Optical absorption spectra and corresponding in vivo photoacoustic visualization of exposed peripheral nerves.

Significance: Multispectral photoacoustic imaging has the potential to identify lipid-rich, myelinated nerve tissue in an interventional or surgical setting (e.g., to guide intraoperative decisions when exposing a nerve during reconstructive surgery by limiting operations to nerves needing repair, with no impact to healthy or regenerating nerves). Lipids have two optical absorption peaks within the NIR-II and NIR-III windows (i.e., 1000 to 1350 nm and 1550 to 1870 nm wavelength ranges, respectively) which can be exploited to obtain photoacoustic images. However, nerve visualization within the NIR-III window is more desirable due to higher lipid absorption peaks and a corresponding valley in the optical absorption of water. Aim: We present the first known optical absorption characterizations, photoacoustic spectral demonstrations, and histological validations to support in vivo photoacoustic nerve imaging in the NIR-III window. Approach: Four in vivo swine peripheral nerves were excised, and the optical absorption spectra of these fresh ex vivo nerves were characterized at wavelengths spanning 800 to 1880 nm, to provide the first known nerve optical absorbance spectra and to enable photoacoustic amplitude spectra characterization with the most optimal wavelength range. Prior to excision, the latter two of the four nerves were surrounded by aqueous, lipid-free, agarose blocks (i.e., 3% w/v agarose) to enhance acoustic coupling during in vivo multispectral photoacoustic imaging using the optimal NIR-III wavelengths (i.e., 1630 to 1850 nm) identified in the ex vivo studies. Results: There was a verified characteristic lipid absorption peak at 1725 nm for each ex vivo nerve. Results additionally suggest that the 1630 to 1850 nm wavelength range can successfully visualize and differentiate lipid-rich nerves from surrounding water-containing and lipid-deficient tissues and materials. Conclusions: Photoacoustic imaging using the optimal wavelengths identified and demonstrated for nerves holds promise for detection of myelination in exposed and isolated nerve tissue during a nerve repair surgery, with possible future implications for other surgeries and other optics-based technologies.

Comparison of compressional and elastic wave simulations for patient-specific planning prior to transcranial photoacoustic-guided neurosurgery.

SIGNIFICANCE: Simulations have the potential to be a powerful tool when planning the placement of photoacoustic imaging system components for surgical guidance. While elastic simulations (which include both compressional and shear waves) are expected to more accurately represent the physical transcranial acoustic wave propagation process, these simulations are more time-consuming and memory-intensive than the compressional-wave-only simulations that our group previously used to identify optimal acoustic windows for transcranial photoacoustic imaging. AIM: We present qualitative and quantitative comparisons of compressional and elastic wave simulations to determine which option is more suitable for preoperative surgical planning. APPROACH: Compressional and elastic photoacoustic k-Wave simulations were performed based on a computed tomography volume of a human cadaver head. Photoacoustic sources were placed in the locations of the internal carotid arteries and likely positions of neurosurgical instrument tips. Transducers received signals from three previously identified optimal acoustic windows (i.e., the ocular, nasal, and temporal regions). Target detectability, image-based target size estimates, and target-to-instrument distances were measured using the generalized contrast-to-noise ratio (gCNR), resolution, and relative source distances, respectively, for each simulation method. RESULTS: The gCNR was equivalent between compressional and elastic simulations. The areas of the -6 dB contours of point spread functions utilized to measure resolution differed by 0.33 to 3.35 mm2. Target-to-instrument distance measurements were within 1.24 mm of the true distances. CONCLUSIONS: These results indicate that it is likely sufficient to utilize the less time-consuming, less memory-intensive compressional wave simulations for presurgical planning.

Simulations and human cadaver head studies to identify optimal acoustic receiver locations for minimally invasive photoacoustic-guided neurosurgery.

