Optical single-pixel volumetric imaging by three-dimensional light-field illumination.

Three-dimensional single-pixel imaging (3D SPI) has become an attractive imaging modality for both biomedical research and optical sensing. 3D-SPI techniques generally depend on time-of-flight or stereovision principle to extract depth information from backscattered light. However, existing implementations for these two optical schemes are limited to surface mapping of 3D objects at depth resolutions, at best, at the millimeter level. Here, we report 3D light-field illumination single-pixel microscopy (3D-LFI-SPM) that enables volumetric imaging of microscopic objects with a near-diffraction-limit 3D optical resolution. Aimed at 3D space reconstruction, 3D-LFI-SPM optically samples the 3D Fourier spectrum by combining 3D structured light-field illumination with single-element intensity detection. We build a 3D-LFI-SPM prototype that provides an imaging volume of ∼390 × 390 × 3,800 µm3 and achieves 2.7-µm lateral resolution and better than 37-µm axial resolution. Its capability of 3D visualization of label-free optical absorption contrast is demonstrated by imaging single algal cells in vivo. Our approach opens broad perspectives for 3D SPI with potential applications in various fields, such as biomedical functional imaging.

Long-distance pattern projection through an unfixed multimode fiber with natural evolution strategy-based wavefront shaping.

Focusing light into an arbitrary pattern through complex media is desired in energy delivery-related scenarios and has been demonstrated feasible with the assistance of wavefront shaping. However, it still encounters challenges in terms of pattern fidelity and focusing contrast, especially in a noisy and perturbed environment. In this work, we show that the strategy relying on natural gradient ascent-based parameter optimization can help to resist noise and disturbance, enabling rapid wavefront optimization towards high-quality pattern projection through complex media. It is revealed that faster convergence and better robustness can be achieved compared with existing phase control algorithms. Meanwhile, a new fitness function based on cosine similarity is adopted for the algorithm, leading to higher focusing contrast without sacrificing similarity to the target pattern. As a result, long-distance projection of an arbitrary pattern can be accomplished with considerably enhanced performance through a 15-meter multimode fiber that is not fixed and susceptible to perturbation. With further engineering, the approach may find special interests for many biomedical applications, such as deep-tissue photon therapy and optogenetics, where free-space localized optical delivery encounters challenges.

Exploiting the potential of commercial objectives to extend the field of view of two-photon microscopy by adaptive optics.

Two-photon microscopy (TPM) has provided critical in situ and in vivo information in biomedical studies due to its high resolution, intrinsic optical sectioning, and deep penetration. However, its relatively small field of view (FOV), which is usually determined by objectives, restricts its wide application. In this paper, we propose a segment-scanning sensorless adaptive optics method to extend the FOV and achieve high-resolution and large-FOV two-photon imaging. We demonstrated the proposed method by imaging fluorescent beads, cerebral nerve cells of mouse brain slices, and cerebral vasculature and microglia of live mice. The method extended the FOV of a commercial objective from 1.8 to 3.46 mm while maintaining a lateral resolution of 840 nm and high signal-to-noise ratio. Our technology is compatible with a standard TPM and can be used for large-scale biological exploration.

Dynamic mutation enhanced particle swarm optimization for optical wavefront shaping.

Particle swarm optimization (PSO) is a well-known iterative algorithm commonly adopted in wavefront shaping for focusing light through or inside scattering media. The performance is, however, limited by premature convergence in an unstable environment. Therefore, we aim to solve this problem and enhance the focusing performance by adding a dynamic mutation operation into the plain PSO. With dynamic mutation, the "particles," or the optimized masks, are mutated with quantifiable discrepancy between the current and theoretical optimal solution, i.e., the "error rate." Gauged by that, the diversity of the "particles" is effectively expanded, and the adaptability of the algorithm to noise and instability is significantly promoted, yielding optimization approaching the theoretical optimum. The simulation and experimental results show that PSO with dynamic mutation demonstrates considerably better performance than PSO without mutation or with a constant mutation, especially under a noisy environment.

Parameter-free optimization algorithm for iterative wavefront shaping.

