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8 Regeneration oftheSkin andPeripheral Nerves intheAdult
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Normal Nerve
A fiber Peak
Regenarated Nerve
A-fiber Peak
Regenarated Nerve
B-fiber Peak
Stimulas
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Fig. 8.4 Evidence of induced regeneration of the peripheral nerve
using collagen-based nerve regeneration template. Histological micrographs of nerve tissue postxed with osmium tetroxide and stained with
toluidine blue. The magnication for each micrograph is the same;
scale bars, 10μm. (a) Tissue regenerated through the midportion of a
matrix-lled large-pore collagen (LC/M) implant at 30weeks. Note the
large number of axons in this cross-section with the majority of axons
being small in diameter. The largest axons have diameters of approximately 7μm. Many Schwann cells are visible with some actively participating in myelination. The blood vessel that is visible in this
micrograph was characteristic of the caliber of most vessels present in
the regenerated tissue. (b) Tissue regenerated through the midportion of
a LC/M implant at 60 weeks. Compared to 30 weeks, the axons are
much larger (diameters up to 12μm) and have thicker myelin sheaths.
Also, fewer small diameter axons are visible. Few nonmyelinating
Schwann cells are visible at 60weeks. (c) Normal nerve tissue from the
level of the lesion is shown as a control. Note the number of large diameter bers and the thickness of the myelin sheaths compared to the
Limitations ofCollagen-Based Scaolds
asRegenerative Devices
As stated earlier, these clinically approved devices do not
induce regeneration of entirely normal organs. For example,
skin regenerated by the use of collagen-based scaffolds may
lack several appendages (i.e., sweat glands, hair follicles),
although there have been increased improvements with such
outcomes [56]. Future work may focus on speeding the rate
of cell migration and angiogenesis within the device (angio-
regenerated nerves. (d) Typical oscilloscope tracings of A-ber and
B-ber compound nerve action potentials for normal sciatic nerve and
nerve regenerated through a LC/M implant at 60weeks postimplantation. The A-ber peak for the regenerated nerve has a signicantly
smaller amplitude than the normal nerve control. This was typical of all
regenerated groups. In contrast, the conduction velocity of the regenerated nerve, although signicantly slower than normal, was approaching
normal values. The latency is measured along the x-axis from the stimulus to the peak and then combined with the constant distance between
electrodes to determine conduction velocity. The dashed line indicating
the B-ber peak has been added on to the tracing for reference. Note
that the normal nerve tracing has no visible B-ber peak. In the regenerated nerves, the B-ber peak was similar and visible in all groups.
(Reproduced from Chamberlain LJ, Yannas IV, Hsu HP, and Spector
M. Collagen-GAG Substrate Enhances the Quality of Nerve
Regeneration through Collagen Tubes up to Level of Autograft. Exp
Neurol 1998: 154: 315–329)
genesis peaks in 7–14days in a murine model) with the goal
of improving regeneration, increasing the safety prole of
the device, and decreasing the risk of infection. Peripheral
nerves that regenerated with tubular collagen-based scaffolds exhibit conduction velocity proles that are somewhat
slower and weaker than with normal nerves (although scaffolds that have been recently synthesized, but are not commercially available, improve signicantly on the clinically
available device).
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Table 8.3 Summary of FDA-approved regeneration devices
Device name Approval year Indications Clinical results
Skin
Integra Dermal
Regeneration Template®
(DRT)
PolyNovo Novosorb
Biodegradable Temporizing
Matrix (BTM)
Peripheral Nerve
Neuragen
Polyganic’s Neurolac 2005 Severe peripheral nerve
GEM’s Neurotube 1999 Severe peripheral nerve
®
1996 and 2002 Severe burns,
reconstructive surgery,
skin ulcers
2015 Second-degree burns,
acute/chronic wounds
2001 Severe peripheral nerve
injury
injury
injury
• 440 clinical cases cited
• 86.7% healing rate in diabetic patients with foot wounds [12]
• Viable option for stable closure of wounds in low-risk patients
[15]
• Synthetic, biocompatible, biodegradable
• Less prone to infection and aggressive wound contraction
compared to DRT [62]
• Successful use in various clinical settings
• Signicantly lower postoperative pain scores than control
group [69]
• Sensory and motor function performance equal to direct
repair group [69]
• Issues with biocompatibility, swelling, degradation rate,
rigidity, patient complaints, and automutilation [77]
