A medical implant with magnetically constricting tubular wall

Abstract

The present invention provides a medical implant, comprising a tubular member having a wall defining a lumen, characterized in that the wall is elastically deformable and comprises a magnetically constricting element incorporated within the wall and being operable by an external magnetic field to elastically constrict the lumen upon application of said magnetic field. The invention further relates to a system for constricting a hollow organ in a body of a subject or an intermittent compression device (IPC) comprising the medical implant of the invention and at least one magnetic field generator. The invention also relates to the use of the medical implant, the IPC or the system of the invention for the treatment of a disease that can be treated by controlled constriction of a hollow organ. Finally, the invention relates to a method for producing the medical implant of the invention.

Description

[0001] A MEDICAL IMPLANT WITH MAGNETICALLY CONSTRICTING TUBULAR WALL

[0002] The present invention provides a medical implant, comprising a tubular member having a wall defining a lumen, characterized in that the wall is elastically deformable and comprises a magnetically constricting element incorporated within the wall and being operable by an external magnetic field to elastically constrict the inner lumen upon application of said magnetic field. The invention further relates to a system for constricting a hollow organ in a body of a subject comprising the medical implant of the invention and at least one magnetic field generator. The invention also relates to the use of the medical implant or the system of the invention for the treatment of a disease that can be treated by controlled constriction of a hollow organ. Finally, the invention relates to a method for producing the medical implant of the invention.

[0003] BACKGROUND OF THE INVENTION

[0004] Chronic venous disease (CVD) is a medical condition of the circulatory system characterized by suboptimal blood return from the legs back to the heart. In healthy individuals, the calf pump together with the vein valves warrantee the efficient transport of blood back to the heart. The debilitation of the lower leg muscles due to aging and inactivity correlates with an increase in the chronic venous disease, which represents a worldwide health problem, affecting between 5 and 33% of the adult population. Intermittent pneumatic compression (IPC) are the so far most advanced compression therapy devices routinely applied in the clinics, and are composed of sleeve- or boot-shaped chambers placed around the legs that fill with air and electrical pumps with gauges that provide intermittent compression to the lower extremities. The idea behind this therapy is to emulate muscle contraction and subsequent leg vein squeezing. However, the current concepts of intermittent compression devices are still far from ideal, and associated with skin problems, including itching, feeling cold or warm and dry skin. Additionally, the device is very cumbersome and hinders mobility, which results in patient's discomfort.

[0005] US 9,615,991 Bl relates to an intermittent pneumatic compression device comprising an inflatable cuff for the foot of the patient, whereby a source of air in combination with vents within a passageway provides alternating higher pressure and a lower or no pressure in the associated inflatable cuff. While the US' 991 provides an improved airflow for the inflatable cuff, it still requires the use of an inflatable cuff to compress the lower extremities and therewith is associated with the known disadvantages such as skin problems. Furthermore, this device is still very cumbersome and hinders mobility, which results in patient's discomfort. US 2020 / 0368100 relates to an intermittent pneumatic compression device comprising an inflatable cuff for the foot of the patient which is controlled by a user interface allowing selection among different categories of circulation insufficiency. While the US' 100 provides improved control mechanisms it still requires the use of an inflatable cuff and this is also associated with the above-mentioned disadvantages.

[0006] WO 2023 / 073342 Al relates to an intermittent pneumatic compression device comprising a sleeve configured to surround a limb of a patient, a bladder attached to the sleeve, and a pumping device configured to inflate and deflate the bladder to apply pressure to the limb of the patient, wherein the pumping device includes a piezoelectric pump. As such, also WO' 342 follows the classical cuff-strategy associated with the known disadvantages.

[0007] Hence, there is still a need for the efficient and safe treatment of venous diseases and especially chronic venous disease.

[0008] The objective of the present invention thus is to provide an improvement or an alternative to the prior art.

[0009] This problem is solved by provision of a medical implant according to claims 1 to 10, a system according to claims 11 and 12, the medical implant or system for use in a treatment according to claim 13, and a method for producing a medical implant according to claims 14 and 15. Specific embodiments are subject matter of further dependent claims.

[0010] SUMMARY OF THE INVENTION

[0011] A first aspect of the invention provides a medical implant comprising a tubular member having a wall defining a lumen, whereby the wall is elastically deformable and comprises a magnetically constricting element incorporated within the wall and being operable by an external magnetic field to elastically constrict the lumen upon application of said magnetic field.

[0012] The medical implant of the first aspect combines many advantages for “lumen-constricting” therapies while avoiding the disadvantages of said therapies.

[0013] As a medical implant, the device can be specifically implanted at the site, where there is need of constricting activity, which minimizes the risks for side effects.

[0014] As a magnetically constricting device, this device can be activated by an external magnetic field. The term “external magnetic field” relates to a magnetic field that is generated from a magnetic field generator located outside the medical implant, which can be within the body or outside the body of the patient. In another embodiment, the medical implant is controlled by the magnetic field generator in a remote way, whereby the magnetic field generator is located outside the body. Such a magnetic field generator can be provided as a wearable device, which might be even worn throughout the day without noticeably impairing the every-day life and thus significantly improving patient compliance.

[0015] The magnetic-induced constriction can be precisely controlled by the magnetic field applied by the external magnetic source. Accordingly, the degree of the constriction can be precisely controlled in order to adapt the function of the device to the therapeutic situation and thereby providing a patient-tailored therapy with reduced side effects.

[0016] Furthermore, the frequency and duration of the constrictions can be precisely controlled and add further treatment parameters to achieve a patient-tailored therapy.

[0017] By using elastically deformable biomaterials, a medical implant with long life time and high compatibility can be generated and used for therapy.

[0018] By selection of an appropriate magnetic material in a suitable concentration, the constrictive properties of the medical implant can be accurately adjusted to the medical need.

[0019] The medical implant thus has the potential to provide a device with lack of toxicity, good biocompatibility, and suitable mechanical properties.

[0020] In sum, the medical implant of the invention has the potential to provide a simple design created from a well-balanced combination of materials to address the clinical symptoms.

[0021] DETAILED DESCRIPTION OF THE INVENTION

[0022] The medical device comprises a tubular member in order to surround a hollow organ or itself constitutes at least a part of hollow organ, such as a part of a blood vessel, within the body and subsequently constricts said hollow organ by magnetically induced constriction of the tubular member.

[0023] As used herein, a “tubular member” is a hollow elongated element having a wall which defines a lumen, which can be circular, elliptical or have a more complex lumen design. In one aspect, the wall might define a circular lumen and therewith represents a classical tube. In another aspect the tubular member defines an elliptical lumen and thus represents an elliptical tube. A more complex design might be established by a combination of a circular and an elliptical shape. Another complex design can include the presence of neckings, bulges or the general shape as a truncated cone. It is to emphasize that the functionality of the medical implant is not restricted to the classical tube-shaped member but is generally given for elongated hollow structures.

[0024] According to the invention, the wall is elastically deformable. The term “elastically deformable” as used herein means a deformation, which is elastic, insofar the wall is able to resume its normal shape spontaneously after undergoing magnetically induced constriction.

[0025] The term “constriction” as used herein is defined as a narrowing of the lumen of the tubular member. This narrowing is induced by an attraction or repulsion of the opposite walls of the tubular member leading to a constriction of the lumen. This can be the result of a narrowing of the diameter of the tubular member or the conversion of the circular form into an ellipsoid or even flat form as resulting from a mere compression of the tubular member.

[0026] Polymers that have the ability to build an elastically deformable structure are identifiable to the skilled person.

[0027] The constriction of the medical implant is induced by the external magnetic field, whereby the constriction of the lumen is maintained as long as the external magnetic field is acting on the medical implant. Hence, the presence and the extent of the constriction is proportional to the current magnetic field acting on the magnetically constricting elements.

[0028] Accordingly, the constriction of the lumen of the medical implant is reduced when the external magnetic field acting on the medical implant is weakened.

[0029] Importantly, the elastically deformable wall allows the lumen of the medical implant to return to an unconstricted state once the external magnetic field acting on the medical implant is eliminated.

[0030] In a preferred embodiment, the wall comprises a matrix of a natural or synthetic polymer preferably selected from the group consisting of elastin, elastin-like polypeptides, elastin-like recombinamers (ELRs), resilin, abductin, byssus, gliadin, glutenin, silk fibroin, fibrin, collagen, expanded polytetrafluoroethylene (ePTFE), polyethylene terephthalate (PET), polycaprolactone (PCL), polydiaxonone (PDO), poly(etherurethane urea) (PEUU), thermoplastic polyurethane (PTU), or any combination thereof. Resilin is an elastomeric protein found in many insects and other arthropods. It provides soft rubber-elasticity to mechanically active organs and tissues. Resilin is one of the most efficient elastic proteins known. The elastic efficiency of the resilin isolated from locust tendon has been reported to be 97% (only 3% of stored energy is lost as heat).

[0031] Abductin is a naturally occurring elastomeric protein found in the hinge ligament of bivalve molluscs. Abductin is unique as it primarily demonstrates compressible elasticity as its mode of action, in contrast to resilin, spider silk, and elastin. Silk fibroin is well known polymer material.

