Virginia Commonwealth University

Center for Innovative Technology

Hemodyne, Incorporated

Organogenesis, Inc.

Marcus E Carr, Jr

Gary E Wnek

Gary L Bowlin

David Simpson

Philippe Lam

Mark J Licata

Kevin R Ward

Helen L Fillmore

Rao R Ivatury

Kelman I Cohen

Peter J Stevens

Jamil A Matthews

Saravanamoorthy Rajendran

Sheryl L Zekert

Wayne Barbee

Ashok Krischnaswami

Erika Martin

High-pressure bleeding wounds (and other bleeding wounds) may be treated by applying direct pressure directly in the bleeding wound, such as by applying a back pressure in a confined space around and in the wound. Certain substances and articles may be inserted into the wound, and the wound may be enclosed with that substance or article (such as a hemostatic substance, which may be polymeric), by swelling on contact with molecules (such as water molecules in the blood) encountered in the wound, generates the desired pressure to stop or at least reduce the bleeding without the detrimental effects of a tourniquet. Clot-inducing substances may be introduced into the wound contemporaneously with direct pressure application directly in the wound. Compressible and non-compressible wounds are treated. Treatment stops bleeding without producing pressure injury or ischemic damage. Medical devices using this technology are provided, including removable, biodegradable, medic-administrable devices.

Treatment for high pressure bleeding

The invention is directed to formation and use of electroprocessed fibrin as an extracellular matrix and, together with cells, its use in forming engineered tissue. The engineered tissue can include the synthetic manufacture of specific organs or tissues which may be implanted into a recipient. The electroprocessed fibrin may also be combined with other molecules in order to deliver the molecules to the site of application or implantation of the electroprocessed fibrin. The fibrin or fibrin/cell suspension is electrodeposited onto a substrate to form the tissues and organs.

Electroprocessed fibrin-based matrices and tissues

The invention is directed to formation and use of electroprocessed collagen, including use as an extracellular matrix and, together with cells, its use in forming engineered tissue. The engineered tissue can include the synthetic manufacture of specific organs or tissues which may be implanted into a recipient. The electroprocessed collagen may also be combined with other molecules in order to deliver substances to the site of application or implantation of the electroprocessed collagen. The collagen or collagen/cell suspension is electrodeposited onto a substrate to form tissues and organs.

Electroprocessed collagen and tissue engineering

Platelet contractile force (PCF) is used as a surrogate marker of thrombin generation. PCF generation occurs concomitant with the burst of prothrombin fragment F 1+2 release. The time between assay start and PCF onset is identified as the thrombin generation time (TGT), and is used in assessing risk of bleeding, in diagnosing various disorders, and in monitoring the effects of pharmaceutical and other treatments. TGT is prolonged in clotting factor deficiencies and in the presence of direct and indirect thrombin inhibitors. TGT shortens to normal with clotting factor replacement and shortens with administration of rVIIa. TGT is short in thrombophilic states such as coronary artery disease, diabetes and thromboangiitis obliterans and prolongs toward normal with oral and intravenous anticoagulants.

Onset of force development as a marker of thrombin generation

Platelet contractile force and/or clot elastic modulus measurements are used to identify patients at risk for atherosclerosis or for bleeding during surgical procedures or other applications. Measurements which are elevated are indicative of atherosclerosis, and measurements which are reduced are indicative of a bleeding risk.

Method of using platelet contractile force and whole blood clot elastic modulus as clinical markers

The invention is directed to use of fibrin as an extracellular matrix and, together with cells, its use in forming engineered tissue. The engineered tissue can include the synthetic manufacture of specific organs or &ldquo;organ-like&rdquo; tissue. A preferred embodiment is a plasma-derived fibrin matrix containing cells.

