Review of intravascular lithotripsy for treating coronary, peripheral artery, and valve calcifications.

Management of intracoronary calcium (ICC) continues to be a challenge for interventional cardiologists. There have been significant advances in calcium treatment devices. However, there still exists a knowledge gap regarding which devices to choose for the treatment of ICC. The purpose of this manuscript is to review the principles of intravascular lithotripsy (IVL) and clinical data. The technique of IVL will then be compared to alternative calcium treatment devices. Clinical data will be reviewed concerning the treatment of coronary, peripheral artery and valvular calcifications. Controversies to be discussed include how to incorporate IVL into your practice, what is the best approach for treating calcium subtypes, how to approach under-expanded stents, what is the ideal technique for performing IVL, how safe is IVL, whether imaging adds value when performing IVL, and how IVL fits into a treatment program for peripheral arteries and calcified valves.

Intravascular laser lithotripsy for calcium fracture in human coronary arteries.

BACKGROUND: Electrical intravascular lithotripsy (E-IVL) uses shock waves to fracture calcified plaque. AIMS: We aimed to demonstrate the ability of laser IVL (L-IVL) to fracture calcified plaques in ex vivo human coronary arteries and to identify and evaluate the mechanisms for increased vessel compliance. METHODS: Shock waves were generated by a Ho:YAG (Holmium: yttrium-aluminium-garnet) laser (2 J, 5 Hz) and recorded by a high-speed camera and pressure sensor. Tests were conducted on phantoms and 19 fresh human coronary arteries. Before and after L-IVL, arterial compliance and optical coherence tomography (OCT) pullbacks were recorded, followed by histology. Additionally, microcomputed tomography (micro-CT) and scanning electron microscopy (SEM) were performed. Finite element models (FEM) were utilised to examine the mechanism of L-IVL. RESULTS: Phantom cracks were obtained using 230 µm and 400 µm fibres with shock-wave pressures of 84±5.0 atm and 62±0.4 atm, respectively. Post-lithotripsy, calcium plaque modifications, including fractures and debonding, were identified by OCT in 78% of the ex vivo calcified arteries (n=19). Histological analysis revealed calcium microfractures (38.7±10.4 µm width) in 57% of the arteries which were not visible by OCT. Calcium microfractures were verified by micro-CT and SEM. The lumen area increased from 2.9±0.4 to 4.3±0.8 mm2 (p<0.01). Arterial compliance increased by 2.3±0.6 atm/ml (p<0.05). FEM simulations suggest that debonding and intimal tears are additional mechanisms for increased arterial compliance. CONCLUSIONS: L-IVL has the capability to increase calcified coronary artery compliance by multiple mechanisms.

Current and Emerging Imaging Techniques for Neurofibromatosis Type 1-Associated Cutaneous Neurofibromas.

A consistent set of measurement techniques must be applied to reliably and reproducibly evaluate the efficacy of treatments for cutaneous neurofibromas (cNFs) in people with neurofibromatosis type 1 (NF1). cNFs are neurocutaneous tumors that are the most common tumor in people with NF1 and represent an area of unmet clinical need. This review presents the available data regarding approaches in use or development to identify, measure, and track cNFs, including calipers, digital imaging, and high-frequency ultrasound sonography. We also describe emerging technologies such as spatial frequency domain imaging and the application of imaging modalities such as optical coherence tomography that may enable the detection of early cNFs and prevention of tumor-associated morbidity.

Erratum: Tissue harvest with a laser microbiopsy (Erratum).

[This corrects the article DOI: 10.1117/1.JBO.27.12.125001.].

Tissue harvest with a laser microbiopsy.

