The global dynamics of cardiovascular surgical and interventional procedures

This is an excerpt from Report #C500, “Cardiovascular Procedures to 2022.”

Cardiovascular Procedures in 2016

• Coronary artery bypass graft (CABG) surgery;
 • Coronary angioplasty and stenting;
 • Lower extremity arterial bypass surgery;
  • Percutaneous transluminal angioplasty (PTA) with and without bare metal and drug-eluting stenting;
  • Peripheral drug-coated balloon angioplasty;
  • Peripheral atherectomy;
  • Surgical and endovascular aortic aneurysm repair;
  • Vena cava filter placement
  • Endovenous ablation;
  • Mechanical venous thrombectomy;
  • Venous angioplasty and stenting;
  • Carotid endarterectomy;
  • Carotid artery stenting;
  • Cerebral thrombectomy;
  • Cerebral aneurysm and AVM surgical clipping;
  • Cerebral aneurysm and AVM coiling & flow diversion;
  • Left Atrial Appendage closure;
  • Heart valve repair and replacement surgery;
  • Transcatheter valve repair and replacement;
  • Congenital heart defect repair;
  • Percutaneous and surgical placement of temporary and permanent mechanical cardiac support devices;
  • Pacemaker implantation;
  • Implantable cardioverter defibrillator placement;
  • Cardiac resynchronization therapy device placement;
  • Standard SVT & VT ablation; and
  • Transcatheter AFib ablation

In 2016, the cumulative worldwide volume of the most prevalent cardiac surgeries and other  cardiovascular procedures (at right) is projected to approach 15.05 million surgical and transcatheter interventions. This will include:

  • in coronart artery disease, roughly 4.73 million coronary revascularization procedures via coronary artery bypass graft (CABG) and percutaneous coronary intervention (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  chronic venous insufficiency, deep vein thrombosis, and pulmonary embolism targeting venous interventions (representing 11.0% of the total);
  • more than 992 thousand surgical and transcatheter heart defect repairs and  valve replacement or valve repair  (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).

During the period 2016 to 2022, the total worldwide volume of covered cardiovascular procedures is forecast to expand on average by 3.7% per annum to over 18.73 million corresponding surgeries and transcatheter interventions in the year 2022. The largest absolute gains can be expected in peripheral arterial interventions (thanks to explosive expansion in utilization of drug-coated balloons in all market geographies), followed by coronary revascularization (supported by continued strong growth in Chinese and Indian PCI utilization) and endovascular venous interventions (driven by grossly underserved patient caseloads within the same Chinese and Indian market geography).

The latter (venous) indications are also expected to register the fastest (5.1%) relative procedural growth, followed by peripheral revascularization (with 4.0% average annual advances) and aortic aneurysm repair (projected to show a 3.6% average annual expansion).

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Geographically, Asian-Pacific (APAC) market geography accounts for slightly larger share of the global CVD procedure volume than the U.S. (29.5% vs 29,3% of the total), followed by the largest Western European states (with 23.9%) and ROW geographies (with 17.3%). Because of the faster growth in all covered categories of CVD procedures, the share of APAC can be expected to increase to 33.5% of the total by the year 2022, mostly at the expense of the U.S. and Western Europe.

However, in relative per capita terms, covered APAC territories (e.g., China and India) are continuing to lag far behind developed Western states in utilization rates of therapeutic CVD interventions with roughly 1.57 procedures per million of population performed in 2015 for APAC region versus about 13.4 and 12.3 CVD interventions done per million of population in the U.S. and largest Western European countries.


Report #C500: “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022.” Request excerpts.

This report may be purchased for immediate download at link.

Market positions in sealants, glues, hemostats fluid in U.S., Europe, Asia/Pacific

Market shares for sales of sealants, glues, and hemostats vary considerably from region to region globally due to the significant variations in the local market demand, rate of adoption of specific manufacturers’ products, the regulatory climate, local economies, and other factors. Consequently, manufacturers with significant share of sales in the U.S. or Europe or Asia/Pacific may have considerably lower or higher shares in other regions.

In the U.S., Ethicon and Baxter have dominant positions in sales of surgical sealants. However, in Europe and Asia/Pacific, Baxter has substantially smaller position, particularly relative to competitors like Takeda Pharmaceuticals and The Medicines Company.

Source: Report #S290, MedMarket Diligence, LLC

In the market for hemostats, similarly, Ethicon and Baxter have dominant position in the U.S. market, but in Asia/Pacific and Europe, Baxter is subordinate to Takeda Pharmaceuticals, CryoLife, and others.

Source: Report #S290, MedMarket Diligence, LLC

In medical glues, CryoLife has risen to the fore with its BioGlue, such that it has a global leading position as well as specifically in the U.S., Europe, and Asia/Pacific.

