WO2009109646A2

WO2009109646A2 - Sternal closure device

Info

Publication number: WO2009109646A2
Application number: PCT/EP2009/052644
Authority: WO
Inventors: Darren Donald Obrigkeit
Original assignee: Dsm Ip Assets B.V.
Priority date: 2008-03-05
Filing date: 2009-03-05
Publication date: 2009-09-11
Also published as: WO2009109646A3

Abstract

The invention relates to a sternal closure device comprising a thermoplastic elastomer comprising a hard phase and soft phase, wherein the hard phase comprises a polymer chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft phase comprises a polymer chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane.

Description

STERNAL CLOSURE DEVICE

The invention relates to a sternal closure device. The invention further relates to the use of a thermoplastic elastomer (TPE) in a sternal closure device and in procedures for surgery, in particular bypass surgery.

A median sternotomy is a surgical procedure in which a vertical incision is made along the midline of the sternum and the sternum is divided. Median sternotomies provide access for thoracic surgical procedures, including coronary artery bypass and heart transplant. When the surgical procedure that necessitated the median sternotomy is complete, the sternum is closed. Typically, needles are used to loop a metal wire through the manubrium, the bone that defines the top of the sternum. Below the manubrium, metal wires are looped through the intercostal spaces and around the sternum. The loops of metal wire are cut to create individual lengths of the wire, and the ends of those lengths of metal wire are twisted together to tension them. Certain difficulties arise with the traditional manner of closing the median sternotomy. First, it can be difficult for the surgeon to estimate the necessary amount of closure force correctly. Additionally, threading the metal wire around and through the sternum creates an increased risk of organ puncture. Moreover, after the procedure is performed, other difficulties may arise. For example, the patient may have a foreign body reaction, and the presence of metal wires may preclude or restrict the use of certain imaging techniques, like magnetic resonance imaging (MRI). Moreover, metal wires can cut bones if pulled too tight, or result in poor healing if not tightened enough. Ultimately 3-5 % of the patients may require a re-sternotomy due to inadequate closure or complications. Additionally, allergy to metal, in particular to nickel, occurs frequently.

The aim of the invention is therefore to provide a sternal closure device that does not show at least some of the aforementioned disadvantages, or at least shows them to a lesser extent.

This aim is achieved by providing a sternal closure device comprising a thermoplastic elastomer (TPE) comprising a hard phase and soft phase, wherein the hard phase comprises a polymer chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft phase comprises a polymer chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane. The TPE according to the invention has a crystalline (hard phase) component which is very resilient to mechanical forces. In particular it is capable of accommodating 400 N forces for periods of 6-8 months, which is a requirement for sternal closure devices, as disclosed in e.g. US2007/0260251A1. Moreover, it can easily be processed due to its relatively low melt viscosity to provide a variety of designs, by for example injection molding, which is particularly advantageous as sternal closure devices ideally have a flat profile to prevent tissue irritation. TPE's can easily be shaped into designs adapted to anatomy and/or surgical procedure, which do not require tying/twisting of steel wire for closure. Moreover, whereas steel wires can cut bones if pulled too tight, this can be avoided by using the sternal closure device according to the invention. The result can further be optimized by using overmolded TPE designs comprising soft TPE pads for contact points with sternal bone. Another advantage of sternal closure devices which are made of the TPE according to the invention is that they are MRI compatible

The TPE according to the invention exhibits low creep and low compression set. Compression set testing is used to determine the ability of elastomeric materials to maintain elastic properties after dynamic stress or prolonged compressive stress. The test measures the somewhat permanent deformation of the specimen after it has been exposed to compressive stress for a set time period. The compression set for TPE's is only about 15-20%. The sternal closure device according to the invention comprises a thermoplastic elastomer comprising a hard phase and a soft phase.

The hard phase in the TPE comprises a rigid polymer phase with a melting temperature (Tm) or a glass transition temperature (Tg) higher than 35 ⁰C. The soft phase in the TPE comprises a flexible, amorphous polymer phase with a Tg lower than 35 ⁰C, preferably lower than 0 ⁰C. The Tm and Tg were determined on a dry sample.

The TPE, used according to the invention, comprises, for example, blends of the above-mentioned hard phase polymers with soft phase polymers and block copolymers. The hard and the soft phase can comprise one polymer type, but can also be composed of a mixture of two or more of the above-mentioned polymeric materials.

Preferably, the TPE, used according to the invention, is a block- copolymer. When the TPE is a block-copolymer, the TPE used in the sternal closure device comprises a thermoplastic elastomer comprising hard blocks and soft blocks, wherein the hard blocks comprise a polymer chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft blocks comprise a polymer chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane.

