HK1114764A - A biodegradable tissue cutting device, a kit and a method for treatment of disorders in the heart rhythm regulation system - Google Patents

Description

Biodegradable tissue cutting devices, kits and methods for treating disorders of the heart rate regulation system

Technical Field

The present invention relates to the treatment of disorders in the heart rhythm regulation system, and more particularly, to tissue ablation devices, kits having shape-changing devices, and methods for treating such disorders.

Background

The circulation of blood in the body is controlled by the pumping action of the heart. The heart is expanded and contracted by the force exerted by the heart muscle under the push of the heart rhythm regulation system. The heart rhythm regulation system delivers electrical signals that activate the heart muscle cells.

The normal electrical impulse through the heart starts at the sinoatrial node, passes through the right atrium, the atrioventricular node, the bundles of atria, and then spreads to the ventricular muscle mass. When the signal finally reaches the muscle cells that produce only contraction, the muscle cells will contract and produce a pumping action of the heart (see fig. 1).

The electrical impulses are delivered by cells specifically adapted for the purpose of delivery. Such cells will create and eliminate the potential on the cell membrane by pumping ions into and out of the cell. Adjacent cells are connected end-to-end by intercalated disks. These discs are cell membranes with very low electrical impedance. Since the impedance of these intercalated disks between cells is low, the activation of the potential in the cell will be transmitted to the adjacent cells. Early in the embryonic stage, all heart cells, myocytes, have the ability to generate and transmit electrical signals. During evolution, muscle cells are specialized, and only those cells necessary to maintain a stable heart rate retain the ability to produce and transmit muscle cells. For a more detailed explanation of the propagation of electrical signals in the heart see Sand ö e, E.and Sigurd, B., Arrhytmia.Diagnosis and Management, and the acidic electrochemical Guide, Pachmed AG, 1984.

When there is a disturbance to the normal transmission of electrical impulses, cardiac function will be impaired. Atrial Fibrillation (AF) is a disorder of electrical disturbances within the heart rhythm regulation system. In this disease, premature and too rapid signals irregularly initiating muscle contraction in the atria and in the ventricles will start from ectopic sites, i.e. areas located outside the sinoatrial node. These signals will be transmitted irregularly to the entire heart. When more than one such ectopic site starts to be delivered, the situation becomes very chaotic, which is quite different from the completely regular situation in a healthy heart, where the rhythm is controlled from the sinoatrial node.

Atrial fibrillation is a common condition, and therefore 5% of patients undergoing cardiac surgery experience AF. AF is found in 0.4-2% of the population, and in 10% of the population over 65 years of age. There are 160000 new cases annually in the united states, and the current total number of patients in the united states is around 3 million. Therefore, treatment of atrial fibrillation is an important issue.

Typical sites for ectopic premature signaling in AF can be anywhere in the atrium, Pulmonary Veins (PV), Coronary Sinus (CS), Superior Vena Cava (SVC), or Inferior Vena Cava (IVC). Inside the SVC, IVC, CS and PV along the circumference of the opening, there is a myocardial cuff. Such ectopic sites are most common especially around the opening of the Left Superior Pulmonary Vein (LSPV) and around the opening of the Right Superior Pulmonary Vein (RSPV). In the case of multiple AF, small cycles of transmitted electrical signals starting at ectopic sites may develop and produce re-entry of signals within the cycle, while the cycle region will remain for a considerable period of time. Atrial fibrillation may also result when only one ectopic site signals, or there may be multiple stimulation sites that cause atrial fibrillation. The disease may be chronic or persistent, as they never stop. In other cases, there may be a period of normal regular sinus rhythm between arrhythmias. Such diseases are described as intermittent.

In chronic or persistent situations, the atrial musculature undergoes electrical remodeling so that the re-entry cycle continues uninterrupted. The patient will experience discomfort from an irregular heart rate and will sometimes experience cannon-like fluctuations in the venous system as the atria contract against the closed arterio-venous heart valve, pushing the blood back within the venous system. The irregular action of the atria produces blood cessation in certain regions of the heart, particularly in the outer ear of the left and right atria. Here, blood clots may also be produced. This blood clot on the left side of the heart becomes transmitted with the blood stream into the brain where it will cause catastrophic damage in the form of a brain stroke. AF is considered to be the leading cause of stroke, which is one of the biggest medical challenges today.

There are several methods for treating disorders of the heart rhythm regulation system. Many drugs have been developed to treat AF, and the use of drugs is not effective for most patients. Thus, many surgical therapies have also been developed.

Surgical therapy was first introduced by Cox, the Boineau physician, and others in the late 80's of the 20 th century. The principle of surgical treatment is to cut open along the atrial wall with a knife and scissors, thereby creating a completely separated tissue. The tissues are then sutured together and healed through fibrous tissue, which does not have the ability to transmit electrical signals to the myocardium. The pattern of cutting is designed to stop the propagation of the pulse, thereby isolating the ectopic sites and thereby maintaining the heart in a sinus rhythm. The rationale for this treatment can be understood from the above description, which explains that there must be a physical link between the muscle cells to communicate information between them. By completely isolating the tissue, the replacement by non-conductive tissue will prevent further ectopic sites from receiving stimulation. Thus, ectopic sites will be isolated and impulses originating at ectopic sites will not propagate to other parts of the heart.

