When Can a Learned Design Surrogate Be Trusted in a Self-Driving Microfluidics Laboratory? An Offline Closed-Loop Framework Built and Tested on Six Public Tables

Zhiyuan Zhang

Self-driving laboratories couple a learned design surrogate to an instrument, and on every new target domain it must answer four questions: when it can be trusted, how many target measurements it needs, which to make first, and when to stop adapting, switch models or escalate. We state a framework making each measurable (a competence ratio, a budget $k^*(\varepsilon)$, a time-to-target and a priced decision) and instantiate it without wet experiments on six public droplet-microfluidic and liposome tables as offline laboratories: 107 leave-one-group tiers whose rows are hidden labels. A sealed, pre-registered programme (two sealed negative validations and a pre-registered test on three more tables) and seven frozen closed-loop protocols, each run twice, yield 23 findings. Shift cost is stratified by shift type; no label-free statistic certifies individual candidates; random-split model-family rankings predicted neither the sealed nor the loop rankings. Warm-start residual boosting returns a surrogate to $1.25\times$ its development reference within 20 target rows in 94% of chemistry tiers (27% under a strict noise-floor reading), 90% of laboratory and 40% of device tiers, and a…