Examples of TPE block-copolymers according to the invention are block-copolyesterester, block-copolyetherester, block-copolycarbonateester, block- copolysiloxaneester, block-copolyesteramide, block-copolymer containing polybutylene terephthalate (PBT) hard blocks and poly(oxytetramethylene) soft blocks, block- copolymer containing polystyrene hard blocks and ethylene butadiene soft blocks (SEBS). The hard blocks in the thermoplastic elastomer consist of a rigid polymer, as described above, with a Tm or Tg higher than 35 ⁰C. In principle the different polymers as described above can be used as the hard blocks. Here and in the rest of the description a polycarbonate is understood to be a polyester.

Also copolymers of esters, amides, styrenes, acrylates and olefins can be used as the hard polymer block as long as the Tm or Tg of the hard polymer block is higher than 35 ⁰C. Preferably, the hard block of the TPE is a polyester block. More preferably, in the TPE comprising a hard polyester block, the hard block consists of repeating units derived from at least one alkylene glycol and at least one aromatic dicarboxylic acid or an ester thereof. The alkylene group generally contains 2-6 carbon atoms, preferably 2-4 carbon atoms. Preferable for use as the alkylene glycol are ethylene glycol, propylene glycol and in particular butylene glycol. Terephthalic acid, 2,6-naphthalenedicarboxylic acid and 4,4'-diphenyldicarboxylic acid are very suitable for use as the aromatic dicarboxylic acid. Combinations of these dicarboxylic acids, and/or other dicarboxylic acids such as isophthalic acid may also be used. Their effect is to influence the crystallisation behaviour, e.g. melting point, of the hard polyester blocks.

Most preferably, the hard block is polybutyleneterephthalate. The soft blocks in the thermoplastic elastomer consist of a flexible polymer, as described above, with a Tg lower than 35 ⁰C. In principle the polymers as described above can be used as the soft blocks. Here and in the rest of the description a polycarbonate is understood to be a polyester.

Also copolymers of ethers, esters, acrylates, olefins and siloxanes can be used as the soft polymer block as long as the Tg of the soft polymer block is lower than 35 ⁰C. - A -

Preferably, the soft block comprises a polyester or a polyether; more preferably an aliphatic polyester or polyether. A particular advantage of TPE's comprising polyester, or polyether soft blocks is that aliphatic polyesters, and polyethers feature a high chemical stability. Especially, alkylene carbonates and aliphatic polyesthers are preferred as the soft block, which result in thermoplastic elastomers with particularly low moisture sensitivity and favourable adhesive properties. Preferably, the soft blocks in the TPE are derived from at least one alkylene carbonate and optionally, a polyester made up of repeating units derived from an aliphatic diol and an aliphatic dicarboxylic acid. The alkylene carbonate can be represented by the formula

-0-(CR₂VO-C-

where

R = H, alkyl or aryl, x = 2 - 20.

Preferably, R = H and x = 6 and the alkylene carbonate is therefore hexamethylene carbonate.

The aliphatic diol units are preferably derived from an alkylenediol containing 2 - 20 C atoms, preferably 3 - 15 C atoms, in the chain and an alkylenedicarboxylic acid containing 2 - 20 C atoms, preferably 4 - 15 C atoms.

More preferably, the soft block comprises a polycarbonate. It has been found that, with respect to their use in the sternal closure device according to the invention, in particular the thermoplastic block-copolyesters have many advantages over metals, such as titanium and stainless steel, and other polymers, such as PEEK because of their better mechanical properties, such as in particular superior flex fatigue performance as well as crack growth resistance, high wear resistance, low creep, low compression set, high dimensional stability and high resistance to moisture.

Most preferably, the TPE comprises a hard block comprising polybutyleneterephthalate and a soft block comprising polycarbonate. Optionally, this

TPE is chain-extended with diisocyanate. Examples and the preparation of block-copolyether esters are for example described in the Handbook of Thermoplastics, ed. O.OIabishi, Chapter 17, Marcel Dekker Inc., New York 1997, ISBN 0-8247-9797-3, Thermoplastic Elastomers, 2nd Ed., Chapter 8, Carl Hanser Verlag (1996), ISBN 1-56990-205-4, and the Encyclopedia of Polymer Science and Engineering, Vol. 12, pp.75-1 17, and the references contained therein.

In another embodiment of the invention polyethylene oxide (PEO) or a combination of polyethylene oxide and polypropylene oxide (PEO-PPO-PEO) can be used as the soft block, which has a good biocompatibility and was found to result in osteoconductive (e.g. bone-bonding) surfaces capable of osteointegration. The PEO soft block can, for example, be combined with a PBT hard block.

