Minimally invasive photoacoustic imaging:Current status and future perspectives

Photoacoustic imaging (PAI) is an emerging biomedical imaging modality that is based on optical absorption contrast, capable of revealing distinct spectroscopic signatures of tissue at high spatial resolution and large imaging depths. However, clinical applications of conventional non-invasive PAI systems have been restricted to examinations of tissues at depths less than a few cm due to strong light attenuation. Minimally invasive photoacoustic imaging (miPAI) has greatly extended the landscape of PAI by delivering excitation light within tissue through miniature fibre-optic probes. In the past decade, various miPAI systems have been developed with demonstrated applicability in several clinical fields. In this article, we present an overview of the current status of miPAI and our thoughts on future perspectives.status: publishe

Patient-Specific Polyvinyl Alcohol Phantoms for Applications in Minimally Invasive Surgery

In biomedical engineering, phantoms are physical models of known geometric and material composition that are used to replicate biological tissues. Phantoms are vital tools in the testing and development of novel minimally invasive devices, as they can simulate the conditions in which devices will be used. Clinically, phantoms are also highly useful as training tools for minimally invasive procedures, such as those performed in regional anaesthesia, and for patient-specific surgical planning. Despite their widespread utility, there are many limitations with current phantoms and their fabrication methods. Commercial phantoms are often prohibitively expensive and may not be compatible with certain imaging modalities, such as ultrasound. Much of the phantom literature is complicated or hard to follow, making it difficult for researchers to produce their own models and it is highly challenging to create anatomically realistic phantoms that replicate real patient pathologies. Therefore, the aim of this work is to address some of the challenges with current phantoms. Novel fabrication methods and frameworks are presented to enable the creation of phantoms that are suitable for use in both the development of novel devices and as clinical training tools, for applications in minimally invasive surgery. This includes regional anaesthesia, brain tumour resection, and percutaneous coronary interventions. In such procedures, imaging is of key importance, and the phantoms developed are demonstrated to be compatible across a range of modalities, including ultrasound, computed tomography, MRI, and photoacoustic imaging

A patient-specific multi-modality abdominal aortic aneurysm imaging phantom

PURPOSE: Multimodality imaging of the vascular system is a rapidly growing area of innovation and research, which is increasing with awareness of the dangers of ionizing radiation. Phantom models that are applicable across multiple imaging modalities facilitate testing and comparisons in pre-clinical studies of new devices. Additionally, phantom models are of benefit to surgical trainees for gaining experience with new techniques. We propose a temperature-stable, high-fidelity method for creating complex abdominal aortic aneurysm phantoms that are compatible with both radiation-based, and ultrasound-based imaging modalities, using low cost materials. METHODS: Volumetric CT data of an abdominal aortic aneurysm were acquired. Regions of interest were segmented to form a model compatible with 3D printing. The novel phantom fabrication method comprised a hybrid approach of using 3D printing of water-soluble materials to create wall-less, patient-derived vascular structures embedded within tailored tissue-mimicking materials to create realistic surrounding tissues. A non-soluble 3-D printed spine was included to provide a radiological landmark. RESULTS: The phantom was found to provide realistic appearances with intravascular ultrasound, computed tomography and transcutaneous ultrasound. Furthermore, the utility of this phantom as a training model was demonstrated during a simulated endovascular aneurysm repair procedure with image fusion. CONCLUSION: With the hybrid fabrication method demonstrated here, complex multimodality imaging patient-derived vascular phantoms can be successfully fabricated. These have potential roles in the benchtop development of emerging imaging technologies, refinement of novel minimally invasive surgical techniques and as clinical training tools

