Performance improvements in instrumentation for optical imaging have contributed greatly to molecular imaging in living subjects. In order to advance molecular imaging in freely moving, untethered subjects, we designed a miniature vertical-cavity surface-emitting laser (VCSEL)-based biosensor measuring 1cm 3 and weighing 0.7g that accurately detects both fluorophore and tumor-targeted molecular probes in small animals. We integrated a critical enabling component, a complementary metal-oxide semiconductor (CMOS) read-out integrated circuit, which digitized the fluorescence signal to achieve autofluorescence-limited sensitivity. After surgical implantation of the lightweight sensor for two weeks, we obtained continuous and dynamic fluorophore measurements while the subject was un-anesthetized and mobile. The technology demonstrated here represents a critical step in the path toward untethered optical sensing using an integrated optoelectronic implant. ©2013 Optical Society of America

Optical molecular imaging is emerging as a powerful preclinical research tool for investigating and quantifying molecular events in living subjects, with applications including earlier detection of disease, therapeutic monitoring and understanding fundamental biology [1]. For example, imaging the fluorescent molecular probe RGD-Cy5.5, which specifically binds to molecules (α v β 3 integrin receptors) that regulate new blood vessel growth in tumors, can be used to quantify this growth [2]. Capturing the fluorescent signal in living subjects with an implanted biosensor would enable continuous monitoring of tumors in freely moving subjects. Continuous monitoring in the setting of cancer would give valuable information on tumor progression, both in assessing drug efficacy and detecting recurrent tumor growth after treatment. Presently, fluorescence imaging in living subjects is performed with bulky instrumentation that does not permit continuous monitoring of freely moving subjects over long time periods. In order to make a fluorescence-detection system implantable, and portable, a laser excitation source, a photodetector and a readout circuit for measuring and digitizing photocurrents are integrated in a single package, and continuous fluorescence detection is demonstrated in live animals. This paper introduces a readout circuit designed to interface with the fluorescence sensor presented in [3], a monolithically integrated GaAs detector and vertical-cavity surface-emitting laser (VCSEL). The detector signals to be measured are low currents in the range of 5pA to 15nA, with bandwidths up to 100Hz. In order to capture binding dynamics of the fluorescent probe, as well as a wide range of possible tumor sizes and depths, the desired current resolution is 5pA.In applications with such low bandwidths and high sensitivity, a capacitive transimpedance amplifier (CTIA) can be used to provide high SNR through noise averaging [4]. The input current is integrated onto a capacitor C int for a period of time T int . The output of the CTIA is usually sampled and held at the end of T int , before being digitized as a DC signal. The readout noise power introduced at the sampling instant, σ 2 read , limits the maximum achievable SNR of this architecture. If, instead, M samples are taken along the integration ramp and line-fitting is performed, the white noise component of σ 2 read is reduced by M/12, as shown in [5]. Figure 17.5.1 shows our readout system architecture, where ΔΣ modulation is used to acquire and digitize samples taken up the integration ramp. The output of a CTIA is sampled by an incremental ΔΣ modulator, without the need for a sample-and-hold stage at the CTIA output. Before each integration cycle, both the CTIA and the ΔΣ modulator are reset. After reset, the detector current accumulates on C int , giving rise to a voltage ramp at the amplifier's output. This ramp is sampled by the ΔΣ modulator M times during the integration period, such that M=T int f ΣΔ , where f ΣΔ is the sampling frequency of the modulator. The...