WO2021013714A1

WO2021013714A1 - Composition and instrument comprising mesna for use in a method of robot-assisted surgery

Info

Publication number: WO2021013714A1
Application number: PCT/EP2020/070249
Authority: WO
Inventors: Gilles CAPART; Laurent FERRIÈRE
Original assignee: Auxin Surgery Sa
Priority date: 2019-07-19
Filing date: 2020-07-17
Publication date: 2021-01-28
Also published as: EP3999048A1

Abstract

The invention relates to a composition comprising Mesna for use in a method of surgery. The invention also relates to a method for producing a composition comprising Mesna for use in a method of surgery, to a kit for obtaining a composition comprising Mesna for use in a method of surgery, to a device for chemically assisted tissue dissection facilitated by Mesna, and to a method of surgery using Mesna.

Description

METHOD OF ROBOT- ASSISTED SURGERY

TECHNICAL FIELD

5

The present invention relates to a composition comprising Mesna for use in a method of robot-assisted surgery, to a method for producing a composition comprising Mesna for use in a method of robot-assisted surgery, to a kit for obtaining a composition comprising Mesna for use in a method of robot-assisted surgery, to0 robot instruments for chemically assisted tissue dissection facilitated by Mesna, and to a method of robot-assisted surgery using composition comprising Mesna.

BACKGROUND 5 There remains a need in the art for improvements in surgery, e.g. in terms of reducing health risks for patients and providing tools for aiding medical practitioners in performing surgery.

Many surgical procedures involve dissection steps where pathologic material must0 be separated from critical organs, such as nerves, muscles, ducts, ovaries, veins, etc., without damaging such organs. In those situations, the use of non-selective dissection tools, such as electric (RF) knives or laser knives may damage irreversibly these organs and cause surgery side effects.

On the other hand, non-cutting mechanical dissectors may fail to separate strongly5 adhering tissues or tear or damage the organs to be preserved.

The use of robots in surgery, which are normally fitted with electric knives and mechanical dissectors can improve the precision of dissections but, in general would not result in a significant reduction of surgery side effects. 0 The present invention targets at solving at least one of the aforementioned disadvantages.

SUMMARY OF THE I NVENTION 5 The invention thereto aims to provide a composition comprising Mesna for use in a method of robot-assisted surgery and the robot instruments adapted to such use. In a first aspect, the invention relates to a composition comprising Mesna for use in a method of robot-assisted surgery, according to claim 1.

A composition comprising Mesna for use in a method of robot-assisted surgery

5 shows the advantages that the surgery is facilitated by breakage of molecular bonds between tissue layers by topical application of Mesna to a targeted cleavage plane between the tissue layers, while at the same time offering the precision and minimally invasive approach of a robot-assisted surgery. Moreover, when applying Mesna, cleavage planes between tissues are revealed. Accordingly, selective0 mechanical detachment of pathological tissues is possible without cutting. The application of Mesna also facilitates the dissection of fibrosis, which is very difficult by other means. This advantageous manner of mechanical detachment of tissues following breakage of molecular bonds by Mesna can be construed as chemically assisted tissue dissection. A method of surgery without the use of composition5 comprising Mesna would require more effort in separating tissue layers from another, resulting in a longer duration of surgery or even undesired tissue damage. In particular, without the use of composition comprising Mesna, dissection would have to be performed by electric or mechanical knives with increased risk of cutting accidentally or unavoidably critical organs.

0

Preferred embodiments of the composition comprising Mesna for use in a method of robotic assisted surgery, according to the first aspect of the invention, are described in claims 2 to 5. 5 The compositions comprising Mesna without added colorants are colorless and the topical deposition of the solution to tissues to be dissected is hardly visible by the robot operator. The addition of a dye is a preferred embodiment. As a further embodiment, the dye is visible in fluorescence for further discrimination of the tissues to be dissected.

0

In a second aspect, the invention relates to a method for producing a composition comprising Mesna for use in a method of robot-assisted surgery, according to claim 6. 5 The measure of preparing the composition by dissolving Mesna in powder form in one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers, at most one day prior to performing the method of surgery, has the advantage that the prepared composition comprising Mesna can be used shortly after dissolving Mesna in powder form, thereby providing maximal Mesna activity for facilitating tissue separation when used in surgery. This maximal Mesna activity can be explained by the high sensitivity of a liquid solution of Mesna, for example of a liquid solution of Mesna in water, to oxidation. Dissolving Mesna in powder form shortly before use thus minimizes Mesna oxidation and as a result maximizes Mesna activity and alleviates the need for chelating and antibacterial agents. Maximization of Mesna activity is advantageous for use of Mesna in a method of surgery. The measure of preparing the composition by dissolving Mesna in powder form in one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers, at most one day prior to performing the method of surgery, also has the advantage that a composition comprising a tailor-made concentration of Mesna and volumes of the composition comprising Mesna can be prepared case-by-case in function of the needs for a method of surgery by dissolving a particular amount of Mesna in powder form in a particular amount of one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers. The use of tailor-made Mesna concentrations and volumes of compositions comprising Mesna is advantageous for facilitating tissue separation during surgery. In a third aspect, the invention relates to a kit for obtaining a composition comprising Mesna for use in a method of robot-assisted surgery, according to claim 7.

A kit comprising Mesna in powder form next to one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers allows Mesna in powder form to be dissolved in the one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers shortly before using the resulting Mesna solution, thus minimizing the risk of Mesna oxidation and maximizing Mesna activity for facilitating tissue separation when used in surgery.

In a fourth aspect, according to claim 8, the invention relates to a robot instrument for chemically assisted mechanical dissection comprising:

- a cartridge comprising a composition comprising Mesna in a liquid form;

- a pump connectable, and preferably connected, to said cartridge in order to feed the composition comprising Mesna to an outlet tubing of said pump, upon actuation of said pump; - a robot arm com prising an irrigation channel with an inlet connectable, and preferably connected, to said outlet tubing of said pum p and com prising an outlet connectable to an irrigation tip mountable, and preferably mounted on said robot arm , wherein said tip com prises at

5 least one surgical tool selected from the group comprising scalpels, scissors, bovies, forceps, dissector, elevators, hooks, probes, needles, knot pushers, retractors, scopes, clamps and graspers and wherein the tip further com prises at least one irrigation orifice on said at least one surgical tool, said irrigation orifice fluidly connected to the0 irrigation channel ;

whereby actuation of the pump supplies com position com prising Mesna from the cartridge through the irrigation channel to said irrigation tip of the mounted robot arm , and whereby the actuation of the pump is controllable by an operating switch . 5 The experience of using robots in surgery com pared to other systems of open surgery or laparoscopic surgery show that the key factor in the success of the surgery is the skill and experience of the surgeon controlling the robot. A key aspect of the invention is to m ake possible the topical dispensing of a Mesna solution by the surgeon operating the mechanical dissection with the robot arms wherein the0 irrigation of Mesna is controlled by an operating switch , which is preferably a pedal under the foot of a surgeon.

Preferred embodim ents of the robot instrum ent according to the fourth aspect of the invention are disclosed in claims 9- 14. Within the robot instrum ent of the5 invention , an irrigation channel featuring an orifice for dispensing the Mesna solution is provided within the dissection tools at the tip of the robot arms for precise concom itant application of the dissection force and of the composition comprising Mesna. 0 The m echanical dissection tools can be of different types: spatulas, hooks, graspers, dissectors, etc. provided that they are suitable for applying a non-cutting mechanical separation force on the tissues.

I n a fifth aspect, the invention relates to a m ethod of robot assisted surgery using5 com position com prising Mesna, according to claim 1 5. DESCRI PTI ON OF FI GURES

Fig.1 shows schematically a perspective view of the robot instrument for chemically assisted mechanical dissection, comprised of a cartridge comprising a composition

5 comprising Mesna in a liquid form, a peristaltic pump, a robot arm comprising an irrigation channel with an inlet connected, to said outlet tubing of said pump and a console whereby an operator surgeon is seated, and whereby the irrigation tip is controllable by an operating pedal.

