System and method for closing a path within an organization

Abstract

To provide a medical device, system and method suitable for lung sealing.SOLUTION: A system for performing a minimally invasive percutaneous procedure comprises a medical device comprising a hydrogel delivery needle (4) with a tip and a hydrogel outlet (6), an injectable, shear-thinning, self-healing viscoelastic hydrogel that exhibits a storage modulus (G') of at least 600 Pa, and a tanδ(G'' / G') from 0.1 to 0.6 in dynamic viscoelasticity measured by a rheometer at 1 Hz and 1% strain rate at 25°C. The system may also comprise a coaxial cannula having a lumen configured for receipt of the hydrogel delivery needle (4), wherein the hydrogel delivery needle comprises an adjustable positioning mechanism (8) configured to limit the advancement depth of the hydrogel delivery needle through the coaxial cannula to a predetermined depth distal to a distal-most end of the coaxial cannula.SELECTED DRAWING: Figure 8-1

Description

Technical Field

[0001] The present invention relates to a system and medical device capable of safely performing a low-impact percutaneous procedure. More particularly, it relates to a system and medical device for reaching internal organs, tissues and cavities without the risk of losing liquid and / or gas. In particular, it provides a device or method of using the device for preventing or reducing the risk of pneumothorax and hemothorax when it is necessary to reach a needle trans-thoracically. It also relates to a method of juxtaposing a viscoelastic hydrogel plug at a target depth in an organ, tissue or space within the body.

Background Art

[0002] Numerous surgical procedures require puncturing to reach the target treatment area, for example, to puncture the chest wall to reach the chest cavity. The most common example is trans-thoracic needle lung biopsy, where a sample is obtained from a tissue suspected of cancer using a special needle. This procedure is typically performed by a radiologist under imaging, utilizing CT (Computed Tomography) guidance, as schematically shown in FIGS. 1A-1D (prior art). When the biopsy needle pierces the outer surface of the lung, air may leak into a space called the pleural cavity between the lung and the chest wall. The air gradually pushes the lung away from the chest wall, causing lung collapse and resulting in a complication called pneumothorax. If the pneumothorax is large, it causes severe pain and distress to the patient. If this pneumothorax is not resolved, hospitalization is required for the treatment and observation of the patient, and often requires the surgical insertion of a chest drain to extract air from the pleural cavity. Pneumothorax causes considerable pain and morbidity to the patient, increases the anxiety and stress of the attending physician, and results in unnecessary and significant costs to the hospital. Approximately 33% of patients undergoing trans-thoracic needle lung biopsy develop pneumothorax, and about one in three of them requires a chest drain.

[0003] Methods for preventing pneumothorax are of great interest from both the perspectives of morbidity and hospital expenditure. Numerous attempts have been described in scientific journals, focusing on occluding the path of the biopsy needle with adhesives or plugs when the biopsy needle is withdrawn. For that purpose, various different substances such as gelatin sponge slurry, fibrin adhesive, autologous blood, a mixture of serum supernatant and autologous blood, and collagen foam have been injected. These attempts have proven ineffective and have not been widely adopted. The lack of such effects may be the result of the physical properties of the injected substances and the uncontrollability of the injection site. Additional literature suitable for lung sealing is outlined in US6,592,608B and US6,790,185B1. This technology is commercially available as BioSentry (registered trademark) from Surgical Specialties Corporation (MA, USA www.biosentrysystem.com). Other publications related to the sealing of the lung and tissues include US2016120528A, US2006025815A, US2013338636A, US2006009801A, US6770070B, US2017232138A, US2002032463A, and US2009136589A (Patent Documents 1 - 8).

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Summary of the Invention

[0005] There is a need for medical devices, systems, and methods that address at least one of the foregoing problems. Such problems are addressed by the medical devices, systems, and methods disclosed herein.

Brief Description of the Drawings

[0006]

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[0007] The present invention provides devices and methods for closing a path within tissue formed during minimally invasive percutaneous procedures, including minimally invasive percutaneous needle access and keyhole surgery. The present invention provides devices and methods for closing a path within tissue during a procedure that requires percutaneous needle access to internal tissue for diagnosis or treatment. The present invention also addresses the need for devices and methods that reduce the risk of leakage of liquid and / or gas during procedures that require percutaneous needle access, including needle biopsy, tissue localization, procedures for placing alignment markers, and resection procedures including microwave and radiofrequency ablation and cryoablation. In particular, organs that tend to leak liquid or gas include the lung, liver, and kidney. The present invention addresses the need for devices and methods that reduce the risk of bleeding during access to the liver or kidney for diagnosis or treatment. The present invention addresses the need for devices and methods that prevent or reduce the risk of pneumothorax and hemothorax when percutaneous thoracic needle access is required.

[0008] For any aspect, the method of the present invention optionally includes a method of reaching a target position in lung tissue distal to the visceral pleura with an injectable viscoelastic thixotropic hydrogel. The physical properties of the viscoelastic hydrogel prevent penetration into the lung tissue. Instead, the hydrogel pushes the tissue away from the delivery needle and forms a closed annular occlusion plug surrounding the delivery needle close to or in contact with the visceral pleura within the lung. Generally, the hydrogel plug is annular when delivered, but may have other shapes depending on the shape, number, and position of the hydrogel outlets. The use of hydrogel outlets on the side of the needle is preferred for achieving an annular occlusion plug. The viscoelastic thixotropic hydrogel has been found to be ideal for this purpose when it exhibits the required stiffness after needle delivery to prevent tissue infiltration. Next, a coaxial cannula is advanced along the delivery needle, penetrating the occlusion plug, and the occlusion plug forms an airtight seal against the coaxial cannula. Subsequently, a lung biopsy needle passes through the coaxial cannula to obtain a biopsy sample from a suspected lesion without air leakage from the lung. When the coaxial cannula is withdrawn from the lung, the viscoelasticity of the occlusion plug quickly fills the path formed by the withdrawal of the cannula, compresses the visceral pleura, and seals the hole in the pleura.

[0009] According to a first aspect of the present invention, a medical device comprising a hydrogel delivery needle (4) having a tip (5) (generally a sharp tip) and a hydrogel outlet (6), and comprising an injectable viscoelastic thixotropic hydrogel a system for closing a path in tissue (e.g., a path formed during a low-invasive percutaneous procedure) is provided.

[0010] As an example, the viscoelastic hydrogel exhibits a storage modulus (G’) of at least 400 Pa as measured with a rheometer at 25°C, 1 Hz, and a strain rate of 1%.

[0011] As an example, the viscoelastic hydrogel exhibits a dynamic viscoelasticity tanδ (G” / G’) of 0.1 to 0.8 as measured with a rheometer at 25°C, 1 Hz, and a strain rate of 1%.

[0012] As an example, the viscoelastic hydrogel is configured to exhibit an in vivo retention time of at least 1, 2, or 3 weeks. Thereby, the gel remains in the tissue while the needle path of the tissue heals. Generally, one week is sufficient, but an in vivo retention time of at least 2 weeks is preferred. Hydrogels formed from crosslinked polymers or containing crosslinked polymers improve the in vivo retention time. For example, a composite hydrogel containing gelatin particles crosslinked with 4-5% non-crosslinkable hyaluronic acid (crosslinked by dehydration heating) achieves an in vivo retention time of at least 2 weeks in the lung needle biopsy path.

[0013] An injectable viscoelastic hydrogel (hereinafter, “viscoelastic hydrogel”, “hydrogel” or “gel”) is a hydrogel that generally has properties sufficient to limit tissue invasion and is juxtaposed to the tissue to displace the tissue. Thus, the hydrogel can form its own space within the tissue or organ. To achieve this, its properties must be present when the target injection site is reached. Typically, the storage modulus (G’) measured with a rheometer at 25°C, 1 Hz and a strain rate of 1% is at least 400 Pa (e.g., 800 - 6000 Pa) and the dynamic viscoelasticity tanδ (G” / G’) shows a value from 0.1 to 0.8.

[0014] For improving tissue resistance and forming a uniform plug surrounding the needle, the viscoelastic hydrogel preferably exhibits an axial compressive stiffness equal to or greater than that of the lung parenchymal tissue, which is measured, for example, using a Zwick universal testing machine with a 5N load cell and a strain rate of 3 mm / min. Preferably, the compression modulus of the viscoelastic hydrogel is greater than 200 Pa, more preferably greater than 400 Pa, and even more preferably greater than 800 Pa.

[0015] In any example, the injectable viscoelastic hydrogel is a shear-thinning gel. For example, the viscoelastic hydrogel can be configured to have a low viscosity under high shear stress or shear rate (i.e., during injection through a needle) and a higher viscosity when the shear stress is removed (i.e., delivered to the target site in the body) (under low shear stress or shear rate). Thereby, these members can form a single hydrogel plug at the delivery site. Materials with these properties are outlined in ’Shear-thinning hydrogels for biomedical applications’, Soft Matter. (2012) 8, 260, ‘Injectable matrices and scaffolds for drug delivery in tissue engineerinG’ Adv Drug Delv Rev (2007) 59, 263-272, and ‘Recent development and biomedical applications of self-healing hydrogels” Expert Opin Drug Deliv (2017) 23: 1-15. Typically, the storage modulus (G’) of the shear-thinning viscoelastic hydrogel is less than 200 Pa, preferably less than 100 Pa, as the dynamic viscoelasticity at a frequency of 1 Hz and a strain of 100%.

[0016] In any example, the hydrogel is self-healing. This means the ability of the hydrogel to spontaneously form new intermolecular bonds when old bonds are broken.

[0017] In any example, the viscoelastic hydrogel contains 2 - 6% (w / v) of the hydrogel-forming polymer. In particular, when the polymer is hyaluronic acid, this concentration has been found to provide ideal injectability and tissue juxtaposition with a pulmonary needle.

[0018] In any example, the hydrogel-forming polymer is a glycosaminoglycan. In any example, the glycosaminoglycan is hyaluronic acid or its salt.

[0019] In any example arbitrarily, hyaluronic acid is a high-molecular-weight hyaluronic acid with a molecular weight exceeding 1000 kDa (1 MDa).

[0020] In any example arbitrarily, the hydrogel is not cross-linked.

[0021] In any example arbitrarily, the hydrogel is cross-linked.

[0022] In any example arbitrarily, the viscoelastic hydrogel is a colloidal hydrogel. In any example arbitrarily, the colloidal hydrogel is preferably produced by hydrating biocompatible polymer particles that are insoluble in biological fluids. In any example arbitrarily, the degradation period of the polymer particles is preferably less than 1 year, more preferably less than 6 months, and even more preferably less than 2 months. In any example arbitrarily, the colloidal hydrogel is composed of a biologically derived polymer, such as gelatin, collagen, fibrin, or hyaluronic acid. In any example arbitrarily, the polymer is cross-linked. In any example arbitrarily, the colloidal hydrogel contains 0.2 - 30%, 15 - 28%, or 20 - 27% (w / v) of the hydrogel-forming polymer. In any example arbitrarily, the colloidal hydrogel has a storage modulus (G’) as the dynamic viscoelasticity measured with a rheometer at 25 °C, 1 Hz, and a strain rate of 1% of at least 400 Pa, more preferably at least 800 Pa, and even more preferably at least 1000 Pa.

[0023] In any example, the viscoelastic hydrogel is a multiphase system, for example, a two-phase system in which colloidal hydrogels are dispersed in a continuous-phase hydrogel. In any example, the continuous-phase hydrogel may be produced from a hyaluronan hydrogel and may be present at a concentration of 1 to 6%, preferably 2 to 5%. In any example, the hyaluronan hydrogel may or may not be cross-linked, or may be lightly cross-linked. In any example, the colloidal hydrogel can be present as a hydrogel-forming polymer at a concentration of 0.2 to 30%, 8 to 20%, 8 to 15%, 8 to 12%, or about 10% (w / v). In any example, the colloidal hydrogel is produced from hydrated polymer particles having an average particle diameter of <100 μm (for example, 5 to 99, 20 to 80, or 30 to 80 microns). In any example, the colloidal hydrogel is insoluble in an aqueous solution. In any example, the colloidal hydrogel is produced from cross-linked polymer particles. In any example, the colloidal hydrogel is a gelatin hydrogel containing dehydrated heat-cross-linked (DHT) gelatin powder having an average particle diameter (D50) of about 10 to 100, 20 to 50, or 30 to 40 microns. In any example, the two-phase hydrogel has a storage modulus (G') as the dynamic viscoelasticity measured with a rheometer at 25°C, 1 Hz, and a strain rate of 1% of at least 400 Pa, more preferably at least 800 Pa, and even more preferably at least 1000 Pa, and tan δ (G" / G') shows 0.1 to 0.6. In any example, the two-phase hydrogel has an axial compression stiffness measured with an axial compression tester equal to or higher than that of lung parenchymal tissue.

[0024] In any example, the viscoelastic hydrogel is degassed, that is, air and / or gas is removed.

[0025] In any example, the hydrogel contains a therapeutic agent.

[0026] In any example, the hydrogel is biodegradable.

[0027] In any example, the hydrogel contains 2 to 6%, preferably 3 to 5% (w / v) of high molecular weight hyaluronic acid. In any example, the hyaluronic acid hydrogel can be combined with 0.2 to 30% of a colloidal hydrogel to form a two-phase hydrogel. In any example, the colloidal hydrogel is composed of hydrogel-forming polymer particles. In any example, the hydrogel-forming polymer particles are gelatin particles, collagen particles or hyaluronic acid particles.

[0028] In any example, the hydrogels described herein may be provided from separate components, for example, as multiple syringes, or may include means for mixing the components prior to injection through a syringe.

[0029] In any example, the systems and methods described herein include the initial step of providing a dehydrated or semi-dehydrated powder of a viscoelastic hydrogel and reconstituting the powder with a suitable liquid to produce a viscoelastic hydrogel.

[0030] In any example, the viscoelastic hydrogel is represented as a microporous hydrogel having interconnected pores that mechanically collapse and reversibly recover. When the hydrogel is delivered by injection using a needle and syringe, water is squeezed out of the pores, the hydrogel collapses, and passage through the needle is enabled. Once the hydrogel leaves the needle, the mechanical constraint by the needle wall is removed, and the hydrogel almost immediately resumes its original shape in the body. Such hydrogels behave like foams and can be compressed up to 90% strain without permanent damage to the network.

[0031] In any example, the viscoelastic hydrogel is provided in a syringe that is fluidly connected to the proximal end of a hydrogel delivery needle.

[0032] In any example, the syringe contains 200 μL to 5000 μL of viscoelastic hydrogel, 200 μL to 2000 μL of viscoelastic hydrogel, or 200 μL to 1000 μL of viscoelastic hydrogel.

[0033] In any example, the diameter of the hydrogel delivery needle ranges from 10 to 24 gauge, preferably from 16 to 20 gauge. This is the range of typical needle sizes used in diagnostic procedures of the lungs. For other procedures, including therapeutic procedures performed with lung, liver, and kidney resections, larger delivery needles (10 to 16 gauge) may be used. For other medical procedures, smaller needles of 20 gauge or above or 10 gauge or above may be used.

[0034] In any example, the hydrogel orifice is located at a proximal interval from the tip of the needle. The hydrogel orifice located in the profile of the needle can form a closed annular occlusion plug surrounding the needle. Due to the viscoelastic properties of the hydrogel, when the device is removed, the central hole of the occlusion plug is blocked and the annular occlusion plug is reformed. In any example, the hydrogel orifice is positioned at an interval of preferably 1 to 15 mm or more, more preferably 3 to 8 mm from the tip of the needle.

[0035] In any example, the hydrogel delivery needle includes a plurality of hydrogel orifices disposed on the side surface of the needle. The hydrogel orifices may be arranged radially along the circumference of the needle. The profile of the hydrogel orifice can be circular, and in that case, its diameter can range from 0.3 to 1.5 mm depending on the diameter of the hydrogel delivery needle. The profile of the hydrogel orifice can also be an extended non - circular shape.

[0036] In any example, the hydrogel orifice is composed of an X - ray transmissive region of the delivery needle where the material has been sufficiently removed by cutting or erosion to provide X - ray impermeable contrast between the delivery needle and the hydrogel orifice.

[0037] In any example, the coaxial cannula consists of an opening near the distal end. This opening is composed of an X - ray transmissive region of the coaxial cannula where the material has been sufficiently removed along the circumference of the cannula.

[0038] In any example, the X-ray transmissive regions of both the delivery needle and the coaxial cannula align when the delivery needle and the coaxial cannula are engaged. This provides a landmark function for the X-ray transmissive regions during X-ray guidance and enables the injection of the viscoelastic hydrogel at this location.

[0039] In any example, the openings of the hydrogel outlet and the coaxial cannula are created by removing some material from the wall of the delivery needle using a laser cut profile or pattern to create a path for the hydrogel material to flow to the intended target. Removing a significant amount of material gives the X-ray transmissivity to that part of the device and enables visual feedback of the hydrogel outlet under guidance by CT or other imaging methods. The X-ray transmissivity (less X-ray opacity) is achieved by removing a significant amount of material from the needle wall using a laser cut pattern without compromising the structural integrity of the needle. The structural stability can be maintained by a laser cut profile including triangles on the circumference and similar structures used for coronary stents. Alternatively, a material erosion technique may be used to create the cut pattern.

[0040] In any example, the medical device consists of an adjustable positioning mechanism configured to limit the advancement depth of the hydrogel delivery needle through the coaxial cannula by indicating it by a measurement scale that forms part of the medical device.

[0041] In any example, the positioning mechanism includes a fixed housing attached to the hydrogel delivery needle and a movable hub mounted on the needle to move axially along the hydrogel delivery needle relative to the fixed housing, with the distal end configured to contact the proximal surface of the coaxial cannula luer lock.

[0042] In any example, the scale is provided with an adjustable positioning mechanism configured to indicate the injection depth P of the hydrogel outlet, and when the distal end of the positioning mechanism is in complete contact with the proximal surface of the coaxial cannula, the hydrogel outlet is positioned at a distance of P + X from the distal end of the coaxial cannula.

[0043] In any example, the positioning mechanism includes a cannula depth guide configured to indicate the coaxial cannula insertion depth relative to the delivery needle, at which insertion depth the distal end of the cannula advances a distance Y beyond the delivery needle to cover the hydrogel outlet, where the positioning mechanism is configured to adjust the preset cannula insertion depth Y indicated on the cannula depth guide in proportion to the preset insertion depth P+X of the hydrogel outlet set by adjustment of the positioning mechanism.