The ratio of the soft and hard blocks in the TPE used in the sternal closure device according to the invention may generally vary within a wide range but is in particular chosen in view of the desired modulus of the TPE. The desired modulus will depend on the structure and size (e.g. thickness) of the sternal closure device and the functionality of the TPE in it. Generally a higher soft block content results in higher flexibility and better toughness.

The TPE according to the invention may contain one or more additives such as stabilizers, anti-oxidants, antimicrobial agents, biostatic/biocidal agents, colorants, fillers, binders, fibers, meshes, substances providing radiopacity, surface active agents, foaming agents, processing aids, plasticizers, and any other known agents which are described in Rubber World Magazine Blue Book, and in Gaether et al., Plastics Additives Handbook, (Hanser 1990). Suitable examples of fillers, e.g. radiopaque fillers and bone-mineral based fillers, and binders are described in U.S. Patent Number 6,808, 585B2 in columns 8-10 and in U.S. Patent Number 7,044,972B2 in column 4, I. 30-43, which are herewith incorporated by reference.

Suitable commercially available TPE's include Arnitel^® TPE (DSM Engineering Plastics), in particular Arnitel^® E (polyether ester, PTMEG), Arnitel^® C (polycarbonate-ester, PHMC) and Arnitel^® P (polyether ester, polyols, polypropylene and polyethylene). Particularly suitable Arnitel^® grades include 55D, EL250, EM400, EM 450, EM550, EM630, EL740, PL380, PL381 , PM381 , PL580, PM581 , 3103, 3104, and 3107.

TPE's, in particular thermoplastic block polyesters have been the subject of numerous FDA regulatory approvals. Specifically, Arnitel^® copolyesters have been listed under the Drug Master Files 13260, 13261 , 13263, 13264, 13259, and 13262. Additionally, these compositions have been cleared for use in permanent implants (510(k) K990952, K896946). According to the FDA MAUDE database, adverse events dating back to prior April, 2000 are mild and due to mechanical failure (see catalog number 8886441433, 447071 , 8886471011 V, and 8886470401 ). The absence of adverse effects due to material confirms the long-term biocompatibility of these compositions.

Arnitel^® E grades are in compliance with the code of Federal regulation, issued by the Food and Drug Administration (FDA) 21 CFR 177.2600 (rubber articles for repeated use) in the USA, the so-called FDA approval. Moreover, US Pharmacopoeia approvals were received for the following Arnitel^® grades: EM400, EM450, EM550, EM740, PL580 and 3104 (USP Class Vl), and PL380 and PM381 (USP Class IV).

Moreover multiblock poly(aliphatic/aromatic ester) (PED) copolymers as described in M. El Fray and V. Altstadt, Polymer, 44 (2003) pp. 4643-4650 can suitably be used as the TPE according to the invention. The sternal closure device according to the invention can be produced in many different ways. Known techniques include (co-)injection molding, (co-)extrusion molding, or injection overmolding.

In one embodiment of the invention TPE is extruded on a metal wire, for example a stainless steel suture. This makes it possible to combine the advantages of the use of metals and TPE, respectively.

The TPE's according to the invention can be applied in multi component molding, for example, two component (2K) molding, either with other TPE's, hybrid metal or other polymers. Multi component molding makes it possible to produce designs comprising hard and soft parts, or parts with different properties. Arnitel^® grades are particularly suitable because of their superior adhesion to other types of Arnitel^®, other polymers and metal. Good adhesion prevents separation of the device parts, which may lead to a number of complications including device migration, blood vessel and/or nerve damage from the migrated device, etc. Additionally, multi component molding enables a number of innovative design features. The temperature and other processing conditions at which the TPE can best be processed depends on the melting temperature, the viscosity and other rheological properties of the TPE and can easily be determined by the person skilled in the art once said properties are known. The above mentioned Arnitel^® grades have melting temperatures (measured according to ISO 11357-1/-3) between 180 and 221 ⁰C and are preferably processed at temperatures between 200 and 250 ⁰C. The TPE's according to the invention, in particular Arnitel^® TPE's, can be sterilized by any known means.

The TPE's according to the invention can be foamed by any known method resulting in open or closed cell foam. For example, a hard TPE, e.g. harder than Shore 8OA or 9OA, can be used to provide a foamed end product with good hydrolytic stability, wear and lipid resistance while still providing softer properties.

Alternatively a similar effect can be accomplished by applying specific designs, in particular open structures, like a spring-like structure.

3-D selective laser sintering, producing open structure device of various porosity and open or closed cell structure can be used to modify the surface texture and properties, e.g. hydrophilicity.

