WO2020038956A1

WO2020038956A1 - Magnesium alloy based implant and method of preparing an implant

Info

Publication number: WO2020038956A1
Application number: PCT/EP2019/072291
Authority: WO
Inventors: Annelie-Martina Weinberg
Original assignee: Bri.Tech
Priority date: 2018-08-20
Filing date: 2019-08-20
Publication date: 2020-02-27
Also published as: GB201813525D0; EP3840793A1; GB2576706A

Abstract

The present invention relates to an implant based on a magnesium alloy and a method of preparing an implant. The implant comprises a first portion being substantially solid and a second portion being substantially porous.

Description

Magnesium alloy based implant and method of preparing an implant

FIELD OF THE INVENTION

The present invention relates to an implant based on a magnesium alloy and a method of preparing an implant, in particular an implant that may be used in the treatment, amelioration or prevention of osteoarthrosis or related joint diseases.

BACKGROUND

The joint disease osteoarthrosis (OA) affects roughly 10% of males and 18% of females over the age of 60 (Glyn-Jones, S. et al. Osteoarthritis. Lancet. 2015 Jul 25; 386(9991) : 376-87). As the number of senior citizens in developed countries continues to increase, the economic cost of treating osteoarthrosis is likely to rise as well. OA is characterized by a loss of cartilage and an overgrowth of bone tissue, leading to pain and reduced mobility. In early stages, the collagen matrix of cartilage becomes disorganized and a decrease in proteoglycans of cartilage is observed. Proteoglycans normally protect the collagen fibers from degradation, therefore their loss worsens the joint degeneration. Additionally, decomposition products of the cartilage may be released into the synovial space, causing the lining of the joint cavity (synovium) to become inflamed, as well as the surrounding joint capsule. The pathogenesis of OA is not fully understood, although several important factors have been identified, such as an increased expression of inflammatory cytokines IL-1, TNFa as well as cartilage degradation and mineralization of the extracellular matrix (Li, Y. et al. The Role of miRNAs in Cartilage Homeostasis. Curr Genomics. 2015 Dec; 16(6) : 393-404). Conventional treatments for OA rely on invasive surgical methods, including joint replacement by prosthesis, joint resurfacing or transferring articular cartilage from non-weight bearing regions of the body. Pharmaceutical treatment focuses on relieving pain, e.g. via non-steroidal anti-inflammatory drugs or cortisone injections, although this approach fails to address the underlying cause of the disease.

Novel therapies to replace or restore the damaged tissue are attracting interest, such as tissue engineering, which involves the combination of cells, biomaterials and bioactive factors to aid cartilage replacement. A different approach would be to repair existing cartilage tissue by a regenerative therapy, rather than replace it.

Magnesium (Mg) is a promising material for use in regenerative therapy (Zhao, D. et al. Current status on clinical applications of magnesium-based orthopaedic implants: A review from clinical translational perspective.

Biomaterials. 2017 Jan; 112: 287-302). As a naturally occurring element in the human body, Mg influences cell homeostasis and functionality. Mg deficiency is also implicated as a major risk factor for OA, involved in pathways such as inflammation and cartilage damage. Supplementation or localized infiltration of Mg appears to be effective for treating OA in animal models (Li, Y. et al.

Unraveling the role of Mg( + + ) in osteoarthritis. Life Sci. 2016 Feb 15; 147: 24- 9).

The use of Mg to regenerate damaged cartilage and thereby address the underlying issue of localized OA represents a new approach. Previous attempts in this field have made use of a functionalized hydrogel to induce cartilage formation (Almeida, H. et al. Anisotropic Shape-Memory Alginate Scaffolds Functionalized with Either Type I or Type II Collagen for Cartilage Tissue Engineering. Tissue Eng Part A. 2017 Jan;23(l-2) : 55-68; Almeida, H. et al. Fibrin hydrogels functionalized with cartilage extracellular matrix and

incorporating freshly isolated stromal cells as an injectable for cartilage regeneration. Acta Biomater. 2016 May; 36: 55-62). However, no cartilage tissue engineering approach has been attempted using Mg-based or Mg- incorporating scaffolds. Furthermore, this approach would involve only a single step operation.

