Flow-based microfluidic biochips are attracting increasing attention with successful biomedical applications. One critical issue with flow-based microfluidic biochips is the large number of microvalves that require peripheral control pins. Even using the broadcasting addressing scheme, i.e., one control pin controls multiple microvalves simultaneously, thousands of microvalves would still require hundreds of control prins, which is unrealistic. To address this critical challenge in control scalability, the control-layer multiplexer is introduced to effectively reduce the number of control pins into log scale of the number of microvalves. There are two practical design issues with the control-layer multiplexer: (1) the reliability issue caused by the frequent control-valve switching, and (2) the pressure degradation problem caused by the control-valve switching without pressure refreshing from the pressure source. This paper addresses these two design issues by the proposed Hamming-distance-based switching sequence optimization method and the XOR-based pressure refreshing method. Simulation results demonstrate the effectiveness and efficiency of the proposed methods with an average 77.2% (maximum 89.6%) improvement in total pressure refreshing cost, and an average 88.5% (maximum 90.0%) improvement in pressure deviation.