[0032] Silk and its component silk fibroin are protein materials used in tissue engineering and biomedical applications because of their mechanical properties, biocompatibility and biodegradability. Silk polymer and silk fibroin includes silkworm fibroin and insect or spider silk protein. Preferably, fibroin is obtained from a solution containing a dissolved silkworm silk or spider silk. Generally, fibroin polymer (or protein) from silk has been treated to substantially remove sericin. The silkworm silk protein is obtained, for example, from Bombyx mori. and the spider silk is obtained, for example, from Nephila clavipes. In the alternative, silk proteins suitable for use in the present invention can be obtained from a solution containing a genetically engineered silk, such as from bacteria, yeast, mammalian cells, transgenic animals or transgenic plants. See, for example, WO 1997 / 108315 and US 5,245,012 which are incorporated by reference herein.

[0033] In a more preferred embodiment, the wall comprises an elastin-like polypeptide or an elastinlike recombinamer (ELR), which are polymers bioinspired on the elastin.

[0034] Elastin is an amorphous protein present in the elastic fibers of tissues such as arteries, blood vessels, skin, tendons and elastic ligaments, the abdominal wall, and lungs. Unlike other fibrous proteins like collagen, elastin is unique in the ability to stretch and recoil, which is crucial for the function of tissues that undergo repeated stretching and contracting. Thus, this property of elastin provides tissues that incorporate it, the required ability to resume their original form after stretching due to blood flow, breathing, or bending. Like collagen protein, elastin contains about 30% glycine amino acid residues and is rich in proline. Elastin differs from collagen in that it contains very little hydroxyproline and no hydroxylysine.

[0035] In a specific embodiment, the elastin-like recombinamer contains the pentapeptide repeat sequence Val-Pro-Gly-Xaa-Gly (VPGXG), where Xaa represents any amino acid except proline. Hereby, it is preferred, that the elastin-like recombinamer contains the pentapeptide repeat sequence VPGIG, VPGVG, or VPGKG, or any combination thereof.

[0036] According to one embodiment, the elastin-like recombinamers form a hydrogel matrix. Therewith they build an elastically deformable wall as basic structure of the tubular member.

[0037] In one embodiment, the elastin-like recombinamers comprise one or more tissue specific protease-cleavage site. These cleavage sites allow the controlled biodegradation within the target organism, which might enable the replacement of the original structure by endogenous cells or tissues.

[0038] In a preferred embodiment, the protease-cleavage site is a cleavage site for a protease selected from the group consisting of MMP-2, MMP-9, MMP-13, Cat K and urokinase.

[0039] In case of urokinase, the cleavage motif DRIR is preferred, since it exhibits a low cleavage efficiency, thus resulting in a delayed proteolytic sensitivity and slower degradation kinetics.

[0040] The proteolytic cleavage of the ELR is performed by invading cells leading to a remodeling of the implant, whereby the ELR is degraded while cells populate the medical implant and start to secrete an extracellular matrix so that finally the implant can be transformed into native-like tissue.

[0041] In a further embodiment, the elastin-like recombinamers comprise a bioactive peptide, being preferably selected from the group consisting of RGD, REDV, YIGSR, IKVAV, PDSGR, RYVVLPR and RNI AEIIKDI.

[0042] Arginylglycylaspartic acid (RGD) is the most common peptide motif responsible for cell adhesion to the extracellular matrix (ECM). Cell adhesion proteins called integrins recognize and bind to this sequence, which is found within many matrix proteins, including fibronectin, fibrinogen, vitronectin, osteopontin, and several other adhesive extracellular matrix proteins. Accordingly, ECM-derived ligands such as RGD can be used to control cellular responses to a biomaterial, and it is known that the addition of RGD can improve cell attachment, alignment, proliferation, and ECM protein expression.

[0043] IKVAV is a laminin-derived peptide that is known for its pro-angiogenic abilities in stromal cells. IKVAV is known for its ability to promote angiogenesis, neurite formation, regeneration of neuronal stem cells, along with spreading and migration of cells. REDV is the minimal active sequence within the CS5 site of the alternatively spliced type III connecting segment (IIICS) region of fibronectin. REDV can mediate adhesion to the IIICS region of plasma fibronectin by binding the integrin alpha 4 beta 1 (a4pi). REDV can be used for the promotion of cell adhesion.

[0044] Laminin-derived peptides, including IKVAV from the laminin a-chain, YIGSR, PDSGR, RYVVLPR from the laminin pi -chain, and RNIAEIIKDI from the laminin y-chain, can be incorporated to induce cell aggregation and cluster formation in angiogenesis and neurogenesis.

[0045] In one embodiment, the elastin-like recombinamers have a size from 50 to 4000 amino acids, preferably from 250 to 2000 amino acids and more preferably from 300 to 1000 amino acids.

[0046] In a preferred embodiment, the elastin-like recombinamer has an amino acid sequence according to one of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, or SEQ ID NO:4.

[0047] In one embodiment, the elastin-like recombinamers are cross-linked directly to each other in a covalent manner to form an ELR matrix.

[0048] In a preferred embodiment, the ELR-crosslinking is performed by click chemistry. The term "click chemistry" as used herein describes a chemical reaction that is high yielding, wide in scope, creates only byproducts that can be removed without chromatography, is stereospecific, simple to perform, and can be conducted in easily removable or benign solvents.

[0049] In one embodiment, the elastin-like recombinamers are functionalized with alkyne and azide groups to introduce the reactivity required to carry out click chemistry.

[0050] Therewith, the click chemistry requires the different functionalization of the two elastin-like recombinamers enabling the specific coupling of the two ELRs to yield a cross-linked hydrogel.

[0051] In a preferred embodiment, the lysine residues of the elastin-like recombinamers are chemically modified to introduce cyclo-octyne for the first ELR-fraction and azide groups for the second ELR-fraction, so that these two fractions will cross-link due to the above defined clickchemistry.

[0052] In one embodiment, the concentration of the elastin-like recombinamer in the hydrogel matrix is preferably between 20 and 300 mg / mL, more preferably between 50 and 150 mg / mL, and especially is 75 mg / mL. In one embodiment, the wall of the medical implant comprises a textile-reinforced matrix layer.

[0053] The textile reinforcement of the wall increases the strength of the medical implant.

[0054] According to one embodiment, the reinforcement structure has a shape which is adapted to the shape of the matrix of the wall. The reinforcement structure is preferably completely embedded within the matrix so that the outer (abluminal) and luminal surfaces of the medical implant are made of the elastically deformable polymer as matrix material and the reinforcement structure is a purely internal structure. This provides a uniform matrix surface, which takes full advantage of the beneficial effects of the respective polymer. The aforementioned adaption thus implies that the reinforcement structure is smaller in at least two dimensions as compared to the wall.

[0055] In a further embodiment, the textile of said textile reinforcement structure is made from polymer fibers, wherein the polymer is preferably selected from the group consisting of polyethylene terephthalate (PET), poly vinylidene fluoride (PVDF), silk, silk fibroin, high- modulus polyethylene (HMPE), polylactic acid (PLA), thermoplastic polyurethane, (TPU), polycaprolactone (PCL), poly(lactic-co-glycolic) acid (PLGA), polyhydroxybutyrate (PHB) or a combination thereof.

[0056] In one embodiment, the textile reinforcement is made from a yarn, which has 1 to 3000 filaments per yarn, more preferably 1 to 100 filaments and even more preferably 1 to 50 filaments per yarn.

[0057] In another embodiment, the textile reinforcement is made from yarns that have a linear density of 5 to 200 dtex, and more preferably of 10 to 100 dtex.

[0058] In another embodiment, the textile reinforcement has a tubular shape, preferably with a diameter of between 1 mm to 10 cm, more preferably with a diameter between 6 and 22 mm.

[0059] In one embodiment, the textile is produced by a technique which is selected from the group consisting of braiding, winding, non-woven, melt electro writing, weaving, weft knitting and warp knitting, whereby the warp-knitting is the preferred method.

[0060] In a specific embodiment, the textile is a warp-knitted textile having a 1 x 1 lapping, a 2 x 1 lapping, or a tulle lapping, whereby the 1 x 1 lapping is preferred.

[0061] In one embodiment, the magnetically constricting element of the medical implant comprises or consists of magnetic particles incorporated within the wall. As used herein, the term “magnetic particle” denotes to a particle responds to a magnetic field. The atoms of the particles have permanent magnetic moments. This encompasses paramagnetic, superparamagnetic, ferromagnetic and ferrimagnetic particles as particles that are magnetized by a magnetic field.

[0062] In a preferred embodiment, the magnetic particles are selected from the group consisting of magnetic nanoparticles, magnetic microparticles and agglomerations of magnetic nanoparticles.

[0063] In a special embodiment the magnetic particles are magnetic nanoparticles. The term “nanoparticle” as used herein relates to a particle with three dimensions below 1000 nm, preferably below 500 nm and more preferably with all three dimensions below 100 nm.

[0064] The term “microparticle” as used herein relates to a spherical particle with a diameter of between 1 and 1000 pm, preferably with a diameter of between 1 and 10 pm and more preferably with a diameter of between 1 and 2 pm.

