Biosensor packaging process

Abstract

The invention relates to a biosensor packaging technology, and relates to the technical field of biosensors, the technology adopts a blister packaging form, a water vapor barrier structure is formed through a hot pressing sealing technology, and a drying agent is added in the packaging process to control the internal microenvironment. The packaging operation is completed under the condition of a clean room, and the packaged sensor unit is stored under the condition of low temperature. According to the packaging scheme, the bioactive components of the sensor can be effectively protected, the environmental tolerance and the storage stability of the sensor are remarkably improved, meanwhile, the degree of dependence on external cold chain conditions is reduced, and reliable guarantee is provided for popularization and application of the biosensor in primary medical treatment and family monitoring scenes.

Description

Technical Field

[0001] This invention relates to the field of biosensor technology, specifically to biosensor packaging technology. Background Technology

[0002] In the field of biosensor technology, the reliability of the packaging process directly determines the product's storage stability and clinical performance. Current common sensor packaging solutions often use ordinary plastic shells or simple blister packs, which have limited barrier capabilities against environmental humidity and temperature, making it difficult to effectively protect bioactive components sensitive to moisture and heat. Especially under long-term storage or suboptimal transportation conditions, environmental factors can easily lead to enzyme activity decay, electrode performance drift, or unstable signal baselines, causing sensor performance degradation before use and severely affecting the accuracy and consistency of detection results.

[0003] Furthermore, existing packaging technologies struggle to balance sealing and ease of use, hindering the widespread adoption of biosensors in diverse scenarios. While traditional rigid packaging offers some protection, it is often bulky, costly, and difficult to integrate into modern automated testing systems. Conversely, while simple packaging is cheaper, it fails to provide sufficient physical and environmental protection, exposing sensors to a higher risk of failure in primary healthcare institutions or home use. This contradiction prevents high-performance sensors from transcending the limitations of specialized laboratories and from realizing their full potential in primary healthcare and home health monitoring fields where convenient and rapid testing is urgently needed. Summary of the Invention

[0004] To address the problems of existing technologies, this invention provides a biosensor packaging process.

[0005] To solve the above-mentioned technical problems, the present invention is achieved through the following technical solution: Firstly, a biosensor packaging process includes the following steps: A blister packaging material is provided on the sensor substrate after the enzyme layer coating and curing are completed; The sensor is placed into the cavity of the blister pack; The blister pack and the cover material are heat-sealed together in a sealed environment to form a water vapor-sealed packaging unit.

[0006] In one specific embodiment of the first aspect, the water vapor permeability of the blister packaging material is lower than the standard requirement to ensure the stability of the sensor under specified storage conditions.

[0007] In one specific embodiment of the first aspect, a desiccant is placed inside the cavity before sealing the blister.

[0008] In one specific embodiment of the first aspect, the temperature range of the hot-press sealing is 120°C to 180°C, the pressure range is 0.3 MPa to 0.8 MPa, and the sealing time is 1 to 5 seconds.

[0009] In one specific embodiment of the first aspect, the packaged sensor is stored and transported under refrigerated conditions at 2–8°C.

[0010] In one specific embodiment of the first aspect, the packaged sensor unit is able to withstand a transport test for at least 48 hours at an ambient temperature of 40°C, and the sensor signal attenuation is ≤ 5%.

[0011] In one specific embodiment of the first aspect, the packaging process completes the sensor filling and blister sealing operations in a Class 10,000 cleanroom environment.

[0012] Secondly, a biosensor product, wherein the sensor is packaged using a biosensor packaging process.

[0013] The beneficial effects of this invention are as follows: 1. Innovative sealed packaging design and stringent environmental control provide crucial long-term stability assurance for high-precision biosensors. This process utilizes blister packaging with special barrier materials, combined with efficient sealing technology, to create a stable, dry microenvironment that effectively isolates external moisture and contaminants. This design allows environmentally sensitive bioactive components to maintain excellent activity over a long period, significantly extending the sensor's lifespan and ensuring consistent product performance throughout storage, laying a solid foundation for the accuracy and reliability of detection results.

