About

Brendan A. Harley is the Robert W. Schaefer Professor in the Department of Chemical & Biomolecular Engineering at the University of Illinois. He serves as the Program Leader for the Cancer Center at Illinois and is a Theme Leader at the Carl R. Woese Institute for Genomic Biology. Professor Harley earned his S.B. in Engineering Sciences from Harvard University in 2000 and his Sc.D. in Mechanical Engineering from MIT in 2006. He completed a postdoctoral fellowship at Children's Hospital Boston in 2008. His professional recognitions include being named a Fellow of the American Association for the Advancement of Science (AAAS) in 2014, the American Institute for Medical and Biological Engineering (AIMBE) in 2018, and the Biomedical Engineering Society (BMES) in 2021. He has received several awards such as the Young Investigator Award in 2014, the Clemson Award for Basic Research in 2021, and the NSF CAREER award in 2013. Professor Harley's research focuses on engineering cellular microenvironments and microstructures, contributing to advancements in biomaterials and tissue engineering, particularly in cancer and regenerative medicine.

Research topics

• Computer Science
• Biology
• Medicine
• Biomedical engineering
• Cell biology
• Materials science
• Anatomy
• Nanotechnology
• Engineering
• Chemistry
• Artificial Intelligence
• Political Science
• Composite material
• Neuroscience
• Engineering ethics
• Medical education
• Biological system
• Immunology
• Surgery
• Biochemistry
• Polymer chemistry
• Public relations
• Cancer research

Selected publications

• Biomimetic model for the identification of distinctive microenvironmental factors in glioblastoma radiosensitivity

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-01-15

  articleOpen access

  Radiation therapy (RT) has long been included in the treatment of glioblastoma (GBM). However, radioresistance in cancer cells as well as toxicity in normal tissues are major obstacles to clinical efficacy. Improved understanding of the mechanisms of tumor microenvironment-induced radioresistance during and after radiation therapy can provide fundamental insights to improve clinical outcomes in GBM. Here, using three-dimensional engineered hydrogel models in vitro, we report the influence of extracellular matrix, hypoxia, and adjacent neuronal cells in radiotherapeutic sensitivity. We find that mechanical cues and oxygen availability regulate cellular response to radiation, with softer matrices allowing for more DNA damage. Hyaluronan fragments from the extracellular matrix also modulate rapid metabolic response to radiation, especially in hypoxic environments. We show that neuronal networks influence tumor metabolic activity and the inflammatory response. Overall, we demonstrate here that alternative radiation strategies, such as low dose rate radiation therapy and microenvironmental regulation, have the potential to be more effective in a specific subset of radiosensitive GBM tumors.

  PublisherOA PDFDOI

• Glioblastoma drives protease-independent extracellular matrix invasion of microglia

  Materials Today Bio · 2025-01-09 · 6 citations

  articleOpen accessSenior authorCorresponding

  Glioblastoma (GBM) is the most common and lethal form of primary brain cancer. Microglia infiltration into the tumor microenvironment is associated with immunosuppression and poor prognosis. Improved physicochemical understanding of microglia activation and invasion may provide novel GBM therapeutic strategies essential for improving long-term treatment efficacy. Here, we combine microfluidic systems with 3-D collagen hydrogels to systematically investigate microglia activation, invasion, contractility and cytokine secretion in response to GBM-microglia crosstalk. GBM inflammatory biomolecules significantly promote activation and 3D invasion of microglia. Interestingly, microglia invasion is not significantly affected by inhibitors of MMP activity or cellular glycolysis. In contrast, ROCK-pathway inhibition significantly impedes microglia invasion. Infrared microscopy analyses show that GBM conditioned media does not significantly alter microglia lipid content. Further, GBM conditioned media resulted in significantly increased collagen hydrogel contraction, suggesting the importance of microglia contractility to physically remodel the local extracellular matrix (ECM). We also identify a panel of soluble proteins that may contribute to microglia chemotaxis, such as TIMP-1 and CXCL12. Taken together, this study suggests that the presence of GBM cells can enhance microglia invasion via increased cellular contractility, independent of MMP activity and cellular glycolysis.

