New Ultra-Thin Surgical Patch Has Endless Possibilities

Throughout the decades, surgeons have typically used stitches and staples to close up wounds. They may even use sheets several millimeters thick coated with fibrin, a protein that makes blood clot and is glue-like but which can cause unwanted sticking to nearby tissue.

Now, Japanese scientists have revealed a new, cutting edge surgical ‘nano-sheet’ they have developed that is one thousand times thinner than Cellophane that can patch up internal wounds before dissolving inside the body.

This transparent adhesive sheeting is made from a substance derived from crab shells and a viscous gum from algae and is only 75 nanometers thick. A nanometer is one-billionth of one meter.

"This is the world's thinnest adhesive plaster," said Toshinori Fujie, a researcher involved in the joint project by Tokyo's private Waseda University and the National Defense Medical College.


"We know food Cellophane clings on to the surface of various objects. We have made a sheet ultimately thin... so that it is highly flexible and can stick to organs well with no glue," he told AFP.

The experiment, which was repeated several times, consisted of using the new nano-sheet to patch a six-millimeter-wide hole in a dog’s lung.

The sheet proved to have the strength to stand up under the pressure of the dog’s respiration and allow the wounds to heal within a month without a visible trace, according to Fujie.

Researchers hope to launch human clinical trials in three years.

The sheets might also prove to be useful in treating external wounds in the future as well.

"Organs repaired with this sheet do not have scars, unlike after stitches," Fujie said. "We believe this could also be true on the skin."

If the tests show that it is effective externally, it could open up a world of applications such as being applied to wounds from surgery in breast cancer patients, he said.

"Some people also want to use this for treating bed sores. The next application will definitely be on the skin," he said.

Fujie says that the inventors have been exploring all possibilities, even cosmetic uses such as stretching out wrinkles or holding skin conditioners in place.

"As this is transparent on the skin, you could be wearing a face pack while working in the office," he said.

Analyst predicts - "high-strength, elastic glue without toxicity concerns would revolutionize the market"

Approximately 70 million surgical and procedure-based wounds are created each year in surgeries worldwide that offer potential for adjunctive products for surgical closure and securement. Some 23 million of these wounds are created during surgical procedures in the United States. Although it is possible that healing of all these wounds would be improved through use of adjunctive products for surgical closure and securement, use of the most advanced of these products has been limited to a fraction of these procedures. For example, there are approximately 3 million procedures which receive sealant products around the world, generating $1.6 billion in sales in 2007. We forecast much greater usage of sealants once clinical efficacy is proven in a broad range of procedures. New sealant products are also being launched. In addition to improvements in adjunctive treatment of bleeding, new procedure-enabling devices for soft tissue repair and securement have been introduced. These products have expanded the total market for securement and closure of soft tissues with bioresorbable materials.

This field is expanding rapidly as new devices allow the surgeon to perform closure more quickly and with improved outcomes for patients. A significant premium is possible when new products and devices enable complex securement procedures to be performed under minimally invasive protocols with significant time-savings in the operating room. New technologies and new biomaterials allow improved tissue repair, and it is possible to revalue segments of this market based on significant improvements in clinical practice. We expect this market segment to triple in value over the next decade.

The total market potential by 2013, driven by procedure volumes, for hemostats, sealants, and glues, addressable by currently available products, nearly $4.5 billion for hemostats and sealants, and more than $1.3 billion for skin wound closure using high-strength glues. The introduction of a high-strength, elastic glue without toxicity concerns would revolutionize the market further and lead to even higher sales potential.

Source: MedMarket Diligence, LLC

Thrombin involved in Myocardial Ischemia-Reperfusion Injury

Several lines of experimental evidence specifically implicate thrombin to be involved in myocardial ischemia-reperfusion injury. Cardiopulmonary bypass increases thrombin generation progressively, but reperfusion after myocardial ischemia induces an additional distinct and rapid increase in thrombin generation. Clinical studies have shown that thrombin formation during cardiac surgery, especially during myocardial reperfusion, is involved with myocardial damage and impaired hemodynamic recovery. Therefore, strategies to improve thrombin control during cardiopulmonary bypass might be beneficial..........article available HERE

FDA Public Health Notification: Paralysis from Absorbable Hemostatic Agent

Dear Surgeon:

This is to remind you of a rare but devastating adverse event that can occur with the use of an absorbable hemostatic agent, a device used to promote coagulation and stop internal bleeding during surgical procedures. Unfortunately, these events continue to occur despite specific advice and warnings in the device labeling. We ask that you take action to minimize the risk in your patients and help spread the message in this announcement.

