阅读说明：本技术 有弹性荷载的医疗装置 (Elastically loaded medical device ) 是由 马尔科·普达斯 尼库·奥克萨拉 于 2020-03-27 设计创作，主要内容包括：提供了一种结构、用于制造该结构的方法、用于将至少一种药用活性剂递送到体内的方法以及ALD沉积涂层在医疗装置中作为粘合剂的用途,该结构包括利用粘合剂(30)连接在一起的多个表面(10、20),所述结构被配置成在粘合剂(30)至少部分降解时重塑形。(A structure comprising a plurality of surfaces (10, 20) joined together with an adhesive (30), the structure being configured to reshape upon at least partial degradation of the adhesive (30), a method for manufacturing the structure, a method for delivering at least one pharmaceutically active agent into the body and the use of an ALD deposited coating as an adhesive in a medical device are provided.)

1. A structure (100) comprising a plurality of surfaces (10, 20) connected together with an adhesive (30), wherein the structure is configured to reshape when the adhesive (30) at least partially degrades.

2. The structure of claim 1, wherein the adhesive is a biocompatible and/or biodegradable adhesive.

3. The structure of any one of claims 1 or 2, wherein the adhesive is a biocompatible and/or biodegradable polymer.

4. The structure of any preceding claim, configured as a medical device.

5. The structure of any preceding claim, configured as an implantable medical device.

6. The structure of any preceding claim, configured as a stent.

7. The structure of any preceding claim, wherein the adhesive (30) is established on the surface (10, 20) in the form of at least one layer provided as an Atomic Layer Deposition (ALD) layer.

8. The structure of any preceding claim, configured to carry a mechanical load, such as an elastic load, which is released when the adhesive (30) at least partially degrades.

9. The structure of any preceding claim, configured for gradual release of elastic load by adjusting the degradation rate of the adhesive (30).

10. The structure of any preceding claim, configured as a container for at least one chemical substance.

11. The structure of any preceding claim, configured to release the at least one chemical substance when reshaped due to at least partial degradation of the adhesive (30).

12. A structure according to any preceding claim, wherein the chemical substance comprises at least one pharmaceutically active agent.

13. A method for fabricating a structure (100), the method comprising: obtaining a structure having a plurality of surfaces (10, 20); and a structure connecting the surfaces (10, 20) together with an adhesive (30), wherein the adhesive (30) is applied onto the surfaces (10, 20) by atomic layer deposition, and wherein the structure is configured to be reshaped when the adhesive (30) is at least partially degraded.

14. A method for delivering at least one pharmaceutically active agent into a body, wherein the at least one pharmaceutically active agent is provided in a structure (100) comprising a plurality of surfaces (10, 20) connected together with an adhesive (30), wherein the structure is configured to release the pharmaceutically active agent when reshaped due to at least partial degradation of the adhesive (30) in the body.

Use of an ALD deposited coating as an adhesive in a medical device (100), wherein the medical device is an implantable medical device, such as a stent.

Technical Field

The present invention generally relates to the manufacture of implantable medical devices. In particular, the present invention relates to spring-loaded medical devices, methods of manufacture thereof, and related uses.

Background

Stents are medical devices used to keep open, i.e., in an open or unobstructed state, various stenotic vessels within the body. The field of application varies from the cardiovascular system, which is characterized by high periodic cavity pressure, to the urinary, gastrointestinal and respiratory tract, which are characterized by lower amplitude and less varying pressure.

Stents are used after angioplasty, e.g. as after Percutaneous Transluminal Angioplasty (PTA), in the treatment of arterial stenosis or occlusion (respectively, abnormal narrowing or blockage of a blood vessel or any other tubular and/or hollow organ or structure). Generally in the treatment of atherosclerosis, PTA is the treatment of choice for patients who require widening narrowed or blocked arteries or veins. The use of a stent is essential due to the fact that: long-term (2 years and beyond) patency rates with PTA only (no stent placed) tend to vary between about 40% to about 70%. After PTA, the stent resists the immediate elastic recoil of the arterial wall and secures the plaque against the arterial wall, thereby establishing optimal flow through the treated area.

A common drawback encountered with some stents, particularly drug eluting stents having thin stent struts and other sensitive stent designs, relates to the fact that these stents may be subject to recoil (stent recoil).

