Lab-on-a-chip platform and method for thrombolysis

Abstract

The present disclosure proposes a micro-fluidic system (100) comprising an inlet (1), an outlet (2) and one or more channels (3) arranged to provide fluid flow communication between the inlet (1) and outlet (2) and extending along a length (L) in a flow direction (FD) from the inlet (1) towards the outlet (2) The one or more channel(s) (3) comprise a first portion (31) and a second portion (32) wherein the first portion (31) is disposed in-between the inlet (1) and the second portion (32) with respect to the flow direction (FD). The first portion (35) has an Ra:Dh ratio between a surface roughness (Ra) and a hydraulic diameter (Dh) of 1:200 or higher. At the one or more channels (3), a Dh:L ratio between the hydraulic diameter (Dh) and the length (L) is within the range between 1:2 and 2:1. The present disclosure further proposes a method for in vitro thrombolysis using the system (100).

Description

[0001] LAB-ON-A-CHIP PLATFORM AND METHOD FOR THROMBOLYSIS

[0002] Technical Field

[0003] The present application relates to a system for clot removal. The present application particularly relates to a microfluidic lab-on-a-chip platform as a system for in vivo or in vitro clot removal and a corresponding method for in vitro investigation of clot removal.

[0004] Background

[0005] Hydrodynamic cavitation (abbreviated as HC) can be defined as formation of vapor cavities which can also be referred to as HC bubbles, when a liquid undergoes a sudden pressure drop. The pressure drop arises from an increase in an extent of fluid flow through flow restrictive elements which decrease the pressure and trigger an inception of the HC. Formation of the HC bubbles occurs when the pressure is below the saturation pressure of the liquid at a constant temperature. Consequently, HC bubbles grow and suddenly collapse (that is, implode) at relatively high-pressure regions.

[0006] When HC bubbles implode, local microjets and shock waves occur, which generate noise and vibrations that distort the shape close to the exposed surfaces. Moreover, implosion of HC bubbles leads to the formation of hot spots, pressure fluctuations, and highly reactive free radicals. Concerning these destructive consequences of HC, this phenomenon should be controlled in hydraulic machinery such as propellers, pipes, and pumps, owing to erosion and malfunction concerns.

[0007] On the other hand, the phenomenon of HC could be utilized in a variety of applications if a better understanding of its physics and control can be achieved. Moreover, the advances in microfabrication and microfluidic technologies during the last decades have paved the way for HC studies in microdomains. WO 2021 / 141547 Al and WO 2022 / 025836 Al disclose microfluidic systems in which HC is desired. The advantages of micro-scale cavitating flows include a high surface-to-volume ratio, reduced fluid consumption, and improved control over cavitation parameters.

[0008] Biological uses of HC include cell lysis, deformation, DNA extraction, cell membrane permeabilization, drug administration and cell sorting / focusing. Furthermore, studies on the biomedical applications of HC in micro-scale revealed that cavitation could ablate diseased tissues. As an example, it is reported that microscale HC (abbreviated as MHC) could be used to destroy kidney stones. In another study, it is reported that HC treatment resulted in significant tissue ablation, reduced prostate size and improved urine flow on BPH tissue in rats. GB2553898A and EP3298161B1 relate to clot on a chip, whereas WO2019178073A1 and EP3298161B1 relate to thrombosis on a chip. To the best of our knowledge, no public disclosure relevant to hydrodynamic cavitation clot on chip, hydrodynamic cavitation thrombosis on chip or hydrodynamic cavitation thrombolysis on chip within the context of the present disclosure is available to date.

