A microfluidic chip-based nuclear medicine synthesis chip and a synthesis method thereof

Abstract

The application relates to the technical field of micro-fluidic chip biological medicine preparation, in particular to a nuclear medicine synthesis chip based on a micro-fluidic chip and a synthesis method thereof, which comprises a first structural layer, a second structural layer, an elastic diaphragm, a compression layer and a fluid interface; the first structural layer is provided with a flow channel, the fluid interface is arranged on the first structural layer and communicates with the flow channel; the second structural layer is arranged between the first structural layer and the elastic diaphragm, the second structural layer is provided with a valve seat, the valve seat communicates with the flow channel in correspondence; the elastic diaphragm is arranged between the second structural layer and the compression layer and covers the opening of the valve seat; the compression layer is provided with an air chamber, the compression layer is provided with a ventilation structure communicating with the air chamber, and the ventilation structure is used for connecting an air source to control the on-off of the flow channel. The application is used for improving the multi-path time sequence control flow effect and eliminating the reagent residual pollution caused by the external valve body.

Description

Technical Field

[0001] This invention relates to the field of microfluidic chip biomedical preparation technology, and in particular to a microfluidic chip-based radiopharmaceutical synthesis chip and its synthesis method. Background Technology

[0002] This section is intended to provide background or context for embodiments of the present invention. The description herein is not intended to imply that it is prior art simply because it is included in this section.

[0003] Radiopharmaceuticals are core preparations for early tumor diagnosis and targeted radiotherapy, with continuously growing demand from clinical positron emission tomography (PET) and nuclear medicine departments. Currently, most commercial radiopharmaceutical synthesis equipment is a large, modular unit relying on numerous tubing connections for consumables. This results in lengthy tubing, high reagent consumption, and low reaction mixing efficiency. Open tubing also increases the risk of radioactive spillage, posing a high risk of ionizing radiation exposure to operators. Furthermore, the equipment requires high-protection-level radiation rooms, leading to high costs for both space and equipment, making it unsuitable for lightweight applications in primary care departments and operating room beds.

[0004] Microfluidic chips can complete reagent delivery, mixing, radiolabeling, product purification, and waste separation in a single step within microchannels. They offer advantages such as miniaturization, closed systems, and low reagent consumption, making them ideal carriers for small-scale, on-the-fly radiopharmaceutical synthesis. However, existing microfluidic radiopharmaceutical devices have significant limitations. Most current chips are only suitable for single-step radioreactions, with only a single flow channel, failing to achieve the independent sequential injection, branch isolation, and directional waste switching required for multi-step synthesis, making it difficult to complete a full multi-stage radiosynthesis process. Furthermore, the accompanying control valves are all external solenoid valves or needle valves, resulting in complex external piping. The external valve bodies also have independent dead zones, making it easy for radioactive reagents to accumulate, leading to material waste, batch-to-batch cross-contamination, and significant challenges in cleaning residual liquids. Summary of the Invention

[0005] Therefore, it is necessary to provide a microfluidic chip-based radiopharmaceutical synthesis chip and its synthesis method to address the above-mentioned technical problems, so as to improve the multi-channel timing control effect and eliminate reagent residue contamination caused by external valves.

[0006] In a first aspect, the present invention provides a radiopharmaceutical synthesis chip based on a microfluidic chip, comprising a first structural layer, a second structural layer, an elastic membrane, and a pressing layer stacked sequentially. The first structural layer has a flow channel, and the side of the first structural layer opposite to the second structural layer has a fluid interface that communicates with the flow channel; A valve seat is provided on the side of the second structural layer opposite to the second structural layer, and the valve seat communicates with the flow channel through a through hole; The elastic diaphragm is disposed inside the valve seat and covers the opening of the valve seat; The press-fit layer has an air chamber, and the press-fit layer is equipped with a ventilation structure that communicates with the air chamber. The ventilation structure is used to connect an external air source to control the opening and closing of the flow channel.

[0007] Optionally, the flow channel includes multiple functional branches, and each branch port is provided with a corresponding air chamber. The valve seat is connected to the port of the corresponding branch, and the air chamber is arranged opposite to the valve seat.

[0008] Optionally, there are multiple air chambers, each air chamber is arranged in a one-to-one correspondence with a valve seat, and each air chamber is connected to a ventilation structure.

[0009] Optionally, the valve seat includes a valve groove disposed on the second structural layer and a through hole disposed at the bottom of the valve groove and penetrating the second structural layer, the through hole connecting to the flow channel of the first structural layer, and the valve groove being used to accommodate an elastic diaphragm.

[0010] Optionally, the first structural layer, the second structural layer, the elastic diaphragm, and the pressing layer are all provided with mounting holes that overlap and are aligned. A positioning pin is inserted into the mounting hole, and the positioning pin locks and fixes the first structural layer, the second structural layer, the elastic diaphragm, and the pressing layer into a whole.

[0011] Optionally, the ventilation structure is an air nozzle, and the air nozzle has a through air hole inside. One end of the air hole is connected to the air chamber, and the other end is used to connect to an external air source.

[0012] Optionally, a sealing ring is provided around the outer periphery of the air chamber.

[0013] Optionally, the first structural layer and the second structural layer are bonded and fixed together using an adhesive-free bonding process.

[0014] Optionally, the first structural layer and the second structural layer are made of radiation-resistant polymer materials or alumina ceramic materials.