Stent recoil after PTA is a problem because if the flow through the channel/lumen is significantly reduced, re-intervention is required. With respect to any such case: airway narrowing and obstruction caused by inflammatory processes or any other process that affects the structural integrity of the airway; tumors that press the airway externally or narrow the airway internally, such as within the bronchi or trachea; stents are used to dilate the stenosis and maintain this condition for the maximum period of time due to loss of cartilage support resulting from tumor destruction or formation of malignant tracheoesophageal fistulas.

The same principle applies to tumours in the gastrointestinal tract and the urinary system. Stents placed at such locations are more susceptible to recoil than stents placed within the circulatory system due to pressure conditions, particularly those created during airway narrowing and to some extent during strictures in the gastrointestinal and urinary systems.

Therefore, it is highly desirable to adjust the radial force exerted by a medical device such as a stent within a body passageway and/or lumen, i.e., the force generated outwardly by the stent against the surrounding tissue. After the initial surgery (such as PTA surgery), the mode of remotely increasing the radial force can realize the reconstruction of the postoperative patency under the condition of the recoil of the bracket at the later stage.

Disclosure of Invention

An object of the present invention is to solve or at least alleviate various problems due to limitations and disadvantages of the related art. This object is achieved by various embodiments of a structure, a method for manufacturing the structure and related uses.

In one aspect, a structure is provided according to what is defined in independent claim 1.

In embodiments, the structure comprises a plurality of surfaces that are joined together with an adhesive, and the structure is further configured to reshape when the adhesive is at least partially degraded.

In embodiments, the adhesive is a biocompatible and/or biodegradable adhesive.

In embodiments, the binder is a biocompatible and/or biodegradable polymer.

In an embodiment, the adhesive is built up on the surface of the structure in the form of at least one layer arranged as an Atomic Layer Deposition (ALD) layer.

In an embodiment, the structure is configured as a medical device. In an embodiment, the structure is configured as an implantable medical device. In an embodiment, the structure is configured as a stent, such as an implantable stent.

In embodiments, the structure is configured to carry a mechanical load, such as an elastic load, which is released when the adhesive at least partially degrades. In embodiments, the structure is configured to gradually release the elastic load by adjusting the degradation rate of the adhesive.

In an embodiment, the structure is configured as a container for at least one chemical substance. In an embodiment, the structure is configured to release the at least one chemical species when reshaped due to at least partial degradation of the adhesive. In an embodiment, the chemical substance comprises at least one pharmaceutically active agent.

In an aspect, a method for manufacturing the structure is provided according to what is defined in independent claim 13.

In another aspect, there is provided a method for delivering a pharmaceutically active agent into the body, as defined in independent claim 14.

In a further aspect, there is provided the use of an ALD deposited coating as an adhesive in a medical device according to the definition in independent claim 15.

Without limiting the scope and interpretation of the patent claims, certain technical effects of one or more of the example embodiments disclosed herein are set forth below.

Thin film deposition, such as Atomic Layer Deposition (ALD), can fill small cavities with very high aspect ratios. Substantially all solid surfaces with gaps and/or holes may be conformally coated. The deposited material acts as a glue when the sidewalls of the gap remain stationary during deposition.

Various materials deposited using ALD may degrade or (bio) decompose due to long term exposure to biological fluids. Alternatively, the mechanical force is caused by embedding in an environment such as a channel and/or cavity within a human body (e.g., when a human has an implant placed into the channel/cavity), or by a physician using various known means such as by applying a particular physical force.

In some cases related to the use of the implanted material, release of the applied force, such as sutures, may occur after healing.

The present invention allows for the creation of a medical device structure, such as a stent structure, that deploys while resisting compressive forces, for example, over a predetermined period of time. This is important in the following cases: this is the case when the stent is intended to be placed in a position within the patient's body which is typically subject to pressure from the outside and is accordingly caused to be prone to narrowing/obstruction. Also, for example, if the lumen of a blood vessel begins to narrow over time, the deployment provided by a medical device according to the present disclosure will effectively resist such a situation.

In the present disclosure, a material having a layer thickness of less than 1 micrometer (μm) is referred to as a "thin film".

The expression "plurality" refers herein to any positive integer starting from one (1), for example to 1, 2 or 3; and the expression "plurality" refers herein to any positive integer starting from two (2), for example to 2, 3 or 4.

The term "element" may also refer herein to a multi-component element having multiple elements functionally and optionally physically connected, in addition to a single component or unitary element.

The terms "first" and "second" are not intended to denote any order, quantity, or importance, but rather are used to distinguish one element from another.