  PublisherDOI

• Abstract 2708: Prediction of radiosensitivity in glioblastoma tumors after standard and low dose rates of ionizing radiation

  Cancer Research · 2025-04-21 · 1 citations

  article

  Glioblastomas (GBM) exhibit high infiltration into the brain parenchyma, impairing surgical resection and leading to recurrence. After standard of care, including tumor resection, radiation therapy (RT) and chemotherapy, most tumors recur at the tumor margins. These tumors show an increased aggressiveness and therapeutic resistance. The underlying mechanisms for these cellular transitions are unclear. Research suggests that RT paradoxically alters the GBM microenvironment promoting cancer cell survival upon recurrence. Some of these alterations in the irradiated tumor microenvironment include increased oxidative stress, hypoxia, cellular senescence, vasculogenesis and ECM compositional and structural changes.We use an ex vivo platform that combines the hallmarks of GBM tumors: high cellularity, the neural circuitry that surrounds tumors, a hydrogel-based ECM that mimics the biophysical and biochemical properties of GBM and the intermittent hypoxic environment present in native tumors, to characterize and evaluate the therapeutic benefits of RT and the underlying mechanisms of neurotoxicity to more effectively treat the tumor while minimizing the deleterious side effects.Our results show that radiation treatment increases glycolysis in tumor cells and that immediate response to radiation produces a more significant ATP production decrease in hypoxia environments. We have also investigated the long-term energy production and mitochondrial dysfunction in the tumor cells at different radiation rates and under low oxygen environments. Interestingly, the maximal respiration capacity in GBM cells increases with the presence of conditioned media from neuronal cultures in normoxic conditions but has the opposite effect in hypoxic environments.Proliferation ability of cells on stiffer matrices is greater than that on softer matrices. In the presence of an altered biomechanical microenvironment, a stiffer tumor tissue is more prone to immunosuppression and epithelial-mesenchymal transition. After cells are irradiated, the cell migration is different with different matrix stiffness. Moreover, softer matrices are more likely to promote cellular radiosensitivity, while stiffer matrices can inhibit cellular radiosensitivity.The use of preclinical tools that can model key features of the GBM and normal brain tissue can give a better understanding of the spatial-temporal characteristics of tumor microenvironment alterations during progression and response to therapy. Citation Format: Isabella Rivera, Ryan Yao, Kim Selting, Catherine Best-Popescu, Brendan Harley, Sara Pedron-Haba. Prediction of radiosensitivity in glioblastoma tumors after standard and low dose rates of ionizing radiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2708.

  PublisherDOI

• Matrix Tropism Influences Endometriotic Cell Attachment Patterns

  Advanced Functional Materials · 2025-06-23

  articleOpen accessSenior authorCorresponding

  The initiation of endometriotic lesions is not well understood or characterized because endometriosis is typically diagnosed at an advanced stage. Endometriotic lesions are most often found on pelvic tissues and organs, especially the ovaries. To investigate the role of tissue tropism on ovarian endometrioma initiation, we adapted a well-characterized polyacrylamide microarray system to investigate the role of tissue-specific extracellular matrix and adhesion motifs on endometriotic cell attachment, morphology, and size. We report the influence of cell origin (endometriotic vs. non-endometriotic), substrate stiffness mimicking aging and fibrosis, and the role of multicellular (epithelial-stromal) cohorts on cell attachment patterns. We identify multiple ovarian-specific attachment motifs that significantly increase endometriotic (vs. non-endometriotic) cell cohort attachment that could be implicated in early disease etiology.

  PublisherOA PDFDOI

• Influence of Hypoxia on a Biomaterial Model of the Bone Marrow Perivascular Niche

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-26

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Hematopoietic stem cell (HSC) fate is shaped by distinct microenvironments termed niches within the bone marrow. Quiescence, expansion, and differentiation are directly and indirectly regulated by complex combinations of cell secretomes, cell-cell interactions, mechanical signals, and metabolic factors including oxygen tension. The perivascular environment in the bone marrow has been implicated in guiding HSC fate. However, bone marrow presents an environment which is hypoxic (∼1-4% O 2 ) relative to traditional cell culture conditions, and the study of hypoxia in vitro is complicated by the speed with which normoxic conditions during HSC isolation induce differentiation. There is a unique opportunity to use engineered models of the bone marrow to investigate the impact of defined hypoxia on HSC fate. Here, we examine the coordinated impact of oxygen tension and the perivascular secretome upon murine hematopoietic stem and progenitor cells (HSPCs) in vitro. Our findings highlight the importance of mitigating oxygen shock during cell isolation in engineered marrow models. We report a shift toward the Lineage - phenotype with hypoxic culture, expansion of HSPCs in response to perivascular niche conditioned medium, and enhanced HSPC maintenance in a hydrogel model of bone marrow in hypoxic culture when oxygen shock is mitigated during isolation using cyclosporin A.