[0015] Secondly, the present invention provides a method for synthesizing radiopharmaceuticals based on a microfluidic chip, employing the aforementioned microfluidic chip-based radiopharmaceutical synthesis chip, and comprising the following steps: The ventilation structure corresponding to the reagent injection branch is controlled to be in a non-driven gas pressure state. Radioactive reagent is introduced into the flow channel. Under the action of fluid pressure, the reagent overcomes the pre-pressure of the elastic diaphragm and opens the valve seat to complete the quantitative injection. Driven air pressure is introduced into the ventilation structure corresponding to the reagent injection branch, causing the elastic diaphragm to press against the valve seat to block the reagent injection branch, and the radiolabeling reaction is completed in the reaction chamber. The ventilation structure corresponding to the target branch is controlled to be in a state of no driving air pressure, and the product or waste liquid is directed out under the drive of microfluidic pressure; at the same time, driving air pressure is introduced into the ventilation structure corresponding to the non-target branch, so that the corresponding elastic diaphragm presses the valve seat to achieve isolation between branches.

[0016] The aforementioned microfluidic chip-based radiopharmaceutical synthesis chip and its synthesis method integrate valve seats, gas chambers, and ventilation structures as valve control components, in conjunction with an elastic diaphragm, into the chip body. The chip body is assembled from a first structural layer, a second structural layer, an elastic diaphragm, and a pressing layer, eliminating the need for external solenoid valves or needle valves. The valve seat is a through-hole structure penetrating the second structural layer, forming a continuous fluid channel with the flow path. This eliminates the dead zones of stagnation in the valve cavity of traditional external valve bodies, effectively reducing the accumulation and residue of radioactive reagents, lowering raw material loss and the risk of cross-contamination between batches, while significantly reducing the difficulty of cleaning radioactive residues. Furthermore, by arranging multiple independent functional branches and configuring one-to-one independent gas chambers for each branch, the opening and closing states of each branch can be controlled according to the requirements of the synthesis process. This enables sequential sample introduction, reaction isolation, and directional separation of products and waste liquids in multi-step radiosynthesis, making it suitable for the entire process of multi-stage radiosynthesis. Attached Figure Description

[0017] The accompanying drawings, which are incorporated in and form part of this specification, illustrate embodiments consistent with the invention and, together with the description, serve to explain the principles of the invention, but do not constitute an undue limitation of the invention.

[0018] Figure 1 This is a top view of the first structural layer of a radiopharmaceutical synthesis chip in one embodiment; Figure 2 This is an assembly diagram of a radiopharmaceutical synthesis chip in one embodiment; Figure 3 An exploded view of a radiopharmaceutical synthesis chip in one embodiment; Figure 4 An exploded view of a radiopharmaceutical synthesis chip in one embodiment; Figure 5 This is a schematic diagram of the flow channel structure of the first structural layer in one embodiment; Figure 6 This is a schematic diagram of the valve seat structure of the second structural layer in one embodiment; Figure 7 This is an exploded view of the press-fit layer in one embodiment.

[0019] Reference numerals: 1. First structural layer; 11. Flow channel; 12. Mounting hole; 2. Second structural layer; 21. Valve seat; 3. Elastic diaphragm; 4. Pressing layer; 41. Air chamber; 42. Air nozzle; 43. Positioning pin; 44. Sealing ring; 5. Fluid interface. Detailed Implementation

[0020] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0021] It should be noted that the terms "first," "second," etc., used in the specification, claims, and accompanying drawings of this invention are used to distinguish similar objects and are not necessarily used to describe a specific order or sequence. It should be understood that such data can be interchanged where appropriate so that the embodiments of the invention described herein can be implemented in orders other than those illustrated or described herein. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with this invention. Rather, they are merely examples of apparatuses and methods consistent with some aspects of the invention as detailed in the appended claims.

[0022] The microfluidic chip-based radiopharmaceutical synthesis chip and its synthesis method provided in this disclosure can be applied to miniaturized and closed-loop synthesis scenarios for radiopharmaceuticals, such as the real-time synthesis of radionuclide probes for positron emission tomography (PET), bedside radiopharmaceutical preparation in the operating room, and miniaturized synthesis in primary nuclear medicine departments. This embodiment integrates the fluid control valve entirely within the chip body through a multi-layered, on-chip integrated pneumatic diaphragm valve architecture. Simultaneously, it utilizes a multi-channel independent gas chamber array to achieve sequential flow control for multi-step synthesis, replacing the traditional separate synthesis scheme with external solenoid valves. This addresses the shortcomings of existing radiopharmaceutical synthesis equipment, such as complex piping, high reagent residue, high radiation risk, and inability to adapt to multi-step continuous synthesis.

[0023] Example 1

[0024] like Figure 1 and Figure 2As shown, this embodiment provides a radiopharmaceutical synthesis chip based on a microfluidic chip. Taking the application scenario described above as an example, the chip has a stacked sheet structure. A first structural layer 1, a second structural layer 2, an elastic diaphragm 3, and a pressing layer 4 are stacked sequentially from top to bottom along the thickness direction. It also includes a fluid interface 5 disposed on the first structural layer 1. The first structural layer 1 has a flow channel 11. The fluid interface 5 is located in the first structural layer 1 and communicates with the flow channel 11. The second structural layer 2 is disposed between the first structural layer 1 and the elastic diaphragm 3. A valve seat 21 is disposed on the side of the second structural layer 2 facing away from the first structural layer, and the valve seat 21 communicates with the flow channel 11. The elastic diaphragm 3 is disposed within the valve seat 21 and covers the opening of the valve seat 21. The pressing layer 4 has an air chamber 41. The pressing layer 4 is equipped with a venting structure communicating with the air chamber 41. The venting structure is used to connect an external air source to control the opening and closing of the flow channel.

