Delivering therapeutic drug molecules to the target site and releasing the cargo site-specifically is of major interest in biomedicine. To carry and release drugs to specific target tissues, different nanotechnology approaches have been utilized. These include light-sensitive liposomal carriers, which have been engineered to release cargo from their aqueous cores when illuminated by certain wavelengths of laser light. To study drug release parameters in vitro, Modulight has designed and automated biomedical illumination system ML8500. ML8500 can be tailored to house up to eight Modulight semiconductor lasers ranging from 400nm-2000nm selected based on the optical properties of dyes and molecules of interest. The illumination system can be configured for different well plate types and includes environmental control of temperature and CO2 to provide stable conditions for the studied cell types. Utilizing the ML8500 illumination system, the safety of laser light illumination for the liposomal drug delivery was investigated in retinal pigment epithelial (ARPE-19) cell line.
Efficient site-specific delivery of systemic therapeutic drugs is crucial especially in oncology but has proved to be challenging. Drugs can be encapsulated into liposomes that offer improved therapeutic index and distribution of the drug. The release of the drug can be efficiently achieved by integrating light-sensitive component into liposomes and applying near-infrared light in a time- and site-specific manner. Modulight has designed a cloud-connected ML8500 automated biomedical illumination system to specifically study in vitro drug release. The design is flexible, allowing up to eight Modulight semiconductor lasers of different wavelengths to be installed in one system, as well as the capability to be configured for different well plates, depending on the application requirements. The system includes an enhanced environmental control unit to ensure that the samples are investigated in physiologically relevant conditions. This enables also mimicking pathological conditions since drug release by light can have very different efficacy in these special conditions. Here we present an important case study regarding the utilization of the ML8500 system to investigate light-activated indocyanine green based liposomes which have been previously demonstrated to have great potential as advanced drug delivery systems.
Here we present novel cloud-connected theranostic medical laser platform specifically designed for activating and simultaneously monitoring multi-component oncological treatment processes. It may incorporate multiple wavelengths for inducing therapeutic effect or monitoring treatment in real-time. The same low-invasive optical probers can be used for treatment and monitoring. We believe that this theranostic laser platform will allow clinicians to develop improved treatment outcomes for cancer patients that may be based on machine learning and AI in the future.
Multiple clinically approved dyes and several new dyes currently in clinical studies are used for fluorescence-guided surgery, diagnosis and imaging. These present a wide range of absorption and emission spectra and create a demand for endoscopic illumination sources with multiple wavelengths. Fluorescent imaging with simultaneous white light overlay image benefit from laser light sources for fluorescence excitation and white light illumination to allow for easy spectral filtering on imaging side. Emerging applications with imaging of two or more complementary fluorescent dyes further adds to desire for a configurable multi-wavelength endoscopic light source. The multi-wavelength configurable and cloud connected oncology laser platform Modulight ML7710 was developed further to accommodate the light engine requirements of real-time multi-wavelength endoscopic fluorescence imaging. The configurable medical illumination platform enables simultaneous multi-wavelength fluorescence excitation with wide dynamic range and color balance adjustable RGB white light illumination. Multi-wavelength light output functionality was further developed to support industry standard endoscopic light guides without the need of additional external optical elements. Laser light sources for imaging typically suffer from unwanted speckle patterns. This issue is solved with internal speckle remover which greatly reduces speckle contrast even when used with high-speed imaging applications. The platform also offers possibility for spectral measurement of fluorescence from the target to the supplement or facilitate high-resolution imaging. The configurable touchscreen user interface allows for simple application for specific operation and cloud-based connectivity enables modern configuration, data logging, planning and control with platform for future machine learning and AI analysis.