Optical focusing through scattering media has a significant impact on optical applications in biological tissues. Recently, iterative wavefront shaping (WFS) has been successfully used to focus light through or inside scattering media, and various heuristic algorithms have been introduced to improve the performance. While these results are encouraging, more efforts are needed to tune parameters towards robust and optimum optimization. Moreover, optimal parameters might differ for different scattering samples and experimental conditions. In this Letter, we propose a "smart" parameter-free algorithm by combining a traditional genetic algorithm with a bat algorithm, and the mutation rate can be automatically calculated through real-time feedback. Using this method in iterative WFS, one can achieve robust and optimum performance without a parameter tuning process.

Single-shot ultrasound-modulated optical tomography with enhanced speckle contrast.

Ultrasound-modulated optical tomography (UOT) images optical contrast deep inside biological tissue. Among existing approaches, camera-based parallel detection is beneficial in modulation depth but is limited to the relatively slow framerate of cameras. This condition prevents such a scheme from achieving maturity to image live animals with sub-millisecond speckle correlation time. In this work, we developed on-axis single-shot UOT by investigating the statistics of speckles, breaking the restriction imposed by the slow camera framerate. As a proof of concept, we experimentally imaged a one-dimensional absorptive object buried inside a moving scattering medium with speckle correlation time down to 0.48 ms. We envision that this single-shot UOT is promising to cope with live animals with fast speckle decorrelation.

Interferometry-free noncontact photoacoustic detection method based on speckle correlation change.

Optical speckle patterns occur when a coherent optical wavefront is randomized but such stochastic yet deterministic information about the medium can be decoded. A simple setup is inspired to monitor the decorrelation of speckle patterns within the memory effect range when the medium is photoacoustically perturbated. Experimentally, a linear relationship is confirmed between the speckle correlation change and the peak-to-peak amplitude of the ultrasonic transducer-detected photoacoustic waves, and the detection sensitivity is comparable. Such a plain specklegram-based method may find special interests when no direct contact is allowed between the sample and the photoacoustic detector.

Expansion of the FOV in speckle autocorrelation imaging by spatial filtering.

Optical imaging through inhomogeneous media based on autocorrelations suffers from a limited field of view (FOV), since the optical memory effect (ME) of a scattering medium has its inherent angular extent. Here we successfully expand the angular ME range by exploiting a spatial filtering technique to select low-frequency components, mainly ballistic light and less scattered light, thereby increasing the FOV of the speckle autocorrelation imaging. Both a simulation and experimental verifications are presented. This technique, which is not limited to the discussed 4f structure, can provide a guideline for the design of an optical system to image through scattering media.

Ultrasound-modulated laser feedback tomography in the reflective mode.

A novel method of ultrasound-modulated optical tomography (UOT) detection based on the laser feedback technology is proposed in this Letter. The system has advantages such as a simple structure, high sensitivity, and reflective configuration. Effective penetration depths of up to 9 cm and 5 cm in phantom and biological tissues, respectively, have been demonstrated experimentally. The detection capability is comparable with the state of the art in the transmission mode but with a much lower photon consumption. Although a lot remains to be improved, the proposed method is promising for further development toward practical applications.

Performance enhancement in wavefront shaping of multiply scattered light: a review.

Significance: In nonballistic regime, optical scattering impedes high-resolution imaging through/inside complex media, such as milky liquid, fog, multimode fiber, and biological tissues, where confocal and multiphoton modalities fail. The significant tissue inhomogeneity-induced distortions need to be overcome and a technique referred as optical wavefront shaping (WFS), first proposed in 2007, has been becoming a promising solution, allowing for flexible and powerful light control. Understanding the principle and development of WFS may inspire exciting innovations for effective optical manipulation, imaging, stimulation, and therapy at depths in tissue or tissue-like complex media. Aim: We aim to provide insights about what limits the WFS towards biomedical applications, and how recent efforts advance the performance of WFS among different trade-offs. Approach: By differentiating the two implementation directions in the field, i.e., precompensation WFS and optical phase conjugation (OPC), improvement strategies are summarized and discussed. Results: For biomedical applications, improving the speed of WFS is most essential in both directions, and a system-compatible wavefront modulator driven by fast apparatus is desired. In addition to that, algorithm efficiency and adaptability to perturbations/noise is of concern in precompensation WFS, while for OPC significant improvements rely heavily on integrating physical mechanisms and delicate system design for faster response and higher energy gain. Conclusions: Substantial improvements in WFS implementations, from the aspects of physics, engineering, and computing, have inspired many novel and exciting optical applications that used to be optically inaccessible. It is envisioned that continuous efforts in the field can further advance WFS towards biomedical applications and guide our vision into deep biological tissues.

