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Drug delivery matrices to enhance wound healing

Inactive Publication Date: 2007-08-30
ETH ZZURICH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] Bioactive molecules are entrapped within a matrix for the controlled delivery of these compounds for therapeutic healing applications. The matrix may be formed of natural or synthetic compounds. The primary method of entrapment of the bioactive molecule is through precipitation of the bioactive molecule during gelation of the matrix, either in vitro or in vivo. The bioactive molecule may be modified to reduce its effective solubility in the matrix to retain it more effectively within the matrix, such as through the deglycosylation of members within the cystine knot growth factor superfamily and particularly within the TGFβ superfamily. The matrix may be modified to include sites with binding affinity for different bioactive molecules, for example, for heparin binding. When these different bioactive molecules are added to the matrix, the bioactive molecules are bound to the matrix both by precipitation within the matrix and by binding to the sites in the matrix, thereby providing enhanced controlled delivery to a patient.

Problems solved by technology

However, these investigators have not recognized the strong advantages of working with non-glycosylated growth factors, and especially non-glycosylated members of the cystine knot growth factor superfamily, in particular of the TGFβ superfamily.
However if growth factors are applied to the body in high concentrations, adverse affects are likely to be observed.

Method used

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  • Drug delivery matrices to enhance wound healing
  • Drug delivery matrices to enhance wound healing
  • Drug delivery matrices to enhance wound healing

Examples

Experimental program
Comparison scheme
Effect test

example 1

Determination of Incorporation into Fibrin Gels

[0078] A test measuring the native enzymatic activity of the coagulation enzyme, factor XIIIa, was performed. This test was performed by measuring the ability of fibrin gel from two different sources to covalently incorporate a synthetic substrate during the coagulation process. One source of the fibrin gel came from a fibrin glue kit, while the second source came from a purified fibrin gel. Peptides derived from α2-plasmin inhibitor can be covalently incorporated into fibrin gels through the action of factor XIIIa. Thus, one method for testing the enzymatic activity in a fibrin gel or dilution thereof involves testing the ability of different fibrin sources to incorporate this same peptide. The gels were synthesized with various amounts of fluorescently labeled peptide and washed with TBS (0.03 M, pH 7.4) to remove free peptide from the matrix. The gels were then degraded with the minimum amount of plasmin necessary and analyzed with ...

example 2

In Vivo Comparison of Fibrin Gels From Different Sources

[0080] A non-glycosylated recombinant form of a bone morphogenetic protein, which was prepared from prokaryotic (E. coli) (rh-BMP-2), was mixed in different fibrin gels, and the gels were tested in a rat femur defect. Because the protein was expressed in a prokaryotic system, it was not glycosylated. Fibrin gels were synthesized from a variety of sources. Purified fibrinogen from Sigma Chemical and a blood bank were employed, as well as fibrin glues (Baxter) at several dilutions. These gels were loaded with rh-BMP-2 and place in a critical size (5 mm full thickness) femur defect. It was observed that all of the fibrin glue dilutions employed and the Sigma fibrin gave a similar healing response, leading to bridging of every critical size defect. The fibrin from the blood bank gave a lower overall response, which was more likely due to cell infiltration properties than to retention of the rh-BMP-2. Therefore, while the healing r...

example 3

Comparison of Retention of Soluble and Insoluble Bioactive Molecules in a Fibrin Matrix

[0081] This invitro assay involved comparing the release kinetics of the entrapped non-glycosylated rh-BMP-2 to the release kinetics of a molecule that is known to have high solubility at physiological pH. Fibrin gels were polymerized using purified fibrinogen (Sigma) at 8 mg / mL and 2 U / mL thrombin at pH 7.4. Calcium was added so that the final concentration was 2.5 mM to increase the rate of gelation

[0082] These gels were synthesized with a bioactive molecule present during the coagulation process and the retention of the molecule inside the fibrin matrix was determined. Gels were washed and kept in phosphate buffered saline (PBS 0.01 M, pH 7.4) at 37° C. and the wash was changed every 12 hours. After thorough washing, the gels were degraded with 0.05 Units of plasmin. The amount of each bioactive molecule present in the washes and in the degraded matrix was determined.

[0083] In the first test...

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Abstract

Bioactive molecules are entrapped within a matrix for the controlled delivery of these compounds for therapeutic healing applications. The matrix may be formed of natural or synthetic compounds. The primary method of entrapment of the bioactive molecule is through precipitation of the bioactive molecule during gelation of the matrix, either in vitro or in vivo. The bioactive molecule may be modified to reduce its effective solubility in the matrix to retain it more effectively within the matrix, such as through the deglycosylation of members within the cystine knot growth factor superfamily and particularly within the TGFβ superfamily. The matrix may be modified to include sites with binding affinity for different bioactive molecules, for example, for heparin binding.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation application of U.S. Ser. No. 10 / 132,619 filed on Apr. 25, 2002, which claims priority to U.S. Provisional Application No. 60 / 286,307 filed Apr. 25, 2001.BACKGROUND OF THE INVENTION [0002] This invention is generally in the field of drug delivery and more specifically in the area of fibrin and synthetic matrices to enhance wound healing. [0003] Fibrin matrices are present naturally in the body and serve as the initial matrix for wound healing. When an injury occurs to tissue, blood vessels are compromised, allowing the precursor molecule, fibrinogen, to invade the wound. The fibrinogen is then enzymatically cleaved and self-catalyzed into a loosely formed gel. The gel is then covalently crosslinked through the action of the transglutaminase, factor XIIIa, resulting in a stable matrix. Pisano, Finlayson and Peyton, Science, 160, 892-893 (1968). [0004] In vivo, the final fibrin matrix includes various pro...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K47/32A61K9/70A61K38/00A61K38/43A61K38/48A61K47/34A61L15/44A61L24/00A61L24/10A61L27/00A61L27/22A61L27/54A61L31/04A61L31/16A61P17/00A61P19/00
CPCA61L24/0015A61L24/106A61L27/225A61L27/227A61L27/54A61L2300/45A61L2300/236A61L2300/252A61L2300/412A61L2300/414A61L31/046A61P17/00A61P17/02A61P19/00A61P19/08
Inventor SCHENSE, JASON C.SCHMOEKEL, HUGOHUBBELL, JEFFREY ALANWEBER, FRANZ
Owner ETH ZZURICH
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