Tissue Repair And Regeneration Notes

Selected Examples Of Tissue Repair

After an understanding of the general aspects of regeneration and repair, we now turn to discuss specific examples of tissue repair. These are discussed under two headings:

Read And Learn More Infammation And Repair Pathology 

Healing of skin wounds, which represents the classic example of a combination of regeneration and repair.

Healing in specialised tissues: Here, examples of healing in bone and a few parenchymal organs are described.

Healing Of Skin Wounds:

Wound healing can be accomplished in one of the following two ways:

1. Healing by first intention (primary union)
2. Healing by second intention (secondary union).

1. Healing By First Intention (Primary Union):

This is defined as the healing of a wound which has the following characteristics:

• Clean and uninfected
• Surgically incised
• Without much loss of cells and tissue; and
• Edges of wounds are approximated by surgical sutures.

The sequence of events in the primary union is illustrated in described below:

• Initial haemorrhage:  Immediately after injury, the space between the approximated surfaces of the incised wound is filled with blood which then clots and seals the wound against dehydration and infection.
• Acute inflammatory response:  This occurs within 24 hours with the appearance of polymorphs from the margins of incision. By 3rd day, polymorphs are replaced by macrophages.
• Epithelial changes: The basal cells of epidermis from both the cut margins start proliferating and migrating towards incisional space in the form of epithelial spurs. A well-approximated wound is covered by a layer of epithelium in 48 hours. The migrated epidermal cells separate the underlying viable dermis from the overlying necrotic material and clot, forming scab which is cast off. The basal cells from the margins continue to divide. By 5th day, a multilayered new, epidermis is formed which is differentiated into superficial and deeper layers.
• Organisation:  By 3rd day, fibroblasts also invade the wound area. By 5th day, new collagen fibrils start forming which dominate till healing is completed. In 4 weeks, the scar tissue with scanty cellular and vascular elements, a few inflammatory cells and epithelialised surface is formed.
• Suture tracks:  Each suture track is a separate wound and incites the same phenomena as in the healing of the primary wound i.e. filling the space with haemorrhage, some inflammatory cell reaction, epithelial cell proliferation along the suture track from both margins, fibroblastic proliferation and formation of young collagen.

When sutures are removed around 7th day, much of epithelialised suture track is avulsed and the remaining epithelial tissue in the track is absorbed. However, sometimes the suture track gets infected (stitch abscess), or the epithelial cells may persist in the track (implantation or epidermal cysts).

Thus, the scar formed in a sutured wound is neat due to close apposition of the margins of wound; the use of adhesive tapes or metal clips avoids removal of stitches and its complications.

2. Healing By Second Intention (Secondary Union);

This is defined as the healing of a wound having the following characteristics:

• Open with a large tissue defect, at times infected
• Having extensive loss of cells and tissues; and
• The wound is not approximated by surgical sutures but is left open.

The basic events in secondary union are similar to the primary union but differ in having a larger tissue defect which has to be bridged. Hence, healing takes place from the base upward and also from the margins inwards. Healing by the second intention is slow and results in a large, at times ugly, scar as compared to rapid healing and neat scar of primary union.

The sequence of events in the secondary union is illustrated and described below:

• Initial haemorrhage: As a result of injury, the wound space is filled with blood and fibrin clot which dries.

