Tissue healing

An understanding of tissue healing allows the clinician to improve their clinical reasoning and to minimise damage throughout the rehabilitation program.

The three commonly cited stages of healing in most tissues of the human body include (1) Inflammation, (2) proliferation, and (3) repair and remodelling (Anemaet & Hammerich, 2014; Prentice, 2011; Sinno & Prakash, 2013). These stages must be understood as a continuum, not as separate entities that occur as lockstep, with no definitive beginning or end points.

Below are summaries for skeletal muscle, bone, tendon, ligament and cartilage healing.

Stage 1 of healing: inflammation

When tissue is damaged, it directly injures the cells of that injured tissue – this is what initiates the inflammatory response due to altered metabolism and release of materials. Inflammation is the process involving leukocytes and other phagocytic cells and exudates being delivered to the injured tissue to dispose of injury by-products to bring the tissue to a near normal state, and allows for the second stage of healing to begin and overlap; the proliferative phase.

Without the inflammatory response, normal healing cannot occur.

The inflammatory phase usually continues for 2 – 4days (Prentice, 2011) or up to 7 days (Sinno & Prakash, 2013).

What does this mean for exercise prescription at this stage?

Exercise aims to control the inflammation through muscle contraction, in a pain-free range of motion to help minimise fibrosis (Anemaet & Hammerich, 2014).
If pain is reproduced in this stage, it may promote further tissue damage, creating further inflammation and nociception.
It is important that muscle contraction is promoted to gradually increase stress on tissues, allowing mechanotransduction and Wolff’s Law to be employed; where tissues respond to the stressors placed upon them.
Exercises can be completed using PROM, AROM or A-AROM.

Stage 2 of healing: proliferation

During the proliferative phase, epithelialisation (within hours), angiogenesis and collagen deposition occur and ends with a haphazard arrangement of granulation tissue which act to fill gaps of tissue (Sinno & Prakash, 2013). This period of granulation tissue formation occurs within the first few hours of injury, and continues until initial healing has occurred while collagen synthesis increases (Prentice, 2011).

The proliferative phase begins within the first few days of injury, and can last from 4 to 6 weeks.

What does this mean for exercise prescription at this stage?

Maximum strength hasn’t occurred during proliferation, rather the tissues integrity has been restored with type 3 collagen before it is replaced by type 1 collagen in the repair and remodelling phases. Therefore, tissue stressors should be gradual with continuous monitoring for signs of further tissue damage i.e. pain or inflammatory signs should encourage reassessment of healing timeframes and exercise prescription.

Stage 3 of healing: repair and remodelling

In this phase macrophages break down type 3 collagen to type 1, giving the tissue it’s new strength due to tension within the tissue. Maximum strength occurs in the granulation tissue creating scar formation.

Then, myofibroblasts and fibroblasts produce type 1 collagen where normal collagen content is produced after 4-5 weeks to further strengthen the new tissue. These collagen fibres are arranged haphazardly however, later aligning to the stresses that are placed upon them.

This is a long-term, ongoing phase that begins ~2 weeks following injury (Sinno & Prakash, 2013).

What does this mean for exercise prescription at this stage?

As the remodelling phase begins, aggressive active range of motion and strengthening exercises should be incorporated to facilitate tissue remodelling and realignment.

Tissue healing

Inflammation

Proliferation

Repair and remodelling

Throughout the inflammatory phase, there are 3 stages that are accompanied by vascular, chemical and clot formation reactions (Anemaet & Hammerich, 2014; Prentice, 2011); (Fig 1.) (Prentice, 2011).

1. Vasoconstriction

To minimise blood loss, vasoconstriction occurs. The vasoconstriction occurs secondary to platelet aggregation at the site of tissue injury, which sends signals to the cardiovascular system to vasoconstrict the vessels. This happens for ~10minutes ultimately resulting in local hypoxia in the tissues.

2. Hypoxia

Intermittent hypoxia caused by vasoconstriction acts as a stimulant for angiogenesis – this angiogenesis is required for healing.

3. Vasodilation

Finally, vasodilation occurs mediated by histamine and other chemical mediators. Histamine increases the permeability of vessel walls, increasing blood flow and allowing other cells to enter the injured area including macrophages and neutrophils to remove debris and damaged tissue. Finally, platelets adhere to the vessels endothelium to form a clot – this allows for localisation of the injury. Additionally, signals for fibroblasts are produced to allow collagen production and new tissue to replace the injured tissue during the next stage of healing; proliferation.

