Ultrasound test phantom for bimodal damage response

Abstract

The application discloses a bimodal damage response ultrasonic test phantom, which comprises a base body and a response medium, wherein the base body comprises at least two gel layers, there is a preset acoustic impedance gradient interface and an image contrast gradient interface between two adjacent gel layers, the response medium is embedded in the gel layer of the base body, the response medium comprises a thermochromic response body and a brittle visible light color developing response body, and then a thermal damage area and a mechanical damage area can be quantitatively evaluated simultaneously or respectively.

Description

Technical Field

[0001] This application relates to a focused ultrasound phantom, and more particularly to an ultrasound testing phantom with dual-modal damage response. Background Technology

[0002] High-intensity focused ultrasound (HIFU) and histotripsy are two non-invasive physical energy therapy techniques based on focused ultrasound. HIFU primarily induces coagulative necrosis of tissue through thermal effects (above 55-60°C); histotripsy, on the other hand, achieves tissue liquefaction and destruction through the mechanical disruption of cavitation mist-like bubbles or boiling bubble clouds induced by single or combined high-sound pressure pulses at the microsecond to millisecond level. Existing test phantoms generally suffer from the following six major drawbacks:

[0003] (1) The damage mechanism is indistinguishable. Existing high-intensity focused ultrasound phantoms generally use BSA (bovine serum albumin) thermal coagulation imaging or agar-barium sulfate layer (which is high-density and X-ray impermeable) mixed imaging; such phantoms cannot simultaneously or separately quantitatively assess the thermal damage area and the mechanical damage area in the same phantom;

[0004] (2) Lack of tissue heterogeneity. Almost all existing test phantoms are homogeneous gel materials, while real human tissues have significant multiphase heterogeneous structures. Homogeneous phantoms cannot simulate the cavitation enhancement effect of real interfaces;

[0005] (3) Mechanical damage cannot be quantified. Current technology lacks the means to quantify the mechanical damage caused by tissue destruction in a phantom body;

[0006] (4) Simulation without blood perfusion. All existing phantoms are static solids and cannot simulate the "thermal deposition" effect caused by in vivo blood perfusion;

[0007] (5) Lack of realistic tissue response. Existing pure chemical phantoms cannot simulate the cavitation threshold and damage morphology of real human tissues, resulting in a serious deviation between in vitro dose prediction and clinical reality;

[0008] (6) Lack of multimodal imaging compatibility design. Existing phantoms are usually designed for a single imaging modality and cannot achieve multimodal fusion testing of ultrasound guidance, MRI localization, CT verification and optical direct vision on the same phantom. Summary of the Invention

[0009] To address the aforementioned technical problems, this application provides a dual-modal damage response ultrasonic testing phantom, which includes:

[0010] The matrix comprises at least two gel layers, wherein adjacent gel layers have a preset acoustic impedance gradient interface and an image contrast gradient interface.

[0011] A responsive medium, wherein the responsive medium is embedded in the gel layer of the matrix, wherein the responsive medium comprises a thermochromic responder and a brittle visible light chromogenic responder.

[0012] Preferably, the ultrasonic testing phantom for dual-modal damage response further includes an inlay embedded in the gel layer.

[0013] Preferably, the inlay embedded in the gel layer includes organic inlays and / or inorganic inlays.

[0014] Preferably, the organic inlay is selected from fresh ex vivo animal organ tissue, frozen tissue, or human-like tissue.

[0015] Preferably, the inorganic inlay is selected from at least one of hydroxyapatite pressed body, silica sintered body or calcium carbonate pressed body.

[0016] Preferably, the surfaces of the organic tissue inlay and / or inorganic inlay are coated with a PAA prepolymer liquid interface coupling coating with a thickness of 0.1 to 0.2 mm.

[0017] Preferably, the dual-modal damage response ultrasound testing phantom further includes a vascular perfusion system for the gel layer, wherein the vascular perfusion system comprises:

[0018] The channel body contains multiple staggered microchannels, an inlet and an outlet communicating with the microchannels, so as to introduce a fluid medium simulating human blood into the microchannels through the inlet, wherein the channel body is embedded in the gel layer;

[0019] A circulation drive assembly, wherein the circulation drive assembly is connected to the inlet and the outlet to guide the fluid medium from the inlet through the microchannel and out of the outlet.

[0020] Preferably, the thermochromic responder comprises an outer wall made of a gelatin-gum arabic composite and a core material made of a reversible thermochromic dye.

[0021] Preferably, the brittle visible light colorimetric responder comprises an outer wall made of highly cross-linked polyacrylamide and a core material made of visible light colorimetric dye.

[0022] Preferably, the thermochromic responder and the brittle visible light chromogenic responder are detachably embedded in the gel layer of the matrix.

[0023] Preferably, the dual-modal injury response ultrasound testing phantom is configured to be at least one of organ phantoms, urinary system phantoms, digestive system phantoms, and brain-adaptive phantoms.

[0024] The organ phantoms mentioned above include at least a liver phantom;

[0025] The urinary system phantom includes at least a kidney-adapted phantom, a bladder-adapted phantom, or a prostate-adapted phantom;

[0026] The digestive system phantoms mentioned therein include at least a stomach-fitting phantom, a gallbladder-fitting phantom, a duodenum-fitting phantom, a small intestine-fitting phantom, a large intestine-fitting phantom, a pancreas-fitting phantom, or a spleen-fitting phantom.

[0027] Preferably, the ultrasonic test phantom for dual-modal damage response is configured to maintain its original shape after sealing under an absolute pressure of 100–1000 Pa, a heat sealing temperature of 160–180°C, a pressure of 0.3–0.5 MPa, and a time of 2–3 s, without compression or deformation.

[0028] Preferably, the ultrasonic test phantom with dual-modal damage response can be refrigerated at 2-8°C for 6-12 months; when containing the thermochromic responder, it can be refrigerated again at 2-8°C after opening and use, and the cumulative number of uses shall not exceed 10; when containing the brittle visible light colorimetric responder, it cannot be refrigerated again after opening and is for single use.

[0029] Technical effects of this application 1. The ultrasonic testing phantom with dual-modal damage response described in this application can be used to quantitatively assess thermal damage areas and mechanical damage areas simultaneously or separately.

