FIELD OF THE INVENTION

The present invention generally relates to the field of implantable technology for recording and stimulation of gastric slow waves (SWs) as well as ultrasound interrogation (wireless power/data) of miniaturized implantable devices.

BACKGROUND OF THE INVENTION

Gastric contractions are initiated and coordinated by an underlying bioelectrical activity, termed slow waves (SWs). Aberrant SW patterns (dysrhythmias) have been associated with gastric dysmotility in several significant gastric motility disorders, notably gastroparesis (GP), chronic nausea and unexplained vomiting, and functional dyspepsia (FD). The GP is a chronic debilitating disease, with symptoms including continuous nausea and vomiting, affecting more than 1.5 million people in the United States (US). Up to 30-50% and 16-30% of patients with Type 1 and Type 2 diabetes suffer from the GP or related symptoms, respectively. This number is increasing due to the diabetes epidemic, with hospitalizations rising 150% in the last decade with major increase in the associated costs. The FD is a chronic disorder characterized by upper abdominal pain, bloating and early satiety. The FD is highly prevalent, affecting up to 15-30% of the US population, with vast associated economic burden. The FD is also associated with gastric emptying impairments in up to 20-40% of FD patients, and among several putative mechanisms, dysrhythmic SW activity has been implicated in some 33-83% of FD patients. The diagnoses of FD and GP are challenging, often requires multiple clinical visits and investigations including radioisotope scans, endoscopy, contrast studies, ultrasound, and SmartPill. However, these diagnostic strategies represent a process of exclusion, rather than analyzing fundamental mechanisms, and none allows real-time continuous monitoring of the SW dysrhythmias in the conscious users that may be directly contributing to pathophysiology and symptoms.

High-resolution mapping technologies have become a fundamental tool for accurately defining electrophysiological properties in multiple fields, including electromyography and electrocardiography. These high-resolution mapping technologies have also recently been advocated as a tool to reveal the mechanisms underlying gastric dysrhythmias, which have been poorly understood using past techniques. Prominent studies have recently revealed a surprising complexity underlying gastric dysrhythmias, comparable to cardiac dysrhythmias, and including complex focal activities and re-entrant patterns. Translating these advances to the clinic to clarify the role of dysrhythmias in conditions such as GP, and FD is now a research priority in this field. Translational advances in high-resolution mapping are also anticipated to guide progress in the therapy field and are critically needed because current therapies for the GP and FD have poor efficacy.

Despite 100 years of intensive investigations, the clinical significance of gastric dysrhythmia remains poorly understood. Current gastrointestinal (GI) therapies, including gastric electrical stimulation (GES) and various pharmaceuticals are delivered and adjusted through trial and error in an open-loop fashion. Consequently, various researchers have reported conflicting therapeutic effects and the role of some of these therapies remains controversial. To better elucidate the pathophysiological significance of gastric electrical abnormalities, chronic studies in the conscious users, in fasting and fed states, are necessary. Non-invasive/indirect techniques such as cutaneous recordings, also called electrogastrography (EGG) and high-resolution EGG (HR-EGG), have limited accuracy and are highly prone to motion artifacts. The SWs taken directly from the stomach currently provide the only reliable and spatially descriptive data. These techniques are invasive in comparison to the EGG and HR-EGG. High-resolution mapping of the SWs has been a critical recent advance, allowing a new era in accurate analysis of the dysrhythmic onset and maintenance. However, the current high-resolution direct mapping approaches are highly invasive, and therefore, cannot be applied in chronic animal studies or patients. Existing serosal or mucosal recording systems currently transmit signals through wires traversing either through the abdominal wall or through a natural orifice. These wires can act as a conduit for infection, induce discomfort, become displaced, and restrict mobility due to their connection to bulky acquisition systems; hence, the monitoring period is often limited to the anaesthetized state of the animal or patient.

