Category Archives: Americas

Growth Factors in Wound Management

Extensive research has demonstrated that wound fluid is rich in growth factors. Growth factors are naturally occurring proteins found primarily in platelets and macrophages. They are needed for normal wound healing to promote growth and migration of fibroblasts, endothelial cells and keratinocytes. The functions of growth factors include; attraction of cells to the wound site (chemotaxis), stimulation of cell division/ proliferation (mitogenic competence/progressive), differentiation of cells into specific phenotypes (transformation), and stimulation of cells to perform functions or secrete other growth factors. Growth factors bind to receptors on the cell surface where they activate cellular proliferation and/or differentiation. There are a number of growth factors which are involved in wound healing at different points in time. Many are quite versatile and capable of stimulating cellular division in different cell types; others are specific to a particular cell type.

Growth factors applied to wound management fall into the following categories:

 

Growth factor
Sources
Effects
Epidermal growth factor (EGF)Activated macrophages. Salivary glands. KeratinocytesKeratinocyte and fibroblast mitogen. Keratinocyte migration. Granulation tissue formation
Transforming growth factor-_ (TGF-_)Activated macrophages. T-lymphocytes. KeratinocytesHepatocyte and epithelial cell proliferation. Expression of antimicrobial peptides. Expression of chemotactic cytokines
Hepatocyte growth factor (HGF)Mesenchymal cellsEpithelial and endothelial cell proliferation. Hepatocyte motility
Vascular endothelial growth factor (VEGF)Mesenchymal cellsVascular permeability. Endothelial cell proliferation
Platelet derived growth factor (PDGF)Platelets. Macrophages. Endothelial cells. Smooth muscle cells. KeratinocytesGranulocyte, macrophage, fibroblast and smooth muscle cell chemotaxis. Granulocyte, macrophage and fibroblast activation. Fibroblast, endothelial cell and smooth muscle cell proliferation. Matrix metalloproteinase, fibronectin and hyaluronan production. Angiogenesis. Wound remodeling. Integrin expression regulation
Fibroblast growth factor 1 and 2 (FGF-1, FGF2)Macrophages. Mast cells. T-lymphocytes. Endothelial cells. FibroblastsFibroblast chemotaxis. Fibroblast and keratinocyte proliferation. Keratinocyte migration. Angiogenesis. Wound contraction. Matrix (collagen fibers) deposition
Transforming growth factor-_ (TGF-_)Platelets. T-lymphocytes. Macrophages. Endothelial cells. Keratinocytes. Smooth muscle cells. FibroblastsGranulocyte, macrophage, lymphocyte, fibroblast and smooth muscle cell chemotaxis. TIMP synthesis. Angiogenesis. Fibroplasia. Matrix metalloproteinase production inhibition. Keratinocyte proliferation
Keratinocyte growth factor (KGF)KeratinocytesKeratinocyte migration, proliferation and differentiation

Source: MedMarket Diligence, LLC; Report #S249

The emergence and rapid adoption of growth factors in wound management is testimony to the expectation that they will hasten wound healing and result in better outcomes, lowered cost or both. While the market for growth factors in wound management is largely represented by the U.S. market (as with most advanced medical technologies), economics, technology diffusion and other forces will lead to more rapid growth in the use of these products in Asia/Pacific (in particular, China will see strong growth, given that powerhouse country’s propensity to bypass progressive development in favor of very rapid adoption of new technologies).

Distribution of Wound Growth Factor Markets, 2013 & 2021

GF-pie-2013-2021

Source: MedMarket Diligence, LLC; Report #S249

Growth of established and advanced wound closure products globally

Sutures and staples are fairly low tech methods to close wounds.  Sutures in one form or another (mostly sheep intestines) have been in use for hundreds of years and staples have been in practice since the early 1900s. At the other end of the extreme are high strength medical adhesives or surgical glues, which are still largely in their infancy.

But the impact of these products in the market for wound closure varies by country and the local nature of medical practice, the impact of culture on the management of wounds, the economic climate and a large number of other factors.

