CHAPTER 2
Wound Repair
General Aspects of Wound Repair
Wound healing, though a common physiologic process, requires a complicated sequence of tissue events. The purpose of wound healing is to restore the anatomical and functional integrity of an organ or tissue as quickly and perfectly as possible. Repair may take a year, and the result of wound healing is a scar with variable consequences (Fig 2-1). A series of reactions follows a wound, including an acute inflammatory phase, regeneration/repair, and contraction:
The acute inflammatory phase may last from minutes to hours. Blood clots quickly in adjacent vessels in response to tissue activators. Neutrophils and fluid enter the extracellular space. Macrophages remove debris from the damaged tissues, new vessels form, and fibroblasts begin to produce collagen.
Regeneration is the replacement of lost cells; this process occurs only in tissues composed of labile cells (eg, epithelium), which undergo mitosis throughout life. Repair is the restructuring of tissues by granulation tissue that matures into a fibrous scar.
Finally, contraction causes the reparative tissues to shrink so that the scar is smaller than the surrounding uninjured tissues.
Healing in Specific Ocular Tissues
The processes summarized in the following sections are also discussed in other volumes of the BCSC; consult the Master Index. Also see the appropriate chapters in this volume for a specific topography.
Cornea
A corneal abrasion, a painful but rapidly healing defect, is limited to the surface corneal epithelium, although the Bowman layer and superficial stroma may also be involved. Within an hour of injury the parabasilar epithelial cells begin to slide and migrate across the denuded area until they touch other migrating cells; then contact inhibition stops further migration. Simultaneously, the surrounding basal cells undergo mitosis to supply additional cells to cover the defect. Although a large corneal abrasion is usually covered by migrating epithelial cells within 24–48 hours, complete healing, which includes restoration of the full thickness of epithelium (4–6 layers) and re-formation of the anchoring fibrils, takes 4–6 weeks. The epithelial cells are labile; that is, some are continuously active mitotically and thus are able to completely replace the lost cells. If a thin layer of anterior cornea is lost with the abrasion, the shallow crater will be filled by epithelium, forming a facet.
Figure 2-1 Sequence of general wound healing with an epithelial surface. 1, The wound is created. Blood clots in the vessels; neutrophils migrate to the wound; the wounded edges begin to disintegrate. 2, The wound edges are reapposed with the various tissue planes in good alignment. The epithelium is lost over the wound but starts to migrate. The subcutaneous fibroblasts enlarge and become activated. Fibronectin is deposited at the wound edges. The blood vessels begin to produce buds. 3, The epithelium seals the surface. Fibroblasts and blood vessels enter the wound and lay down new collagen. Much of the debris is removed by macrophages. 4, As the scar matures, the fibroblasts subside. Newly formed blood vessels recanalize. New collagen strengthens the wound, which contracts. Note that the striated muscle cells (permanent cells) at bottom are replaced by scar (arrow).
Corneal stromal healing is avascular. Unlike with other tissues, healing in the corneal stroma occurs by means of fibrosis rather than by fibrovascular proliferation. This avascular aspect of corneal wound healing is critical to the success of penetrating keratoplasty as well as photorefractive keratectomy (PRK), laser in situ keratomileusis (LASIK), laser epithelial keratomileusis (LASEK), and other corneal refractive surgical procedures.
Following a central corneal wound, neutrophils are carried to the site by the tears (Fig 2-2), and the edges of the wound swell. Healing factors derived from vessels are not present. The matrix glycosaminoglycans, which in the cornea are keratan sulfate and chondroitin sulfate, disintegrate at the edge of the wound. The fibroblasts of the stroma become activated, eventually migrating across
the wound, laying down collagen and fibronectin. The direction of the fibroblasts and collagen is not parallel to stromal lamellae. Hence, cells are directed anteriorly and posteriorly across a wound that is always visible microscopically as an irregularity in the stroma and clinically as an opacity. If the wound edges are separated, the gap is not completely filled by proliferating fibroblasts, and a partially filled crater results.
