Yu Hang Liu

Encapsulated Conjugated Oligomer Nanoparticles for Real-Time Photoacoustic Sentinel Lymph Node Imaging and Targeted Photothermal Therapy.

Noninvasive and nonionizing imaging of sentinel lymph nodes (SLN) is highly desirable for the detection of breast cancer metastasis through sentinel lymph node biopsy. Photoacoustic (PA) imaging is an emerging imaging technique that can serve as a suitable approach for SLN imaging. Herein, novel conjugated oligomer based nanoparticles (NPs) with strong NIR absorption, good biocompatibility, excellent PA contrast, and good photothermal conversion efficiency are reported. Real-time PA imaging of SLN reveals high resolution of the NPs via injection from the left forepaw pad. In addition, the surface functionalized NPs can target breast cancer cells and kill them efficiently and specifically through photothermal therapy upon 808 nm laser irradiation. This work shows great potential of the nanoparticle PA contrast agent to serve as a multifunctional probe for photothermal therapy at SLNs to achieve the inhibition of cancer cell metastasis in the near future.

Progress of Flexible Electronics in Neural Interfacing - A Self-Adaptive Non-Invasive Neural Ribbon Electrode for Small Nerves Recording.

A novel flexible neural ribbon electrode with a self-adaptive feature is successfully implemented for various small nerves recording. As a neural interface, the selective recording capability is characterized by having reliable signal acquisitions from the sciatic nerve and its branches such as the peroneal nerve, the tibial nerve, and the sural nerve.

Rescue of cortical neurovascular functions during the hyperacute phase of ischemia by peripheral sensory stimulation

To investigate the potential therapeutic effects of peripheral sensory stimulation during the hyperacute phase of stroke, the present study utilized electrophysiology and photoacoustic imaging techniques to evaluate neural and vascular responses of the rat cortex following ischemic insult. We employed a rat model of photothrombotic ischemia (PTI), which targeted the forelimb region of the primary somatosensory cortex (S1FL), due to its high reproducibility in creating localized ischemic injury. We also established a hybrid, dual-modality system, including six-channel electrocorticography (ECoG) and functional photoacoustic microscopy (fPAM), termed ECoG-fPAM, to image brain functional responses to peripheral sensory stimulation during the hyperacute phase of PTI. Our results showed that the evoked cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) recovered to 84±7.4% and 79±6.2% of the baseline, respectively, when stimulation was delivered within 2.5 h following PTI induction. Moreover, neural activity significantly recovered, with 77±8.6%, 76±5.3% and 89±8.2% recovery for the resting-state inter-hemispheric coherence, alpha-to-delta ratio (ADR) and somatosensory evoked potential (SSEP), respectively. Additionally, we integrated the CBV or SO2 with ADR values as a recovery indicator (RI) to assess functional recovery after PTI. The RI indicated that 80±4.2% of neurovascular function was preserved when stimulation was delivered within 2.5h. Additionally, stimulation treatment within this optimal time window resulted in a minimal infarct volume in the ischemic hemisphere (4.6±2.1%). In contrast, the infarct volume comprised 13.7±1.7% of the ischemic hemisphere when no stimulation treatment was applied.

Improving neurovascular outcomes with bilateral forepaw stimulation in a rat photothrombotic ischemic stroke model

Abstract. Restoring perfusion to the penumbra during the hyperacute phase of ischemic stroke is a key goal of neuroprotection. Thrombolysis is currently the only approved treatment for ischemic stroke. However, its use is limited by the narrow therapeutic window and side effect of bleeding. Therefore, other interventions are desired that could potentially increase the perfusion of the penumbra. Here, we hypothesized that bilateral peripheral electrical stimulation will improve cerebral perfusion and restore cortical neurovascular response. We assess the outcomes of bilateral forepaw electrical stimulation at intensities of 2 and 4 mA, administered either unilaterally or bilaterally. We developed a combined electrocorticogram (ECoG)-functional photoacoustic microscopy (fPAM) system to evaluate the relative changes in cerebral hemodynamic function and electrophysiologic response to acute, focal stroke. The fPAM system is used for cerebral blood volume (CBV) and hemoglobin oxygen saturation (SO2) and the ECoG for neural activity, namely somatosensory-evoked potential (SSEP), interhemispheric coherence, and alpha-delta ratio (ADR) in response to forepaw stimulation. Our results confirmed the neuroprotective effect of bilateral forepaw stimulation at 2 mA as indicated by the 82% recovery of ADR and 95% improvement in perfusion into the region of penumbra. This experimental model can be used to study other potential interventions such as therapeutic hypertension and hypercarbia.

