Patent Application
20160367987
The invention relates to health monitoring. More specifically, the invention relates to a wearable microfluidic analyte monitoring device capable of persistent health monitoring.
Tremendous growth in healthcare costs worldwide has necessitated the need for innovation in the prevention, diagnosis, and treatment of chronic diseases. Digital health monitoring can play a key role in reducing the overall healthcare costs, especially in the case of diseases such as diabetes. Monitoring of advanced health metrics, like blood glucose, face multiple significant challenges. Achieving very high specificity is the most critical challenge for such a biosensor, in addition to high sensitivity, rapid detection, portability, and low cost.
To address the needs in the art, an analyte monitoring device is provided that includes a microfluidic channel, where the microfluidic channel is configured for holding a sample under test, an electromagnetic excitation source disposed on a first side of the microfluidic channel, an ultrasonic transducer disposed on a second side of the microfluidic channel, or disposed on the first side of the microfluidic channel, and an appropriately programmed computer, where the electromagnetic excitation source is disposed to induce an thermoacoustic response in the microfluidic channel when holding the sample under test, where the ultrasonic transducer is disposed to receive the thermoacoustic response, where the ultrasonic transducer outputs a voltage to the appropriately programmed computer, where the appropriately programmed computer outputs an analyte value according to the thermoacoustic response.
In one aspect of the invention, the microfluidic channel includes materials such as cross-linked polystyrene, polystyrene (HIPS), polyethylene (LDPE or HDPE), polypropylene, Polytetrafluoroethylene (PTFE), Polyethylene Terephthalate (PET), glass, silicon dioxide, silicon nitride, aluminum oxide, or aluminum nitride.
According to another aspect of the invention, the microfluidic channel includes a living blood vessel or a living plant vessel.
In a further aspect of the invention, the electromagnetic excitation includes an applicator having material such as duraluminum, tin, aluminum, titanium, copper, gold, and platinum. In one aspect the electromagnetic excitation applicator includes an insulating dielectric covering, where the insulating dielectric covering includes a material such as glass, silicon oxide, silicon nitride, aluminum oxide, aluminum or nitride.
According to another aspect, the invention further includes a housing, where the housing includes insulating dielectric materials such as cross-linked polystyrene, polystyrene (HIPS), polyethylene (LDPE or HDPE), polypropylene, Polytetrafluoroethylene (PTFE), or Polyethylene Terephthalate (PET)).
In one aspect of the invention, the electromagnetic excitation source includes an RF source, or an optical source.
In yet another aspect of the invention, a magnetic source is disposed proximal to the sample under test, where the electromagnetic excitation source is disposed to induce a magnetoacoustic response in the microfluidic channel when holding the sample under test, where the ultrasonic transducer is disposed to receive the magnetoacoustic response, where the ultrasonic transducer outputs a voltage proportional to the magnetoacoustic response. In one aspect, the appropriately programmed computer is configured to match a waveform shape and amplitude of the thermoacoustic or the magnetoacoustic response in a time domain to known signatures from analytes of interest. In another aspect, the appropriately programmed computer is configured to match a frequency shape and phase content of the thermoacoustic or the magnetoacoustic response in a frequency domain to known signatures from analytes of interest. In a further aspect, the sample under test includes a contrast agent, where the contrast agent interacts with an analyte that is disposed to provide an identifiable thermoacoustic response or a magnetoacoustic response, where the analyte includes a biomolecule, cells, or synthetic compounds. Here, the contrast agent includes materials such as iron oxide, super-paramagnetic iron oxide nanoparticles (SPION), where the SPION is selected from the group consisting of hematite (α—Fe2O3), maghaemite (γ—Fe2O3), or aluminum substitutes in Iron Oxide (ε—AlxFe2—xO3).
According to one aspect of the invention, the electromagnetic excitation source is modulated, where the modulated electromagnetic excitation source is disposed to generate a modulated thermoacoustic response.
In another aspect of the invention, the ultrasonic transducer includes a MEMS sensor.
In a further aspect of the invention, the sample under test includes blood, saliva, urine, bodily fluids, agricultural fluid extracts, water system, sewer, or industrial fluid extracts.
According to another aspect of the invention, the thermoacoustic response includes an acoustic shock wave in the microfluidic channel formed by microthermal heating and expansion.
The current invention provides a multi-modality sensing device that uses the electromagnetic and thermo-elastic (Thermoacoustic) response of target compounds for achieving a high specificity. According to one embodiment, the invention is scaling down to smaller dimensions using higher acoustic frequencies, where a next-generation biosensor for the non-invasive and continuous monitoring of advanced health metrics like blood glucose, medication concentrations and eventually circulating tumor cells is provided. Demonstrated herein are two critical aspects of a Thermoacoustic biosensor. The first is reduction, by 4 orders of magnitude, in the required operating peak power, which allows 10 kV vacuum sources to be replaced by 48V solid-sate devices consuming 0.5 W average power. The second is experimental confirmation that both acoustic and electrical properties of samples or analytes contribute to their unique identification through Thermoacoustic sensing.
