EP4665214A1

EP4665214A1 - Biomedical imaging device

Info

Publication number: EP4665214A1
Application number: EP23707186.5A
Authority: EP
Inventors: Hylke Broer Akkerman; Daniel Tordera Salvador; Ezequiel DELVITTO; Albert Jos Jan Marie van Breemen
Original assignee: Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Current assignee: Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek TNO
Priority date: 2022-02-17
Filing date: 2023-02-16
Publication date: 2025-12-24
Also published as: WO2024172644A1; JP2026505504A

Abstract

Aspects of the present disclosure relate to an imaging device, an imaging system comprising the device, a method of operating the system and to a wearable comprising the device or system. An imaging device (1) comprises: an imaging arrangement (3) to determine a length of a pulse propagation trajectory (V) within a section of biological tissue (1000) imaged by the imaging arrangement (3); and a pulse sensing arrangement (4) comprising a set of a discrete photodiode sensing elements (41,42) that are arranged in a first zone (40a) and a second zone (40b) that are laterally separated by at least a portion of the imaging arrangement (3), wherein each of the discrete photodiode sensing elements is configured direct interrogation at a rate higher than a rate of interrogating the imaging arrangement (3) to determine a propagation time of a pulse event (P) travelling along the trajectory.

Description

Title: BIOMEDICAL IMAGING DEVICE

TECHNICAL FIELD AND BACKGROUND

The present disclosure relates to an imaging device, an imaging system comprising the device, a method of operating the system and to a wearable.

Thin film imagers operating in the near- and short wavelength infrared (NIR & SWIR) can capture in reflection high resolution images of anatomy located underneath the skin surface, such as veins.

In general, such an imager consists of an array of light sensitive pixels which can be tailored to achieve a sensitivity over a broad wavelength range (UV, visible, NIR, SWIR).

A speed of physiological processes, such as a pulse wave travelling through a blood vessel can provide, regarding a condition the individual. However, present imagers are considered incapable of accurate pulse propagation detection. WO2011/026986 Al concerns a system for detecting signals of the PPG type (photopietysmogram) from a biological tissue, including a matrix of nxm elementary optical receivers. This invention does describe using an array of n x m elements which is unsuitable for accurate imaging of the tissue.

US2022031182A1 describes a device having an imager that consists of an array of photodetection elements that are interrogated by a gate driver and a readout including a signal line selection circuit connected to a detection circuit. The array can be used to image a vessel structure. In addition it is described to calculate a pulse wave velocity of the blood vessel from outputs of PDs along opposing ends of the array.

SUMMARY

Aspects of the present disclosure relate to an imaging device as well as to an imaging system comprising the imaging device that improves on the limitations of known devices. Both the imaging device and the system can be used to simultaneously image biological tissue at a relevant resolution while being capable of determining a speed of a pulse event travelling trough said tissue.

The imaging device comprises an imaging arrangement and a pulse sensing arrangement that each comprise a plurality of light responsive elements that are responsive to an amount of light within a particular frequency range that is either transmitted or reflected thereto.

The imaging arrangement is operably connected to a gate driver (driver IC) and to a readout circuit (readout IC) for interrogation. The plurality of light sensitive elements comprised in the imaging arrangement are preferably arranged in an active matrix configuration, e.g. in a plurality of addressable rows/columns for sequential addressing by the gate driver and the readout circuit.

The imaging device also comprises pulse sensing arrangement. The pulse sensing arrangement comprises a set of a discrete photodiode sensing elements that are arranged in at least two zones, including a first zone and a second zone. The zones are laterally separated by at least a portion of the imaging arrangement. Each of the discrete photodiode sensing elements is operatively connected, e.g. by a direct wiring, to the readout circuit, preferably the same read out circuit as the imaging arrangement, or to one or more further readout circuit, for direct interrogation at a rate that is higher than a rate of interrogating the imaging arrangement.

The imaging arrangement and the pulse sensing arrangement are configured in a known, e.g. fixed, spatial relation to each other at least during a use operation. In a preferred embodiment, the imaging arrangement and the pulse sensing arrangement are carried by a single substrate. Alternatively, or in addition, the imaging arrangement and the pulse sensing arrangement or parts thereof can be carried by a plurality of carriers that are configured by be associated, preferably reversibly, each other. The imaging arrangement can advantageously be used to image a section of biological tissue, e.g. a section of skin, at a first comparatively high resolution. The output of the imaging arrangement can be used to construct a topological map of the section of tissue, e.g. subcutaneous tissue, between the two parts of the pulse sensing arrangement. The obtained output can also be used to determine a length of a pulse propagation trajectory within the section of biological tissue imaged by the imaging arrangement, e.g. a venous structure.

