1
Gastrointestinal Healing

Eric Monnet and Daniel D. Smeak

Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA

The gastrointestinal tract heals as any other tissue in an orderly manner, with an inflammatory phase, a debridement phase, a granulation phase, and a maturation phase. However, there are some characteristics very specific to the gastrointestinal tract that sets it apart from other healing tissues.

The healing process of the gastrointestinal tract should not only re-establish the anatomical integrity of the tract but also its function. Healing should happen with minimal scaring and stricture formation that could impede the motility of the gastrointestinal tract. Additionally, the formation of adhesions, even though rare in small animal surgery, could deteriorate gastrointestinal motility and should be minimized.

1.1 Anatomy

The wall of the gastrointestinal tract has a mucosa, a submucosa, a muscularis, and a serosa, except the esophagus and the distal rectum.

The mucosa has three distinct layers: the epithelium, the lamina propria and the muscularis mucosa. The lamina propria layer is made of vessels, lymphatics, and mesenchymal cells whereas the muscularis mucosa is a thin muscle layer. After completing the anastomosis, the mucosa heals very fast by epithelial cells migration over the defect providing a rapid barrier from the intestinal content. For intestinal healing to occur, a good surgical apposition of layers is required; everting or inverting patterns interfere with mucosal healing.

The submucosa layer, incorporating the bulk of the collagen, is the holding layer in intestinal surgery. Type I collagen (68%) predominates in the submucosa, followed by type III (20%) and finally collagen type V (12%) (Thornton and Barbul 1997). It is a loose connective tissue with lymphatic, nerve fibers, ganglia, and blood vessels that should be preserved during surgery. The muscularis layer consists of an inner circular muscle layer, a longitudinal outer muscle layer and collagen fibers. The serosal surface is made of connective tissue with mesothelial cells, lymphatics, and blood vessels. The serosa is important in the healing process because it helps prevent leakage of the gastrointestinal content in the immediate post-operative period.

1.2 Phases of Wound Healing

1.2.1 Partial Thickness Injury

A partial thickness injury affecting only the mucosa or the serosa heals with epithelial cells and mesothelial cells proliferation without scaring. A full-thickness trauma of the gastrointestinal tract results in an inflammatory reaction and a non-epithelial cell proliferation that can result in scaring secondary to fibroblast activity (Thornton and Barbul 1997; Thompson et al. 2006).

1.2.2 Full-Thickness Injury

As soon as the wall of the gastrointestinal tract is incised, hemorrhage occurs but it is rapidly controlled by an intense vasoconstriction. Following this initial phase, vasodilation occurs with migration of neutrophils, macrophages, platelets, and liberation of inflammatory mediators which characterizes the inflammatory phase. The platelets, by releasing diverse platelet-derived growth factors (PDGF) and cytokines, contribute to hemostasis and cell recruitment like macrophages and fibroblasts. The neutrophils predominate during the first 24?hours but then macrophages become predominant past 48?hours following the initial injury. The macrophages play an important role in healing of the gastrointestinal tract by controlling local infection with phagocytosis, production of oxygen radicals, and nitric oxide. They also participate in debridement with phagocytosis and production of collagenase and elastase. The macrophages also regulate matrix synthesis and cell recruitment and activation. They release several growth factors (PDGF, transforming growth factor (TGFß), fibroblast growth factor (FGF), IGF) and cytokines (TNFa, IL-1) important for tissue healing. The macrophages recruit lymphocytes that liberate interleukin (IL-6) and interferon (IFN) and promote angiogenesis with production of VEGF (Vasculogenic Endothelial Growth Factor). Finally, the capillary permeability is increased resulting in inflammation and edema on the edges of the incision that can persist for two weeks. Care should be taken initially when the sutures are placed to not induce tissue strangulation and necrosis. A fibrin seal develops over the serosa very quickly to provide a leakage protection of the surgical site (Pascoe and Peterson 1989; Thornton and Barbul 1997; Thompson et al. 2006).