[0044] In any example, the cannula depth guide is axially connected to a fixed housing of the positioning mechanism to move together and includes an arm extending distally of the movable hub.

[0045] In any example, a mark is applied proximal to the tip of the delivery needle, where the distance between the mark and the tip (represented as distance H) is equal to the length of the coaxial cannula (coaxial cannula length = H). When the delivery needle is inserted into the lumen of the coaxial cannula, this mark can be used to indicate that the distal end of the coaxial cannula is adjacent to the tip.

[0046] In any example, the system further includes a core needle having a penetrating distal end attached to the coaxial cannula lock and configured to be inserted into the lumen of the coaxial cannula.

[0047] In any example, the system further comprises a syringe configured to be fluidly connected to the hydrogel delivery needle, and a viscoelastic hydrogel is provided in the syringe.

[0048] According to one aspect of the present invention, there is provided a medical device suitable for delivering a substance to a target location within a tissue, the device comprising a coaxial cannula having a lumen and a hydrogel delivery needle advancing through the lumen of the coaxial cannula, the hydrogel delivery needle including a distal needle tip, a hydrogel outlet, and a positioning mechanism associated with the hydrogel delivery needle defined such that the insertion depth of the needle outlet relative to the distal end of the coaxial cannula can be adjusted axially.

[0049] Optionally, in any example, the positioning mechanism may be additionally introduced into the hydrogel delivery needle.

[0050] Optionally, in any example, the medical device is provided with a measuring instrument including a measuring scale configured to provide means for determining the insertion depth of the needle outlet relative to the distal end of the coaxial cannula. The measuring instrument can include a ruler, a scale, calipers, a micrometer, or other mechanical or digital measuring mechanisms.

[0051] Optionally, in any example, the positioning mechanism includes a fixed housing attached to the hydrogel delivery needle and a movable hub mounted to the fixed housing so as to move axially along the axis of the needle, the distal end being configured to contact the proximal end of the coaxial cannula, and the fixed housing being configured to move relative axially in cooperation with the movable hub so as to define a predetermined needle adjustment depth.

[0052] Optionally, in any example, the fixed housing and / or the movable hub include a measuring scale and graduations configured such that a user can adjust the preset needle insertion depth. A micrometer scale or a vernier scale may be used for the positioning mechanism, with one element of the scale provided on the fixed housing and a second scale element provided on the movable hub.

[0053] Optionally, in any example, the fixed housing and the movable hub are typically coaxially connected by a screw fit.

[0054] In any example, the positioning mechanism includes a set screw (mechanism) that operates to lock the fixed housing and the movable hub together.

[0055] In any example, the positioning mechanism is associated with the proximal end of the delivery needle and is axially adjustable so as to be able to define the insertion depth of a pre-set delivery needle outlet relative to the coaxial cannula, at which insertion depth the hydrogel outlet is located at a pre-set distance from the distal end of the coaxial cannula, where the positioning mechanism consists of a cannula depth guide configured to indicate the coaxial cannula insertion depth relative to the needle, at which insertion depth the distal end of the cannula advances over the delivery needle to cover the hydrogel outlet, where the positioning mechanism is configured to adjust the pre-set cannula insertion depth indicated on the cannula depth guide in proportion to the insertion depth of the pre-set hydrogel outlet by adjustment of the positioning mechanism.

[0056] In any example, the cannula depth guide is axially connected to the fixed housing of the positioning mechanism so as to move together and includes an arm extending distally of the movable hub.

[0057] In any example, the length of the arm extending distally of the movable hub is preferably equal to the cannula insertion depth.

[0058] In any example, the cannula depth guide is configured to guide the axial movement distally of the cannula over the delivery needle when the pre-set cannula insertion depth is reached.

[0059] In any example, the cannula depth guide has a distal end that contacts the proximal end of the cannula and a proximal end that extends proximally to the movable hub of the positioning mechanism, and includes an axially adjustable cannula extension member, whereby distal movement of the cannula extension member achieves distal movement of the cannula beyond the needle. When the positioning mechanism adjusts the fixed housing and the movable hub to define a preset needle insertion depth, the distance between the proximal end of the movable hub of the positioning mechanism and the proximal end of the cannula depth guide is preferably equal to the preset needle insertion depth. The cannula extension member is coaxially mounted to the needle for axial movement relative to the needle and includes a slot that is stretched so as to accommodate the connection between the fixed housing and the movable hub of the positioning mechanism.

[0060] In any example, the present invention uses an imaging method such as a CT scan (computed tomography) to accurately position a hydrogel delivery needle for delivering a hydrogel to the distal end (visceral pleura) of the lung surface. The coaxial cannula can be inserted into the intercostal muscle such that its distal end is positioned proximal to the parietal pleura. After the core of the coaxial cannula is removed, an image is taken to determine the distance P from the distal end of the cannula to the lung surface (or pleural cavity). Then, prior to insertion of the cannula, by adjusting a hydrogel delivery needle having an adjustable depth positioning mechanism, when the hydrogel port has advanced completely through the cannula, the hydrogel port is at a distance P + X from the distal end of the cannula, where the distance X is a preset distance from within the lung tissue to the lung surface (visceral pleura). Then, the hydrogel delivery needle advances completely through the cannula, and the hydrogel is delivered to the target site and forms an annular occlusion plug that closes around the needle. Then, the coaxial cannula is advanced along the needle beyond the seal, preferably covering the position where the hydrogel port has advanced. The positioning mechanism of the hydrogel delivery needle may include a cannula depth guide such that the user can advance the cannula beyond the needle by a distance Y greater than P + X to cover the hydrogel port. The positioning mechanism may be configured such that adjustment of the correct positioning during advancement of the needle proportionally adjusts the cannula depth guide.

[0061] In any example, the positioning mechanism is configured to position the hydrogel outlet on the needle at a distance (P+X) of preferably 3 to 30 mm, or more preferably 5 to 20 mm, from the distal end of the cannula when the needle is fully advanced into the cannula.

[0062] In any example, the device includes a cannula depth lock configured to fix the axial position of the coaxial cannula relative to the patient. The cannula depth lock can be positioned adjacent to the patient's skin and may be fixed to the patient's skin using a skin adhesive. The coaxial cannula can be inserted through the cannula depth lock, and the cannula depth lock locks the cannula by means of a tightening screw, a collet or other means and is fixed to prevent the coaxial needle from being inserted further into the patient.

[0063] In any example, the device includes a locking arm configured to connect the cannula depth lock and the delivery device to fix the axial position of the delivery device relative to the patient. The locking arm may be attached to any part of the positioning mechanism and may be removable.

[0064] In any example, the proximal end of the hydrogel delivery needle includes a luer lock configured to attach to a substance delivery device such as a pump or syringe that stores a substance such as hydrogel.

[0065] In another aspect, there is provided a system including a medical device according to the present invention and a core biopsy needle configured to advance through a coaxial cannula.

[0066] In any example, the system includes a coaxial cannula and a core needle configured to be used for forming an endobiopsy pathway in tissue. The core needle typically consists of a single elongated rod with a needle tip and includes a male Luer lock attached to its proximal end. The male Luer lock is configured to be attached to the female Luer lock of the coaxial cannula. When the male and female Luer locks are attached, the needle tip of the core needle extends from the distal end of the coaxial cannula, typically at a distance of 1 to 6 mm.

[0067] In any example, the system includes a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) suitable for injection through a hydrogel delivery needle.

[0068] In any example, the viscoelastic hydrogel is a shear-thinning hydrogel.

[0069] In any example, the viscoelastic hydrogel is a hyaluronic acid hydrogel.

[0070] In any example, the viscoelastic hydrogel has a storage modulus (G’) of dynamic viscoelasticity measured with a rheometer at 25 °C, 1 Hz, and a strain rate of 1% of at least 400 Pa, more preferably at least 800 Pa, even more preferably at least 1000 Pa, and shows a tanδ (G” / G’) of 0.1 to 0.6.

[0071] In any example, the viscoelastic hydrogel contains about 3 to 6% (w / v) of a hydrogel-forming polymer.

[0072] The present invention provides a method for delivering a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) to a target location in the lung adjacent to the visceral pleura of a patient, the method including the following steps: Inserting a coaxial cannula into the patient's chest wall such that the distal end of the coaxial cannula is positioned proximal to the parietal pleura; Taking a first image of a portion of the lung showing the patient's lung, chest wall, and the coaxial cannula disposed in the chest wall; Determine the distance P from the distal end of the coaxial cannula to the target path in the lung using the first image; Provide a hydrogel delivery needle including a hydrogel outlet and a positioning mechanism configured to adjust the insertion depth of the needle when fully advanced through the coaxial cannula; Actuate the positioning mechanism of the hydrogel delivery needle to adjust the insertion depth of the needle such that the hydrogel outlet is positioned at a distance P+X from the distal end of the cannula when the needle is fully advanced through the coaxial cannula; and Inject a hydrogel plug through the needle into the target location to create an occlusive plug that surrounds the needle and optionally contacts the visceral pleura.

[0073] Optionally in any example, the distance P is determined by measuring the distance from the distal end of the coaxial cannula to the pleural cavity. The pleural cavity can be defined as the boundary between the lung and the chest wall. By adding a pre-set distance X within the lung to the measured distance P, a known injection depth within the lung can be targeted.

[0074] Optionally in any example, the method may include the step of advancing the coaxial cannula beyond the hydrogel delivery needle and through the seal plug distally.

[0075] Optionally in any example, the positioning mechanism consists of a cannula depth guide configured to indicate a pre-set insertion depth of the cannula relative to the needle, at which insertion depth the distal end of the cannula advances beyond the delivery needle and covers the hydrogel outlet by a distance greater than X, where the step of advancing the coaxial cannula beyond the hydrogel delivery needle and through the seal plug distally is guided by the cannula depth guide.

[0076] Optionally in any example, the method may include an initial step of imaging the patient's chest wall to determine an appropriate insertion depth of the coaxial cannula into the chest wall such that the needle is positioned 1-15 mm from the parietal pleura.

[0077] Optionally in any example, the hydrogel is a viscoelastic hydrogel.

[0078] In any example, the hydrogel delivery needle includes a hydrogel outlet disposed laterally of the needle.

[0079] In another aspect, the present invention provides a method of performing a lung needle biopsy that includes the following steps: delivering a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) to a target location in the lung adjacent to the visceral pleura of the patient's lung; advancing a coaxial cannula beyond the hydrogel delivery needle and through the seal plug distally; removing the hydrogel delivery needle through the cannula; advancing a biopsy needle through the cannula to a biopsy site within the lung; activating the biopsy needle to obtain a lung tissue sample from the biopsy site; removing the biopsy needle through the cannula; and sealing the visceral pleura with the seal plug by withdrawing the cannula.

[0080] In any example, after removing the hydrogel delivery needle and before advancing the biopsy needle, the method may include inserting a core needle into the coaxial cannula, advancing the core needle and the coaxial cannula to a biopsy site within the lung, and removing the core needle.

[0081] In any example, before removing the hydrogel delivery needle, the method may include advancing the hydrogel delivery needle to a biopsy site within the lung and then advancing the coaxial cannula beyond the hydrogel delivery needle to the biopsy site within the lung.

[0082] In any example, the step of advancing the coaxial cannula beyond the hydrogel delivery needle distally to a biopsy site within the lung is guided by a cannula depth guide.

[0083] In any aspect, the present invention provides a method of performing a lung needle biopsy procedure that includes the following steps: Inject a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) from a hydrogel delivery needle into the lung adjacent to the visceral pleura of the lung, and generate a seal plug that surrounds the needle and contacts the visceral pleura; Advance a coaxial cannula along the hydrogel delivery needle through a closed annular seal plug; Remove the hydrogel delivery needle through the cannula; Advance a biopsy needle through the cannula to a target site within the lung; Operate the biopsy needle to collect a lung tissue sample from the biopsy site; Remove the biopsy needle through the cannula; and Prevent pneumothorax by closing the visceral pleura with a seal plug by withdrawing the cannula.

[0084] According to another aspect, the present invention provides a method for performing a lung nodule localization procedure comprising the following steps: Inject a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) from a hydrogel delivery needle into the lung adjacent to the visceral pleura of the lung, and generate a seal plug that surrounds the needle and contacts the visceral pleura; Advance a coaxial cannula along the hydrogel delivery needle through a closed annular seal plug; Remove the hydrogel delivery needle through the cannula; Advance a tissue staining delivery needle through the cannula to a target site within the lung; Operate the tissue staining needle to collect a lung tissue sample from the target site; Remove the tissue staining needle through the cannula; and Prevent pneumothorax by closing the visceral pleura with a seal plug by withdrawing the cannula.

[0085] According to another aspect, the present invention provides a method comprising delivering a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) to the lung adjacent to the visceral pleura of a patient's lung and generating a seal plug that contacts the visceral pleura entirely within the lung.

[0086] Optionally, in any example, the viscoelastic hydrogel is a shear-thinning hydrogel.

[0087] In any example, the viscoelastic hydrogel is a hyaluronic acid hydrogel.

[0088] In any example, the viscoelastic hydrogel is a high molecular weight hyaluronic acid hydrogel with a molecular weight of 1000 kDa or more.

[0089] In any example, the hydrogel delivery needle includes a hydrogel outlet disposed at the distal end of the needle.

[0090] In any example, the hydrogel delivery needle includes a hydrogel outlet disposed on the side of the needle.

[0091] In any example, the hydrogel delivery needle includes a plurality of hydrogel outlets disposed on the side of the needle.

[0092] In any example, the seal plug is a hydrogel with a volume of 100 to 3000 μl, a hydrogel with a volume of 100 to 1000 μl, or a hydrogel with a volume of 200 to 900 μl.

[0093] In any example, the method of the present invention includes delivering a hydrogel with a volume of 100 to 3000 μl. In any example, the method includes delivering a hydrogel with a volume of 100 to 1000 μl. In any example, the method includes delivering a hydrogel with a volume of 200 to 900 μl. In any example, the method includes delivering a hydrogel with a volume of 200 to 500 μl.

[0094] In any example, the viscoelastic hydrogel is delivered to the lung through a needle having a hydrogel outlet disposed at the needle tip and laterally away from the needle tip along the needle.

[0095] According to another aspect, the present invention provides the use of a viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) to create a seal plug in a patient's lung during a lung needle biopsy procedure to prevent pneumothorax, wherein the seal plug is delivered to the lung in contact with the visceral pleura.

[0096] In any example, the biopsy needle penetrates the seal plug during the needle biopsy procedure.

[0097] In any example, the coaxial cannula penetrates the seal plug, and the biopsy needle penetrates the seal plug via the coaxial cannula.

[0098] In any example, the target position in the lung is located 0.2 to 6.0 mm away from the visceral pleura. In any example, the delivery target position of the hydrogel material is within the thoracic cavity. In this case, the hydrogel outlet is located inside or across the thoracic cavity.

[0099] In any example, the hydrogel delivery needle may have a hydrogel outlet at the tip of the needle rather than laterally. Also, the hydrogel outlet may be at the tip and / or the side of the needle. The delivery devices and systems described herein also provide an effective solution for preventing bleeding during procedures that require low-invasive percutaneous access to other organs such as the liver and kidneys. These procedures include the diagnosis or treatment of some or all organs.

[0100] In any example, the systems and viscoelastic hydrogels described herein can be used to separate tissues during surgical procedures. This is necessary to create a path for the instrument to the tissue or to protect the tissue from unwanted irritation such as tumor resection or radiation therapy. For this purpose, for example, a larger volume of viscoelastic hydrogel, such as 1 - 25 ml, is delivered.

[0101] In any example, the systems and / or viscoelastic hydrogels described herein can be used to fill the voids of tissues and organs.

[0102] In any example, the systems and / or viscoelastic hydrogels described herein can be applied to prevent adhesion of adjacent tissues and organs.

[0103] In any example, the systems and / or viscoelastic hydrogels described herein can be applied as drug delivery carriers. Drugs or other bioactive substances are loaded onto the viscoelastic hydrogels, and these substances gradually diffuse from the hydrogels after being implanted in the body, and the diffusion rate can be easily controlled by changing the composition parameters of the hydrogels.

[0104] In any example, the systems and / or viscoelastic hydrogels described herein can be used as embolization agents for occluding arteries and veins. The viscoelastic hydrogel is placed in an artery or vein to occlude blood flow temporarily or permanently. In this specification, the hydrogel is used for the treatment of vascular diseases such as aneurysms, venous aneurysms, venous insufficiency, varicose veins, and telangiectasia.

[0105] As an alternative, the delivery device may be used to deliver non-viscoelastic hydrogels or other substances to the target locations in the patient's lungs, chest cavities, or other organs, cavities, or tubes. These substances include biocompatible polymer agents, particles, spheres, small expandable balloons, structures containing cells, therapeutic agents, chemotherapeutic agents, and suspensions.

[0106] In any example, the devices and components described herein are made using biocompatible materials including polymers, metals, and ceramics. Polymers include polyetheretherketone, polyethylene terephthalate, nylon, polyimide, polyurethane, polyester, Pebax®, and copolymers thereof. Metals include stainless steel, nitinol, titanium, and cobalt chrome. The needles and cannulas may include laser cut or braided portions that bend completely or partially to provide flexibility. Also, both the needles and cannulas may be long and flexible, such as in a catheter-type assembly.

[0107] In a preferred form, the composition of the system or the entire system can be provided in a sterile state for clinical use. A syringe filled with hydrogel can be prepared through aseptic formulation, mixing, filling, and packaging processes. Also, the syringe for filling hydrogel may ultimately be sterilized by heat or steam treatment, for example, by an autoclave. For sterilization of the system, sterilization processes known in the art including ethylene oxide, hydrogen peroxide, gamma rays, and electron beams can be performed.

[0108] Optionally in any example, the composition of the system is provided in packaging suitable for sterilization, which includes, but is not limited to, pouches, blister packs, bags, treatment sets, buckets, clam shells, skin packs, trays (including lids), cartons, needle sheaths. All of the composition of the system can be constructed as a single packaging device. Alternatively, multiple packages containing different compositions can be prepared and sterilized separately. The composition of the system includes, but is not limited to, a coaxial cannula with a core needle, a hydrogel delivery needle, a cannula depth lock, a locking arm, one or more syringes filled with viscoelastic hydrogel, empty syringes, hypodermic needles, scalpels, skin markers, radiopaque guides, forceps, biopsy needles, surgical drapes, disinfectant solutions, swabs, swab holders, sponges, saline, and histological sample containers.