[0025] The chip features a planar, stacked microfluidic chip structure, with the layers stacked sequentially from top to bottom along the thickness direction. The four layers—first structural layer 1, second structural layer 2, elastic diaphragm 3, and bonding layer 4—are coaxially aligned and stacked to form the complete chip body. The upper surface of the second structural layer 2 is attached to the lower surface of the first structural layer 1, and the lower surface of the second structural layer 2 is attached to the upper surface of the elastic diaphragm 3. The elastic diaphragm 3 is sandwiched between the second structural layer 2 and the bonding layer 4 without lateral displacement or local suspension, ensuring the overall structure is aligned precisely.

[0026] Specifically, in combination Figure 5 As shown, the first structural layer 1 is the fluid carrier substrate of this chip, and is the core fluid layer responsible for reagent input, reaction flow, and product output. The flow channel 11 in the first structural layer 1 can refer to the flow channel 11 being a microscale fluid channel formed inside or on the surface of the first structural layer 1. It belongs to the built-in fluid passage of the chip, which is different from traditional external pipelines and external pipe fittings. The flow channel 11 is an integrated structure of the chip body and is used to transport radioactive reagents, reaction solutions, washing solutions, and synthesis products.

[0027] Combination Figure 6 As shown, the second structural layer 2 is stacked below the first structural layer 1 and above the elastic diaphragm 3, serving as the valve port substrate support layer. A valve seat 21 is disposed in the second structural layer 2 corresponding to the flow channel 11. The valve seat 21 extends through the flow channel 11 along its thickness direction and is aligned and connected to the flow channel 11 of the first structural layer 1, forming a valve-controlled section of the fluid passage. After flowing from the flow channel 11 through the valve seat 21, the fluid can reach the upper surface of the elastic diaphragm 3.

[0028] The elastic diaphragm 3 is a sheet-like elastic film disposed between the lower surface of the second structural layer 2 and the upper surface of the lamination layer 4. The upper surface of the elastic diaphragm 3 completely covers the opening of the valve seat 21. Relying on its own elastic deformation capability, the opening and closing control of the valve seat 21 opening is achieved by adhering to or detaching from the end face of the valve seat 21.

[0029] The press-fit layer 4 is stacked below the elastic diaphragm 3 and serves as the pneumatic drive support layer. An air chamber 41 is recessed into the upper surface of the press-fit layer 4 at the position corresponding to the valve seat 21. The opening of the air chamber 41 faces upwards and is directly opposite the lower surface of the elastic diaphragm 3. The coverage area of ​​the air chamber 41 is larger than the opening area of ​​the valve seat 21 to ensure that the driving air pressure can fully act on the diaphragm surface in the valve control area.

[0030] The press-fit layer 4 is equipped with a venting structure, which is connected to the interior of the air chamber 41 and is used to connect to an external pneumatic air source. By inputting or discharging driving gas into the air chamber 41, the pressure difference between the upper and lower sides of the elastic diaphragm 3 can be changed, causing the elastic diaphragm 3 to deform, thereby controlling the on / off state of the fluid in the flow channel 11.

[0031] Furthermore, the fluid interface 5 is located in the first structural layer 1 and communicates with the flow channel 11. Specifically, the fluid interface 5 can be an external port structure fixedly assembled on the outer wall or upper surface of the first structural layer 1. The communication is a fluid-through communication, with the internal through hole of the fluid interface 5 seamlessly connected to the channel of the flow channel 11, enabling stable entry of external reagents into the flow channel 11, while allowing products and waste liquid inside the chip to be exported.

[0032] It should be noted that the second structural layer 2 is a dedicated valve-controlled bearing layer, specifically designed for arranging the valve seat 21. It serves as a transitional substrate connecting the upper fluid passage and the lower diaphragm sealing structure. The valve seat 21 is connected to the flow channel 11, allowing for precise alignment and connection between the fluid end passage of the flow channel 11 and the upper opening of the valve seat 21. Fluid within the flow channel 11 can flow directly into the valve seat 21, making the valve seat 21 a controllable on / off port at the end of the flow channel 11, thus constituting a key valve-controlled section of the fluid passage.

[0033] The elastic diaphragm 3 covers the opening of the valve seat 21. The elastic diaphragm 3 is a whole piece of elastic thin film component. Its plate surface completely covers the entire opening area of ​​the valve seat 21 facing the pressing layer 4. The coverage area is larger than the opening area of ​​the valve seat 21. There is no partial coverage or half coverage.

[0034] It can be understood that this structure ensures that the elastic diaphragm 3 can completely block or open the valve seat 21 opening through its own elastic deformation, thereby realizing the physical opening and closing of the fluid passage.

[0035] The pressing layer 4 is a pneumatically driven bearing layer. The air chamber 41 is formed on the upper end of the pressing layer 4 as a closed pneumatic cavity, located below the elastic diaphragm 3. The opening of the cavity faces the elastic diaphragm 3 and is used to gather and store driving gas to provide a stable pneumatic driving force for diaphragm deformation.

