A system for analyzing tissue samples subjected to mechanical deformation and chemical gradients
Patent Information
- Application Number
- PCT/IN2026/050491
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2025-03-26
- Filing Date
- 2026-03-19
- Publication Date
- 2026-10-01
Smart Images
Figure IN2026050491_01102026_PF_FP_ABST
Abstract
Description
[0001] TECHNICAL FIELD
[0002] The present disclosure generally relates to the field of analysis of tissue samples. Particularly but not exclusively the present disclosure relates to a system for analyzing at least one tissue sample subjected to mechanical deformation i.e., stretching-relaxing and chemical gradient stimulation. The system integrates simultaneous tissue mechanical and chemical gradient stimulation (analyte exposure - for reaction analysis with regulated biochemical gradients).
[0003] BACKGROUND
[0004] Conventional flask and petri plate based tissue culture techniques have been an essential aspect of a biomedical research, yet the techniques often fail to accurately replicate an intricate microenvironment and mechanical forces experienced by human tissues in vivo. The static nature of conventional culture methods limits the ability to model dynamic biological processes of tissues such as fluid flow-induced shear stress and cyclic mechanical stretching-relaxation. This variance in physiological relevance has spurred a development of advanced culture platforms that better mimic in vivo conditions. Typically, organ-on-a-chip technology has emerged as a promising solution, offering microscale platforms capable of replicating key organ-specific microenvironments and physiological functions. These platforms have enabled more accurate disease modelling, drug testing, and tissue response studies, thus enhancing the predictive capabilities of in vitro models.
[0005] A recent breakthrough in this field has been an integration of microfluidic technologies, which have revolutionized biomedical research by enabling precise control over fluid dynamics and mechanical stimuli. The microfluidic platforms are designed to recreate critical tissue behaviours, including fluid flow-imposed stretching-relaxation cycles and pulsatile shear stress. Further, significant contributions have been made towards developing these platforms, with studies demonstrating their utility in replicating the biomechanical forces experienced by tissues. Various designs and applications of microfluidic tissue culture systems have been explored, further advancing the capabilities of organ-on-a-chip models.Among these developments, conventional microfluidic systems have introduced micro platforms featuring parallel channels separated by a porous membrane, with vacuum chambers on either side. This design facilitated the simulation of fluid flow-imposed tissue stretching-relaxation cycles, leading to the development of organ-on-a-chip models for various tissues, including the heart, liver, kidney, gut, and lungs. The success of these systems has underscored a potential of microfluidic technologies in enhancing the physiological relevance of in vitro models. By incorporating controlled mechanical forces, these systems have improved the study of cellular responses under dynamic conditions, thereby advancing our understanding of tissue mechanics and pathology.
[0006] Despite these advances, a critical challenge remains in developing a microfluidic platform that not only emulates conventional microfluidic designs but also integrates essential chemical gradients such as acidosis and hypoxia. The ability to recreate both mechanical deformation and chemical gradinet stimuli is crucial for accurately modelling disease states and tissue responses under pathophysiological conditions. Existing platforms have primarily focused on mechanical cues, without the integration of biochemical gradientsthat play a significant role in cellular behaviour. Additionally, user-friendliness and ease of construction remain key concerns, as complex fabrication processes may hinder widespread adoption in research and clinical applications.
[0007] Addressing these limitations through innovative structural and functional aspects that enable dynamic adjustments in mechanical, chemical, and cellular conditions is essential for developing an advanced testing and analysis system.
[0008] The present disclosure is directed to overcome one or more limitations stated above or any other limitations associated with the prior arts.
[0009] SUMMARY OF THE DISCLOSURE
[0010] One or more shortcomings of existing systems for analysing at least one tissue sample subjected to mechanical deformation and chemical gradient stimulation have been overcome, and additional advantages are provided through the system as claimed in thepresent disclosure. Additional features and advantages are realized through the techniques of the present disclosure. Other embodiments and aspects of the disclosure are described in detail herein and are considered a part of the claimed disclosure.