The pulse sensing arrangement can advantageously be to be used to follow variations in the amount of detected light, e.g. by constructing a photoplethysmogram from the output of each of the discrete photodiode sensing elements. These variations can be related to a condition within the imaged tissue, such as a cardiac cycle within a venous structure or a variation in an oxygen saturation level. Because the discrete photodiode sensing elements are sampled at a comparatively higher rate the output can be used to particular advantage to determine a temporal delay (At) between a pulse event, e.g. as defined by variations in the amount of detected light, within an output received from one or more discrete photodiode sensing elements within the first second zone and a corresponding pulse within an output received from one or more discrete photodiode sensing elements within the second zone. As the spatial relation between the imaging arrangement and the pulse sensing arrangement is fixed over the imaging period a speed of pulse propagation can be readily derived with improved accuracy. For example, from the determined delay between the corresponding photodiode elements in the first and the second zones across the imaging arrangement in combination with the determined length of the pulse propagation trajectory.

Accordingly, the device (and system) benefit from a combination of a comparatively high spatial imaging resolution offered by the imaging arrangement for identifying a pulse propagation trajectory and determining the length thereof, and a comparatively high temporal resolution offered by the discrete photodiode sensing elements comprised in the respective zones of the pulse sensing arrangement across the imaging arrangement for determining a temporal delay between events across opposing ends of the trajectory.

The biological imaging according to the present disclosure comprises the imaging device as disclosed herein, and one or more gate driver operatively connected to the imaging arrangement and one or more readout circuit operatively connected to the imaging arrangement and each of discrete photodiode sensing elements comprised in the pulse sensing arrangement. Preferably, the system further comprises a controller for one or more of controlling the one or more gate drivers and readout circuits, and to receive and/or store output collected by the readout circuits. Preferably, the controller includes a processing unit to determine, from the received output, a speed of pulse propagation across an imaged section of biological tissue from the determined temporal delay and the length of the pulse propagation trajectory. Optionally the storing, controlling and/or data processing can be integrated in a single integrated circuit (IC) such as a readout IC or performed remotely.

In a preferred embodiment, the imaging arrangement and each of the discrete photodiode sensing elements are connected to respective inputs of a single integrated readout circuit. Alternatively, or in addition, the system can comprise a single integrated gate driver IC. Optimally the driver IC and/or readout IC can be carried on the substrate carrying the respective imaging arrangement and the pulse sensing arrangement, e.g. a single substrate. Using a single readout IC and/or driver IC reduces an overall form factor of the device and/or system, energy consumption, and/or a use of comparatively expensive components.

The present disclosure further relates to a method of operating the device and/or system as disclosed herein. The method comprises positioning the imaging device along an area of interest of a biological tissue, e.g. a section of skin; exposing the biological tissue with light, e.g. IR light, with a wavelength within a responsive range of the imaging arrangement and the pulse sensing arrangement; deriving a length of a pulse propagation trajectory within a section of biological tissue imaged by the imaging arrangement, e.g. by detecting edges (contrast) in an image obtained from the imaging arrangement; and determining a temporal delay between a pulse event within an output received from one or more discrete photodiode sensing elements within the first second zone and a corresponding pulse within an output received from one or more discrete photodiode sensing elements within the second zone, whereby the discrete photodiode sensing elements are interrogated at a rate higher than a rate of interrogating the imaging arrangement.

BRIEF DESCRIPTION OF DRAWINGS

These and other features, aspects, and advantages of the device, systems and methods of the present disclosure will become better understood from the following description, appended claims, and accompanying drawing wherein:

FIG 1 is a schematic top-view illustration of a system according to the invention comprising an imaging device according to the invention;

FIG 2 A provides a top -view of an imaging arrangement;

FIG 2B provides top -view of a pulse sensing arrangement;

FIGs 3A-3C depict schematic top-view illustrations of imaging devices;

FIG 4A schematically illustrates a method according to the invention;

FIG 4B provides a schematic side-view illustration of a system according to the invention in a use;

FIG 5A illustrates a wearable worn by an individual; and FIG 5B depicts experimental results.

DESCRIPTION OF EMBODIMENTS

The invention is described more fully hereinafter with reference to the accompanying drawings, in which embodiments of the invention are shown. In the drawings, the absolute and relative sizes of systems, components, layers, and regions may be exaggerated for clarity. Embodiments may be described with reference to schematic and/or crosssection illustrations of possibly idealized embodiments and intermediate structures of the invention. In the description and drawings, like numbers refer to like elements throughout. Relative terms as well as derivatives thereof should be construed to refer to the orientation as then described or as shown in the drawing under discussion. These relative terms are for convenience of description and do not require that the system be constructed or operated in a particular orientation unless stated otherwise.