Source: Report #S290, MedMarket Diligence, LLC

Medtech fundings for March 2017

Medtech fundings for March 2017 totaled over $2 billion, led by the $1.2 billion raise by ConvaTec, the $59 million IPO of Symetics, the $50 million Series C funding of Moximed, the $45 million funding of Corindus, and the $40 million funding round of VertiFlex.

The complete list of fundings in medtech for March 2017 are shown at link. Below are the top fundings for the month.

Source: Compiled by MedMarket Diligence, LLC

For a historical list of fundings by month since 2009, see link.

MedMarket Future: Developments in Growth Technologies

Proliferation of graphene applications

The nature of graphene’s structure and its resulting traits are responsible for a tremendous burst of research focused on applications.

  • Find cancer cells. Research at the University of Illinois at Chicago showed that interfacing brain cells on the surface of a graphene sheet allows the ability to differentiate a single hyperactive cancerous cell from a normal cell. This represents a noninvasive technique for the early detection of cancer.
  • Graphene sheets capture cells efficiently. In research similar to that U. Illinois, modification of the graphene sheet by mild heating enables annealing of specific targets/analytes on the sheet which then can be tested. This, too, offers noninvasive diagnostics.
  • Contact lens coated with graphene. While the value of the development is yet to be seen, researchers in Korea have learned that contact lenses coated with graphene are able to shield wearers’ eyes from electromagnetic radiation and dehydration.
  • Cheaply mass-producing graphene using soybeans. A real hurdle to graphene’s widespread use in a variety of applications is the cost to mass produce it, but Australia’s CSIRO has shown that an ambient air process to produce graphene from soybean oil, which is likely to accelerate graphenes’ development for commercial use.

Materials

Advanced materials development teams globally are spinning out new materials that have highly specialized features, with the ability to be manufactured under tight control.

  • 3D manufacturing leads to highly complex, bio-like materials. With applications across many industries using “any material that can be crushed into nanoparticles”, University of Washington research has demonstrated the ability to 3D engineer complex structures, including for use as biological scaffolds.
  • Hydrogels and woven fiber fabric. Hokkaido University researchers have produced woven polyampholyte (PA) gels reinforced with glass fiber. Materials made this way have the structural and dynamic features to make them amenable for use in artificial ligaments and tendons.
  • Sound-shaping metamaterial. Research teams at the Universities of Sussex and Bristol have developed acoustic metamaterials capable of creating shaped sound waves, a development that will have a potentially big impact on medical imaging.

Organ-on-a-chip

In vitro testing models that more accurately reflect biological systems for drug testing and development will facilitate clinical diagnostics and clinical research.

  • Stem cells derived neuronal networks grown on a chip. Scientists at the University of Bern have developed an in vitro stem cell-based bioassay grown on multi-electrode arrays capable of detecting the biological activity of Clostridium botulinum neurotoxins.
  • Used for mimicking heart’s biomechanical properties. At Vanderbilt University, scientists have developed an organ-on-a-chip configuration that mimics the heart’s biomechanical properties. This will enable drug testing to gauge impact on heart function.
  • Used for offering insights on premature aging, vascular disease. Brigham and Women’s Hospital has developed organ-on-a-chip model designed to study progeria (Hutchinson-Gilford progeria syndrome), which primarily affects vascular cells, making this an affective method for the first time to simultaneously study vascular diseases and aging.

Untapped potential for sealants, glues, hemostats in wound caseloads and procedures

Today’s surgeon has a broad range of products from which to choose for closing and sealing wounds. These include sutures, stapling devices, vascular clips, ligatures, and thermal devices, as well as a wide range of topical hemostats, surgical sealants and glues.

However, surgeons still primarily use sutures for wound closure and securement—sutures are cheap, familiar and work most of the time. Now, in addition to reaching for a stapling device, the surgeon must frequently decide at what point to augment or replace the commonly used items in favor of other products, which product is best for what procedure or condition, how much to use, and ease of use in order to achieve optimal patient outcomes. Because of budget pressures, the surgeon must also consider price when selecting a product. Of course in the USA, the product must also be FDA-approved, although the surgeon still has the choice of using a product off-label.

In the areas of sealants, hemostats and glues, there is room for both improvement and additional products.  There are a number of products already on the market, but the fact is that there is no one product that meets all needs in all situations and procedures. There are few products that stand out from the rest, apart, perhaps, from DermaBond® and BioGlue®. There are unmet needs, and companies having the necessary technology, or which may acquire and further develop the technology, can enter this market and launch novel items. These products have yet to significantly tap the potential for wound management and medical/surgical procedures.

Note: Log10 scale; Chronic wounds includes pressure, venous/arterial and diabetic ulcers.