[0011] In a non-limiting embodiment of the present disclosure a system for analysing at least one tissue sample subjected to mechanical deformation and chemical gradient stimulation is disclosed. The system includes a microfluidic device and a slide. The microfluidic device comprises a platform defined with a hollow chamber adapted to accommodate a balloon of a balloon catheter. The hollow chamber is configured to receive at least one tissue sample. The platform is defined with a source channel and a sink channel fluidly connected to two opposing ends of the hollow chamber. Each of the source channel and the sink channel comprises an inlet channel and an outlet channel to supply and flow of one or more analyte solutions. Further, the platform includes one or more open channels connected with the hollow chamber for arranging the balloon catheter therein. The microfluidic device comprises a top cover removably mounted to the platform and enclosing the hollow chamber. The top cover is defined with inlet passages and outlet passages in fluid a communication with the inlet channel and the outlet channel of each of the source channel and sink channel. Furthermore, at least one pressure-controlled pump is operatively connected to the balloon catheter for selectively supplying fluid to inflate and deflate the balloon for stretching and relaxation dynamics. The at least one tissue sample is subjected to stretching and relaxation dynamics through the controlled inflation and deflation of the balloon of the balloon catheter, while simultaneously supplying two or more analyte solutions towards the hollow chamber and interact with the tissue sample, for analysing the tissue’s sample reaction to the two or more analytes in the microfluidic device. The slide is receivable underside of the platform for visualization of the hollow chamber during analysis of the tissue sample.
[0012] In an embodiment, the platform is defined with protrusions extending at the opposing ends of the hollow chamber. Each protrusion is defined with one or more open channels extending from one end of the protrusion towards the hollow chamber in an angular configuration to securely position the balloon catheter within the hollow chamber.In an embodiment, the slide is a transparent glass slide, for visualization of the hollow chamber during the analysis of the tissue sample.
[0013] In an embodiment, the balloon catheter comprises at least one of the one-way or two-way or three-way balloon catheter.
[0014] In an embodiment, the system comprises a microscope operatively connected to the microfluidic device, wherein the microscope is having an objective lens aligned to the microfluidic device for in situ analysis of the tissue sample within the hollow chamber through the slide.
[0015] In an embodiment, wherein the platform and the top cover are made from a transparent polymer material comprising at least one of polydimethylsiloxane (PDMS) elastomer, Vero ultra-clear material, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyethersulfone (PES), polyimide, or combinations thereof.
[0016] In an embodiment, the platform and the top cover are produced in combination of additive manufacturing and soft lithography process.
[0017] In an embodiment, the tissue sample in hollow chamber is a tissue scaffold injected with cells wrapped around the balloon to undergo cyclic stretching and relaxation dynamics.
[0018] In an embodiment, the system comprises a pressure sensor operatively connected to the at least one pressure-controlled pump to monitor pressure of the fluid supplied to the balloon catheter.
[0019] In an embodiment, at least one syringe pump is fluidly connected to the outlet passages for the draining of the one or more analyte solutions to maintain continuous flow within the source channel and the sink channel.
[0020] In an embodiment, the source channel is configured to supply a first predefined concentration of the analyte, and the sink channel is configured to supply a second predefined concentration of the analyte, respectively towards the hollow chamber fordiffusion of the first predefined concentration of the analyte and the second predefined concentration of the analyte.
[0021] In an embodiment, the diffusion of the first predefined concentration of the analyte and the second predefined concentration of the analyte is configured to subject the tissue sample on the balloon to simultaneous simulation of stretching-relaxation dynamics and an analyte gradient maintenance.
[0022] It is to be understood that the aspects and embodiments of the disclosure described above may be used in any combination with each other. Several of the aspects and embodiments may be combined to form a further embodiment of the disclosure.
[0023] The foregoing summary is illustrative only and is not intended to be in any way limiting. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.
[0024] DEFINITION
[0025] Mechanical deformation: Mechanical deformation refers to the change in shape, size, or structure of a material or object due to an applied force or stress. This can occur through stretching, compressing, bending, twisting, or shearing.
[0026] Chemical Gradient stimulation: Chemical gradient stimulation refers to the process of exposing a system and observing it response to a controlled variation in chemical concentration across space or time. Chemical gradient stimulation method can be applied in areas such as engineering, environmental science, and biomedical research to analyze diffusion, fluid dynamics, and stimulus-response mechanisms.
