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7 Physiology andPathophysiology ofWound Healing inDiabetes
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Regeneration oftheSkin andPeripheral
https://t.me/med1917
Nerves intheAdult
AlanZ.Yang, DanielaLee, DaniellaDennis,
andSamuelJ.Lin
8
Abstract
In response to severe injury to the skin or peripheral
nerves, adult mammals typically undergo an irreversible
repair process that results in contraction and the formation of non-physiologic scar tissue. However, recent
advancements with induced regeneration using biologically active scaffolds have demonstrated that it is possible
to intervene during the healing process to partially or
near-completely restore the physiologic function of damaged skin or peripheral nerves. The aim of these scaffolds
is to promote regeneration and minimize the contraction
and scar formation mediated by stromal broblasts. For
instance, some scaffolds appear to downregulate TGF-β
signaling, a key inductor of myobroblasts which promote contraction and scar formation. Two collagen-based
and three synthetic-based regenerative devices have been
approved by the Food and Drug Administration (FDA),
two for the regeneration of the skin and three for the
regeneration of peripheral nerves. Increasingly, these
devices are establishing themselves as a viable alternative
to autografting.
Introduction
Injury to the mammalian fetus is reversible during early
stages of gestation, and the spontaneous wound response is
capable of restoring the structure and function of the original
organ, a process called regeneration. In contrast, the unim-
paired response to severe injury in adult mammals is an irre-
Alan Z. Yang, Daniela Lee and Daniella Dennis contributed equally
with all other contributors.
A. Z. Yang · D. Lee · D. Dennis · S. J. Lin (*)
Division of Plastic and Reconstructive Surgery, Beth Israel
Deaconess Medical Center, Harvard Medical School,
Boston, MA, USA
e-mail: sjlin@bidmc.harvard.edu
versible repair process leading to the closure of the injured
site by contraction and formation of scar, a nonphysiological
tissue (Table8.1). The consequences of irreversible healing
at the organ scale are far-reaching: they typically result in an
essentially nonfunctional organ.
Numerous approaches have been investigated to restore
the loss of organ function in adults following irreversible
injury. These strategies include transplantation, autografting,
implantation of permanent prostheses, the use of stem cells,
in vitro synthesis of the organ, and regenerative medicine
[1]. The last of these strategies is also referred to as induced
organ regeneration, or the recovery of physiological structure and function of non-regenerative tissues in an organ
(also known as de novo synthesis) by the use of elementary
reactants, such as biologically active scaffolds, either
unseeded or seeded with cells.
There is accumulating evidence that the spontaneous
healing process of an injured organ in the adult mammal can
be modied to yield a partially or completely regenerated
organ. Regenerative medicine is an emerging eld of study
involving the implantation of biomaterials to facilitate formation (regeneration) of tissue invivo. This eld is undergoing rapid growth at this time, as evidenced by the observation
of regeneration or reported progress in ongoing research
efforts in a wide range of organs including the skin [2], conjunctiva [3], peripheral nerves [4], bone [5], heart valves [6],
Table 8.1 Methods of tissue healing
Type of tissue
Method of
healing
Spontaneous
regeneration
Repair Nonphysiological tissue
synthesized during
healing Examples
Physiological tissue that
restores function,
anatomy, and cellular
architecture
(scar) via tissue
contraction
Skin and myocardium
regeneration in
mammalian fetus,
replacement of amputated
appendage in certain adult
urodeles [35]
Transdermal skin wounds,
myocardial injury in adult
mammalian tissue
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. Veves et al. (eds.), The Diabetic Foot, Contemporary Diabetes, https://doi.org/10.1007/978-3-031-55715-6_8
135
136
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A. Z. Yang et al.
liver [7], articular cartilage [8], urological organs [9], and the
spinal cord [10].
The basic outline of a hypothetical mechanism for induced
organ regeneration has become clear. It is based on regenerative studies in three organs (the skin, conjunctiva and peripheral nerves), which started much earlier and have progressed
much further than research in other organs. From these studies a pattern has emerged, based on two observations: (i)
regeneration was successfully induced, at least partially,
when contraction was blocked, following grafting with a
class of scaffolds that were characterized by a highly specic
structure (collectively referred to as “regeneration templates”) and (ii) when a class of “inactive scaffolds” with
slightly different properties than their biologically active
counterparts was used, regeneration was thwarted and vigorous contraction ensued. The available data support the
hypothesis of contraction blocking as a plausible mechanism
for induced organ regeneration in the adult mammal. In
almost all such processes, the critical reactant supplied by
the investigators was a scaffold, a highly porous, degradable
macromolecular solid that has a specic contraction- blocking
activity as well as the ability to mimic the invivo environment, and particularly the stroma, of the organ.
