Methods of fabricating heterogeneous optical phantoms and uses of such optical phantoms

Abstract

In some aspects, methods for making biomedical phantoms, biomedical targets, and the like, using techniques that deposit a plurality of differing material formulations having differing compositional optical properties into each of one or more regions in a manner, such as in discrete volumes (e.g., voxels), that the differing compositional optical properties combine at a macroscale to manifest as a macroscale optical performance for that region. In some embodiments, biomedical phantoms and targets further include one or more photoluminescent materials and / or one or more self-emitting materials, depending on design requirements. In some embodiments, biomedical phantoms and targets made in accordance with disclosed methods are designed and configured to simulate one or more biological materials, such as, biological tissue and blood, and / or one or more biological masses, such as a part of a human body. Other embodiments are described.

Description

METHODS OF FABRICATING HETEROGENEOUS OPTICAL PHANTOMS AND USES OF SUCH OPTICAL PHANTOMSRELATED APPLICATION DATA

[0001] The present application claims the benefit of priority of U.S. Provisional Patent Application Serial No. 63 / 534,172, filed on August 23, 2023, and titled “Methods of Fabricating Heterogeneous Photoluminescent Optical Phantoms, Optical Phantoms Made Thereby and Uses of Such Optical Phantoms”, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION

[0002] The present disclosure relates to biomedical optical sensing and imaging. More particularly, this disclosure is directed to methods of fabricating photoluminescent optical phantoms, optical phantoms made thereby, and uses of such optical phantoms.BACKGROUND

[0003] Phantoms are used to represent certain material properties of a target system, for example human tissue, for the purpose of characterizing, demonstrating capabilities, and / or user training of instrumentation, such as sensors or imaging systems. Optical phantoms mimic properties such as light absorption and scattering over a specific range of relevant wavelengths. These phantoms can be liquid, semi-solid or solid materials. Manufacturing complexity has limited many phantoms to homogeneous materials or heterogeneous materials with simple geometries. Additive manufacturing has been used to make more complex shapes of primarily homogeneous phantoms. Phantoms containing photoluminescent additives can degrade with extended exposure to light.SUMMARY

[0004] In one implementation, the present disclosure is directed to a biomedical phantom that provides a designed use with an instrument having an optical sensing system. The biomedical phantom includes a body having a light-incidence side and a light-emitting side spaced from the light-incidence face and that includes a first region having a first macroscale optical performance through the body from the light-incidence to light-emitting side, wherein: the first optical performance is designed for the use with the instrument, the optical sensing system, or both of the instrument and the optical sensing system; and the first region is formed from a plurality of first differing material formulations that provide first differing compositional optical properties present, wherein the first differing material formulations are located in a plurality of discrete volumes withinthe region so that the combination of the first differing compositional optical properties in the discrete volumes manifests as the first macroscale optical performance over the first region.

[0005] In another implementation, the present disclosure is directed to a method of fabricating a multi-material optical phantom. The method includes additively manufacturing the multi-material optical phantom using one or more photo-curing base resins deposited in discrete volumes so as to form a plurality of sequential layers; wherein: optical properties of one or more resin formulations that use the one or more photo-curing base resins are known; a combination of the one or more resin formulations in specific ratios provide the ability to select from a range of desired optical properties; and the plurality of sequential layers are cured through photo-activation to produce software-defined 3-dimensional geometries having heterogeneous optical properties.

[0006] In yet another implementation, the present disclosure is directed to an optical phantom. The optical phantom includes heterogeneous materials arranged in a designed 3-dimensional pattern, wherein: the heterogeneous materials have differing optical absorption, scattering, anisotropy, and / or refractive index; and the 3-dimensional pattern is configured to approximate model-based photon fluence rate estimates for one or more wavelengths.

[0007] In yet another implementation, the present disclosure is directed to a method of designing and fabricating an optical phantom utilizing, in the designing, model-based approximations of fluence rate at depth into the optical phantom.

[0008] In yet another implementation, the present disclosure is directed to a method of designing and fabricating a photoluminescent phantom having a surface on a light-incident side of the photoluminescent phantom. The method includes utilizing, in the designing, model-based approximations of excitation fluence rate at depth into the photoluminescent phantom; and utilizing, in the designing, model-based approximations of photoluminescence remission rates reaching the surface.

[0009] In yet another implementation, the present disclosure is directed to a method of designing and fabricating a photoluminescent phantom using model-based approximations of excitation fluence rate at depth into the photoluminescent phantom to predict localized photobleaching.

[0010] In yet another implementation, the present disclosure is directed to a method of predicting photon fluence rates within a phantom using model-based look-up table(s).

[0011] In yet another implementation, the present disclosure is directed to a method of designing and fabricating an optical phantom. The method includes providing a specific 2- dimensional intensity array as an input for the design; and utilizing, in the designing, model-based approximations of fluence rate at depth into the optical phantom; wherein the optical phantom provides narrowband optical emissions to enhance contrast of the input 2-dimensional intensity array.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] For the purpose of illustration, the accompanying drawings show aspects of one or more embodiments of the disclosure. However, it should be understood that the scope of this disclosure is / are not limited to the precise arrangements and instrumentalities shown in the drawings, wherein:

[0013] FIGS. 1A and IB are, respectively, a cross-sectional view and a plan view of one region of a simplified biomedical phantom made in accordance with the present disclosure;

[0014] FIG. 2 is a flow diagram for an example process of manufacturing some embodiments of a spatially modulated photoluminescent phantom of the present disclosure;

[0015] FIGS. 3A and 3B are, respectively, a schematic plan view and a schematic cross- sectional view, along line i of FIG. 2A, of an example phantom made in accordance with the present disclosure;

[0016] FIGS. 4A and 4B are, respectively, a schematic plan view and a schematic cross- sectional view, along line ii of FIG. 3 A, of another example phantom made in accordance with the present disclosure;

[0017] FIGS. 5A and 5B are, respectively, a schematic plan view and a schematic cross- sectional view, along line iii of FIG. 4A, of a further example phantom made in accordance with the present disclosure;

[0018] FIGS. 6A, 6B, and 6C are, respectively, a visible-light color photograph (converted to grayscale), a broad- spectrum grayscale image, and a narrowband fluorescent image of an example instantiation of a phantom made in accordance with the present disclosure;

[0019] FIG. 7 is a narrowband fluorescent image of another example instantiation of another phantom made in accordance with the present disclosure,

[0020] FIGS. 8A-8C are, respectively, a cross-sectional view through an example three-region photoluminescent phantom, a plan view of the photoluminescent phantom showing intensities of light emitted from the three regions at time, z, and a plan view of the photoluminescent phantom showing intensities of light emitted from the three regions at time, z + TV; in each of FIGS. 8B and 8C, the intensity of the light reflected from the material surrounding the three regions is shown in the negative to avoid large expanses of black;

[0021] FIG. 8D is a graph of percent of initial emittance versus time for the three regions of the photoluminescent phantom of FIGS. 8A-8C;

[0022] FIG. 8E is a graph of normalized ratios versus time for various ratios of the three regions relative to one another;

[0023] FIGS. 9A and 9B are graphs of modeled normalized fluence versus depth for a tuned material 2a of, respectively, 0.4 mm and 1.6 mm thickness, located between a transparent material [3] having a thickness of 1.6 and 0.4 mm, respectively, and a photoluminescent material [4];

[0024] FIGS. 9C and 9D are graphs of modeled normalized fluence versus depth for a tuned material 2d of, respectively, 0.4 mm and 1.6 mm thickness, located between a transparent material [3] having a thickness of 1.6 mm and 0.4 mm, respectively, and a photoluminescent material [4];

[0025] FIGS. 9E and 9F are graphs of modeled normalized fluence versus depth for, respectively, the tuned material 2a and the tuned material 2d, each having a 0.5 mm thickness applied over a transparent material [3] having a 1 .5 mm thickness and applied over a photoluminescent material [4];

[0026] FIG. 10 is a block diagram illustrating a software algorithm to analyze image data of an exemplary embodiment of a spatially modulated photoluminescent phantom to estimate the state of photodegradation; and

[0027] FIGS. 11 A and 1 IB are, respectively, a plan view and an enlarged cross-sectional view, as taken along line 1 IB-1 IB of FIG. 11A, of an example flow phantom made in accordance with the present disclosure so as to include an internal void that, in this example, is designed to receive a flowing photoluminescent material.DETAILED DESCRIPTION

[0028] The entire contents of the appended claims are incorporated into this Detailed Description section in their entireties as if originally disclosed in this Detailed Description section.

