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L. Mota et al.
the most studied models of diabetic wound healing, both the
STZ-induced diabetic and the db/db murine models have limitations. While some authors argue that type 1 diabetes models are not ideal to study DFU, others claim that the wound
healing impairment observed in db/db mice may be more
related to other underlying abnormalities, such as obesity, different skin properties, and leptin pathway disruption, than to
diabetes. Other polygenic type 2 diabetic strains, namely, the
NONcNZO10 [354] and the TALLYHO [355] mouse models,
have been developed and reported to have wound healing
defects. Genetically modied rat models of diabetic wound
healing are also available. They include the models of type 2
diabetes, such as the Goto-Kakizaki (GK) nonobese and the
JCR:LA-cp/cp obese rats [356–358]. Although Otsuka LongEvans Tokushima fatty (OLETF) rats are typically models of
corneal diabetic wound healing, they have also been used to
study cutaneous diabetic wounds [359].
Of interest, as previously mentioned in the earlier sections
of this chapter, multiple mouse models of neuropeptide, neuropeptide receptor, and mast cell deciency have been developed and used in wound healing studies. Examples of murine
models that lack specic neuropeptides or neuropeptide
receptors involved in wound healing are the tachykinin 1
knock-out (TAC1KO) mice that lack substance P (SP) or
neurokinin A [19], neurokinin 1 receptor knock-out
(NK1RKO) mice that lack SP receptor [19], and neuropeptide Y (NPY) 2 receptor knock-out mice [88]. Other
neuropeptide- decient models exist but have yet to be used
in wound healing studies. On the other hand, multiple models of mast cell (MC) deciency are available and have been
employed to study the role of MCs in wound healing. The
most studied MC-decient models include Kit
sh/W-sh
mice [293, 299, 306, 321, 336]. The Kit
W/Wv
and Kit
W/Wv
W- -
mouse
model has truncated W and point-mutated Wv alleles, resulting in reduced Kit expression, severe MC deciency, and
other non-MC-related abnormalities, including neutropenia,
anemia, and lack of certain subpopulations of germ cells and
melanocytes. The Kit
W-sh/W-sh
model possesses an inversion
mutation upstream of the c-Kit promoter region, leading to a
selective reduction in Kit expression; therefore, in contrast
with the Kit
W/Wv
strain, the Kit
W-sh/W-sh
mouse has normal levels of other differentiated hematopoietic and lymphoid cells
[360, 361]. However, these mice also present other problems,
likely related to the reduced Kit expression, such as splenic
myeloid and megakaryocytic hyperplasia. In order to overcome such limitations, researchers have either performed
MC reconstitution experiments, as accomplished by Weller
and colleagues [299], or developed and used new strains of
Kit-independent MC-decient mice, including Cre
recombinase- mediated carboxypeptidase A3 (Cpa3Cre)
[320] or mast cell protease 5 (Mcpt5Cre) eradication [322].
However, the observed wound repair phenotypes differed
between the models used. Nonetheless, despite the inconsis-
tent results in normal noncomplicated wound healing, our
recent ndings implicate MCs in diabetic wound healing,
since skin MC degranulation is increased both in diabetic
human subjects and STZ-induced diabetic mice [336], suggesting that pharmacological blockade of MC degranulation,
rather than ablation of MCs, may be a useful tool to further
evaluate diabetic wound healing and potentially develop
treatments.
Not only different mouse models but also different wound
models have resulted in different wound healing outcomes,
complicating the predictability for translation into humans.
The most common wound models are full-thickness excisions or full-thickness incisions, created on the shaved dorsal
skin of the animal. Wounds can then be left exposed (healing
by secondary intention, which comprises greater wound contraction), dressed (dressings have the particularity of preventing excessive “dry” conditions and creating a “moist”
environment [362]), splinted (with the goal of minimizing
contraction [363]), or sutured (usually following incisional
wounds). While different models are used to address different scientic questions, for example, incisional sutured
wounds are often used as a tool for investigating scarring,
there is still little consensus regarding the ideal model for
diabetic wound healing.
