Local pressure loading regulation and control device suitable for body surface tumor

Abstract

The invention discloses a local pressure loading regulation and control device suitable for body surface tumors, and relates to the technical field of biomedical engineering. The shell fixing module is provided with a fixing part used for being fixedly connected to the body surface around a tumor; the pressure transmission module is connected to the shell fixing module, the pressure transmission module comprises an elastic pressure applying piece and an adjusting assembly, and the adjusting assembly is configured to adjust the deformation quantity of the elastic pressure applying piece so as to generate a controllable pressure load; the tumor contact module is connected to the pressure output end of the elastic pressure applying piece; wherein the tumor contact module comprises a bearing chassis, a pressure sensor and a flexible adaptation layer; the pressure sensor is configured to detect the magnitude of the pressure load; the flexible adaptation layer is arranged on the side, facing the tumor, of the bearing base plate and used for being attached to the surface of the tumor under the action of pressure loads. The invention aims to design a local pressure loading device which can be accurately fitted with a tumor form and has real-time feedback and dynamic regulation and control capabilities.

Description

Technical Field

[0001] This invention relates to the field of biomedical engineering technology, and in particular to a local pressure loading and regulation device suitable for tumors on the body surface. Background Technology

[0002] Nanomedicines have become an important research direction in the field of cancer treatment due to their high bioavailability and low toxicity. However, the enrichment efficiency of nanomedicines in solid tumors is often low due to the continuous monolayer endothelium of tumor blood vessels and the high stromal pressure of tumors. Existing research shows that by applying controllable external physical stimulation to tumors through physical-mechanical regulation, it is possible to modulate the tumor mechanical microenvironment and improve the extravasation efficiency of nanoparticles.

[0003] However, existing mechanical modulation techniques struggle to achieve precise control. Macroscopic mechanical loading devices can easily lead to tumor ischemia and necrosis or hemodynamic disturbances, while non-invasive acoustic or optical modulation, although less damaging, has limited penetration depth and makes it difficult to quantify local stress distribution. Furthermore, existing pressure loading devices typically cannot closely conform to the diverse morphologies of tumor surfaces and lack real-time pressure feedback systems, making it impossible to dynamically adjust loading parameters to avoid excessive damage to the vascular barrier or delayed repair.

[0004] Therefore, designing a local pressure loading device that can accurately fit the morphology of the tumor and has real-time feedback and dynamic control capabilities has become an urgent technical challenge. Summary of the Invention

[0005] The main objective of this invention is to provide a local pressure loading control device suitable for tumors on the body surface.

[0006] To achieve the above objectives, the present invention proposes a local pressure loading control device suitable for tumors on the body surface, comprising: a shell fixing module having a fixing part for fixing to the body surface surrounding the tumor; a pressure transmission module connected to the shell fixing module, the pressure transmission module including an elastic pressure applying element and an adjustment component, the adjustment component being configured to adjust the deformation of the elastic pressure applying element to generate a controllable pressure load; and a tumor contact module connected to the pressure output end of the elastic pressure applying element; wherein, the tumor contact module includes a support chassis, a pressure sensor, and a flexible adaptation layer; the pressure sensor is configured to detect the magnitude of the pressure load; the flexible adaptation layer is disposed on the side of the support chassis facing the tumor, for conforming to the tumor surface under the action of the pressure load.

[0007] Preferably, the housing fixing module includes a fixed housing and a rotating housing that cooperate with each other; the fixed housing is used to support the overall structure of the device and form the fixing part; the rotating housing is connected to the pressure transmission module and is configured to drive the elastic pressure-applying member to deform through its own rotational movement.

[0008] Preferably, the adjustment component includes a threaded structure or a rotating screw disposed inside the rotating housing; the rotating housing cooperates with the elastic pressure member through the threaded structure or rotating screw to convert the rotational motion of the rotating housing into a linear compression motion along the direction pointing towards the tumor.

[0009] Preferably, the fixation part is configured to be fixedly connected to the skin surface around the tumor by biocompatible adhesive, so that the device remains in a fixed position relative to the tumor.