It is necessary to cut the atria, SVCs and IVCs into strips. When these strips are sutured together, they guide the impulse from the sinoatrial node to the atrioventricular node like a labyrinth, and the procedure is therefore also named maze. The pattern of cleavage is illustrated in FIG. 2, disclosed for The first time in JL Cox, TE Canavan, RBSchuessler, ME Cain, BD Lindsay, C Stone, PK Smith, PB Corr, and JPBoineau, The scientific treatment of The experimental hybridization.II. Intra-operative electrophoretic mapping and description of The electrophoretic basic access flow and experimental hybridization, J-Thorac Carboviral Surg, 1991101: 406, 426. This procedure has long been successful in curing 90% of patients with AF. 406 426. the procedure has achieved long-term success in curing 90% of patients with AF. However, the maze procedure tends to require many suture operations and the incision needs to be completely sutured, which is a labor intensive task for each surgeon attempting the procedure. The operation takes a lot of time, especially when the patient's own circulation needs to be stopped and replaced by extracorporeal circulation by means of a heart-lung machine. Thus, mortality has been high and only very small trained talent surgeons have access to truly surgical results. Thus, the original maze operation is simplified by eliminating the number of incisions to a minimum, but still good results are obtained in many cases. The most commonly used incision pattern at present is called maze III (see fig. 3).

Recently, other methods of isolating the ectopic sites have also been developed. In these methods, the actual cutting and suturing of the tissue is replaced by a method that kills the muscle cells. Thus, in the maze mode, tissue may be destroyed by heat or cold, etc. to avoid separating the tissue, thereby achieving damage to the entire heart wall. The damaged myocyte tissue is no longer able to transmit signals and the same result can be obtained. But still the chest cavity needs to be opened to stop the heart and open the heart. In addition, the energy source needs to be very carefully controlled to affect only the tissue that needs to be destroyed.

A number of devices have been developed to destroy muscle cell tissue using various energy sources. Such devices may use high radio frequency energy, such as disclosed in U.S. patent 5,938,660, or microwave, ultrasonic or laser energy. More recently, devices have been developed that use catheter-based delivery of high radio frequency energy into the venous and or arterial systems. However, this has to date met with limited success due to difficulties in navigation and energy application, and has been reported with late PV stenosis. In addition, devices using cooled tissue employ expanded argon or helium gas to generate temperatures of-160 ℃. Tissue can be frozen and destroyed using a tipped instrument.

WO03/003948 discloses devices for the treatment, prevention and termination of cardiac arrhythmias. The device is implanted and left at the target site with tissue-piercing projections, either by self-expansion or balloon expansion, to enter cells at the target site. The protrusions are used to introduce drugs into the cells that cause cell death, thereby inducing cellular changes and treating cardiac arrhythmias. But no device is described in WO03/003948 which disturbs the heart pulses by expanding to penetrate completely through the wall of the blood vessel and which can then be bioabsorbed and thereby gradually disappear at the target site. The device according to WO03/003948 does not belong to a cutting device. Thus, the device of WO03/003948 must be removed from the site of action to ensure that it does not harm or in any way cause damage to tissue in the vicinity of the site of action. Furthermore, in order to influence the mechanism of action, the prior art devices must be provided with other active substances which can be released at the preferred treatment site, and therefore additional provision steps must be included in the manufacture of such devices.

Disclosure of Invention

The present invention therefore aims to mitigate or obviate one or more of the above-mentioned disadvantages and to provide a new device, kit, adapted for use in a method of treating the above-mentioned types of disorders of the heart rhythm regulation system, in accordance with the content of the appended independent claims.

For this purpose, a tissue cutting device according to claim 1 is provided, wherein the device is constructed and arranged to be inserted into a temporary delivery shape through the vascular system into a body vessel adjacent to the heart and/or into the heart, and then to be subjected to a change of shape from the temporary delivery shape to an expanded delivery shape to a further expanded shape extending beyond at least the inner surface of the tissue, thereby generating a cutting action for cutting the heart tissue and/or the body vessel, wherein the cutting device is biodegradable.

Advantageous features of the invention are defined in the dependent claims.

Drawings

The invention will now be described in further detail by way of example and with reference to the accompanying drawings, in which:

FIG. 1 is a schematic representation of the transmission of electrical signals in the heart;

FIG. 2 is a schematic illustration of a cutting pattern of heart wall tissue for treating disorders of the heart rhythm regulation system according to the maze method;

fig. 3 is a simplified model of the method according to maze III, in which the heart is seen from the back.

FIGS. 4a-4c are schematic views of a tissue cutting device according to an embodiment of the present invention, wherein FIG. 4a shows the tissue cutting device with a first temporary shape, FIG. 4b shows the tissue cutting device with a second permanent shape, and FIG. 4c shows the tissue cutting device with a sharp edge, respectively;

fig. 5a-5b illustrate the tissue cutting device of fig. 4a-4b inserted into a body vessel.

Detailed Description

Referring to fig. 1-3, the problems of disorders to the heart rhythm regulation system and the current primary methods of addressing these problems are described. In fig. 1, a heart 2 is shown and the control of the heart rhythm is indicated. The heart rhythm is normally controlled by the sinoatrial node 4. The sinoatrial node 4 transmits electrical signals through the heart wall through special cells that form an electrical pathway. The electrical signals conducted along the electrical pathways will coordinate the cardiomyocytes to contract with the atrial and ventricular cells almost simultaneously and in coordination. The normal electrical impulse through the heart starts at the sinoatrial node 4, travels through the right atrium, the atrioventricular node 5, the bundles of atrioventricular vessels 6, and then spreads to the ventricular muscle mass. In case of a disorder, electrical signals will start in heart cells outside the sinoatrial node 4, so called ectopic sites. These electrical signals will disturb the coordination of the cardiomyocytes. When a plurality of ectopic sites are present, signal transmission becomes abnormally disordered. This will lead to arrhythmic diseases such as atrial fibrillation and atrial flutter.