[0014] 2. This packaging technology significantly improves the sensor's environmental adaptability and ease of use. Its robust sealed structure enables the sensor to withstand harsh transportation conditions, reducing absolute reliance on cold chain logistics and thus broadening the product's applicable regions and scenarios, particularly benefiting primary healthcare and home monitoring. The independent, unitized packaging not only facilitates storage and retrieval but also reduces the risk of operational errors due to its user-friendly design. Ultimately, this technology transforms high-performance sensors into stable, portable, and ready-to-use end products, bridging the final link from precision manufacturing to reliable clinical application and providing crucial support for its large-scale commercialization. Attached Figure Description

[0015] Figure 1 This is a schematic diagram of the signal drift of the four sensors in this invention.

[0016] Figure 2 This is a schematic diagram of the basic current signals of the four sensors of the present invention during the initial wetting stage.

[0017] Figure 3 This is a schematic diagram of the sensor response for a glucose sample within the normal range (5.0 mmol / L) of this invention.

[0018] Figure 4 This is a schematic diagram of the rinsing time for sensor recovery after measuring 5 mmol / L glucose according to the present invention.

[0019] Figure 5 This is a schematic diagram of the sensor recovery flushing time after measuring 40 mmol / L glucose according to the present invention.

[0020] Figure 6 This is a schematic diagram of the linearity of the four sensors of the present invention, wherein (a) is the relationship between the current change rate of sensor 1 and glucose concentration, (b) is the relationship between the current change rate of sensor 2 and glucose concentration, (c) is the relationship between the current change rate of sensor 3 and glucose concentration, and (d) is the relationship between the current change rate of sensor 4 and glucose concentration.

[0021] Figure 7 This is a schematic diagram of the VS YSI-2300 measurement values ​​of the control samples for batches #CNB001, #CNB002 and #CNB003 of the present invention.

[0022] Figure 8 This is a schematic diagram of the patient sample measurement values ​​VS YSI-2300 for batch #CNB001 of the present invention.

[0023] Figure 9 This is a schematic diagram of the patient sample measurement VS YSI-2300 for batch #CNB002 of the present invention.

[0024] Figure 10 This is a schematic diagram of the patient sample measurement values ​​VS YSI-2300 for batch #CNB003 of the present invention. Detailed Implementation

[0025] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0026] like Figures 1 to 10 The biosensor packaging process shown.

[0027] Description of the production process: The production process consists of two main parts: 1. Manufacturing of the basic sensor structure in the screen printing process; 2. Fixing the receptor components during the formulation process.

[0028] Screen printing process: The first production step is a third-party manufacturer service, based on customized production according to specifications. The basic sensor structure undergoes pre-delivery inspection and is then delivered in a 4 x 4 inch format.

[0029] Enzyme Immobilization Process: The second production step involves the immobilization of the biosensor receptor assembly. A measured mass of lyophilized GOx is mixed with a polymer-based emulsion. The liquid prepared in this way is then dispensed using an automated dispenser under cleanroom conditions. The drying and hardening of the enzyme-polymer layer are also controlled under cleanroom conditions. Preliminary tests are then performed on the sensor wettability and sensor signal (sensitivity). After confirmation, the sensor is packaged in blister packs and then stored in a refrigerator.

[0030] Bill of Materials (BOM) Table 1 shows the bill of materials.

[0031] Table 1: Bill of Materials (BOM) Biosensor performance testing: Biosensor performance testing encompasses all processes following sensor manufacturing. Typically, these processes cover storage and key functional testing.

[0032] The investigation included three different sensor batches (#CNB001, #CNB002, #CNB003), each containing a total of 51 sensors. Seven samples were randomly selected from each batch for different tests. The sensor was designed for use with hemolyzed whole blood samples pre-diluted 1:51 with system fluid. Concentrations given herein always refer to this dilution rate. Unless otherwise stated.

[0033] Wetting Time: Wetting time is the necessary time span between initial insertion of the sensor into the analyzer and operational readiness. This "delay" is due to the conditioning process that begins from the sensor's first contact with the system solution. The sensor layer absorbs water and electrolyte components and expands. During this period, the sensor is not yet ready for measurement because the signal is not stable enough to properly meet sensor specifications. A 30-minute time span is reasonable for wetting.