[0036] The venting structure is connected to the air chamber 41 and is used to connect an external air source to control the flow channel opening and closing. The venting structure is an air circuit docking component, through which the external air source inflates or depressurizes the air chamber 41. When inflated, the air pressure inside the air chamber 41 increases, pushing the elastic diaphragm 3 upward to press against the valve seat 21, blocking the fluid flow in the flow channel 11. When depressurized, the elastic diaphragm 3 rebounds and resets, disengaging from the valve seat 21 opening, and the flow channel 11 is reopened. This achieves on-chip valve control opening and closing function with pure pneumatic drive, no electromagnetic interference, and no external valve body.

[0037] This structure fully discloses the stacking relationship of the four core layers of the chip, the fluid pathway structure, the valve-controlled sealing structure, and the pneumatic drive structure, and constructs an integrated on-chip valve-controlled radiopharmaceutical synthesis chip basic architecture. It solves the basic defects of traditional radiopharmaceutical synthesis equipment, such as reliance on external valves, complicated pipelines, high radiation risk, or serious residual pollution. It provides a complete basic carrier for the advanced optimization structure such as multi-channel timing control of the present invention.

[0038] It should be noted that, in one example, the cross-section of the flow channel can be set to a circle, rectangle or trapezoid, and the channel size is designed to be adapted to the reagent flow rate and mixing requirements. This invention does not impose any limitations.

[0039] In one example, such as Figure 5 and Figure 6 As shown, the flow channel 11 includes multiple functional branches, and each branch port is provided with a corresponding air chamber 41. The valve seat 21 is connected to the port of the corresponding branch, the air chamber 41 is arranged opposite to the valve seat 21, and the ventilation structure is connected to the corresponding air chamber.

[0040] Specifically, the flow channel 11 includes multiple functional branches, which can be microfluidic channels integrated within the first structural layer 1 and arranged independently. Each functional branch is a native flow channel structure built into the chip, not an externally connected pipeline. Each functional branch performs differentiated functions according to the division of labor in the radiopharmaceutical synthesis process, and can be used for different processes such as reagent injection, reaction medium delivery, product extraction, or waste liquid discharge. The branches do not cross-flow with each other, forming a multi-channel parallel microfluidic fluid network.

[0041] Multiple branches can refer to two or more independent fluid branches, which is different from the traditional single-channel, single-direction flow channel structure.

[0042] Each branch port is equipped with a set of air chambers 41. The corresponding configuration can include a precise matching assembly relationship. For example, each functional branch's fluid end port position is individually matched with an air chamber 41, realizing a one-to-one correspondence between one branch and one set of valve control. The branch port is the end opening position of the fluid output of each functional branch, and it is the docking position where the branch fluid enters the valve seat 21. The air chamber 41 is precisely arranged at this port position to realize dedicated control over the flow of fluid in a single branch.

[0043] Valve seat 21 serves as the valve control docking base for the branch fluid, directly and precisely docking with the port of the corresponding functional branch, receiving the fluid flowing out of the branch, and is the sealing mating part for the on / off of a single branch fluid. Air chamber 41 is a pneumatic drive cavity, arranged vertically opposite to the corresponding valve seat 21, forming a direct-drive layout, providing a dedicated pneumatic drive area for the corresponding valve position. The venting structure is a pneumatic access component, independently connected to the corresponding air chamber 41, used to independently provide air pressure input and pressure relief channels for air chamber 41, realizing independent drive control of a single air chamber.

[0044] The valve seat connects to the port of the corresponding branch, and the connection method can include fluid-through connection, with seamless alignment between the branch port and the valve seat inlet, allowing fluid to flow into the valve seat without loss or dead zones. The air chamber is arranged opposite to the valve seat, and its arrangement can include spatially aligned arrangement, with the cavity area of ​​the air chamber completely covering the sealing opening area of ​​the valve seat, ensuring that the pneumatic driving force is accurately applied to the sealing position of the valve seat. The venting structure communicates with the corresponding air chamber, and the communication relationship can include dedicated communication, with each venting structure corresponding to only one air chamber, and there are no shared air passages or cross-venting situations.

[0045] By independently configuring gas chambers at the ports of each functional branch, this chip possesses a basic structure for independent control of multiple fluid streams, overcoming the shortcomings of traditional microfluidic radiopharmaceutical chips that lack segmented flow control in a single channel and cannot control the overall on / off state in a time-sharing manner. Each branch can be independently opened and closed by relying on its corresponding gas chamber, providing structural support for the sequential sample introduction, stepwise reaction, and directional flow splitting required for multi-step radiopharmaceutical synthesis processes. This avoids the mixing problem caused by the simultaneous conduction of fluids in multiple branches, structurally improving the adaptability and process controllability of multi-step radiopharmaceutical synthesis processes.

[0046] In one example, the press layer 4 has multiple independently arranged air chambers 41, each air chamber 41 is arranged corresponding to each valve seat 21, and each air chamber 41 is connected to an independent ventilation structure.

[0047] Specifically, such as Figure 7The multiple air chambers 41 inside the lamination layer 4 are independent cavity structures that are separated from each other. The multiple air chambers 41 can be arranged in a non-interconnected layout. Any two air chambers 41 are separated by the solid structure of the lamination layer 4, so there will be no air pressure exchange or cross-flow interference. The multiple air chambers 41 can be arranged in an array on the board area of ​​the lamination layer 4. The number of air chambers matches the number of functional branches of the chip, and can correspond one-to-one with the valve control requirements of each branch.

[0048] The corresponding arrangement between each air chamber 41 and each valve seat 21 can include an alignment structure with the chambers facing each other vertically. The cavity area of ​​each independent air chamber 41 corresponds to the sealing opening position of the valve seat 21 above it. The coverage area of ​​the air chamber 41 completely corresponds to the diaphragm deformation area of ​​the valve seat 21, so that the air pressure change inside the air chamber 41 can act precisely and individually on the elastic diaphragm at the corresponding position, ensuring that the driving area of ​​each valve position does not interfere with each other.

