HK40084040A - Elastin formation using fibrous implants - Google Patents

Description

Formation of elastin using fibrous implants

Technical Field

The present disclosure relates to the field of regenerative medicine, and more particularly, to in situ tissue engineering using fibrous implants for the purpose of reconstituting elastin.

Background

Elastin

Elastin is a key extracellular matrix (ECM) component that provides elasticity and resiliency. Elastin is present in many dynamic tissues and organs, such as the lung, skin and ligaments, and also in cardiovascular tissues, such as blood vessels and heart valves. In addition to providing mechanical functions, elastin has a bioprotective function, modulating cellular responses through biomechanical transduction to maintain homeostasis.

Elastin is a protein composed of cross-linked monomers called tropoelastin (tropoelastin), which is produced by synthetic cells such as fibroblasts, endothelial Cells (ECs), chondrocytes and Smooth Muscle Cells (SMCs). Elastin is produced mainly during late fetal, neonatal and early postpartum growth, and is almost completely arrested after puberty. The formation of elastin is also known as elastogenesis (elastogenesis).

In healthy tissue, elastin degrades slowly, having a half-life of approximately 70 years. However, genetic and acquired cardiovascular diseases, such as atherosclerosis, aneurysm formation, vascular sclerosis and calcification, are all associated with a progressive loss of elastin or elasticity, which damages vital organs, leading to hypertension, stroke, ischemia, internal bleeding or valve failure.

The development of cardiovascular implants that can bind elastin or stimulate its biosynthesis has become an attractive approach to ensure the integrity and functionality of these alternatives.

Smooth muscle cells

SMCs are specialized contractile cells, present in organs such as blood vessels, gastrointestinal tract and respiratory system. Under physiological conditions, SMCs have a quiescent contractile phenotype that controls vasoconstriction and dilation. However, under pathological conditions, they switch to a non-contracting and synthetic phenotype, resulting in increased cell proliferation and ECM production.

In natural blood vessels, SMCs are embedded between elastic sheets or fibers. The protective effect of this structure is important in regulating SMCs responses, controlling their phenotypic transitions, proliferation and migration. The production of ECM components is dependent on signaling through elastin. Thus, damage to the elastic fibers can cause migration and proliferation of SMC to the innermost layers of the vessel, resulting in vessel stenosis. To prevent SMC responses, immunosuppressive agents may be used to act on the metabolism, growth and proliferation of cells in order to inhibit intimal hyperplasia. However, the temporary action of the drug may lead to late occlusion.

No technology exists to adequately overcome elastin damage. Since the body no longer naturally synthesizes elastin after the age of the young, the development of cardiovascular implants that bind elastin or trigger SMCs to stimulate its biosynthesis, is an attractive approach to prevent intimal hyperplasia and achieve good long-term results. Herein, restoration of elastin may induce a phenotypic transition in which SMCs transition from a proliferative and non-contractile state in the absence of elastin to a resting and contractile state in the presence of elastin (fig. 1).

Outer cover implant

For the treatment of cardiovascular diseases, current surgical procedures require the use of grafts to bypass the blocked blood vessels. Due to its natural nature, a preferred graft is a blood vessel taken from another part of the patient's body or other donor. The long-term patency rate of such autologous implants is also related to elastin content. Grafts made from the Left Internal Mammary Artery (LIMA) that are rich in elastin are known to have superior clinical outcomes compared to the Superficial Femoral Artery (SFA) that is low in elastin. When such a biological graft is not available, a synthetic graft made of, for example, polytetrafluoroethylene and dacron may be used. However, the long-term function of synthetic implants is not as straightforward, as reocclusion remains an important failure mode, particularly for small diameter applications.

Endovascular implant

In another aspect, minimally invasive techniques for treating obstructive vascular disease involve the use of balloons and stents. These techniques are effective methods for immediately unblocking and restoring blood flow without surgery. However, their use may lead to vascular tissue damage and SMC activation which triggers in-stent restenosis. Therefore, drugs are included in the stent and balloon to inhibit SMC activation. However, the attenuating effects of the drug do not address the potential damage to the elastic fibers and can still lead to late in-stent restenosis.

In vitro tissue engineering

Tissue engineered blood vessels are an attractive alternative to designing reactive live catheters with properties similar to those of natural tissues. This allows for providing viability, usability and compatibility in the absence of native vessels in the patient or donor. This concept, in addition to directing new tissue formation, also includes the use of three-dimensional biological or synthetic scaffolds to support cell adhesion, migration, differentiation and proliferation.

Activation of synthetic cells is key to reconstituting important ECM components. It is known that SMC cultured in conventional tissue culture dishes secrete elastin. Static stretching of the SMC stimulates the formation and crosslinking of elastin. In addition, exposure of SMCs to a certain level of shear stress can determine whether elastin is formed. Thus, elastin production in three-dimensional tubular structures in vitro can continue, provided the scaffold ensures the chemicals and stimulation required for elastin secretion by the seed SMC. This approach may provide the possibility of ensuring the presence of critical tissue components in the cultured blood vessel, which may later be implanted into the patient as a bypass or an intervention.

In situ tissue engineering

Tissue engineering vessels in situ aim to exploit the regenerative potential of the human body in order to recruit endogenous cells to the scaffold in vivo. This exposes the scaffold to a cascade of inflammatory events in which immune cells such as monocytes and macrophages are able to direct cellular responses and new tissue formation. Polarization of macrophages to either the pro-inflammatory M1 type (which wraps the implant and causes chronic inflammation) or the healing M2 type (which reabsorbs the implant and causes SMC activation, leading to synthesis or degradation of ECM components) again depends on the structure of the scaffold. Thus, the formation of elastin in three-dimensional tubular structures in vivo can continue, provided that: 1) The synthetic cells of the patient, such as SMC, can reach the scaffold, 2) the scaffold can ensure that the synthetic cells secrete sufficient chemicals and stimuli required for elastin. This approach may offer the possibility of gradually replacing the surgically implanted scaffold with new blood vessels created by the patient's own cells.

To date, minimally invasive techniques have been aimed at alleviating obstructions without removing the native artery, while surgical techniques have been aimed at replacing or bypassing arterial segments. Combinations of these available and developing concepts, such as scaffolds and stent-mounted grafts, may offer new possibilities and allow for minimally invasive implantation of artificial blood vessels. However, a variety of factors affecting these techniques may lead to poor therapeutic results. The use of conventional stents can temporarily or permanently affect the elastic properties of the artery, which can have an adverse effect on the functionality and long-term patency of the implanted segment. Reduction of proliferative responses with drugs after stent placement may inhibit the ability of the scaffold to remodel in situ.