[0027] Tissue sample: A tissue sample is a small portion of biological tissue collected from a living / dead organism for examination, analysis, or diagnostic purposes. It can be obtained through biopsies, surgical procedures, or minimally invasive techniques.BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0028] The novel features and characteristics of the disclosure are set forth in the appended claims. The disclosure itself, however, as well as a preferred mode of use, further objectives and advantages thereof, will best be understood by reference to the following detailed description of an illustrative embodiment when read in conjunction with the accompanying figures. One or more embodiments are now described, by way of example only, with reference to the accompanying figures wherein like reference numerals represent like elements and in which:
[0029] Figure 1 illustrates a schematic diagram of a system for analysing at least one tissue sample subjected to mechanical deformation and chemical gradient stimulation, in accordance with an embodiment of the present disclosure;
[0030] Figure 2 illustrates a perspective view of a microfluidic device of the system of Figure 1, in accordance with an embodiment of the present disclosure;
[0031] Figure 3 illustrates a top view of a platform of the microfluidic device of Figure 2, in accordance with an embodiment of the present disclosure;
[0032] Figure 4 illustrates a front view of the platform of the microfluidic device of Figure 2, in accordance with an embodiment of the present disclosure;
[0033] Figure 5 illustrates a perspective view of top cover of the platform of the microfluidic device of Figure 2, in accordance with an embodiment of the present disclosure;
[0034] Figure 6 illustrates a block diagram of the system of Figure 1, in accordance with an embodiment of the present disclosure;
[0035] Figure 7 illustrates a plot representing a cyclic stretching-relaxation patterns corresponding to high-frequency tissue dynamics, in accordance with an embodiment of the present disclosure;Figure 8 illustrates a plot of cyclic stretching-relaxation for moderate-frequency conditions, in accordance with an embodiment of the present disclosure;
[0036] Figure 9 illustrates a plot of cyclic movements at lower frequencies, in accordance with an embodiment of the present disclosure;
[0037] Figure 10 illustrates a plot representing stretching-relaxation cycles with significantly longer durations (90-225 seconds per cycle) and very low frequencies, in accordance with an embodiment of the present disclosure;
[0038] Figure 11 illustrates a plot representing different muscle stretching-relaxation profiles, in accordance with an embodiment of the present disclosure.
[0039] The figures depict embodiments of the disclosure for purposes of illustration only. One skilled in the art will readily recognize from the following description that alternative embodiments of the apparatus and methods illustrated herein may be employed without departing from the principles of the disclosure described herein.
[0040] DETAILED DESCRIPTION
[0041] While the embodiments in the disclosure are subject to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the figures and will be described below. It should be understood, however, that it is not intended to limit the disclosure to the particular forms disclosed, but on the contrary, the disclosure is to cover all modifications, equivalents, and alternative falling within the scope of the disclosure.
[0042] It is to be noted that a person skilled in the art would be motivated from the present disclosure and modify construction of a system for analysing at least one tissue sample. However, such modifications should be construed within the scope of the disclosure. Accordingly, the drawings show only those specific details that are pertinent to understand the embodiments of the present disclosure, so as not to obscure the disclosure with detailsthat will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
[0043] The terms “comprises,” “comprising,” or any other variations thereof used in the disclosure, are intended to cover a non-exclusive inclusion, such that an apparatus that comprises a list of components does not include only those components but may include other components not expressly listed or inherent to such apparatus, or device. In other words, one or more elements in apparatus proceeded by “comprises... a” does not, without more constraints, preclude the existence of other elements or additional elements in the system or device.
[0044] The following paragraphs describe the present disclosure with reference to Figures 1 to Figure 11. In the figures, the same element or elements which have similar functions are indicated by the same reference signs.
[0045] Referring to Figure 1 to Figure 6 which are exemplary embodiments of the present disclosure illustrating system for analysing at least one tissue sample subjected to mechanical deformation and chemical gradient stimulation [interchangeably referred as “system (200)”].
[0046] The system (200) comprises a microfluidic device (100) and a slide (60). The microfluidic device (100) comprises a platform (10) is defined with a hollow chamber (12). The hollow chamber (12) may be defined at a central portion of the platform (10). The hollow chamber (12) is adapted to accommodate a balloon (22) of a balloon catheter (20). More particularly, the hollow chamber (12) may be structured as a cavity to securely support the balloon catheter (20) such that the portion of balloon (22) is positioned at a central portion of the hollow chamber (12) as seen in Figure 2 to Figure 3. The balloon catheter (20) may be a flexible tube with an inflatable balloon (22) defined at a portion of the balloon catheter. The balloon (22) can be inflated and deflated as needed to perform specific functions. In an embodiment, the balloon catheter (20) comprises at least one of the one-way or two-way or three-way balloon catheter. In a preferred embodiment, a two-way balloon catheterarranged in the hollow chamber (12). The balloon catheter (20) may be arranged along an axis (A-A’) such that the balloon (22) is positioned within the hollow chamber (12), and a first end and a second end of the catheter (20) extends outwardly away from eithers ends of the balloon (22).