[0030] 2. The ultrasonic testing phantom with dual-modal damage response described in this application can better simulate the corresponding human body parts. Attached Figure Description

[0031] Figure 1 A schematic diagram of an ultrasonic testing phantom for dual-modal damage response according to the first embodiment of this application is shown.

[0032] Figure 2 A schematic diagram of an ultrasonic testing phantom with dual-modal damage response according to an embodiment of this application is shown.

[0033] Figure 3 A schematic diagram of an ultrasonic testing phantom for dual-modal damage response according to another embodiment of this application is shown.

[0034] Figure 4 A schematic diagram of an ultrasonic testing phantom for dual-modal damage response according to yet another embodiment of this application is shown.

[0035] Figure 5A A layered schematic diagram of the first example of the ultrasonic testing phantom indication for the dual-modal damage response of this application is shown.

[0036] Figure 5B A layered schematic diagram of a second example of the ultrasonic testing phantom indication for the dual-modal damage response of this application is shown.

[0037] Figure 5C A layered schematic diagram of the third example of the ultrasonic testing phantom indication for the dual-modal damage response of this application is shown.

[0038] Figure 5D A layered schematic diagram of the fourth example of the ultrasonic testing phantom indication for the dual-modal damage response of this application is shown.

[0039] Figure 5E A layered schematic diagram of the fifth example of the ultrasonic testing phantom indication for dual-modal damage response of this application is shown.

[0040] Figure 5F A layered schematic diagram of the sixth example of the ultrasonic testing phantom indication for the dual-modal damage response of this application is shown.

[0041] Figure 6 The first example of the ultrasound testing of the bimodal damage response phantom indication of this application is shown in the first figure under ultrasound.

[0042] Figure 7 The second image shows the first example of the ultrasound testing of the bimodal damage response phantom indication of this application under ultrasound. Detailed Implementation

[0043] The following description is intended to disclose the present invention and enable those skilled in the art to implement it. The preferred embodiments described below are merely examples, and other obvious variations will occur to those skilled in the art. The basic principles of the invention defined in the following description can be applied to other embodiments, modifications, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the invention.

[0044] refer to Figure 1 and Figure 2 A preferred embodiment of the ultrasonic testing phantom for dual-modal damage response according to this application will be described in detail below. Specifically, the ultrasonic testing phantom for dual-modal damage response includes a substrate 100 and a response medium 200, wherein the substrate 100 includes at least two gel layers 110, wherein adjacent gel layers 110 have a preset acoustic impedance gradient interface and an image contrast gradient interface, wherein the response medium 200 is embedded in the gel layer 110 of the substrate, wherein the response medium 200 includes a thermochromic reactivity medium 210 and a brittle visible light chromogenic reactivity medium 220.

[0045] It is understood that the number of gel layers 110 in the substrate 100 can be selected according to actual needs. For example, in one example, when the ultrasound testing phantom is used to simulate a stone test in a joint, three gel layers 110 can be formed; in another example, when the ultrasound testing phantom is used to simulate a liver phantom structure test, seven gel layers 110 can be formed. This application is not limited in this respect.

[0046] Preferably, the two adjacent gel layers 110 have a preset acoustic impedance gradient interface that satisfies at least one of the following conditions: acoustic impedance gradient ΔZ ≥ 0.15 MRayls; attenuation coefficient adjustable from 0.2 to 20.0 dB / cm / MHz; sound velocity adjustable from 1400 to 1700 m / s; elastic modulus adjustable from 5 to 500 kPa; and microbubbles (0.1 to 0.5% v / v) simulating cavitation nuclei.

[0047] Preferably, the two adjacent gel layers 110 have a preset image contrast gradient interface that satisfies at least one of the following conditions:

[0048] T1 relaxation time matching (CuSO4 / glycerol regulation, T1≈800–1200 ms); T2 relaxation time matching (crosslinking density / SiO2 regulation, T2≈40–100 ms); MRI positive / negative contrast; no magnetic susceptibility artifacts; and / or

[0049] HU value matching: fat -100 to ~50 HU; parenchyma 0 to 30 HU; bone 400 to 1000 HU; contrast enhancement simulation (potassium iodide / iodine contrast agent); stone / calcification simulation (inorganic hard inlay); and / or

[0050] It is worth mentioning that the acoustic impedance gradient interface and image contrast gradient interface formed between the adjacent gel layers enable the ultrasound testing phantom to not only be used for ultrasound detection, but also to present clear images in CT, X-ray / DSA, MRI, and optical fluorescence imaging; thus, the ultrasound testing phantom will not only have multimodal imaging compatibility. More importantly, the acoustic impedance gradient interface and image contrast gradient interface formed between the adjacent gel layers can simulate the significant multiphase heterogeneous structure of real human tissue, and can also simulate the cavitation enhancement effect of real interfaces.

[0051] In one embodiment, the gel layer 110 comprises propylene and / or N,N'-methylenebisacrylamide; in another embodiment, the gel layer 110 further comprises at least one selected from bovine serum albumin, tetramethylethylenediamine, gelatin, gum arabic, PDMS, silicone oil, hydroxyapatite, etc. Specifically, the components of the gel layer 110 can be configured according to different application scenarios. Those skilled in the art will understand that the gel layer 110 can be prepared by a layered casting method.

[0052] In one embodiment, the gel layer 110 is formed by layered casting. In one embodiment, the method for preparing the gel layer 110 includes:

[0053] S101, mold pretreatment; that is, the aluminum alloy mold (6061-T6) is ultrasonically cleaned with acetone for 10 min → rinsed with deionized water → dried at 120°C for 30 min → the inner wall is sprayed with food-grade silicone oil release agent (Shin-Etsu KM-9782, wet film thickness 5-8μm) → cured at 60°C for 10 min.

[0054] S102, deaerated water preparation: reverse osmosis pure water, then mixed bed ion exchange, then 0.22μm terminal filtration, then resistivity detection (≥18.2 MΩ·cm), then vacuum deaeration tank (absolute pressure 800Pa, 3h, dissolved oxygen ≤2mg / L), then transferred to the batching room under nitrogen protection.