Nature of Problem

Since 1996, FDA has received reports of over 110 adverse events related to absorbable hemostatic agents. Eleven of the events resulted in paralysis or other neural deficits. The last reported paralysis occurred in October, 2003. The common thread in all 11 events was an absorbable hemostatic agent that was used on or near a bony or neural space and left inside the patient. When wetted, the material swelled and exerted pressure on the spinal cord or other neural structures, resulting in pain, numbness or paralysis. In some cases, blood pooled behind the implanted absorbable hemostatic agents, forming a hematoma that exerted pressure on neural tissues and caused a range of neural deficits.

Although these events are rare, they can have serious consequences. These consequences are preventable.

Recommendations

FDA recommends that users of absorbable hemostatic agents review the device labeling, especially the contraindications, warnings and precautions.

If you use an absorbable hemostatic agent on or near bony or neural spaces:

• use the minimum amount necessary to achieve hemostasis; and,
• remove as much of the agent as possible after hemostasis is achieved.

This will reduce the likelihood of neural and other soft tissue damage from swelling of the absorbable hemostatic agent, and/or migration and swelling of fragments of the agent.

Reporting Adverse Events to FDA

FDA requires hospitals and other user facilities to report deaths and serious injuries associated with the use of medical devices. If you suspect that a reportable adverse event was related to the use of an absorbable hemostatic agent, you should follow the reporting procedure established by your facility.

We also encourage you to report adverse events related to absorbable hemostatic agents that do not meet the requirements for mandatory reporting. You can report these directly to the device manufacturer. You can also report to MedWatch, the FDA’s voluntary reporting program. You may submit reports to MedWatch by phone at 1-800-FDA-1088; by FAX at 1-800-FDA-0178; by mail to MedWatch, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857-9787; or online.

Getting More Information

If you have questions about this notification, please contact Ms. Quynh Hoang, Office of Surveillance and Biometrics (HFZ-510), 1350 Piccard Drive, Rockville, Maryland, 20850, Fax at 240-276-3356, or by e-mail at phann@cdrh.fda.gov. You may also leave a voice mail message at 240-276-3357 and we will return your call as soon as possible.

FDA medical device Public Health Notifications are available on the Internet. You can also be notified through email on the day the safety notification is released by subscribing to our listserv. To subscribe, visit: http://service.govdelivery.com/service/subscribe.html?code=USFDACDRH_10.

Sincerely yours, David W. Feigal, Jr., MD, MPH Director Center for Devices and Radiological Health Food and Drug Administration Issued: 4-2-2004

The Most Important Factor in a Hemostatic Agent - Poll Results

The Question for this Poll........"The Most Important Factor in a Hemostatic Agent is?".

Bit of a landslide for Efficacy with 50%. Following up was Safety with 23%, which is interesting when compared to our previous poll .

Cost was voted at 12% the equal of Ease of Use also with 12%.

Cryolife - Bioglue Hits 500,000 Procedure Milestone

CryoLife, Inc., (NYSE: CRY) an implantable biological medical device and cardiovascular tissue processing company, today announced that, according to company data, CryoLife's BioGlue(R) Surgical Adhesive has been used in more than 500,000 surgical procedures throughout the world since its introduction into the international market in 1998 and in the United States in 2001. BioGlue is a leading surgical adhesive used in cardiovascular surgeries worldwide.

This link will give you the IFU for BioGlue® Surgical Adhesive (BioGlue).