The present invention advances the art by disclosing a fibrous implant for cardiovascular applications, wherein host cells interact with the fibrous implant using in situ tissue engineering methods to initiate elastin synthesis.

Disclosure of Invention

The present invention provides a fibrous implant for cardiovascular applications that is capable of reconstituting valuable ECM components, such as elastin. The fibrous implant is composed of fibers having diameters in the micrometer and nanometer range. These fibers form a stacked fiber network that allows host cells to adhere and synthesize elastin.

In one variation, the pore size of the fiber network can be controlled to achieve or prevent host cell infiltration and/or to manipulate cell signaling. In another variation, the fibrous implant is made of a bioabsorbable polymer. In another variation, the fibrous implant may at least partially include a drug. In another variant, the fibrous implant is pre-tensioned and/or retains residual stress. In another variation, the morphology of the network includes a random or aligned fiber organization, or a combination thereof. In another variation, the stiffness of the fibrous implant (stiff) has been optimized to achieve elastin formation. In another variation, the fibrous implant is exposed to a dynamic mechanical stimulus.

Further disclosed are different positioning of the implant relative to the host tissue, wherein, in one embodiment, at least a portion of the fibrous implant is in direct contact with the host tissue, and wherein the host tissue may be damaged. In another embodiment, the fibrous implant is applied to a recipient whose immune response is in equilibrium. In another example, the embodiment is in direct contact with blood flow exposed to shear stress. In addition, one embodiment describes that the fibrous implant is capable of controlling osmotic pressure and gradient.

Methods of application are also disclosed, wherein certain embodiments can be used to partially replace or repair an existing structure, while other embodiments can be used to create a new structure or to completely replace an existing structure. In some embodiments, the fibrous implant is a tubular catheter that can be used as a stent, scaffold, graft, or shunt and can be placed within a lumen, or it can be used as an insert in which endoluminal elastin can be formed. In another embodiment, the fibrous tubular implant may contain a valve or mesh to provide additional functionality or to serve as an embolization or occlusion device. In another embodiment, the fibrous implant is a patch of restitution elastin inside or on top of the body site.

In addition, clinical applications of these fibrous implants are disclosed. Some embodiments describe use for intravascular applications, such as balloon angioplasty, atherectomy, subintimal bypass, aneurysm repair, or as an occlusion device. Another embodiment describes use for surgical applications. One embodiment discloses the use of a fibrous implant to repair luminal elastin so as to inhibit disease progression (such as neointimal hyperplasia and/or atherosclerosis). Another embodiment utilizes the reconstruction of the media layer with elastin to control the hemodynamic load, prevent aneurysm vessel rupture and restore vessel compliance. In another embodiment, elastin may be repaired at ventricular or atrial septum defects to reduce compliance with atrial septum deformation, restore the heart wall, repair valve leaflets or provide external reinforcement of an aneurysm.

Even further, a production method is described, disclosing the possibility of producing elastin forming implants and combining them with additional support of the delivery device. Other embodiments relate to methods of producing elastin directly on and/or within a target body site to form a fibrous network. Also provided herein are methods of detecting and evaluating elastin forming ability of a fibrous implant.

Drawings

FIG. 1: and (4) graphically representing. How elastin interacts with SMCs transforms the cellular phenotype from a proliferative and non-contractile state in the absence of elastin to a resting and contractile state in the presence of elastin.

FIG. 2: examples of fibrous implant networks capable of inducing elastin formation.

FIG. 3: an example of a fibrous implant placed in the lumen of a rabbit's peripheral artery, shows the formation of endoluminal elastin 3 months after implantation.

FIG. 4 is a schematic view of: two fibrous implants placed within the lumen of a rabbit's peripheral artery. The upper bilayer implant did not show major elastin formation after 3 months, but the lower monolayer implant did.

FIG. 5 is a schematic view of: data for endoluminal fibrous implants. Luminal smooth muscle cell migration coexists with luminal elastin formation.

Detailed Description

Unless defined otherwise herein, scientific and technical terms related to the present invention shall have the meanings that are commonly understood by one of ordinary skill in the art. Furthermore, unless the context requires otherwise, singular terms shall include the plural and plural terms shall include the singular. The disclosed methods and techniques are generally performed according to conventional methods well known in the art, and as described in various general and more specific references discussed in the present specification, unless otherwise indicated.

As used herein, the term "elastin" refers to the ECM component elastin. It refers to both its precursor form (as tropoelastin) and its mature form (as a protein formed by cross-linking tropoelastin). It also includes elastic fibers, and their reticulated arrangement to form a window (venetian sheets) or film (lamella).

As used herein, the terms "regeneration", "restoration", "repair", "reconstruction", "renewal", "repair" refer to the ability to form new biological components. In the context of elastin, it refers to the ability to produce neoelastin.

As used herein, the term "synthetic cell" refers to a biological cell that has the ability to synthesize a protein, ECM component, or tissue. For example, these synthetic cells may be fibroblasts, SMCs, ECs, mesenchymal stem cells and immune cells such as, but not limited to, monocytes and macrophages.

As used herein, the terms "bioabsorbable," "biodegradable," and "biodegradation" refer to the ability of a material to be broken down in the body and cleared from the body.

As used herein, the term "tubular" is or belongs to an approximate cylindrical shape.

The "intima layer" (alternatively, the intima (tunica intima) or intima (intima)) refers to the innermost layer of an unaltered healthy blood vessel. It consists of a layer of ECs in direct contact with the blood stream and is supported by an internal elastic membrane.

"middle layer" (or, tunica media) refers to the middle layer of a blood vessel. It consists of SMCs and elastic tissue, and it is located between the inner intima on the inside and the outer adventitia on the outside.

The terms "recipient", "patient", "host", "subject" are used interchangeably herein and include, but are not limited to, an organism; mammals, including, for example, humans, non-human primates, mice, pigs, cows, goats, cats, rabbits, rats, guinea pigs, mini-pigs, hamsters, horses, monkeys, sheep, or other non-human mammals; and non-mammals, including, for example, non-mammalian vertebrates, such as birds (e.g., chickens or ducks), amphibians, and fish, as well as non-mammalian invertebrates.

The present invention describes a bioabsorbable fibrous implant for cardiovascular applications with the ability to reconstitute elastin. The implant is composed of micro-and/or nano-fibers forming a three-dimensional fiber network. The fibers may be spaced apart, forming a plurality of interconnected pores throughout the perimeter and thickness of the network, providing the host cell with the ability to adhere to the fibers and migrate over and/or into the network. Such a host cell may be an immune cell responsive to the implant. Due to the micro-and/or nano-sized fibers in the network, immune cells can be primed to initiate a favorable healing-promoting immune response. Capable of initiating the synthesis of synthetic cells attached to the fibrous implant in order to synthesize new biological components into and/or onto the implant, including elastin. In order to trigger the formation of elastin by the host cells, it is necessary to control the properties of the fibrous implant. The following mentions defining parameters that influence the characteristics of the elastic cause.

