"The 4Dx function analysis is unique because it can provide the spatial and functional information we need to optimize treatment for each patient."
Assistant Clinical Professor, Children’s Hospital Los Angeles
Professor of Clinical Radiation Oncology, USC Keck School of Medicine
4DxV four-dimensional X-ray imaging technology uniquely and non-invasively measures lung airflow in real-time within the breathing lungs. This enables highly detailed maps of patterns of lung ventilation and airflow, with disease detected and monitored through deficits in ventilation.
4DxV provides, for the first time in medical history, the capacity to simply, safely and effectively see lung function in fine detail. Consequently, there is massive opportunity for diagnosing and monitoring debilitating respiratory conditions such as COPD, cystic fibrosis, asthma and lung cancer with unprecedented insight and precision. The applications for 4Dx’s technology are essentially unlimited, from diagnostic uses to radiotherapy to pharmaceutical research. The end result: improving millions of lives through earlier disease detection and more accurate monitoring of chronic respiratory conditions.
The 4Dx image analysis technology receives X-ray images acquired from X-ray imaging equipment already installed in every major medical center and through our software converts those images into 4D lung function data.
The business context
This software-as-a-service business model vastly increases the potential scope of application and customer base, as well as accelerates take-up of the technology. It’s an approach that provides rapid scalability.
4Dx has patent protection across all global markets.
The lungs make up an essential human organ responsible for vital gas exchange, transporting atmospheric oxygen into the bloodstream, and releasing carbon dioxide from the bloodstream back into the atmosphere. The air is drawn into the body through the nose and mouth, travelling through the body’s air channels until it reaches the tiny gas exchange end points (called alveoli) embedded deep within the lung structure.
The trachea (windpipe) divides into two main bronchi, the left and the right, at the entrance to the lungs. The bronchi then subdivide into smaller bronchioles and continue subdividing until reaching the alveoli, which are small air sacs grouped into bunches and wrapped tightly in blood vessels. This is where the gas exchange occurs.
Mammalian lungs are spongy and soft in texture, and are located in two cavities on either side of the heart, directly above the thoracic diaphragm. Each lung is separated into lobes by fissures, and each lobe is encased by a pleural cavity which is a self-lubricating membrane that helps the lungs slide and function effortlessly during the action of breathing.
The lung region is very moist and warm, a perfect breeding ground for bacteria. Most illnesses of the lung relate to bacterial and viral infection, which often lends itself to inflammation of the lung tissue (known as pneumonia), or inflammation of the pleura (known as pleurisy). The lungs’ natural defense to foreign agent infection is through mucociliary clearance. The tissue lining the airways produces sticky mucus which traps foreign bodies (like dust or bacteria) in it. The body then moves the mucus up and out of the lungs through a coordinated rhythmic beating action of the hair-like cilia that lines the airways.
Respiratory disease is a medical term for all conditions affecting the organs and tissues responsible for gas exchange in humans, including conditions of the upper respiratory tract, the trachea, the bronchi, bronchioles, alveoli, pleura and pleural cavity, as well as the nerves and muscles associated with breathing. Respiratory disease may be mild, such as the common cold, but range to life-threatening, such as pulmonary embolism and lung cancer.
Lung diseases place an enormous and growing burden on society, resulting in one-in-six (16.7%) deaths globally (World Health Organisation 2008), and are predicted to cause one-in-five deaths by 2030 (European Respiratory Society White Book 2012). Lung diseases often originate in the periphery of the lung where the flow of air is lowest, and therefore hard to detect using standard tools in the clinic today. Monitoring disease progression or treatment efficacy also relies on detecting subtle changes in lung function, and are therefore just as difficult to detect.
Lung Imaging Modalities
Current modalities for both diagnosis and lung disease monitoring can be categorised broadly into two categories; pulmonary function tests (PFTs) to measure functional aspects of the lung, and imaging techniques for organ structure visualisation.