In light of the foregoing, there may be a need for a medical device, such as an implant, capable of providing a controlled release of magnesium in joints, which may be suitable for the treatment, amelioration or prevention of osteoarthrosis or related joint diseases.

OBJECTS OF THE INVENTION

Thus, an object of the present invention is to provide an implant based on a magnesium alloy which may be able to provide a controlled release of magnesium (in particular magnesium ions) in joints, which may improve cartilage regeneration and/or which may be suitable for the treatment, amelioration or prevention of osteoarthrosis or related joint diseases.

SUMMARY OF THE INVENTION

The present inventors have made diligent studies for solving these objects and have found that a controlled release of magnesium ions (in particular an optimized degradation or corrosion rate (gradual dissolution) of the implant, such as exhibiting a slow initial corrosion after implantation and gradually increasing the corrosion), while at the same time providing a secure

anchorage or attachment of the implant at the location of intended use, can be achieved by configuring the implant with two distinct portions, one (first) portion being substantially solid which may be configured for fixing (attaching, adhering, anchoring) the implant in a body material, in particular a bone, and another (second) portion being substantially porous which may be configured for releasing magnesium ions, in particular in a controlled manner.

Accordingly, the present invention relates to an implant based on a

magnesium alloy and comprising a first portion being substantially solid and a second portion being substantially porous. The present invention further relates to a method of preparing an implant based on a magnesium alloy comprising the steps of forming a first portion such that the first portion is substantially solid and forming a second portion such that the second portion is substantially porous.

Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following detailed description of embodiments.

DETAILLED DESCRIPTION OF THE INVENTION

Hereinafter, details of the present invention and other features and

advantages thereof will be described. However, the present invention is not limited to the following specific descriptions, but they are rather for illustrative purposes only.

It should be noted that features described in connection with one exemplary embodiment or exemplary aspect may be combined with any other exemplary embodiment or exemplary aspect, in particular features described with any exemplary embodiment of an implant may be combined with any exemplary embodiment of a method of preparing an implant and vice versa, unless specifically stated otherwise.

Where an indefinite or definite article is used when referring to a singular term, such as "a", "an" or "the", a plural of that term is also included and vice versa, unless specifically stated otherwise, whereas the word "one" or the number "1", as used herein, typically means "just one" or "exactly one".

The expression "comprising", as used herein, includes not only the meaning of "comprising", "including" or "containing", but also encompasses "consisting essentially of" and "consisting of". Unless specifically stated otherwise, the expressions "at least partially", "at least a partial" or "at least a part of", as used herein, may mean at least 5 % thereof, in particular at least 10 % thereof, in particular at least 15 % thereof, in particular at least 20 % thereof, in particular at least 25 % thereof, in particular at least 30 % thereof, in particular at least 35 % thereof, in particular at least 40 % thereof, in particular at least 45 % thereof, in particular at least 50 % thereof, in particular at least 55 % thereof, in particular at least 60 % thereof, in particular at least 65 % thereof, in particular at least 70 % thereof, in particular at least 75 % thereof, in particular at least 80 % thereof, in particular at least 85 % thereof, in particular at least 90 % thereof, in particular at least 95 % thereof, in particular at least 98 % thereof, and may also mean 100 % thereof.

In a first aspect, the present invention relates to an implant based on a magnesium alloy and comprising a first portion being substantially solid and a second portion being substantially porous.

The term "implant", as used herein, may in particular mean a (medical) device that may be implanted in a human or animal body. The implant may have various two- or three-dimensional shapes, such as a pin, a rod, a screw, a wire, a plate, a disc, a dome or a hemisphere. The implant may in particular be at least partially resorbable (biodegradable) by a human or animal body once implanted.

The expression "implant based on a magnesium alloy", as used herein, may in particular mean that the implant comprises a magnesium alloy (such as one magnesium alloy), in particular as an essential constitutional component thereof. It may even mean that the implant (substantially) consists of a magnesium alloy or is made of a magnesium alloy, in particular of one magnesium alloy.

The term "solid", as used herein, may in particular mean that the material concerned has a substantially homogenous and/or dense structure or texture, in particularly with only few or substantially no voids or pores. The term "solid", as used herein, may thus also be designated as "non-porous".

Typically, a solid material may be characterized by a relatively low specific surface area (small ratio of surface area to mass).

