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Tissue-Engineered Wound Dressings
https://t.me/med1917
forDiabetic Foot Ulcers
SimonMatoori, SaharRahmani, andDavidJ.Mooney
16
Abstract
As the prevalence of patients with diabetes is rising, the
number of patients at risk of developing diabetic foot
ulcers (DFUs) is increasing. DFU is one of the most
debilitating complications of diabetes because of the high
risk of infections and lower extremity amputations. The
standard of care for DFU treatment is limited to nonspecic diagnostics (wound size, depth) and therapeutic
interventions (debridement, wet gauze, antibiotics if
needed), and has moderate healing rates. In the past three
decades, a number of FDA-approved therapies have been
developed that take advantage of advances in biomaterials
and tissue engineering to manufacture materials that provide a favorable physicochemical environment and prohealing cues (e.g., extracellular matrix, growth factors).
However, these treatments have not led to strongly
increased healing rates. As our understanding of diabetic
wound pathophysiology is deepening, new therapeutic
targets have emerged, particularly around inammatory
processes in diabetic wounds. In the last decade, the
emergence of these targets has led to the development of
wound dressings that release diagnostic and therapeutic
agents that specically address these processes. While
many of these therapies have yet to provide a clinical
proof-of-concept, the variety of strategies raises hope that
novel and more specic diagnostic and therapeutic
options will be available in the next decade.
S. Matoori
Faculté de Pharmacie, Université de Montréal,
Montréal, QC, Canada
e-mail: simon.matoori@umontreal.ca
S. Rahmani · D. J. Mooney (*)
John A. Paulson School of Engineering and Applied Sciences,
Harvard University, Cambridge, MA, USA
Wyss Institute for Biologically Inspired Engineering, Harvard
University, Boston, MA, USA
e-mail: rahmani@seas.harvard.edu; mooneyd@seas.harvard.edu
Introduction
Diabetes mellitus is dened as “a group of metabolic diseases
characterized by hyperglycemia [increased blood glucose levels] resulting from defects in insulin secretion, insulin action,
or both” [1]. Insulin deciency and hyperglycemia stem from
the destruction of pancreatic β-cells by an autoimmune reaction in type 1 diabetes or from a decreased tissue response to
insulin (insulin resistance) and reduced insulin production by
β-cells in type 2 diabetes [1]. Diabetes mellitus is one of the
fastest-growing chronic diseases worldwide, with an estimated
prevalence of 537 million adults (10.5%) in the adult population in 2021 [2]. In the United States, the prevalence of the
disease was at 12.1% for non- Hispanic white, 20.4% for nonHispanic black, 22.1% for Hispanic, and 19.1% for non-Hispanic Asian adults in 2016, a number that is expected to grow
continuously [3]. Global diabetes-related health expenditures
were estimated at 966 billion USD in 2021 [2]. Diabetic
patients are likely to develop atherosclerotic macrovascular
diseases and diabetes- specic microvascular pathology, especially in the retina, renal, and peripheral nerves, which may
consequently result in blindness, end-stage renal disease, and
various neuropathies [4–6]. Diabetic peripheral neuropathy,
peripheral vascular disease, and an impaired healing cascade
often result in the development of diabetic foot ulcers (DFUs),
with a 25% lifetime risk of developing a DFU for a diabetic
patient [7, 8]. DFUs are often classied based on their severity
using a Wagner Ulcer Classication system, which ranges
from supercial diabetic ulcers (Grade 1) to extensive gangrene of the foot (Grade 4) [9]. When untreated, DFUs often
lead to lower extremity amputations [10, 11]. Amputations are
necessary in approx. 20% of patients with moderate or severe
DFU [12]. With 130′000 amputations in the United States in
2016 according to the Centers for Disease Control, DFUs are
the leading cause for non-traumatic lower limb amputations
[13]. In addition to the human cost, the nancial burden of
DFU on the healthcare system is considerable. In 2014, the
cost for DFU wound care (including the cost of infections)
was 6.2 billion USD for Medicare [14]. A recent study found
© 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_16
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that one DFU patient caused mean healthcare costs of 44′200
USD per year in the United States in 2015 [15].