The current invention enables proactive, routine, and unobtrusive health monitoring that facilitates early diagnosis and preventative maintenance, thus reducing doctor visits and hospital waiting lines. The invention includes wearable electronics, internet-of-things connectivity, data on the Cloud, and emerging biosensing technologies configured in an affordable smartwatch, as shown in
Currently, smartwatches can monitor some common vital signs and physical activity. In general, low power and portable sensors for monitoring pulse, electrocardiogram, blood pressure, and temperature, motion, sweat and skin conductance are commonplace. The current invention provides advanced biosensing capabilities that enable the synchronous monitoring of clinically relevant biomarkers along with vital signs and activity that shifts the paradigm from treatment and therapy to continual monitoring and preventive care. The current invention enables a move away from the “one-size fits all” mentality of current pharmaceuticals to the personalized and dynamically tuned pharmaceuticals of the future.
Early diagnosis of cancer is one example where biomarkers such as circulating-tumor-cells (metastatic cancer), Prostate-Specific Antigen (prostate cancer), and others need to be monitored continuously. Early warnings for heart disease and stroke may also be detected by long term monitoring of biomarkers such as B-type Natriuretic Protein (BNP), Cardiac Troponin (cTn), and Ischemia-Modified Albumin (IMA). More generally, new applications will emerge once they are enabled by new biosensing technologies.
Because the Thermoacoustic technique of the current invention relies on electromagnetic excitation, achievable with integrated electronics, and acoustic detection, achievable with MEMS sensors, it is implemented with existing semiconductor technologies to provide biosensors based on Thermoacoustic phenomenon.
The two key defining attributes of a biosensing platform are non-invasive, in-vivo detection (and drug modulation) and Label-free detection. Each of these two major attributes is very challenging to obtain in itself and hence three categories of monitoring styles are embodied by the invention:
The first style emphasizes label-free detection, ex-vivo, in the controlled environment of a microfluidic biosensing chip. This permits various sample filtering mechanisms, including ultrasound techniques, that can remove large quantities of known undesired biomolecules and cells from the sample under test, enabling higher specificity and label-free detection simultaneously. For example, it is common to filter out white and red blood cells from a blood sample on a microfluidic chip and only analyzing the rest of the sample. In the Thermoacoustic biosensor in particular, ultrasound sensors and RF applicators are integrated into the microfluidic channels. This reduces the field of view, enhancing signal-to-noise ratio (SNR) and ultimately enabling greater specificity in a label-free detection scheme. Multiple biomarkers can be monitored with one Thermoacoustic biosensor as long as the each exhibits a unique Thermoacoustic signature, where the combined electromagnetic and mechanical properties of each biomarker are unique.
The second monitoring style emphasizes non-invasive, in-vivo operation without the need for extracting a blood sample. This necessitates a larger separation between ultrasound sensors and RF applicators located on the skin and the biomarkers located in the blood stream. This larger separation means more attenuation of ultrasound at higher acoustic frequency, and less electromagnetic focusing, which would limit resolution and detection capabilities. To compensate for this, safe and biocompatible Thermoacoustic contrast agents are ingested in the form of a pill as in
The third and final monitoring style combines the previous two and simultaneously achieves non-invasive and label-free detection. This requires highly refined and optimized system design which is likely to be only possible in particular applications and for particular biomarkers. Thus each compatible biomarker requires its own uniquely designed and optimized biosensor.
Different materials based on their Thermoacoustic response to pulsed microwave excitation are identified, as illustrated in
Contrast agents are commonplace in imaging applications, where they improve image quality through enhanced contrast. In Thermoacoustic imaging and sensing this is achieved through the interaction of the contrast agent with microwave excitation to more effectively convert the electrical energy into heat. Iron oxide nanoparticles are small enough to have a single ferromagnetic domain where their magnetization can flip randomly due to thermal fluctuations. The characteristic time between such flipping events is called the Neel relaxation time. Such particles are called Superparamagnetic Iron Oxide Nanoparticles (SPIONs). Macroscopically, a solution containing such particles exhibits a real and lossless permeability at most frequencies except for a particular resonance frequency, related to the reciprocal of the Neel relaxation time, where the permeability becomes complex and lossy. At this resonant frequency electromagnetic energy is converted into heat. This electrical-to-thermal energy conversion produces significantly larger Thermoacoustic pressure waves than pure water, which constitutes the majority of cells and tissue. It is important to note that SPIONs have been exploited in other imaging applications, including MRI, and there is a growing effort in their commercialization.
Microscopically, SPIONs convert microwave energy into heat via spin resonances. Here, unpaired electrons spin under an applied external magnetic field (e.g. a miniature permanent magnet), creating a magnetic moment similar to nuclear spins in MRI. This phenomenal is called ferromagnetic resonance (FMR). The unpaired electrons align either parallel or anti-parallel to the external magnetic field, with the magnetic moments precessing at the Lamor frequency, which lies within the microwave frequency region:
ω0=−γμ0Heff (1)
Where γ is the gyromagnetic ratio, μ0 is the permeability of free space, and Heff is the effective magnetic field strength. Materials with asymmetries, impurities, and remnant magnetization can exhibit FMR without the application of an external magnetic field. By modifying the size, material composition, and shape of the nanoparticles it is possible to tune the resonant frequency of FMR. This allows the production and use of multiple contrast agents simultaneously, where each is detected at its own unique resonant frequency without disturbing other contrast agents. Thus, such a label-assisted biosensing scheme is able to simultaneously track multiple biomarkers. Moreover, these contrast agents can be paired with the appropriate anti-body in order to target any desired biomolecules or cell. In this way a general purpose, non-invasive, in-vivo, label-assisted biosensing platform with a single, common detection platform, the smartwatch, and multiple customized contrast agents in pill format is enabled.
