fabrication-an-expandable-brain-matrix-customizable-across

Fabrication of an Expandable Brain Matrix Customizable Across Developmental Stages

Increasing interest in using newborn piglets as a study model for neonatal development and pathology has raised the need for a brain matrix to accurately ...

University of Kentucky

We report a low-cost compact diffuse speckle contrast flowmeter (DSCF) consisting of a small laser diode and a bare charge-coupled-device (CCD) chip, which can be used for contact measurements of blood flow variations in relatively deep tissues (up to ∼ 8  mm). Measurements of large flow variations by the contact DSCF probe are compared to a noncontact CCD-based diffuse speckle contrast spectroscopy and a standard contact diffuse correlation spectroscopy in tissue phantoms and a human forearm. Bland–Altman analysis shows no significant bias with good limits of agreement among these measurements: 96.5%±2.2% (94.4% to 100.0%) in phantom experiments and 92.8% in the forearm test. The relatively lower limit of agreement observed in the in vivo measurements (92.8%) is likely due to heterogeneous reactive responses of blood flow in different regions/volumes of the forearm tissues measured by different probes. The low-cost compact DSCF device holds great potential to be broadly used for continuous and longitudinal monitoring of blood flow alterations in ischemic/hypoxic tissues, which are usually associated with various vascular diseases.

Low-cost compact diffuse speckle contrast flowmeter using small laser diode and bare charge-coupled-device.

A noncontact electron multiplying charge-coupled-device (EMCCD)-based speckle contrast diffuse correlation tomography (scDCT) technology has been recently developed in our laboratory, allowing for noninvasive three-dimensional measurement of tissue blood flow distributions. One major remaining constraint in the scDCT is the assumption of a semi-infinite tissue volume with a flat surface, which affects the image reconstruction accuracy for tissues with irregular geometries. An advanced photometric stereo technique (PST) was integrated into the scDCT system to obtain the surface geometry in real time for image reconstruction. Computer simulations demonstrated that a priori knowledge of tissue surface geometry is crucial for precisely reconstructing the anomaly with blood flow contrast. Importantly, the innovative integration design with one single-EMCCD camera for both PST and scDCT data collection obviates the need for offline alignment of sources and detectors on the tissue boundary. The in vivo imaging capability of the updated scDCT is demonstrated by imaging dynamic changes in forearm blood flow distribution during a cuff-occlusion procedure. The feasibility and safety in clinical use are evidenced by intraoperative imaging of mastectomy skin flaps and comparison with fluorescence angiography.

Noncontact speckle contrast diffuse correlation tomography of blood flow distributions in tissues with arbitrary geometries.

Continuous and longitudinal imaging of cerebral blood flow (CBF) variations provide vital information to investigate pathophysiology and interventions for a variety of neurological and cerebral diseases. An innovative noncontact speckle contrast diffuse correlation tomography (scDCT) system was downscaled and adapted for noninvasive imaging of CBF distributions in rat brain through intact scalp and skull. Algorithms for 2D mapping and 3D image reconstruction of CBF distributions were developed and optimized. The continuous imaging capability of the system was shown by imaging global CBF increases during CO inhalations and regional CBF decreases across two hemispheres during sequential unilateral and bilateral common carotid artery ligations. The longitudinal imaging capability was demonstrated by imaging CBF variations over a long recovery period of 14 days after an acute stroke. Compared to the 2D mapping method, the 3D imaging method reduces partial volume effects, but needs more computation time for image reconstruction. Results from this study generally agree with those reported in the literature using similar protocols to induce CBF changes in rats. The scDCT enables a relatively large penetration depth (up to ∼10 mm), which is sufficient for transcranial brain measurements in small animals and human neonates. Ultimately, we expect to provide a noninvasive noncontact cerebral imager for basic neuroscience research in small animal models and clinical applications in human neonates.

Noninvasive noncontact speckle contrast diffuse correlation tomography of cerebral blood flow in rats.

The Role of Intraoperative Laser Speckle Imaging in Reducing Postoperative Complications in Breast Reconstruction.

Tissue injuries are often associated with abnormal blood flow (BF). The ability to assess BF distributions in injured tissues enables objective evaluation of interventions and holds the potential to improve the acute management of these injuries on battlefield.

Noncontact Speckle Contrast Diffuse Correlation Tomography of Blood Flow Distributions in Burn Wounds: A Preliminary Study.

