Angiographic Features of Meningiomas Predicting Extent of Preoperative Embolization.

BACKGROUND AND OBJECTIVES: Preoperative embolization is used as an endovascular adjunct to surgical resection of meningiomas. However, there is no standardized system to assess the efficacy or extent of embolization during the embolization procedure. We sought to establish a purely angiographic grading system to facilitate consistent reporting of the outcome of meningioma embolization and to characterize the anatomic and other features of meningiomas that predict the degree of devascularization achieved through preoperative embolization. METHODS: We identified patients with meningiomas who underwent preoperative cerebral angiography and subsequent resection between 2015 and 2021. Demographic, clinical, and imaging data were collected in a research registry. We defined an angiographic devascularization grading scale as follows: grade 0 for no embolization, 1 for partial embolization, 2 for majority embolization, 3 for complete external carotid artery embolization, and 4 for complete embolization. RESULTS: Eighty consecutive patients were included, 60 of whom underwent preoperative tumor embolization (20 underwent angiography with an intention to treat but ultimately not embolization). Embolized tumors were larger (59.0 vs 35.9 cc; P = .03). Gross total resection, length of stay, and complication rates did not differ among groups. The distribution of arterial feeders differed significantly across tumors in a location-specific manner. Both the tumor location and the identity of arterial feeders were predictive of the extent of embolization. Anterior midline meningiomas were associated with internal carotid (ophthalmic, ethmoidal) supply and lower devascularization grades (P = .03). Tumors fed by meningeal feeders (convexity, falcine, lateral sphenoid wing) were associated with higher devascularization grades (P < .01). The procedural complication rate for tumor embolization was 2.5%. CONCLUSION: Angiographic outcomes can be graded to indicate the extent of tumor embolization. This system may facilitate consistency of reported angiographic results. In addition, arterial feeders vary in a manner predicted by tumor location, and these patterns correlate with typical degrees of devascularization achieved in those tumor locations.

Non-Destructive Tumor Aggregate Morphology and Viability Quantification at Cellular Resolution, During Development and in Response to Drug.

Three-dimensional (3D) tissue-engineered in vitro models, particularly multicellular spheroids and organoids, have become important tools to explore disease progression and guide the development of novel therapeutic strategies. These avascular constructs are particularly powerful in oncological research due to their ability to mimic several key aspects of in vivo tumors, such as 3D structure and pathophysiologic gradients. Advancement of spheroid models requires characterization of critical features (i.e., size, shape, cellular density, and viability) during model development, and in response to treatment. However, evaluation of these characteristics longitudinally, quantitatively and non-invasively remains a challenge. Herein, Optical Coherence Tomography (OCT) is used as a label-free tool to assess 3D morphologies and cellular densities of tumor spheroids generated via the liquid overlay technique. We utilize this quantitative tool to assess Matrigel's influence on spheroid morphologic development, finding that the absence of Matrigel produces flattened, disk-like aggregates rather than 3D spheroids with physiologically-relevant features. Furthermore, this technology is adapted to quantify cell number within tumor spheroids, and to discern between live and dead cells, to non-destructively provide valuable information on tissue/construct viability, as well as a proof-of-concept for longitudinal drug efficacy studies. Together, these findings demonstrate OCT as a promising noninvasive, quantitative, label-free, longitudinal and cell-based method that can assess development and drug response in 3D cellular aggregates at a mesoscopic scale.

Laser-based 3D bioprinting for spatial and size control of tumor spheroids and embryoid bodies.

3D multicellular aggregates, and more advanced organotypic systems, have become central tools in recent years to study a wide variety of complex biological processes. Most notably, these model systems have become mainstream within oncology (multicellular tumor spheroids) and regenerative medicine (embryoid bodies) research. However, the biological behavior of these in vitro tissue surrogates is extremely sensitive to their aggregate size and geometry. Indeed, both of these geometrical parameters are key in producing pathophysiological gradients responsible for cellular and structural heterogeneity, replicating in vivo observations. Moreover, the fabrication techniques most widely used for producing these models lack the ability to accurately control cellular spatial location, an essential component for regulating homotypic and heterotypic cell signaling. Herein, we report on a 3D bioprinting technique, laser direct-write (LDW), that enables precise control of both spatial patterning and size of cell-encapsulating microbeads. The generated cell-laden beads are further processed into core-shelled structures, allowing for the growth and formation of self-contained, self-aggregating cells (e.g., breast cancer cells, embryonic stem cells). Within these structures we demonstrate our ability to produce multicellular tumor spheroids (MCTSs) and embryoid bodies (EBs) with well-controlled overall size and shape, that can be designed on demand. Furthermore, we investigated the impact of aggregate size on the uptake of a commonly employed ligand for receptor-mediated drug delivery, Transferrin, indicating that larger tumor spheroids exhibit greater spatial heterogeneity in ligand uptake. Taken together, these findings establish LDW as a versatile biomanufacturing platform for bioprinting and patterning core-shelled structures to generate size-controlled 3D multicellular aggregates. STATEMENT OF SIGNIFICANCE: Multicellular 3D aggregates are powerful in vitro models used to study a wide variety of complex biological processes, particularly within oncology and regenerative medicine. These tissue surrogates are fabricated using environments that encourage cellular self-assembly. However, specific applications require control of aggregate size and position to recapitulate key in vivo parameters (e.g., pathophysiological gradients and homotypic/heterotypic cell signaling). Herein, we demonstrate the ability to create and spatially pattern size-controlled embryoid bodies and tumor spheroids, using laser-based 3D bioprinting. Furthermore, we investigated the effect of tumor spheroid size on internalization of Transferrin, a common ligand for targeted therapy, finding greater spatial heterogeneity in our large aggregates. Overall, this technique offers incredible promise and flexibility for fabricating idealized 3D in vitro models.