Fig. 2 shows schematically a perspective view of the robot arm comprising an0 irrigation tip mounted on said robot arm.

Fig.3 shows schematically a perspective view of the irrigation tip mounted on the robot arm .

Fig. 4 shows schematically a cross-section in the longitudinal direction of the irrigation tip mounted on the robot arm, whereby said irrigation tip comprises a5 Maryland dissector and wherein the tip mounted on the robot arm further comprises one irrigation orifice within said Maryland dissector.

Fig. 5 shows schematically a cross-section in the longitudinal direction of the irrigation tip mounted on the robot arm. 0 DETAI LED DESCRI PTI ON OF THE I NVENTI ON

The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within that range, as well as the recited endpoints. 5 The term “chemically assisted tissue dissection”, as disclosed herein, refers to a method of dissection using Mesna as auxiliary chemical substance for use in surgery.

The term“chemically assisted tissue dissection systems”, as disclosed herein, refers to systems indicated for the cleavage and separation of tissue layers to facilitate the0 detachment of tissues and the dissection of fibrosis in various surgical procedures for patients. In particular, the systems are suitable for use in open surgery as well as in non-invasive surgery (endoscopic and laparoscopic surgery). Preferably, chem ically assisted tissue dissection systems are selected that are classified as Class III devices per Rule 13 of Annex IX to Medical Device Directive 93/42/EEC, as5 amended, or as combination devices by the US FDA.

The term “robotic assisted surgery”, as disclosed herein, is to be understood as a surgical technology that places a computer-assisted electromechanical device, also to be construed as a robot or a robotic device, in the path between a medical practitioner perform ing the surgery and a patient being operated. Robotic-assisted surgery can be applied in open surgery as well as in non-invasive surgery, with endoscopic and laparoscopic surgery as exam ples of non-invasive surgery. Types of

5 applications wherein robotic-assisted surgery can be applied include skull base surgery, open surgery, non-invasive surgery, thoracic surgery, cardiovascular surgery, dentistry, orthopedic surgery, plastic surgery, ophthalm ic surgery, neck surgery, neurosurgery, m axillo-facial surgery, gallbladder surgery, endoscopic surgery laparoscopic surgery, vascular surgery, colorectal surgery, general surgery,0 gynecologic surgery, heart surgery, endom etriosis, head and neck surgery, transoral head and neck surgery, urologic surgery. Robotic assisted surgery shows m any benefits. Robotic assisted surgery benefits a patient directly, in terms of a shorter recovery time, as well as indirectly, in terms of a better visualization available to a m edical practitioner perform ing the surgery, leading to a more precise5 surgery. Other benefits include a greater range of motion and dexterity for a m edical practitioner perform ing the surgery, the availability of a highly-m agnified, high- resolution image of an operating field related to a surgical procedure, better access to body parts being operated, a shorter hospital stay, less risk of infection, less blood loss and fewer blood transfusions, less pain, faster recovery and a quicker0 return of a patient to daily routine. Preferably, said com puter-assisted electromechanical device, for which“robotic surgical system” is used as a synonym in the present text, com prises at least one steerable robotic arm . Said at least one steerable robotic arm m ay be directly or indirectly supportable, and preferably supported, by a cart. Preferably, such robotic surgical system further com prises a5 console from which the at least one robotic arm can be controlled by providing instructions to the console. The at least one arm is configured to hold objects and/or comprises one or more term inally located surgical tools. I n case of laparoscopy, such tools may be construed as laparoscopic instruments. Non- lim iting exam ples of said tools are cannulas, scalpels, scissors, bovies, forceps, dissector, elevators,0 hooks, probes, needles, knot pushers, retractors, scopes and graspers. The term “dissector”, as used herein , can be understood as forceps which are configured to operate interchangeably in a grasping mode, i.e. for grasping and exerting a pulling force on a tissue and in a dissection mode, i.e. for dissecting tissues. According to a preferred em bodim ent, a dissector comprises two opposite j aws which can be5 closed into tissue to exert a pulling force (grasping mode) , and, when the jaws are opened, which dissector is configured to m echanically separate tissues by lateral forces (dissection mode) . The term “laparoscopy” or “laparoscopic surgery”, as disclosed herein, refers to minimally invasive abdomen surgery performed with the aid of an optical system. The term “laparoscopic instruments”, as used in the present text, is to be understood as one or more instruments suitable for enabling laparoscopy performed

5 on a patient.

The term “pharmaceutically acceptable solvent”, as disclosed herein, refers to a solvent capable of dissolving relevant quantities of Mesna, and preferably capable of dissolving relevant quantities of Mesna in powder form. Non-limiting examples of0 pharmaceutically acceptable solvents are water, physiological serum, and water comprising 0.9 mass/volume percent sodium chloride. Bases, such as sodium hydroxide, may be added to the pharmaceutically acceptable solvent. Preferable, said pharmaceutically acceptable solvent is sterile. Further examples of pharmaceutically acceptable solvents are known to the person skilled in the art.5

The term “pharmaceutically acceptable buffer”, as disclosed herein, refers to a solution comprising at least one buffer excipient, capable of keeping pH of a composition comprising Mesna at a nearly constant value. The buffer might be obtained by mixing a solvent with at least one buffer excipient. The solvent might0 be water, might consist of water of high purity (e.g. water for injection as per pharmaceutical standard) and may contain between 0 and 0.9 mass/volume percent of NaCI. The presence of NaCI reduces the side-effects due to chlorine ion depletion. In particular, lack of sufficient chlorine ions may trigger unexpected hyperactivity of some cells such as neurons in brain and in the nerves. Pharmaceutically acceptable5 buffers are known to the person skilled in the art. According to preferred embodiments, said buffer excipient is selected from the group comprising sodium acetate, acetic acid, glacial acetic acid, ammonium acetate, arginine, aspartic acid, benzoate sodium, benzoate acid, carbonate sodium, bicarbonate sodium, citrate acid, citrate sodium, citrate disodium, citrate trisodium, glucono delta lactone,0 glycine, glycine HCI, histidine, histidine HCI, hydrobromic acid, meglumine, phosphate acid, phosphate monobasic potassium, phosphate dibasic potassium, phosphate monobasic sodium, phosphate dibasic sodium (Na₂HPC>₄), tartrate sodium, tartrate acid, tromethamine (tris) or any combination thereof. In preferred embodiments, the concentration of the buffer excipient is of from 2 mM to 60 mM,5 preferably from 2.5 mM to 50 mM, more preferably from 5 to 40 mM, more preferably from 7.5 mM to 35 mM, most preferably from 10 mM to 30 mM. According to a preferred embodiment, the pH of the buffer may be adjusted using pH adjustment agents to reach a desired pH of at least 8.5. Said pH of the buffer allows obtaining a composition comprising Mesna having a pH of from 6 to 8 by only adding solid Mesna in powder form or in lyophilized form to the buffer and without addition of pH adjustment agents. This avoids manipulation of the obtained composition comprising Mesna, to adjust the pH for instance, thereby providing for the

5 immediate use of the obtained composition. This ensures a maximal sterility of the composition and a maximal safety for a patient thanks to the use of a solution with a pH close to physiological pH. According to a preferred embodiment, the buffer comprises phosphate such that the phosphate to Mesna ratio of the composition comprising Mesna is at least 1/500, preferably at least 1/400, more preferably at0 least 1/300, even more preferably at least 1/250, most preferably at least 1/150, even most preferably at least 1/100. Said ratio is at most 1/1, preferably at most

1/1.5, more preferably at most 1/2, most preferably 1/3.

