## 2 Materials and Methods  
### Setup  
Figure 1 (left) shows a block schematic of the designed instrument. The core part is the probe, which embeds the eight SiPM channels. Each channel is a custom-made optode based on a SiPM, whose design, characterization, and preliminary in vivo use were already presented in Ref. [31]. To ensure uniform performances among channels, for this work we selected detectors (S13081-050 CS, Hamamatsu Photonics, Japan; active area of 1.3 \(\times\) 1.3 mm\({}^{2}\); for other specifications see [38]) that showed similar breakdown voltage (i.e., average value of 52.2 V, with a maximum dispersion around \(\pm\)100 mV among the various devices). A detailed characterization of the employed SiPMs is reported in [30]. The overall electronics that is needed to drive the detector is a small custom-designed Printed Circuit Board (PCB, dimension: 30 \(\times\) 6 mm) that is hosted inside a small plastic cap. As it is described in Ref. [31], the PCB embeds: (i) a passive network for the sensing of the avalanche signal generated inside the SiPM due to a single-photon absorption, (ii) a radio-frequency Monolithic Microwave Integrated Circuit (MMIC) amplifier that provides an amplified copy of the avalanche signal to the probe output, (iii) a capacitor network to stabilize the bias of both the detector and the MMIC, and (iv) micro coaxial connectors to interface the optode with the system. Optodes are held in place by means of a drilled neoprene plate, following a circular geometry where a source optical fiber is placed in the center and detectors are placed in a circular arrangement around the source (with source-detectorseparation--i.e., the radius of the circumference--of 3 cm) without using optical fibers. The choice of this radius has been piloted by simulations to obtain the best compromise between probed volume, spatial resolution, and signal-to-noise ratio of in vivo measurements. As a laser source, we employed a 689 nm wavelength pulsed diode laser (PDL 800, Picoquant GmbH, Berlin, Germany) working at a repetition frequency of 40 MHz and featuring an average output power of about 1 mW. The light is injected into the sample by means of a 100 \(\upmu\)m core optical fiber and the intensity is adjusted by a Neutral Density (indicated by n.d. in Figure 1) variable attenuator. Eight custom-designed signal converters PCBs translate the analog pulses of the SiPM probes (about 50 mV amplitude) into well detectable Low Voltage Transistor-Transistor Logic (LVTTL) signals. To reconstruct the Distribution of Time of Flights (DTOF) of photons, each converter output is connected to one input channel of a TDC (SC-TDC-1000/08S Surface Concept GmbH, Germany). The Nuclear Instrumentation Module standard laser synchronism is provided to the TDC using an additional signal converter to obtain a LVTTL signal. In this way, the eight channels simultaneously reconstruct the DTOF curves that are emitted by the sample where detectors are placed. The TDC is linked, thanks to a Universal Serial Bus 3.0 plug, to a personal computer, whose task it is to store and display the acquired data. Two benchtop power supply units provide all of the needed polarization voltages to the system: an 8 V voltage for the avalanche amplification network hosted on the probe and a 58 V supply to bias the detectors 5.8 V above their breakdown voltage. Finally, a small fixed-voltage enclosed power supply module provides the \(\pm\)5 V supplies that are required by the LVTTL translator boards. Figure 1 (right) shows a picture of the overall system. It is worth appreciating the extremely compact dimensions of the eight-channel system (for further detail about the size of the building blocks see Table 1), which can of course be further squeezed by designing custom power supply modules instead of using benchtop devices.