[0029] In some aspects, the present disclosure is directed to biomedical phantoms, such as biomedical phantoms that are used to simulate biological material, such as human tissue and / or blood, among other biological materials, or that are otherwise provided as an optical target. As those skilled in the art will readily appreciate, biomedical phantoms have optical characteristics and features that can be used, for example, to characterize performance of medical instruments having optical sensing or imaging systems (more broadly, “optical sensing systems”), either by simulating one or more types of biological tissue or by providing a suitable optical target for the characterization. Biomedical phantoms of the present disclosure can be used for other purposes, as well. For example, biomedical phantoms can be used for demonstration of medical instruments and / or their corresponding optical systems, for designing medical instruments and / or their corresponding optical system, standardizing the comparison of system performance, instructional purposes, for monitoring system performance, and for research purposes, among others. Examples of instruments with which a biomedical phantom of the present disclosure may be used include, but are not limited to, fluorescence guidance surgical systems, intraoperative photoluminescent imagers, pre-clinical photoluminescent imagers, and photoluminescent lifetime imagers, photoluminescence spectrometers, narrowband imagers, hyperspectral imagers, wearable optical sensors, among others. Those skilled in the art will readily understand the variety of instruments with which a biomedical phantom of the present disclosure can be used such that an exhaustive list is not necessary for such skilled artisans to appreciate the broad applicability of the present disclosure.

[0030] In the context of instrument characterization, a biomedical phantom of the present disclosure can be any type of characterization needed for the particular instrument, such as, but not limited to, characterization needed to adjust instrument settings for the use at hand, assessment of performance of the instrument, assessment of performance of the optical sensing system (e.g., optical distortion, sensitivity to differing wavelengths of light, etc.), standardized comparison of multiple instruments, among others. As with the relevant types of instruments, those skilled in the art will readily understand the variety of characterizations of instruments that can be performed with a biomedical phantom of the present disclosure such that an exhaustive list is not necessary for such skilled artisans to appreciate the broad applicability of the present disclosure.

[0031] Referring now to FIGS. 1 A and IB, in some embodiments a biomedical phantom 100 of the present disclosure includes a body 104, for example, a cap, and, optionally, a photoluminescent material 108 (FIG. 1A) located outside of the body. As used herein and in the appended claims, the term “cap” is to be construed as a generic term for a structure that is located between one or moreelectromagnetic radiation sources (not shown, but e.g., one or more sources of light of any suitable wavelengths, including any wavelength(s) in any one or more of the infrared, visible, and ultraviolet regimes) and the photoluminescent material 108, such that the cap effectively covers the photoluminescent material relative to the incident light. Importantly, the term “cap” should not be construed to connote any particular shape, unless a particular shape is particularly mentioned. Consequently, a cap of the present disclosure may have any workable shape, from a flat plate-like shape to a curved shaped (e.g., concave, convex, undulating, etc.) to a cup shape (see, e.g., FIGS. 3B, 4B, 5B), an anthropomorphic shape (e.g. breast lumpectomy, finger, skull, etc ), among others. In addition, unless described otherwise for a particular embodiment, the term “body” should not be construed as denoting physical discreteness relative to any other component(s) of the biomedical phantom 100, such as any photoluminescent material 108 that may be present. Indeed, the photoluminescent material 108 may be monolithic with the body 104 and, as desired, formed using the same techniques used for forming the body.

[0032] In the example of FIGS. 1A and IB, the body 104 includes a region 112 having a lightincidence side 1121 and a light-emitting side 112E that are spaced apart from one another by a thickness, T. In this connection, it is noted that the term “light-incident side” relates to the side of the region 112 that receive light from outside of the biomedical phantom, and the term “lightemitting side” relates to the side of the region that emits the light entering the light-incident side after passing through the region. Of course, when a photoluminescent material, such as the photoluminescent material 108 or a photoluminescent material that is part of the body 104, is present and emits in response to receiving the light that passes through the region 112, some of the emitted light travels through the region from the light-emitting side 112E and a light-incident side 1121, wherein the phantom 100 emits the photoluminescent light. Also in this example, the region 112 has a rectangular shape having a length, L, and a width, W. The volume of the region 112, i.e., L x W x T, is composed of a plurality of discrete volumes 112D (only a few labeled to avoid clutter; 27 shown in FIG. 1 A, 54 shown in FIG. IB) that each contain a corresponding material formulation, here, one of Formulations 1 through 5 as identified in FIG. 1A. It is noted that the term “discrete volume” as used herein and in the appended claims is not intended to be limiting of any physical size of the volume. For example, while the discrete volumes 112D illustrated have relatively large length, width, and height dimensions, in other instantiations even a monolayer of a material formulation applied over an area results in a discrete volume as defined herein. In addition, it is noted that while five differing formulations, i.e., Formulations 1 through 5, are illustrated, thenumber of differing formulations for any particular application can be any number needed, which can be more or fewer than five. Those skilled in the art will readily understand the number of differing formulations needed / desired for any particular application.

[0033] As will become apparent from reading this entire disclosure, each of the Formulations 1 through 5 has a compositional formulation that differs from each other one of the Formulations 1 through 5, with each Formulation 1 through 5 designed to have one or more specific compositional optical properties. Compositional optical properties relate to the wavelength(s) of light with which the biomedical phantom 100 will be used, and examples include, but are not limited to, absorption, scattering, anisotropy, transparency, selective transparency, and refractive index, among others.

[0034] Tn this example, the discrete volumes 1 12D all have the same shape and size as one another and are located in three layers 112L(1) through 112L(3) (FIG. 1 A), and the positions of the discrete volumes within each of the layers is such that discrete volumes in differing layers are aligned with one another in the vertical direction (relative to FIG. 1A). It is noted that FIG. 1 A may be considered to be simplified to easily illustrate the various features. Other embodiments may differ in one or more of a variety of ways. For example, the sizes and / or shapes of the discrete volumes can be varied relative to one another, the number of layers can be more or fewer than three, and / or the alignment of discrete volumes in differing layers may be different from the alignment shown.

[0035] The region 112 may be formed using any one or more suitable fabrication techniques, such as, but not limited to, any suitable 3 -dimensional (3D) additive manufacturing techniques (e.g., digital 3D printing) and any suitable technique(s) used in conventional microelectronics fabrication, such as lithography, various types of deposition, coating, polishing, etching, among others. Fundamentally, there is no limitation on the type of fabrication technique(s) used, as long as the discrete volumes 112D can be properly formed, sized, and shaped to meet a particular design for the region 112. In an example and in the context of the embodiment of FIGS. 1A and IB, each discrete volume 112D may be a voxel that is individually 3D printed by a suitable printer system capable of printing at least the five Formulations 1 through 5.

[0036] Regarding material formulations for Formulations 1 through 5, each material formulation may take any state of matter, such as, for example, a liquid, a semi-liquid (e.g., a gel), or a solid. When multiple liquids are used for two formulations that are located side-by-side with one another, if the liquids are immiscible with one another, they may be provided without any separator.In other embodiments, side-by-side liquid material formulations may be separated from one another by a separator (not shown), which may be, for example, 3D printed or formed by etching a base structure (not shown) to form side-by-side wells that then receive the liquid material formulations. In some embodiments, each material formulation, such as any of the Material Formulations 1 through 5, may be based on a curable polymer that is deposited (e g., 3D printed) while in a flowable form and then permitted or caused to cure using any suitable curing technique, such as ultravioletlight curing, heat curing, etc. Fundamentally, there are no limitations on the composition of each of the Formulations 1 through 5, other than the composition provides the desired compositional optical property(ies).

[0037] The material formulations used for any one of the Formulations 1 through 5 can be any suitable formulation for achieving the desired compositional optical property(ies) of that material formulation. For example, a material formulation may be a single material, such as an optically transparent polymer. Another example material formulation may comprise a base polymer (e.g., an optically transparent or semitransparent polymer) that contains one or more additives to provide the desired compositional optical property(ies). Examples of additives include, but are not limited to, material(s) that promote scattering, material(s) that promote absorption, material(s) that provide photoluminescence, and material(s) that control anisotropy, among others. A further example material formulation is a highly absorptive material. Other examples are described elsewhere in this disclosure. Those skilled in the art will readily understand how to formulate each material formulation needed to achieve the desired compositional optical properties for a particular application.

