Compositions for regenerating tissue that has deteriorated, and methods for using such compositions

Abstract

A composition for promoting regeneration of tissue which has degenerated in a subject as a result of a disease or disorder and a method of using the composition is provided. The composition comprises a biodegradable acellular matrix, and passaged autologous fibroblasts substantially free of immunogenic proteins, e.g., culture medium serum-derived proteins, integrated within the matrix. The method of using the composition to promote regeneration of tissue involves placing the composition on a site of degenerated tissue in a subject so that the composition promotes tissue regeneration at the site. The composition and the method of its use have applications promoting regeneration of tissue (i) that has degenerated as a result of numerous diseases or disorders or (ii) that has a defect, including, but not limited to, defects of the oral mucosa, trauma to the oral mucosa (e.g., extraction of a tooth), periodontal disease, diabetes, cutaneous ulcers, venous stasis, scars of the skin, or wrinkles of the skin. Also provided is an injectable composition comprising any type of collagen and passaged autologous fibroblasts substantially free of immunogenic proteins, e.g., culture medium serum-derived proteins, for correcting defects in skin, such as wrinkles or scars, and for augmenting tissue in the subject, particularly facial tissue.

Description

[0001] This application is a continuation-in part and claims priority of U.S. application Ser. No. 09 / 316,245, filed May 21, 1999, which is a continuation-in-part and claims priority of U.S. application Ser. No. 09 / 083,618, filed May 22, 1998. U.S. application Ser. Nos. 09 / 316,245 and 09 / 083,618 are incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention concerns the regeneration of tissues in a subject that have degenerated as a result of a disease or disorder in the subject. More particularly, the present invention concerns novel compositions for use in surgical and nonsurgical techniques that promote regeneration of tissue whose mass has been diminished due to a disease or disorder in a subject, correct defects in the skin of subjects, or augment tissue in subjects. Also disclosed is the use of a novel composition in conjunction with a biodegradable acellular matrix for ameliorating defects in the tissues, and methods for using the n...

AI Technical Summary

Benefits of technology

"The present invention provides a method for promoting regeneration of tissue in a subject that has degenerated as a result of a disease or disorder. The method involves injecting a pharmaceutical composition of autologous fibroblasts into the tissue to be regenerated. The fibroblasts are taken from the subject's own body and are expanded in a culture medium before being injected back into the subject. The method can be used to treat various tissue degeneration and defects, including those of the oral mucosa, periodontal tissue, skin, and bone. The invention also includes a device for delivering the pharmaceutical composition to the site of tissue degeneration or defect."

Problems solved by technology

Particularly with respect to severe periodontitis, none of the currently available treatments are wholly satisfactory.

However, without resorting to surgical procedures, access to root surfaces and bony defects is restricted, and only limited debridement is possible.

As a result, nonsurgical scaling and root planing is insufficient to treat more severe cases of periodontitis, and it is necessary to resort to more aggressive surgical techniques.

Currently available surgical approaches entail substantial patient discomfort and fail to consistently provide satisfactory outcome.

Yet none of these approaches have achieved more than marginal success [Jeffcoat, M. K., et al., J. Am. Dent. Assoc., 128:713-724 (1997)].

In particular, there are a number of deleterious side effects associated with the use of antibiotics, along with risks such as drug sensitivity and the emergence of antibiotic-resistant pathogens.

Tetracyclines in particular have shown promise as inhibitors of extracellular collagenases, but cause the same side effects associated with antibiotics in general.

Modified forms of tetracycline have been developed which are non-antimicrobial and retain their ability to inhibit collagenases, but these chemically modified tetracyclines are not commercially available.

In summary, none of the nonmechanical approaches to treating periodontitis have been able to offer more than modest, short term enhancement of traditional mechanical debridement.

A great deal of research has been directed to methods of regenerating periodontal tissue lost as a consequence of periodontal disease, but as yet no wholly satisfactory method is available.

Clinicians using natural bone grafts have had limited success in inducing new bone growth.

Problems associated with the use of autografts include the need for a second surgical site and, in some cases, fresh grafts may be associated with root resorption.

Histologic findings, however, indicate that, in general, synthetic grafts act primarily as space fillers, with little if any regeneration.

A significant disadvantage of using a nonresorbable membrane is the requirement of a second surgical procedure after approximately six weeks to remove the membrane.

In summary, none of the currently available treatments for periodontal disease is wholly satisfactory, particularly with regards to regenerating periodontal tissue lost as a result of periodontitis.

There is currently no wholly satisfactory means of correcting these defects.

However, the use of these compositions comprises inherent limitations.

For example, the use of mineral oil, paraffin and similar oils and waxes has resulted in complications such as local chronic edema, lymphadenopathy, scarring and ulcerations (Devore et al., Effectiveness of injectable filler materials for smoothing wrinkle lines and depressed scars.

The use of reconstituted bovine collagen to correct defects or augment tissue also possesses inherent limitations.

For example, it has been reported that reconstituted bovine collage is only moderately effective, and is associated with infrequent, but controversial, adverse reactions.

However, this material also possess inherent limitations.

Specifically gelatin matrix does not appear to have applications in the treatment of wrinkle lines.

Moreover, since a large bore needle (27 gauge or greater) is used to inject the gelatin matrix into the subject's skin, treatment with gelatin results in greater discomfort and pain to the subject as opposed to the injection of other fillers.

Also, a very large bore needle (as large as 16 gauge) is needed to inject the fat into a subject, resulting in great pain, moderate bruising, and formation of visible puncture holes.

Moreover, fat injections are subject to rapid resorption, and must be repeated in order to maintain skin augmentation or defect correction.

The use of autologous, injectable dermal collagen to correct defects or augment tissue has also met with limited success.

For example, if large concentrations of collagen are injected, a 27 gauge needle or larger is used, resulting in the infliction of pain on the subject.