Photodynamic therapy is a cancer treatment modality with great potential but moderate clinical success. One reason for the sub-optimal clinical success is the limited knowledge about light distribution in tissues and lack of ways to monitor treatment real-time. Modulight has developed a laser platform for glioblastoma which will utilize real-time treatment monitoring based on spectral properties of the tissue and the drug. This therapy modality is based on photodynamic therapy with 5-aminolevulinic acid (5-ALA) primarily because the approved use of 5-ALA in fluorescence guided resections for glioblastoma and because of the known photobleaching properties of 5-ALA metabolite Protoporphyrin-IX (PPIX). Photobleaching means the photochemical alteration of a dye or a fluorophore in a way that it becomes permanently unable to fluoresce, and the real-time spectral monitoring is based on monitoring the intensity of PPIX fluorescence emission at 703 nm upon excitation with treatment wavelength 635 nm. Modulight glioblastoma platform enables monitoring PPIX fluorescence throughout the treatment to inspect the decline in fluorescence intensity. This photobleaching phenomenon represents the time region where the maximal therapeutic effect occurs so the ability to monitor this would ultimately enable optimizing the treatment time individually for each patient. Novel Modulight lasers are internet connected so that the treatment monitoring data can be immediately uploaded to cloud improving data management and review and possible future machine learning and AI based medicine.
The demand for fiber lasers has increased due to widening of application areas and higher power levels. As fiber lasers have become the main workhorse for high power material processing applications and competition among fiber laser manufacturers have become more evident, the laser manufacturers are in the process to find ways to lower overall cost of ownership to become more competitive. Key areas to look at are the efficiency of the fiber laser, especially the efficiency of the diode pump modules, and the higher reliability of its’ components. There is increasing demand for high power, high brightness, and higher efficiency laser diodes for kW-level fiber laser pumping. We present high-efficiency and high brightness laser diode optimized for lowered operating voltage while maintaining high power conversion efficiency of 60%. The laser diode design is a single quantum-well InGaAs/AlGaAs structure with graded index profile and large optical cavity design. The laser is fabricated into 4 mm long chips with a 94 μm emitter stripe indented for standard 105/125 μm core fiber laser pumping. The chips are mounted on AlN carrier and characterized as chip-on-submount. The laser produces 12.6 W optical power at 13 A and 1.62 V, reaching 60% conversion efficiency at operating point. The beam divergence angles are 8.5° horizontal and 34° vertical enabling high brightness and efficient fiber coupling. Furthermore, the lasers are reliability tested where they show outstanding reliability without sudden failures and ware-out rate less than 1% per 1000 hour over several thousand hours of testing.
There is a demand for a robust and flexible illumination and screening instrument for preclinical light-sensitive drug development and optogenetic research. While there is a great selection of different types of commercial plate readers available on the market, these instruments do not provide enough versatility for high-throughput illumination experiments. In addition, plate readers typically utilize xenon flash lamps or LEDs for sample analysis, which have wider spectral output and lower excitation powers compared to lasers. To answer this unmet need, we have developed an automated, laser-based well-plate illuminator, the ML8500. It enables flexible setup of illumination parameters like wavelength, light irradiance and fluence well-by-well within a single experiment. The fluorescence monitoring possibility expands the applicability beyond sample illumination to support various fluorescence applications. The built-in incubator minimizes unspecific cellular stress and ensures consistent data even during long measurement cycles. The system is also Cloud-connected, supporting data collection and analysis, and enabling machine learning and AI based biomedical research in the future. The ML8500 can be a useful tool for many biomedical fields such as optogenetics, where the activation of light-responsive opsins and simultaneous fluorescence monitoring of sensor proteins enables spatiotemporally controlled, all-optical electrophysiology. Independent of the field of use, the ML8500 can reduce the cost of experimental labor while increasing the reproducibility and data throughput of experiments. In this presentation, we describe the key features of the ML8500, how it is operated, proof-of-concept testing results as well as present some application areas where the ML8500 is especially useful.