Source: MedMarket Diligence, LLC; Report #S290.

Sealants, Fibrin and Others

Numerous variants of fibrin sealant exist, including autologous products. “Other” sealants refers to thrombin, collagen & gelatin-based sealants.

Fibrin sealants are used in the US in a wide array of applications; they are used the most in orthopedic surgeries, where the penetration rate is thought to be 25-30%. Fibrin sealants can, however, be ineffective under wet surgical conditions. The penetration rate in other surgeries is estimated to be about 10-15%.

Fibrin-based sealants were originally made with bovine components. These components were judged to increase the risk of developing bovine spongiform encephalopathy (BSE), so second-generation commercial fibrin sealants (CSF) avoided bovine-derived materials. The antifibrinolytic tranexamic acid (TXA) was used instead of bovine aprotinin. Later, the TXA was removed, again due to safety issues. Today, Ethicon’s (JNJ) Evicel is an example of this product, which Ethicon says is the only all human, aprotinin free, fibrin sealant indicated for general hemostasis. Market growth in the Sealants sector is driven by the need for improved biocompatibility and stronger sealing ability—in other words, meeting the still-unsatisfied needs of physician end-users.

High Strength Medical Glues

Similar to that of sealants, the current market penetration of glues in the US is about 25% of eligible surgeries. There are several strong points in favor of the use of medical glues: their use can significantly reduce healthcare costs, for example by reducing time in the surgical suite, reducing the risk of a bleed, which may mean a return trip to the OR, and general ease of use. Patients seem to prefer the glues over receiving sutures for external wound closure, as glues can provide a suture-free method of closing wounds. In addition, if glues are selected over sutures, the physician can avoid the need (and cost) of administering local anesthesia to the wound site.

Hemostats

Hemostats are normally used in surgical procedures only when conventional methics to stop bleeding are ineffective or impractical. The hemostat market offers opportunities as customers seek products that better meet their needs. Above and beyond having hemostatic agents that are effective and reliable, additional improvements that they wish to see in hemostat products include: laparoscopy-friendly; work regardless of whether the patient is on anticoagulants or not; easy to prepare and store, with a long shelf life; antimicrobial; transparent so that the surgeon continues to have a clear field of view; and non-toxic; i.e. preferably not made from human or animal materials.


Drawn from, “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.” Report #S290.

Biologically-based medical glues to start sticking in A/P

The bulk of medical/surgical glues are biologically-based, and soon the bulk of medical glue sales will come from Asia/Pacific.

The two graphs below show the changes in regional shares in biologically-based glues. It can be seen that from 2015 to 2022, the US and Asia-Pacific will practically switch places in terms of revenue share per region. This significant change will come about because of the intensive and enormous healthcare modernization taking place in the PRC. In 2012, the Chinese government announced its 12th five-year plan which includes the construction of 20,000 new hospital and healthcare facilities.

Source: 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 (Report #S290).

Abdominal and thoracic aortic aneurysm repair: procedures forecast

Below is an excerpt from, “Global Dynamics of Surgical and Interventional Cardiovascular Procedures, 2015-2022,” (Report #C500 described, available online).

Selection of specific management protocols for patients with aortic aneurysms depends on the disease morphology as well as patient’s age, overall health status, and comorbidities involved. In cases involving smaller and relatively stable abdominal or thoracic aortic aneurysm (AAA or TAA), watchful waiting represents a commonly preferred approach. Radical surgical or endovascular interventions are generally reserved for cases when the diameter of the aneurismal sac is larger than 5cm to 5.5cm, or the annual expansion rate exceeds 1.0 cm, or when the aneurysm becomes symptomatic.

Surgical Repair of Aortic Aneurysms

Prior to the advent of AAA/TAA endovascular repair tools and techniques, a highly invasive and risky surgical repair procedure constituted the only curative option for patients with advanced and rupture prone aortic aneurysm. Conducted under the general anesthesia the procedure takes a few hours and entails a major and highly traumatic operation with a 10-15 inch cut in abdominal wall, clamping and isolation of aneurysmic segment of aorta, incision into the aneurysm, evacuation of the clot contained within, placement of a synthetic graft, and wrapping of the graft with remnants of the aortic wall.

The typical surgical aneurysm repair is associated with a substantial (5% to 8%) mortality rate and serious complications, such as stroke, myocardial infarction, renal failure etc.

Due to the close proximity to the heart, the risk and complication rates of surgical intervention for aneurysm repair on the thoracic aorta increase multifold resulting in an average procedural mortality rate of up to 30 percent.

The high cost of the procedure is largely the result of extended ICU and hospital stays, which can last upwards of a week (but average roughly 10-12 days). Further, postoperative recovery may require up to six additional weeks subsequent to discharge, making temporary disability a major consideration for many patients.