High-security learning-based optical encryption assisted by disordered metasurface.

Artificial intelligence has gained significant attention for exploiting optical scattering for optical encryption. Conventional scattering media are inevitably influenced by instability or perturbations, and hence unsuitable for long-term scenarios. Additionally, the plaintext can be easily compromised due to the single channel within the medium and one-to-one mapping between input and output. To mitigate these issues, a stable spin-multiplexing disordered metasurface (DM) with numerous polarized transmission channels serves as the scattering medium, and a double-secure procedure with superposition of plaintext and security key achieves two-to-one mapping between input and output. In attack analysis, when the ciphertext, security key, and incident polarization are all correct, the plaintext can be decrypted. This system demonstrates excellent decryption efficiency over extended periods in noisy environments. The DM, functioning as an ultra-stable and active speckle generator, coupled with the double-secure approach, creates a highly secure speckle-based cryptosystem with immense potentials for practical applications.

High-sensitivity ultrasound-modulated optical tomography with a photorefractive polymer.

By detecting ultrasonically tagged diffuse light, ultrasound-modulated optical tomography images optical contrast with ultrasonic resolution deep in turbid media, such as biological tissue. However, small detection etendues and weak tagged light submerged in strong untagged background light limit the signal detection sensitivity. In this Letter, we report the use of a large-area (~5 cm×5 cm) photorefractive polymer film that yields more than 10 times detection etendue over previous detection schemes. Our polymer-based system enabled us to resolve absorbing objects embedded inside diffused media thicker than 80 transport mean free paths, by using moderate light power and short ultrasound pulses.

Multi-Bioinspired Functional Conductive Hydrogel Patches for Wound Healing Management.

Many hydrogel patches are developed to solve the pervasive and severe challenge of complex wound healing, while most of them still lack satisfactory controllability and comprehensive functionality. Herein, inspired by multiple creatures, including octopuses and snails, a novel muti-functional hydrogel patch is presented with controlled adhesion, antibacterial, drug release features, and multiple monitoring functions for intelligent wound healing management. The patch with micro suction-cup actuator array and a tensile backing layer is composed of tannin grafted gelatin, Ag-tannin nanoparticles, polyacrylamide (PAAm) and poly(N-isopropylacrylamide) (PNIPAm). In virtue of the photothermal gel-sol transition of tannin grafted gelatin and Ag-tannin nanoparticles, the patches exert a dual anti-microbial effect and temperature-sensitive snail mucus-like features. In addition, as the "suction-cups" consisting of thermal responsive PNIPAm can undergo a contract-relax transformation, the medical patches can adhere to the objects reversibly and responsively, and release their loaded vascular endothelial growth factor (VEGF) controllably for wound healing. More attractively, benefiting from their fatigue resistance, self-healing ability of the tensile double network hydrogel, and electrical conductivity of Ag-tannin nanoparticles, the proposed patches can report multiple wound physiology parameters sensitively and continuously. Thus, it is believed that this multi-bioinspired patch has immense potential for future wound healing management.

Deep Penetrating and Sensitive Targeted Magnetic Particle Imaging and Photothermal Therapy of Early-Stage Glioblastoma Based on a Biomimetic Nanoplatform.