• More mixed results due to slower rate of recovery, sensory
changes, and uncommon complications
A. Z. Yang et al.
The Defect Closure Rule
Careful review of the literature suggests that no more than
three distinct processes are used to close an anatomically
well-dened defect (dermis-free defect) in skin wounds:
contraction originating from the edges of the defect, scar formation by stromal broblasts (followed by epithelialization
of scar), and regeneration.
Kinetic data extending continuously over lengthy periods
are rarely available from regeneration experiments and often
difcult to compare from one study to another. One approach
to studying the regenerative activity of exogenous agents on
the healing process is to establish two standardized conguration states (e.g., initial and nal state) and to evaluate the total
change that is caused during this xed period in the healing
process. In the absence of kinetic data, the defect closure rule
bridges the gap by presenting a quantitative description of the
healing process through comparison of snapshots of the initial and nal stages of wound healing. The initial state of conguration is the anatomical description of the recently
generated defect, characterized by the loss of structural continuity in one or more tissues, beginning of exudate ow, and
loss of physiological homeostatic control of the organ. As
defect healing progresses, the original area, A0, eventually
diminishes spontaneously due to one or more of the three processes mentioned. The area of the closed defect (the closed
wound) comprises tissues that result either from contraction
(%C), scar formation (%S), or regeneration (%R), and the
conguration of the nal state can be described by the following simple relation, called the defect closure rule:
Equation 8.1 states that the defect closure in any organ
can be described by only three outcomes: contraction, scar
(8.1)
formation (neuroma or brosis), and regeneration (partial or
total). For the idealized case of early fetal wound healing
(spontaneous regeneration), contraction and scarring are
absent (C, S = 0) and R = 100 (regeneration). For normal
defect closure in adult mammals following irreversible injury
(repair), regeneration is absent (R = 0) and C + S = 100
(repair).
The literature describes several assays, such as simple
measurements, histopathologic grading, biochemical testing,
and image analysis, that can be used to determine the conguration of the nal state (recently closed defect) [80].
Functional assays especially can be used to qualitatively
identify the physiological nature of the tissue and assist in
providing a quantitative measure of its incidence in the nal
state in terms of the numerical values of these three quantities (C, S, R). The defect closure rule may be interpreted as a
conservation principle: provided that the magnitude of two
individual terms have been determined, the magnitude of the
remaining process may be calculated. Defect closure data is
expressed using the following convention: [%C, %S, %R].
The defect closure rule is useful in evaluating the activity
of unknown reactants as inductive agents of regeneration.
This quantitative description of the structure and function of
the injured organ at its nal state has shed interesting light on
the relationship between the characteristic elements of the
adult healing response (contraction or scar synthesis, or
both) and regeneration.
Prevalence ofContraction During Spontaneous
Healing
In the skin, the defect closure rule has been used to present
data on the conguration of the nal state following spontaneous healing of the anatomically well-dened defect
(dermis- free defect) in several species. In all cases of sponta-
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143
neous healing of full-thickness skin wounds, it was ensured
that the contribution of regeneration to defect closure was
negligible (R=0). Skin contraction was measured directly as
the reduction in initial wound surface area by inward (centripetal) movement of the skin from the margins of the
wound. Scar formation was frequently studied qualitatively
by histology. In a few cases, scar formation was conrmed
quantitatively by the use of laser light scattering, which was
used to measure the average degree of collagen ber orientation and thereby deduce on the identity of the tissue present
in the healed injury site [81]. More recently, various advanced
imaging techniques, such as optical coherence tomography
and confocal microscopy, have allowed greater visibility of
the scar microstructure, allowing for both qualitative observations and quantitative spatial pattern analysis [82–84].
