Needle to needle robot‐assisted manufacture of cell therapy products

Abstract

Advanced therapeutic medicinal products (ATMPs) have emerged as novel therapies for untreatable diseases, generating the need for large volumes of high‐quality, clinically‐compliant GMP cells to replace costly, high‐risk and limited scale manual expansion processes. We present the design of a fully automated, robot‐assisted platform incorporating the use of multiliter stirred tank bioreactors for scalable production of adherent human stem cells. The design addresses a needle‐to‐needle closed process incorporating automated bone marrow collection, cell isolation, expansion, and collection into cryovials for patient delivery. AUTOSTEM, a modular, adaptable, fully closed system ensures no direct operator interaction with biological material; all commands are performed through a graphic interface. Seeding of source material, process monitoring, feeding, sampling, harvesting and cryopreservation are automated within the closed platform, comprising two clean room levels enabling both open and closed processes. A bioprocess based on human MSCs expanded on microcarriers was used for proof of concept. Utilizing equivalent culture parameters, the AUTOSTEM robot‐assisted platform successfully performed cell expansion at the liter scale, generating results comparable to manual production, while maintaining cell quality postprocessing.

Robotics-driven manufacturing of cartilaginous microtissues for the bio-assembly of skeletal implants

“…To date the adoption of robotics for cell therapy and regenerative medicine applications has been carried out for the expansion of single cell populations such as adult MSC expanded in bioreactor systems (34). Moreover, robotic based expansion and differentiation to induced pluripotent stem (IPS) cells towards retinal pigment epithelial cells showed a high level of cell purity and functionality (51,52).…”

“…A well-characterised process and manufacturing line is imperative towards a successful translation (Rousseau et al, 2018, ten Ham et al, 2018. Significant progress has been made in automated cell culture, passaging and organoid seeding (31)(32)(33)(34), showing the feasibility and advantages of automating manual processes. Furthermore, robotic platforms using microtissues to create complex tissue constructs are appearing (35,36).…”

Transformative Materials to Create 3D Functional Human Tissue Models In Vitro in a Reproducible Manner

“…For the development of an advanced therapy medicinal product (ATMP), reproducible quality has to be assured to meet the quality-related regulation requirements. For personalized treatment, it is mandatory to define optimal stem cell expansion and differentiation protocols, for example, to create iPSCderived patient-specific therapies, such as allogeneic cardiomyocyte patches, joint implants, and CAR-T-cell therapy [28,58] To enable large-scale cell production and clinically GMP-compliant manufacturing, stirred bioreactor-based platforms have been established to expand and differentiate MSCs and iPSCs under controlled conditions, [57,71,72] for example, to produce iPSC-derived hematopoietic cells [73] and cardiomyocytes. [74] Bioreactor-derived ) Initial epithelial tissue models such as those from (i) the airway epithelia and (ii) skin, have shown that these models require complex environments that include interfaces and other forces such as flow.…”

“…These standardized production platforms avoid batch deviations and can enable reproducible and quality-assured cell cultures. [57][58][59] Stem cell factories, as they are known, have successfully been used to generate and expand iPSCs using defined and userindependent conditions with the economic advantage of a fully automated stem cell production and increased throughput. [59][60][61][62] As such, the integration of deep-learning-based algorithms into robotic pipelines has resulted in noninvasive routine assessment of iPSCs, concerted by the use of fluorescent reporter lines, to ascertain a standardized protocol for monitoring, e.g., the proliferation rate and cell confluency prior to splitting cells and further propagation.…”

Women’s contribution to stem cell research for osteoarthritis: an opinion paper

“…Development and use of bio-inspired, fabricated bio-printed constructs will require validated and relevant cell sources and/or use of appropriate factors to attract endogenous stem cells to the constructs. The cost of producing GMP-grade MSCs, or even iMSCs, using manual processes is such that translation to patient use at scale to enable widespread use is prohibitive and a critical impediment in the field as noted by the group of M. Murphy* ( Ochs et al, 2022 ). The automation of production of advanced therapy medicinal products (ATMPs), state-of-the-art medicines for human use based on genes, tissues or cell-derived EVs can address this hurdle to clinical translation as reported by the group of M. Murphy* ( Ochs et al, 2022 ).…”