UCLA researchers in the Department of Bioengineering have developed a novel combinational library of biomimetic hydrogels that aids in the more advanced screening for precision medicine.
BACKGROUND
Drug screening utilizing advanced 3D cell culture is rapidly growing in the biotech industry for its more accurate representation of human physiology than 2D monolayer culture. Despite early advances, the 3D culture condition has several limitations that have yet to be addressed. Currently, diverse extracellular biomolecules in the culture system have yet to be exploited to harness their essential roles in regulating cellular behaviors. The recreation of physiologically relevant physical parameters like stiffness, pore size, and degradability is currently difficult to achieve. However, incorporating all these parameters increases model complexity in a factorial manner and quickly becomes the limiting factor in both cost and workforce metrics. Therefore, alternative methods to screen and investigate these large parameter spaces are of strong interest to drug development stakeholders.
INNOVATION
UCLA researchers in the Department of Bioengineering have developed a novel combinational library of biomimetic hydrogels that can orthogonally change multiple physiological parameters, such as polymer content, physical stiffness, and bioactive ligands. These multivariate hydrogels were constructed by modifying an FDA-approved natural polymer, hyaluronic acid (HA), thiol moiety, multi-armed, norbornene-modified polyethylene glycol (PEG). Different compositions mimic various microenvironment conditions. These HA-based hydrogels are also biocompatible with cells of varying origins (human, animal), number, and mixtures for 3D culturing. Combined with automated liquid handlers, the 3D multivariate biomimetic culture can be developed to a high-throughput screening platform that enables the precise interrogation of biomaterials on cellular activities. This will enable more physiologically relevant ex vivo drug screening to develop personalized medicine, potentially narrowing the currently wide gap between bench and bedside.
POTENTIAL APPLICATIONS
• Personalized medicine
• Drug screening platform
ADVANTAGES
• 3D culture system with multivariate conditions, capturing both physical and biochemical parameters
• Biocompatible hydrogels for diverse cell types and conditions
• Extensive handling (e.g., 96, 384 plates) for various screening formats
DEVELOPMENT-TO-DATE: A brain-mimetic 3D culture platform has been utilized to identify extracellular matrix-dependent mechanisms on therapeutic resistance in patient-derived glioblastoma cell lines. A generalizable platform for high-throughput drug screening has been developed based on this finding. A provisional patent has been submitted.
RELATED PAPERS:
W. Xiao, S. Wang, R. Zhang, et al., Bioengineered scaffolds for 3D culture demonstrate extracellular matrix-mediated mechanisms of chemotherapy resistance in glioblastoma, Matrix Biology, https://doi.org/10.1016/j.matbio.2019.04.003
W. Xiao, R. Zhang, S. Sun, et al. Brain-mimetic, 3D culture platforms for investigating cooperative effects of extracellular matrix features on treatment resistance in glioblastoma. Cancer Research, http://doi.org/10.1158/0008-5472.CAN-17-2429
W. Xiao, A. Ehsanipour, A. Sohrabi, et al. Hyaluronic-acid based hydrogels for 3-dimensional culture of patient-derived glioblastoma cells. Journal of Visualized Experiments, https://doi.org/10.3791/58176