[0055] S103, prepolymer solution preparation (taking the surface layer as an example): Weigh 10g AAM + 0.53g Bis (1:19 molar ratio), dissolve in 80mL degassed water, and magnetically stir (300rpm, 10min, 20°C); then add 8mL of silicone oil microdroplets (pre-emulsified by high-speed shearing, particle size 50-200μm), and ultrasonically disperse (40kHz, 5min); then add CuSO4 stock solution (to adjust T1, optional); subsequently, purge with nitrogen for 15min to remove oxygen; finally, add 0.15g APS and 0.10mL TEMED, mix quickly for 10s, and immediately cast.

[0056] S104, First layer casting and pre-gelling: The prepolymer liquid in S103 is injected into the mold to the designed height (e.g., 10mm for the fat layer), placed horizontally, and pre-gelled at 20°C for 20-25 minutes. Judgment criteria: The surface loses its fluidity, is not sticky to the touch but leaves indentations (gel conversion rate is about 60-70%).

[0057] S106, Vascular Network / Inlay Placement (if applicable); that is, in the semi-gel state (after step 4 is deemed satisfactory), press the pre-formed PDMS vascular channel insert or organic / inorganic inlay to the designed depth, and gently press to remove interlayer air bubbles. The inlay surface is pre-coated with PAA prepolymer solution (0.1-0.2mm coupling layer).

[0058] S106, second layer casting; that is, prepare the intermediate layer prepolymer solution according to S103 (note to adjust the dispersion order of SiO2 and cellulose: first disperse SiO2 ultrasonically for 30 minutes, then stir cellulose at low speed), pour to the designed height (e.g., 25 mm for glandular layer), and allow to stand horizontally for pregelation.

[0059] S107, Target layer and insert interface forming; that is, before the prepolymer liquid of the target layer is poured, a conical snap-fit ​​female mold (busbar inclination angle 15°, stainless steel 316L, surface polishing Ra≤0.8μm) needs to be installed in the center of the mold. After pouring, pregel for 20 minutes, remove the female mold to form a standardized conical groove.

[0060] S108, complete curing and demolding: Curing at room temperature (20-25°C) for 24 hours; or accelerated curing at 37°C for 6 hours (but curing at 37°C will cause the thermochromic microresponder to respond prematurely, and is only applicable to the outer substrate without the responder). Demolding: Turn the mold over and use the elastic deformation of the silicone insert to assist in demolding. Do not pry it off forcefully.

[0061] S109, PBS equilibration: After demolding, immerse in PBS (pH 7.4, 0.01M) and equilibrate at 4°C for 48 hours, changing the PBS every 12 hours. Purpose: To wash away unreacted monomers (AAM residue <50ppm, meeting GB / T 16886.12 cytotoxicity requirements).

[0062] S1001, Dimensional and Acoustic Quality Inspection; namely, dimensional deviation detected by coordinate measuring machine <2%; sound velocity detected by pulse transmission method (sound velocity target of liver phantom target area 1540±30m / s).

[0063] Furthermore, since the thermochromic responder 210 and the brittle visible light chromogenic responder 220 included in the response medium 200 are embedded in the gel layer, when the dual-modal damage-responsive ultrasound testing phantom is used for high-intensity focused ultrasound testing, the coagulative necrosis area of ​​the tissue caused by the thermal effect will be stained by the thermochromic responder 210, thereby enabling high-intensity focused ultrasound testing. Similarly, when the dual-modal damage-responsive ultrasound testing phantom is used for tissue destruction ultrasound testing, the tissue liquefied and destroyed by the mechanical disruption of cavitation mist bubbles or boiling bubble clouds induced by single or combined high-sound-pressure pulses at the microsecond to millisecond level will be stained by the brittle visible light chromogenic responder 220 and thus detected.

[0064] Therefore, the ultrasonic test phantom with dual-modal damage response described in this application can be used to quantitatively evaluate thermal damage areas and mechanical damage areas simultaneously or separately.

[0065] In a preferred embodiment, the thermochromic responder 210 and the brittle visible light chromogenic responder 220 are detachably embedded in the gel layer 110 of the substrate, so that the thermochromic responder 210 and / or the brittle visible light chromogenic responder 220 can be selectively coupled to the gel layer 110 as needed for testing.

[0066] In one embodiment, the thermochromic responder 210 comprises an outer wall made of a gelatin-gum arabic composite and a core material made of a reversible thermochromic dye. The thermochromic responder has a phase transition temperature of 55–60°C, a particle size of 50–100 μm, and a volume fraction of 1–3%.

[0067] In a preferred embodiment, the thermochromic responder 210 can be manufactured by a complex condensation method;

[0068] For example, in one embodiment, the method for preparing the thermochromic responder 210 includes:

[0069] S201, preparation of gelatin solution: Specifically, dissolve 50g of gelatin in 1L of 60°C deionized water, stir (200rpm) until completely dissolved, and keep warm at 50°C.

[0070] S202, preparation of gum arabic solution: dissolve 50g of gum arabic in 1L of 40°C deionized water, stir (200rpm) until transparent, and keep warm at 40°C.

[0071] S203, core material emulsification: Specifically, 8g of thermochromic dye is heated to 70°C to melt, 20mL of liquid paraffin is added, and emulsification is carried out at high speed (8000rpm, 2min, 60°C) to form a core material emulsion. Target particle size: 30–50μm.

[0072] S204, preparation of the colostrum: specifically, the core material emulsion is added to the gelatin solution (50°C) and mechanically stirred (400 rpm, 10 min) to form a W / O type colostrum.

[0073] S205, Coagulation Reaction; Specifically, the gum arabic solution is slowly added dropwise to the primary emulsion (5 mL / min, with stirring at 400 rpm). During the addition, the pH is adjusted to 4.2 ± 0.1 with glacial acetic acid (monitored with an online pH meter). At this point, the system changes from clear to milky white, indicating that coagulation has occurred. Continue stirring for 30 min.

[0074] S206 was cross-linked and cured by cooling to 10°C (ice-water bath, cooling rate 1°C / min), adding 2.0 mL of 25% glutaraldehyde (final concentration 0.1%), and stirring for 2 hours (200 rpm). After cross-linking, the wall material changed from a soft gel to an elastic capsule.