Drawings

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

FIG. 1 is a cross-section of two exemplary surfaces held together with an adhesive;

FIG. 2 illustrates an exemplary configuration of a structure configured as a stent, according to an embodiment; wherein the scaffold collapses under mechanical force;

fig. 3 is a cross-section of two exemplary surfaces separated after degradation of the adhesive.

Detailed Description

According to one aspect, the present invention is directed to providing a structure 100 comprising a plurality of surfaces or elements 10, 20 (FIG. 1) joined together with an adhesive 30. The structure may include any number of surfaces 10, 20. Thus, a relatively simple exemplary structure (container with lid) employing substantially two surfaces may be provided. The structure may be provided as a complex structure comprising hundreds (or more) of surfaces/elements denoted 10, 20 in fig. 1.

The adhesive 30 is established on the surfaces 10, 20 in the form of at least one coating layer or film. The coating layer may be provided as an Atomic Layer Deposition (ALD) layer. The adhesive 30 is built up on all available (within the structure 100) surfaces 10, 20. In some cases, the adhesive layer is established on/between a (pre-) selected number of surfaces 10, 20.

In practice, the adhesive 30 is applied to all surfaces 10, 20 provided within the structure. An ALD coating is a conformal coating and it covers all surfaces equally. However, a selectively applied growth inhibitor may be used to enable ALD growth only on selected locations (surfaces 10, 20). Self-assembled monolayers, such as those of long chain alkyl silanes, hinder or prevent the growth of an electrolessly deposited coating film/layer on a substrate, and may be used as film growth inhibitors. Additionally or alternatively, photon enhanced ALD or plasma assisted ALD may utilize a mask to effect patterning, causing deposition to form only in exposed areas.

The basic principles of the ALD growth mechanism are known to the skilled person. ALD is a special chemical deposition method based on the sequential introduction of at least two reactive precursors to at least one substrate. However, it should be understood that when using, for example, photon enhanced ALD or plasma assisted ALD such as PEALD, one of these reactive precursors may be replaced with energy, resulting in a single precursor ALD process. For example, only one precursor is required to deposit a pure element such as a metal. When the precursor chemistry contains both elements of the binary material to be deposited, one precursor chemistry can be utilized to produce a binary compound such as an oxide. The thin films grown by ALD are dense, pinhole free and uniform in thickness. In some cases, Chemical Vapor Deposition (CVD) may be employed.

The at least one substrate is typically exposed to temporally separated precursor pulses in a reaction vessel to deposit material on the substrate surface by sequential self-saturating surface reactions. In the context of the present application, the term ALD encompasses all applicable ALD-based techniques and any equivalent or closely related techniques, such as, for example, the following ALD subtypes: MLD (molecular layer deposition); plasma assisted ALD such as PEALD (plasma enhanced atomic layer deposition); and photon enhanced atomic layer deposition (also known as photo ALD or flash enhanced ALD). The process may also be an etching process, one example of which is an ALE process.

ALD is based on alternating self-saturating surface reactions, wherein different reactants (precursors) provided as chemical compounds or elements in a non-reactive (inert) gaseous carrier are sequentially pulsed into a reaction space accommodating a substrate. The substrate is purged with an inert gas after the deposition of the reactants. A conventional ALD deposition cycle performs two half-reactions (pulse a-purge a; pulse B-purge B) to form a layer of material in a self-limiting (self-saturating) manner, typically 0.05 to 0.2nm thick. Typical substrate exposure times for each precursor range from 0.01 to 1 second.

Pulse a includes a first precursor (first precursor vapor) in a vapor phase, and pulse B includes a second precursor (second precursor vapor) in a vapor phase. The gaseous reaction by-products and residual reactant molecules are typically purged out of the reaction space during purge a and purge B using an inert gas and a vacuum pump. The deposition sequence includes at least one deposition cycle. The deposition cycle is repeated until the deposition sequence produces a film or coating of the desired thickness. The deposition cycle may also be simpler or more complex. For example, the cycle may include three or more reactant vapor pulses separated by purge steps, or some purge steps may be omitted. On the other hand, photon enhanced ALD has multiple options, such as only one reactive precursor with various purging options. All these deposition cycles form a timed deposition sequence controlled by a logic unit or microprocessor.

In the following description, Atomic Layer Deposition (ALD) techniques are used as a preferred method.

Thus, fig. 1 shows two surfaces (elements) 10, 20 which are held together during deposition, whereby the surfaces are adhered to each other by a material deposited thereon, i.e. an adhesive 30. The surfaces 10, 20 are held together fixedly by the adhesive 30.

