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Updated: Jan 7, 2026
Laboratory-Engineered Glioblastoma Organoid Culture and Drug Screening
Published on: January 10, 2025
Bioengineering Stem Cell-Derived Glioblastoma Organoids: A Comprehensive Review
Alexandra D Avera1, Yonghyun Kim1
1Department of Chemical and Biological Engineering, The University of Alabama, Tuscaloosa, AL 35487, USA.
Abstract:
The development of novel therapeutics for deadly diseases such as glioblastoma (GBM) is bottlenecked by poor preclinical models. GBM is the most common and deadliest primary brain tumor in adults, with an average prognosis of 12-15 months, primarily due to its high cellular heterogeneity and treatment resistance from GBM stem cells. The advancement of in vitro models into organoids, three-dimensional tissue-like modeling systems, has been a promising approach to improving translational medicine for GBM. However, the critical tradeoff between technical convenience and physiological relevance threatens the integrity and reproducibility of GBM organoid (GBO) biomanufacturing. This comprehensive review breaks down and discusses the key features of GBM tumor microenvironment (TME), traces the advancement of in vitro models from two-dimensional cultures to three-dimensional stem cell-derived GBOs, evaluates the process through an engineering perspective (genetic, biochemical, biophysical, and process engineering), and addresses critical translational gaps. Reviewing trends over the last fifteen years in biomanufacturing approaches to GBOs revealed fundamental oversights that address previous review focuses on the limitations of organoids (i.e., maturity, vasculature, and immune defense). To summarize, GBO's translational gap and reproducibility challenges are rooted in the prioritization of technical convenience over physiological relevance. To achieve clinical relevance, future GBO development must focus on transitioning to fully defined components (excluding animal-derived ECM), developing sufficiently large-sized constructs to recapitulate the full TME, and integrating non-destructive and enhanced functional readouts of the GBOs.
Insights
Glioblastoma organoids (GBOs) show promise for developing new treatments, but current manufacturing prioritizes convenience over biological accuracy, hindering clinical translation. Future GBOs need better defined components and larger sizes for improved relevance.
Area of Science:
- Biomedical Engineering
- Cancer Research
- Translational Medicine
Background:
- Glioblastoma (GBM) is a fatal brain cancer with poor prognosis due to tumor heterogeneity and treatment resistance.
- Current preclinical models inadequately represent GBM's complexity, limiting therapeutic development.
- Organoids offer a more physiologically relevant in vitro model, but challenges remain in their biomanufacturing.
Purpose of the Study:
- To review the advancements in glioblastoma organoid (GBO) biomanufacturing.
- To analyze GBO development from an engineering perspective, focusing on the tumor microenvironment (TME).
- To identify critical translational gaps and propose future directions for clinically relevant GBO models.
Main Methods:
- Comprehensive literature review of GBO biomanufacturing over the last 15 years.
- Analysis of GBM tumor microenvironment (TME) features.
- Evaluation of GBO development through genetic, biochemical, biophysical, and process engineering lenses.
Main Results:
- GBO biomanufacturing often prioritizes technical convenience over physiological relevance, impacting integrity and reproducibility.
- Existing GBO models face limitations in maturity, vasculature, and immune cell integration.
- Fundamental oversights in GBO development hinder their clinical applicability.
Conclusions:
- The translational gap in GBOs stems from prioritizing ease of use over biological accuracy.
- Future GBO development requires fully defined components, larger constructs for TME recapitulation, and enhanced functional readouts.
- Improving GBOs is crucial for advancing novel therapeutics for glioblastoma.
