Status: approval recently withdrawn

Organizations involved:

Fusion Medical Technologies, Inc. – Manuf.; R&D; Tech.; Former

Baxter Intl. Inc. – Parent; World mark.; Former

Sulzer Spine-Tech – World mark.; Former

Cohesion Technologies, Inc. – Patent dispute

Baxter International – Patent dispute

Cross ref.: See the entry #808 for the currently-marketed FloSeal product, in which bovine thrombin has been replaced by human plasma-derived Thrombin. See also the Thrombin Products entry (#919), the other Thrombin product entries, and the Fibrin Sealant Products entry (#735).

Description: FloSeal Matrix Hemostatic Sealant (and the equivalent Proceed Hemostatic Sealant) was an adsorbable hemostatic (halts bleeding) product combining topical lyophilized (freeze-dried) bovine-derived Thrombin Component and a granular collagen or cross-linked Gelatin Matrix component. [FDA uses the term cross-linked gelatin; Fusion Medical/Baxter uses the term collagen]. The thrombin component is Thrombin, Topical, USP (bovine origin) manufactured by GenTrac, Inc. and sold commercially by Jones Pharma Inc. as Thrombin-JMI (see entry #920). The gelatin/collagen component is derived from bovine corium through heat denaturation, chemically cross-linking, and terminal sterilization by gamma irradiation. The source cattle are of U.S. origin.

The collagen/gelatin matrix exists as small granules that are hydrated within a syringe prior to use. The Thrombin Component is reconstituted with saline diluent (0.9% sodium chloride USP), and this is used to reconstitute the Gelatin Matrix, with FloSeal Matrix Hemostatic Sealant resulting from the mixture of the two components. The mixing is performed in the operating suite prior to use to form a gel for application to bleeding areas. FloSeal may be extruded directly from its supplied syringe, or applicator tips of various lengths can be attached to the syringe to facilitate delivery.

Proceed Hemostatic Sealant is essentially FloSeal repackaged and marketed in a special configuration for use during spinal operations.

FloSeal containing bovine thrombin was packaged as a Kit including a gelatin matrix component [a 5 mL syringe filled with Gelatin Matrix with a needle attached, a 1 mL syringe with a dispersion needle assembly, and a mixing bowl] and a Thrombin component [a 5,000 Unit vial of Thrombin, a vial of 0.9% sodium chloride diluent, and a syringe with needle attached]. The lyophilized Thrombin is reconstituted with 0.8 mL of saline diluent and placed in the bowl. A syringe is filled with the reconstituted Thrombin, attached to the syringe filled with the Gelatin Matrix, the components are mixed, and the mixture is extruded or otherwise applied onto the bleeding areas. FloSeal Kits are stored at 2-25˚C (refrigerated or room temperature).

Nomenclature: Thrombin-Collagen gel/old [BIO]; Gelatin Matrix Hemostatic Sealant [FDA]; FloSeal Matrix Hemostatic Sealant [TR]; Proceed Hemostatic Sealant [TR]; FloSeal [SY]

Biological.: The gelatin granules and thrombin that comprise FloSeal act synergistically to control active bleeding. The particulate nature of the gelatin facilitates extrusion of FloSeal from the syringe for direct delivery to the bleeding site. Prior to use, thrombin solution is dispersed into the syringe containing the gelatin matrix, thereby coating the granules. With a single-barrel delivery syringe, FloSeal is precisely applied to the tissue surface at the base of the lesion. It fills the wound and conforms to its irregular shape, including irregular bleeding surfaces. FloSeal is hydrophobic and adheres well to wet tissues, including vertical and moving surfaces. Upon contact with blood or other fluids, the FloSeal particles swell about 20%, with maximum swell within 10 minutes. This swelling and the formation of fibrin clots physically restrict blood flow. Besides adding mechanical strength to the resulting gel matrix, collagen is a potent platelet activator and assists with clotting.

As blood flows through the FloSeal Matrix particles, the Thrombin converts fibrinogen to fibrin (clotting), forming a fibrin clot incorporating FloSeal particles that seals the bleeding site. Blood percolating through the spaces among the granules is exposed to high concentrations of thrombin, which converts fibrinogen into fibrin polymer, which forms a clot around the mechanically stable matrix provided by the granules. The structural integrity of the gelatin-fibrin matrix enables it to remain in place at the tissue surface. FloSeal granules not incorporated in the clot can be removed with gentle irrigation without disrupting the hemostatic seal. FloSeal is biocompatible and is resorbed within 6-8 weeks, consistent with the course of normal wound healing, and may be left in place at the discretion of the surgeon.