While prevention of DFUs, especially using a multidisciplinary team of healthcare professionals (e.g., podiatrist, diabetologist, orthopedic and vascular surgeons,
microbiologist, and tissue viability nurses) has been shown
to reduce their occurrence rate [8, 9], DFUs are still a major
complication faced by diabetic patients. Traditional treatments of DFUs include controlling the patient’s glycemic
levels (slows the progression of neuropathy), improving vascularization (increases blood ow to the wound, especially in
ischemic legs), debridement of the wound (removes necrotic
tissue for improved healing), off-loading (reduces the pressure to the wound), negative pressure wound therapy
(removes wound exudates via vacuum to promote healing
and promotes regeneration), treatment of infections (local
and systemic depending on the severity of the infection), and
traditional wound dressings (provides a barrier to contaminants and further injury to the wound) [7–9, 16–20]. Of great
importance is the complete debridement of the wound and
the presence of a clean wound bed before the start of further
therapies, since a lack of full debridement is believed to
impede the progress of wound healing [9, 21–23]. While
these systems can be effective, the patients still often suffer
from amputations or secondary DFUs. A possible route for
enhancing the treatment of DFUs might be to use more
advanced wound dressings that not only function as a barrier,
but also take an active role in the healing of ulcers [24].
One approach for the development of active wound dressings is to address the issue as an engineering challenge, where
the properties and characteristics of an ideal therapy are seen
as the design requirements and an ideal product is fabricated
to meet these specications. Main design requirements for
active wound dressings can be divided into three categories
(Fig. 16.1), which include those involved in: (i) material
Fig. 16.1 Representative design requirements for the fabrication of
successful wound dressings for the treatment of DFUs
selection, (ii) creation and control of the wound environment,
and (iii) encapsulation and delivery of therapeutics. When
selecting a material for wound healing, several parameters
should be considered including biocompatibility, immunogenicity, and ease of removal without further damage [10]. Once
selected, such material should be able to create the proper
environment for wound healing and should provide gas
exchange, thermal insulation, moisture, drainage of exudates,
and antimicrobial capabilities [10, 25]. The material may also
be capable of encapsulating and controlling the release of
various therapeutics from small molecules to macromolecules and various types of cells [10, 16, 25].
Additionally, several cost-related and regulatory aspects
must also be considered when developing new wound dressings. In order to make these products marketable, and given
the high cost associated with the development of such systems, the results need to be considerably more effective than
the current standard treatments in order to make them protable. Moreover, the products need to be user-friendly and
require minimum additional training on the part of the caregiver. Lastly, while a number of promising treatments are
currently being developed, the long regulatory process
required to achieve FDA approval is costly, which must especially be considered for smaller companies [26]. In this
chapter, we review some of the current, next-generation, and
futuristic wound healing systems and discuss their potential
with respect to meeting these design requirements.
Current Materials forWound Healing
There are a number of FDA-approved active wound dressings
currently available on the market that are in use for the treatment of DFUs in patients [10, 25]. The materials used for the
fabrication of these dressings can be broadly categorized as
natural, synthetic, or a combination of both. Natural wound
dressing materials are derived from a natural source, and
include cellulose, collagen/gelatin, hyaluronic acid, chitosan,
and alginate [10, 27]. The natural materials have the advantage of typically being considered biocompatible, have some
versatility in mechanical properties, are absorptive, antibacterial, and, certain types, are present as part of the natural healing process [28]. However, their isolation, batch- to- batch
variability, processing, potential immunogenicity, and limited
range of physical properties can make the use of such material problematic [10, 29]. On the other hand, synthetic materials, including polyvinyl alcohol, polyurethanes, polyesters,
and polyethylene oxide/glycol, can be fabricated on a large
scale and often inexpensively, are much more well dened
with lower batch-to-batch variability, provide a broad range
of physical properties, and can be chemically modied to better address various processing and biological aspects [10, 25].
However, the basic synthetic materials often lack some of the
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289
inherent capabilities of the natural products and often require
further chemical modications to achieve the desired traits,
which can result in higher manufacturing costs. Often, the
natural and synthetic materials are combined to take advantage of capabilities from both groups [25].
The currently used wound dressings made from these
materials can be categorized into hydrocolloids, hydrogels,
foam dressings, lms, and skin substitutes, using the terminology common to the eld [8, 10, 27]. The common terminology can be somewhat confusing, as hydrocolloids, for
example, while by scientic denition a type of material that
forms a hydrogel in the presence of water, are typically categorized in this eld as a distinct type of dressing from hydrogels. As wound dressing materials, hydrocolloids are typically
composed of an adhesive, lm-like dressing and absorbent
particulates [10]. These dressings absorb wound exudates to
form a gel that protects the wound and creates a moist environment [8]. Unfortunately, there is a limit to the amount of
exudates this type of dressing can absorb, leading to accumulation at the wound site or the breakdown of the wound dressing [9]. Hydrocolloid dressings typically need to be changed
multiple times a week to address these issues [30].
