Abstract Computational simulations of traumatic brain injury (TBI) are commonly used to advance understanding of the injury–pathology relationship, tissue damage thresholds, and design of protective equipment such as helmets. Both human and animal TBI models have developed substantially over recent decades, partially due to the inclusion of more detailed brain geometry and representation of tissues like cerebral blood vessels. Explicit incorporation of vessels dramatically affects local strain and enables researchers to investigate TBI-induced damage to the vasculature. While some studies have indicated that cerebral arteries are rate-dependent, no published experimentally based, rate-sensitive constitutive models of cerebral arteries exist. In this work, we characterize the mechanical properties of axially failed porcine arteries, both quasi-statically (0.01 s−1) and at high rate (>100 s−1), and propose a rate-sensitive model to fit the data. We find that the quasi-static and high-rate stress–stretch curves become significantly different (p < 0.05) above a stretch of 1.23. We additionally find a significant change in both failure stretch and stress as a result of strain rate. The stress–stretch curve is then modeled as a Holzapfel–Gasser–Ogden material, with a Prony series added to capture the effects of viscoelasticity. Ultimately, this paper demonstrates that rate dependence should be considered in the material properties of cerebral arteries undergoing high strain-rate deformations and provides a ready-to-use model for finite element implementation.
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Characterization of neural mechanotransduction response in human traumatic brain injury organoid model
The ability to model physiological systems through 3D neural in-vitro systems may enable new treatments for various diseases while lowering the need for challenging animal and human testing. Creating such an environment, and even more impactful, one that mimics human brain tissue under mechanical stimulation, would be extremely useful to study a range of human-specific biological processes and conditions related to brain trauma. One approach is to use human cerebral organoids (hCOs) in-vitro models. hCOs recreate key cytoarchitectural features of the human brain, distinguishing themselves from more traditional 2D cultures and organ-on-a-chip models, as well as in-vivo animal models. Here, we propose a novel approach to emulate mild and moderate traumatic brain injury (TBI) using hCOs that undergo strain rates indicative of TBI. We subjected the hCOs to mild (2 s−1) and moderate (14 s−1) loading conditions, examined the mechanotransduction response, and investigated downstream genomic effects and regulatory pathways. The revealed pathways of note were cell death and metabolic and biosynthetic pathways implicating genes such as CARD9, ENO1, and FOXP3, respectively. Additionally, we show a steeper ascent in calcium signaling as we imposed higher loading conditions on the organoids. The elucidation of neural response to mechanical stimulation in reliable human cerebral organoid models gives insights into a better understanding of TBI in humans.
more » « less- Award ID(s):
- 1946456
- PAR ID:
- 10516251
- Publisher / Repository:
- Scientific Reports
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 13
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Abstract Objective Brain organoids are miniaturized in vitro brain models generated from pluripotent stem cells, which resemble full‐sized brain more closely than conventional two‐dimensional cell cultures. Although brain organoids mimic the human brain's cell‐to‐cell network interactions, they generally fail to faithfully recapitulate cell‐to‐matrix interactions. Here, an engineered framework, called an engineered extracellular matrix (EECM), was developed to provide support and cell‐to‐matrix interactions to developing brain organoids.
Methods We generated brain organoids using EECMs comprised of human fibrillar fibronectin supported by a highly porous polymer scaffold. The resultant brain organoids were characterized by immunofluorescence microscopy, transcriptomics, and proteomics of the cerebrospinal fluid (CSF) compartment.
Results The interstitial matrix‐mimicking EECM enhanced neurogenesis, glial maturation, and neuronal diversity from human embryonic stem cells versus conventional protein matrix (Matrigel). Additionally, EECMs supported long‐term culture, which promoted large‐volume organoids containing over 250 μL of CSF. Proteomics analysis of the CSF found it superseded previous brain organoids in protein diversity, as indicated by 280 proteins spanning 500 gene ontology pathways shared with adult CSF.