[0049] It is understandable that by setting up multiple completely independent gas chambers 41 and independent ventilation structures, each gas chamber 41 of the chip has an independent gas pressure drive system, enabling the control effect of individual opening and closing of a single branch and arbitrary combination of multiple branches. This completely avoids the problems of valve position linkage malfunction and gas pressure interference caused by traditional shared gas paths, and can accurately match the timing of sample introduction, step-by-step reaction, and isolation switching process requirements of multi-step continuous synthesis of radiopharmaceuticals, greatly improving the controllability and stability of the microfluidic radiopharmaceutical synthesis process.

[0050] In one example, such as Figure 3 , Figure 4 and 6 As shown, the valve seat 21 includes a valve groove disposed on the second structural layer 2 and a through hole disposed at the bottom of the valve groove and penetrating the second structural layer 2. The through hole is connected to the flow channel of the first structural layer, and the valve groove is used to accommodate the elastic diaphragm 3.

[0051] Specifically, the valve seat 21 is formed on the second structural layer 2. The valve seat 21 may include a through-hole structure that is completely through the thickness direction of the second structural layer 2. The overall shape is a straight hollow channel without internal steps or recessed dead corners. Compared with the traditional built-in valve cavity structure, the overall channel of this through-hole structure is smoother and more regular, which can ensure smooth fluid flow.

[0052] The valve seat 21 has openings at both ends along its thickness direction, wherein the upper opening may include a structure that precisely aligns with the port of the flow channel 11 of the first structural layer 1. The upper opening of the valve seat 21 is interconnected with the end channel of the flow channel 11, allowing the reagent inside the flow channel 11 to be directly and smoothly introduced into the valve seat 21, thus achieving continuous connection of the fluid passage.

[0053] The lower opening of the valve seat 21 may be arranged facing the upper surface of the elastic diaphragm 3. The lower opening of the valve seat 21 is completely exposed and faces the elastic diaphragm 3. This port position is the key position where the fluid finally flows out and forms a sealing fit with the elastic diaphragm 3. The elastic diaphragm 3 can be directly attached to or detached from the lower opening of the valve seat 21, thereby achieving the blocking and conduction of the valve seat 21 channel.

[0054] This example uses a through-hole structure for the valve seat 21, completely eliminating the retention cavity inherent in traditional valve bodies. The channel is straight and unobstructed, effectively avoiding the problem of radioactive reagents accumulating in dead corners of the valve cavity, and significantly reducing the waste of valuable radiopharmaceutical raw materials. At the same time, the dead-corner-free channel structure facilitates subsequent rinsing and decontamination of residual radioactive liquid, eliminates cross-contamination of reagents between batches, significantly improves the purity and batch stability of radiopharmaceutical synthesis, and is suitable for long-term continuous clinical synthesis conditions.

[0055] In one example, such as Figure 1 , Figure 5 and Figure 7 As shown, the first structural layer 1, the second structural layer 2, the elastic diaphragm 3 and the pressing layer 4 are all provided with mounting holes 12 that are aligned and overlapped. A positioning pin 43 is inserted into the mounting hole 12, and the positioning pin 43 locks and fixes the first structural layer 1, the second structural layer 2, the elastic diaphragm 3 and the pressing layer 4 into a whole.

[0056] Specifically, the mounting holes 12 formed on the first structural layer 1, the second structural layer 2, the elastic diaphragm 3, and the laminating layer 4 have completely overlapping projection positions along the chip thickness direction. The mounting holes 12 can be evenly distributed around the chip board surface, and multiple sets of mounting holes 12 form a multi-point positioning layout. The positioning pins 43 pass through the four mutually aligned mounting holes 12 in sequence, and rely on the pin shaft body to complete the lateral positioning of each layer structure, avoiding lateral offset and misalignment between the layers.

[0057] In addition to its positioning function, the positioning pin 43 can also work with locking accessories to achieve axial clamping, tightly pressing the four layers of sheet together into an integral component that cannot be loosened, and relying on uniform clamping force to stably adhere the elastic diaphragm to the valve seat end face.

[0058] This example utilizes locating pins to achieve precise alignment and assembly of multi-layer chips, preventing misalignment in flow channels, valve seats, and air chambers, and ensuring the sealing accuracy of the on-chip valve body. The overall locking structure can maintain a tight fit between layers for a long time, preventing loosening due to repeated air pressure impacts, continuously ensuring the sealing of fluid and air passages, and reducing the probability of leakage or air leakage during long-term chip use.

[0059] In one example, such as Figure 1 and Figure 7As shown, the ventilation structure is a nozzle 42, and a through ventilation hole is provided inside the nozzle 42. One end of the ventilation hole is connected to the air chamber 41, and the other end is used to connect to an external air source.

[0060] Specifically, the nozzle 42, as a physical component of the ventilation structure, may include a cylindrical plug-in structure. The nozzle has an axially penetrating vent hole machined inside, forming a dedicated channel for gas flow. The upper end of the nozzle is embedded and mounted on the bottom surface of the press-fit layer 4, and the top of the vent hole directly connects to the internal cavity of the corresponding air chamber 41. The downwardly protruding exposed section of the nozzle may include a standard pipe plug-in structure, enabling direct connection to external pneumatic pipelines.

