Wound closure and healing via sealants, glues, hemostats in development

Natural tissue healing is a highly complex dance of processes that need to be working properly in order for the body to heal. Mammals have developed the ability to heal wounds rapidly through a cascade of processes that starts with hemostasis (blood clotting) to slow or stop the loss of blood. From the moment of injury, platelets start to aggregate, as well as starting to release cytokines, chemokines and hormones. Vasoconstriction takes place as the body tries to limit the loss of blood, and several vasoactive mediators come into play, including, norepinephrine, epinephrine, prostaglandins, serotonin, and thromboxane. Activated platelets lead to formation of a clot. Next, the inflammatory steps kick in, targeting and killing microbes and launching a natural internal debridement process, which serves to clean up any damaged tissue so that reconstruction may occur. Last in the cascade are the proliferative and maturation phases. These involve the deposition of new tissue matrix materials, and are intended to lead to reconstruction of tissue organelles and cellular structure. These healing steps actually overlap one another, and do not have strict times when each process begins or ends.

A delicate physiological balance must be maintained during the healing process to ensure timely repair or regeneration of damaged tissue. Wounds may fail to heal or have a greatly increased healing time when unfavorable conditions are allowed to persist. An optimal environment must be provided to support the essential biochemical and cellular activities required for efficient wound healing and to remove or protect the wound from factors that impede the healing process.

Factors affecting wound healing may be considered in one of two categories depending on their source. Extrinsic factors impinge on the patient from the external environment, whereas intrinsic factors directly affect the performance of bodily functions through the patient’s own physiology or condition. Factors which strongly affect wound healing include smoking, diabetes, age, oxygenation, stress, obesity, certain medications, alcoholism and nutrition.

Timescales for Development of
Sealants, Glues and Hemostat Products

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Source: MedMarket Diligence, LLC; Report #S290.

While product development continues apace, and companies are launching their products in new countries, launches of actual new products has been relatively slow. This is due most likely to the highly technical (read: expensive) nature of the product development, as well as the cost and time involved in running clinical trials, and the strong patent protection which has been erected, especially by the leading companies. The need for the products is there, but the required clinical testing is putting a brake on the markets.

In July 2015, HyperBranch announced the product launch of Adherus® AutoSpray Dural Sealant in the US. FDA clearance to market the product was obtained in March 2015. The absorbable sealant is intended for use in brain surgery and is applied over the sutures for dura repair to prevent cerebrospinal fluid from leaking out of the incision site. The Adherus® AutoSpray Dural Sealant is made of two solutions: a PEG ester solution and a polyethylenimine (PEI) solution. When mixed together, the solutions combine to form a sealant gel that is applied to the incision site. According to the company, the sealant is fully absorbed in about 90 days.

Cohera Medical launched its TissuGlu® in select US cities in November 2015. At this point, TissuGlu® is available in ten cities in the USA, while B. Braun is the distributor for the product in Germany, Spain and Portugal.

Sanyo Chemical launched its first medical device, Hydrofit, in February 2014. The company obtained the approval of the medical device under the Pharmaceutical Affairs Law in December 2011, filing it as a novel surgical hemostatic agent intended for anastomosing the arterial blood and artificial blood vessel in surgical procedures. According to the company, the product will be produced by Sanyo and marketed by Terumo.

In 2014, Cohera Medical, Inc. launched Sylys Surgical Sealant, which can be used in gastrointestinal surgery to decrease anastomotic leak. In the same year, Baxter also gained the FDA permission for Tisseel® fibrin sealant, which, according to the company, is used in almost all types of surgical procedures.

Mallinckrodt will invest in the commercial launch and ongoing market development of both PreveLeak and Raplixa in FY 2016. According to the company, both products are faster to prepare and easier to use and store than competing products. PreveLeak, a surgical sealant, is allegedly more flexible than hemostasis glue products. It is indicated for use in vascular reconstructions to achieve adjunctive hemostasis by sealing areas of leakage. PreveLeak is currently marketed in Europe through distributors.

