Angiogenesis is Essential for Wound Healing

Angiogenesis—new blood vessel growth—is a critical part of the normal healing process. New blood vessels deliver oxygen, nutrients, and essential growth factors to injured tissues. Angiogenesis facilitates not only the healing of injured skin, but the growth of hair and fat tissue, nerve regeneration, and muscle and bone repair.

Insufficient angiogenesis is a hallmark feature of chronic wounds. Angiogenesis is often impaired in the elderly, in people with high cholesterol, diabetes, and in heavy drinkers and smokers. Certain medications can also impair angiogenesis, including some common pain medications, diuretics, and high blood pressure drugs (Table 1).

TABLE 1. FACTORS KNOWN TO INHIBIT ANGIOGENESIS

Patient factors
• Increased age
• High cholesterol
• Alcohol use
• Diabetes

Prescription Medications
• Antibiotics (clarithromycin, doxycycline, tetracycline)
• High blood pressure medications (captopril, enalapril, metoprolol)
• Diuretics (bumetanide, furosemide)
• Nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen)
• COX-2 inhibitors (celecoxib)
• PPAR-+ agonists (pioglitazone, rosiglitazone)

Cancer Drugs
• Adriamycin*
• Cyclophosphamide*
• Docetaxel*
• Doxorubicin*
• Interferon alpha
• Methotrexate*
• Paclitaxel
• Thalidomide
• Topotecan*
• Vinblastine*

Antiangiogenic Agents
• Bevacizumab
• Sunitinib
• Sorafenib
• Pazopanib
• Temsirolimus
• Everolimus

Arthritis agents
• Etanercept
• Infliximab

Source: The Angiogenesis Foundation (http://www.angio.org).
*At low-dose metronomic scheduling.

Therapeutic angiogenesis refers to the use of drugs, cells, genes, or mechanical devices to stimulate blood vessel growth in tissue that is deprived of blood or oxygen. Medical therapy for chronic wounds now incorporates a number of angiogenesis-stimulating treatments. There are presently five major categories of wound therapies based on stimulating angiogenesis: 1) growth factor therapies; 2) tissue engineered products; 3) bioactive matrices; 4) mechanical systems; and 5) hyperbaric oxygen therapy (Table 2).

• Growth factor therapies. Angiogenesis is dependent upon an array of proteins called growth factors produced by injured tissues. If these ‘proangiogenic’ growth factors are not produced in sufficient quantities, normal wound healing cannot occur. Topical growth factors are applied directly to wounds to stimulate angiogenesis, and include genetically engineered (recombinant) proteins and autologous (derived from the same individual) growth factor preparations.
  
  Becaplermin (Regranex) Gel is a recombinant angiogenic growth factor preparation that has been shown to accelerate wound healing in diabetic patients when used in combination with best clinical practices.³ Autologous growth factor preparations (AutoloGel; SmartPReP) are derived from the patient’s own platelets. Platelets are a specialized type of blood cell that promotes clotting following an injury, and also contain a wide spectrum of angiogenesis-promoting growth factors that are released as needed to sites of tissue injury.


• Tissue-engineered products. Bioengineered skin replacement products are designed to replicate the function of newly formed skin. These products contain living cells on a biodegradable scaffold. In addition to protecting the wound from infection and keeping it moist, the living cells secrete angiogenic growth factors into the wound bed. Tissue engineered products include bi-layered skin substitutes (Graftskin, Apligraf) and fibroblast-seeded scaffolds (Dermagraft).


• Bioactive matrices. Bioactive matrices are collagen-based products that neutralize the activity of proteases (enzymes that split proteins into smaller parts) in wound fluid. Proteases break down certain proangiogenic growth factors, rendering them ineffective. These products include oxidized regenerated cellulose (ORC)-collagen dressings (Promogran; PRISMA Matrix) and porcine small intestines submucosa (OASIS Wound Matrix). The ORC/collagen dressing can be combined with topical becaplermin to prevent its breakdown. PRISMA Matrix combines 1.0% silver, a potent antibiotic, with the ORC/collagen dressing that combines protease inhibition, growth factor protection, and antimicrobial activity into a single product.


• Mechanical devices. Mechanical wound healing devices, rather than using biological proteins, are designed to mechanically change the environment of the wound to favor faster healing. One mechanical technique is negative pressure wound therapy (VAC Therapy; Wound Vacuum System). The application of sub-atmospheric pressure in the wound bed stimulates both angiogenesis and tissue growth.⁵ Another mechanical technique (MIST Therapy System) uses low-frequency sound waves to stimulate angiogenesis in tissues.


• Hyperbaric oxygen. Hyperbaric oxygen therapy (HBO) promotes wound healing by dramatically raising the oxygen levels in the wound. Stimulation of angiogenesis is an important component of HBO therapy.⁴ The alternation of high wound oxygen during HBO and low wound oxygen between sessions increases production of proangiogenic growth factors.