[0038] Importantly, the particular selections of the Formulations 1 through 5 and the particular selections of the locations for the selected Formulations 1 through 5 are made so that the entire lightincident area (L x W) (FIG. IB) of the light-incident side 1121 of the region 112 provides a designed macroscale optical performance, which is the optical performance that the region is designed to exhibit for the biomedical phantom 100 to provide its designed function. In this connection, it is noted that any one or more of the Formulations 1 through 5 may include a photoluminescent compound. In such embodiments that include the photoluminescent material 108, the photoluminescent material 108 would not be the only photoluminescent material in the optical phantom 100, as photoluminescent material would also be included in the body 104.

[0039] To assist with a fuller understanding of the concepts of “macroscale optical performance” and “compositional optical properties,” a rough, but incomplete, analogy can be made to digital RGB color monitors, wherein primary red (R), green (G), and blue (B) pixels are controlled at a microscale to provide thousands or millions of colors at a macroscale depending on the relative intensities of the three primary colors. In this analogy, the differing material formulations of the present disclosure correspond to the differing primary colors of the RGB example, with their differing compositional optical properties corresponding to the differing intensities of the differing pixels. Of course, this analogy is not complete at least because an RGB monitor has only one layer of pixels and a non-varying pixel pattern of the RGB pixels, whereas in a region of a biomedical phantom, such as the region 112 of the biomedical phantom 100 of FIGS. 1 A and IB, the discrete volumes (e.g., discrete volumes 112D) for the differing material formulations (e.g., Formulations 1 through 5) can be arranged in any pattern and / or may be present in multiple layers. Regardless, the manner in which the combination of the discrete red, green, and blue pixels in the RGB monitor can manifest as a color other than the red, green, and blue of the pixels, is generally analogous to manner in which the combination of the discrete volumes of the differing compositional optical properties combine manifest as a macroscale optical performance across the entire area (e.g., L x W) of the region at issue (e.g., region 112).

[0040] As mentioned above and discussed below, in some embodiments the biomedical phantom 100 is designed to simulate the optical response that certain biological material may have to a certain type of electromagnetic radiation, e.g., light, that the instrument at issue is designed to sense. As those skilled in the art will readily appreciate, the macroscale optical performance of the region 112 can be quite complex to engineer for a variety of reasons that include, but are not limited to, the need to consider the effects of the region on both the original incident light and the light emitted from the photoluminescent material 108, the complexity of the behavior of any biological material being simulated, the complexity of biological behavior across the electromagnetic spectrum, any constraints on the formulations of the various materials used in the discrete volumes 112D, and the wide variety in which the differing formulations can be combined and located within the region, among others.

[0041] In the context of the example of FIGS. 1 A and IB, this simulation is accomplished by, or partly by, making the macroscale optical performance of the region 112 equivalent to the optical response of actual biological material. Such optical response may be determined by testing suitable actual biological material. Then, the optical response can be embodied into a digital model (notshown) of the region 112 of the biomedical phantom 100 as the desired macroscale optical performance of the region. The deployments of the Formulations 1 through 5 are then made to the discrete volumes so that the region 112 exhibits the desired macroscale optical performance. Ways in which various constructions (e.g., combinations of Formulations 1 through 5 or any subset thereof and deployment locations of such Formulation(s)) of a region of a biomedical phantom, such as region 112 of the biomedical phantom 100 of FIGS. 1A and IB, can be determined for providing the desired macroscale optical performance can include running Monte Carlo simulations of various constructions. More information about designing biomedical phantoms of the present disclosure, such as the biomedical phantom 100 of FIGS. 1 A and IB, are described below.

[0042] It is noted that the biomedical phantom 100 of FIGS. 1A and IB is highly simplified and includes only a single region. As discussed below and illustrated in the accompanying drawings, biological phantoms of the present disclosure can have any level of complexity and any number of regions having differing or the same macroscale optical performance relative to one another.

[0043] As alluded to above, one or more photoluminescent materials may be located within the region 112 of the biomedical phantom 100. This can be the case, for example, when the body 104 is configured to simulate a relatively large volume of biological tissue, such as a relatively large volume of breast tissue, complete with simulated glandular tissue, blood vessels, adipose tissue, etc., with differing 3D subregions (not shown) within the body simulating the differing structures and corresponding biological materials of the actual breast tissue. In this example, each of the simulated biological materials, each of which may be considered a region similar to the region 112 shown or an agglomeration of regions similar to the regions 112 shown, will have a differing composition in terms of the material formulation(s) and arrangement of such formulation(s), as determined and needed to appropriately simulate the macroscale optical performance of that biological material.This is but one example and should not be considered limiting in any way. On the contrary, those skilled in the art will readily appreciate the wide variety of biological simulations that can be constructed and embodied into a biological phantom of the present disclosure using the fundamental techniques disclosed herein and exemplified at a high level by FIGS. 1A and IB.

[0044] FIG. 2 illustrates an example method 200 of making a spatially modulated photoluminescent phantom, such as any one of the biomedical phantoms described and / or illustrated herein, such as any one of the biomedical phantoms 100, 300, 400, 500, 600, 700, 800, and 1100 of, respectively, FIGS. 1A-1B, 3A-3B, 4A-4B, 5A-5B, 6A-6C, 7, 8A-8C, and 11 A-l IB. It is noted thatin this example the discrete volumes that receive the material formulations are voxels, but one or more other types of discrete volumes can be used, either apart from voxels or in combination with voxels. In the method 200, knowledge of material electromagnetic (i.e., optical) properties is used to design and make heterogeneous phantoms capable of spatially modulating the excitation fluence and photoluminescent output. At block 205, a 3D model describing the geometry of the target phantom is developed using computer-aided design (CAD) software with the desired material formulations assigned to the phantom components and the individual voxels. At block 210, during the making, the material formulations are selected, via the model, from a set of stock material formulations (block 215). The stock material formulations may be made, for example, by mixing discrete base materials (e.g., photocuring resin or thermoset polymers) with one or more additives to provide a wide range of materials having differing final optical properties.

[0045] At blocks 220 and 225, a layer composed of one or more of the selected material formulations having the designed spatial pattern (see, e.g., layers 112L(1) through 112L(3) of FIG. 1 A) is formed by additive manufacturing. When a plurality of layers are required for a particular design, the deposition at block 220 is repeated at a loop 230 as many times as necessary, each time in accordance with the pattern that the model requires for the corresponding layer. A result of the blocks 220 and 225 and the loop 230, is a 3D phantom, body, cap, etc. (block 235) having spatially modulated optical properties that provide one or more macroscale optical properties in differing regions of the phantom. If photoluminescent material was not added in the blocks 220 and 235, then a result of the blocks 220, 225, and 230 is a cap (see, e.g., the body 104 of FIG. 1 A). An example embodiment can use one or more resin materials, spatially combined during the manufacturing process, to modify one or more final material properties such as, for example, optical scattering, anisotropy, absorption, photoluminescence, or any combination or sub-set of these properties, to provide the corresponding component(s) with the designed macroscale optical performance(s). At block 235, if a photoluminescent material was not added in blocks 220 and 225, then it can be added to the phantom at optional block 240. A result of performing the method 200 is a spatially modulated photoluminescent phantom. As described below in more detail, wavelengthspecific material-formulation properties, which are controlled to spatially modulate the optical properties of the phantom, may include, but are not limited to, refractive index, absorption, scattering, and / or anisotropy. As also described below in detail, characterization of material properties for an array of mixtures and base materials for the material formulations can be used to determine properties of arbitrary material combinations. As just demonstrated by the method 200,these material formulations can be deposited in, effectively, 2-dimensional (2D) layers that effectively build up to 3D arrays to mimic designed heterogeneous shapes and optical performance.