Real-time intraoperative guidance during minimally invasive neurosurgical procedures (e.g., endonasal transsphenoidal surgery) is often limited to endoscopy and CT-guided image navigation, which can be suboptimal at locating underlying blood vessels and nerves. Accidental damage to these critical structures can have severe surgical complications, including patient blindness and death. Photoacoustic image guidance was previously proposed as a method to prevent accidental injury. While the proposed technique remains promising, the original light delivery and sound reception components of this technology require alterations to make the technique suitable for patient use. This paper presents simulation and experimental studies performed with both an intact human skull (which was cleaned from tissue attachments) and a complete human cadaver head (with contents and surrounding tissue intact) in order to investigate optimal locations for ultrasound probe placement during photoacoustic imaging and to test the feasibility of a modified light delivery design. Volumetric x-ray CT images of the human skull were used to create k-Wave simulations of acoustic wave propagation within this cranial environment. Photoacoustic imaging of the internal carotid artery (ICA) was performed with this same skull. Optical fibers emitting 750 nm light were inserted into the nasal cavity for ICA illumination. The ultrasound probe was placed on three optimal regions identified by simulations: (1) nasal cavity, (2) ocular region, and (3) 1 mm-thick temporal bone (which received 9.2%, 4.7%, and 3.8% of the initial photoacoustic pressure, respectively, in simulations). For these three probe locations, the contrast of the ICA in comparative experimental photoacoustic images was 27 dB, 19 dB, and 12 dB, respectively, with delay-and-sum (DAS) beamforming and laser pulse energies of 3 mJ, 5 mJ, and 4.2 mJ, respectively. Short-lag spatial coherence (SLSC) beamforming improved the contrast of these DAS images by up to 15 dB, enabled visualization of multiple cross-sectional ICA views in a single image, and enabled the use of lower laser energies. Combined simulation and experimental results with the emptied skull and >1 mm-thick temporal bone indicated that the ocular and nasal regions were more optimal probe locations than the temporal ultrasound probe location. Results from both the same skull filled with ovine brains and eyes and the human cadaver head validate the ocular region as an optimal acoustic window for our current system setup, producing high-contrast (i.e., up to 35 dB) DAS and SLSC photoacoustic images within the laser safety limits of a novel, compact light delivery system design that is independent of surgical tools (i.e., a fiber bundle with 6.8 mm outer diameter, 2 mm-diameter optical aperture, and an air gap spacing between the sphenoid bone and fiber tips). These results are promising toward identifying, quantifying, and overcoming major system design barriers to proceed with future patient testing.

Expression of the TEL-Syk fusion protein in hematopoietic stem cells leads to rapidly fatal myelofibrosis in mice.

The TEL-Syk fusion protein was isolated from a patient with myelodysplasia with megakaryocyte blasts. Expression of TEL-Syk transforms interleukin-3 (IL-3)-dependent Ba/F3 cells in vitro by deregulating STAT5-mediated signal transduction pathways. In vivo, TEL-Syk expression in pre-B cells blocks B cell differentiation, leading to lymphoid leukemia. Here, we demonstrate that TEL-Syk introduced into fetal liver hematopoietic cells, which are then adoptively transferred into lethally irradiated recipients, leads to an aggressive myelodysplasia with myelofibrosis that is lethal in mice by 60-75 days. Expression of TEL-Syk induces a short-lived myeloexpansion that is rapidly followed by bone marrow failure and extreme splenic/hepatic fibrosis accompanied by extensive apoptosis. The disease is dependent on Syk kinase activity. Analysis of serum from TEL-Syk mice reveals an inflammatory cytokine signature reminiscent of that found in the sera from patients and mouse models of myeloproliferative neoplasms. TEL-Syk expressing cells showed constitutive STAT5 phosphorylation, which was resistant to JAK inhibition, consistent with deregulated cytokine signaling. These data indicate that expression of TEL-Syk in fetal liver hematopoietic cells results in JAK-independent STAT5 phosphorylation ultimately leading to a uniquely aggressive and lethal form of myelofibrosis.