[0009] Summary

[0010] Mammal blood includes erythrocytes, leukocytes, platelets and fibrin elements. Thrombosis, characterised by the formation of clots in venous or arterial vessels, leads to obstruction of the blood flow. There are cases where this phenomenon is both beneficial and harmful to an individual. Endothelial damage in blood vessels increases prothrombotic factors and enables the activation of platelets. Through the interaction of leukocytes and endothelial cells, adhesion molecules reproduce and clot formation initiates, which is also known as hemostasis. Thus, platelets gather in a wound area, form a first plug, and then fibrin fibres ensure the strength of the plug. Normally, anticoagulants such as protein C, S and Antithrombin-Ill prevent thrombosis and ensure body homeostasis. However, thrombosis also emerges when an imbalance in body homeostasis develops, which is known as Virchow's triad and involves venous stasis, vascular damage and hypercoagulability. If a piece of the clot that breaks off from thrombosis for any reason, the piece of clot circulates freely and blocks an artery, vein or organ, causing emboli; resulting in various health disorders. Arterial thrombosis can cause myocardial infarction (abbreviated as Ml) and stroke, while venous thrombosis can lead to deep vein thrombosis (abbreviated as DVT) and pulmonary embolism (abbreviated as PE). DVT is the formation of thrombi inside the veins of the legs. PE which is considered as the most serious complication of DVT, and occurs when a detached deep vein thrombus travels through the blood flow and occludes pulmonary arteries. For high-risk PE patients, systemic thrombolysis using tissue-type plasminogen activator (abbreviated as t-PA) pharmacological dissolution, catheter-directed thrombolysis, or surgical removal can be necessary. Current treatment modalities have limitations such as low thrombolytic efficiency, frequent bleeding complications, high failure rate, vein injury-associated severe regional dysfunction, high recurrence rates, and the risk of distal embolism due to the relatively large size of clot debris. For these reasons, the medical community has long grappled with the challenge of efficiently and safely removing pathological clots, thrombi, and emboli from biological systems. Traditional methods such as surgical intervention and thermal therapies have often yielded suboptimal results. These approaches tend to lack the extent of precision that is suitable for selectively targeting and disintegration of clots while preserving adjacent healthy tissues. Additionally, invasive procedures and the use of thermal energy can pose significant risks to patients, making it necessary to explore innovative and minimally invasive alternatives. Ultrasound assisted thrombolysis is introduced as an alternative treatment modality to overcome the limitations of conventional treatment procedures. Cavitation mechanically damages clot during sonothrombolysis. Among ultrasound assisted thrombolysis methods, catheter-delivered transducertipped ultrasound is considered to have several advantages (EkoSonic® intravascular infusion catheter, Boston Scientific). Since this method utilizes low power waves which cannot dissolve the clots, it is also utilized in combination with t-PA and / or microbubbles. Furthermore, commercially available catheters utilizing hydrodynamics for thrombectomy (AngioJet™ Peripheral Thrombectomy System, Boston Scientific) use pressurized saline jet flows and suction as well as pharmacological dissolution for evacuating thrombi. On the other hand, studies on biomedical applications of hydrodynamic cavitation (HC) in micro scale revealed the capability of HC to ablate undesired tissue. In this regard, within the context of the present disclosure, it is expected that micro-scale HC could be a useful for thrombolysis in a much more efficient way compared to acoustic cavitation (AC) considering the low energy consumption and highly efficient functionalization.

[0011] The present disclosure introduces a ground-breaking solution to the technical problem outlined above. By harnessing the power of HC, the present disclosure distinguishes itself by its unique approach to clot removal. The structure of the system proposed herein is leveraged to address the key technical problem, offering a solution that selectively disrupts pathological clots based on their mechanical properties and structural vulnerabilities. The present approach ensures that only clots are disintegrated, leaving healthy tissues untouched due to fine targeting of HC; and the psoposed system is suitable for use as a platform to investigate effects of HC on clot removal. The extent of precision in targeting clots by HC can be considered to represent a revolutionary advancement over existing methods in which the risk of collateral damage remains a significant concern. HC that is achieved in accordance with the present disclosure is a nonthermal phenomenon, which utilizes controlled formation and collapse of vapor-filled cavities within an operating fluid medium, and eliminates the need for invasive surgeries or thermal treatments.

[0012] The non-invasive nature of this method addresses the technical problem by significantly reducing the risks associated with traditional clot-removal procedures, improving patient safety, and enhancing the overall patient experience. One of the unique qualities of the present disclosure is its versatility and adaptability. Its adaptability and potential for wide-ranging medical applications set it apart from traditional approaches.

[0013] In conclusion, the technical problem of efficient and safe clot removal is addressed through the application of HC in the system according to the present disclosure. The present disclosure offers a highly precise, non- invasive, and real-time monitoring approach to selective clot disruption, thereby revolutionizing the field of clot removal and significantly enhancing patient safety and outcomes.

[0014] In various embodiments, the present disclosure relates to a system and method that overcome the shortcomings in the prior art.

[0015] A further object of the present application is to propose a compact system for in vivo or in vitro mechanical destruction of blood clots.