In an example of a delayed launch, CryoLife has been working towards launch of PerClot in the US, but ran into litigation trouble with Medafor, a wholly-owned subsidiary of CR Bard. In November 2015, CryoLife announced that it had entered into a resolution with Medafor to end the patent dispute in the US District Court for the District of Delaware between the companies regarding PerClot. Under terms of the resolution, all parties agreed to end the litigation, jointly dismissing all claims and counterclaims with prejudice and waiving all appeal rights in this case.  Each party is to pay its own attorneys’ fees and costs associated with the litigation.  However, the court’s preliminary injunction entered March 31, 2015 with respect to CryoLife’s marketing and sale of PerClot in the US will remain in effect until the expiration of Medafor’s US Patent No. 6,060,461 (the “‘461 Patent”) on February 8, 2019. CryoLife management says that this will not upset their plans, as CryoLife does not expect to receive FDA market approval for PerClot before 2018, if then.


From “Sealants, Glues, Hemostats to 2022” (#S290).

Materials used in sealants, glues, and hemostats

Sealants are most often used to stop widespread, diffuse internal bleeding. The product may be sprayed on a bleeding surface, or applied internally using a patch. Sealants are considered inappropriate for heavy bleeding. Surgical sealants may be made of glutaraldehyde and bovine serum albumin, polyethylene glycol polymers, and cyanoacrylates. Fibrin sealants are made of a combination of thrombin and fibrinogen. Sealants may also be made from a patient’s blood (autologous), which limits immunological and other risks.

Although the terms ‘glues’ and ‘adhesives’ are frequently used interchangeably, medical glues are products used to make two tissue surfaces adhere securely to each other without coming apart under normal physical stress. The definition of medical glues does not include medical adhesives such as those coating a bandage to make it stick to the skin.

A hemostat is commonly used in both surgery and emergency medicine to control bleeding, such as from a torn blood vessel. Active hemostats contain thrombin products which may be derived from several sources, such as bovine pooled plasma purification, human pooled plasma purification, or through human recombinant manufacturing processes. Flowable-type hemostats are made of a granular bovine or porcine gelatin that is combined with saline or reconstituted thrombin, forming a putty that may be applied to the bleeding area. Mechanical hemostats, which generally require pressure to stop the bleeding, include items such as hemostatic clamps, absorbable gelatin sponge, collagen, cellulose, or polysaccharide-based hemostats applied as sponges, fleeces, bandages, or microspheres, and do not contain thrombin or any other active biologic compounds.

Global Market for Wound Sealants, Glues and Hemostats, 2015-2022

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Source: “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022.” (report #S290.)

Six Key Trends in Sealants, Glues, Hemostats Markets to 2022

From July 2016 published Report #S290.

Here are six key trends we see in the global market for surgical sealants, glues, and hemostats:

  1. Aggressive development of products (including by universities, startups, established competitors), regulatory approvals, and new product introductions continues in the U.S., Europe, and Asia/Pacific (mostly Japan, Korea) to satisfy the growing volume of surgical procedures globally.
  2. Rapid adoption of sealants, glues, hemostats in China will drive much of the global market for these products, but other nations in the region are also big consumers, with more of the potential caseload already tapped than the rising economic China giant. Japan is a big developer and user of wound product consumer. Per capital demand is also higher in some countries like Japan.
  3. Flattening markets in the U.S. and Europe (where home-based manufacturers are looking more at emerging markets), with Europe in particular focused intently on lowering healthcare costs.
  4. The M&A, and deal-making that has taken place over the past few years (Bristol-Myers Squibb, The Medicines Company, Cohera Medical, Medafor, CR Bard, Tenaxis, Mallinckrodt, Xcede Technologies, etc.) will continue as market penetration turns to consolidation.
  5. Growing development on two fronts: (1) clinical specialty and/or application specific product formulation, and (2) all purpose products that provide faster sealing, hemostasis, or closure for general wound applications for internal and external use.
  6. Bioglues already hold the lead in global medical glue sales, and more are being developed, but there are also numerous biologically-inspired, though not -derived, glues in the starting blocks that will displace bioglue shares. Nanotech also has its tiny fingers in this pie, as well.

See Report #S290, “Worldwide Sealants, Glues, and Hemostats Markets, 2015-2022”.

USA and Asia/Pacific Size Versus Growth in Sealants, Glues, Hemostats

The market dynamics in Asia/Pacific stand apart from those in the U.S. In the case of surgical sealants, glues, and hemostats, what stands out is the Size versus Growth metric.

Much of the potential in China, in particular, remains untapped (low volume, high growth), while in the U.S., these markets are more well established and, therefore, more penetrated.

Below are the size/growth “bubbles” for, alternating, the U.S. and Asia/Pacific.

