Hindawi Publishing Corporation

Journal of Nanomaterials
Volume 2012, Article ID 714134, 11 pages
doi:10.1155/2012/714134

Review Article
Nanotechnology-Based Therapies for Skin Wound Regeneration

Ilaria Tocco,1 Barbara Zavan,2 Franco Bassetto,1 and Vincenzo Vindigni1

1 Institute of Plastic Surgery, University Hospital of Padova, 35128 Padova, Italy
2 Department of Histology, Microbiology and Biomedical Technologies, University of Padova, 35128 Padova, Italy

Correspondence should be addressed to Ilaria Tocco, [email protected]

Received 8 February 2012; Revised 19 February 2012; Accepted 24 February 2012

Academic Editor: Xiaoming Li

Copyright © 2012 Ilaria Tocco et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The cutting-edge combination of nanotechnology with medicine offers the unprecedented opportunity to create materials and de-
vices at a nanoscale level, holding the potential to revolutionize currently available macroscale therapeutics. Nanotechnology
already provides a plethora of advantages to medical care, and the success of nanoparticulate systems suggests that a progressive
increase in the exploration of their potential will take place in the near future. An overview on the current applications of nanotech-
nology to wound healing and wound care is presented.

1. Introduction developing diabetic ulcers [5]. Nonhealing wounds are the

results of a stop in the progression of the normal sequence
Nobel Prize winner Richard Feynman was the first in 1959 to of cellular and biochemical events towards the restoration of
predict the future emergence of a new science which could be the skin’s integrity. Factors delaying wound healing include
able to deal with structures on a scale 1–100 nm. Fifty years either preexisting comorbidities (diabetes, chronic periph-
after, the unpredictable result is the ability to manipulate eral vasculopathy, and immunosuppression), leading to lack
materials on the same unimaginably small scale which is of appropriate metabolism and clearance from toxic sub-
used by nature [1]. The repercussions that nanotechnology is stances of the wound, and/or sudden complications, such as
having in our lives nowadays are towering: the current appli- infections, exalting the inflammatory state. Nanobiotechnol-
cations to molecular biology are leading to the development ogy combined with the knowledge on cellular and subcellular
of structures, devices, and systems bearing a capacity to re- dysfunctional events occurring in delayed wound healing
volutionize medical therapeutics and diagnostics, which has offers great opportunities for improving wound care.
never been seen before.
This paper will focus on the currently available nanotech-
Nanodevices are innovative and can provide a wide range
of advantages: from the ability of nanoparticles to enter into nology-based therapies in the field of wound healing and skin
the cytoplasmic space across cellular barriers, like Trojan regeneration. To appreciate the importance of the functions
horses, and activate specific transport mechanisms [2, 3]; to of the innovative nanosystems, an understanding of the
the modulation of drugs biocompatibility, bioavailability and wound healing process is essential.
safety profiles through nanodelivery systems [4]. Further-
more, therapeutic selection can increasingly be tailored to
each patient’s profile. Nanotherapies represent a great oppor- 1.1. The Wound Healing Process. The wound healing process
tunity to enhance currently available medical treatments, im- is classically defined as a series of continuous, sometimes
proving standard care and prognosis for challenging health- overlapping, events. These are haemostasis, inflammation,
care issues, like impaired wound healing. proliferation, epithelisation, maturation, and remodelling of
The public health impact of chronic wounds is stagger- the scar tissue [6] (Figure 1).
ing. An estimated 1.3 to 3 million US individuals are be- Haemostatic events occur immediately after injury. The
lieved to have pressure ulcers and as many as 10% to 15% of exposure of subendothelial collagen and the formation of
the 20 million individuals with diabetes are at risk of thrombin lead to the activation of the platelets, located in
2 Journal of Nanomaterials

Wounding

Haemostasis
Vasoconstriction
Platelet aggregation and PDGF; FGF;
TGF-β
degranulation
es Growth
Blood clotting
factors
W-3 days

Inflammation EGF;
VEGF
Leucocyte migration es
Neutrophils, secretion of chemicals killing bacteria
Removal of cellular debris by macrophages
Release of growth factors

PDGF; EGF;
Proliferation FGF; TGF-β;
Neovascularisation TNF
3 days–10 months

Fibroblasts proliferation and secretion of glycoprotein and collagen

Keratinocytes migration from the wound edge
Granulation tissue
3–12 days

PDGF; FGF;
Remodelling EGF
Fibroblasts secretion of collagen and matrix proteins to strengthen wound
Wound remodelling MMPs
Wound contraction