[0016] An even further object of the present application is to propose a simple, robust, low-cost and durable system for mechanical destruction of blood clots, that is benign to venous tissues. An even further object to the present application is to propose a method for mechanical destruction of blood clots, that is performed at conditions that are benign to venous tissues.

[0017] These objects are achieved by the set of features that constitute the appended independent claims.

[0018] The present disclosure proposes a micro-fluidic system comprising an inlet, an outlet and one or more channels arranged to provide fluid flow communication between the inlet and outlet. The one or more channels extend along a length (L) in a flow direction (FD) from the inlet (1) towards the outlet (2).

[0019] The channel(s) comprise a first portion and a second portion, wherein the first portion is disposed between the inlet and the second portion with respect to the flow direction.

[0020] In the first portion, a ratio of a surface roughness to a hydraulic diameter is 1:200 or higher. At the one or more channels, a ratio of the hydraulic diameter to the length is within the range between 1:2 and 2:1;

[0021] In an embodiment, the Ra:Dh ratio can be within the range between 1:75 and 1:125; for instance, within the range between 1:90 and 1:110; e.g., the Ra:Dh ratio can be 1:100.

[0022] In an embodiment, the first portion can extend along a first length in the flow direction; and an L: LI ratio of the length to the first length can be within the range between 2:1 and 5:1, for instance within the range between 2.5:1 and 3.5:1; e.g., the L: LI ratio can be 3:1.

[0023] An embodiment of the system can further comprise an outlet path arranged to provide hydraulic communication between the outlet and the one or more channels.

[0024] An embodiment of the system can further comprise one or more reservoirs for receiving one or more pieces of blood clots. Here, the one or more reservoirs can be in hydraulic communication with the outlet and the one or more reservoirs can be disposed at a downstream side with regard to the one or more channels.

[0025] An embodiment of the system can be attached to an intravenous catheter, thereby being arranged for in vivo thrombolysis.

[0026] The present disclosure further proposes a method for in vitro mechanical erosion of one or more blood clots, comprising the following steps: a) obtaining a micro-fluidic system comprising an inlet, an outlet and one or more channels arranged to provide fluid flow communication between the inlet and outlet and extending along a length in a flow direction from the inlet towards the outlet; arranging that the one or more channel(s) comprise a first portion and a second portion such that the first portion is disposed in-between the inlet and the second portion with respect to the flow direction; arranging the first portion with an Ra:Dh ratio between a surface roughness and a hydraulic diameter of 1:200 or higher; arranging that, at the one or more channels, a Dh:L ratio between the hydraulic diameter and the length is within the range between 1:2 and 2:1; b) introduction of an operating fluid in the form of liquid through the inlet, such that the operating fluid flows along the flow direction; c) provision of the operating fluid with a pressure at the inlet; at an extent that is suitable for inception of hydrodynamic cavitation inside the one or more channel(s), therefore providing a cavitating flow; d) directing the cavitating flow towards one or more blood clots.

[0027] The method ensures that, by means of the measures discussed in step (a), achieving cavitating flow in the operating fluid that can be selected to mimic a mammal blood (e.g., phosphate buffer saline, abbreviated as PBS), with a low extent of fluid pressure at the inlet, and with a small extent of channel length.

[0028] The pressure in step (c) has a value of up to 70 psi. When the above-discussed system is used with an operating fluid such as PBS, 70 psi is already sufficient to achieve an intense extent of shear-induced HC.

[0029] The pressure in step (c) can have a value is within the range between 20 psi and 70 psi. When the abovediscussed system is used with an operating fluid such as PBS, 20 psi is already sufficient to achieve cavitation in the one or more channels.

[0030] Brief Description of the Drawings

[0031] Fig.l schematically depicts an exemplary embodiment of the system according to the present disclosure.

[0032] Fig.2 schematically depicts another exemplary embodiment of the system according to the present disclosure.

[0033] Fig.3 schematically depicts an exemplary further embodiment of the system according to the present disclosure.

[0034] Fig.4 shows preliminary experimental results in in vitro thrombolysis at upstream pressures of 10 and 70 psi, respectively.