Hydrogels are scientically dened as a broad category of
materials comprised of hydrophilic, cross-linked polymers
that are swollen in a large quantify of water, typically
30–90%. In the common terminology used for wound dressing materials, hydrogel dressings are capable of absorbing
more liquid than the hydrocolloids, and can create a moist
environment for the wound without excess exudates [31].
Hydrogels can be cross-linked ionically or covalently to control their degradation and other chemical/physical characteristics, can be exible, inert, easily removable, and can allow
for gas/liquid/metabolite exchange [10, 32]. While, in the
way terminology is used in this eld, hydrogel dressings can
typically absorb more liquid than hydrocolloid dressings,
there is a limit on the amount they can absorb, and in the case
of wounds with excess exudates, these dressings will need to
be frequently replaced [9]. Hydrogels can also be used as
scaffolds for the release of active substances such as in
Regranex, an FDA-approved topical formulation for DFU
treatment that is composed of a carboxymethylcellulose
hydrogel containing recombinant human platelet-derived
growth factor (becaplermin) [33, 34].
One way to address wounds with excess exudates is to use
foam-type dressings that can absorb a large amount of liquid
based on their polymeric makeup and thickness [9, 10]. A
foam is technically a type of colloid in which a discontinuous gas phase is distributed in a continuous liquid phase. As
this term is used in the wound dressing eld, once exudates
are absorbed, a foam dressing is considered to exhibit a gellike texture and creates a moist environment for the wound.
Foam dressings can also act as a cushion and a protective
layer on the wound, which can enhance their functionality
and the comfort level for the patient [10]. This type of dressing can be left on the wound for up to a week due to its excellent absorbance capabilities.
Film dressings are typically transparent, exible, easy-tomanipulate adhesives that allow for gas exchange, but are
non-permeable to liquids and bacterial infections [35]. These
dressings are not liquid absorbent and are not typically used
with wounds that have more than a moderate amount of exudates [36]. While this might limit their applicability for the
treatment of DFUs on their own, their combination with
some of the dressings mentioned above can create a more
comprehensive system, as they can provide better xation of
the dressing to the surrounding tissue and create a barrier for
liquid transport and bacterial infections [10].
Perhaps the most advanced dressings that are currently in
use for the treatment of wounds are acellular and cellular skin
substitutes [37]. A variety of acellular dermal matrices have
been developed as temporary extracellular matrix replacements for diabetic wounds [38]. These extracellular matrix
products allow the inux of host cells and promote matrix
deposition, angiogenesis, re-epithelialization [38]. The FDAapproved acellular bandage Integra® Dermal Regeneration
Template is composed of an inner layer of collagen and glycosaminoglycan, and an outer silicone layer, and resulted in a
moderate improvement in complete wound healing [39]. A
number of other bandages made from human (e.g., Epix®
and Amnioexel®, amniotic membrane) or animal origin materials (e.g., OASIS®, porcine small intestinal mucosa and
Matristem®, urinary bladder matrix), have shown encouraging results in clinical studies in DFU patients [38].
Cellular skin substitutes are typically composed of natural or synthetic scaffolds that have been seeded with various
cells involved in the wound healing process, especially broblasts and keratinocytes. These scaffolds provide cellular
support and structural integrity to aid in the wound-healing
process [37]. The cells incorporated in these scaffolds are
allogenic [27], and while they typically do not persist in
patients for more than 6weeks, they do tend to be clinically
more effective as compared to their non-cellular counterparts
[39–43]. This is in part attributed to the secretion of cytokines, proteoglycans, growth factors, and ECM components
by the cells, that support the physiologic progression of the
wound-healing cascade [44, 45]. A number of these skin substitutes are FDA-approved to treat DFUs, and have been
shown to improve the rate of wound closure [46, 47].
