(A-8) A minimally invasive subcutaneous implant for in-situ production of biologic therapeutics

Introduction:: Biologics like peptides, proteins, and monoclonal antibodies (mABs) are a class of therapeutics derived from living sources. As the fastest-growing class of therapeutics, they have shown great potential for treating a range of pathologies, such as cancer, diabetes, and infectious disease. However, biologics are also one of the most expensive forms of treatment with the average annual cost of mAB therapy exceeding $95,000 per patient. Moreover, the need for frequent injections and their instability are critical challenges that must be addressed for durable delivery and widespread clinical translation. To overcome these limitations, we are developing a minimally invasive trocar injectable and retrievable device that houses cell-based factories engineered to secrete a range of mAB and peptide biologics. The device can be implanted subcutaneously (SubQ) or intraperitoneally (IP) and removed or replaced when needed, allowing for sustained and controlled release of a desired biologic in-vivo.

Materials and Methods:: Here, we designed, and 3D printed a porous lattice structure implant from a biocompatible polymer that is SubQ and IP insertable using a minimally invasive Trocar. Then, a clinically relevant human epithelial cell line (ARPE-19) was engineered to secrete mAB and peptide biologics, such as anti-HIV mABs or leptin peptides. The viability and function of encapsulated therapeutic cell-based factories was validated in-vitro with diffusion, cell viability, and ELISA assays. Cell potency was further optimized by screening the productivity of engineered cells encapsulated in hydrogels with a variety of compositions. Therapeutic durability is demonstrated in SubQ and IP spaces in in-vivo murine models via analysis of cell survival and biologic concentration in blood serum.


Results, Conclusions, and Discussions:: Our results demonstrate that a 3D-printed porous lattice structure provides robust mechanical containment of multiple hydrogel form factors within its core chassis. Characterization of protein diffusion kinetics revealed the sustained release of proteins up to 500kDa, suggesting the potential encapsulation of cells engineered to secrete a wide range of biologics. High cell viability ( >97%) and therapeutic production of anti-HIV mAbs and Leptin peptides were demonstrated in-vitro. We also show that variable therapeutic dosing can be achieved by adjusting encapsulated cell density and leveraging 3D printing for scaling device volume. Finally, we demonstrate that 10e6 cells/mL is an optimal cell density for sustained encapsulated cell survival in-vivo and show that implanted devices can deliver mABs and peptide biologics in in-vivo murine models.


Acknowledgements (Optional): : Support and funding was provided by the Bill & Melinda Gates Foundation INV-051204.

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