About

Dr. Brian Aguado is an Assistant Professor of Bioengineering at the University of California, San Diego. His laboratory research focuses on studying sex differences in cardiovascular disease through the use of biomaterial technologies. Dr. Aguado earned his Bachelor of Science degree in Biomechanical Engineering from Stanford University, followed by a Master of Science and PhD in Biomedical Engineering from Northwestern University. He also holds a certificate in Management for Scientists and Engineers from the Kellogg School of Management at Northwestern. He completed his postdoctoral fellowship in Chemical and Biological Engineering at the University of Colorado Boulder. Dr. Aguado has been recognized with numerous prestigious awards supporting his research, including the NIH K99/R00 Pathway to Independence Award, the American Heart Association Career Development Award, the Chan Zuckerberg Initiative Science Diversity Leadership Award, the NIH Director's New Innovator DP2 Award, and the NSF CAREER Award. His laboratory's work has also earned him the Society for Biomaterials Young Investigator Award, the American Society for Matrix Biology Junior Investigator Award, the Cellular and Molecular Bioengineering Society Rising Star Award, and election as an AIMBE Emerging Leader. Beyond his research, Dr. Aguado is a committed science communicator who actively engages historically excluded and marginalized populations in the sciences. He co-founded LatinXinBME, a nonprofit social media organization dedicated to fostering a diverse and inclusive community of Latinx biomedical engineers and scientists, which has received awards from the Society for Biomaterials, the Biomedical Engineering Society, and the American Society for Engineering Education. Dr. Aguado has been named one of the 100 Most Inspiring Latinx Scientists in America by Cell Press and has received the Teacher of the Year Award from the Jacobs School of Engineering as well as the GEMINI Faculty Mentor Award from the Institute for Engineering in Medicine.

Research topics

• Medicine
• Biochemistry
• Chemistry
• Biology
• Pathology
• Cell biology
• Internal medicine
• Immunology
• Cancer research

Selected publications

• Precision Biomaterials: Incorporating Sex, Age, and Social Descriptors in Biomaterials Research

  ACS Biomaterials Science & Engineering · 2026-03-09

  article
  PublisherDOI

• Determining sex differences in aortic valve myofibroblast responses to drug combinations identified using a digital medicine platform

  Science Advances · 2025-06-06 · 6 citations

  articleOpen accessSenior authorCorresponding

  Aortic valve stenosis (AVS) is a sexually dimorphic disease where aortic valve leaflets develop fibrosis and calcification, leading to heart failure if untreated. Sex differences in AVS progression depend on valvular interstitial cells (VICs) activating to myofibroblasts that drive aberrant extracellular matrix remodeling. To date, no treatment strategies have leveraged cellular sex differences to determine drug combinations that target VIC myofibroblast activation. Here, we harnessed IDentif.AI, an artificial intelligence (AI)-derived platform, to optimize sex-biased synergistic drug combinations that may prevent and reverse VIC myofibroblast activation on hydrogel biomaterials. The results reveal that sex-specific drug response models can be used to predict sex biases in drug efficacy and combinatorial interactions. This study provides a framework for developing AVS treatments through the integration of high-throughput hydrogel cell culture platforms and AI-driven drug optimization. Designing targeted AVS drug combinations may help accelerate AVS drug development and address health disparities in AVS treatment outcomes.

  PublisherDOI

• Spatial transcriptomic profiling of the human aortic valve reveals cellular sex differences near sites of calcification

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-24 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Sex differences in aortic valve stenosis (AVS) progression have been documented clinically, but the underlying cellular mechanisms that drive sex-dependent calcification in aortic valve tissue remain poorly understood. Here, we harnessed single cell and spatial transcriptomics to investigate mechanisms that drive sex dependent spatial organization of valvular interstitial cell (VIC) and macrophage gene expression near calcification sites in human male and female aortic valve tissue. Histological analyses of aortic valve tissues stratified into healthy and diseased cohorts based on degree of calcification reveal increased valve calcification area in diseased male aortic valves relative to female, and increased valve thickening in diseased female aortic valves. Single cell sequencing analysis of heterogeneous valvular interstitial cell (VIC) populations reveals male-dependent gene expression of the Activator Protein 1 (AP-1) transcription factor complex. Spatial transcriptomics and RNA-FISH analyses of VIC populations near sites of calcification revealed male-dependent gene expression localization of Cartilage Oligomeric Matrix Protein ( COMP ), as opposed to diffuse COMP expression in female VICs. Cell-cell communication analyses were used to determine female-specific macrophage-VIC interactions. Secreted phosphoprotein 1 (also known as osteopontin) expressed from macrophages interacts with the cell surface receptor CD44 expressed by VICs to drive a pro-fibrotic phenotype in female aortic valves. Together, our results reveal sex differences in VIC and macrophage heterogeneity and functions near sites of calcification in aortic valve tissue. Our results highlight the importance of sex-based transcriptomics analyses to understand the cellular phenotypes responsible for causing sex differences in aortic valve fibrosis calcification.