•  Inflammatory phase:  There is an initial acute inflammatory response followed by the appearance of macrophages which clear off the debris as in primary union.
• Epithelial changes:  As in primary healing, the epidermal cells from both the margins of the wound proliferate and migrate into the wound in the form of epithelial spurs till they meet in the middle and re-epithelialise the gap completely.
  • However, the proliferating epithelial cells do not cover the surface fully until granulation tissue from the base has started filling the wound space.
  • In this way, pre-existing viable connective tissue is separated from necrotic material and clot on the surface, forming scab which is cast off.
  • In time, the regenerated epidermis becomes stratified and keratinised.
• Granulation tissue: Main bulk of secondary healing is by granulations. Granulation tissue is formed by the proliferation of fibroblasts and neovascularisation from the adjoining viable elements.
  • The newly-formed granulation tissue is deep red, granular and very fragile. With time, the scar on maturation becomes pale and white due to an increase in collagen and decrease in vascularity.
  • Specialised structures of the skin like hair follicles and sweat glands are not replaced unless their viable residues remain which may regenerate.
• Wound contraction: 
  • Contraction of wound is an important feature of secondary healing, not seen in primary healing. Due to the action of myofibroblasts present in granulation tissue, the wound contracts to one-third to one-fourth of its original size.
• Presence of infection:
  • Bacterial contamination of an open wound delays the process of healing due to release of bacterial toxins that provoke necrosis, suppuration and thrombosis.
  • Surgical removal of dead and necrosed tissue, and debridement, helps in preventing the bacterial infection of open wounds.
  • Differences between primary and secondary union of wounds are given in Table

Complications In Healing Of Skin Wounds:

During the course of healing of skin wounds, the following complications may occur:

• Infection The wound may get infected due to the entry of bacteria which delays healing.
• Implantation (epidermal) cyst Formation of implantation epidermoid cyst may occur due to the persistence of epithelial cells in the wound after healing.
• Pigmentation Healed wounds may at times have rust-like colour due to staining with haemosiderin. Some coloured particulate material left in the wound may persist and impart colour to the healed wound.
• Deficient scar formation This may occur due to inadequate formation of granulation tissue.
• Incisional hernia A weak scar, especially after a laparotomy, may be the site of the bursting open of a weakly healed wound (wound dehiscence) or may develop incisional hernia later.
• Hypertrophied scars and keloid formation At times the scar formed is excessive, ugly and painful.
• Excessive formation of collagen in healing may result in keloid (claw-like) formation, in certain races such as in Blacks and Asians.
• Hypertrophied scar differs from keloid as under

Differences between primary and secondary union of wounds:

• The hypertrophied scar is confined to the borders of the initial wound and has hyalinised collagen bundles which are parallel.
• Keloid is non-neoplastic reactive proliferation of connective tissue that grows beyond the boundaries of injury and is composed of haphazardly arranged collagen.Excessive contraction An exaggeration of wound contraction may result in the formation of contractures or cicatrisation e.g. Dupuytren’s (palmar) contracture, plantar contracture and
• Peyronie’s disease (contraction of the cavernous tissues of penis).
• Neoplasia Rarely, scar may be the site for the development of carcinoma later cough (due to tracheal compression by mediastinal lymphadenopathy) and dyspnoea are common.
• Squamous cell carcinoma in Marjolin’s ulcer i.e. a scar following burns on the skin.

Healing of skin wounds:

• Healing of skin wounds can be accomplished by first intention (primary union) and by second intention (secondary union).
• Primary union is healing of a wound which is clean and uninfected, surgically incised, without much loss of cells and tissue. In this, edges of wound are approximated by surgical sutures.
• Secondary union of a wound is for open with a large tissue defect which are at times infected, having extensive loss of cells and tissues. Here, the wound is not approximated by surgical sutures.
• The basic events in both primary and secondary union are similar but differ in having a larger tissue defect in secondary union which has to be bridged. Hence, healing takes place from the base upward as well as from the margins inwards.
• The healing by second intention is slow and results in a large, at times ugly, scar as compared to rapid healing and neat scar of primary union.
• Complications of wound healing are infection, inclusion cyst formation, pigmentation, incisional hernia, hypertrophied scar and contracture

Healing In Specialised Tissues:

• While healing of the skin wound is an example of tissue repair by regeneration and repair proceeding side by side, in many specialised tissues, either the process of repair is modified (cough (due to tracheal compression by mediastinal lymphadenopathy) or dyspnoea are common.
• In fracture healing, peripheral nerves), or there is a predominance of regeneration or repair (cough (due to tracheal compression by mediastinal lymphadenopathy) and dyspnoea are common. In healing in parenchymal tissues). Some of these examples are described here.