The term "porous", as used herein, may in particular mean that the material concerned exhibits a plurality of voids or pores within its structure or texture, typically substantially uniformly distributed within its structure or texture. A porous material within the meaning of the present specification may also comprise a lattice and/or a scaffold. Typically, a porous material may be characterized by a relatively high specific surface area (large ratio of surface area to mass).

In an embodiment, the second portion of the implant may in particular have a porosity of at least 5 %, in particular of at least 7.5 %, in particular of at least 10 %, in particular of at least 12.5 %, in particular of at least 15 %, in particular of at least 20 %, in particular of at least 25 %. The upper limit of the porosity of the second portion of the implant is not particularly limited and the second portion of the implant may have for instance a porosity of not more than 90 %, in particular not more than 85 %, in particular not more than 80 %, in particular not more than 75 %, in particular not more than 70 %. In the context of the present specification, the term "porosity" may in particular denote the ratio of the volume of voids to the total volume. The porosity can be determined by conventional porosimetric methods known to a person skilled in the art, for instance by microscopy, such as atomic force microscopy (AFM), confocal microscopy or scanning electron microscopy (SEM).

In an embodiment, the first portion of the implant may in particular have a porosity of less than 5 %, in particular less than 3 %, in particular less than 2 %, in particular less than 1 %, in particular less than 0.5 %, and in particular approximately 0 %. In an embodiment, the first portion may constitute 20 to 80 wt.-% of the implant, in particular 25 to 75 wt.-% of the implant, such as 30 to 70 wt.-% of the implant. Likewise, the second portion may constitute 20 to 80 wt.-% of the implant, in particular 25 to 75 wt.-% of the implant, such as 30 to 70 wt.- % of the implant.

In an embodiment, the implant comprises one first portion being substantially solid and one second portion being substantially porous. In other words, the (entire) first portion may in particular be integral (i.e. not divided in parts) and the (entire) second portion may in particular be integral (i.e. not divided in parts) as well. By taking this measure, it may be possible that the first portion may be particularly efficiently configured for fixing the implant in a body material of a human or animal being and that the second portion may be particularly efficiently configured for regenerating cartilage tissue and/or for allowing an immigration of cartilage cells and/or for accommodating stem cells, as will be explained in further detail below.

In an embodiment, the first portion is configured for fixing (attaching, adhering) the implant in a body material of a human or animal being, in particular in or at a bone. Being substantially solid, the first portion may exhibit particular mechanical properties, such as mechanical strength, which enable an appropriate and secure fixation or attachment of the implant in a body material (such as a bone) of a human or animal being. In addition, being substantially solid, the first portion does not substantially disintegrate or corrode so that the secure fixation of the implant in the body material can be maintained over a long period of time, in particular over the entire life time of the implant.

In an embodiment, the second portion is configured for releasing magnesium ions, in particular in a controlled manner, into the surrounding tissue or body material, such as an interstitial fluid of a joint. Being substantially porous, the second portion possesses a relatively high specific surface area allowing for a substantial interaction between the magnesium alloy material of the second portion of the implant and for instance the interstitial fluid. As a result, the magnesium alloy material of the second portion of the implant may gradually disintegrate or corrode, thereby releasing magnesium ions into the interstitial fluid or the like.

In an embodiment, the second portion is configured for regenerating cartilage tissue and/or for allowing an immigration of cartilage cells and/or for accommodating stem cells, in particular (human or animal) mesenchymal stem cells, more specifically synovial mesenchymal stem cells. Without wishing to be bound to any theory, the present inventors currently assume that magnesium ions released from the second portion of the implant may enter chondrocytes (or cartilage cells) via transporters of divalent cations, such as TRPM7 or MAGT1, and may have an effect on master regulators of osteogenic and chondrogenic differentiation (such as RUNX2 and SOX9, respectively) in the chondrocytes, thereby promoting cartilage cell growth resulting in a regeneration of cartilage tissue. This effect may be further promoted or synergistically enhanced by an immigration of cartilage cells within the porous structure of the second portion of the implant. Likewise, stem cells, in particular synovial mesenchymal stem cells, may be

accommodated at and/or within the porous structure of the second portion of the implant, thereby further improving regeneration of cartilage tissue.

