Annual Review of Biomedical Engineering - Current Issue

Questions in cancer have engaged systems biologists for decades. During that time, the quantity of molecular data has exploded, but the need for abstractions, formal models, and simplifying insights has remained the same. This review brings together classic breakthroughs and recent findings in the field of cancer systems biology, focusing on cancer cell pathways for tumorigenesis and therapeutic response. Cancer cells mutate and transduce information from their environment to alter gene expression, metabolism, and phenotypic states. Understanding the molecular architectures that make each of these steps possible is a long-term goal of cancer systems biology pursued by iterating between quantitative models and experiments. We argue that such iteration is the best path to deploying targeted therapies intelligently so that each patient receives the maximum benefit for their cancer.

People who have lost the ability to speak due to neurological injuries would greatly benefit from assistive technology that provides a fast, intuitive, and naturalistic means of communication. This need can be met with brain–computer interfaces (BCIs): medical devices that bypass injured parts of the nervous system and directly transform neural activity into outputs such as text or sound. BCIs for restoring movement and typing have progressed rapidly in recent clinical trials; speech BCIs are the next frontier. This review covers the clinical need for speech BCIs, surveys foundational studies that point to where and how speech can be decoded in the brain, describes recent progress in both discrete and continuous speech decoding and closed-loop speech BCIs, provides metrics for assessing these systems’ performance, and highlights key remaining challenges on the road toward clinically useful speech neuroprostheses.

Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood. In contrast to ATP, cytokines are a class of signaling molecule that are much larger, with longer signaling and farther diffusion. We posit that neuron-expressed cytokines are an essential mechanism of neuron–microglia communication that arises as part of both normal learning and memory and in response to tissue pathology. Thus, neurons are underappreciated immunomodulatory cells that express diverse immunomodulatory signals. While neuronally sourced cytokines have been understudied, new technical advances make this a timely topic. The goal of this review is to define what is known about the cytokines expressed from neurons, how they are regulated, and the effects of these cytokines on microglia. We delineate key knowledge gaps and needs for new tools to define and analyze neuronal roles in immunomodulation. Given that cytokines are central regulators of microglial function, a broad new body of work is required to illuminate functional links between these neuronally expressed cytokines and sustained and transient microglial function.

The lymphatic vasculature plays critical roles in maintaining fluid homeostasis, transporting lipid, and facilitating immune surveillance. A growing body of work has identified lymphatic dysfunction as contributing to the severity of myriad diseases and to systemic inflammation, as well as modulating drug responses. Here, we review efforts to reconstruct lymphatic vessels in vitro toward establishing humanized, functional models to advance understanding of lymphatic biology and pathophysiology. We first review lymphatic endothelial cell biology and the biophysical lymphatic microenvironment, with a focus on features that are unique to the lymphatics and that have been used as design parameters for lymphatic-on-chip devices. We then discuss the state of the art for recapitulating lymphatic function in vitro, and we acknowledge limitations and challenges to current approaches. Finally, we discuss opportunities and the need for further development of microphysiological lymphatic systems to bridge the gap in model systems between lymphatic cell culture and animal physiology.

Gene therapy is a rapidly developing field, finally yielding clinical benefits. Genetic engineering of organs for transplantation may soon be an option, thanks to convergence with another breakthrough technology, ex vivo machine perfusion (EVMP). EVMP allows access to the functioning organ for genetic manipulation prior to transplant. EVMP has the potential to enhance genetic engineering efficiency, improve graft survival, and reduce posttransplant complications. This will enable genetic modifications with a vast variety of applications, while raising questions on the ethics and regulation of this emerging technology. This review provides an in-depth discussion of current methodologies for delivering genetic vectors to transplantable organs, particularly focusing on the enabling role of EVMP. Organ-by-organ analysis and key characteristics of various vector and treatment options are assessed. We offer a road map for research and clinical translation, arguing that achieving scientific benchmarks while creating anticipatory governance is necessary to secure societal benefit from this technology.