[0046] Two of the design parameters described in connection with the method 200 of FIG. 2 involve modifications to the phantom material properties and how these materials are deposited to achieve the design geometry. FIGS. 3A-3B illustrate the photoluminescent phantom 300 that is an example embodiment wherein the photoluminescent material [4], in the form of an inclusion, is covered with a pattern to modulate excitation fluence rate reaching the photoluminescent inclusion surface as well as the emission or remission fluence rate generated by the photoluminescent inclusion. While the excitation surface irradiance can be estimated using a tool such as a photodiode, the fluence rate through the photoluminescent phantom 300 can be difficult to measure. Estimates of the fluence rate are related to the properties of the excitation light and properties of the materials of the photoluminescent phantom 300. The excitation light properties may include changes to the wavelength, spot size, or irradiance uniformity. Modifications to the material properties of the material formulations can be used to either attenuate or amplify the total number of photons delivered at depth into the photoluminescent phantom 300.

[0047] Example embodiments of heterogeneous photoluminescent phantoms 300, 400, and 500 are shown, respectively, in figure pairs FIGS. 3A-3B, 4A-4B, and 5A-5B. For simplicity, each of these photoluminescent phantoms 300, 400, and 500 comprises three or more of the following material types: highly light-absorbing material [1] (the black portions shown in each of FIGS. 3A- 5B), “tuned” material(s) having various optical properties (e g., scattering, absorption, anisotropy, refractive index) [2], optically transparent or selectively translucent properties [3], or any combination of materials [2] and / or [3], with at least one photoluminescence material [4], Each of the photoluminescent phantoms 300, 400, and 500 may be made using the method 200 of FIG. 2 or other suitable fabrication technique(s). For example, the material properties of materials [1], [2], [3], and [4] can be modified on a voxelized or other discrete-volumed basis using techniques described in FIG. 2 and as discussed in detailed below. An example embodiment can use 3D CAD software to define the geometry of components and assign optical performance properties to each component or assign heterogeneous properties to subcomponents.

[0048] Example embodiments of absorbing material [1] use highly absorptive pigments mixed with the base material to attenuate light at the desired wavelength. Example embodiments of tuned material [2] can use different combinations of additives to achieve the desired optical properties.Optical material properties can be altered for one or more wavelengths, depending on the desired design parameters. Scattering may be controlled by including additives such as TiO2, AI2O3, BaSO4, microspheres, commercial pigments and / or lipid emulsions, among others. Absorption may be controlled by additives such as india ink, nigrosin, hemin, and / or commercial pigments, among others.

[0049] Anisotropy is a property of how likely scattering events are to be forward-directed, which may be controlled, for example, by the particle size of a primary scatterer. Anisotropy may be controlled using additives such as TiCh and / or microspheres, among others, by specifying the particle size or controlling aggregation of additives in the final mixtures.

[0050] The refractive index can be slightly altered due to the additives used to control other optical properties. A wider range of control of the refractive index is related to the base material (e.g. photocurable resin or thermoset polymer). Example embodiments of the transmissive material [3] can use a clear base material or air to achieve minimal absorption or scattering but provide control of refractive index, which can be used to minimize surface reflections.

[0051] Example embodiments of the photoluminescent material [4] can utilize any combination of additives described in tuned material [2], with the additional of at least one photoluminescence material such as indocyanine green (ICG), methylene blue, quantum dots (QD), and / or other organic or inorganic luminescent compound(s), among others.

[0052] Prior work has demonstrated the utility of phantoms to estimate optical sensing system performance. Examples include phantoms used to measure system sensitivity to fluorescence concentration or sensitivity for fluorescence detection as a function of depth, with each design optionally incorporating tissue-mimicking optical properties. This prior work has focused on assembled phantoms utilizing homogeneous components to achieve the desired characteristics.Phantoms used to measure system resolution have also been demonstrated using a glass plate affixed to a photoluminescent material, where the glass plate incorporates a lithographic pattern. Optical sensing system characterizations using images of these phantoms and knowledge of the excitation irradiance at the phantom surface can be used, for example, to compare performance between imaging sessions or between different systems.

[0053] Example embodiment illustrated herein show how heterogeneous materials combined in 3D arrangements can be utilized to modify the attenuation or amplification of light within thephotoluminescent phantom. The number of photons absorbed by the photoluminescent material is directly related to the output emission for a wide range of photoluminescence concentrations. In an example embodiment, when controlling the optical properties of materials for wavelengths beyond those easily perceivable by the human eye, in conjunction with photoluminescent materials emitting at wavelengths in a similar range, patterns and images can be generated that are perceivable with enhanced contrast when using narrowband optical sensing systems, such as those used during fluorescence guided surgery. FIGS. 6A-6C illustrate an example photoluminescent phantom 600 that is based on the construction of the photoluminescent phantom 300 of FIGS. 3A-3B that illustrate some of these principles.

[0054] Referring to FIGS. 6A-6C, when the above technique is used in a designed pattern, photoluminescence can be modulated to form specific images, such as illustrated by the stylized “Q” 604 seen vividly in the narrowband fluorescent image of the photoluminescent phantom 600 in FIG. 6C. In this example and as illustrated in FIGS. 3A-3B, the construction of the photoluminescent phantom of FIGS. 6A-6C includes a layer of scattering and absorbing material [2] (FIGS. 3A-3B) placed over highly absorbing [1] and clear material [3] (FIG. 3B). The bottom layer contains a photoluminescent material [4] (FIG. 3B), which in one case can include scattering and absorbing properties and near-infrared fluorophores, such as ICG. In FIG. 6A, when the actual photograph is viewed in color, the inner circular region 608 is entirely uniformly gray in color, and the annular region 612 outside the inner circular region is black in color). While the stylized “Q” 604 (FIG. 6C) pattern is not observable in the color photograph represented in FIG. 6A, the wideband grayscale image of FIG. 6B shows a low-contrast design generated by the patterns of materials [1] and [3] and attenuated by [2] (FIGS. 3A-3B). In FIG. 6B, a stylized “Q” 604 appears centered in the inner circular region 608 as the lightest shade of gray within the figure. When the same phantom is imaged using a narrowband configuration, for example, using 785 nm laser or LED excitation and 800 nm longpass or 830 nm bandpass emission filtering on the detector (not shown), the detected image (FIG. 6C) has much higher contrast.

[0055] In one embodiment, the design of a photoluminescent phantom of the present disclosure could incorporate a logo (such as the stylized “Q” in Figures 3 B-C) or other image to demonstrate contrast enhancements provided by the optical sensing system. As observed in the broad-spectrum color photo of FIG. 6A, the design or logo is difficult to perceive, but a narrowband fluorescence optical sensing system is able to excite the underlying photoluminescent compound (see, e.g., material [4] of FIG. 3B, to generate the high-contrast pattern seen in FIG. 6C, as noted above.

[0056] Heterogeneous patterns embodied in a photoluminescent phantom of the present disclosure can also be utilized for performance characterization of instruments. Examples of such an embodiment are depicted in photoluminescent phantoms 400 and 700 shown in, respectively, FIGS. 4A-4B and 7, wherein repeating geometric patterns of highly transmissive and highly absorptive materials, e.g., materials [3] and [1], respectively (FIGS. 4A-4B), are used to generate grids of differing component sizes. The photoluminescent phantom 400 of FIGS. 4A-4B comprises a simple window-type grid pattern 404, wherein the materials of fabrication are alternating transparent material [3] and light-absorbing material [1] spatially printed in 40 um thick heterogeneous 2D-like-layers to build up a 1 mm height and arranged over the photoluminescent material [4], In an example of this embodiment, the photoluminescent material [4] is designed to have optical properties that mimic the absorption and reduced scattering of biological tissue.

[0057] The photoluminescent phantom 700 of FIG. 7 comprises four checkerboard patterns 704(1) through 704(4) of differing size scales, and that are formed in generally the same way as the photoluminescent phantom 400 of FIGS. 4A-4B, except that the grid is formed by alternating abutting cells of absorbing material [1] and a tuned material [2] formed over the photoluminescent material [4], Prior work has demonstrated the use of a checkerboard pattern consisting of highly reflective and highly absorptive squares manufactured through photolithography on a glass or film substrate, which can be used to generate high contrast and measure a wide-band optical sensing system’s flat-field response or utilized for distortion corrections. The flat-field performance characteristic provides information on how uniform camera detection is over an entire field of view. The distortion correction utilizes a known pattern to correct for lens distortions introduced on the image sensor. When a narrowband fluorescence optical sensing system is used, highly reflective components provide less contrast, or in some cases generate imaging artifacts where the excitation light interfaces with detecting the photoluminescent emission. While lithography-based glass or plastic films can be used to generate a surface pattern placed over photoluminescent material, high levels of specular reflection can generate imaging artifacts. The use of base and tuned materials [1], [2], [3], and / or [4] in accordance with aspects of the present disclosure provides more design control than existing options, and the surface finish can be optimized, for example, using wet sanding to reduce specular reflections.

