Clinical Papers - Fibrin Sealants, BioGlue, Perclot, HaemoCer, Thrombin

Clinical Papers - Bonewax, Oxidized Cellulose, Surgicel,

Clinical Papers Hemostats Reviewed - Oxi Cell, Gelatin, Collagen, Thrombin, Polysaccharide Powders

A lot of our earlier embedded  document links have gone since our previous embedding agency sold (these things happen in 5 years of blogging). Now Google have this facility I am happy to provide you clinical data for your interest in the links below. 

Powder Hemostatic Medical Devices Segment

To date there are many types of Hemostatic Medical Devices on the market, there are also a plethora of formats utilized e.g. gauze, liquid, pastes and powders. Today I will introduce a list of powders, and while not comprehensive it is indicative of current technologies available to the surgeon. Initially Oxi Cell, Gelatin and Avitene powders were the main products. However now Chitin, and Starch/polysacharides have increased in visibility originally, and now with a very large program of out-licensing of the same technologies under different names. Powders face application and procedural technique issues, as do all formats. Over the following weeks I would like to explore needs, demands and evaluate these systems. Repetitive technology re-branding is also something I hope Blog followers will offer further thoughts on, another item to be considered is sourcing, manufacturing source such as China and due diligence of some of these companies. If you wish to contribute experience or thoughts please feel free to contact me at hemostatguy@gmail.com. We will also explore geographic factors, manufacturing,. distribution and due diligence

Pro Fibrix - Fibrocaps thrombin fibrinogen
 A dry powder based on a mixture of fibrinogen and thrombin, Fibrocaps is a ready-to-use preparation designed to be stable at room temperature and applied in different formats. This is a product and company that shows innovation! Pro Fibrix feel free to contact me.....hemostatguy@gmail.com

HemostasisLLC - Starch

BioCer Entwicklungs-GmbH is a Bayreuth, Germany based company which commercializes innovative technologies developed in conjunction with leading German Research Institutes and Universities.
Biocer have the most powerful of the plant based Starch products with HaemoCer Plus which was commercialized in Q3 2013. The video shows HaemoCer Pl;us compared to the other powdered polysaccharides with double speed and double absorbency. 

Starch Medical - PerClot Starch (AKA OrthoClot)
Absorbable Modified Polymer (AMP™) Chinese technology is a proprietary engineering process that modifies plant starch into ultra-hydrophilic, adhesive forming hemostatic polymers. AMP™ materials are biocompatible, absorbable polysaccharides containing no animal or human components. 

ClotPlus - OrthoClot Starch (AKA PerClot)
OrthoClot™ China made Polysaccharide Haemostatic System Administrator (PHS) is a natural plant-based haemostatic system composed of Absorbable Modified Polymer (AMP™). OrthoClot™ is intended as an absorbable haemostatic system

Medafor - Arista Starch (Outlicensed as Hemostase and Vitasure)
Arista™AH is an absorbable hemostat, based on Medafor's patented MPH® (Microporous Polysaccharide Hemospheres) Technology that is used in the control of profuse bleeding in general surgery when conventional procedures are ineffective or impractical.

CryoLife - Hemostase starch (AKA Arista and Vitasure) 
HemoStase is a plant-based powder that rapidly dehydrates blood and promotes clotting on contact.

Orthovita - Vitasure Starch (AKA Arista, Hemostase)
Vitasure Absorbable Hemostat is comprised of many powerful polysaccharide spheres packaged within a bellows applicator.






Celox - Chitin
Celox™ is made with chitosan, a natural polysaccharide. Chitosan has a known metabolic pathway. That means any left in the body is broken down by the bodies normal enzymes and converted into materials normally present in the body.

Hemcon (Alltracel) - Oxi Cell

Davol - Avitene

Ethicon - Gelatin Powder

Comparison of Topical Hemostats

Topical Hemostat Comparison - others available HERE

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

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

Vascular Closure an interesting comparison

All VCDs have demonstrated rapid hemostasis and a decreased time to ambulation when compared to manual compression(1-4). Vasoseal™ has been associated with the highest risk of infection, while Angiolink™ and Starclose™ are felt to have the lowest risk (1-4). Angioseal™ theoretically has a higher risk of thromboembolic events due to the intravascular collagen anchor. The suture-mediated devices utilize primary healing (end to end anastomosis at the arteriotomy site), but are the most complex technically and have the highest rate of device and operator failure. Collagen and ProcoagulantsThe Vasoseal™ closure device (Datascope Corp., Montvale, NJ) was introduced in 1995 (revised in 1999and 2002) and utilizes an extravascular Type-1 collagen produced from bovine tendons. When deployed at the arteriotomy site the collagen initiates coagulation by activating platelets (secondary healing). Vasoseal™ isFDA approved for both diagnostic and interventional procedures, with a single device used for 5-8 French sheath sizes. The Angio-Seal™ device (St. Jude Medical, St. Paul, MN) achieves hemostasis by sandwiching the puncture site between an intravascular bio-absorbable (over 8-12 weeks) anchor and an extravascular bovine.......................Read more HERE (its a verified safe download from Adrive)