Early diagnosis can effectively improve the survival of glioblastoma multiforme (GBM). A specific imaging technique that is simultaneously deep penetrating and sensitive to small tissue changes is desired to identify GBM. Due to its excellent features in signal contrast, detection sensitivity, and none or little attenuation in tissue, magnetic particle imaging (MPI) possesses great potential in cancer diagnosis, especially when the imaging modality is equipped with specifically targeted nanoprobes. However, when gliomas are small, the blood-brain barrier (BBB) is complete and prevents nanoprobes from entering the brain, which negates the theranostic effect. This study proposes a biomimetic nanoplatform that assist the MPI tracers in breaking through the BBB and then demonstrate a targeted and sensitive diagnosis of GBM. Afterward, the photothermal therapy and immune regulation show an excellent therapeutic effect on the GBM. It is experimentally confirmed that the MPI signal does not decay with tissue depth and shows excellent sensitivity for thousands-cells. Only small animals are conducted in this study due to the limitations of the current commercial MPI scanner, however, this research theoretically enables large animal and human studies, which encourages a promising pathway toward the noninvasive diagnosis of early-stage GBM in clinics.

Recent advances of cellular stimulation with triboelectric nanogenerators.

Triboelectric nanogenerators (TENGs) are new energy collection devices that have the characteristics of high efficiency, low cost, miniaturization capability, and convenient manufacture. TENGs mainly utilize the triboelectric effect to obtain mechanical energy from organisms or the environment, and this mechanical energy is then converted into and output as electrical energy. Bioelectricity is a phenomenon that widely exists in various cellular processes, including cell proliferation, senescence, apoptosis, as well as adjacent cells' communication and coordination. Therefore, based on these features, TENGs can be applied in organisms to collect energy and output electrical stimulation to act on cells, changing their activities and thereby playing a role in regulating cellular function and interfering with cellular fate, which can further develop into new methods of health care and disease intervention. In this review, we first introduce the working principle of TENGs and their working modes, and then summarize the current research status of cellular function regulation and fate determination stimulated by TENGs, and also analyze their application prospects for changing various processes of cell activity. Finally, we discuss the opportunities and challenges of TENGs in the fields of life science and biomedical engineering, and propose a variety of possibilities for their potential development direction.

Bio-Inspired Fractal Robust Hydrogel Catheter for Intra-Abdominal Sepsis Management.

To deal with intra-abdominal sepsis, one of the major global causes of death in hospitalized patients, efficient abscess drainage is crucial. Despite decades of advances, traditional catheters have demonstrated poor drainage and absorption properties due to their simple tubular structures and their dense nonporous surface. Herein, inspired by porous sponges and fractal roots, a multifaceted hydrogel catheter with effective drainage, absorptive, and robust properties, is presented. Its unique fractal structures provide extensive internal branching and a high specific surface area for effective drainage, while the hierarchical porous structures provide a wide range of absorption capabilities. Additionally, its distinctive multi-interpenetration network maintains robust and appropriate mechanical properties, even after absorption multiple times of liquid and mechanical disturbance, allowing for intact removal from the abdominal cavity without harm to the animal in vivo. Besides, the loaded antimicrobial peptides are capable of being released in situ to inhibit the potential for infections. In vivo experiments have demonstrated that this hydrogel catheter efficiently removes lethal abscesses and improves survival. It is believed that this innovative and practical catheter will create a future precedent for hydrogel drainage devices for more effective management of intra-abdominal sepsis.

Enhancing spatiotemporal focusing of light deep inside scattering media with Time-Gated Reflection Matrix.

Time-gated reflection matrix (RM) has been successfully used for optical imaging deep inside scattering media. Recently, this method was extended to enhance the spatiotemporal focusing of light ultra-deep inside scattering media. This is achieved by calibrating the decomposition of the RM with the Tikhonov regularization parameter to convert multiply scattered photons that share the same time of flight with the singly scattered photons into singly scattered photons. Such a capability suggests a reshaping to the interaction mechanism between light and scattering media, which may benefit or inspire wide optical applications that desire enhanced spatiotemporal focusing of light at depths inside scattering media.

Light on osteoarthritic joint: from bench to bed.