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Source: MedMarket Diligence, LLC; Report #S290.

Recent Merger and Acquisition Activity in Sealants, Glues and Hemostats

Growth in sealants, glues, and hemostats markets has been strong enough for long enough to have attracted a lot of players. With growth slowing as the untapped potential is reducing more rapidly, consolidation has now appeared in the natural order of things.

Recent Merger and Acquisition Activity in Sealants, Glues and Hemostats

Original Company/ ProductAcquiring or Collaborating CompanyDate of Acquisition/Collaboration DealFinancial Details (where revealed)
Bristol-Myers Squibb/ Recothrom¨ Thrombin topical hemostatThe Medicines Company2012/2014$105 million collaboration fee
Cohera Medical/TissuGlu¨Collaboration with B. Braun Surgical S.A. to distribute in Germany, Spain and Portugal.Jan. 2015B. Braun Surgical S.A. will exclusively market and sell TissuGlu in the territories of Germany, Spain and Portugal through its existing Closure Technologies commercial teams.
Profibrix/ FibroCapsThe Medicines Company2013$90 million, with $140 million contingent upon milestones
Medafor/Arista¨ AH Absorbable Hemostatic ParticlesCR Bard (Bard Davol)2013$200 million upfront payment
Tenaxis Medical, with ArterX (among other products)The Medicines Company2014$58 million in upfront payments
The Medicines Company/ PreveLeakª (formerly known as ArterX), Raplixaª(formerly known as FibroCaps) fibrin sealant, Recothrom¨ Thrombin topical (Recombinant) sealantMallinckrodt plc2016The entire deal has a potential value of $410 million.
Xcede Technologies, Inc./Resorbable Hemostatic PatchCollaboration with Cook BiotechJan-16Signed three collaboration agreements with Cook Biotech, including a Development Agreement, a License Agreement and a Supply Agreement to complete development, seek regulatory clearance and produce XcedeÕs resorbable hemostatic patch.

Source: MedMarket Diligence, LLC; Report #S290.

To request a set of report excerpts, click here.

Sealants, Glues, Hemostats to 2022

 

Below is our bubble chart giving the segment size (bubble size and horizontal axis position) and growth (vertical axis position) of the products detailed in our 2014 report #S192.

Source: MedMarket Diligence, LLC; Report #S192 (published Oct. 2014)

Given the interest by companies actively involved in sealants, glues, and hemostats, we are publishing Report #S290 (June 2016), “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022.”

From Skitch

Sealants, hemostats, glues — future markets foreseen

From our past coverage of surgical sealants, glues, hemostats in our 2014 Report #S192.  (See the forthcoming June 2016 report, “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022”, Report #S290.)

Fibrin and synthetic sealants offer a significant advantage over pure hemostats because they do not rely on the full complement of blood factors to produce hemostasis. Sealants provide all the components necessary to prevent bleeding and will often prevent bleeding from tissues where blood flow is under pressure and the damage is extensive.

CryoLife
Source: CryoLife

These products have the potential to replace sutures in some cases where speed and strength of securement are priorities for the surgical procedure.

Biologically active sealants typically contain various formulations of fibrin and/or thrombin, either of human or animal origin, which mimic or facilitate the final stages of the coagulation cascade. The most common consist of a liquid fibrin sealant product in which fibrinogen and thrombin are stored separately as a frozen liquid or lyophilized powder. Before use, both components need to be reconstituted or thawed and loaded into a two-compartment applicator device that allows mixing of the two components just prior to delivery to the wound. Because of the laborious preparation process, these products are not easy to use. However, manufacturers have been developing some new formulations designed to make the process more user friendly. Leaders in biologic surgical sealant space include Baxter International and Johnson & Johnson’s Ethicon Biosurgery division, but there are a number of smaller suppliers as well, in what has become an increasingly crowded field.

Compared to biologically active sealants containing fibrin and other human- or animal-derived products, synthetic sealants represent a much larger segment of the sealant market in terms of the number of competitors, variety of products, and next-generation products in development. Non-active synthetic sealants do not contain ingredients such as fibrin that actively mediate the blood clotting cascade, rather they act as mechanical hemostats, binding with or adhering to the tissues to help stop or prevent active bleeding during surgery.