Existing methods for treating these diseases are based on isolating ectopic sites, thereby preventing electrical signals from originating at these ectopic sites and propagating in the heart wall. Thus, the heart wall needs to be completely cut through in order to break the connections between the cells that transmit erratic signals. The resulting lesion is healed by fibrous tissue, which is not able to transmit electrical signals. Thus, the passage of electrical signals is blocked by these lesions. However, since the position of the ectopic sites is not always known and may be difficult to determine, or since there are many ectopic sites possible, it is necessary to develop a special cutting pattern to effectively separate the ectopic sites. Thus, the same pattern is always used, although the specific location of the ectopic sites differs in individual cases. With a complex cutting pattern, this method is called the "maze" method. The maze pattern is illustrated in fig. 2.

However, as can be seen in fig. 2, the cutting pattern involves a range of light and is complex, requiring difficult surgery to perform. Thus, the maze-pattern has been further evolved to minimize the required cuts and simplify the pattern as soon as possible. The maze III-pattern shown in figure 3 is currently used. This pattern is not so complex, but in most cases it also effectively isolates ectopic sites. Maze III-pattern contains incisions 8 around the Left Superior Pulmonary Vein (LSPV) and the Left Inferior Pulmonary Vein (LIPV), and corresponding incisions 10 around the Right Superior Pulmonary Vein (RSPV) and the Right Inferior Pulmonary Vein (RIPV); an incision 12 surrounding the Pulmonary Vein (PV) and connecting the two incisions 8 and 10; an incision 14 from the connecting incision to the Coronary Sinus (CS); an incision 16 from the left PV to the left atrial appendage; an incision 18 from the Inferior Vena Cava (IVC) to the Superior Vena Cava (SVC); an incision 20 connecting incision 10 around the right PV and incision 18 between IVC and SVC; from the incision 18 between the IVC and SVC; a cut 22 along the right atrial wall; and an incision 24 isolating the right atrial appendage. Hereby a simpler pattern of effective isolation of ectopic sites is established. In some cases, not all of the cuts may be needed. For example, ectopic sites usually occur starting around the opening of the PV, and it may therefore be sufficient to form incisions 8, 10 around the PV. In addition, as shown by lines 8 'and 10', a cut around the PV can be made along each PV opening rather than around the outside of both PV openings.

According to the invention, the possibility of cutting through the heart wall in a new manner is provided. Thus, according to this new approach, it should also be possible to obtain a pattern similar to the maze III-pattern. However, as mentioned above, not all cuts in the maze III-pattern need to be formed in all cases.

Referring to fig. 4-5, a heart wall tissue lesion creating cutting device 26 according to an embodiment of the present invention will be described and a new manner of making cuts through the heart wall will be explained. The heart wall tissue lesion creating cutting device 26 (hereinafter referred to as cutting device) is shown in fig. 4a in a first state, in which the cutting device 26 is tubular and has a first diameter d. The cutting device 26 is shown in a second state in fig. 4b, in which the cutting device 26 is tubular and has a second diameter D, which is larger than the first diameter D. The cutting device 26 is formed from a shape memory material that is capable of remembering a permanent shape that can differ significantly from a temporary shape. The shape memory material will change from its temporary shape to its memorized permanent shape upon suitable stimulation. The stimulus may be exposure to an elevated temperature, for example a temperature above e.g. 30 ℃, which may be caused by body temperature. The stimulus may also be suitably combined with the release of a restraining means that restricts the shape memory material from assuming its permanent shape.

The use of shape memory materials allows the cutting device 26 to be designed to collapse into a small temporary shape prior to insertion into a patient. In this way, the cutting device 26 can be inserted into its display shape and through the vascular system to the heart of a patient. The temporary shape of the cutting device 26 is also flexible to facilitate navigation of the cutting device 26 through the vasculature. Insertion of the cutting device 26 may be performed using well-known percutaneous catheter techniques. This method is non-invasive and can be used on a beating heart. Thus, the cutting device 26 can easily be placed in a desired position in the vascular system close to the heart wall tissue to be treated. The cutting device 26 may then be allowed to transition to its memorized, permanent shape after insertion into the vessel at the desired location.

As shown in fig. 5a, the cutting device 26 is inserted in its temporary shape to a desired location in a blood vessel 28. When responding to a stimulus, such as body temperature, the cutting device 26 will strive to change its shape and obtain a permanent shape. The memorized permanent shape of the cutting device 26 will not be able to be localized within the blood vessel 28, so that the cutting device 26 will force itself through the tissue to obtain the permanent shape shown in fig. 5 b. In this way, the cutting device 26 will first penetrate the vessel wall and thereafter the tissue surrounding the blood vessel 28. The penetrated tissue cells will be killed and a healing response in vivo will begin. When the cutting device 26 is placed in the desired position to create a deformation through the heart wall tissue, cells that are capable of transmitting electrical signals will be killed. The healing process does not restore the ability to transmit electrical signals and thus the cutting device 26 may diminish the ability to transmit electrical signals through the heart wall. By skillfully placing a plurality of cutting devices and designing the permanent shape of the cutting device 26, the cutting device 26 can penetrate the heart wall tissue to create a pattern of cuts corresponding to the maze III-pattern.