FIG 1 displays a schematic top-view illustration of a system 100 according to the invention. The system comprises am imaging device 1, a gate driver IO 10 and a readout IO 11. Indicated by dashed lines is a projection of a pulse propagation trajectory V within an imaged section of biological tissue 1000 (See FIG 4B).

The imaging device 1 comprises an imaging arrangement 3 that is flanked along opposing edged by two zones 40a, 40b of a pulse sensing arrangement.

The imaging arrangement 3 and the pulse sensing arrangement 4 each comprise a plurality, a set, of photodiode sensing elements. The photodiode sensing elements are configured to, upon interrogation, provide an output signal in response to an amount (intensity) of light received, e.g. light reflected from or transmitted through a section of imaged biological tissue (e.g. skin). As used herein the photodiode sensing elements are also referred to as pixels. In the imaging arrangement 3, or imager, the pixels are generally arranged in an active matrix array, typically comprising a plurality of sequentially addressable rows/column. As known a configuration in an array allows maximizing an imaging resolution by minimizing an overall area used by to address the pixels. In contrast, the pixels in the respective zones of pulse sensing arrangement 4 are configured as discrete photodiode sensing elements, that is, configured for a direct readout. Configuring the pixels in the first and the second zone for a direct read out, e.g. by direct wiring to the readout IC 11, advantageously allows interrogating the pixels at a comparatively higher rate that the pixels comprised in the imaging arrangement. Details as to the arrangement of pixels in the imaging arrangement 3 and the pulse sensing arrangement 4 will be described with further detail with regard to the embodiments shown in FIG 2A and 2B.

In a preferred embodiment, e.g. as shown, the imaging arrangement 3 and the pulse sensing arrangement 4 are carried by a single substrate 2. Providing the imaging arrangement 3 and the pulse sensing arrangement 4 along a face of a single substrate advantageously fixes a spatial relation between the imaging arrangement 3, the first zone, and the second zones of the pulse sensing arrangement 4. Preferably, the substrate/carrier is a flexible substrate such as a polymer film allowing the device to follow a 3D geometry of a section of tissue to be images.

Alternatively, the imaging arrangement 3, the first zone 40a, and the second zone 40b can be provided on a plurality of carriers, e.g. three flexible carriers. These carriers may be provided along a face of a subject of interest, e.g. affixed thereto, in a known spatial relation. In another or further embodiment, the carriers may be configured to be affixable relative to each other in a known spatial relation. Preferably, the carriers are configured to be reversibly affixable to each other in a number of different spatial configurations, e.g. by clamps, buttons, adhesive regions or the like. This allows reconfiguring a position of the first and/or the second zones relative each other and to the imaging arrangement 3, e.g. to position the sensing zones adjacent a corner point of the imager, e.g. to match a geometry of an underlying venous structure within the imaged tissue.

In a preferred embodiment the imaging arrangement 3 is connected to a single integrated gate driver 10, e.g. as shown by interconnecting wiring dw30. Alternatively, or in addition, the imaging arrangement 3 and the pulse sensing arrangement 4 can be connected to respective inputs of a single integrated readout circuit 11. For example, as shown by wiring rw30, rw40a, rw40b respectively connecting the readout circuit 11 to the imaging arrangement 3 and the pixels comprised in first and the second zone of the pulse sensing arrangement 4. Obviously, one or more of the gate driver 10, the readout circuit 11 and the interconnecting wiring can be carried by the one or more substrates 2 for providing a more compact integrated device/system.

A readout integrated circuit (readout IC) can be understood as relating to an integrated circuit (IC) specifically used and known for reading detectors including light sensitive pixels as used herein. A purpose of readout ICs is to accumulate a photocurrent from each pixel and store and/or transfer a resultant signal for further processing (e.g. by a separate or integrated data processing unit 11.

The device comprises a plurality of light sensitive pixels (photodiodes, PDs) in an array, preferably as a thin film imager 3. For thin film imagers the individual photodiode pixels are connected, e.g. by the bottom electrode, to an electrode of a TFT, which is connected via a gate electrode to the gate driver ICs. The source electrode of the TFT is connected to the readout ICs. This configuration is very similar to that of a flat panel display and allows the use of standardized designs and/or IC components, with an exception in a display no readout is required. As compared to known imagers the device according to the present disclosure can offer advantages in terms of combining relevant spatial and temporal resolution.

