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Traumatic brain injury poses a major public health challenge with significant immediate and long-term effects. Repetitive head trauma is an ongoing area of research, and little is known about the response of cerebral blood vessels to such loading. This study investigated the mechanical response of cerebral arteries to repetitive overstretch, hypothesizing that repeated overstretch leads to cumulative damage. To test this hypothesis, middle cerebral artery segments from twelve piglets were subjected to sub-yield, high-rate overstretch of varying severities, with up to 10 repetitions. The stress-stretch behavior of the vessels revealed that repetitive overstretch caused progressive softening that increased with both overstretch magnitude and number of exposures. This softening was notably limited to the toe region, with no changes occurring in the higher-stress, linear portion of the repeated overstretch curves. Mild-to-moderate overstretches resulted in gradual softening, while severe overstretches caused dramatic softening with the first exposure and little further change with subsequent overstretches. Mildly damaged vessels displayed a small amount of recovery with time, but the magnitude of this recovery was minimal and declined with increasing repetitions and severity. No clear relationship was observed between collagen denaturation and the magnitude and number of overstretches. These findings provide important insights into the mechanics of cerebral vessels under repetitive loading, suggesting that vascular damage from repeated trauma accumulates, potentially exacerbating existing injury. These results increase understanding of soft tissue damage and inform the development of constitutive damage models for cerebral arteries, a critical tool needed to improve predictions of traumatic brain injury progression. STATEMENT OF SIGNIFICANCE: This study investigates the mechanical response of cerebral arteries to repetitive overstretch, revealing cumulative softening effects. Unlike previous studies focusing on single overstretch events, our research is the first to explore repetitive exposures in cerebral arteries and to report softening as a function of both overstretch magnitude and number of exposures. Given the role of cerebral vessels in maintaining a healthy brain and their contributions to the structural response of the brain in TBI events, progressive vessel softening in repetitive TBI may lead to increased vulnerability with the potential to exacerbate existing injury. These findings enhance understanding of soft tissue damage mechanisms, providing critical insights for developing constitutive damage models and improving injury predictions in repeated TBI.
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Characterization of neural mechanotransduction response in human traumatic brain injury organoid model
Abstract 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.
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- 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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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s41598-023-40431-y
