Supplemented and unsupplemented tissue sealants, methods of their production and use

Abstract

This invention provides methods for the localized delivery of supplemented tissue sealants, wherein the supplemented tissue sealants comprise at least one composition which is selected from one or more antibodies, analgesics, anticoagulants, anti-inflammatory compounds, antimicrobial compositions, antiproliferatives, cytokines, cytotoxins, drugs, growth factors, interferons, hormones, lipids, demineralized bone or bone morphogenetic proteins, cartilage inducing factors, oligonucleotides polymers, polysaccharides, polypeptides, protease inhibitors, vasoconstrictors or vasodilators, vitamins, minerals, stabilizers and the like. Further provided are methods of using the site-specific supplemented tissue sealants, including preparation of a biomaterial.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a Continuation-in-Part Application of U.S. application Ser. No. 08 / 351,006, filed Dec. 7, 1994, now abandoned, which is a Continuation-in-Part Application of U.S. application Ser. No. 08 / 328,552, filed Oct. 25, 1994 now abandoned which is a Continuation application of U.S. application Ser. No. 08 / 031,164, filed Mar. 12, 1993, abandoned, which is a Continuation-in-Part Application of U.S. Application Ser. Nos. 07 / 618,419 and 07 / 798,919, filed Nov. 27, 1990, and Nov. 27, 1991, respectively, both of which are abandoned, all of which are herein incorporated by reference.RIGHTS OF THE UNITED STATES GOVERNMENT IN THIS INVENTION[0002]Under a Cooperative Research and Development Agreement between The American National Red Cross and The U.S. Army Institute of Dental Research, the U.S. Government may have a non-exclusive, irrevocable, paid-up license in one or more embodiments of this invention.FIELD OF INVENTION[0003]This inven...

AI Technical Summary

Benefits of technology

[0096]A fourth advantage is that because of its initial liquid nature, the TS of the present invention can cover surfaces more thoroughly and completely than many previously available delivery systems. This is especially important for the use of the present invention in coating biomaterials and in the endothelialization of vascular prostheses because the growth factor-supplemented FG will coat the interior, exterior and pores of the vascular prosthesis. As a result of this, plus the ability of endothelial cells to migrate into and through the TS, engraftment of autologous endothelial cells will occur along the whole length of the vascular prosthesis, thereby decreasing its thrombogenicity and antigenicity. With previously used TSs, engraftnent started at the ends of the vascular prosthesis and proceeded, if at all, into the interior of the same, thus allowing a longer period for thrombogenicity and antigenicity to develop. Previously used TSs for vascular prostheses also primarily were seeded with nonautologous cells which could be rejected by the body and could be easily washed off by the shearing force of blood passing through the prosthesis.

[0097]A fifth advantage is that the supplemented and unsupplemented TS of this invention can be molded and thus can be custom made into almost any desired shape. For example, TS such as FG can be supplemented with BMPs and/or DBM and can be custom made into the needed shape to most appropriately treat a bone wound. This cannot be done with DBM powder alone because DBM powder will not maintain its shape.

[0098]A sixth advantage is that the AB-supplemented FG of this invention, such as TET-FG, has unexpectedly increased the longevity and stability of the FG compared to that of the unsupplemented FG. This increased stability continues even after appreciable quantities of the AB are no longer remaining in the FG. For example, soaking a newly formed FG clot in a saturated solution of TET produced from free base TET, or in a solution of CIP HCl, produces a FG clot which is stable and preserved even after substantially all the TET or CIP has left the FG clot. While not wishing to be bound by any theory as to how this effect is produced, it is believed that the AB, such as TET or CIP, inhibits plasminogen which is in th

Problems solved by technology

However, it has not been established if any FGF growth factor is chemotactic for fibroblasts.

However, their use to promote wound healing has yielded inconsistent results (see, e.g., Carter et al., in Growth Factors and Other Aspects of Wound Healing: Biological and Clinical Implications, Alan R. Liss, Inc., New York, New York, pp.

The reasons for such inconsistent results are not known, but might be the result of difficulty in applying growth factors to a wound in a manner in which they can exhibit their normal array of biological activities.

However, this heat inactivation method may produce denatured proteins in the FG which may also be allergenic.

In addition, there is concern that this inactivation method will not inactivate prions which cause bovine spongiform encephalopathy, “mad cow disease,” which may be present in the TS due to the use of bovine proteins therein.

Although FG maintains hemostasis and reduces blood loss, it has not yet been shown to possess true wound healing properties.

Unfortunately, DBM materials have little clinical use unless combined with particulate marrow autografts.

There is a limit to the quantity of DBM that can be surgically placed into a recipient's bone to produce a therapeutic effect.

Soft-tissue collapse into the wound bed may likewise inhibit the proper migration of osteocompetent stem cells into the wound bed.

However, DBM in powder form is difficult to use.

Therefore, these results are inconsistent and confusing.

However, commercially available preparations of FG and other TSs are too dense to allow cell migration into and through them.

This limits their effectiveness in some in vivo uses.

However, the source of bone autografts is usually limited and the use of allgeneic bones involves a high risk of viral contamination.

However, one general problem with these techniques is that nonautologous cells were used for the seeding (see, e.g., Schrenk et al., supra) thus raising the possibility of tissue rejection.

In addition, a confluent endothe

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