[0047] Further, the hollow chamber (12) is configured to receive at least one tissue sample. In an embodiment, the tissue sample in hollow chamber (12) is a tissue scaffold injected with cells wrapped around the balloon (22) to undergo cyclic stretching and relaxation dynamics. Further, at least one pressure-controlled pump (70) is operatively connected to the balloon catheter (20) for selectively supplying fluid to inflate and deflate the balloon (22) for mechanical deformation to obtain stretching and relaxation dynamics. The pump is configured to selectively supply fluid to the balloon (22), enables controlled inflation and deflation. As the balloon (22) expands, the tissue scaffold experiences mechanical stretching, and when the balloon (22) deflates, the tissue sample undergoes relaxation. This cyclic process replicates in vivo biomechanical forces found in tissues such as heart, blood vessels, lungs, muscles and the like. In an embodiment, the at least one tissue sample is not restricted to be subjected to cyclic stretching and relaxation dynamics but may also be subjected to any non-cyclic stretching and relaxation dynamics as per application requirement.
[0048] In an operative configuration, when the pump (70) supplies fluid, the balloon (22) expands thus, exerting a tensile force on the tissue sample wrapped around the balloon (22). This expansion stretches the tissue sample, mimicking physiological conditions experienced by heart, blood vessels, lungs, muscles, and other dynamic tissues in the body. Further, the cells embedded in the scaffold experience mechanotransduction, a process where mechanical forces influence cellular behaviour, gene expression, and tissue remodelling. Alternatively, when the pump (70) stops the fluid supply, the balloon (22) deflates, allowing the tissue sample to relax. This relaxation phase enables the tissue to return to original state, similar to the natural pulsatile force observed in cardiovascular, pulmonary, and musculoskeletal tissues. Therefore, the tissue sample undergoes cyclic deformation, which can enhance cell proliferation, extracellular matrix (ECM) production, and tissuematuration. In an embodiment, a pressure sensor (72) may be operatively connected to the at least one pressure-controlled pump (70) to monitor pressure of the fluid supplied to the balloon catheter (20). In an embodiment, the pressure sensor is operatively connected to the at least one fluid line that connects the pressure controller pump to balloon catheter (20).
[0049] The platform (10) is further defined with a source channel (30) and a sink channel (40). The source channel (30) and the sink channel (40) are fluidly connected to two opposing ends of the hollow chamber (10). The source channel (30) and the sink channel (40) are configured axially to the hollow chamber (12). More specifically, the source channel (30) and the sink channel (40) are configured along the axis (B-B’) of the microfluidic device (100). In an embodiment, an interconnecting channel (36) connects each of the source channel (30) and the sink channel (40) with the hollow chamber (12). Further, the source channel (30) is configured to supply a first predefined concentration of the analyte towards the hollow chamber (12) and the sink channel (40) is configured to supply a second predefined concentration of the analyte towards the hollow chamber (12). These first and second predefined concentration of analytes are configured to flow towards the hollow chamber (12) for diffusion. As the first predefined concentration analyte and second predefined concentration of the analyte solutions enter the hollow chamber (12) from both ends, a concentration gradient is established and the tissue sample is subjected to chemical gradient stimulation. This causes diffusion of the first and the second predefined concentrations of analytes and diffuse across the hollow chamber (12), exposing the tissue sample to varying analyte concentrations along its length, forming a gradient. This controlled diffusion ensures that cells within the tissue scaffold sample subject to differential biochemical exposure, mimicking physiological environments where tissues are subjected to spatially varying chemical signals. The system (200) of the present disclosure is configured to simulate a dynamic interplay between mechanical deformation / forces and biochemical gradients via chemical stimulation, that regulate cellular behaviour in vivo with the tissue sample. Further, each of the source channel (30) and the sink channel (40) comprises an inlet channel (32,42) and an outlet channel (34,44) to supply and flow of one or more analyte solutions. More particularly at the inlet channel (32) of the sourcechannel (30) is configured to supply the first predefined concentration of the analyte, similarly the inlet channel (42) of the sink channel (40) is configured to supply the second predefined concentration of analyte. Furthermore, the output channel (34) of the source channel (30) is configured to dispense at least one diffused solution or the first predefined concentration of the analyte. Similarly, the output channel (44) of the sink channel (40) is configured to dispense at least one diffused solution or the second predefined concentration of the analyte. In an embodiment, the diffused solution may be generated after the first and the second predefined concentrations of analytes pass thorough the tissue sample. Therefore, the diffusion of the first predefined concentration of the analyte and the second predefined concentration of the analyte is configured to subject the tissue sample on the balloon (22) to simultaneous simulation of stretching-relaxation dynamics and an analyte gradient maintenance.