The cutting device may also be spherical and/or globular. The cutting device may have the advantage that the cutting movement in all directions can be influenced simultaneously.

One example of a shape memory material is nitinol, which is an alloy of nickel (54-60%) and titanium. Traces of chromium, cobalt, magnesium and iron may also be present in the alloy. This alloy returns to a permanent shape by martensitic transformation. Shape memory materials can also be formed from shape memory polymers, where the effect of shape memory is based on glass transition or melting point. Such shape memory polymers may be prepared by forming polymers of the material or a combination of materials having suitable properties. For example, the shape memory polymer may be formed from dimethyl oligo (epsilon-caprolactone) acrylate in combination with n-butyl acrylate. In addition, biodegradable or bioabsorbable materials can also be used to form these shape memory polymers. Such biodegradable or bioabsorbable materials can be, for example, polymeric, ceramic, or metallic materials.

Biodegradable materials, such as biodegradable polymers, have bonds that are cleavable under physiological conditions. Biodegradable is the term used in the context of materials that break down as a result of or in biological systems losing mechanical properties. The outer shape and size of the implant may remain virtually intact during the disassembly process. This means that the biodegradable cutting device can also generate a cutting action by a transition from the temporary shape to the memory shape. The meaning with respect to degradation time, without further additional valid data, refers to the time required to complete the loss of the full mechanical properties.

Particularly suitable biodegradable materials provide polymer compositions with polymers which behave hydrolytically degradable, in particular poly (hydroxy carboxylic acids) or corresponding copolymers. Hydrolytic degradation has the advantage that the rate at which degradation occurs is independent of the position of the implant, since water is present in the entire system.

However, in other embodiments, enzymatically degradable polymers may also be used. Particularly feasible polymer composites are polymer networks which exhibit a biodegradable thermoplastic amorphous polyurethane-copolyester. Likewise, a requirement for the chemical composition of the polymer composite used in the cutting device of the present invention is that the polymer composite exhibits a biodegradable elastomeric polymer network, which is obtained by crosslinking oligomers of diols with diisocyanates. A possible alternative to the above is a polymer composite formed with a covalent network based on oligo (epsilon-caprolactone) dimethacrylate and butyl methacrylate. For the braid constituting the cutting device of the present invention, a hydrolytically and enzymatically degradable polymer composite is claimed as a biodegradable polymer. As mentioned above, hydrolytic degradation has the advantage that the rate at which degradation occurs is independent of the position of the implant. In contrast, local enzyme concentrations can vary greatly. For biodegradable polymers or materials, degradation may occur by simple hydrolysis, by reactions of unknown origin, or by a combination thereof.

The hydrolysable chemical bonds in the polymer composite of the cutting device are typically amide, ester or acetal bonds. For actual degradation, two mechanisms are notable. For surface degradation, hydrolysis of the chemical bond occurs only at the surface. Due to the hydrophobic nature, the polymer degrades faster than water diffuses through the material. This mechanism is particularly common in poly (anhydrides) and poly (orthoesters). In the case of poly (hydroxy carboxylic acids), such as poly (lactic acid) or poly (glycolic acid), and the respective copolymers, which are of particular importance for the present invention, the degradation of the polymer takes place over the entire volume.

The rate-fixing step here is the hydrolytic cleavage of the bonds, since the diffusion rate of water in the hydrophilic polymer matrix is relatively high to some extent. The choice of biodegradable polymers depends on the one hand on their degradation at a controlled or varying rate and on the other hand on the fact that the decomposition products are non-toxic.

The concept of resorption of polymeric materials means that by natural metabolism, substances or masses are degraded and the material is completely removed from the body. In case the cutting device is only a degradable polymer, resorption starts at the moment when the mechanical properties are completely lost. The specific resorption time covers the period from the start of implantation of the cutting device, the operation until the complete elimination of the cutting device.

Among those most important biodegradable synthetic polymers, advantageous for the synthesis of the cutting device fabric of the present invention are: polyesters, such as poly (lactic acid), poly (glycolic acid), poly (3-hydroxybutyric acid), poly (4-hydroxyvalerate), or poly (. epsilon. -caprolactone), or copolymers of each, polyanhydrides synthesized from dicarboxylic acids, such as glutaric, succinic, or sebacic acid, poly (amino acids), or polyamides, such as poly (serine esters), or poly (aspartic acid).

In summary, it can be said that shape memory properties play an important role in the cutting device, in particular in minimally invasive medicine. In this regard, biodegradable cutting devices having shape memory properties are particularly effective. For example, degradable cutting devices of this type may be introduced into the body through a small incision in a compressed (temporary) shape and, once in place, return to a memorized shape associated with its application upon warming at body temperature, as described above. The cutting device will then degrade over a determined period of time, thereby eliminating the need for a second surgery to remove it.

From the known biodegradable polymers, structural elements for the synthesis of biodegradable shape memory polymers can be derived. To this end, suitable cross-linking in permanent form, and network chains as transformation elements, may be chosen so that, on the one hand, a temperature shift may be achieved by physiological conditions and, on the other hand, toxicity problems associated with any decomposition products may be eliminated. Thus, the transition segment suitable for the biodegradable shape memory polymer can be selected based on the thermal properties of the degradable material. Of particular interest in this regard is the thermal transition of the variable element in the temperature range between room temperature and body temperature. For this range of transition temperatures, biodegradable polymer segments can be selectively synthesized by varying the quantitative ratios of known starting monomers; the molecular weight of the polymer formed is in the range of about 500-10000 g/mol.