[0010] Preferably, the elastic pressure-applying component is a helical spring, one end of which receives the driving force from the adjusting component, and the other end converts the elastic force into a downward compressive force and transmits it to the tumor contact module.

[0011] Preferably, the deformation of the elastic pressure-applying member is expressed as a compression distance, which is adjustable from 0 mm to 7 mm to control the pressure load applied to the tumor.

[0012] Preferably, the spring constant k is 40.78 g / mm, the wire diameter is 0.4 mm, the pitch is 6.5 mm, and the total number of turns is 4.

[0013] Preferably, the flexible adaptor layer is made of polydimethylsiloxane gel, which is configured to have a flexible shape that can conform to the morphology of the tumor.

[0014] Preferably, the polydimethylsiloxane gel is a gel with a preset hardness prepared by adjusting the component ratio, the preset hardness being configured to induce an increase in the intercellular space of tumor vascular endothelial cells under the pressure load.

[0015] Preferably, the pressure sensor is configured to monitor the value of the pressure load in real time and output pressure monitoring data for feedback adjustment of the adjustment component, so that the pressure load is maintained at a preset constant value; wherein the preset constant value is in the range of 0.5 N to 1.5 N.

[0016] The above technical solution has the following advantages: The local pressure loading control device for tumors on the body surface provided in this invention uses a shell fixing module to stably fix the device to the tumor site. By utilizing the adjustment component in the pressure transmission module in conjunction with the elastic pressure application element, rotational motion can be converted into precise linear compression force, achieving controllable adjustment of the pressure load. The device employs a tumor contact module containing a flexible adaptable layer. This flexible adaptable layer can deform under pressure to closely conform to the irregular tumor surface, ensuring uniform pressure application. Combined with real-time monitoring by a pressure sensor, it achieves precise, uniform, and real-time feedback-based local pressure loading on tumors on the body surface, effectively solving the problems of uncontrollable pressure application, poor conformity, and lack of quantitative feedback in existing technologies. Attached Figure Description

[0017] The present invention will now be described in detail with reference to specific embodiments and accompanying drawings, wherein: Figure 1 A three-dimensional structural schematic diagram of a local pressure loading control device for tumors on the body surface provided in an embodiment of the present invention.

[0018] Figure 2 This is an exploded structural diagram of a local pressure loading control device for tumors on the body surface, provided in an embodiment of the present invention.

[0019] Figure 3 This is a schematic diagram illustrating the application of the local pressure loading control device for surface tumors provided in this embodiment of the invention on mouse tumors.

[0020] Figure 4 This is a comparative diagram of experimental results showing the effect of flexible adaptor layers with different hardness on the enrichment efficiency of nanomedicines, as provided in the embodiments of the present invention.

[0021] Figure 5 This is a comparative graph showing the experimental results of the effect of different pressure levels on the enrichment efficiency of nanomedicines, provided in an embodiment of the present invention.

[0022] Figure 6 This is a comparative graph showing the experimental results of the effect of different pressure durations on the enrichment efficiency of nanomedicines, provided in an embodiment of the present invention.

[0023] Figure 7 These are in vivo fluorescence microscopy confocal images of changes in tumor vascular permeability before and after pressure treatment, provided in an embodiment of the present invention.

[0024] Figure 8 This is a comparison of experimental results regarding the intravascular enrichment efficiency of different types of nanoparticles before and after pressure treatment, as provided in an embodiment of the present invention.

[0025] Figure 9Transmission electron microscopy images showing changes in the intercellular spaces of tumor vascular endothelial cells after pressure treatment, provided in an embodiment of the present invention.

[0026] Figure 10 A statistical chart showing the changes in tumor volume and mass after mechanical pressure combined with nanomedicine treatment, provided in an embodiment of the present invention. Detailed Implementation

[0027] 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 specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without inventive effort are within the scope of protection of this invention.

[0028] Example 1: like Figures 1 to 3 As shown, this embodiment provides a local pressure loading control device suitable for tumors on the body surface, aiming to regulate the tumor microenvironment through physical and mechanical means. The device mainly comprises three core modules: a shell fixation module 1, a pressure transmission module 2, and a tumor contact module 3. This modular design not only ensures the compactness of the device structure but also facilitates assembly and component replacement for tumors of different sizes.