[0050] The microfluidic device (100) further includes one or more open channels (24) connected with the hollow chamber (12) for arranging the balloon catheter (20) therein. The platform (10) is defined with protrusions (26) extending at the opposing ends of the hollow chamber (12). The protrusions (26) are configured to extend upwardly from a top surface of the platform (10) at each opposing end of the hollow chamber (12). The protrusion (26) is arranged in spaced apart configuration to the source channel (30) and the sink channel (40). The protrusions (26) are configured as structural extensions that facilitate the integration of the balloon catheter (20), ensuring precise alignment of the balloon catheter (20) within the microfluidic device (100). Further, each protrusion (26) is defined with one or more open channels (24) extending from one end of the protrusion (26) towards the hollow chamber (12) in an angular configuration to securely position the balloon catheter (20) within the hollow chamber (12). More specifically, one or more channels (24) extends from one end of the protrusion (26) and extend along a length of the protrusion (26), for other end of the one or more channels (24) to be in fluid communication with the hollow chamber (12), thus one or more channels (24) are formed at a predetermined angle with respect to the axis (B-B’). Therefore, the open channels (24) extending from one end of each protrusion (26) towards the hollow chamber (12) at the angular configuration, optimizes the balloon catheter’s (20) insertion path and secures in a fixed position. The angularconfiguration of these open channels (24) enables an effective distribution of mechanical forces during balloon (22) inflation and deflation, minimizing misalignment and ensuring repeatable cyclic stretching dynamics. In an embodiment, the integration of protrusions (26) with angularly aligned open channels (24) also facilitates ease of assembly and repeatability in performing the analysis and testing. The predefined orientation of these open channels allows to insert and remove the balloon catheter (20) without compromising a structural integrity of the platform (10). In an embodiment, this configuration of the protrusion (26) and the open channels (24) for a two-way balloon catheter (20) is illustrated in Figure3, however, the this configuration of the protrusion (26) and the open channels (24) may cannot be construed as a limitation only to the two-way balloon catheter (20) but the configuration of the same can be modified to accommodate other one-way, three way balloon catheter as well.
[0051] The microfluidic device (100) further includes a top cover (50), removably mounted to the platform (10) enclosing the hollow chamber (12). The top cover (50) is defined with an inlet passages (52a, 54a) and outlet passages (52b, 54b) is in fluid communication with the inlet channel (32,42) and the outlet channel (34,44) of each of the source channel (30) and sink channel (40). The inlet passages (52a, 54a) and outlet passages (52b, 54b). The top cover (50) aids in enclosing and sealing the hollow chamber (12) within the microfluidic device (100), ensuring a controlled microenvironment for tissue sample analysis. Further, the top cover (50) is provided to maintain a sterile and enclosed environment, preventing contamination and ensuring consistent analyte interactions within the hollow chamber. Additionally, the inlet passages (52a, 54a) of top cover align with the inlet channel (32, 42) of the source channel (30) and the sink channel (40) to supply the first and second predefined concentration of analyte. Further, the outlet passages (52b, 54b) of top cover align with the outlet channel (34, 44) of the source channel (30) and the sink channel (40) to receive the diffused analyte or the first and second predefined concentration of analyte.
[0052] The top cover (50) with the inlet passages (52a, 54a) and the outlet passages (52b, 54b), which establish a fluidic communication network with the inlet channels (32, 42) and outlet channels (34, 44) of the source channel (30) and sink channel (40). These inlet and outletpassages (52a, 54a), (52b, 54b), facilitate a precise delivery and removal of analyte solutions within the hollow chamber (12), allowing continuous perfusion of biochemical agents, nutrients, or drugs for tissue sample analysis. The fluidic interconnectivity between the top cover (50) and the platform (10) ensures a controlled exchange of fluids, maintaining a stable chemical and biochemical gradient microenvironment necessary for cellular interactions. In an embodiment, the system (200) comprises at least one syringe pump (74) fluidly connected to the outlet passages (52b, 54b) for the draining of the one or more analyte solutions to maintain continuous flow within the source channel (30) and the sink channel (40). In an embodiment, the platform (10) and the top cover (50) are made from a transparent polymer material comprising at least one of polydimethylsiloxane (PDMS) elastomer, Vero ultra-clear material, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyethersulfone (PES), polyimide, or combinations thereof. Further, the platform (10) and the top cover (50) are produced in combination of additive manufacturing and soft lithography process.