Suitable polymer segments are, for example, poly (. epsilon. -caprolactone) diols having melting points of between 46 and 64 ℃ or amorphous copolyesters based on lactic acid and glycolic acid having glass transition temperatures of between 35 and 40 ℃. Thus, the phase transition temperature, i.e. the melting point or glass transition temperature, of the polymer transition segment can be further reduced by their chain length or by degradation of specific end groups. Such tailored polymer transition elements can then be incorporated into a physically or covalently crosslinked polymer network, resulting in a selectively composed biodegradable shape memory polymer material.

In one possible embodiment, a biodegradable thermoplastic amorphous polyurethane copolyester polymer network having shape memory properties is used as the material for the cutting device. First, a suitable biodegradable star-shaped copolyester polyol was synthesized based on commercially available cyclic lactic acid dimer (dimer of lactic acid), cyclic glycolic acid dimer (dimer of diglycolic acid), and trimethylolpropane (functionality F ═ 3) or pentaerythritol (F ═ 4), having a glass transition temperature between 36 and 59 ℃, and then, crosslinked with commercially available trimethylhexamethylene diisocyanate to form a biodegradable polyurethane network.

The formed amorphous polyurethane copolyester polymer network with shape memory property has glass transition temperature T kappa of 48-66 ℃, and shows elastic modulus of 330-600MPa and corresponding tensile strength of 18.3-34.7 MPa. Heating the network to a temperature about 20 c above the transition temperature produces an elastic material that can be deformed by 50-265% to a temporary shape. The reduction to room temperature promotes the formation of a deformed shape memory polymer network having a significantly higher modulus of elasticity, between 770-5890 MPa. After subsequent reheating to 70 ℃, the deformed sample will transform, returning to a permanent shape after about 300 seconds. Finally, the complete decomposition of the polyurethane copolyester polymer network in phosphate water buffer at 37 ℃ occurred in about 80-150 days. By optimizing the composition of the biodegradable transition segment, a biodegradable polyurethane copolyester polymer network with shape memory properties can be produced more quickly, for example, within 14 days.

Similar biodegradable elastic shape memory polymer networks can be made by crosslinking diol oligomers with diisocyanates, which have melting points between 38-85 ℃ and are also suitable for use in cutting devices. Final analysis was also performed on degradability and it was observed that these polymers lost 50% of their mass after approximately 250 days in phosphate water buffer at 37 ℃.

In one embodiment of the cutting device, the braid is formed from a biodegradable shape memory polymer based on oligo (epsilon-caprolactone) dimethacrylate and butyl acrylate on a covalent network. It has been demonstrated that the polymer composite does not negatively affect the wound healing process during subsequent implantation. Thus, the wound created by the cutting device may heal into scar tissue, which may prevent the transmission of undesired signals. Due to the glass transition temperature of pure poly (n-butyl acrylate) as low as-55 ℃, the synthesis of such biodegradable shape memory polymers can start with n-butyl acrylate, which can be used as a segment forming a component.

Subsequently, the network is synthesized by photopolymerization. The transition temperature and the mechanical properties of the covalent network can be controlled based on the molar mass of the macromolecular oligo (epsilon-caprolactone) dimethacrylate and the content of the comonomer n-butyl acrylate. Thus, in the preparation of the cleavage apparatus carried out in the embodiment, the molar mass of the oligo (. epsilon. -caprolactone) dimethacrylate was varied between 2000 and 10000g/mol, while the content of n-butyl acrylate was between 11 and 90% by weight. A melting point of 25 ℃ is achieved when the polymer network is based on low molecular weight oligo (. epsilon. -caprolactone) dimethacrylate and 11% by weight n-butyl acrylate.

Biodegradable polymer networks formed by covalent and physical forces having a shape memory effect as described above may also be used as matrices for the controlled release of active substances. Also achievable are biodegradable polyurethane multiblock copolymers based on poly (p-dioxanone) and trimethylhexamethylene diisocyanate as diisocyanate and having a shape memory effect.

By combining with a copolymeric (cyclic lactic acid dimer-cyclic diolic acid dimer) or poly (. epsilon. -caprolactone) transition segment, a multi-block copolymer with a transition temperature of 37 or 42 ℃ is produced, respectively. Hydrolytic degradation of the polymer shows a lower degradation rate for poly (epsilon-caprolactone) -based polymers. In the experiments on poly (. epsilon. -caprolactone) polymers, 50-90% of the initial mass was still present after 266 days of hydrolysis, whereas in the case of poly (cyclic lactic acid dimer-cyclic glycolic acid dimer) polymers, only 14-26% of the mass was detected after 210 days only.

The biodegradable shape memory polymer network can also be synthesized from a physical or covalent shape memory polymer network having biodegradable polymer segments. By selective selection of the components, optimum parameters can be set for each application, such as mechanical properties, deformability, phase transition temperature, and decomposition rate of the polymer.

In this regard, the present invention claims all of the aforementioned biodegradable shape memory polymers as materials for cutting devices.