Fracture Healing:

Healing of fracture by callus formation depends upon some clinical considerations whether the fracture is:

• Traumatic (in previously normal bone), or pathological (in previously diseased bone)
• Complete or incomplete like green-stick fracture; and simple (closed), comminuted (splintering of bone), or compound (communicating to skin surface).

However, basic events in the healing of any type of fracture are similar and resemble the healing of skin wounds to some extent.

Primary union of fractures:

Occurs when the ends of fracture are approximated surgically by application of compression clamps or metal plates. In these cases, bony union takes place with the formation of medullary callus without periosteal callus formation. The patient can be made ambulatory early but there is more extensive bone necrosis and slow healing.

Secondary union: Secondary union is a more common form of fracture healing when plaster casts are applied for the immobilisation of a fracture.

Though it is a continuous process, the secondary bone union is described under the following 3 headings:

1. Procallus formation
2. Osseous callus formation
3. Remodelling

These processes are illustrated in and described below:

1. Procallus Formation :

The steps involved in the formation of precalculus are as follows:

• Haematoma: Haematoma forms due to bleeding from torn blood vessels, filling the area surrounding the fracture. Loose meshwork is formed by blood and fibrin clot which acts as a framework for subsequent granulation tissue formation.
• Local inflammatory response:  A local inflammatory response occurs at the site of injury with exudation of fibrin, polymorphs and macrophages. The macrophages clear away the fibrin, red blood cells, inflammatory exudate and debris. Fragments of necrosed bone are scavenged by macrophages and osteoclasts.
• Ingrowth of granulation tissue: Ingrowth of granulation tissue begins with neovascularisation and proliferation of mesenchymal cells from the periosteum and endosteum. A soft tissue callus is thus formed which Joins the ends of a fractured bone without much strength.
• Callus composed of woven bone and cartilage: Callus composed of woven bone and cartilage starts within the first few days. The cells of an inner layer of the periosteum have osteogenic potential and lay down collagen as well as osteoid matrix in the granulation tissue.
  • The osteoid undergoes calcification and is called a woven bone callus.
  • A much wider zone over the cortex on either side of fractured ends is covered by the woven bone callus and united to bridge the gap between the ends, giving the spindle-shaped or fusiform appearance to the union.
  • In poorly immobilised fractures ( for example, Fracture ribs), the subperiosteal osteoblasts may form cartilage at the fracture site.
  • At times, the callus is composed of woven bone as well as cartilage, temporarily immobilising the bone ends.
  • This stage is called a provisional callus or precalculus formation and is arbitrarily divided into external, intermediate and internal precalculus.

2. Osseous Callus Formation

• The precalculus acts as scaffolding on which an osseous callus composed of lamellar bone is formed. The woven bone is cleared away by incoming osteoclasts and the calcified cartilage disintegrates.
• In their place, newly-formed blood vessels and osteoblasts invade, laying down osteoid which is calcified and lamellar bone is formed by developing a Haversian system concentrically around the blood vessels.

3. Remodelling:

• During the formation of lamellar bone, osteoblastic laying and osteoclastic removal are taking place remodelling the united bone ends, which after some time, is indistinguishable from normal bone.
• The external callus is cleared away, compact bone (cortex) is formed in place of the intermediate callus and the bone marrow cavity develops in the internal callus.

Complications of Fracture Healing:

These are as under:

• A fibrous union may result instead of the osseous union if the immobilisation of fractured bone is not done. Occasionally, a false joint may develop at the fracture site (pseudo-arthrosis).
• Non-union may result if some soft tissue is interposed between the fractured ends.
• Delayed union may occur from causes of delayed wound healing in general such as Infection, inadequate blood supply, poor nutrition, movement and old age.

Healing Of Nervous Tissue  Central Nervous System:

The nerve cells of the brain, spinal cord and ganglia are permanent cells, and therefore once destroyed are not replaced. Axons of CNS also do not show any significant regeneration.