Unfortunately, this type of wound dressing on its own is not
capable of absorbing exudates and will require an additional
dressing for this function. Additionally, they typically lack
dermal structures, such as sweat glands and hair follicles
[48]. While further side-by-side studies are needed to properly compare the effectiveness of different types of wound
dressings for the treatment of DFUs, and other factors such
as cost and availability must also be considered, skin substi-
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Table 16.1 A list of FDA-approved therapeutic wound dressings commonly used in DFUs
Dressing type Product Company Description
Hydrocolloids Aquacel ConvaTec Antimicrobial hydro-ber with carboxy-methyl cellulose and ionic silver [50–54]
Comfeel Coloplast Corp A semi-permeable polyurethane lm embedded with calcium alginate and
carboxymethylcellulose particles
DuoDerm
CGF
Hydrogels Restore Hollister Woundcare Calcium alginate dressing with silver lining for antimicrobial properties [58–60]
Carrasyn Medline industries Hydrogel containing aloe vera for simple hydration of wound site [17, 61]
Regranex Smith+nephew Hydrogel made of carboxymethylcellulose containing becaplermin
Foam
dressings
Films OpSite Smith & nephew, Inc. A thin, semi-permeable polyurethane foam sheet with an acrylic adhesive
Skin
substitutes
Tielle Johnson&Johnson
Allevyn Smith & nephew, Inc. Combination of polyurethane foam & lms, with 5% silver sulphadiazine.
Lyofoam Seton healthcare
X-cell Medline industries A non-adherent cellulose dressing with polyhexamethylene biguanide for
Tegaderm 3M healthcare A thin, semi-permeable polyurethane membrane with an acrylic adhesive
Apligraf Organogenesis, Inc. Bovine type I collagen scaffold with human broblasts & keratinocytes [75–77]
Dermagraft Organogenesis, Inc. Bio-absorbable poly(lactic-co-glycolic acid) mesh with neonatal foreskin
Epix MiMedx group Inc. Human amniotic membrane with epithelial cells [77, 80,
Integra Integra LifeSciences Collagen and glycosaminoglycan (inner layer), silicone (outer layer) [39]
ConvaTec A semi-permeable polyurethane foam dressing [56, 57]
(recombinant human platelet-derived growth factor)
A semi-permeable, thin sheet of hydrophilic polyurethane with acrylic
medical
group, PLC
adhesive coating
Contains an acrylic adhesive that aids in easy removal of the bandage
A semi-permeable polyurethane foam sheet [68, 69]
coating
broad-spectrum antimicrobial function.
coating
broblasts
S. Matoori et al.
[17, 55]
[33, 34]
[62–64]
[65–67]
[70, 71]
[35, 72]
[73, 74]
[41, 42,
78, 79]
81]
tutes open the door for more advanced wound treatment
options that can take a more active role in enhancing wound
healing in diabetic patients. Table16.1 outlines a representative sample of the FDA-approved current therapies from
each of these categories and outlines their signicant capabilities. A more complete list of the current therapies has
been published in a number of recent reviews [22, 49].
The current set of FDA-approved therapies is certainly an
improvement over traditional therapies, especially with
respect to the design parameters that were outlined earlier in
this chapter. The majority of the materials outlined here are
biocompatible, do not elicit a harmful immune response, and
can be easily removed without further damage to the wounds.
Additionally, they can provide gas exchange, thermal insulation, a moist environment, and provide a barrier to infections. The different materials perform variably with respect
to the absorption and drainage of exudates from wounds,
with foams capable of absorbing the largest amount of liquids, followed by hydrogels, hydrocolloids, and lms. Since
DFUs have differing amounts of exudates depending on their
severity and the stage of healing, this provides the caregiver
with a range of options to choose from, but it does not guarantee a one-size-ts-all mentality. Additionally, while skin
substitutes provide a means for the delivery of various therapeutics to the wounds via secretions from their loaded cells,
few of the other FDA-approved wound dressings contain
therapeutics to enhance healing. As such, while the current
wound dressings address some of the design requirements
for an ideal system (material properties and control over the
environment), they often fall short in encapsulating drugs
and providing controlled drug release kinetics which limits
their pro-healing effects in diabetic patients.
Next-Generation Materials forWound
Healing
To address some of the challenges faced by the FDAapproved wound dressing systems, current research is
focused on developing materials that can address their physical/chemical shortcomings as well as to provide the ability to
deliver therapeutics, including small molecules, peptides,
proteins, nucleic acids, natural products, and various cell
types (Fig.16.2) [37]. While the majority of these systems
have not been tested in humans and/or are currently in the
early stages of clinical testing, or they have been tested for
general wound healing and not specically for treating
DFUs, there is certainly a number of promising materials
that could be used to enhance healing and wound closure in
diabetic patients.