When the cutting device is degradable in a biological environment, such as the human body, the cutting device will start to elute substances. These substances are part of the substance from which the cutting device is made. For example, if the cutting device is made of a polymer, the cutting device will start to release organic material when the cutting device degrades in a biological environment, such as the human body. This release may affect the mechanism of action of the cardiac electrical signal transmission, since these are based on physiochemical diffusion effects leading to changes in pH, organic concentration, and/or ion concentration, which may be affected by substances released upon degradation of the cutting device. The cardiomyocytes will assume an activation potential and a charging status for the operative state. These potentials and conditions depend on their electrolytic environment, and the substances are located in the vicinity of the muscle cells. Thus, the function of the cell membrane may be affected due to the change in pH, resulting in the release of substances from the cutting device during degradation. The change in organic concentration may result in a chelating effect of ions and a hydrophobic effect in the vicinity of the cell membrane and/or a pharmacological effect on the cell membrane function when substances are released upon degradation of the cutting device. Organic release, even with carbon dioxide and water released, can affect membrane potential and function. This can be achieved, for example, by changing the pH, changing the ionic activity of ions required for a particular function, such as Na or Ca. For example, the release of oxalate ions can have a chelating effect on Ca. This can result in a degenerative effect on the cell membrane of muscle cells, such as the cardiac muscle cell and/or postsynaptic membranes, etc. In addition, ceramic or metallic biodegradable materials can also release ions. These ions may, for example, affect cardiomyocyte activity, for example by increasing the concentration of Li and/or Mg, resulting in short-term and/or long-term changes in electrical signal transmission. According to the Fleed and Ferrans article, in particular Li, Mg, Ni, Co and V may have these effects.

The release of substances from the cutting device itself may be combined and the combination will affect the propagation of the myocardial signal, which may be used as a synergistic effect in the treatment of atrial fibrillation. Thus, the effect of the cutting device may be enhanced by obtaining more direct effects than the cutting action.

The change in pH can lead to an increase in local inflammation in the myocardial tissue. Rapidly absorbing polymers, such as poly (ethylene glycol) acid, can have such effects on tissue. In addition, it is clear from tests on resorbable copolymers that their tissue reaction is more efficient, since they degrade faster than the corresponding homopolymers with higher crystallinity. Examples of such copolymers are lactide and caprolactone copolymers. In one embodiment, this effect is utilized because an increase in inflammation will result in a large area of scar tissue. Large areas of scar tissue will increase the effect of isolated signal transmission. In this regard, the polymers are designed as resorbable polymers whose purpose is to release, by hydrolysis, non-toxic known monomers, such as glycolic acid or oxalic acid. Resorbable ceramic species, because they are made of metal oxides, can be designed to release ions that cause the pH to change to a basic environment. Most resorbable ceramics are based on hydroxyapatite (Ca phosphate). From a chemical standpoint, hydroxyapatite is a buffer that produces either basic or acidic behavior. It is also within the scope of the invention to fill the resorbable system with acid anhydride or base. The release of known substances, such as monomers or ions, is advantageous for their utilization since their safe metabolism and non-toxic behaviour is known. Thus, without obtaining an increase of local inflammation in the myocardial tissue, the cutting device may be made of a polymer having these advantages and possibilities.

In this way, the cutting device 26 may be designed such that it is capable of being degraded or absorbed by the body after the deformation has been completed. For example, polylactic acid polymers and/or polyglycolic acid polymers, poly (epsilon-caprolactone), or polydioxanone may be used to form biodegradable shape memory polymers. A particular point of resorbable shape memory polymers is that these polymers will disappear from the tissue after having performed their function, limiting the negative effects that may exist when there is polymer or nitinol material left, such as perforation and damage to adjacent tissues, like the lungs, the oesophagus and the major vessels, like the aorta.

Both the temporary shape of the cutting device 26 and its permanent shape may be tubular as shown in fig. 4-5. The memory of the shape may be used to change the cutting device 26 between any shape. Some examples of at least not completely tubular shapes are, for example, spherical, helical, corkscrew, and shapes suitable for placement in a particular location, such as the heart. The specific site in the heart may be an atrium or a ventricle. Adaptation of the cutting device may be performed by first taking a picture of said tissue or region and then adapting the cutting device according to the obtained picture. The shape of the cutting device 26 in its first state is preferably compact to facilitate insertion of the cutting device 26 through the vascular system. Thus, a tube shape is a suitable shape, but as mentioned above, other shapes may also be suitable. In addition, the shape of the cutting device 26 in its second state is designed such that by deforming it will be able to penetrate specific heart tissue, thereby blocking the transmission of undesired electrical signals. Furthermore, the cutting device 26 in its second state may also be adjusted to fix the cutting device 26 in a desired position in the body.

The cutting device 26 may also be constructed as a mesh; i.e. its shape may comprise a mesh or a ring. This means that no solid surface needs to be used for penetrating the tissue, which thereby facilitates the penetration of the tissue and the formation of differently shaped cutting devices 26.