Significance: Traditional pathology workflow suffers from limitations including biopsy invasiveness, small fraction of large tissue samples being analyzed, and complex and time-consuming processing. Aim: We address limitations of conventional pathology workflow through development of a laser microbiopsy device for minimally invasive harvest of sub-microliter tissue volumes. Laser microbiopsy combined with rapid diagnostic methods, such as virtual hematoxylin and eosin (H&E) imaging has potential to provide rapid minimally invasive tissue diagnosis. Approach: Laser microbiopsies were harvested using an annular shaped Ho:YAG laser beam focused onto the tissue surface. As the annulus was ablated, the tissue section in the center of the annulus was ejected and collected directly onto a glass slide for analysis. Cryogen spray cooling was used before and after laser harvest to limit thermal damage. Microbiopsies were collected from porcine skin and kidney. Harvested microbiopsies were imaged with confocal microscopy and digitally false colored to provide virtual H&E images. Results: Microbiopsies were successfully harvested from porcine skin and kidney. Computational and experimental results show the benefit of cryogen pre- and post-cooling to limit thermal damage. Virtual H&E images of microbiopsies retained observable cellular features including cell nuclei. Conclusions: Laser microbiopsy with virtual H&E imaging shows promise as a potential rapid and minimally invasive tool for biopsy and diagnosis.

Er:YAG laser brain surgery with vascular specific coagulation.

BACKGROUND AND OBJECTIVE: Erbium:yttrium-aluminum-garnet (Er:YAG) laser ablation can effectively resect water-bearing tissues. Application of Er:YAG resection in neurosurgery is complicated by unpredictable bleeding in surgical field. Recently, an integrated theranostic system combining a dual-wavelength laser surgery system using a thulium (Tm) fiber-laser for coagulation and Er:YAG for resection, combined with optical coherence tomography (OCT) guidance was demonstrated for the in vivo resection of tumor tissue. However, lateral thermal spread in the range of 100s of micrometers is common due to lack of vascular specificity using a Tm fiber-laser for coagulation. In this study, a vascular specific ytterbium (Yb) fiber-laser is utilized for enhanced photocoagulation during in vivo neurosurgery improving the precision of Er:YAG tissue resection with minimal lateral thermal spread. METHODS: Mice underwent stereotactic laser surgery with the proposed Yb/Er:YAG dual wavelength vascular specific neurosurgery in vivo. An OCT system (wavelength range 1310 ± 70 nm) and OCT derived angiography  images were used to record cortical images to confirm the coagulation of blood vessels and guide subsequent Er:YAG resection steps. After the laser surgery, mice were killed, and histological analysis was carried out using hematoxylin and eosin staining and Nissl staining to compare the lateral thermal spread with our previously reported Tm/Er:YAG neurosurgery where a continuous wave  Tm fiber-laser was used for coagulation. RESULTS: Coagulation scheme using a Yb fiber-laser allowed stoppage of blood flow in disparately sized blood vessels encountered in the mice brain. Histological analysis of murine brain slices post Yb/Er:YAG laser surgery yielded lower thermal spread compared with Tm/Er:YAG laser surgery, maximizing the efficiency in both hemostasis (blood flow stoppage) and maximizing tissue ablation efficiency with minimal residual thermal damage zone. CONCLUSION: In this study, a vascular specific coagulation scheme with Yb/Er:YAG dual-wavelength surgery is presented for neurosurgery. Additionally, Yb/Er:YAG study results are compared with that of a tissue coagulation approach in Tm/Er:YAG surgery previously reported to highlight improved coagulation, reduced nonspecific thermal damage and limited lateral thermal spread. Experimental results suggest that the developed dual-wavelength laser system can effectively resect neural tissues with high localization, minimal lateral thermal spread at the micrometer level while maintaining a bloodless surgical field.

Laser coagulation and hemostasis of large diameter blood vessels: effect of shear stress and flow velocity.

Photocoagulation of blood vessels offers unambiguous advantages to current radiofrequency approaches considering the high specificity of blood absorption at available laser wavelengths (e.g., 532 nm and 1.064 µm). Successful treatment of pediatric vascular lesions, such as port-wine stains requiring microvascular hemostasis, has been documented. Although laser treatments have been successful in smaller diameter blood vessels, photocoagulation of larger sized vessels is less effective. The hypothesis for this study is that a primary limitation in laser coagulation of large diameter blood vessels (500-1000 µm) originates from shear stress gradients associated with higher flow velocities along with temperature-dependent viscosity changes. Laser (1.07 µm) coagulation of blood vessels was tested in the chicken chorio-allantoic membrane (CAM). A finite element model is developed that includes hypothetical limitations in laser coagulation during irradiation. A protocol to specify laser dosimetry is derived from OCT imaging and angiography observations as well as finite element model results. Laser dosimetry is applied in the CAM model to test the experimental hypothesis that blood shear stress and flow velocity are important parameters for laser coagulation and hemostasis of large diameter blood vessels (500-1000 µm). Our experimental results suggest that shear stress and flow velocity are fundamental in the coagulation of large diameter blood vessels (500-1000 µm). Laser dosimetry is proposed and demonstrated for successful coagulation and hemostasis of large diameter CAM blood vessels.