Fused deposition modelling, as described in for example

Biomaterials, 2004 Aug: 25 (18), pp. 4149-4161 , can also be used to produce open structures with varying degrees of void volume and mechanical properties. In addition, these have been demonstrated to be effective in culturing cells and tissues.

Products, for example those produced by 3-D selective laser sintering or fused deposition modelling, can be tailored for e.g. bone in-growth or bone fusion by adding osteoconductive filler, for example hydroxyapatite.

The TPE's according to the invention can be cut with a fluid jet for customizing the sternal closure device shape to the patient's anatomy. Such fluid jets are described in patent US6960182 and are commercially provided by Hydrocision, Inc. (Billerica, MA). The ability to customize a sternal closure device with a fluid jet represents a significant advance over the current standard of practice.

For this type of applications hard-soft phase systems are unique because they have a crystalline (hard phase) component which is very resilient to mechanical forces. Moreover they are easily processable to provide a variety of designs and possess exceptional flex fatigue, which can be measured according to e.g. ISO 132 in which Arnitel^® TPE has been demonstrated to survive an excess of 15 million cycles. Sternal closure devices comprising TPE's according to the invention can be produced in radiopaque versions for easy visualization of the device under X- ray. This can be accomplished by one skilled in the art of polymeric fillers and biocompatible materials. For example, barium sulfate, zirconium dioxide, hydroxyapatite, tricalcium phosphate, and other substances which impart radiopacity are described in US6808585 and US7044972 and incorporated here by reference. Moreover it is possible to produce a fully MRI/CT - compatible sternal closure device by making it entirely of the TPE according to the invention.

As already mentioned above, a particular advantage of the use of a TPE according to the invention, in particular a block-copolyester, is its very good adhesion to different materials, for example to a different TPE, e.g. a TPE with a different stiffness or modulus, or a metal. This makes the material particularly suitable for application with for example a different TPE or a metal, for example stainless steel or titanium, in molding. This property is expressed as a high peel strength. Preferably the peel strength is higher than 6 N/cm, measured according to ISO/IEC standard 7810.

In Biomaterials, 1992 13(9), pp 585-593 it was demonstrated that the hydrolytic stability of the TPE according to the invention clearly outperforms that of polyurethanes.

Examples of known sternal closure device designs that can be made partially or completely from the TPE according to the invention, or that can be partially or completely overmolded with the TPE according to the invention are referred to in Table 1 ; details of the sternal closure devices can be found in the reference publications. In each sternal closure device one grade of TPE can be used or different grades of TPE with different properties. Moreover, the TPE according to the invention can be combined with other materials, for example metals, such as stainless steel or titanium, or other polymer materials, such as polyesters or polydioxanones.

Table 1. Examples of sternal closure devices.

The present invention will now be illustrated by the following examples that by no means limit the scope of the invention.

EXAMPLES

Materials

• Arnitel^® EL740 (hard block polybutylene terepthalate (PBT), soft-block: polytetramethyleneoxide (PTMO), modulus 1 100 MPa) from DSM N.V.

• Arnitel^® EL630 (hard block polybutylene terepthalate (PBT), soft-block: polytetramethyleneoxide (PTMO), modulus 310 MPa) from DSM N.V.

• Arnitel^® EL740 (hard block: polybutylene terepthalate (PBT), soft-block: polytetramethyleneoxide (PTMO), modulus 50 MPa) from DSM N.V.

• Arnitel^® EL250 (hard block: polybutylene terepthalate (PBT), soft-block: polytetramethyleneoxide (PTMO), modulus 25 MPa) from DSM N.V.

Example I

Arnitel^® EL740 is injection molded into a sternal closure device with a cable-tie-like device (as in Fig. 9, US5462542) with a cross-sectional area of 1 1.5 mm²

(i.e. 5 mm wide x 2.3 mm high). The sternal closure device is placed under tensile strain of 20 % resulting in a tensile stress of 35 MPa (ISO 527). This tensile stress is sufficient to carry a load of 400 N, the maximum load expected for a sternal closure device (see for example US 2007/0260251 A1 ).

Example Il The sternal closure device as produced in Example 1 is overmolded with a softer grade of TPE (Arnitel^® EL630) at the points where the sternal closure device is in contact with the sternum (at the edges of the sternum between the ribs).