In the present text, “Mesna” is used as an abbreviation for sodium-2-5 mercaptoethane sulfonate. Mesna is a white hygroscopic powder with a characteristic odor. The liquid solution in water is highly sensitive to oxidation and rapidly decomposes on contact with oxygen to form di-Mesna also called disulphide Mesna, which is poorly absorbed, particularly in a humid atmosphere. Mesna is known to break molecular bonds between tissue layers, thereby facilitating tissue0 separation. Specifically, Mesna breaks disulfide bonds of polypeptide chains and proteins, which disulfide bonds are responsible for the adherence of pathological tissues and for the strength of fibrosis.

WO2017/157670 A1 describes a device for delivering a Mesna formulation to tissues5 and/or organs. The device comprises a first chamber comprising Mesna in solid form, a second chamber comprising a buffer and at least one outlet for delivering the Mesna formulation, said outlet is in fluid communication with at least one of the chambers. The chambers are separated from each other by at least one disruptable separation means and are in fluid communication with each other upon disruption0 of said separation means thereby forming the Mesna formulation. The pH of the buffer comprised in the second chamber is at least 8.5. The invention further provides a process for the preparation of a Mesna formulation. According to WO 2017/157670 A1 , the outlet of the device is connectable to at least one second device selected from the group comprising surgical devices, high pressure pumps,5 delivery tubes, applicators, minimally invasive surgery systems, robot assisted device and low pressure pump. US 2007/016174 A1 discloses a robotic surgical instrument for the control of flows of one or more fluids into and out of a surgical site. The robotic surgical instrument may include a housing, a flow control system, a hollow tube, and one or more hose fittings. The housing to couple the instrument to a robotic arm. The flow control

5 system mounted in the housing includes one or more controlled valves to control the flow of one or more fluids. The hollow tube has a first end mounted in the housing coupled to the flow control system. A second end of the hollow tube has one or more openings to allow the flow of fluids into and out of the surgical site. The hose fittings have a first end coupled to the flow control system and a second end0 to couple to hoses.

US 4 191 176 A describes an enzymatic intralenticular cataract treatment for removal of nuclear cortical and subcapsular regions of the cataractous lens through enzymatic digestion thereof which comprises introduction of a concentrated solution5 of a trypsin enzyme into the nuclear and cortical regions of a cataractous lens, and after enzymatic digestion removing the liquefied cataractous material. The procedure allows subsequent removal of the nuclear, cortical and subcapsular portions of a cataractous lens through a very tiny incision in the eye and lens capsule, leaving all other structures within the eye intact. Bovine and porcine0 trypsins are preferred. According to US 4 191 176 A, for an enzyme containing solution injected into the lens, the distribution pattern of the injected fluid may be observed by incorporating a soluble, inert dye such as fluorescein into the injection fluid in amounts of 0.01 -1.0% w/v. 5 US 5 273 751 A discloses compositions for killing undifferentiated epithelial cells during cataract surgery on an eye to prevent posterior capsule clouding after the surgery and to a method for performing cataract surgery on an eye including injecting a cell-killing substance between the anterior capsule and the natural lens prior to removing the natural lens from the eye. The cell-killing substance is0 preferably an acid or base adjusted aqueous solution having a pH in the range between about 1.0 to below 6.5 or about above 7.5 to 14.0; or a hypotonic solution having a salinity less than 0.9% or a pH adj usted hypotonic solution having a salinity less than 0.9% and a pH either below 6.5 or above 7.5. The compositions of US 5 273 751 A also incorporate a viscoelastic material, a dye or a mixture thereof, in5 combination with the cell-killing substance. According to US 5273 751 A, for the purpose of visually determining that cell-killing substance has completely filled the pocket and expanded all portions of the anterior capsule segment, a dye is admixed with the cell-killing substance prior to or after injection of the cell-killing substance between the inner surface of the anterior capsule and the lens.

In a first aspect, the invention relates to a composition comprising Mesna for use in

5 a method of robot-assisted surgery.

A composition comprising Mesna for use in a method of surgery shows the advantages that the surgery is facilitated by breakage of molecular bonds between tissue layers by application of Mesna to a targeted cleavage plane between the0 tissue layers. Moreover, when applying Mesna, cleavage planes between tissues are revealed. Accordingly, a very precise and selective mechanical detachment of pathological tissues is possible without cutting. This advantageous manner of mechanical detachment of tissues following breakage of molecular bonds by Mesna can be construed as chemically assisted tissue dissection. A method of surgery5 without the use of Mesna would require more effort in separating tissue layers from another, resulting in a longer duration of surgery or even undesired tissue damage. In particular, without the use of Mesna, dissection would have to be performed by electric or mechanical knives with increased risk of cutting accidentally or unavoidably critical organs. Chemically assisted tissue dissection also facilitates“en0 bloc” dissection of non-infiltrating tumors, with less risks of damaging underlying tissues or leaving behind tumor material.

The use of a composition comprising Mesna in a method of robotic assisted surgery shows the advantages that simultaneously Mesna can be applied very precisely to a targeted cleavage plane between tissue layers to be separated from another.5 Moreover, when applying Mesna, cleavage planes between tissues are revealed. The application of a composition containing Mesna can also facilitate the dissection of fibrosis. Accordingly, a more precise mechanical detachment of pathological tissues is possible without cutting. This advantageous cooperation between Mesna as a chemical compound facilitating tissue dissection and robotic assisted surgery can be0 construed as both robotic and chemically assisted tissue dissection. Manual application of Mesna, without a computer-assisted electromechanical device, on the one hand, would not allow such precise application of Mesna, resulting in a less precise separation of tissue layers. In particular, manual application of Mesna would require a separate surgical tool, such as a cannula, operated by a medical5 practitioner separately or through an additional trocar without direct coordination with a robot-assisted electromechanical device and could be insufficiently precise or could result in excessive spillage of Mesna. A method of robotic assisted surgery without the use of Mesna, on the other hand, would require more effort in separating tissue layers from another, resulting in a longer duration of surgery or even undesired tissue damage. I n particular, without the use of Mesna, dissection would have to be perform ed by electric or mechanical knives with increased risk of cutting accidentally or unavoidably critical organs.

Preferably, the com position comprising Mesna is sterile. This is of particular im portance in the current context of the preparation of a composition com prising Mesna for use in a m ethod of surgery, in order to avoid infections during surgery.

I n a preferred embodim ent, the invention relates to a composition comprising Mesna for use in a method of surgery according to the first aspect of the invention, wherein the method of surgery is selected from the group comprising skull base surgery, open surgery, non-invasive surgery, thoracic surgery, cardiovascular surgery, dentistry, orthopedic surgery, plastic surgery, ophthalm ic surgery, neck surgery, neurosurgery, m axillo-facial surgery, gallbladder surgery, endoscopic surgery, laparoscopic surgery, vascular surgery, colorectal surgery, general surgery, gynecologic surgery, heart surgery, endom etriosis, head surgery, neck surgery, transoral neck surgery, transoral head surgery and urologic surgery.

I n a preferred embodim ent, the invention relates to a composition comprising Mesna for use in a method of surgery according to the first aspect of the invention, wherein the composition com prises 1 % by weight to 30% by weight, more preferably 2% by weight to 22% by weight, yet even more preferably 3% by weight to 14% by weight, yet even more preferably 4% by weight to 6% by weight of Mesna, supplemented up to 1 00% by weight with one or more pharmaceutically acceptable solvents and/or one or more pharm aceutically acceptable buffers, based on the overall weight of the com position . Compositions according to said weight percentages allow for complete solubilization of Mesna in the one or more pharm aceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers. Also, said concentrations of Mesna in the composition are high enough for facilitating tissue separation and are low enough to avoid excessive wastage of Mesna in a body of a patient where not necessary, thereby not exceeding a m axim um amount of Mesna acceptable to prevent system ic potential toxicity.

I n a preferred embodim ent, the invention relates to a composition comprising Mesna for use in a method of surgery according to the first aspect of the invention, wherein the one or more pharm aceutically acceptable solvents are selected from the group comprising water, preferably sterile water, and a solution of 0.9 mass/volume percent of NaCI in water, preferably a sterile solution of 0.9 mass/volume percent of NaCI in water.