For example, as compared to the device known from US2022031182A1 or other systems based on a conventional type imager having an array of PDs, the present device can provide a live image at relevant resolution (topological map of the tissue for identifying a vessel structure) in combination with a fast readout (high temporal resolution for pulse velocity determination) of the discrete photodiode sensing elements.

Additionally, the present solution can advantageously interrogate the opposing zones of the pulse sensing arrangement while also interrogating the imaging arrangement since, since the photodiode sensing elements comprised in pulse sensing arrangement are wired for a direct readout and thus avoiding limitations as to intermitted collection of the output of PDs within the imager array.

In addition, the present solution can be used to advantage to increase a sensitivity of the pixels within the pulse sensing arrangement, for example, by increasing a size of the photoactive layer within the discrete photodiode sensing elements with respect to the elements in the imager. These and further benefits, will be described in further detail below.

FIG 2A provides a schematic partial top-view of an imaging arrangement 3. The imaging arrangement 3 is formed as photodiode array operated with a TFT backplane and comprises a plurality of pixels 31,32,33,34 from in an array M with sequentially addressable rows rl, r2 and columns cl, c2. The embodiment shows only a 2x2 part of the array which typically includes a large number of light sensitive pixels, preferably a majority of the pixels comprised in the device. The pixels can be addressed, interrogated, via interconnects 31b, 31c, 32d, 31e connected to wiring rw30, rw30-l, rw30-2 and wiring dw30, dw30-l, dw30-2, which are respectively form an electrical interconnect to the driver and readout ICs 10, 11.

The arrangement in an array allows for a dense stacking of pixels, and with comparatively high areal density of photoactive layers 3 la, 32b enabling a high resolution and sensitivity. The mode of operation is that for a single column in the array all transistors are switched to an on-state and in parallel all the pixels within that column are read (and re-set) out by the readout IC. Then the gate driver switches the TFTs for the next column of the array on and the charge is readout, etc. The overall readout speed, imaging rate, is dominated by the speed of the readout IC (r) and the number of lines (n) within the array. As an example: a 500x500 pixel array and a readout IC with a maximum line speed of 20 ps, operate at a maximum rate of 100 frames per second (fps).

Typically, the readout circuit is configured for reading out at a rate >10kHz, preferably > 50kHz. The faster the readout, the better the temporal resolution of the output of the pulse sensing arrangement 4 can be and accordingly the better the ability to detect traveling pulse waves, which can be too fast to be detectable by conventional imagers. For example, the pulse wave velocity typically ranges between 5 - 15 m/s which would translate to a time delay of the signal over a distance of 2 cm (as an example for a measurement within in a patch form factor) of only 2 milliseconds.

The configuration of pixels comprised in the pulse sensing arrangement 4 will now be detailed with reference to FIG 2B, which provides a partial top-view of a zone 40a of an exemplary pulse sensing arrangement. In comparison to the imager the pixels 41,42,43 comprised in the pulse sensing arrangement 4 are configured for a direct interrogation, e.g. by dedicated readout tracks rw40, rw40-l, rw40-2, rw40-3, rw40-4, etc., that interconnect output terminals of each pixel to a respective input of the one or more readout ICs 11. Since readout ICs have a limited number of connections, the number of pixels in the pulse sensing arrangement 4 will generally be limited by the number of available connections. In preferred embodiments the minority of the pixels will be configured in the pulse sensing arrangement 4, preferably in one or more arrays of directly addressable pixels as will be explained with reference to FIG 2B.

Furthermore, each directly addressable pixel will generally have a connection (or lead) passing through the array to reach the readout IC. This limits the smallest possible pixel pitch d40 relative to the pitch d30 in the active matrix array M thereby a resolution and areal density. However, for a direct connection to the readout IC the maximum line speed can advantageously be essentially determined by a maximum readout speed of the array. In case of the above example, that would mean a maximum readout speed at 50.000 frames per second.

In some embodiments the number of directly addressable pixels in each of the first and the second zone may be as low as one, e.g. one large pixel extending along opposing edges of the imaging arrangement 3. Preferably, however, each of the first and second zones comprises a plurality of pixels, that can be arranged in one or more rows (array), e.g. as shown. Incorporating a plurality of pixels in each of the zones advantageously allows some redundancy within each zone. Additionally, an array allows for collection of image data along areas of tissue under the respective zones, which image data can subsequently be used to track or follow progression of pulse propagation within the tissue.