Translation of Intravascular Optical Ultrasound Imaging

ances in the field of intravascular imaging have provided clinicians with power ful tools to aid in the assessment and treatment of vascular pathology. Optical Ultra sound (OpUS) is an emerging modality with the potential to offer significant bene fits over existing commercial technologies such as intravascular ultrasound (IVUS) or optical coherence tomography (OCT). With this paradigm ultrasound (US) is generated using pulsed or modulated light and received by a miniaturised fibre-optic hydrophone (FOH). The US generation is facilitated through the use of engineered optically-absorbing nanocomposite materials. To date pre-clinical benchtop stud ies of OpUS have shown significant promise however further study is needed to facilitate clinical translation. The overall aim of this PhD was to develop a pathway to clinical translation of OpUS, enabled by the development of a catheter-based device capable of high resolution vascular tissue imaging during an in-vivo setting. A forward-viewing OpUS imaging probe was developed using a 400 µm mul timode optical fibre, dip-coated in a multi-walled carbon nanotube-PDMS com posite, paired with a FOH comprising a 125 µm single mode fibre tipped with a Fabry-Perot cavity. With this high US pressures were generated (21.5 MPa at the transducer surface) and broad corresponding bandwidths were achieved (−6 dB of 39.8MHz). Using this probe, OpUS imaging was performed of an ex-vivo human coronary artery. The results demonstrated excellent correspondence, in the detec tion of calcification and lipid infiltration, with IVUS, OCT and histological analysis. A side-viewing OpUS imaging probe, employing a reflective 45 °angle at the dis tal fibre surface, was used to demonstrate rotational B-mode imaging of a vascular structure for the first time. This provided high-resolution imaging (54 µm axial resolution) with deep depth penetration (>10.5 mm). Finally the clinical utility of this technology was demonstrated during an in-vivo endovascular procedure. An OpUS imaging probe, incorporated into an interventional device, allowed guidance of in-situ fenestration of an endograft during a complex abdominal aortic aneurysm repair. Through this work the potential clinical utility of OpUS, to assess pathology and guide vascular intervention, has been demonstrated. These results pave the way for translation of this technology and a first in man study

Photoacoustic Reporter Gene Imaging And Optical Coherence Computed Tomography

Advances in imaging technologies have always been the major driving forces for the evolution of biomedical research. Compared with other modalities, optical imaging possesses several prominent merits. Because light interacts with tissue at the microscopic level through many distinct physical mechanisms, optical methods allow sensitive exploration of various aspects of the life down to the single-molecule level. From the technical perspective, optical systems utilize safe non-ionizing radiation, could be implemented at relatively low cost, also have the potential to be miniaturized for portable or endoscopic applications. As a result, optical imaging tools are playing an increasingly important role in both laboratorial research and clinical practice. Among them, photoacoustic imaging: PAI) and optical coherence tomography: OCT) are the two fastest growing branches. PAI measures the laser-induced acoustic wave, and produces high-resolution images of the optically absorbing features of tissue at multiple length-scales. OCT detects singly backscattered photons, and enables real-time high-resolution in vivo biopsy of tissue up to an optical transport mean-free-path. My doctoral research is focused on developing three novel optical imaging techniques based on the spirits of PAI and OCT. In the first part of this study, we established a new paradigm to visualize gene expression in vivo based on optical absorption. In the post-genomic era, we are now being challenged to develop novel molecular imaging methods to identify the functions of genes. PAI can detect specific molecules according to their characteristic absorption spectra, thus is a promising candidate for molecular imaging of gene expression. The full potential of photoacoustic molecular imaging still remains to be explored. For the first time, we demonstrated imaging gene expression by PAI in living mice and rats, using a chromogenic lacZ/X-gal reporter gene system. We demonstrated the expression of the lacZ reporter gene can be detected by PAI as deep as 5 cm inside tissue. In addition, we showcased that PAI could follow gene expression from the microscopic to the macroscopic level. This work represents one of the pioneering efforts to extend photoacoustic methods for molecular imaging. In the second part of this study, we developed a novel multimodal microscope, called the integrated photoacoustic and optical coherence microscope: iPOM), which combines PAI and OCT in a single imaging platform. PAI is predominantly sensitive to optical absorption, while OCT exploits optical scattering. By combining their naturally complementary imaging contrasts, iPOM can provide comprehensive information about biological tissue. We designed and built a reflection-mode prototype of iPOM, which fuses optical-resolution photoacoustic microscopy with spectral-domain optical coherence tomography. The potential applications of iPOM in studying cutaneous and ocular microcirculation, and tissue engineering were demonstrated. Finally, we invented a new optical tomography, named optical coherence computed tomography: optical CCT), which overcomes several major limitations of OCT. OCT relies on singly backscattered photons to obtain high-resolution images. Its image quality degrades fast with the increase of the depth, because the multiply scattered photons quickly become dominant at a penetration larger than 500 &mum. As a result, OCT can only effectively penetrate ~1 mm into highly scattering tissue like skin. In addition, OCT is mainly sensitive to optical scattering, which does not reflect the molecular content of tissue directly. Optical CCT measures both singly and multiply scattered photons using a low-coherence interferometer. We make use of both types of photons by adopting a model-based reconstruction algorithm. The light-tissue interaction model was established using the time-resolved Monte Carlo method. The optical properties of the tissue were reconstructed from measurements by solving the inverse radiative transport problem under the first Born approximation. As a result, optical CCT could image deeper than OCT, and provide extra molecule-specific contrasts, such as optical absorption. We designed and built the first optical CCT system. In experiments, absorbing inclusions of 100 &mum diameter were imaged with consistent quality through a 2.6-mm-thick: equivalent to ~3 transport mean-free-paths) tissue-mimicking phantom