[0109] Optionally in any example, the cannula depth guide can be configured to be additionally introduced onto the hydrogel delivery needle. This is useful because the cannula depth guide can be attached when needed and removed when not needed.

[0110] Optionally in any example, the cannula depth guide includes engagement or locking features configured to fix the delivery needle to the coaxial cannula in a second position.

[0111] Optionally in any example, the method described herein includes a first step of flushing the syringe with gel (or saline or water) before inserting the needle into the body. The syringe may also be flushed with hydrogel before inserting it into the body.

[0112] In any example, the different needle tips of the delivery needle are designed to prevent bleeding when inserted into the lung. For example, a pencil point type needle or a similar non-cutting and non-damaging needle tip profile is used to prevent bleeding.

[0113] In any example, to minimize the collapse of the parietal and visceral pleural layers as the needle advances through the lung, the needle tip is designed to have a sharp inclined profile.

[0114] In any example, the tip of the delivery needle may be blunt. In any example, the hydrogel outlet may be located away from the blunt tip. In any example, the delivery needle may be composed of a beveled needle tip that combines a blunt core actuated by a spring and a sharp needle tip.

[0115] In any example, the delivery needle is a single lumen. In any example, the delivery needle is composed of a multi-lumen tube. The multi-lumen tube may be composed of a single tube or multiple individual tubes within another lumen (e.g., a stainless-steel needle). The tubes may be connected to different outlets. For example, one lumen may be connected to a delivery outlet located away from the needle tip, while another lumen may be directly connected to the needle tip. The individual delivery lumens may be used for the delivery of hydrogel, the delivery of devices, measurement (pressure, temperature, impedance), tissue extraction (e.g., FNA or core biopsy). The tubes may also be used for the delivery of cross-linking agents, chemotherapeutic agents, and cell fluids (e.g., stem cells).

[0116] In any example, the delivery needle may be composed of a single tube. The single tube may optionally include a tissue-penetrating end. The delivery needle may optionally be composed of two or more tubes joined together, such that the distal tube forms the tissue-penetrating end. The various tubes used to include the delivery needle can be made from radiation density contrast materials such as, for example, stainless steel or polymers.

[0117] In any example, the delivery needle can be provided with a central lumen through which a guide wire can pass. The guide wire is provided for accessing body cavities or lumens.

[0118] In any example, the delivery needle and the coaxial cannula can be made non-damaging or given anti-friction properties by surface coating or surface modification with polytetrafluoroethylene or silicone-based paints. In any example, the coaxial cannula can have a bevel profile by fillet cutting or chamfering the distal end to ease the insertion force into body tissues.

[0119] In any example, the hydrogel delivery needle and the coaxial cannula can be marked with external graduations on their outer surfaces to monitor the insertion depth into the tissue and to determine the position of the coaxial cannula relative to the delivery needle. Such depth graduations can be created by laser marking, ink pad printing, or similar methods. The width of the graduations is typically 5 - 10 mm.

[0120] In any example, the methods described herein include a suction step to confirm that major blood vessels have not been punctured. This suction step can be performed when the delivery needle is inserted into the target position, before the hydrogel plug is injected. This is desirable to limit or prevent the hydrogel from entering the vascular system and causing a pulmonary embolism. Suction of dark blood indicates puncture of a major blood vessel.

[0121] In any example, a syringe filled with hydrogel can be configured to require suction before injecting the hydrogel material. This can be achieved by incorporating into the syringe a mechanism such that the forward movement of the syringe plunger is restricted unless a backward suction action is performed.

[0122] In any example, the methods described herein may include an additional empty syringe for performing the suction step.

[0123] In any example, the device includes a two-way or three-way medical stopcock fluidly attached to the delivery device. Either or both of the hydrogel-filled syringe and the aspiration syringe are attached to the delivery device via the medical stopcock, and the fluid delivery path can be changed or restricted between the hydrogel-filled syringe and the aspiration syringe. This enables faster aspiration and injection steps and is advantageous for reducing the time taken in the lungs before injecting the hydrogel plug.

[0124] In any example, optionally, the syringe is an ergonomic syringe with improved deliverability. As examples, it is described in US20090093787 A1 'Ergonomic syringe' and US6616634 B2 'Ergonomic syringe'. The system also includes an ergonomic syringe adapter that can be mounted on the syringe. As an example, it is described in USD675317 S1 'Ergonomic syringe adapter'. The syringe may be equipped with a mechanism for injecting the viscoelastic hydrogel under high pressure. This may be in the form of a syringe assist device.

[0125] In any example, optionally, the coaxial needle may have an internal seal / flap to prevent the gel from entering the coaxial needle.

[0126] In any example, optionally, the hydrogel delivery needle may be used as the core needle within the coaxial needle.

[0127] In any example, optionally, the positioning mechanism also includes a firing mechanism, such as a spring-loaded firing mechanism, for quickly advancing the delivery needle through the coaxial cannula to a pre-set depth. The required distance can be the set distance of the penetration depth or can be adjusted considering the position of the coaxial cannula relative to the target injection position. The device can be positioned using measurements taken from the captured images.

[0128] The system, device and method of the present invention may use a coaxial needle with a core having radiopaque markers for more accurate positioning.

[0129] Optionally, in any example, a locking feature may be provided in the positioning mechanism to enable locking and unlocking of the positioning mechanism to the delivery needle. This feature allows the positioning mechanism to be independent of the delivery needle, enables the use of delivery needles of different lengths, and allows compatibility with coaxial cannulas of different lengths.

[0130] Optionally, in any example, the delivery device can be configured to be flexible when extended, thereby enabling it to be passed through an endoscope and perform an injection at a preset injection depth via the endoscope. The extended member can include both the coaxial cannula of the delivery device and the delivery needle element.

[0131] Optionally, in any example, the delivery device can be provided with one or more energy delivery elements capable of delivering to the target position sufficient energy to produce a therapeutic effect. The element can be located at the distal end of the needle or proximal to the distal end of the needle. The energy delivered can be in the form of electrical, radio wave, heat (including heating and cooling effects), microwave, shortwave, or acoustic energy. The energy delivery device is connected at its proximal end to a power source that includes control and feedback functions. The delivery device can incorporate an irrigation path for providing a coolant to the treatment site during treatment. A typical application of this treatment includes cancer resection.

[0132] Optionally, in any example, the delivery device can be provided with sensors that provide feedback including electrical, chemical, optical, acoustic, mechanical, and thermal parameters from the local and / or surrounding tissue. The sensors can be placed in proximity to, or distal or proximal to, the hydrogel port.

[0133] According to another aspect, the present invention provides a method of performing a lung treatment (e.g., lung needle biopsy or lung resection) including the following steps: Advance a coaxial cannula into the lung, where the distal portion of the coaxial cannula has one or more openings in its side wall; Advance the pulmonary treatment needle through the cannula to the treatment site within the lung; Actuate the pulmonary treatment needle to perform a pulmonary treatment at the treatment site; Remove the pulmonary treatment needle through the cannula; Advance the hydrogel delivery needle through the coaxial cannula, where the distal portion of the hydrogel delivery needle has one or more openings on its sidewall corresponding to one or more openings on the sidewall of the coaxial cannula; Align one or more openings of the coaxial cannula with the hydrogel delivery needle; Inject viscoelastic hydrogel (e.g., the viscoelastic hydrogel of the present invention) into the lung from one or more outlets of the hydrogel delivery needle and one or more outlets of the coaxial cannula to generate a seal plug surrounding the coaxial cannula and contacting the visceral pleura; and Withdraw the coaxial cannula and the hydrogel delivery needle through the seal plug.

[0134] According to one form, the viscoelastic hydrogel is delivered adjacent to the visceral pleura of the lung. According to one form, the pulmonary treatment needle is a biopsy needle. According to one form, the pulmonary treatment needle is a tissue resection probe.

[0135] According to another aspect, the present invention provides a composite viscoelastic hydrogel comprising a continuous phase and a dispersed polymer phase. According to one form, the dispersed phase is a colloidal polymer. Examples include gelatin and collagen. According to one form, the viscoelastic hydrogel comprises 2-20% colloidal polymer. According to one form, the viscoelastic hydrogel comprises 5-15% colloidal polymer. According to one form, the viscoelastic hydrogel comprises 8-12% colloidal polymer. According to one form, the viscoelastic hydrogel comprises about 10% colloidal polymer. According to one form, the colloidal polymer comprises gelatin or collagen. According to one form, the continuous phase polymer comprises, or consists of, hyaluronic acid (or other glycosaminoglycan). According to one form, the viscoelastic hydrogel comprises about 2-6% continuous phase polymer (i.e., hyaluronic acid). According to one form, the viscoelastic hydrogel comprises about 3-5% continuous phase polymer (i.e., hyaluronic acid). According to one form, the viscoelastic hydrogel comprises about 4-5% continuous phase polymer (i.e., hyaluronic acid). According to one form, the continuous phase polymer (i.e., hyaluronic acid) is either uncrosslinked or lightly crosslinked.

[0136] According to one form, the present invention provides a composite viscoelastic hydrogel comprising a continuous phase polymer comprising 2-6% polymer (i.e., hyaluronic acid) and a dispersed phase polymer comprising 2-20% colloidal polymer (i.e., gelatin) in the form of crosslinked polymer microbeads typically smaller than 100 microns in average dimension.

[0137] According to one form, the present invention provides a composite viscoelastic hydrogel comprising a continuous phase polymer comprising 2-6% hyaluronic acid and a dispersed phase polymer comprising 5-15% colloidal polymer in the form of crosslinked polymer microbeads smaller than 100 microns in average dimension. Detailed Description of the Invention All publications, patents, patent applications, and other references cited herein are incorporated by reference in their entirety for all purposes as if each individual publication, patent, or patent application were specifically and individually incorporated by reference in its entirety.

[0138] The high efficacy shown by the exemplary embodiments disclosed herein is due to the specific viscoelasticity of the delivered hydrogel. The hydrogel has both fluid and elastic properties. Elasticity is reversible deformation, i.e., a deformed object returns to its original shape. The mechanical properties of an elastic solid can be investigated by applying stress and measuring the strain of deformation. The fluid property is defined as the resistance to flow (i.e., viscosity), and can be measured by applying a shear force between two surfaces in a liquid and determining the resistance to flow. The physical properties of the gel due to viscoelasticity are represented by dynamic viscoelastic properties such as storage modulus (G’), loss modulus (G”), and tanδ (G” / G’). The storage modulus characterizes the stiffness of the composition and represents the storage of energy from the motion of the composition. The viscous modulus, also known as the loss modulus, represents the energy lost as viscous dissipation. tanδ is the ratio of the viscous modulus to the elastic modulus, tanδ = G” / G’. A high storage modulus and a low loss modulus indicate high elasticity and mean a hard gel. Conversely, a high loss modulus and a low storage modulus mean a highly viscous gel.

[0139] When the hydrogels described herein are used as biomedical materials, such as biodegradable hydrogel plugs used around the lungs to prevent pneumothorax, for example, the greater stiffness and storage modulus of the gel are thought to improve the sealing and barrier effects between tissues. Also, particularly when the elasticity is greater than that of the surrounding tissues, it contributes to an extended period (increased residence time) at the target site. The fluid nature of the hydrogel is due to a high tanδ, which improves juxtaposition with the surrounding tissues at rest. This fluid property also gives the hydrogel self-healing properties.

[0140] Therefore, it is desirable that gels for such applications have a good balance between viscosity and elasticity. If the zero-shear viscosity of the hydrogel is too high and the gel does not exhibit sufficient shear thinning behavior, injection into the target site through the delivery device may become difficult. The gel may not be easily juxtaposed to the surrounding tissue to create a barrier to prevent leakage of the liquid. Also, once the needle is withdrawn, the gel may not be able to easily flow back into the needle path. On the other hand, when tanδ exceeds 0.8, the gel behaves like a liquid and may infiltrate the surrounding tissue or be discharged from the needle path. That is, the hydrogels described herein are considered to have the most suitable physicochemical and rheological properties as viscous plugs for lung biopsy.

[0141] Therefore, the term "viscoelastic hydrogel" refers to a hydrogel that exhibits viscoelastic properties. Its storage modulus (G') is generally greater than 400 Pa, more preferably greater than 800 Pa, and even more preferably greater than 1000 Pa. The viscoelastic hydrogel has a tangent delta (tanδ; G" / G') of dynamic viscoelasticity at a frequency of 1 Hz of from 0.01 to 0.8, preferably from 0.1 to 0.5, and more preferably from 0.2 - 0.5. Preferably, the viscoelastic hydrogel exhibits a loss modulus (G") of from 200 to 6000 Pa, more preferably from 400 to 2000 Pa, in dynamic viscoelasticity at 25°C and a frequency of 1 Hz. The viscoelastic hydrogel may be uncrosslinked, lightly crosslinked, or strongly crosslinked in order to impart appropriate characteristics such as increasing the storage modulus (G') and in vivo retention time.

[0142] The term "shear thinning" as applied to the hydrogels herein means that when a shear stress is applied to the hydrogel, the storage modulus (G') decreases, the tanδ increases, and the overall viscosity decreases. This property imparts injectability to the hydrogel and enables injection through a thin needle used in minimally invasive procedures such as lung biopsy (17 - 20 gauge) and lung resection (10 - 14 gauge). The shear thinning hydrogels described herein typically have a storage modulus (G') of 1 - 100 Pa, more preferably 1 - 50 Pa, at a dynamic viscoelasticity of 1 Hz and 100% strain. Further, the hydrogels described herein have self - healing properties and retain a high storage modulus (G') and loss modulus (G") when the shear stress is removed.

[0143] The hydrogels described herein have shear thinning properties. That is, when a shear stress is applied, the storage modulus (G') decreases, the tanδ increases, and the overall viscosity decreases. This property enables the gel to be injected through a thin needle used in minimally invasive procedures such as lung biopsy. The gels described herein exhibit physical properties with a storage modulus (G') less than 100 Pa, preferably less than 50 Pa, at a dynamic viscoelasticity of 1 Hz and 100% strain. Further, the gels described herein exhibit rapid thixotropic recovery properties and immediately retain a high storage modulus (G') and loss modulus (G") when a high shear rate is removed.

[0144] Measurements of dynamic viscoelasticity and dynamic viscosity were performed using an AR2000 type rheometer manufactured by TA Instruments Japan Co., Ltd. under the following conditions. Measurement method: Vibration method, strain control Measurement temperature: 25 °C Shape: Cone - plate angle 4° Measurement shape: 4 cm Cutting gap: 112 μm Frequency: 1 Hz As used herein, the term "self-healing" as applied to the viscoelastic hydrogels of the present invention refers to the ability of the hydrogel to be reconstituted. "Self-healing" also refers to the ability of the hydrogel to spontaneously form new bonds when old bonds within the material are broken. For example, when an annular seal plug of a viscoelastic hydrogel is delivered around a delivery needle, upon removal of the needle, the self-healing viscoelastic hydrogel flows back to form a non-annular seal plug typically consisting of a single, cohesive matrix.

[0145] Optionally, in any example, the occlusive hydrogel plug can self-heal through the center of the path independently of the in vivo environment. This refers to the ability of the hydrogel to fill the path by a time-dependent viscoelastic flow mechanism.

[0146] Optionally, in any example, the occlusive hydrogel plug can self-heal through the center of the path depending on the in vivo environment. The stress from the in vivo environment applied to the hydrogel plug may improve the ability to self-heal in a shorter time compared to a non-disrupted plug.

[0147] Optionally, in any example, the hydrogel should be able to self-heal under its own weight without the influence of the surrounding environment. This is demonstrated by a single mass of the hydrogel, for example, a sphere of hydrogel produced using about 0.5 ml of hydrogel. A 17-gauge needle can be passed through the center and withdrawn to create a cylindrical path. The sphere with the cylindrical path in the center can be placed on a pedestal such that the axis of the cylindrical path is perpendicular to the pedestal. The size of the path can be measured over time. For the viscoelastic hydrogels of the present invention described herein, particularly hydrogels containing 2-6% hyaluronic acid, the following was observed: Initially, the path in the sphere is visible, but over time (depending on the hydrogel composition, 1-15 minutes), due to the self-healing of the hydrogel, this path becomes blocked. This is the result of the time-dependent flow of the hydrogel.

[0148] In any example, some or all of the viscoelastic hydrogel comprises a hyaluronic acid hydrogel. The hyaluronic acid polymer forms a continuous layer through the three-dimensional substrate. In any example, the viscoelastic hydrogel is a high molecular weight hyaluronic acid hydrogel. In any example, the viscoelastic hydrogel is a shear-thinning hydrogel (where the viscosity decreases when a shear stress is applied). The polymer materials employed to form the viscoelastic hydrogel include hyaluronic acid, particularly high molecular weight hyaluronic acid. Other hydrogel materials suitable for use in the present invention are outlined in the review articles of 'Shear-thinning hydrogels for biomedical applications', Soft Matter, (2012) 8, 260, 'Injectable matrices and scaffolds for drug delivery in tissue engineerinG' Adv Drug Deliv Rev (2007) 59, 263-272, and 'Recent development and biomedical applications of self-healing hydrogels' Expert Opin Drug Deliv (2017) 23: 1-15.

[0149] As used herein, "hyaluronan", "hyaluronic acid" or "HA" refers to an anionic non-sulfated glycosaminoglycan that forms part of the extracellular matrix of humans and consists of the repeating disaccharide 4)-β-d-GlcpA-(1→3)-β-d-GlcpNAc-(1→ or any salt thereof. Hyaluronan is the conjugate base of hyaluronic acid, but the two terms are used interchangeably. When salts of hyaluronic acid are used, the salt is generally the sodium salt, but calcium salts and potassium salts can also be used. Hyaluronic acid or hyaluronan can be obtained from any source, including bacteria. Sodium hyaluronate derived from Streptococcus equi is sold by Sigma-Aldrich under product reference numbers 53747-1G and 53747-10G. The production of hyaluronic acid using microorganisms is described in Liu et al (Microb Cell Fact. 2011; 10:99). The term also includes derivatives of hyaluronic acid, such as those derived from cationic groups disclosed in US2009 / 0281056 and US2010 / 0197904, and other functionalized derivatives disclosed in Menaa et al (J. Biotechnol Biomaterial S3:001 (2011)), Schante et al (Carbohydrate Polymers 85 (2011)), EP0138572, EP0216453, EP1095064, EP0702699, EP0341745, EP1313772 and EP1339753.