FDA Approves Treatment for Rare Genetic Defect

RiaSTAP, a new drug for treatment for patients living with congenital fibrinogen deficiency, a condition that affects blood coagulation, has reportedly gained FDA approval.
According to FDA officials, the condition, which affects only 150-300 people in the U.S., can lead to potentially life-threatening bleeding without treatment and is usually diagnosed at birth.
An intravenous fibrinogen concentrate made from the plasma of healthy human blood donors, RiaSTAP is indicated for patients who have no fibrinogen or low levels of the substance. The FDA warns that RiaSTAP is not indicated for patients with dysfibrinogenemic (those who may have normal fibrinogen levels but defective fibrinogen function) as these individuals are at risk for both bleeding and clotting complications.
Fever and headache were the most common adverse reactions to the drug, the FDA reported.

A keratin biomaterial gel hemostat derived from human hair

Aboushwareb Tamer; Eberli Daniel; Ward Catherine; Broda Christopher; Holcomb John; Atala Anthony; Van Dyke Mark A keratin biomaterial gel hemostat derived from human hair: evaluation in a rabbit model of lethal liver injury. Journal of biomedical materials research. Part B, Applied biomaterials
Effective hemostatic dressings that are compatible with tissues are needed. Keratins are a class of biomaterials that can be derived by extraction of proteins from human hair. We have recently discovered that keratin biomaterials have hemostatic characteristics and hypothesize that a keratin hydrogel having the ability to absorb fluid and bind cells may be an effective hemostat. The goal of this study was to test a keratin hydrogel and evaluate it compared to current hemostats. Thirty-two New Zealand white rabbits received a lethal liver injury. Eight animals each were assigned to negative control, QuickClot, HemCon bandage, and keratin treatment groups. Vital stats and other data were recorded during surgery and all surviving animals were sacrificed after 72 h. Histology was conducted on all surviving animals. Twenty-four-hour survival rates were 0%, 62.5%, 62.5%, and 75% for the negative control, QuickClot, HemCon, and keratin groups, respectively. Other outcomes included blood loss, mean arterial pressure, heart rate, shock index, and liver histology. All of the hemostats were statistically better than the negative control group at late operative time points. The keratin group consistently performed as well as, or better than, the commercial hemostats. Histology showed an interesting healing response at the hemostat-liver interface in the keratin group.

Phase II clinical trial for Fibrocaps

SEATTLE, Washington, and LEIDEN, The Netherlands, June 18 /PRNewswire/ -- ProFibrix B.V. today announced the start of the company's Phase II clinical trial for Fibrocaps(TM), the company's lead topical Hemostat product, with the successful treatment of the first patients for mild to moderate bleeding during liver surgery. ProFibrix expects to complete the study before the end of 2009.
Fibrocaps is based on a mixture of two essential blood clotting proteins, fibrinogen and thrombin, and is a unique dry powder topical tissue sealant that rapidly stops bleeding after or during surgery. Fibrocaps has major advantages over existing liquid tissue sealants: it is ready for immediate use, is stable at room temperature, highly effective and fast acting.
ProFibrix expects to submit an Investigational New Drug Application (IND) for Fibrocaps to the U.S. Food and Drug Administration in the first half of 2010, and conduct a combined phase II/III pivotal study in various surgical indications.
Jaap Koopman, PhD, Chief Executive Officer, said: "The successful treatment of the first patients with our lead product Fibrocaps is an important milestone for the company. With focus and dedication we have made enormous progress over the past two years, and we are on track to bring Fibrocaps to the point of market approval."
About ProFibrix
ProFibrix was founded in 2004 and is headquartered in Leiden, The Netherlands, with a subsidiary in Seattle, WA. The company leverages its expertise in fibrinogen technology to develop and market innovative products for the hemostasis and regenerative medicine markets. Human fibrinogen plays a pivotal role in blood clotting and tissue healing. ProFibrix is led by a team with extensive commercial, clinical and scientific experience in the hemostasis field.

Hemostasis Market - Review of Gelfoam, Surgicel, Avitene, Floseal, Bovine Thrombin

This post is to provide further commentary to a readily available 2005 article posted early last year from an online source. The source of the original article is linked below*.