[0035] Fig.5 schematically depicts an exemplary further embodiment of the system according to the present disclosure, attached to an intravenous catheter. Reference signs

[0036] 1 inlet

[0037] 11 inlet path

[0038] 2 outlet 21 outlet path

[0039] 3 channel

[0040] 31 first portion

[0041] 32 second portion

[0042] 4 reservoir 5 body

[0043] 6 intravenous catheter

[0044] 100 system

[0045] L length

[0046] LI first length FD flow direction

[0047] Detailed Description

[0048] With reference to the appended drawings, the present disclosure proposes a system (100) comprising an inlet (1), an outlet (2) and one or more channels (3) arranged to provide fluid flow communication between the inlet (1) and outlet(2). The system (100) can further comprise an outlet path (21) arranged for providing hydraulic communication between the outlet (2) and the one or more channels (3).

[0049] The system (100) can be also referred to as a lab-on-a-chip platform. Considering that the inlet (1) and outlet (2) are inherently disposed at upstream and downstream sides relative to the channel (3), respectively; an outlet path (21) that can provide hydraulic communication between the channel(s) (3) and outlet (2) can be also referred to as an extension. Within the context of the present disclosure, the one or more channels (3) can be regarded as flow restrictive element(s) and can be also referred to as orifices.

[0050] The channel (3) comprises a first portion (31) and a second portion (32), wherein the first portion (31) is between the inlet (1) and the second portion (32). In other words, the first portion (31) is more proximal to the inlet (1) than the second portion (32); thus, the first portion (31) is inherently more distal to the outlet (2) than the second portion (32). The first portion (31) and second portion (32) can be considered to have respective surface roughness (Ra) values that can be different from one another.

[0051] Ra:Dh ratio

[0052] The first portion (35) has a ratio between a surface roughness (Ra) and a hydraulic diameter (Dh) of 1:200 or higher. The ratio between the surface roughness (Ra) and the hydraulic diameter (Dh) can be referred to as Ra:Dh ratio.

[0053] Roughness (Ra) values in accordance with the Ra:Dh ratios above provide a high HC intensity even at relatively low upstream pressures.

[0054] Dh:L ratio

[0055] The channel (3) can be considered to extend along a length (L) in a flow direction (FD) from the inlet (1) to the outlet (2) (and / or outlet path (21), if applicable). At the channel (3), a ratio of the hydraulic diameter (Dh) to the length (L) is within the range between 1:2 and 2:1. The ratio between the hydraulic diameter (Dh) to the length (L) can be referred to as Dh:L ratio.

[0056] L:L1 ratio

[0057] The first portion (31) can be considered to extend along a first length (LI) in the flow direction (FD). A ratio of the length (L) of the channel (3) to the first length (LI) can be within the range between 2:1 and 5:1. The ratio between the length (L) of the channel (3) to the first length (LI) can be referred to as L:L1 ratio. First length (LI) values in accordance with the L:L1 ratios above provide an early inception of HC even at relatively low inlet pressures. So, the system (100) according to this measure can have a great extent of compactness in terms of length (L) along the flow direction (FD), and still effectively provides HC for blood clot erosion or thrombolysis.

[0058] Thanks to the Ra:Dh, Dh:L and L:L1 ratios indicated above, shear HC can be achieved with small values of orifice lengths (L) and low upstream pressures (that is, shear HC occurs with a pressure value at the inlet (1) that is even lower than 70 pound-force per square inches (psi), e.g., 50 psi). The low extent of upstream pressure being sufficient for shear HC results in a low extent of downstream pressure that is in accordance with intravenous fluid pressures. That is, the resulting pressure value at the outlet (2) (or outlet path (21), if applicable) can be as low as circa 20 psi, without compromising shear HC. Such low extents of downstream pressure can be considered benign to venous tissues, thereby protecting the venous tissues against mechanical damages when the system (100) is used in in vivo thrombolysis.

[0059] The Ra:Dh ratio can be preferably within the range between 1:75 and 1:125, more preferably between 1:90 and 1:110. For instance, the Ra:Dh ratio can be 1:100 and such value can be considered even more preferable.

[0060] The Dh:L ratio can preferably be within the range between 1:1.5 and 1.5:1, more preferably between 0.8:1 and 1.1:1. For instance, the Dh:L ratio can be 0.92:1, and such value can be considered even more preferable.

[0061] The L: LI ratio can preferably be within the range between 2.5:1 and 3.5:1. For instance, the L: LI ratio can be 3:1, and such value can be considered even more preferable.

[0062] For use in an in vivo cavitation-induced thrombolysis, the present disclosure further proposes an intravascular catheter comprising the system (100).