5 In a preferred embodiment, the invention relates to a composition comprising Mesna for use in a method of surgery according to the first aspect of the invention, wherein a solution of Na2HPC>4 in water or a solution of Na2HPC>4 and NaCI in water is selected as pharmaceutically acceptable buffer. More preferably, the buffer is an aqueous solution of 10 mM Na2HPC>4 or an aqueous solution of 10 mM Na2HPC>4 and 75 mM0 NaCI. Preferably, the water is water of high purity (e.g. water for injection as per pharmaceutical standard) and may contain between 0 and 0.9 mass/volume percent of NaCI. Preferably, the water is sterile.

In a preferred embodiment, the invention relates to a composition comprising Mesna5 for use in a method of surgery according to the first aspect of the invention, wherein the composition comprises one or more chelating agents.

I n a preferred embodiment, the invention relates to a composition comprising Mesna for use in a method of surgery according to the first aspect of the invention, wherein0 edetate disodium is selected as chelating agent.

According to embodiments, preservation agents such as benzyl alcohol may be added to the composition comprising Mesna. However, when storing Mesna in powder form and only dissolving Mesna prior to its use in a method of surgery, the5 use of preservation agents can be avoided.

In a preferred embodiment the composition comprising Mesna further comprises one or more dyes in order to make the topical deposition visible by the surgeon operating the mechanical dissectors. In this way the extent of coverage of the0 tissues and the cleavage planes can be made more easily identified, which greatly facilitates the dissection.

In a further preferred embodiment, said one or more dyes are selected from the group consisting of indocyanine green, riboflavin, riboflavin 5’-phosphate sodium, methylene blue and fluorescein.

5

In a preferred embodiment, the dye is selected among substance visible in fluorescence or epifluorescence. I n a second aspect, the invention relates to a method for producing a composition com prising Mesna for use in a m ethod of robotic assisted surgery , wherein at most one day, more preferably at most 12 hours, even more preferably at most 8 hours, even more preferably at most 6 hours, yet even more preferably at most 4 hours, yet even more preferably at most 3 hours, yet even more preferably at most 2 hours prior to perform ing the m ethod of surgery, the com position is prepared by the step of dissolving Mesna in powder form in one or more pharmaceutically acceptable solvents and/or one or more pharm aceutically acceptable buffers.

The m easure of preparing the composition by dissolving Mesna in powder form in one or more pharm aceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers, at most one day prior to perform ing the method of surgery, has the advantage that the prepared com position com prising Mesna can be used shortly after dissolving Mesna in powder form , thereby providing maxim al Mesna activity for facilitating tissue separation when used in surgery. This maxim al Mesna activity can be explained by the high sensitivity of a liquid solution of Mesna, for example of a liquid solution of Mesna in water, to oxidation . Dissolving Mesna in powder form shortly before use thus m inim izes Mesna oxidation and as a result maxim izes Mesna activity and alleviates the need for chelating and antibacterial agents. Maxim ization of Mesna activity is advantageous for use of Mesna in a m ethod of surgery. The m easure of preparing the com position by dissolving Mesna in powder form in one or more pharm aceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers, at most one day prior to perform ing the method of surgery, also has the advantage that a com position com prising a tailor-m ade concentration of Mesna and volumes of the com position com prising Mesna can be prepared case-by-case in function of the needs for a m ethod of surgery by dissolving a particular amount of Mesna in powder form in a particular amount of one or more pharmaceutically acceptable solvents and/or one or more pharm aceutically acceptable buffers. The use of tailor- made Mesna concentrations and volumes of compositions com prising Mesna is advantageous for facilitating tissue separation during surgery.

Additionally, the m easure of preparing the composition by dissolving Mesna in powder form in one or more pharm aceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers, at most one day prior to perform ing the m ethod of surgery, appears to be specially advantageous when com paring with com mon uses of Mesna as known from the state of the art. Most pure Mesna dosage forms used until today are liquid form ulations. Since Mesna is very sensitive to oxidation and reacts in the presence of oxygen to form di-Mesna, the aqueous solutions have to be protected against oxygen. In addition, Mesna in liquid form is highly prone to oxidation in presence of metals. Therefore, Mesna solutions are usually sealed into glass ampoules, preferably in low iron glass containers under nitrogen blanket with stabilizers, anti-oxidants and metals chelating agents. Aseptic filling of said glass containers under nitrogen blanket is rather expensive. Furthermore, in some procedures, Mesna solutions are needed at different concentrations from those readily available in commercial glass vials, making the use of said vials tedious or inadequate. When being used, the practitioner has to transfer the solution from glass containers to delivery device or to tube in order to incorporate the solution in the desired application. This step increases the chances of oxidation and contamination of the Mesna solution thereby having reduced Mesna activity or reduced sterility when used, for example in chemically assisted surgery.

In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein the step of dissolving is performed at most 1 hour, more preferably at most 45 minutes, even more preferably at most 30 minutes, even more preferably at most 20 minutes, even more preferably at most 15 minutes, even more preferably at most 10 minutes, yet even more preferably at most 5 minutes prior to performing the method of surgery. Accordingly, Mesna activity for facilitating tissue separation when used in surgery is maximized.

In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein the Mesna in powder form is sterile. In a preferred embodiment, the Mesna in powder form is lyophilized Mesna. In a preferred embodiment, the sterilized Mesna powder is obtained by drying, a sterilized Mesna solution. According to preferred embodiments, said Mesna solution is sterilized by microfiltration or ultrafiltration. Sterility of the Mesna in powder form is desired, and especially in the current context of the preparation of a composition comprising Mesna for use in a method of surgery, in order to avoid infections during surgery.

In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein the Mesna in powder form is lyophilized Mesna. Lyophilized Mesna has improved stability and shelf-life compared to technical Mesna. Technical Mesna is Mesna obtained as a stable crystalline powder from synthesis, but this form is not sterile and therefore not suitable to medical applications. In a preferred embodiment, the Mesna in powder form is sterile lyophilized Mesna. In preferred embodiment, the sterilized lyophilized Mesna is obtained by freeze-drying or lyophilizing a sterilized Mesna solution. According to preferred embodiments, said Mesna solution is sterilized by microfiltration or ultrafiltration.

In another preferred embodiment, the Mesna crystalline powder obtained by synthesis is placed in a container and sterilized by terminal gamma ionizing radiation, preferably a ionizing radiation of a dose between 25 and 45 Gy. In a further preferred embodiment, said container is a cartridge of the invention. It should be understood by a skilled person that other conditions of gamma ionizing radiation could be used to sterilize the Mesna powder in a container, without departing from the scope of the present invention.

In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein the one or more pharmaceutically acceptable solvents are selected from the group comprising water, preferably sterile water, and a solution of 0.9 mass/volume percent of NaCI in water, preferably a sterile solution of 0.9 mass/volume percent of NaCI in water.

In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein a solution of Na2HP04 in water or a solution of Na2HPC>4 and NaCI in water is selected as pharmaceutically acceptable buffer. More preferably, the buffer is an aqueous solution of 10 mM Na2HPC>4 or an aqueous solution of 10 m M Na2HPC>4 and 75 m M NaCI. Preferably, the water is water of high purity (e.g. water for injection as per pharmaceutical standard) and may contain between 0 and 0.9 mass/volume percent of NaCI. Preferably, the water is sterile.

In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein one or more chelating agents are added to the one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers. In a preferred embodiment, the invention relates to a method for producing a composition comprising Mesna for use in a method of surgery according to the second aspect of the invention, wherein edetate disodium is used as chelating agent. However, when storing Mesna in powder form and only dissolving Mesna prior to its use in a method of surgery, the use of chelating agents for binding metals can be avoided, since Mesna oxidation is avoided.