[0150] Hyaluronic acid is classified by its molecular weight: high molecular weight (preferably > 1000 kDa (1 MDa)), medium molecular weight (preferably 250 - 1000 kDa), low molecular weight (preferably 10 - 250 kDa) and oligo - hyaluronic acid (preferably < 10 kDa). The effect of molecular weight on the viscosity of hyaluronic acid hydrogels has been reported previously. The final rigidity and viscosity of the gel depend on both molecular weight and solution concentration. In a study of the rheological properties of hyaluronic acid with different molecular weights, Falcone et al. (J Biomed Mat Res, 76A, 4, pp.721 - 728) found that high - molecular - weight hyaluronic acid is considerably more cohesive than low - molecular - weight hyaluronic acid in terms of its rheological and binding properties. The presence of high - molecular - weight hyaluronic acid hydrogels at the wound has been shown to lead to a reduction in scarring. High - molecular - weight hyaluronic acid is anti - inflammatory and has been shown to result in enhanced angiogenesis and enhanced immunosuppression. Jiang et al. found that high - molecular - weight hyaluronic acid protects against epithelial cell death in lung injury “Regulation of lung injury and repair by Toll - like receptors and hyaluronan” Nature Medicine (2005) 11, 11 1173 - 1179. Furthermore, inhalation of high - molecular - weight hyaluronic acid has been applied to the treatment of lung diseases such as bacterial nasopharyngitis, chronic bronchitis, cystic fibrosis, and asthma. In some embodiments, the hyaluronic acid composition of the hydrogel is not cross - linked and does not contain other therapeutic agents. A hyaluronic - acid - based hydrogel with characteristics potentially suitable for this use is described in US9492474B2 ‘Compositions of hyaluronan with high elasticity and uses thereof’. This document describes a material called Elastovisc™ composed of high - concentration, high - molecular - weight hyaluronic acid. Its intended use is injection into joints for pain relief and treatment of osteoarthritis.

[0151] As used herein, the term 'hyaluronan hydrogel' preferably includes a three-dimensional network of hyaluronan polymers in an aqueous dispersion medium. The hyaluronan polymers form a continuous phase throughout the three-dimensional matrix. Optionally, in any example, the hyaluronan polymers are uncrosslinked. Optionally, in any example, the hydrogel does not use a crosslinking agent. Optionally, in any example, the matrix is formed from a homopolymer, typically a hyaluronic acid homopolymer. Optionally, in any example, the hydrogel is a single gel system that substantially does not contain other polymers. Optionally, in any example, the hydrogel is pH-adjusted or matched to the pH of the physiological environment by a buffer. Optionally, in any example, the matrix is lightly crosslinked. For this purpose, any crosslinking agent known for crosslinking hyaluronic acid can be used. Crosslinking agents include epichlorohydrin, divinyl sulfone, 1,4-bis(2,3-epoxypropoxy)butane, (or 1,4-bis(glycidyloxy)butane or 1,4-butanediol diglycidyl ether = BDDE), 1,2-bis(2,3-epoxypropoxy)ethylene, 1-(2,3-epoxypropyl)-2,3-epoxycyclohexane.

[0152] In any example, the viscoelastic hydrogel is composed of a 'multicomponent' hydrogel in which at least two hydrogels are evenly mixed and dispersed as a homogeneous hydrogel mixture. Each hydrogel forms a continuous phase throughout the entire hydrogel mixture. This configuration is also called a semi-interpenetrating polymer (hydrogel) network or an interpenetrating polymer (hydrogel) network composed of two or more hydrogels. As an example, a hyaluronic acid hydrogel (in a concentration range of 1 - 5%) can be mixed with a methylcellulose hydrogel (in a concentration range of 3 - 15%). Similarly, two or more hydrogels can be combined to form a single bundled network, where each hydrogel improves the properties of the entire network. The properties of each hydrogel are provided for improving rigidity, increasing viscosity, improving injectability (shear thinning), improving self-healing properties, extending the in-vivo retention (biodegradation) time of the hydrogel, imparting hemostatic properties, imparting antibacterial properties, imparting anti-inflammatory properties, imparting anticoagulant properties, imparting coagulation-promoting properties, imparting coloring and imprinting performance (visible light and X-ray detection), imparting diagnostic or therapeutic effects (e.g., chemotherapy), imparting resistance to harsh heat (high and low temperatures), improving biocompatibility, and improving the overall adjustment and manufacturability of the hydrogel. These one or more hydrogels can be crosslinked to improve properties such as increasing the in-vivo retention time of the hydrogel.

[0153] In any example, the viscoelastic hydrogel is a "colloidal hydrogel", which refers to a composition formed by combining subunits of small hydrogels to form a homogeneous bound substrate. In a colloidal hydrogel, the solution or dispersion medium is typically water or saline, but can also be other biocompatible liquids. Colloidal hydrogels are typically produced by hydrating nano-scale or micronized biocompatible polymer particles such as, for example, nanoparticles, microparticles, microcapsules, microfibers, microspheres and / or broken particles. The particles can be uniform or irregular in shape and size. Examples of polymers include proteins such as gelatin, collagen (e.g., soluble collagen), albumin, hemoglobin, dextran, fibrinogen, fibrin, fibronectin, elastin, keratin, laminin, casein, their derivatives, and combinations thereof. Polymers include polysaccharides such as glycosaminoglycans (e.g., hyaluronic acid, hyaluron or chondroitin sulfate), starch derivatives, cellulose derivatives, hemicellulose derivatives, xylan, agarose, alginate, chitosan, and combinations thereof. As yet another alternative, polymers include non-biological hydrogel-forming polymers such as polyethylene glycols, polyacrylates, polymethacrylates, polyacrylamides, polyvinyl polymers, polylactide glycolides, polycaprolactones, polyoxyethylenes, their derivatives, and combinations. These particles can be crosslinked by various means known in the art, including physical (heating, cooling, irradiation) and chemical crosslinking. As an example, crosslinked polymers include dehydrated heat-crosslinked gelatin powder obtained by dehydrating gelatin at high temperature for a long time to make it insoluble. Typically, a temperature above 100 °C is used in this process, and dry heat or vacuum heat can be used. The degree of crosslinking of the gelatin powder during dehydration affects the degree of swelling due to water absorption. In any example, the viscoelastic hydrogel optionally contains about 0.2 to 30%, 15 to 28% or 20 to 25% (w / v) of a hydrogel-forming polymer.

[0154] In any example, the viscoelastic hydrogel is a "biphasic" hydrogel, which refers to a hydrogel formed by combining a colloidal hydrogel with a continuous-phase hydrogel (by mixing or blending). The colloidal hydrogel forms a phase evenly dispersed within the continuous hydrogel phase. A natural or synthetic biodegradable polymer can be used to form the continuous phase. An example thereof is glycosaminoglycans, such as hyaluronan and its derivatives. Hyaluronan is preferably uncrosslinked or lightly crosslinked in order to retain its viscoelastic properties, particularly its thixotropic and self-healing properties. In any example, hyaluronan is provided at a concentration of 1 to 6%, preferably 3 to 5%. In any example, hyaluronan governs the rheological properties of the biphasic hydrogel. As mentioned above, various biodegradable polymers (two examples being collagen and gelatin) are suitable for the formation of the colloidal hydrogel phase. By adding a sufficient amount of the colloidal hydrogel phase, the residence time of the hydrogel in vivo can be advantageously increased. This provides the period required for tissue healing. An additional advantage is that the increased residence time confers a long-term imprinting function on the biopsy site, making it usable for video-assisted thoracoscopic surgery (VATS). Suitable polymers are insoluble in an aqueous environment and can be achieved by crosslinking the polymer in a conventional manner. An example is heat-dehydration crosslinked gelatin. It should be noted that introducing too large an amount of the colloidal hydrogel phase impairs the injectability and self-healing properties of the composition. In any example, the "biphasic" hydrogel contains the colloidal hydrogel at a concentration of 0.2 to 30%, 15 to 28% or 20 to 25% (w / v) in the hydrogel-forming polymer.

[0155] In any example, the viscoelastic hydrogel exhibits a storage modulus (G') greater than 400 Pa, preferably greater than 600 Pa, more preferably greater than 800 Pa, and even more preferably greater than 1000 Pa. In any example, the viscoelastic hydrogel exhibits a tanδ (G" / G') of dynamic viscoelasticity measured with a rheometer at 25 °C, 1 Hz, and a strain rate of 1% from 0.01 to 0.8, more preferably from 0.1 to 0.6.

[0156] In any example, the viscoelastic hydrogel is provided as a powder and reconstituted with a physiologically acceptable liquid such as water, saline, autologous blood, or autologous plasma prior to a surgical procedure. Synthetic liquids such as low molecular weight PEG or glycerol can also be used. The powder is composed of any suitable biocompatible polymer or combination of polymers. As an example, the powder may be supplied to a hydrogel delivery needle. As an example, the powder can be supplied to a syringe and an appropriate reconstitution liquid can be supplied to a second syringe along with it. As an example, the powder has an average particle size of 1 to 500, 10 to 100, or 30 to 40 microns. The powder may be uniform or irregular in its shape, morphology, and size distribution and is produced by milling or other means known in the art. According to one example, the hydration of the powder can be controlled, for example, in the case of a collagen-like substrate such as collagen or gelatin, by varying the degree of drying of the powder particles.

[0157] In any example, the hydrogels described herein may be provided as separate components, for example, supplied to a number of syringes, and equipped with means to mix the components prior to injection through the syringes. A cross-linking agent can be supplied to one or more of these components to impart the material properties necessary to achieve a thixotropic and self-healing hydrogel. Mixing can be achieved by reciprocating the contents of the syringe, but a static mixer can be used to shorten the process.

[0158] In any example, the viscoelastic hydrogel composition is supplied in a physiological buffer such as, for example, a phosphate buffer or a bicarbonate buffer. According to one example, the pH of the composition is between pH7 and pH9 or between pH7.5 and pH8.5. According to one example, the pH of the composition is pH8.0. According to one example, the pH of the composition is pH7.5. According to one example, the pH of the composition is pH8.5. If necessary, acids (such as HCl) and bases (such as NaOH) can be added to the composition to achieve the desired pH. According to a specific example, the hyaluronic acid hydrogel described herein essentially has hyaluronic acid with an average molecular weight between 1-2 MDa present at a concentration of 50 mg / ml (or about 5% w / v), and the average molecular weight is 1-2 Mda. Ranges intermediate the cited values are also within the scope of the present invention. For example, the hyaluronan content of the composition described herein is between about 3% and about 15% (w / v), between about 3% and about 10% (w / v), between about 3.5% and about 9% (w / v), between about 4% and about 8% (w / v), or between about 5% and about 7% (w / v). Further, the amount of hyaluronan in a specific volume can be expressed in alternative units (for example, g / l or mol / l). The amount of hyaluronan in a specific volume expressed in various units can be converted by those with ordinary skill in the art.

[0159] As used herein, the terms "occluding plug", "hydrogel plug" or "gel plug" mean a single viscoelastic hydrogel, for example, a hyaluronic acid hydrogel suitable for delivery through a needle to a site in the lung, having sufficient viscoelasticity to push apart the tissue surrounding the needle and coalescing to form a single annular occluding plug around the needle. The viscoelastic properties and rigidity of the gel prevent tissue invasion and allow the gel to accurately oppose the tissue and form an effective seal around the needle and subsequently around the cannula, thereby preventing air in the lung from leaking past the plug. Due to the viscoelastic behavior of the hydrogel, when the cannula is removed, the annular plug coalesces, closing the hole in the annular plug and withstanding and sealing against the visceral pleura after removal of the coaxial cannula.

[0160] In any example, the hydrogel plug should exhibit "restricted swelling" behavior, which means that in vivo, for example, when placed under the surface of the lung to prevent pneumothorax, its volume should not increase significantly. A hydrogel plug that swells to a significant extent may have unwanted physiological or biological effects. Some swelling of the hydrogel in vivo can be assumed, but the swelling of the hydrogel plug should be restricted in order to preserve the original tissue. Swelling is characterized by generating and measuring a sphere of hydrogel of a given size. For example, 500 μl of hydrogel is rounded into a sphere, and this sphere of hydrogel is placed in an aqueous solution. This 500 μl volume initially corresponds to a sphere with a diameter of approximately 10 mm. The aqueous solution is a saline solution or a solution mimicking body fluid and may contain the correct enzyme activity found in vivo. The size, shape, and dissolution of the hydrogel sphere are observed over a long period of time. The swelling rate is: Swelling rate (%) = (Ws - Wd) / Wd x 100 [Wd = weight of the polymer; Ws = weight of the swollen polymer] and is determined from

[0161] Preferably, the swelling rate should not exceed 250%, more preferably not exceed 150%, and even more preferably not exceed 130%. The degradation of the sample can be determined by comparing the dry weight of the polymer over time. The dry weight is determined by lyophilizing the sample. The degradation rate of the sample can be calculated from the weight of the remaining hydrogel: Remaining hydrogel (%) = (W2 - W1) / W1 x 100 [W1 = dry weight of the original polymer; W2 = dry weight of the polymer dependent on time].

[0162] By combining polymer materials with different thermal responsiveness, thixotropicity, shape memory, and biological properties, a composite hydrogel with improved properties for this application can be obtained. The improvements include increased biocompatibility, injectability, viscosity, altered degradation, drug conjugation, tissue adhesion, cohesion, sealing ability stability, and hydrophilicity. Gelatin and hyaluronic acid are given as two examples. Substances that can be combined with these polymers include methylcellulose, oxidized cellulose, carboxymethyl cellulose, and carboxylic acids.

[0163] Optionally, in any example, the viscoelastic hydrogel is formed from a thermoresponsive substance. The range of thermoresponsive hydrogels suitable for this purpose is described in the prior Klouda: ‘Thermoresponsive hydrogels in biomedical applications: a seven year update’ Eur J Pharm Biopharm 2015 97(PtB) 339-49 and Ruel-Gariepy: ‘In situ-forming hydrogels - review of temperature-sensitive systems’ Eur J Pharm Biopharm 2005 58 409-426. Of particular note is a family of nonionic triblock copolymers in which a hydrophobic polypropylene oxide (PPO) central block called poloxamer is flanked by two hydrophilic polyethylene oxide (PEO) blocks. The Food and Drug Administration has designated poloxamer 407 as an inactive material for different types of formulations. At solution concentrations of 20% or more, poloxamer 407 undergoes thermoreversible gelation between room temperature and body temperature. For drug delivery applications, the generation of thermoresponsive hydrogels by the addition of hyaluronic acid to poloxamer solutions is described in Moyol et al: ‘A novel poloxamer / hyaluronic acid in situ forming hydrogel for drug delivery: rheological, mucoadhesive and in vitro release properties’ Eur J Pharm Biopharm 2008 70 199-206.

[0164] In any example, the viscoelastic hydrogel can be produced by mixing a certain amount of a thermoresponsive hydrogel with a certain amount of a shear-thinning hydrogel such as hyaluronic acid, thereby increasing the stiffness of the final hydrogel and being able to affect biodegradability and biocompatibility. This addition provides additional benefits but has little effect on the injection force required to inject the hydrogel through a delivery needle.

[0165] In any example, the viscoelastic hydrogel can contain a contrast agent, which can be mentioned as an additive that can be contained in an appropriate amount in the gel, and the hydrogel can create contrast against surrounding tissues. Thus, for example, during a surgical procedure or a follow-up surgical procedure, the hydrogel plug and the injection site can be visually identified and / or targeted. The identification can be visual or via a guidance system such as a CT scan, ultrasound, or fluoroscopy. Additives added to the hydrogel at various concentrations to achieve effective visual contrast include ionic and non-ionic contrast agents, methylene blue, indigo carmine, toluidine blue, lymphazurin, hematoxylin, eosin, indocyanine green (ICG), ink, and also carbon-based powders such as carbon black, carbon nanotubes, graphene, ceramic powders such as aluminum oxide, titanium oxide, calcium sulfate. The hydrogel also contains a detectable marking agent. Detectable marking agents suitable for use in the hydrogels described herein include any composition that can be detected by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical, or chemical means. A wide variety of detection markers including luminescent labels, radioisotope labels, enzyme labels are known in the art. These marking agents are either mixed with the hydrogel or chemically conjugated to the hydrogel molecules.

[0166] In any example, the viscoelastic hydrogel can be composed of a therapeutic agent or a biologically active agent. Therapeutic agents that may be linked to or embedded in the hydrogel include, but are not limited to, analgesics, anesthetics, antifungal agents, antibiotics, anti-inflammatory agents, anthelmintics, antidotes, antiemetics, antihistamines, antihypertensives, antimalarials, antibacterial agents, antioxidants, antipsychotics, antipyretics, disinfectants, anti-arthritis agents, antituberculosis agents, antitussives, antivirals, cardiotonics, cathartics, chemotherapeutic agents, coloring or fluorescent imaging agents, corticosteroids (such as steroids), antidepressants, inhibitors, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetics, potassium supplements, radiosensitizers, radioisotopes, sedatives, stimulants, sympathomimetics, tranquilizers, anti-urinary tract infection agents, vasoconstrictors, vasodilators, vitamins, xanthine derivatives, etc. In any example, the hydrogels described herein contain one or more anesthetics. Examples of anesthetics include, but are not limited to, proparacaine, cocaine, procaine, tetracaine, hexylcaine, bupivacaine, lidocaine, benoxinate, mepivacaine, prilocaine, mexiletine, budecaine, and etidocaine. In any example, the viscoelastic hydrogel further contains foaming agents, foam stabilizers, surfactants, thickeners, diluents, lubricants, wetting agents, and plasticizers.