So what do we want in a good hemostatic agent? First, the ideal hemostatic agent would of course be such that the agent itself is as well as any of its metabolic breakdown products would be safe to use within the body. Second, you want it to work and you want it to be efficacious.
The definition of efficacy can vary between the different uses, for example a vascular surgeon may want something that polymerizes very quickly in order to stop bleeding, but does not cause clot of the vessel that they spent all this time anastomosing, where as a reconstructive surgeon for example may want something that polymerizes very slowly to give them time to reposition their flaps or grafts.
Third is usability; you want something that is easy to use and that you can use in a variety of different circumstances. Fourth is affordability. This may be more relevant to a hospital administrator or pharmacist who actually does the purchasing, but it impacts the surgeon because that determines what you have available to you in the operating room. And finally, fifth, approvability. Any of these agents need to be approved by the FDA in order to be used in the US. So the different types of hemostatic agents, which I will be addressing in this talk are listed below and I am going to go through each one of these specifically.Gelatin sponge or Gelfoam®, which is also known as commercially as Surgifoam again was first introduced in the 1940s by Dr. Gray in the neurosurgical procedures. What it is is purified pork skin gelatin which you can kind think of like Jello®, as it is the same thing that Jello® is made out of.
It has a very amorphous form and has a lot of air spaces and it stains very eosinophilic on H&E stain. Basically the way it works is that its surface essentially acts in the intrinsic pathway causing contact activation and thus platelets. Since it works very proximally within this cascade, you have to have functioning cofactors or clotting factors in order for this to work in helping create clot. Of note, it does absorb approximately 45 times its weight in blood and can expand to approximately 200% of its initial volume. It is absorbed in approximately four to six weeks and on the nasal mucosa it liquifies within two to five days. In the case presentation, this child was initially packed with Gelfoam® approximately a week prior to the time she was seen in the ER and at that point there was no evidence of any Gelfoam left within her nasal cavity. Now the way Gelfoam® can be used, you can either apply dry, directly to the bleeding surface and hold pressure over it or you can wet it in saline and then squeeze out all the air bubbles and use it that way.
Oxidized regenerated cellulose is also known as Surgicel or Oxycel in its commercial forms. It is derived from alpha-cellulose that is actually plant-based. As you can see on microscopic view, Surgicel comes in knit formwhere as Oxycel comes in a microfibrillar form and on microscopic view Surgicel has these fibers which are knit together and they are solid fibers whereas Oxycel has the hollow fibers but they essentially work the same way. Surgicel is relatively acidic and is thought to cause some small vessel contraction. Like Gelfoam, it works at the same point in the intrinsic pathway of clotting causing contact activation. So again the same thing holds that functional clotting factors are needed in order for this to work. It is thought to berelatively bacteriostatic when compared to other hemostatic agents. The theory behind this is that because of its relatively low pH, it deactivates and denatures some of the bacterial proteins especially those related to antibiotic resistance, thus making them more susceptible to antibiotics. It needs to be applied dry and absorbs within four to eight weeks. Of note, on postop imaging Surgicel sometimes causes a ring-enhancing lesion as you can see here on postop imaging, which can be mistaken for an abscess cavity or tumor recurrence. That is something to keep in mind if you are imaging a patient within two months of having operated on them and Surgicel was used during the procedure. On microscopic view, you can see a giant cell reaction.
Our next agent is microfibrillar collagen commercially known as Avitene ®. It is most commonly used in a light flour form, but it does also come in a non-woven web form. This is collagen, which is derived from bovine skin. Under the microscope it is very eosinophilic and of note, under polarizing light it does have periodicity. It binds tightly to blood surfaces, so you do not actually need to achieve a relatively dry field in order to apply it. It causes minimal swelling especially when compared to Gelfoam ®. T he way it works is slightly different because in addition to being collagen and causing contact activation, it does somehow directly activate platelets. But again, it works very proximally within the intrinsic pathway. It is absorbed in three months and it needs to be applied dry.
Collagen sponges, these come in a wide variety of different commercial forms. Again it is similar to Avitene ® and it is derived from bovine Achilles tendon or bovine skin and it works in basically the exact same way as Avitene works and it absorbs in 8-10 weeks.