Notwithstanding these drawbacks, open surgical aortic aneurysm repair is still commonly regarded as highly effective treatment modality that virtually eliminates the risk of aneurismal sac rupture and does not require extensive postoperative follow-up exams or revisions.

However, because of high prevalence of elderly and health-impaired persons in diagnosed aortic aneurysm caseloads and traumatic nature of AAA/TAA surgery, only a fraction of the patients who could benefit from surgical aneurysm repair is deemed eligible for such a procedure.

Abdominal Aortic Aneurysm Repair with Endovascular Stent-Grafts

During the past two decades, advances in interventional technologies paved the way for the advent of a considerably less invasive and risky endovascular AAA repair procedure. The procedure involves a transcatheter deployment of the specially designed endovascular prosthesis (typically combining sealing functions of the vascular graft and full or partial stenting support structure) into a defective segment of aorta with the goal of excluding the aneurysmal sac from blood circulation.

The endovascular stent-grafts (SGs) – which come both in self-expanding or balloon-expandable versions – are typically anchored to an undamaged part of the aorta both above and below the aneurysm via a compression fit or/and with a special fixation mechanism like hooks, barbs, etc.

To accommodate a great morphological diversity of aortic aneurysms the vast majority of endovascular SGs is employing a modular design concept providing the aorto iliac, bifurcated and straight tubular device configurations to cover a variety of AAA indications. Several SG systems also feature an open stenting structure at proximal end to enable suprarenal device deployment required in about 30% to 35% of all AAA cases warranting intervention.

In its idea, the endovascular repair of abdominal aortic aneurysm was intended to produce clinical outcomes comparable to these yielded by the open surgery, while reducing the associated trauma, recovery time, morbidity and the overall treatment cost. It was also generally expected that availability of less-invasive endovascular treatment option would allow to extend caseloads coverage to sizable rupture-prone AAA patient subsets who are poor surgical candidates.

Limitations of Endovascular AAA Repair

Findings from numerous clinical studies and real-life experience in the field seem to indicate that endovascular aortic aneurysm repair via stent-graft placement tends to provide immediate procedural outcomes comparable to these obtainable with open surgery. Furthermore, the typical ICU and hospital stay for endovascular AAA repair averages 2 days (though it may last twice longer for patients with significant comorbidities). All of these translates into reduced inpatient costs of AAA repair relative to open surgery, although the high price of stent-grafting devices largely offsets these cost savings. Post-discharge recovery is also shortened from weeks or months to an average 7-10-day period.

Unfortunately, comparative long-term clinical efficacy and cost-effectiveness of the endovascular approach to aortic aneurysm repair appears to be problematic due to unavoidable shortcomings of available aortic stent-graft designs and complications associated with their less than perfect performance in situ.

The major problems associated with the endovascular AAA repair approach include relatively high incidence of endoleaks (up to 15%), endotension, and device failure, which multiply the risk of catastrophic aneurysm rupture and necessitate costly revisions (in up to 35% of the cases) as well as long-term (or life-long) patient surveillance (with mandatory imaging exams). Due to that, the actual overall cost of endovascular repair in many considerably exceeds expenses incurred in traditional open surgery.

Another limitation of endovascular stent-grafting relates to its ability to accommodate complex aortic aneurysm morphology and branch involvement. Based on some end-user and industry reporting, only about 50% of patients that develop intervention-warranting AAAs are considered good candidates for endovascular repair with currently available product configurations.

According to some recent reporting, endovascular aneurysm repair (EVAR) treatment with certain stent grafts also appears to be associated with higher late mortality rates (due to aneurysm rupture) compared to surgical AAA repair. Based on available long-term follow-up data, mortality in AAA patients retrofitted with the market-leading SG averages 1.3% and 1.5% at four and five years compared to 0.7% and 0.9% for AAA surgery.

Endovascular Repair of TAA

Introduced in Europe and the U.S. in 1998 and 2005, accordingly, endovascular techniques for aneurysm (and aortic dissection) repair on thoracic aorta represented a logical extension of the very same basic concept and technology platforms that enabled the development of AAA stent-grafts.

Because of extremely high mortality and morbidity rates associated with TAA surgery, the need for minimally invasive endovascular treatment option was even more compelling than that in AAA case.

Similar to AAA endovascular repair devices, TAA stent-grafts are intended to minimize the risk of catastrophic thoracic aortic aneurysm rupture via effective exclusion (isolation) of the aneurismal sac from blood circulation.

Unlike AAA implants, commercially available TAA stent-grafting devices feature relatively simple tubular unibody architecture with sealing cuffs (or flanges) at proximal and distal end.