[0167] In any example, some or all of the viscoelastic hydrogel can be "biodegradable" and configured to degrade over time in vivo. Different phases or components of the viscoelastic hydrogel can be configured to degrade at different rates. The biodegradable material is preferably eliminated from the body without causing inflammation or an immune response. In the viscoelastic hydrogels described herein, the time required for complete biodegradation is less than 1 year, preferably less than 1 month, more preferably less than 1 week and even more preferably less than 72 hours. An additional benefit of a short degradation period is to allow the lung tissue to return to normal and prevent excessive scar tissue formation at the delivery site. Also, limiting the residence time and scar tissue formation ensures that the delivery of the hydrogel plug does not interfere with the radiographic analysis of the follow-up of the lung suspected of having a lesion. Non-crosslinked systems result in a shorter in vivo residence time compared to crosslinked systems. The high molecular weight (>1000 kDa) and high concentration (40 - 60 mg / ml) hyaluronic acid hydrogels described herein have a degradation period of less than 1 week and also less than 72 hours. A longer degradation time is possible by modifying the original molecular structure of hyaluronic acid by crosslinking or other means. A longer degradation time is also possible by combining the hyaluronic acid hydrogel with one or more hydrogels or colloidal hydrogels to form a composite hydrogel. While the other type of hydrogel is removed, one type of hydrogel remains at the target site for a longer time. For example, the hyaluronic acid hydrogel can be combined with a crosslinked polymer (e.g., hyaluronan, hylan, collagen or gelatin) to form a composite hydrogel. The crosslinked polymer can be configured to have a residence time longer than 1 week and often longer than 2 weeks using various crosslinking methods known in the art. Crosslinking agents used as part of an implantable precursor include aldehydes, polyaldehydes, esters and other chemical functional groups suitable for crosslinking proteins. For example, physical crosslinking methods such as exposing the polymer to heat, low temperature, or radiation can also be used. A crosslinking agent can be added to improve binding, rigidity, mechanical strength and barrier properties.

[0168] As used herein, the term "in vivo residence time" as applied to the occlusion plugs of the viscoelastic hydrogel means the period during which an occlusion plug of 0.1 to 1 ml, preferably 0.2 to 0.8 ml, more preferably 0.3 to 0.5 ml, exists in the lung tissue of the living body without losing significant structural integrity. The in vivo residence time is a period sufficient for the hole in the visceral pleura to heal and, ideally, for the surrounding lung tissue to heal. The method for estimating the in vivo residence time of the hydrogel is as described below. To achieve an appropriate in vivo residence time sufficient for healing, the hydrogel is composed of certain unmodified materials (including proteins) with longer residence times. Examples include collagen, oxidized cellulose, starch, and extracellular matrix (ECM). The cross-linked hydrogels described herein have been found to have an in vivo residence time longer than two weeks. Optionally, the thixotropic viscoelastic hydrogel can have an in vivo residence time of at least one week, preferably at least two weeks, and ideally at least three weeks.

[0169] In any example, the positioning mechanism can adjust the insertion depth of the delivery needle through the coaxial cannula when it is fully advanced within the cannula (first adjustment) and when guiding the insertion depth of the coaxial cannula beyond the needle (subsequent second adjustment). In the first movement, the needle is positioned within the tissue to deliver a substance (hydrogel) for forming an occlusion plug to the lung, and in the second adjustment, the cannula is advanced beyond the needle to cover the hydrogel outlet through the occlusion plug. The positioning mechanism can be pre-adjusted to define a pre-set insertion depth X. The pre-set insertion depth X is generally the depth at which the hydrogel outlet of the needle is positioned at the target site of the lung tissue, for example, immediately distal to the visceral pleura. The positioning mechanism generally includes a cannula depth guide configured to display the coaxial cannula insertion depth Y to the user, at which depth the distal end of the cannula penetrates the occlusion plug. The positioning mechanism is configured such that when the user adjusts the insertion depth of the needle, the cannula depth guide is also adjusted. In any example, the positioning mechanism includes a movable hub mounted on the needle to move axially from a distal position indicating a first insertion depth along the needle to a proximal position indicating a second insertion depth deeper than the first insertion depth. The positioning mechanism consists of a fixed housing attached to the hydrogel delivery needle and a movable hub mounted on the needle to move axially along the needle, configured such that the distal end contacts the proximal surface of the coaxial cannula, where the fixed housing is configured to cooperate with the movable hub to define a pre-set needle adjustment depth by relative axial movement. The positioning mechanism includes a cannula depth guide consisting of an arm that is axially connected to the fixed housing of the positioning mechanism and extends distally of the movable hub to move together. The length of the arm distally of the movable hub is preferably equal to the cannula insertion depth. Generally, the cannula is first inserted into the muscle tissue proximal to the chest cavity, and then an image is taken to determine the distance P from the distal end of the cannula along the target direction of the lung to the chest cavity. Next, using this distance P, the positioning mechanism is adjusted by the scale marks 20, 16A of the positioning mechanism so that the hydrogel outlet is arranged at a distance P + X, which is the target position, when the needle is fully inserted into the cannula.This adjustment automatically adjusts the cannula depth guide as well and displays to the user the cannula insertion depth Y.

[0170] In any of the optional examples, the procedures described herein require image guidance such as, for example, CT scan, fluoroscopy, or ultrasound. The methods described herein may include imaging of one or more of the lung / intercostal muscles to assist with the procedure. An image is first taken to determine the initial insertion depth of the cannula. An image is taken to determine the distance P from the most distal end of the cannula along the desired needle trajectory direction to the intended organ when the coaxial cannula is in the first position. The methods described herein may take additional images of the lung to determine the distance the cannula is advanced towards the target organ such that the cannula is positioned at the tip of the delivery needle. Generally, these images are taken under the guidance of an interventional radiologist or radiologic technologist.

[0171] Illustration The present invention will be described more specifically below with reference to examples, which are merely exemplary and for illustrative purposes only and do not in any way limit the present invention as recited in the scope of the exclusive rights claim. These examples constitute the presently contemplated optimal mode for practicing the invention.

[0172] The mechanism of pneumothorax resulting from transthoracic needle biopsy is illustrated in FIGS. 1A-1D (prior art). FIG. 1A is a cross-sectional view of the thoracic cavity A, including the pleural cavity E defined by the chest wall muscle B, rib C, lung tissue D, and the serosa of the chest wall (parietal pleura F) and the serosa of the lung (visceral pleura G). During a lung biopsy procedure (FIG. 1B), the core needle H and the coaxial cannula I are advanced transcutaneously through the skin O and the pleural cavity E toward the suspected lung nodule J. In FIG. 1C, the core needle H is withdrawn and replaced with a biopsy needle K, which is advanced through the cannula 2 to obtain a tissue specimen from the suspected lung nodule J. As shown in FIG. 1D, the withdrawal of the biopsy needle K and the cannula I leaves a gap L in the lung tissue D and a hole L1 in the visceral pleura G. The dense muscle tissue of the chest wall B contracts around the gap created by the withdrawal of the needle. However, the holes L and L1 created in the lung tissue D and the visceral pleura G by the biopsy needle are not completely sealed. Due to the pressure gradient between the lung tissue D and the pleural cavity E, air escapes through the hole L1 created in the visceral pleura G and enters the pleural cavity E, creating a collection of air in the pleural cavity E called pneumothorax M. If a relatively large blood vessel is punctured during the biopsy procedure, the pleural cavity may also be filled with blood, resulting in a condition called hemothorax. The frequency of hemothorax is not as high as that of pneumothorax. Hemothorax and pneumothorax M can grow to a significant size, causing partial or complete collapse of the lung, leading to respiratory difficulty and requiring treatment.

[0173] Referring to FIGS. 2A-2E, a method for overcoming the drawbacks of the prior art is presented. FIGS. 2A-2E illustrate a method for delivering a viscoelastic hydrogel plug to the target location in the lung. In this example, a medical device system is used that includes a coaxial cannula 2 with proximal connectors such as a distal end 2A and a luer lock 2B, a core needle 3, and a hydrogel delivery needle 4 with a tissue-penetrating end 5 at the distal end and a hydrogel vent 6 disposed on the side of the needle proximal to the penetrating end 5. The system also includes a syringe 15 with a reservoir 15b filled with any of the viscoelastic hydrogel materials described herein. The syringe may be replaced with a pump, plunger, fluid delivery mechanism, or any element suitable for delivering a viscous hydrogel.

[0174] As shown in FIG. 2A, the assembly of the core needle 3 and the cannula 2 is inserted into the patient's chest wall to a depth such that the assembly is located in the chest wall B and does not penetrate the lung D. The coaxial cannula 2 refers to a needle device having a lumen for receiving a penetrating device such as, for example, the core needle 3, where the constructed core needle and cannula 2 are used for insertion into the chest through the skin surface. Generally, the coaxial cannula is sized from 10 to 19 gauge. In additional examples, the coaxial cannula also refers to a sheath, introducer, plug / probe assembly, guide catheter, trocar needle, port device or other guiding device known in the art.

[0175] As shown in FIG. 2B, the core needle 3 is withdrawn from the cannula 2 and the hydrogel delivery needle 4 is advanced through the cannula 2. The hydrogel delivery needle 4 typically has a penetrating tip and typically has a hydrogel outlet 6 disposed on the side of the needle proximal to the penetrating tip 5, for example, from 0.5 to 15 mm from the penetrating tip 5. The delivery needle 4 has a distal end configured to be inserted into the body and a proximal end located outside the body during use. The needle is generally made of metal, although the positioning (adjusting) mechanism may be made of plastic, polymer or metal. The needle has a proximal end made of a polymer tube and includes a luer lock to facilitate fluid connection of the needle (or polymer tube portion) to a pump or syringe 15. Generally, the hydrogel delivery needle 4 is sized from 13 to 20 gauge. The hydrogel delivery needle 4 is inserted to a depth such that the hydrogel outlet 6 is located in the lung tissue distal from the pleural cavity E and the visceral pleura G. Positioning of the hydrogel outlet 5 (as in the original text) to the target site can be achieved using a radiopaque or radiolucent marker 32 on the delivery needle located at a known distance X from the hydrogel outlet 6 under CT guidance. By superimposing the radiolucent marker 32 over the pleural cavity E, the hydrogel outlet can be positioned at a predetermined distance X from the pleural cavity E into the lung. The pleural cavity E is a very thin space approximately 25 μm wide and is often referred to as a virtual space. As seen in FIG. 7 described below, the pleural cavity E can be identified as the transition between the lung (dark region) and the chest wall (bright region) under CT guidance. Positioning of the radiolucent marker 32 over the pleural cavity E can be achieved by stepwise scanning and fine adjustment of the needle 4, or by fine adjustment under continuous fluoroscopic guidance.

[0176] As shown in FIG. 2C, a syringe 15 with a storage container 15B filled with a hydrogel is attached to a delivery needle 4 via a luer lock 12. A predetermined amount of viscoelastic hydrogel is injected into the lung through a hydrogel outlet 6, forming an annular viscoelastic occlusion plug 7 closed around the delivery needle 4. Following this step, the coaxial cannula 2 is advanced beyond the delivery needle 4 through the occlusion plug 7 towards a suspected pulmonary nodule J. The hydrogel delivery needle 4 is withdrawn and left within the hydrogel occlusion plug 7 surrounding the cannula 2 so that a lung biopsy needle K can be received. Next, as shown in FIG. 2D, the lung biopsy needle K is advanced through the cannula 2 to perform a lung biopsy. After the biopsy is performed, both the lung biopsy needle K and the cannula 2 are withdrawn. As shown in FIG. 2E, even after the needles are withdrawn, the occlusion plug 7 remains at that position in the lung tissue. Due to the physical properties of the viscoelastic hydrogel material, the occlusion plug 7 reflows into the space left by the needle and seals the hole L1 left in the visceral pleura G by the coaxial cannula 2. These steps illustrate a method of performing a lung biopsy that reduces the possibility of causing pneumothorax. The efficacy of the occlusion plug 7 depends on its ability to prevent air in the ventilated lung tissue D from escaping through the hole L1 in the visceral pleura G.

[0177] For several reasons, it may be difficult to position the delivery device as described above. First, the clinician may not have access to fluoroscopic guidance and may not be able to accurately position the delivery needle 4 with the marker band 32. Second, repeated CT scans can be harmful to the patient, and accurate positioning of the marker band 32 on the needle may result in high radiation exposure. Furthermore, a delay in the placement of the hydrogel plug can lead to an increased risk of pneumothorax while the needle is in the unprotected lung tissue. To quickly, easily, and accurately target the injection depth into the lung so that the viscoelastic hydrogel can achieve effective sealing, the delivery needle 4 for the hydrogel is provided with a positioning mechanism described below.

[0178] Referring to FIGS. 3A-3B and FIGS. 4A-4F, in the illustrated medical device, parts referred to in the previous embodiments are assigned the same reference numbers. FIG. 3A shows a medical device generally designated by reference numeral 10, which includes a single-lumen hydrogel delivery needle 4 having a distal penetrating tip 5, a hydrogel vent 6 disposed on the side of the needle proximal to the penetrating tip 5, a marker band 32 disposed on the needle proximal to the hydrogel vent 6, a positioning mechanism 8 disposed along the delivery needle 4, and a luer lock 12 attached to the proximal end of the delivery needle 4. A visible mark 32A is attached to the delivery needle 4 proximal to the penetrating tip 5, where the distance between the visible marks 32A (the distance represented by H) is equal to the length of the coaxial cannula 2. When the delivery needle 4 is inserted through the lumen of the coaxial cannula 2, this visible mark 32A can be used to indicate that the distal end of the coaxial cannula 2 is adjacent to the penetrating tip 5. The components of the positioning mechanism 8 are shown as a cross-sectional view for illustrative purposes and include a movable hub 17 that can move freely along the axis of the delivery needle 4. The movable hub 17 is a single member that includes a central passage through which the delivery needle 4 passes. A threaded set screw 18 is mounted perpendicular to the axis of the delivery needle 4 beside the movable hub 17 and passes through the movable hub 17 to reach the delivery needle 4. Rotation of the threaded set screw 18 fixes the axial position of the positioning mechanism 8 at a selected location along the delivery needle 4. The medical device 10 also includes a coaxial cannula 2 that includes a central lumen that extends from a proximal female luer lock 2B to a distal face 2A. The lumen of the coaxial cannula 2 is configured to receive the central passage of the delivery needle 4. The medical device also includes a measuring device 19 that includes a graduated measuring scale 20. The measuring device 19 can include a caliper, a micrometer, or other mechanical or digital measuring mechanism. The purpose of the measuring device 19 is to position the hydrogel vent 6 at a predetermined target distance from the distal face 2A of the coaxial cannula 2 when the delivery needle 4 is advanced through the coaxial cannula 2 and when the distal face 17A of the positioning mechanism 8 contacts the luer lock 2B of the coaxial cannula 2. The positioning mechanism 8 can be fixed in position at the target distance by the threaded set screw 18.Since the overall length of the coaxial cannula 2 is known, the measuring device 19 can set the target distance from the most distal surface 17A of the hydrogel discharge port positioning mechanism 8 taking this length into account. For ease of use, the measuring device 19 is configured to be able to engage with and disengage from the delivery needle 4 and the positioning hub 8 (as in the original text). (The importance of distances P and X is further outlined in FIGS. 4A - 4F.). FIG. 3B shows a medical device generally designated by reference numeral 10 having features generally similar to those presented in FIG. 3A. The positioning mechanism 8 is composed of two engaged members (17, 17B) both of which can move freely along the axis of the delivery needle 4. The movable members (17, 17B) are shown in cross - section for illustrative purposes and have a central lumen for the passage of the delivery needle. The members (17, 17B) have a threaded engagement mechanism 36 and include a collet - type assembly such that rotation of the opposing position members fixes the positioning mechanism 8 to the delivery needle 4 and restricts its movement. The delivery needle may not have a marker band.

[0179] With reference to FIGS. 4A - 4F, the use of the devices of FIGS. 3A - 3B in a transthoracic biopsy procedure is described.

[0180] FIG. 4A: Under an imaging method such as CT guidance, align the coaxial cannula 2 containing the core needle 3 with the suspected pulmonary nodule J, and advance it transcutaneously through the chest wall by a defined distance such that the tip of the core needle 3 is positioned within the pectoral muscle B proximal to the pleural cavity E. The required needle advancement distance is determined by a prior CT scan of the chest wall.

[0181] FIG. 4B: Once positioned and aligned in the target direction, the core needle 3 is removed from the coaxial cannula 2, and a CT image of the chest wall along the central side of the cannula 2 is taken (see FIG. 9). Using CT scan software, determine the distance (P) from the most distal end 2A of the cannula to the pleural cavity E. This distance typically ranges from 4 to 20 mm. If distinguishable on the CT scan, the distance P is determined by measuring from the most distal end 2A of the cannula to the surface of the lung (visceral pleura G).

[0182] Figure 4C: The positioning mechanism 8 of the delivery device 10 (as shown in Figure 3A) moves the movable hub 17 relative to the delivery needle 4 and is manually adjusted outside the coaxial cannula. Using the measuring device 19 described in Figure 3A, the distance from the farthest surface 17A of the positioning mechanism 8 to the hydrogel outlet 6 can be adjusted to be equal to ((the length of the coaxial cannula) + P + X), where X is the desired injection depth within the lung tissue distal from the pleural cavity E. The positioning mechanism 8 can fix its position using the set screw 18. Once the required injection depth is set, the hydrogel delivery needle 4 of the medical device 10 can be fully advanced through the coaxial cannula 2 until the farthest surface 17A of the movable hub 17 of the positioning mechanism 8 contacts the proximal luer lock 2B of the coaxial cannula 2. At this depth, the hydrogel outlet 6 of the delivery needle 4 is positioned at a distance calculated as P + X from the farthest end 2A of the cannula, where X is the desired injection depth within the lung tissue distal from the pleural cavity E. In particular, for this application, the injection depth into the lung tissue distal from the pleural cavity is from 0.1 to 10 mm, preferably from 1 to 3 mm.

[0183] Figure 4D: A syringe 15 containing a high-viscosity hydrogel is attached to the luer lock 12 of the device, and an amount of the high-viscosity hydrogel is injected through the delivery needle 4 and extruded from the hydrogel outlet 6. The viscoelastic hydrogel surrounds the needle, pushes away the lung tissue, and forms a single annular viscoelastic occlusion plug 7 around the needle. Under CT guidance, both the delivery needle 4 and the coaxial cannula 2 penetrate the viscoelastic occlusion plug 7 and advance to the vicinity towards the pulmonary nodule J (not shown).

[0184] Figure 4E: The delivery needle 4 is removed from the coaxial cannula 2 and replaced with a core biopsy needle K for performing a biopsy of the suspected pulmonary nodule J.

[0185] Figure 4F: The biopsy needle K and the coaxial cannula 2 are removed from the patient, and the viscoelastic occlusion plug 7 fills the hole L1 distal from the visceral pleura created by the device 10.

