In reviewing patents, fundings, technology development trends, market development, and other hard data sources, we feel these are some of the strongest areas for investment in not only the medical device side of medtech, but also the broader biomedical technology arena:
Cancer probes (e.g., fluorescent or optical coherence tomography, frozen section, cytologic imprint analysis, ultrasound, micro-computed tomography, near-infrared imaging, and spectroscopy)
neurostimulation and neuromodulation
In addition, there are many areas in healthcare in which there is much untapped demand with problems that, so far, seem to have eluded medtech solutions. These include infection control (Zika, MRSA, TB, nosocomial infections, etc.), chronic wound treatment (including decubitus/stasis/diabetic ulcers), type 2 diabetes and obesity.
The market for wound management products — as varied as negative pressure wound therapy, skin grafts, hydrogel dressings, and growth factors — is a sort of free-for-all of offerings designed to accelerate healing, reduce treatment costs, yield better outcomes, or all of these and more. With so many sectors, and with well-established ones tending toward commodity, there can be many competitors, with few having significant market shares. Yet in several areas, quite remarkable growth is still available. Excluding traditional bandage and dressings, three companies — S&N, Acelity and Mölnlycke — control over half the worldwide market.
The MedMarket Diligence report #S251, “Worldwide Wound Management, Forecast to 2024: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World,” is detailed at link and is available for purchase and download online.
Sales of sealants, glues, and hemostats projected to 2022 for the U.S. and Asia/Pacific. While these products have had tremendous success in Japan, their sales in the rest of Asia/Pacific have not yet caught up to Japan, let alone to the U.S.
But that is expected to change as the most significant growth in these markets will indeed be coming from China, Korea, Australia, India, and elsewhere in these emerging markets.
Sales of Sealants, Glues, and Hemostats in the U.S. and Asia/Pacific Markets, 2015-2022
Note: For direct comparative purposes, sales in these markets are shown on the same vertical scale.
The number of options that are in use or development for coronary revascularization or other treatment for ischemic heart disease is extraordinary. Given the mortality associated with coronary artery disease, it is unsurprising that it has been the focus of so much development.
Below are the options that have evolved for treatment of ischemic heart disease, inclusive of surgical, interventional, and other medical approaches.
Coronary Revascularization and Other Ischemic Heart Treatment Options
Source: MedMarket Diligence, LLC
See also “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022”, report #C500. Order online.
There are several different classes of surgical sealants, glues and hemostatic products used to prevent or stop bleeding, or to close a wound or reinforce a suture line. These include fibrin sealants, surgical sealants, mechanical hemostats, active hemostats, flowable hemostats, and glues. Both sealants and medical glues are increasingly used either as an adjunct to sutures or to replace sutures.
Fibrin sealants are made of a combination of thrombin and fibrinogen. These sealants may be sprayed on the bleeding surface, or applied using a patch. Surgical sealants might be made of glutaraldehyde and bovine serum albumin, polyethylene glycol polymers, and cyanoacrylates.
Sealants are most often used to stop bleeding over a large area. If the surgeon wishes to fasten down a flap without using sutures, or in addition to using sutures, then the product used is usually a medical glue.
The surgeon and the perioperative nurse have a variety of hemostats from which to choose, as they are not all alike in their applications and efficacy. Selection of the most appropriate hemostat requires training and experience, and can affect the clinical outcome, as well as decrease treatment costs. Some of the factors that enter into the decision-making process include the size of the wound, the amount of hemorrhaging, potential adverse effects, whether the procedure is MIS or open surgery, and others.
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 flowable putty that may be applied to the bleeding area. Mechanical hemostats, such as absorbable gelatin sponge, collagen, cellulose, or polysaccharide-based hemostats applied as sponges, fleeces, bandages, or microspheres, are not included in this analysis.
Sealants and glues are terms which are often used interchangeably, which can be confusing. In this report, a medical glue is defined as a product used to bond two surfaces together securely. Surgeons are increasingly reaching for medical glues to either help secure a suture line, or to replace sutures entirely in the repair of soft tissues. Medical glues are also utilized in repairing bone fractures, especially for highly comminuted fractures that often involve many small fragments. This helps to spread out the force-bearing surface, rather than focusing weight-bearing on spots where a pin has been inserted.
Thus, the surgeon has a fairly wide array of products from which to choose. The choice of which surgical hemostat or sealant to use depends on several factors, including the procedure being conducted, the type of bleeding, severity of the hemorrhage, the surgeon’s experience with the products, the surgeon’s preference, the price of the product and availability at the time of surgery. For example, a product which has a long shelf life and does not require refrigeration or other special storage, and which requires no special preparation, usually holds advantages over a product which must be mixed before use, or held in a refrigerator during storage, then allowed to warm up to room temperature before use.