[0053] The system (200) further discloses a slide (60) receivable underside of the platform (10) for visualization of the hollow chamber (12) during analysis of the tissue sample. The slide (60) positioned underside of the platform (10) is a transparent glass slide structured to facilitate real-time visualization of the hollow chamber (12) during the analysis of the tissue sample. Its transparency ensures that light transmission is optimal for microscopy-based observations, allowing researchers to monitor cellular performance, tissue deformation, and analyte interactions in real-time. The slide (60) provides a stable optical interface, ensuring clear and unobstructed imaging of the tissue sample as it undergoes stretching and relaxation dynamics and biochemical interactions due to the analytes gradients within the hollow chamber (12). The system (200) may further comprise a microscope, operatively connected to the microfluidic device (100). The microscope may be integrated with the system (200) for high-resolution, in situ analysis. The objective lens (62) of the microscope is precisely aligned with the hollow chamber (12) through the transparent slide (60), allowing direct visualization of the tissue sample's structural and cellular changes. This configuration enables imaging in real-time and quantitative assessments, such as cell morphology analysis, migration tracking, extracellular matrix remodelling, fluorescence-based biochemical assays and the like. This configuration of the slide (60) below the hollow chamber (12) enhances the microscopy capabilities, making it possible to capture dynamic cellular responses under controlled mechanical and biochemical conditions. This enables analysing the tissue sample for tissue engineering studies, drug testing, and mechanotransduction research, where real-time monitoring of cellular behaviour under physiologically relevant conditions is crucial. The combination of the slide (60) and the objective lens (62) of the microscope allows to perform non-invasive, continuous observation of the tissue sample, thereby improving experimental accuracy and reproducibility.
[0054] The platform (10) comprises a hollow chamber (12), which is structured as the primary containment unit for the balloon (22) of the balloon catheter (20) and the tissue sample. The balloon catheter (20) is secured within the hollow chamber (12) via protrusions (26), each containing angularly configured open channels (24) that guide and hold the balloon catheter (20) in place, ensuring axial alignment within the hollow chamber (12). In an operative configuration, the hollow chamber (12) is fluidly interfaced with a source channel (30) and a sink channel (40), positioned at opposing ends along the chamber’s longitudinal axis. The source and the sink channels (30, 40) enable a controlled introduction and removal of analyte solutions of first and second predefined concentration, facilitating the establishment of a chemical gradient for diffusion-based interactions with the tissue sample. Each of the source and sink channels (30, 40) comprising an inlet channel (32, 42) and an outlet channel (34, 44), regulate the directed flow of analytes and prevent unwanted recirculation or stagnation within the hollow chamber (12). Further, a removably mounted top cover (50) encloses the hollow chamber (12), thereby preventing external contamination and minimizing evaporative losses. The top cover is integrated with inlet passages (52a, 54a) and outlet passages (52b, 54b), maintaining a fluidic continuum between the source and sink channels (30,40) and their respective inlet and outlet ports. A pressure-controlled pump (70) is operatively connected to the balloon catheter (20), enabling the selective inflation and deflation of the balloon (22) within the hollow chamber (12). This controlled actuation induces cyclic stretching and relaxation of the tissue scaffold wrapped around the balloon (22), thereby simulating the biomechanical forcescharacteristic of native tissues such as cardiac tissue, vascular walls, pulmonary structures, and musculoskeletal tissues. The pressure sensor (72), integrated within the system, continuously monitors the applied pressure, ensuring precision in mechanical loading conditions. Simultaneously, the source channel (30) and sink channel (40) deliver first and second predefined concentrations of analytes into the hollow chamber (12), subjecting the tissue sample to a controlled biochemical environment while undergoing mechanical deformation. This configuration replicates in vivo conditions, where cells in the tissue sample are subject to both dynamic mechanical forces and diffusive biochemical gradients. The slide (60), positioned on the underside of the platform (10), is a transparent glass slide that facilitates high-resolution imaging of the tissue sample during testing and analysis of the tissue sample. The microscope, operatively connected to the microfluidic device (100), enables in situ, real-time visualization of cellular responses. The optical system allows for high-magnification imaging, which is critical for analyzing cellular morphology, mechanotransduction, and biochemical interactions under controlled experimental conditions. Additionally, a syringe pump (74) is fluidly connected to the outlet passages (52b, 54b) to regulate the drainage of analyte solutions, ensuring the maintenance of continuous laminar flow conditions within the system. This prevents fluid stagnation, enhances diffusive transport, and enables the precise control of chemical gradient microenvironments surrounding the tissue sample.
[0055] In an embodiment, the system (200) of the present disclosure operates as a controlled biomechanical and biochemical gradient simulation platform, enabling the concurrent analysis of mechanically induced cellular adaptations and biochemical gradient mediated signalling pathways. The integration of microfluidic flow control, pressure-regulated mechanical actuation, and real-time imaging ensures that cellular responses can be studied under physiologically relevant conditions. This system is particularly suited for applications in tissue engineering, regenerative medicine, drug screening, and mechanobiology research, providing a highly reproducible and modular experimental setup for studying tissue mechanics and biofluid interactions at the microscale.Further, the system (200) may comprise a controller connected to and selectively operate the pressure sensor, at least one syringe pump and the at least one pressure control pump. It is to be understood that a person of ordinary skill in the art may develop an apparatus of similar configuration without deviating from the scope of the present disclosure. Such modifications and variations may be made without departing from the scope of the present invention. Therefore, it is intended that the present disclosure covers such modifications and variations provided they come within the ambit of the appended claims and their equivalents.
