Device to inject cells into tissue

Abstract

The invention is directed to a catheter (1) for injecting a cell suspension into an organism comprising an outer canula (2) and an inner canula (3) characterized in that - the inner canula (3) is designed to be inserted into the outer canula (2) and the inner canula (3) is axially and / or rotationally movable in the outer canula (2) - the catheter is provided with a tapered shaped tip (4), - the outer canula (2) and / or the inner canula (3) is provided with at least one radial opening from which a cell suspension is injected into the organism.

Description

DEVICE TO INJECT CELLS INTO TISSUE

[0001] The invention is directed to a device that makes the injection of cells into tissue safe, reliable, precise in the amount and position, minimal invasive and avoids carryover of cells during and after an injection.

[0002] The device for injection constructed from coaxial cannulas, at least one of which contains at least one lateral or radial outlet near the tip. Possibilities of axial and relative movement of the cannulas allow controlled closure of the outlet and precise positioning and movement of the whole device. In embodiments, relative rotation is also used. In one embodiment, the injection tip is asymmetrically shaped so that tissue is tangentially displaced during advancement by rotation of the tip, thereby protecting the tissue from microlesions.BACKGROUNDCell Therapy in solid tissue

[0003] Parkinson's disease is a neurodegenerative disorder that primarily affects the motor system, leading to symptoms such as tremors, rigidity, and difficulty with movement. Over the years, several activities have been tried or proposed to cure Parkinson's disease, with a special emphasis on the injection of dopaminergic cells. Dopaminergic cells are cells capable of releasing dopamine or progenitor cells of such cells, which can mature in vitro or in vivo to dopamine releasing cells

[0004] The following methods are the subject of research:

[0005] Dopaminergic Cell Transplantation: One approach involves transplanting dopaminergic neurons into the brain to replenish the depleted dopamine levels. Fetal tissue transplantation has been attempted, where developing dopamine-producing cells from aborted fetuses are implanted into the recipient's brain.

[0006] Stem Cell Therapy: Embryonic stem cells (ESCs) constitute an alternative starting material from which differentiated dopaminergic cells can be generated. Stem cell research offers promising potential for Parkinson's disease treatment. Induced pluripotent stem cells (iPSCs) can be generated from adult cells and then differentiated into dopaminergic neurons. These cells can be transplanted into the brain to restore dopamine production.

[0007] Gene Therapy: Gene therapy involves modifying the genes in cells to enhance or suppress their function. It holds promise for Parkinson's disease by targeting specific genesassociated with the condition. For example, researchers are exploring the use of viral vectors to deliver genes that promote the production of dopamine or reduce neuroinflammation.

[0008] Deep Brain Stimulation (DBS): DBS is a surgical procedure that involves implanting electrodes into specific regions of the brain and delivering electrical impulses. It can alleviate motor symptoms of Parkinson's disease by modulating abnormal brain activity. While not a cure, DBS is an established treatment option for managing symptoms.

[0009] The invention relates to the treatment of Parkinson's disease using dopaminergic neurons, but may also be applied to other diseases. There are two different approaches to achieve active cells in the brain. The invention potentially supports both approaches.

[0010] Direct Implantation: In some experimental cases, researchers have directly implanted dopaminergic neurons, often derived from cell cultures, into specific brain regions mainly the striatum. This method typically involves stereotactic neurosurgery, where precise coordinates are used to target the brain regions accurately.

[0011] Encapsulated Cell Grafts (e.g. Penna V): In this approach, encapsulated cells that produce dopamine are implanted into the brain. The encapsulation allows for the diffusion of dopamine while protecting the implanted cells from the immune system. This method aims to provide a continuous and controlled supply of dopamine, potentially reducing the risk of immune rejection.Surgical procedure:

[0012] Stereotactic frames are crucial instruments for various neurosurgical procedures, such as brain biopsies, deep brain stimulation (DBS) surgery, brain tumor resection, and the placement of electrodes or other medical devices. Here, a stereotactic frame is firmly attached to the patient's head or skull. The main purpose of a stereotactic frame (see Fig 1, Stereotactic Frame (inomed Medinzintechnik GmbH)) is to provide a stable reference system for the brain or body, allowing precise localization of target areas and planning of the injection trajectory. In the context of the injection the same approach is used to precisely puncture and penetrate the injection device to the target location. The frame incorporates a three-dimensional coordinate system that allows the surgeon or medical professional to define specific target points within the patient's brain or body. These coordinates are based on preoperative imaging, such as MRI (Magnetic Resonance Imaging) or CT (Computed Tomography) scans. These images are then used to plan the procedure and determine the optimal target coordinates for the surgery.