[0061] It is understandable that the assembly method between the air nozzle 42 and the pressure layer 4 can be the form of interference fit and threaded locking, so that the assembly gap remains airtight and the gas will not leak from the assembly gap.

[0062] The standardized external structure of the air nozzle allows for quick disassembly and connection of the air source pipeline, making assembly more convenient; the integrated through-hole air passage has low air resistance, fast air pressure response, and sensitive valve opening and closing action, improving the responsiveness and synchronization of the entire chip valve control action.

[0063] In one example, such as Figure 7 As shown, a sealing ring 44 is provided on the outer periphery of the air chamber 41.

[0064] Specifically, the sealing ring 44 may include an annular sealing gasket structure. The pressing layer 4 faces the surface of the elastic diaphragm 3, and an annular groove may be formed on the periphery of each air chamber 41, with the sealing ring 44 embedded inside the groove. After the chip is locked and pressed together, the upper end face of the sealing ring 44 tightly abuts against the bottom surface of the elastic diaphragm, forming a closed airtight barrier around the outer ring of each air chamber. The sealing rings can be independently arranged for each individual air chamber, and the sealing rings corresponding to each air chamber are separated from each other and do not interfere with each other's sealing areas.

[0065] It is understandable that the sealing ring 44 isolates the path of gas inside the gas chamber 41 from overflowing into the interlayer gap. This can not only avoid the problem of insufficient gas pressure and valve not closing tightly caused by the leakage of driving gas, but also prevent cross-flow interference between adjacent gas chambers, ensuring that the gas pressure value of each gas chamber is accurate and controllable, and improving the stability of independent control of multiple valves.

[0066] In one example, such as Figure 2 As shown, the first structural layer 1 and the second structural layer 2 are bonded and fixed together using an adhesive-free bonding process.

[0067] Adhesive-free bonding achieves a permanent molecular-level seal between the first structural layer 1 and the second structural layer 2, eliminating interlayer fluid leakage channels. The mechanical locking of the locating pin 43 provides uniform axial clamping force for the four-layer assembly, tightly holding the second structural layer, elastic diaphragm, and bonding layer, ensuring long-term leak-free contact between the elastic diaphragm and the valve seat and gas chamber sealing ring. These two components work together: adhesive-free bonding ensures permanent sealing of the fluid core layer, while the locking of the locating pin 43 dynamically compresses the pneumatic sealing layer, achieving dual sealing of both the liquid and gas paths.

[0068] Specifically, the interface between the first structural layer 1 and the second structural layer 2 is not coated or filled with any organic adhesive. The bonding method can include molecular bonding processes such as plasma-activated bonding, thermoforming bonding, or laser melting bonding, relying on the molecular forces at the material interface to achieve a seamless and airtight bond between the two layers. The bonded surface is dense and continuous, without any interlayer structure such as an adhesive layer. After the bonding process is completed, the connection between the flow channel 11 and the valve seat 21 remains regular and connected throughout the entire process, and the bonding process will not cause problems such as channel narrowing or blockage.

[0069] Understandably, this example completely abandons the organic adhesive layer structure, avoiding the defects of the adhesive swelling, cracking or leakage caused by high-energy radiation and strong corrosive organic solvents under the conditions of nuclear drug synthesis. The interlayer sealing performance is stable and reliable in the long term, extending the service life of the chip in the radiation environment and avoiding the safety hazards of radioactive reagent leakage caused by interface leakage.

[0070] In one example, the first structural layer and the second structural layer are made of radiation-resistant polymer materials or alumina ceramic materials.

[0071] Specifically, radiation-resistant polymer materials can include materials such as COC cyclic olefin copolymers or COP cyclic olefin polymers. These polymer materials are easy to machine into microchannels and micropores with precision, and also possess excellent radiation resistance and resistance to organic solvent swelling. Alumina ceramics have extremely high structural stability and radiation corrosion resistance, making them suitable for high-intensity and long-term radioactive synthesis applications.

[0072] Neither material will be corroded or aged by radioactive media or organic reactive solvents, and the structural dimensions of the board itself will not deform with the duration of irradiation.

[0073] Understandably, the fluid-contact substrate structure is well-suited to the demanding conditions of radiopharmaceutical preparation, preventing the substrate from aging and breaking, thus reducing the frequency of chip replacement. The material itself does not release harmful substances and will not contaminate radioactive synthesis products, ensuring the purity and safety of the prepared PET radiopharmaceutical.

[0074] The elastic diaphragm 3 can be made of radiation-resistant fluororubber or silicone rubber ultra-thin elastic film. The sealing ring 44 is made of perfluororubber, which is resistant to organic reagents and radiation aging. The gas nozzle and sealing layer can be made of radiation-resistant COC polymer, alumina ceramic or stainless steel, to meet the long-term use requirements of radiation conditions.

[0075] In summary, firstly, this chip adopts a four-layer stacked integrated on-chip valve control architecture, integrating the fluid channel sealing valve body and pneumatic drive structure entirely within the chip's internal structure. This eliminates the need for external solenoid valves and numerous external pipelines found in traditional solutions. The chip's overall structure is compact and sealed, significantly reducing the length of the channel through which radioactive media are exposed, effectively lowering the safety risks of ionizing radiation to personnel. Secondly, the valve seat uses a through-hole structure, eliminating dead zones for material stagnation within the fluid pathway. Simultaneously, multiple independent gas chambers provide zoned control for each flow channel branch. This reduces material loss due to residual valuable radioactive reagents and facilitates cleaning and decontamination of the chip's internal pipelines. Structurally, this prevents cross-contamination between different batches of reagents, improving the purity of radiopharmaceutical products and the overall stability of the preparation process. Meanwhile, each gas chamber and nozzle adopts a one-to-one independent matching layout, and each fluid branch is equipped with a dedicated pneumatic drive circuit. The valve body opening and closing action is sensitive, and the control process of different pipelines will not produce crosstalk. It can accurately adapt to the step-by-step process requirements of sequential sample introduction, closed reaction and product waste liquid directional diversion in the nuclear drug synthesis process, and optimize the controllability of the entire preparation process.