[0065] Preferably, the nanoparticles or microparticles are spherical or quasi-spherical.

[0066] In one embodiment, the magnetic nanoparticles comprise a magnetic material selected from cobalt, nickel, manganese or iron.

[0067] In a further embodiment, the magnetic particles are selected from the groups consisting of ferrite particle, coated ferrite particle, iron oxide particle, coated iron oxide particle, metal particle, coated metal particle, alloy particle, coated alloy particle.

[0068] The magnetic material of said magnetic particle is preferably selected from the group consisting of MnO, FesCU, y-Fe2O3, Fe, FePt, CoFe2O4, Fe@FeO and magnetic graphene oxide. Notably, y-Fe2O3 and FesCU nanoparticles are the most favorable particles for use in the present biomedical application because of their excellent biocompatibility, good chemical stability, and no obvious intrinsic toxicity.

[0069] As a composite of iron oxide nanoparticles and graphene oxide, magnetic graphene oxide combines the excellent chemical and physical characteristics of both, like para-magnetism, an excellent oxidation-specific surface area, large surface-binding site activity, strong chemical stability, size coordination, easy functionalization, and biocompatibility. Hereby it is preferred to produce magnetic metal oxide merged into graphene oxide-based nano-composites, called MGO, such as FesO graphene oxide, magnetic reduced graphene oxide, MnsO graphene oxide, and other hybrid nanocomposites.

[0070] In a preferred embodiment, the magnetic particle is a coated magnetite nanoparticle. The coating can help to avoid an agglomeration of the particles and might also induce a coupling of the particle with the elastin-like recombinamer or other matrix materials.

[0071] Examples of coating materials include gelatin, dextran, chitosan, silica, lauric acid, citric acid, polyethylene glycol, polyacrylamide, and co-polymers thereof.

[0072] In one embodiment, the magnetic core of the magnetic particle has a size of between 1 nm and 2 pm, preferably of between 10 nm and 100 nm, and more preferably of between 10 nm and 30 nm.

[0073] In another embodiment, the magnetic core of the magnetic particle has a size of between 1 and 10 nm.

[0074] In a preferred embodiment, the magnetic particle further comprises a coating agent, being more preferably citric acid.

[0075] In one embodiment, the concentration of the magnetic particles within the wall is between 0.1 and 50 wt.%, preferably between 1 and 25 wt.%, and more preferably between 4 and 20 wt.%.

[0076] In one embodiment, the magnetic particles are evenly distributed throughout the wall so that the constrictive activity is evenly provided throughout the tubular member.

[0077] In a further embodiment, the tubular member of the medical implant has a length of between 0.5 and 20 cm, preferably of between 1 and 10 cm, and more preferably of between 2 and 5 cm. The length depends on the hollow target organ to be treated and can be adjusted by the skilled person, especially in order to prepare a customized implant with a patient-tailored geometry.

[0078] In one embodiment, the wall of the tubular member has a wall-thickness of between 20 pm and 10 mm, preferably of between 50 pm and 2 mm and more preferably of between 100 pm and 1.5 mm.

[0079] In a further embodiment, the tubular member of the medical implant has a diameter of between 1 mm to 10 cm, more preferably with a diameter between 6 and 22 mm. The diameter depends on the hollow target organ to be treated and can be adjusted by the skilled person, especially in order to prepare a customized implant with a patient-tailored geometry.

[0080] In a preferred embodiment, the tubular member of the medical implant is a tubular member with a closed wall. In order to encompass a hollow organ as result of an implantation this requires that the hollow organ is cut to surround it with the tubular member or that the tubular member is cut longitudinally to enclose the hollow organ followed by a closure of the wall to yield a tubular member with a closed wall. For the case that the medical implant functions as a part of the hollow organ, the medical implant is introduced by anastomosis.

[0081] In an alternative embodiment, the tubular member of the medical implant has a longitudinally slotted wall. In this form, it represents an open tube which can be introduced easily to enclose the target hollow organ and can be closed afterwards by use of a suitable closing member.

[0082] In a further embodiment, the longitudinally slotted tubular member is further provided with a closing member, preferably selected from the group consisting of suturing tabs, detents, hooks, Velcro glue, interlocking closure ridges, tissue glue, staples.

[0083] System comprising medical implant and magnetic field generator

[0084] In a second aspect, the invention provides a system for constricting a hollow organ in a body of a subject, whereby the system comprises a. at least one medical implant according to the invention; and b. at least one magnetic field generator configured to be placed inside or outside the body of a subject, and configured to generate a magnetic field that attracts or repulses the magnetic constriction element to elastically constrict the lumen of the medical implant and thereby also the hollow organ enclosed by the medical implant or the medical implant substituting a hollow organ in the body.

[0085] In a preferred embodiment the magnetic field generator is separated from the medical implant and is acting from the outside of the medical implant onto the magnetic elements. In this embodiment the magnetic field generator is not positioned within the medical implant, and thereby also not positioned within the lumen of the implant.

[0086] In one embodiment, the system of the invention comprises a magnetic field generator being a portable or implantable device.

[0087] In a further embodiment, the magnetic field generator of the system is permanent magnet or an electromagnet, preferably powered by a battery or rechargeable battery as part of said device. In a preferred embodiment, the magnetic field generator being an electromagnet is suited to generate a magnetic field strength of 1 to 200 kA / m.

[0088] In a further embodiment, the magnetic field generator being an electromagnet is suited to generate a frequency of 0.1 to 100 Hz, and preferably of 0.1 to 10 Hz.

[0089] In one embodiment, the system further comprises a control device that controls the magnetic field generator, which is preferably configured for wireless control, and more preferable is a hand-held wireless remote-control device;

[0090] In a further embodiment, the system further comprise a garment configured to be attached to the magnetic field generator, and worn by the subject in a manner that places the magnetic field generator in a desired location near the body of the subject. Exemplary garments include pants, skirt, stocking, pantyhose, underwear, t-shirt, polo-shirt, shirt, jacket and pullover.

[0091] Intermittent compression device

[0092] In a further aspect the invention relates to an intermittent compression device comprising: a. at least one medical implant according to any of claims 1 to 13 configured to surround or substitute a hollow organ, being preferably a vein or a lymphatic vessel; and b. at least one magnetic field generator configured to be placed inside or outside the body of a subject, and configured to generate an intermittent magnetic field to elastically constrict the lumen of the medical implant and thereby also the hollow organ enclosed by the medical implant or the medical implant representing a segment of a hollow organ, allowing the medical implant to return to a less-constricted or unconstricted state when the magnetic field is attenuated or eliminated.

[0093] In order to induce an intermittent compression, the magnetic field generator generates a periodically changing magnetic field, so that the lumen of the medical implant changes also periodically from a constricted status to an unconstricted status. Hereby, the magnetic field is only responsible for the constriction of the lumen by acting on the magnetically constricting elements. The reversal to an unconstricted status is induced by the removal of the magnetic field together with the fact that the wall of the implant is elastically deformable. As an elastic deformation, the magnetically induced deformation / constriction ceases to exist after the magnetic field is removed. In this case, the medical implant completely recovers its original configuration. For intermittent compression, the periodically changing magnetic field is preferably based on high local magnetic field gradients which can be applied in a pulsed manner.

[0094] In a preferred embodiment the magnetic field generator is separated from the medical implant and is acting from the outside of the medical implant onto the magnetic elements. In this embodiment the magnetic field generator is not positioned within the medical implant, and thereby not within the lumen of the implant.

[0095] Use for treatment

[0096] In a third aspect the invention relates to the medical implant of the invention or the system containing said medical implant for use in the treatment of a disease, whereby the disease can be treated by controlled constriction of a hollow organ.

[0097] In a preferred embodiment the medical implant or the system containing said medical implant are used to treat one of the diseases as described below.

[0098] By constricting veins and lymphatic vessels in the extremities, the medical implant or the system can be used to treat subjects with a variety of lymphatic and venous disorders of the limbs.

[0099] Venous disorders occur, when the normal venous blood flow, as described in the following, is impaired: venous blood flow from the extremities must overcome gravity to return to the heart when the body is upright. Contractions of the muscles of the thigh, calf and foot force the venous blood upwards against the forces of gravity. Valves within the veins prevent the venous blood from flowing backward and away from the heart. The valves open again when the leg muscles contract allowing the blood to flow towards the heart.

[0100] Effective return of venous blood to the heart depends on normal muscle activity and a properly functioning venous system. The venous system in the lower leg is a network of superficial veins that are connected to deep veins in the interior of the leg by the perforator veins. If the valves of the superficial veins, perforator veins or the deep veins do not function properly, venous drainage and effective venous return to the heart are impaired. Valve failure or valve incompetence will allow the venous blood to flow back down to the previous section of the vein, ultimately reducing the return of venous blood back to the heart and causing venous hypertension. Venous valve failure can be idiopathic or caused by damage from a variety of diseases or conditions such as venous thrombosis, venous obstruction or damage due to trauma. Venous valve insufficiency can also be amplified by patient immobility, inactivity or an abnormal gait that reduce the effectiveness of the natural calf muscle pumping action. Ultimately, venous valve failure leads to venous hypertension and results in chronic venous disorder.