Both the epithelium and the endothelium are critical to good central wound healing. If the epithelium does not cover the wound within days, the subjacent stromal healing is limited and the wound is weak. Growth factors from the epithelium stimulate and sustain healing. The endothelial cells adjacent to the wound slide across the posterior cornea; a few cells are replaced through mitotic activity. Endothelium lays down a new thin layer of the Descemet membrane. If the internal margin of the wound is not covered by Descemet membrane, stromal fibroblasts may continue to proliferate into the anterior chamber as fibrous ingrowth, or the posterior wound may remain permanently open. The initial fibrillar collagen is replaced by stronger collagen in the late months of healing. The Bowman layer does not regenerate when incised or destroyed. In an ulcer, the surface is covered by epithelium, but little of the lost stroma is replaced by fibrous tissue. Modification of the healing process by use of topical antimetabolites, such as 5-fluorouracil and mitomycin C, may be desirable in certain clinical situations (see BCSC Section 10, Glaucoma, Chapter 8).
Figure 2-2 Clear corneal wound. 1, The tear film carries neutrophils with lysozymes to the wound within an hour. 2, With closure of the incision, the wound edge shows early disintegration and edema. The glycosaminoglycans at the edge are degraded. The nearby fibroblasts are activated. 3, At 1 week, migrating epithelium and endothelium partially seal the wound;
fibroblasts begin to migrate and supply collagen. 4, Fibroblast activity and collagen and matrix deposition continue. The endothelium, sealing the inner wound, lays down new Descemet membrane. 5, Epithelial regeneration is complete. Fibroblasts fill the wound with type I collagen and repair slows. 6, The final wound contracts. The collagen fibers are not parallel with the surrounding lamellae. The number of fibroblasts decreases.
Sclera
The sclera differs from the cornea in that the collagen fibers are randomly distributed rather than laid down in orderly lamellae, and the glycosaminoglycan is dermatan sulfate. Sclera is relatively avascular and hypocellular. When stimulated by wounding, the episclera migrates down the scleral wound, supplying vessels, fibroblasts, and activated macrophages. The final wound contracts, creating a pinched-in appearance. If the adjacent uvea is damaged, uveal fibrovascular tissue may enter the scleral wound, resulting in a scar with a dense adhesion between uvea and sclera. Indolent episcleral fibrosis produces a dense coat around an extrascleral foreign body such as an encircling scleral buckling element or a glaucoma drainage device.
Limbus
The limbus is a complex region of corneal, scleral, and episcleral tissues. Wounds of the limbus cause swelling in the cornea and shrinking of the sclera. Healing involves episcleral ingrowth and clear corneal fibroblastic migration. Collector channels in the sclera do not contribute to the healing. Alterations in surgical technique between clear corneal and limbal incisions may produce different healing responses. Differences include
the potential for vascular ingrowth from episcleral vessels into a limbal wound and the absence of vascularity of a clear corneal wound
surface remodeling of epithelium over a clear corneal wound that does not occur over a limbal wound
Uvea
Under ordinary circumstances, wounds of the iris do not stimulate a healing response in either the stroma or the epithelium. Though richly endowed with blood vessels and fibroblasts, the iridic stroma does not produce granulation tissue to close a defect. The pigmented epithelium may be stimulated to migrate in some circumstances, such as excessive inflammation, but its migration is usually limited to the subjacent surface of the lens capsule, where subsequent adhesion of epithelial cells occurs. When fibrovascular tissue forms, it usually does so on the anterior surface of the iris as an exuberant and aberrant membrane (eg, rubeosis iridis) that may cross iridectomy or pupillary openings. The fibrovascular tissue may arise from the iris, the chamber angle, or the cornea.
Stroma and melanocytes of the ciliary body and choroid do not regenerate after injury. Debris is removed, and a thin fibrous scar develops that appears white and atrophic clinically.
Dunn SP. Iris repair: putting the pieces back together. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2002, module 11.
Lens
Small rents in the lens capsule are sealed by nearby lenticular epithelial cells. When posterior synechiae make the lenticular epithelium anoxic or hypoxic, a metaplastic response occurs,