In this chapter we present elements of a theory of induced
regeneration that is organ nonspecic. We proceed by discussing, in order, the macroscopic outcome of irreversible
healing in adults, the evidence for induced regeneration, the
association between contraction blocking and regeneration,
and a proposed mechanism for the regenerative activity of
certain scaffolds.
Most regeneration data available to date comes from acute
wound models that prove to be far more amenable to control
by the investigator than chronic wound models. When healing is unimpaired, the adult mammalian spontaneous healing
response to severe acute injury is contraction and scar synthesis. Nevertheless, the results of recent clinical studies
indicate that the discussion in this chapter is relevant to
severe chronic wounds. Increasingly, FDA-approved versions of collagen-based devices are demonstrating efcacy
in the clinical management of these injuries [11–15]. Detailed
indications for their use in the treatment of chronic wounds
(classied by both anatomy and pathology/diagnosis) have
been presented [16].
The majority of available induced regeneration data
described in this chapter comes from the skin [17–24] and
peripheral nerve models [25–34]; these are two organs that
have been studied extensively. In particular, skin wounds can
be studied with relative ease, and for this reason studies of
skin wound healing comprise the bulk of quantitative wound
healing data in the literature. In organs other than the skin,
wound healing has been studied mostly qualitatively.
Nevertheless, the observations made so far form a body of
evidence that suggests certain strong similarities, as well as
identifying differences, between wound healing in skin and
in less studied organs, such as peripheral nerves. Taken
together, the wealth of regenerative data for these two very
different organs has aided the development of a general theory of induced regeneration that may have value in studies of
induced regeneration in other organs as well [1].
Irreversible Injury intheSkin andNerves
The complex inammatory response of the adult mammal to
injury is elucidated by ongoing research at the cellular and
molecular level. While the formation of an accurate mechanistic perspective of wound healing is essential both in
understanding the effect of current clinical treatment and in
the development of emergent therapies, an examination of
the macroscopic outcome of healing also provides a uniquely
valuable viewpoint. An introductory phenomenological discussion of spontaneous wound healing at the tissue level provides a framework that forms a focus for future discussion of
detailed cellular/molecular mechanisms and facilitates the
derivation of concepts and rules of induced regeneration that
may conceivably apply to almost any organ in the body.
Macroscopic Outcomes ofHealing: Repair vs.
Regeneration
When exposed to injury, in the form of either acute trauma or
chronic insult, the organism mounts a spontaneous wound
healing process that typically closes the discontinuity in
organ mass caused by the injury in a matter of days. Two
macroscopic outcomes to injury have been observed experimentally: regeneration and repair. These fundamentally different processes are clearly distinguished by the identity of
tissue present in the nal state, that is, the newly synthesized
tissue that closes the injured site. In the early mammalian
fetus and in many species of amphibians, wound healing is
largely reversible and proceeds via spontaneous regenera-
tion, a process that restores the structure and physiological
function through synthesis of the missing organ structures
[1]. Certain adult urodeles exhibit an impressive capacity for
spontaneous regeneration: replacement of an amputated
appendage occurs by direct outgrowth of the severed crosssection (epimorphic regeneration), a reversible process [35].
In clear contrast, severe injury to normal adult mammalian tissue typically results in an irreversible healing response.
Spontaneous healing of severe skin wounds proceeds via
repair, in which the wound closes with a combination of tissue deformation and translation (collectively referred to as
contraction) and synthesis of a nonphysiological tissue (scar)
in place of the normally functioning tissue that has been
injured [1]. By replacing the lost organ mass with scar, the
basement membrane
Skin
Perpheral nerve
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137
injured organ is condemned, while the organism is spared as
a result of the healing process. The immediate consequence
of irreversible injury is a loss of normal organ function. Skin
injury may have additional detrimental effects, such as loss
of mobility and lack of social acceptance, e.g., following formation of disguring scars from burns. It appears that nearly
every adult mammalian organ can be injured irreversibly and
the extent of irreversibility seems to depend both on the identity of the tissue injured and the severity of the injury [1].