Assuming a sternal thickness ranging from 3-12 mm (see US-4,161 ,951 ) and a device width (at the portions of the device in contact with the intercostal spaces) of 5 mm, the total contact area ranges between 15mm² and 60mm², resulting in contact stresses between 13 and 50 MPa. These are suitable for Arnitel^® EL630, a significantly softer material than traditional metal wires and cables. Example III

A USP #5 steel suture is overmolded with Arnitel^®EL630 to form two cylindrical sections with 8 mm outer diameter and 10 mm long, spaced such that the cylinderical sections come in contact with the intercostal spaces when implanted as a sternal closure device. This results in a system with traditional tensile properties and implantation methods, yet the overmolded contact points greatly increase the contact area with the bone and reduce stress on the bone compared to the bare USP #5 steel suture.

Traditional USP #5 suture has a diameter of 0.7 mm. Assuming 400 N hoop tensile stress on the suture after implantation as a sternal closure device this results in 800 N force on the bone at the intercostal spaces. Because the sternum ranges from roughly 3 to 12 mm in thickness, the total estimated contact area of the USP #5 suture against the bone is 2.2 and 8.4 mm². Resulting stresses on the sternum at this point range between 95 and 370 MPa, often well above the strength of human bone (see Table 2).

Using the same overmolds as in Example II, these stresses can be reduced to between 13 and 50 MPa while still allowing a similar surgical procedure.

Table 2. Strength of human bone (data form Lewandrowski et al., lnforma Healthcare, Spinal Reconstruction, 2007, p. 396).

Example IV

0.2 mm of Arnitel^® EL630 is extruded on traditional #5 USP stainless steel suture. This produces an overall diameter of 1.1 mm and increases the contact area to the range of 3.4-41 mm², reducing estimated stress on the sternum to between 20 and 230 MPa. This represents a significant decrease still over the 95-365 MPa with conventional steel suture and still offers almost virtually identical handling and processing compared to conventional steel suture. Furthermore, an extruded layer also enables substituting braided steel sutures for monofilaments which have many known advantages in strength, abrasion, etc. known to people skilled in the art while preserving the ease of handling and lower irritant and infection characteristics of a monoline suture.

Example V Samples of Arnitel^® EL250, EM400, and EL740 were tested under

GLP conditions according to ISO 10993 parts 3, 5, 6, 7, 10, and 11 :

ISO10993-3 Tests for genotoxicity, carcinogenicity, and reproductive toxicity. ISO 10993-5 Tests for in vitro cytotoxicity. ISO 10993-6 Test for local effects after implantation. ISO 10993-7 Ethylene oxide residuals.

ISO 10993-10 Test for irritation and delayed-type hypersensitivity. ISO 10993-11 Test for systemic toxicity

Each of these material grades passed all of the above biocompatibility tests, demonstrating the safety of Arnitel^® TPE as an material for a sternal closure device.

Example Vl

Samples of Arnitel^® types EL250, EM400, and EL740 were tested for the effects of gamma sterilization up to 100 KGray (roughly 4 times a typical sterilization dose). These samples were subsequently mechanically tested to determine the effects on E-modulus, Stress at Break, and Strain at Break. In all instances little or no changes in the material properties were observed.

Claims

1. Sternal closure device comprising a thermoplastic elastomer comprising a hard phase and soft phase, wherein the hard phase comprises a polymer chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft phase comprises a polymer chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane.

2. Sternal closure device according to Claim 1 , where in the hard phase and the soft phase are present in a block copolymer, wherein the hard blocks are chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft blocks are chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane.

3. Sternal closure device according to Claim 2, wherein the hard block is a polyester hard block.

4. Sternal closure device according to Claim 3, wherein the polyester hard block consists of repeating units derived from at least one alkylene glycol and at least one aromatic dicarboxylic acid or an ester thereof.

5. Sternal closure device according to Claim 4, wherein the polyester hard block is polybutyleneterephthalate.

6. Sternal closure device according to any one of Claims 1-5, wherein the soft block is an aliphatic polyester or polyether.

7. Sternal closure device according to Claim 6, wherein the soft block comprises polycarbonate.

8. Sternal closure device according to any one of Claims 2-7, wherein wherein the hard block is polybutyleneterephthalate and the soft block comprises polycarbonate.

9. Use of a thermoplastic elastomer comprising a hard phase and soft phase, wherein the hard phase comprises a polymer chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft phase comprises a polymer chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane in a sternal closure device.

10. Use of a thermoplastic elastomer comprising a hard phase and soft phase, wherein the hard phase comprises a polymer chosen from the group consisting of polyester, polyamide, polystyrene, polyacrylate and polyolefin and the soft phase comprises a polymer chosen from the group consisting of polyether, polyester, polyacrylate, polyolefin and polysiloxane in median sternotomy.

11. Use of the sternal closure device according to according to any one of Claims 1-8 in median sternotomy.