Development of a novel bioengineered 3D brain‐like tissue for studying primary blast‐induced traumatic brain injury

Abstract

Primary blast injury is caused by the direct impact of an overpressurization wave on the body. Due to limitations of current models, we have developed a novel approach to study primary blast‐induced traumatic brain injury. Specifically, we employ a bioengineered 3D brain‐like human tissue culture system composed of collagen‐infused silk protein donut‐like hydrogels embedded with human IPSC‐derived neurons, human astrocytes, and a human microglial cell line. We have utilized this system within an advanced blast simulator (ABS) to expose the 3D brain cultures to a blast wave that can be precisely controlled. These 3D cultures are enclosed in a 3D‐printed surrogate skull‐like material containing media which are then placed in a holder apparatus inside the ABS. This allows for exposure to the blast wave alone without any secondary injury occurring. We show that blast induces an increase in lactate dehydrogenase activity and glutamate release from the cultures, indicating cellular injury. Additionally, we observe a significant increase in axonal varicosities after blast. These varicosities can be stained with antibodies recognizing amyloid precursor protein. The presence of amyloid precursor protein deposits may indicate a blast‐induced axonal transport deficit. After blast injury, we find a transient release of the known TBI biomarkers, UCHL1 and NF‐H at 6 h and a delayed increase in S100B at 24 and 48 h. This in vitro model will enable us to gain a better understanding of clinically relevant pathological changes that occur following primary blast and can also be utilized for discovery and characterization of biomarkers.

Reactive gliosis in traumatic brain injury: a comprehensive review

“…Using 2D or 3D human cell cultures for in vitro modeling also has its limitations ( Fang and Eglen, 2017 ; Qian et al, 2019 ). Snapper et al (2023) introduced a new in vitro model based on a bioengineered 3D brain-like culture system that can mimic the human pathology fairly well ( Snapper et al, 2023 ). Using this novel bTBI model they revealed increased axonal varicosities following primary bTBI, persisting for a week with a peak at 72 h. These varicosities, indicative of traumatic axonal injury, show the accumulation of amyloid precursor protein (APP), suggesting a blast-induced deficit in axonal transport.…”

“…GFAP didn’t increase, possibly due to elevated pre-injury levels. This novel in vitro culture system without a BBB may allow controlled screening for new biomarkers that are pivotal in diagnose blast-induced mTBI ( Snapper et al, 2023 ).…”

Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies

“…Various research groups have successfully developed TBI-related assays employing the iPSC technology. The majority of these studies concentrate on specific modeling targets, such as the primary impact (PI) effects [198,199], SI neuroinflammatory response [200], and PI traumatic axonal injury [201].…”

The Impact of the Cellular Environment and Aging on Modeling Alzheimer's Disease in 3D Cell Culture Models

“…They store large amounts of water and provide a high diffusivity to the solute due to their porous structure and can be functionalized with cell adhesion sites. Hydrogels can be classified into the following three classes according to their origin: Biological (Matrigel, [40,41] collagen I, [42][43][44] alginate [45,46] ), synthetic (polyacrylamide, polyethylene glycol (PEG) [12,47] ), or hybrid (hyaluronic acid, polypeptides, silk, fibrin) materials [48][49][50][51][52][53][54] (Table 1). Alginate-based ionotropic hydrogels or synthetic hydrogels like PEG offer superior standardization compared to cell culture-derived options.…”