Overlapping with the inflammatory phase is the debridement phase, with removal of injured tissue by macrophages. The debridement phase should not exceed 1-2?mm from the edges of the incision. During this process, collagen is resorbed by collagenase and synthesized by smooth muscle and fibroblast. The smooth muscles are the major contributor in collagen production within the gastrointestinal tract. The collagen degrade by the collagenase activity weakens the strength of the anastomosis. In the colon, the collagenase activity is increased over the entire length of the colon while in the small intestine, it is increased only at the site of the anastomosis (Hawley 1970; Jiborn et al. 1978a). The risk of dehiscence is high between 3 and 10?days after surgery. Usually, after 4 to 5?days, collagen synthesis is superior to lysis and the anastomosis regains strength. This collagenase activity can be increased by the amount of trauma induced by tissue manipulation at the time of surgery or the presence of a foreign body, and by the degree of contamination. The amount of collagen synthesized is affected by hypotension, hypovolemia, shock, and certain medications.

The granulation tissue appears at the beginning of the proliferative phase of intestinal healing. Fibroblast is the major cell type present past day 4 after surgery. The fibroblasts migrate under the control of PDGF, TGFß and FGF. Fibroblast and smooth muscle lay down collagen fibers and new capillaries appear in the field.

After one to two weeks following the anastomosis, the epithelial layer is fully restored. The epithelialization of the anastomosis reduces the formation of excessive fibrosis tissue secondary to inflammation. The excessive fibrosis could lead to stricture formation. During the maturation phase, the collagen fibers are reorganized and the anastomosis is becoming thinner.

In summary, an intestinal anastomosis loses bursting strength during the first 3 to 5 days to finally regain 50-70% of the initial bursting strength in 2 to 3 weeks (Jiborn et al. 1978a, 1978b; Thompson et al. 2006; Munireddy et al. 2010).

1.3 Factors Affecting Gastrointestinal Tract Healing

1.3.1 Ischemia and Tissue Perfusion

Ischemia interferes with healing of any tissue and especially the gastrointestinal tract. The oxygen delivery to the peripheral tissue depends on the anatomy of the capillaries, vasomotor control, and oxygen saturation. The tissue perfusion depends on the amount of soft tissue trauma and especially trauma to the blood supply of the loop of intestine. The placement of tight sutures interferes with tissue perfusion and may increase the risk of dehiscence, especially in the colon and esophagus (Shikata et al. 1982; Chung 1987; Jonsson and Hogstrom 1992; Thornton and Barbul 1997). Hypovolemia and hypotension are critical factors that divert blood flow to essential organs, and oxygen delivery is also very important for collagen synthesis. A partial pressure of oxygen of at least 40?mmHg is required for collagen synthesis. During a hypovolemic event, the gastrointestinal tract downregulates its own blood flow. Anemia does not interfere with healing as long as the patient has a good cardiac output to compensate (Thompson et al. 2006).

1.3.2 Suture Intrinsic Tension

Incising oral and visceral tissues stimulate an initial vasoconstriction, followed by secondary vasodilation and increased vascular permeability mediated largely by kinins, ultimately causing edema and swelling of tissue edges. This should be kept in mind when tensioning suture lines or stitches because ischemic necrosis may develop as the suture strangulates the swelling tissue. In general, sutures in viscera of the digestive tract should be tensioned such that the incision edges are held firmly together without crushing or cutting through the needle purchase. When inverting suture patterns are used, the suture line is firmly tensioned such that the incised edges are fully inverted and minimal suture is exposed on the surface of the organ (Thornton and Barbul 1997).

1.3.3 Surgical Technique

A simple apposition of the submucosa of the gastrointestinal tract is desired to achieve primary healing because it is associated with the least amount of fibrous tissue and better function. An apposition of the submucosa is important for the rapid healing of the mucosa and preventing migration of microorganisms within the surgical site. An eversion or inversion of the mucosa has been shown to...