the surgeon.

Results: Patients with primary pterygium, underwent surgery with PANIS method. Last follow-up session in 1 year, showed significant improvement in astigmatism and 1 line in BCVA. There were no complications and side effects during and after the surgery and also other reported complication included diplopia in lateral gaze, granuloma and scarring was not observed and no recurrence have been seen in the follow-up period and patients were satisfied. Additionally 1 day and 1 week slit-lamp examination showed plasma spots caused good attachment of conjunctival tissue with ocular surface.

Conclusion: After treating 2 patients with PANIS method, it seems that plasma spots can be a good substitute for suture or glue in pterygium surgery with conjunctival rotational flap, because it’s easy and fast way for fusing the conjunctival flap without any complication or side effect.

Vögeli, B., Kola, V., Poltavskaya, M. G., Saner, H., & Arenja, N. (2022)


This review serves as a synopsis of current knowledge about electrical muscle stimulation in patients with heart failure. It summarizes actual data, emphasizes the beneficial effects of electrical muscle stimulation in heart failure and tries to characterize a target population. Improvements of functional capacity and quality of life are knowingly achieved by variable stimulation protocols to the lower extremities. The population most likely to benefit from this therapy is of older age, has relevant comorbidities or reduced left ventricular ejection fraction. While short-term outcomes are mostly positive, there are few data on long-term outcomes that should be further investigated. Overall, electrical muscle stimulation can be considered a safe and efficacious therapy alternative to conventional physical exercise in patients with heart failure. Despite promising and increasing evidence for over two decades of scientific research on this topic, there are no recommendations in recent published guidelines concerning the use of electrical muscle stimulation in heart failure patients.

Dashek, R. J., Higashi, Y., Das, N. A., Russell, J. A., Martínez-Lemus, L. A., Rector, R., & Chandrasekar, B. (2022)


Aims: Chronic intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), contributes to cardiovascular diseases, including atherosclerosis, potentially through persistent oxidative stress and inflammation. TRAF3IP2 (TRAF3 Interacting Protein 2) is an oxidative stress-responsive proinflammatory adapter molecule and plays a causal role in a preclinical model of atherosclerosis. Since SGLT2 (Sodium/Glucose Cotransporter 2) inhibitors have shown protective effects in CVD by inhibiting oxidative stress and inflammation, we hypothesized that IH promotes the crosstalk between oxidative stress and TRAF3IP2, resulting in IL-6-dependent human aortic smooth muscle cell (SMC) proliferation, and that these effects are inhibited by the SGLT2 inhibitor empagliflozin.

Materials and methods: Primary human aortic SMC were exposed to various cycles of IH. Normoxia served as a control. To understand the molecular mechanisms underlying IH-induced nitroxidative stress, TRAF3IP2 and IL-6 induction, and SMC proliferation and those targeted by empagliflozin were determined by treating SMC with various pharmacological inhibitors and viral vectors.

Results: IH upregulated TRAF3IP2 expression, TRAF3IP2-dependent superoxide, hydrogen peroxide and nitric oxide generation, NF-kB and HIF-1a activation, IL-6 induction, and SMC proliferation. Exposure to IL-6 by itself induced SMC proliferation in part via TRAF3IP2, IL-6R, gp130, JAK, and STAT3. Further, SMC express SGLT2 at basal conditions, and is upregulated by both IH and IL-6. Importantly, empagliflozin inhibited IH-induced TRAF3IP2 upregulation, reactive oxygen and nitrogen species generation, TRAF3IP2-dependent HIF-1a and NF-kB activation, IL-6 induction, and IL-6-dependent JAK-STAT3-mediated SMC proliferation. Moreover, empagliflozin inhibited IL-6-induced STAT3-dependent SMC proliferation.

Conclusions: These results suggest the therapeutic potential of empagliflozin in IH and inflammatory vascular proliferative diseases associated with OSA.

Mun, S. K., Lo, S. B., Wong, K. H., Koh, D., & Prior, F. (2023)


Radiology has a long history of adopting state-of-the-art digital technology to provide better diagnostic services and facilitate advances in image-based therapeutics throughout the healthcare system. The radiology community has been developing diagnostic artificial intelligence (AI) tools over the past 20 years, long before AI became fashionable in the public press. Currently, there are approximately four hundred Food and Drug Administration approved imaging AI products. However, the clinical adoption of these products in radiology has been relatively dismal, indicating that the current technology-push model needs to evolve into the demand-pull model. We will review the current state of AI use in radiology from the perspective of clinical adoption and explore the ways in which AI products will become an ensemble of critically important tools to help radiology transition from volume-based service to value-based healthcare. This transition will create new demands for AI technologies. We contrast the current “technology-push” model with a “demand-pull” model that will aligns technology with user priorities.

We summarize the lessons learned from AI experience over the past twenty years, mainly working with computer-aided detection for breast cancers and lung cancers. The radiology community calls for AI tools that can do more than detection with increasing attention toward higher workflow efficiency and higher productivity of radiologists. Major radiological societies of North America and Europe promulgated the emerging concept of value-based radiology service, an integral part of overall value-based healthcare. The transition to value-based radiology will happen and that higher value will come from the effective use of AI throughout the radiology workflow.

The value-based radiology will need to work with a full range of machine learning tools, including supervised, unsupervised, and reinforcement learning, as well as natural language processing and large language models (e.g., chatbots). The engineering community is rapidly developing many concepts and sophisticated software tools for data orchestration, AI orchestration, and automation orchestration. Current radiology operation has been supported by PACS, a monolithic IT infrastructure of past generations. This system will need to migrate to an intelligence management system to support the new workflow needed for high value radiology. 

Boni, A., York, J. D., Boyette, N., & Im, D. (2023)


This update on life science innovation extends Boni’s 2018 works1,2 to include industry stakeholder expert opinion. This paper’s focus is to address three research questions relevant to innovation within the biopharmaceutical industry concerning 1) its current state, 2) challenges, opportunities, and frameworks, and 3) existing examples in the extant literature and practice relevant to progress and challenges. It utilizes mixed methods involving a 1) narrative review to establish a current understanding of the extant literature and frameworks and 2) qualitative interviews to coalesce themes around the core research questions. The first section summarizes current industry challenges, successes, and best practices that support sustained and disruptive innovation in the biopharma industry. It charts a brief overview of proven models for innovation, entrepreneurial thinking, and for development of open innovation as applied to this complex, challenging, continuously evolving industry. This initial discussion advocates the pursuit of commercialization that 1) incorporates a phased, interdisciplinary, collaborative approach and 2) blends the principles of business, science, and technology through diverse, collaborative teams, networks, and alliances. The paper transitions to a second section. This effort builds on these concepts and provides insights and alternative perspectives from a cohort of leading experts within the biomedical investment, development, and commercialization space. It also illustrates and leverages collective intelligence through interdisciplinary perspectives across the life science landscape and reinforces trends for pursuing innovation.