(Prentice, 2011).

Skeletal muscle

Skeletal muscle healing

Similar healing principles of other tissues apply to skeletal muscle injury. The amount of tissue healing that occurs in skeletal muscle depends on the extent of the tissue damage (Anemaet & Hammerich, 2014). If the basement membrane is damaged, muscle cells do not regenerate – lending itself for healing through scar formation - healing through the process of repair and decreasing the muscles force-generating capabilities.

Initially, haemorrhage and edema follow injury, and phagocytosis occurs to clear unwanted cells. Then proliferation of ground substance occurs and fibrosis and scarring begin to occur. Concurrently, satellite cells begin to aggregate into the area and new myofirbrils are made. The new collagen undergoes maturation and orients itself along the lines of applied stress.

In the first 10 days of injury, the newly formed scar tissue is at its weakest. Initial healing takes 6-8 weeks and continues for 12-14 weeks, when the muscle tissue demonstrates almost normal strength. Remodelling can take from 6 months to a year following it's injury.

What does this mean for exercise prescription of skeletal muscle:

Early active contraction is imperative to induce capillary growth, muscle fibre regeneration and orientation of new fibers (Jarvinen, Jarvinen & Kalimo, 2013; Tero et. Al., 2005), regaining normal tensile strength (Prentice, 2011) and improves return to sport timeframes (Bayer, Magnusson, & Kjaer, 2017).
- Monitoring of an increase in symptoms or signs of inflammation is required, especially early in the rehabilitation.
Prolonged immobilisation should be avoided and gradual mobilisation should be progressively loaded to increase strength, prevent atrophy and extensibility as muscle is highly responsive to changes in load (Clarsen, 2016).

Bone healing

Dissimilar to skeletal muscle healing, the bone heals primarily by regeneration and remodelling without scarring as it is resorbed over time. Initially, blood vessels in bone and periosteum are damaged, ultimately forming a clot. Concurrently, a collagen network is formed allowing a framework for proliferating vessels. Then, chondroblasts begin to form a callus between the broken ends of bone.

The initial callus formation occurs in about 2 weeks and is initially soft and firm. Over the next ~4 weeks the hyaline cartilage and woven bone is replaced with trabecular bone through osteoblasts and the bone strength increases (Khosla, Westendorf & Modder, 2010). However, the healing process continues over 5 years where osteoclasts will resorb trabecular bone, and osteoblasts replace compact bone according to the stresses placed upon it.

What does this mean for exercise prescription of bone:

Bone responds to appropriate loading through mechanotherapy which stimulates osteoblast proliferation and formation of new bone (Clarsen, 2016) however, inadequate or excessive loading can lead to osteoclast activity, breaking down bone tissue.
Bone must withstand torsion, bending and compression and therefore dynamic loading is more effectual than static loading in stimulating bone remodelling (Clarsen, 2016).
Fracture sites should be protected until initial callus formation ~2 weeks – then a gradual load on the tissue can begin while the woven bone is replaced with trabecular bone over the next ~4 weeks (Mirhadi, Ashwood & Karagkevrekis, 2013). Then as bone strength has increased, and the hard callus has formed, full activity can be resumed which is usually obtained through radiographs.

Tendon

Tendon healing

Tendons heal similarly to other tissue, with inflammation, proliferation and remodelling occurring (Yang, Rothrauff & Tuan, 2013). Regardless, tendon healing is relatively slow due to its hypocellular and hypovascular nature (Yang, Rothrauff & Tuan, 2013) and requires dense fibrous union of its ends, alongside extensibility at it’s attachment to bone (Prentice, 2011).

Tendon adaptation occurs through an increased stiffness of the tendon and an increase in matrix protein production. In normal tendons, type I collagen response to loading peaks ~3 days after intense exercise, with this response to load in pathological tendon requiring longer to respond (Cook & Purdam, 2014).