[0063] The system (100) can be arranged for use in an in vitro clot erosion. To this end, the system (100) can further comprise one or more reservoirs (4) for receiving one or more pieces of blood clots. In such embodiment, the one or more reservoirs (4) are in hydraulic communication with the outlet (2) and disposed at a downstream side with regard to the one or more channels (3). It can be contemplated that cavitating flow streams from the outlet (2) towards the one or more reservoirs (4) when the system (100) is in use. Thus, a blood clot placed into a respective reservoir (4) is subjected to erosion by cavitating flow. In a possible embodiment, the one or more reservoirs (4) can be formed in a housing that can be attached at the downstream side of the outlet (2). The one or more reservoirs (4) can be formed from a flexible polymeric material, e.g., polydimethyl siloxane (abbreviated PDMS). When performing in vitro clot erosion, phosphate buffered saline (abbreviated as PBS) can be used as an operating fluid for hydrodynamically mimicking blood. In any embodiment, the flow direction (FD) can be considered to overlap with a -x / +x orientation which is perpendicular to a -y / +y orientation and to further orientation that is perpendicular to both of -x / +x orientation the -y / +y orientation. Said further orientation can be hereinafter referred to as a -z / +z orientation.

[0064] In an exemplary embodiment of the system (100), the channel (3) can have a rectangular cross-section across the flow direction (FD).

[0065] For such embodiment, Table 1 below shows exemplary dimensions in micrometers, relevant to the channel (3) and a body (5) that includes the inlet (1), channel(s) (3), outlet path (21) and outlet (2). Here; respective width values correspond to a distance between opposing (side-) walls of the channel (3) in the -y / +y orientation; whereas respective depth values correspond to a distance between opposing (bottom and top-) walls of the channel (3) in the -z / +z orientation; and respective length values correspond to a distance to be traversed by an operating fluid along the channel (3) in the -x / +x orientation, that is, in the flow direction (FD).

[0066] In the system (100), one or more of the inlet (1), outlet (2), outlet path (21) and channel (3) can be formed by, e.g., a subtractive manufacturing from a rigid body (5) to create a depth for supporting and guiding an operating fluid when the system (100) is in use, such as (micro-) machining or etching. Such a way of manufacturing results in formation of respective side walls (that oppose one another regarding -y / +y orientation) to have a height which corresponds to the depth in -z / +z orientation. In-between the side walls, a respective bottom wall is inherently formed, which has a respective width that corresponds a distance between respective opposing side walls in the -y / +y orientation. The body (5) can be then provided with a cover with a planar surface that opposes the bottom wall at a distance to the bottom wall in the -z / +z orientation and which corresponds to a respective depth. The planar surface of the cover serves as an upper wall when the system (100) is in use.

[0067] Alternatively, a body (5) that involves geometric features of the system (100) can be formed such that it is open in the -z / +z orientation; and then covered and sealed at both sides in the -z / +z orientation with two respective covers; namely, a bottom and a top cover (in other words, bottom and top walls). As a result, a distance between the bottom and top covers can be considered to correspond to the depth. The bottom and top covers can be made form respective optically transparent materials. For instance, the bottom cover can be made from PDMS and the top cover can be made from a relatively rigid material such as glass.

[0068] Table 1. Exemplary dimensions in micrometres. width _ depth _ length body (5) 900 60 2000 channel (3) 200 60 100 In view of the discussions above, several further considerations related to the present disclosure can be provided as follows without intending undue limitation to the scope of the present application:

[0069] - The present disclosure involves a system (100) which can be considered as a lab-on-a-chip platform. The system (100) can be considered containing a cavitation reactor that can be formed from silicon and glass wafers outfitted with surface roughness components (first portion (31)) and a polydimethylsiloxane (abbreviated as PDMS) reservoir (4) for clot deposition when for use in in vitro clot erosion. This platform can be thus presented as a clot-on-a-chip (COC) model for clot removal investigation and is used to create a cavitation-induced thrombolysis as a substitute to in vivo tests. When the system (100) is in use, HC bubbles can be directed to neighboring clot blocks in the reservoirs (4) to investigate the influence of bubble implosion on thrombus ablation. The clot formation process can be initiated by infusing a combination of blood and calcium chloride solution into the reservoirs (4), and the resulting clots can be stabilized by incubating the COC. The cavitating flow can be visualized using visualization techniques such as shadowgraph technique, in particular when the system (100) includes a cover which is made of a transparent material such as glass. The present disclosure also proposes a method; that is, the use of the system (100). The proposed method can be considered as a drug-free endovascular therapy method. The proposed technology will serve as a foundation for future research on the cavitation-aided clot removal process.