[0101] Chronic venous disorder can manifest as spider veins, varicose veins, various skin changes as well as venous ulcerations. As an example, venous leg ulcers (VLU) result from venous hypertension due to superficial, perforator and / or deep venous valve failure or incompetence. Venous hypertension activates the inflammatory system and changes the microvasculature which leads to the formation of a VLU and can impede the healing of the ulcer.

[0102] Venous hypertension also causes capillaries in tissues to become more permeable allowing leakage of various blood cells, proteins and fluid into surrounding tissues. This also results in reduced tissue oxygenation and microvascular abnormalities. Common secondary conditions arising from this milieu include hyperpigmentation, eczema, edema, lipodermatosclerosis, and other changes in tissue hardness and skin appearance.

[0103] As much as 50% of the adult population may suffer from some form of chronic venous insufficiency and related symptoms. For example, venous leg ulceration occurs in up to 5% of the population over 65 years of age and in 1.5% of the general population. It poses a substantial healthcare challenge in the Western hemisphere, and this issue is expected to escalate with the global increase in the aging population. In the United States alone, this condition affects an estimated 2 to 3 million people. Notably, it results in the loss of 2 million workdays annually, potentially leading to early retirement and disability. The financial impact is also significant, with the cost of treating venous leg ulcerations conservatively estimated at $3 billion per year, representing a major healthcare expense.

[0104] Compression therapies directed to the extremities have been developed and used to treat patients with a variety of lymphatic and venous disorders of the limbs. The aim of compression therapy is also fulfilled by the medical implant or the system of the invention, namely: 1) to improve the velocity and flow of venous blood and lymph return 2) to decrease edema and reduce venous hypertension and its long-term complications.

[0105] The medical implant or the system of the invention can thus be used to prevent chronic venous disease progression and as a prophylaxis of venous thromboembolism. The systematic use of medical implant or the system of the invention might provide an improved treatment strategy for venous leg ulcers.

[0106] By constricting the respective leg vein, the chronic venous disease of a subject can be treated.

[0107] In case that the medical implant itself represents a blood vessel for treatment of a venous disease, it is preferred that the tubular member is implanted between two valves or that the tubular member comprises two valves, an inlet and an outlet valve, located above and below the constricting middle segment of the tubular member and representing one-way (unidirectional) valves to prevent backflow (regurgitation) of the venous blood. Under influence of the magnetic field, the tubular member is constricted leading to an opening of the proximal (outlet) valve and enabling the blood flow towards the heart, while the distal (inlet) valve closes due to the constriction and thereby prevents body fluid to flow backwards (towards the feet). When the magnetic field is switched off again, the outlet valve closes and the inlet valve opens to refill the lumen of the tubular member with blood.

[0108] In case that the medical implant is implanted to surround a segment of a vein for treatment of a venous disease, it is preferred that the tubular member is implanted between two venous valves, located above and below the tubular member. Under influence of the magnetic field, the tubular member is constricted leading to an opening of the proximally located venous valve and enabling the blood flow towards the heart, while the distally located venous valve closes due to the constriction and thereby prevents body fluid to flow backwards (towards the feet). When the magnetic field is switched off again, the proximally located venous valve closes and the distally located venous valve opens to refill the lumen of the tubular member with blood.

[0109] In another embodiment, the magnetic field is applied to a segment of the tubular member in the distal end. This leads to a focal constriction of the tubular member. Then, this localized magnetic field moves along the tubular member and the respective focal constriction moves towards the outlet of the tube and thus directs the blood from the distal to the proximal direction in a squeeze-out manner. In this case, the presence of the valves in not necessary.

[0110] By using the medical implant or the system as a Fontan conduit, it can be used to treat the hypoplastic left heart syndrome. Hereby the use in pediatric patients is preferred.

[0111] During the Fontan procedure, the surgeon disconnects the inferior vena cava (IVC) from the heart and connects it to the pulmonary artery using a conduit, the so-called Fontan conduit. 1 out of 100 newborns in Germany suffer from a congenital heart defect. Most congenital heart defects (e.g. ventricular septal defect, atrial septal defect) are compatible with good postoperative quality of life. However, some heart defects, such as hypoplastic left heart syndrome (HLHS), are severe and the newborns suffering from them will need expert medical attention for the rest of their lives.

[0112] In patients with HLHS, the left ventricle is too small, and therefore the right ventricle has to pump blood not only to the lungs, but also to the rest of the body. The limitation to have only one functional ventricle to pump blood to both locations is accompanied by an undesired mixture of oxygen-rich and oxygen-poor blood.

[0113] Treatment of babies with HLHS usually consists of a heart transplant or, in the case of children who are candidates for surgery, three cardiac operations performed during the first two years of life. The goal of these operations is to rebuild the heart so that the functional right ventricle can be used to pump oxygenated blood exclusively out to the body. The third of these surgeries is named as Fontan procedure, and it is done when the child is about two years old. In this procedure, the inferior vena cava is disconnected from the heart, and connected to the pulmonary artery using a tube (called the Fontan tube or the Fontan conduit).

[0114] GORE- TEX® tubular grafts are clinically employed during the Fontan procedure for this purpose. However, their passive and inert nature leads to abnormal flow profile, potentially causing impaired blood oxygenation and life-threatening respiratory distress.

[0115] These adverse effects could be palliated if the Fontan tube would not be inert, but would have contractility / pulsatility (so that it helps the blood circulation). A contractile Fontan- tube flanked by two valves could propel blood actively to the lungs and avoid end-organ damage.

[0116] As a therapy, the present invention provides the use of the medical implant as a Fontan Conduit, which can be remotely controlled by a magnetic field produced by the magnetic field generator to change the cross-sectional area, and thus to collapse and expand (pulsatility). The medical implant enables a wireless actuation by magnetic fields, providing an unprecedented approach to improve the quality of life and expectancy of children with hypoplastic left-heart syndrome.

[0117] In case that the medical implant itself represents a blood vessel, it is preferred that the tubular member comprises two valves, an inlet and an outlet valve, located below and above the constricting middle segment of the tubular member and representing one-way (unidirectional) valves to prevent backflow (regurgitation) of the venous blood. In a more preferred embodiment said valves are in principle construed as venous valves. Herewith, they are formed in one example by bulges in the luminal side of the tubular member, which can be, for example, created by molding a tube with bulges in the luminal side in the shape of leaflets. In another example, the two valves / leaflets are fabricated in an independent manner from the tube, and then attached to the tube. The attachment can comprise for example suturing, or it can involve the use of a stent. The leaflets are preferentially made from an elastic material and strengthened with a textile fabric. The leaflets are directed with the forward flow lying against the wall. When the blood tries to reverse its direction (due to low venous pressure and the pull of gravity), the space between the leaflet and the wall will be filled by the blood leading to a closing of the leaflets while keeping them together.

[0118] Under influence of the magnetic field, the tubular member is constricted leading to an opening of the outlet valve and enabling the blood flow towards the pulmonary artery, while the inlet valve closes due to the constriction and thereby prevents body fluid to flow backwards to the lower body. When the magnetic field is switched off again, the outlet valves closes and the inlet valves open to refill the lumen of the tubular member acting as contractile Fontan conduit with blood.

[0119] In another embodiment, the magnetic field is applied to a segment of the tubular member in the inlet side. This leads to a focal constriction of the tubular member. Then, this localized magnetic field moves along the tubular member and the respective focal constriction moves towards the outlet of the tube and thus directs the blood from the inlet (coming from the lower body) to the outer direction (towards the pulmonary artery) in a squeeze-out manner.

[0120] The medical implant or system of the invention can be used to treat diseases caused by impaired functionality of a sphincter. The function of the sphincters consists in the regulation of the content flux in visceral canals by means of a tonic contraction of their musculature that surrounds as a ring the lumen of the visceral canal. The sphincters prevent in some cases the abnormal retrograde flux of content (reflux) and in other cases the abnormal anterograde flux (incontinence). When the sphincter musculature becomes weak due to a disease, surgical intervention or without an apparent cause (idiopathic forms), the tone of closure decreases, up to a complete absence in some cases, and, consequently, the sphincter become unable to control the content flux (incompetent sphincter). By constricting the urethral sphincter, the medical implant or the system can be used to treat urinary incontinence.

[0121] The urethral sphincter is represented by an internal ring of smooth muscle fibers and another external ring of striated muscle, that surround the proximal portion of the urethra and with their tonic contraction prevent the loss of urine. The decrease or loss of the sphincter tone may be caused by organic or functional alterations of the muscle (surgical interventions, traumatic lesions, myopathies, drugs, pregnancy, delivery, menopause, etc) or by diseases of the innervation (spinal cord or spinal nerve lesions, etc).

[0122] In one embodiment, the constriction exerted by the medical implant must have a force that creates a closure sufficient to prevent the passage in the wrong direction, but at the same time must allow the passage in the right direction.

[0123] By constricting the anal sphincter, the medical implant or the system can be used to treat fecal incontinence.

