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 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.

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.

Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study aims to assess the influence and evaluate the predictive ability of IH measures on Type 1 ROP, a stage beyond which ROP treatment is indicated.

The Impact of Intermittent Hypoxemia on Type 1 Retinopathy of Prematurity in Preterm Infants.

Frequent assessment of cerebral blood flow (CBF) is crucial for the diagnosis and management of cerebral vascular diseases. In contrast to large and expensive imaging modalities, such as nuclear medicine and magnetic resonance imaging, optical imaging techniques are portable and inexpensive tools for continuous measurements of cerebral hemodynamics. The recent development of an innovative noncontact speckle contrast diffuse correlation tomography (scDCT) enables three-dimensional (3D) imaging of CBF distributions. However, scDCT requires complex and time-consuming 3D reconstruction, which limits its ability to achieve high spatial resolution without sacrificing temporal resolution and computational efficiency.

Depth-sensitive diffuse speckle contrast topography for high-density mapping of cerebral blood flow in rodents.

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.

Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants.

Wearable fiber-free optical sensor for continuous monitoring of neonatal cerebral blood flow and oxygenation.

Intermittent hypoxemia (IH) may influence retinopathy of prematurity (ROP) development in preterm infants, however, previous studies had mixed results. This study tests the hypothesis that increased IH is associated with Type 1 ROP; a stage beyond which treatment is indicated.

The impact of intermittent hypoxemia on type 1 retinopathy of prematurity in preterm infants.

Cerebral blood flow (CBF) imaging is crucial for diagnosing cerebrovascular diseases. However, existing large neuroimaging techniques with high cost, low sampling rate, and poor mobility make them unsuitable for continuous and longitudinal CBF monitoring at the bedside.

Programmable scanning diffuse speckle contrast imaging of cerebral blood flow.

Measuring cerebral blood flow (CBF) is crucial for diagnosing various cerebral diseases. An affordable, wearable, and fiber-free continuous-wave speckle contrast flowmetry (CW-DSCF) technique has been developed for continuous monitoring of CBF variations. However, its application in adult humans is limited by shallow tissue penetration.

An affordable, wearable, fiber-free pulsed-mode diffuse speckle contrast flowmetry (PM-DSCF) sensor for noninvasive measurements of deep cerebral blood flow.

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.

Detection of low-frequency oscillations in neonatal piglets with speckle contrast diffuse correlation tomography.

Continuous monitoring of cerebral blood flow (CBF) with high spatiotemporal resolution and depth sensitivity is essential for accurate diagnosis and effective management of neurological disorders. Although conventional laser speckle contrast imaging (LSCI) enables widefield, high-resolution CBF mapping, its limited penetration depth and signal integration across all tissue layers hinder depth-resolved imaging. To address these limitations, we developed an advanced time-resolved LSCI (TR-LSCI) system that employs picosecond-pulsed laser illumination and a customized SPAD512 camera operating in gated mode, enabling noncontact, widefield, and depth-sensitive CBF imaging. However, photon scattering and diffusive noise still degrade image quality, particularly at greater depths. To overcome this challenge, we incorporated a multiscale latent diffusion model (LTDiff++) into the TR-LSCI analysis pipeline to suppress photon diffusion noise. Trained and validated using overlapping image patches from head-simulating phantoms and neonatal rat CBF images with high-quality ground truth references, LTDiff++ effectively suppressed photon diffusion noise while preserving structural and vascular features at greater imaging depths. Moreover, in vivo studies demonstrated that LTDiff++ maintained image quality using only 5-frame averaging, reducing acquisition time by a factor of 20 compared to the conventional 100-frame averaging approach without deep learning enhancement. The integrated TR-LSCI and LTDiff++ framework thus enables robust, high-speed, and depth-resolved imaging of cerebral hemodynamics, offering a promising platform for preclinical research and future clinical applications in bedside neuroimaging and patient monitoring.

Using the latent diffusion model to enhance time-resolved laser speckle contrast imaging (TR-LSCI) of cerebral blood flow.