Manufacturing method

A variety of attributes are capable of initiating elastin in situ tissue engineering with fibrous implants, as further disclosed below, which may act alone or in combination to facilitate induction of elastin formation.

Fiber

Fiber size can affect immune cells and tissue producing cells. Immune cells associated with smaller fibers initiate a pro-healing (type M2) response, while larger size fibers lead to more pro-inflammatory (type M1) responses. The initiation of the pro-healing or pro-inflammatory response can indirectly affect the behavior of the synthetic cells in order to induce a regenerative response in which elastin can be restored or a chronic inflammatory response in which the implant is fibroencapsulated.

Regardless of the immune response initiated, the size of the fiber also affects the behavior of synthetic cells in direct contact, which can be translated into a regenerative or fibrotic response depending on the fiber size.

One embodiment has fibers with fiber diameters ranging between 1 nanometer (nm) to 500 micrometers (μm) and any value in between, depending on the production setup and materials used. To achieve a healing-promoting response that promotes elastin formation, the fiber diameter may be 500 μm or less, 250 μm or less, 150 μm or less, 100 μm or less, 50 μm or less, 25 μm or less, 15 μm or less, 10 μm or less, 9 μm or less, 8 μm or less, 7 μm or less, 6 μm or less, 5 μm or less, 4 μm or less, 3 μm or less, 2 μm or less, 1 μm or less, 500nm or less, 250nm or less, 150nm or less, 100nm or less, 50nm or less, 25nm or less, 15nm or less, 10nm or less, 9nm or less, 8nm or less, 7nm or less, 6nm or less, 5nm or less, 4nm or less, 3nm or less, 2nm or less, or 1nm or less.

In another embodiment, preferably, the fiber diameter ranges, for example, from 1nm to 500 μm, from 1nm to 250 μm, from 1nm to 150 μm, from 1nm to 100 μm, from 1nm to 50 μm, from 1nm to 25 μm, from 1nm to 15 μm, from 2nm to 15 μm, from 3nm to 15 μm, from 4nm to 15 μm, from 5nm to 15 μm, from 6nm to 15 μm, from 7nm to 15 μm, from 8nm to 15 μm, from 9nm to 15 μm, from 10nm to 15 μm, from 15nm to 15 μm, from 25nm to 15 μm, from 50nm to 15 μm, from 100nm to 15 μm, from 150nm to 15 μm, from 250nm to 15 μm, from 500nm to 10 μm, from 500nm to 9 μm, from 500nm to 8 μm, from 500nm to 7 μm, from 500nm to 6 μm, from 500nm to 5 μm, from 500nm to 4 μm, from 500nm to 3 μm, from 1nm to 3 μm.

Hole(s)

By adjusting the fiber distance and fiber diameter, the pore size can be controlled. Depending on the production setup and the materials used, the pores may be in the micro-, macro-, micro-, or nano-range or a combination thereof. Pore size affects cell infiltration as well as cell signaling, both of which affect elastin formation. In this way, the three-dimensional fibrous tubular network can be filled with cells or tissue components capable of producing biological tissue.

Cell infiltration

In one embodiment, the host cells adhere to the fibers and reside on the surface. In another embodiment, the pore size is large enough to allow infiltration of host cells into the network. By controlling the pore size, cell migration through the implant can be promoted or inhibited. In this way, the cells are able to produce tissue elements on top of and/or inside the fibrous implant. Thus, the production of tissue elements, such as elastin, can be controlled at a particular site or location of the fibrous implant.

To achieve cell infiltration that promotes elastin formation, the pore size of one embodiment is, for example, 1nm or greater, 10nm or greater, 100nm or greater, 150nm or greater, 250nm or greater, 500nm or greater, 750nm or greater, 1 μm or greater, 2 μm or greater, 3 μm or greater, 4 μm or greater, 5 μm or greater, 6 μm or greater, 7 μm or greater, 8 μm or greater, 9 μm or greater, 10 μm or greater, 15 μm or greater, 25 μm or greater, 50 μm or greater, 100 μm or greater, 150 μm or greater, 250 μm or greater, 500 μm or greater, 1000 μm or greater, 1500 μm or greater, 2500 μm or greater, 5000 μm or greater, or 10000 μm or greater.

Cell signaling

Pore size affects the cellular signals that trigger elastin production by synthetic cells. For example, priming may be related to the curvature of such a pore, or, because the pore is sufficiently small to allow a cell to span multiple fibers rather than adhere to a single fiber. In the case of immune cells, a similar mechanism may initiate a healing-promoting M2 immune response.

To achieve a cellular signal that promotes elastin formation, the pore size of another embodiment is, for example, 10000 μm or less, 5000 μm or less, 2500 μm or less, 1500 μm or less, 1000 μm or less, 500 μm or less, 250 μm or less, 150 μm or less, 100 μm or less, 50 μm or less, 25 μm or less, 15 μm or less, 10 μm or less, 9 μm or less, 8 μm or less, 7 μm or less, 6 μm or less, 5 μm or less, 4 μm or less, 3 μm or less, 2 μm or less, 1 μm or less, 750nm or less, 500nm or less, 250nm or less, 150nm or less, 100nm or less, 10nm or less, or 1nm or less.

Shear stress

In one example, the embodiment is exposure to shear stress. Shear stress has a mechanical regulatory effect on cells that can trigger elastin formation. Synthetic cells in the vicinity of the blood stream react differently than cells located within the network. Synthetic cells exposed to the shear stress of the blood stream will synthesize elastin, encapsulating themselves in deposited extracellular elastin. Over time, extracellular elastin will mature further and combine with elastin formed by nearby cells, creating an elastin layer on and/or in the fibrous implant.

The implant thickness enables control of the level of shear stress. In an exemplary embodiment, increasing the thickness of the tubular fiber structure results in a decrease in the intraluminal diameter and an increase in blood flow velocity, resulting in increased shear stress. Vice versa, reducing the thickness of the implant results in lower shear stress.

Cells within the fiber network are primarily shielded by the blood flow and are therefore exposed to less shear stress, while cells on the outer surface are exposed to shear stress. In another exemplary embodiment, shear stress may be further increased within the network by reducing the density of the fibrous implant, by adjusting the pore size and/or fiber diameter.