A number of the currently developing wound care systems
use the same natural and synthetic materials discussed earlier
16 Tissue-Engineered Wound Dressings forDiabetic Foot Ulcers
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Fig. 16.2 Therapeutic agents
at different length scales can
be encapsulated in wound
dressing materials, and their
release prole can be
controlled to optimize their
therapeutic effects
291
in this chapter. However, what makes these systems often
unique is their altered chemical structures, which enhance
their capabilities. Whether these alterations result from the
blends of multiple polymers, copolymerization of two or
more different polymers, or the modication of monomers/
polymers to add functional groups, these chemical changes
result in products intended to better meet the design parameters, such as their biocompatibility/degradability, inertness,
swelling ratios, and adhesiveness [32]. Additionally, these
modications can enhance the encapsulation of therapeutics
and create better control over their release proles. As an
example, alginate is a natural polymer that is traditionally
used as a wound dressing by cross- linking it via cations to
form alginate hydrogels. Research in various groups in the
past decades have resulted in a number of different modications to the alginate polymer or how it is used to fabricate
hydrogels, ranging from providing covalent cross-linking that
enhances durability and improves mechanical characteristics
to modifying the polymer to include peptides or signaling
molecules to enhance the loading and delivery of cells [32].
Modied polymers, in combination with the appropriate payload, might be an avenue for the fabrication of wound dressings for the treatment of DFUs that meet all of the required
design requirements.
Building on previous successful cell delivery systems,
numerous research groups are focused on expanding the
range of cells delivered or their delivery vehicles [22]. While
further research has been conducted in the delivery of broblasts and their role in regeneration [82, 83], a number of
studies have instead focused on the delivery of stem cells to
treat wound healing [84]. Mesenchymal stem cells have been
shown to accelerate wound healing in DFUs and prevent the
formation of secondary ulcers by controlling the inammatory phase, providing a well-vascularized environment,
attracting keratinocytes, and preventing apoptosis of cells
involved in the wound healing process [32, 85, 86]. While
some studies have applied the cells directly to the wound
[84], others have used various materials, such as brin, to
deliver the cells [85]. A number of these strategies are currently in various phases of regulatory approval [87].
Additionally, other cell types have been incorporated into
skin substitute products to enhance wound healing, including
melanocytes to improve the aesthetic outcomes [88], endothelial cells to improve blood supplies and lymphatic drainage [89–91], and eccrine sweat gland cells to enable sweating
and the creation of a moist environment for healing [92].
Immune cells have also been delivered to diabetic wounds.
The key role of macrophages in diabetic wound healing
motivated the investigation of macrophage delivery into the
wound bed [37]. Encapsulating pro-inammatory (M1) or
anti-inammatory (M2) macrophage phenotypes in alginate
hydrogels improved wound healing, potentially due to the
therapeutic effects of inducing acute inammation (M1 macrophages) and of the secretion of pro-healing growth factors
and extracellular matrix deposition (M2 macrophages) [93].
In addition to delivering cells, a number of studies have
shown a signicant improvement in the healing rate of DFUs
by delivering various therapeutics (Fig.16.2). Traditionally,
such therapeutics are applied topically either in liquid form
or as a more viscous ointment during the placement of dressings on wounds. However, due to the large amount of exudates leaving the wound in most DFUs, the fast clearance of
many biological therapeutics, and the need for a continuous
presence of these therapeutics to be clinically applicable,
their topical delivery is often not successful [94]. To address
this challenge, many of the current wound healing systems
under development take advantage of research in the drug
delivery eld to incorporate therapeutics into their wound
dressings, which allows for the protection of the encapsulated therapeutic over longer durations and their controlled
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release over a more clinically relevant period. As demonstrated in Fig.16.2, the encapsulated therapeutics include a
wide variety of substances such as macromolecules, cells,
small molecules, and nucleic acid-based therapeutics that are
encapsulated in the dressing material and released over time
in the wound environment to enhance the therapeutic effect
of the dressing. Here, we review different wound dressings
loaded with various therapeutics ranging from small molecules to various macromolecules that are currently under
investigation for use in wound healing.