Fiber-laser platform for precision brain surgery.

Minimally invasive neurological surgeries are increasingly being sought after for treatment in neurological pathologies and oncology. A critical limitation in these minimally invasive procedures is lack of specialized tools that allow for space-time controlled delivery of sufficient energy for coagulation and cutting of tissue. Advent of fiber-lasers provide high average power with improved beam quality (lower M2), biocompatible silica fiber delivery, reduced cost of manufacturing, and radiant output stability over long operating periods. Despite these advancements, no fiber-laser based surgical tools are currently available for tissue resection in vivo. Here we demonstrate a first to our knowledge, fiber-laser platform for performing precise brain surgery in a murine brain model. In this study, our primary aims were to first demonstrate efficacy of fiber-lasers in performing precise blood-less surgery in a murine brain with limited non-specific thermal damage. Second, fiber-lasers' ability to deliver radiant energy through biocompatible silica fibers was explored in a murine brain model for blood less resection. A bench-top optical coherence tomography (OCT) guided fiber-laser platform was constructed with a stereotactic stage for performing precision brain surgery. A pulsed quasi-continuous wave ytterbium (Yb) fiber-laser (1.07 µm) was used to perform vascular specific coagulation while a pulsed nanosecond thulium fiber-laser (1.94 µm) was used to conduct bloodless cutting, all under the guidance of a swept-source OCT system centered at 1310 +/- 70 nm. Specialty linear and circular cuts were made in an in vivo murine brain for bloodless brain tissue resection. The two fiber-lasers were combined into a single biocompatible silica fiber to conduct brain surgery resection under the bench-top OCT system's imaging microscope. Vascular specific coagulation was demonstrated in all five mice studied. Bloodless linear cuts and point cuts were demonstrated in vivo. Histologically, thermal injury was measured to be less than 100 µm while a removal rate of close to 5 mm3/s was achieved with an average Tm fiber-laser power of 15 W. To the authors' knowledge, this is the first demonstration of a fiber-laser platform for conducting in vivo bloodless brain tissue resection with a pulsed thulium (Tm) fiber-laser and a quasi-continuous wave (QCW) Yb fiber-laser. The demonstrated fiber-laser platform, if successfully configured for use in the operating room (OR), can provide surgeons a tool for rapid removal of tissue while making surgical resections of brain regions more precise, and can be basis for a flexible cutting tool capable of reaching hard-to-operate regions.

Mechanisms of Pulse Modulated Holmium:YAG Lithotripsy.

Introduction: This study aimed at answering three research questions: (1) Under the experimental conditions studied, what is the dominant mechanism of Holmium:YAG lithotripsy with or without pulse modulation? (2) Under what circumstances can laser pulse modulation increase crater volume of stone ablation per joule of emitted radiant energy? (3) Are BegoStone phantoms a suitable model for laser lithotripsy studies? Materials and Methods: The research questions were addressed by ablation experiments with BegoStone phantoms and native stones. Experiments were performed under three stone conditions: dry stones in air, hydrated stones in air, and hydrated stones in water. Single pulses with and without pulse modulation were applied. For each pulse mode, temporal profile, transmission through 1 mm water, and cavitation bubble collapse pressures were measured and compared. For each stone condition and pulse mode, stones were ablated with a fiber separation distance of 1 mm and crater volumes were measured using optical coherence tomography. Results: Pulses with and without pulse modulation had high (>80%) transmission through 1 mm of water. Pulses without pulse modulation generated much higher peak pressures than those with pulse modulation (62.3 vs 11.4 bar). Pulse modulation resulted in similar or larger craters than without pulse modulation. Trends in BegoStone crater volumes differed from trends in native stones. Conclusions: This results of this study suggest that the dominant mechanism is photothermal with possible photoacoustic contributions for some stone compositions. Pulse modulation can increase ablation volume per joule of emitted radiant energy, but the effect may be composition specific. BegoStones showed unique infrared ablation characteristics compared with native stones and are not a suitable model for laser lithotripsy studies.