[0034] Please refer to Figure 1The graph shows the signal drift of four sensors (batch number #CNB003). It compares the normalized signals (current change rate dI / dt) of the four sensors at time points of 180 seconds, 480 seconds, 780 seconds, 1080 seconds, 1380 seconds, 1680 seconds, 1980 seconds, and 2280 seconds. It can be used to observe the consistency and stability of the sensor signals. The wetting process of the glucose biosensor (four sensors, numbers 1-4, from the same batch, batch #CNB003) is exemplarily shown. Figure 1 In the initial wetting phase of 3 minutes, samples of 12.0 mmol / L glucose were measured every 5 minutes, and signal drift was assessed. A key criterion for proper wetting was the signal drift at the end of the wetting period. The signal was set to 100% after 3 minutes, with a drift period of 35 minutes. After wetting, drift should not exceed 3%, for more than 20 samples (one complete sample rack), or drift within 10 minutes individually. Clearly, after 1680 seconds (28 minutes), the signal drift was already within the <2% range for the next 10 minutes, as shown in all four sensors.

[0035] Sensor base current: The base current of glucose biosensors is typically in the low nA / mm² range. 2 Measurements are taken within the specified range. Only in the initial period after the sensor comes into contact with the system solution will the sensor base current show a higher value. This is due to charge reversal and oxidation processes in the dense electrode region. The first cycle is exemplarily as follows: Figure 2 As shown. After 3 minutes, the typical base current is <10 nA / mm. 2 .

[0036] Please refer to Figure 2 The figure shows the basic current signals of the four sensors during the initial wetting phase (0 to 180s). The figure shows the current of sensor 1 (linear), sensor 2 (linear), sensor 3 (linear), and sensor 4 (linear) of batch #CNB003. The current of each sensor rises rapidly in the initial phase (approximately 0-50 seconds), then gradually decreases and tends to stabilize. The current change trends of different sensors are somewhat different. Sensor signal value and accuracy: The signal strength of a biosensor is a crucial parameter for signal resolution and accuracy. Long-term experience clearly shows that a sensor signal strength between 0.5 and 3 nA / (mmol / L·mm²) is optimal. 2 ) is the best. Figure 3The signal magnitudes of 10 subsequent measurements at 12 mmol / L glucose are shown. The signal for each measurement is listed in Table 2.

[0037] Table 2: Examples of signal magnitude and accuracy measurements for all four sensors, all from batch #CNB003.

[0038] Response time: Biosensor response time is a critical parameter as it is a key parameter in the overall measurement cycle time, and therefore crucial for sample throughput. Response time primarily depends on the transport rate into the enzyme layer of the biosensor considered for glucose. It is defined as the time span between the appearance of the sample at the sensor and the sensor's maximum signal reading. Note the small signal effect caused by air bubbles between the system solution and the sample. A clear fluid isolation interface between the system solution and the sample solution is essential to prevent sample residue. Figure 3 As shown, the sensor's response time can be determined by analyzing the rising edge of the response curve, resulting in a response time of <4 s. This is a typical value.

[0039] Please refer to Figure 3 The sensor response of a glucose sample within the normal range (5.0 mmol / L) is shown in the figure. The initial current change rate is stable. After the sample is added (corresponding to the "sample" label), there is a slight fluctuation due to factors such as the "bubble" label. Then it gradually rises, reaches the maximum signal ("maximum signal" label), and then slowly decreases.

[0040] The rinsing time and response time together determine the total duration of the detection cycle, thus limiting the system's maximum sample throughput. Therefore, shortening the rinsing time is crucial for improving detection efficiency. This study optimized the rinsing process without degrading sensor performance, achieving a shorter rinsing time and enabling the system throughput to typically exceed 100 samples per hour, with a maximum of 120 samples per hour.

[0041] Please refer to Figure 4 : Rinse time for sensor recovery after measuring 5 mmol / L glucose; Batch #CNB002. This figure shows that after the start of rinsing, the current change first rises rapidly to form a peak, then falls, and stabilizes after about 24 seconds, reaching the end of rinsing. Please refer to Figure 8 The graph shows the sensor recovery flushing time after measuring 40 mmol / L glucose; batch #CNB002. It illustrates that after the start of flushing, the current initially rises rapidly to a peak, then drops sharply, gradually stabilizing after approximately 29 seconds, reaching the end of the flushing process. Figure 4 and Figure 5The same sensor from batch #CNB002 was used to verify the full range adaptability of a single device.