[0029] The outer casing fixing module 1 serves as the support and positioning foundation for the entire device. It includes a fixed outer casing 11 and a rotating outer casing 12 that cooperate with each other, as well as a tumor contact plate 13 located at the bottom. The fixed outer casing 11 mainly supports the overall structure of the device, and its bottom is designed with a fixing part for conforming to the skin surface around the tumor. In actual use, the tumor contact plate 13 serves as an auxiliary positioning or connecting structure, and is fixed to the skin surface around the tumor with biocompatible adhesive in conjunction with the bottom of the fixed outer casing 11. This fixing method can effectively prevent the device from shifting due to movement during free movement or feeding of mice or experimental animals, ensuring the continuity and accuracy of mechanical stimulation. The rotating outer casing 12 is mounted on the fixed outer casing 11 and connected to the pressure transmission module 2. The rotating outer casing 12 is configured as a power input component, and the operator can drive the internal components to move by rotating the outer casing.

[0030] The pressure transmission module 2 is connected to the outer shell fixing module 1 and is mainly responsible for converting rotational motion into linear pressure. This module includes an elastic pressure-applying component and an adjustment assembly. In this embodiment, the adjustment assembly uses a threaded structure or a rotating screw 22 and a matching screw 23 disposed inside the rotating outer shell 12. When the rotating outer shell 12 rotates, the internal threaded structure, in conjunction with the rotating screw 22, converts this rotational motion into linear compression motion in the direction pointing towards the tumor. The elastic pressure-applying component is selected as a helical spring 21, one end of which receives the driving force from the adjustment assembly, i.e., the displacement caused by the downward pressure of the rotating outer shell 12, and the other end converts the elastic force into a downward compressive force and transmits it to the tumor contact module 3. Using the helical spring 21 as an intermediary, Hooke's law can be used to achieve linear adjustment of pressure, buffering rigid impacts and protecting fragile tumor tissue.

[0031] The tumor contact module 3, connected to the pressure output end of the helical spring 21, is the component that directly acts on the tumor surface. This module includes a support chassis 31, a pressure sensor, and a flexible adapter layer. The support chassis 31 acts as a rigid support, receiving pressure from the spring. The pressure sensor, integrated into the module, is configured to detect the magnitude of the pressure load currently applied to the tumor in real time. This design overcomes the limitation of existing technologies in quantifying local stress distribution, allowing operators to precisely adjust the pressure based on readings.

[0032] A flexible adaptor layer is disposed on the side of the support chassis 31 facing the tumor. In this embodiment, the flexible adaptor layer is made of flexible biomimetic PDMS gel. Flexible biomimetic PDMS gel has excellent biocompatibility and flexibility, and can deform under external force, thus perfectly conforming to the irregularly shaped tumor surface. This conformal design is crucial, ensuring that pressure is not concentrated on a single protruding point of the tumor, which could easily lead to local ischemia and necrosis, but is uniformly distributed across the entire tumor surface, achieving all-around mechanical pressure loading. For tumors located deeper, this uniform surface pressure also enables effective deep transmission.

[0033] Example 2: Based on Example 1, this embodiment further optimizes and limits the key parameters of the device to achieve the best nanomedicine delivery effect.

[0034] In pressure transmission module 2, the parameters of the helical spring 21 were precisely selected. The selected helical spring 21 has an elastic constant k of 40.78 g / mm, a wire diameter of 0.4 mm, a pitch of 6.5 mm, a total of 4 turns, and a length of approximately 5 mm. The adjustment component is configured to adjust the deformation of the helical spring 21, expressed as the compression distance, with an adjustment range of 0 mm to 7 mm. According to the formula... in For pressure, The elastic coefficient, The compression distance is used to calculate the pressure load applied to the tumor. The calculation results need to be converted to Newton units. Operators can precisely control the pressure load applied to the tumor by controlling the compression distance.