Values for the percentage of initial defect area closed by epithelialized scar (S) were determined using the simplied
defect closure rule for repair (S=100– C).
The contribution of the various methods of defect closure
in anatomically well-dened defects is species-dependent. In
rodents, where the integument is mobile, contraction is by
far the main engine of closure of skin wounds, while scar
formation has been shown to be quantitatively much less
important. The spontaneous healing of a full-thickness skin
wound in the guinea pig is characteristic of several rodents
and lagomorphs (rabbits) and results in the following nal
state conguration: [91, 9, 0] [85, 86]. In general, C>>S
and defect closure for adult rodents and rabbits reduces to
C≈100. Alternatively, the approximation of the nal state in
rodents is expressed as [100, 0 0]. In humans, where the
integument is tethered more securely onto subcutaneous tissues, contraction and scar formation contribute approximately equally to wound closure. Experimentally, the
spontaneous healing of full-thickness skin defects in the
human (R=0) results in a nal state represented by [37, 63,
0] [87].
In the absence of direct quantitative observations, histological analysis was used to describe the closure of the fully
transected peripheral nerve in the adult rat. Spontaneous
healing results in the reduction of the initial area of crosssections of nerve trunks by 95% with neuroma formation
(neural scar) accounting for the remaining 5%. The resulting
estimation of the nal state conguration was [95, 5, 0] [88,
89].
The contraction of a wide array of organs in response to
trauma is well documented in both animals and humans, yet
these reports are almost exclusively of a qualitative nature
[90–94]. With very few exceptions, the sole organ in which
contraction has been studied systematically to date is the
skin. Despite the dearth of widespread quantitative data, the
prevalence of contraction must not be overlooked; it appears
to be a critical outcome of the spontaneous healing response
throughout the adult organism.
The Antagonistic Relation Between Contraction
andRegeneration
The characteristic elements of the adult healing response
(contraction or scar synthesis, or both) must be controlled in
order for induced regeneration to occur. Extensive data,
including empirical data on the nal state of the defect in
response to various reactants, suggest that during healing of
a severe injury, contraction antagonizes regeneration [1].
Induced regeneration of the skin, peripheral nerve trunks,
and the conjunctival stroma was accompanied in each case
by direct observation of a signicant reduction in contraction
as a mode of defect closure. Conjunctival and peripheral
nerve regeneration studies were guided by earlier studies of
skin regeneration. The partial skin was rst induced to regenerate in the adult guinea pig. The spontaneous healing behavior of the untreated dermis-free defect in this organism
resulted in a nal conguration of [91, 9, 0]. Grafting an
identical well-dened skin defect with a highly porous copolymer of type I collagen and chondroitin 6-sulfate (referred
to as a dermis regeneration template, DRT) (Fig.8.5a) abolished scar synthesis and led to the regeneration of a small
mass of dermis and subsequent synthesis of an overlying epidermis within the defect. In the context of the defect closure
rule, the regenerative activity of the cell-free DRT on the
conguration of the nal state [1] was as follows:
In addition, the DRT led to a signicant delay in wound
contraction over 25days.
When a DRT seeded with keratinocytes (KC) was grafted
into an identical defect, the result was much more
pronounced:
KC-seeded DRTs accomplished rapid wound closure
through the partial regeneration of the skin (simultaneous
synthesis of a physiological dermis and epidermis, described
earlier) and completely arrested contraction at 35–40 days
[17].
The cell-free DRT that induces partial skin regeneration
comprises the regenerative component of the two-layer
device (Integra Dermal Regeneration Template (DRT)®)
approved by the FDA for the restoration of a physiological
epidermis and dermis in patients suffering from severe burns
as well as those undergoing plastic and reconstructive surgery of the skin, as described in an early study [19] and
reviewed recently [95].
Growth factors [96, 97], epidermal cell suspensions, and
cell sheets [98] exhibited negligible regenerative activity
when added to full-thickness skin wounds in other rodent
models. These reactants did not signicantly alter the conguration of the nal state or the extent of contraction delay.