[0076] This chip employs a dual sealing assembly mechanism combining glue-free bonding and locating pin locking, which work together to ensure long-term sealing performance. Glue-free bonding achieves a permanent, seamless fit with the upper fluid layer, while locating pin locking applies uniform pressure to all four layers, including the elastic diaphragm and the bonding layer, stabilizing the sealing interface between the gas chamber sealing ring and the elastic diaphragm and preventing interlayer loosening or leakage caused by reciprocating air pressure impacts. Furthermore, the locating pin structure ensures precise alignment and overall locking of the multi-layer substrate. Combined with the sealing ring structure outside the gas chamber and the glue-free bonding structure between the first and second structural layers, the use of organic adhesive layers is completely eliminated. This avoids the problem of swelling, cracking, and leakage of adhesives under strong organic solvent erosion in irradiated environments. The overall sealing effect of the chip's gas and liquid circuits can remain stable over a long period, and the chip is less prone to leakage-related failures during extended operation. Finally, the substrate material that comes into direct contact with the fluid is made of radiation-resistant polymer material or alumina ceramic material. This type of material can withstand high-energy radiation and corrosive solvents under radiopharmaceutical preparation conditions. The substrate will not age, deform or precipitate impurities, which can extend the actual service life of the chip and ensure the safety of the final radiopharmaceutical product. It is suitable for the routine radiopharmaceutical synthesis operation scenarios in hospital clinical departments.

[0077] Example 2

[0078] Based on the same inventive concept, this embodiment provides a radiopharmaceutical synthesis method based on a microfluidic chip. This method relies on the microfluidic chip hardware structure described in Example 1 to execute the complete radiopharmaceutical preparation process. The basic hardware structures, such as layer stacking, valve sealing, and gas pressure actuation, will not be repeated. This method controls the on / off state of each fluid channel by switching gas pressure. The entire process, including reagent delivery, chemical reaction, and product collection, is completed within the microfluidic system inside the chip. There are no open operation stages where radioactive media are exposed to the outside. The process switching is completed using the chip's built-in on-chip valve structure, eliminating the need for additional external valves for control. The method includes the following steps: Step 1: Control the ventilation structure corresponding to the reagent injection branch to be in a non-driven gas pressure state, and introduce radioactive reagent into the flow channel. Under the action of fluid pressure, the reagent overcomes the pre-pressure of the elastic diaphragm and opens the valve seat to complete the quantitative injection.

[0079] Step 2: Introduce driving air pressure into the ventilation structure corresponding to the reagent injection branch, so that the elastic diaphragm presses against the valve seat to block the reagent injection branch, and complete the radiolabeling reaction in the reaction chamber.

[0080] Step 3: Control the ventilation structure corresponding to the target branch to be in a state of no driving air pressure, and direct the product or waste liquid out under the drive of microfluidic pressure; at the same time, introduce driving air pressure into the ventilation structure corresponding to the non-target branch, so that the corresponding elastic diaphragm presses the valve seat to achieve isolation between branches.

[0081] Specifically, in step one, a quantitative sample injection operation is first carried out. The operator controls the ventilation structure corresponding to the reagent injection branch to maintain a normal pressure state without driving gas pressure. At this time, no positively pressurized gas environment is generated inside the corresponding gas chamber. The elastic diaphragm is only attached to the open end face of the lower end of the valve seat by the static pre-pressure formed by the multi-layer chip locking assembly. The operator delivers the prepared radioactive reagent and the matching reaction substrate into the internal flow channel through the fluid interface set on the chip surface. During the delivery process, the delivery pressure carried by the fluid itself will continuously act on the end face of the elastic diaphragm facing the flow channel. When the pressure generated by the fluid exceeds the assembly pre-tightening force of the elastic diaphragm, the fluid can push open the elastic diaphragm and flow into the interior of the valve seat, and converge into the reaction chamber area pre-set by the chip along the flow channel, thereby completing the quantitative feeding operation.

[0082] Understandably, the total amount of sample introduced at this stage can be precisely controlled by the microfluidic pressure and the duration of medium introduction. The microscale flow channel cavity can significantly reduce the amount of radioactive reagent used per feeding, which can not only save scarce radioactive nuclide raw materials, but also simultaneously reduce the total amount of radioactive waste generated after the reaction ends.

[0083] In step two, the radiolabeling reaction process is carried out. After all the necessary reagents have been delivered into the reaction chamber, a fixed driving pressure is introduced into the ventilation structure corresponding to the reagent injection branch. The high-pressure gas fills the corresponding chamber and pushes the elastic diaphragm upwards, tightly sealing it against the valve seat opening. The pressure generated by the diaphragm completely blocks the valve seat channel, directly cutting off the fluid connection between the reaction chamber and the front-end injection line. At this point, the reaction chamber is enclosed by the surrounding valve structure, forming a completely sealed, independent reaction space. All reagents are sealed inside the fixed cavity, and the radiolabeling reaction proceeds according to the preset process time.