[0186] Referring to FIGS. 5A-5B, 6A-6B and 7A-7B, a medical device is illustrated and components that are referenced in the previous embodiments are assigned the same reference numbers. FIG. 5A shows a medical device generally designated by reference numeral 10, which device includes a single lumen hydrogel delivery needle 4 having a distal penetrating tip 5, a hydrogel vent 6 disposed on the side of the needle proximal to the penetrating tip 5, a positioning mechanism 8 disposed at the proximal end of the delivery needle 4, and a luer lock 12 at the proximal end of the delivery needle 4. The positioning mechanism 8 is mounted on the proximal side of the delivery needle 4, just distal to the luer lock 12. The components of the positioning mechanism 8 are shown in cross-section for illustrative purposes and include a fixed housing 16 coupled to the delivery needle 4 and a movable hub 17 that engages the fixed housing 16 and is free to move along the axis of the delivery needle 4 but is not rotatable or movable in a direction perpendicular to the axis of the delivery needle 4 (a detailed description of the components of the positioning mechanism 8 is presented in FIGS. 6A-6B below). A threaded set screw 18 that is rotatable and tightenable is provided to fix the position of the movable hub 17 relative to the fixed housing 16 (and the delivery needle 4). The movable hub 17 is provided with a scale 20 that aligns with the scale line or scale ruler 16A of the fixed housing 16. (By positioning the scales 20, 16A of the positioning mechanism 8, the external measuring device 19 described in FIG. 3A can be omitted.) Figure 5B shows a medical device generally designated by reference numeral 10, which device incorporates additional features to those presented in Figure 5A. The device includes a hydrogel delivery needle 4 having a distal penetrating tip 5, a hydrogel vent 6 disposed on the side of the needle proximal to the penetrating tip 5, a positioning mechanism 8 disposed at the proximal end of the delivery needle 4, and a polymeric tube 11 fluidly connected to the proximal end of the needle terminating as a connector such as a luer lock 12 configured to attach to a hydrogel delivery syringe 15. The delivery needle 4 is configured to advance through a coaxial cannula 2. The coaxial cannula typically consists of a single lumen stainless steel tube having a luer lock 2B proximally and is shown as a cross-sectional view for illustrative purposes. The delivery device 10 includes a cannula depth lock 25 through which the coaxial cannula 2 can be inserted. The cannula depth lock 25 is a multi-component construction that secures the cannula 2 and prevents axial movement of the cannula 2 with the patient's skin in contact with the most distal surface. The cannula depth lock 25 can include a threaded set screw 25A that tightens the cannula 2 and fixes its position relative to the cannula depth lock 25. A removable locking arm 26 is attached to the depth lock and is configured to fix the axial position of the delivery device 10 relative to the depth lock 25. The locking arm 26 is in the shape of an elongated bar or tube and has cylindrical or spherical elements at both ends and can 'snap-fit' engage both the cannula depth lock 25 and the positioning mechanism 8. This allows for connection and disconnection of the construct. The device 10 may also include a polymeric tube 11 located intermediate and connecting the delivery needle 4 and the luer lock 12. The polymeric tube 11 is a braided or solid polymeric tube that is heat cured to be angled with respect to the delivery needle 4 and preferably oriented at right angles to the delivery needle 4. This feature allows the connection and disconnection of the syringe 15 and the luer lock 12 and further allows the actuation of the syringe 15 for injecting the hydrogel material without direct force being applied along the axis of the delivery needle 4 and without significantly shifting the injection depth of the hydrogel vent 6.The positioning mechanism 8 shown in FIG. 5B has the following features: A fixed housing 16 is coupled to the hydrogel delivery needle 4, and a movable hub 17 is mounted on the delivery needle 4 for movement relative to the fixed housing 16 along the axis of the delivery needle 4. The movable hub 17 is configured such that its most distal surface 17A contacts the proximal luer lock 2B of the coaxial cannula 2. Movement of the fixed housing 16 along the axial direction relative to the movable hub 17 changes the distance that the hydrogel outlet 6 extends from the most distal end 2A of the coaxial cannula. A series of measurement graduations 20 aligned with the graduation line 16A of the fixed housing 16 are provided on the surface of the movable hub 17, allowing the user to adjust the positioning mechanism 8 to reflect the desired hydrogel outlet 6 depth relative to the most distal end 2A of the coaxial cannula 2. The movable hub 17 can include a male luer lock 38 disposed distally that can engage the female luer lock 2B proximal of the coaxial cannula 2.

[0187] Figures 6A-6B are exploded assembly views regarding components of the delivery device 10, in particular, the engagement of the positioning mechanism 8 and its delivery needle 4. The components of the positioning mechanism 8 are shown as sectional views for illustrative purposes. The positioning mechanism 8 includes a fixed housing 16 coupled to the delivery needle 4. As shown in Figure 6A, the fixed housing 16 is permanently fixed or coupled to the delivery needle 4 by means of adhesive, screws, welding, overmolding, or other means. The fixed housing 16 preferably consists of injection-molded components. The movable hub 17 can move freely relative to the fixed housing 16 along the axis of the delivery needle 4. The movable hub 17 includes a through-hole or path through which the delivery needle 4 can pass. This may be offset from the delivery needle 4. The movable hub 17 slidably engages with the fixed housing 16 so as to overlap through a mating function. The mating function can have a 'T'-shaped cross-section and prevent movement of the movable hub 17 other than in the axial direction (along the axis of the delivery needle 4). The mating function also prevents rotation of the movable hub 17. This mechanism is similar to a caliper in terms of function and shape - the movable hub 17 can slide axially relative to the fixed housing 16. By overlapping and aligning the scale lines 16A, 20 of both the fixed housing 16 and the movable hub 17, the delivery depth of the hydrogel dispensing port 6 regarding the farthest surface 17A of the movable hub 17 can be indicated. The movable hub 17 can be fixed to the fixed housing 16 by a locking function 18 installed on either the fixed housing 16 or the movable hub 17. The locking function 18 can also include a collet-type mechanism or other means for restricting the movement of the fixed housing 16 and the movable hub 17. In an additional example, the fixed housing 16 can be temporarily attached to the delivery needle 4. The temporary attachment of the fixed housing 16 to the delivery needle 4 can be achieved by additional mechanisms such as clamping screws or collets.

[0188] Figure 6B shows an example of a positioning mechanism 8 in which both the fixed housing 16 and the movable hub 17 are of cylindrical or tubular construction and are configured to engage with each other along the axis of the delivery needle 4. Both structures include a lumen through which the delivery needle 4 passes. Again, a portion of the positioning mechanism 8, namely, the fixed housing 16 and the movable hub 17, are shown in cross-section for illustrative purposes. Both the fixed housing 16 and the movable hub 17 have a threaded engagement function 36 (formation of a series of accurately spaced circumferential notches), where rotation of the movable hub 17 relative to the fixed housing 16 results in axial movement of the components along the delivery needle 4 relatively. Rotation of the movable hub 17 relative to the fixed housing 16 changes the distance of the movable hub 17 from the farthest surface 17A of the hydrogel outlet 6. The threaded engagement function 36 can be located on either the inner surface or the outer surface of both members, but typically their positions are on opposite sides of both members for engagement purposes. By the engagement of the threaded engagement function 36, this positioning mechanism 8 may not require a locking function 18 to hold the axial position of the delivery needle 4, but a locking function can be included in this construction. The scale lines 16A, 20 of both the fixed housing 16 and the movable hub 17 overlap and align to indicate the delivery depth of the hydrogel outlet 6 relative to the farthest surface 17A of the movable hub 17.

[0189] Figures 7A-7B show two different depth positions of the positioning mechanism 8, indicating that the positioning mechanism 8 is configured to be axially adjustable so that the distance that the delivery needle hydrogel outlet 6 extends from the coaxial cannula 2 can be varied. For example, from the first configuration shown in FIG. 7A where the hydrogel outlet 6 is at an interval of a first distance P1+X from the distal end 2A of the coaxial cannula, to the second configuration shown in FIG. 7B where the hydrogel outlet 6 is at an interval of a second distance P2+X from the distal end 2A of the coaxial cannula, where P2>P1. It is clear that when the value of P is larger, the movable hub 17 engages more with the fixed housing and overlaps. The positioning mechanism 8 can include a cannula depth guide 21 and, optionally, depth marks 21A at the distal end, which indicate the depth at which the distal end 2A of the cannula should proceed beyond the delivery needle 4 so that it is located just proximal to the needle tip 5. The cannula depth guide 21 includes an extension arm 21 mounted to the fixed housing 16 so as to move together, extending distally from the proximal luer lock 2B of the coaxial cannula, a distance Y1 in FIG. 7A and a distance Y2 in FIG. 7B. The extension arm of the cannula depth guide 21 extends outside and is designed to be narrower than the proximal luer lock 2B of the cannula 2 so as not to interfere with the handling and advancement of the proximal luer lock 2B and the cannula 2. The depth marks 21A include visual aids such as color contrast marks and physical depressions in the extension arm 21 that increase the depth marking ability. The positioning mechanism is configured to adjust the cannula depth guide 21 in proportion to the movement of the delivery needle 4 relative to the movable hub 17 and the fixed housing 16. Thus, referring to FIG. 7A, when the positioning mechanism 8 is adjusted so that the delivery needle 4 is advanced a distance P1 through the cannula 2, the cannula depth guide 21 is adjusted to indicate a depth of Y1. Similarly, in FIG. 7B, when the positioning mechanism 8 is adjusted so that the delivery needle 4 is advanced a distance P2 - greater than the distance P1 - through the cannula 2, the cannula depth guide 21 is adjusted to indicate a depth of Y2, which is proportionally greater than Y1.

[0190] With reference to FIGS. 8A - 8H, the use of the devices of FIGS. 5A - 5B, 6A - 6B and 7A - 7B in a transthoracic needle lung biopsy procedure will be described.

[0191] FIG. 8A: Under CT guidance, the coaxial cannula 2 containing the core needle 3 is aligned with a suspected pulmonary nodule J, and the cannula is advanced percutaneously through the chest wall by a defined distance such that the tip of the core needle 3 is positioned within the pectoral muscle B proximal to the pleural cavity E. The distance of needle advancement is determined by a prior CT scan of the chest wall. Once positioned and aligned in the target direction, the cannula depth lock 25 is axially moved along the cannula to the position where it contacts the patient's skin O, and at this position, a screw integral with the cannula depth lock 25 is tightened (not shown) to fix the cannula 2. If there is sufficient traction between the coaxial cannula 2 and the surrounding tissue, fixation of the depth lock 25 is not necessary.

[0192] FIG. 8B: The core needle 3 is removed from the coaxial cannula 2, and a CT image of the chest wall along the central side of the cannula 2 is taken (see FIG. 9). Using CT scan software, the distance (P) from the most distal end 2A of the cannula to the pleural cavity E is determined. This distance typically ranges from 4 to 20 mm. If distinguishable on the CT scan, the distance P is determined by measuring from the most distal end 2A of the cannula to the surface of the lung (visceral pleura G).

[0193] Figure 8C: The positioning mechanism 8 of the delivery device 10 (as shown in Figure 5A) is manually adjusted relative to the fixed housing 16 so that the scale line 16A aligns with the distance P (as previously measured) on the scale ruler 20. The positioning mechanism 8 can fix its position using the locking function 18 if fixation is required. Through the coaxial cannula 2, the hydrogel delivery needle 4 of the medical device 10 is advanced completely until the most distal surface 17A of the movable hub 17 of the positioning mechanism 8 contacts the proximal Luer lock 2B of the coaxial cannula 2. At this depth, the hydrogel outlet 6 of the delivery needle 4 is positioned at a distance calculated as P + X from the most distal end 2A of the cannula, where X is the desired injection depth within the lung tissue distal to the pleural cavity E. In particular for this application, the injection depth into the lung tissue distal to the pleural cavity ranges from 0.1 to 10 mm, preferably from 1 to 3 mm.

[0194] Figure 8D: A removable locking arm 26 is fixed in position between the cannula depth lock 25 of the positioning mechanism and the movable hub 17, thereby fixing the depth of the delivery needle 4. A syringe 15 containing the viscoelastic hydrogel is attached to the Luer lock 12 of the device, and a certain amount of viscoelastic hydrogel is injected through the delivery needle 4 and extruded from the hydrogel outlet 6. The viscoelastic hydrogel surrounds the needle, pushes the lung tissue apart, and forms a single annular viscoelastic occlusion plug 7 around the needle.

[0195] Figure 8E: Loosen the cannula depth lock 25 so that the cannula 2 can be moved. Advance the cannula 2 beyond the delivery needle 4 to the depth indicated by the cannula depth indicator 21A, and at this position, advance the most distal end 2A of the cannula through the occlusion plug 7 until just before the distal tip 5 of the delivery needle 4 and also so as to cover the hydrogel outlet of the needle. At this point, the sealed annular occlusion plug 7 forms a seal around the cannula 2.

[0196] Figure 8F: The locking arm 26 is disengaged from the cannula depth lock 25, and the delivery device 10 is pulled back from the cannula. This can be replaced with the core needle 3 and attached to the Luer lock 2B of the cannula 2.

[0197] Figure 8G: The core needle 3 and the cannula 2 are advanced through the occluding plug 7 to the suspected pulmonary nodule J. This step is also performed under CT guidance. The core needle 3 is removed from the cannula 2, and a core biopsy needle K (or a percutaneous aspiration needle) is advanced through the cannula to perform a biopsy of the suspected pulmonary nodule J through the cannula 2.

[0198] Figure 8H: The biopsy needle K and the coaxial cannula 2 are removed from the patient, and the viscoelastic occluding plug 7 fills the hole L1 distal to the visceral pleura created by the device 10.

[0199] Figure 9 is a partial cross-sectional view of a CT scan image showing the alignment of the coaxial cannula 2 to the intended biopsy site within the chest wall. The core needle is removed from the coaxial cannula 2 so that a flat edge is visible at the distal tip 2A of the coaxial cannula 2, as previously described in Figure 8B. A CT scan is taken perpendicular to the central axis of the coaxial cannula 2. The pleural cavity E can be easily identified as the boundary between the dark area = lung and the gray area = chest wall. Using CT scan software, the distance P - the distance from the most distal tip of the coaxial cannula to the center of the pleural cavity E - can be determined. The flat edge of the distal tip 2A of the coaxial cannula 2 enables the accurate determination of the distance P. In other cases, when the pleural cavity E space increases and the physical gap (typically >0.5 mm) is more prominent by the black band or the space around the lung, the surface of the lung (visceral pleura) can be distinguished from the surface of the chest wall (parietal pleura). In such cases, it is more appropriate to measure the distance P to the surface of the lung. The surface of the lung is also referred to as the visceral pleura.

[0200] Figure 10 is a partial CT scan view showing an 18G hydrogel delivery needle 4 before biopsy in a porcine in vivo study where a hydrogel plug 7 was delivered to the periphery of the lung under the visceral pleura G. The weight of the pig is approximately 30 kg, and the viscous plug is composed of approximately 500 μl of sodium hyaluronate in water with an average molecular weight of 1.8 - 2 MDa at 50 mg / ml. This hydrogel delivery needle 4 is composed of a radiopaque region and a radiopaque marker band 32 to assist in identifying the position of the hydrogel outlet 6 relative to the pleural cavity or the surface of the lung.

[0201] Figure 11A is a detailed schematic view of the hydrogel delivery needle 4 within a patient's body after delivery of the hydrogel plug 7. The distal tip 2A of the coaxial cannula 2 is positioned at a distance P from the pleural cavity of the chest wall B. A typical distance for P is 3 - 20 mm.

[0202] In other examples and in other surgical procedures, for example when targeting different organs, P represents the distance from the distal tip of the coaxial cannula to any tissue interface, body cavity, organ or extravascular surface.

[0203] The delivery needle 4 is inserted through the coaxial cannula 2 into the lung tissue D. The hydrogel outlet 6 is positioned distally at a distance X from the pleural cavity E, or at a distance P + X from the distal tip 2A of the coaxial cannula. A typical distance for X is 0.1 - 6 mm, preferably 1 - 4 mm.

[0204] The hydrogel outlet 6 is also positioned at a distance T from the proximal side of the penetrating end 5 of the needle, corresponding to the proximal side of the standing area of the penetrating needle tip. A typical distance for T is 0.5 - 15 mm, preferably 1 - 7 mm.

[0205] The distal tip 2A of the coaxial cannula 2 is positioned at a distance Y from the proximal side of the tip 5 of the needle, corresponding to the proximal side of the standing area of the needle tip. The total distance of Y is Y ≒ P + X + T.

[0206] For procedures requiring trans-thoracic needle access, positioning the hydrogel outlet 6 at a distance from the needle tip 5 has several advantages. If the hydrogel outlet 6 is at the end of a conventional needle with an angled tip, the sharp tip of the needle would come very close to the visceral pleura and around the lung in order to deliver the hydrogel plug to the correct position. At this time, the sharp angled tip is likely to tear the visceral pleura and lung tissue that is constantly moving due to breathing. Therefore, it is necessary to position the sharp needle tip at a certain distance from the visceral pleura E. In addition, having the hydrogel outlet 6 away from the distal tip 5 has the advantage of being able to form a uniform and concentric gel plug 7 seal around the delivery needle 4.

[0207] Figure 11B shows another example that can include any of the examples presented herein. In this example, the hydrogel outlet 6 is located at the distal tip 5 of the delivery needle 4 and can be formed by standard multi-inclination grinding or a similar method. In this setting, Y ≈ P + X.

[0208] Figures 12A - 12C are images of lung tissue sections excised after injection of a hydrogel plug during a percutaneous biopsy procedure and fixed with ethanol. The injected hydrogel plug consists of 50 mg / ml of sodium hyaluronate in 500 μl of water, and the average molecular weight of sodium hyaluronate is 1.8 - 2 MDa. The gel is formed using 5% aqueous India ink staining for visualization. Figure 12A shows the gel plug (encircled by the dashed circle) visible under the lung surface. Figure 12B is an image of a section dissected along the central plane of the gel plug using a scalpel. Figure 12C is a close-up image of the dissected gel plug. The fixation process left most of the gel plug intact. It is clear that the gel plug is formed from a single substance. There is a distinct boundary between the lung tissue and the plug, indicating that the viscous gel material does not infiltrate the lung tissue during and after the procedure, at the injection site or any site.