  PublisherOA PDFDOI

• Matrix tropism influences endometriotic cell attachment patterns

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-27

  preprintOpen accessSenior authorCorresponding

  Due to the extended period for clinical diagnosis, the etiology of endometriotic lesion initiation is not well understood or characterized. Endometriotic lesions are most often found on pelvic tissues and organs, especially the ovaries. To investigate the role of tissue tropism on ovarian endometrioma initiation, we adapted a well-characterized polyacrylamide microarray system to investigate the role of tissue-specific extracellular matrix and adhesion motifs on endometriotic cell attachment, morphology, and size. We report the influence of cell origin (endometriotic vs. non-endometriotic), substrate stiffness mimicking aging and fibrosis, and the role of multicellular (epithelial-stromal) cohorts on cell attachment patterns. We identify multiple ovarian-specific attachment motifs that significantly increase endometriotic (vs. non-endometriotic) cell cohort attachment that could be implicated in early disease etiology.

  PublisherOA PDFDOI

• Abstract 6495: Development of a drug screening platform of glioblastoma utilizing microgel encapsulation

  Cancer Research · 2025-04-21

  articleSenior author

  Abstract Background. We report a method to encapsulate glioblastoma (GBM) cells in maleimide-functionalized gelatin (GelMAL) microparticles for in vitro drug screening. GBM is the most common primary malignant brain tumor. Standard of care is surgical resection followed by treatment with the alkylating agent temozolomide (TMZ). GBM cells that evade surgery eventually become resistant to TMZ and lead to recurrence of tumors in patients. Hydrogels have been implemented as matrices for 3D culture that can recapitulate tumor biology and tumor microenvironment. However, bulk hydrogels require large numbers of cells per construct and possess inherent diffusional limits. With only four drugs currently FDA-approved for GBM treatment, there is a need for a platform capable of accelerating the identification of new therapies in a highly controlled and physiologically relevant environment. Hydrogel microparticles allow encapsulation of GBM cells in a tailorable 3D matrix, rapid diffusion to limit spatial hypoxia gradients, and ease of handling for high-throughput screens (HTS). Methods. U87MG cells are encapsulated in GelMAL microparticles using a flow-focusing microfluidic device. Viability and proliferation of GBM cells is assessed via LIVE/DEAD cell imaging kit and double stranded DNA (dsDNA) quantification, respectively. We record a response from encapsulated cells after TMZ exposure (0-1000 µM) via cellular activity using alamarBlue. Results. Cellular viability within microfluidic emulsion is limited by shear forces exhibited in the microfluidic device. Here, we report a method to encapsulate GBM cells in microgels and retain cellular viability. Increasing levels of dsDNA suggest maintenance of cellular health in microgels and indicate a proliferative population of encapsulated cells. Metabolic profile of encapsulated cells shows a decrease in cellular activity in response to increasing concentrations of TMZ, concurrent with 2D and bulk hydrogel culture. Ongoing experiments will assess cellular behavior post-movement by liquid handler of encapsulated cells to establish a drug screening platform amenable for HTS. Conclusion. We have developed a method to reliably encapsulate GBM cells into GelMAL microgels while retaining viability. The recorded cellular activity of encapsulated cells in response to TMZ demonstrates the utilization of microgels as an in vitro drug screening platform. We will leverage this platform to examine drug response in vitro amenable for high-throughput screening to identify possible therapeutics for TMZ resistant tumors. Citation Format: Brittany A. Payan, Annika Carrillo Diaz de Leon, Tejasvi Anand, Gunnar B. Thompson, Brendan A. C. Harley. Development of a drug screening platform of glioblastoma utilizing microgel encapsulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6495.

  PublisherDOI

• Radiation Damage to a Three-Dimensional Hydrogel Model of the Brain Perivascular Niche

  Tissue Engineering Part C Methods · 2025-05-01 · 1 citations

  articleOpen accessSenior author

  experiments.