Enhanced near-infrared photoacoustic imaging of silica-coated rare-earth doped nanoparticles

Near-infrared photoacoustic (PA) imaging is an emerging diagnostic technology that utilizes the tissue transparent window to achieve improved contrast and spatial resolution for deep tissue imaging. In this study, we investigated the enhancement effect of the SiO2 shell on the PA property of our core/shell rare-earth nanoparticles (REs) consisting of an active rare-earth doped core of NaYF4:Yb,Er (REDNPs) and an undoped NaYF4 shell. We observed that the PA signal amplitude increased with SiO2 shell thickness. Although the SiO2 shell caused an observed decrease in the integrated fluorescence intensity due to the dilution effect, fluorescence quenching of the rare earth emitting ions within the REDNPs cores was successfully prevented by the undoped NaYF4 shell. Therefore, our multilayer structure consisting of an active core with successive functional layers was demonstrated to be an effective design for dual-modal fluorescence and PA imaging probes with improved PA property. The result from this work addresses a critical need for the development of dual-modal contrast agent that advances deep tissue imaging with high resolution and signal-to-noise ratio.

Assessment of neurovascular dynamics during transient ischemic attack by the novel integration of micro-electrocorticography electrode array with functional photoacoustic microscopy

This study developed a novel system combining a 16-channel micro-electrocorticography (μECoG) electrode array and functional photoacoustic microscopy (fPAM) to examine changes in neurovascular functions following transient ischemic attack (TIA) in rats. To mimic the pathophysiology of TIA, a modified photothrombotic ischemic model was developed by using 3 min illumination of 5 mW continuous-wave (CW) green laser light focusing on a distal branch of the middle cerebral artery (MCA). Cerebral blood volume (CBV), hemoglobin oxygen saturation (SO2), somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were measured pre- and post-ischemia over a focal cortical region (i.e., 1.5×1.5 mm(2)). Unexpectedly, the SO2, peak-to-peak amplitude (PPA) of SSEPs and ADR recovered and achieved levels greater than the baseline values at the 4th hour post-ischemia induction without any intervention, whereas the CBV value only partially recovered. In other words, transient ischemia led to increased neural activity when the relative CBV was reduced, which may further compromise neural integrity or lead to subsequent vascular disease. This novel μECoG-fPAM system complements currently available imaging techniques and represents a promising technology for studying neurovascular coupling in animal models.

Imaging of temperature dependent hemodynamics in the rat sciatic nerve by functional photoacoustic microscopy

BackgroundVascular hemodynamics is central to the regulation of neuro-metabolism and plays important roles in peripheral nerves diseases and their prevention. However, at present there are only a few techniques capable of directly measuring peripheral nerve vascular hemodynamics.MethodHere, we investigate the use of dark-field functional photoacoustic microscopy (fPAM) for intrinsic visualizing of the relative hemodynamics of the rat sciatic nerve in response to localized temperature modulation (i.e., cooling and rewarming).Results and conclusionOur main results show that the relative functional total hemoglobin concentration (HbT) is more significantly correlated with localized temperature changes than the hemoglobin oxygen saturation (SO2) changes in the sciatic nerve. Our study also indicates that the relative HbT changes are better markers of neuronal activation than SO2 during nerve temperature changes. Our results show that fPAM is a promising candidate for in vivo imaging of peripheral nerve hemodynamics without the use of contrast agents. Additionally, this technique may shed light on the neuroprotective effect of hypothermia on peripheral nerves by visualizing their intrinsic hemodynamics.