[0013] The frame ensures that the instruments move along the predefined paths, providing accuracy and minimizing damage to surrounding tissues. The planning of the paths avoids the crossing of larger blood vessels. The crossing of smaller capillaries however cannot be avoided leaving a non-vanishing risk that bleeding will occur during the surgery. Typical length of the injection devices are more than 150 mm, which makes all regions of the brain accessible.

[0014] One approach to cure Parkinson's disease requires the establishment of small amounts of viable dopamine-producing cells distributed over several precise positions in the striatum. The cells are usually in a suspension, of which only the smallest possible quantities are to be produced for cost reasons. Precise dosage of small volumes of cell suspension is further a mechanical challenge. As an alternative to a suspension, the cells can also be encapsulated in a gel. A reduction of the dead volume of the injection device is therefore of great interest. In addition, passing the cell suspension through a cannula creates shear stress, which can reduce cell viability. Pushing embedded cells through a cannula is only possible at low viscosity and a relatively large internal diameter of the cannula, which increases the dead volume. The insertion and extraction of a cannula further introduces the risk of carryover of cells to regions along the injection path.OBJECT OF THE INVENTION

[0015] The task of the invention is to make the injection of cells into tissue safe, reliable, precise in the amount and position, minimal invasive and avoids carryover of cells during and after an injection. Accordingly, object of the invention is a catheter (1) for injecting a cell suspension into an organism comprising an outer canula (2) and an inner canula (3) characterized in that- the inner canula (3) is designed to be inserted into the outer canula (2) and the inner canula (3) is axially and / or rotationally movable in the outer canula (2)- the catheter is provided with a tapered shaped tip (4),- the outer canula (2) and / or the inner canula (3) is provided with at least one radial opening from which a cell suspension is injected into the organism.

[0016] Further variants or embodiments of the invention are objects of the depended claims.BRIEF DESCRIPTION OF THE FIGURES

[0017] Fig. 1 shows a stereotactic frame for mounting the injection device on a human being

[0018] Fig. 2 to 8 show embodiments of the invention using the following reference numbers1. Injection device (catheter)2. Guide tube (outer cannula)3. Inj ection cannula (inner cannula)4. Injection tip5. Radial outlet6. Cell suspension7. Buffer solution8. Syringe or reservoir9. Injection stop10. Extension distance11. Frame connector12. Inner radial outlet13. Means for relative rotational motion14. Second inner volume (lumen)15. Outer guide tube16. Mandrin17. Mandrin stopDESCRIPTION OF THE INVENTION

[0019] The device for injection (1) is constructed from coaxial cannulas, at least one of which contains at least one lateral or radial outlet (5) near the injection tip (4). Possibilities of axial and relative movement of the cannulas allow controlled closure of the outlet and precise positioning and movement of the whole device. In embodiments, relative rotation is also used.

[0020] Details of the invention and its different embodiments are explained within the description of the figures:

[0021] Figure 1 shows a typical commercially available stereotactic frame, which can be utilized for mounting the injection device and fix it in the desired position to access targetregions for cell deposition in the human brain (Source: https : / / www . en . inom ed . com / products / functi onal-neurosurgery / stereotactic- system s / rm-stereotacti c-sy stem / ) .

[0022] In Figure 2, a double walled variant of the injection device (1) is outlined. The injection cannula (3) containing the cell suspension (6) and on top a buffer solution (7) is enclosed in a guide tube (2). The buffer solution (7) is preloaded for means of precise loading by air removal. The injection cannula (3) has a lateral radial outlet (5) near its atraumatically shaped tip (4), whereas the guide tube (2) has an open ending and no lateral outlet. After insertion of the injection device (1) into the tissue and its fixation in the desired position, the injection cannula (3) can be pushed forward within the extension distance (10) and the syringe (8) is used to deposit the cell suspension (6).

[0023] Figure 3 depicts another variant of the injection device (1), in which the guiding tube (2) contains a lateral radial outlet (5) that is utilized to release the cell suspension (6) from the injection cannula (3). This happens via superposition of both outlets by pushing the injection cannula (3) forward within the guiding tube (2) and turning it by means for relative rotational movement (13) or alternatively by forward movement of the injection cannula (3) via the injection stop (9).

[0024] Figure 4 shows an advanced version of the injection device (1) drawn in Figure 3, which has three radial outlets (5) positioned one above the other in the guiding tube (2) and three inner radial outlets (12) positioned one above the other, but laterally offset from one each other in the injection cannula (3). This design enables the temporally delayed application of cell suspension (6) in adjacent tissue regions.