[0070] - Preliminary results related to the present disclosure showed that HC on a chip idea supplemented by surface changes (that is, deliberate use of surface roughness) is successful in the formation of inception of HC at relatively low upstream pressures, paving the way for ablating blood clots in a more energyefficient compared to prior art methods.

[0071] - The proposed technology provides in vitro blood clots erosion (on a microfluidic chip as the system (100)); yet, with the proposed technology it is possible to eliminate clots formed in veins without requiring any medication or invasive surgery.

[0072] - The proposed technology provides precision and selectivity. Traditional approaches often lack the ability to distinguish between clots and healthy tissues, resulting in collateral damage, while the proposed technology allows manipulation and control of the veins as a medium and clots as a target. The proposed technology overcomes this limitation through distinct mechanical properties of clots, ensuring targeted disruption thereof.

[0073] - The proposed technology provides a minimal invasive thrombolysis, unlike many conventional procedures which may require invasive surgeries or treatments. This reduces the risks to patients and enhances overall safety.

[0074] - The proposed technology allows a real-time monitoring of the clot-removal process, by means of the use of transparent microfluidic devices in combination with the system (100) according to the present disclosure. This level of monitoring and control is unparalleled in existing technologies.

[0075] - The proposed technology provides adaptability across medical disciplines. The proposed technology can be considered to extend beyond clot removal only. Its effectiveness and customizable nature make it suitable for diverse medical applications, from cancer therapies to targeted drug delivery. The following section refers to various further considerations regarding one or more exemplary embodiments of the system (100) and method according to the present disclosure, without any intention to limit the envisaged scope of protection:

[0076] The inlet (1), micro orifice(s) as channel(s) (3) and extension (that can involve outlet channel(s) (21) and outlet (2)) can be considered as parts of the proposed system (100). A pressure gradient for HC bubble nucleation, growth, and implosion cycles is provided by managing the properties of these parts. Channel(s) (3) as flow restrictive element(s) where the flow can be considered to reach a largest linear velocity are the loci where bubbles form. As the flow approaches outlet (2) (or outlet channel (21) where applicable) as a pressure recovery zone, static pressure rapidly decreases and then begins again to rise. When designing the geometry of the body (5), considerations were made for possible locations where HC bubbles could emerge, how these bubbles could be preserved and grown stably later on. Microelectromechanical system (MEMS) fabrication method can be used for achieving a pre-determined surface roughness (Ra) at the first portion (31) of the channel(s) (31). For example, a mass flow rate control (MFC) method can be applied in an optimized deep reactive ion etching (DRIE) system to form a smooth extent of surface roughness (Ra). Sulphur hexafluoride (SF6) gas can be for establishing a pre-determined extent of surface roughness (Ra), and MFC can be used at controlling the flow rate of said gas. A width and length of the body (5) (that includes the inlet (1) and channels (3)) could be 900 and 2000 um (micrometers), respectively. The width(s), depth(s) and length(s) of the channel(s) (3) can be e.g. 200, 60 and 100 um, suitable for generating a shear- induced cavitating flow at relatively lower upstream pressures for an operating fluid at entering the channel(s) (3). The system (100) can include one (see Fig.l), two (see Fig.2) or more reservoirs (4) in fluid communication with a downstream side of the channel(s) (3), for receiving clots. In the case where the system (100) includes two reservoirs (4), these can be disposed symmetrically with regard to the channel(s) (3); that is, the reservoirs (4) can be arranged equidistantly, with regard to a gravitational center of the fluid flow exiting the channel(s) (3), as visually exemplified in Fig.2.

[0077] HC bubbles can be thus considered as directed towards the reservoirs (4) benefitting the micro scale nature of the system (100). Surface roughness (Ra) at the first portion (31) of the channel(s) (3) facilitate the implementation and control of the cavitating flow.

[0078] In the case where the system (3) includes a transparent cover, formation of HC bubbles along the channel(s) (3) can be visually monitored in real-time.