  PublisherOA PDFDOI

• Mesenchymal stem cell activity across a graded scaffold-hydrogel composite biomaterial for tendon-to-bone enthesis repair

  Bioactive Materials · 2025-07-16 · 5 citations

  articleOpen accessSenior authorCorresponding

  The severity of rotator cuff injury outcomes and a lack of tendon-to-bone enthesis regeneration strategies have inspired advances in biomaterials science to develop methods for interfacial tissue engineering. Here, we demonstrate a triphasic biomaterial comprising a non-mineralized, anisotropic collagen scaffold and a mineralized isotropic collagen scaffold linked via a continuous thiolated gelatin (Gel-SH) interface. This material provides a stratified environment in composition and porous architecture, and we report functional activity of human mesenchymal stem cells (hMSCs) across the scaffold. Notably, MSCs can be seeded onto the triphasic biomaterial and remain viable for up to 21 days. In addition, MSCs within the interfacial Gel-SH interfacial zone express markers associated with the rotator cuff fibrocartilaginous enthesis, including gene upregulation of COL1A1, COL3A1, SOX9, BMP4, TGFβ1 and functional secretion of TGF-β1. Altogether, these findings suggest that this triphasic scaffold design could create a permissive environment for fibrochondrogenic activity in support of eventual enthesis interfacial tissue engineering applications. - A novel triphasic tendon-to-bone scaffold contains multiscale structural gradients - Human mesenchymal stem cells are viable and active in all regions over 3 weeks - Upregulation of enthesis-associated genes COL1A1, COL3A1, SOX9, BMP4 - Functional secretion of TGF-β1, particularly in the first week of culture

  PublisherDOI

• Size-dependent invasion and therapeutic phenotype of 42MGBA glioblastoma spheroids

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-07-14

  preprintOpen accessSenior authorCorresponding

  Glioblastoma (GBM) is one of the most common malignant brain tumors, with patient mortality driven by invasion into the surround brain microenvironment and drug resistance. Multicellular spheroids are increasingly a common model to study GBM invasion and drug response in engineered biomaterials. However, a key design feature of tumor spheroid studies is the size of each spheroid (number of cells, diameter). Given the heterogenous growth of GBM cells at the surgical margin, spheroids of different sizes may also have clinical relevance. Here, we define shifts in behavior and drug response of wild type and temozolomide (TMZ) resistant GBM spheroids as a function of initial spheroid size. GBM spheroids ranging from 100 to 12,000 cells in size were embedded into a methacrylamide-functionalized gelatin (GelMA) hydrogel. GBM spheroid size had an inverse relationship with the number of apoptotic cells. We observed significant spheroid size dependent effects on TMZ efficacy for both TMZ resistant and wild type cells. Interestingly, high single doses of TMZ were more effective in reducing three-dimensional migration from smaller spheroids than metronomic dosing while high single dose and metronomic dosing were equally effective in reducing invasion for large TMZ-resistant spheroids. Our study highlights the importance of considering and reporting spheroid size for cancer tissue engineering studies considering invasion and drug resistance. It also informs future studies of residual GBM at the tumor margins most responsible for patient relapse and mortality.

  PublisherOA PDFDOI

Recent grants

• Catch and Release: Biomolecular Ligation and Cleavage Strategies for Generating Instructive and Dynamically Responsive 3D Biomaterials

  NSF · $450k · 2011–2014

• Label-free interrogation of heterogeneities in HSC fate decision signatures

  NIH · $420k · 2015–2019

• CAREER: Building bone marrow

  NSF · $400k · 2013–2018

• Biomimetic Scaffold Anisotropy and Biomolecule Conjugation to Direct Tendon

  NIH · $212k · 2013–2016

• Amniotic Membrane Derived Matrix for Large Bone Defect Repair

  NIH · $660k · 2018–2022

Frequent coauthors

• Justine C. Lee

  University of California, Los Angeles

  53 shared

• Marley J. Dewey

  University of Pittsburgh

  42 shared

• Xiaoyan Ren

  Chengdu Medical College

  41 shared

• Daniel W. Weisgerber

  University of California, San Francisco

  39 shared

• Qi Zhou

  34 shared

• Sara Pedrón

  Illinois College

  31 shared

• Timothy A. Miller

  26 shared

• Ji Sun Choi

  26 shared

Labs

• Harley Research LabPI

  Engineering cellular microenvironments and microstructures

Education

• Ph.D., Bioengineering

  University of California, Berkeley

  1997

• M.S., Bioengineering

  University of California, Berkeley

  1993

• B.S., Bioengineering

  University of California, Berkeley

  1991

Awards & honors

• NSF CAREER award (2013)
• Young Investigator Award from the Society for Biomaterials (…
• Fellow of the American Association for the Advancement of Sc…