In one embodiment, the fibrous implant may have a uniform fine mesh network facing the blood flow, which can prevent blood flow disturbance and instead bring about a uniform blood flow distribution that causes lower shear stress and promotes elastin formation. In this way, cells exposed to shear stress along the length of the implant can form a uniform elastin layer. By perfecting the network, the transition from turbulent to uniform flow distribution can be controlled.

Material

The choice of material from which the fibrous implant is made affects elastin formation. If immune cells are able to clear foreign implants, degraded objects may initiate an M2 pro-healing response, leading to elastin formation, while responses to non-eradicating permanent implants may lead to pro-inflammatory M1 responses.

Material composition

To facilitate elastin formation, one embodiment consists of fibers made of materials including, but not limited to:

bioabsorbable polymers (such as polylactic acid (PLA), including poly (L-lactide), poly (D, L-lactide), and polyglycolic acid (PGA), polycaprolactone, polydioxanone, polytrimethylene carbonate, poly (4-hydroxybutyric acid), poly (ester amide) (PEA), polyurethane, polytrimethylene carbonate, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, polyhydroxyalkanoates, polyfumarates, and copolymers thereof),

non-bioabsorbable polymers such as polypropylene, polyethylene terephthalate, polytetrafluoroethylene (PTFE), polyaryletherketones, nylon, fluorinated ethylene propylene, polybutyl esters or copolymers thereof,

biological components (such as hyaluronic acid, collagen, tropoelastin, elastin, fibrin, gelatin, chitosan, alginate, aloe/pectin, cellulose or other biological material derived from tissue of autologous, allergenic or xenogenic origin),

or a combination thereof.

The polymer may be the D-isomer, the L-isomer or a mixture of both. Multiple polymers and copolymers may be mixed and blended in different proportions. The polymer fibers may be crosslinked. Some embodiments may include supramolecular chemistry, including supramolecular polymers, linking mechanisms, or moieties. Some embodiments may include a shape memory polymer.

Rate of degradation

Even if the material is biodegradable, the rate of degradation can affect elastin formation. Slowly degrading materials can elicit an immune response similar to a permanent implant. The rapidly degrading material may degrade even before elastin is formed. When undergoing degradation, the material primarily reduces its average molecular weight first, followed by a loss of mechanical properties, and then a loss of polymer mass. Thus, one embodiment has an optimized degradation rate to promote elastin formation. Another embodiment uses materials with faster or slower biodegradation characteristics or a combination thereof. Furthermore, in one variation, this embodiment is composed in part of biodegradable materials (to achieve elastin formation) and non-degradable materials.

To promote elastin formation, the implant should remain in the body for a sufficient time. Thus, in an exemplary embodiment, the fibrous implant loses 50% of its initial average molecular weight after, for example, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, or 4 months, 5 months, 6 months. In an exemplary variant, this embodiment loses 50% of the initial mechanical properties after 1 month, after 2 months, after 3 months, after 6 months, after 9 months, after 12 months, after 18 months. In another exemplary variation, this embodiment experiences a 50% loss in initial polymer quality after 3 months or after 6 months or after 9 months or after 12 months or after 18 months or after 24 months or after 30 months or after 36 months or after more than 36 months.

Furthermore, the mechanical properties of the implant may be affected during degradation. Rigid implants may soften due to mechanical problems. This may result in a mechanical transduction effect on the cell, resulting in the production of elastin.

Implant site

Placement of the fibrous implant in the body causes local tissue damage, thereby activating resident synthetic cells. Thus, in an exemplary embodiment, synthetic cells migrate into or onto the fibrous implant from the following options: 1) an anastomosis, 2) adjacent tissue, 3) blood flow, or 4) a combination of options 1, 2, and/or 3. In another embodiment, different cell types associated with the protocol, such as endothelial cells or monocytes and macrophages, are transformed into synthetic cells.

Tissue damage

The level of tissue damage that promotes elastin formation can be controlled and induced before, during or after the implantation step. Induction of the lesion may be the result of an intervention or may be a deliberate increase in induction in addition to an intervention. Fibrous implants may benefit from this infiltration of activated synthetic cells, as they may be a source of tissue production and elastin formation. In one embodiment, the fibrous implant is implanted in the vicinity of the tissue lesion.

For example, tissue loss may be induced by endovascular procedures such as, but not limited to, balloon angioplasty, stenting, atherectomy, laser ablation, intravascular ultrasound, subintimal access, or other surgical interventions such as anastomosis, shunt, bypass, or MIDCAB procedures.

Medicine

In one embodiment, a drug is used to control elastin formation. In this way, the synthetic cells are affected by affecting, for example, their metabolism, growth, proliferation, migration.

In another embodiment, the drug is contained in a concentration gradient throughout the network or on a specific surface. In another embodiment, the drug is contained within and/or coats the fiber. In another embodiment, the drug is contained by filling the mesh with a drug-containing filler (e.g., a drug-loaded hydrogel).

The drugs may have different functions and are useful as immunosuppressive, antiproliferative, migration inhibitory, anti-inflammatory, antithrombotic and/or healing promoting agents. Depending on the desired effect, drugs or combinations of drugs may be included to prevent cell migration, cell proliferation, cell differentiation, limit the inflammatory response when the vessel wall is damaged, or stimulate vessel healing. The drug may act on virtually any cell type or tissue type, for example, synthetic cell types such as SMCs and fibroblasts, as well as endothelial cells or immune cells.

Examples of immunosuppressive agents may be sirolimus, tacrolimus, everolimus, zotarolimus, M-prednisolone, dexamethasone, cyclosporine, mycophenolic acid, mizoribine, interferon-1 b, tranilast, leflunomide, myolimus, known Wo Mosi, pimecrolimus and pimecrolimus A9.

Examples of antiproliferative drugs may be taxol, actinomycin, methotrexate, angiopeptin, vincristine, mitomycin, statins, c-myc antisense nucleic acids, abbott ABT-578, restenASE, 2-chloro-deoxyadenosine, BCP678, taxol derivatives (QP-2), PCNA ribozymes.

Examples of migration inhibitors may be batimastat, prolyl hydroxylase inhibitors, halofuginone, C-protease inhibitors, probucol and metalloproteinase inhibitors.

Examples of drugs that promote healing may be BCP671, VEGF, 17-beta-estradiol, NO donor compounds, EPC antibodies, TK enzyme inhibitors, HMG CoA reductase inhibitors, biorest, MCP-1, SDF-1-alpha, IL-4, IL-8, MIP-1 beta, TGF-beta, bFGF, PDGF, MMPs, TIMPs, IL-12, IL-6, IL-1 beta, TNF-alpha, IL-13, IL-4, IL-10, PGE ₂ And IFN-gamma.

Examples of antithrombin are heparin, hirudin and iloprost, abciximab.

