The prevalence of dementia and other neurodegenerative diseases continues to rise as age demographics in the population shift, inspiring the development of long‐term tissue culture systems with which to study chronic brain disease. Here, it is investigated whether a 3D bioengineered neural tissue model derived from human induced pluripotent stem cells (hiPSCs) can remain stable and functional for multiple years in culture. Silk‐based scaffolds are seeded with neurons and glial cells derived from hiPSCs supplied by human donors who are either healthy or have been diagnosed with Alzheimer's disease. Cell retention and markers of stress remain stable for over 2 years. Diseased samples display decreased spontaneous electrical activity and a subset displays sporadic‐like indicators of increased pathological β‐amyloid and tau markers characteristic of Alzheimer's disease with concomitant increases in oxidative stress. It can be concluded that the long‐term stability of the platform is suited to study chronic brain disease including neurodegeneration.
Traumatic brain injury (TBI) survivors suffer long term from mental illness, neurodegeneration, and neuroinflammation. Studies of 3D tissue models have provided new insights into the pathobiology of many brain diseases. Here, a 3D in vitro contusion model is developed consisting of mouse cortical neurons grown on a silk scaffold embedded in collagen and used outcomes from an in vivo model for benchmarking. Molecular, cellular, and network events are characterized in response to controlled cortical impact (CCI). In this model, CCI induces degradation of neural network structure and function and release of glutamate, which are associated with the expression of programmed necrosis marker phosphorylated Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL). Neurodegeneration is observed first in the directly impacted area and it subsequently spreads over time in 3D space. CCI reduces phosphorylated protein kinase B (pAKT) and Glycogen synthase kinase 3 beta (GSK3β) in neurons in vitro and in vivo, but discordant responses are observed in phosphprylated ribosomal S6 kinase (pS6) and phosphorylated Tau (pTau) expression. In summary, the 3D brain‐like culture system mimicked many aspects of in vivo responses to CCI, providing evidence that the model can be used to study the molecular, cellular, and functional sequelae of TBI, opening up new possibilities for discovery of therapeutics.
Stroke, traumatic brain injuries, and other similar conditions often lead to significant loss of functional brain tissue and associated disruption of neuronal signaling. A common strategy for replacing lost neurons is the injection of dissociated neural stem cells or differentiated neurons. However, this method is unlikely to be suitable for replacing large brain cavities, and the resulting distribution of neurons may lack the necessary architecture to support appropriate brain function. Engineered neural tissues may be a viable alternative. Cell death is a prominent concern in neuronal grafting studies, a problem that could be magnified with the transplantation of engineered neural tissues. Here, we examined the effect of one contributor to cell death, acute cerebral inflammation, on neuronal survival after the transplantation of bioengineered constructs based on silk scaffolds. We found evidence of a high degree of inflammation and poor neuronal survival after introducing engineered constructs into the motor cortex of rats. Integrating a corticosteroid (methylprednisolone) into the constructs resulted in significantly improved neuron survival during the acute phase of inflammation. The improved construct survival was associated with decreased markers of inflammation and an anti-inflammatory state of the immune system due to the steroid treatment.
Background: High tibial osteotomy (HTO) and distal femoral osteotomy (DFO) are well-recognized treatments to address varus and valgus malalignment, respectively, in the setting of symptomatic unicompartmental arthritis of the tibiofemoral joint. The existing literature is limited in its ability to characterize complications after HTO or DFO procedures. Purpose: The objective of this study was to determine the rate of early (≤90 days) postoperative complications and associated variables from the 15-year experience of a single academic institution. Study Design: Case series; Level of evidence, 4. Methods: Patients treated at a single academic institution between 2008 and 2022 who underwent HTO or DFO procedures were identified. All patients with minimum 90-day follow-up were considered for inclusion in the study. Exclusion criteria were inadequate follow-up, unavailable medical records, age <14 years, and revision osteotomy. Patient demographic characteristics, surgical history, and concomitant procedures were identified, and risk factor analysis was performed to identify variables associated with early postoperative complications. All intraoperative complications were recorded. Results: A total of 243 knees in 232 patients met eligibility and were included in the final analysis. Three intraoperative complications (1.2%) involving fracture extension of the osteotomy occurred. There were 127 early postoperative complications (121 surgical, 6 medical) in 102 knees (68 with HTO and 34 with DFO). Medical complications included pulmonary embolus in 3 patients (1.2%), urinary tract infection in 2 patients (0.8%), and postoperative ileus requiring prolonged hospitalization in 1 patient (0.4%). The most common complications were stiffness requiring a non–standard of care intervention (17.7%), superficial wound infection or wound dehiscence (13.2%), and hemarthrosis or effusion requiring aspiration (6.6%). The rate of deep infection requiring irrigation and debridement was 4.1%. Variables associated with early postoperative complications included smoking (odds ratio [OR], 3.05; 95% CI, 1.34-6.94; P = .008), concomitant chondroplasty and/or loose body removal (OR, 2.55; 95% CI, 1.50-4.33; P = .001), and concomitant ligament reconstruction (OR, 3.97; 95% CI, 1.37-11.53; P = .011). Conclusion: These 15-year data revealed a low rate of intraoperative complications (1.2%) and a relatively high rate of early (≤90 days) postoperative complications (42.0%) after an HTO or DFO procedure. Surgeons should be aware of the increased postoperative complications associated with smoking, concomitant chondroplasty, and concomitant ligament reconstruction and should use this information to counsel patients regarding appropriate expectations in the postoperative period.
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