[0058] An example use-case of the photoluminescent phantoms 400 and 700 of FIGS. 4A-4B and 7, respectively, is for measuring flatfield response of a fluorescence mode of a camera system. This flatfield measurement provides information on excitation uniformity and detection sensitivityover the entire imaging field of view. When a high-contrast pattern of known arrangement is generated over a large portion of the image sensor, it can also be used for distortion correction. Relative to the photoluminescent phantom 700 of FIG. 7, the narrowband fluorescence image of the checkerboard patterns 704(1) through 704(4) provides high contrast suitable for both flatfield and distortion corrections. Flatfield and distortion corrections are an important step in performing quantitative imaging. Distortion corrections are also important when performing image registration, which can be used to overlay an enhanced contrast fluorescence image on a white light image. In the photoluminescent phantom 700 of FIG. 7, each checkerboard pattern 704(1) through 704(4) is composed of alternating squares in a checkerboard arrangement. In the photoluminescent phantom 400 of FIGS. 4A-4B, the checkerboard pattern is a grid of scattering tuned material [2] surrounded by absorbing material [1], In one embodiment (not shown), a combination of diffing patterns is used. In one embodiment, the photoluminescence pattern is used to perform image registration with a wideband color or grayscale image.

[0059] As noted above relative to FIGS. 1A, IB, 3A, and 3B, in one aspect multi-component biological phantoms may be assembled using distinct components. For example, a component may utilize photoluminescent material provided as an inclusion, for example, to a cap, such as the body 104, or other structure of a photoluminescent phantom of the present disclosure. The properties of the material surrounding the photoluminescent inclusion can be designed in such a way to spatially modulate the excitation light fluence reaching the photoluminescent inclusion. Material properties are used to locally increase or attenuate the relative light fluence rate within the phantom. As one example, incident light entering highly scattering material will have a higher photon flux beneath the surface, relative to the surface irradiance, sometimes referred to as a build-up region. The surface irradiance is considered the excitation light entering the phantom, and easily measured. The rate of attenuation as a function of depth can also be modulated based on material properties. These optical interactions can be described analytically for a simple homogeneous geometry and extended source using Equation (1), below:wherein, 0(z) is the fluence rate as a function of depth (z) into the material. The effective attenuation (pe / y ) may be calculated using Equation 2, above, based on the attenuation attributed toabsorption ( / za) and reduced scattering ( / ), where reduced scattering considers the anisotropy factor(g) and is calculated using Equation 3, below: gs' = ^s(i - g (3)The anisotropy factor (g) is a probability confined between -1 and 1, where -1 is representative of 100% probability of backwards scattering (to the source), 1 is 100% probability of forward scattering, and 0 represents isotropic scattering or equal probability for all directions.

[0060] While analytical equations can provide an approximation of light fluence rates into homogeneous materials with known optical properties, they generally assume is' »ga- This assumption is often true for biological tissue at wavelengths in the near infrared (NIR) region. Additionally, these analytical solutions are poor at describing photon fluence rates in the first few hundred microns of turbid media or for heterogeneous materials. Monte Carlo simulations provide a solution to overcome these challenges by considering a larger set of input parameters, for example, refractive index changes and complex geometries. Monte Carlo simulations provide an approximate solution of photon interactions by tracking a large number of photon events where each step along a single photon trajectory has a random probability dictated by the simulation parameters. If enough events are simulated, the error of the approximation is reduced to provide actionable results.

[0061] The photoluminescent phantom 500 of FIGS. 5A-5B incorporates a design modulating fluence rates, wherein tuned materials [2] (with differing shades of gray corresponding to differing material formulations) with specific tuned absorbing and scattering properties are spatially combined with more-transmissive materials [3] in different layered arrangements. In this example, these patterned arrangements are placed over a photoluminescent inclusion [4], An example embodiment, such as the photoluminescent phantom 500 shown in FIGS. 5A-5B, could separate differences in the tuned and transmissive materials [2] and [3], respectively, in immediately adjacent cells with a segment of absorbing material [1] to prevent interference or cross-talk between regions. The dimensions of absorbing material [1] can be optimized to reduce photon travel between the immediately adjacent cells and direct photon paths towards the photoluminescent material [4], or from the photoluminescent material [4] towards the surface. An example embodiment, wherein the tuned material [2] has high scattering and low absorption at a boundary interface, is illustrated in the fluence graphs of FIGS. 9A-9D, and shows that there is a build-up of photons, which is primarily attributed to material optical properties and geometry of the input light source (not shown).FIGS. 9A-9D are described below in detail. The transmissive material [3] can be used as a light guide, wherein minimal scattering or absorption events occur.

[0062] One application of the example photoluminescent phantom 500 of FIGS. 5A-5B is to estimate photobleaching of the photoluminescent inclusion. The ability to select the material properties and manufacture them in specific arrangements according to a desired design provides the means to deliver different photon fluence distributions throughout one or more regions of a photoluminescent phantom. In a nonlimiting example, localized regions of the photoluminescent component could receive: 1) higher photon fluence than the surface irradiance, 2) photon fluence similar to the surface, or 3) attenuated photon fluence relative to the surface. In one embodiment, differential fluence rates into a photoluminescent component of a photoluminescent phantom can be used to create high contrast narrowband fluorescence images. In an example, differential fluence rates can be used to determine the lifespan of the photoluminescent material. When photoluminescent material is prone to photobleaching, for example when utilizing organic fhiorophores, images of the differential photobleaching can be used as a quality-assurance (QA) check of the photoluminescent phantom. For example, a photoluminescent phantom designed for differential photobleaching can be used for a QA check during manufacturing of a fluorescence optical sensing system. In one embodiment, a photoluminescent phantom designed for differential photobleaching can be used for a routine QA check of a clinical or preclinical fluorescence optical sensing system. An example photoluminescent phantom 800 that can be used for performing a QA check is described in detail below in connection with FIGS. 8A-8C, and an example of how that photoluminescent phantom can be used to assess degradation of the phantom via photobleaching is described below in connection with FIGS. 8D and 8E. In one embodiment, a phantom designed for differential photobleaching, such as the photoluminescent phantom of FIGS. 8A-8C, can be used with software to analyze the photodegradation of the photoluminescent material.

[0063] As noted above, FIGS 8A-8C illustrate the example photoluminescent phantom 800, which is designed with selectively translucent regions 804(1), 804(2), and 804(3) for performing a self-referencing photo bleaching assessment. Figure 8A shows that the selectively translucent regions 804(1) through 804(3) are located above (relative to FIG. 8A) a photoluminescent material 808, such as the photoluminescent material [4] described above. As seen in FIG. 8A, the region 804(1) is composed of a cell 812(1) that contains a transparent material, such as the transparent material [3] discussed above. Each of the regions 804(2) and 804(3) is composed of a corresponding cell 812(2), 812(3) and includes corresponding tuned materials [2a] and [2b] havingone or more of various optical properties (e.g., scattering, absorption, anisotropy, refractive index) that is / are designed to reduce the optical fluence through the cell, which is a macroscale optical performance feature of each region. In this example, the tuned material(s) [2b] of the region 804(3) has a greater attenuation than the tuned material(s) [2a] of the region 804(2). In this example, each of the cells 812(2) and 812(3) also includes the transparent material [1],

[0064] FIG. 8B provides a representative photoluminescent intensity image (i.e. fluorescence intensity) at initial time, i, whereas FIG. 8C represents times after photobleaching, i.e., time i+N. As can be seen by comparing FIGS. 8B and 8C with one another, the photoluminescent material 808 undergoes photobleaching between the time that FIGS. 8B represents and the later time that FIG. 8C represents. FIG. 8D is a graph of the intensities relative to region 804(1) at time z, where a continuous irradiance is applied to the surface of the photoluminescent phantom 800. Statistics (e.g., mean, median, standard deviation, etc.) collected from image analysis of the regions of interest, here, the regions 804(1) through 804(3), can be used to further quantify the differential photobleaching decay rates, relative to the starting ratios collected from time = i. A predefined ratio threshold could be used to determine the useful lifetime of a photoluminescent phantom, such as the photoluminescent phantom 800 of FIGS. 8A-8C. For example, when the normalized ratio between regions 1 and 3 is less than 0.9 in FIG 8E, could be used to indicate when to replace the phantom under test. FIG. 8E is a graph of normalized ratios of A) region 804(1) to region 804(2), B) region 804(1) to region 804(3), and C) region 804(2) to region 804(3), where all are normalized to their respective ratio at time = i.