The Pennsylvania State University in collaboration with the New York Institute of Technology (NYIT) have developed wireless and implantable technologies to acquire SWs from the GI tract. This technology is composed of 1) a wireless 64-channel implant (size: 30×10×6.7≈2000 mm3) that is placed in the stomach submucosa space through an endoscopic procedure, 2) a wearable unit that powers the implant by inductive coupling and receives the SWs via inductive backscattering, and 3) a stationery unit that is connected to a computer and can display the SWs in real time (FIG. 1). An implantable Complementary Metal-Oxide-Semiconductor (CMOS) Application-Specific Integrated Circuit (ASIC) (i.e. CMOS-ASIC) integrates 64 low-noise amplifiers (LNAs) and filters, an 8-bit analog-to-digital-converter (ADC), a power management circuit, and a data transmitter (FIG. 2). The CMOS-ASIC connects to an array of flexible electrodes to wirelessly record and then map the SWs. Although this system acquires the gastric SW activity, it still suffers from the following multiple shortcomings, such as 1) due to the stomach motility and the implant's bulkiness, the electrodes (or implant) detach from the muscle's surface (or submucosa space), resulting in signal loss or a serious complication, 2) due to the implant's size and implantation procedure, enteric nervous system under the submucosa space can be damaged, resulting into failure of the implantation procedure or signal acquisition, 3) due to limitations in the endoscopic implantation method (i.e. making a pocket in the submucosa space) this system can acquire the SWs from a limited portion of the GI tract (i.e., limited spatial coverage), and 4) this system can only record gastric SWs without any stimulation capability, i.e. it is a open-loop system. In addition, gastric motility cannot be measured by this system. The above-discussed existing approaches do not use a distributed addressable network, and employ either power-hungry carrier-based data transfer or weak backscattering via load modulation, which serves short distances.

The current high-resolution mapping approaches are highly invasive in that electrode wires traversing the abdominal wall or a natural orifice pose risks of discomfort, dislodgement or infection. Thus, it is desirable to enhance the current therapies to provide a better solution in order to overcome limitations of the existing technologies.

SUMMARY OF THE INVENTION

As a result, closed-loop methods are required to enhance the existing therapies. For instance, synchronized closed-loop GES has been applied on anesthetized canine models to modulate gastric contractions and enhance gastric motility. Robust and real-time acquisition of SW data in the conscious patients can be used as the feedback signal to develop a closed-loop therapy. This disclosure outlines a free-floating, minimally invasive, implantable technology for both recording and stimulation of the gastric SWs at a large scale inside the whole stomach using a network of ultrasonically or inductively powered and communicated millimeter-sized implants called gastric seeds. This technology features ultrasonic self-regulated integrated power management, low-power pulse-based data transfer, addressability of each gastric seed in the network, and a self-image-guided ultrasound interrogation technique for robust and efficient wireless power and data transfer to any network of miniaturized implants particularly in actively mobile environments like stomach.

The proposed gastric seeds are 1) small (millimeter scale), light, free-floating, and wireless to minimize the motion artifacts, tissue damage, and risk of infection and expulsion, 2) modular to acquire SWs from the whole stomach through independent interrogation of each addressable gastric seed with unique identification (IDs), 3) capacitively or electrically coupled to the tissue, and 4) implanted in the stomach submucosa space through an endoscopic procedure. The gastric seeds either use ultrasound or RF signals (inductive link) for wireless power and bidirectional data transmission for a distributed addressable network as discussed in this disclosure. This disclosure discusses ultrasonic wireless power/data transmission, but similar techniques can also be employed for inductive power/data transmission. When the gastric seeds communicate with ultrasound using sharp pulses, the received pulses are used to image the location of the gastric seeds and to measure gastric motility of the user as well.