Similarly, a number of synthetic polymer scaffolds [99, 100]
92 80 89 011,, ,, DRT
91 90 28 072,, ,, DRTKC
144
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A. Z. Yang et al.
Fig. 8.5 Induced regeneration of the dermis and peripheral nerve using
scaffold composed of type I collagen and chondroitin 6-sulfate. (a, top)
A scaffold that has induced regeneration of the dermis in animals and
humans. Composition: graft copolymer of type I collagen and chondroitin 6-sulfate. Scanning electron micrograph. Pore channel orientation is almost completely random. Average pore diameter, 80 μm
(courtesy of E.Soller, MIT). (b, bottom) Peripheral nerve was induced
failed to induce physiological dermis (or skin) regeneration.
These observations focus attention on the mechanism of
scaffold regenerative activity, to be discussed later.
Quantitative studies of induced regeneration of peripheral
nerves were conducted in the adult rat. The spontaneous
healing behavior of the untreated transected peripheral nerve
in this organism resulted in a nal conguration of [95, 5, 0]
that was estimated using histological analysis. Insertion of
the fully transected nerve stumps into a silicone tube lled
with a collagen-based tubular regeneration template (referred
to as a nerve regeneration template or NRT) resulted in
reduced contraction (as determined by histological analysis
of cross-sectional areas of regenerates) and partial regeneration over a 10-mm-gap length [31, 32]. Contraction was
abolished and the quality of regeneration improved signicantly when the NRT was used in conjunction with a degradable collagen tube. In the context of the defect closure rule,
the regenerative activity of the NRT in each experimental
conguration can be evaluated by inspecting the estimated
characteristics of the nal state, as follows (the arrow indicates the change observed following use of the scaffold):
95 50 53 047,, ,, NRTinside silicone tube
95 50 00100,, ,, NRTinside collagen tube
The relative importance of each method of defect closure
(C, S, and R) changes during animal development. A sharp
change occurs during the fetal-adult transition in mammals
(roughly during the third trimester of gestation), in which
contraction replaces regeneration as the dominant method of
to regenerate across a 15-mm-gap (and eventually longer gaps) in the
rat sciatic nerve using this scaffold as a bridge between the two stumps
inside a silicone tube. In later studies the chemical composition of this
scaffold was changed to GAG-free type I collagen. Pore channel orientation along the major nerve axis. Scanning electron micrograph.
Average pore diameter, 20 μm [1]. Yannas I V. Tissue and Organ
Regeneration in Adults. NewYork: Springer; 2001
closure [101–103]. Similarly, as amphibian (frog) development progresses, contraction becomes a more prominent
method of wound closure, as regeneration recedes and scar
formation becomes more evident [58, 104, 105].
While scar has been widely considered the key barrier to
regeneration in adults, quantitative study reveals that contraction is the dominant mode of spontaneous closure in the
skin and peripheral nerve defects. Studies of induced regeneration in the skin, peripheral nerves using analogs of the
extracellular matrix, indicate that scar formation is a process
that is secondary to contraction: in studies of induced regeneration in these organs, when contraction was even slightly
inhibited, scar formation was totally abolished [1].
95 50 53 047,, ,,
95 50 00100,, ,,
Suppression of contraction in certain cases of impaired
healing, e.g., following use of pharmacological agents, such
as steroids was not accompanied by regeneration, indicating
that suppression of contraction alone did not sufce to induce
regeneration [1].