[0075] S207, post-treatment: Add 500 mL of isopropanol for dehydration (10 min), and allow to settle. Discard the supernatant, and wash the precipitate three times with deionized water. Wet sieve (50 μm and 100 μm standard sieves), and take the 50-100 μm fraction.

[0076] S208, Quality Inspection and Storage; Quality Inspection: Wall thickness (target 2-5 μm) and roundness can be observed under a microscope; Water bath heating test (60°C / 5min, color development response time <3s, fading recovery time <5min@25°C). Suspended in deionized water containing 0.02% sodium azide, protected from light at 4°C, shelf life 6 months.

[0077] In a preferred embodiment, the mass ratio of gelatin to gum arabic is strictly 1:1, and the pH is strictly 4.0–4.5. A pH below 3.8 results in excessive agglomeration of the wall material, leading to uneven particle size; a pH above 4.8 results in incomplete agglomeration and insufficient wall material strength. The core material phase transition temperature must be 55–60°C, matching the HIFU thermal coagulation threshold (55°C). A phase transition temperature deviation of ±3°C will directly lead to errors in thermal damage calibration. The final glutaraldehyde concentration is 0.1% (v / v), and the crosslinking time is 2 hours. Excessive concentration or excessive time will cause excessive embrittlement of the wall material, leading to premature cracking during the phantom preparation stirring process.

[0078] In a preferred embodiment, the brittle visible light colorimetric responder 220 comprises an outer wall made of highly crosslinked polyacrylamide and a core material made of a visible light colorimetric dye; wherein the core material is a visible light colorimetric dye; as an example, the visible light colorimetric dye includes at least one selected from methylene blue, brilliant blue, indigo, carmine, and sodium copper chlorophyll. Preferably, the concentration of the visible light colorimetric dye is 0.1–1.0% w / v.

[0079] In one embodiment, the brittle visible light chromogenic receptive 220 can be fabricated via microfluidic controlled start-up (SOP); for example, in one embodiment, the fabrication method includes:

[0080] S301, aqueous phase preparation: Weigh 20g acrylamide, 5.0g N,N'-methylenebisacrylamide, 0.5g methylene blue, and 0.5g photoinitiator (Irgacure 2959), and dissolve them in 80mL of degassed water (if dissolving Irgacure first, add 2mL N-methylpyrrolidone to aid dissolution). Stir magnetically (500rpm, 20°C, 15min) until completely dissolved. Purify with nitrogen for 20min (nitrogen purity ≥99.99%, flow rate 0.5L / min).

[0081] S302, oil phase preparation: 200 mL of liquid paraffin and 4.0 mL of emulsifier Span 80, magnetically stirred (300 rpm, 20°C, 10 min) until transparent and homogeneous.

[0082] S303, microfluidic emulsification; employing a flow-focusing glass-PDMS microfluidic chip (channel depth 100μm, focusing aperture width 50μm, Beijing Chuangshijie / customized). The continuous phase (oil phase) flow rate is 500μL / min, the dispersed phase (aqueous phase) flow rate is 50μL / min, and the two-phase flow rate ratio is 10:1. Droplets form a monodisperse W / O emulsion 3mm downstream of the focusing aperture, with a target particle size of 100±20μm. Real-time monitoring of the particle size CV value is performed using online microscopy (CCD camera, 10× objective lens), requiring CV < 8%.

[0083] S304, UV-induced interfacial polymerization; specifically, an external 365nm UV-LED ring light source (power density 10mW / cm², irradiation time 45s) is placed on the emulsion collection tube. Crucially, the irradiation time must be precisely controlled; ±5s will result in a shell thickness deviation >3μm. After irradiation, the emulsion changes from milky white to pale blue (shell formation, methylene blue is encapsulated).

[0084] S305, Demulsification and Washing: Transfer the emulsion to a separatory funnel, add an equal volume of n-hexane, gently agitate (avoid vigorous shaking to prevent breakage of the microresponders), and allow to separate into layers. Discard the lower layer (containing Span 80 and residual monomers). Repeat washing 3 times. Finally, wash with deionized water by centrifugation (3000 rpm, 5 min, repeated twice).

[0085] S306, Sieving and Quality Inspection, i.e., wet sieving: standard sieve groups (80μm, 100μm, 150μm, 200μm). Target particle size 80-150μm, target yield ≥65%. Quality inspection items: First, observe the shell integrity using an optical microscope (integrity rate >95%); second, use a laser particle size analyzer to detect D50 and Span value (Span <1.2); finally, sample 10% for mechanical response testing (ultrasonic cavitation field 10MPa negative pressure pulse, breakage rate >90%).

[0086] S307, storage: after sieving, the microresponsible body is suspended in degassed water, with 0.02% sodium azide added for preservation, stored at 4°C away from light, with a shelf life of 3 months.

[0087] It is worth noting that the Bis:AAM molar ratio is strictly controlled between 1:4 and 1:6. Below 1:8, the shell's elastic modulus drops sharply, resulting in elastic deformation rather than brittle fracture under cavitation shock waves, leading to a color release rate of <10%. Above 1:3, the shell becomes too rigid, with a response threshold >15MPa, exceeding the commonly used sound pressure range for clinical Histotripsy. Shell thickness is precisely controlled through microfluidic channel geometry (focusing port width 50μm, depth 100μm) and the two-phase flow rate ratio (continuous phase:dispersed phase = 10:1). The shell thickness to droplet diameter ratio is approximately 8–12%.

[0088] In one example, the thermochromic responder 210 is made of a reversible physical phase change material; while the mechanical color development is due to irreversible structural breakage; in one instance, the thermochromic response is black / magenta, while the mechanical color development is blue / red, and the two damage modes can be directly identified by the naked eye in the same ultrasonic test phantom without interference between them.

[0089] More preferably, the thermochromic responder 210 and / or the brittle visible light chromogenic responder 220 are detachably embedded in the gel layer 110. In this way, if the brittle visible light chromogenic responder 220 is broken after testing, only the brittle visible light chromogenic responder 220 in the target area needs to be replaced to restore a completely new testing state; and in one embodiment, the thermochromic responder 210 can be reused because its thermochromic change is reversible and its structure is not damaged.

[0090] In another embodiment, the thermochromic responder 210 and / or the brittle visible light chromogenic responder 220 are dispersed in the gel layer 110.