The rise in popularity of two-photon polymerization (TPP) as an additive manufacturing technique has impacted many areas of science and engineering, particularly those related to biomedical applications. Compared with other fabrication methods used for biomedical applications, TPP offers 3D, nanometer-scale fabrication dexterity (free-form). Moreover, the existence of turnkey commercial systems has increased accessibility. In this review, we discuss the diversity of biomedical applications that have benefited from the unique features of TPP. We also present the state of the art in approaches for patterning and reading 3D TPP-fabricated structures. The reading process influences the fidelity for both in situ and ex situ characterization methods. We also review efforts to leverage machine learning to facilitate process control for TPP. Finally, we conclude with a discussion of both the current challenges and exciting opportunities for biomedical applications that lie ahead for this intriguing and emerging technology.

Over the last decade, a plethora of organoid models have been generated to recapitulate aspects of human development, disease, tissue homeostasis, and repair. Organoids representing multiple tissues have emerged and are typically categorized based on their origin. Tissue-derived organoids are established directly from tissue-resident stem/progenitor cells of either adult or fetal origin. Starting from pluripotent stem cells (PSCs), PSC-derived organoids instead recapitulate the developmental trajectory of a given organ. Gene editing technologies, particularly the CRISPR-Cas toolbox, have greatly facilitated gene manipulation experiments with considerable ease and scalability, revolutionizing organoid-based human biology research. Here, we review the recent adaptation of CRISPR-based screenings in organoids. We examine the strategies adopted to perform CRISPR screenings in organoids, discuss different screening scopes and readouts, and highlight organoid-specific challenges. We then discuss individual organoid-based genome screening studies that have uncovered novel genes involved in a variety of biological processes. We close by providing an outlook on how widespread adaptation of CRISPR screenings across the organoid field may be achieved, to ultimately leverage our understanding of human biology.

Biochemical signals in native tissue microenvironments instruct cell behavior during many biological processes ranging from developmental morphogenesis and tissue regeneration to tumor metastasis and disease progression. The detection and characterization of these signals using spatial and highly resolved quantitative methods have revealed their existence as matricellular proteins in the matrisome, some of which are bound to the extracellular matrix while others are freely diffusing. Including these biochemical signals in engineered biomaterials can impart enhanced functionality and native-like complexity, ultimately benefiting efforts to understand, model, and treat various diseases. In this review, we discuss advances in characterizing, mimicking, and harnessing biochemical signals in developing advanced engineered biomaterials. An overview of the diverse forms in which these biochemical signals exist and their effects on intracellular signal transduction is also provided. Finally, we highlight the application of biochemically complex biomaterials in the three broadly defined areas of tissue regeneration, immunoengineering, and organoid morphogenesis.

Microscale sensors and actuators have been widely explored by the scientific community to augment the functionality of conventional medical implants. However, despite the many innovative concepts proposed, a negligible fraction has successfully made the leap from concept to clinical translation. This shortfall is primarily due to the considerable disparity between academic research prototypes and market-ready products. As such, it is critically important to examine the lessons learned in successful commercialization efforts to inform early-stage translational research efforts. Here, we review the regulatory prerequisites for market approval and provide a comprehensive analysis of commercially available microimplants from a device design perspective. Our objective is to illuminate both the technological advances underlying successfully commercialized devices and the key takeaways from the commercialization process, thereby facilitating a smoother pathway from academic research to clinical impact.

Electrical stimulation of the brain is being developed as a treatment for an increasing number of neurological disorders. Technologies for delivering electrical stimulation are advancing rapidly and vary in specificity, coverage, and invasiveness. Supracortical microstimulation (SCMS), characterized by microelectrode contacts placed on the epidural or subdural cortical surface, achieves a balance between the advantages and limitations of other electrical stimulation technologies by delivering spatially precise activation without disrupting the integrity of the cortex. However, in vivo experiments involving SCMS have not been comprehensively summarized. Here, we review the field of SCMS, focusing on recent advances, to guide the development of clinically translatable supracortical microelectrodes. We also highlight the gaps in our understanding of the biophysical effects of this technology. Future work investigating the unique electrochemical properties of supracortical microelectrodes and validating SCMS in nonhuman primate preclinical studies can enable rapid clinical translation of innovative treatments for humans with neurological disorders.