According to embodiments, preservation agents such as benzyl alcohol may be added to the one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers. However, when storing Mesna in powder form and only dissolving Mesna prior to its use in a method of surgery, the use of preservation agents can be avoided, since Mesna oxidation is avoided.

In a third aspect, the invention relates to a kit for obtaining a composition comprising Mesna for use in a method of robot assisted surgery, wherein the kit comprises Mesna in powder form next to one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers.

In a preferred embodiment, the invention relates to a kit for obtaining a composition comprising Mesna for use in a method of robot assisted surgery according to the third aspect of the invention, wherein the one or more pharmaceutically acceptable solvents are selected from the group comprising water, preferably sterile water, and a solution of 0.9 mass/volume percent of NaCI in water, preferably a solution of 0.9 mass/volume percent of NaCI in water.

In a preferred embodiment, the invention relates to a kit for obtaining a composition comprising Mesna for use in a method of surgery according to the third aspect of the invention, wherein a solution of Na₂HPC>₄ in water or a solution of Na₂HPC>₄ and NaCI in water is selected as pharmaceutically acceptable buffer. More preferably, the buffer is an aqueous solution of 10 mM Na₂HPC>₄ or an aqueous solution of 10 m M Na₂HPC>₄ and 75 m M NaCI. Preferably, the water is water of high purity (e.g. water for injection as per pharm aceutical standard) and may contain between 0 and 0.9 m ass/volum e percent of NaCI. Preferably, the water is sterile.

5 I n a preferred embodim ent, the invention relates to a kit for obtaining a composition comprising Mesna for use in a m ethod of surgery according to the third aspect of the invention, wherein the kit comprises one or more chelating agents.

I n a preferred embodim ent, the invention relates to a kit for obtaining a composition0 comprising Mesna for use in a method of surgery according to the third aspect of the invention, wherein edetate disodium is selected as chelating agent.

I n a fourth aspect, the invention relates to a robot instrum ent for chem ically assisted m echanical dissection com prising :

5 -a cartridge comprising a composition comprising Mesna in a liquid form ;

-a pump connectable, and preferably connected, to said cartridge in order to feed the com position comprising Mesna to an outlet tubing of said pum p, upon actuation of said pump;

-a robot arm com prising an irrigation channel with an inlet connectable, and0 preferably connected , to said outlet tubing of said pum p and com prising an outlet connectable to an irrigation tip mountable, and preferably mounted on said robot arm , wherein said tip comprises at least one surgical tool selected from the group comprising scalpels, scissors, bovies, forceps, dissector, elevators, hooks, probes, needles, knot pushers, retractors, scopes, clam ps and graspers and wherein the tip5 further com prises at least one irrigation orifice on said at least one surgical tool, said irrigation orifice fluidly connected to the irrigation channel ;

whereby actuation of the pum p supplies com position com prising Mesna from the cartridge through the irrigation channel to said irrigation tip of the mounted robot arm , and whereby the actuation of the pump is controllable by an operating switch .0

Due to the cartridge com prising a composition comprising Mesna in liquid form , the robot instrum ent for chem ically assisted tissue dissection makes use of Mesna for facilitating separation of tissue layers, resulting from breakage of molecular bonds between tissue layers by application of Mesna to a cleavage plane between said5 tissue layers. Moreover, when applying com position comprising Mesna, cleavage planes between tissues are revealed. Accordingly, a mechanical detachment of pathological tissues is possible without cutting. Without the use of Mesna, more effort would be required in separating tissue layers from another, resulting in a longer duration of surgery or even undesired tissue dam age. I n particular, without the use of Mesna, dissection would have to be performed by electric or mechanical knives with increased risk of cutting accidentally or unavoidably critical organs. Chem ically assisted tissue dissection also facilitates“en bloc” dissection of non

5 infiltrating tumors, with less risks of damaging underlying tissues or leaving behind tumor m aterial. Chem ically assisted tissue dissection also facilitates the dissection of fibrotic tissues

I n surgery, the accuracy of topical deposition of Mesna is important for two reasons.0 Firstly, Mesna m ust wet a cleavage plane between tissues that are to be dissected.

This is not always obvious when a patient is in the Trendelenburg position and the liquid does not flow upwards. For this reason , the outlet of an irrigation channel for providing a composition comprising Mesna m ust be at the tip of a chem ically assisted mechanical dissector placed accurately on the cleavage plane, to ensure proper5 wetting of the cleave plane with Mesna. Secondly, the amount of Mesna m ust be lim ited in order to avoid toxicity effects on the tissues and on the cells. Flooding the surgical cavity in order to make sure that all tissues to be dissected are wetted by Mesna is not an option.

The preferred embodim ent of the robot system according to the fourth aspect of the0 invention is shown in Fig . 1 .

The cartridge of the robot instrum ent according to the fourth aspect of the invention contains Mesna in solid form and a solvent. The Mesna is dissolved in the solvent less than 24 hours, preferably less than 1 2 hours before use. I n a preferred5 em bodim ent, a lam inate of the said cartridge holds a piercing cylinder which slides into a solvent compartm ent and leads to a rupturing of a m em brane and m ixing of a solvent with a Mesna in the solid form to obtain a composition comprising Mesna, whereby said com position is in a liquid form .

I n a preferred embodim ent, the composition comprising Mesna further comprises at0 least one dye. I n one em bodiment, said at least one dye is in a solvent com partm ent. I n another embodim ent, dye is in a solid form in a compartm ent separated from the solvent.

I n a preferred embodim ent, said at least one dye can be activated in fluorescence. I n a further preferred embodim ent, said robot instrum ent is equipped by a5 fluorescence surgical google. This embodim ent allows im age assisted surgical operations, which are of high precision and pose less risk to inj uring the surrounding tissues and organs. The im age assisted surgery allows easier differentiation of the tissues to be treated from the surrounding tissues. In a preferred embodiment, the fluid connection between the cartridge and the robot arm is made by a disposable tubing, with a connector at each end. In a further preferred embodiment, said connector is a male Luer lock connector.

In a particularly preferred embodiment, the female Luer connection of the cartridge

5 includes a normally closed valve which open upon connection of the male Luer from the tubing.

In a further preferred embodiment, a particle filter is inserted at the inlet side of the tubing. A non-limiting example of such filter is a 5 micron particle filter. It should be understood by a skilled person that any filter suitable for filtering composition0 comprising Mesna in liquid form may be used in the robot instrument of the invention without departing form the scope of the invention. The filter is intended to retain potential undissolved particles and thus enable the safe application of the Mesna solution. 5 A peristaltic pump cassette is inserted in the tubing. The cassette is attached to the pump motor before use. The motor is turned on when the foot pedal is depressed by the operator of the robot. In a preferred embodiment, a peristaltic pump cassette is disposable. In a preferred embodiment, a peristaltic pump cassette is sterilized. In a particularly preferred embodiment, the peristaltic pump cassette is sterilized0 by ionization, application of sterilizing gas and the like.

The speed and the function of a pump motor is controllable by an operator sitting at a console by an operating switch. In a preferred embodiment, said operating switch is a foot pedal placed under the foot of an operator. In a preferred embodiment, the speed of the pump motor is variable. In a particularly preferred5 embodiment, the whereby the speed of irrigation is controllable by a pump. In a further preferred embodiment, the speed of irrigation can be adjusted between 5 ml/min and 50 ml/min. In a preferred embodiment, the maximum outlet pressure is of the pump 2 bars.

The outlet of the tubing of said peristaltic pump is connected to the gearbox of the0 robot arm. In a preferred embodiment, the pump motor can be attached to a pole or laid down on a flat surface near the robot.

In a preferred embodiment, the cartridge is hung on a hanger attached to the pump motor.

According to the third aspect of the invention, the robot arm robot arm comprises5 an irrigation channel with an inlet connectable, and preferably connected, to said outlet tubing of said pump and comprises an outlet connectable to an irrigation tip mountable, and preferably mounted on said robot arm . I n a preferred em bodim ent, said tip is mounted on said robot arm .