With Thermoacoustic sensing, the same contras-agent SPIONs designed for electrical-to-thermal energy conversion is exploited for drug modulation. This dual use of SPIONs makes the Thermoacoustic technique more competitive than alternative sensing technologies. The feasibility of biocompatible polymers that undergo large structural changes with modest, local, temperature changes around 37° C. has been demonstrated. These changes include shrinkage, swelling, and transitions in wettability, which have been harnessed to produce drug delivery carriers. In particular, soft-material/hard-material hybrids, where magnetic metals or oxides are embedded in a temperature-responsive polymer matrix are used to link thermal sensitivity with selective electromagnetic activation through resonance. This permits reliable drug release on demand and slow drug modulation applications.
Linear polypeptides made of amino acid monomers also exhibit shape changes at a well-defined collapse temperature determined by the hydrophilicity of the respective amino acid. For example, valine monomers have a collapse temperature of 24° C. while for glycine monomers this increases to 55° C. By combining these amino acids it is possible to engineer a polymer with a desired collapse temperature. For example, polymers having Valine-Proline-Glycine-Valine-Glycine repeats exhibit a collapse temperature of 26° C. which is increased to 42° C. after randomly substituting 50% Valine, 30% Glycine and 20% Alanine for the second Valine in the repeats. A widely used temperature-responsive polymer is poly(ethylene oxide)-poly(propylene oxide)-poly(ethyleneoxide) or PEO-PPO-PEO for short. Another commonly used temperature-responsive polymer is Poly(N-isopropylacrylamide) or PNOPAAm for short. Both of these polymers as well as iron oxide nanoparticles have been shown to be readily and safely digested and gradually cleared from body.
A self-assembly strategy of aqueous nanocapsules intended for drug deliver on demand under magnetic stimulation has been shown. Magnetic heating of these magnetic nanocolloids was shown to gradually increase the temperature of the entire solution by several degrees at a rate of 0.1° C./s to 1° C./s. This would correspond to a local heating rate, in the near vicinity of the nanoparticles, on the order of 100° C./s.
Moreover, evidence from microscopy suggested that the local temperature rise of the nanoparticles is several hundred degrees Celsius even if the solution temperature increased by several degrees only. This evidence shows that very efficient and localized heating, required for activating the temperature-responsive polymers, is possible. In fact, experiments were performed to compare drug release triggered by local magnetic heating against the response to external heating of the entire solution. These results point to the feasibility of selective drug delivering and modulation via electromagnetic triggers. According to one aspect of the invention, modification of the triggering technique from simple magnetic heating to ferromagnetic resonance heating in order to take advantage of multi-frequency operation enables simultaneous and independent control of multiple drugs.
For the detection and differentiation of cells, microparticles, nanoparticles, and potential contrast agents a Thermoacoustic microfluidic platform a required resolution (˜10 um) and SNR is required. Several factors must be considered, including:
To address these constraints a two-part approach includes a process suitable for prototyping and a process suitable for mass-production. The prototyping process uses lower processing temperatures, and can incorporate higher performance materials such as fused silica (glass), contains manufacturing steps, and permits the peeling, cleaning, and resealing of the microfluidic channels. In contrast, the mass-production process uses higher processing temperatures, incorporates economical and high-volume materials, contains more complex manufacturing steps, and produces permanently sealed microfluidic channels. Observations and experimental test on various materials include:
When considering these aspects, three main processing techniques for manufacturing Thermoacoustic microfluidic chips are provided. As shown in
As shown in
As shown in
The present invention has now been described in accordance with several exemplary embodiments, which are intended to be illustrative in all aspects, rather than restrictive. Thus, the present invention is capable of many variations in detailed implementation, which may be derived from the description contained herein by a person of ordinary skill in the art. All such variations are considered to be within the scope and spirit of the present invention as defined by the following claims and their legal equivalents.
This application is a continuation-in-part of U.S. patent application Ser. No. 14/939105 filed Nov. 12, 2015, which is incorporated herein by reference. U.S. patent application Ser. No. 14/939105 filed Nov. 20, 2015 claims priority from U.S. Provisional Patent Application 62/247101 filed Oct. 27, 2015, which is incorporated herein by reference. U.S. patent application Ser. No. 14/939105 filed Nov. 20, 2015 claims priority from U.S. Provisional Patent Application No. 62/078899 filed Nov. 12, 2014, which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 62247101 | Oct 2015 | US | |
| 62078899 | Nov 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14939105 | Nov 2015 | US |
| Child | 15165811 | US |