The damaged neuroglial cells, however, may show proliferation of astrocytes called gliosis.

Peripheral Nervous System:

• In contrast to the cells of CNS, the peripheral nerves show limited regeneration, mainly from the proliferation of Schwann cells and fibrils from the distal end. Briefly, it consists of the following:
• The Myelin sheath and axon of the intact distal nerve undergo Wallerian degeneration up to the next node of Ranvier towards the proximal end.
• Degenerated debris is cleared away by macrophages.
• Regeneration in the form of sprouting of fibrils takes place from the viable end of the axon.
• These fibrils grow along the track of degenerated nerve so that in about 6-7 weeks, the peripheral stump consists of a tube filled with elongated Schwann cells.
• One of the fibrils from the proximal stump enters the old neural tube and develops into a new functional axon.

Healing Of Muscle Skeletal Muscle:

The regeneration of striated muscle is similar to peripheral nerves. On injury, the cut ends of muscle fibres retract but are held together by stromal connective tissue.

• The injured site is filled with fibrinous material, polymorphs and macrophages. After clearance of damaged fibres by macrophages, one of the following two types of regeneration of muscle fibres can occur:
• If the muscle sheath is intact, sarcolemmal tubes containing histiocytes appear along the endomysial tube which, in about 3 months, restores properly oriented muscle fibres for example, In Zenker’s degeneration of muscle in typhoid fever.
• If the muscle sheath is damaged, it forms a disorganised multinucleate mass and scar composed of fibrovascular tissue e.g. in Volkmann’s ischaemic contracture.

Smooth Muscle:

Non-striated muscle has limited regenerative capacity, for example, Appearance of smooth muscle in the arterioles in granulation tissue. However, in large destructive lesions, the smooth muscle is replaced by permanent scar tissue.

Cardiac Muscle:

Destruction of heart muscle is replaced by fibrous tissue. However, in situations where the endomysium of individual cardiac fibre is intact (for example, In diphtheria and coxsackie virus infections), regeneration of cardiac fibres may occur in young patients.

Healing Of Mucosal Surfaces:

• The cells of mucosal surfaces have very good regeneration and are normally being lost and replaced continuously for example, the Mucosa of the alimentary tract, respiratory tract, urinary tract, uterine endometrium etc.
• This occurs by proliferation from margins, migration, multilayering and differentiation of epithelial cells in the same way as in the epidermal cells in the healing of skin wounds.

Healing Of Solid Epithelial Organs:

Following gross tissue damage to organs like the kidney, liver and thyroid, the replacement is by fibrous scar for example, In chronic pyelonephritis and cirrhosis of the liver. However, in parenchymal cell damage with an intact basement membrane or intact supporting stromal tissue, regeneration may occur.

For example:

• In tubular necrosis of the kidney with an intact basement membrane, proliferation and slow migration of tubular epithelial cells may occur to form renal tubules again
• In viral hepatitis, if part of the liver lobule is damaged with the intact stromal network, the proliferation of hepatocytes may result in the restoration of the liver lobule

Healing in Specialised Tissues:

• Fracture healing may be primary union when the ends of fracture are approximated as is done by application of compression clamps. In these cases, the bony union takes place with the formation of the medullary callus without periosteal callus formation.
• Secondary union of fractures is more common and includes precalculus and osseous callus
  formation followed by remodelling of the bone.
• While neurons of the brain and spinal cord lose their ability for regeneration and fail to get replaced, healing of peripheral nerves occurs from limited regeneration, mainly from the proliferation of Schwann cells and fibrils from the distal end.
• Regeneration of skeletal muscle is similar to peripheral nerves, while damaged myocardium heals by fibrosis. Smooth muscle, however, has limited regenerative capacity.
• Healing of mucosal surfaces is by regeneration of the epithelial surface and replacement continuously.
• Healing of organs such as kidneys, liver and thyroid is by limited regeneration and some healing by fibrosis.