Data automated bag breathing unit for COVID-19 ventilator shortages.

BACKGROUND: The COVID-19 pandemic has caused a global mechanical ventilator shortage for treatment of severe acute respiratory failure. Development of novel breathing devices has been proposed as a low cost, rapid solution when full-featured ventilators are unavailable. Here we report the design, bench testing and preclinical results for an 'Automated Bag Breathing Unit' (ABBU). Output parameters were validated with mechanical test lungs followed by animal model testing. RESULTS: The ABBU design uses a programmable motor-driven wheel assembled for adult resuscitation bag-valve compression. ABBU can control tidal volume (200-800 ml), respiratory rate (10-40 bpm), inspiratory time (0.5-1.5 s), assist pressure sensing (- 1 to - 20 cm H2O), manual PEEP valve (0-20 cm H2O). All set values are displayed on an LCD screen. Bench testing with lung simulators (Michigan 1600, SmartLung 2000) yielded consistent tidal volume delivery at compliances of 20, 40 and 70 (mL/cm H2O). The delivered fraction of inspired oxygen (FiO2) decreased with increasing minute ventilation (VE), from 98 to 47% when VE was increased from 4 to 16 L/min using a fixed oxygen flow source of 5 L/min. ABBU was tested in Berkshire pigs (n = 6, weight of 50.8 ± 2.6 kg) utilizing normal lung model and saline lavage induced lung injury. Arterial blood gases were measured following changes in tidal volume (200-800 ml), respiratory rate (10-40 bpm), and PEEP (5-20 cm H2O) at baseline and after lung lavage. Physiological levels of PaCO2 (≤ 40 mm Hg [5.3 kPa]) were achieved in all animals at baseline and following lavage injury. PaO2 increased in lavage injured lungs in response to incremental PEEP (5-20 cm H2O) (p < 0.01). At fixed low oxygen flow rates (5 L/min), delivered FiO2 decreased with increased VE. CONCLUSIONS: ABBU provides oxygenation and ventilation across a range of parameter settings that may potentially provide a low-cost solution to ventilator shortages. A clinical trial is necessary to establish safety and efficacy in adult patients with diverse etiologies of respiratory failure.

Clinical Translation and Evaluation of a Handheld and Biocompatible Mass Spectrometry Probe for Surgical Use.

BACKGROUND: Intraoperative tissue analysis and identification are critical to guide surgical procedures and improve patient outcomes. Here, we describe the clinical translation and evaluation of the MasSpec Pen technology for molecular analysis of in vivo and freshly excised tissues in the operating room (OR). METHODS: An Orbitrap mass spectrometer equipped with a MasSpec Pen interface was installed in an OR. A "dual-path" MasSpec Pen interface was designed and programmed for the clinical studies with 2 parallel systems that facilitated the operation of the MasSpec Pen. The MasSpec Pen devices were autoclaved before each surgical procedure and were used by surgeons and surgical staff during 100 surgeries over a 12-month period. RESULTS: Detection of mass spectral profiles from 715 in vivo and ex vivo analyses performed on thyroid, parathyroid, lymph node, breast, pancreatic, and bile duct tissues during parathyroidectomies, thyroidectomies, breast, and pancreatic neoplasia surgeries was achieved. The MasSpec Pen enabled gentle extraction and sensitive detection of various molecular species including small metabolites and lipids using a droplet of sterile water without causing apparent tissue damage. Notably, effective molecular analysis was achieved while no limitations to sequential histologic tissue analysis were identified and no device-related complications were reported for any of the patients. CONCLUSIONS: This study shows that the MasSpec Pen system can be successfully incorporated into the OR, allowing direct detection of rich molecular profiles from tissues with a seconds-long turnaround time that could be used to inform surgical and clinical decisions without disrupting tissue analysis workflows.

Differentiation of Brain Tumor Microvasculature From Normal Vessels Using Optical Coherence Angiography.