Below is illustrated, for comparison, the compound annual growth rate in sales of sutures/staples versus high strength adhesives/glues.  What is clear is that the more rapid growth of high strength adhesives reflects the fact that their potential is a long way from being fully penetrated.  What is not as clear from growth rates is the relative size of the markets — or the absolute sales volume associated with the growth rates given.  Sutures and staples still represent an enormous ($5.5 billion) global market while high strength glues are less than a quarter of this.

CAGRs-sealants-high-strength

Source: MedMarket Diligence, LLC; Report #S190.

The complete picture — growth and current revenues — is represented in the sales by country, which (for the sake of this snapshot) is illustrated below in summary by geographic region.

regional-sealant-sales-2012

Source: MedMarket Diligence, LLC; Report #S190.


“Surgical Sealants, Glues, Sutures, Other Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017″, Report #S190 from MedMarket Diligence, details the current and forecast market by country for the range of products in wound closure and related wound applications including tapes, sutures/staples/mechanical closure, hemostats, fibrin sealants/glues and high-strength medical adhesives and anti-adhesion products.

Growth in posterior pedicle screw fusion systems in spine surgery

Posterior pedicle screw fusion systems are used extensively in spine surgery; eight or more screws may be used in a single procedure.

The posterior pedicle screw fusion system will continue to be used in spine surgery for the foreseeable future. Industry managers believe that, even as new treatments come on to the market, spinal fusion will continue to be the gold standard treatment for degenerative disc disease unresponsive to conservative measures.

The global market for posterior pedicle screw fusion systems was nearly $3 billion 2012, and is forecast to reach a value of almost $6 billion by 2020. The average selling price (ASP) is expected to drop over this period, due largely to strong competition and the sheer number of companies manufacturing and selling these devices.

pedicle-screw

Source: MedMarket Diligence, LLC: Report #M520.

A variable number of pedicles screws are used in each procedure but this number on average will remain the same through 2020.  Consequently, with prices being squeezed, unit growth will outpace dollar volume sales growth.

The global leader for posterior pedicle screw fusion systems is Zimmer, followed by Medtronic, with the two companies controlling almost 75% of the market. There are many smaller companies in this market, and all of these are targeting the same customers, creating intense pricing pressure for devices that are generally ‘me-too’ and leading to consolidation as manufacturers hit their lowest limits on cost.

 

Wound healing physiology

Skin_layers.svgWhen body tissue is damaged by trauma, surgery, hypoxia, or other destructive processes, it quickly reacts to protect itself and begin the process of healing. Clean surgical wounds closed by primary intention heal rapidly and do not usually require additional medical intervention and support. Chronic wounds and those left to heal by secondary intention will require more attention from the medical team. Most of the literature describing the phases of wound healing has been written following investigation of clean, acute wounds, and the sequence and timing of the events described thus only relates to acute wounds. It is assumed that the chronic wound follows a similar wound-healing course with the timing of events delayed or prolonged compared with acute wounds.

All wounds must pass through three recognized physiological processes in order to achieve healing: the inflammatory phase, proliferative phase, and maturation phase. It is useful to view the stages of wound healing as distinct events with endpoints or goals that must be achieved in the proper sequence for healing to succeed. In reality, there is overlap between the phases, and an individual wound may be in several phases at the same time. When all the stages have been accomplished over the entire wound surface, complete wound healing is achieved.

Unlike acute or surgical wounds, which heal by “primary intent” – the joining of the wound edges by sutures, staples, or adhesive strips – skin ulcers and severe burns heal by “secondary intent,” through the formation of granulation tissue, contraction of the wound, and epithelialization. A normal wound heals in approximately 21 days in organized phases of inflammation, proliferation, and remodeling, but chronic wounds often stall between the inflammatory and proliferation stages, creating wounds that can last for months or even years.

