Chapter
4 Pankaj Sharma
Basic Science of Tendon Healing
Tendon injuries account for considerable morbidity, and often
prove disabling for several months. Significant advances have
been made in our understanding of tendon healing, in recent
times. Improved knowledge of the basic science underlying
tendon healing should allow the development of management
modalities that can enhance the process of tendon healing
(1,2). This chapter presents a synopsis of current knowledge of
the complex interplay involved in tendon healing.
Tendon Healing
Tendon healing occurs in three overlapping phases. In the ini-
tial inflammatory phase, erythrocytes and inflammatory cells,
particularly neutrophils, enter the site of injury. In the first
24 hours, monocytes and macrophages predominate, and
phagocytosis of necrotic materials occurs. Vasoactive and che-
motactic factors are released with increased vascular perme-
ability, initiation of angiogenesis, stimulation of tenocyte pro-
liferation, and recruitment of more inflammatory cells (3).
Tenocytes gradually migrate to the wound, and type III colla-
gen synthesis is initiated (4).
After a few days, the regenerative stage begins. Synthesis of
type III collagen peaks during this stage, which lasts for a few
weeks. Water content and glycosaminoglycan concentrations
remain high during this stage (4). After approximately 6 weeks,
the remodeling stage commences. During this stage, the heal-
Copyright © 2012. Wolters Kluwer Health. All rights reserved.
ing tissue changes in size and shape. A corresponding decrease
in cellularity, collagen, and glycosaminoglycan synthesis occurs.
The remodeling phase can be divided into a consolidation and
maturation stage (5). The consolidation stage commences at
about 6 weeks and continues up to 10 weeks. In this period,
repair tissue changes from cellular to fibrous, tenocyte metabo-
lism remains high, and tenocytes and collagen fibers become
aligned in the direction of stress (6). A higher proportion
of type I collagen is synthesized during this stage (7). After
10 weeks, the maturation stage occurs, with gradual change
of fibrous tissue to scar-like tendon tissue over the course of
1 year (6). During the latter half of this stage, tenocyte metabo-
lism and tendon vascularity decline (8).
Tendon healing can occur intrinsically, via proliferation
of epitenon and endotenon tenocytes, or extrinsically, by
invasion of cells from the surrounding sheath and synovium
(9). Epitenon tenoblasts initiate the repair process through
44
Altchek, David W.. <i>Foot and Ankle Sports Medicine</i>, Wolters Kluwer Health, 2012. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/unud-ebooks/detail.action?docID=2031739.
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LWBK1132-Ch04_p44-45.indd 44
Nicola Maffulli
proliferation and migration (10). Healing in severed tendons
can be performed by cells from the epitenon alone, without
relying on adhesions for vascularity or cellular support (11).
Internal tenocytes contribute to the intrinsic repair process
and secrete larger and more mature collagen than epitenon
cells (12). Although both fibroblasts in the epitenon and
internal tenocytes synthesize collagen during repair, it is pos-
sible that different cells produce different collagen types at
different time points. Initially, collagen is produced by epi-
tenon cells, with endotenon cells synthesizing collagen later
(13). The relative contribution of each cell type may be
influenced by the type of trauma sustained, anatomical posi-
tion, presence of a synovial sheath, and the amount of stress
induced by motion after repair has taken place (14).
Intrinsic healing results in improved biomechanics and
fewer complications. In particular, a normal gliding mecha-
nism within the tendon sheath is preserved (15). In extrinsic
healing, the scar tissue results in adhesion formation, which
disrupts tendon gliding (16). Different healing patterns may
predominate in particular locations. For example, extrinsic
healing tends to prevail in torn rotator cuffs (17).
Modulators of Healing
Matrix metalloproteinases (MMPs) are important regulators
of extracellular matrix remodeling, and their levels are altered
during tendon healing (18). Fluctuation in the levels of various
different MMPs suggests that these proteolytic enzymes play a
key role in the sequence of events that occurs during tendon
healing (19). Wounding and inflammation provokes release of
growth factors and cytokines from platelets, neutrophils, mac-
rophages and other inflammatory cells (20). These growth fac-
tors induce neovascularization and chemotaxis of fibroblasts
and tenocytes and stimulate fibroblast and tenocytes prolifera-
tion and synthesis of collagen (21).
Nitric oxide is a short-lived free radical, with many bio-
logic functions: It increases collagen synthesis by human
tenocytes in vitro, and also affects tenocyte adhesion (22,23).
Inhibition of nitric oxide synthase–reduced healing, result-
ing in decreased cross-sectional area and a reduced failure
load after tenotomy of rat Achilles tendons (24). Delivery
of nitric oxide using glyceryl trinitrate patches produces
beneficial effects in patients with Achilles tendinopathy at
6 months (25).
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In a rat Achilles tendon rupture model, peak nerve fiber for-
mation occurred between weeks 2 and 6, in concert with peak
levels of the neuronal isoform of nitric oxide synthase (26).
These nerve fibers presumably deliver neuropeptides which act
as chemical messengers and regulators, and may play an impor-
tant role in tendon healing. Substance P and calcitonin gene–
related peptide (CGRP) are pro-inflammatory and cause vasodi-
lation and protein extravasation (27,28). In addition, substance P
enhances cellular release of prostaglandins, histamines, and cyto-
kines (29). Peak levels of substance P and CGRP occur during the
regenerative phase, suggesting a possible role during this phase.
Limitations of Healing
Synovial sheath disruption at the time of injury or surgery
allows granulation tissue and tenocytes from surrounding tissue
to invade the repair site, leading to adhesion formation (30).
Exogenous cells predominate over endogenous tenocytes, allow-
ing the surrounding tissues to attach to the repair site resulting
in adhesion formation. Despite remodeling, the biochemical
and mechanical properties of healed tendon tissue never match
those of intact tendon. In spontaneously healed transected sheep
Achilles tendons, rupture force was only 56.7% of normal at
12 months (31). One possible reason for this may be the absence
of mechanical loading during the period of immobilization.
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Copyright © 2012. Wolters Kluwer Health. All rights reserved.
Altchek, David W.. <i>Foot and Ankle Sports Medicine</i>, Wolters Kluwer Health, 2012. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/unud-ebooks/detail.action?docID=2031739.
Created from unud-ebooks on 2019-09-05 10:54:05.
LWBK1132-Ch04_p44-45.indd 45
Chapter 4 ■ Basic Science of Tendon Healing      45
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