Insertion of TAA SGs is done under fluoroscopic guidance via a singular femoral puncture with the use of standard transcatheter techniques. Depending on the aneurysm morphology, one or two overlapping devices might be used to ensure proper aneurismal sac isolation.

The average ICU and hospital stays and post-discharge recovery period for endovascular TAA repair procedure are generally similar to these for AAA stent-grafting intervention.

Although practical clinical experience with endovascular repair of thoracic aortic aneurysm remains somewhat limited, findings from European and U.S. clinical studies with TAA stent-grafting tend to be very encouraging. Based on these findings, stent-grafting of rupture-prone aneurysm on ascending thoracic aorta can be performed with close to perfect technical success rate yielding radical reduction in intraoperative mortality and complications compared to TAA surgery as well as impressive improvement in long-term patient survival.

Similar to AAA endografting, the main problems associated with the use of TAA SG systems include significant incidence of endoleaks and occasional device migration which require reintervention.

Aortic Aneurysm Repair Procedure Volumes

Based on the industry reporting, national and international healthcare authority data, and MedMarket Diligence estimates, in 2015, approximately 915 thousand patients worldwide were diagnosed with rupture-prone abdominal or thoracic aortic aneurysms and aortic dissections warranting radical intervention, of which roughly 359.5 thousand (or about 39.3%) were actually referred for surgical or transcatheter treatment. Covered APAC market geography (with combined population of about 2,63 billion) accounted for the largest 37.6% share of all aortic aneurysm repairs performed, followed by the U.S. with 25.6%, largest Western European states with 21.3% and the rest-of-the-world with the remaining 15.5%.

Endovascular stent-grafting techniques were utilized in approximately 162.5 thousand aortic aneurysm repair procedures in 2015, which included an estimated 133 thousand AAA-related and about 29.5 thousand TAA-related interventions (including these targeting selected thoracic aortic dissections).

The cited figures reflected a disparity both in the relative volumes of treated AAA and TAA patients and, especially, in the share of these managed with the less invasive EVAR techniques. The latter indicator was the highest for the U.S. (~75%), compared to 52% for Western Europe, 39% for APAC and only 36.6% for the ROW market geography.

During the forecast period covered in the report, the total global volume of endovascular aortic aneurysm repairs is projected to grow 5.7% per annum to approximately 243 thousand procedures, combining a 5.5% annual expansion in AAA-related interventions with a 6.6% average annual increase in TAA (aortic dissection)-related interventions.

Projected healthy gains in endovascular aortic aneurysm repair procedures should reflect continuous penetration of non-surgical (no option) AAA and TAA patient caseloads, coupled with significant incursion into surgery-eligible patient subsets both in AAA, TAA, and aortic dissection indications. Increasing reliance on utilization of less traumatic AAA and TAA stent-grafting techniques will be expedited by ongoing qualitative improvements in the endograft and delivery tools design that keep yielding more reliable, durable, versatile, and end-user friendly systems with reduced propensity to mechanical and functional failure (device kinking, fracture, endoleaks, migration, etc.) and associated clinical complications.

The largest relative gains in AAA and TAA EVAR procedures (10.9% and 11.8%, accordingly) can be expected in covered APAC territories (mostly China and India) and grossly underserved ROW zone (6.5% and 7.5%). Largely mature U.S., Western European (and Japanese) markets are likely to register a low single digit advances in utilization of endovascular AAA/TAA repair techniques.

The global procedure volume forecast for aortic aneurysm repair is presented below.

Projected Dynamics of Aortic Aneurysm Repair Procedures,
World Total, 2015-2022 (#000)

Indications / Procedures20152016201720182019202020212022CAGR 2016-2022
Total EVAR AAA/TAA Procedures1516.317.618.920.221.522.824.16.70%
Diagnosed AAA & TAA Caseloads1651701751801851901952002.80%
Treated AAA & TAA Patients5658.56163.56668.57173.53.90%
Abdominal Aortic Aneurysm (AAA) Repair
Treated AAA Patient Caseloads45474951535557593.90%
Surgical Repair Procedures33343536373839402.80%
Endovascular Repair Procedures12131415161718196.50%
Thoracic Aortic Aneurysm (TAA) Repair
Treated TAA Patient Caseloads1111.51212.51313.51414.53.90%
Surgical Repair Procedures88.28.48.68.899.29.42.30%
Endovascular Repair Procedures33.33.63.94.24.54.85.17.50%
Total Surgical AAA/TAA Repairs4142.243.444.645.84748.249.42.70%

Notes: AAA = abdominal; aortic aneurysm. EVAR = endovascular aneurysm repair. TAA = thoracic aortic aneurysm.

Source: MedMarket Diligence, LLC; Report #C500. (Full cardiovascular procedures report online.)