In a preferred embodiment, the photodiode pixels comprised in the imaging arrangement are connected to a single integrated gate driver IC, whereby a majority of the pixels is comprised in the imager and a minority is comprised in the pulse sensing arrangement 4 for direct readout. Incorporating a majority of the pixels in the imager and a minority in the pulse sensing arrangement 4 advantageously enables imaging a sample of interest with a compact device, whereby data from the imager can be used to collect, e.g. in reflection mode, images in comparatively high resolution of anatomy of a biological sample, e.g. veins located underneath a skin surface, such as veins, and whereby data from the pulse sensing arrangement 4 can be used to collect optical response data at a comparatively high rate but lower resolution from areas adjacent the section imaged by the imager.

Preferably, the imaging arrangement and the discrete photodiode elements are configured for operating in the near- and short wavelength infrared range. Light having a wavelength in then near and/or short wavelength infrared range offers a particular beneficial balance in absorption and penetrating depth for subcutaneous imaging. Accordingly, in a preferred embodiment, the imaging arrangement and the discrete photodiode elements sensing elements comprise photodiode elements having a photoactive layer 31a, 32a, 41a configured for absorbing light in a 600 - 1200nm range, preferably in the 700-1100 nm range.

Photoactive layers configured for operating in the near- and short wavelength infrared range are known in the field and include layers based on crystalline Si (c-Ci), GaAs, etc. Such layers offer a good range but its manufacturing is limited to wafer-based fabrication technology and are generally comparatively expensive. Alternative layers, such as layers based on amorphous Si (a-Si) are not necessarily limited to wafer technol but offer a comparatively poor optical range that is not as suitable for operating in an IR regime. Preferably, the photoactive layers (3 la, 41a) comprise an organic photo-active composition. Accordingly, in a preferred embodiment the device comprise so-called organic photodiodes (OPDs). Organic photodiodes are advantageously not limited to wafer-based technology and can advantageously be manufactured on a variety of substrates including flexible carriers such as polymer foils using known processing methods such as printing. Suitable photo-responsive organic materials capable of operating in over an IR/VIS regime are known per se and include low bandgap materials, e.g. polymers CTIC-4F, CO1-4F. Publications by J. Lee, et al. (ACS Energy Lett. 2019, 4, 1401) and H. Ren, et al (Advanced Science, Vol8, issue 1, January 6, 2021, 2002418), which are hereby incorporated by reference, describe a numerous materials and processing methods for forming OPD.

In other or further preferred embodiments, the imaging substrate (e.g. a common substrate) is transparent or at least translucent for light over the 700-1100 nm range, proving a trans parent or at least translucent substrate advantageously allows illumination the substrate to from a back side of the device whereby the biological imaging device can be in contact with, or at least direct proximity of, a face the substrate to be imaged, e.g. as will be described in more detail with reference to FIG 4B. In contrast conventional imagers, as based on wafer technology having an essentially opaque carrier are typically operated a distance and/or at angle from a surface of an object to be imaged, optionally with the use of lenses, to allow illuminating the area of interest.

Without wishing to be bound by any theory inventors inventively find that direct backside illumination can already be enabled in the device according to the present disclosure due to a presence of a comparatively large interspace regions between pixels comprised in the pulse sensing arrangement (4), which due to their direct interconnect to the readout leave a comparatively large free surface A4 between adjacent pixels as compared to a rather limited free area A3 between pixels in the imager.

In a preferred embodiment, individual imaging elements, pixels 31,32, as comprised in the imaging arrangement 3 and the discrete sensing elements 41,42 are configured so that an accumulated response between respective interrogation periods is balanced. Balancing the output can be realized by increasing the area of the photoactive layer 41a in the directly addressable pixels relative to the active layer of pixels comprised in the imaging arrangement 3 so that the output from the respective pixels between respective interrogation periods is within a range of 1:10 to 10:1, preferably between 5:1 and 1:5. Balancing the outputs of the respective pixels can be of particular benefit in embodiments wherein the output of one or more of the pixels comprised in the imaging arrangement and one or more of the pixels comprised in the pulse sensing arrangement 4 are collected by a common, e.g. a single, readout IC. In such embodiments balancing the output of pixels comprised in the imaging to the output of the directly interrogated pixels mitigates digitization artifacts due to a dynamic range of the IC readout.

Of course, the imaging arrangement 3 and the pulse sensing arrangement 4 can be arranged in configurations other than the configuration described in relation to FIG 1. Alternative positionings of the pulse sensing arrangement 4 are envisioned.