Patient-specific polyvinyl alcohol phantom fabrication with ultrasound and x-ray contrast for brain tumor surgery planning

Phantoms are essential tools for clinical training, surgical planning and the development of novel medical devices. However, it is challenging to create anatomically accurate head phantoms with realistic brain imaging properties because standard fabrication methods are not optimized to replicate any patient-specific anatomical detail and 3D printing materials are not optimized for imaging properties. In order to test and validate a novel navigation system for use during brain tumor surgery, an anatomically accurate phantom with realistic imaging and mechanical properties was required. Therefore, a phantom was developed using real patient data as input and 3D printing of molds to fabricate a patient-specific head phantom comprising the skull, brain and tumor with both ultrasound and X-ray contrast. The phantom also had mechanical properties that allowed the phantom tissue to be manipulated in a similar manner to how human brain tissue is handled during surgery. The phantom was successfully tested during a surgical simulation in a virtual operating room. The phantom fabrication method uses commercially available materials and is easy to reproduce. The 3D printing files can be readily shared, and the technique can be adapted to encompass many different types of tumor

Optical Properties and Optoelectronic Applications of Nano-size Metallic Films and Metamaterials.

Future optical and optoelectronic devices are desired to have compact sizes, high efficiencies, robust performance, and low manufacturing costs. All these advances demand developments both in their constituent materials and design concepts. Silver (Ag) is one of the most widely used materials for optoelectronic devices and metamaterials. However, Ag is well known to have several issues, including difficulty to form high-quality thin films, poor stability in an ambient environment and under elevated temperatures, and inferior adhesion with substrates. In light of this, a new kind of silver: doped silver is developed. With the aid of a small amount of doping elements during the Ag deposition, ultra-thin, smooth, and low-loss Ag films are obtained. Compared to pure Ag films, doped Ag films have a significantly improved long-term and thermal stability, as well as good adhesion to various substrates. Doped Ag films have facilitated diverse high-performance optical and optoelectronic devices, such as organic solar cells, organic light emitting diodes, optical metamaterials, and plasmonic devices. Metamaterials are artificially designed materials with extraordinary optical properties. Nano-size metamaterials (metasurfaces) are demonstrated for controlling various properties of light. An asymmetric light transmitting metasurface consisting of coupled metallic sheets is demonstrated. It has a measured transmission efficiency of 80%, extinction ratio of 13.8 dB around 1.5 µm, and a full width half maximum bandwidth of 1.7 µm. It is as thin as 290 nm, has good performance tolerance against the angle of incidence and constituent nano-structure geometry variations. In addition, a large-area, printed metasurface is designed and fabricated. It is made of lossless dielectric (silicon) materials and offers the functionality of converting a linearly polarized incident light into a radially polarized transmitted light. These optical and optoelectronic devices also provide valuable solutions to problems in other fields, such as acoustic wave detection. It is shown that optical resonant structures provide a unique approach for acoustic wave detection. Nanoimprinted polymer microring resonators are investigated as high-performance ultrasound detectors. To further reduce the detector size, polymer filled silicon metasurfaces on fiber tips are also designed and fabricated.PhDElectrical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/133414/1/chengzh_1.pd

High-resolution 3D printing enabled, minimally invasive fibre optic sensing and imaging probes