[0209] Figures 13A1 - 13B2 show a medical device generally designated by reference numeral 70 according to an additional example of the present invention, and the same reference numerals are assigned to the components referred to in the embodiment of FIGS. 8A - 8H above. This embodiment is similar to the embodiment of FIGS. 8A - 8H, but has an alternative cannula depth guide with a cannula extension member 31 whose most distal end 31A contacts the proximal luer lock 2B of the cannula and a proximal end 31B that extends proximally to the proximal of the fixed housing 16 of the positioning mechanism 8. The cannula extension member 31 is a structure having a central slot or lumen that houses the passage in the central portion of the delivery needle 4. This is coaxially mounted on the delivery needle 4 for axial movement relative to the delivery needle and the positioning mechanism 8. The cannula extension member 31 also includes an axially extended slot that connects the fixed housing 16 and the delivery needle 4. In the first position shown in FIG. 13A1, the most distal end 31A of the cannula extension member is in line with the most distal end 17A of the movable hub. The most distal end 17A of the movable hub can be held by a snap - fit or interference function of the most distal end 31A of the cannula extension member. In this position, the proximal end 31B of the cannula extension member is in a space at a distance Y1 from the fixed housing 16. In the second position shown in FIG. 13A2, the cannula extension member 31 is advanced to push the cannula 2 forward. In the most advanced position, the proximal end 31B contacts the proximal most end of the fixed housing 16. In this position, the most distal end 2A of the cannula covers the delivery needle 4 and the hydrogel vent 6 to a position that does not cover its penetrating distal tip 5. As shown in FIG. 13B1, the positioning mechanism 8 is adjusted by the movement of the fixed housing 16 relative to the movable hub 17, and moves the delivery needle 4 distally through the coaxial cannula 2 to a distance P2 displayed on the scale 20 (where P2 > P1). At the position of P2, the separation between the movable hub 17 and the most distal end 31B of the cannula extension member increases proportionally to the distance Y2 (where Y2 > Y1). In the second position shown in FIG. 13B2, the cannula extension member 31 is advanced to push the cannula 2 forward. In the most advanced position, the proximal end 31B contacts the most distal end of the fixed housing 16. In this position, the most distal end 2A of the cannula covers the delivery needle 4 and the hydrogel vent 6 to a position that does not cover its penetrating distal tip 5.The mechanism described with reference to FIGS. 13A - 13B functions as a depth guide, allowing the user to advance the cannula 2 to the correct position where the distal end 2A is located at the needle tip 5 and covers the hydrogel outlet 6, without physically touching the cannula 2.

[0210] FIGS. 14A - 14H show a method using the device of FIGS. 13A - 13B, which is substantially the same as the method described with reference to FIGS. 8A - 8H. The treatment description is as follows.

[0211] FIG. 14A: Under CT guidance, align the coaxial cannula 2 containing the core needle 3 with the suspected pulmonary nodule J, and advance it transcutaneously through the chest wall by a defined distance such that the tip of the needle is placed within the pectoralis muscle B proximal to the pleural cavity E.

[0212] FIG. 14B: Remove the core needle 3 from the coaxial cannula 2 and take a CT image of the chest wall along the longitudinal central section of the cannula 2. Use the CT scan software to determine the distance (P) from the distal end 2A of the cannula to the pleural cavity E.

[0213] FIG. 14C: The positioning mechanism 8 of the delivery device 10 (as shown in FIG. 13A1) is adjusted by moving the movable hub 17 relative to the fixed housing 16 such that the scale line 16A aligns with the distance P (as previously measured) on the scale ruler 20. Through the coaxial cannula 2, advance the hydrogel delivery needle 4 of the device 70 until the distal face 17A of the movable hub 17 contacts the proximal luer lock 2B of the coaxial cannula 2. The distal face 31A of the cannula extension member 31 also contacts the proximal luer lock 2B. At this depth, the hydrogel outlet 6 of the delivery needle 4 is positioned at a distance calculated as P + X from the end of the cannula. This is equal to the desired injection depth of the hydrogel outlet 6 within the lung tissue distal to the pleural cavity E. Use the position of the radiopaque marker band 32 attached to the delivery needle 4 relative to the pleural cavity E to adjust the final depth of the hydrogel outlet 6 if necessary. This is achieved by aligning the marker band 32 with the pleural cavity E.

[0214] Figure 14D: Syringe 15 containing the hydrogel is attached to the luer lock 12 of the device, and a certain amount of hydrogel is injected through the delivery needle 4 and extruded from the hydrogel outlet 6 that is distally at a target distance X from the pleural cavity E of the lung. The viscoelastic hydrogel surrounds the needle, pushes away the lung tissue, and forms a single continuous annular viscoelastic occlusion plug 7 around the needle.

[0215] Figure 14E: Under CT guidance, the entire medical device 10 including the coaxial cannula 2 and the delivery needle 4 with the positioning mechanism 8 is advanced all at once towards the suspected pulmonary nodule J. Position the penetrating needle tip 5 adjacent to or inside the pulmonary nodule J. (In this process, the female luer lock 2B of the coaxial cannula 2 may be provided with a mechanism that engages with the male luer lock at the distal end of the positioning mechanism 8 - not shown in the figure.) Figure 14F: Advance the cannula extension member 31 so that its proximal end 31B contacts the proximal surface of the fixed housing 16 of the positioning mechanism 8. As the cannula extension member 31 extends through the positioning mechanism 8, its farthest end 31A contacts the cannula luer lock 2B, pushing the cannula 2 forward by a preset distance. As a result, the farthest tip 2A of the coaxial cannula 2 is positioned immediately in front of the penetrating needle tip 5 of the delivery needle 4, covering the hydrogel outlet 6. This process is desirable because the farthest tip 2A of the cannula is positioned adjacent to or inside the pulmonary nodule J where the biopsy is to be performed. Through these processes, repositioning of the coaxial cannula 2 within the nodule J can be achieved without additional CT scan measurements.

[0216] Figure 14G: The delivery device 70 is removed from the coaxial cannula 2 and replaced with a biopsy needle K (in this case, a core biopsy needle) for performing a biopsy on the pulmonary nodule J.

[0217] Figure 14H: Both the biopsy needle K and the coaxial cannula 2 are removed from the patient, and the viscoelastic occlusion plug 7 fills the hole L1 distal to the visceral pleura G left by the device 10.

[0218] Figures 15A - 15C show a medical device of one embodiment generally referred to by reference numeral 40 that can be incorporated into any embodiment of the present invention, and the parts referred to in the embodiment of FIGS. 13A - 13B above are assigned the same reference numerals. This embodiment can be used with any of the devices described herein, and the fixed housing 16 and the movable hub 17 of the positioning mechanism 8 have a threaded engagement function 36, and except that the rotation of the fixed housing 16 relative to the movable hub 17 results in relative axial movement of a member similar to a micrometer device, it is similar to the embodiment of FIGS. 13A - 13B. FIG. 15A is a view of the device 40 with the cannula extension member 31 in the first position, and the proximal luer lock 2B of the coaxial cannula 2 contacts the farthest surface 17A of the movable hub. The farthest surface of the cannula extension member 31 is also in line with the farthest end 17A of the movable hub. A scale 20 is attached to the movable hub 17 and a scale line 16A is attached to the fixed housing 16. The coaxial cannula 2 is not shown in cross - section. FIG. 15B shows a cross - section of the device 40 of FIG. 15A. The threaded engagement function 36 disposed on the inner surface of the fixed housing 16 and the outer surface of the movable hub 17 can be seen. A spring 39 is provided to keep the delivery needle 4 in contact with the fixed housing 16 of the positioning mechanism 8. The spring 39 also serves to cancel the backlash of the threaded function. The spring 39 also acts as a resistance force to overcome the rotation of the fixed housing 16 relative to the movable hub 17. FIG. 15C shows the device 40 with the cannula extension member 31 in the second position, and the coaxial cannula 2 is advanced to the penetration distal tip 5 of the delivery needle 4 by advancing the cannula extension member 31 to its most forward position such that the proximal end 31B contacts the farthest end of the fixed housing 16.

[0219] FIG. 16 shows a medical device according to an additional embodiment generally designated by reference numeral 50, and parts referenced in the embodiment of FIGS. 8A-8H are assigned the same reference numerals. This embodiment is similar to the embodiment of FIGS. 8A-8H, but in addition includes a digital depth gauge 51 and a sensor 52 used to detect and compare peripheral tissue characteristics as a means for positioning the hydrogel port 6 relative to the pleural cavity and the chest wall. The characteristics (parameters) measured by the sensor may be electrical, chemical, optical, acoustic, mechanical, and thermal characteristics. Tissue electrical parameters include bioimpedance, capacitance, and resistivity. Tissue chemical parameters include pH level, blood concentration, and temperature. Optical characteristics include X-ray permeability and response to light. Mechanical characteristics include stiffness, compliance, strength, and elasticity. Thermal characteristics include thermal conductivity and temperature. The sensors used herein may be configured to detect parameters of the tissue. The following terms can be used interchangeably with'sensor': 'transducer','sender','switch', 'transistor', and 'actuator'. Various types of sensors are contemplated for use in the delivery devices described herein. The sensor may or may not require an external power source for operation. The sensor may be an integrated sensor with a signal emitting and detecting module. The sensor may include separate signal emitting and detecting modules arranged adjacent to each other circumferentially on the needle, axially along the needle, or by other arrangements. The sensor may include an electronic sensor and may be configured to detect electrical characteristics of the tissue, mechanical characteristics of the tissue, or chemical characteristics of the tissue. The sensor may be external to the delivery needle 4 or may be incorporated within the delivery needle 4. The sensor may consist of a pressure sensor, for example, a MEMS-based pressure sensor, configured to detect the force applied to the needle from the surrounding tissue when the needle is inserted through the tissue towards the target site. The device may also be provided with an electronic control unit and a user interface 55, which may be part of the positioning mechanism 8 or located outside the positioning mechanism and attached via an electronic cable 54.The electronic control unit and user interface 55 may be battery-powered or charged by an external power source. LED illumination 53 and an electronic display 51 may be provided in the user interface 55 to inform the clinician of depth and tissue characteristics. The sensor may be used at the target site for diagnostic purposes, for example, to distinguish malignant tissue from healthy tissue. The digital depth gauge 51 and / or sensor 52 and additional features shown in FIG. 16 may optionally be used in any of the embodiments disclosed herein. The sensor 52 may also be replaced and / or combined with a heating or cooling element to effect a therapeutic effect. For example, radio wave, ultrasonic, and microwave ablation electrodes can be incorporated into the delivery needle 4. The device can include other elements such as coil electrodes, magnetic electrodes, and other energy delivery elements.

[0220] FIG. 17 shows a medical device according to an additional embodiment generally designated by reference numeral 60, and components referenced in the embodiments of FIGS. 8A-8H above are assigned the same reference numerals. This embodiment is similar to the embodiments of FIGS. 8A-8H but includes a path 61 and a lateral port 63 for pleural pressure measurement at the distalmost end of the delivery needle 4 as means for positioning the hydrogel outlet 6 opposite the pleural cavity. The path 61 can take the form of a tube internal or external to the delivery needle 4. The path is attached to a pressure gauge 62 at the proximal end of the device. The pressure gauge 62 is of mechanical or electronic nature and is located internal or external to the positioning mechanism 8. These functions can be used in any of the device and system embodiments described herein.

[0221] Regardless of any theory, FIGS. 18A-18E show in vitro study results regarding variables considered desirable for the effect of the hydrogel plug seal described herein. FIG. 18A illustrates the experimental setup. For this study, an 18G hydrogel delivery needle 4 with a 17G coaxial needle 2 in a similar fashion as shown in FIG. 2B was prepared. To determine the injection depth through the hydrogel outlet 6 within the surface of the lung 82, a visible black line 83 was engraved on the outer surface of the 18G delivery needle 4 at a known distance from the hydrogel outlet 6. This line was visually aligned with the surface of the lung to target the injection depth X. Lungs 82 from mature pigs (80-120 kg pigs) were obtained from a local slaughterhouse and connected to positive pressure ventilation of 11 cmH2O through an intubation tube 81. The pressure was constant in all studies. In all tests, a 1 ml syringe 15 containing a fixed amount of hydrogel was used to inject the hydrogel plug 7 through the hydrogel delivery needle 4 under the surface of the lung at a distance X. Next, both the hydrogel delivery needle 4 and the 17G coaxial cannula 2 were advanced through the same hole and through the hydrogel plug 7 into the lung to a depth of 30 mm from the farthest tip of the coaxial cannula 2. Next, the lung tissue was placed in a water bath 84 at room temperature and the needle construct was withdrawn from the lung tissue underwater. The presence of air bubbles was recorded. When the air bubbles emerging from the lung stopped, it was determined that the hydrogel seal worked. The results are shown in FIGS. 18B-18E as the percentage of effectiveness equivalent to 100*((number of tests without bubbles) / (total number of tests)). The following is a description of the results from these individual studies. For each variable, 10 tests were conducted and all tests were recorded for future analysis.

[0222] FIG. 18B shows the effectiveness at different hydrogel concentrations (which is related to the gel viscosity and rigidity shown in FIGS. 19 and 20 below). The hydrogel was produced by mixing sodium hyaluronate powder with an average molecular weight of 1.8-2 MDa with pure water at various concentrations: 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml. During testing the effects of different concentrations, the injection depth (2 mm under the surface of the lung), the injection volume (500 μl), and the injection rate (normal) were all kept constant. The results were that at concentrations lower than 40 mg / ml, the hydrogel seal had a low effect in preventing air leakage from the lung.

[0223] Figure 18C shows the effectiveness at different injection volumes. During the test of the effects of the hydrogel at different injection volumes, the hydrogel concentration (60 mg / ml), injection depth (1 mm below the lung surface), and injection rate (normal) were all kept constant. The results showed a significant decrease in effectiveness at 100 μl compared to 300 μl and 500 μl. Preliminary tests were conducted at a lower volume of 50 μl, but they were all ineffective in preventing air leakage from the lung.

[0224] Figure 18D shows the effectiveness at different injection depths. During the test of the effects of different injection depths of the hydrogel into the lung, the gel volume (300 μl), gel concentration (60 mg / ml), and injection rate (normal) were all kept constant. The results showed that the best results were achieved when the gel plug was closer to the peripheral part of the lung up to the visceral pleura. In preliminary tests conducted at a deeper injection depth ≥ 4 mm from the peripheral part of the lung, the effect further decreased.

[0225] Figure 18E shows the effectiveness of the hydrogel at different injection rates into the lung. During the test of the effects of different injection rates of the hydrogel, the hydrogel volume (500 μl), gel concentration (60 mg / ml), and gel depth (2 mm below the lung surface) were all kept constant. The approximate injection rates were slow (6 seconds), normal (3 seconds), and fast (< 1 second). Based on the result that the best result was at the normal injection rate, the relationship between the injection rate and the effect is not clear.

[0226] Figure 19 shows the viscosity data of the gels used in the experiments outlined in Figures 18A - 18E above. The hydrogels were produced by mixing sodium hyaluronate powder with an average molecular weight of 1.8 - 2 MDa with pure water at various concentrations. Viscosity measurements were performed using an AR2000 type rheometer manufactured by TA Instruments Japan Co., Ltd., with a cone - plate shape of 4 cm, a cone - plate angle of 4°, a shear gap of 112 μm, and a measurement temperature of 25°C. The results showed an increase in viscosity with an increase in hydrogel concentration. The zero - shear viscosity of the hyaluronic acid hydrogels changed from approximately 1000 Pa·s at 30 mg / ml to approximately 8000 Pa·s at 60 mg / ml (1 Pa·s = 1000 cP). All gels showed shear - thinning characteristics at increasing shear rates, and all gels had a viscosity of <50 Pa·s at a shear rate of 10 s−1.

[0227] Figure 20 shows the results of a compression test to determine the stiffness of the hydrogels used in the injection tests presented in Figures 18A - 18E. Hydrogels with increasing concentrations of hyaluronic acid were prepared as described above. The hydrogels were formed into 5 - mm - thick sheets by pressing the hydrogel against a die, and a cylindrical core biopsy punch was used to create cylinders with a height of 5 mm and a diameter of 6 mm. To compare the results with lung tissue, cylindrical lung parenchyma samples with the same height of 5 mm and diameter of 6 mm were excised from the lung parenchyma around the lungs of a cadaver pig. The compression tests of the lung tissue and the hydrogel cylindrical samples were measured using a Zwick universal testing machine with a 5 N load cell and a strain rate of 3 mm / min. As is clear from the results, the compression stiffness of all gels was greater than that of the lung parenchyma. The stiffness of the lung tissue was 825 ± 95 Pa. The stiffness of the hydrogels changed from 1075 ± 125 Pa at 40 mg / ml to 3125 ± 403 Pa at 60 mg / ml. The results for the hyaluronic acid hydrogels containing 30 mg / ml are not presented because cylindrical samples with a diameter of 6 mm could not be created.

[0228] Figures 21A - 21C show the viscoelastic properties of the gels measured by the dynamic vibration test method. The test rheometer used was the AR2000 type manufactured by TA Instruments Japan Co., Ltd. The dynamic vibration test was conducted under strain control with a cone - plate shape of 4 cm, a cone - plate angle of 4°, a shear gap of 112 μm, a measurement temperature of 25°C, and a frequency range of 0.1 - 10 Hz. The gels were produced by mixing sodium hyaluronate powder with a molecular weight of 1.8 - 2 MDa with pure water at various concentrations: 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml. Figures 21A - 21C present the dynamic viscoelasticity (storage modulus G’, loss modulus G”, tangent delta tanδ (G” / G’)) in the frequency range of 0.1 - 10 Hz. As the gel concentration increases, both G’ and G” increase significantly. For all gels, tanδ is in the range of 0.2 - 0.6 at a frequency of 1 Hz. The gel with the lowest concentration of 30 mg / ml shows the highest tanδ of approximately 0.55 at 1 Hz. In a similar test (results not presented), the analysis temperature was increased to 37°C, but there was no change or only a slight change (<5%) compared to the values at the analysis temperature of 25°C presented here.

[0229] Figure 22 shows the strain sweep data of the hydrogels measured using the dynamic vibration test. The test was conducted under strain control with a cone - plate shape of 4 cm, a cone - plate angle of 4°, a shear gap of 112 μm, a measurement temperature of 25°C, a frequency of 1 Hz, and a strain range of 0.001 - 100%. All hydrogels with concentrations higher than 30 mg / ml were relatively stable up to 1% strain. All gels showed shear - thinning behavior, and all gels showed a storage modulus G’ of less than 100 Pa at 100% strain. In a similar test (results not presented), the analysis temperature was increased to 37°C, but there was no change or only a slight change (<5%) compared to the values at the analysis temperature of 25°C presented here.