The available evidence supports the theory that selectively suppressed contraction in adult defects is required, but
not sufcient to induce regeneration of the skin and periph-
92 80 89 011,, ,, DRT
91 90 28 072,, ,, skin,DRT KC
→
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peripheral nerve,
NRTin silicone tube
peripheral nerve,
NRTin collagen tube
0
di
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eral nerves. This can be expressed in the context of the defect
closure (Eq.8.1) rule as follows:
00
This condition describes an antagonistic relationship
between contraction and regeneration in the closure of a
defect. It suggests that successful induced regeneration strategies consist of reactants that block contraction without
blocking other aspects of the healing process.
an
f
(8.2)
Repair: Mechanism ofContraction
Similarities in the mechanistic hypotheses for inducing
regeneration of the skin and peripheral nerves originate in
their common response to irreversible injury. Both organs
spontaneously respond to injury by recruiting contractile
cells that, if not properly suppressed, drive closure of the
defect by contraction and scar synthesis rather than by regeneration. Contraction of skin defects starts from a cell cluster
at the edge of the defect and later extends across the entire
defect area. In peripheral nerves, contraction primarily
results from the activity of a circumferential sheath of contractile cells.
The Contractile Fibroblast Is theMain Cell Type
Associated withContraction
The well-documented, macroscopic contraction that drives
the closure of skin defects nds its origin at the cellular scale,
arising from the individual contribution of contractile forces
generated by differentiated myobroblasts [106–113]. The
current consensus is that myobroblasts (MFB) that are
present in granulation tissue following skin wounding derive
directly from broblasts and comprise an intermediate, contractile, cellular phenotype between the broblast and the
smooth muscle cell. There is also evidence that undifferentiated broblasts may contribute to macroscopic contraction
by applying traction to the ECM very soon after coming into
contact with it [93, 109, 114–118].
In response to external tension, broblasts exert sustained
isometric force on their surrounding environment via a Rho/
Rho-kinase (ROCK)-mediated, actomyosin contractile apparatus [119–121]. This three-dimensional, transcellular structure consists of bundles of actin and non-muscle myosin
microlaments called “stress bers.”
Of the many ultrastructural and biochemical factors that
distinguish myobroblasts from their broblast precursors,
the most useful operational distinction of MFB differentiation is the expression of the α-smooth muscle actin (α-SMA)
phenotype [93, 114, 115]. Stress bers of immature myobroblasts (called proto-myobroblasts) contain only betaand gamma-cytoplasmic actins [93]. Additionally,
differentiated myobroblasts exhibit stress bers typically
arranged parallel to the long axis of the cell, nuclei which
consistently show multiple indentations or deep folds, and
two cell-matrix adhesion macromolecules (vinculin and
bronectin) [122, 123].
Simplistically, the myobroblast differentiation process
can be described as a positive feedback loop that requires the
concurrent action of at least three factors: the cytokine transforming growth factor-beta1 (TGF-β1), the presence of
mechanical tension, and the ED-A splice variant of cellular
bronectin (an extracellular matrix component) [115].
Fibroblasts respond to the development of mechanical tension by upregulating TGF-β1 production and expressing the
α-SMA isoform; in turn, α-SMA expression strengthens the
contractile apparatus and increases tension development
[115]. Recent work suggests that mature myobroblasts in
skin granulation tissue link their cytoskeletons together
using cadherin proteins, which allow them to generate even
higher levels of force to drive wound closure [124].
Mechanism ofScaold Regenerative Activity
Structural Determinants ofScaold Regenerative
Activity
Scaffolds that induce regeneration of the partial skin
(Fig. 8.5a) possess a highly specic structure that is distinctly different in pore structure and degradation rate from
scaffolds that regenerate peripheral nerves (Fig.8.5b). The
nature and duration of the contractile response as well as the
structure of the two organs differ greatly as do the values for
several of the structural parameters of the early scaffolds that
were used to control contraction and induce regeneration in
each organ. The scaffolds have a common ligand identity due
to an identical chemical composition (type I collagen/glycosaminoglycan, 98/2 w/w ratio), yet they differ in average
pore diameter (higher in the case of the DRT), the pore channel orientation (axial for the nerve guide, random for the
DRT), and degradation rate (a higher average molecular
weight between cross-links, Mc [kDa] in the nerve guide
leads to faster degradation) (Table8.4).