[0124] At anal level there is the anal sphincter, that prevents the leakage of feces contained in the rectal ampulla (fecal incontinence). The fecal incontinence is due to a loss of tonic contraction of the anal sphincter that does not retain anymore the feces into the rectum. The anal sphincter is formed by a ring of smooth muscle fibers (internal sphincter) and by a ring of a striated muscle fibers (external sphincter), has a length of 2.5-5 cm and a tone of closure of about 50-80 mmHg. The cause of decrease in tone of the sphincter may be due to muscle alterations for a disease (myopathy), traumatic lesions, surgical interventions, botulinum toxin infiltrations, or to a spinal cord or nerve alterations, or to an unknown cause (idiopathic). In addition, in patients with idiopathic fecal incontinence there are spontaneous relaxations of the sphincter not only during the night but also during the day, that facilitate the fecal loss.

[0125] By constricting the lower esophageal sphincter, the medical implant or the system can be used to treat the gastroesophageal reflux syndrome.

[0126] The gastroesophageal reflux is due to an inability of the lower esophageal sphincter. The oesophageal sphincter keeps closed the communication between the stomach cavity and the oesophageal lumen, avoiding the passage of acid gastric content to the esophageal lumen. The malfunction of this sphincter may give rise to more or less severe lesions not only of the oesophageal mucosa (such as esophagitis, Barrett metaplasia and oesophageal adenocarcinoma, etc.), but also in some cases of the mucosa of the airways (laryngitis, laryngospasm, larynx adenocarcinoma, cough, asthma, etc).

[0127] By constricting the sphincter of Oddi, the medical implant or the system can be used to treat sphincter of Oddi dysfunction. The sphincter of Oddi is a muscular valve that plays a vital role in digestion. It controls the flow of bile and pancreatic juice. It opens and closes to let the juices flow from the liver and pancreas into the small intestine. If the sphincter does not open at the right time, it can lead to a backup of digestive juices (bile and pancreatic juice), resulting in severe abdominal pain.

[0128] By providing phasic contractions that propel food through the digestive system, the medical implant or the system can be used to treat gastrointestinal disorders characterized by decreased motility.

[0129] Impaired motility and emptying are important pathophysiological factors involved in the intolerance of enteral feeding in critically ill patients but also in different gastrointestinal (GI) diseases and disorders. Examples of respective GI disorders are gastroparesis, functional dyspepsia (FD), gastrointestinal motility disorder, achalasia, intestinal dysmotility, intestinal pseudo-obstruction and Hirschsprung’s disease.

[0130] By constricting the stomach, the medical implant or the system of the invention can be used to treat obesity.

[0131] In a further aspect of the invention, the medical implant is used as a drug pump. In this aspect, the lumen is filled with the drug which will be accordingly released from the tubular member as result of the magnetically induced constriction. For this purpose, the tubular member can be provided with sealed tube endings, with valves or with a nozzle or combination thereof. In a further embodiment, this drug pump can be connected to a drug reservoir acting as a release member for controlled release of the drug into the body.

[0132] In one embodiment, the tubular member is used as release member of an intracorporeal drug pump, whereby it is connected to a drug reservoir which is filled with a drug-containing liquid. The tubular member might possess an inlet valve and an outlet valve.

[0133] When the magnetic field is switched off, the tube remains unconstricted with the lumen being filled by the drug from the drug reservoir. Under influence of the magnetic field, the tubular member is constricted leading to an opening of the outer valve and a controlled release of a portion of the drug while the inlet valve closes due to the constriction and thereby prevents body fluid from entering the drug reservoir. When the magnetic field is switched off again, the outlet valves closes and the inlet valves open to refill the lumen of the tubular member with a new portion of the drug.

[0134] In an alternative embodiment, tubular member is connected to the drug reservoir which is filled with a drug-containing liquid. When selectively applying a magnetic field to a segment of the tubular member in proximity to the drug reservoir this leads to a focal constriction of the tubular member. While this localized magnetic field moves along the tubular members, the respective focal constriction moves towards the outlet of the tube and releases the drug from the tube into the body in a squeeze-out manner. Optionally, a further proximal constriction can be introduced to prevent body fluid from entering the main drug reservoir while also generating an isolated drug containing compartment within the tubular member for further drug release.

[0135] Method for producing the medical implant

[0136] In a fourth aspect, the invention provides a method for producing a medical implant, which is preferably provided with a textile reinforcement, according to the invention, comprising the following steps:

[0137] (a) Providing a first solution containing an elastin-like recombinamer functionalized with alkyne groups and a second solution containing an elastin-like recombinamer functionalized with azide groups;

[0138] (b) Providing magnetic particles;

[0139] (c) Dispersing the magnetic particles of step (b) in the first and / or second solution according step (a) to generate two dispersions;

[0140] (d) Optionally providing a textile fabric configured for reinforcing the wall of the medical implant, and having preferably a tubular shape;

[0141] (e) Providing a mold consisting of an outer tube and an inner cylinder placed coaxially to the outer tube, whereby optionally a textile fabric of step (d) is positioned in the annular space between the cylinder and the tube;

[0142] (f) Injection of the mixed dispersions of step (c) into the mold of step (e), while allowing the crosslinking of the two elastin-like recombinamers; (g) Optionally moving the mold containing the dispersion in order to prevent sedimentation of the magnetic particles;

[0143] (h) Removing the tubular medical implant containing magnetic particles as constriction member from the mold, whereby the medical implant is preferably a textile-reinforced medical implant

[0144] According to step (a) of the method two different ELR-containing solutions are provided: The first solution contains an elastin-like recombinamer functionalized with alkyne groups and the second solution contains an elastin-like recombinamer functionalized with azide groups.

[0145] The above-described functionalization of the two elastin-like recombinamers enabling the specific coupling of the two ELRs to yield a cross-linked hydrogel. In a preferred embodiment, the lysine residues of the elastin-like recombinamers are chemically modified to introduce cyclo-octyne for the first solution and azide groups for a second solution, so that upon mixing the two ELRs will cross-link due to the principle of click-chemistry.

[0146] In step (b) magnetic particles are provided, which are preferably coated magnetite particles. In a further preferred embodiment, these particles are nanoparticles, whereby the magnetic core of the magnetic nanoparticle has size of between 1 nm and 2 pm, preferably of between 10 nm and 100 nm, and more preferably of between 10 nm and 30 nm.

[0147] According to step (c) the magnetic particles are dispersed in the first and / or second solution according step (a) to generate two ELR dispersions, whereby the magnetic particles are preferably homogenously dispersed within the solution containing the functionalized elastinlike recombinamer.

[0148] In step (d), a textile fabric is optionally provided which is configured for reinforcing the wall of the medical implant. Accordingly, it is preferred that this textile fabric has a tubular shape.

[0149] The textile fabric is configured to be completely embedded within the matrix so that the outer and luminal surfaces of the wall are made of the elastically deformable ELR as matrix material and the textile fabric as reinforcement structure is a purely internal structure. This provides a uniform wall surface, which takes full advantage of the beneficial effects of the biopolymer ELR. The aforementioned adaption thus implies that the textile fabric as a reinforcement structure is smaller in at least two dimensions as compared to the outer wall. In one embodiment, the textile is produced by a technique which is selected from the group consisting of braiding, winding, melt electro writing, weaving, weft knitting and warp knitting, whereby the warp-knitting is the preferred method.

[0150] In a specific embodiment, the textile is a warp-knitted textile having a 1 x 1 or 2 x 1 lapping or a tulle lapping, whereby the 1 x 1 lapping is preferred.

[0151] In step (e), a mold consisting of an outer tube and an inner cylinder placed coaxially to the outer tube is provided, whereby in one option a textile fabric of step (d) is positioned in the annular space between the cylinder and the tube. Therewith, the mold is primed to generate a fiber- reinforced ELR tube member.

[0152] In step (f), the two mixed dispersions of step (c) are injected into the mold of step (e), while allowing the crosslinking of the two elastin-like recombinamers.

[0153] In step (g), the mold containing the dispersion is optionally moved in order to prevent sedimentation of the magnetic particles.

[0154] In step (h), the (optionally textile-reinforced) tubular medical implant containing magnetic particles as constriction member is removed from the mold.

[0155] In a further embodiment, the method of the invention is modified as follows in order to generate an implant with a porous wall structure. It has to be noted that the above-described production process has the advantage that it is compatible with the implementation of a salt-leaching gasfoaming (SL / GF) approach, resulting in highly porous elastin-like structures. The implementation of a SL / GF step during the fabrication process allows to tune the microstructure of the elastin matrix by incorporating a porogen.

[0156] In step a. of the modified process, porogen particles are added to the two solutions of step (a) in order to generate two dispersions, each containing the functionalized elastin-like recombinamer, magnetic particles and the porogen particles.

[0157] After removing the textile-reinforced medical implant from the mold, the textile-reinforced medical implant is washed in an acidic solution to remove the porogen particles, and washed thereafter with water or an aqueous solution, to generate a medical implant with a porous wall structure. The porous wall structure has the advantage that it favors cell colonization after implantation and thereby facilitates the remodeling of the medical implant into a native-like tissue.