Source: MedMarket Diligence, LLC; Report #C500. (Full cardiovascular procedures report online.)

 

Medtech fundings for February 2017

Medtech fundings for February 2017 stand at $500.4 million, led by the $75 million credit facility secured by BioDelivery Sciences, the $45 million private placement by Corindus Vascular Robotics, the $41 million funding of Rhythm, Inc., the $37.2 million funding of Entellus Medical, and the $33 million funding of startup Surrozen.

Below are the top fundings for the month. For a complete list of fundings, see link.

Source: Compiled by MedMarket Diligence, LLC

For a historical listing of fundings in medtech, see link.

Factors Affecting Wound Healing

Excerpted from, “Worldwide Wound Management, Forecast to 2024: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World”, Report #S251.

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.

Preparation of the wound bed (WBP) is essential for the support of efficient and effective healing, especially when advanced wound care products are to be used. WBP involves removing localized barriers to healing, such as exudate, dead tissue or infected tissue.

Wound Bed Preparation: the TIME and DIMES acronyms

WBP involves debridement, reduction and neutralization of the bioburden and management of exudate from the wound. The TIME acronym provides a systematic way to manage wounds by looking at each stage of wound healing. The goal is to have the best, thoroughly-vascularized wound bed possible.

TIME stands for:

  • T: Tissue, non-viable or deficient.

The wound care professional should look for non-viable tissue, which includes necrotic tissue, tissue which has sloughed off, or non-viable tendon or bone.

  • I: Infection or Inflammation

Examine the wound for infection, inflammation or other signs of infection. Are there clinical signs that there may be a problem with bacterial bioburden?

  • M: Moisture Balance

Is the wound too dry, or does it have excess exudate?

What is the objective of topical therapy: absorption or drainage?

  • E: Edge of wound—non-advancing or undermined

Examine the edges of the wound. Are the edges undermined, or is the epidermis failing to migrate across the granulation tissue?

The DIMES acronym is very similar to TIME:

  • Debridement (autolytic)

For wounds with the ability to heal, adequate and repeated debridement is an important first step in removing necrotic tissue. Debridement may also help healing by removing both senescent cells that are no longer capable of normal cellular activities and biofilms that may be shielding bacterial colonies.

  • Infection/Inflammation

The level of bacterial damage may include contamination (organisms present), colonization (organisms present which may cause surface damage if critically colonized) or infection. Treatment needs to make a match between the individual patient’s wound and the appropriate product.

  • Moisture balance

Clinicians need to create a careful balance in the wound such that the environment is neither too wet nor too dry. The environment itself will change as the wound heals.

  • Edge/Environment

The clinician should carefully examine and monitor the wound edge. If the wound edge is not migrating after appropriate wound bed preparation, and if healing appears to be stalled, then more advanced wound care therapies should be considered.

  • Supportive Products and Services

There are additional products which support wound healing yet don’t fall into one of these steps. For example, proper nutritional support is important to achieving the goal of a fully healed wound.

Extrinsic Factors

Extrinsic factors affecting wound healing include:

  • Mechanical stress
  • Debris
  • Temperature
  • Desiccation and maceration
  • Infection
  • Chemical stress
  • Medications
  • Other factors such as alcohol abuse, smoking, and radiation therapy

Mechanical Stress

Mechanical stress factors include pressure, shear, and friction. Pressure can result from immobility, such as experienced by a bed- or chair-bound patient, or local pressures generated by a cast or poorly fitting shoe on a diabetic foot. When pressure is applied to an area for sufficient time and duration, blood flow to the area is compromised and healing cannot take place. Shear forces may occlude blood vessels, and disrupt or damage granulation tissue. Friction wears away newly formed epithelium or granulation tissue and may return the wound to the inflammatory phase.

Debris

Debris, such as necrotic tissue or foreign material, must be removed from the wound site in order to allow the wound to progress from the inflammatory stage to the proliferative stage of healing. Necrotic debris includes eschar and slough. The removal of necrotic tissue is called debridement and may be accomplished by mechanical, chemical, autolytic, or surgical means. Foreign material may include sutures, dressing residues, fibers shed by dressings, and foreign material which were introduced during the wounding process, such as dirt or glass.

Temperature

Temperature controls the rate of chemical and enzymatic processes occurring within the wound and the metabolism of cells and tissue engaged in the repair process. Frequent dressing changes or wound cleansing with room temperature solutions may reduce wound temperature, often requiring several hours for recovery to physiological levels. Thus, wound dressings that promote a “cooling” effect, while they may help to decrease pain, may not support wound repair.