Wound physiology is divided into three phases: defensive, proliferative, and maturation; each phase must be allowed to occur without impediment for healing to be complete. The defensive phase occurs from the time of injury to three days and is characterized by hemostasis and inflammation. The clotting cascade is initiated, and white blood cells mobilize to defend and protect the area from bacterial invasion. Vasodilatation and serous exudate facilitate the removal of debris and deliverance of nutrients to injured tissue. Proliferation lasts from day two until the area is healed and features granulation, contraction, and epithelialization. Granulation includes neoangiogenesis and collagen formation. Granular tissue is pale pink to beefy red, glistening, and has a rough surface due to blood vessels and collagen deposits Contraction occurs as a result of myofibroblasts pulling collagen toward the cell body, and epithelialization is the migration of epithelial cells to resurface the area. Maturation is the last phase of healing, and involves scar remodeling after wound closure and may take years. Maturation sees a scar change from red to purple/pink to white, and from bumpy to flat.

Wound management priorities include: 1) reducing or eliminating causative factors (pressure, shear, friction, moisture, circulatory impairment, and/or neuropathy), 2) providing systemic support for healing (blood, oxygen, fluid, nutrition, and/or antibiotics), and, 3) applying the appropriate topical therapy (remove necrotic tissue or foreign body, eliminate infection, obliterate dead space, absorb exudate, maintain moist environment, protect from trauma and bacterial invasion, and provide thermal insulation).

The diversity of wounds and wound care products complicates the dressing selection process; many wounds have several options for dressings that are effective. Matching wound characteristics with dressing features is one important goal in the healing process. For example, a heavily exudating wound needs an absorptive dressing, and a wound with necrotic eschar needs a dressing that facilitates debridement. Dressings fall into several categories: gauze, hydrogel, hydrocolloid, transparent film, alginate, foam, and accessory products such as enzymes, growth factors, biological dressings, compression devices, support surfaces, and methods for securing dressings.

Factors affecting healing include tissue perfusion and oxygenation, presence or absence of infection, nutrition, medications, underlying disease, mobility and sensation, and age. Circulation and adequate oxygen saturation deliver nutrients for wound healing and gas exchange. All wounds disrupting the integument are contaminated, but not necessarily infected. Bacteria compete with tissues for nutrients, prolonging the inflammatory stage and delay collagen synthesis and epithelialization. Vitamin C, the B vitamins, zinc, and copper are necessary for collagen synthesis. Vitamin A combats the effects of steroids and protein is needed for collagen and skin growth. Steroids and immunosuppressive drugs suppress the inflammatory phase thus slowing the entire healing process. Underlying chronic disease(s) also competes for nutrients, increases risk of infection, and stresses the healing process. Limited mobility and/or sensation contribute to wound formation and impair the perception of wound presence or complications.

Debridement is necessary when necrotic eschar or fibrinous slough is present in the wound base. Necrotic eschar is thick, leathery, devitalized, black tissue, and slough is white or yellow tenuous tissue. Methods of debridement are described as sharp (surgical), mechanical (dressings), autolytic (dressings) and enzymatic (enzymes). Sharp debridement is indicated for extensive necrosis or for large wounds. Mechanical and autolytic debridement are indicated for many pediatric wounds and is accomplished with dressings. Mechanical debridement is done with a wet to dry dressing using woven gauze; as wet fibers dry, tissue adheres to the fiber and is removed when the dressing is removed. Autolytic debridement is also indicated for many pediatric wounds and is done with an occlusive dressing that retains moisture on the wound and allows white blood cells and enzymes to break down necrotic tissue. Hydrocolloids, transparent films, and hydrogels are effective for autolytic debridement. Enzymatic debridement is indicated when selective debridement is desired because enzymes only work on necrotic tissue. Enzymatic preparations contain fibrinolysin, collagenase, papain or trypsin in a cream or ointment base. Enzymatic debridement is slow, but effective, and instructions for using enzymes must be followed closely.