Hemostat sales are exceptionally strong in the well developed economies (Japan, Australia, Korea) of Asia, and will continue to expand there with the rapidly growing contribution of China’s hemostat sales.
In 2016, the cumulative worldwide volume of the the following CVD procedures is projected to approach 15.05 million surgical and transcatheter interventions:
roughly 4.73 million coronary revascularization procedures via CABG and PCI (or about 31.4% of the total),
close to 4 million percutaneous and surgical peripheral artery revascularization procedures (or 26.5% of the total);
about 2.12 million cardiac rhythm management procedures via implantable pulse generator placement and arrhythmia ablation (or 14.1% of the total);
over 1.65 million CVI, DVT, and PE targeting venous interventions (representing 11.0% of the total);
more than 992 thousand surgical and transcatheter heart defect repairs and valvular interventions (or 6.6% of the total);
close to 931 thousand acute stroke prophylaxis and treatment procedures (contributing 6.2% of the total);
over 374 thousand abdominal and thoracic aortic aneurysm endovascular and surgical repairs (or 2.5% of the total); and
almost 254 thousand placements of temporary and permanent mechanical cardiac support devices in bridge to recovery, bridge to transplant, and destination therapy indications (accounting for about 1.7% of total procedure volume).
Coronary artery bypass grafting (CABG) is the most common type of cardiovascular surgical intervention, which “bypasses” acute or chronic coronary artery obstructions via a newly created vascular conduit and thus reinstate normal or sufficient blood flow to the ischemic but still viable areas of the myocardium.
The majority of CABG surgeries (up to 75%) are still performed on the fully arrested heart which is accessed via a foot-long incision over the sternum and completely separated patient’s rib cage. Following a full sternotomy, the CABG patient is typically placed on extracorporeal cardiopulmonary bypass (CPB) with a heart-lung machine, which allows the surgeon to operate on a still and bloodless field. Simultaneously, the patient’s greater saphenous vein or internal mammary artery, or both are harvested (mobilized) for use as a bypass conduit in the ongoing procedure. Depending on the location, character and number of the coronary artery occlusions, the surgery might involve between one and seven coronary bypasses.
Once the bypasses are completed, the heart is restarted and, if it functions normally, the patient is removed from the heart-lung machine and the chest is closed up, the sternum is stabilized with stainless steel wire, and the chest and leg wounds are closed with sutures or clips. Patient’s recovery from a routine uncomplicated CABG usually involves seven to ten days of hospital stay, including two to three days spent in the cardiac intensive care unit.
Less Invasive CABG
Over the past decade, several less-invasive versions of the CABG were developed with the view of reducing morbidity and potentially serious complications associated with extensive surgical trauma and the use of aortic clamping and CPB. The current arsenal of less-invasive coronary artery bypass techniques includes minimally-invasive direct CABG (MIDCAB), full-sternotomy “off-pump” CABG (OPCAB), port-access CABG (P-CAB) with peripheral cannulation and endoclamping of aorta, and endoscopic computer (robotics)-assisted CABG (C-CAB).
Designed to limit surgical trauma of conventional CABG, the MIDCAB procedure is best suited for patients with occluding lesions either in the left anterior descending (LAD) artery, or the right coronary artery (RCA). In contrast to conventional CABG, it is performed on a beating heart without the use of CPB. In MIDCAB surgery, access to targeted arteries is achieved through a limited left anterior thoracotomy in the case of occluded LAD, and right thoracotomy or limited lateral thoracotomy in cases involving diseased proximal RCA or circumflex artery. Because of the smaller surgical trauma and off-pump performance (without aorta clamping), the MIDCAB procedure typically results in fewer complications, lower morbidity and shorter hospital stays compared to conventional CABG. However, its utility is limited to a subset of patients with one or two coronary vascular targets, which constitute a small fraction (<3%) of the total caseloads referred for CABG.
The OPCAB procedure is performed on a beating heart after reduction of cardiac motion with a variety of pharmacological and mechanical devices. These include slowing the heart rate with ß-blockers and calcium channel blockers and the use of special mechanical devices intended to stabilize the myocardium and mobilize target vessels. The use of various retraction techniques allows to gain access to vessels on the lateral and inferior surfaces of the heart. Because the OPCAB technique also involves surgical access via median sternotomy, its primary benefit is the avoidance of complications resulting from the use of cardiopulmonary bypass, not surgical trauma.
Over the past decade, the OPCAB surgery emerged as the most popular form of less-invasive coronary artery bypass procedures in the U.S, and Western Europe. By the beginning of this decade, an estimated 25% of all CABGs performed in these geographies were done without the use of CPB. However, in recent years, the relative usage of OPCAB techniques remained largely unchanged. In the view of many cardiac surgeons, the latter was predicated by the increasing morphological complexity of cases referred for CABG (rather than PCI) and generally superior immediate and longer-term bypass graft patency and patient outcomes obtainable with technically less-demanding on-pump CABG surgery.