Regenerative Similarity. TheTissue Triad
Standard pathology texts describe three generic tissue types
that comprise the majority of organs in the body: epithelia,
basement membrane, and stroma [1, 36–38] (Fig. 8.1).
Collectively, we will refer to these three tissue types as the
tissue triad for a specic organ. This classication provides a
useful framework for comparing the regenerative capacity of
specic tissue types from one organ to another. The composition of each member of the triad is markedly different.
Epithelial tissue forms a completely cellular covering on
every surface, tube, and cavity in the body, performing a
wide array of vital functions including protection, secretion,
absorption, and ltration. As epithelial tissue is devoid of
extracellular matrix (ECM) and blood vessels, it is sustained
by the diffusion of nutrients from the underlying vascular
connective tissue, or stroma. Epithelia are separated from
underlying stroma by the basement membrane (basal lamina), a very thin, noncellular tissue layer, comprising exclusively ECM.The stroma is a connective tissue layer that is
vascularized, containing both cells and ECM.
epidermis
myelin
sheath
dermis
Fig. 8.1 The tissue triad structure in the skin and peripheral nerves.
The basement membrane (basal lamina), a thin noncellular layer consisting of extracellular matrix, separates the cellular, nonvascular epithelia (epidermis, myelin sheath) from the stroma (dermis, endoneurium)
which contains cells, ECM, and blood vessels. Epithelia and the basement membrane regenerate spontaneously; stroma does not. Adapted
from [1]
endoneurium
The skin, as one example, consists of the epidermis (epithelia) attached to the basement membrane and the underlying dermis (stroma). Considerable evidence from peripheral
nerve studies indicates that Schwann cells function as epithelial cells following synthesis of a completely cellular layer
(myelin sheath) around axons [39]. Nerve bers (Schwann
cell-axon units) are attached to a basement membrane that
separates them from the outlying endoneurial stroma, a tissue consisting of a vascularized extracellular matrix. Further
evidence for the epithelial nature of the myelin sheath comes
from the observed polarity of Schwann cells which is very
similar to that of keratinocytes, the epithelial cells that form
the epidermis in the skin. In each case, one epithelial cell
surface is rmly attached to a basement membrane, and
another is part of the epithelial tissue, endowed in each case
with function unique to the respective organ that characterizes the epidermis (in the case of the skin) or the nerve ber
insulation of peripheral nerves [39].
Tissues that are “regeneratively similar” appear in different organs yet share a common spontaneous healing response,
be it regeneration or repair. The spontaneous healing behavior of each layer of the tissue triad in skin and peripheral
nerves is well documented and will be briey reviewed.
Provided the stroma is still intact to facilitate epithelial
cell spreading, injury to the epithelial layer of either of the
two organs (the epidermis in the skin and myelin sheath in
peripheral nerves, respectively) results in spontaneous regeneration of the injured tissue by remaining epithelial cells in
the defect [1, 40–43]. Following nerve crushing with myelin
disruption but with no injury to the endoneurium, the myelin
sheath regenerates spontaneously, and no contraction is
observed. Similarly, epidermal excision is a reversible injury
that closes exclusively by spontaneous regeneration rather
than contraction. The epidermis in the skin and the myelin
sheath in peripheral nerves exhibit spontaneous regeneration, a reversible healing response leading to a full recovery
of structure and function, and are therefore regeneratively
similar [1]. Injuries that interrupt the continuity of the basement membrane in both organs without injuring the stroma
also exhibit spontaneous regeneration by epithelial cells;
basement membranes are regeneratively similar in the two
organs. However, when a wound is severe enough to cause
injury to the stroma of either organ (the dermis in skin or the
endoneurial stroma in peripheral nerves), the organism
achieves wound closure by a combination of contraction and
scar synthesis (irreversible healing response) [44]. The dermis and non-neuronal peripheral nervous tissue, such as the
endoneurium, heal by repair; since they are both nonregenerative, they are considered to be regeneratively
similar.