Extremely preterm infants' hemodynamic instability places them at high risk of brain injury. Currently there is no reliable bedside method to continuously monitor cerebral hemodynamics in the neonatal intensive care unit (NICU). This paper reports a feasibility study to adapt and test an innovative speckle contrast diffuse correlation tomography (scDCT) device for noncontact, high-density, 3D imaging of cerebral blood flow (CBF) in preterm infants. The scDCT scans a focused point near-infrared illumination to multiple source positions for deep tissue penetration, and controls an electron multiplying charge-coupled-device camera with thousands of pixels to achieve a high-density sampling. The optimized scDCT for use in preterm infants was first evaluated against an established diffuse correlation spectroscopy in an infant-head-simulating phantom with known properties. The observed significant correlation between the two measurements verified the capability of scDCT for transcranial brain imaging. The insignificant influence of transparent incubator wall on scDCT measurements was then confirmed by comparing adult forearm blood flow responses to artery cuff occlusions measured inside and outside the incubator. Finally, the scDCT device was moved to the NICU to image CBF variations in two preterm infants. Infant #1 with no major organ deficits showed little CBF fluctuation over the first 3 weeks of life. Infant #2 showed a significant CBF increase after the 2 h pharmacotherapy for patent ductus arteriosus closure. While these CBF variations meet physiological expectations, the fact that no significant changes are noted with peripheral monitoring of blood oxygen saturation suggests necessity of direct cerebral monitoring. This feasibility study with timely technology development is an important and necessary step towards larger clinical studies with more subjects to further validate it for continuous monitoring and instant management of cerebral pathologies and interventions in the NICU.

Noncontact optical imaging of brain hemodynamics in preterm infants: a preliminary study.

We adapted and tested an innovative noncontact speckle contrast diffuse correlation tomography (scDCT) system for 3D imaging of cerebral blood flow (CBF) variations in perinatal disease models utilizing neonatal piglets, which closely resemble human neonates. CBF variations were concurrently measured by the scDCT and an established diffuse correlation spectroscopy (DCS) during global ischemia, intraventricular hemorrhage, and asphyxia; significant correlations were observed. Moreover, CBF variations associated reasonably with vital pathophysiological changes. In contrast to DCS measurements of mixed signals from local scalp, skull and brain, scDCT generates 3D images of CBF distributions at prescribed depths within the head, thus enabling specific determination of regional cerebral ischemia. With further optimization and validation in animals and human neonates, scDCT has the potential to be a noninvasive imaging tool for both basic neuroscience research in laboratories and clinical applications in neonatal intensive care units.

Speckle contrast diffuse correlation tomography of cerebral blood flow in perinatal disease model of neonatal piglets.

Measurement of blood flow in tissue provides vital information for the diagnosis and therapeutic monitoring of various vascular diseases. A noncontact, camera-based, near-infrared speckle contrast diffuse correlation tomography (scDCT) technique has been recently developed for 3D imaging of blood flow index (αD) distributions in deep tissues up to a centimeter. A limitation with the continuous-wave scDCT measurement of blood flow is the assumption of constant and homogenous tissue absorption coefficient (  ). The present study took the advantage of rapid, high-density, noncontact scDCT measurements of both light intensities and diffuse speckle contrast at multiple source-detector distances and developed two-step fitting algorithms for extracting both   and αD. The new algorithms were tested in tissue-simulating phantoms with known optical properties and human forearms. Measurement results were compared against established near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) techniques. The accuracies of our new fitting algorithms with scDCT measurements in phantoms (up to 16% errors) and forearms (up to 23% errors) are comparable to relevant study results (up to 25% errors). Knowledge of   not only improved the accuracy in calculating αD but also provided the potential for quantifying tissue blood oxygenation via spectral measurements. A multiple-wavelength scDCT system with new algorithms is currently developing to fit multi-wavelength and multi-distance data for 3D imaging of both blood flow and oxygenation distributions in deep tissues.

Extraction of tissue optical property and blood flow from speckle contrast diffuse correlation tomography (scDCT) measurements.

Insufficient blood flow causes mastectomy skin flap necrosis in 5 to 30 percent of cases. Fluorescence angiography with the injection of indocyanine green dye has shown high sensitivities (90 to 100 percent) but moderate specificities (72 to 50 percent) in predicting mastectomy skin flap necrosis. However, a number of challenging issues limit its wide acceptance in clinical settings, including allergic reaction, short time-window for observation, and high cost for equipment and supplies. An emerging inexpensive speckle contrast diffuse correlation tomography technology enables noninvasive, noncontact, and continuous three-dimensional imaging of blood flow distributions in deep tissues. This preliminary study tested the hypothesis that speckle contrast diffuse correlation tomography and indocyanine green-fluorescence angiography measurements of blood flow distributions in mastectomy skin flaps are consistent. Eleven female patients undergoing skin-sparing or nipple-sparing mastectomies were imaged sequentially by the dye-free speckle contrast diffuse correlation tomography and dye-based commercial fluorescence angiography (SPY-PHI). Resulting images from these two imaging modalities were co-registered based on the ischemic areas with the lowest blood flow values. Because the ischemic areas have irregular shapes, a novel contour-based algorithm was used to compare three-dimensional images of blood flow distribution and two-dimensional maps of indocyanine green perfusion. Significant correlations were observed between the two measurements in all contours from a selected area of 10 × 10 mm 2 with the lowest blood flow ( r ≥ 0.78; p < 0.004), suggesting that speckle contrast diffuse correlation tomography provides the information for identifying ischemic tissues in mastectomy skin flaps. With further optimization and validation in large populations, speckle contrast diffuse correlation tomography may ultimately be used as a noninvasive and inexpensive imaging tool for intraoperative assessment of skin flap viability to predict mastectomy skin flap necrosis.