[0084] It should be noted that the sealed cavity environment can prevent the backflow of media or the cross-flow of different materials during the reaction process, maintain the stable state of the environment in which the radiolabeling reaction takes place, effectively improve the overall conversion efficiency of the labeling reaction, and at the same time, the sealed cavity structure can block the outward diffusion and leakage of radioactive materials throughout the process, reducing the actual dose of radiation exposed to workers.

[0085] In step three, the directional export of products and waste liquid and the isolation of branch channels are carried out. After the radiolabeled chemical reaction is completely completed, the ventilation structure corresponding to the target branch is adjusted to a normal pressure relief state. The elastic diaphragm corresponding to this branch loses the clamping force brought by the air pressure and naturally rebounds and resets itself based on its own material properties, and the valve seat channel is switched back to the conducting state. Relying on the microfluidic pressure remaining inside the flow channel, the target product generated by the reaction or the waste liquid generated after the reaction can be transported outward along the target branch in the conducting state and collected. Throughout the entire process of material export, the staff continuously supply driving air pressure to all other non-target branches that are not involved in the work, so that the elastic diaphragms corresponding to the non-target branches are always pressed and sealed to the corresponding valve seats, physically separating the working branches from the other idle branches.

[0086] Understandably, this design prevents waste liquid or residual impurities from contaminating the target product during product collection, thus affecting the purity of the final product. It also prevents crosstalk between different process pipelines. Workers can cycle through and switch the on / off states of different target branches according to the sequence of the entire radiopharmaceutical synthesis process, sequentially completing various supporting processes such as waste liquid discharge, product purification, and pipeline cleaning, fully covering the entire process of radiopharmaceutical preparation.

[0087] In summary, the entire synthesis method relies on the chip's built-in pneumatic on-chip valve system to complete the entire process control. The overall control logic is simple and easy to understand, and it can be easily matched with conventional pneumatic control systems to achieve fully automated program operation. It does not require a complex fluid pumping and control mechanism, and can be adapted to the miniaturized and real-time radiopharmaceutical preparation scenarios in primary nuclear medicine departments.

[0088] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0089] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the appended claims.

Claims

1. A radiopharmaceutical synthesis chip based on a microfluidic chip, characterized in that, It includes a first structural layer, a second structural layer, an elastic diaphragm, and a pressing layer that are stacked sequentially. The first structural layer has a flow channel, and the side of the first structural layer opposite to the second structural layer has a fluid interface that communicates with the flow channel; A valve seat is provided on the side of the second structural layer opposite to the second structural layer, and the valve seat communicates with the flow channel through a through hole; The elastic diaphragm is disposed inside the valve seat and covers the opening of the valve seat; The press-fit layer has an air chamber, and the press-fit layer is equipped with a ventilation structure that communicates with the air chamber. The ventilation structure is used to connect an external air source to control the opening and closing of the flow channel.

2. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, The flow channel includes multiple functional branches, each branch port is provided with a corresponding air chamber, the valve seat is connected to the port of the corresponding branch, and the air chamber and valve seat are arranged opposite to each other.

3. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 2, characterized in that, There are multiple air chambers, and each air chamber is arranged in a one-to-one correspondence with the valve seat. Each air chamber is connected to a ventilation structure.

4. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, The valve seat includes a valve groove disposed on the second structural layer and a through hole disposed at the bottom of the valve groove and penetrating the second structural layer. The through hole is connected to the flow channel of the first structural layer, and the valve groove is used to accommodate an elastic diaphragm.

5. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, The first structural layer, the second structural layer, the elastic diaphragm, and the pressing layer are all provided with mounting holes that overlap and are aligned. A positioning pin is inserted into the mounting hole, and the positioning pin locks and fixes the first structural layer, the second structural layer, the elastic diaphragm, and the pressing layer into a whole.

6. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, The ventilation structure is an air nozzle, and the air nozzle has a through air hole inside. One end of the air hole is connected to the air chamber, and the other end is used to connect to an external air source.

7. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, A sealing ring is provided on the outer periphery of the air chamber.

8. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, The first structural layer and the second structural layer are bonded and fixed together using a glue-free bonding process.

9. The radiopharmaceutical synthesis chip based on a microfluidic chip according to claim 1, characterized in that, The first structural layer and the second structural layer are made of radiation-resistant polymer materials or alumina ceramic materials.

10. A method for synthesizing radiopharmaceuticals based on a microfluidic chip, comprising using a radiopharmaceutical synthesis chip based on a microfluidic chip as described in any one of claims 1 to 9, characterized in that, Includes the following steps: The ventilation structure corresponding to the reagent injection branch is controlled to be in a non-driven gas pressure state. Radioactive reagent is introduced into the flow channel. Under the action of fluid pressure, the reagent overcomes the pre-pressure of the elastic diaphragm and opens the valve seat to complete the quantitative injection. Driven air pressure is introduced into the ventilation structure corresponding to the reagent injection branch, causing the elastic diaphragm to press against the valve seat to block the reagent injection branch, and the radiolabeling reaction is completed in the reaction chamber. The ventilation structure corresponding to the target branch is controlled to be in a state of no driving air pressure, and the product or waste liquid is directed out under the drive of microfluidic pressure; at the same time, driving air pressure is introduced into the ventilation structure corresponding to the non-target branch, so that the corresponding elastic diaphragm presses the valve seat to achieve isolation between branches.

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