[0065] When geometries of phantoms of the present disclosure become more complicated, analytic solutions for photon fluence rates as a function of depth become increasingly challenging to solve. The fluence rate of excitation light into the phantom can be modeled using Monte Carlo simulations for both simple and more complex geometries. Monte Carlo simulations are also able to estimate photon distributions through multi-layer and heterogeneous materials. The photoluminescent emissions can also be modeled using Monte Carlo simulations.

[0066] An example embodiment of estimating the excitation fluence rate as a function of depth into a phantom using Monte Carlo simulations is illustrated via the graphs of FIGS. 9A-9F. These embodiments show two layers of materials, namely a tuned material [2a or 2d] and a transmissive material [3], consisting of a total of 2 mm depth on top of a photoluminescent material [4], While two layers are shown, the number of layers could be increased or decreased as needed to suit aparticular design. Similarly, only one set of optical properties are used for the photoluminescent material [4], but many others are possible. The intention of this example is to provide the context needed to describe how a model-based platform uses this information for more complex design.

[0067] In one embodiment, Monte Carlo models of specific phantom designs can be used to estimate the excitation light fluence into the phantom. In an example, such a model considers the optical properties (absorption, scattering, anisotropy and refractive index), phantom geometry, excitation source geometry and wavelength. Voxelized photon fluence rate maps can be generated from these models. In one embodiment, the fluence rate distributions within the phantom model can be used to predict total light dose or fluence, relative to surface irradiance, for specific 3D coordinates within the phantom. In one embodiment, the simulated 3D light fluence rate can be used as the input source for a subsequent Monte Carlo simulation of photoluminescent emissions.

[0068] In FIGS. 9A and 9B, the transmissive material [3] placed on top of a scattering and absorbing layer [2a], in FIGS. 9C and 9D, the transmissive material [3] is placed on top of a differing scattering and absorbing layer [2d], and in FIGS. 9E and 9F, the corresponding scattering and absorbing layer [2a] or [2d] is located on top of the transmissive material. In the Monte Carlo models, the refractive indices for the materials [2], [3], and [4] are assumed to be 1.5; however, higher or lower values could be utilized. It is noted that the graphs of FIGS. 9A-9D are for two of the five tuned materials [2a] - [2e] having differing formulations that were used for the simulations, i.e., tuned materials [2a] and [2d], and for two thicknesses, namely 0.4 mm and 1.6 mm, of each of the two materials, as illustrated in Table 1, below. The corresponding fluences determined from the Monte Carlo simulations represented in FIGS. 9A-9C are shown in boldface in Table 1. Similarly, the graphs of FIGS. 9E and 9F are for the same two materials but having a thickness of 0.5 mm. The corresponding fluence values appearing in Table 2, below. Tables 1 and 2 provide the estimated normalized fluence at 2 mm, the top of the photoluminescent inclusion. In these normalized tables, a value of 1 represents equivalence to the surface irradiance, whereas higher numbers are fluence rates higher than the surface irradiance. A fluence rate build-up region is often observed and is primarily related to scattering and anisotropy. The effective attenuation of the materials [2a] - [2e] are, respectively, 0.257 mm’1, 0.259 mm’1, 0.709 mm’1, 1.103 mm’1, and 0.296 mm’1.

[0069] The ability, afforded by aspects of the present disclosure, to design phantoms having complex arrangements of materials such as materials [1], [2], [3], and [4] provides flexibility to control the photon fluence rates at arbitrary locations within the phantom. Using knowledge of the optical build-up regions provides an added flexibility to deliver more light to locations within a phantom relative to the light-incident surface of the phantom. When these properties are considered in the design, an aspect of the present disclosure is the ability to locally control photobleaching rates of the photoluminescent material(s) [4], Another aspect utilizes arrangements of absorptive material(s) [1] and transmissive material(s) [3] to selectively direct, or collimate, the light traveling through a region of the phantom, or a layer thereof.

[0070] Optical sensing systems (not shown) capable of detecting specific photoluminescent output consist of one or more cameras equipped with excitation light(s) and optical filters. These optical sensing systems enhance the contrast of the detected photoluminescence. Software imageanalysis algorithms are used to analyze the intensity of spatially distributed photoluminescence. In one aspect, these software algorithms can utilize customized regions of interest, specific to a phantom design, to determine the intensity differences between phantom regions. In one aspect, these intensity differences can be used to determine the state of photodegradation of the phantom or components.

[0071] FIG. 10 illustrates a computer-based method / software algorithm 1000 for characterizing photodegradation of a photoluminescent phantom, such as the phantoms 500 and 800 illustrated in FIGS. 5A-5B and FIGS. 8A-8C, respectively. A model of light fluence based on Monte Carlo methods (or similar) is used to generate a simulated reference image (1005). When a narrowband fluorescent image of the phantom is collected (1010), the software algorithm 1000 can compare the fluorescent image to one or more reference images (1015) and perform a model -based registration to match key features of the image (1020). A region of interest mask or similar feature definitions of the reference image (1025) can then be aligned with the experimental image to determine regions of interest (1030). The intensity and other statistics for each region of interest are determined (1035) and then tabulated for comparison (1040). Previous analysis of simulated photon fluence or experimental degradation data may be organized in a lookup table (1045) and can then be compared to the tabulated intensity statistics to estimate photo-degradation (1050).

[0072] The example computer-based method / software algorithm 1000 of FIG. 10 uses total deposited light fluence to estimate photodegradation of a photoluminescent material [4] within a phantom, such as a phantom made in accordance with the present disclosure. In one aspect, the material properties of the phantom can be designed to deliver differential total fluence, for example as shown in FIGS. 9A-9F, resulting in localized modulation of photodegradation, which are observable through photoluminescent imaging. The photobleaching rate ( / >) of the photoluminescent material [4] can be estimated through experimental data collection, or provided as a known material property. The photobleaching rate is wavelength dependent and is characterized by the total light fluence delivered per area (e.g., J / cm2). The rate of photobleaching is used to describe the concentration of photoluminescent material at a specific location and time (C(z,t)), as shown in Equation 4, below:wherein, 0(z) is the fluence at depth z (defined in Equation 1, above, or through Monte Carlo simulations), and Co is the initial photoluminescent concentration at time ( / = 0). In Equation 4, z can be replaced by a vector coordinate ( , ,z) to describe the interaction in 3D space. If the photobleaching rate (fi) is provided for a specific wavelength, the absorption profile can be used to account for excitation at different wavelengths.

[0073] Measurements or approximations of surface irradiance at a given wavelength can be combined with model-informed designs to estimate 0(z) for any location within the phantom. Model-based photon fluence rate approximations combined with known photoluminescence starting concentrations and absorption profiles, can be used to estimate C(z, t). Monte Carlo models provide estimates of the photon fluence rates within the phantom model, relative to the surface irradiance. Lookup tables can be generated, from simulation outputs for specific wavelengths and phantom designs, to approximate absolute fluence at locations within the phantoms, relative to measurable surface irradiance. In one embodiment, model-based lookup tables can be used to estimate the concentration of photoluminescent material [4] after photobleaching has occurred. In one embodiment, Monte Carlo simulations can be used to design phantoms to alter localized photoluminescent output over the lifetime of the phantom’s intended use.