I n a preferred embodim ent, said tip mountable, and preferably mounted on said robot arm comprises at least one surgical tool selected from the group comprising scalpels, scissors, bovies, forceps, dissector, elevators, hooks, probes, needles, knot pushers, retractors, scopes, clam ps and graspers and wherein the tip of the robot arm further com prises at least one irrigation orifice within said at least one surgical tool.

The arm is comprised of a shaft of suitable length onto which a tip is mountable and preferably mounted, and whereby said shaft is housing the cables for moving the irrigation tip and the fluid channel for dispensing composition com prising Mesna by the irrigation tip and a gear box housing the pulleys connected to the driver motors. I n a preferred embodim ent, said gear box is connected to electric motors. The gear box is also fitted with a Luer connection for the supply of the com position comprising Mesna.

The fluid channel is preferably provided by extruding a lum en in the stainless-steel shaft in order to leave enough room for the cables between the gear box and the instrument tips. I n preferred em bodim ent, the shaft is electrically isolated. The electrically isolated shaft is suitable for operation in high-frequency mode. I n a preferred em bodim ent, the shaft is isolated electrically by an insulating sheath .

The length of the shaft and the gearbox can be adapted to different types of robots for open or m inimally invasive surgeries. Som e non-lim itive examples of a shaft length are at least 1 0 cm and at most 45 cm . I t should be understood by a skilled person that any suitable shaft length can be used without departing from the scope of the invention.

The irrigation tips are capable of dispensing topically the composition com prising Mesna on the tissues to be dissected while exerting a mechanical separation force, both controlled by the robot operator.

I n a preferred embodim ent, the irrigation tip mountable and preferably mounted on the robot arm comprises a surgical tool, such as, but not lim ited to a forceps, dissector, elevator or hook. The function of the elevator of lifting tissues is especially convenient for reaching a cleavage plane between tissues to be treated with a com position comprising Mesna, enabling a proper wetting of the cleavage plane with Mesna. The function of the forceps of grasping tissues is especially convenient for stabilizing and positioning of tissues to be dissected. The dissector is able to interchangeably switch between said latter function and a function of spreading tissues. A hook functions to grab onto tissues and, due to its shape, is especially convenient for stabilizing and positioning of tubular body parts such as ducts and arteries.

In a preferred embodiment, a hook comprising a curved end which is connectable, and preferably connected, to said outlet of said irrigation channel is selected as said surgical tool comprised within a tip mounted on the robot arm. This location of the outlet of the irrigation channel at the curved end of the hook is ideally suited for providing a composition comprising Mesna to a cleavage plane between tissues while the tissues are grabbed by the curved end of the hook.

In a preferred embodiment, depicted in Fig. 3, the irrigation tip mounted on the robot arm is a Maryland type of dissector tip. The Maryland type of dissector used in the robot instrument, preferably comprises two jaws. Said jaws can be moved independently by the robot operator and can be used either in pulling mode or dissection mode.

At least one the jaws comprises an orifice for dispensing the composition comprising Mesna on the tissues to be dissected before exerting the mechanical separation force. In a preferred embodiment, a diameter of a robot tip orifice is in range from 100 miti-500 pm. In another embodiment, the diameter of a robot tip orifice is adjustable. The diameter of an orifice can influence the mode of irrigation of Mesna. In a preferred embodiment of the invention, the orifice allows for dispensing Mesna in at least two modes. In one preferred embodiment, said mode of Mesna dispensing is a dripping mode. In another preferred embodiment, said mode of Mesna dispensing is a jet mode. The said orifice features allow for a more safe and more precise Mesna application to the surgical cavity. The risks normally connected to Mesna application are minimised, as the flow can be adjusted to the specific nature of the tissues to be treated. Furthermore, the Mesna flow is controllable by an actuation of the pump, and also on a level of an orifice, which can be adjusted to the specific operating procedure to be completed.

The distal part of the robot arm irrigated tip holds at least one surgical tool. In the preferred embodiment, the said distal part holding the jaws of Maryland dissector, whereby said jaws can be rotated independently around the axis. The proximal part is mounted mechanically to the shaft of the robot arm. It holds the distal piece of the robot arm tip which can be rotated around the axis. The jaws of the Maryland dissector are connected electrically to the metallic shaft by the metallic distal and proximal pieces. At least one of the jaws is connected fluidly to the fluid channel provided in the shaft through the distal and proximal pieces.

In a preferred embodiment, a fluid connection channel of the orifice on the tip mounted onto the robot arm and lumen of the robot arm is provided in the proximal piece of said tip in front of the outlet of the channel for tight fluid connection. Preferably, a groove is provided in the pulley provided in the said proximal piece which is rotating the distal piece around its axis. The fluid channel in the proximal piece has its orifice in front of the groove.

In a preferred embodiment, a fluid connection channel is also provided in the distal piece of the tip. The proximal orifice of this channel is located in front of the groove. In this way, the fluid can pass from the proximal piece to the distal piece. In a preferred embodiment, the fluid tightness is obtained by the flat flanges and the like elements present on the pulleys and the pieces which are closing the groove.

In a preferred embodiment, a groove is provided in the basis of the tip mounted on the robot arm. The distal orifice of the fluid channel provided in the distal piece is placed in front of the groove. The proximal orifice of the fluid channel provided in the irrigated jaw is preferably located in front of the groove. Fluid tightness is obtained by the flat flanges on the jaw basis and the distal piece. The more detailed description of a preferred embodiment of the invention is disclosed in Fig.4 and 5.

In a preferred embodiment, the dispensing of the composition comprising Mesna at the orifice of one of the jaws is controlled. The control of the dispensing is achieved by the robot operator by depressing an operating switch, which is preferably a foot pedal placed under the foot of an operator.

It should be understood by a skilled person that the fluid connection with other types of irrigation tips, such as hook dissectors or elevators, is achieved in the above- mentioned manner.

In a further preferred embodiment, the robot arm tip is made of one or more conductive materials connected to a radio frequency source and can also be operated in electric mode for cutting or cauterizing without changing instruments. In a preferred embodiment, the Mesna irrigated robot arms described above can be used as electrical knives by connecting the shaft to an radio frequent generator in conventional way.

In the preferred embodiment of the invention, by a robot instrument allows additional, or alternative, dissection of tissue layers by application of electrical energy, and also cauterization of tissues by applying electrical energy. Preferably, the dissection or cauterization of tissues by electrical energy is performed by applying heat produced on the surgical tool by the electrical energy. The one or more conductive materials may be selected from any of conductive materials known from the state of the art. The electrical energy providing means may comprise an electrical energy source with a connecting wire for connecting to the surgical tool.

The inclusion of a computer-assisted electromechanical device, which can also be construed as a robotic device, increases the accuracy and precision of said tissue separation facilitated by Mesna, by a more precise and stable positioning of the chemically assisted mechanical irrigation tip by the computer-assisted electromechanical device when compared with manual handling of the dissector. In particular, the at least one steerable robotic arm shows the advantages of being steerable at great precision. The advantageous cooperation between Mesna as a chemical compound facilitating tissue dissection and robotic assisted surgery can be construed as both robotic and chemically assisted tissue dissection. Manual application of Mesna, without a computer-assisted electromechanical device, on the one hand, would not allow such precise application of Mesna, resulting in a less precise separation of tissue layers. In particular, manual application of Mesna would require a separate surgical tool, such as a cannula, operated by a medical practitioner separately or through an additional trocar without direct coordination with a robotic device and could be insufficiently precise or could result in excessive spillage of Mesna. A device for chemically assisted tissue dissection including a robotic device without the use of Mesna, on the other hand, would require more effort in separating tissue layers from another, resulting in a longer duration of surgery or even undesired tissue damage. In particular, without the use of Mesna, dissection would have to be performed by electric or mechanical knives with increased risk of cutting accidentally or unavoidably critical organs.