Autonomous driving and automated ships are in increasing demand and the performance for pattern recognition and safety functions are essential. Harsh weather conditions lower the atmospheric transmission for useable eye-safe wavelengths and water vapor peaks prevent most laser light propagation for longer distances. In LIDAR application this problem can be solved with increased peak power. However, high peak power solutions with high repetition rate do not exist or they are bulky and expensive. Moreover, not all applications need the highest peak powers or high repetition rates. We present a collection of eye-safe LIDAR laser sources with varying laser pulse parameters for demanding conditions. Wavelengths ranging from 1400 nm to 1560 nm with peak powers from a few Watts to up to 18 kW and repetition rates up to 100 kHz. Naturally, for a good temporal resolution a short pulse operation is necessary and best sources presented here produce sub-10 ns pulses. Such high peak power, high repetition rate lasers present the state-ofthe-art performance for long range LIDAR, enabling hundreds of meters detection distance in poor weather, currently unavailable in earlier commercial solutions.
There is an ongoing need in photodynamic therapy (PDT) research to develop highly active photosensitizers (PSs) with improved characteristics combined with optimized treatment protocols to produce effective treatment with minimal side effects. While several novel PSs have undergone clinical trials or been approved in recent years, there remain few available instrumentation options for high-throughput screens (HTS) with in vitro PDT. The Modulight ML8500 was developed to address this need, facilitating HTS of potential PSs with its precisely specific control over the light component. The instrument can select from a variety of high-power, monochromatic wavelengths for screening in the context of a tumor-centered approach, whereby the light dose can be tailored to optimize for physiological conditions or limitations specific to the type of cancer. In the present case, the ML8500 was used here to characterize a series of promising ruthenium-based complexes specifically designed to target melanoma. These PSs could be activated over a broad range of wavelengths, and most importantly including in the near-infrared range, where light penetrates tissue more effectively. In a second study, osmium-based PSs were characterized with the ML8500 in normoxic and hypoxic conditions with variable light parameters (wavelength, light dose, light fluence), showing high activity even in hypoxic conditions. These are specific examples where the ML8500 successfully increased experimental flexibility, reproducibility, and throughput.
Traditionally one of the biggest challenges with light-based treatment modalities such as photodynamic therapy or different tumor ablation techniques is to determine how much light should be applied to the tissue and how that will be distributed to activate a bio-photonic process or a drug. Different tools have been developed to model light distribution in tissue, but this has not solved the problem of how to know what happens in the tissue during the treatment. Modulight has assessed this problem and developed a state-of-the-art laser platform with real-time treatment monitoring capability. Modulight ML7710i platform enables illumination and detection with up to eight illumination channels on same or different wavelength(s). Spectral measurements can be measured and collected with the same fibers that are used for illumination which is minimally invasive and eliminates the need for complicated measurement set-ups with moving fibers around in the tumor tissue or having separate monitoring probes. The system also is connected to cloud making treatment planning, data collection and analysis easy and reliable enabling machine learning and AI based medicine in the future. ML7710i type of medical device makes it possible not only to measure the light intensity at tumor margins but also monitor the progress of the treatment by measuring photosensitizer photobleaching, drug release or activation of multimodal drugs. Photobleaching monitoring with ML7710i is currently utilized in 5-ALA mediated clinical trials for glioblastoma and the data looks very promising. In addition, also drug release from novel light activated nanoparticles or other drug carriers can be effectively monitored for pharmaceuticals that possess fluorescent potential or carry fluorescence labels.
Fighting cancer involves more and more combination of modalities and drugs to maximize the long-term tumor resistance and cure. The rationale for combination therapy is to use treatment modalities or drug combinations that work by different mechanisms, decreasing the likelihood that resistant cancer cells will develop. The combination of light induced therapy like photodynamic therapy (PDT) and chemotherapy has the potential to overcome the limitations traditionally associated with light-based therapies and simultaneously limit the well-known adverse effects of chemotherapy by controlling local release and dose. Modulight ML7710i medical laser systems have not only been shown to unleash the cytotoxic potential of different photochemotherapeutic compounds but also to effectively monitor the drug release process providing clinicians real-time information on treatment progress and preliminary projections on treatment outcome. In vitro and in vivo experiments suggest that Modulight ML7710i lasers are capable of inducing drug release from liposomes with different mechanisms depending on the nano-construct and laser wavelength. Near infrared wavelengths such as 808 nm are capable of disturbing liposomal bilayer upon light energy conversion to heat by dyes like indocyanine green.1 Red wavelengths such as 665 nm in turn can induce photodynamic effect also causing drug release from hydrophobic core of the liposome.2 Modulight ML7710i medical lasers are being validated for both use-cases and also for use with other dyes. The only limitation in using treatment monitoring capability is that the chemotherapeutic must have fluorescent potential. Modulight medical lasers can host multiple wavelengths within one system so that the drug release and the excitation can happen with different wavelengths if required.