Projection radiography, commonly called X-ray, is a widely utilised medical imaging method to examine the type and extent of bone fractures, as well as pathological changes in the lungs. A beam of X-rays is projected towards the body. According to the different composition and densities of the bodily materials along its path, the X-rays are absorbed at different rates. The X-rays are captured on a detector plate behind the patient showing a 2-dimensional representation of the structures that form a superimposed image.
Since bone has a large density difference to the soft tissue that surrounds it, X-rays produce vivid detail of bone structures, hence X-rays’ extensive use in dentistry and for detecting bone fractures. Although relatively cheap in terms of cost and radiation dose, plain chest X-rays lack the sensitivity required to provide intricate detail of soft tissue structures and therefore are poor at detecting early stages of lung disease.
X-ray computed tomography (CT) or computed axial tomography (CAT scan) uses tomography of X-rays to construct a 3-dimensional image of structures inside the body. Tomography involves taking a succession of 2-dimensional images of the same object, taken around a single axis of rotation. Once complete, the large volume of data can be manipulated in various planes or created into a volumetric representation, of much higher sensitivity than plain X-ray.
CT use has increased dramatically in the last two decades, however large radiation doses are received by the patients due to the long scan time of the large series of images required, and it is estimated that 0.4% of all current cancers in the US are due to CTs performed in the past (Brenner & Hall; 2007), with that figure likely to dramatically rise with the current CT usage growth rates. Further to this, the best quality chest scans require patient sedation, especially of young patients, and it has been suggested that age at exposure to diagnostic radiation has been correlated to higher death rates due to cancer in people exposed in childhood.
Magnetic Resonance Imaging (MRI) uses the property of nuclear magnetic resonance (NMR) to image the nuclei of atoms inside of the body to produce detailed internal structures. An MRI machine uses a powerful magnetic field to align the magnetization of some atoms in the body. Radio frequency fields are then used to systematically alter the alignment. The nuclei rotate in accordance, producing a detectable rotating magnetic field picked up by the scanner that is then used to construct images of the body.
In contract to X-rays and CT, MRI provides contrast between different soft tissues, making it suitable for imaging the brain, muscles, the heart and cancers, however MRI is widely regarded as lacking sufficient resolution to image the lung. Research is currently being conducted to improve the sensitivity, but is currently not available.
Pulmonary function tests are a group of tests that measure how well the lungs are functioning. They measure how much air is taken in and released by the lungs and how well the lungs move gases, such as oxygen, from the atmosphere into the body’s circulation.
Spirometry is a common functional test of the lung, measuring the volume and also the flow speed of air that can be inhaled and exhaled through sustained deep breaths into the spirometer device. Plotted graphs, called spirograms, of volume and flow are output and used to assess conditions of the lung.
Although PFTs are not an imaging technique, and therefore have no radiation dose associated with their use, they are global measures of the lung, and do not pinpoint where functional deficits are present. They also cannot measure for compensation of different areas of lung, returning regular results. A significant drop in overall lung function must be present to be seen.
Ultrasound (pressure waves with a frequency more than 20kHz) is typically used to either supply a focused energy source or to penetrate a medium in order to investigate the properties of that medium. The reflection signature can reveal details about the inner structure of the medium. It has been widely used in clinic over the past half century due to its portability and relatively low cost, especially in comparison with CT and MRI. It is also a safer alternative as no radiation dosage is administered, but simply lacks the resolution required for visualising lung disease.
A PET scan detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide, a glucose-analogue tracer, which is introduced into the body. Dependent on regions of glucose uptake within the body, three-dimensional images of tracer concentration are reconstructed with computer analysis. This imaging modality is relatively new for use with the lungs, but is potentially suitable for certain types of lung function investigation where inflammation causes greater glucose uptake.
Our 4D lung imaging technology
Rather than looking to the fine detail of the lungs’ shape (the approach of the last 100 years), our 4D lung imaging technology looks at the way the lung functions by targeting patterns of motion in the lung. This high performance X-ray imaging technology precisely captures a breathing lung, without the use of contrast agents or dangerous levels of radiation. This technology allows patients and clinicians to safely and effectively measure and image airflow in and out of the each section of the lung for the first time.