[0079] Referring to Fig.l, Fig.2 and Fig.3, the reservoire(s) (4) (as well as the outlet (2) and the outlet channel (21) where applicable) can be formed from PDMS, which also provides optical transparency in addition to mechanical flexibility, biocompatibility and durability. In such case, an integrally formed PDMS structure that includes the reservoire(s) (4) can be referred to as a PDMS chip. Molds for forming the PDMS chip can be produced with microfabrication or 3D molding technologies. Geometric dimensions of said molds can be larger than the those of the resulting PDMS chip, taking into account the shrinkage of PDMS under heat. During the fabrication of the PDMS chip, an elastomer base and curing agent can be mixed and then heated in an oven set to a pre-determined molding temperature. The PDMS chip is then left at room temperature, separated from the mold, and cleaned, e.g., using ethanol and deionized water. When designing the PDMS chip, a series of experimental production tests can be conducted to determine an optimal mixing ratio. UV- Vis, compression test, and production tests after heat exchange can be applied to determine whether the PDMS production process is appropriate. PDMS chips with a 10:1 weight ratio between the elastomer base and curing agent can be considered suitable. When the system (100) is in use, the durability of the PDMS chip decreases by time. Therefore, as visually exemplified in Fig.l, Fig.2 and Fig.3, the reservoir(s) (4) can be arranged to have a radial distance in +y / -y orientation to the channel(s) (3), thereby increasing the service life of the PDMS chip.

[0080] Within the context of the present disclosure, HC offers a transformative solution in the field of clot removal. Clots, thrombi and emboli, often responsible for ischemic events, cover formidable challenges in the medical engineering. Traditional interventions have long grappled with balancing the efficient removal of these obstructions while minimizing damage to surrounding healthy tissues. HC is envisaged to emerge as a pioneering approach, driven by the principles of innovation and precision medicine, to address this critical issue. The effects of HC on the clot-removal process can be multifaceted and hold great promise. HC can substantially or entirely be considered as a non-thermal phenomenon. Collapsing HC bubbles generate intense shockwaves, microjets, and high-velocity fluid flows to disintegrate clots upon fine-targeting. The extent of energy for generating HC bubbles is typically high. Even on micro scale, our previous experimental attempts show that upstream pressures up to 4 MPa are required to generate intense flow patterns induced by turbulence. Hence, the priority to develop the system (100) as a lab-on-a-chip platform is to decrease the pressure drop in channel(s) (3) without compromising the formation of HC. To this end, a low extent of length (L) such as 100 micrometers is employed in channel(s) (3), to generate shear-induced HC rather than sheet cavitation. In this concept, the cavitation inception occurs at a low upstream pressure such as 20 psi regarding the channel(s) (3), thereby creating a localized zone of low pressure and high turbulence. Regarding clot removal, these HC bubbles serve as initiators of the erosion process. Implosion of HC bubbles creates zones of high shear stress, intense microstreaming, and mechanical disruption on clots. These localized efforts are responsible for loosening the clot and initiating the disintegration thereof.

[0081] A further increase in the upstream pressure leads to a fully developed HC. The upstream pressure at which fully developed HC appears on as low as 70 psi which is still to be considered low for such an intense extent of shear-induced HC. As the upstream pressure further increase, microscopic HC bubbles generated during initial cavitation evolve and grow into larger, more stable cavities. These cavities, which can be referred to as cavity clouds, are responsible for exerting significant forces on the liquid medium (that is, operating fluid). In the context of clot removal, fully developed cavitation plays a more aggressive effect. The stresses generated by cavity clouds cause rapid and substantial erosion of the clot. As the clot is exposed to these effects, it experiences severe disruption, fragmentation and erosion. Fig.4 shows preliminary experimental results in decreasing a diameter of clot in 60 seconds under 10 psi (left hand side) and then under 70 psi (right hand side) of upstream pressure with respect to the channel(s) (3), that is, at the inlet (1). A clot with an initial diameter of 3.38 millimetres was placed into the reservoir (4). At an upstream pressure of 10 psi, no erosion is observed on the clot; that is, the diameter of clot is retained at the end of 60 seconds. On the other hand, when the upstream pressure is increased to 70 psi, the diameter of clot decreased from 3.38 millimetres to 1.21 millimetres; that is, effective erosion is achieved on the clot. These results confirm that no HC formation takes place at 10 psi, whereas a fully developed HC is achieved at 70 psi.

[0082] The proposed system (100), the short extent of length (L) of the channel(s) (3) and the structural surface roughness (Ra) at the first portion (31) of the channel(s) (3) enable the inception of HC and full development of HC at low extents of upstream pressures that are 20 and 70 psi, respectively. When the system (100) is in use, cavitating flow of the operating fluid from the channel(s) (3) are directed towards the clot(s), which can be placed in reservoir(s) (4) for in vitro thrombolysis. As the pressure inside the system (100) increases by increasing the upstream pressure (in other words, inlet pressure), the HC develops into fully developed HC which provides a more destructive impact on the clot.