[0074] Photodegradation can be estimated through the use of model-informed lookup tables. Model-based photon fluence rate approximations, such as the examples provided in Table 1 and Table 2, above, can be used with Equation 4, above, to predict the photodegradation rate. As an example, Table 1 provides the normalized fluence at the surface of the photoluminescent material [4], In this example, if two regions of interest are defined, where one has the configuration described by FIG 9A and the other region of interest can be described by FIG 9D, the respective relative fluence at the photoluminescent surface at depth of 2mm would be 1.539 and 0.152, respectively, as shown in Table 1. These are relative to the surface irradiance and can be used to determine 0(z) in Equation 4. A lookup table for both regions of interest can be used to calculate the photoluminescent concentration as a function of depth and exposure time C(z, t) for times t = i to t = i + N. Multiple lookup tables could be generated for different ranges of surface irradiance and time resolutions. In this model, surface irradiance and photodegradation rate are assumed to be constant, but more complex scenarios could be estimated through iterative analysis, however these are too complicated to present in the current example. Additional experimental validations can also be used to refine the model and update the lookup-tables. While Equation 4 can be used to generate lookup tables for the estimated concentration of photoluminescent material [4] over extended periodsof time at a given surface irradiance, the emitted light reaching surface, for example 1121 (FIG 1 A), could be estimated by applying Equation 1, above. In practicality, if an image is collected at time t = i, the ratio of the intensities from time t = i + A for corresponding regions can be used in place applying Equation 1. In this example, the graphs shown in FIG 8D provides surrogate measures of applying Equation 4 over time / / to time t = i N. Furthermore, FIG 8E shows how the ratio of intensities for corresponding regions at different times, normalized to the ratio at time t = / , can be used as a self-refencing metric of photobleaching.

[0075] Multi-material phantoms can be designed to modify the fluence rate at depth into the phantom, as shown in 500, 600 and 800. The fluence rate delivered to the photoluminescent material can be higher or lower than the surface irradiation, as shown in FIG 9 and FIG 10. In some cases where the photoluminescent material exhibits photodegradation, the emitted light intensity can change over the duration of the use of the phantom. The emitted light intensity of the is related to the concentration of the photoluminescent material, which is described in relation to the excitation light fluence in Equation 4. The rate of decay will be altered based on the delivered fluence, so regions of the photoluminescent material receiving high fluence excitation will photodegrade faster than regions receiving lower fluence. The decay rate shown in Equation 4 is a single exponential, but other factors, such as non-linear photodegradation or non-uniform illumination, among others, may change the rate relation. Estimated concentration changes due to photodegradation can be tabulated in lookup tables and used by designers to achieve modified contrast between regions during the lifetime of the phantom. These contrast modifications may be used for purely cosmetic reasons, or used for a functional purpose such as a self-reference of photodegradation.

[0076] FIGS. 11A and 1 IB illustrates an example flow phantom 1100 that is made in accordance with aspects of the present disclosure, such as the methodologies and fabrication techniques described above in connection with FIGS. 1 A, IB, and 2. In the embodiment shown, the flow phantom 1100 includes a target body 1104, which comprises a material mass 1108 containing one or more voids, here a single void 1112 (FIG. 1 IB), and a pair of fluid connectors 1116(1) and 1116(2) for connecting the flow phantom, for example, to a fluid circuit (not shown) for causing a suitable fluid (not shown) to flow through the void during use of the flow phantom. As those skilled in the art will readily appreciate, flow phantoms that the simplified flow phantom 1100 represents can be used for a variety of purposes, such as simulating a biological mass, for example, breast tissue, organ tissue, etc., with the material mass 1108 simulating biological tissue(s) (e.g., muscle tissue, adipose tissue, blood-vessels, glandular tissue, skin tissue, etc., and any combinationthereof) of the biological mass and the flowing liquid within the void 1112 simulating fluid flow (e.g. blood, urine, contrast agent, etc.) within the biological tissue(s).

[0077] The material mass 1108 is made of one or more tuned materials [2] that each may be composed using a plurality of differing material formulations having differing compositional optical properties (see, e.g., the discussions of material formulations, above) that, when combined using the discrete-volume fabrications techniques discussed above in connection with FIGS. 1 A and IB, provide the material mass with one or more macroscale optical performances that correspond to the optical performance exhibited by the real biological tissue(s) that the material mass is simulating. In this example, the fluid connectors 1116(1) and 1116(2) are made of a different material relative to the tuned material(s) [2] of the material mass 1108, such as a light-absorbing material [1], The flowing fluid (not shown), when present within the void 1112, may be composed of any suitable material(s), such as one or more photoluminescent compounds [4] and / or one or more self-emitting compounds, as may be needed for the application at issue. Those skilled in the art will understand how to select the various materials used to construct the various components of the flow phantom 1100 using only ordinary skill in the art and the present disclosure as a guide.

[0078] The void 1112 may be formed in any suitable manner. For example, if the geometry of the void 1112 and the additive manufacturing techniques used to make the material mass 1108 permit, the void may be formed as a true void, meaning that no added (e.g., printed) material is used, and the void initially contains only the gas (e.g., air) present during the additive manufacturing of the material mass. As another example, the void 1112 may be created by, for example, printing a removable material (not shown) in the volume of the void while building the entire target body 1104. Then, after the entire target body 1104 has been printed, the removable material is removed. Examples of removing the removable material include, but are not limited to, removing by dissolving the removable material, removing by heating the removable material, and removing by exposing the material to a liquifying agent, among others. Those skilled in the art will understand the variety of ways that the void 1112 can be formed in the material mass 1108.

[0079] As noted above, the flow phantom 1100 illustrated in FIGS. 11A and 1 IB is highly simplified, because useful flow phantoms will often 1) have shapes that mimic shapes of biological masses, 2) simulate multiple types of biological tissue, 3) have many voids (representing, e.g., veins, arteries, capillaries, etc., and 4) having complex networks of voids (e.g., highly branched blood vessels, multiple blood-vessel branches, etc.). Regardless of the complexities of actual useful flowphantoms, those skilled in the art will readily be able to make them using the basic techniques illustrated by the simplified flow phantom 1100 of FIGS. 11 A and 1 IB.

[0080] While FIGS. 11 A and 1 IB show a flow phantom 1100, modifications can be readily made so that FIGS. 11A and 1 IB can also be considered to represent a biomedical phantom 1120. For example, one modification would be to fill the void 1112 (FIG. 1 IB) with one or more suitable materials 1124, such as, for example, one or more photoluminescent compounds [4] and / or one or more self-emitting compounds, as may be needed for the application at issue. In some embodiments, the material(s) 1124 (FIG. 1 IB) may be provided using the same additive manufacturing techniques used to make the material mass 1108, for example, the discrete-volume techniques described above in connection with FIGS. 1 A and IB. In some embodiments, the void 1112 may be formed and later filled with the material(s) 1 124. Those skilled in the art will understand the manners in which a biomedical phantom, such as the biomedical phantom 1100 of FIG. 11 A and 1 IB can be made in accordance with the present disclosure using the present disclosure as a guide in combination with ordinary knowledge in the art.

[0081] While the foregoing disclosure largely focuses on embodiments of phantoms and targets that include one or more photoluminescent materials, it is noted that one or more self-emitting materials, such as one or more solid-state emitters, can be used in place of any photoluminescent material or in addition to any photoluminescent material. For context and example, each photoluminescent material of any one of the illustrated embodiments can be replaced by a selfemitting material that contains one or more self-emitting compounds, such as, but not limited to solid-state light-emitters, chemiluminescent material, bioluminescent material, and electroluminescent material, among others. Examples of reasons why a self-emitting material may be used in place of a photoluminescent material include, but are not limited to, providing a demonstration wherein the actual light source is too wieldy for demonstration purposes and providing a phantom or target for instrument characterization that does not require use of an external excitation light source, among others.

[0082] Various modifications and additions can be made without departing from the spirit and scope of this disclosure. Features of each of the various embodiments described above may be combined with features of other described embodiments as appropriate in order to provide a multiplicity of feature combinations in associated new embodiments. Furthermore, while the foregoing describes a number of separate embodiments, what has been described herein is merelyillustrative of the application of the principles of the present invention. Additionally, although particular methods herein may be illustrated and / or described as being performed in a specific order, the ordering is highly variable within ordinary skill to achieve aspects of the present disclosure. Accordingly, this description is meant to be taken only by way of example, and not to otherwise limit the scope of this invention.

