Three-dimensional bioreactors
Inventors
Ling, Jian • Wellinghoff, Stephen T. • RUBAL, Michael Joseph
Assignees
Southwest Research Institute SwRI
Publication Number
US-11912971-B2
Publication Date
2024-02-27
Expiration Date
2039-09-24
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Abstract
Design, fabrication and applications of three-dimensional (3D) bioreactor for cell expansion and cell secreted substance production. The bioreactors have relatively low levels of potentially cytotoxic compounds, can be coated with substituted or unsubstituted poly(p-xylene) type coatings and can also be separately formed from liquid crystal photopolymerizable monomers.
Core Innovation
The invention concerns three-dimensional (3D) bioreactors designed for cell expansion and the production of cell-secreted substances. These bioreactors are constructed to have a plurality of voids with specified diameters and interconnected pore openings with diameters that are less than those of the voids. At least 90% or more of the voids and 90% or more of the pore openings must maintain their dimensions within a narrow tolerance (±10.0%), establishing a highly regular, non-random structure optimized for cell growth.
The bioreactors can be coated with substituted or unsubstituted poly(p-xylene) type coatings to reduce leaching of residual monomers and cytotoxic compounds, thereby improving biocompatibility. Additionally, the bioreactor can be formed from specifically defined liquid crystal photopolymerizable monomers, resulting in mechanically robust, non-degradable structures suitable for use in aqueous environments during cell expansion. The surface of the bioreactor may be further functionalized with polydopamine and subsequently with proteins or antibodies as required by particular cell types.
The background identifies problems with current T-cell and stem cell expansion techniques, including reliance on magnetic beads, multi-stage manual processing, high costs, susceptibility to contamination, and challenges in achieving cellular scale-up and critical process control in conventional devices. The patent addresses these issues by offering a scalable 3D bioreactor with a highly controlled void and pore architecture, reduced cytotoxicity, and customizable surface functionalization, enabling efficient, cost-effective, and GMP-compliant cell expansion for therapeutic applications.
Claims Coverage
The claims of this patent focus on a single independent claim, specifying key inventive features related to the precise geometric, structural, and material properties of the 3D bioreactor.
Highly regular 3D bioreactor structure with controlled voids and pores
The invention covers a 3D bioreactor comprising a plurality of voids for cell expansion, each having a diameter D, and a plurality of pore openings between the voids with diameter d, with D>d. Critically, at least 90% or more of the voids have a void volume that does not vary by more than ±10.0%, and at least 90% or more of the pore openings have a value of d that does not vary by more than ±10.0%. This ensures a highly uniform, non-random configuration supporting efficient and predictable cell culture.
Bioreactor material formed from specific photopolymerizable monomer
The 3D bioreactor is formed from the polymerization product of a defined monomer structure, wherein X and Y are polymerizable groups, R2 is a bulky organic group adapted to provide steric hindrance to achieve a nematic state at room temperature, and R1 and R3 are groups less bulky than R2. This composition achieves both desired mechanical stability and compatibility with additive manufacturing techniques.
The claims collectively protect a 3D bioreactor architecture with precisely controlled geometric tolerances and material compositions, enabling scalable and reproducible manufacturing along with optimized performance for cell expansion and related bioprocesses.
Stated Advantages
Provides a scalable, high surface-to-volume ratio environment for large-scale cell expansion with a significantly smaller footprint than traditional methods.
Reduces the levels of potentially cytotoxic compounds through post-printing treatments and impermeable poly(p-xylene) coatings, enhancing biocompatibility.
Offers highly regular and reproducible internal void and pore structures, minimizing variability in manufacturing and optimizing process control.
Reduces or eliminates shear-induced cell differentiation by shielding cells from high flow-induced stress.
Enables functionalization of surfaces for specific cell types and applications, supporting versatile use in both immunotherapy and regenerative medicine.
Facilitates automation and cost-effective good manufacturing practice (cGMP) cell manufacturing due to a bead-free, closed-loop system.
Allows cell migration across continuous surfaces, enhancing cell culture uniformity and flexibility.
Documented Applications
Expansion of T-cells for immunotherapy applications, including chimeric antigen receptor (CAR) T-cell therapies.
Expansion of stem cells for regenerative medicine, including therapies that require large-scale stem cell growth.
Production of cell secreted substances.
Use as a bead-free, closed-loop perfusion-based bioreactor for T-cell activation and expansion, supporting automation and cGMP compliance.
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