Effects of Perioperative Antiinflammatory and Immunomodulating Therapy on Surgical Wound Healing

Anthony J. Busti, PharmD; Justin S. Hooper, PharmD; Christopher J. Amaya, PharmD; Salahuddin Kazi, MBBS

Disclosures

Pharmacotherapy. 2005;25(11):1566-1591. 

In This Article

Wound Healing: A Multistep Process

The process of soft tissue wound healing is complex and is different from the processes for effective bone healing. Soft tissue healing occurs by either primary or secondary intention.[7] Healing by primary intention occurs after direct closure of the wound by the surgeon, whereas healing by secondary intention occurs when the wound is left open after surgery. Regardless of the healing method, wounds must progress through three distinct phases of healing: acute, proliferative, and remodeling. The acute phase of wound healing is partially triggered by activation of platelets through the release of platelet-derived growth factor (PDGF) and eicosanoids (prostaglandins and leukotrienes), which are known to facilitate hemostasis and the inflammatory response.[8] The inflammatory response lasts 24-48 hours and is characterized by warmth, swelling, redness, and pain.[9] Platelet-derived growth factor is responsible for chemotactic and mitogenic effects on fibroblasts, smooth muscle cells, macrophages, monocytes, and neutrophils. Neutrophils, in particular, migrate rapidly to the site of injury and reach a maximal level at 2 days after wounding.[10] In addition, neutrophils help secrete growth factors that stimulate the migration of fibroblasts, epithelial cells, and vascular endothelial cells into damaged tissue.[7,11] After approximately 48 hours, macrophages become the predominant inflammatory cells in the wound bed and serve to scavenge bacteria and tissue debris and to destroy neutrophils.[7] As the process of wound healing progresses, the number of macrophages in the wound tapers off while fibroblasts become the major constituent of the wound bed.

The proliferative phase of wound healing is dominated by cellular activity and repair of damaged tissue. Within 48-72 hours of injury, fibroblasts migrate into the damaged area where they synthesize structural proteins, reorganize the wound matrix, and promote wound contraction.[7,8] During fibroplasia, new dermal matrix and granulation tissue form. Fibroblasts also produce fibronectin and hyaluronic acid, which act as a scaffold for collagen deposition and promote a network to facilitate cell migration.[8] Collagen, which is partially secreted by fibroblasts, then acts as a constituent of fibrous connective tissue.

As fibroplasia takes place, the process of angiogenesis is initiated by the release of growth factors such as basic fibroblast growth factor.[12] Angiogenesis involves the formation of new blood vessels by either de novo generation in the wound space or by anastomosis to preexistent vessels.[7] Tumor necrosis factor-α, which is secreted by macrophages, also promotes angiogenesis and the formation of new blood vessels.[13]

The final phase of wound healing, contraction, involves wound size reductions. The end result is a stable wound with a constant turnover of collagen and remodeling of the matrix.[7] It is the deposition of matrix materials such as fibronectin, hyaluronic acid, proteoglycans, and collagen that makes up the remodeling phase of wound healing.[7] Collagen is synthesized by wound fibroblasts and serves to provide strength and stiffness within the dermal tissue. These macromolecules then act as a scaffold for cellular migration and support of new tissue growth.

Bone fracture healing also involves three distinct phases: inflammation, reparation, and bone remodeling.[14] Immediately after a bone fracture, the inflammatory phase is initiated by the formation of a hematoma. The actual healing process begins when local platelets and inflammatory cells release both transforming growth factor-β1 and PDGF.[15] Bone fragments at the site of injury also undergo necrosis, leading to osteoclast recruitment and proliferation of mesenchymal cells.[16] Finally, during the first 2 weeks after injury, prostaglandin production and COX-2 expression are increased within the callus formation.[17,18] The expression of COX-2 in this area is essential for mesenchymal stem cells to differentiate into osteoblasts.[19]

The reparation phase begins when mesenchymal cells undergo rapid chondrogenesis (development of cartilage) and ossification (development of bone). These cellular processes initiate appositional growth of the callus, which occurs adjacent to old bone surrounding the fracture site, thereby resulting in fracture union. Vascular endothelial growth factor, PDGF, and COX-2 also appear to play a role in the process of angiogenesis, which occurs during the reparation phase of bone healing.[20,21,22] This process typically requires 4-16 weeks to complete.

Newly formed cartilage is then followed by osteoclastic degradation of the matrix. Osteoblasts then migrate into the cavities that are formed by osteoclasts to produce the bone matrix. This process is repeated by additional cycles of bone remodeling for further strengthening. It can take up to 6 months before healed bone returns to maximum strength.[14]

Many of the above steps are vulnerable to inhibition by drug therapy. Corticosteroids can inhibit fibroplasia, vascular proliferation, and wound contraction in soft tissue healing.[23] Anticoagulants and antiplatelet agents may increase the risk of wound hematoma, thereby impairing healing.[23] In addition, nonselective NSAIDS, COX-2-selective inhibitors, and DMARDs may impair the acute phase of healing and compromise the normal process of wound healing.[7,23,24]

Similarly, bone healing is also affected at various stages by common drug therapy. Corticosteroids, nonselective NSAIDs, and COX-2-selective inhibitors can impair the inflammatory responses needed for adequate bone healing. Specifically, COX-2-selective inhibitors can inhibit mesenchymal cell differentiation into osteoblasts, which is critical for adequate bone repair.[17,18,19,20,21,22]

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....