Interpretation Engineered EECM matrices represent a major advancement in neural engineering as they have the potential to significantly enhance the structural, cellular, and functional diversity that can be achieved in advanced brain models.
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Human cerebral organoids derived from induced pluripotent stem cells (iPSCs) provide novel tools for recapitulating the cytoarchitecture of the human brain and for studying biological mechanisms of neurological disorders. However, the heterotypic interactions of neurovascular units, composed of neurons, pericytes (i.e., the tissue resident mesenchymal stromal cells), astrocytes, and brain microvascular endothelial cells, in brain-like tissues are less investigated. In addition, most cortical organoids lack a microglia component, the resident immune cells in the brain. Impairment of the blood-brain barrier caused by improper crosstalk between neural cells and vascular cells is associated with many neurodegenerative disorders. Mesenchymal stem cells (MSCs), with a phenotype overlapping with pericytes, have promotion effects on neurogenesis and angiogenesis, which are mainly attributed to secreted growth factors and extracellular matrices. As the innate macrophages of the central nervous system, microglia regulate neuronal activities and promote neuronal differentiation by secreting neurotrophic factors and pro-/anti-inflammatory molecules. Neuronal-microglia interactions mediated by chemokines signaling can be modulated in vitro for recapitulating microglial activities during neurodegenerative disease progression. In this review, we discussed the cellular interactions and the physiological roles of neural cells with other cell types including endothelial cells and microglia based on iPSC models. The therapeutic roles of MSCs in treating neural degeneration and pathological roles of microglia in neurodegenerative disease progression were also discussed.more » « less
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Abstract Traumatic brain injury (TBI), particularly from explosive blasts, is a major cause of casualties in modern military conflicts. Computational models are an important tool in understanding the underlying biomechanics of TBI but are highly dependent on the mechanical properties of soft tissue to produce accurate results. Reported material properties of brain tissue can vary by several orders of magnitude between studies, and no published set of material parameters exists for porcine brain tissue at strain rates relevant to blast. In this work, brain tissue from the brainstem, cerebellum, and cerebrum of freshly euthanized adolescent male Göttingen minipigs was tested in simple shear and unconfined compression at strain rates ranging from quasi-static (QS) to 300 s−1. Brain tissue showed significant strain rate stiffening in both shear and compression. Minimal differences were seen between different regions of the brain. Both hyperelastic and hyper-viscoelastic constitutive models were fit to experimental stress, considering data from either a single loading mode (unidirectional) or two loading modes together (bidirectional). The unidirectional hyper-viscoelastic models with an Ogden hyperelastic representation and a one-term Prony series best captured the response of brain tissue in all regions and rates. The bidirectional models were generally able to capture the response of the tissue in high-rate shear and all compression modes, but not the QS shear. Our constitutive models describe the first set of material parameters for porcine brain tissue relevant to loading modes and rates seen in blast injury.more » « less
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Abstract The evolution of tissue on a chip systems holds promise for mimicking the response of biological functionality of physiological systems. One important direction for tissue on a chip approaches are neuron‐based systems that could mimic neurological responses and lessen the need for in vivo experimentation. For neural research, more attention has been devoted recently to understanding mechanics due to issues in areas such as traumatic brain injury (TBI) and pain, among others. To begin to address these areas, a 3D Nerve Integrated Tissue on a Chip (NITC) approach combined with a Mechanical Excitation Testbed (MET) System is developed to impose external mechanical stimulation toward more realistic physiological environments. PC12 cells differentiated with nerve growth factor, which were cultured in a controlled 3D scaffolds, are used. The cells are labeled in a 3D NITC system with Fluo‐4‐AM to examine their calcium response under mechanical stimulation synchronized with image capture. Understanding the neural responses to mechanical stimulation beyond 2D systems is very important for neurological studies and future personalized strategies. This work will have implications in a diversity of areas including tissue‐on‐a‐chip systems, biomaterials, and neuromechanics.
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41598-023-40431-y