[0083] Exemplary embodiments have been disclosed above and illustrated in the accompanying drawings. It will be understood by those skilled in the art that various changes, omissions and additions may be made to that which is specifically disclosed herein without departing from the spirit and scope of the present invention.

[0084] The subject matter of the appended claims is incorporated by reference into this Detailed Description section so as to have the effect of being literally present in this section.

Claims

What is claimed is:1 . A biomedical phantom that provides a designed use with an instrument having an optical sensing system, the biomedical phantom comprising: a body having a light-incidence side and a light-emitting side spaced from the light-incidence face and that includes a first region having a first macroscale optical performance through the body from the light-incidence to light-emitting side, wherein: the first optical performance is designed for the use with the instrument, the optical sensing system, or both of the instrument and the optical sensing system; and the first region is formed from a plurality of first differing material formulations that provide first differing compositional optical properties present, wherein the first differing material formulations are located in a plurality of discrete volumes within the region so that the combination of the first differing compositional optical properties in the discrete volumes manifests as the first macroscale optical performance over the first region.

2. The biomedical phantom of claim 1, wherein the discrete volumes are voxels.

3. The biomedical phantom of claim 1, wherein the first region comprises at least one layer, and at least some of the discrete volumes are located in the at least one layer.

4. The biomedical phantom of claim 1, wherein the first region comprises a plurality of layers, and the discrete volumes are distributed throughout the plurality of layers.

5. The biomedical phantom of claim 4, wherein the discrete volumes are voxels.

6. The biomedical phantom of claim 1, further comprising a photoluminescent material located adjacent to the first region on the light-emitting side of the first region.

7. The biomedical phantom of claim 1, wherein the first optical performance is designed to simulate an optical performance of a biological material.

8. The biomedical phantom of claim 7, wherein the biological material comprises biological tissue.

9. The biomedical phantom of claim 7, wherein the biological material comprises blood or one or more constituents of blood.

10. The biomedical phantom of claim 1, wherein: the use is to characterize or demonstrate performance of the instrument, the optical sensing system, or both of the instrument and the optical sensing system; and the first region has a pattern on the light-incidence side, wherein the pattern is selected based on the use.

11. The biomedical phantom of claim 1, further comprising a second region having a second macroscale optical performance different from the first macroscale optical performance of the first region, wherein: the second region is discrete from the first region; and the second region is formed from a plurality of second differing material formulations that provide second differing compositional optical properties present, wherein the second differing material formulations are located in a plurality of discrete volumes within the second region so that the combination of the second differing compositional optical properties in the discrete volumes manifests as the second macroscale optical performance over the second region.

12. The biomedical phantom of claim 11, wherein one or more of the second differing material formulations are the same as one or more of the first differing material formulations.

13. The biomedical phantom of claim 11, wherein the first region simulates a first biological material and the second region simulates a second biological material different from the first biological material, and the first and second macroscale optical performances differ from one another.

14. The biomedical phantom of claim 13, wherein the biomedical phantom simulates a 3D volume of biological tissue, with the first and second regions simulating differing types of biological tissue.

15. The biomedical phantom of claim 1, wherein the body comprises a cap, and the biomedical phantom further comprises a photoluminescent material located immediately adjacent to the light-emitting side of the body.

16. The biomedical phantom of claim 1, wherein at least one of the first differing material formulations comprises a photoluminescent compound.

17. The biomedical phantom of claim 1, further comprising at least one solid-state self-emitter.

18. The biomedical phantom of claim 1, wherein: the differing material formulations are arranged in a designed 3 -dimensional pattern, wherein the differing material formulations have differing optical absorption, scattering, anisotropy, and / or refractive index; and the biomedical phantom further comprises a photoluminescent component.

19. The biomedical phantom of claim 18, wherein the photoluminescent component is enclosed within the designed 3-dimensional pattern of the heterogeneous materials.

20. The biomedical phantom of claim 18, wherein the photoluminescent components are exposed to a surface of at least one of the heterogeneous materials.

21. The biomedical phantom of claim 18, wherein the designed 3-dimensional pattern is designed and configured to produce an optical pattern at an imaging surface with enhanced photoluminescent contrast.

22. The biomedical phantom of claim 18, wherein the designed 3-dimensional pattern is designed and configured to spatially modulate excitation light fluence delivered to the photoluminescent component.

23. The biomedical phantom of claim 18, wherein the designed 3-dimensional pattern is designed and configured to produce an optical pattern at an imaging surface that is visible only under narrowband photoluminescent imaging and is not visible under standard wideband visible light conditions.

24. The biomedical phantom of claim 18, further comprising at least one solid-state self-emitter.

25. A method of using the photoluminescent phantom of claim 28, wherein the photoluminescent component undergoes photobleaching, the method comprising: monitoring degradation over time of the photoluminescent component caused by the photobleaching so as to provide a self-referencing mechanism for monitoring an optical sensing system.

26. A method of fabricating a multi-material optical phantom, the method comprising: additively manufacturing the multi-material optical phantom using one or more photo-curing base resins deposited in discrete volumes so as to form a plurality of sequential layers;wherein: optical properties of one or more resin formulations that use the one or more photo-curing base resins are known; a combination of the one or more resin formulations in specific ratios provide the ability to select from a range of desired optical properties; and the plurality of sequential layers are cured through photo-activation to produce software- defined 3-dimensional geometries having heterogeneous optical properties.

27. The method of claim 26, further comprising producing a photoluminescent component using additive manufacturing using a photo-curing resin containing a photoluminescent compound.

28. The method of claim 26, further comprising adding a self-emitting source.

29. The method of claim 26, further comprising producing a photoluminescent component using a two-part setting polymer containing a photoluminescent compound.

30. The method of claim 26, further comprising forming one or more voids within the plurality of sequential layers.

31. The method of claim 30, wherein forming one or more voids includes 3-dimensionally printing the plurality of sequential layers so as to include the one or more voids.

32. The method of claim 30, wherein forming the one or more voids includes 3-dimensionally printing the plurality of sequential layers so as to include a removable material where the one or more voids are located within the plurality of sequential layers.

33. The method of claim 32, wherein forming the one or more voids further includes removing the removable material so as to create the one or more voids.

34. The method of claim 33, wherein the removable material is a soluble material, and removing the removable material includes dissolving the soluble material.

35. The method of claim 30, wherein a photoluminescent material is flowed into the one or more voids.

36. An optical phantom comprising: heterogeneous materials arranged in a designed 3-dimensional pattern, wherein:the heterogeneous materials have differing optical absorption, scattering, anisotropy, and / or refractive index; and the 3-dimensional pattern is configured to approximate model-based photon fluence rate estimates for one or more wavelengths.

37. A method of designing and fabricating an optical phantom utilizing, in the designing, modelbased approximations of fluence rate at depth into the optical phantom.

38. A method of designing and fabricating a photoluminescent phantom having a surface on a lightincident side of the photoluminescent phantom, the method comprising: utilizing, in the designing, model-based approximations of excitation fluence rate at depth into the photoluminescent phantom; and utilizing, in the designing, model-based approximations of photoluminescence remission rates reaching the surface.

39. A method of designing and fabricating a photoluminescent phantom using model-based approximations of excitation fluence rate at depth into the photoluminescent phantom to predict localized photobleaching.

40. A method of analyzing photoluminescent images of a photoluminescent phantom fabricated according to either claim 38 or 39, wherein the photoluminescent phantom comports with a phantom design, the method comprising: defining regions of interest based on knowledge of the phantom design; collecting regional statistics of local image intensity for each of the regions of interest; and calculating ratios or differences of the regional statistics and comparing the ratios or the differences to a look-up-table of associated photo-degradation estimates.

41. A method of predicting photon fluence rates within a phantom using model-based look-up table(s).

42. A method of designing and fabricating an optical phantom, comprising: providing a specific 2-dimensional intensity array as an input for the design; and utilizing, in the designing, model-based approximations of fluence rate at depth into the optical phantom;wherein the optical phantom provides narrowband optical emissions to enhance contrast of the input 2-dimensional intensity array.

43. The method of claim 42, further comprising using optical remission of one or more photoluminescent inclusions to provide enhanced contrast of the input 2-dimensional intensity array.

44. The method of claim 42, further comprising using one or more solid-state light emitters to provide enhanced contrast of the input 2-dimensional intensity array.

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