Wound cleansing removes dressing residue, microbes, and cellular debris (may include healing tissue). Cleansing products need to be safe for healing tissue and effective at removing debris. The adage “don’t put anything in a wound you wouldn’t put in your eye” are safe words to work by. Many topical cleansing agents and antiseptics are cytotoxic, and it is imperative to weigh the risks of cytotoxicity against the benefits of cleansing effectiveness and antimicrobial activity. Normal saline is safe, effective, readily available, and inexpensive. Wound irrigation pressure needs to be high enough to remove debris and low enough to avoid traumatizing tissue. Pressures ranging from 4-15 pounds per square inch (psi) are effective for cleaning. For example, a 60cc catheter tip syringe delivers 4.2 psi, a 35cc syringe with a 19 guage needle delivers 8.0 psi, and a Water Pik at its highest setting delivers >50 psi. Frequency of wound cleansing varies with wound characteristics and dressing selection, but once a day cleansing is a minimum4,5. Clean versus sterile technique for dressing changes is constantly debated with varying outcomes and supporting arguments. Most importantly, consider the host system defenses and type of wound when deciding whether to use a clean or sterile technique for dressing changes and cleansing.

Wound assessment involves many parameters, but the following indices should be included in continued documentation of wound healing: size (length, width, depth), extent of tissue involvement (partial or full thickness; stage of pressure ulcer), presence of undermining or tracts, anatomic location, type of tissue in base (viable or nonviable), color (red, yellow, black categories), exudate, edges, presence of foreign bodies, condition of surrounding skin, and duration2. Photography is useful for documenting progress and should include a measuring scale and date.

For Inflammatory Phase, Proliferative Phase, Angiogenesis and Maturation Phase, see Report #S249.


Drawn from Report #S249: “Wound Management, Worldwide Market and Forecast to 2021: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World.”

See also Report #S190: “Surgical Sealants, Glues, Sutures, Other Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017.”

High growth spine surgery markets worldwide

Growth of sales for medical technologies can be determined almost as much by geography as by whether the market is emerging or displacing existing competitive technologies.  For this reason, we review spine surgery markets globally considering the growth of specific spine surgery technologies in specific countries.

Clearly, the geographic markets that are, in general, demonstrating the most rapid adoption of new medical technologies will show even higher rates of adoption of the newest medical technologies than in other geographies.

Case in point, the spine surgery technologies demonstrating the highest growth geographically are among the newest medical technologies being introduced in rapidly growing economies:

growth-country-segments

Source: MedMarket Diligence, LLC; Report #M520, “Worldwide Spine Surgery: Products, Technologies, Markets and Opportunities 2010-2020.”

Requirements for effective surgical sealants

Tourniquet, pressure and sutures have been used for controlling excessive bleeding during surgical procedures for many hundreds of years. Fibrin sealants represented a revolution in local hemostatic measures for both bleeding and nonbleeding disorders. Fibrin sealant has the potential to provide life-saving control of excessive bleeding in many critical surgical operations and during a number of elective procedures. The terms “sealant” and “glue” are frequently used interchangeably in the surgical context, but there is actually a difference in adhesive strength between sealants, pioneered by fibrin products (sometimes homemade) and the later, stronger glues of which cyanoacrylate-based products were the leaders.

In order for a sealant to be effective, the product should meet several parameters, depending upon the application. Among these are:

  • Ability to close the wound
  • Strength of bond
  • Speed of curing
  • Protection of the wound from infection
  • Low surface friction
  • Breathability in order to aid healing
  • Lack of adverse side effects to skin and internal tissues
  • Cost-effectiveness
  • Ease of handling

Fibrin and other sealant products have been approved and used outside the United States for many years and their use has created strong awareness of their surgical and economic benefits in Europe, Latin America and Asia. As a result, many such products have been marketed in these regions for 20 years or more, and have been developed for a variety of surgical uses. In the U.S., these products were initially approved as hemostatic adjuncts to suturing. They are increasingly being used for sealing of tissues, but their use beyond hemostasis (i.e., as sealants and low-strength glues) lags that of markets outside the U.S.

There are more than 30 companies worldwide developing fibrin sealants and driving a market that will exceed $2.2 billion by 2017.

sealants-regional-forecast

 

Source: MedMarket Diligence, LLC; Report #S190.

For complete analysis of the global market for fibrin sealants, see the MedMarket Diligence Report #S190, “Worldwide Surgical Sealants, Glues, Wound Closure and Anti-Adhesion Markets, 2010-2017.”