In one embodiment, e.g. as shown in FIG 3A, the discrete photodiode sensing elements 41,42 comprised in the pulse sensing arrangement 4 are arranged along an outer perimeter 3p of the imaging arrangement 3. Such configuration can be beneficial to track pulse propagation in tissue with an a priori unknown orientation of the pulse propagation trajectory V without a need for reorienting the device. Additionally, disposing the discrete photodiode sensing elements 41,42 can enable tracking of pulse propagation in a tissue having a plurality of pulse propagation trajectories or a branching structure VI, V2, V3, e.g. as shown.

In other or further embodiments, the pulse sensing arrangement 4 comprises one or more further zones 4c, 4d, each with one or more, preferably an array, discrete sensing elements, each further zone separated from adjacent zones by respective portions 3a, 3b, 3c of the imaging arrangement 3. A device/system comprising a multitude of laterally separated zones with discrete photodiode sensing elements 41,42 can advantageously allow tacking of pulse propagation speed Ptl, Pt2, Pt3, Ptn, along a plurality of portions of an elongate pulse propagation trajectory V.

In other or further embodiments, e.g. as shown in FIG 30 the discrete photodiode sensing elements 41,42 can be provided in a plurality of zones 4 that are distributed regularly or semi-regularly. Optionally, the substrate may be provided with one or more transparent areas A40, or even apertures, between adjacent regions/zones 4,3 from imaging and pulse sensing to allow a more intense and/or homogenous illumination of a sample of interest by a light source provided at a backside of the device.

In another or further preferred embodiment, the device or system is comprising a means to reversibly secure it along an area of a biological tissue to be imaged. A non-limiting list of a suitable means includes a patch, a band, and reversible adhesives.

In a preferred embodiment, the device or system is part of a wearable for biomedical analysis of an individual. For example, garment, a patch, or a band configured to be worn by an individual along an area of interest. FIG 5A illustrates a patch 101 provided onto a torso 1001 of an individual. The patch comprises an imaging device 1 as described in relation to FIG 1.

As will be appreciated the device can advantageously be comprised in a system, e.g. a biological imaging system 100,101, further comprising one or more gate driver 10 operatively connected to the imaging arrangement 3 and one or more readout circuit 11 operatively connected to the imaging arrangement 3 and each of discrete photodiode sensing elements 41,42 comprised in the pulse sensing arrangement 4. Preferably, the system also comprises a controller or processing unit 13 configured to process data collected by the readout IO. The controller or processing unit 13 may be integrated into a single IO, e.g. together with the driver and/or readout IO. Alternatively, the controller or processing unit can be provided as a separate unit. In a preferred embodiment, the controller or processing unit is configured to calculate a speed of pulse propagation across an imaged section of biological tissue 1000 from the determined temporal delay At and the length of the pulse propagation trajectory V. In a preferred embodiment, e.g. as shown in FIG 4B, the system or device according to the present disclosure comprises a backlight element 6 configured to illuminate an area of a tissue 1000 to be imaged through apertures and/or transparent or at least translucent regions A3, A4, A40 of the substrate 2 between adjacent sensing elements.

As will be appreciated the device/system according to the invention can be of particular benefit as a medical device for measuring of a high resolution image of an biological tissue, e.g. an organ, that can be applied in direct contact with the tissue, and that is capable of fast measurements to track propagation of pulse events, e.g. a pulse wave travelling through a blood vessel within said tissue, which in turn can be indicative for a number of physiological processes including arterial stiffness, blood pressure, organ failure, or hypertension.

The method of operating the system/device according to the present disclosure will now be explained in further detail with reference to FIGs 4A and 4B, wherein FIG 4A schematically illustrates a method 200 according to the invention and FIG 4B provides a schematic side-view illustration of a system 100 according to the invention during use.

The method, comprising positioning 201 the imaging device 1 along an area of interest of a biological tissue 1000, preferably in direct contact with a face of the tissue; exposing 202 the biological tissue with light L, e.g. from an integrated source 6 or otherwise, with a wavelength within a responsive range of the pixels 31,32,41,42 comprised in the imaging arrangement and the pulse sensing arrangement 4; deriving 203 a length of a pulse propagation trajectory V within the section of biological tissue 1000 imaged by the imaging arrangement 203; and determining 204 a temporal delay (At) between a pulse event P within an output S41 received from one or more discrete photodiode sensing elements within the first second zone and a corresponding pulse within an output S42 received from one or more discrete photodiode sensing elements within the second zone, whereby the discrete photodiode sensing elements 41,42 are interrogated at a rate higher than a rate of interrogating the imaging arrangement 3. It will be understood that the method typically includes a number of data processing steps prior to determining 204 the temporal delay, which may be performed by one or more of the readout IC and the processing or computing unit 13. These steps include collecting output signals S31, S32, S33 from pixels comprised in the imaging arrangement 3 and processing the data to construct a topological map of the underlying tissue. The constructed image can subsequently be used to derive 203 the length of a pulse propagation trajectory V within the section of biological tissue 1000, e.g. by image analysis. In addition, the method typically includes collecting and processing output data from the pixels comprised in the pulse sensing arrangement 4 to identify a presence of pulse events in the output from the respective zones prior to determining 204 the temporal delay (At) therebetween.