  PublisherOA PDFDOI

• Y chromosome–linked UTY modulates sex differences in valvular fibroblast methylation in response to nanoscale extracellular matrix cues

  Science Advances · 2025-03-12 · 14 citations

  articleOpen accessSenior authorCorresponding

  Aortic valve stenosis (AVS) is a progressive disease, wherein males more often develop valve calcification relative to females that develop valve fibrosis. Valvular interstitial cells (VICs) aberrantly activate to myofibroblasts during AVS, driving the fibrotic valve phenotype in females. Myofibroblasts further differentiate into osteoblast-like cells and produce calcium nanoparticles, driving valve calcification in males. We hypothesized that the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing Y-linked) decreases methylation uniquely in male VICs responding to nanoscale extracellular matrix cues to promote an osteoblast-like cell phenotype. Here, we describe a hydrogel biomaterial cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found that UTY modulates the osteoblast-like cell phenotype in response to nanoscale cues uniquely in male VICs. Overall, we reveal a previously unidentified role of UTY in the regulation of calcification processes in males during AVS progression.

  PublisherDOI

• Secreted Cytokines From Inflammatory Macrophages Modulate Sex Differences in Valvular Interstitial Cells on Hydrogel Biomaterials

  Journal of Biomedical Materials Research Part A · 2025-02-24 · 15 citations

  articleOpen accessSenior authorCorresponding

  Patients with aortic valve stenosis (AVS) experience fibrosis and/or calcification in valve tissue, which leads to heart failure if left untreated. Inflammation is a hallmark of AVS, and secreted cytokines from pro-inflammatory macrophages are thought to contribute to valve fibro-calcification by driving the activation of valvular interstitial cells (VICs) to myofibroblasts. However, the molecular mechanisms by which inflammatory cytokines differentially regulate myofibroblast activation as a function of biological sex are not fully defined. Here, we developed an in vitro hydrogel culture platform to culture male and female valvular interstitial cells (VICs) and characterize the sex-specific effects of inflammatory cytokines on VIC activation to myofibroblasts and osteoblast-like cells. Our data reveal that tumor necrosis factor alpha (TNF-α) modulates female-specific myofibroblast activation via MAPK/ERK signaling, nuclear chromatin availability, and osteoblast-like differentiation via RUNX2 nuclear localization. In parallel, our data also suggest that male-specific myofibroblast deactivation in response to TNF-α occurs via alternative pathways outside of MAPK/ERK signaling. Collectively, hydrogel biomaterials as cell culture platforms are critical for distinguishing sex differences in cellular phenotypes.

  PublisherOA PDFDOI

• Signals from the extracellular matrix: Region- and sex-specificity in cardiac aging

  Current Opinion in Cell Biology · 2025-05-09 · 2 citations

  reviewOpen access

  During aging, the cardiac extracellular matrix (ECM) undergoes gradual remodeling that reduces the heart's ability to function. Specific ECM changes cause alterations in cellular signaling pathways, eliciting maladaptive responses. Here, we provide insight into the current knowledge of how age-specific ECM changes contribute to altered ligand-receptor interactions, dysregulated mechanotransduction, and the propagation of pro-fibrotic signaling cascades that underpin dysfunction. We also highlight regional and sex differences that new biomolecular and bioengineered technologies have recently uncovered. We call for new biomaterial strategies that mimic spatiotemporal and sex-specific ECM alterations to equip researchers with the tools to unravel complex cellular signaling events. We believe this can be achieved through interdisciplinary cooperation amongst researchers spanning matrix biology, biomaterials, spatial omics, and biomedical engineering.

  PublisherDOI

• Determining sex differences in drug combinations targeting aortic valve myofibroblast activation using an artificial intelligence derived platform

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-10-03 · 4 citations

  preprintSenior authorCorresponding

  Abstract Aortic valve stenosis (AVS) is a sexually dimorphic disease where aortic valve leaflets develop fibrosis and calcification, leading to heart failure if untreated. Sex differences in AVS progression depend on valvular interstitial cells (VICs) activating to myofibroblasts that drive aberrant extracellular matrix remodeling. To date, no treatment strategies have leveraged cellular sex differences to determine drug combinations that effectively target VIC myofibroblast activation. Here, we harnessed IDentif.AI, an artificial intelligence (AI)-derived drug optimization platform, to optimize sex-specific synergistic drug combinations that may prevent and reverse VIC myofibroblast activation on hydrogel biomaterials. The results reveal that anti-fibrotic drug efficacy and combinatorial interactions are dependent on cell sex. This study provides a framework for developing clinically relevant AVS treatment strategies through the integration of high-throughput hydrogel cell culture platforms and AI-driven drug optimization. The workflow towards designing targeted AVS drug combinations may help accelerate AVS drug development for male and female patients and address health disparities in AVS treatment outcomes.