The drug may also be a motif (moieties), protein, enzyme, peptide, molecule or atom.

Immune response

Immune cells that are responsive to fibrous implants can elicit a healing-promoting response that favors elastin formation. However, patients receiving implants may develop comorbid diseases such as diabetes, atherosclerosis, or other local or systemic diseases. This disease environment may have an impact on the immune system, which may lead to a skewed pro-inflammatory response.

To produce a localized pro-inflammatory response, one embodiment may be to include a healing-promoting immunomodulatory drug.

Dependence on age

Age plays a role in elastin formation. Contact of the fibrous implant with young or old people may affect elastin formation. Younger children have a less developed adaptive immune response that matures over time. This may explain why the formation of native elastin stops at the end of puberty, as this may be related to the maturity of the adaptive immune response.

Furthermore, it should not be overlooked that aging itself is affecting the condition of the vascular system. In addition, patients may have potential co-morbidities such as diabetes or atherosclerosis, which may interfere with elastin formation.

In one embodiment, elastin is formed in selective recipients grouped by age and/or co-morbid condition.

Mechanical factors

Prestress and residual stress

Pretension and residual stress have a direct or indirect impact on the biomechanical behavior of many biological tissues. Pretension can be described as a geometric change while maintaining volume. When the boundary conditions are released in vivo, the pre-stretching causes the tissue to contract. On the other hand, residual stress can be defined as the stress still present in the tissue after its original cause is removed. When released at the boundary conditions, the residual stress causes the arterial loop to spring open into the quadrant after the radial cut. It is known that stretching can stimulate the synthesis of matrix components by SMC in vitro. It is also known that residual stress is critical to maintain arterial homeostasis, and is closely related to elastin expression. Thus, one embodiment is pre-stretching in vivo to induce residual stress and promote elastin formation.

The fibers may have different spatial arrangements in the network. The network may be comprised of straight fibers, wavy fibers, fibers forming loops, or combinations thereof, wherein the straight fibers may be parallel to each other or form an angle with respect to the other fibers. These fiber arrangements can be altered by mechanical stimuli acting on the implant (e.g. internal pressure in the tubular structure) or by exposure to (cyclic) tension in a dynamic position. The initial alignment of the network prior to mechanical loading determines the final level of pre-tension in the implant. A web based on straight fibres will experience a higher level of pretension than a wavy or even a circular web, which first has to be opened circularly before entering the stretching stage. In this way, the level of pre-tension in the fibrous implant network can be controlled by adjusting the spatial arrangement of the individual fibers forming the network, affecting the waviness of the individual fibers or the angle between the straight fibers. Thus, prior to the mechanical loading condition, one embodiment is comprised of at least partially straight fibers, while another embodiment is comprised of at least partially undulating fibers, while another embodiment is comprised of at least partially looped fibers, or another embodiment is comprised of a combination of at least partially straight, undulating, or looped fibers.

Stiffness of substrate

The rigidity of the substrate to which tissue producing cells adhere is known to modulate proliferation, migration and differentiation of cell types, as well as the composition and amount of ECM produced. In addition, immune cells such as macrophages and monocytes will respond to the rigidity of the matrix, whereby careful selection of the implant material may direct the initial immune response.

In one embodiment, the substrate stiffness has been optimized for elastin formation. The stiffness of the substrate can be controlled by the choice of material from which the fibers are made. Fiber thickness can be increased to affect local fiber stiffness. Other possibilities may be to cross-link the network to enhance the overall stiffness of the network. Other methods are to increase the network density or make the structures thicker, whereby they react less to mechanical problems.

The stiffness of the substrate can also be affected by degradation of the implant. If the fibrous implant is made of a biodegradable material, the bioadsorption will result in a loss of mechanical properties over time, which will change the stiffness of the substrate.

Dynamic stimulation

Certain biological locations are susceptible to dynamic loading conditions. For example, an implant in the bloodstream may be subjected to pulsatile flow, whereby the interaction of an artery with an endovascular implant creates a dynamic loading condition. Switching from a constant loading state to a dynamic loading state under stress and/or strain conditions can affect the response of tissue-producing cells and immune cells, thereby affecting elastin formation. Thus, one embodiment is exposure to a dynamic mechanical stimulus to induce elastin formation.

Network morphology

The fiber network organization can be controlled, where more randomly organized networks are created or more controlled (aligned) networks are formed. The morphology of this network may have a downstream impact on elastin formation, where elastin formation may or may not be triggered in a random or controlled configuration or a mixture thereof.

Even so, the fibers of the network may result in contact guidance of cells, wherein the cells are arranged with the organization of the fiber network. If a more controlled network with surrounding tissue is present, the formation of surrounding elastin can be achieved as such. Thus, one embodiment may be comprised of random and/or controlled fibers.

Osmotic pressure

The density of the fiber network may affect the exchange of molecules, proteins and cytokines, whereby osmotic gradients may occur. A dense structure can be obtained, especially when the cells start to fill the pores with tissue. This can lead to differences in osmotic gradients over and/or within the fibrous implant, leading to cell migration. In this manner, one embodiment includes at least one layer in which the density of the network (with or without tissue generation) can promote cellular interactions to control elastin formation.

Application method

In one embodiment, the implant is used to repair or replace a cardiovascular tissue, organ, or portion thereof. By using fibrous implants for cardiovascular applications, these devices can be used to restore damaged or diseased biological tissue in need of elastin repair. Accordingly, disease progression may be slowed, halted, or even reversed, and damaged tissue may be repaired to prevent associated complications. In the field of cardiovascular applications, the use of elastin for restoration of blood vessels and valves is of particular interest. For cardiovascular applications, they are, for example, arteries, veins, capillaries, arterioles, or lymphatic vessels, or heart valves such as the lungs, aorta, tricuspid and mitral valves, and venous and lymphatic valves.

Implant surgery

In one embodiment, the fibrous implant can be used to repair or replace an existing structure or create a new structure. In one embodiment, the existing structure is first removed and then the fibrous implant is placed. In another embodiment, the existing structure is first at least partially removed and then the fibrous implant is placed. In another embodiment, the existing structure is left unchanged, and the fibrous implant is placed outside/inside/on the existing structure.

In another embodiment, the fibrous implant may be used to block and/or seal a hole, duct, or cavity.

In another embodiment, the fibrous implant may be used as a carrier comprising mesh, filter, coil, drug, valve, stenosis or membrane.

One embodiment may be performed using conventional medical intervention, which may be invasive or minimally invasive, such as by open surgery, MIDCAB, or intravascular intervention. Such embodiments may be placed between body parts to act as an intermediary, connect two body parts as a bypass or shunt, be placed inside the body as an endoluminal prosthesis, or be attached to or inserted into a body part.

