Collagen: Providing a Key to the Wound Healing Kingdom

Collagen plays a key role in each phase of wound healing. As a major extracellular matrix (ECM) protein, collagen is the most abundant protein in humans, contributing 25% of total protein mass and ~80% of the skin’s dry weight. Collagen acts as structural scaffold in tissues due to its stiff, triple-stranded helical structure; collagen 1, 2, and 3 are the main types found in connective tissue.¹ 

Structurally, collagen is a natural substrate for cellular attachment, proliferation, and differentiation. Functionally, it is chemotactic and modulates cellular responses. Xenogenic dermal matrices have been developed from a variety of sources. Polymers such as hyaluronic acid, fibrinogen, heparin sulfate, laminin, and collagen (all components of natural ECMs) often are preserved or combined. These biomaterials are nonimmunogenic (unlike epidermis or vasculature), biocompatible, and nontoxic to tissues. They stimulate and recruit specific cells, enhancing the healing cascade.^1,2 

Collagen dressings usually are formulated with bovine, avian, or porcine collagen; rarer types include equine and piscine. Collagen dressings are available as sheets, pads, gels, paste, and powder and can be combined with antimicrobial agents, oxidized regenerated cellulose, or silicone. Numerous indications for collagen wound dressings include pressure injuries, second-degree burns, surgical and traumatic wounds, abrasions, and donor sites; contraindications include third-degree burns and wounds with dry eschar. Various collagen-based products have been used in pediatric wounds. 

To appreciate the role of collagen, it is helpful to understand the wound healing process. Wound closure involves timed and balanced activity of various chemokines and cells that move a wound through hemostasis, inflammation, proliferation, and remodeling. Each phase has accepted brackets of time, but there seems to be no consensus regarding the definition of acute versus chronic wounds in pediatrics. An acute wound implies organized, timely, uncomplicated healing, with cellular signaling and chemokines orchestrating granulation tissue development. A chronic, stalled, or (maybe better termed) complex wound in pediatrics implies deviation from an expected trajectory, resistance to appropriate treatment, or deficiency of a substrate (common etiology in adults but rarely thought of in pediatrics).

A quick review of wound healing illuminates important elements for each stage of repair.³ 

Hemostasis. Platelets aggregate and degranulate, leading to clot formation and release of growth factors (GFs) and cytokines. Those, in turn “call” neutrophils, eosinophils, and monocytes to initiate the inflammatory phase (IF).

IF. Proteolytic enzymes secreted by inflammatory cells nudge the ECM to give rise to peptides, which in turn activate macrophages and additional neutrophils to secrete proinflammatory cytokines (tumor necrosis factor-α and interlukin-1b), which directly influence deposition of collagen in the wound by inducing collagen synthesis via fibroblasts and downregulating tissue inhibitors of matrix metalloproteinases (MMPs). Various GFs stimulate fibroblast, epithelial, and endothelial cell migration.

Proliferative. Cleavage products from collagen degradation stimulate fibroblast proliferation and GF production, leading to ECM and vascular endothelial proliferation. Collagen cleavage products also stimulate keratinocyte migration from the edge of the wound over new granulation tissue, leading to reepithelialization.

Remodeling. The goal is to achieve balance between synthesis of new matrix and degradation by MMPs. This phase also involves tensile strength acquisition.

ion leads to depressed angiogenesis; increased biofilm formation; reduced keratinocyte and fibroblast differentiation, migration, and proliferation; reduced collagen synthesis; and lack of epithelialization.⁴

Abnormal hypothalamic-pituitary-adrenal (HPA) axis. HPA (ie, hypothyroidism) can lead to dry skin and require systemic steroids due to adrenocorticotropic (ACTH) deficiency.⁵ Systemic glucocorticoids (GCs), which frequently are used as anti-inflammatory agents, are well-known to inhibit wound repair via global anti-inflammatory effects and suppression of cellular wound responses, including fibroblast proliferation and collagen synthesis. Systemic GCs cause wounds to heal with incomplete granulation tissue and reduced wound contraction; GCs also inhibit production of hypoxia-inducible factor-1, a key transcriptional factor in healing wounds.^6,7 Beyond their effects on repair itself, systemic GCs may increase the risk of wound infection. 