[0035] To investigate the optimal treatment parameters, the following experiments were conducted in this embodiment: The effect of PDMS gel hardness on delivery efficiency: Flexible biomimetic PDMS gels with two hardnesses, "soft" and "hard," were prepared by adjusting different component ratios. Figure 4 The small animal imaging results and statistical data shown indicate that applying pressure treatment to the tumor using a flexible biomimetic PDMS gel with higher stiffness significantly improves the accumulation of nanoparticles in the tumor; while treatment with a softer gel showed no significant difference compared to the control group. This suggests that the flexible adapter layer on the surface of the bearing chassis 31 needs to have a certain preset stiffness to effectively conduct pressure, and a stiffer flexible biomimetic PDMS gel has a better permeation-promoting effect.

[0036] The effect of pressure magnitude on delivery efficiency: Adjusting the rotating housing 12 changes the spring compression distance, setting gradient pressure magnitudes of 0.5 N, 1 N, and 1.5 N. For example... Figure 5 As shown, increasing pressure can promote nanoparticle accumulation, but when the pressure increases to 1.5 N, the enrichment degree of nanoparticles within the tumor is actually lower than that of the 1 N pressure group. This is because excessive pressure leads to excessive compression of blood vessels and obstruction of blood perfusion. Therefore, the present invention preferably sets the preset constant pressure value to 1 N, within the range of 0.5 N to 1.5 N. The pressure sensor monitors this value in real time and provides feedback adjustment to avoid excessive damage to the vascular barrier.

[0037] The effect of pressure duration on delivery efficiency: such as Figure 6 As shown, the device was continuously loaded for 1, 3, and 5 days after installation. The results showed that extending the pressure time promoted accumulation, and applying a pressure of 1 N for 5 consecutive days maximized the enrichment efficiency of nanomedicines in tumors.

[0038] By combining the above parameters, this device utilizes a mechanobiological strategy to induce the contraction of actin fibers in tumor vascular endothelial cells through activation of the integrin signaling pathway. This microscopic change leads to a significant increase in the intercellular space of tumor vascular endothelial cells, from approximately 12.6 nm to approximately 350.9 nm, thereby allowing nanomedicines with particle sizes in the range of 90–280 nm to cross the vascular barrier, with an enrichment efficiency 3–5 times higher than the untreated group. The nanomedicines include, but are not limited to, liposomes, polymer nanoparticles, lipid nanoparticles (LNPs), inorganic nanoparticles, or mRNA lipid nanoparticles; the therapeutic agents loaded on the nanomedicines include nucleic acid drugs, chemotherapeutic drugs, such as doxorubicin, and other drugs.

[0039] Example 3: This embodiment verifies the device's enhancement effect on vascular permeability using in vivo imaging. Preparation of nanoparticles (NPs): DiD-labeled polymer nanoparticles were prepared by dialysis using polyethylene glycol block-poly(D,L-lactic acid-glycolic acid copolyester) and the fluorescent dye DiD.

[0040] The specific steps are as follows: DiD (5 µL, 5 mg / mL) and PEG-b-PLGA (1 mL, 10 mg / mL) were dissolved together in dimethylformamide; the mixture was then added dropwise to ultrapure water (5 mL) with stirring, followed by dialyzing using a dialysis membrane with a molecular weight cutoff of 14 kDa for 12 hours. The resulting DiD-labeled nanoparticles were concentrated to 0.75 mL using an ultrafiltration tube and stored at 4 °C for further use. The hydrodynamic dimensions and zeta potential of the nanoparticles were measured using a Malvern Zetasizer Nano ZS90 equipped with a 6 nm helium-neon laser and 90° detection optics via a dynamic light scattering system.

[0041] Fluorescence confocal live imaging: Mice were anesthetized with isoflurane, and the skin at the tumor site was shaved. DiD-labeled nanoparticles were then injected intravenously, and images were taken at 645 nm emission wavelength using a confocal laser scanning microscope system (Nikon, Ti2). The images were analyzed using ImageJ software. Results: As shown... Figure 7 As shown, in the control group, no significant leakage occurred in the tumor vessels within 2 hours after nanoparticle injection. However, in the mechanical stress treatment group (using this device), multiple eruptions occurred in the tumor vessels approximately 30 minutes after nanoparticle injection, demonstrating that the mechanical stress applied by the device can significantly increase the leakage of tumor vessels to nanoparticles. This phenomenon was verified in CT26 colon cancer tumors, Panc02 pancreatic cancer tumors, and 4T1 breast cancer tumor models.