[0056] A system (200) in accordance with the present disclosure that is simple and easy to operate. The system with the source channel (30) and sink channel (40) enable continuous flow of different concentration of analytes, ensuring a stable chemical gradient within the hollow chamber (12). This facilitates accurate diffusion-based studies while minimizing fluid stagnation and unwanted turbulence.
[0057] A system (200) in accordance with the present disclosure integrates cyclic mechanical loading via a pressure-controlled balloon catheter (20) with precisely regulated mechanical deformations and biochemical gradients, allowing for realistic in vitro modelling of in vivo conditions found in tissues such as heart, blood vessels, lungs, and muscles.
[0058] A system (200) in accordance with the present disclosure includes the pressure-controlled pump (70) with an integrated pressure sensor (72) providing controlled inflation and deflation dynamics of the balloon (22), while the syringe pump (74) connected to outlet passages (52b, 54b) maintains continuous fluid drainage, ensuring precise regulation of mechanical forces and fluid exchange.
[0059] The system (200) of the present disclosure can simulate in vivo conditions within a controlled microenvironment minimizes a need for costly models and large-scale experimental setups as used conventionally, thus making the system of the present disclosure an economical solution for biomedical research and drug testing applications.Experimental data:
[0060] Referring Figure 7, the plot represents cyclic stretching-relaxation patterns corresponding to high-frequency tissue dynamics, such as cardiac muscle contractions. The inflationdeflation cycles occur at frequencies ranging from 40-150 BPM (beats per minute), generating sinusoidal pressure waves that closely mimic pulsatile cardiac tissue stretchingrelaxation. The smooth, periodic waveforms validate the platform’s (10) capability to simulate dynamic cardiac conditions suitable for cardiomyocyte culture and cardiovascular research.
[0061] Figure 8 illustrates a cyclic stretching-relaxation for moderate-frequency conditions (lung alveoli and respiratory muscles). This plot depicts medium-frequency cyclic expansion and contraction, characteristic of alveolar dynamics and respiratory mechanics. The pressure curves correspond to frequencies of 12-60 BPM, generating smooth inflation-deflation waves. These patterns are critical for replicating lung expansion and contraction, enabling studies on alveolar biomechanics, pulmonary disease models, and ventilatory support mechanisms.
[0062] Figure 9 describes cyclic stretching-relaxation for slow, rhythmic tissue motions (gastrointestinal peristalsis). This plot illustrates cyclic movements at lower frequencies, specifically designed to replicate intestinal peristalsis. With frequencies of 2.5-8 cycles per minute, the waveform mimics the slow, rhythmic stretching and relaxation of digestive tract tissues. This simulation is valuable for investigating intestinal motility disorders, drug absorption kinetics, and gut-on-a-chip models.
[0063] Figure 10 illustrates extremely slow stretching-relaxation cycles for gradual tissue deformation. This plot represents stretching-relaxation cycles with significantly longer durations (90-225seconds per cycle) and very low frequencies (0.27-0.67 cycles per minute), simulating slow tissue deformations such as menstrual cycle’s uterus contractionrelaxation, bladder filling-emptying cycles or vascular remodelling processes. The waveform demonstrates controlled, gradual stretching, making it useful for studying chronic mechanical loading effects on soft tissues.Figure 11 illustrates a plot representing different skeletal and smooth muscle stretchingrelaxation profiles. The diversity in waveforms reflects the adaptability of the platform, allowing fine-tuned frequency and amplitude adjustments for tissue-specific experiments. These representations emphasizes the system’s versatility for dynamic tissue analysis, making it an ideal tool for multi-organ simulation, tissue engineering, and drug screening applications. These plots collectively validate the microfluidic platform’s ability to replicate physiologically relevant cyclic stretching-relaxation dynamics, providing precise mechanical loading environments for tissue studies in organ-on-a-chip systems, regenerative medicine, and biomechanics research.
[0064] In another experimental embodiment, to demonstrate the capability of the developed platform to simulate fluid flow imposed cyclic stretching-relaxation dynamics, a 2% agarose hydrogel was used to mimic tissue. The hydrogel solution was heated until fully dissolved and then poured into the central chamber containing the balloon catheter. After polymerization, the microfluidic device (100) was sealed with a transparent cap (fabricated from Vero or PDMS) to ensure a closed system for consistent mechanical stimulation. Table 1: The following parameters were used to simulate the respective cyclic behaviors:
[0065]
[0066]
[0067] Equivalents:
[0068] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity.