  PublisherDOI

• Secreted cytokines from inflammatory macrophages modulate sex differences in valvular interstitial cells on hydrogel biomaterials

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-11-15 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Abstract Patients with aortic valve stenosis (AVS) experience fibrosis and/or calcification in valve tissue, which leads to heart failure if left untreated. Inflammation is a hallmark of AVS and secreted cytokines from pro-inflammatory macrophages are thought to contribute to valve fibro-calcification by driving the activation of valvular interstitial cells (VICs) to myofibroblasts. However, the molecular mechanisms by which inflammatory cytokines differentially regulate myofibroblast activation as a function of biological sex are not fully defined. Here, we developed an in vitro hydrogel culture platform to culture male and female valvular interstitial cells (VICs) and characterize the sex-specific effects of inflammatory cytokines on VIC activation to myofibroblasts and osteoblast-like cells. Our data reveal that tumor necrosis factor alpha (TNF-α) modulates female-specific myofibroblast activation via MAPK/ERK signaling, nuclear chromatin availability, and osteoblast-like differentiation via RUNX2 nuclear localization. Collectively, hydrogel biomaterials as cell culture platforms are critical for distinguishing sex differences in cellular phenotypes.

  PublisherOA PDFDOI

• <i>Call for Special Issue Papers: Diversity, Equity, and Inclusion in Biotechnology</i>

  GEN Biotechnology · 2024-02-01

  article1st authorCorresponding
  PublisherDOI

• Y chromosome linked UTY modulates sex differences in valvular fibroblast methylation in response to nanoscale extracellular matrix cues

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-05-14 · 2 citations

  preprintOpen accessSenior authorCorresponding

  Aortic valve stenosis (AVS) is a progressive disease wherein males more often develop valve calcification relative to females that develop valve fibrosis. Valvular interstitial cells (VICs) aberrantly activate to myofibroblasts during AVS, driving the fibrotic valve phenotype in females. Myofibroblasts further differentiate into osteoblast-like cells and produce calcium nanoparticles, driving valve calcification in males. We hypothesized the lysine demethylase UTY (ubiquitously transcribed tetratricopeptide repeat containing, Y-linked) decreases methylation uniquely in male VICs responding to nanoscale extracellular matrix cues to promote an osteoblast-like cell phenotype. Here, we describe a hydrogel biomaterial cell culture platform to interrogate how nanoscale cues modulate sex-specific methylation states in VICs activating to myofibroblasts and osteoblast-like cells. We found UTY modulates the osteoblast-like cell phenotype in response to nanoscale cues uniquely in male VICs. Overall, we reveal a novel role of UTY in the regulation of calcification processes in males during AVS progression.

  PublisherOA PDFDOI

Recent grants

• Investigating sex differences in persistent valvular myofibroblast activation using hydrogel culture substrates

  NIH · $1.1M · 2021–2024

• Development of a nanotherapy for aortic valve stenosis

  NIH · $134k · 2017–2020

• Investigating sex differences in persistent valvular myofibroblast activation using hydrogel culture substrates

  NIH · $256k · 2019–2021

Frequent coauthors

• Kristi S. Anseth

  University of Colorado Boulder

  34 shared

• Brandon J. Vogt

  17 shared

• Joseph C. Grim

  14 shared

• Nicole E. Félix Vélez

  University of California, San Diego

  14 shared

• Rayyan Gorashi

  La Jolla Bioengineering Institute

  13 shared

• Cierra J. Walker

  University of Colorado Boulder

  12 shared

• Brisa Peña

  University of Colorado Anschutz Medical Campus

  12 shared

• Luisa Mestroni

  University of Trieste

  11 shared

Labs

• Aguado iBiomaterials LabPI

Education

• B.S.

  Stanford University

• M.S.

  Northwestern University

• Ph.D.

  Northwestern University

• Other, Management for Scientists and Engineers

  Kellogg School of Management at Northwestern University

Awards & honors

• NIH Pathway to Independence Award (K99/R00)
• Burroughs Wellcome Fund Postdoctoral Enrichment Program
• NIH NRSA Postdoctoral Fellowship (F32)
• National Science Foundation Graduate Research Fellowship Pro…