Accordingly, the binder 30 is formed in the form of at least one coating layer produced in at least one cycle of the electroless deposition process. In some cases, the at least one chemical deposition cycle is an ALD deposition cycle.

In some configurations, adhesive 30 includes or is comprised of a biocompatible and/or biodegradable material. In some other configurations, adhesive 30 includes or is comprised of a biocompatible and/or biodegradable polymer. The adhesive 30 may be configured to be gradually released.

In some configurations, the structure 100 is a medical device, such as an implantable medical device. The structure may be a grid structure (e.g. grid lines), optionally grid tubes. In an embodiment, the structure 10 is a stent.

The structure 100 is configured so as to withstand a mechanical (pre) load, such as an elastic load, which is released when the adhesive 30 at least partially degrades. At least partial degradation of the adhesive 30 causes the structure 100 to reshape. Reshaping can be considered as a process (starting from a state with a pre-applied mechanical load) of restoring the "original" (intended use or operation) shape of the structure.

Accordingly, the present disclosure provides a structure 100 configured as a mechanical assembly that reshapes and/or self-deforms (e.g., pops) itself when the (biocompatible and/or biodegradable) adhesive material 30 deposited on/between the elements/ surfaces 10, 20 at least partially degrades or dissolves.

As the adhesive 30 degrades, reshaping occurs by releasing a mechanical (pre) load, such as an elastic load, applied to the structure.

The release of the elastic load may be caused by applying an (external) mechanical force on the structure. Thus, the structure may be configured to reshape/deform upon collapse of the vascular stent, e.g., whereby a mechanical force is applied to the structure, causing release of the elastic load.

Fig. 2 illustrates a situation where an exemplary medical structure configured as a stent collapses under a mechanical force (F). In its open shape, the stent is provided in a substantially tubular configuration. In the example shown in fig. 2, a mechanical force (F) is applied to the structure 100 when the structure is pressed with a finger.

The same situation (collapse of the stent) can occur, for example, on a conventional stent placed in the human body. To address this situation (remodeling stents), medical intervention such as vascular surgery is often required. By providing a resiliently loaded structure 100 according to the present disclosure, the release of the resilient load triggered by the dissolution of the adhesive 30 causes localized stress at the contact points established at these predetermined elements/surfaces 10, 20 that were previously joined together by the adhesive (and separated from each other when the adhesive dissolved). Introducing more stress in the stent structure causes the stent to again acquire a substantially tubular (open) shape.

Fig. 3 shows the structure 100 after reshaping (release of the elastic load) and thus dissolution of the adhesive 30. The parts 10 and 20 are free to move.

In practice, for example, a stent 100 is inserted into a blood vessel, the stent having a pre-applied mechanical load (e.g., an elastic load) created by "gluing" together predetermined elements or surfaces 10, 20 thereof with an adhesive 30. As the adhesive is gradually degraded/released in the biological fluid, the stent structure 100 remodels itself into a substantially tubular (open) form, thereby acting as a scaffold in the blood vessel and keeping the blood vessel open to ensure unimpeded blood flow therethrough.

In other or alternative configurations, the structure 100 is configured as a container for at least one chemical substance. In this case, the structure may include: a set of elements forming a container; and optionally a set of elements forming a lid or any other suitable arrangement that is connected to the container by adhesive 30. The elements having surfaces 10, 20 are separated from each other when the adhesive is at least partially degraded and/or dissolved in vivo.

The structure 100, consisting of or comprising a container for at least one chemical substance, is preferably configured to release said chemical substance when reshaped due to at least partial degradation of the adhesive 30.

The chemical substance includes at least one pharmaceutically active agent. In some cases, the chemical substance is a pharmaceutical formulation that includes the at least one pharmaceutically active agent. Accordingly, the medical device 100 may be configured to carry at least one drug agent therein. The medical device may be configured to carry a plurality of medical preparations (drugs) at a time.

Accordingly, the structure 100 according to the present disclosure is configured to release the at least one pharmaceutically active agent when reshaped and/or self-deformed due to at least partial degradation of the adhesive 30 in vivo.

By applying an adhesive to the predetermined elements 10, 20 within the structure 100, the elastic load release action can be adjusted to cause at least partial opening of the predetermined section of the implanted article (i.e., medical device), which action releases a pharmaceutical/drug formulation comprising at least one pharmaceutically active agent.

Various medical applications may benefit from the placement of the dissolvable adhesive in a medical device. Which includes controlled drug release occurring as the medical device structure 100 dissolves, optionally stepwise. In a non-limiting manner, the adhesive 30 may be made from a variety of materials and different methods in order to accommodate different surfaces (e.g., surfaces made of metal, plastic, or combinations thereof).