Our 4D lung imaging technology takes a unique approach to imaging lung function. X-ray images are acquired simultaneously from different directions on existing hospital X-ray imaging systems. Using image-processing methods adapted from aerospace engineering, the movement of the lung tissue from each view is collectively tracked. Our unique, proven algorithms combine this information to reconstruct the flow of air throughout all airways of the lung. Since our technology uses images from a very limited number of different angles (compared to many hundreds of different angles in a full CT scan), the radiation dose is dramatically lower than CT. Furthermore, the limited number of angles means that scans are captured quickly: a breath is scanned in the time required to take that breath – just a few seconds.
Our technology fills critical and unmet needs in lung imaging. This technology has clear applications in both a human clinical setting for medical imaging and diagnostics and in contract research for drug development. The technology is proven in small animal models and clinical study applications are underway. We, along with many collabotors from various research groups have already used the technology to investigate conditions including cystic fibrosis and asthma, as well as in developing infant resuscitation techniques. In addition to these early stage studies, this technology has the potential to assist in the development of new respiratory drug treatments and refine or accelerate the progress of respiratory drugs already under development.
More than $25 billion is spent each year on respiratory diagnostic procedures globally, but today’s respiratory patients are often treated with medical equipment and technology created in the 1970s. 4Dx image analysis technology has enormous scope for life-changing advancement, enhancing diagnostic performance and accuracy across the following three market segments:
Radiation therapy is one of the most common forms of treatment for cancer, including cancers of the breast, spine and lungs. Radiotherapy will be the key to 4DxV’s first major introduction into the market.
4Dx’s patented technology revolutionises diagnosis by delivering high-resolution, quantitative functional information, from low-dose and non-invasive scanning. It’s far reaching potential provides unprecedented levels of detail for the diagnosis and monitoring of debilitating respiratory conditions such as Chronic Obstructive Pulmonary Disease, Cystic Fibrosis and Asthma. It is a true breakthrough for providing invaluable information to improve patient outcomes through better treatment planning and monitoring of treatment effectiveness.
Further applications of the 4Dx technology include Neonatal and Pediatrics plus Pharmaceutical Research.
Neonatal and Pediatrics
4Dx is developing groundbreaking imaging technology for doctors treating critically ill children. Unlike current technology, which uses scaled-down adult systems to diagnose and treat infants with conditions of the lung, 4Dx aims to develop systems specifically for use in both neonatal and broader pediatric settings. 4Dx technology is non-invasive and does not require patients to remain still during imaging. These are clear benefits for all patients and particularly for infants and children who cannot describe symptoms and may be anxious or distressed.
4Dx has the potential to fast track promising drug discoveries, determine effectiveness early and enable clear evaluation of performance in a pre-clinical space. 4Dx provides the advantage of faster, more accurate and sensitive assessment, the value of which cannot be underestimated – not least of which to those suffering from lung disease.
4DxV can enter this market with a significant and attractive point of difference non-invasive and in vivo imaging techniques that provide far greater detail and information from fewer scans, reducing the overall cost of R&D. Due to the limitations in existing technologies, 4Dx is perfectly suited to capitalize on this industry.
Respiratory function tests have been the staple of the respiratory physician for decades. That is set to change with the introduction of technology that has the capability to image a patient’s lung function directly.
Dedicated hardware development will offer advantages over current equipment, including increased temporal resolution, reduction in X-ray dose and increased throughput leading to greater efficiency.
The systematic uptake and use of conventional images in data mining has been hampered due to large data volumes and the need for highly qualified professionals to make assessments of the images.
4DxV data (small, digital and quantitative) represents a giant leap forward, enabling computer-based data mining techniques. Data that can be kept and used for further analysis and data mining has the advantage of providing value many times throughout its life cycle.