In an embodiment, the second portion could also be pre-incubated with stem cells, in particular with mesenchymal stem cells, for instance with

mesenchymal stem cells that were isolated from a patient in vitro, before performing the implantation in a two-step procedure. Alternatively, a one-step procedure may be employed, whereby mesenchymal stem cells are taken directly from fat deposits of a patient and inserted into the implant portion, which is then implanted directly.

In an embodiment, the second portion comprises a lattice and/or a scaffold. Hereby, an immigration of cartilage cells within the porous structure of the second portion of the implant and/or an accommodation of stem cells may be further promoted. In addition, a degradation rate (corrosion rate) may hereby be appropriately adjusted or adapted, providing for a release of magnesium ions in a specifically controlled manner.

In an embodiment, a magnesium release rate (degradation rate) of the second portion is higher than a magnesium release rate of the first portion, in particular by a factor of at least two, in particular by a factor of at least five, in particular by a factor of at least ten. Hereby, it may be suitably achieved that a sufficient gradual release of magnesium ions can be attained, while a secure fixation of the implant in a body material can be maintained over a long period of time.

In an embodiment, the first portion and/or the second portion is at least partially covered by a biocompatible (thin) film. In other words, at least part of the implant may be surface- modified. The biocompatible (thin) film does preferably not form part of the first portion and/or the second portion covered by the biocompatible (thin) film. In particular, the first portion and the second portion themselves are preferably not in the shape of a film or layer. Rather, the first portion and the second portion preferably have a three-dimensional body.

In particular, the first portion may be at least partially covered by a (first) biocompatible film, which may be in particular configured for controlling (in particular reducing) the corrosion or degradation of the magnesium alloy material of the first portion, i.e. controlling (in particular reducing) a

magnesium release rate of the first portion. The first biocompatible film may thus also be referred to as a protective coating. Additionally or alternatively, the second portion may be at least partially covered by a (second)

biocompatible film, which may be different from the first biocompatible film. The second biocompatible film may also be configured for controlling (in particular reducing, but typically to a less extent than the first biocompatible film) the corrosion or degradation of the magnesium alloy material of the second portion, i.e. controlling (in particular reducing) a magnesium release rate of the second portion. Additionally or alternatively, the biocompatible (thin) film, in particular the second biocompatible film, may be configured for controlling (such as increasing or decreasing) adsorption of biological molecules on a surface of the implant (in particular of the second portion), and/or for enhancing cell growth.

In an embodiment, the biocompatible (thin) film comprises a calcium

phosphate, in particular at least one of the group consisting of tricalcium phosphate (Ca3(P0₄)2), octacalcium phosphate (03₈H₂(R0₄)₆·5H₂0), and hydroxyapatite (Caio(P0₄)₆(OH)2). These materials may ensure

biocompatibility and may efficiently control the corrosion rate of the

magnesium alloy material coated by the film. In particular, the biocompatible film may comprise hydroxyapatite (Caio(P0₄)₆(OH)₂), which may enhance osseointegration and/or promote bone growth, thereby rendering it

particularly suitable for coating at least part of the first portion of the implant.

In an embodiment, the biocompatible (thin) film comprises one or more pharmaceutical agents, in particular one or more pharmaceutical agents that promote cell death of non-dividing stem cells. Suitable examples thereof include dasatinib, quercetin, and navitoclax. Hereby, it may be for instance possible to allow dividing stem cells to proliferate further.

In an embodiment, the biocompatible (thin) film comprises at least one of a polymer or a glass (i.e. an amorphous silica-based material, such as bioglass). By taking this measure, the corrosion or degradation of the magnesium alloy material may be particularly efficiently controlled (in particular reduced). In addition, a polymer- or glass-based biocompatible (thin) film may be

particularly suitable for containing, in particular embedding, a pharmaceutical agent.

In an embodiment, the first portion and the second portion are made of the same material (disregarding an optional first and/or second biocompatible film). In particular, the first portion and the second portion may comprise the same magnesium alloy. Hereby, it may be possible to efficiently and easily manufacture the implant. Moreover, any undesired (electrical or

electrochemical) potential differences between the first and the second portion may hereby be efficiently avoided.