[0091] The ultrasound testing phantom for bimodal injury response can be configured as a urinary system phantom, such as a kidney-adapted phantom, a bladder-adapted phantom, or a prostate-adapted phantom.

[0092] For example, the kidney is an important target organ for HIFU treatment of renal cancer, renal cysts, and to assist in the expulsion of kidney stones. Its structural features include: the outer layer of renal cortex with rich blood supply, the middle layer of renal medulla containing renal pyramids and collecting ducts, and the central renal pelvis for urine collection.

[0093] refer to Figure 5A , Figure 6 and Figure 7 In this example, the substrate 100 includes at least six gel layers 110, as detailed in the table below:

[0094]

[0095] refer to Figure 5B In the second example, the substrate 100 includes at least eight gel layers 110; it is configured as a prostate-adaptive phantom, as detailed in the table below:

[0096]

[0097] The ultrasound testing phantom for bimodal damage response can be configured as a digestive system phantom, such as a stomach-fitting phantom, a gallbladder-fitting phantom, a duodenum-fitting phantom, a small intestine (jejunum / ileum)-fitting phantom, a large intestine (colon)-fitting phantom, a pancreas-fitting phantom, or a spleen-fitting phantom.

[0098] For example, in the third example of this application, the pancreas is a highly challenging target organ for HIFU treatment of pancreatic cancer and pancreatic neuroendocrine tumors. The dense fibrous stroma of pancreatic cancer results in extremely high sound attenuation, among the highest of any soft tissue.

[0099] refer to Figure 5C In this example, the substrate 100 includes at least seven gel layers 110, as detailed in the table below:

[0100]

[0101] The dual-modal injury response ultrasound testing phantom can be configured as a thyroid-adapted phantom system phantom, a brain-adapted phantom, a respiratory system phantom, a reproductive system phantom, a musculoskeletal system phantom, a vascular system phantom, a sensory system phantom, etc.

[0102] For example, in the fourth example of this application, the bimodal damage response ultrasound testing phantom can be configured as a thyroid-adapted phantom. The thyroid gland is an important target organ for HIFU treatment of thyroid nodules, thyroid cancer, and primary hyperthyroidism.

[0103] refer to Figure 5D In this example, the substrate 100 includes at least eight gel layers 110, as detailed in the table below:

[0104]

[0105] For example, in the fifth example of this application, the bimodal injury response ultrasound testing phantom can be configured as a brain-adaptive phantom. The brain is a cutting-edge target organ for HIFU treatment of brain tumors (such as gliomas and metastases), Parkinson's disease (thalamic destruction), and epilepsy (amygdala destruction).

[0106] refer to Figure 5E In this example, the substrate 100 includes at least eight gel layers 110, as detailed in the table below:

[0107]

[0108] In the sixth example of this application, the bimodal damage response ultrasound testing phantom can be configured as a skin-adaptive phantom. The skin is a direct target organ phantom for HIFU treatment of skin tumors (such as basal cell carcinoma and squamous cell carcinoma), keloids, acne, and cosmetic skin tightening (ultrasound knife).

[0109] refer to Figure 5F In this example, the substrate 100 includes at least seven gel layers 110, as detailed in the table below:

[0110]

[0111] refer to Figure 3 Preferably, the ultrasonic testing phantom for dual-modal damage response further includes an inlay 300 embedded in the gel layer 110, and the inlay 300 embedded in the gel layer 110 includes organic inlays and / or inorganic inlays.

[0112] The organic inlay includes, but is not limited to, tissues selected from fresh, excised animal organs, human-like tissues, or frozen tissues; such as pig liver, bovine kidney, pig heart, sheep liver, canine spinal muscle, rabbit liver, rat liver, etc., bovine liver, pig tenderloin, sheep, etc. Those skilled in the art will understand that the organic inlay can be embedded in the gel layer 110, thereby simulating the cavitation threshold and damage morphology of some tissues during ultrasonic simulation testing.

[0113] The inorganic inlay includes, but is not limited to, materials selected from hydroxyapatite pressed bodies, silica sintered bodies, and calcium carbonate pressed bodies, and its shape includes blocks, spheres, ellipsoids, and irregular bodies. Preferably, the shape of the inorganic inlay can be pre-defined; more preferably, the acoustic impedance of the inorganic inlay is 2.50 to 6.00 MRayls.

[0114] In the first example above, by implementing the inorganic inlay as an inorganic inlay, a detection map as shown is obtained.

[0115] In a preferred embodiment, the surface of the organic inlay and / or the inorganic inlay is coated with a PAA prepolymer liquid interface coupling coating with a thickness of 0.1–0.2 mm. It is worth noting that the PAA prepolymer liquid interface coupling coating applied to the surface of the organic inlay and / or the inorganic inlay can effectively reduce the acoustic impedance difference between the organic inlay and / or the inorganic inlay and the gel layer.

[0116] refer to Figure 4More preferably, in one embodiment, the dual-modal damage response ultrasound testing phantom further includes a vascular perfusion system 400 of the gel layer, wherein the vascular perfusion system 400 includes a channel body 410 and a circulation drive component 420, wherein the channel body 410 has multiple staggered microchannels formed inside, an inlet and an outlet communicating with the microchannels, so as to introduce a fluid medium simulating human blood into the microchannels through the inlet, wherein the channel body is embedded in the gel layer.

[0117] The circulation drive assembly 420 is connected to the inlet and the outlet to guide the fluid medium from the inlet through the microchannel and out of the outlet.

[0118] In a preferred embodiment, the hollow microchannel formed by the channel body 410 has a wall material of PDMS or low melting point agarose, a wall thickness of 0.1 to 0.2 mm, and a channel diameter of 0.3 to 5.0 mm.

[0119] Also preferably, the infused fluid medium is a 37°C constant-temperature circulating fluid. In one embodiment, the fluid medium is configured as glycerol:water = 1:3 (v / v) with the addition of 0.5 mM CuSO4.

[0120] In one embodiment, the circulation drive component 420 is implemented as a microfluidic pump or a pulsatile pump; more preferably, the regulated flow rate of the circulation drive component 420 is 0.1 to 10 mL / min; in one example, the liver phantom has a peak velocity of 1 Hz and a peak velocity of 20 cm / s; in another example, the blood vessel phantom has a peak velocity of 1.0 to 1.5 Hz and a peak velocity of 50 to 100 cm / s.