The proposed technology is briefly discussed herewith and has three key modules (i.e. a network of implantable gastric seeds, a Wearable Unit (WU), and a Processing Unit (PU)). An array of millimeter-scale gastric seeds is placed in the stomach's submucosa layer of a user. In accordance with the present disclosure, the volume of an individual gastric seed may be 10 mm3or less in scale, and not in cm3scale or more. As discussed above, the wireless 64-channel implant has an approximate volume of about 2000 mm3and is not be considered as millimeter-sized according to this disclosure. The millimeter-sized gastric seeds according to this disclosure may be defined as having a volume range from about 1 mm3to 10 mm3. None of the millimeter-sized gastric seeds of this disclosure have a volume of more than 100 mm3. The gastric seeds are placed either surgically e.g. endoscopically (minimally invasive) or through other suitable techniques in the submucosa layer or other layers of the stomach of the user. In some embodiments, the gastric seeds may be placed in a plurality of layers of the user's stomach. The gastric seeds may be positioned in a defined area of the stomach, equally distributed throughout the stomach, or have a varying concentration in one layer/area of the stomach in comparison to other layers/areas of the stomach. In a non-limiting example, the gastric seeds may be partially, subtotally, or completely implanted or embedded in one or more layers of the stomach.

In comparison to the above-discussed existing technologies, the small size of the gastric seeds does not interfere with stretching and contractions of the gastrointestinal (GI) tract muscles in the stomach. These muscle movements partly occur due to peristalsis and segmentation (mixing). The small size also reduces the likelihood of any damage caused by the gastric seeds to the user's stomach due to muscle movement or the user's normal routine lifestyle.

The gastric seeds are operable to measure the gastric SWs, wirelessly transmit the measured value, and to stimulate the stomach tissues based on wirelessly received data to influence gastric motility related disorders. A human user's stomach consists of different layers. These layers, starting from the innermost layer, are named mucosa, sub-mucosa, muscularis externa, and the serosa. The gastric seeds placed in one stomach layer may be able to measure the gastric SWs and/or stimulate the stomach tissues of another stomach layer. Moreover, the gastric seeds may be powered wirelessly to meet the operational power requirements of the gastric seeds. Bidirectional wireless communication satisfies all the data and power requirements of the gastric seeds. Thus, each of the in-vivo gastric seeds is a discreet unit that does not require any wired circuitry for power/data communication extraneous to the stomach layers.

The second module of the proposed technology is the external WU. The external WU is a flexible printed circuit board (PCB) in the form of a bellyband worn by the user. In some embodiments, the WU may be not be flexible and/or have a self-contained cuboidal, spherical, or cylindrical or other suitable form/shape. In other embodiments, the user may carry the WU instead of wearing the WU. The shape and flexibility of the WU should be determined such that the WU is able to wirelessly communicate with and power each implanted gastric seed. Each gastric seed within the stomach has a unique address and location that is used by the WU for identification. The WU receives the measured value of the gastric SWs from each gastric seed and transmits the desired stomach tissue stimulation parameters. The WU also delivers a minimum power to each gastric seed regardless of its location (whole stomach) and alignment/orientation. In some embodiments, each gastric seed is aligned/oriented with respect to the WU. In a non-limiting example, the gastric seed(s) and the WU are parallel or perpendicular to each other for maximum wireless power/data transmission efficiency. Although not all the implanted gastric seeds may be totally parallel or perpendicular with respect to the WU, the WU is operable to deliver a predetermined minimum power and bidirectional data transmission for each gastric seed.

The third module of the proposed technology is the PU that is located a few meters from the user to wirelessly receive the measured SWs from the WU for real-time display and mapping the stomach activity. The PU has the location/coordinate parameter information, address of each gastric seed and uses it to generate a stomach activity map of the user. The PU acts as a central processing unit of the proposed technology. The PU receives and records the measured SWs, and determines the amount and duration of tissue stimulation that each of the gastric seed may deliver to improve upon gastric motility disorders of the user. The PU transmits the stimulation and power related parameters for each gastric seed to the WU that further transmits this information to each gastric seed. Thus, it is a closed-loop system that measures the SWs in real time, generates the stomach activity map, and based on the map determines and stimulates the stomach tissues of the user.