Continuous and longitudinal monitoring of cerebral blood flow (CBF) is critical for understanding brain pathophysiology and guiding interventions. Although rodents are the primary models in neuroscience, existing imaging modalities often fail to provide the optimal combination of low cost, high spatiotemporal resolution, wide head coverage, and sufficient penetration depth for small-animal brain imaging.

Affordable miniaturized speckle contrast diffuse correlation tomography device for depth-sensitive mapping of cerebral blood flow in rodents.

Perioperative identification of ischemic-hypoxic tissue is essential for reducing the risk of mastectomy skin flap necrosis (MSFN), a major complication following mastectomy. Implant-based breast reconstruction is jeopardized in the presence of MSFN. However, existing technologies are limited by depth insensitivity, dye-related risks, the need for contact sensors, and an inability to simultaneously assess both blood flow and oxygenation. A multi-wavelength speckle contrast diffuse correlation tomography (MW-scDCT) system was developed for noncontact, dye-free, and depth-sensitive imaging of tissue hemodynamics in a rat model incorporating four distinct flap scenarios: sham (SH), implant (IM), half necrosis (HN), and full necrosis (FN), representing varying degrees of tissue viability. MW-scDCT measured longitudinal changes in relative blood flow index (  ) and oxy- and deoxy-hemoglobin concentrations (  and  ) over seven days. Repeated measures analysis of variance and quadratic discriminant analysis were employed for statistical analysis. MW-scDCT enabled longitudinal imaging of tissue blood flow and oxygenation distributions, revealing significant differences across flap types and over time. In terms of discriminative power, integrating  ,  , and  into a multivariable classification model substantially improved accuracy, achieving 80-95% compared to 40-70% using individual parameters. Binary classification of necrotic (FN + HN) versus non-necrotic (SH + IM) flaps showed up to 50% improvement in accuracy gains. MW-scDCT effectively distinguished necrotic from viable flaps and provided critical early postoperative insights into MSFN. These findings support its potential clinical utility as a perioperative monitoring tool to guide decision-making, reduce flap failure risk, and improve reconstructive outcomes.

Article	Year
Speckle contrast diffuse correlation tomography of cerebral blood flow in perinatal disease model of neonatal piglets. Journal of biophotonics\| PubMed ID: 33295142	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
The Impact of Intermittent Hypoxemia on Type 1 Retinopathy of Prematurity in Preterm Infants. medRxiv : the preprint server for health sciences\| PubMed ID: 37808800	2023
Depth-sensitive diffuse speckle contrast topography for high-density mapping of cerebral blood flow in rodents. Neurophotonics\| PubMed ID: 38076725	2023
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
Wearable fiber-free optical sensor for continuous monitoring of neonatal cerebral blood flow and oxygenation. Pediatric research\| PubMed ID: 38503982	2024
The impact of intermittent hypoxemia on type 1 retinopathy of prematurity in preterm infants. Pediatric research\| PubMed ID: 38600299	2024
Programmable scanning diffuse speckle contrast imaging of cerebral blood flow. ArXiv\| PubMed ID: 39253639	2024
Programmable scanning diffuse speckle contrast imaging of cerebral blood flow. Neurophotonics\| PubMed ID: 39872020	2025
An affordable, wearable, fiber-free pulsed-mode diffuse speckle contrast flowmetry (PM-DSCF) sensor for noninvasive measurements of deep cerebral blood flow. ArXiv\| PubMed ID: 39990801	2025
Detection of low-frequency oscillations in neonatal piglets with speckle contrast diffuse correlation tomography. Journal of biomedical optics\| PubMed ID: 40060305	2023
Using the latent diffusion model to enhance time-resolved laser speckle contrast imaging (TR-LSCI) of cerebral blood flow. Biomedical optics express\| PubMed ID: 41112794	2025
Affordable miniaturized speckle contrast diffuse correlation tomography device for depth-sensitive mapping of cerebral blood flow in rodents. Journal of biomedical optics\| PubMed ID: 41140550	2025
Noncontact diffuse optical imaging of blood flow and oxygenation distributions in reconstructive rat skin flaps. Biomedical optics express\| PubMed ID: 41368087	2025

Mehrana Mohtasebi

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