The edge of the cutting device 26 facing the tissue to be penetrated may be made particularly sharp, as in fig. 4c, in order to increase its efficiency. Another feature is to coat the surface facing the tissue to be penetrated with a drug to enhance the cutting effect or to prevent thickening of the vessel wall into which the device is inserted. Examples of such drugs are cyclosporin (ciclosporin), tacrofibrol (taxol), rapamycin (rapamycin), tacrolimus (tacrolimus), alcohol, glutaraldehyde, formaldehyde, and proteolytic enzymes such as collagenase. Collagenase is effective in degrading tissue, particularly fibrin tissue, which is difficult to penetrate without collagenase. Thus, coating the surface of the cutting device 26 with collagenase may, among other things, accelerate the process of penetrating tissue. The drug is attached to the surface of the cutting device 26 according to known methods of attaching a drug to a medical device. One such method is to embed or place the drug under a polymer layer and then cover the surface with a polymer layer. Equivalent, other methods may also be employed. Similarly, drugs that prevent thrombosis after penetration of the cutting device 26 and drugs that promote endothelial in-growth on the endothelial surface may be attached to the cutting device 26. Such drugs are for example endothelial growth factor and heparin. In addition, other drugs designed to treat arrhythmias may also be attached to the surface of the cutting device 26. Such drugs are amiodarone and tatarol.

Since the cutting device according to the invention is made of a biodegradable material, it is also possible to add drugs, such as those mentioned above, to the biodegradable material. Thus, the drug will be continuously eluted as the biodegradable material degrades in the biological environment. In one embodiment, the one or more drugs may be contained in the biodegradable material in the form of a sheet. This embodiment provides the possibility to elute the drug within separate time intervals, or to elute different drugs at different times. In another embodiment, the one or more drugs are homogeneously contained within the biodegradable material.

Of course, it is also possible to clamp the drug or drugs in the biodegradable material of the cutting device and to coat the surface of the cutting device with a coating of the drug or drugs. This type of coating may cover all or part of the cutting device, e.g. the cutting edge.

In another embodiment, the cutting device containing one or more drugs is coated with a biodegradable material that does not contain any drugs. Thus, it is possible to adjust the elution timing of the drug. This moment can be adjusted by varying the thickness of the coating without any drug. When the coating degrades, the material containing the drug or drugs will be exposed and, since this material is also biodegradable, will begin to degrade and elute the drug or drugs at the same time.

For example, it is possible to add one drug to the cutting device, which is active on collagenase or elastin, while another drug may be added to act on the muscle tissue.

Preferably, the inside of the cutting device 26 inserted into the blood vessel will be in contact with the blood flow inside the blood vessel. The inner surface of the cutting device 26 may also be coated with an anti-thrombotic drug. Such drugs may be, for example, heparin, clopidogrel (Klopidogrel), heparin sodium, ticlopidine, abciximab, and tirofiban. These drugs can also be added to the biodegradable material in different ways as described above.

Another way to increase the effectiveness of the cutting device 26 is to connect the metallic part of the cutting device 26 to an electric current, thereby providing heating of the cutting device 26. In this way, the tissue may also be killed by this heat, thereby enhancing the action of the cutting device 26. In addition, the forces tending to deform also increase, accelerating the deformation of the cutting device.

And, other design parameters of the cutting device may be selected according to the patient specific anatomy. Such design parameters may be, for example, wire thickness profiles, attachment points, fasteners such as hooks, bistable portions or features, material selection, installation of drug delivery portions, timing design of cutting action, etc., as described in co-pending applications concurrently filed by the same applicant as the present application, and the entire contents of which are hereby incorporated by reference herein.

Some potential uses of the invention will be described below.

A method for treating a disorder of the heart rate regulation system, comprising:

inserting a tissue cutting device in a temporary delivery shape through the vasculature into a body vessel adjacent the heart and/or into the heart;

changing the shape of the tissue cutting device from said temporary delivery shape, through the expanded delivery shape, to a further expanded shape, extending beyond at least the outer surface of said tissue, thereby

Generating a cutting action for cutting the heart tissue and/or the body vessel, thereby

The ectopic sites of the heart tissue are isolated by cutting the tissue with the thus configured tissue cutting device, thereby reducing undesired signal transfer within the heart tissue, and

biodegrading the tissue cutting device during or after said deformation of the tissue cutting device from said expanded delivery shape to said further expanded shape.

The method as described above, comprising inserting the tissue cutting device through the vascular system to a desired location in a body vessel, and providing a change of shape of the tissue cutting device at said desired location for penetrating heart tissue adjacent to said body vessel.

The method of above, wherein the tissue cutting device is inserted into a desired location in the coronary sinus, any of the pulmonary veins, the superior vena cava, the inferior vena cava, or the left or right atrial appendage.

The method of the above, further comprising inserting another tissue cutting device to another desired location.

The method as described above, further comprising inserting a tissue cutting device to each desired location.

The method as described above, further comprising constraining the tissue cutting device in the insertion shape during insertion of the tissue cutting device.

The method of any preceding claim, wherein constraining comprises positioning the tissue cutting device within a tube.

The method of above, wherein restraining comprises cooling the tissue cutting device.

The method as described above, further comprising releasing the restriction on the tissue cutting device when the tissue cutting device is inserted to the desired position, thereby allowing the deformation of the tissue cutting device.

The method of above, wherein the biodegradable tissue cutting kit comprises degrading the tissue cutting device by hydrolytic degradation or enzymes.

It should be emphasized that the preferred embodiments described herein are not to be considered in any way limiting, and that many alternative embodiments are possible within the scope of the invention, which is defined in the appended claims.

Claims (28)

1. A tissue cutting device configured to isolate ectopic sites of heart tissue by cutting said tissue, thereby reducing undesired signal transfer within the heart tissue,

wherein the device is constructed and arranged to be inserted through the vascular system into a body vessel adjacent to the heart and/or into the heart in a temporary delivery shape, and then the device is subjected to a change of shape from said temporary delivery shape to an expanded delivery shape extending beyond at least the inner surface of said tissue, thereby generating a cutting action for cutting said heart tissue and/or said body vessel, wherein said cutting device is biodegradable.