In skin wounds, the mechanism of induced regeneration
has been elucidated through careful modulation of the DRT’s
structural properties that impart contraction blocking activity. DRTs that actively block contraction in skin wounds (and
induce regeneration) have structural properties that accomplish three main processes: (1) reduction in MFB number
present in the wound, possibly due to inhibition of TGF-β
synthesis, leading to downregulation of myobroblast
recruitment; (2) blocking orientation of myobroblast axes
in the plane of the defect where macroscopic contraction is
observed; and (3) ensuring that DRT degradation time is sufciently long to ensure that contraction blocking persists for
the duration of the interim myobroblast contractile response
but not so long as to interfere with key regenerative
processes.
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Table 8.4
Structural parameter required
for regenerative activity Skin regeneration
Type I collagen/GAG (w/w)
residual collagen ber banding
Average molecular weight
between cross-links (kDa)
Average pore diameter (μm)
Pore channel orientation
GAG glycosaminoglycan
Adapted from: Yannas IV, Tzeranis DS, Harley BA, So PT.Biologically active collagen-based scaffolds: advances in processing and characterization. Philos Trans A Math Phys Eng Sci. 2010 Apr 28;368(1917):2123–39
a
Approximate levels of structural determinants observed in skin regenerative studies conducted by grafting the scaffold on a full-thickness skin
wound [18]
b
Approximate levels of structural determinants observed in peripheral nerve regeneration studies performed by inserting the scaffold inside a nerve
conduit (the conduit connected the two stumps of the transected nerve across an experimental gap of dened length) [27, 28]
1. Apparent downregulation of TGF-β synthesis. The qua-
2. Blocking orientation of MFB axes in the plane of the
Structural determinants of regenerative activity of collagen/GAG scaffolds
a
98/2 approximately 5% of native
collagen
5–15 40–60 Controls duration of undegraded
20–120 random 5–10 axial Ligand density
Nerve regeneration
98/2 approximately 5% of native
collagen
ternary structure of collagen bers is a requirement for
the aggregation of platelets, an early component of the
wound response. Platelet aggregation initiates a cascade
of events that include the release of the cytokine TGF-β1,
one of the main inductors of the myobroblast phenotype. Collagen bers in the DRT maintain their tertiary
(triple helical) structure but are practically free of banding (due to treatment with acetic acid during scaffold
preparation). DRT apparently disrupts platelet aggregation within the defect, reducing production of TGF-β1,
and the recruitment of contractile myobroblasts to the
wound site [125].
wound as well as MFB-MFB binding. Contraction of
wound edges appears to require orientation of MFB axes
in the plane of the wound as well as MFB-MFB binding
and MFB-ECM binding. MFB binding on the extensive
surface of the highly porous three-dimensional scaffold
inhibits such orientation as well as inhibiting MFB-MFB
and MFB-ECM binding. It is suggested that these mechanisms are additionally responsible for contraction blocking by the scaffold. According to this suggested
mechanism, contraction blocking requires extensive
MFB binding onto a sufciently large scaffold surface,
which must take place via specic integrin-ligand interactions. Fibroblasts bind onto a specic GFOGER ligand
on a collagen surface via the α1β1 and α2β1 integrins
[126]. When other structural properties are held constant,
the ligand density of a scaffold increases with decreasing
average pore size (since the specic surface area of the
scaffold available for attachment is thereby increased).
An appropriate ligand density appears to be necessary to
disrupt extensive MFB-ECM binding responsible for the
onset of macroscopic contraction in skin wounds.
When myobroblasts bind to specic DRT integrins
that are distributed evenly in a three-dimensional, interconnecting porous network, the axes of their contractile
b
Structural feature hypothetically
responsible for contraction blocking
Ligand identity
Reduction in recruitment of
contractile cells
scaffold during contraction
Ligand orientation
apparatus become disoriented. At the cellular level, the
randomized conguration of the preferential contractile
axes that individual myobroblasts adopt in the presence
of DRT leads to approximate cancellation of the macroscopic mechanical forces that lead to two-dimensional
contraction and scar synthesis in ungrafted skin wounds.