In a preferred embodiment, the method according to claim 12, further comprising calculating 205, e.g. by the computing unit 13, a speed of pulse propagation Vp across the imaged section of biological tissue 1000 from the determined temporal delay (At) and the length of the pulse propagation trajectory V.

FIG 5B depicts exemplary experimental results 15 to demonstrate the concept using an imager at 500 ppi and a 16x16 array of discrete photodiodes (approximately 1 mm² pixels, utilizing the same frontplane technology. The picture on the left shows a high resolution readout of veins in reflection using NIR illumination at a frame rate of around 25 fps. The skin was marked to serve as a reference for the 16x16 array. The overlay indicated by dashed lines indicates a relative position of regions 3, 4a, 4b as comprised in an integrated imager as described in relation to FIG 1. The insert at the right shows a readout low resolution readout of the 16x16 array at very high speeds, > 10.000 fps. As a next step, by means of signal processing, photoplethysmogram (PPG) are recorded for each of the pixels in the 16x16 array, where there is looked at changes in reflected NIR due to the arterial pulse. To link PPG and changes therein throughout the array, a signal comparison is performed that is based on the shape of the PPG for each row in the matrix, meaning for each pixel starting from the top (row 1) the shape of the PPG is compared to the recordings from the next row. The match between signals is expressed by a value from 0 to 1 wherein the match in represented by coloration the pixels (black/low match to white/high match). When continued row by row through the array, most starting pixels do not form a continuous trace, meaning PPG signal shape appears to be random. For some pixels, as shown in the insert starting with pixel 9 on row 1, a pattern emerges that shows a best match in PPG shape and that resembles the shape, albeit at a lower resolution, of the vein seen in the image to the right. Clearly, the result indicate the potential of fast readout and high resolution imaging for biomedical biological imaging devices.

Terminology used for describing particular embodiments is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. The term "and/or" includes any and all combinations of one or more of the associated listed items. It will be understood that the terms "comprises" and/or "comprising" specify the presence of stated features but do not preclude the presence or addition of one or more other features. It will be further understood that when a particular step of a method is referred to as subsequent to another step, it can directly follow said other step or one or more intermediate steps may be carried out before carrying out the particular step, unless specified otherwise. Likewise, it will be understood that when a connection between structures or components is described, this connection may be established directly or through intermediate structures or components unless specified otherwise. In interpreting the appended claims, it should be understood that the word "comprising" does not exclude the presence of other elements or acts than those listed in a given claim; the word "a" or "an" preceding an element does not exclude the presence of a plurality of such elements; any reference signs in the claims do not limit their scope; several "means" may be represented by the same or different item(s) or implemented structure or function; any of the disclosed devices or portions thereof may be combined together or separated into further portions unless specifically stated otherwise. Where one claim refers to another claim, this may indicate synergetic advantage achieved by the combination of their respective features. But the mere fact that certain measures are recited in mutually different claims does not indicate that a combination of these measures cannot also be used to advantage. The present embodiments may thus include all working combinations of the claims wherein each claim can in principle refer to any preceding claim unless clearly excluded by context.

Claims

1. An imaging device (1) comprising: an imaging arrangement (3) comprising a plurality of photodiode sensing elements operably wired to a gate driver (10) and to an integrated readout circuit (readout IC) (11) for interrogation for determining a length of a pulse propagation trajectory (V) within a section of biological tissue (1000) imaged by the imaging arrangement (3), and a pulse sensing arrangement (4) comprising a set of a discrete photodiode sensing elements (41,42) that are arranged in a first zone (40a) and a second zone (40b) that are laterally separated by at least a portion of the imaging arrangement (3), wherein each of the discrete photodiode sensing elements is wired to a respective individual input terminal of the readout IC (11) or to an individual input terminal of an optional further readout IC for direct interrogation at a rate higher than a rate of interrogating the imaging arrangement (3) for determining a temporal delay between a pulse event (P) within an output (S41) received from one or more discrete photodiode sensing elements within the first second zone and a corresponding pulse within an output (S42) received from one or more discrete photodiode sensing elements within the second zone.

2. The device according to claim 1, wherein the imaging arrangement (3) and the discrete photodiode sensing elements (41,42) comprise a photoactive layer (31a, 41a) configured for absorbing light in a 700-1100 nm range.

