Coated Medical Device and Method of Coating a Medical Device to Reduce Fibrosis and Capsule Formation

Abstract

Coating for a medical device comprising cell-adhesive proteins having the ability to reduce fibrous reaction, said coating being in the form of separate islets having an individual area which is less than 12 m.sup.2 and wherein the distance between the islets is less than 50 m.

Claims

1. A medical device comprising a covalently attached coating, the coating comprising cell-adhesive proteins having the ability to reduce fibrous reaction, wherein the cell-adhesive proteins comprise collagen, fibronectin, vitronectin, or combinations of fibronectin and vitronetic, wherein the coating is in the form of separate islets each having an individual area that is less than 12 m.sup.2, and wherein the distance between the islets is between 1 m and 50 m.

2. The medical device of claim 1, wherein the distance between the islets is less than 6 m.

3. The medical device of claim 1, wherein the islets have a uniform geometrical shape.

4. The medical device of claim 1, wherein the islets have a non-uniform geometrical shape.

5. The medical device according to claim, wherein the islets have a length that is less than 6 m, a width that is less than 2 m and a distance between islets that is less than 6 m.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0041] FIG. 1 shows a medical device before and after being coated according to one embodiment of the invention; and

[0042] FIG. 2 shows examples of islet shapes according to a preferred embodiment of the invention.

[0043] FIG. 3 The deposited proteins of the coating are organized in islets of a length that is <6 m, a width that is <2 m and distance between them that is <6 m. The fibroblasts attach to the surface and do not become myofibroblasts.

[0044] FIG. 4 On the left, fibroblasts become myofibroblasts (white cells) on control surfaces without coating. On the right, islets f a length that is <6 m, a width that is <2 m and distance between them that is <6 m impaired the formation of myofibroblasts.

[0045] FIG. 5 In the presence of a coating with islets >6 m in length, a width >2 m and distance between them >6 m, fibroblasts attach and become myofibroblasts (white cells).

[0046] FIG. 6 Control implants, on the left, induce fibrosis (in black, myofibroblasts) and capsular contraction at the interface with living tissues. The coating organized in islets of proteins of a length that is <6 m, a width that is <2 m and distance between them that is <6 m reduces this reaction several folds.

DETAILED DESCRIPTION OF THE INVENTION

[0047] The invention describes a new method of micro-deposition of cell-adhesive proteins and molecules onto the surface of medical devices, such as, but not limited to highly deformable and elastic substrates (such as, but not limited to silicone), Titanium, Plastic, Polyurethane and generally all materials used for medical devices and implants.

[0048] The micro-deposited islets of proteins guide cell adhesion on medical devices with the objective to reduce the fibrotic reaction of the cells and tissues in contact with the device.

[0049] As shown in FIG. 1 according to an embodiment of the invention a microperforated stencil or mask is used to transfer proteins to coat a medical device. 1. Deposition of the proteins and molecules is in the form of specific islets. 2. Protein islets include any possible geometrical shape and spatial organization and individual area. Protein islets (2) are deposited to modulate cell and tissue adhesion to medical devices (1).

[0050] The distance between the islets may vary from 1 to 50 m. The area of the single islets being less than 12 m.sup.2.

[0051] The distribution of protein islets according to a preferred embodiment of the invention to best reduce fibrosis includes single islets, wherein the islets have a length that is <6 m, a width that is <2 m and distance between them that is <6 m.

[0052] In another embodiment, deposited islets could have any geometrical shape. Examples to which the invention is not limited are illustrated in FIG. 2.

[0053] The mask or a stencil to transfer the islets is micro fabricated using technology as for example photolithography, dry and wet etching, laser cutting.

[0054] As type of mask or stencil should be mentioned soft stencils made from silicone and flexible polymers and hard stencils from silicon, hard polymer and metal.

[0055] To deposit proteins onto medical device as for example an implant surface, the stencil is first brought in conformal contact with the surface and then the proteins are transferred on the surface through the micro-holes of the stencil by covalent binding using 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde or formaldehyde. After the crosslinking of proteins, the stencil is removed and the pattern remains on the implant surface.

[0056] Another possible method is electro deposition or precipitation of proteins on implant or medical device surface through the micro-holes of stencil or mask. These possibilities are just examples and should not limit the invention to this approach of deposition.

[0057] Our results in vitro and in vivo illustrate the importance of the size of the islets in reducing fibrosis and contraction around implants proving the relevance of this invention. We found that the main mechanism responsible for limiting the differentiation of human dermal fibroblasts in myofibroblasts (the main cell responsible for fibrosis and contraction) is the area of adhesion.

[0058] In our experiments, the islets represent areas of adhesion (focal adhesions) for the cells and dimensions of the islets of a length that is <6 m, a width that is <2 m and distance between them that is <6 m impaired the formation of myofibroblasts (FIG. 3).

[0059] The specific islet size and distribution with a length <6 m, a width <2 m and distance between them <6 m does not allow fibroblasts to exert forces on the surface where they attach and become myofibroblasts (the main cell responsible for fibrosis and contraction).

[0060] In vitro, we showed that this specific size and distribution of proteins reduced 10-fold the differentiation of human dermal fibroblasts to myofibroblasts compared to devices coated with other size and distribution of proteins (FIG. 4). The deposition of islets of higher size allowed the differentiation of fibroblasts in myofibroblasts. These later cells were seen in high percentage (up to 20%) when the surface was coated with larger islets than the specific ones provided by this invention (FIG. 5).

[0061] In vivo, silicone pads (11 cm) covalently coated with a stencil or mask, as described in the methods, on both side with protein islets with a length <6 m, a width <2 m and distance between them <6 m, were inserted in subcutaneous pockets, in female Wistar rats (250-350 g). On the scapular region of the dorsum of these animals, 4 coated silicone pads were placed. Each animal received four implants: two implants coated with islets with a length <6 m, a width <2 m and distance between them <6 m; and two non coated silicone implants, alternating the location on successive animals. Results at 6 months show a 3-fold decrease in capsule formation around implants coated with islets of proteins with a length <6 m, a width <2 m and distance between them <6 m (FIG. 6).

[0062] In vitro and in vivo results show that the transformation of fibroblasts into myofibroblasts is crucial in the development of fibrosis and capsule

[0063] contraction around medical implants and underline the importance of this invention specifically limiting this event.

[0064] The optimized protein islets deposition with e.g. a length <6 m, a width <2 m and distance between them <6 m can be applied to any medical device such as, but not limited to: [0065] Silicone breast implants [0066] Tissue expanders and inflatable pumps [0067] Bone, and cartilage and orthopaedic implants [0068] Tendon, nerve, and ligament transplants, substitutes and implants [0069] Implantable pumps, such as insuline pumps and drug delivery systems [0070] Cardiovascular devices, such as pace makers, vascular prosthesis, heart valves, vascular stents [0071] Skin substitutes and cell scaffolds [0072] Wound dressings, including dressings and wound interfaces connected to a vacuum (negative pressure dressings) [0073] Acoustic waves (such as shockwave therapy) [0074] Ear, throat, nose and eye implants [0075] Brain, central and peripheral nervous system implants and prosthesis [0076] Tubes, connecting tubes, drainage tube systems