With increasing demands for continuous health monitoring remotely, wearable and implantable devices have attracted considerable interest. To fulfill such demands, novel materials and device structures have been investigated, since commercial biomedical devices are not compatible with flexible and conformable form factors needed for soft tissue monitoring and intervention. Among various materials, piezoelectric materials have been widely adopted for multiple applications including sensing, energy harvesting, neurostimulation, drug delivery, and ultrasound imaging owing to their unique electromechanical conversion properties. In this review, we provide a comprehensive overview of piezoelectric-based wearable and implantable biomedical devices. We first provide the basic principles of piezoelectric devices and device design strategies for wearable and implantable form factors. Then, we discuss various state-of-the-art applications of wearable and implantable piezoelectric devices and their design strategies. Finally, we demonstrate several challenges and outlooks for designing piezoelectric-based conformable biomedical devices.

Medical ultrasound is a diagnostic imaging modality used for visualizing internal organs; the frequencies typically used are 2–10 MHz. Scanning acoustic microscopy (SAM) is a form of ultrasound where frequencies typically exceed 50 MHz. Increasing the acoustic frequency increases the specimen's spatial resolution but reduces the imaging depth. The advantages of using SAM over conventional light and electron microscopy include the ability to image cells and tissues without any preparation that could kill or alter them, providing a more accurate representation of the specimen. After scanning the specimen, acoustic signals are merged into an image on the basis of changes in the impedance mismatch between the immersion fluid and the specimens. The acoustic parameters determining the image quality are absorption and scattering. Surface scans can assess surface characteristics of the specimen. SAM is also capable of elastography, that is, studying elastic properties to discern differences between healthy and affected tissues. SAM has significant potential for detection/analysis in research and clinical studies.

Despite the advances in detection, diagnosis, and treatments, cancer remains a lethal disease, claiming the lives of more than 600,000 people in the United States alone in 2024. To accelerate the development of new therapeutic strategies with improved responses, significant efforts have been made to develop microfabricated in vitro models of tumor microenvironments (TMEs) that address the limitations of animal-based cancer models. These models incorporate several advanced tissue engineering techniques to better reflect the organ- and patient-specific TMEs. Additionally, microfabricated models integrated with next-generation single-cell omics technologies provide unprecedented insights into patient's cellular and molecular heterogeneity and complexity. This review provides an overview of the recent understanding of cancer development and outlines the key TME elements that can be captured in microfabricated models to enhance their physiological relevance. We highlight the recent advances in microfabricated cancer models that reflect the unique characteristics of their organs of origin or sites of dissemination.

Cochlear implants are the most successful neural prostheses used to restore hearing in severe-to-profound hearing-impaired individuals. The field of cochlear implant coding investigates interdisciplinary approaches to translate acoustic signals into electrical pulses transmitted at the electrode–neuron interface, ranging from signal preprocessing algorithms, enhancement, and feature extraction methodologies to electric signal generation. In the last five decades, numerous coding strategies have been proposed clinically and experimentally. Initially developed to restore speech perception, increasing computational possibilities now allow coding of more complex signals, and new techniques to optimize the transmission of electrical signals are constantly gaining attention. This review provides insights into the history of multichannel coding and presents an extensive list of implemented strategies. The article briefly addresses each method and considers promising future directions of neural prostheses and possible signal processing, with the ultimate goal of providing a current big picture of the large field of cochlear implant coding.

Cancer remains a leading cause of mortality worldwide, and the demand for improved efficacy, precision, and safety of management options has never been greater. Focused ultrasound (FUS) is a rapidly emerging strategy for nonionizing, noninvasive intervention that holds promise for the multimodal treatment of solid cancers. Owing to its versatile array of bioeffects, this technology is now being evaluated across preclinical and clinical oncology trials for tumor ablation, therapeutic delivery, radiosensitization, sonodynamic therapy, and enhancement of tumor-specific immune responses. Given the breadth of this burgeoning domain, this review places a spotlight on recent advancements in breast cancer care to exemplify the multifaceted role of FUS technology for oncology indications—outlining physical principles of FUS-mediated thermal and mechanical bioeffects, giving an overview of results from recent preclinical and clinical studies investigating FUS with and without adjunct therapeutics in primary or disseminated breast cancer settings, and offering perspectives on the future of the field.

