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1. Intranasal Delivery of Cell-Penetrating Therapeutic Peptide Enhances Brain Delivery, Reduces Inflammation, and Improves Neurologic Function in Moderate Traumatic Brain Injury

   https://doi.org/10.3390/pharmaceutics16060774  

   Yanamadala, Yaswanthi; Roy, Ritika; Williams, Afrika Alake; Uppu, Navya; Kim, Audrey Yoonsun; DeCoster, Mark A; Kim, Paul; Murray, Teresa Ann (June 2024, Pharmaceutics)

   Following traumatic brain injury (TBI), secondary brain damage due to chronic inflammation is the most predominant cause of the delayed onset of mood and memory disorders. Currently no therapeutic approach is available to effectively mitigate secondary brain injury after TBI. One reason is the blood–brain barrier (BBB), which prevents the passage of most therapeutic agents into the brain. Peptides have been among the leading candidates for CNS therapy due to their low immunogenicity and toxicity, bioavailability, and ease of modification. In this study, we demonstrated that non-invasive intranasal (IN) administration of KAFAK, a cell penetrating anti-inflammatory peptide, traversed the BBB in a murine model of diffuse, moderate TBI. Notably, KAFAK treatment reduced the production of proinflammatory cytokines that contribute to secondary injury. Furthermore, behavioral tests showed improved or restored neurological, memory, and locomotor performance after TBI in KAFAK-treated mice. This study demonstrates KAFAK’s ability to cross the blood–brain barrier, to lower proinflammatory cytokines in vivo, and to restore function after a moderate TBI. 

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2. Rational hydrogel design to improve brain modulus matching for implantation

   https://doi.org/10.1016/j.matlet.2025.138187  

   Garifo, Molli; Bethel, Keturah; Davis, Eric M; Larsen, Jessica (April 2025, Materials Letters)

   Treating the brain is challenging due to the restrictive blood–brain barrier, and modulus-mismatched implants often cause problems. Herein, we have fabricated copolymer hydrogels from thermoresponsive polymer, poly(N-isopropylacrylamide) (PNIPAAm), -r-hydrophilic polymer, poly(acrylic acid) (PAA), which are injectable and transform into soft implants above their lower critical solution temperature (LCST). PAA concentration can be leveraged to tune the LCST and viscosity of the PNIPAAm–r–PAA hydrogel in solution. Furthermore, the Young’s moduli of these materials, ranging from 1-4 kPa, are close to rat and human brain tissue, potentially leading to less inflammation and rejection due to significant modulus mismatch. 

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3. Modeling HIV-1 infection in the brain

   https://doi.org/10.1371/journal.pcbi.1008305  

   Barker, Colin T.; Vaidya, Naveen K. (November 2020, PLOS Computational Biology)

   Regoes, Roland R. (Ed.)

   While highly active antiretroviral therapy (HAART) is successful in controlling the replication of Human Immunodeficiency Virus (HIV-1) in many patients, currently there is no cure for HIV-1, presumably due to the presence of reservoirs of the virus. One of the least studied viral reservoirs is the brain, which the virus enters by crossing the blood-brain barrier (BBB) via macrophages, which are considered as conduits between the blood and the brain. The presence of HIV-1 in the brain often leads to HIV associated neurocognitive disorders (HAND), such as encephalitis and early-onset dementia. In this study we develop a novel mathematical model that describes HIV-1 infection in the brain and in the plasma coupled via the BBB. The model predictions are consistent with data from macaques infected with a mixture of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV). Using our model, we estimate the rate of virus transport across the BBB as well as viral replication inside the brain, and we compute the basic reproduction number. We also carry out thorough sensitivity analysis to define the robustness of the model predictions on virus dynamics inside the brain. Our model provides useful insight into virus replication within the brain and suggests that the brain can be an important reservoir causing long-term viral persistence. 

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4. A 3D-printed blood-brain barrier model with tunable topology and cell-matrix interactions

   https://doi.org/10.1088/1758-5090/ad0260  

   Paone, Louis S.; Benmassaoud, Mohammed Mehdi; Curran, Aidan; Vega, Sebastián L.; Galie, Peter A. (October 2023, Biofabrication)

   Abstract Recent developments in digital light processing (DLP) can advance the structural and biochemical complexity of perfusablein vitromodels of the blood–brain barrier. Here, we describe a strategy to functionalize complex, DLP-printed vascular models with multiple peptide motifs in a single hydrogel. Different peptides can be clicked into the walls of distinct topologies, or the peptide motifs lining channel walls can differ from those in the bulk of the hydrogel. The flexibility of this approach is used to both characterize the effects of various bioactive domains on endothelial coverage and tight junction formation, in addition to facilitating astrocyte attachment in the hydrogel surrounding the endothelialized vessel to mimic endothelial–astrocyte interaction. Peptides derived from proteins mediating cell-extracellular matrix (e.g. RGD and IKVAV) and cell–cell (e.g. HAVDI) adhesions are used to mediate endothelial cell attachment and coverage. HAVDI and IKVAV-lined channels exhibit significantly greater endothelialization and increased zonula-occluden-1 (ZO-1) localization to cell–cell junctions of endothelial cells, indicative of tight junction formation. RGD is then used in the bulk hydrogel to create an endothelial–astrocyte co-culture model of the blood–brain barrier that overcomes the limitations of previous platforms incapable of complex topology or tunable bioactive domains. This approach yields an adjustable, biofabricated platform to interrogate the effects of cell-matrix interaction on blood–brain barrier mechanobiology. 

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5. Optimization and Technical Considerations for the Dye-Exclusion Protocol Used to Assess Blood–Brain Barrier Integrity in Adult Drosophila melanogaster

   https://doi.org/10.3390/ijms24031886  

   Bhasiin, Kesshni; Heintz, Olivia; Colodner, Kenneth J. (February 2023, International Journal of Molecular Sciences)

   The blood–brain barrier (BBB) is a multicellular construct that regulates the diffusion and transport of metabolites, ions, toxins, and inflammatory mediators into and out of the central nervous system (CNS). Its integrity is essential for proper brain physiology, and its breakdown has been shown to contribute to neurological dysfunction. The BBB in vertebrates exists primarily through the coordination between endothelial cells, pericytes, and astrocytes, while invertebrates, which lack a vascularized circulatory system, typically have a barrier composed of glial cells that separate the CNS from humoral fluids. Notably, the invertebrate barrier is molecularly and functionally analogous to the vertebrate BBB, and the fruit fly, Drosophila melanogaster, is increasingly recognized as a useful model system in which to investigate barrier function. The most widely used technique to assess barrier function in the fly is the dye-exclusion assay, which involves monitoring the infiltration of a fluorescent-coupled dextran into the brain. In this study, we explore analytical and technical considerations of this procedure that yield a more reliable assessment of barrier function, and we validate our findings using a traumatic injury model. Together, we have identified parameters that optimize the dye-exclusion assay and provide an alternative framework for future studies examining barrier function in Drosophila. 

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