3. The device according to any of the preceding claims, wherein the imaging arrangement (3) and the pulse sensing arrangement (4) are supported by a common substrate that is transparent or at least translucent for light over the 700-1100 nm range.

4. The device according to any of the preceding claims, wherein the photodiode sensing elements comprised in the imaging arrangement and the discrete photodiode sensing elements are wired to a single readout IC, and wherein the individual imaging elements (31,32) comprised in the imaging arrangement (3) and the discrete sensing elements (41,42) are configured so that an accumulated response between respective interrogation periods is balanced within a range of 5:1 to 1:5.

5. The device according to any of the proceeding claims, wherein the discrete photodiode sensing elements (41,42) are arranged along an outer perimeter of the imaging arrangement (3).

6. The device according to any of the proceeding claims, wherein the pulse sensing arrangement (4) comprises one or more further zones (4c, 4d) with discrete sensing elements, each further zone separated from adjacent zones by respective portions (3a, 3b, 3c) of the imaging arrangement (3).

7. The device according to any of the preceding claims comprising a means to reversibly secure the device along an area of a biological tissue to be imaged.

8. An imaging system (100) comprising: an imaging device (1), preferably the imaging device according to any of the preceding claims 1-7, said imaging device comprising an imaging arrangement (3) comprising a plurality of photodiode sensing elements operably wired to a gate driver (10) and to an integrated readout circuit (readout IC) (11) for interrogation for determining a length of a pulse propagation trajectory (V) within a section of biological tissue (1000) imaged by the imaging arrangement (3), and a pulse sensing arrangement (4) comprising a set of a discrete photodiode sensing elements (41,42) that are arranged in a first zone (40a) and a second zone (40b) that are laterally separated by at least a portion of the imaging arrangement (3), wherein each of the discrete photodiode sensing elements is wired to a respective individual input terminal of the readout IC (11) or to an individual input terminal of an optional further readout IC for direct interrogation at a rate higher than a rate of interrogating the imaging arrangement (3) for determining a temporal delay between a pulse event (P) within an output (S41) received from one or more discrete photodiode sensing elements within the first second zone and a corresponding pulse within an output (S42) received from one or more discrete photodiode sensing elements within the second zone; and a controller (13) operably connected to the gate driver (10), the readout circuit (11), and the optional further readout IC, whereby the controller is configured for calculating a speed of pulse propagation across the section of biological tissue (1000) imaged by the imaging arrangement from the determined temporal delay and the length of the pulse propagation trajectory (V).

9. The system (100) according to claim 8, wherein the imaging arrangement (3) is connected to a single integrated gate driver (10) and wherein the imaging arrangement (3) and each of the discrete photodiode sensing elements (41,42) are connected to respective inputs of a single integrated readout IC (11).

10. The system (100) according to claim 8 or 9, wherein the imaging arrangement (3) and the pulse sensing arrangement (4) are supported by a common substrate, and wherein the system further comprises a backlight element (6) configured to illuminate an area of a tissue to be imaged with light having a wavelength in the range of 700-1100 nm through apertures and/or regions (A30, A50) of the substrate (2) between adjacent sensing elements that are transparent or at least translucent to said light .

11. The system (100) according to any of the preceding claims 8-10, wherein the readout IC (11) is configured for reading out at the input terminals at a rate of >10kHz.

12. A method (200) of operating the system (100) according to any of claims 8-11, comprising positioning (201) the imaging device (1) according to any of the preceding claims 1-7 along an area of interest of a biological tissue (1000); exposing (202) the biological tissue with light with a wavelength within a responsive range of the imaging arrangement (3) and the pulse sensing arrangement (4); deriving (203) a length of a pulse propagation trajectory (V) within a section of biological tissue (1000) imaged by the imaging arrangement (203); and determining (204) a temporal delay between a pulse event (P) within an output (S41) received from one or more discrete photodiode sensing elements within the first second zone and a corresponding pulse within an output (S42) received from one or more discrete photodiode sensing elements within the second zone, whereby the discrete photodiode sensing elements (41,42) are interrogated at a rate higher than a rate of interrogating the imaging arrangement (3).

13. The method (200) according to claim 12, further comprising calculating (205) a speed of pulse propagation (Vp) across the imaged section of biological tissue (1000) from the determined temporal delay and the length of the pulse propagation trajectory (V).

14. The method (200) according to claim 12 or 13, wherein the device is in direct contact with the biological sample (1000).

15. A wearable (101) for biomedical analysis comprising the device or the system according to any of the preceding claims 1-11.