[0042] Linearity: According to the function c=f(dI / dt), the sensor signal dI / dt is linearly correlated with the glucose concentration. A single-point calibration is sufficient to obtain the linear correlation function. In the study described here, 12 mmol / L glucose was used as the calibration solution.

[0043] Figure 6 Strong linearity was observed in four sensors across three batches, typically up to 50 mmol / L. Normally, a concentration range up to 30 mmol / L is sufficient, as high glucose concentrations in human blood are very rare and are usually due to erroneous patient sample extraction. In any case, linearity was observed up to 50 mmol / L in glucose.

[0044] Please refer to Figure 6 Linearity of 4 sensors (Sensor 1 is from batch #CNB001; Sensor 2 is from batch #CNB002; Sensors 3 and 4 are from batch #CNB003). In-use testing: In-use testing again includes 3 sensor batches #CNB001, #CNB002 and #CNB003.

[0045] Selectivity / Interference Substances: The selectivity of glucose biosensors can be affected by electrochemically active substances that can be oxidized on the working electrode, or by substances that inhibit enzyme activity.

[0046] The selective assay was performed according to the Clinical and Laboratory Standards Institute (CLSI) guideline document EP07 (3rd edition). The assay was conducted on human serum samples, investigating the presence of eight important interfering substances in addition to glucose levels within the normal range. See Table 3 for details. The figures shown are averages from three sensors. The effect on uric acid was the highest, at 5.4 / 5.5%.

[0047] The measured interference effect was significantly lower than 10%.

[0048] Table 3: Interference tests for batches #CNB002 and #CNB003; Control sample: The control sample is compared with the YSI-2300 (Yellow Springs Instruments, USA).

[0049] All three sensor batches showed good correlation.

[0050] Please refer to Figure 7The comparison of the control sample measurements of batches #CNB001, #CNB002, and #CNB003 with YSI-2300 shows the mean measurement values ​​of batches #CNB001, #CNB002, and #CNB003 under different glucose quality control samples, demonstrating the measurement results of each batch under different samples. Patient samples: Patient samples were compared with the YSI-2300 (Yellow Springs Instruments, USA). Figure 8 , Figure 9 and Figure 10 The graph shows the correlation between #CNB001 (113 blood samples), #CNB002, and #CNB003 (80 blood samples).

[0051] Please refer to Figure 8 (Based on the clinical sample set "LT12040"): Patient sample measurements VSYSI-2300 from batch #CNB001 are shown, illustrating the linear relationship between batch #CNB001 measurements and YSI-2300 measurements, along with the coefficient of determination (R²). 2 (The closer to 1, the stronger the linear correlation), indicating the degree of correlation between the measurement results of the two. Please refer to Figure 9 (Based on clinical sample set "LT14195"): Patient sample measurements VSYSI-2300 from batch #CNB002, linear relationship equation and coefficient of determination (R²) between batch #CNB002 measurements and YSI-2300 measurements. 2 The closer to 1, the stronger the linear correlation, indicating the degree of correlation between the measurement results of the two. Please refer to Figure 10 (Based on clinical sample set "LT18331"): Patient sample measurements VSYSI-2300 from batch #CNB003, linear relationship equation and coefficient of determination (R²) between batch #CNB003 measurements and YSI-2300 measurements. 2 The closer to 1, the stronger the linear correlation, indicating the degree of correlation between the measurement results of the two. In summary, the test data from batches #CNB001, #CNB002, and #CNB003 fully demonstrate that this sensor possesses excellent anti-interference characteristics and measurement specificity, and its performance meets the stringent requirements of clinical testing.

[0052] Example 1: Standard Packaging Process This example demonstrates the standard packaging process for biosensors: Pre-treatment: The sensor substrate, which has completed enzyme coating, curing and initial performance testing, is transferred to a Class 10,000 cleanroom environment in the form of a 4×4-inch wafer or a single unit.

[0053] Blister preparation: Using a water vapor transmission rate (WVTR) ≤ 0.5 g / (m²) 2 Rigid PVC or PETG blister material (day). A pre-formed blister substrate with a cavity that matches the sensor's shape is used.

[0054] Filling: Precisely insert individual sensor units into the cavity of the blister pack. The operation is performed in a clean bench to prevent particulate contamination.

[0055] Place desiccant: Place a small packet of silica gel desiccant at the edge of each blister cavity to absorb any trace moisture that may remain after encapsulation and maintain a low humidity environment inside.