In an embodiment, the magnesium alloy comprises zinc in an amount of not more than 1.0 wt.%, and calcium in an amount of not more than 1.0 wt.%, with the balance being magnesium and inevitable impurities.

More specifically, the magnesium alloy may comprise 0.1 to 0.6 wt.% zinc, and 0.2 to 0.6 wt.% calcium, with the balance being magnesium and inevitable impurities, wherein each impurity is contained in an amount of not more than 0.01 wt.% and the sum of impurities is 0.1 wt.% or less, and wherein a quotient of the percentages by weight of zinc and calcium being less than or equal to 1, as described for instance in EP 2 857 536 Al, the entire disclosure of which is hereby incorporated herein by reference. Hereby, it may be possible to achieve strengths of up to 250 MPa and elongations of up to 20% and to tackle alloy corrosion in a twofold approach through (1) the use of distilled (highly pure) Mg, and (2) the reduction of Zn content, so that a 100- fold reduction of the degradation rate and thus of hydrogen gas production could be achieved. Such alloy composition uniquely combines strength, ductility, degradation resistance, and biocompatibility for most orthopedic applications.

In an embodiment, the implant is shaped as a screw and/or a nail. In particular, the implant may be shaped as a screw, wherein the first portion is shaped as a screw thread and the second portion is shaped as a screw head. Hereby, a secure fixation of the fixation of the implant in the body material (via the screw thread-shaped first portion) and a sufficient release of magnesium ions (via the screw head-shaped second portion) can be achieved.

In an embodiment, the first portion and the second portion are manufactured separately. In other words, the implant may be configured as a modular system from a first portion and a second portion provided separately. Hereby, the implant may be provided with a particular high freedom of design from individual components of a first and a second portion, so as to individually adapt the implant to actual needs of a patient in a specific situation. In this embodiment, the first portion and the second portion are preferably configured for being assembled, in particular via an interlocking screw system, during implantation. Thus, several smaller parts (rather than one large integral part) may be implanted which might reduce the stress for the patient upon surgery and may even allow for a minimally invasive or endoscopic surgery.

In an embodiment, the first portion and/or the second portion is obtained by a three-dimensional printing procedure. Hereby, the desired structure or shape of the implant, for example with a second portion comprising a scaffold or lattice, may be easily and reliably achieved.

In a second aspect, the present invention relates to a method of preparing an implant based on a magnesium alloy (such as an implant as described in the foregoing). The method comprises the steps of forming a first portion such that the first portion is substantially solid and forming a second portion such that the second portion is substantially porous.

In an embodiment, the forming of the first portion and/or the forming of the second portion comprises three-dimensional printing. Hereby, the desired structure or shape of the implant, for example with a second portion

comprising a scaffold or lattice, may be easily and reliably achieved.

In an embodiment, the method further comprises the step of forming a biocompatible (thin) film at least partially covering the first portion and/or the second portion.

In an embodiment, the step of forming a biocompatible (thin) film comprises (or involves) atomic layer deposition (ALD). Atomic layer deposition, which may be referred to as a sequential chemical vapor deposition (CVP), is particularly suitable because it allows the deposition of a uniform film of atomic dimensions over a rough surface. In addition, by means of ALD, uniformity in terms of morphology and crystallinity of the thin film may be suitably achieved, in contrast to other deposition techniques, such as pulsed laser deposition, plasma spraying or sol gel techniques, which often provide poor coating/substrate adhesion and/or no uniformity in terms of morphology and crystallinity, even often resulting in amorphous layers, which have a high dissolution rate in solution. ALD is based on successive, surface controlled reactions of precursors from gas phase to produce thin films and overlayers with perfect conformity to surface topography and process controllability. Surface reactions (gas/solid) are saturated, auto limiting and separated between at least two components. All the reactions are cyclically repeated. In other words, ALD allows processing uniform and homogeneous thin films, in general dense and non-porous, over small or large areas, by building one mono-atomic layer after another (or a distinct fraction thereof). Atomic level control ensures that extremely thin films and complex nanostructures can be processed. ALD can also be used to modify the interfaces or to dope a thin film at a level required, including delta-doping. ALD processes work under relatively soft conditions (T_deposition = 25-600°C and P = 1-1000 mbar) that allow the use of fragile substrates like polymers or biological supports, porous or dense. Generally, water (H₂0), ozone (0₃) or oxygen (O2) may be chosen as oxygen source for the formation of oxide layer, depending on the

precursors used.