[0158] Based on the above described, different versions of the medical implant can be generated as listed in the following table:

[0159] DEFINITIONS

[0160] The expression "comprise", as used herein, besides its literal meaning also includes and specifically refers to the expressions "consist essentially of' and "consist of’. Thus, the expression "comprise" refers to embodiments wherein the subject-matter which "comprises" specifically listed elements does not comprise further elements as well as embodiments wherein the subject-matter which "comprises" specifically listed elements may and / or indeed does encompass further elements. Likewise, the expression "have" is to be understood as the expression "comprise", also including and specifically referring to the expressions "consist essentially of' and "consist of'. The term "consist essentially of', where possible, in particular refers to embodiments wherein the subject-matter comprises 20% or less, in particular 15% or less, 10% or less or especially 5% or less further elements in addition to the specifically listed elements of which the subject-matter consists essentially of.

[0161] Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and / or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and / or chemical phenomena. Approximately: The term “approximately” as used herein may be applied to modify any quantitative comparison, value, measurement, or other representation that could permissibly vary without resulting in a change in the basic function to which it is related.

[0162] A / an: As used herein the specification, “a” or “an” may mean one or more. As used herein in the claim(s), when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one.

[0163] Or / and / or: The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.”

[0164] The term “about” means, in general, within a standard deviation of the stated value as determined using a standard analytical technique for measuring the stated value. The terms can also be used by referring to plus or minus 5% of the stated value.

[0165] Essentially: The term “essentially” is to be understood that methods or compositions include only the specified steps or materials and those that do not materially affect the basic and novel characteristics of those methods and compositions.

[0166] As used herein, the term “medical implant” refers to an implantable material, a prosthesis, an artificial organ, a repair device, or a patch. The site of implantation can be anywhere in or onto a body of a subject. Indeed, any implant as would be apparent to one of ordinary skill in the art upon review of the present disclosure falls within the scope of the presently disclosed subject matter.

[0167] As used herein, the term “hollow organ” relates to an organ that is a hollow tube or pouch or that includes a cavity as of the heart or bladder which subserves a vital function. As such they consist of a lumen and a surrounding wall. In one example, the tubular hollow organs of the body encompass the GI tract and therefore the larynx, oesophagus, stomach, small intestine and large intestine. Further hollow organs are bladder, uterus and gall bladder. The vascular system is explicitly included in the above definition. The vascular system is made up of the vessels that carry blood and lymph fluid through the body. As such, it includes the veins, the arteries, the lymph vessels and the heart. In the present application, the term "polymer" refers to a macromolecular compound prepared by polymerizing monomers of the same or different types. The term "polymer" includes homopolymers, copolymers, terpolymers, interpolymers, and so forth.

[0168] Protein / polypeptide: The terms “protein,” “peptide,” and “polypeptide,” are used interchangeably herein, and refer to a polymer of amino acid residues linked together by peptide (amide) bonds. The terms refer to a protein, peptide, or polypeptide of any size, structure, or function. Typically, a protein, peptide, or polypeptide will be at least three amino acids long. A protein, peptide, or polypeptide may refer to an individual protein or a collection of proteins. One or more of the amino acids in a protein, peptide, or polypeptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation, functionalization, or other modification, etc. A protein, peptide, or polypeptide may also be a single molecule or may be a multi-molecular complex. A protein, peptide, or polypeptide may be just a fragment of a naturally occurring protein or peptide. A protein, peptide, or polypeptide may be naturally occurring, recombinant, or synthetic, or any combination thereof.

[0169] As used herein, the term “elastin-like recombinamer” or “ELR” means a biocompatible recombinant protein-based polymer comprising a repeat sequence found in the mammalian elastic protein elastin, or a modification thereof. The most well-known members within the ELR family are based on the pentapeptide VPGVG (or its permutations), and a wide variety of polymers with the general formula (VPGXG), where X represents any natural amino acid except proline. ELR’s are described in Spanish Patent Application No: ES2012030474; and European Patent Application No: 2397150.

[0170] As used herein, the term “magnetic field generator” relates to means which are suitable to generate a magnetic field. It therefore includes permanent magnets as well as electro magnets.

[0171] As used herein, the term “cross-linked” as applied to an ELR polymer means that the ELR polymer chains are covalently cross-linked with a crosslinking agent to form a three- dimensional network. The hydrogel of the invention may be crosslinked, crosslinkable, or not crosslinked.

[0172] The term “biocompatible” as used herein refers to a material that, upon contact with a living element, such as a cell or tissue, causes little or no toxicity. The term "patient" means according to the invention a human being, a nonhuman primate or another animal, in particular a mammal such as a cow, horse, pig, sheep, goat, dog, cat or a rodent such as a mouse and rat. In a particularly preferred embodiment, the patient is a human being.

[0173] As used herein, the term “disease” is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from infection, trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.

[0174] Treatment / treating: “Treatment” or “ treating” includes (1) inhibiting a disease, disorder or condition in a subject or patient experiencing or displaying the pathology or symptomatology of the disease (e.g., arresting further development of the pathology and / or symptomatology), (2) ameliorating a disease, disorder or condition in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease (e.g., reversing the pathology and / or symptomatology), and / or (3) effecting any measurable decrease in a disease, disorder or condition in a subject or patient that is experiencing or displaying the pathology or symptomatology of the disease.

[0175] In the context of treatment and effective amounts as defined above, the term subject (which is to be read to include "individual”, "animal”, "patient" or "mammal" where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; and rodents such as mice, rats, hamsters and guinea pigs. In preferred embodiments, the subject is a human. BRIEF DESCRIPTION OF THE FIGURES

[0176] To illustrate the technical features of embodiments of the present invention more clearly, the accompanying Figures provided for describing the embodiments are introduced briefly in the following. The accompanying figures in the following description are merely some embodiments of the present invention, modifications on these embodiments are possible without departing from the scope of the present invention as defined in the claims.

[0177] FIG. 1 shows in A a perspective schematic drawing of a medical implant of the invention. An elastically deformable tubular member 1 with a wall 5 made from hydrogel containing the elastin-like recombinant elastomer creates a lumen 6 for surrounding or replacing the hollow organ after implantation. Fig. 1 B shows a cross section of the tubular member with the embedded textile layer 7 as reinforcement structure. Fig. 1 C shows an enlarged section of the wall with the magnetic particles 8 incorporated in the ELR- hydrogel as matrix of the wall.

[0178] FIG. 2 shows a prototype of a medical implant of the invention, located in a buffer solution mimicking the placement within a body. In this embodiment, the tubular member with the embedded magnetic nanoparticles exhibits an elongated tubular member with closed wall structure. As shown in the left photos, the tube has an almost circular lumen since no magnetic field is present. As shown in the middle, the application of a magnetic field by an externally located magnet induces an attraction or repulsion of the opposing wall segments and causes a collapse of the tubular member which thereby should lead to a constriction of any hollow organ that is surrounded by said tubular member, or pump the blood if the tubular member is implanted to form a part of a blood vessel, for which case the presence of an outlet and an inlet valve is preferred. As shown in the right panel, when the magnetic field is removed again (e.g. by removing an externally located permanent magnetic or by switching off an electromagnet, both not shown herein), the tube regains its almost circular lumen since no magnetic field is present.

[0179] FIG.3 shows the therapeutic application of the device of the invention for the treatment of CVD in a schematic manner, whereby the medical implant 1 is implanted to surround a leg vein 10 (e.g., the vena femoralis) of a patient and positioned between a distally located vein valve 9a and proximally located vein valve 9b. On the left side the tubular member provides a circular lumen 6a, with the lumen tightly surrounding the vein. On the right side, a magnetic field causes the constriction of the tubular member and the respective lumen 6b, leading to a blood flow towards the heart 11 whereas the distal vein valve closes due to the constriction, thereby mimicking the function of the calf pump.

[0180] FIG. 4 shows another embodiment of the medical implant of the invention, whereby the tubular member 1 is used as release member of an intracorporeal drug pump. The drug reservoir positioned on the left (not shown) is filled with a drug-containing liquid and is connected to the tubular member 1, possessing an inlet valve 2 and an outlet valve 3. In the upper panel, the magnetic field is switched off and the tube remains unconstricted with the lumen filled by the drug from the drug reservoir. Under influence of the magnetic field 4 (middle panel) the tubular member is constricted leading to an opening of the outer valve and a controlled release of a portion of the drug while the inlet valve closes due to the constriction and thereby prevents body fluid from entering the drug reservoir. When the magnetic field is switched off again, the outlet valves closes and the inlet valves open to refill the lumen of the tubular member with a new portion of the drug.

[0181] FIG. 5 shows another embodiment of the medical implant of the invention, whereby the tubular member 1 is used as release member of an intracorporal drug pump. The drug reservoir positioned on the left (not shown) is filled with a drug-containing liquid and is connected to the tubular member 1 which is also filled with the drug. In the upper panel, the magnetic field is selectively applied to a segment of the tubular member in proximity to the drug reservoir which leads to a focal constriction of the tubular member. Local magnetic field gradients can be created by spatial variation of the magnetic field strength. As a result, the tubular member is attracted toward the highest gradient field (as shown in the second and third panel), and the respective focal constriction moves towards the outlet of the tube and releases the drug from the tube into the body in a squeeze-out manner. As shown in the fourth panel, a further proximal constriction can be introduced to prevent body fluid from entering the drug reservoir while also generating an isolated drug compartment within the tube for further release. This same mechanism can be used to direct blood along the tubular member in a unidirectional manner. FIG. 6 shows another embodiment of the medical implant of the invention, whereby the tubular member 1 is controlled by the magnetic field in order to show as peristaltic (i.e. “squeeze-out”) behaviour. In A, the magnetic field is selectively applied to the left part of the tubular member which leads to a respective focal constriction of the tubular member. Local magnetic field gradients can be created by spatial variation of the magnetic field strength. This variation can be created by simple movement of the magnet or by an array of electro magnets which are controlled in order to create said spatial variation of the magnetic field. As a result, the tubular member is attracted toward the highest gradient field (as shown in the middle and the right panel), and the respective focal constriction moves from A via B to C towards the right part of the tube and presses the content of the tubular member (or its enclosed hollow organ in a unidirectional manner from left to right).

