Healing and Repair Inflammation and repair should be viewed as two parts of a single vital

function, the physiologic response to tissue injury, the objective of which is restoration of normal
structure and function. Up until now we have focused on the inflammation portion, but it is
good to remember that repair starts pretty soon after inflammation does and then continues
during and beyond the inflammatory phase.

Perfect restoration of function is dependent upon the regeneration of lost cells by similar cells
(repair by regeneration), and the orderly arrangement of these new cells in relation to preexisting
cells so that tissue functions are restored.

If the original cells cannot be replaced by their own kind then they are replaced by other cell types
(repair by replacement), usually by fibrous connective tissue. If necrosis is extensive, even
tissues that are capable of regeneration are replaced by fibrous connective tissue.

There are three cell types based on ability to regenerate: permanent cells ( almost never divide) -
nerve cell bodies, cardiac myocytes, cells of the lens stable cells (will divide if stimulated) -
fibroblasts, osteoblasts, parenchyma of liver, kidney, pancreas and endocrine glands, smooth
muscle, vascular endothelium labile cells (multiply through life) - epithelial cells of surfaces or
linings of ducts and hollow viscera, lymphoid and hematopoietic cells

Wound healing is typically divided into two types: first intention (primary union) and second
intention (secondary union). It should be remembered, however, that all wounds heal in roughly
the same way; new cells are formed from preexisting cells where possible, and these then fill in
the area of tissue loss. All wounds contain a certain amount of connective tissue replacement
depending on the degree of injury and stromal damage and the tissue’s ability to regenerate
itself.

First intention healing occurs in wounds that are closely approximated and not infected. Ideally,
most surgical wounds would fit into this category. To illustrate the normal sequence of repair,
let’s use the classic example of a sterile surgical incision.

First, the incision causes hemorrhage and death of a limited number of epithelial cells and
dermal elements. Once the incision is closed, the narrow space is filled with a fibrin clot that
temporarily seals the defect. Fibrin is derived from fibrinogen, a plasma protein, and has no
tensile strength.

A typical acute inflammatory response ensues. Within 24 hours, neutrophils and lesser numbers
of lymphocytes and macrophages are present along with fluid exudate in the margins of the
incision. Edema and exudate can accumulate so it’s a good thing you left those sutures just a
little loose! The dead cells and all other debris resulting from the injury are removed by the
phagocytic cells of the inflammatory response.

As the defect is colonized by the various proliferating cells, the inflammatory exudate and fibrin
are progressively digested and removed by neutrophils and macrophages.

Fibroblasts from the margin of the wound begin proliferation and migration using the fibrin strands as
a foundation. At the same time, endothelial cells from injured capillaries and lymphatics
proliferate into the clot as solid cords of cells that eventually form a lumen. Epithelial cells of
the epidermis begin proliferation at the edge of the wound.

In 2-3 days, fibroblasts have bridged the wound and the endothelial cords have canalized
(formed a lumen) and anastomosed to permit the flow of blood from one margin of the wound to
the other. Also epithelial cells grow across the incision in a single layer to meet in 2-3 days.

The highly vascular connective tissue, with a small component of acute inflammatory exudate
that now populates the wound, is known as granulation tissue. This is minimal in first intention
healing. Fibroblasts begin deposition of collagen. Although collagen production begins early, deposition
of significant amounts (as related to wound strength) begins at 4-5 days. Considerable
collagenous support is present within 7-8 days.

By two weeks the wound has gained almost as much tensile strength as the normal tissue.

Continued production of collagen, and its shrinkage, leads to compression of capillaries, and in
the course of weeks and months leads to the production of an avascular, collagenous connective
tissue scar. Scarring will be minimal in first intention healing.

Thin layers of elastic fibers are formed, thus making the wound capable of some stretching.

Adnexal elements are usually not regenerated. That means no new hair or sweat or sebaceous
glands. Nerves grow slowly into the new connective tissue and are mainly vasomotor.