[0121] Those skilled in the art will understand that the vascular perfusion system 400 can be used to simulate blood vessels at corresponding locations, thereby enabling the dual-modal damage response ultrasound testing phantom to better simulate the corresponding human body parts.

[0122] It is worth mentioning that the ultrasonic test phantom with bimodal damage response is particularly suitable for vacuum sealing packaging. Specifically, the sealing conditions are: absolute pressure of 100–1000 Pa, heat sealing temperature of 160–180°C, pressure of 0.3–0.5 MPa, and time of 2–3 s. After sealing, the phantom retains its original shape and remains uncompressed and undeformed.

[0123] It is worth mentioning that before vacuum sealing, the water can be degassed first. The degassed water process can be implemented as follows: first, reverse osmosis pure water, then mixed bed ion exchange and 0.22 μm filtration to achieve a resistivity ≥18.2 MΩ·cm, then vacuum degassing (500~1000 Pa, 2~4 h, dissolved oxygen ≤2 mg / L), and aseptic filtration to comply with YY0592-2016.

[0124] More notably, the ultrasonic test phantom with dual-modal damage response can be refrigerated at 2–8°C and has a shelf life of 6–12 months; the phantom containing the thermochromic responder can be refrigerated again at 2–8°C after opening and use, and the cumulative number of uses shall not exceed 10; the Histotripsy phantom containing the brittle visible light colorimetric responder cannot be refrigerated again after opening and is for single use only.

[0125] Example 1: Breast Imaging Verification

[0126] 1. Mold preparation: Transparent acrylic mold (100×100×60 mm), with silicone oil release agent coated on the inner wall and a pre-installed conical buckle base at the bottom.

[0127] 2. Fat layer casting: PAA prepolymer (10% acrylamide, Bis:AAM=1:19, silicone oil microdroplets 8% v / v) was injected to a height of 10 mm. Acoustic impedance 1.42 MRayls, CT value approximately -80 HU, MRI T1 high signal.

[0128] 3. Glandular layer casting: PAA prepolymer (12% acrylamide, Bis:AAM=1:19, SiO2 3% w / v, cellulose 1% w / v, CuSO4 0.5 mM, thermochromic microresponse polymer 2% v / v) was injected to a height of 35 mm. Acoustic impedance 1.62 MRayls, CT value approximately 15 HU.

[0129] 4. Vascular network embedding: Embedded in PDMS hollow microchannel network (0.5 mm in diameter, dendritic branching) in a semi-gel state.

[0130] 5. Preparation of target core: PAA-BSA prepolymer (acrylamide 12%, BSA 30% v / v, pH 4.6, brittle visible light chromogenic responder 3% v / v, thermochromic microresponder 2% v / v) was injected into an ellipsoidal mold (major axis 20 mm, minor axis 15 mm), pre-gelled at 4°C for 20 min, and then cured at room temperature for 24 h.

[0131] 6. Assembly: Insert the snap-fit ​​into the center of the glandular layer and allow it to swell and equilibrate with PBS for 48 h.

[0132] 7. Multimodal image verification results

[0133] Ultrasound: The matrix is ​​clearly shown to consist of three gel layers 110, which is a three-layer structure. The surface fat layer is hypoechoic, the middle gland is isoechoic, and the core is slightly hypoechoic.

[0134] MRI (3.0T): T1WI showed high signal intensity in the fat layer, intermediate signal intensity in the glandular layer, and slightly low signal intensity in the core layer; T2WI showed consistent contrast between layers with breast MRI anatomy.

[0135] CT scan: fat layer -75 HU, glandular layer 18 HU, core 15 HU; vascular network was significantly enhanced after perfusion fluid containing potassium iodide.

[0136] Optical: After HIFU, a black thermochromic area (approximately 8 mm in diameter) appeared in the target area, with no blue diffusion; after Histotripsy, a blue diffusion area (approximately 12 mm in diameter) appeared, with no black residue.

[0137] Example 2: Liver Imaging Verification

[0138] 1. Liver capsule (L1): Highly cross-linked PAA (15% acrylamide, Bis:AAM=1:10, 5% silk fibroin short fibers w / v), 1.5 mm thick. Acoustic impedance 1.75 MRayls, elastic modulus ~120 kPa.

[0139] 2. Superficial liver parenchyma (L2): Standard PAA (acrylamide 12%, SiO2 3% w / v, cellulose 1% w / v, CuSO4 0.3 mM), 12 mm thick.

[0140] 3. Implantation of the hepatic sinusoidal network: sacrificial template method (sugar wire diameter 0.3 mm, dissolved in warm water at 37°C).

[0141] 4. Connective tissue septum (L4): Highly cross-linked PAA-silk fibroin, 0.8 mm thick, without doped with responsive microreactive bodies.

[0142] 5. Deep liver parenchyma (L5): Standard PAA + thermochromic microresponder 2% v / v, 12 mm thick.

[0143] 6. Portal vein branch implantation: PDMS hollow tube (main channel diameter 4 mm, wall thickness 0.2 mm), connected to a pulsatile pump (1 Hz, peak velocity 20 cm / s).

[0144] 7. Tumor insert (L7): PAA-BSA prepolymer + 3% v / v brittle microresponsor + 2% v / v thermochromic microresponsor, S6 fit ellipsoid (major axis 25 mm, minor axis 18 mm).

[0145] 8. Multimodal image verification results

[0146] Ultrasound: Ultrasound showed that the matrix consisted of seven gel layers 110, with L1 being a hyperechoic membrane, L2 / L5 being a medium-echoic solid, and L4 being a slightly hyperechoic diaphragm; the portal vein branches were anechoic tubular structures; elastography showed that L1 was significantly harder than L2 / L5.

[0147] MRI: On T1WI, L1 shows slightly low signal, and L2 / L5 shows intermediate signal; portal vein pulsation shows flow void signal.

[0148] CT: L1 layer approximately 30 HU, L2 / L5 approximately 20 HU; the portal vein showed significant enhancement after infusion with iodine-containing contrast agent.