Obesity. Obese individuals frequently face wound complications, including skin wound infection, wound dehiscence, hematoma and seroma formation, and pressure ulcers. Many of these complications may be a result of relative hypoperfusion and ischemia that occurs in subcutaneous adipose tissue, decreased delivery of antibiotics, and (in surgical wounds) increased tension on the wound edges, resulting in decreased microperfusion and increased dehiscence.⁸ 

Suppressive or toxic chemotherapeutic agents. Antiangiogenic therapy suppresses growth of new blood vessels, leading to tissue ischemia, lack of granulation tissue, and increased wound dehiscence. This therapy is not recommended 28 days before or after surgery or in a patient with an open wound.⁹ Multiple chemotherapeutic agents suppress cell metabolism and division and protein synthesis, deplete amino acid building blocks, and suppress various white blood cells necessary for ECM production.⁶

Defective ECMs. Recent illness, ischemia, and immunosuppressive medications may contribute to an ECM that lacks important building blocks or, as in case of certain immunosuppressed individuals or neonates with not enough of an anti-inflammatory response and overexpression of pro-inflammatory mediators, ECM destruction.

Wound practitioners have learned to use collagen dressing as a compass to wound healing navigation. A fully incorporated dressing implies inflammatory process and continuous need for a “sacrificial lamb” or exogenous substrate. A dressing that is still on the surface, especially mixed with granulation tissue, points to the path of success. Secondary dressings are used to protect collagen products; in my practice, we usually use silicone-based products. 

Patient 1. A 12-year-old obese girl was admitted to pediatric intensive care with a diagnosis of septic shock, respiratory failure, pneumonia, and bilateral pleural effusions. Her comorbidities included panhypopituitarism noted at birth, interactable seizures, and progressive debilitation and wheelchair confined-based muscular degenerative disease. The patient also had endocrine abnormalities, including growth hormone deficiency evidenced by short stature/obesity, adrenocorticotropic hormone deficiency (she received continuous GCs/mineralocorticoids), hypothyroidism, and abnormalities in fluid/electrolyte balance. Abnormal neurodevelopment with decreased IQ, poor speech, and septo-optic dysplasia also were present. Her daily medications included prednisone, L-thyroxine, desmopressin, growth hormone, and anti-seizure drugs. Upon admission to pediatric intensive care, chest tubes were placed emergently to evacuate bilateral pneumothoraces; incision to place the chest tubes was performed bilaterally at the fourth intercostal space. The patient required vasopressors, prolonged intubation, and parenteral nutrition. Nonhealing surgical wounds developed after the chest tubes were removed. When no granulation tissue developed and the wound size was unchanged after 7 days of packing with a silver hydrofiber and a secondary dressing, I was consulted.

Patient 2. A 14-year-old boy with a history of colon cancer had undergone partial tumor resection and had been receiving multiple cycles of chemotherapy that involved bevacizumab (antivascular endothelial factor-a), steroids, and 2 other immunosuppressive medications, which had negative cutaneous effects. His most recent complications involved an infected mediport that required removal. I met this patient 7 days post mediport removal, at which point he had a stagnant, open, nongranulating wound. 

Both the patients described had morbidities contributing to lack of ECM deposition, lack of cellular chemotaxis and differentiation, deficiency of angiogenesis, and ultimately, lack of granulation tissue. My first choice for these wounds was a collagen product. It jumped-started the transition from the inflammatory to the proliferative phase and continuously offered support as new granulation tissue was forming (see Figure 1 and Figure 2).

The product of choice was Endoform natural dermal template (Aroa Biosugery Limited, Auckland, New Zealand), an ovine-, forestomach-derived porous ECM. It contains 85% collagen types 1 and 4, as well as secondary molecules, including hyaluronic acid, glycosaminoglycans, heparin sulfate, fibronectin, and laminin. These molecules facilitate cell infiltration, bind to water to keep the matrix hydrated, regulate remodeling, adhere to epithelial cells, connect scaffold proteins, and guide epithelial migration. While recruiting fibroblasts and epithelial cells, collagen may serve as a sacrificial magnet for overactive MMPs (ie, in cases where MMPs inhibitors are lacking, such as in the wounds of preterm, immunocompromised, and certain medical patients) and for elastase, which tends to convert pro-MMPs to MMPs in stalled wounds.

In addition, I often add negative pressure wound therapy (specifically portable, single-use units) as a secondary dressing. Both of the patients I described were able to go home with dermal template packing covered by a contact layer and a portable, single-use canisterless NPWT unit.

In summary, different collagen preparations and sources have been used successfully to treat recalcitrant wounds in challenging young patients. I encourage you to consider collagen in your pediatric wound care practice.

Dr. Boyar is Director of Neonatal Wound Services, Cohen Children’s Medical Center of New York, New Hyde Park; and an Assistant Professor of Pediatrics, Zucker School of Medicine, Hofstra/Northwell, Hempstead, NY. This column was not subject to the Wound Management & Prevention peer-review process.