Granulation tissue (= vascular fibrous connective tissue)

The term “granulation tissue” is derived from its pink soft granular appearance on the surface of
wounds. It looks all pink and pebbly because fibroblasts and capillaries are busy doing their thing.
Granulation tissue is recognized histologically by the presence of newly formed fibrous tissue and
numerous small blood vessels.

The new capillaries most commonly run in a perpendicular direction to the outer surface of the
wound since their function is to carry supplies to the free surface, while fibroblasts tend to grow in
from the side of the defect to bridge the gap. This often produces a histological picture of
capillaries running at right angles to the direction of the fibroblasts. The formation of new
capillaries is termed angiogenesis or neovascularization.
It is important to distinguish the term granulation from granulomatous inflammation. Although
they sound similar, they are really quite different. As different as fibrinous is from fibrous (know
that distinction too). Both of these sound-alikes are frequent traps that students fall into. Sorry
about that.

Remember, granulation tissue is part of the repair process and consists of proliferating fibrous
tissue, and granulomatous refers to inflammatory infiltrates characterized by macrophages.

And sometimes granulation tissue doesn’t know when to quit growing and start turning into the
permanent scar it is supposed to form. Think “exuberant granulation tissue” in horses, also
known as “proud flesh.” Healing process that got stuck and can’t move on.

Second intention healing is the term used to designate what happens when there is a wide gap
to bridge and also what happens when there is impairment of healing following infection or the
accumulation of fluids that require surgical drainage. The healing process is similar to first
intention healing, but differs in the following respects:

 Greater tissue defect, thus a larger area for granulation tissue to fill
 Larger amounts of dead cells, tissue debris, exudate, or foreign material are all in the
way
 Inflammation is prolonged and healing is therefore slower
 Residual fibrosis (scarring) is more prominent, impairing return to function

If the process continues too long, granulation tissue will accumulate in excessive amounts and
bulge above the surface, causing severe disfigurement of the structure. This excessive
granulation tissue is termed “proud flesh” or “exuberant granulation.” Exuberant granulation tissue
is a common complication to flesh wounds in the horse. To obtain healing, this excessive
growth has to be removed by excision or cautery.

All this healing takes energy and if an animal is in a compromised state, the repair will take a
whole lot longer.

Mediators

Recently our understanding of all of the mediators involved in tissue repair has expanded.

Below is a list of some of these factors that are responsible for growth and healing. YOU ARE NOT
RESPONSIBLE FOR KNOWING THE DETAILS OF ANY OF THESE. JUST BE AWARE THAT IT IS ALL
ORCHESTRATED BY THESE MEDIATORS THAT COME FROM A VARIETY OF CELLS.

Repair of bone

Repair of bone is a specialized category of healing and repair and deserves individual attention.
Immediately following fracture of bone, blood flows out of the broken vessels into the gap
between the broken ends of bone and displaced or disrupted periosteum, and into the
surrounding soft tissue. A big callus forms with fibrovascular tissue. The osteoprogenitor cells
eventually invade into this callus and slowly new bone is formed and then remodeled. Don’t worry
about knowing this now, there will be more detail at the appropriate moment (Systemic
Pathology I in the spring).

Repair of Nervous Tissue

Repair in the central nervous system (CNS) is very limited because mature neurons do not divide.
When damage occurs in the CNS, neurons and their processes are lost forever; they cannot be
regenerated. Take care of your neurons! In the peripheral nervous system (PNS), injury to the
nerves may be followed by regeneration if the nerve cell body remains alive. This type of
regeneration is more common in the PNS than in the CNS where injury to axons is more likely
to result in death of the neuron cell body rather than regeneration.

Repair of the Myocardium

Myocardial cells have very poor regenerative capacity. When they die, as in a heart attack, they
are usually gone forever and repair can only take place by fibrosis. This replacement by fibrosis
decreases myocardial contractility.