[0149] Optical: After Histotripsy test, cavitation cloud near L4 diaphragm preferentially expands along diaphragm, and blue color area clearly shows the damage path; after HIFU test, the volume of the heat discoloration area next to portal vein (<5 mm) is reduced by about 42% compared with the non-perfusion area.

[0150] Example 3: Brain Imaging Verification

[0151] 1. Skull simulation layer (BR0): Highly mineralized PAA complex (30% w / v hydroxyapatite micropowder + highly cross-linked PAA), 5 mm thick. Acoustic impedance 3.50–4.00 MRayls, CT value >800 HU, MRI extremely low signal.

[0152] 2. Dura mater (BR1): Highly cross-linked PAA + collagen fibers 4% w / v, thickness 0.8 mm.

[0153] 3. Cerebrospinal fluid simulation (BR2): Hollow cavity filling to simulate CSF.

[0154] 4. Ash (BR3): Standard PAA + SiO2 3% w / v + cellulose 1% w / v + thermochromic microresponder 2% v / v, 3 mm thick. CT value approximately 35 HU.

[0155] 5. White material (BR4): Medium cross-linked PAA + oriented PVA fiber 4% w / v, 10 mm thick. Sound velocity 1450 m / s.

[0156] 6. Ventricular system (BR5): Hollow cavity filled to simulate CSF.

[0157] 7. BBB simulation (BR6): Nanoporous PDMS film (pore size 50–100 nm).

[0158] 8. Tumor insert (BR7): PAA-BSA + brittle microresponder 3% v / v + thermochromic microresponder 2% v / v, diameter 20 mm.

[0159] 9. Multimodal image verification results

[0160] CT scan: Extremely high density in the skull (>800 HU), 25–40 HU in the brain parenchyma, and 0–5 HU in the ventricles.

[0161] MRI: T1WI showed slightly low signal in gray matter and slightly high signal in white matter; the skull showed extremely low signal; the core showed slightly high signal on T2WI.

[0162] Ultrasound: The matrix is ​​clearly shown to include seven layers of the gel layer 110. Transcranial ultrasound shows significant sound attenuation and beam distortion in the skull layer; the focal point can be observed in the brain parenchyma layer.

[0163] Optical: After HIFU ablation of deep brain nuclei, a black thermochromic area appears in the gray matter layer; after Histotripsy, a blue diffusion area appears.

[0164] Example 4: Preparation and Imaging Verification of Organic-Inorganic Composite Mummy

[0165] 1. Organic inlay: Commercially available vacuum-packed frozen pork liver (stored at -18℃), thawed and cut into 15×10×8 mm tissue blocks.

[0166] 2. Inorganic inlay: Hydroxyapatite micro powder is pressed into a cylindrical shape (8 mm in diameter and 5 mm in height), sintered at 800°C for 2 h, with an acoustic impedance of 3.80 MRayls and a CT value of approximately 600 HU.

[0167] 3. Interface coupling: The surfaces of the organic and inorganic blocks are dipped in PAA prepolymer (0.1–0.2 mm thin layer).

[0168] 4. Embedding and gelling: The coated tissue block and ceramic block were placed at the target position of the L5 layer of the liver phantom mold, and the PAA prepolymer liquid matrix was poured. After pregeling at 4°C for 20 min, it was cured at room temperature for 24 h.

[0169] 5. Image verification results

[0170] Ultrasound: The organic inlay showed the echo of real liver tissue, while the inorganic ceramic block showed strong echoes with posterior acoustic shadowing.

[0171] CT: Organic inlays are approximately 50 HU, and inorganic ceramic blocks are approximately 600 HU.

[0172] MRI: The organic inlay T1 / T2 matched well with the surrounding gel; the inorganic ceramic block showed extremely low signal.

[0173] HIFU / Histotripsy: Organic inlays produce realistic cavitation responses under Histotripsy, with the blue color area boundary highly consistent with the morphology of real liver tissue damage; inorganic ceramic blocks cause significant reflection and scattering of the HIFU sound beam.

[0174] Example 6: Vacuum Sealing Packaging and Degassed Water Standards

[0175] Vacuum sealing: Absolute pressure 100–1000 Pa, heat sealing temperature 160–180°C, pressure 0.3–0.5 MPa, time 2–3 s. After sealing, the phantom retains its original shape and is neither compressed nor deformed.

[0176] Degassed water: Reverse osmosis pure water → mixed bed ion exchange + 0.22 μm filtration → resistivity ≥18.2 MΩ·cm → vacuum degassing (500–1000 Pa, 2–4 h, dissolved oxygen ≤2 mg / L) → 0.22 μm sterile filtration → conforms to YY0592-2016.

[0177] Example 5: Mass Production Preparation Scheme of Vascular Perfusion Simulation System

[0178] Path A (Sacrificial Template Method): Sugar / Agar filament weaving → PAA casting → Dissolving in 37°C warm water → Channel wall roughness Ra 50–100 μm.

[0179] Path B (3D printing mold method): Photopolymerization 3D printing of biocompatible resin mold → casting PAA → isopropanol expansion and removal → channel wall roughness Ra 10–20 μm.

[0180] Path C (Injection Molding Method): Aluminum alloy mold + silicone insert → Low-pressure injection molding (1.0 MPa, 4°C mold) → Curing for 30 min → Insert can be reused more than 1000 times → Cost per piece < 50 yuan / piece.

[0181] Example 6: Vacuum Sealing Packaging and Degassed Water Standards

[0182] Vacuum sealing: Absolute pressure 100–1000 Pa, heat sealing temperature 160–180°C, pressure 0.3–0.5 MPa, time 2–3 s. After sealing, the phantom retains its original shape and is neither compressed nor deformed.

[0183] Degassed water: Reverse osmosis pure water → mixed bed ion exchange + 0.22 μm filtration → resistivity ≥18.2 MΩ·cm → vacuum degassing (500–1000 Pa, 2–4 h, dissolved oxygen ≤2 mg / L) → 0.22 μm sterile filtration → conforms to YY0592-2016.

[0184] Example 7: Validation of HIFU Treatment Plan Guided by Multimodal Image Fusion

[0185] 1. Phantom preparation: A liver-adapted phantom (including portal vein pulsation perfusion + S6 segment tumor core insert) is placed on the MRI-compatible HIFU treatment bed.