Synthetic sealants represent an active category for R&D investment in large part because they offer several advantages over fibrin-based and other biologically active sealants. First and foremost, they are not derived from animal or human donor sources and thus eliminate the risks of disease transmission. Moreover, they are typically easier to use than biological products, often requiring no mixing or special storage, and many of these products have demonstrated improved sealing strength versus their biological counterparts. Synthetic products also have the potential to be more cost-effective than their biologically active counterparts. Leaders in the synthetic surgical sealants space include Baxter International Inc., CryoLife, CR Bard, and Ethicon/J&J; however, there are many up-and-coming competitors operating in this segment of the market with some interesting next-generation technologies that could gain significant traction in the years ahead. Moreover, unlike the fibrin sealants segment, where most products have more general indications for surgical hemostasis, a good number of competitors in the synthetic sealant field are focused on specific clinical applications for their products, such as cardiovascular surgery, plastic surgery, or ophthalmic surgery.

Sealants-Hemostats-Glues-companies-by-type
Source: Report #S192 (pub. 2014)

The non-active hemostats segment of the market includes a variety of scaffolds, patches, sponges, putties, powders, and matrices made of various nonactive materials that act mechanically to stop/absorb active bleeding, often in conjunction with manual compression, during surgical procedures as well as emergency use. Many of the companies active in the first two market segments discussed above also participate in this sector, including Ethicon/J&J, CR Bard, Baxter, and CryoLife, but there are also many other companies that compete in the hemostats market worldwide.


MedMarket Diligence is completing a global analysis of medical and surgical sealants, glues, and hemostats to reveal the patterns of sales, product adoption rates, and the realized/unrealized opportunities for extant stakeholders inclusive of manufacturers, buyers, and the investment arena. Publishing in June 2016, Report #S290, “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022”.

 

Surgical Procedures with Potential for Sealants, Glues, Hemostats

See the published report #S290, “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World”.

Sealants, glues, and hemostats must offer benefit to be adopted in clinical practice, or surgical procedures. Benefits can fall into a number of categories. These range from preventing serious complications from surgery (blood loss), improved patient outcomes (fewer complications, reduction in repeats), reductions in procedure time or other time- or cost-saving benefits, or improved aesthetic and perceived benefits. See these detailed below.

Criteria for Adjunctive Use of Hemostats, Sealants, Glues and Adhesion Prevention Products in Surgery

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Source: MedMarket Diligence, LLC; Report#S192.

We have assessed surgical sealants, glues, and hemostats for their potential in general surgery, aesthetics, neurology, urological, gastroenterology, orthopedics, and cardiovascular medicine.

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Source: MedMarket Diligence, LLC; Report #S192, “Worldwide Surgical Sealants, Glues, and Wound Closure Markets, 2013-2018”.


See the published report #S290, “Worldwide Markets for Medical and Surgical Sealants, Glues, and Hemostats, 2015-2022: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World”.

Growth in Sealants, Glues, Hemostats, and Wound Closure is Absolute, Relative

(See the 2016 published report #S290, “Sealants, Glues, Hemostats, 2016-2022”.)

Of late, I have needed to re-emphasize the difference between absolute and relative growth in medtech markets (and its importance). So, here it is again, this time regarding surgical sealants and other wound closure products.

The lowest relative rate of growth in this industry is the well-established sutures and staples segment. Sales of these products globally, even supported by innovations in bioresorbables and laparoscopic delivery technologies, are only growing at a 5.6% compound annual growth rate from 2013 to 2018. By comparison, growth of sales of surgical glues and sealants is at 9.4% for 2013-2018.

But from an absolute sales growth point of view, sales of sutures and staples will go from $5.2 billion to $6.9 billion, or absolute growth of $1.7 billion. Simultaneously, the relatively high growth in surgical glues and sealants translates to the absolute growth from 2013 to 2018 of only $0.9 billion.

Obviously, both absolute and relative growth are of interest.

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Source: MedMarket Diligence, LLC; Report #S192.

Bioactive Agents in Wound Sealing and Closure

Excerpt from Report #S192, “Worldwide Surgical Sealants, Glues, and Wound Closure 2013-2018”.

Screen Shot 2015-03-30 at 10.14.59 AMBiologically active sealants typically contain various formulations of fibrin and/or thrombin, either of human or animal origin, which mimic or facilitate the final stages of the coagulation cascade. The most common consist of a liquid fibrin sealant product in which fibrinogen and thrombin are stored separately as a frozen liquid or lyophilized powder. Before use, both components need to be reconstituted or thawed and loaded into a two-compartment applicator device that allows mixing of the two components just prior to delivery to the wound. Because of the laborious preparation process, these products are not easy to use. However, manufacturers have been developing some new formulations designed to make the process more user friendly.