[0025] In general, the shape of the tip of the injection device (1) must be optimized so that minimum lateral force is generated during the movement in the viscoelastic tissue. In one embodiment, also depicted in Figure 4, the injection tip (4) is asymmetrically shaped so that the tip performs a slow lateral oscillatory movement during penetration in case of oscillatory rotation of the injection device (1) during insertion. This helps to laterally displace capillaries, thereby protecting the tissue from bleeding and microlesions. With this design, as with a symmetric tip, it must be ensured that maximum targeting accuracy is provided. In an embodiment in which the tip of the injection device (1) is the tip of the injection cannula (3), as shown in Figure 2, the tip of the injection cannula (3) is asymmetrically shaped. In an embodiment in which the tip of the injection device (1) is the tip of the guiding tube (2), as shown in Figure 3, the tip of the guiding tube (2) is asymmetrically shaped.

[0026] Figure 5 shows a variant of the injection device (1) in which the cross-section of the injection cannula (3) is not round, but has a pocket on the opposite side of the radialoutlets (5). This pocket forms a second inner volume (14) that can act as a reservoir for buffer, and by rotating the injection cannula (3) using the means for relative rotational movement (13), the buffer solution (7) can be dispensed via the three radial outlets (5) of the guiding cannula (3). This rinsing process serves as a means of preventing cell carryover when the injection device (1) is pulled out of the tissue after application of the cell suspension (6). This requires two syringes (8), both loaded with buffer solution (7), one of them to be further filled with cell suspension (6) via the inner radial outlet (12).

[0027] Another variant of the injection device (1) is illustrated in Figure 6. A threewalled system is sketched here. By forward movement within the extension distance (10), the injection cannula (3) along with the guiding tube (2) is pushed out of an outer guide tube (15). By means for relative rotational movement (13), the radial outlets (5,12) of the injection cannula (3) and guiding tube (2) are superimposed to release the cell suspension (6) at the target location.

[0028] In some embodiments of the invention, as depicted in Figure 3, the injection cannula (3) is initially replaced by a solid rod without opening, a so-called mandrin (16). This mandrin (16) should completely fill the lumen and close the radial outlet (5) so that the guide tube (2) cannot punch out any tissue during inserting into the tissue, as depicted in Figure 8. In cases where the radial outlet (5) is just opened after the final position in the brain tissue is reached, the use of a mandrin might obsolete, as for example in case of the variant shown in Figure 6.

[0029] In a further embodiment, in which the tip of the injection device (1) is also the tip of the injection cannula (3), as shown in Figure 2, the tip of the mandrin (16) is shaped accordingly. In respect to the design shown in Figure 4, the tip of the mandrin (16) can be also asymmetrically shaped.

[0030] In an embodiment in which the tip of the injection device (1) is also the tip of the injection cannula (3), as shown in Figure 2, and the tip of the injection cannula (3) is asymmetrically shaped, as shown in Figure 4, the tip of the mandrin is also asymmetrically shaped.

[0031] In another embodiment in which the mandrin accounts to the injection device (1) stability, it might be also used in cases where it would not be required to close the radial outlet (5).

[0032] In one embodiment, the injection cannula (3) is loaded with cell suspension (6) and inserted into the injection device (1) just before cell injection into the tissue, to providebest cell viability and prevent spilling of cells during the positioning of the injection device (1).Use of the Catheter

[0033] Further object of the invention is a method of injecting a cell suspension into an organism using the catheter (1) as disclosed characterized by inserting the catheter with a tapered shaped tip (4) into the organism and injecting the cell suspension through at least one radial opening into the organism.

[0034] Preferable, the catheter (1) is used for injecting cells into the human brain.

[0035] Optionally, before inserting the catheter (1) into the organism, the at least one radial opening is closed and after inserting the catheter (1) into the organism, the at least one radial opening is opened by axially and / or rotationally

