In Vivo Evaluation of Preconditioned Adipose‐Derived Stromal Cells Reveals Limited Impact on Vascular and <scp>ECM</scp> Remodeling in Polymer Scaffolds

Polymer scaffolds are a promising platform for the transplantation of insulin-producing cells in Type 1 Diabetes. While vascularization has been a primary focus due to its role in oxygen and nutrient delivery, the interplay between blood vessels and the extracellular matrix (ECM) is increasingly recognized as critical for establishing a stable and functional graft microenvironment. Adipose-derived stromal cells (ASC) have shown potential to support both vascular and ECM remodeling, and their therapeutic profile may be modulated through preconditioning. However, the in vivo effects of ASC preconditioning and their delivery remain poorly defined. This study aims to evaluate whether preconditioned ASC can enhance vascular and ECM outcomes in a polymer scaffold. To this end, rat ASC were preconditioned within porous polycaprolactone (PCL) scaffolds under normoxic, hypoxic, or hypoxic + high-glucose conditions. Subsequently, scaffolds were implanted subcutaneously in immunodeficient rats and explanted at 7, 14, 21, and 28 days for analysis of vascular and ECM markers. This study showed that the addition of ASC did not enhance vascularization or ECM remodeling within the scaffolds, regardless of whether the ASC were preconditioned. This indicates that previously reported in vitro benefits of ASC preconditioning do not necessarily translate in vivo. Moreover, the results highlight the critical importance of the delivery method: the current scaffold-based ASC delivery method may require further optimization or alternative delivery strategies may be needed to maintain ASC function and achieve efficacy in scaffold-based tissue engineering applications.