2. The tissue cutting device according to claim 1, wherein the biodegradable material is a hydrolytically degradable material.

3. The tissue cutting device as claimed in claim 2, wherein the hydrolytically degradable material is poly (hydroxy carboxylic acid), poly (anhydride) or poly (orthoester).

4. The tissue cutting device as claimed in claim 3, wherein the poly (hydroxy carboxylic acid) is poly (lactic acid) or poly (glycolic acid), or a copolymer thereof.

5. The tissue cutting device according to claim 1, wherein the biodegradable material is an enzymatically degradable material.

6. The tissue cutting device of claim 5, wherein the enzymatically degradable material is selected from oligo (epsilon-caprolactone) dimethacrylate or butyl acrylate.

7. The tissue cutting device of claim 1, wherein the biodegradable material is selected from the group consisting of: polyesters, such as poly (lactic acid), poly (glycolic acid), poly (3-hydroxybutyric acid), poly (4-hydroxyvalerate), or poly (. epsilon. -caprolactone), or copolymers of each, polyanhydrides synthesized from dicarboxylic acids, such as glutaric, succinic, or sebacic acid, poly (amino acids), or polyamides, such as poly (serine esters), or poly (aspartic acid).

8. The tissue cutting device of claim 1, wherein the biodegradable material is a ceramic or metallic material.

9. The tissue cutting device of claim 8, wherein the metallic material comprises Li, Mg, Ni, Co, and/or V.

10. The tissue cutting device as claimed in claim 1, wherein the biodegradable material elutes at least one substance when degraded in a biological environment in use.

11. The tissue cutting device as claimed in claim 10, wherein said at least one substance is an organic substance or an ion.

12. The tissue cutting device according to claim 11, wherein the ions are selected from the group comprising Li, Mg, Ni, Co, and/or V.

13. The tissue cutting device as claimed in any one of the preceding claims, comprising at least one drug.

14. The tissue cutting device as claimed in claim 13, wherein said at least one drug is contained in a coating or as a coating of said tissue cutting device.

15. The tissue cutting device of claim 13, comprising a coating of non-drug containing biodegradable material.

16. The medical device of claim 1, wherein the device is constructed and arranged to be inserted into a body vessel and subsequently deformed, wherein the device is constructed and arranged to be deformed to extend around at least a portion of an outer wall of the vessel or outside of an opening in the vessel in the further expanded shape.

17. A kit for the transformable cutting device of claim 1 for treating disorders of the heart rate regulation system, the kit comprising:

the shape-changing cutting devices, each device having a first delivery state and a second delivery state, wherein the device in the first delivery state has a size insertable into a desired location in the vasculature, and upon reaching the desired location, the device is deformable into the second state, the device in the second state having an at least partially spherical shape that strives to reach a diameter larger than the diameter of the vessel at the desired location, such that the device embeds into tissue surrounding the vessel at the desired location, damaging the tissue in an attempt to prevent it from transmitting electrical signals,

wherein the at least one shape changing device is adapted to be inserted into a desired location at an opening of a pulmonary vein in the heart and the at least one shape changing device is adapted to be inserted into a desired location in the coronary sinus, and wherein the tissue cutting device is made of a biodegradable material.

18. A method for treating a disorder of the heart rate regulation system, comprising:

inserting a tissue cutting device in a temporary delivery shape through the vasculature into a body vessel adjacent the heart and/or into the heart;

changing the shape of the tissue cutting device from said temporary delivery shape, through the expanded delivery shape, to a further expanded shape, extending beyond at least the outer surface of said tissue, thereby

Generating a cutting action for cutting the heart tissue and/or the body vessel, thereby

The ectopic sites of the heart tissue are isolated by cutting the tissue with the thus configured tissue cutting device, thereby reducing undesired signal transfer within the heart tissue, and

biodegrading the tissue cutting device during or after said deformation of the tissue cutting device from said expanded delivery shape to said further expanded shape.

19. The method of claim 18, comprising:

inserting a tissue cutting device through the vascular system to a desired location in a body vessel, and providing a change of shape of the tissue cutting device at the desired location for penetrating heart tissue adjacent to the body vessel.

20. The method of claim 18, wherein the tissue cutting device is inserted into a desired location in the coronary sinus, any of the pulmonary veins, the superior vena cava, the inferior vena cava, or the left or right atrial appendage.

21. The method of any of claims 18-20, further comprising inserting at least one further tissue cutting device to a further plurality of desired positions.

22. The method of claim 21, further comprising inserting a tissue cutting device to each of the plurality of desired positions.

23. The method of any of claims 18-21, further comprising constraining the tissue cutting device in the insertion shape during insertion of the tissue cutting device.

24. The method of claim 23, wherein constraining comprises positioning the tissue cutting device within a tube.

25. The method of claim 23, wherein restraining comprises cooling the tissue cutting device.

26. The method of any of claims 23-25, further comprising releasing a constraint on the tissue cutting device when the tissue cutting device is inserted to the desired position, thereby allowing the tissue cutting device to be deformed.

27. The method of any one of claims 18-26, wherein the biodegradable tissue cutting kit comprises degrading the tissue cutting device by hydrolytic degradation or enzymes.

28. The method of any one of claims 18-27, comprising eluting at least one drug from the tissue cutting device.