Osteoarthritis (OA) is one of the rapidly growing disability-associated conditions with population aging worldwide. There is a pressing need for precise diagnosis and timely intervention for OA in the early stage. Current clinical imaging modalities, including pain radiography, magnetic resonance imaging, ultrasound, and optical coherent tomography, are limited to provide structural changes when the damage has been established or advanced. It prompts further endeavors in search of novel functional and molecular imaging, which potentially enables early diagnosis and intervention of OA. A hybrid imaging modality based on photothermal effects, photoacoustic imaging, has drawn wide attention in recent years and has seen a variety of biomedical applications, due to its great performance in yielding high-contrast and high-resolution images from structure to function, from tissue down to molecular levels, from animals to human subjects. Photoacoustic imaging has witnessed gratifying potentials and preliminary effects in OA diagnosis. Regarding the treatment of OA, photothermal-triggered therapy has exhibited its attractions for enhanced therapeutic outcomes. In this narrative review, we will discuss photoacoustic imaging for the diagnosis and monitoring of OA at different stages. Structural, functional, and molecular parameter changes associated with OA joints captured by photoacoustics will be summarized, forming the diagnosis perspective of the review. Photothermal therapy applications related to OA will also be discussed herein. Lastly, relevant clinical applications and its potential solutions to extend photoacoustic imaging to deeper OA situations have been proposed. Although some aspects may not be covered, this mini review provides a better understanding of the diagnosis and treatment of OA with exciting innovations based on tissue photothermal effects. It may also inspire more explorations in the field towards earlier and better theranostics of OA.

Video-Rate Dual-Modal Wide-Beam Harmonic Ultrasound and Photoacoustic Computed Tomography.

Dual-modal ultrasound (US) and photoacoustic (PA) imaging has tremendous advantages in biomedical applications, such as pharmacokinetics, cancer screening, and imaging-guided therapy. Compared with ring-shaped arrays, a linear piezoelectric transducer array applies to more anatomical sites and has been widely used in US/PA imaging. However, the linear array may limit the imaging quality due to narrow bandwidth, partial detection view, or sparse spatial sampling. To meet clinic demand of high-quality US/PA imaging with the linear transducer, we develop dual-modal wide-beam harmonic ultrasound (WBHUS) and photoacoustic computed tomography at video rate. The harmonic US imaging employs pulse phase inversion to reduce clutters and improve spatial resolution. Wide-beam US transmission can shorten the scanning times by 267% and enables a 20-Hz imaging rate, which can minimize motion artifacts in in vivo imaging. The harmonic US imaging does not only provide accurate anatomical references for locating PA features but also reduces artifacts in PA images. The improved image quality allows us to acquire high-resolution anatomical structures in deep tissue without labeling. The fast-imaging speed enables visualizing interventional procedures and monitoring the pulsations of the thoracic aorta and radial artery in real-time. The video-rate dual-modal harmonic US and single-shot PA computed tomography use a clinical-grade linear-array transducer and thus can be readily implemented in clinical US imaging.

High-resolution photoacoustic microscopy with deep penetration through learning.

Optical-resolution photoacoustic microscopy (OR-PAM) enjoys superior spatial resolution and has received intense attention in recent years. The application, however, has been limited to shallow depths because of strong scattering of light in biological tissues. In this work, we propose to achieve deep-penetrating OR-PAM performance by using deep learning enabled image transformation on blurry living mouse vascular images that were acquired with an acoustic-resolution photoacoustic microscopy (AR-PAM) setup. A generative adversarial network (GAN) was trained in this study and improved the imaging lateral resolution of AR-PAM from 54.0 µm to 5.1 µm, comparable to that of a typical OR-PAM (4.7 µm). The feasibility of the network was evaluated with living mouse ear data, producing superior microvasculature images that outperforms blind deconvolution. The generalization of the network was validated with in vivo mouse brain data. Moreover, it was shown experimentally that the deep-learning method can retain high resolution at tissue depths beyond one optical transport mean free path. Whilst it can be further improved, the proposed method provides new horizons to expand the scope of OR-PAM towards deep-tissue imaging and wide applications in biomedicine.