[0182] FIG. 7 shows the therapeutic application of the device of the invention for the treatment of left hypoplastic heart syndrome in a schematic manner, whereby the medical implant 1 is introduced by anastomosis during the Fontan procedure. In the Fontan procedure the inferior vena cava (I VC) is disconnected from the heart and connected to the pulmonary artery using the medical implant of the invention, whereby the implant is flanked by two valves to ensure unidirectional flow. Under influence of the magnetic field 4 the tubular member is constricted (not shown herein) to bypass the blood from the inferior vena cava to the pulmonary artery.

[0183] FIG. 8 shows the amino acid sequence of four elastin-like recombinamers as preferred embodiment for preparation of the medical implant of the invention.

[0184] LIST OF REFERENCE SIGNS

[0185] 1 Tubular member as medical implant

[0186] 2 Inlet valve

[0187] 3 Outlet valve

[0188] 4 Magnetic field

[0189] 5 Wall of the tubular member

[0190] 6 Lumen

[0191] 6a Circular lumen

[0192] 7 Textile fabric as reinforcement structure

[0193] 8 Magnetic nanoparticles 9 Venous valve

[0194] 9a Distally located venous valve

[0195] 9b Proximally located venous valve

[0196] 10 Leg vein

[0197] 11 Blood flow towards the heart

[0198] EXAMPLES

[0199] The following examples are for illustrative purpose only and are not to be construed as limiting this invention in any manner.

[0200] 1. Preparation of a medical implant according to the invention

[0201] 1.1 Preparation of the elastin-like recombinamer

[0202] The ELRs used in this study are available from the company Technical Proteins Nanobiotechnology, S.L. ((TPNBT), Valladolid, Spain) and given by amino acid sequence according to SEQ ID NO.: 1 (also called “VKV-ELR”), SEQ ID NO.:2 (also called “RGD- ELR”), SEQ ID NO. :3 (also called “DRIR-ELR”), and SEQ ID NO.:4 (also called “GTAR- ELR”), each selected for their specific properties. VKV-ELR is a structural elastin-like recombinamer lacking bioactive sequences, whereas RGD-ELR contains a tripeptide (Arg-Gly- Asp) that promotes cell attachment, DRIR-ELR includes the cleavage site for urokinase plasminogen activator (Asp-Arg-Ile-Arg) and GTAR-ELR includes the fast-proteolytic sequence motif GTAR.

[0203] 1.2 Functionalization of the elastin-like recombinamer

[0204] The recombinamers were chemically modified to carry azide and cyclooctyne groups by transformation of the 8-amine group present in the lateral chain of the lysine residue. The elastin recombinamers DRIR-ELR, GTAR-ELR and VKV-ELR modified with cyclooctyne groups are available as TP20257, TP20258 and and TP70904 from the company TPNBT. The elastin recombinamer RGD-ELR modified with the azide group is available as TP71254 from TPNBT.

[0205] 1.3 Generation of magnetic nanoparticles

[0206] 8 g ofFeCh 6H2O (29.5 mmol) and 4 g FeCh AEhO (31.5 mmol) were dissolved in 33.7 ml of distilled water. Subsequently, 16.7 ml of a 14M NH3 solution was added dropwise under vigorous stirring at 25 °C. A black precipitate (iron oxides) resulted, which was separated from the clear supernatant by magnetic decantation and washed repeatedly with 60 ml of 0.7M NH3. The iron oxide precipitate was heated up in an oil bath at 90 °C and stabilized by adding 4 ml of 0.7M NH3 and 0.75 g lauric acid (3.75 mmol) under vigorous stirring. After cooling, the stabilized iron oxides were centrifuged for 10 min at 984 g and dried.

[0207] 1.4 Preparation of a textile fabric for use as reinforcement structure

[0208] The warp knitted textiles are produced using a double needle bed raschel machine. The gauge of the machine is 18 to 32 needles / inch, preferably 22 to 28 needles / inch, particularly preferably 24 to 26 needles / inch, and specifically, we used 24 needles / inch. To produce the textile, PET multifilament yarns (36 filaments) were placed on warp beams or bobbins on a creel. The yarns were fed into the warp knitting machine by active drive of the warp beams or actively driven feed rollers. From the feeder, the yarns run via tensioning rails or single yarn tension fingers into the guide bars. Depending on the lapping, 4, 6 or 8 guide bars are used. Specifically, we fabricated the textile with a 1x1 lapping and therefore, we used 4 guide bars. The guide bars were driven fully electronically via linear motors. The lapping was programmed on the control panel of the warp knitting machine or on a computer with subsequent digital transfer of the lapping file to the machine. From the knitting elements, the textile fabric run out of the machine via an electronic fabric take-off. After the textile production, the fabric was heat-set to reduce internal stresses in the yarn by hot steam at 121 °C for 20 minutes.

[0209] 1.5 Generation of the tubular member by mould casting

[0210] For the production of the textile-reinforced biohybrid ELR graft, a custom-made mold was used. It consisted of an inner core cylinder (outer diameter = 6mm), with spacers at the top and bottom (outer diameter = 7.5mm), fixed to a base plate. A heat set warp-knitted PET-textile was positioned concentrically to the core cylinder and held in place by the spacers. This assembly was then encased in a concentrical Polycarbonate (PC) shell (inner diameter = 9mm), consisting out of two clamped halves screwed to the base. A hole in the shell, positioned close to the base of the mold allowed for injection of a hydrogel precursor.

[0211] Two chemically modified ELRs as prepared according Example 1.2 (ELR-DRIR-cyclo-octyne and ELR-RGD-azide) were dissolved for 30 min in a 1 : 1 (v / v) mixture of PBS (pH: 7.4) and ethanol at a concentration of 75mg / mL.

[0212] The magnetic nanoparticles, produced as described in example 1.3 were added to the ELR- solutions at a concentration of 200 mg / mL. The two solutions were sequentially loaded into the two syringes that were connected to a mixing nozzle, and co-injected into the mold. After incubating for 30min at room temperature, the shell of the mold was opened, and the ELR- textile scaffold was carefully removed from the core and washed three times in aqueous solution. 2.1 Characterization of the medical implant

[0213] The implant was immersed in saline aqueous media (PBS) inside a glass container, and a magnetic field of approx. 150 mT was applied by an externally located permanent magnet. This induced an attraction of the opposing wall segments and caused a collapse of the tubular member. When the externally located magnet was removed, the tube regained its almost circular lumen since no magnetic field is present.

[0214] Additionally, the implant was located in aqueous media in a petri dish, and subjected to the magnetic field generated by a magnetic coil. Specifically, the magnetic field generator (Intertec electromagnet - in the non- magnetic state (zero-current state) 400 N 12 V / DC 11 W ITS-MS- 5030-12VDC) was controlled with a custom-developed Lab VIEW program (Lab VIEW 2020; National Instruments) that enabled to adjust through the software interface, the frequency of the pulsation (constriction-expansion) of the medical device.

Claims

CLAIMS1. A medical implant comprising a tubular member having a wall defining a lumen, characterized in that the wall is elastically deformable and comprises a magnetically constricting element incorporated within the wall and being operable by an external magnetic field to elastically constrict the lumen upon application of said magnetic field.

2. The medical implant according to claim 1, characterized in that the constriction of the lumen is maintained as long as the external magnetic field is acting on the medical implant.

3. The medical implant according to claim 1 or 2, characterized in that the constriction of the lumen is reduced when the external magnetic field acting on the medical implant is weakened.

4. The medical implant according to claim 1 to 3, characterized in that the elastically deformable wall allows the lumen to return to an unconstricted state once the external magnetic field acting on the medical implant is eliminated.

5. The medical implant according to any of the above claims, characterized in that the wall comprises a matrix of a natural or synthetic polymer preferably selected from the group consisting of elastin, elastin-like polypeptides, elastin-like recombinamers (ELR), resilin, abductin, silk fibroin, fibrin, collagen, expanded polytetrafluoroethylene (ePTFE), polyethylene terephthalate (PET), polycaprolactone (PCL), polydiaxonone (PDO), poly(etherurethane urea) (PEUU), thermoplastic polyurethane (PTU), or any combination thereof.

6. The medical implant according to claim 5, characterized in that the elastin-like recombinamers contains the pentapeptide repeat sequence Val-Pro-Gly-Xaa-Gly (VPGXG), where Xaa represents any amino acid except proline, and whereby the elastinlike recombinamers preferably contains VPGIG, VPGVG, or VPGKG, or any combination thereof.