[0069] It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to inventions containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should typically be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations.
[0070] In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted tomean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”
[0071] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.
[0072] List of Reference Numerals:
[0073]
[0074]
Claims
We Claim:
1. A system (200) for analyzing tissue samples subjected to mechanical deformation and chemical gradient stimulation, comprising:a microfluidic device (100), comprising:a platform (10), defined with:a hollow chamber (12) adapted to accommodate a balloon (22) of a balloon catheter (20), wherein the hollow chamber (12) is configured to receive at least one tissue sample to be subjected to mechanical deformation;a source channel (30) and a sink channel (40) fluidly connected to two opposing ends of the hollow chamber (10), wherein each of the source channel (30) and the sink channel (40) comprises an inlet channel (32,42) and an outlet channel (34,44) to supply and flow of one or more analyte solutions; andone or more open channels (24) connected with the hollow chamber (12) for arranging the balloon catheter (20) therein; anda top cover (50), removably mounted to the platform (10) enclosing the hollow chamber (12), wherein the top cover (50) is defined with inlet passages (52a, 54a) and outlet passages (52b, 54b) in fluid communication with the inlet channel (32,42) and the outlet channel (34,44) of each of the source channel (30) and sink channel (40), at least one pressure-controlled pump (70) operatively connected to the balloon catheter (20) for selectively supplying fluid to inflate and deflate the balloon (22) for mechanical deformation of the tissue sample to obtain stretching and relaxation dynamicswherein at least one tissue sample is subjected to stretching and relaxation dynamics through the controlled inflation and deflation of the balloon (22) of the balloon catheter (20), while simultaneously supplying two or more analyte solutions through the source (30) and sink channels (40) towards the hollow chamber (12) and interact with the tissue sample, for analysing the tissue’s sample reaction to the two or more analytes in the microfluidic device (100); anda slide (60), receivable underside of the platform (10) for visualization of the hollow chamber (12) during analysis of the tissue sample.
2. The system (200) as claimed in claim 1, wherein the platform (10) is defined with protrusions (26) extending at the opposing ends of the hollow chamber (12), wherein each protrusion (26) is defined with one or more open channels (24) extending from one end of the protrusion (26) towards the hollow chamber (12) in an angular configuration to securely position the balloon catheter (20) within the hollow chamber (12).
3. The system (200) as claimed in claim 1, wherein the slide (60) is a transparent glass slide, for visualization of the hollow chamber (12) during the analysis of the tissue sample.
4. The system (200), as claimed in claim 1, wherein the balloon catheter (20) comprises at least one of a one-way, a two-way or a three-way balloon catheter.
5. The system (200) as claimed in claim 1, comprises a microscope having an objective lens (62) aligned to the microfluidic device (100) for in situ analysis of the tissue sample within the hollow chamber (12) via the slide (60).
6. The system (200) as claimed in claim 1, wherein the platform (10) and the top cover (50) are made from a transparent polymer material comprising at least one of poly dimethylsiloxane (PDMS) elastomer, Vero ultra-clear material, polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyethersulfone (PES), polyimide, or combinations thereof.
7. The system (200) as claimed in claim 1, wherein the platform (10) and the top cover (50) are produced in combination of additive manufacturing and soft lithography process.
8. The system (200) as claimed in claim 1, wherein the tissue sample in hollow chamber (12) is a tissue scaffold injected with cells wrapped around the balloon (22) to undergo cyclic stretching and relaxation dynamics.
9. The system (200) as claimed in claim 1, comprises a pressure sensor (72) operatively connected to the at least one pressure-controlled pump (70) to monitor pressure of the fluid supplied to the balloon catheter (20).
10. The system (200) as claimed in claim 1, comprises at least one syringe pump (74) fluidly connected to the outlet passages (52b, 54b) for the draining of the one or more analyte solutions to maintain continuous flow within the source channel (30) and the sink channel (40).
11. The system (200) as claimed in claim 1, wherein the source channel (30) is configured to supply a first predefined concentration of the analyte and the sink channel (40) is configured to supply a second predefined concentration of the analyte, respectively towards the hollow chamber (12) for diffusion of the first predefined concentration of the analyte and the second predefined concentration of the analyte.
12. The system (200) as claimed in claim 11, wherein the diffusion of the first predefined concentration of the analyte and the second predefined concentration of the analyte is configured to subject the tissue sample on the balloon (22) to simultaneous stimulation of stretching-relaxation dynamics and an analyte gradient maintenance.