Desiccation and Maceration

Desiccation of the wound surface removes the physiological fluids that support wound healing activity. Dry wounds are more painful, itchy, and produce scab material in an attempt to reduce fluid loss. Cell proliferation, leukocyte activity, wound contraction, and revascularization are all reduced in a dry environment. Epithelialization is drastically slowed in the presence of scab tissue that forces epithelial cells to burrow rather than freely migrate over granulation tissue. Advanced wound dressings provide protection against desiccation.

Maceration resulting from prolonged exposure to moisture may occur from incontinence, sweat accumulation, or excess exudates. Maceration can lead to enlargement of the wound, increased susceptibility to mechanical forces, and infection. Advanced wound products are designed to remove sources of moisture, manage wound exudates, and protect skin at the edges of the wound from exposure to exudates, incontinence, or perspiration.

Infection

Infection at the wound site will ensure that the healing process remains in the inflammatory phase. Pathogenic microbes in the wound compete with macrophages and fibroblasts for limited resources and may cause further necrosis in the wound bed. Serious wound infection can lead to sepsis and death. While all ulcers are considered contaminated, the diagnosis of infection is made when the wound culture demonstrates bacterial counts in excess of 105 microorganisms per gram of tissue. The clinical signs of wound infection are erythema, heat, local swelling, and pain.

Chemical Stress

Chemical stress is often applied to the wound through the use of antiseptics and cleansing agents. Routine, prolonged use of iodine, peroxide, chlorhexidine, alcohol, and acetic acid has been shown to damage cells and tissue involved in wound repair. Their use is now primarily limited to those wounds and circumstances when infection risk is high. The use of such products is rapidly discontinued in favor of using less cytotoxic agents, such as saline and nonionic surfactants.

Medication

Medication may have significant effects on the phases of wound healing. Anti-inflammatory drugs such as steroids and non-steroidal anti-inflammatory drugs may reduce the inflammatory response necessary to prepare the wound bed for granulation. Chemotherapeutic agents affect the function of normal cells as well as their target tumor tissue; their effects include reduction in the inflammatory response, suppression of protein synthesis, and inhibition of cell reproduction. Immunosuppressive drugs reduce WBC counts, reducing inflammatory activities and increasing the risk of wound infection.

Other Extrinsic Factors

Other extrinsic factors that may affect wound healing include alcohol abuse, smoking, and radiation therapy. Alcohol abuse and smoking interfere with body’s defense system, and side effects from radiation treatments include specific disruptions to the immune system, including suppression of leukocyte production that increases the risk of infection in ulcers. Radiation for treatment of cancer causes secondary complications to the skin and underlying tissue. Early signs of radiation side effects include acute inflammation, exudation, and scabbing. Later signs, which may appear four to six months after radiation, include woody, fibrous, and edematous skin. Advanced radiated skin appearances can include avascular tissue and ulcerations in the circumscribed area of the original radiation. The radiated wound may not become evident until as long as 10-20 years after the end of therapy.

Intrinsic Factors

Intrinsic factors that directly affect the performance of healing are:

  • Health status
  • Age factors
  • Body build
  • Nutritional status

Health Status

Chronic diseases, such as circulatory conditions, anemias and autoimmune diseases, influence the healing process as a result of their influence on a number of bodily functions. Illnesses that cause the most significant problems include diabetes, chronic obstructive pulmonary disease (COPD), arteriosclerosis, peripheral vascular disease (PVD), heart disease, and any conditions leading to hypotension, hypovolemia, edema, and anemia. While chronic diseases are more frequent in the elderly, wound healing will be delayed in any patient with a pre-existing underlying illness.

Chronic circulatory diseases which reduce blood flow, such as arterial or venous insufficiency, lower the amount of oxygen available for normal tissue activity and replacement. Anemias such as sickle-cell anemia result in reduced delivery of oxygen to tissues and decreased ability to support wound healing.

Normal immune function is required during the inflammatory phase by providing the WBCs (white blood cells) that orchestrate or coordinate the normal sequence of events in wound healing. Autoimmune diseases such as lupus and rheumatoid arthritis interfere with normal collagen deposition, and impair granulation.

Diabetes is associated with delayed cellular response to injury, compromised cellular function at the site of injury, defects in collagen synthesis, and reduced wound tensile strength after healing. Diabetes-related peripheral neuropathy (DPN), which reduces the ability to feel pressure or pain, contributes to a tendency to ignore pressure points and avoid pressure relief strategies.

Acquired Immune Deficiency Syndrome

Patients with acquired immunodeficiency syndrome (AIDS) have significant impact on the wound healing market as their numbers rise and their average life expectancy increases. Patients in the latter stages of the disease experience drastic reductions in mobility, activity, and nutritional status, placing them at high risk for the development of pressure ulcers. Minor scrapes or abrasions are at high risk for infection and may progress to full-thickness wounds requiring antibiotic therapy and aggressive wound management. Skin tumors, such as Kaposi’s sarcoma, lead to surgical incisions closed by secondary intention requiring the use of appropriate dressings.