7. The medical implant according to claims 5 or 6, characterized in that the elastin-like recombinamers form a hydrogel matrix and have one or more of the following characteristics:i. comprise a tissue specific protease-cleavage site, selected from the group consisting of MMP-2, MMP-9, MMP-13, Cat K, urokinase; ii. comprise a bioactive peptide motif, being preferably selected from the group consisting of RGD, REDV, YIGSR, IKVAV, YIGSR, PDSGR, RYVVLPR, RNIAEIIKDI; iii. have a size from 50 to 4000 amino acids, preferably from 250 to 2000 amino acids and more preferably from 300 to 1000 amino acids; iv. have an amino acid sequence according to one of SEQ ID NO: 1, SEQ ID NO:2; SEQ ID NO: 3, or SEQ ID NO:4; v. are functionalized with alkyne and azide groups to introduce the reactivity required to carry out click chemistry, whereby preferably the lysine residues are chemically modified to introduce cyclo-octyne and azide groups; vi. are cross-linked directly to each other in a covalent manner to form an ELR matrix, whereby the crosslinking is preferably performed by click chemistry, whereby the concentration of the elastin-like recombinamer in the hydrogel matrix is preferably between 20 and 300 mg / mL, more preferably between 50 and 150 mg / mL, and especially is 75 mg / mL.

8. The medical implant according to any of the above claims, characterized in that the wall comprises a textile-reinforced matrix layer, wherein the textile has preferably one or more of the following characteristics: a. is made from polymer fibers, wherein the polymer is preferably selected from the group consisting of polyethylene terephthalate (PET), poly vinylidene fluoride (PVDF), silk, high-modulus polyethylene (HMPE), polylactic acid (PLA), thermoplastic polyurethane, (TPU), polycaprolactone (PCL), poly(lactic-co- glycolic) acid (PLGA), polyhydroxybutyrate (PHB) or a combination thereof; b. is made from yarns that have a linear density of 5 to 200 dtex, and more preferably of 10 to 100 dtex; c. is made from a yarn, which has preferably 1 to 3000 filaments per yarn, more preferably 1 to 100 filaments and even more preferably 1 to 50 filaments per yarn; d. the textile has a tubular shape, preferably with a diameter of between 1 mm to 10 cm, more preferably with a diameter of between 6 and 22 mm;e. the textile is produced by a technique which is selected from the group consisting of braiding, winding, non-wovens, melt electro writing, weaving, weft knitting and warp knitting, and preferably is made by warp-knitting; f. the textile is a warp-knitted textile having a 1 x 1 lapping, a 2 x 1 lapping or a tulle lapping, whereby the 1 x 1 lapping is preferred.

9. The medical implant according to any of the above claims, characterized in that the magnetically constricting element comprises or consists of magnetic particles incorporated within the wall, whereby the magnetic particles are preferably selected from the group consisting of magnetic nanoparticles, magnetic microparticles and agglomerations of magnetic nanoparticles, and more preferably are magnetic nanoparticles.

10. The medical implant according to claim 9, characterized in that the magnetic nanoparticles have one or more of the following characteristics: a. comprise a magnetic material selected from cobalt, nickel, manganese or iron, b. represents one of the following types: ferrite particle, coated ferrite particle, iron oxide particle, coated iron oxide particle metal particle, coated metal particle, alloy particle, coated alloy particle, whereby coated magnetite nanoparticles are preferred; c. have a size of the magnetic core of between 1 nm and 2 pm, preferably of between 10 nm and 100 nm, and more preferably of between 10 nm and 30 nm; d. further comprise a coupling agent, being preferably citric acid11. The medical implant according to claim 9 or 10, characterized in that the concentration of the magnetic particles within the wall is between 0.1 and 50 wt.%, preferably between 1 and 25 wt.%, and more preferably between 4 and 20 wt.%.

12. The medical implant according to any of the above claims, characterized in that the tubular member has one or more of the following characteristics: a. A length of between 0.5 and 20 cm, preferably of between 1 and 10 cm, and more preferably of between 2 and 5 cm; b. a wall-thickness of between 20 pm and 10 mm, preferably of between 50 pm and 2 mm and more preferably of between 100 pm and 1.5 mm; c. a diameter of between 1 mm to 10 cm, more preferably with a diameter for between 6 and 22 mm;d. is a tubular member with a closed wall or a longitudinally slotted tubular member.

13. The medical implant according to claim 12, characterized in that the longitudinally slotted tubular member is further provided with a closing member, preferably selected from the group consisting of suturing tabs, detents, hooks, Velcro glue, interlocking closure ridges, tissue glue, staples.

14. A system for constricting a hollow organ in a body of a subject, the system comprising: a. at least one medical implant according to any of claims 1 to 13; and b. at least one magnetic field generator configured to be placed inside or outside the body of a subject, and configured to generate a magnetic field that attracts or repulses the magnetic constriction element to elastically constrict the lumen of the medical implant and thereby also the hollow organ enclosed by the medical implant or the medical implant representing a segment of a hollow organ, whereby the magnetic field generator is preferably separated from the medical implant and is acting from the outside of the medical implant onto the magnetically constricting elements.

15. An intermittent compression device comprising: a. at least one medical implant according to any of claims 1 to 13 configured to surround or substitute a hollow organ, being preferably a vein or a lymphatic vessel; and b. at least one magnetic field generator configured to be placed inside or outside the body of a subject, and configured to generate an intermittent magnetic field to elastically constrict the lumen of the medical implant and thereby also the hollow organ enclosed by the medical implant or the medical implant representing a segment of a hollow organ, allowing the medical implant to return to a less- constricted or unconstricted state when the magnetic field is attenuated or eliminated, whereby the magnetic field generator is preferably separated from the medical implant and is acting from the outside of the medical implant onto the magnetic elements.

16. The system according to claim 14 or the intermittent compression device according to claim 15, characterized in that the system has one or more of the further characteristics: a. the magnetic field generator of the system is a portable or implantable device;b. the magnetic field generator is a permanent magnet or an electromagnet, preferably powered by a battery or rechargeable battery as part of said device; c. the magnetic field generator being an electromagnet is suited to generate a magnetic field strength of 1 to 200 kA / m and / or a frequency of 0.1 to 100 Hz; d. further comprises a control device that controls the magnetic field generator, which is preferably configured for wireless control, and more preferable is a handheld wireless remote-control device; e. further comprise a garment configured to be attached to the magnetic field generator, and by worn by the subject in a manner that places the magnetic field generator in a desired location near the body of the subject.

17. The medical implant of any of claims 1 to 13, the intermittent compression device of claim 15 or 16, or the system of claims 14 or 16 for use in the treatment of a disease that can be treated by controlled constriction of a hollow organ, being preferably one of the following diseases: a. Lymphatic and venous disorders of the limbs by constricting veins and lymphatic vessels in the limbs; b. Chronic venous disease by constricting a leg vein; c. Hypoplastic left heart syndrome by use as a Fontan conduit, being preferably applied in pediatric patients; d. Urinary incontinence by constricting the urethral sphincter; e. Fecal incontinence by constricting the anal sphincter; f. Gastroesophageal reflux syndrome by constricting the lower esophageal sphincter; g. Sphincter of Oddi dysfunction by constricting the sphincter of Oddi; h. Gastrointestinal disorders characterized by decreased motility such as gastroparesis, functional dyspepsia (FD), gastrointestinal motility disorder, achalasia, intestinal dysmotility, intestinal pseudo-obstruction and Hirschsprung’s disease, by providing phasic contractions that propel food through the digestive system; i. Obesity by constricting the stomach.

18. A method for producing a medical implant according to any of claims 1 to 13, comprising the following steps:(a) Providing a first solution containing an elastin-like recombinamer functionalized with alkyne groups and a second solution containing an elastin-like recombinamer functionalized with azide groups;(b) Providing magnetic particles;(c) Dispersing the magnetic particles of step (b) in the first and / or second solution according step (a) to generate two dispersions;(d) Optionally providing a textile fabric configured for reinforcing the wall of the medical implant, and having preferably a tubular shape;(e) Providing a mold consisting of an outer tube and an inner cylinder placed coaxially to the outer tube, whereby in one option the textile fabric of step (d) is positioned in the annular space between the cylinder and the tube;(f) Injection of the mixed dispersions of step (c) into the mold of step (e), while allowing the crosslinking of the two elastin-like recombinamers;(g) Optionally moving the mold containing the dispersion in order to prevent sedimentation of the magnetic particles;(h) Removing the tubular medical implant containing magnetic particles as constriction member from the mold, whereby the medical implant is preferably a textile-reinforced implant.

19. The method according to claim 18, characterized in that for the generation of a medical implant with a porous wall structure the method is modified as follows: i. Addition of porogen particles to the two solutions of step (a) in order to generate two dispersions, each dispersion further containing porogen particles; ii. After removing the textile-reinforced implant from the mold in step (h), the medical implant is washed in an acidic solution to remove the porogen particles, and washed thereafter with water or an aqueous solution, to generate a medical implant with a tubular member having a porous wall structure.

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