Implant characteristics

The fibrous implant may be a mesh or tube having different geometries, for example, one embodiment is planar, curved, concave, convex, twisted, rounded, spherical, or any combination thereof. This embodiment may include valves, meshes, filters, coils, local stenoses or other additional components, which may also be made of fibers, whereby these additional components may also induce elastin formation.

In some embodiments, the fibrous implant may have other properties, such as the following properties or combinations thereof: structural support ability, mechanical support ability, expandability, self-expandability, curling ability, adhesion ability, shape memory, swelling ability, contractile ability, stiffening ability, or reacting to a change in, for example, temperature or acidity, or to an external stimulus such as ultrasound, a magnetic field, and/or radiation, for example, light, heat, or sound.

In some embodiments, the fibrous implant can be used in conjunction with other implantable devices. Other implantable devices will retain their function, while the addition of fibrous implants will effect elastin formation. Here, the fibrous implant may be contained, fixed, adhered, coated, wrapped or mounted in any other way on an additional implantable device. Additional implantable devices can, for example, provide deliverability, provide mechanical support, relieve flexibility, prevent kinking, enable securement to a body part, block and/or close a body part such as a blood vessel, conduit, orifice, side branch, appendix, fistula, and lumen. Such additional implantable devices are, for example, stents, (bypass) grafts, valves, (balloon) catheters, closure devices, occlusion devices, embolization devices, wires, coils, patches, covers, tubes, meshes, inner or outer prosthesis sheets.

Implant device

The fibrous implant that enables elastin formation can be made into different medical devices. In this case, the formation of elastin can inhibit or prevent disease progression and/or improve the mechanical properties of the tissue or implant. Such an implant may be a single mesh, e.g. for use as a patch, or have a tubular shape, e.g. for use as a stent, scaffold, (bypass) graft or shunt, and may also be a prosthesis, such as a heart valve, or as an occlusive device.

Example 1: patch

In one embodiment, the fibrous implant is a mesh used as a patch. In another embodiment, the patch may be made in any particular shape that is predetermined during the manufacturing process, or in another embodiment, the patch may be customized by the clinician according to a record (sheet). When placed on an organ, it is desirable that elastin is formed on the side facing inwards. The patch may be applied by suture or staple, using an adhesive composition, or the patch may even be self-adhesive.

Example 2: support (STENT) and Support (SCAFFOLD)

In another embodiment, the fibrous implant may be tubular and deployed inside the vascular system. These structural support devices are known as stents or scaffolds. When such devices are comprised of a fiber network, these scaffolds may be considered stent grafts or stent grafts. Here, it is desirable that elastin is formed inside the cavity of the implant. The structural support means may be made entirely of fibres or mounted on/in additional support means.

Example 3: (bypass) graft and shunt

In another embodiment, the fibrous implant may be tubular in shape, wherein each end may be attached to a blood vessel to act as a bypass graft or fistula, placed between existing blood vessels to act as an intermediate graft, or used to connect different blood vessels or body parts to act as a shunt. Here, it is desirable that elastin is formed inside the cavity of the implant. These implants are mainly placed by surgery.

Example 4: valve with a valve body

In another embodiment, a tubular fibrous implant comprises a valve having a single, two, three, or more leaflets. The valve may also be composed entirely of a fibrous mesh, or such a fibrous mesh may be used to at least partially cover a portion of the valve. Here, it is desirable to form elastin on the inflow side of the valve.

Example 5: embolization and occlusion devices

In another embodiment, the tubular fibrous implant comprises a membrane, an embolizing member or an expanding member, which may be used to occlude or embolize a body site. They can be implanted in a blood vessel whereby the fibrous implant blocks blood flow. In addition, they may be placed in the ostium to prevent the passage of blood, and are used, for example, to close atrial septal defects or close the appendix. The occluding device may be made entirely of fibers or mounted on/in additional support devices.

Clinical application

Fibrous implants can be used in different applications where elastin formation is of clinical significance. In the cardiovascular system, elastin is present in the cardiovascular and valvular vessels, and also in the diaphragm, atrium and myocardium of the heart.

Intravascular intervention

For vaso-occlusive therapy, several intravascular techniques are used to restore blood flow. Each technique has the ability to cause damage to native vascular tissue, which can lead to disease progression. To prevent reocclusion, a fibrous implant may be placed into the lumen of the vessel after treatment. This can be accomplished by intravascular implantation (whether with or without additional support devices) using self-expansion or balloon expansion of the fibrous implant.

Example 1: balloon angioplasty

In one embodiment, the fibrous implant is used in conjunction with a delivery balloon. Planar balloon angioplasty is used to open vascular occlusions. With this, damage to the vessel wall may occur, resulting in intimal hyperplasia, which can be prevented by restoring the luminal elastin layer. In this way, the fibrous implant may be mounted on the balloon of a balloon catheter that allows implantation. When delivered, the balloon inflates the fibrous implant, leaving it in the vessel.

Example 2: percutaneous intervention

In another embodiment, the fibrous implant may be used as a stent, for example, which may be used to open a vascular occlusion, reconstruct an aneurysm, close a side branch, or include other implantable devices for placement within a blood vessel. Here, the stent is mounted on a balloon catheter or provides self-expansion whereby the stent/scaffold may be positioned as an intraluminal prosthesis to maintain patency of the target vessel. Common sites where such stents can be placed are cardiovascular such as in the coronary arteries, peripheral arteries such as the upper and lower extremities or the carotid arteries, and also treatment of bypass grafts and reocclusion of neuro-vessels such as the brain.

Example 3: atherectomy

One embodiment is for post-atherectomy treatment. Atherectomy is used to remove vascular occlusions. There are several possible atherectomy techniques, such as directional, circum-orbital, or rotational. These methods can damage the intraluminal lining and thus exacerbate the disease, which can be prevented by restoring the luminal elastin layer.

Example 4: under-intima bypass

If the vessel is blocked such that true luminal access is no longer feasible, a new access can be created using the subintimal bypass technique. In this manner, the subintimal layer of the occluded vessel is penetrated and the medical device is advanced through the subintimal space. After passing through the lesion, the medical device re-enters the true lumen, thereby creating a new blood passageway. This technique can be used to treat chronic total occlusions in the heart or peripheral vessels. However, such interventions can damage the subintimal layer and are prone to reocclusion. Here, one embodiment is used to cover the subintimal cavity to restore the luminal elastin layer.