In a preferred embodiment of the invention, said robot arm and feeding of the composition comprising Mesna is steerable by a computer-assisted electromechanical device by the robot operator. The operator sits behind a control console equipped by a device for a remote com puter assisted steering of the robot arms. The control console preferably com prises a control pedals and one or more control sticks for steering of a robot arm . The console is preferably equipped with a stereoscopic oculars, which enable an operator to see a single three-dim ensional image. The stereoscopic oculars enable actually viewing the operation cavity in reality, m aking an accurate sim ulation of the natural viewing experience and without causing an eye strain and fatigue. The stereoscopic oculars m ake the operation easier and m inim ize the risks and inj ury of the surrounding tissue.

According to a preferred em bodiment, the com puter-assisted electromechanical device further com prises a console configured for providing instructions to the com puter-assisted electrom echanical device, preferably for providing instructions to the at least one steerable robotic arm , by m eans of input provided to the console.

Preferably the robot instrument of the invention com prises manual steering m eans for manually steering the at least one controllable robotic arm , and wherein the com puter-assisted electrom echanical device com prises m echanical feedback m eans configured to connect, and preferably connecting, the at least one controllable robotic arm with the m anual steering means.

I n a preferred embodim ent said robot instrum ent is equipped by a haptic feedback to an operator. The haptic feedback gives the better overview and control to an operator surgeon , and thus m inim izes the risk of inj ury or dissecting of the surrounding tissue. The haptic feedback m eans functions for enabling control of force exerted on tissue layers by the surgical tool of the chem ically-assisted electromechanical device steered by the at least one robotic arm . Manually steering of the at least one controllable robotic arm can be perform ed by manual handling of the control m eans by a m edical practitioner.

The use of computer-assisted electrom echanical devices, also to be construed as robotic devices or robots, is spreading in m any surgical procedures. Most robots are equipped with arms that are equipped with electrical knives and/or m echanical forceps or dissectors, none of which are irrigated. Electrical knives are cutting precisely but not selectively. They would cut indifferently pathologic tissues and organs such as nerves or veins, which do not repair, causing potentially serious side effects. The robot instrum ent of the invention has the advantages of the computer- assisted electrom echanical devices, and at the sam e tim e enables using the com positions comprising Mesna as fluids which chem ically facilitate the tissue dissection. Thus, the robot instrum ent of the invention is particularly suitable for complex interventions of a high risk, as it allows better control of dissection and less risk for affecting the surrounding tissue.

In a fifth aspect, the invention relates to a method of robotic-assisted surgery using Mesna, including a step of separation of tissue layers along a cleavage plane between said tissue layers, wherein the separation of tissue layers is facilitated by applying a composition comprising Mesna to said cleavage plane.

Use of Mesna in a method of surgery shows the advantages that the surgery is facilitated by breakage of molecular bonds between tissue layers by Mesna. Moreover, when applying Mesna, cleavage planes between tissues are revealed. Use of Mesna in a method of robotic assisted surgery has the additional advantage that Mesna can be applied very precisely to a targeted cleavage plane between tissue layers to be separated from another. Accordingly, a very precise mechanical detachment of pathological tissues is possible without cutting. This advantageous cooperation between Mesna as a chemical compound facilitating tissue dissection and robotic assisted surgery can be construed as both robotic and chemically assisted tissue dissection. Manual application of Mesna, without a computer-assisted electromechanical device, on the one hand, would not allow such precise application of Mesna, resulting in a less precise separation of tissue layers. In particular, manual application of Mesna would require a separate surgical tool, such as a cannula, operated by a medical practitioner separately or through an additional trocar without direct coordination with a computer-assisted electromechanical device and would not be sufficiently precise or result in excessive spillage of Mesna. A method of surgery or robotic assisted surgery without the use of Mesna, on the other hand, would require more effort in separating tissue layers from another, resulting in a longer duration of surgery or even undesired tissue damage. In particular, without the use of Mesna, dissection would have to be performed by electric or mechanical knives with increased risk of cutting accidentally or unavoidably critical organs. Chemically assisted tissue dissection also facilitates “en bloc” dissection of non infiltrating tumors, with less risks of damaging underlying tissues or leaving behind tumor material.

According to embodiments of the fifth aspect of the present invention, the used Mesna may be in the form of a composition comprising Mesna as described in the first aspect of the present invention. Also, such composition comprising Mesna may be prepared according to a method according to the second aspect of the present invention. The invention is further described by the following non-limiting examples which further illustrate the invention, and are not intended to, nor should they be interpreted to, limit the scope of the invention.

5

EXAMPLES

Examples 1-15: Compositions comprising Mesna for use in a method of robotic assisted surgery according to embodiments of the first aspect of the invention0

Examples 1-15 concern compositions with different concentrations of Mesna ranging from 4% by weight to 22% by weight, according to embodiments of the first aspect of the invention. The compositions according to Examples 1-15, shown in Table 1, are optimally suited for use in a method of robotic assisted surgery.

5

When used in a method of robotic assisted surgery, weight percentages of Mesna of 4% by weight to 22% by weight in the composition, as shown in Examples 1-15, are high enough for facilitating tissue separation and are low enough to avoid excessive wastage of Mesna in a body of a patient where not necessary, thereby not0 exceeding a maximum amount of Mesna acceptable to prevent systemic potential toxicity..

Water (cf. Examples 1-3 and 10-15), in combination with NaCI (cf. Examples IQ- 15) to be construed as physiological serum, owing to its pH and solubilizing5 properties for solubilizing Mesna, is desired as a pharmaceutically acceptable solvent in the present context.

10 mM Na2HPC>4 (aqueous) solution (cf. Examples 4-6) and a 10 mM Na2HPC>4 and 75 mM NaCI (aqueous) solution (cf. Examples 7-9) are desired pharmaceutically0 acceptable buffers in the present context, owing to their solubilizing properties for solubilizing Mesna and their buffering properties for stabilizing the pH of the composition at a pH from 6 to 8. The two aforementioned pharmaceutically acceptable buffers, taken on their own, have a pH of at least 9. 5 Disodium edetate is added as a chelating agent in Examples 10-15 for stabilization purposes. Sodium hydroxide is added in Examples 10-15 for pH adjustment purposes. Table 1 : Compositions of Examples (Ex.) 1-15 with different concentrations of Mesna ranging from from 4 % by weight to 22 % by weight, according to embodiments of the first aspect of the invention

Examples 16-19: Methods for producing a composition comprising Mesna for use in a method of robotic assisted surgery according to embodiments of the second aspect of the invention

5 The methods according to Examples 16-19 are performed at most one day prior to performing a method of robotic assisted surgery.

According to Example 16, one first volume of a Mesna solution comprising 100 mg/mL Mesna solubilized in a mixture of disodium edetate, sodium hydroxide and0 sterile water was mixed with a second equal volume of sterile water comprising 0.9 mass/volume percent sodium chloride, resulting a composition comprising 5% by weight of solubilized Mesna.

According to Examples 17-19, sterile Mesna in powder form is solubilized in a volume5 of water, preferably in a volume of sterile water, in order to produce compositions comprising 4-6% by weight of Mesna and 94-96% by weight of water, 8-12% by weight of Mesna and 88-92% by weight of water, or 18-22% by weight of Mesna and 78-82% by weight of water, respectively. 0 The measure of preparing the composition by dissolving Mesna in powder form in water has the advantages that Mesna oxidation is avoided and that compositions comprising tailor-made concentrations of Mesna and volumes of the composition comprising Mesna can be prepared case-by-case in function of the needs for a method of robotic assisted surgery.

5

One skilled in the art can be assumed to appreciate that more examples of methods for producing a composition comprising Mesna for use in a method of robotic assisted surgery are covered by the present teachings, as for example methods resulting in the compositions according to Examples 1-15 described above.