Low molecular compounds used for the treatment of
DFUs include immune system modulators (e.g., mast cell
stabilizer) [95], antioxidant substances (e.g., deferoxamine)
[96, 97], matrix metalloprotease-9 inhibitors [98, 99], and
antibiotics [100], have been successfully delivered using a
number of material systems including polyvinyl alcohol,
various polyesters, polyvinyl pyrrolidone, alginate hydrogels, and hyaluronic acids to aid in the healing of the wounds
as well as to provide an antimicrobial environment [37]. To
slow down the usually fast release of hydrophilic small molecules from hydrogels, different drug delivery strategies
were employed such as encapsulation in reverse micelles and
adsorption to clay microparticles [95, 97]. Peptides, proteins
including growth factors, DNA plasmids, and siRNAs are
among the macromolecules that have been explored to
enhance wound healing. A number of peptides and proteins
have been incorporated into scaffolds to aid in the adhesion,
migration, and proliferation of pro-healing cells into the
wound bed, including integrin-binding peptides [101], laminin [102–104], bronectin [105–107], and brin [108]. The
role of growth factors in aiding wound healing is well established, and numerous studies have used materials to deliver
these potential therapeutics to improve wound healing [9, 17,
37, 83, 109–117]. Growth factors, such as FGF [118–120],
EGF [114, 121], TGF-β [122], KGF [123], and PDGF [115],
have also been incorporated into skin substitutes to successfully promote healing. In the area of gene therapy, various
nucleic acid-based therapies, such as DNA plasmids [124,
125], siRNAs [126], and adenoviruses [127, 128], have been
explored as therapies, as these act by modulating the expression of target genes responsible for wound healing and
regeneration [94, 128–132]. Additionally, a number of natural substances that are a combination of amino acids,
enzymes, vitamins, and polysaccharides have also been
delivered using wound dressings and have been reported to
improve wound healing in diabetic wounds. These natural
substances include honey [133], aloe vera extract [134, 135],
essential oils [136, 137], and plant extracts [138].
Current research in tissue-engineered materials for wound
healing address some of the short-comings faced by the
already FDA-approved products. These new technologies
aim to meet the design specications with regard to the mate-
rial selection (high biocompatibility, low immunogenicity,
and ease of removal), environmental control (providing gas
exchange, thermal insulation, a moist environment, drainage
of exudates, and antimicrobial properties), and specically
the ability to encapsulate and control the release of various
therapeutics from small molecules to macromolecules and
various types of cells. Materials able to deliver a wide range
of therapeutics and simultaneously control the wound environment might be best suited to create the next generation of
therapies for wound healing in diabetic patients since they
could impact a wide array of key features, including cell
migration and proliferation into the wound, and can have
control over the physiochemical environment by presenting
pro-healing agents rather than inammatory ones. Key challenges that still need to be addressed, though, include the
fabrication of materials that can both absorb a large amount
of exudates and release therapeutics in a controlled manner.
Hydrogels, for example, swell as they absorb liquids and this
may lead to a burst release of the encapsulated therapeutics
instead of their controlled release over time. The incorporation of multiple therapeutics that are diverse in their chemical makeup (e.g., simultaneous delivery of small, hydrophobic
molecules, and hydrophilic growth factors or nanoparticles
in the same wound dressing) is another challenge. A possible
solution might be the use of materials that have multiple
functionalities or compartments, or are fabricated using a
combination of materials. However, in doing so one must
always consider the loss of capabilities of each material
when combined together. Perhaps more pressing is that while
all of the current therapies mentioned in this section have
been explored for wound healing, not all of them were necessarily used for the treatment of DFUs. As such, further studies are required to demonstrate their viability in the diabetic
patients.
Future Directions inWound Healing
Biomaterials
As our understanding of the diabetic wound pathophysiology has grown, novel therapeutic targets have emerged.
While current DFU bandages often provide non-specic
physicochemical cues (e.g., moist environment, exudate
absorption, gas exchange) to provide a pro-healing environment, the next generation of wound dressings is likely
to specically address molecular targets. These targets
include the lack of an acute immune response, macrophage
recruitment and polarization, chronic oxidative stress, and
matrix metalloprotease activity. Therefore, rather than
adding to the large library of wound dressings that at times
differ only slightly from each other, next-generation
wound dressings will address the molecular pathophysiol-
16 Tissue-Engineered Wound Dressings forDiabetic Foot Ulcers
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293
ogy of an individual wound. As the molecular and cellular
composition of diabetic wounds can strongly differ
between patients, molecular ngerprinting of wounds will
likely become essential to select the most appropriate
treatment and to assess treatment success. In this nal section, we review some of these novel therapeutic and diagnostic bandages.