Integrated treatment modality of cathodal-transcranial direct current stimulation with peripheral sensory stimulation affords neuroprotection in a rat stroke model

Abstract. Cathodal-transcranial direct current stimulation induces therapeutic effects in animal ischemia models by preventing the expansion of ischemic injury during the hyperacute phase of ischemia. However, its efficacy is limited by an accompanying decrease in cerebral blood flow. On the other hand, peripheral sensory stimulation can increase blood flow to specific brain areas resulting in rescue of neurovascular functions from ischemic damage. Therefore, the two modalities appear to complement each other to form an integrated treatment modality. Our results showed that hemodynamics was improved in a photothrombotic ischemia model, as cerebral blood volume and hemoglobin oxygen saturation (SO2) recovered to 71% and 76% of the baseline values, respectively. Furthermore, neural activities, including somatosensory-evoked potentials (110% increase), the alpha-to-delta ratio (27% increase), and the (delta+theta)/(alpha+beta) ratio (27% decrease), were also restored. Infarct volume was reduced by 50% with a 2-fold preservation in the number of neurons and a 6-fold reduction in the number of active microglia in the infarct region compared with the untreated group. Grip strength was also better preserved (28% higher) compared with the untreated group. Overall, this nonpharmacological, nonintrusive approach could be prospectively developed into a clinical treatment modality.

An integrated neuroprotective intervention for brain ischemia validated by ECoG-fPAM

Brain ischemia is a neurological deficit caused by a reduction in the blood supply to tissue, and one of the leading causes of disability in the world. Currently, the most well-known therapeutic agent for ischemia recovery is recombinant tissue plasminogen activator (rtPA), but it is viable for only a small portion (approximately 3.6%) of ischemic patients and may cause side effects such as tissue damage. Thus, introducing a new therapeutic concept for ischemia, we proposed an integrated intervention combining global and focal stimulations in this article. To investigate the potential therapeutic effect of cathodal-transcranial direct current stimulation (C-tDCS) with peripheral sensory stimulation (PSS) during the hyperacute phase of stroke, the present study evaluated neurovascular and neuroprotective responses of the rat cortex following ischemic insult. A hybrid, dual-modality system, including electrocorticography (ECoG) and functional photoacoustic microscopy (fPAM), termed ECoG-fPAM, was used to image cortical functional responses pre- and post-ischemia. Using ECoG-fPAM, results showed that cerebral blood volume (CBV) was able to be recovered during the intervention. In addition, neural activity including somatosensory evoked potentials (SSEPs) and alpha-to-delta ratio (ADR) were restored and greater than the baseline value when the integrated intervention was administered. The results of NeuN/ED-1 immunohistochemical staining and TTC staining also supported the neuroprotective effect of this intervention, protecting more neurons and decreasing the infarct size. Overall, the results acquired from the ECoG-fPAM system demonstrated that C-tDCS + PSS administered immediately following ischemia induction can significantly promote neuroprotection via inhibition of ischemia expansion and reversed cortical neurovascular functions, suggesting effective recovery.

Simultaneous functional photoacoustic microscopy and electrocorticography reveal the impact of rtPA on dynamic neurovascular functions after cerebral ischemia

The advance of thrombolytic therapy has been hampered by the lack of optimization of the therapy during the hyperacute phase of focal ischemia. Here, we investigate neurovascular dynamics using a custom-designed hybrid electrocorticography (ECoG)-functional photoacoustic microscopy (fPAM) imaging system during the hyperacute phase (first 6 h) of photothrombotic ischemia (PTI) in male Wistar rats following recombinant tissue plasminogen activator (rtPA)-mediated thrombolysis. We reported, for the first time, the changes in neural activity and cerebral hemodynamic responses following rtPA infusion at different time points post PTI. Interestingly, very early administration of rtPA (< 1 h post PTI) resulted in only partial recovery of neurovascular dynamics (specifically, neural activity recovered to 71 ± 3.5% of baseline and hemodynamics to only 52 ± 2.6% of baseline) and late administration of rtPA (> 4 h post PTI) resulted in the deterioration of neurovascular function. A therapeutic window between 1 and 3 h post PTI was found to improve recovery of neurovascular function (i.e. significant restoration of neural activity to 93 ± 4.2% of baseline and hemodynamics to 81 ± 2.1% of baseline, respectively). The novel combination of fPAM and ECoG enables direct mapping of neurovascular dynamics and serves as a platform to evaluate potential interventions for stroke.