[0186] 2. MRI scan: 3.0T scan to acquire T1WI, T2WI and enhanced images. Identify the liver capsule (low signal line), portal vein branches (flow void signal), and tumor core (slightly high signal on T2), and measure the coordinates (x, y, z) of the core center.

[0187] 3. Treatment plan: Import MRI DICOM data into the HIFU treatment planning system, set the ablation target area as the core insertion center, and plan the ultrasound path (avoiding portal vein branches).

[0188] 4. Ultrasound-guided HIFU: HIFU (1.5 MHz, 150 W, 10 s) was performed under real-time ultrasound guidance according to the planned coordinates. Real-time ultrasound images showed enhanced echoes in the target area, with no damage to the portal vein branches.

[0189] 5. CT verification: Immediate CT scan after HIFU. Low-density necrosis area was observed in the core insertion area (CT value decreased by approximately 10 HU), the portal vein perfusion fluid still showed enhancement (the vessel was patent), and the liver capsule remained intact.

[0190] 6. Optical direct vision verification: When the phantom is cut open, a black heat discoloration area (about 8 mm in diameter) appears in the center of the insert, with no blue diffusion; the portal vein wall does not show heat discoloration.

[0191] 7. Data Comparison: Compare the three-dimensional deviations of the MRI planned target area, ultrasound real-time target area, CT verified target area, and optically measured target area. A target area center deviation of <2 mm between each modality indicates that the image fusion guidance accuracy is qualified.

[0192] Those skilled in the art should understand that the embodiments of the present invention described above and shown in the accompanying drawings are merely examples and do not limit the invention. The advantages of the present invention have been fully and effectively realized. The functional and structural principles of the present invention have been demonstrated and explained in the embodiments; any variations or modifications can be made to the implementation of the present invention without departing from these principles.

Claims

1. An ultrasonic testing phantom with dual-modal damage response, characterized in that, The ultrasonic testing phantom for the dual-modal damage response includes: The matrix comprises at least two gel layers, wherein adjacent gel layers have a preset acoustic impedance gradient interface and an image contrast gradient interface. A responsive medium, wherein the responsive medium is embedded in the gel layer of the matrix, wherein the responsive medium comprises a thermochromic responder and a brittle visible light chromogenic responder.

2. The ultrasonic testing phantom with dual-modal damage response according to claim 1, characterized in that, The ultrasonic testing phantom for dual-modal damage response also includes an inlay embedded in the gel layer.

3. The ultrasonic testing phantom with dual-modal damage response according to claim 2, characterized in that, The inlays embedded in the gel layer include organic inlays and / or inorganic inlays.

4. The ultrasonic testing phantom with dual-modal damage response according to claim 3, characterized in that, Organic inlays are selected from fresh, isolated animal organs or tissues, frozen tissues, or human-like tissues.

5. The ultrasonic testing phantom with dual-modal damage response according to claim 3, characterized in that, The inorganic inlay is selected from at least one of hydroxyapatite pressed body, silica sintered body or calcium carbonate pressed body.

6. The ultrasonic testing phantom with dual-modal damage response according to any one of claims 3-5, characterized in that, The surfaces of organic tissue inlays and / or inorganic inlays are coated with a PAA prepolymer liquid interface coupling coating with a thickness of 0.1–0.2 mm.

7. The ultrasonic testing phantom with dual-modal damage response according to claim 1, characterized in that, The dual-modal damage response ultrasound testing phantom further includes a vascular perfusion system for the gel layer, wherein the vascular perfusion system comprises: The channel body contains multiple staggered microchannels, an inlet and an outlet communicating with the microchannels, so as to introduce a fluid medium simulating human blood into the microchannels through the inlet, wherein the channel body is embedded in the gel layer; A circulation drive assembly, wherein the circulation drive assembly is connected to the inlet and the outlet to guide the fluid medium from the inlet through the microchannel and out of the outlet.

8. The ultrasonic testing phantom with dual-modal damage response according to claim 1, characterized in that, The thermochromic responder comprises an outer wall made of a gelatin-gum arabic composite and a core material made of a reversible thermochromic dye, wherein the phase transition temperature of the thermochromic responder is 55–60°C.

9. The ultrasonic testing phantom with dual-modal damage response according to claim 1 or 8, characterized in that, The brittle visible light colorimetric responder comprises an outer wall made of highly cross-linked polyacrylamide and a core material made of visible light colorimetric dye, wherein the core material of the brittle visible light colorimetric responder is a visible light colorimetric dye.

10. The ultrasonic testing phantom with dual-modal damage response according to claim 9, characterized in that, The thermochromic responder and the brittle visible light chromogenic responder are detachably embedded in the gel layer of the matrix.

11. The ultrasonic testing phantom with dual-modal damage response according to claim 1, characterized in that, The ultrasound testing phantom for the dual-modal injury response is configured to be at least one of the following: organ phantom, urinary system phantom, digestive system phantom, and brain-adaptive phantom. The organ phantoms mentioned above include at least a liver phantom; The urinary system phantom includes at least a kidney-fitting phantom, a bladder-fitting phantom, or a prostate-fitting phantom; The digestive system phantoms mentioned therein include at least a stomach-fitting phantom, a gallbladder-fitting phantom, a duodenum-fitting phantom, a small intestine-fitting phantom, a large intestine-fitting phantom, a pancreas-fitting phantom, or a spleen-fitting phantom.

12. The ultrasonic testing phantom with dual-modal damage response according to claim 1, characterized in that, The ultrasonic test phantom for the dual-modal damage response is configured to maintain its original shape after sealing under an absolute pressure of 100–1000 Pa, a heat sealing temperature of 160–180°C, a pressure of 0.3–0.5 MPa, and a time of 2–3 s, without compression or deformation.

13. The ultrasonic testing phantom with dual-modal damage response according to claim 1, characterized in that, The ultrasonic test phantom with dual-modal damage response can be refrigerated at 2–8°C and has a shelf life of 6–12 months. When it contains the thermochromic responder, it can be refrigerated again at 2–8°C after opening and can be used a total of no more than 10 times. When it contains the brittle visible light colorimetric responder, it cannot be refrigerated again after opening and is for single use only.

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