In summary, when the spontaneous regenerative capacity
of corresponding tissue types in the skin and peripheral
nerves is directly compared, a useful similarity emerges [1]:
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A. Z. Yang et al.
epithelia and the basement membrane are regeneratively
similar tissue layers, exhibiting a reversible healing response
even in the case of severe injury. Likewise, the stroma in both
organs is distinctly non-regenerative. Hence, the central
objective of induced organ regeneration is the synthesis of
the non-regenerative stroma.
Experimental Considerations
Importance ofanAnatomically Well-Dened
Defect
The appropriate experimental volume for studies of induced
organ regeneration is the anatomically well-dened defect
[1]. The above discussion of the differential regenerative
capacity of the various layers of the tissue triad calls for an
experimental injury that is free of non-regenerative tissue. In
this manner, the effects of an exogenous regenerative agent
on the potential synthesis of non-regenerative tissue can be
evaluated without ambiguity. In addition, the experimental
volume should also have well-dened anatomical boundaries
to reduce contributions from extraneous healing processes
occurring elsewhere in the organ (e.g., caused by collateral
damage during the surgical procedure) and to improve the
reproducibility of the surgical protocol from one animal to
the next as well as between independent laboratories. The
treatment of the defect should include the prevention of loss
of extravascular tissue uid (exudate), which contains important growth factors and regulators that are crucial both to
regeneration and to repair. Inability to prevent exudate loss
from the injured site radically affects the outcome of both
spontaneous and induced healing processes in both the skin
and peripheral nerves [45–47]. Physical containment is also
necessary to prevent detrimental extraneous processes, such
as bacterial infection in the skin, from interfering with the
outcome of the healing response.
For studies of induced regeneration in the skin, the most
widely used well-dened defect is the dermis-free fullthickness wound in the rodent or swine. In the case of peripheral nerves, the fully transected peripheral nerve in the rat or
mouse has been studied extensively [1]. Both the introduction of various grafts or sheet-like covers to skin defects and
tubulation to transected nerves using a variety of materials
typically imparts signicant activity that either assists or hinders regeneration; their use must be controlled carefully.
Synthetic Protocol: InVitro or InVivo?
A detailed comparison of the synthetic regeneration processes carried out in vitro and invivo shows that in studies of
the skin and peripheral nerves, various protocols for invitro
synthesis have so far resulted largely in the formation of epithelia and the associated basement membrane but not the
physiological stroma. In contrast, several protocols conducted invivo have yielded not only the physiological epithelia and basement membrane but a near-physiological
stroma as well. The following section highlights these
observed cases of induced regeneration.
Overview ofInduced Organ Regeneration
Evidence ofInduced Organ Regeneration in
Adults
Starting in the early 1970s, studies from the Fibers and
Polymers Laboratory at Massachusetts Institute of
Technology (MIT) have shown that the adult mammal can be
induced to regenerate selected organs that have been accidentally lost or excised [48]. In every case, the excised adult
organ in question did not regenerate spontaneously; that is,
in the absence of experimental intervention that cancels the
effects of wound contraction, the adult excised site generally
closed spontaneously by contraction and scar formation
rather than by regeneration. The organs in question were
induced to regenerate partially with the aid of certain insoluble substrates (scaffolds) that were optionally seeded with
cells. The development of these scaffolds, or highly porous
macromolecular networks, in the 1980s marked the earliest
years of the eld of tissue engineering.
The parts of the body with the most extensive data and
understanding on induced organ regeneration are the skin
and peripheral nerves [49]. The most recent data with other
organs from the work of several investigators include other
ectodermal organs, heart, appendages, liver, reproductive
organs, and eyes [50–55]. Induced organ regeneration data
obtained from the Fibers and Polymers Laboratory at MIT
included three anatomical sites, which were induced to
regenerate partially including (1) full-thickness skin wounds,
with epidermis and dermis completely excised, in the adult
guinea pig, adult swine, and adult human; (2) full-thickness
excision of the conjunctiva, with complete excision of the
stroma, in the adult rabbit; and (3) the fully transected rat
sciatic nerve, with stumps initially separated by a gap of
15mm (later 22mm and recently 30 mm). A summary of
induced regeneration data for the constitutive tissues of each
organ is presented in Table8.2.