[0083] The body (5) that encompasses all of the essential features (inlet (1), outlet (2), channel(s) (3)) can be formed to have a millimetric size along the flow direction (FD), e.g., below 5000 micrometers, for instance, 2000 micrometers, or even lower.

[0084] Thus, system (100) according to the present disclosure is to be considered as microfluidic, because it can have geometric dimensions even within one or more hundreds of micrometres. For instance, for use in in vivo thrombolysis by the system (100) being attached to an intravenous catheter (6); no extension such as reservoirs (4) is necessary, and the size of the system (100) from the inlet (1) and outlet (2) in the flow direction (FD) can be arranged substantially equal to the length (L) of the one or more channels (3) (see Fig.5).

Claims

Claims1. A micro-fluidic system (100) comprising an inlet (1), an outlet (2) and one or more channels (3) arranged to provide fluid flow communication between the inlet (1) and outlet (2) and extending along a length (L) in a flow direction (FD) from the inlet (1) towards the outlet (2); the one or more channel(s) (3) comprise a first portion (31) and a second portion (32) wherein the first portion (31) is disposed in-between the inlet (1) and the second portion (32) with respect to the flow direction (FD); characterized in that the first portion (35) has an Ra:Dh ratio between a surface roughness (Ra) and a hydraulic diameter (Dh) of 1:200 or higher; at the one or more channels (3), a Dh:L ratio between the hydraulic diameter (Dh) and the length (L) is within the range between 1:2 and 2:1.

2. The system according to claim 1; wherein the Ra:Dh ratio is within the range between 1:75 and 1:125.

3. The system according to claim 2; wherein the Ra:Dh ratio is within the range between 1:90 and 1:110.

4. The system according to claim 3; wherein the Ra:Dh ratio is 1:100.

5. The system according to any of claims 1 to 4; wherein the first portion (31) extends along a first length(LI) in the flow direction (FD); and an L:L1 ratio between the length (L) and the first length (LI) is within the range between 2:1 and 5:1.

6. The system according to claim 5; wherein the L: LI ratio is within the range between 2.5:1 and 3.5:1.

7. The system according to claim 6; wherein the L: LI ratio is 3:1.

8. The system according to any of claims 1 or 2; further comprising an outlet path (21) arranged for providing hydraulic communication between the outlet (2) and the one or more channels (3).

9. The system according to any of claims 1 to 8; further comprising one or more reservoirs (4) for receiving one or more pieces of blood clots, the one or more reservoirs (4) being in hydraulic communication with the outlet (2) and disposed at a downstream side with regard to the one or more channels (3).

10. The system according to any of claims 1 to 8, attached to an intravenous catheter (6).

11. A method for in vitro mechanical erosion of one or more blood clots, comprising the following steps: a) obtaining a micro-fluidic system (100) comprising an inlet (1), an outlet (2) and one or more channels (3) arranged to provide fluid flow communication between the inlet (1) and outlet (2) and extending along a length (L) in a flow direction (FD) from the inlet (1) towards the outlet (2); arranging that the one or more channel(s) (3) comprise a first portion (31) and a second portion (32) such that the first portion (31) is disposed in-between the inlet (1) and the second portion (32) with respect to the flow direction (FD); arranging the first portion (35) with an Ra:Dh ratio between a surface roughness (Ra) and a hydraulic diameter (Dh) of 1:200 or higher; arranging that, at the one or more channels (3), a Dh:L ratio between the hydraulic diameter (Dh) and the length (L) is within the range between 1:2 and 2:1; b) introduction of an operating fluid in the form of liquid through the inlet (1), such that the operating fluid flows along the flow direction (FD); c) provision of the operating fluid with a pressure at the inlet (1); at an extent that is suitable for inception of hydrodynamic cavitation inside the one or more channel(s), therefore providing a cavitating flow; d) directing the cavitating flow towards one or more blood clots.

12. The method according to claim 11; wherein the pressure in step (c) has a value of up to 70 psi.

13. The method according to claim 11, wherein the pressure in step (c) has a value is within the range between 20 psi and 70 psi.

14. The method according to any of claims 11 to 13; wherein the operating fluid is phosphate buffer saline.

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