[0230] Figures 23A-23B show the tests of the shear thinning and recovery of the gel under repeated shear stress. The step strain test was performed using a 50 mg / ml hyaluronic acid hydrogel with a cone and plate shape of 4 cm, a cone plate angle of 4°, a cutting gap of 112 μm, a measurement temperature of 25°C, a frequency of 1 Hz, and a step strain rate of 1% to 100% to 1% with a 6-second delay between different strain rates. G’ dropped from 1900 Pa at 1% to about 20 Pa at 100%, and tanδ increased from about 0.4 at 1% to about 0.9 at 100%. This means that the rigidity and viscosity decrease significantly when a high shear stress is applied. Interestingly, when the strain rate returned to 1%, both G’ and tanδ almost completely recovered.

[0231] Figures 24A - 24C show the positioning and volume data analysis of the hydrogel gel plugs collected using a 3D - CAD model created using SolidWorks®. The analysis shows the size and depth constraints regarding the delivery of the gel plugs beneath the lung surface. Figure 24A shows a 3D - CAD model representing the delivery of a viscous hydrogel plug 7 through an 18G delivery needle 4 immediately beneath the visceral pleural surface G of the lung periphery. The gel plug is injected through the bevel 6 of the delivery needle 4 so as to form an annular spherical profile around the delivery needle 4. The injection depth of the hydrogel bevel 6 is presented as the distance from the lung surface G of the bevel and is represented by X. In this analysis, it is assumed that the gel plug 7 is filled and expands radially outward ideally to form a spherical profile. The central diameter of the plug is represented by Cφ. When the plug expands to contact the visceral pleura G, it forms a spherical fragment with a circular seal profile at the visceral pleura G. The diameter of this seal profile is represented by Sφ. Figure 24B shows the relationship between the seal diameter at the lung surface and different injection volumes and depths. At a shallow injection depth of 1 mm beneath the lung surface, most of the gel material is present at the lung surface. For example, when the injection volume is 500 μl and the depth is 1 mm, a plug seal with a diameter of approximately 11.4 mm can be formed at the lung surface. Similarly, when the injection volume is 200 μl and the depth is 1 mm, a plug seal with a diameter of approximately 8 mm can be formed at the lung surface. As the injection becomes deeper, less material is present at the lung surface, thereby reducing the effect of the seal. As the data clearly shows, when the injection depth is 5 mm beneath the lung surface, a volume greater than 500 μl is required for some gel to be present at the lung surface. Similarly, when the injection depth is 4 mm beneath the lung surface, a volume exceeding 300 μl is required for some gel to be present at the lung surface. Figure 24C represents the central diameter data of the plugs at different injection depths and injection volumes. Intuitively, the larger the injection volume, the larger the gel plug diameter. At shallower depths, less injection volume is required to achieve an equivalent gel plug central diameter. To achieve a gel plug diameter of 12 mm, 556 μl is required at an injection depth of 1 mm, whereas 873 μl is required to achieve the same diameter at an injection depth of 5 mm. The lung tissue is composed of a ventilated parenchyma and interconnected pathways extending to the lung periphery.Therefore, any non-sealed or unobstructed area around the lung may lead to pneumothorax. The range and size of the seal plug are also relevant. The presence of additional material at the periphery of the lung forms a stronger seal against air leakage.

[0232] Figures 25A - 25C illustrate a method of performing a lung biopsy procedure using a system according to another embodiment of the present invention, and the components referred to in the previous embodiments of the present invention are assigned the same reference numbers. In this embodiment, the system includes a coaxial delivery system for delivering a viscoelastic hydrogel seal plug before or after performing a diagnostic or therapeutic procedure. Referring to Figure 25A, a coaxial cannula 2 spanning the chest wall B and lung tissue D is shown. The biopsy needle has been removed. The cannula 2 in this case has an opening 2C, which may be a single opening or composed of multiple circumferential openings, and is located proximal to the distal tip of the cannula 2. The opening 2C may be designed to remove a significant member of the tube along the cross-section for identification under fluoroscopic guidance or to provide an X-ray impermeable marker band containing a high-density substance on the cross-section of the tube. The axial length of the opening is about 0.3 - 2 mm. Figure 25B shows a diagram in which the hydrogel delivery needle 4 is inserted into the cannula 2 and adjusted so that the opening 2C within the cannula aligns with the hydrogel outlet 6 within the hydrogel delivery needle 4. The hydrogel delivery needle 4 may include a male luer lock 4B or a similar connector that engages with the female luer lock 2B of the coaxial cannula 2. Next, a CT image of the lung is taken to determine the distance between the aligned openings and the pleural cavity E. Next, the cannula 2 and the needle 4 are retracted together by a certain distance so that the opening is located immediately distal to the pleural cavity of the lung tissue (Figure 25C). Next, the syringe 15 is actuated to inject the viscoelastic hydrogel into the lung, forming an annular seal plug 7 around the cannula within the lung tissue immediately distal to the pleural cavity E. Next, the needle and the cannula are retracted, and the annular plug flows together and closes due to the self-healing property of the hydrogel, filling the needle path immediately distal to the pleural cavity.

[0233] Figures 26A through 26C show a medical device according to an additional embodiment of the invention, generally designated by reference numeral 80, and components referenced in the previous embodiments (including FIGS. 25A through 25C) are assigned the same reference numerals. FIG. 26B shows a cross-sectional view of FIG. 26A. The medical device 80 includes a proximal hub 2B and a cannula 2 having an opening 2C located proximal to the distal most tip of the cannula 2. The medical device 80 also includes a delivery needle 4 having a hydrogel port 6 at its distal most tip. The delivery needle 4 is connected at its proximal end to a male luer lock 4B. The delivery needle 4 terminates as a connector such as a luer lock 12 configured such that a polymeric tube 11 fluidly connected to the delivery needle 4 via the male luer lock 4B is attached to a hydrogel delivery syringe. A central rod 81 is connected to the male luer lock 4B and extends beyond the distal end of the delivery needle 4 that forms (or couples to) a penetrating tip 5 through the central lumen of the delivery needle 4. The central rod 81 may be constructed from a radiopaque material such as rigid plastic or composite material. FIG. 26C (shown as a cross-sectional view) shows the medical device with the delivery needle 4 inserted through the cannula 2. The penetrating tip 5 of the delivery needle construct extends beyond the distal most tip of the cannula 2. The hydrogel port 6 of the delivery needle 4 is located proximal to the opening 2C of the cannula 2. During an X-ray image-guided procedure (such as a CT-guided procedure), this configuration of the medical device has the advantage of providing radiopacity to the opening 2C, allowing the clinician to position the opening 2C for delivery of the sealed hydrogel plug. When the hydrogel material is injected, the gel material is extruded from the hydrogel port 6 and subsequently through the opening 2C. Since the penetrating tip 5 mainly fills the lumen of the cannula 2, the gel material is prevented from passing through the tip of the cannula 2.

[0234] Figures 27A - 27B show a medical device according to an additional embodiment of the invention, generally designated by reference numeral 90, and like parts referred to in the previous embodiments (including Figures 8A - 8H) are assigned the same reference numerals. This embodiment is similar to the embodiment of Figures 8A - 8H, but additionally incorporates a firing mechanism 91 designed to advance the delivery needle tip 5 and the lateral flow orifice 6 to a depth set beyond the distal tip of the coaxial cannula. The advantage of providing a firing mechanism on the delivery needle is to avoid the possibility of protrusion of an organ membrane, such as the lung pleura, when positioning the delivery lateral port 6 beneath the surface of the lung or other organs. Protrusion is an inward indentation of the membrane that can occur due to the slow advancement of the delivery needle. Similar to the embodiments described in Figures 8A - 8H, the medical device 90 includes a fixed housing 16 coupled to the delivery needle 4. The fixed housing 16 is free to move within the handle 92, and the fixed housing 16 is held in the advanced position by a compression spring 97 maintained in a compressed state between the proximal face of the fixed housing 16 and the inner proximal face of the handle 92. The compression spring 97 presses against a positioning mechanism 8 housed within the handle 92 and incorporated therein. The positioning mechanism 8 includes a forward rotating screw 94 with an external thread 95 and is composed of a parent screw type mechanism that engages the internal thread of a movable carrier 93 with a depth indicator 93A. By rotating the screw 94, the user can move the position of the movable carrier 93 relative to the scale 20 provided on the handle 92. This positioning mechanism 8 effectively provides a variable depth setting function to the firing mechanism 91 and can change the distance that the needle tip and the lateral outlet extend from the most distal face of the firing mechanism 91 (and the coaxial cannula 2) during firing. As shown in Figure 27B, to engage the firing mechanism 91, the delivery needle 4 is pulled back by pulling the luer lock 12 attached to the delivery needle 4. When the delivery needle 4 is in the fully retracted position and the spring 97 is fully compressed, the outward tooth stop 17D of the movable hub 17 engages the inward tooth stop 92D of the handle 92, preventing forward movement of the delivery needle 4. In this configuration, the needle is under treatment. Figure 27B also shows the delivery needle 4 advanced through the coaxial cannula 2 such that the most distal face of the firing mechanism 91 contacts the nearest face of the coaxial cannula luer lock 2B.In this configuration, the tip 5 of the delivery needle is either exactly at the distal most end of the coaxial cannula 2 or proximal to the distal most end of the coaxial cannula 2. To fire the needle forward, a button 98 is provided, and when it is pressed, the engagement between the movable hub 17 and the detents (92D, 17D) of the handle 92 is disengaged.

[0235] Based on the results presented in both FIGS. 18A - 18E and FIGS. 24A - 24C, ideal hydrogel delivery is about 1 mm below the surface of the lung. However, for several reasons, it may be difficult to target this depth using the delivery devices described herein. FIG. 9 shows a CT scan of the measurement of the distance P from the distal most end of the coaxial cannula to the pleural cavity E. The error in the measurement of P may be due to the influence of the shadow of the distal tip of the coaxial cannula. The error may also be because the CT scanner was scanned at an angle rather than perpendicular to the axis of the coaxial cannula. In this case, P is underestimated by its value. For these reasons, a target depth greater than 1 mm is preferred. A target depth of 0.1 - 6 mm, preferably 1 - 4 mm, is considered appropriate as the target injection depth.

Example

[0236] Example 1: A biphasic viscoelastic hydrogel containing hyaluronic acid and cross-linked gelatin was produced by the following method. Type A porcine-derived gelatin (300 Bloom) was completely dissolved in water at 40 °C at 7% w / v and solidified at 4 °C overnight. Then, the obtained gel was frozen at -40 °C and lyophilized by drying at 25 °C and a constant vacuum of 0.1 mbar. Next, the dried composition was heated at 140 °C for 24 hours under vacuum (0.001 mbar) to cross-link it. Next, the sponge was roughly cut and ground into fine powder using a cryogenic milling device (Model: 75 Spex SmplePrep, LLC). The powder was sieved using a 125 μm sieve, and the resulting powder had a particle size distribution measured using a Mastersizer 3000 laser diffraction particle size distribution analyzer (Malvern Panalytical ltd.) with Dx10 = 7.4 μm, Dx50 = 32.8 μm, and Dx90 = 95 μm. The dehydrated heat-cross-linked gelatin powder was mixed with sodium hyaluronate powder (molecular weight: 1.8 - 2 MDa), and the mixed powder was hydrated with phosphate-buffered saline at the following concentrations; gelatin: 130 mg / ml, sodium hyaluronate: 35 mg / ml. The resulting hydrogel was filled into a syringe. The hydrogel was used to prevent pneumothorax during a CT-guided transthoracic needle biopsy procedure outlined in FIGS. 8A - 8F. This procedure was performed using a porcine model. During the biopsy procedure, the hydrogel formed an annular seal plug around the needle, and after the needle was removed, the hydrogel self-recovered and prevented pneumothorax. With CT scan follow-up, the hydrogel remained at the site for at least one week.

[0237] Example 2: A biphasic viscoelastic hydrogel containing hyaluronic acid and crosslinked gelatin was produced by the following method. Type A porcine-derived gelatin powder (300 Bloom) was pulverized into fine powder using a cryogenic pulverizer (Model: 75 Spex SmplePrep, LLC). The powder was sieved using a 125 μm sieve, and the resulting powder had a particle size distribution measured using a Mastersizer 3000 laser diffraction particle size analyzer (Malvern Panalytical ltd.) with Dx10 = 5.4 μm, Dx50 = 35.5 μm, and Dx90 = 90 μm. The resulting fine powder was heat-treated at 160 °C for 24 hours under vacuum conditions (0.001 mbar) to crosslink it. The dehydrated heat-crosslinked gelatin powder was mixed with sodium hyaluronate powder (molecular weight: 1.8 - 2 MDa), and the mixed powder was hydrated with phosphate-buffered saline at the following concentrations; gelatin: 100 mg / ml, sodium hyaluronate: 45 mg / ml. The resulting hydrogel was filled into a syringe. The hydrogel was used to prevent pneumothorax during a CT-guided transthoracic needle biopsy procedure outlined in the same manner as FIGS. 8A - 8F. This procedure was performed using a porcine model. During the biopsy procedure, the hydrogel formed an annular seal plug around the needle, and after the needle was removed, the hydrogel self-recovered and prevented pneumothorax.

[0238] Using the above method, biphasic gels of various concentrations were evaluated rheologically and experimentally. The measurement of the dynamic viscoelastic properties and dynamic viscosity of the hydrogel was performed using an AR2000 type rheometer manufactured by TA Instruments Japan Co., Ltd. under the following conditions. Measurement method: Vibration method, strain control Measurement temperature: 25 °C Shape: Cone plate angle 4° Measurement shape: 4 cm Cutting gap: 112 μm Frequency: 1 Hz

[0239] [Table 1]

[0240] In a preferred embodiment, when performing a procedure that requires transthoracic needle access, the viscoelastic hydrogel is injected just below the visceral pleura of the lung and can prevent pneumothorax by having the following characteristics: 1. The hydrogel has a sufficiently low viscosity when shear stress is applied to the syringe, and the hydrogel can be injected through a needle, catheter, or other cannula-like device to the target site.

[0241] 2. Once the needle is withdrawn, the hydrogel has sufficient rigidity due to rapid thixotropic recovery to prevent infiltration of lung tissue.

[0242] 3. Once the needle is removed, the gel flows back due to the element of viscous flow and forms a single body. The gel flows back to fill the space in the lung tissue and visceral pleura left by the needle. This is preferably achieved by sufficient fluidity depending on a high tanδ.

[0243] 4. The gel has sufficient rigidity and storage modulus (G'), is not prematurely discharged from the lung, and remains at the target site until healing occurs.

[0244] The foregoing description is of the presently preferred embodiments of the invention. In these embodiments, numerous modifications and variations are contemplated by those skilled in the art in view of these descriptions. These modifications and variations are also intended to be included within the scope of the claims appended hereto.

Claims

1. A medical device comprising a hydrogel delivery needle (4) having a hydrogel outlet (6) and a coaxial cannula (2) having a lumen configured to receive the hydrogel delivery needle (4), and containing an injectable hydrogel, wherein the injectable hydrogel is a viscoelastic shear-thinning hydrogel composed of hyaluronic acid (HA) configured to exhibit sufficient viscoelasticity and rigidity to prevent lung tissue infiltration after needle delivery and sufficient viscoelasticity to push the lung tissue away from the delivery needle, and the injectable viscoelastic shear-thinning hydrogel exhibits a storage modulus (G') of at least 400 Pa in dynamic viscoelasticity measured with a rheometer at 25°C, 1 Hz, and a strain rate of 1%, characterized in that A system for closing a path in lung tissue formed during a low-impact percutaneous procedure.

2. The system according to claim 1, wherein the injectable viscoelastic shear-thinning hydrogel exhibits a tanδ (G'' / G') of 0.1 to 0.8 in dynamic viscoelasticity measured with a rheometer at 25°C, 1 Hz, and a strain rate of 1%.

3. The system according to claim 1 or 2, wherein the compressive modulus of the injectable viscoelastic shear-thinning hydrogel is greater than the compressive modulus of lung tissue.

4. The system according to any one of claims 1 to 3, wherein the shear-thinning hydrogel is configured to exhibit a body retention time of at least one week.

5. The system according to any one of claims 1 to 4, wherein the hydrogel outlet (6) is disposed at a position 1 to 15 mm from the tip (5) of the hydrogel delivery needle (4).

6. The system according to any one of claims 1 to 5, wherein the viscoelastic hydrogel is composed of a continuous phase consisting of a continuous phase polymer and a dispersed phase consisting of micron-sized insoluble polymer particles.

7. The system according to claim 6, wherein the micron-sized insoluble polymer particles have an average dimension smaller than 100 microns.

8. The system according to claim 6 or 7, wherein the continuous phase polymer comprises hyaluronic acid (HA) or a salt thereof.

9. The system according to any one of claims 6 to 8, wherein the micron-sized insoluble polymer particles are formed from crosslinked gelatin.

10. The system according to any one of claims 6 to 9, wherein the viscoelastic hydrogel contains 2 to 20% (w / v) of micron-sized insoluble polymer particles.

11. The system according to any one of claims 6 to 9, wherein the tip (5) of the hydrogel delivery needle (4) is a penetrating tip.

12. The system according to any one of claims 8 to 11, wherein the hyaluronic acid is not cross-linked and the insoluble polymer particles in micron units are cross-linked by dehydration heating.

13. The system according to any one of claims 6 to 12, wherein the insoluble polymer particles in micron units are cross-linked gelatin particles.

14. The system according to any one of claims 1 to 13, further comprising a syringe (15) configured to be fluidly connected to the hydrogel delivery needle (4), wherein the viscoelastic hydrogel is provided in the syringe (15).

15. The system according to any one of claims 1 to 14, further comprising an adjustable positioning mechanism (8) configured to limit the penetration depth of the hydrogel delivery needle (4) through the coaxial cannula (2).

16. The system according to any one of claims 1 to 15, wherein the injectable viscoelastic thixotropic hydrogel exhibits a storage modulus (G') of 800 to 6000 Pa in dynamic viscoelasticity measured with a rheometer at 25°C, 1 Hz, and a strain rate of 1%.

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