Observations of induced regeneration in adults made over
the last several decades have been tested repeatedly by morphological and functional tests, as follows: (a) conrmation
of the partial regeneration of the skin (including both a dermis and an epidermis) with hair follicles and sweat glands
was made by histological, immunohistochemical, ultrastructural, and functional studies [17–19, 56]; (b) conrmation of
8 Regeneration oftheSkin andPeripheral Nerves intheAdult
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Table 8.2 Constitutive tissues of skin, peripheral nerves, and conjunctiva that were induced to regenerate in adults
Organ
Skin (guinea
pig. swine,
human) (I)
Peripheral
nerve (mouse,
rat, cat,
monkey,
human)
Conjunctiva
(rabbit)
Adapted from: Yannas [1]
Regeneration
observed
Keratinized
epidermis,
basement
membrane, dermis,
nerve endings,
blood vessels
Myelin sheath,
nerve bers (Large
and small
diameter), blood
vessels,
endoneurial
stroma?
Epithelia,
conjunctival stroma
Regeneration
observed
Appendages
(e.g., hair
follicles, sweat
glands)
Regeneration
not studied
Endoncurial
stroma?
Perineurium
Basement
membrane
139
capillary loops
the regeneration of the conjunctiva (including the conjunctival stroma) was made using histological data [34]; (c) conrmation of the regeneration of peripheral nerves was made
using both morphological and functional (electrophysiological and neurological) data [25–32, 57]. More recent studies
within the past decade have further elucidated the biochemical mechanisms behind these observations [58–60].
The available evidence in the above studies strongly supports the conclusion that these severely injured anatomical
sites were not closed by contraction and scar formation. The
regenerated skin was histologically and functionally different from scar and identical to the physiological skin in almost
all respects, including a physiological epidermis, wellformed basement membrane, well-formed capillary loops at
the rete ridges of the dermal-epidermal junction, nerve endings with conrmed tactile and heat-cold feeling, hair follicles, sweat glands, and a physiological dermis. Evidence for
the induced regeneration of the partial skin is presented in
Fig. 8.2, and the kinetics of this process are presented in
Fig. 8.3. The supportive data for induced regeneration of
peripheral nerves is presented in Fig.8.4.
Clinical Experiences withCollagen-Based
Scaolds
The clinical signicance of induced regeneration studies is
readily apparent. Two collagen-based and three syntheticbased regenerative devices have been approved thus far by
the Food and Drug Administration (FDA), two for the regeneration of the skin and three for the regeneration of peripheral nerves (Table 8.3). Increasingly, these devices are
establishing themselves as a viable alternative to
autografting.
75 mm
Fig. 8.2 Evidence for induced regeneration of the skin using collagenglycosaminoglycan scaffold. (Top) A schematic diagram of physiologically normal skin shows characteristic rete ridges at the dermal-epidermal
junction and is contrasted with that of partially regenerated skin in the
swine, following grafting with the keratinocyte-seeded dermal regeneration template scaffold (bottom). The new skin is not scar, as evidenced by the presence of rete ridges and capillary loops inside the
ridges. Immunostaining for Factor VIII 35days after grafting revealed
that capillary loops had formed in the rete ridges of the regenerated
dermis (arrow) similar to those observed in physiological skin. Bar:
75 μm. (Top, from Burkitt HG, Young B, Heath JW. Wheater’s
Functional Histology. Edinburgh, Scotland: Churchill Livingstone;
1993. Bottom, from Compton CC, Butler CE, Yannas IV, Warland G,
Orgill DP.Organized skin structure is regenerated invivo from collagenGAG matrices seeded with autologous keratinocytes. J Invest Dermatol.
1998;110:908–916)
Skin Regeneration Devices
In 1996, the FDA approved the Integra Dermal Regeneration
Template® (DRT, as previously described), as an urgent treatment modality for patients suffering from severe burns.
Since that time, DRT has been approved by regulatory agencies in several other countries. In 2002, the FDA approved
DRT for a second application: restorative or reconstructive
surgery of skin scars. The efcacy of DRT for the induced
regeneration and treatment of chronic and pathological deep
skin ulcers (chronic skin wounds) has been established, and
modied versions of this device have been designed specically for the treatment of these wounds. Over 440 clinical
cases of DRT use have been cited thus far.