[0036] In one example, the injection device (1) is utilized for application of a cell suspension (6) into a specific region within the human brain. Here, the following steps are carried out:1) The stereotactic frame (as for example shown in Figure 1) is placed and fixed on the patient’s head.2) Computer tomography or magnet resonance imaging is performed to determine the coordinates of the desired target region within the brain relative to the frame coordinates.3) Placement of the injection device (1) is planned using a computer based planning system and a target point simulator.4) The targeting ark carrying the injection device (1), containing the injection cannula (3) loaded with the cell suspension (6), is positioned on the frame. In some embodiments of the invention, as depicted in Figure 3, the injection cannula (3) is initially replaced by a mandrin.5) A skin incision is made and a small hole is drilled into the skull under local anesthesia.6) The mounted injection device (1) is moved downward into the brain tissue, an oscillatory rotational movement supports a reduced axial friction.7) The injection device (1) is fixed at the target position.8) A desired volume of the cell suspension, e.g. 5 pL, is taken up into the injection cannula (3) prefilled with buffer solution (7) through the radial outlet(s) (5 and / or 12) by pulling the plunger of the connected syringe (8).9) Optionally, the mandrin is removed from the injection device (1), if present.10) The injection cannula (3) is introduced into the injection device (1), if not yet present.1 l)The lateral radial outlet (5) is utilized to release the cell suspension (6) from the injection cannula (3). In double walled designs, as shown in Figure 2, this happens via superposition of both the inner and the outer radial outlet (5, 12) by pushing the injection cannula (3) forward within the guiding tube (2) in the range of the extension distance (10) and turning it by means for relative rotational movement (13).12) The cell suspension is dispensed into the desired tissue region by pushing the plunger of the connected syringe (8). This can be either done manually or via an (semi)automated delivery system.13) Optionally, for rinsing - in order to prevent cell spilling in the next step a physiological buffer solution (7) is applied to the tissue, i.e. utilizing a second syringe and optionally a buffer reservoir system, as described in one embodiment illustrated in Figure 5.14) The injection device (1) is removed from the brain tissue and the procedure is repeated in other target regions or the surgical procedure is completed.ReferencesPenna V, M. N. (April 2022). Extracellular Matrix Biomimetic Hydrogels, Encapsulated with Stromal Cell-Derived Factor 1, Improve the Composition of Foetal Tissue Grafts in a Rodent Model of Parkinson. Int J Mol Sci. 2022 , S. 4646.

Claims

Claims1. Catheter (1) for injecting a cell suspension into an organism comprising an outer canula (2) and an inner canula (3) characterized in that- the inner canula (3) is designed to be inserted into the outer canula (2) and the inner canula (3) is axially and / or rotationally movable in the outer canula (2)- the catheter is provided with a tapered shaped tip (4),- the outer canula (2) and / or the inner canula (3) is provided with at least one radial opening from which a cell suspension is injected into the organism.

2. Catheter (1) according to claim 1 characterized in that the inner canula (3) is in fluid communication with a fluidic reservoir (8) providing the cell suspension.

3. Catheter according to claim 1 or 2 characterized in that the outer canula (2) is provided with an injection stop means (9).

4. Catheter (1) according to any of the claims 1 to 3 characterized in that the outer canula (2) is provided with a frame connector (11) provided as mechanical stop for axial movement of the inner canula (3) relative to the outer canula (2).

5. Catheter (1) according to any of the claims 1 to 4 characterized in that the tapered shaped tip (4) is asymmetrical in respect to the axis of the catheter.

6. Catheter (1) according to any of the claims 1 to 5 characterized in that the outer and inner canula (2, 3) are provided with at least one opening (12) positioned to be brought into alignment with each other by rotational or axial relative movement of the outer canula (2) and / or inner canula (3).

7. Catheter (1) according to claim 6 characterized in that the outer canula (2) and inner canula (3) are provided with 2 to 20 openings (5, 12) which are positioned to be simultaneously or sequentially brought into alignment with each other.

8. Catheter (1) according to any of the claims 1 to 6 characterized in that providing an outer guiding tube (15) which is enclosing the outer canula (2).

9. Catheter (1) according to any of the claims 1 to 7 characterized in that the outer canula (2) and / or the inner canula (3) is designed to take up a mandrin (16).

10. Catheter (1) according to any of the claims 1 to 9 characterized in that the inner canula (3) is shaped to provide a second channel between the outer cannula (2) and the inner canula (3) and wherein the chambers are sequentially brought in fluidic communication with at least one radial opening.

11. Catheter (1) according to any of the claims 1 to 10 characterized in that the at least one radial opening is designed to be opened and closed to the organism by axially and / or rotationally moving the outer canula (2) relative to the inner canula (3).

12. Method of injecting a cell suspension into an organism using a catheter (1) according to claims 1 to 11 characterized by inserting the catheter with a tapered shaped tip (4) into the organism and injecting the cell suspension through at least one radial opening into the organism.

13. Method according to claim 12 characterized in that before inserting the catheter (1) into the organism, the at least one radial opening is closed and after inserting the catheter (1) into the organism, the at least one radial opening is opened by axially and / or rotationally moving the outer canula (2) relative to the inner canula (3).

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