Medical structures 100 configured as stents (see fig. 2) may be positioned in various tubular structures within a patient, particularly those formed by low pressure lumens (lumens ) and exposed to external pressure changes (e.g., respiration and intrathoracic pressure).

The present disclosure generally provides structures configured as medical devices, such as stents for human patients. However, the structure is also applicable to non-human animals, such as mammals, when modified in an appropriate manner.

The structure may also be configured to gradually release the spring load over time, for example, whereby the recoil sensitive stent can "automatically" (i.e., self-expand).

In embodiments, the structure is thus configured to gradually release the elastic load by adjusting the degradation rate of the adhesive 30. The degradation/dissolution rate of the adhesive 30 in body fluids and tissues can be controlled in terms of at least composition and/or thickness or ALD layer.

By varying the deposition chemistry (precursor) and/or the multiple deposition layers, the adhesive 30 can be configured to adjust the release rate of the drug (constant, accelerated, decelerated) and/or to establish drug release with a distinct phase (e.g., initially constant or accelerated or decelerated (phase i); followed by another phase (phase ii) different from the previous phase, etc.). Furthermore, the adhesive 30 may be applied to predetermined locations (elements 10, 20) within the structure to create compartments, for example, to enable the structure 100 to hold and release different drugs at different points in time.

The adhesive 30 may be made of various materials; however, it is crucial that when the material ruptures/dissolves, no toxic substances are eluted into the body-which may block microvascular access and/or have a deleterious effect on the patient. Thus, it is beneficial that the applicable adhesion layers obtained by ALD techniques are very thin (0.1 to 100 nm).

For example, the adhesive 30 may include aluminum oxide (Al)₂O₃) Magnesium oxide (MgO), silicon dioxide (SiO)₂) And/or combinations thereof. It should be noted that the mentioned compounds and/or combinations thereof, for example, in order to be soluble in biological fluids, should be manufactured under predetermined reaction conditions and utilize predetermined precursors to produce compounds of suitable quality.

The thin layer may also be applied to very small structures such as sub-millimeter sized capsules, articles, or exemplary structures such as the walls of a stent. The benefit of using ALD is that it enables the deposition of thin, pinhole-free layers of adhesive and also provides versatility in the choice of the adhesive material.

For example, in an exemplary installation of the Picosun R-200 advanced ALD system provided by Picosun Oy, finland, the aspect ratio of the sub-micron cavity filling has been demonstrated to be higher than 1000:1(1000:1 ═ depth-to-width aspect ratio).

The invention also relates to a method for manufacturing a structure 100, the method comprising: obtaining a structure having surfaces 10, 20; and joining together a plurality of surfaces, optionally (pre) selected surfaces, with an adhesive 30. The structure thus obtained is configured to reshape, i.e. to recover its original shape in such a way as to acquire its shape before the surfaces are joined together, when the adhesive 30 is at least partially degraded (as in body fluids). In this method, the adhesive 30 is applied to the surfaces 10, 20 by Atomic Layer Deposition (ALD). Adhesive may be applied to all available surfaces 10, 20 within the structure 100 to create a mechanical loading effect (such as the elastic loading effect discussed above). In some cases, the adhesive may be applied to some (pre) selected surfaces.

Furthermore, the present invention relates to a method for delivering at least one pharmaceutically active agent into the body. In this method, a pharmaceutically active agent is disposed in a structure 100 comprising a plurality of surfaces 10, 20 connected together with an adhesive 30, the structure being configured to release the pharmaceutically active agent when the adhesive 30 is at least partially degraded in vivo. In this method, the structure 100 is preferably configured to release the at least one pharmaceutically active agent when reshaped due to at least partial degradation of the adhesive 30 in vivo, in particular in a body fluid. The method allows for the delivery of at least one pharmaceutically active agent into the body of a human patient or, alternatively, into the body of a non-human animal, such as a non-human mammal.

In one aspect, there is also provided the use of an electrolessly deposited coating, such as an ALD deposited coating, as an adhesive in a medical device. The mentioned use preferably relates to a medical device configured as an implantable medical device, such as a stent.

It will be understood by those skilled in the art that the embodiments set forth in the present disclosure may be modified and combined as desired. Accordingly, the disclosure is intended to encompass any possible modifications of the apparatus and deposition method that would be understood by a person of ordinary skill in the art to be within the scope of the appended claims.