In brain tumor therapy, the key factor for improved patient outcome is complete resection.¹ Even though fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA)-induced protoporphyrin IX (PpIX) allows the surgeon to locate malignant tissue, its use is mostly limited to high-grade tumors.² As a consequence, current research has focused on more sensitive detection schemes to visualize fluorescence that is not visible to the surgeon’s eye. However, most of the proposed in vivo methods rely on endoscopic platforms with limited field of view (FOV).³ Hence, visualization methods with increased FOV and working distance (WD) are needed to inspect larger areas. More sensitive detection of PpIX fluorescence is limited among others by tissue autofluorescence. Therefore, spectrally resolved fluorescence imaging³ has been proposed to detect nonvisible PpIX accumulations. However, it relies on the knowledge or parallel measurement of the optical tissue properties. This requires additional measurement channels making these devices more complex. On the other hand, fluorescence lifetime imaging (FLIM) relies on the time delay between the excitation and subsequent fluorescence emission and is thereby intrinsically independent of any intensity variations due to altered scattering or absorption in the tissue.⁴

Fluorescence guided neurosurgery based on 5-aminolevulinic acid (5-ALA) has significantly increased maximal safe resections. Fluorescence lifetime imaging (FLIM) of 5-ALA could further boost this development by its increased sensitivity. However, neurosurgeons require real-time visual feedback which was so far limited in dual-tap CMOS camera based FLIM. By optimizing the number of phase frames required for reconstruction, we here demonstrate real-time 5-ALA FLIM of human high- and low-grade glioma with up to 12 Hz imaging rate over a wide field of view (11.0 x 11.0 mm). Compared to conventional fluorescence imaging, real-time FLIM offers enhanced contrast of weakly fluorescent tissue.

We present and validate a computationally efficient lower limb musculoskeletal model for the control of a rehabilitation robot. It is a parametric model that allows the customization of joint kinematics, and it is able to operate in real time. Methods: Since the rehabilitation exercises corresponds to low-speed movements, a quasi-static model can be assumed, and then muscle force coefficients are position dependent. This enables their calculation in an offline stage. In addition, the concept of a single functional degree of freedom is used to minimize drastically the workspace of the stored coefficients. Finally, we have developed a force calculation process based on Lagrange multipliers that provides a closed-form solution; in this way, the problem of dynamic indeterminacy is solved without the need to use an iterative process. Results: The model has been validated by comparing muscle forces estimated by the model with the corresponding electromyography (EMG) values using squat exercise, in which the Spearman’s correlation coefficient is higher than 0.93. Its computational time is lower than 2.5 ms in a conventional computer using MATLAB. Conclusions: This procedure presents a good agreement with the experimental values of the forces, and it can be integrated into real time control systems.

Precise intraoperative brain tumor visualization supports surgeons in achieving maximal safe resection. In this sense, improved prognosis in patients with high-grade gliomas undergoing protoporphyrin IX fluorescence-guided surgery has been demonstrated. Phase fluorescence lifetime imaging in the frequency-domain has shown promise to distinguish weak protoporphyrin IX fluorescence from competing endogenous tissue fluorophores, thus allowing for brain tumor detection with high sensitivity. In this work, we show that this technique can be further improved by minimizing the crosstalk of autofluorescence signal contributions when only detecting the fluorescence emission above 615 nm. Combining fluorescence lifetime and spectroscopic measurements on a set of 130 ex vivo brain tumor specimens (14 low- and 56 high-grade gliomas, 39 meningiomas and 21 metastases) coherently substantiated the resulting increase of the fluorescence lifetime with respect to the detection band employed in previous work. This is of major interest for obtaining a clear-cut distinction from the autofluorescence background of the physiological brain. In particular, the median fluorescence lifetime of low- and high-grade glioma specimens lacking visual fluorescence during surgical resection was increased from 4.7 ns to 5.4 ns and 2.9 ns to 3.3 ns, respectively. While more data are needed to create statistical evidence, the coherence of what was observed throughout all tumor groups emphasized that this optimization should be taken into account for future studies.