Reports have demonstrated the efcacy of the DRT in
healing foot wounds in diabetic patients. A study of 30 diabetic patients who underwent surgical debridement of diabetic foot wounds followed by grafting with DRT reported
an 86.7% healing rate and a signicantly more distal level of
140
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E
D
Day 14
E
D
Day 18
E
D
Day 25
Fig. 8.3 Kinetics of early skin synthesis in the swine with collagenglycosaminoglycan scaffold between days 14 and 25. In this case, the
collagen-glycosaminoglycan scaffold was seeded with autologous
keratinocytes before grafting onto full-thickness skin wounds in the
swine. Newly formed epidermis is denoted as E and the neodermis is
denoted as D. The scaffolds degrade with a half-life of 15 days.
(Reproduced from Butler CE, Orgill DP, Yannas IV, Compton CC.Effect
of keratinocyte seeding of collagen glycosaminoglycan membranes on
the regeneration of skin in a porcine model. Plast Reconstr Surg.
1998;101:1572–1579)
amputation (p<0.003) [12]. A retrospective review of 105
patients with diabetic foot ulcers receiving dermal regeneration template for lower extremity salvage indicates DRT as a
viable option for a stable closure of these wounds in patients
with low risk of amputation [15]. DRT efcacy for patients
with an already high risk of amputation (based on available
blood supply and presence of infection) seems to be limited.
In another study, 307 patients received DRT grafting as a
method of closure for select refractory pathological wounds.
Patients were treated predominantly in an outpatient setting
with 92% healing with two applications or less [61].
More recently, in 2015, the FDA approved the PolyNovo
Novosorb Biodegradable Temporizing Matrix (BTM) for the
treatment of second-degree burns and acute or chronic
wounds. Unlike DRT, which is collagen-based, BTM is a
synthetic, biocompatible, and biodegradable device that
A. Z. Yang et al.
induces dermis to grow within a polyurethane matrix. A
comparative study using porcine wound models showed that
BMT was less prone to infection and aggressive wound contraction as opposed to DRT [62]. When studied in mice, the
two devices yielded similarly high-quality results, except
with more neovascularization, tissue growth, and inammation in the BMT group [63, 64]. Within the past few years,
there have been increasing reports of the successful use of
BMT in various clinical settings [65–67].
Using templates for skin regeneration has the potential to
replace the need for a full-thickness autograft in a patient
population already suffering from large and deep wounds, in
those patients where a simplied reconstruction can be
designed, and in those in whom less scarring may be desired
[68].
Peripheral Nerve Regeneration Devices
In 2001, Neuragen®, an early version of the collagen-based
tubular devices that have been described above, was approved
for the regeneration of peripheral nerves to treat individuals
suffering from paralysis of the extremities. Further studies
have shown that, as with studies of skin regeneration, the
structure of collagen requires extensive optimization in order
to increase the regenerative activity of this natural protein.
One such study identied an optimized version of the device:
a cell-permeable collagen tube with controlled degradation
rate, higher cell-permeability, and an overall superior quality
of regeneration. A multicenter human trial (using randomized, blind, parallel groups) compared the NeuraGen™ nerve
guide to direct suturing repair (control group), which is the
current clinical gold standard for treatment of short-gap injuries [69]. The study followed 32 patients who had complete
traumatic nerve injuries to the median and/or ulnar nerves in
the distal third of the forearm over 2years. Patients treated
with the collagen devices had signicantly lower postoperative pain scores than controls at early time points and at the
completion of the study demonstrated sensory and motor
function performance equal to the direct repair group.
Synthetic tubular devices were also approved by the FDA
for the regeneration of peripheral nerves after their clinical
trials, including Polyganics’s Neurolac in 2005 and GEM’s
Neurotube in 1999 [70–74]. However, results for synthetic
nerve guides are more mixed due to the slower rate of recovery, sensory changes, and other uncommon complications.
The Neurolac specically has had recent data showing issues
with biocompatibility, swelling, degradation rate, rigidity,
patient complaints, and automutilation [75–77]. Taken
together, the results indicate that the nerve guide tube is a
realistic alternative to conventional end-to-end nerve repair
[78]. However, the devices require extensive redesign in
order to optimize the regenerative activity of collagen to
make it useful at longer gap lengths, more biocompatible,
and have better outcomes compared to autografts [79].
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