The skin of AIDS patients becomes drier as the syndrome progresses. As the CD4+ T cell count falls below 400/mm3, pruritus increases and erythematous patches appear on the skin, progressing to ichthyosis and appearing as large polygonal scales, especially on the lower limbs. Histological changes include hyperkeratosis and thinning of the granular layer of the epidermis. As skin becomes more fragile, care must be exercised in the selection of tapes and adhesive dressings to avoid skin stripping and skin tears.

Age Factors

Observable changes in wound healing in the elderly include increased time to heal and the fragile structure of healed wounds. Delays are speculated to be the result of a general slowing of metabolism and structural changes in the skin of elderly people. Structural changes include a flattening of the dermal-epidermal junction that often leads to skin tears, reduced quality and quantity of collagen, reduced padding over bony prominences, and reduction in the intensity of the immune response.

Body Build

Body build can affect the delivery and availability of oxygen and nutrients at the wound site. Underweight individuals may lack the necessary energy and protein reserves to provide sufficient raw materials for proliferative wound healing. Bony prominences lack padding and become readily susceptible to pressure due to the reduced blood supply of wounds associated with bony prominences. Poor nutritional habits and reduced mobility of overweight individuals lead to increased risk of wound dehiscence, hernia formation, and infection.

Nutritional Status

Healing wounds, especially full-thickness wounds, require an adequate supply of nutrients. Wounds require calories, fats, proteins, vitamins and minerals, and adequate fluid intake. Calories provide energy for all cellular activity, and when in short supply in the diet, the body will utilize stored fat and protein. The metabolism of these stored substances causes a reduction in weight and changes in pressure distribution through reduction of adipose and muscle padding. Sufficient dietary calories maintain padding and ensure that dietary protein and fats are available for use in wound healing. In addition, adequate levels of protein are necessary for repair and replacement of tissue. Increased protein intake is particularly important for wounds where there is significant tissue loss requiring the production of large amounts of connective tissue. Protein deficiencies have been associated with poor revascularization, decreased fibroblast proliferation, reduced collagen formation, and immune system deficiencies.

Reduced availability of vitamins, minerals, and trace elements will also affect wound healing. Vitamin C is required for collagen synthesis, fibroblast functions, and the immune response. Vitamin A aids macrophage mobility and epithelialization. Vitamin B complex is necessary for the formation of antibodies and WBCs, and Vitamin B or thiamine maintains metabolic pathways that generate energy required for cell reproduction and migration during granulation and epithelialization. Iron is required for the synthesis of hemoglobin, which carries oxygen to the tissues, and copper and zinc play a role in collagen synthesis and epithelialization.

Adequate nutrition is an often-overlooked requirement for normal wound healing. Inadequate protein-calorie nutrition, even after just a few days of starvation, can impair normal wound-healing mechanisms. For healthy adults, daily nutritional requirements are approximately 1.25-1.5 g of protein per kilogram of body weight and 30-35 calories/kg.  These requirements should be increased for those with sizable wounds.

Malnutrition should be suspected in patients presenting with chronic illnesses, inadequate societal support, multisystem trauma, or GI or neurologic problems that may impair oral intake. Protein deficiency occurs in about 25% of all hospitalized patients.

Chronic malnutrition can be diagnosed by using anthropometric data to compare actual and ideal body weights and by observing low serum albumin levels. Serum prealbumin is sensitive for relatively acute malnutrition because its half-life is 2-3 days (vs 21 d for albumin). A serum prealbumin level of less than 7 g/dL suggests severe protein-calorie malnutrition.

Vitamin and mineral deficiencies also require correction. Vitamin A deficiency reduces fibronectin on the wound surface, reducing cell chemotaxis, adhesion, and tissue repair. Vitamin C is required for the hydroxylation of proline and subsequent collagen synthesis.

Vitamin E, a fat-soluble antioxidant, accumulates in cell membranes, where it protects polyunsaturated fatty acids from oxidation by free radicals, stabilizes lysosomes, and inhibits collagen synthesis. Vitamin E inhibits prostaglandin synthesis by interfering with phospholipase-A2 activity and is therefore anti-inflammatory. Vitamin E supplementation may decrease scar formation.

Zinc is a component of approximately 200 enzymes in the human body, including DNA polymerase, which is required for cell proliferation, and superoxide dismutase, which scavenges superoxide radicals produced by leukocytes during debridement.


From, “Worldwide Wound Management, Forecast to 2024: Established and Emerging Products, Technologies and Markets in the Americas, Europe, Asia/Pacific and Rest of World”. Report #S251. Available online.