In contrast to that, the relative usage of “neurological complications sparing” OPCAB techniques is significantly higher in major Asia-Pacific states reaching over 60% of all CABG procedures in China, India, and Japan.
The rarely used P-CAB procedure involves the use of cardiopulmonary bypass and cardioplegia of a globally arrested heart. Vascular access for CPB is achieved via the femoral artery and vein. Compared to the MIDCAB technique, the use of multiple ports allow access to different areas of the heart, thus facilitating more complete revascularization, and the motionless heart may allow a more accurate and reliable anastomosis. In distinction from conventional CABG, median sternotomy is avoided, which reduces trauma and complications. However, potential morbidity of the port-access operation includes multiple wounds at port sites, the limited thoracotomy, and the groin dissection for femoral-femoral bypass. The procedure is also technically difficult and time consuming and therefore has not achieved widespread popularity.
The Hybrid CABG-PCI procedure combines the use of surgical bypass (typically MIDCAB) and percutaneous coronary interventional techniques (angioplasty and stenting) for optimal management of multi-vessel coronary occlusions in high risk patients. The main rationale behind the utilization of hybrid procedure is to achieve maximally possible myocardial revascularization with minimally possible trauma and reduced probability of post-procedural complications. The most common variation of the hybrid revascularization involves MIDCAB-based radial anastomosis between the left anterior descending artery and left internal thoracic artery accompanied by the PTCA/stenting-based recanalization of less critical coronary artery occlusions.
CABG Utilization Trends and Procedure Volumes
Since the advent of coronary angioplasty in the late 1970s, the relative role and share of CABG procedures in myocardial revascularization have been steadily declining due to a continuing penetration of treated patient caseloads by a less invasive PTCA. This general trend was further expedited by the advent of coronary stents. At the very end of the past decade, the rate of transition towards percutaneous coronary interventions in myocardial revascularization started tapering off, primarily due to growing maturity of PTCA/stenting technology and nearly full coverage of patient caseloads with one- or uncomplicated two-vessel disease amendable through angioplasty and stenting. At the same time, a growing popularity of the less-invasive CABG regimens resulted in some additional influx into CABG caseloads from a no-option patient cohort. A less-invasive surgical coronary bypass also emerged as a preferred treatment option for some gray-area patients that were previously referred for sub-optimal PTCA and stenting to avoid potential complications of conventional CABG.
In 2006 – for the first time in about two decades – the U.S. and European volumes of CABG procedures experienced a visible increase, which was repeated in 2007 and reproduced on a smaller and diminishing scale in the following two years.
The cited unexpected reversal of a long established downward procedural trend reflected an acute (and, probably, somewhat overblown) end-users’ concern about long-term safety (AMI-prone late thrombosis) of drug-eluting stents (DES), which prompted a steep decline in utilization of DES in 2006, 2007, followed by a smaller and tapering decreases in 2008 and 2009 with corresponding migration of advanced CHD patients referred for radical intervention to bare metal stenting and CABG surgery.
In 2010 – 2015 the volume of CABG surgeries remained relatively unchanged, notwithstanding a visible decline in percutaneous coronary interventions and overall myocardial revascularization procedures.
In the forthcoming years, the cumulative global volume of CABG procedures is unlikely to experience any significant changes, while their relative share in coronary revascularization can be expected to decline from about 15.4% in 2015 to roughly 12.3% by the end of the forecast period (2022). The cited assertion is based on the expectation of eventual stabilization and renewal of nominal growth in utilization of PCI in the U.S. and Europe coupled with continuation of robust expansion in the usage of percutaneous revascularization techniques in Asia-Pacific (especially India and China, where PCI volumes were growing by 20% and 10% annually over the past half decade, according to local healthcare authorities).
In 2016, the worldwide volume of CABG surgeries leveled at approximately 702.5 thousand procedures, of which roughly 35.2% involved the use of less-invasive OPCAB techniques. During the forecast period, the global number of CABG procedures is projected to experience a nominal 0.1% average annual increase to about 705.9 corresponding surgical interventions in the year 2022. Within the same time frame, the relative share of less-invasive bypass surgeries is expected to register modest gains expanding to approximately 36.7% of the total in 2022.
Coronary Revascularization Procedures, 2015-2022 (Figures in thousands)
In, “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022”, Report #C500, we forecast cardiovascular procedure utilization, caseload, technology trends, and device market impacts, for the U.S., Western Europe, Asia/Pacific, and Rest of World.
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
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).