The thus obtained implant may be suitably used in the treatment, amelioration and/or prevention of osteoarthrosis or related joint diseases. Additional suitable application fields include dental (such as tooth implant screws), orthopedics (such as hip and knee implants, fractures) and spinal (such as spinal cage screws).

While the present invention has been described in detail by way of specific embodiments and examples, the invention is not limited thereto and various alterations and modifications are possible, without departing from the scope of the invention.

Claims

C L A I M S

1. An implant based on a magnesium alloy and comprising

a first portion being substantially solid; and

a second portion being substantially porous.

2. The implant according to claim 1, wherein the first portion is configured for fixing the implant in a body material, in particular in a bone.

3. The implant according to claim 1 or 2, wherein the second portion is configured for regenerating cartilage tissue and/or for allowing an immigration of cartilage cells and/or for accommodating stem cells.

4. The implant according to any one of the preceding claims, wherein the second portion is pre-incubated with stem cells, in particular with

mesenchymal stem cells.

5. The implant according to any one of the preceding claims, wherein the second portion comprises a lattice and/or a scaffold.

6. The implant according to any one of the preceding claims, wherein a magnesium release rate of the second portion is higher than a magnesium release rate of the first portion, in particular by a factor of at least two.

7. The implant according to any one of the preceding claims, wherein the first portion and/or the second portion is at least partially covered by a biocompatible film.

8. The implant according to claim 7, wherein the biocompatible film is configured for

- controlling a magnesium release rate of the first portion and/or the second portion, - controlling adsorption of biological molecules on a surface of the implant, in particular of the second portion, and/or

- enhancing cell growth.

9. The implant according to claim 7 or 8, wherein the biocompatible film comprises a calcium phosphate, in particular at least one of the group consisting of tricalcium phosphate (Ca3(P0₄)2), octacalcium phosphate

(Cash CPO^e-Sh O), and hydroxyapatite (Cai₀(PO₄)₆(OH)₂).

10. The implant according to any one of claims 7 to 9, wherein the biocompatible film comprises one or more pharmaceutical agents, in particular one or more pharmaceutical agents that promote cell death of non-dividing stem cells.

11. The implant according to any one of claims 7 to 10, wherein the biocompatible film comprises at least one of a polymer or a glass.

12. The implant according to any one of the preceding claims, wherein the first portion and the second portion are made of the same material and/or comprise the same magnesium alloy.

13. The implant according to any one of the preceding claims, wherein the magnesium alloy comprises

zinc in an amount of not more than 1.0 wt.%, and

calcium in an amount of not more than 1.0 wt.%,

the balance being magnesium and inevitable impurities.

14. The implant according to claim 13, wherein the magnesium alloy comprises

0.1 to 0.6 wt.% zinc, and

0.2 to 0.6 wt.% calcium, the balance being magnesium and inevitable impurities, wherein each impurity is contained in an amount of not more than 0.01 wt.% and the sum of impurities is 0.1 wt.% or less,

wherein a quotient of the percentages by weight of zinc and calcium being less than or equal to 1.

15. The implant according to any one of the preceding claims, wherein the implant is shaped as a screw and/or a nail.

16. The implant according to claim 15, wherein the implant is shaped as a screw, wherein the first portion is shaped as a screw thread and the second portion is shaped as a screw head.

17. The implant according to any one of the preceding claims, wherein the first portion and the second portion are manufactured separately and are configured for being assembled, in particular via an interlocking screw system, during implantation.

18. The implant according to any one of the preceding claims, wherein the first portion and/or the second portion is obtained by a three-dimensional printing procedure.

19. A method of preparing an implant based on a magnesium alloy comprising the steps of:

forming a first portion such that the first portion is substantially solid; and

forming a second portion such that the second portion is substantially porous.

20. The method according to claim 19, wherein the forming of the first portion and/or the forming of the second portion comprises three-dimensional printing.

21. The method according to claim 19 or 20, wherein the method further comprises the step of forming a biocompatible film at least partially covering the first portion and/or the second portion.

22. The method according to claim 21, wherein the step of forming a biocompatible film comprises atomic layer deposition (ALD).