Photodynamic therapy (PDT) is bringing new, effective, and less invasive, possibilities for cancer treatment. ML7710 (Modulight Inc.) medical laser system offers a platform for performing PDT for multiple indications and drugs. Latest avenue is glioblastoma treatment with 5-Aminolevulinic acid (ALA-5) and 635-nm light, where clinical trials are about to begin. Preliminary work suggests major advantages in treatment control, including active in-situ feedback. ML7710 platform has already proven itself for clinical work with intrabronchial obstructive tumors. Preliminary result with 10 patients show that intrabronchial tumors, that strongly affect both the survival and the performance of the patient, can be significantly reduced with ML7710 operated at 665 nm and sodium chlorine E6 photosensitizer. The aim in most of the patients has been a palliative recanalization of the bronchial lumen in order to alleviate the symptoms such as breathlessness and hemoptysis. The illumination dose for the target area was 50–75 J/cm2. All the patients have received multimodality cancer treatment using other intrabronchial interventions, radiotherapy and chemotherapy as needed. In most of the patients, satisfactory treatment results were achieved and it was possible to restart chemotherapy in several patients. In one patient with local cancer a complete remission was established. PDT has also the advantage that it is possible to give PDT after a maximum dose of radiation therapy has already been used and fewer side effects if used in locally advanced intraluminar lung cancer.
We demonstrate here an all-fiber passively mode-locked laser using an integrated fiber-end mirror and photonic band-gap
fiber-based dispersion compensator. The refined technology of thin-film coatings made with electron beam
evaporation on a single-mode fiber facet results in a compact dichroic pump combiner/output coupler. The dichroic
mirror made of ZrO2 and SiO2 provides a low reflectivity (0.4 %) for the 980 nm pump and over 40 % reflectivity for the
1040 nm signal wavelength, which enabled us to build a short-length mode-locked ytterbium fiber laser. The laser cavity
consisted of 8 cm of highly doped ytterbium fiber, 10 cm of anomalous dispersion photonic bandgap fiber, a
semiconductor saturable absorber mirror (SESAM) and the dichroic mirror. Pump and signal wavelengths were
separated by a fiber coupler placed outside the cavity contrary to conventional geometry. A butt-coupled SESAM
provided reliable self-starting at a pump power of 150 mW. The all-fiber design using dichroic fiber mirror combined
with photonic bandgap fiber dispersion compensator is highly stable and requires virtually no alignment. The mode-locked
laser produces 572-fs soliton pulses at 571.03 MHz fundamental repetition rate. To the best of our knowledge,
this is the highest fundamental repetition rate fiber laser operating around 1 μm reported to date.
Owing to their good beam quality and high output power, near-infrared semiconductor disk lasers provide an attractive
opportunity for visible light generation via frequency conversion. The typical cavity arrangement of a semiconductor
disk laser, consisting of a semiconductor multiple quantum well gain mirror and one or more external mirror, offers a
convenient configuration for intracavity frequency doubling. Recent progress in the disk laser development has led to
demonstrations of multi-watt green-blue-yellow sources. These achievements have been enabled by the possibility to
integrate high performance InGaAs/GaAs gain media and Al(Ga)As/GaAs Bragg reflectors operating in the 940-1160
nm wavelength range. In order to achieve ~620 nm red emission, a laser emitting near the fundamental wavelength of
1240 nm is needed. To achieve this spectral range we have developed GaInNAs/GaAs gain mirrors and we have
achieved 1 W of output power at 617 nm by frequency doubling in a BBO crystal. This is to our knowledge the highest
power reported to date for intracavity doubled disk laser based on dilute nitride gain material.
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