Minimally invasive surgical procedures have become more favourable to their traditional surgical counterparts due to their reduced risks, faster recovery times and decreased trauma. Despite this, there are still some limitations involved with these procedures, such as the spatial confinement of operating through small incisions and the intrinsic lack of visual or tactile feedback. Specialised tools and imaging equipment are required to overcome these issues. Providing better feedback to surgeons is a key area of research to enhance the outcomes and safety profiles of minimally invasive procedures. This thesis is centred on the development of new microfabrication methods to create novel fibre optic imaging and sensing probes that could ultimately be used for improving the guidance of minimally invasive surgeries. Several themes emerged in this process. The first theme involved the use and optimisation of high-resolution 3D injection of polymers as sacrificial layers onto which parylene-C was deposited. One outcome from this theme was a series of miniaturised parylene-C based membranes to create fibre optic pressure sensors for physiological pressure measurements and for ultrasound reception. The pressure sensor sensitivity was found to vary from 0.02 to 0.14 radians/mmHg, as the thickness of parylene was decreased from 2 to 0.5 μm. The ultrasound receivers were characterised and exhibited a noise equivalent pressure (NEP) value of ~100 Pa (an order of magnitude improvement compared to similarly sized piezoelectric hydrophones). A second theme employed high-resolution 3D printing to create microstructures of polydimethylsiloxane (PDMS) and subsequently formed nanocomposites, to create microscale acoustic hologram structures. This theme included the development of innovative manufacturing processes such as printing directly onto optical fibres, micro moulding and precise deposition which enabled the creation of such devices. These microstructures were investigated for reducing the divergence of photoacoustically-generated ultrasound beams. Taken together, the developments in this thesis pave the way for 3D microfabricated polymer-based fibre optic sensors that could find broad clinical utility in minimally invasive procedures

CMUT array design and fabrication for high frequency ultrasound imaging

High frequency ultrasound imaging is utilized in a broad range of applications from intravascular imaging to small animal imaging for preclinical studies. Capacitive micromachined ultrasonic transducers (CMUTs) possess multiple preferable characteristics for high frequency imaging systems, such as simpler fabrication methods, simpler integration to electronics, and greater variety of array geometries. Adequate performance and optimization of CMUT based systems require a comprehensive analysis of multiple design parameters. This research utilizes a nonlinear lumped model, capable of simulating the pressure output, electrical input-output, and echo response to a planar reflector of CMUT arrays with arbitrary membrane shape and array geometry, to determine the performance limitations of high frequency CMUT arrays and the effect of different design parameters on its performance. Receiver performance is analyzed through parameters extracted from simulations, namely, thermal mechanical current noise, plane wave pressure sensitivity, and pressure noise spectrum. Transmitter performance is analyzed through pressure output simulation, and the overall performance is analyzed through the simulated pulse-echo response from a perfect planar reflector and the thermal mechanical current noise limited SNR. It is observed that the frequency response is dominated by two vibroacoustic limiting mechanisms: Bragg’s scattering, determined by array lateral dimensions, and crosstalk actuated fundamental and antisymmetric array modes, determined by individual membrane dynamics. Based on the limiting mechanism frequencies, a simplified design methodology is developed and used to design two CMUT array sets covering a broad frequency range of 1-80MHz. These CMUT arrays are fabricated and their limiting mechanisms are experimentally verified through pressure and admittance measurement and simulation comparison. CMUT arrays for guidewire IVUS application are implemented and successfully interfaced with ASICs to demonstrate imaging at 40MHz. Considering that CMUT array performance is also susceptible to the electrical termination conditions, the simulation model is utilized to investigate the effect of different impedance matching scenarios. Receiver performance of the integrated CMUT array and termination circuitry is analyzed through the system’s SNR and acoustic reflectivity.Ph.D

Wireless, battery-free optoelectronic systems as subdermal implants for local tissue oximetry

Monitoring regional tissue oxygenation in animal models and potentially in human subjects can yield insights into the underlying mechanisms of local O2-mediated physiological processes and provide diagnostic and therapeutic guidance for relevant disease states. Existing technologies for tissue oxygenation assessments involve some combination of disadvantages in requirements for physical tethers, anesthetics, and special apparatus, often with confounding effects on the natural behaviors of test subjects. This work introduces an entirely wireless and fully implantable platform incorporating (i) microscale optoelectronics for continuous sensing of local hemoglobin dynamics and (ii) advanced designs in continuous, wireless power delivery and data output for tether-free operation. These features support in vivo, highly localized tissue oximetry at sites of interest, including deep brain regions of mice, on untethered, awake animal models. The results create many opportunities for studying various O2-mediated processes in naturally behaving subjects, with implications in biomedical research and clinical practice.Center for Bio-Integrated Electronics at Northwestern University; Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF) [ECCS-1542205]; Materials Research Science and Engineering Center [DMR-1720139]; State of Illinois; Northwestern University; Developmental Therapeutics Core at Northwestern University; Robert H. Lurie Comprehensive Cancer Center [NCI CA060553]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]