The next class of hemostatic agents is slightly different: topical thrombin. The idea of topical thrombin has been around since the early 1900s in order to try to achieve clot and in addition the idea of using topical thrombin plus other hemostatic agents such as Gelfoam ® has been around for quite a longtime. In 1999 a new agent was introduced called Floseal™ which basically consists of bovine thrombin plus cross-linked gelatin granules mixed together. So the way it works is your bovine thrombin directly activates fibrinogen and converts it into fibrin monomers. So you can see that this works in a completely different place within the clotting cascade. It works down here in the common pathway bypassing all of the other necessary clotting factors. You do however have to have functional fibrinogen in order for this to work. The product Floseal™ itself is a little bit different from just using topical thrombin plus Gelfoam ® because the gelatin granules have been cross linked in such a way that they do not swell to nearly the same extent. It is absorbed in approximately 6-8 weeks.
Fibrin sealants are the last class of the hemostatic agents that I am going to address. Commercially it comes in many forms including tisseal and crosseal and there are many variations on the idea of fibrin sealants. One of those basic ideas is that you take pure human fibrinogen and combine it with bovine thrombin and they usually throw in an antifibrinolyticagent into the mix as well. So the way this works is that we take the bovine thrombin, it then converts this exogenous human fibrinogen to fibrin monomers, but you do need intrinsic, you need the patient’s own factor XIII and calcium, which then converts it into fibrin polymer. In addition, they usually add an antifibrinolytic agent to the mix as well in order to stabilize the clot. So this does require functional factor XIII and calcium in order for these fibrin sealants to work. They are absorbed within 10-14 days and need a relatively dry field in order to work.
I am going to briefly mention some of the other classes of agents which are out there, but I am not going to address these in detail. There are some completely autologous fibrin sealants. The patient’s own serum is taken and the fibrinogen and thrombin are purified. This achieves essentially the same effect as the fibrin sealants previously mentioned. There are a target platelet gels where again you purify the platelet with plasma and the patient’s own serum combined with thrombin and you get similar agent to the fibrin sealants only there are some additional benefits: you do have some platelet direct growth factors involved which help with wound healing. There are some completely synthetic agents, which are made from polyethylene glycol gels that when you combine them make a completely synthetic hydrogel. Another product is bovine serum plus albumin plus glutaraldehyde, and poly N-acetyl glucosamine is something that the military is investigating as a hemostatic agent and it is a seaweed-based agent. This is just an idea of what is out there in addition to the agents I addressed previously.
Gelfoam ® and Surgicel, work here very proximally in the intrinsic coagulation pathway via contact activation. Collagen also works via contact activation, but also activates platelets. In a completely separate class we have agents that work in the common pathway, which includes Flowseal™, which is essentially topical thrombin and as well as fibrin glue and its variants.
Safety, three things to remember that Gelfoam® swells and it swells a lot. This has proven to be a problem when used within confined spaces such as the spinal foramina where in it can cause spinal cord nerve compression and brain compression. (Gelfoam adverse events HERE and HERE).
Surgicel, of note, even though it does have an antimicrobial effect relative to the other hemostatic agents, it is still a nidus for infection.( Links of interest HERE and Adverse events HERE and HERE and HERE ). Avitene®, and in fact all of these agents, do cause a certain amount of foreign body reaction and granulation formation. But Avitene® has been found to be the worst offender in this way. You can see in this particular slide, they have the Avitene® cavity here, and then a large amount of surrounding edema and a foreign body reaction with giant cells here surrounding the Avitene®. In this picture you can see the periodic nature of Avitene® under polarized light. In fact, the manufacturers recommend that you apply these agents, then hold pressure and wait a while for a clot to form and then you remove the agent afterwards so that you do not leave it within the cavity in order to try to prevent foreign body reaction as much as possible. In addition, Avitene® because it comes in a light fluffy form, has been known to occasionally cause arterial embolization and it had been reported that it is causing laryngospasm when used in tonsillectomy. Collagen sponge has many of the same side effects as any of the bovine derived agents because there are known allergic reactions to some of these bovine antigens, which are containing these agents. (Avitene adverse events HERE and HERE ).