It has become increasingly clear in recent years that the
inammatory phase of diabetic wound healing is likely the
most dysregulated process [37]. There is growing evidence
that the lack of an acute inammatory reaction to tissue
injury is one of the main contributors to the chronic inammatory state of diabetic wounds [37]. Novel proinammatory treatments are currently being investigated to
induce an acute inammatory response and jump-start the
healing process. The preventive application of a mast cell
stabilizer, that leads to a stronger pro-inammatory mast
cell response after tissue injury, and local application of the
pro-inammatory neuropeptide substance P or the neutrophil-attracting cytokine interleukin-8 decreased chronic
inammation and accelerated wound healing [95, 139, 140].
These local therapies demonstrate the previously counterintuitive hypothesis that inducing an acute inammatory
response can reduce chronic inammation and improve
wound healing.
In the absence of an acute inammatory response, diabetic wounds are stalled in a chronic inammatory state that
prevents the progression into the proliferation phase and
impairs key processes of tissue repair such as angiogenesis,
ECM remodeling, and re-epithelialization [37]. A variety of
anti-inammatory wound dressings are currently being
investigated as treatments for diabetic wounds. The chronic,
low-grade inammation is being directly targeted by modulating the circle of macrophage inux, polarization to the
pro-inammatory M1 phenotype, and secretion of
macrophage- attracting cytokines, that lead to further macrophage recruitment. Bandages that actively capture
macrophage- attracting cytokines demonstrated that this
cycle can be broken in diabetic wounds [141]. Furthermore,
wound dressings have been designed to detoxify factors
secreted by immune cells (e.g., ROS, MMP-9) that impair
the proliferative and remodeling phases of tissue repair. The
strategies include small molecule antioxidants such as the
FDA-approved drug deferoxamine, which inhibits the conversion of hydrogen peroxide to the highly toxic hydroxyl
radical [96, 142] and low molecular weight inhibitors of
matrix metalloprotease-9 [98, 99]. In addition to small molecules, lipid nanoparticles for the delivery of short interfering RNAable to downregulate oxidative stress-inducing
genes and matrix metalloprotease-9 improved wound healing in diabetic animal models [125, 143].
Another aspect to consider is how differences in molecular
and cellular composition of DFUs may impact prognosis and
treatment success. As mentioned previously, DFUs are currently classied using macroscopic and unspecic criteria
(wound size, depth), but this does not address the complexity
of the underlying molecular pathophysiology [144]. As more
knowledge on key pathophysiologic factors in diabetic wound
healing is emerging, fabrication of adaptive or “smart” materials that can sense these biomarkers in the wound environment has been proposed [144, 145]. Among others, these
diagnostic wound dressings sensed markers of inammation,
oxidative stress, bacterial infection, and mechanical stress
[144]. Molecular ngerprinting of wounds promises to transform disease staging, evidence-based treatment selection, and
assessment of treatment success in DFU.This trend toward
personalized medicine in DFU has the potential to improve
the outcome for individual patients but will only be widely
adopted if the cost/benet ratio is favorable.
Conclusions
With the growing prevalence of diabetes, the number of
patients at risk of developing DFU is increasing. This disease
has low healing rates and is the most common reason for lower
extremity amputations in North America, which can have
debilitating effects on the lives of patients with DFU. The
standard of care for DFU treatment is still based on non-specic interventions (debridement, wet gauze, antibiotics if
needed). Advances in the eld of tissue engineering have
resulted in a number of FDA-approved wound dressings that
provide more specic pro-healing cues such as extracellular
matrix and growth factors, and have resulted in moderately
improved healing rates. As our understanding of diabetic
wound pathophysiology is growing, new therapeutic targets
have emerged, particularly regarding the inammatory processes in diabetic wounds. In the last decade, the emergence of
these targets has led to the development of therapeutic dressings that specically address these processes, for instance
using strategies to induce an acute inammatory response or
reduce chronic inammation by modulating macrophage
recruitment and polarization, lowering oxidative stress, and
inhibiting protease activity. Looking into the future, it will be
important to test these novel strategies in clinical studies, and
to combine these treatments with molecular diagnostics that
allow the identication of individuals that could most benet
from the intervention. and to evaluate treatment success on a
molecular level. In the past several decades, this eld has seen
a dramatic change in the way it has addressed wound healing,
and equally or more impactful changes are anticipated as the
eld heads into its next transformative phase.
294
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S. Matoori et al.
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