Companies.: FloSeal was developed and originally manufactured and marketed by Fusion Medical Technologies Inc. In May 2002, Baxter International Inc. completed acquisition of Fusion Medical Technologies for approximately $157 million in a stock-for-stock merger. The Baxter BioSurgery division of Baxter now markets FloSeal in the U.S. and internationally. The acquisition of Fusion Medical allowed Baxter to market two hemostatic products – Tisseel VH fibrin sealant (see entry #737) and FloSeal (#922).

Proceed Hemostatic Sealant is marketed for spinal applications by Sulzer Spine-Tech, which also has rights for cranial applications.

FDA class: Medical device; PMA

Approvals: Date = 19991208; PMA (P990009)

Date = 20010725; PMA supplement; Indication = approval of second generation FloSeal (faster acting)

Indications: [historical only; full text of the "Indications” section of product insert/labeling]

FloSeal Matrix is indicated in surgical procedures (other than neurological, ophthalmic, and urological) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical

Status: Note, this FloSeal product was replaced in 2005 by comparable product containing human, rather than bovine, thrombin. See entry #808.

The PMA for this medical device received “streamlined processing” due to FDA having reviewed similar devices. FloSeal received CE Mark certification (European Union medical device approval) in April 1999. The product is also available internationally.

In Jan. 2014, Baxter International Thursday filed suit alleging that Johnson & Johnson’s SurgiFlo family of products violate six patents relating to Baxter’s Floseal hemostatic matrix.

Tech. transfer: In Dec. 2000, Cohesion Technologies, Inc. filed a suit in U.S. District Court against Fusion Medical alleging that FloSeal/Proceed infringes its U.S. patent 6,110,484. This patent has only one claim, “A method for forming a fibrin matrix at a tissue site comprising the steps of: providing particulate cross-linked gelatin or particulate collagen in dry, liquid or solid form; mixing an effective fibrin-forming amount of thrombin with the particulate cross-linked gelatin to form a mixture; and allowing the mixture to further mix with fibrinogen at the tissue site.” This claim/patent substantially describes FloSeal/Proceed, although the patent primarily concerned fibrin matrix for implants, controlled release of incorporated drugs, etc. The companies settled their dispute out of court. Cohesion’s press release does not mentioning any licensing, compensation, royalties, etc., and a Fusion Medical representative would not comment on this topic.

In Jan. 2014,

Trials: The pivotal trial was a 10-center randomized trial in 39 patients who underwent cardiac, vascular or spinal/orthopedic surgery. Patients were treated with either FloSeal or thrombin (Thrombin-JMI; see the entry above) plus gelatin sponge (Gel-foam; currently used by a majority of surgeons). FloSeal stopped bleeding within 1 minute in 96% of patients, vs. 77% with thrombin/Gelfoam. FloSeal stopped bleeding about 2.5-fold faster based on median times to hemostasis. Of the patients who underwent cardiac surgery and experienced heavy bleeding (flowing or spurting), FloSeal stopped bleeding within three minutes in 77%, compared with 0% of those in the control group.

Medical: FloSeal/Proceed stops bleeding quickly in time-sensitive surgical procedures. FloSeal works on wet and actively bleeding tissues. It only requires adequate circulating fibrinogen to clot (is not dependent on platelet activation). The gel stays where it is applied, permitting accurate delivery to hard to reach areas, and conforms to irregular wound geometries. FloSeal use may reduce operating costs. Baxter estimates it may save $108-$291 per patient (based on clinical study data and average operating room costs).

With its particulate nature, FloSeal Matrix may be easily extruded from a syringe or applicator for delivery to the bleeding site. It conforms to irregular bleeding surfaces, is hydrophilic and adheres to wet tissues, including vertical and moving surfaces. The particles swell ~20% upon contact with fluids, achieving maximal swelling in ~10 minutes, allowing the material to restrict blood flow, and the particles are not easily displaced by blood flow. As blood percolates through the bed of FloSeal Matrix particles, the thrombin converts fibrinogen in the patient’s blood to fibrin. The resulting fibrin clot composite seals the bleeding site. Excess FloSeal Matrix not incorporated in the clot may be removed by irrigation without disturbing the hemostatic seal. Since FloSeal Matrix is biocompatible and is bioresorbed within 6-8 weeks, it may be left in place at the discretion of the surgeon.

FloSeal is effective in presence of anticoagulants such as heparin; effective in patients placed on cardiopulmonary bypass; and useful in ENT/nead and neck surgery, urology, spinal surgery and general surgery

Market: Upon approval, Fusion Medical estimated the total potential market for controlling bleeding with FloSeal (approved indications:) to exceed $4 million annually. See the entry for FloSeal containing human-derived thrombin (#808), which has replaced this product.