Scar tissue

Figure 1: The main biological phases in wound healing. The events in wound healing and the soluble factors involved in each phase are
well defined. Although presented as separated for absolute clarity, no phase is initiated exactly at the complexion of the previous one, and all
phases overlap to a certain degree (see arrows on the left).

the intravascular space. Activated platelets play a trigger role injured area. Neutrophils are the first inflammatory cells to
in a number of events: enter the wound, followed by monocytes. Once chemotaxis
(i) activation of the coagulation cascade. This eventually is completed, local mediators activate the inflammatory cells.
leads to the formation of a fibrin clot that acts as Activated neutrophils release a number of lysosomal enzymes
scaffolding for other cells that later enter the wound; (such as elastase, neutral proteases, and collagenase) which
proteolytically remove damaged components of extracel-
(ii) activation of the complement system;
lular matrix (ECM) [8]. Activated monocytes acquire the
(iii) platelet degranulation: cells release an array of cyto- macrophage phenotype and aid in host defence [8].
kines, growth factors, and vasoactive substances from The proliferation phase is characterised by the formation
the platelet α-granules, such as platelet-derived of the ECM and the beginning of angiogenesis. The primary
growth factor (PDGF), transforming growth factor-β cells involved in this phase are fibroblasts and endothelial
(TGF-β), fibroblast growth factor (FGF), endothelial cells. They proliferate in response to growth factors and
growth factor (EGF), platelet-derived angiogene- cytokines that are released from macrophages, platelets and
sis factor, serotonin, bradykinin, platelet-activating mesenchymal cells, or have been stored in the fibrin clot.
factor, thromboxane A2, platelet factor IV, prost- In addition to chemotactically drawing fibroblasts into the
aglandins, and histamine. These platelet releasates wound, PDGF, FGF, and EGF induce fibroblast activation
initiate the early events of wound healing [6, 7]. and proliferation [9]. During the first 2-3 days after-injury,
The inflammatory phase begins immediately after injury fibroblasts activity predominantly involves migration and
and may continue for up to 6 days [8]. Growth factors re- proliferation. After this time, fibroblasts release collagen and
leased from the platelets diffuse into tissues surrounding the glycosaminoglycans (mainly hyaluronic acid, chondroitin-
wound and chemotactically draw inflammatory cells into the 4-sulphate, dermatan sulphate, and heparin sulphate) in
Journal of Nanomaterials 3