Intraoperative Optical and Fluorescence Imaging of Blood Flow Distributions in Mastectomy Skin Flaps for Identifying Ischemic Tissues.

Malignant glioma (MG) is the most common type of primary malignant brain tumors. Surgical resection of MG remains the cornerstone of therapy and the extent of resection correlates with patient survival. A limiting factor for resection, however, is the difficulty in differentiating the tumor from normal tissue during surgery. Fluorescence imaging is an emerging technique for real-time intraoperative visualization of MGs and their boundaries. However, most clinical grade neurosurgical operative microscopes with fluorescence imaging ability are hampered by low adoption rates due to high cost, limited portability, limited operation flexibility, and lack of skilled professionals with technical knowledge. To overcome the limitations, we innovatively integrated miniaturized light sources, flippable filters, and a recording camera to the surgical eye loupes to generate a wearable fluorescence eye loupe (FLoupe) device for intraoperative imaging of fluorescent MGs. Two FLoupe prototypes were constructed for imaging of Fluorescein and 5-aminolevulinic acid (5-ALA), respectively. The wearable FLoupe devices were tested on tumor-simulating phantoms and patients with MGs. Comparable results were observed against the standard neurosurgical operative microscope (PENTERO® 900) with fluorescence kits. The affordable and wearable FLoupe devices enable visualization of both color and fluorescence images with the same quality as the large and expensive stationary operative microscopes. The wearable FLoupe device allows for a greater range of movement, less obstruction, and faster/easier operation. Thus, it reduces surgery time and is more easily adapted to the surgical environment than unwieldy neurosurgical operative microscopes. Clinical and Translational Impact Statement-The affordable and wearable fluorescence imaging device developed in this study enables neurosurgeons to observe brain tumors with the same clarity and greater flexibility compared to bulky and costly operative microscopes.

A Wearable Fluorescence Imaging Device for Intraoperative Identification of Human Brain Tumors.

Low-frequency oscillations (LFOs) (  ) with respect to cerebral blood flow (CBF) have shown promise as an indicator of altered neurologic activity in the abnormal brain. Portable optical instruments have evolved to offer a noninvasive alternative for continuous CBF monitoring at the bedside compared with many large neuroimaging modalities. However, their utilization for acquiring LFOs of CBF has only been studied to a limited extent.

Article	Year
Low-cost compact diffuse speckle contrast flowmeter using small laser diode and bare charge-coupled-device. Journal of biomedical optics\| PubMed ID: 27533437	2016
Noncontact speckle contrast diffuse correlation tomography of blood flow distributions in tissues with arbitrary geometries. Journal of biomedical optics\| PubMed ID: 30251483	2018
Noninvasive noncontact speckle contrast diffuse correlation tomography of cerebral blood flow in rats. NeuroImage\| PubMed ID: 31112789	2019
The Role of Intraoperative Laser Speckle Imaging in Reducing Postoperative Complications in Breast Reconstruction. Plastic and reconstructive surgery\| PubMed ID: 31425417	2019
Noncontact Speckle Contrast Diffuse Correlation Tomography of Blood Flow Distributions in Burn Wounds: A Preliminary Study. Military medicine\| PubMed ID: 31498406	2020
Noncontact optical imaging of brain hemodynamics in preterm infants: a preliminary study. Physics in medicine and biology\| PubMed ID: 33113516	2020
Speckle contrast diffuse correlation tomography of cerebral blood flow in perinatal disease model of neonatal piglets. Journal of biophotonics\| PubMed ID: 33295142	2021
Extraction of tissue optical property and blood flow from speckle contrast diffuse correlation tomography (scDCT) measurements. Biomedical optics express\| PubMed ID: 34692223	2021
Intraoperative Optical and Fluorescence Imaging of Blood Flow Distributions in Mastectomy Skin Flaps for Identifying Ischemic Tissues. Plastic and reconstructive surgery\| PubMed ID: 35653513	2022
A Wearable Fluorescence Imaging Device for Intraoperative Identification of Human Brain Tumors. IEEE journal of translational engineering in health and medicine\| PubMed ID: 38196823	2024
Detection of low-frequency oscillations in neonatal piglets with speckle contrast diffuse correlation tomography. Journal of biomedical optics\| PubMed ID: 40060305	2023

Siavash Mazdeyasna

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