High and low growth wound care sales by country

Wound care product sales are growing at wildly variable rates around the world, with extremes spanning from the emergence of new technologies in rapidly growing economies to the technologies with low innovation in sluggish economies.

MedMarket Diligence’s global analysis of wound care products, technologies, companies and markets reveals the full spectrum of growth rates for well established to rapidly emerging products.

Below is illustrated the high growth country/product segments in wound management, reflecting the rapid adoption of new technologies such as growth factors and bioengineered skin, as well as older products such as alginates that are gaining sales in rapidly developing economies.

wound-country-high

Source: MedMarket Diligence, LLC; Report #S249, “Wound Management, Worldwide Market and Forecast to 2021:  Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World.”

At the other end of the extreme are those very well established products growing at less than anemic rates in countries where the economy is not as robust and/or where the growth has been superseded by sales of more novel products. Conventional dressings and bandages offer considerably less demand than do growth factors, bioengineered skin and skin substitutes and similar new products.

wound-country-low

Source: MedMarket Diligence, LLC; Report #S249

Of course, growth of sales in wound management products (and any product) is defined as the percentage change in sales volume over time. Smaller markets (typically soon after they have formed as a result of their initial commercialization) tend to grow on a percentage basis much faster. Indeed, a $1 dollar sale in year 1 followed by a $2 sale in year 2 represents a 100% growth rate, while a $1 increase in sales from year 1 to year 2 for a $100 million market represents virtually zero growth. Conversely, a 1% increase in a $1.75 billion market is a $17.5 million increase. This is indeed obvious, but must be kept in mind when considering the growth rates discussed above.

Growth factors in wound management

MedMarket Diligence has expanded its global wound care market analysis to address the current market and forecast outlook for growth factors developed and applied to accelerating wound care.

Extensive research has demonstrated that wound fluid is rich in growth factors. Growth factors are naturally occurring proteins found primarily in platelets and macrophages. They are needed for normal wound healing to promote growth and migration of fibroblasts, endothelial cells and keratinocytes.

For this reason, growth factors have been heavily studied and already have demonstrated their potential to advance wound care.

Report #S249, “Wound Management, Worldwide Market and Forecast to 2021: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World,” provides detailed global, regional and country-specific data on growth factors in wound care.

Variable distribution of med/surg sealants and related products in global markets

Sealants, glues, hemostats, other wound-closure and anti-adhesion products in medical/surgical applications are penetrating world markets at variable rates as a result of differences in clinical practices, incidence/prevalence or other clinical caseload differences, differences in regulatory approval, differences in reimbursement and even differences in cultural mores from country-to-country.

For the sake of illustrating these differences as they impact the balance of the market for  the range of these advance closure, sealant and related products, we drew from our 2012 report on the topic (Report #S190) to compare the distribution of revenues for these products in the United States versus the “Rest of Asia-Pacific” category, or the Asia-Pacific region excluding Japan and Korea.  While the USA market for these products is 73% higher than the same market in Asia-Pacific ($4.2 billion versus $2.4 billion, respectively), a significant difference is also found in the distribution of the product revenues comprising each market.  Below is illustrated the percent of the total market for these products in the USA market and in the Asia-Pacific market.

Sealants-USA-v-Rest-AP

Source: Report #S190; “Surgical Sealants, Glues, Wound Closure and Anti-Adhesion, Worldwide Markets, 2012-2017.”

Wound management products sell at different rates regionally

The global market for wound management products — like most medtech markets — is dominated by sales in Europe and, in particular, the Americas.  Most new medical technology, with few exceptions, emerges first in these western markets, then migrates to other, developing markets. But the migration of technologies to markets outside the U.S. and Europe varies on the basis of differences in product demand, barriers to adoption and other constraints or drivers.

One expects to see the global market for wound management products to reflect the distribution like the following:

wound-region-product-sales

Source: Worldwide Wound Management Market 2012-2020; Report #S249.

But the makeup of the wound management market in different regions (as well as specific countries) is less predictable:

wound-region-product-pct

Source: Worldwide Wound Management Market 2012-2020; Report #S249.