Example 5: aneurysm repair

For aneurysm treatment, endovascular prostheses are used to create new blood passages within existing dilated vessels and to prevent internal bleeding. These devices lack sufficient compliance and can lead to angiosclerosis, which can produce downstream effects, leading to heart failure associated with thickening or dilation of the ventricles. Fibrous implants that restore elastin can restore vascular elasticity and maintain vascular compliance. Thus, one embodiment is an endoprosthesis for use in treating an aneurysm.

Example 6: occlusion, embolism and occlusion

In one embodiment, the fibrous implant can be used to close a blood vessel or hole in a tissue. For example, in case a fistula must be closed or the blood supply of a cancer must be blocked. In addition, they may be used to close the holes of the atrial or ventricular septum. In addition, patent ductus arteriosus closure is an interventional procedure in which an intravascular plug is used to close a blood passage. They can even be used for placement in a cavity to prevent debris from entering the bloodstream in applications such as atrial appendix.

Example 7: valve replacement

One embodiment that includes a valve can be used to treat a patient with a congenital defect such as an Epstein anomaliy (Epstein anomaliy), occlusion, or pulmonary stenosis. It can also occur that the leaflets do not separate properly or lack the ability to close completely. Even so, valve disease can be acquired, leading to stenosis and calcification of the regurgitated valve. As a minimally invasive alternative to intravascular valve positioning, a transapical approach to placement of a prosthetic valve may be used. The valve may also be placed in other locations than the heart, for example for treating patients suffering from deep vein thrombosis, in order to replace venous valves.

Surgical intervention

As an alternative to the intravascular approach, surgical intervention may still be required in order to overcome the acquired or congenital deficiencies. Sometimes, the affected tissue is either first removed and replaced with a fibrous implant, left in place and repaired, or left in place and replaced.

Example 8: repair of

In one embodiment, the fibrous implant is a patch that can be used for wound healing or closure of a hole by congenital or acquired defect such as disease or accident or surgical reconstruction. This may be useful, for example, if the vessel branches are separated to repair a puncture in the vessel wall. In the case of an aneurysm indication, it may function to reinforce the vessel wall from the outside. It may also be used to repair organs such as the heart, where, for example, these fibrous patches may be affixed to the heart to restore the heart muscle, or to repair individual heart valve leaflets, for example, by placing patches within the heart to close septal defects.

In one embodiment, the surgeon may apply the fibrous patch to install the patch by, for example, gluing, stitching, stapling, self-adhering, heating, or any other external stimulus. The patch may be mounted on the surface of an organ, such as the heart, and may also be used to repair tubular shapes, and may also be used to repair or replace at least a portion of a damaged valve.

Example 9: bypass and intermediate positioning

In another embodiment, the surgeon replaces or repairs a vascular structure with a tubular structure. Here, an embodiment as a bypass graft may be either sutured to the existing vasculature by anastomosis at least one end, or contain at least one structural support device (such as a stent or scaffold) at the end for placement in the existing vasculature. Another embodiment is an intermediate graft that is used instead of, for example, a portion of the carotid artery or the abdominal aorta. Another embodiment is as a shunt for treatment of acquired or congenital heart defects, as an inlet graft for kidney dialysis or brain, lung or portal indications.

Example 10: valve repair or replacement

In another embodiment, the embodiment is a tubular catheter and comprises a valve. This embodiment may be surgically implanted whereby it replaces an existing valve. The catheter may have different shapes and include, for example, a keyhole shape, and it forms an inflow channel of the coronary artery at the time of aortic valve replacement. In another embodiment, the tubular catheter may include a single valve or multiple valves in series for use as an insert or bypass graft for venous indications in, for example, the leg.

Example 11: pediatric use

Embodiments are particularly useful for pediatric applications. Here, young patients whose body is also growing and suffering from congenital or acquired cardiovascular diseases or disorders would benefit from an implant that is capable of restoring elastin to regain function (such as vascular motion) in the case of vascular applications. Moreover, the potential additional benefits of using biodegradable embodiments in these situations would provide even more benefits by regulating body growth.

Production method

In an exemplary embodiment, the implant can be manufactured using production techniques in which the fibers are preferably obtained by electrospinning. Other techniques capable of manufacturing the fibrous implant can be variants of electrospinning, such as melt electrospinning, wet electrospinning, emulsion electrospinning, coaxial electrospinning, steady jet electrospinning and near field electrospinning, but also other fiber production techniques, such as 3D printing, electrostatic mapping, weaving, knitting, additive manufacturing, bioprinting, electrospraying, polymer jetting, injection molding, casting or any combination thereof.

When electrospinning is used, fiber diameter, fiber orientation, and pore size can be adjusted by applying different combinations of settings such as voltage, rotational speed, rotational distance, coaxial flow, polymer inflow velocity, target size, target needle diameter, and environmental settings such as humidity and temperature. Further, multiple spinning nozzles may be used simultaneously, wherein each nozzle spins in a different fiber configuration.

In one variant, the embodiment is composed at least in part of different layers. The fiber web can be obtained by forming a fiber layer by stacking a plurality of fibers on each other. By varying the production setup, the layers can have different densities, fiber diameters, or pore sizes. In addition, the number of layers will determine the implant thickness. In this way, for example, the inner surface of the tubular conduit may have a different layer of fibres than the outer surface of the tube.

In another variation, the embodiments are at least partially composed of different materials. The network may be composed of fibers of the same material or of different materials. The layers may also be made of different fibers of different material compositions. In this way, for example, the inner surface of the tubular conduit may have a different degradation rate than the outer surface.

In another variation, an embodiment is at least partially comprised of fibers comprising different materials. Furthermore, the individual fibers may be composed of different material compositions, possibly by means of coaxial or multiaxial spinning, wherein the individual fibers may be composed of different cores and outer layers or layers.

Embodiments using electrospinning can be made into sheets by spinning on a flat collector or into tubes by using a tube collector that either rotates itself or around which the nozzle rotates. The collector can have any conceivable shape, on which the fibrous implant can be produced.

In one variation, embodiments may be at least partially self-adhesive or include an adhesive (such as glue) or bioadhesive component on one or more sides of the implant and/or within the implant.

Some embodiments may be combined with other implantable devices by adhering, suturing, crimping, stapling, or physically closing with a sandwich, for example.

In another variation of the embodiment, the fibrous implant is applied directly to the additional support or delivery device, for example using electrospinning, and the fibrous network can be provided to the implant at any portion of the implant, on the surface of, within, or adhered to the additional implantable device. In this way, the fibrous implant can be combined with additional implantable devices, such as balloon catheters, stents, grafts, valves or occlusion devices.

In an exemplary embodiment, the additional delivery device is a stent, the fibrous implant being provided inside the stent facing the lumen and/or outside the stent facing the natural wall. In another variation, the embodiment is sandwiched between a plurality of stents.