Organ-on-a-chip (OOC) and organoid technologies are at the forefront of developing sophisticated in vitro systems that replicate complex host–microbiome interactions, including those associated with vaginal health and lung infection. We explore how these technologies provide insights into host–microbiome and host–pathogen interactions and the associated immune responses. Integrating omics data and high-resolution imaging in analyzing these models enhances our understanding of host–microbiome interactions' temporal and spatial aspects, paving the way for new diagnostic and treatment strategies. This review underscores the potential of OOC and organoid technologies in elucidating the complexities of vaginal health and lung disease, which have received less attention than other organ systems in recent organoid and OCC studies. Yet, each system presents notable characteristics, rendering them ideal candidates for these designs. Additionally, this review describes the key factors associated with each organ system and how to choose the technology setup to replicate human physiology.

Understanding interaction mechanisms within cells, tissues, and organisms is crucial for driving developments across biology and medicine. Mathematical modeling is an essential tool for simulating such biological systems. Building on experiments, mechanistic models are widely used to describe small-scale intracellular networks. The development of sequencing techniques and computational tools has recently enabled multiscale models. Combining such larger scale network modeling with mechanistic modeling provides us with an opportunity to reveal previously unknown disease mechanisms and pharmacological interventions. Here, we review systems biology models from mechanistic models to multiscale models that integrate multiple layers of cellular networks and discuss how they can be used to shed light on disease states and even wellness-related states. Additionally, we introduce several methods that increase the certainty and accuracy of model predictions. Thus, combining mechanistic models with emerging mathematical and computational techniques can provide us with increasingly powerful tools to understand disease states and inspire drug discoveries.

Preclinical modeling of human circulation has been instrumental in advancing cardiovascular medicine. Alongside clinical research, the armamentarium of computational (e.g., lumped parameter or computational fluid dynamics) and experimental (e.g., benchtop or animal) models have substantially enhanced our understanding of risk factors and root causes for circulatory diseases. Recent innovations are further disrupting the boundaries of these preclinical models toward patient-specific simulations, surgical planning, and postoperative outcome prediction. This fast-paced progress empowers preclinical modeling to increasingly delve into the intricacies of single ventricle physiology, a rare and heterogeneous congenital heart disease that remains inadequately understood. Here, we review the current landscape of preclinical modeling (computational and experimental) proposed to advance clinical management of a prominent yet complex subset of single ventricle physiology: patients who have undergone Fontan-type surgical corrections. Further, we explore recent innovations and emerging technologies that are poised to bridge the gap between preclinical Fontan modeling and clinical implementation.

The microvasculature, a complex network of small blood vessels, connects systemic circulation with local tissues, facilitating the nutrient and oxygen exchange that is critical for homeostasis and organ function. Engineering these structures is paramount for advancing tissue regeneration, disease modeling, and drug testing. However, replicating the intricate architecture of native vascular systems—characterized by diverse vessel diameters, cellular constituents, and dynamic perfusion capabilities—presents significant challenges. This complexity is compounded by the need to precisely integrate biomechanical, biochemical, and cellular cues. Recent breakthroughs in microfabrication, organoids, bioprinting, organ-on-a-chip platforms, and in vivo vascularization techniques have propelled the field toward faithfully replicating vascular complexity. These innovations not only enhance our understanding of vascular biology but also enable the generation of functional, perfusable tissue constructs. Here, we explore state-of-the-art technologies and strategies in microvascular engineering, emphasizing key advancements and addressing the remaining challenges to developing fully functional vascularized tissues.

Physics-inspired generative models (GMs), in particular diffusion models and Poisson flow models, enhance Bayesian methods and promise great utility in medical imaging. This review examines the transformative role of such generative methods. First, a variety of physics-inspired GMs, including denoising diffusion probabilistic models, score-based diffusion models, and Poisson flow generative models (including PFGM++), are revisited, with an emphasis on their accuracy, robustness and acceleration. Then, major applications of physics-inspired GMs in medical imaging are presented, comprising image reconstruction, image generation, and image analysis. Finally, future research directions are brainstormed, including unification of physics-inspired GMs, integration with vision-language models, and potential novel applications of GMs. Since the development of generative methods has been rapid, it is hoped that this review will give peers and learners a timely snapshot of this new family of physics-driven GMs and help capitalize their enormous potential for medical imaging.