[0042] Example 4: This embodiment verifies the enhancement effect of this device on the enrichment of different types of nanoparticles at tumor sites using in vivo spectral imaging in small animals. Preparation of DiD-labeled liposome particles (DiD@LNPmLuc): Using an LNP formulation and the fluorescent dye DiD, DiD dye was added to a lipid mixture at a mass ratio of 1:200, and DiD-labeled liposome nanoparticles were prepared by microfluidic method.

[0043] Small animal live spectral imaging: Mice were anesthetized with isoflurane, and the skin at the tumor site was shaved. DiD-labeled nanoparticles were injected intravenously 48 hours later, and DiD fluorescence and luciferase-mediated bioluminescence were detected simultaneously. Before bioluminescence imaging, mice were intraperitoneally injected with potassium D-luciferin (75 mg / kg). Bioluminescence images were acquired using the IVIS Spectrum system 10 min after luciferin administration. Regions of interest were defined around the signal areas, and signal intensity was quantitatively analyzed using Living Image software (v4.5.0). Results: As shown. Figure 8 As shown, in the control group of tumor vessels, a small amount of nanoparticles were enriched within the tumor 48 hours after nanoparticle injection; however, in the mechanical stress treatment group (using this device), a large amount of nanoparticles were enriched within the tumor, demonstrating that the mechanical stress applied by the device can significantly increase the enrichment of nanoparticles within the tumor. This phenomenon was observed in LNP, Cy5, and Dextran. 70kDa This was verified in three different types of particles.

[0044] Example 5: This embodiment quantifies the effect of pressure treatment on the endothelial space through microstructural observation. Experimental method: [The following text appears to be a separate, unrelated section:] 4T1 breast cancer tumor cells were seeded subcutaneously into the backs of mice. Two weeks later, the tumors in the experimental group mice were subjected to a 1 N pressure treatment for 5 days using this device. After the pressure treatment was relieved, the mice carrying the 4T1 tumors were sacrificed, and the tumor tissues of the control group and the pressure-treated group were dissected and excised. The tumor samples were fixed with 0.2 M Sorensen buffer containing 2.5% glutaraldehyde at pH 7.2, with a sample volume of approximately 1 mm³. The tumors were dehydrated in a gradient of ethanol concentrations, such as 40%, 70%, 90%, and 100%, for 30 min at each gradient, and then in propylene oxide, and then embedded in epoxy resin. The tumor tissues were cut into ultrathin sections, such as approximately 70 nm thick, using a microtome, stained with uranyl acetate and lead citrate, and imaged using TEM (JEOL, JEM1400). Results: As shown. Figure 9 As shown, statistical results of the endothelial cell gaps captured by the images indicate that the average intercellular gap in the tumor tissue of the control group was about 12.6 nm, while the average intercellular gap in the tumor tissue of the pressure-treated group was 350.9 nm. This demonstrates that pressure treatment can significantly increase the intercellular gap of tumor vascular endothelial cells and open the tumor vascular endothelial cell barrier.

[0045] Example 6: This embodiment verifies the effectiveness of the device in actual treatment. Mechanical pressure combined with nucleic acid nanomedicine therapy: A 4T1-Luc orthotopic breast cancer tumor model was constructed. The experimental group received continuous 1 N pressure treatment for 5 days, after which the device was removed, and the patient received four intravenous injections of mPTEN@LNPs (mRNA dose of 0.75 mg / kg). Results showed (e.g.) Figure 10 As shown), pressure treatment combined with mPTEN@LNPs resulted in a 42.7% reduction in tumor volume (compared to the untreated control group). Mechanical pressure combined with chemotherapy nanomedicine therapy: An ectopic breast cancer tumor model was constructed. Pressure of 0.5 N or 1 N was applied for five consecutive days, followed by intravenous injection of Lipodox (10 mg / kg). Results showed (as shown) Figure 10 As shown), 1 N pressure combined with therapy completely inhibited tumor growth, reducing tumor weight by 85.9%. An orthotopic SCC-7 squamous cell carcinoma tumor model was established. The experimental group received 1 N pressure treatment for 5 consecutive days, after which the device was removed, and the group received three intravenous injections of PTX@NPs (PTX dose 3 mg / kg). Results showed (as shown) Figure 10 As shown in the figure, 1 N of pressure combined with treatment can completely inhibit tumor growth and prolong the survival of mice.