[0056] Hot-press sealing: Cover the blister pack containing the sensor with an aluminum-plastic composite film cover.

[0057] Using a heat sealer, heat seal for 3 seconds at a temperature of 150°C and a pressure of 0.5 MPa.

[0058] After sealing, ensure that the sealing edges are flat and airtight, forming an independent packaging unit with water vapor sealing.

[0059] Storage and Packaging: Pack the sealed blister units into outer packaging boxes, immediately transfer them to a cold storage at 5±3°C, and ship them under these conditions.

[0060] Example 2: Verification of process parameters To verify the robustness of the packaging process, the following key parameters were tested: Seal strength test: The peel strength test was performed on the blister packs sealed according to the process of Example 1. The results were all greater than 1.5N / 15mm, which met the sealing requirements.

[0061] Stability testing: Three different batches of packaged sensors (#CNB001, #CNB002, #CNB003) were placed in a 40°C constant temperature chamber for accelerated aging for 48 hours. After being removed and allowed to return to room temperature, the sensor signal attenuation was ≤ 5%, indicating that the packaging process can effectively protect the sensor performance under non-ideal transportation conditions.

[0062] Barrier performance test: The packaged sensor was stored in an environment of 40°C and 75% relative humidity for 14 days. Its wetting time and sensitivity were then tested. Compared with the sensor stored under refrigeration, the performance changes were all within acceptable range (deviation <3%), proving that the water vapor barrier effect of blister packaging is good.

[0063] Example 3: Alternative Solution In another embodiment, the desiccant in step 4 can be replaced with a molecular sieve drying coating integrated into the inside of the cover material. Meanwhile, the hot-press sealing parameters can be adjusted according to the cover material. For example, when using cold aluminum with higher barrier properties, the sealing temperature can be adjusted to 120°C and the time extended to 5 seconds, achieving the same desired sealing effect.

[0064] Summary of technical effects Through the above-described packaging process, the present invention achieves the following beneficial effects: Long-term stability: The water vapor-sealed blister packaging combined with a desiccant provides optimal protection for the humidity-sensitive enzyme layer, ensuring stable sensor performance throughout its shelf life.

[0065] Environmental impact resistance: Verification shows that the packaged sensor can withstand short-term high-temperature transportation, breaking through the absolute dependence of traditional solutions on the cold chain and reducing logistics costs.

[0066] Cleanliness Guarantee: Final packaging is completed in a Class 10,000 cleanroom, eliminating microbial and particulate contamination and meeting the production standards for medical products.

[0067] Industrial application: The process steps are clear and the parameters are well-defined, making it easy to integrate into automated production lines to achieve large-scale, high-efficiency, and highly consistent packaging production.

[0068] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A packaging process for a biosensor, characterized in that, Includes the following steps: A blister packaging material is provided on the sensor substrate after the enzyme layer coating and curing are completed; The sensor is placed into the cavity of the blister pack; The blister pack and the cover material are heat-sealed together in a sealed environment to form a water vapor-sealed packaging unit.

2. The packaging process according to claim 1, characterized in that, The water vapor transmission rate of the blister packaging material is lower than the standard requirement to ensure the stability of the sensor under specified storage conditions.

3. The packaging process for the biosensor according to claim 1, characterized in that, Before sealing the blister, place a desiccant inside the cavity.

4. The packaging process for the biosensor according to claim 1, characterized in that, The temperature range for hot-press sealing is 120°C to 180°C, the pressure range is 0.3 MPa to 0.8 MPa, and the sealing time is 1 to 5 seconds.

5. The packaging process for the biosensor according to claim 1, characterized in that, After packaging, the sensor is stored and transported under refrigerated conditions at 2–8°C.

6. The packaging process for the biosensor according to claim 5, characterized in that, The packaged sensor unit can withstand at least 48 hours of transport testing at an ambient temperature of 40°C, and the sensor signal attenuation is ≤ 5%.

7. The packaging process for the biosensor according to claim 1, characterized in that, The encapsulation process is performed in a Class 10,000 cleanroom environment, where the sensor is filled and the blister pack is sealed.

8. A biosensor product, characterized in that, The sensor is packaged using the packaging process of the biosensor described in any one of claims 1 to 7.

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