BACKGROUND AND OBJECTIVES: Despite rapid advances and discoveries in medical imaging, monitoring therapeutic efficacy for malignant gliomas and monitoring tumor vasculature remains problematic. The purpose of this study is to utilize optical coherence angiography for vasculature characterization inside and surrounding brain tumors in a murine xenograft brain tumor model. Features included in our analysis include fractional blood volume, vessel tortuosity, diameter, orientation, and directionality. STUDY DESIGN/MATERIALS AND METHODS: In this study, five tumorous mice models at 4 weeks of age were imaged. Human glioblastoma cells were injected into the brain and allowed to grow for 4 weeks and then imaged using optical coherence tomography. RESULTS: Results suggest that blood vessels outside the tumor contain a greater fractional blood volume as compared with vessels inside the tumor. Vessels inside the tumor are more tortuous as compared with those outside the tumor. Results indicate that vessels near the tumor margin are directed inward towards the tumor while normal vessels show a more random orientation. CONCLUSION: Quantification of vascular microenvironments in brain gliomas can provide functional vascular parameters to aid various diagnostic and therapeutic studies. © 2021 Wiley Periodicals LLC.

Group Refractive Index of Nanocrystalline Yttria-Stabilized Zirconia Transparent Cranial Implants.

Transparent "Window to the Brain" (WttB) cranial implants made from a biocompatible ceramic, nanocrystalline Yttria-Stabilized Zirconia (nc-YSZ), were recently reported. These reports demonstrated chronic brain imaging across the implants in mice using optical coherence tomography (OCT) and laser speckle imaging. However, optical properties of these transparent cranial implants are neither completely characterized nor completely understood. In this study, we measure optical properties of the implant using a swept source OCT system with a spectral range of 136 nm centered at 1,300 nm to characterize the group refractive index of the nc-YSZ window, over a narrow range of temperatures at which the implant may be used during imaging or therapy (20-43°C). Group refractive index was found to be 2.1-2.2 for OCT imaging over this temperature range. Chromatic dispersion for this spectral range was observed to vary over the sample, sometimes flipping signs between normal and anomalous dispersion. These properties of nc-YSZ should be considered when designing optical systems and procedures that propagate light through the window, and when interpreting OCT brain images acquired across the window.

Laser nanobubbles induce immunogenic cell death in breast cancer.

Recent advances in immunotherapy have highlighted a need for therapeutics that initiate immunogenic cell death in tumors to stimulate the body's immune response to cancer. This study examines whether laser-generated bubbles surrounding nanoparticles ("nanobubbles") induce an immunogenic response for cancer treatment. A single nanosecond laser pulse at 1064 nm generates micron-sized bubbles surrounding gold nanorods in the cytoplasm of breast cancer cells. Cell death occurred in cells treated with nanorods and irradiated, but not in cells with irradiation treatment alone. Cells treated with nanorods and irradiation had increased damage-associated molecular patterns (DAMPs), including increased expression of chaperone proteins human high mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and heat shock protein 70 (HSP70). This enhanced expression of DAMPs led to the activation of dendritic cells. Overall, this treatment approach is a rapid and highly specific method to eradicate tumor cells with simultaneous immunogenic cell death signaling, showing potential as a combination strategy for immunotherapy.

Laser brain cancer surgery in a xenograft model guided by optical coherence tomography.

Higher precision surgical devices are needed for tumor resections near critical brain structures. The goal of this study is to demonstrate feasibility of a system capable of precise and bloodless tumor ablation. An image-guided laser surgical system is presented for excision of brain tumors in vivo in a murine xenograft model. The system combines optical coherence tomography (OCT) guidance with surgical lasers for high-precision tumor ablation (Er:YAG) and microcirculation coagulation (Thulium (Tm) fiber laser). Methods: A fluorescent human glioblastoma cell line was injected into mice and allowed to grow four weeks. Craniotomies were performed and tumors were imaged with confocal fluorescence microscopy. The mice were subsequently OCT imaged prior, during and after laser coagulation and/or ablation. The prior OCT images were used to compute three-dimensional tumor margin and angiography images, which guided the coagulation and ablation steps. Histology of the treated regions was then compared to post-treatment OCT images. Results: Tumor sizing based on OCT margin detection matched histology to within experimental error. Although fluorescence microscopy imaging showed the tumors were collocated with OCT imaging, margin assessment using confocal microscopy failed to see the extent of the tumor beyond ~ 250 µm in depth, as verified by OCT and histology. The two-laser approach to surgery utilizing Tm wavelength for coagulation and Er:YAG for ablation yielded bloodless resection of tumor regions with minimal residual damage as seen in histology. Conclusion: Precise and bloodless tumor resection under OCT image guidance is demonstrated in the murine xenograft brain cancer model. Tumor margins and vasculature are accurately made visible without need for exogenous contrast agents.