[0046] The above description is merely a preferred embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent structural transformations made using the contents of the present invention's specification and drawings under the inventive concept of the present invention, or direct / indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A local pressure loading and control device suitable for tumors on the body surface, characterized in that, include: The outer casing fixation module has a fixation part for fixing it to the body surface surrounding the tumor; A pressure transmission module is connected to the housing fixing module. The pressure transmission module includes an elastic pressure-applying component and an adjustment component. The adjustment component is configured to adjust the deformation of the elastic pressure-applying component to generate a controllable pressure load. A tumor contact module is connected to the pressure output end of the elastic pressure-applying component. The tumor contact module includes a support chassis, a pressure sensor, and a flexible adapter layer. The pressure sensor is configured to detect the magnitude of the pressure load. The flexible adapter layer is disposed on the side of the support chassis facing the tumor and is used to conform to the tumor surface under the action of the pressure load.

2. The local pressure loading and control device for tumors on the body surface according to claim 1, characterized in that, The outer casing fixing module includes a fixed outer casing and a rotating outer casing that cooperate with each other; the fixed outer casing is used to support the overall structure of the device and form the fixing part; the rotating outer casing is connected to the pressure transmission module and is configured to drive the elastic pressure application member to deform through its own rotational motion.

3. The local pressure loading and control device for tumors on the body surface according to claim 2, characterized in that, The adjustment component includes a threaded structure or a rotating screw disposed inside the rotating housing; the rotating housing cooperates with the elastic pressure member through the threaded structure or rotating screw to convert the rotational motion of the rotating housing into a linear compression motion along the direction pointing towards the tumor.

4. The local pressure loading and control device for tumors on the body surface according to claim 1, characterized in that, The fixation part is configured to be fixedly connected to the skin surface around the tumor by biocompatible adhesive, so that the device remains in a fixed position relative to the tumor.

5. The local pressure loading and control device for tumors on the body surface according to claim 1, characterized in that, The elastic pressure-applying component is a helical spring. One end of the helical spring receives the driving force from the adjustment component, and the other end converts the elastic force into a downward compressive force and transmits it to the tumor contact module.

6. The local pressure loading and control device for tumors on the body surface according to claim 5, characterized in that, The deformation of the elastic pressure-applying component is manifested as a compression distance, which is adjustable from 0 mm to 7 mm to control the pressure load applied to the tumor.

7. The local pressure loading and control device for tumors on the body surface according to claim 5, characterized in that, The spring constant k is 40.78 g / mm, the wire diameter is 0.4 mm, the pitch is 6.5 mm, and the total number of turns is 4.

8. The local pressure loading and control device for tumors on the body surface according to claim 1, characterized in that, The flexible adaptor layer is made of polydimethylsiloxane gel, which is configured to have a flexible shape that can conform to the morphology of the tumor.

9. The local pressure loading and control device for tumors on the body surface according to claim 8, characterized in that, The polydimethylsiloxane gel is a gel with a preset hardness prepared by adjusting the component ratio. The preset hardness is configured to be sufficient to induce an increase in the intercellular space of tumor vascular endothelial cells under the pressure load.

10. The local pressure loading control device for tumors on the body surface according to claim 1, characterized in that, The pressure sensor is configured to monitor the pressure load value in real time and output pressure monitoring data for feedback adjustment of the adjustment component, so that the pressure load is maintained at a preset constant value; wherein the preset constant value is in the range of 0.5 N to 1.5 N.

Images