A major caveat of the rodent models is their intrinsic anatomical and physiological differences to human skin and
wound repair. Compared to humans, rodents exhibit higher
epidermal appendage density with different hair follicles and
a distinct hair growth cycle and have thinner epidermis and
dermis, are “loose-skinned” animals, and heal more rapidly,
mostly by contraction with less reepithelization [364–367].
While splinting was developed as a strategy to minimize
wound contraction in rodents [363], with the goal of making
healing more comparable to humans, concerns that splinting
may alter the wound healing phenotype due to the mechanical tension created have been raised [323]. Another drawback of mice and rats is the limited number of wounds that
can be produced in each animal, often requiring the use of a
larger number of animals per experimental condition.
The most commonly used large animals in wound healing
studies are the rabbit and porcine models, and both heal more
similarly to humans than rodents. Rabbits are usually made
diabetic by Alloxan injections and pigs by STZ.Multiple
wounds can then be created either in the rabbit ear or in the
porcine dorsum. Unlike rodents and similarly to humans, the
rabbit ear skin is highly vascularized and is important for
thermoregulation [368–371]. Contrary to mice and rats, the
rabbit ear skin lacks panniculus carnosus, and therefore
wound repair occurs mostly via reepithelization rather than
contraction. In addition, when creating wounds, the cartilage
is usually kept intact, contributing to stent the wound open
and further minimizing contraction [30]. Another advantage
of using the rabbit ear model to study DFU is that it is rela-
9 Neuropeptides, Inammation, andDiabetic Wound Healing: Lessons fromExperimental Models andHuman Subjects
https://t.me/med1917
173
tively simple to create ischemic, neuropathic, and neuroischemic wounds, since the major blood vessels in the rabbit ear
and nerves are easy to view, access, and manipulate. Ischemia
is achieved by ligating the central and the rostral artery leaving the caudal artery and all the veins intact, whereas neuroischemia is created by ligating the central and rostral
arteries along with central and rostral nerve resection [31].
This allows studying diabetic wounds that present the two
most common long-term complications of diabetes, which
are also major risk factors for DFU development—neuropathy and ischemia.
The porcine dorsal skin also resembles human skin in
turnover time, epidermal and dermal layer thickness, skin
appendages (with the exception of eccrine glands), welldened rete pegs and dermal papillae, dense elastic bers,
similar collagen structure, abundant subcutaneous adipose
tissue, and lack of panniculus carnosus [365, 372, 373].
Differences include reduced dermal vascularity, absence of
eccrine sweat glands, and distinct distribution of apocrine
glands in the pig [372]. Transgenic pig lines have been
recently generated, including a pig model of permanent neonatal diabetes by introduction of a mutation in the insulin
gene [374]. The INS
C94Y
diabetic pig manifested hyperglyce-
mia soon after birth and signicantly reduced β-cell mass at
4.5months of age; however, no nervous tissue changes were
observed during the rst year [374], suggesting that the STZinduced diabetic pig model is preferred to study diabetic
wound healing.
It is clear that a high degree of phenotypic skin and wound
repair exists between animal species and that an ideal model
for diabetic wound healing has yet to be developed. Despite
their limitations, mice are likely to remain an essential tool to
investigate the mechanisms of diabetic wound healing [375,
376]. However, the consensus is that ndings should be
reproduced in multiple animal models.
As the diabetes epidemic continues to rise, it is expected
that its complications, namely, chronic nonhealing DFUs,
will also increase in number, severity, and economic burden.
Neuropathy and inammation are gaining increasing attention, and studies on the role of neuropeptides and immune
cells, such as mast cells and macrophages, in diabetes, obesity, cutaneous inammation, and wound repair are emerging. Genetically modied mouse models and invitro studies
help researchers mechanistically probe the diabetic wound
healing process, and conrmation in different animal models, such as the rabbit ear model, and in human skin specimens is extremely important to evaluate the relevance of the
ndings in preclinical studies. Neuropeptides and mast cell
degranulation inhibitors are promising targets in the development of novel therapeutic strategies for diabetic wound
healing, but further clinically driven translational research is
required to validate them.
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