Plasma-derived fibrin-based matrices and tissue

Blood clot analysis instrumentation used to evaluate platelet function and clot structure by monitoring force development during clot retraction or upon application of a known amount of force can have a calibration check automatically performed by using a top member with a known amount of mass which is detachable from the instrumentation, and preferably is a disposable component. The calibration check is performed by monitoring force or displacement on a holding member with and without the top member attached. If the difference measured is within a preferred tolerance range, then the instrumentation can be deemed to be within the specifications deemed best suited for the instrument. The top member may also be modified to allow for mixing reagents with the clot, thereby avoiding the need to pre-mix blood with reagents before measurement. This can be accomplished by providing the top member with a rotation mechanism, such as an air driven fin assembly, that permits the top member to rotate forwards and/or backwards relative to the receptacle which holds the blood sample. The top member may also carry on board one or more reagents used for the diagnostic tests to be performed on the blood sample. Different top members might be used to perform different tests by being capable of dispensing different reagents. Moreover, a bar code or other indicia may be used to have the instrumentation automatically identify the test being performed, and this can also be used to provide information useful in regulating the mixing operation to be performed by the top member. Furthermore, a disposable liner may also be positionable within the receptacle such that the entire test can be performed with disposable components, thereby reducing clean up time, improving performance of the instrumentation, and enhancing the safety for the clinicians. Finally, the shape of the top and bottom members are configured in such a way as to have the evaporation force vector perpendicular to the clot retraction force vector.

Disposable cup and cone used in blood analysis instrumentation

The performance of platelets can be best understood by monitoring both the force development and the elastic modulus of the blood clot during both clotting and dissolution of the blood clot. Intermittent application and removal of a compressive force on a blood sample (8) positioned between a pair of plates (12 and 14) throughout clot formation and dissolution provides a standard for using voltage output from a transducer (22) to determine force and elastic modulus parameters. Force development arises from the internal actions of the platelets during clot retraction. Elastic modulus provides a measure of the stiffness of the clot. Clotting can be measured as an increase in force development and clot elastic modulus. Clot dissolution can be determined by a dramatic decrease in force development and in elastic modulus. Providing the blood sample with a clot dissolving agent such as tPA allows determining the fibrinolytic potential of whole blood and, thus, aids in identifying patients at risk for thrombosis due to a decreased ability to dissolve clots. Clot elastic modulus provides a measure of erythrocyte flexibility.

Instrumentation and method for evaluating platelet performance during

The compression elastic modulus of a blood sample is determined by compressing a blood sample (12) between plates (14 and 16) and comparing the voltage signal (32) output from the transducer (22) with a displacement calibration constant C.sub.d. The compression elastic modulus is determined on the same sample as the platelet mediated force development.

Apparatus and method for measuring clot elastic modulus and force

Experiments have been conducted which demonstrate that gel optical density is a linear function of the fibrin fiber mass/length ratio (.mu.) and that the slope of the linear function is dependent on the concentration of fibrinogen in the sample. Once the linear function is known, knowledge of a gel optical density at one wavelength is adequate to determine .mu.. Such measurements allow quantitative monitoring of fibrin structure, and are clinically relevant.

Method for determining fibrin fiber size from a single gel optical

Experiments have been conducted which demonstrate that gel optical density is a linear function of the fibrin fiber mass/length ratio (.mu.). Once the linear function is known, knowledge of a gel optical density at one wavelength is adequate to determine .mu.. Such measurements allow quantitative monitoring of fibrin structure, and are clinically relevant.

An instrument for measuring the internal force characteristics of a blood sample (12) during clotting has been developed. The blood sample (12) is held between a cup (10) and a plate (16). The plate (16) is connected to a force displacement transducer (22). As the clot forms, platelets contract and exert an inward pulling force on the plate (16). This inward pulling force is sensed by the transducer (22) which outputs a corresponding voltage signal. The voltage signal is amplified (24) and recorded on strip chart paper (28). The voltage signal (32) can be directly translated into force parameters by first calibrating the instrument with standard weights. It has been found that the maximum force measurements are obtained under controlled temperature, ionic strength and calcium concentration conditions which approximate those of the blood while in the body. A particular feature of the invention includes a water jacket (14) which is used to maintain the temperature of the blood sample (12) at 37.degree. C. (body temperature).

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Midlothian, VA, United States of America

Marcus E Carr, Jr