Selected Biologically Active Sealants, Glues, and Hemostats 

CompanyProduct NameDescription/(*Status)
Asahi Kasei MedicalCryoSeal FS SystemFibrin sealant system comprising an automated device and sterile blood processing disposables that enable autologous fibrin sealant to be prepared from a patient’s own blood plasma in about an hour. Approved in the US for liver resection surgery and CE marked in Europe. Also sold in Japan and other Asian countries.
BaxterArtissFibrin sealant spray
TisseelBiodegradable fibrin sealant made of human fibrinogen and human thrombin. For oozing and diffuse bleeding.
FloSealHemostatic bioresorbable sealant/glue containing human thrombin and bovine-derived, glutaraldehyde-crosslinked proprietary gelatin matrix. For moderate to severe bleeding.
GelFoam PlusHemostatic sponge comprising Pfizer’s Gelfoam hemostatic sponge, made of porcine skin and gelatin, packaged with human plasma-derived thrombin powder.
Behring/NycomedTachoComb (sold OUS only). Manufactured by NycomedFleece-type collagen hemostat coated with fibrin glue components.
Bristol-Myers Squibb/ZymoGenetics (sold by The Medicines Company in the US and Canada)RecothromFirst recombinant, plasma-free thrombin hemostat; approved in US in 2008.
CSL BehringBeriplast P/Beriplast P Combi-Set (sold OUS only)Freeze dried fibrin sealant. Comprised of human fibrinogen-factor XIII and thrombin in aprotinin and calcium chloride solution.
Haemocomplettan P, RiaSTAPFreeze-dried human fibrinogen concentrate.
Haemocomplettan is sold in US and RiaSTAP is on the market in Europe.
J&J/EthiconEvicelEvicel is a new formulation of the previously available fibrin sealant Quixil (EU)/Crosseal (US). Does not contain the antifibrinolytic agent tranexamic acid, which is potentially neurotoxic, nor does it contain synthetic or bovine aprotinin, which reduces potential for hypersensitivity reactions.
EvarrestAbsorbable fibrin sealant patch comprised of flexible matrix of oxidized, regenerated cellulose backing under a layer of polyglactin 910 non-woven fibers and coated on one side with human fibrinogen and thrombin. FDA approved December 2012.
BIOSEAL Fibrin SealantLow-cost porcine-derived surgical sealant manufactured in China by J&J company Bioseal Biotechnology and targeted to emerging markets.
EvithromHuman thrombin for topical use as hemostat. Made of pooled human blood.
Pfizer/King PharmaceuticalsThrombin JMIBovine-derived topical thrombin hemostat.
Stryker/OrthovitaVitagel SurgicalBovine collagen and thrombin hemostat.
Takeda/NycomedTachoSilAbsorbable surgical patch made of collagen sponge matrix combined with human fibrinogen and thrombin. FDA approved as adjunct to hemostasis in cardiovascular surgery. This is the latest version of TachoComb (see above).
Teijin Pharma Ltd/Teijin Group (Tokyo, Japan)KTF-374Company is working with Chemo-Sero-Therapeutic Research Institute (KAKETSUKEN) to develop a sheet-type surgical fibrin sealant. Product combines KAKETSUKEN’s recombinant thrombin and fibrinogen technology with Teijin’s high-performance fiber technology to create the world’s first recombinant fibrin sealant on a bioabsorbable, flexible, nonwoven electrospun fiber sheet.
The Medicines Company (TMC)Raplixa (formerly Fibrocaps)Sprayable dry-powder formulation of fibrinogen and thrombin to aid in hemostasis during surgery to control mild or moderate bleeding.
In development: Fibropad patchFDA accepted company’s BLA application for Fibrocaps in April 2014 and set an action date (PDUFA) of January 31, 2015. In November 2013, the European Medicines Agency agreed to review the firm’s EU marketing authorization application. Company anticipates US and European launch in early to mid-2015.
Vascular SolutionsD-Stat FlowableThick, but flowable, thrombin-based mixture to prevent bleeding in the subcutaneous pectoral pockets created during pacemaker and ICD implantations.

Note: Status of products detailed in Report #S192.

Source: MedMarket Diligence, LLC