Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-12-08
2003-11-04
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S055100
Reexamination Certificate
active
06642213
ABSTRACT:
This application is a 371 of PCT/EP99/04167, filed Jun. 16, 1999.
FIELD OF THE INVENTION
The present invention describes three-dimensional prostheses and process for their preparation.
Three-dimensional prostheses of the present invention can be used alone or in association with pharmaceutically or biologically active substances, and can be used as such or can act as scaffolds for cell cultures. Said three-dimensional prostheses are useful for reconstruction of human or animal body part, surgery or neurosurgery.
TECHNICAL BACKGROUND
Prostheses intended for implant are usually made of synthetic materials or natural, treated materials.
Defects of the body walls, such as the abdominal walls, that cannot be repaired by autogenous tissues because of the extent of the trauma, may be treated, for example, with synthetic meshes.
Indeed, the materials normally used for prostheses to reinforce or repair traumatised abdominal walls are tantalum gauze, stainless steel meshes, polypropylene tissues, microporous e-PTFE, polygalactin 910, polyester, polyglycolic acid, cross-linked bovine pericardium.
It has not, however, been possible to date to obtain satisfactory recovery of damaged tissue or impaired organs by implanting artificial prostheses such as cardiovascular or bone prostheses made of synthetic polymers or metals. Indeed, these types of prostheses are prone to provoke inflammatory reactions in the host, they rarely integrate easily with the surrounding microenvironment, they cause the formation of fibroses and they are subject to mechanical wear and tear, thus requiring regular checks.
One alternative is to transplant autologous tissues or organs, or more frequently allogenic or even xenogenic ones. This solution has various disadvantages, such as immunogenic reactions, infections and the dearth of donors. Recently, a new biomedical practice known as tissue engineering has been gaining ground. By this means, tissues similar to those of the organism can be obtained by taking cells by minor biopsies, expanding them in culture and cultivating them on biodegradable scaffolds. Such tissues, for example skin, cartilage and bone, are created in vitro and then grafted onto the patient (EP 0462426, WO 97/18842).
Other tissues for which work is in progress to improve the reconstruction techniques are those of the visible parts or appendices of the human body such as the ears, nose, nipples, lips and breasts.
It has proved particularly difficult, to date, to reconstruct the auricula because of the difficulties linked with the anatomical location of the ear, where any asymmetries of size, shape or position are instantly noticeable. Moreover, it is difficult to reproduce the complex form of irregularly-shaped cartilage covered with skin.
Various techniques are used to reconstruct the ear, according to the severity of the trauma.
In cases where only part of the ear has been severed, pieces of the same ear or the surrounding tissues are used to reconstruct the damaged part, or portions of intercostal cartilage are grafted into place and then covered with strips of adjacent skin, so that the implant can become vascularised.
When the auricula has been almost completely severed, synthetic auricular prostheses can be used. These have numerous disadvantages, however, such as the need for daily care, damage to the surrounding skin both on account of the direct contact with the prosthesis and because of the strong adhesives required to fix them in place. Some prostheses, however, are directly implanted into the bone. Another reconstruction method consists in increasing the volume of tissue still available by means of expanders.
Lastly, a very complex surgical technique is sometimes used that involves several steps carried out at different times, which gives acceptable results only after months of treatment.
Briefly, this technique consists in taking a portion of intercostal cartilage from the patient and shaping it into a form resembling the outer ear. The cartilage is usually first implanted subcutaneously on the forearm or back in order for it to become vascularised, and is removed several times for reshaping.
When the implant has reached a satisfactory stage of maturity, it is implanted in place of the ear and covered with a strip of adjacent skin.
Lastly, the patient has to undergo further operations to improve the aesthetic quality of the implant.
Besides the disadvantage of having to perform so many different operations on the patient, this technique involves the use of intercostal cartilage which has different characteristics from that of the ear, such as its lesser elasticity.
Unfortunately, these prostheses often do not take and degenerate to the point of generalised necrosis and failure of the transplant or, more rarely, the cartilage may transform into bony tissue (calcification).
The ideal material for such prostheses is therefore chemically inert, non-carcinogenic, able to stand up to mechanical stress and able to be shaped into the desired form, sterilizable, not prone to physical modification by the tissue fluids, they must not induce inflammatory, immunological, allergic or hypersensitivity reactions and they must not promote visceral adhesions (Jenkins S. D. et al. Surgery 94 (2); 392-398, 1983).
SUMMARY OF THE INVENTION
The present invention describes a three-dimensional prosthesis in the shape of a body part comprising at least one three-dimensional matrix having an essentially fibrous or porous structure and containing at least one hyaluronic acid derivative, said prosthesis, when contains at least two of said three-dimensional matrixes, the first of said three-dimensional matrixes incorporating or being adhered to the second and possible further matrixes, said three-dimensional matrix(es) optionally incorporating and/or being adhered to a bidimensional perforated matrix and containing a hyaluronic acid derivative.
Said three-dimensional prostheses further comprise cells chosen from the group consisting of autologous or endogenous mature or mesenchymal cells, or complex systems of mesenchymal and different type of mature cell types.
DETAILED DESCRIPTION OF THE INVENTION
According to a preferred embodiment the prosthesis of the present invention comprises a matrix (A) selected from the group consisting of:
A1. A three-dimensional matrix having an essentially fibrous structure
A2. A three-dimensional matrix having an essentially porous structure
A3. A bidimensional perforated matrix
said matrix (A) incorporating and/or being adhered to a matrix selected from the group consisting of
B. A three-dimensional matrix having an essentially porous structure in case (A) is (A1) or (A3)
C. A three-dimensional matrix having an essentially fibrous structure in case (A) is (A2) or (A3)
D. A bidimensional perforated matrix in case (A) is (A1) or (A2)
said matrix (A), (B), (C), (D) comprising at least one hyaluronic acid derivative.
Of the hyaluronic acid derivatives to be used in the preparation of the three-dimensional prostheses according to the present invention, the following are the ones of choice:
hyaluronic acid esters wherein a part or all of the carboxy functions are esterified with alcohols of the aliphatic, aromatic, arylaliphatic, cycloaliphatic, heterocyclic series (EP 0216453 B1 entirely incorporated by reference), especially with benzyl alcohol;
cross-linked esters of hyaluronic acid wherein part or all of the carboxy groups are esterified with the alcoholic functions of the same polysaccharide chain or of other chains (EP 0341745 B1 entirely incorporated by reference);
cross-linked compounds of hyaluronic acid wherein part or all of the carboxy groups are esterified with polyalcohols of the aliphatic, aromatic, arylaliphatic, cycloaliphatic, heterocyclic series, generating cross-linking by means of spacer chains (EP 0265116 B1 entirely incorporated by reference);
hemiesters of succinic acid or heavy metal salts of the hemiester of succinic acid with hyaluronic acid or with partial or total esters of hyaluronic acid (WO 96/357207 entirely incorporated by reference);
O-sulphated deriv
Callegaro Lanfranco
Pastorello Andrea
Radice Marco
Fidia Advanced Biopolymers S.r.l.
O'Sullivan Peter
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