Initially, inflammatory cells complete the process of phagocytosis to remove necrotic debris. Tenocytes are also recruited for the initial 72hours. In the proliferative phase, beginning at around 2 weeks and occurring over the next 6 weeks, proliferating fibroblasts and tenocytes aggregate in the injured area to create new fibrils and an extracellular matrix which consist of high amounts of water and only small amounts of collagen (Yang, Rothrauff & Tuan, 2013) – lending itself to a small amount of strength to withstand forces. Strong pull on the tendon is not indicated until at least 4-5 weeks. The final remodelling phase occurs 1-2months following injury and the tenocytes and collagen align parallel with the direction of stress applied, and type III collagen is gradually replaced with type I collagen and vascularity decreases. After about 10 weeks, fibrous scar tissue mimics tendon tissue which continues for years (Prentice, 2011; Yang, Rothrauff & Tuan, 2013).

What does this mean for exercise prescription of tendon:

Similar to muscle injury, gentle isometric in the proliferative phase allows for increasing blood flow without disrupting healing segments before a graded exposure to loads is introduced.
Tendons respond to mechanical loading programs by increasing their stiffness. They respond to high-intensity loading programmes that include eccentric, concentric-eccentric and isometric exercises (Clarsen, 2016).
Especially during rehabilitation of tendinopathic tendons, consistent high-loads must be counteracted with lower loads to allow healing to occur because of the slower turnover rate of type I collagen

Ligament healing

When ligaments are appropriately loaded over a period of time, they respond by increasing in size, stiffness, and the ability to tolerate load before failure (Houser et al, 2013). However, overloading the tissue can cause disruptions in the continuation of the ligament. Following this disruption, the ligament heals through the familiar inflammatory, proliferative and remodelling phases.

The acute inflammatory phase begins within moments of the injury and continue over the next 2-3 days where clot formation occurs to allow further healing to occur. Concurrently, other immune cells migrate to the injured area to remove debris to initiate matrix turnover. Then, the proliferative phase gradually takes over the inflammatory phase ~day 3, through fibroblast activity to rebuild an immature ligamentous tissue. This tissue is thinner and smaller in diameter than uninjured tissue, producing type III collagen that is not as tightly packed. The remodelling phase begins to predominate ~3 weeks, where maturation of the new collagen is attempted. This process can last from months to years, where the tissue begins to resemble, but not replicate, the pre-morbid tissue (Houser et al, 2013). New tissue has altered proteoglycan amounts, collagen types and size, high amounts of neovascularisation and disorganised scar tissue. Since ligaments are usually primarily composed of type I collagen - increasing stability, strength of the tissue. The increase in type III collagen results in weakness in strength and stiffness.

Ligaments respond poorly to immobilisation and decreased loading as matrix degradation exceeds matrix formation (Houser et al, 2013) and respond best to an approach that consists of variable loading including across joint positions and ranges to restore full function (Glasgow, Phillips, & Bleakley, 2015). Those who avoid immobilisation return to work and sports quicker (Kerkhoffs et al, 2004) and experience decrease pain, swelling and stiffness, improved ROM (Nash, Mickan, Nel Mar, & Glasziou, 2004). Additionally, there is an increase in blood flow and cellular activity, tissue size, strength, matrix organization and collagen content.

What does this mean for exercise prescription of ligament:

Early ROM is important to decrease pain, swelling and stiffness and to improve ROM!
Ligaments may never resemble their former-self - so strengthening of the kinetic chain is imperative
Ligaments take a longer period of time to heal; be patient and progressively load in various joint positions.

Cartilage

healing

Cartilage is difficult to heal because it is largely avascular, similar to tendons. Healing is slow and is greatest at the periphery of the cartilage, closer to adjacent blood supply. Also, prognosis is better if tissues beneath the cartilage are also damaged to facilitate healing. To assist cartilage healing, motion is important because it stimulates synovial fluid, which contains all the cells needed for healing.

What does this mean for exercise prescription of cartilage:

Unloaded motion is considered important for cartilage healing to promote the stimulation of synovial fluid. This fluid contains cells required for healing.

Factors impeding healing

Factors impacting healing

(Guo & DiPietro, 2010)

oxygenation

infections

stress

sex hormones

diabetes

medications

obesity

alcohol

smoking

nutrition

age

With age, there are fewer satellite cells which can differentiate into any type of cell.

Slower phagocytosis which delays healing

Greater fibrosis with muscle injury

Lower production of growth factors