When the pore diameter of DRT is increased much
beyond the level of 120μm, the effective DRT ligand
density drops to a value that does not provide sufcient
binding of myobroblasts, and the contraction-blocking
activity of the scaffold is lost [1, 127]. Similarly, a minimal average pore size exists that is necessary to ensure
MFB migration inside the scaffold. According to this
interpretation if the pore size is too small, MFB does not
inltrate the scaffold, MFB-DRT ligand bonds do not
form, and MFB contractile activity is not cancelled [18].
Experimentally, the highly planar orientation of myobroblast axes that is characteristic of the spontaneous
contractile response in ungrafted skin wounds is negligible in the presence of DRT [128].
3. Duration of DRT in an undegraded state over the entire
contraction process. It is known that the regenerative
activity of the scaffold depends sensitively on its degradation rate during skin regeneration [129] as well as during
regeneration in the peripheral nervous system. To explain
the data, it has been hypothesized that the DRT is required
to undergo a process of isomorphous tissue replacement,
in which the regenerate (dermis or nerve tissue) is synthesized at a rate which is of the same order as the rate of
degradation of the DRT. The requirement for an optimal
scaffold duration may reect the need to have the scaffold
persist in an undegraded (insoluble) state over a period
that matches the length of the contraction process in skin
wounds and nerve wounds, thereby ensuring that the contraction blocking activity is operative when it matters. In
skin wounds the optimal half-life of degradation (tb) for
DRT invivo is 14days, roughly matching the irreversible
contraction response in ungrafted wounds (th) [17]. In
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peripheral nerve wounds the optimal degradation half-life
is about 2weeks, again matching roughly the half-life for
the healing process in the transected nerve stump [119].
When the scaffold degraded at a slower rate (tb>>14days),
the persisting DRT appeared to interfere with synthesis of
the regenerate and scar formed around the scaffold. When
the half-life of the DRT was signicantly lower than the
half-life of the contractile response (tb<<14days), the
DRT had little effect on blocking contraction or scar synthesis, and regeneration was not observed [18].
In summary, DRT dramatically blocks contraction while
inducing skin regeneration. Scaffolds that are close in structure to DRT but do not block contraction and do not induce
regeneration. There is evidence that DRT prevents recruitment of MFB and formation of oriented structures of MFB,
two processes that characterize spontaneous healing in the
adult mammal, over the duration of the normal contraction
process.
Discussion andConclusions
The experimental protocols that were used by several independent investigators to induce synthesis of elements of the
skin and peripheral nerves both invitro and invivo were analyzed in an effort to identify the minimal reactants required
for organ regeneration. Despite the structural differences
between the two organs, the simplest reactants required for
induced regeneration of either the skin or peripheral nerves
were found to be similar. The empirical evidence supports
the conclusion that partial synthesis of either the skin or
peripheral nerves requires only the implantation of a scaffold
with the requisite structure, appropriately seeded with epithelial cells dissociated from the organ of interest. The scaffold should possess a minimal density of specic ligands for
contractile cells and an optimal persistence time in the insoluble state [1]. Exogenous reactants utilized widely in many
regeneration protocols, notably cytokines and stromal cells
(broblasts), were redundant. While the experimental evidence derives only from the two organs that have been studied extensively to date in this context, the conclusions
reached above may be interpreted as a “trans-organ”
approach for future regeneration efforts.
The evidence presented in this chapter shows that severe
wounds in several organs in adults heal primarily by contraction, the same mechanism by which the skin and peripheral
nerves heal in adults. Contraction blocking in the skin and in
peripheral nerves is associated with induced regeneration.
The available data suggest, therefore, the possibility that the
mechanism of contraction blocking by scaffolds is similar in
these two organs. It now becomes possible to seriously consider the possibility that the adult organism can be enabled to
regenerate most of its organs.
References
1. Yannas IV. Tissue and organ regeneration in adults. NewYork:
Springer; 2001.
2. Butler CE, Orgill DP.Simultaneous in vivo regeneration of neodermis, epidermis, and basement membrane. Adv Biochem Eng
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