0

Example 20: A robot instrument for chemically assisted mechanical dissection according to the fourth aspect of the invention.

In Fig. 1-5 the preferred embodiment of the robot instrument for chemically5 assisted mechanical dissection of the invention are disclosed.

The general arrangement of the components for chemically assisted surgery with robots is shown on Fig.1. The source of composition comprising Mesna is obtained from the cartridge (1 ). The cartridge contains Mesna in solid form apart from a solvent. The Mesna is dissolved in the solvent by a rupture of a separating membrane preferably less than 12 hours before use.

The fluid connection between the cartridge (1) and the robot arm (2) is made by a disposable tubing (3), with male Luer lock connectors at both ends.

In a special embodiment, the female Luer connection of the cartridge (4) includes a normally closed valve which open upon connection of the male Luer from the tubing. In a preferred embodiment, a particle filter (5) is inserted at the inlet side of the tubing (3). A disposable peristaltic pump cassette (6) is inserted in the tubing. The cassette is attached to the pump motor (7) before use. The motor is turned on when the foot pedal (8) which is under the foot of an operator, seated behind a console (30). The outlet of the tubing is connected to the gearbox of the robot arm (2).

In a preferred embodiment, the pump motor (7) can be attached to a pole (10) or laid down on a flat surface near the robot. In a preferred embodiment, the cartridge (1) is hung on a hanger attached to the pump motor (7).

Fig. 2 represents a robot arm for chemically assisted dissection intended for laparoscopic procedures.

The arm is composed of an irrigated tip (11 ) described in more details below, a shaft (12) whereby the irrigation tip is mounted on and housing the cables for moving the irrigation tip and the fluid channel (14) for dispensing the Mesna composition by the irrigation tip and a gear box (2) housing the pulleys connected to the driver motors. The gear box (2) is also fitted with a Luer connection for the supply of the Mesna composition.

The fluid channel is preferably provided by extruding a lumen (14) in the stainless- steel shaft in order to leave enough room for the cables between the gear box (2) and the irrigation tips (11). The irrigation tips (11) are capable of dispensing topically the Mesna composition on the tissues to be dissected while exerting a mechanical separation force, both controlled by the robot operator.

Fig.3 describes a Maryland type of dissector tip. The jaws (15) and (16) can be moved independently by the robot operator and can be used either in pulling mode (forceps) or dissection mode.

At least one the jaws is fitted with an orifice (17) for dispensing the Mesna composition on the tissues to be dissected before exerting the mechanical separation force. The distal part (18) holds the jaws which can be rotated independently around the axis (19). The proximal part (20) is attached mechanically to the shaft. It holds the distal piece which can be rotated around the axis (21). The jaws are connected electrically to the metallic shaft by the metallic distal and proximal pieces. At least one of the jaws is connected fluidly to the fluid channel provided in the shaft through the distal and proximal pieces.

The provision of the fluid connection to the jaws is described on Fig.4 and 5. A fluid channel (13) is provided in the proximal piece (20) in front of the outlet of the channel (14) for tight fluid connection. A groove (22) is provided in the pulley (23) provided in the proximal piece which is rotating the distal piece around its axis. The fluid channel (13) in the proximal piece has its orifice (24) in front of the groove.

A fluid channel (25) is also provided in the distal piece (18). The proximal orifice of this channel is located in front of the groove (22). In this way, the fluid can pass from the proximal piece (20) to the distal piece (18). Fluid tightness is obtained by the flat flanges on the pulleys and the pieces which are closing the groove (22). Similarly, a groove (26) is provided in the basis of the irrigated jaw (15). The distal orifice (28) of the fluid channel (25) provided in the distal piece is placed in front of the groove (26). The proximal orifice (29) of the fluid channel provided in the irrigated jaw (15) is also located in front of the groove (26). Fluid tightness is obtained by the flat flanges on the jaw basis and the distal piece.

In this way, the dispensing of the Mesna composition is made at the orifice (17) of one of the jaws. The control of the dispensing is achieved by the robot operator by depressing the foot pedal (8).

Claims

CLAI MS

1 . Composition com prising Mesna for use in a method of robot-assisted surgery.

2. Composition com prising Mesna for use according to claim 1 , wherein the method of surgery is selected from the group com prising skull base surgery, open surgery, non-invasive surgery, thoracic surgery, cardiovascular surgery, dentistry, orthopedic surgery, plastic surgery, ophthalm ic surgery, neck surgery, neurosurgery, m axillo-facial surgery, gallbladder surgery, endoscopic surgery, laparoscopic surgery, vascular surgery, colorectal surgery, general surgery, gynecologic surgery, heart surgery, endom etriosis, head surgery, neck surgery, transoral neck surgery, transoral head surgery and urologic surgery.

3. Composition comprising Mesna for use according to any of the claims 1 to 2, wherein the com position com prises 1 % by weight to 30% by weight of Mesna, supplem ented up to 1 00% by weight with one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers, based on the overall weight of the com position .

4. Composition com prising Mesna, characterized in that the composition further com prises one or more dyes.

5. Composition according to claim 4, wherein the one or more dyes are selected from the group consisting of indocyanine green , riboflavin , riboflavin 5’- phosphate sodium , m ethylene blue and fluorescein .

6. Method for producing a com position com prising Mesna for use in a m ethod of robot assisted surgery, characterized in t hat at most one day prior to perform ing the m ethod of surgery, the com position is prepared by the step of dissolving Mesna in powder form in one or more pharmaceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers.

7. Kit for obtaining a composition comprising Mesna for use in a m ethod of robot assisted surgery, characterized in t hat the kit comprises Mesna in powder form next to one or more pharm aceutically acceptable solvents and/or one or more pharmaceutically acceptable buffers.

8. Robot instrument for chem ically assisted m echanical dissection com prising :

- a cartridge com prising a com position comprising Mesna in a liquid form ;

- a pum p connectable, and preferably connected, to said cartridge in order to feed the composition com prising Mesna to an outlet tubing of said pum p, upon actuation of said pump; - a robot arm comprising an irrigation channel with an inlet connectable, and preferably connected, to said outlet tubing of said pump and com prising an outlet connectable to an irrigation tip mountable, and preferably mounted on said robot arm , wherein said

5 tip comprises at least one surgical tool selected from the group comprising scalpels, scissors, bovies, forceps, dissector, elevators, hooks, probes, needles, knot pushers, retractors, scopes, clam ps and graspers and wherein the tip further com prises at least one irrigation orifice on said at least one surgical tool, said irrigation orifice fluidly0 connected to the irrigation channel ;

whereby actuation of the pum p supplies com position com prising Mesna from the cartridge through the irrigation channel to said irrigation tip of the mounted robot arm , and whereby the actuation of the pump is controllable by an operating switch . 5 9. Robot instrum ent according to claim 8, wherein said robot arm and feeding of the Mesna solution is steerable by a computer-assisted electromechanical device by the robot operator.

1 0. Robot instrum ent according to claims 8 to 9 wherein said robot instrument is equipped by a haptic feedback to an operator.

0 1 1 . Robot instrum ent according to claims 8 to 1 0 wherein the cartridge com prises the com position of Mesna further com prising at least one dye.

1 2. Robot instrum ent according to claim 8 to 12, whereby the speed of irrigation is controllable by a pump, (preferably in a range of 5 to 50 m l/m in) .

1 3. Robot instrument according to claim 8 to 1 3, whereby a diam eter of a robot5 tip orifice is in range from 1 00 miti-500 pm .

1 4. Robot instrum ent to any of the claims 8 to 13, wherein the robot arm tip is m ade of one or more conductive materials connected to a radio frequency source and can also be operated in electric mode for cutting or cauterizing without changing instrum ents.

0 1 5. Method of robotic-assisted surgery using com position com prising Mesna, including a step of separation of tissue layers along a cleavage plane between said tissue layers, characterized in t hat the separation of tissue layers is facilitated by applying a composition comprising Mesna to said cleavage plane.

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