In another exemplary embodiment, the additional delivery device is a balloon catheter to which the fibrous implant is provided by applying the fibrous implant directly to the balloon in an inflated or deflated state.

In another exemplary embodiment, the fibrous implant may be provided to the occluding device on the inside, outside, between, or a combination thereof of the implanted structure.

In another exemplary embodiment, the clinician may spray the web directly onto the target tissue or organ where elastin formation is desired.

Test method

The fibrous implant may be partially characterized by Scanning Electron Microscopy (SEM). With a high imaging magnification, one can define (average) fiber diameter, (average) pore size. Lower SEM imaging magnification may be used to characterize the network tissue, where post-processing using image analysis software (such as ImageJ) may be used to determine the network tissue and fiber alignment level.

Differential Scanning Calorimetry (DSC) can be used to measure the crystallinity of polymer fibers before, during, and after production. The molecular weight of the polymer can be measured using Gel Permeation Chromatography (GPC).

The ability of the fibrous implant to induce elastin formation may be tested in animals such as rats, even more preferably in more transformed animal models (translational animal models) such as rabbits or pigs.

Histology may be used to assess the ability of the implant to induce elastin after elucidation. This can be achieved by using, for example, verhoeff staining, or a combination staining including Verhoef staining (such as Russell-Moval five color staining), or immunofluorescence staining using a primary antibody specific for elastin. This can be done at predefined time points to assess migrating cell and tissue formation over time.

Example 1: effect of elastin formation Using Endoluminal prostheses of different fiber diameters

Their ability to induce elastin formation has been evaluated for two different embodiments. One embodiment is a tubular endoluminal implant comprised of small fibers. A second embodiment is also a tubular endoluminal implant consisting of two distinct layers with large fibers on the outside and small fibers on the inside. The effect of fiber thickness on elastin formation was evaluated in rabbits. Two fibrous implants were placed as endoluminal prostheses in the rabbit femoral artery using balloon catheters. After 12 weeks, the implants were transplanted and assessed for the presence of elastin using Russell-Moval five color staining. Prior to implantation, the fibrous implants were characterized using SEM.

Prior to implantation, an exemplary embodiment consisting of fibrils was characterized using SEM. The luminal side of the balloon catheter after expansion shows the following network morphology, as shown in fig. 2. This 3 month explant showed abundant formation of luminal elastin as shown in figure 3. Compared to other exemplary embodiments with an additional outer layer consisting of larger fibers, this bilayer structure did not induce elastin formation to the extent observed in embodiments consisting of only small fibers 3 months after implantation (fig. 4). Since both embodiments consist of the same material and the inner layer of the bi-layer implant has the same fiber network morphology as the single layer implant, this may indicate that fiber size may be used to control elastin formation.

Example 2: effect of alpha-SMA positive cells on elastin formation

To investigate the origin of the elastin in situ generation, several comparable embodiments have been placed in the endoluminal prostheses in the rat abdominal aorta for 2, 4, 6 and 8 weeks using balloon catheters. These embodiments consist of fibrils only, as compared to the embodiment described in example 1. Immunofluorescent staining was used for alpha-smooth muscle actin (alpha-SMA) and elastin. The gradual infiltration of α -SMA positive cells from the adventitia to the luminal side of the implant was seen (fig. 5). Over time, luminal elastin formation was observed, at 6 and 8 weeks, in coexistence with the presence of α -smooth muscle actin positive cells.

This may indicate that cells expressing alpha-smooth muscle actin are involved in elastin formation. Since elastin is formed on the luminal side of the implant rather than inside the fibrous mesh, the proximity to the blood flow may have a positive effect on elastin formation.

Claims (15)

1. A cardiovascular fibrous implant for the reconstitution of elastin, wherein the implant is comprised of fibers that form a network characterized by fibers in the network having a fiber diameter of 150 μ ι η or less.

2. The fibrous implant of claim 1, wherein the fibrous implant is at least partially bioabsorbable.

3. The fibrous implant according to claim 1 or 2, wherein the fibrous implant comprises a drug and/or an adhesive component.

4. Fibrous implant according to any of the preceding claims, wherein the fibres are coated with a coating and wherein the coating comprises a drug and/or an adhesive component.

5. Fibrous implant according to any of the preceding claims, wherein the fibrous implant comprises fibers and/or pores allowing cells to adhere, migrate, infiltrate, proliferate, (trans) differentiate, synthesize tissue or a combination thereof.

6. The fibrous implant according to any of the preceding claims, wherein the fibrous implant consists of a plurality of layers of fibers, wherein the plurality of layers of fibers comprises at least a first layer of fibers and a second layer of fibers, and wherein the first layer of fibers is different from the second layer of fibers.

7. The fibrous implant of claim 6, wherein the first layer of fibers differs from the second layer of fibers by a parameter selected from the group consisting of fiber diameter, pore size, density, stiffness, fibrous texture, material composition, drug composition, adhesive composition, degradation rate, and combinations thereof.

8. The fibrous implant according to any of the preceding claims, wherein the fibrous implant comprises:

i) A planar shape;

ii) tubular, wherein the tubular optionally comprises:

a. a valve for use as a prosthetic valve;

b. as a membrane, embolic member, or inflatable member for a closure device, embolic device, or occlusion device.

9. Fibrous implant according to any of the preceding claims, wherein the fibrous implant is capable of at least partially reconstructing the media and/or intima layers of a blood vessel by reconstructing the smooth muscle layer and/or the endothelial cell layer other than elastin.

10. Use of a fibrous implant according to claim 8, wherein the planar shaped fibrous implant is used as a patch.

11. Use of a fibrous implant according to claim 8 wherein the tubular fibrous implant is used as a scaffold, stent graft, bypass graft, fistula or shunt.

12. Use of a fibrous implant according to any one of claims 1 to 9 for implantation in a host in any combination of:

i) In direct contact with the bloodstream; and/or

ii) in direct contact with a natural tissue, wherein the natural tissue is selected from the group consisting of healthy natural tissue, injured natural tissue, damaged natural tissue, diseased natural tissue, and combinations thereof,

provided that the use does not include introducing the fibrous implant into a host.

13. The use according to claim 12, wherein the fibrous implant is connected to an additional support or delivery device.

14. Use according to claim 12 or 13, wherein the fibrous implant used is exposed to a mechanical loading condition, wherein the mechanical loading condition is a static mechanical loading condition and/or a dynamic mechanical loading condition, and wherein the mechanical loading condition is selected from the group consisting of shear stress, pre-strain, residual stress, tension, compression and combinations thereof.

15. Use of a cardiovascular fiber implant according to any of claims 1-9 for the reconstitution of elastin.