Optical coherence tomography image-guided smart laser knife for surgery.

BACKGROUND AND OBJECTIVE: Surgical oncology can benefit from specialized tools that enhance imaging and enable precise cutting and removal of tissue without damage to adjacent structures. The combination of high-resolution, fast optical coherence tomography (OCT) co-aligned with a nanosecond pulsed thulium (Tm) laser offers advantages over conventional surgical laser systems. Tm lasers provide superior beam quality, high volumetric tissue removal rates with minimal residual thermal footprint in tissue, enabling a reduction in unwanted damage to delicate adjacent sub-surface structures such as nerves or micro-vessels. We investigated such a combined Tm/OCT system with co-aligned imaging and cutting beams-a configuration we call a "smart laser knife." METHODS: A blow-off model that considers absorption coefficients and beam delivery systems was utilized to predict Tm cut depth, tissue removal rate and spatial distribution of residual thermal injury. Experiments were performed to verify the volumetric removal rate predicted by the model as a function of average power. A bench-top, combined Tm/OCT system was constructed using a 15W 1940 nm nanosecond pulsed Tm fiber laser (500 µJ pulse energy, 100 ns pulse duration, 30 kHz repetition rate) for removing tissue and a swept source laser (1310 ± 70 nm, 100 kHz sweep rate) for OCT imaging. Tissue phantoms were used to demonstrate precise surgery with blood vessel avoidance. Depth imaging informed cutting/removal of targeted tissue structures by the Tm laser was performed. RESULTS: Laser cutting was accomplished around and above phantom blood vessels while avoiding damage to vessel walls. A tissue removal rate of 5.5 mm3 /sec was achieved experimentally, in comparison to the model prediction of approximately 6 mm3 /sec. CONCLUSION: We describe a system that combines OCT and laser tissue modification with a Tm laser. Simulation results of the tissue removal rate using a simple model, as a function of average power, are in good agreement with experimental results using tissue phantoms. Lasers Surg. Med. 50:202-212, 2018. © 2017 Wiley Periodicals, Inc.

Nondestructive tissue analysis for ex vivo and in vivo cancer diagnosis using a handheld mass spectrometry system.

Conventional methods for histopathologic tissue diagnosis are labor- and time-intensive and can delay decision-making during diagnostic and therapeutic procedures. We report the development of an automated and biocompatible handheld mass spectrometry device for rapid and nondestructive diagnosis of human cancer tissues. The device, named MasSpec Pen, enables controlled and automated delivery of a discrete water droplet to a tissue surface for efficient extraction of biomolecules. We used the MasSpec Pen for ex vivo molecular analysis of 20 human cancer thin tissue sections and 253 human patient tissue samples including normal and cancerous tissues from breast, lung, thyroid, and ovary. The mass spectra obtained presented rich molecular profiles characterized by a variety of potential cancer biomarkers identified as metabolites, lipids, and proteins. Statistical classifiers built from the histologically validated molecular database allowed cancer prediction with high sensitivity (96.4%), specificity (96.2%), and overall accuracy (96.3%), as well as prediction of benign and malignant thyroid tumors and different histologic subtypes of lung cancer. Notably, our classifier allowed accurate diagnosis of cancer in marginal tumor regions presenting mixed histologic composition. Last, we demonstrate that the MasSpec Pen is suited for in vivo cancer diagnosis during surgery performed in tumor-bearing mouse models, without causing any observable tissue harm or stress to the animal. Our results provide evidence that the MasSpec Pen could potentially be used as a clinical and intraoperative technology for ex vivo and in vivo cancer diagnosis.