## Appendix A PLGA: Poly(lactic-co-glycolic acid)  
Figure 12: Chemical structure of PLGA (**A**) and cartoon (**B**) suggesting how the PLGA/gelatin mix might resemble. (**A**) Structure of PLGA. (**B**) Tight and dense nano-fibrous structure of embedded gelatin on PLGA fibers. The interaction between the two polymers is non-covalent. The uniform distribution of the gelatin allows the formation of a biodegradable MC with cell adhesion suitable surfaces. During these studies, we had the opportunity to understand the drawbacks of biodegradable PLGA based MCs. First, lactic acid is continuously released from this MC type during the cell culture procedure and adds to that secreted by cells. Indeed, as shown in Table 4, we measured about three times more lactic acid when the ASC52 telo were grown on _BR44_ (qLac: \(\sim\)138 pmol/cell/d) compared to the value found when ProNectin-F MCs (coated polystyrene microsphere, qLac: \(\sim\)41 pmol/cell/d) were used for the experiments. Lactic acid can inhibit cell growth [44]: ASC52 telo growing on _BR44_ could experience a much higher local lactic acid concentration than the cells cultured on ProNectin-F MCs. Therefore, this could explain the lower growth rate and the higher doubling time of a _BR44_ MC-based culture compared to one dependent on ProNectin-F MCs. The type of MC used to culture the ASC52 telo cells influences their metabolism. Indeed, with _BR44_, there is also a higher ammonia production per cell and per day. It is known that a low level of ammonia in the cell culture medium inhibits cell growth. This, together with the lactic acid production, could explain the lower cell yield obtained with MC _BR44_. Second, the _BR44_ MC is more challenging to handle than the synthetic ProNectin-F counterpart since it easily sticks to pipettes and other equipment commonly used in the laboratory to transport or measure a powder or a liquid. However, we noticed that this characteristic is also shared by other MCs manufactured with organic or biological polymers, such as Culisipere S and G, Cytodex 3, and Celnest' Macroporous MCs (Fujifilm). This problem can be alleviated by using \"low retention\" (Repel Polymer Technology, RPT) tips and pipettes. Third, this innate propensity, typical for MCs with a biopolymer core to stick together, is also maintained in culture with cells. Thus, even under dynamic conditions, this can lead to the formation of large aggregates. Therefore, it is necessary to optimize the stirring conditions to reduce this phenomenon, which may lead to a decrease in cell density due to the limitation in the diffusion of nutrients to the center of large cell-MC clusters. Therefore, MCs with a biopolymer core require a more laborious setup concerning the seeding densities and the agitation parameters compared to classic MCs with a synthetic core. Fourth, despite the sedimentation velocity of the _BR44_ being excellent (\(\approx\)0.63 mm/s) and comparable to the commercial MC ProNectin-F (\(\approx\)1.46 mm/s), the impeller speed necessary to keep the _BR44_ in suspension was up to 2.1-fold higher than the one used for the MC ProNectin-F. [PERSON] et al. [39, 69] have recently shown that cells start to experience increased hydrodynamic stress above a specific impeller speed, which leads to a significant decrease in the specific growth rate. Thus, together with the higher concentration of lactate and ammonia, this observation can explain the decreased cell yield when the _BR44_ is used to culture ASC52 telo cells. A possible explanation for this observation is that _BR44_ is very porous and has an irregular shape. This could increase the hydrodynamic drag and require a higher impeller speed to keep the carriers in suspension. Finally, while synthetic MCs, such as ProNectin-F, have perfectly spherical, smooth, and are all approximately the same size, those made with organic or biological polymers often have an irregular shape, inhomogeneous dimensions, and can be very porous (see Figures S2 and S3).