For Current US Vascular Closure Trials go HERE

Vascular Closure

Lets take a look at the vascular closure hemostat range starting with a look at the market with Kensey Nash. There is a full presentation available HERE but key slides featured below.

Comparison of Celox, Hemcon and Quikclot

Celox sent me this report comparing Hemcon and Z-medica with Celox HERE (its a verified safe Pdf download from adrive).
Given the positive results I was left wondering why this product was not the sole choice of the Military, in particular the US forces?
So I emailed Craig Hardy, CEO, MedTrade Products Ltd and asked him........

Me: According to the Jan. ’08 Portsmouth pdf study (comparing Celox with Hemcon and Z-medica’s, Quikclot) the results indicate Celox shows a 100% survival rate. Is this product currently undergoing any evaluation by the military?

Craig: Yes. Celox is used in some performance critical areas of the military and being evaluated in many others. Its an ongoing process.

Me: Given that Medtrade is a U.K. based company what (if any) impact has this had for the uptake of Celox by the U.S. military?

Craig: In the US, Celox is distributed to the Military through Sam Medical in Portland Oregon. The UK is a very close ally of the US. We have heard of no decisions made on the basis of location. However our head office location means we are not as politically connected as some competitors and I believe this may have a significant effect.

ZymoGenetics to Webcast Presentation at Needham Conference

SEATTLE--(BUSINESS WIRE)--ZymoGenetics, Inc. (NASDAQ: ZGEN) announced today that James A. Johnson, Executive Vice President and Chief Financial Officer, will provide an update on company activities at the Needham Biotechnology and Medical Technology Conference in New York on Wednesday, June 11, 2008 at 11:30 a.m. Eastern Time.

A live webcast of the presentation can be accessed by going to: www.zymogenetics.com. The webcast will be archived for 30 days.
Here are some slides from a previous presentation

Cryolife Presentation

Cryolife full presentation is available for 90 days scroll down this page to find the link.
KEY Slides CLICK TO IMAGE TO ENLARGE

Hemostat Technologies

You can find a technology comparitive overview HERE . All downloads are verified safe via Adrive.

PTV - Pharma TV a great resource for Companies

I am pleased to offer this link to PTV they are a wonderful resource especially for start-up companies. New companies will definitely appreciate these insights, I highly recommend for excellent insight from market leaders, and detail on financing pitfalls. There are interviews available online with firms in our industry such as Zymogenetics and a great resource for financing and acquisitions information. Please click HERE .

Haemacure Fibrin Market Comparison (featured key slides click to enlarge).

CLICK IMAGE TO ENLARGE

Haemacure Full Investor presentation with Audio available HERE

Technology Comparison

Click Image to Enlarge

Potential Hemostat Surgical Market

Source Mediligence

Hemostasis Market and Technologies

Topical hemostats and tissue sealants are assured of continued end-user interest due to their ability to improve the effectiveness of surgery and feasibility of minimally invasive surgery, as well as reduce complications and operating time. They also help prevent excess blood loss and aid reconstruction during surgical repair. However, these products are perennially locked in a battle for market dominance. While surgeons have shown a preference for topical hemostats for their lower costs, greater reliability, and established clinical record, there exist significant concerns regarding their use of animal source products.
The current total hemostat market size worldwide is 2B US$, 9% growth rate
–70 million surgical and procedure-based wounds annually worldwide
–20 million surgical procedures in the US
–“10-15% procedures would benefit from increased use of newly-developed adjunctive surgical closure and securement products”
The rising complexities of surgeries have triggered a simultaneous urgency for topical hemostats to control bleeding. These products are particularly useful in burn and wound care and a wide range of surgeries including cardiothoracic, neurosurgery, spine, orthopedic, vascular, dermatology/plastic, and many others. The increasing popularity of minimally invasive procedures is also boosting demand for topical hemostats, encouraging the development of niche products and application devices.

• Topical Hemostats:
  Collagen-based
  Oxygen regenerated cellulose-based
  Gelatin-based
  Thrombin-based
  Combination products
• Tissue Sealants:
  Fibrin
  Synthetic polymer-based
  Protein-based