Development of an ex vivo model for predicting in vivo tissue back pressure for subcutaneous injections.

Tissue back pressure is an important indicator of tissue resistance during subcutaneous injection and is associated with injection performance and patient experience. Currently, assessments of tissue back pressure during injection are mostly conducted in vivo, which are inconvenient, costly, and difficult to standardize. To overcome these limitations, this study used a pork belly-based model to develop an ex vivo-in vivo correlation (EVIVC) for tissue back pressure during injection. Subsequently, using the model developed, the effect of multiple factors on back pressure was evaluated, including (1) tissue-related factors: subcutaneous tissue thicknesses and pork belly freeze-thaw cycles; (2) injection operation-related factors: needle insertion angle; and (3) formulation- and device-related factors: formulation viscosity, temperature, osmolarity, and needle gauge. The mechanical properties of subcutaneous tissue were characterized using rheological and unconfined compression tests. As a result, an EVIVC was established, with a linear correlation between ex vivo and in vivo values (R2 = 0.87). Among all factors examined, formulation viscosity was the dominant determinant of tissue back pressure during injection, whereas subcutaneous tissue thickness, needle insertion angle, needle gauge, and formulation osmolarity had minimal influence. Also, freezing-thawing pork belly for three cycles had no significant effect on back pressure, supporting the appropriateness of storage conditions and the robustness of the model. The subcutaneous tissue thickness (< 2.5 cm vs. ≥ 2.5 cm) exhibited comparable viscoelastic behavior, but the normal-thickness tissue was more elastic. In summary, this ex vivo model can serve as a convenient, ethically preferable tool to reduce/replace in vivo studies for tissue back pressure assessment, potentially facilitating subcutaneous combination product development.