Floseal™ again as I mentioned before has much less swelling than the Gelfoam so it can be used within some of the more enclosed spaces. Because it is Gelfoam beads it can cause arterial embolization if it is used near a larger vessel. In fact Gelfoam beads themselves have been used in order to embolize arterial malformation. Because it contains bovine antigens, it can have antibody formation, which I am going to talk about a little bit more in detail later. Some of the fibrin sealants use pooled human fibrinogen, in which there is always the potential for transmission of infectious agents. Also again, risks of arterial embolization and antibody formation. ( Floseal, Tisseel, CoSeal and Bioglue discussion HERE  and bioglue HERE).
Antithrombin antibodies: These are foreign antigens. A study of 200 patients showed 90% of those exposed to topical thrombin do have a transient elevation in IgG titers. Tadokoro et al in Japan also noted that you can have development of IgE antibodies. This can result in a prolonged thrombin time. Of note, thrombin time is actually a measure of fibrinogen count.
Thrombin time: the way this test was done, you add bovine thrombin to the patient’s fibrinogen and see how long it takes for it to form a monomer. Because you have development of antibodies to bovine thrombin, you can have elevation in your thrombin time. This antibovine thrombin antibody can cross-react with human thrombin, but interestingly enough, this rarely ever causes any sort of clinical bleeding.
The real problem is with antifactor V antibody, as most commercial form of thrombin is contaminated with a certain amount of other bovine antigens and most importantly bovine factor V. So if you can get these antibovine factor V antibodies, which then cross-react with human factor V this can lead to a very severe coagulopathy and because this antibody can act as an inhibitor of factor V. On laboratory tests you can find a very decreased factor V level, increased PT and PTT, which does not correct when you add FFP and vitamin K. When you mix the patient’s sera with a normal human sera, you do not get correction of the PT and PTT which suggest that it is not a cofactor deficiency, but it is actually an inhibitor causing the problem. So as you can see here the factor V is an activator of the conversion of prothrombin to thrombin and this is where you end up with problems. The same study noted that 50% of the 200 patients that they found that were exposed to topical thrombin did develop human factor V antibodies. The problem usually does not happen on the initial exposure, but it is when they are exposed again in the later point to the topical thrombin is when the potential for coagulopathy is exposed. Fortunately these IgG titers do fall off rapidly three to four weeks after the exposure and the treatment if you do encounter this is steroids, cyclophosphamides, IVIG plasmapheresis and platelet transfusion. Of note, I did not see actually any reports of this in the head and neck literature per se; most of the case reports of these events are in the cardiovascular and vascular literature. (Gelfoam or Thrombin adverse event HERE link of interest HERE . Of course we now have J&J human thrombin HERE and Zymogenetics recombinant HERE).
Another requirement of a good hemostatic agent is efficacy. Basically there have been lots of studies both in vitro and in vivo using various animal models as well as human studies comparing these various hemostatic agents. The general gist of them is that fibrin sealant work better than Floseal™ which is better than Avitene® and then the collagen sponge, Surgicel and Gelfoam® are essentially equivocal. They do work better than placebo but can barely differentiate efficacy between any of them. Of note, Floseal™ and Avitene® do cause more inflammatory reactions than the others.
Usability: Gelfoam®, Surgicel, Avitene® and these collagen sponge can be stored at the room temperature and are basically ready to use out of the box. Floseal™ does require two to five minute prep time, you combine the thrombin with calcium and combine that to the gelatin granules. Fibrin sealants on the other hand need to be kept in cold storage and thawed prior to usage; it depends on what company you are using and what type and the prep time can be anywhere up to 20-30 minutes. So it is something to keep in mind if you think you want to use fibrin sealant during your case you should be prepared ahead of time in order to do so.
Affordability: This is an average or sort of an idea of what the cost is for some of these agents. Gelfoam®, Surgicel, collagen sponges are relatively inexpensive in a $10-20 per individual piece, whereas Avitene®, Floseal™ and fibrin sealants are much more expensive.
Approvability: All of these agents are regulated through the FDA as a class III medical device, which means they are subjective to this medical device reporting systems so that the manufacturers are obligated to report to the FDA when an adverse event happens. In fact, in 2004 the FDA released notification to users about Gelfoam® and its swelling and use in neurosurgical procedures because of the potential for paralysis.
*The Full article is available HERE. Links have been added here regarding adverse events and are placed within parentheses.

There is a solution to many of the issues faced with Hemostat requirements with HaemoCer Plus.......read more HERE