response to macrophage-released growth factors, hypoxia growth factor—recombinant human PDGF-BB—has been
and by-products of anaerobic metabolism. The combination approved by the United States Food and Drug Administra-
of collagen and fibronectin forms the new ECM, which is es- tion, and only for use in diabetic foot ulcers [45]. In fact, the
sential for the development of granulation tissue that even- major limitation to the topical use of growth substances is
tually fills the wound [6]. Angiogenesis accompanies fibrob- that in human plasma the half-life of proteins involved in
last proliferation and allows nutrients and healing factors to signalling cascades is very short (few seconds) due to close
enter the wound space. It is also essential for the growth of control and inactivation by protease inhibitors [46]. There-
granulation tissue. The principle growth factors that regulate fore, the clinical use of endogenous factors as pure com-
angiogenesis are FGF, released by damaged endothelial cells pounds is limited by the breakdown by the proteolytic
and macrophages, and vascular endothelial growth factor enzymes that enrich the wound site [47]. Several attempts
(VEGF) which is released by keratinocytes and macrophages have been already made to provide biological molecules
[6]. long-term protection from enzymatic degradation (liquids,
The maturation phase usually begins 3 weeks after injury gels, collagen sponges, and gene transfer). Recently, the
and can take up to 2 years to complete [10]. Unlike uninjured development of nanoscale systems for drug delivery has
skin, the arrangement of newly formed collagen fibres in the opened new possibilities to enhance the biological efficacy of
wound is random and disorganised. The remodelling of col- molecules through a controlled release for extended periods
lagen fibres into a more organised lattice structure gradually of time [48]. Endogenous active molecules that have been en-
increases the tensile strength of the scar tissue, though this gineered nowadays include thrombin, nitric oxide, growth
never exceeds 80 percent of the strength of intact skin. Re- factors, opioids, and protease inhibitors.
modelling of the ECM involves a balance between collagen Thrombin (also termed activated factor II or factor IIa) is
synthesis and degradation, which is operated by several en- a protein involved in the final stage of the coagulation cascade
zymes, like matrix metalloproteinases (MMPs), neutrophil- activated by wounding. In addition to its well-documented
released elastase and gelatinase, collagenases and stromely- role in the formation of fibrin clots and platelet activation,
sins [11]. thrombin has direct effects on inflammatory cells, fibrob-
Wounds that do not heal within three months are con- lasts, and endothelial cells: it stimulates chemotaxis and ag-
sidered chronic. In acute wounds, there is a precise balance gregation of neutrophils, lymphocytes, and monocytes cells,
between production and degradation of molecules such as and the proliferation of fibroblasts, epithelial and endothelial
collagen; in chronic wounds this balance is lost and degrada- cells [49, 50]. Thus, thrombin may play an important role
tion plays too large a role. Chronic wound bed has been de- in initiating early cellular events in tissue repair [49]. Since
monstrated to differ from acute wounds for a higher concen- 1988 researchers suggested that thrombin receptor-activating
trations of proteases (such as MMPs) [12] and lower levels peptides could be useful in vivo to mimic the natural effects
of growth factors and cytokines [13]. A high and prolonged of thrombin interaction with receptors on various types of
proteolytic activity may lead to the degradation of growth cells [51], a delivery systems that could provide thrombin a
factors, detaining the wound in the inflammatory stage for long-term protection from its natural inhibitors (antithrom-
too long [14]. bin and activated protein C) has been pursued. In recent
years, nanobiotechnology has provided the means to en-
2. Nanotherapies for Wound Healing hance the bioavailability of thrombin by conjugation with
iron oxide nanoparticles (γ-Fe2 -O3 conjugation) [15]. Ani-
An increasing number of products emerging from the appli- mal models were tested for wound response to the treatment
cation of nanotechnology to the science of wound healing is with conjugated thrombin: on a 28-day treated wound, re-
currently under clinical investigation. The current nanoscale sults obtained analysing tensile strength indicated a signi-
strategies, both carrier, drug related and scaffold (Figure 2), ficant acceleration of healing process when compared
that target the main phases of wound repair will be discussed, with free-thrombin-treated wounds and untreated wounds.
highlighting the cellular signals involved (Table 1). Obtaining a greater tensile strength may potentially reduce
surgical complications such as wound dehiscence.
Nitric oxide (NO) is a small radical, formed from the
2.1. Nanoparticle-Bearing Endogenous Molecules. As we
amino acid L-arginine by three distinct isoforms of nitric
pointed out previously, soluble active proteins (cytokines
oxide synthase. The inducible isoform (iNOS) is synthesized
and growth factors) govern the progression of the healing
phases through the modulation of the cellular and molecular in the early phase of wound healing by inflammatory cells,
components involved [43]. Because of the control they exert mainly macrophages. However, many cells participate in NO
on wound repair, bioactive proteins have gained progres- synthesis during the proliferative phase after wounding. NO
sive interest for the treatment of chronic dehiscent wounds. regulates collagen formation, cell proliferation, and wound
Clinical trials involving the application of exogenous recom- contraction in distinct ways in animal models of wound
binant growth factors to chronic wounds have been con- healing [52]. NO is also a well-known antimicrobial agent,
ducted for the past 10 years in anattempt to find a way to interfering directly with DNA replication and cell respiration
accelerate healing [44]. Although the results of several pilot through the inactivation of zinc metalloproteins [53]. Treat-
trials have been encouraging, the overall results have been ment of acute and chronic wound failure with NO has been
somewhat discouraging. To date, only a single recombinant for years a major unresolved goal. Attempts at novel nitric
4 Journal of Nanomaterials

Inflammation Remodelling Wound contraction

nanoparticles

VAN EGF PDGF Lipoxin A

Embedded

VAN analog
Anti-VEGF Resolvin D1
PDGF TGF-β plasmid DNA
Embedded Embedded Embedded
antibiotic nitric oxide Embedded growth factors Embedded opioids Embedded DNA protease inhibitors
Nanoscaffolds

Silver-loaded nanofibers Stem cells-seeded scaffolds 2D/3D

nanofibrous sheets
nanoparticles
Conjugated

Fe Fe
O O O THR N VAN
O
H
Conjugated thrombin Conjugated antibiotics
nanoparticles
Pure

Silver nanoparticles

Gelatin microparticle
Poly(lactic acid) nanoparticle
Poly(lactide-co-glycolide)
nanoparticle Hyaluronan
nanoparticle
Carboxymethyl chitosan
Neutrophil-derived
nanoparticle nanoparticle
Polyacrylate nanoparticle Solid lipid nanoparticle
Silica nanoparticle

Figure 2: Nanostrategies currently in use for promoting skin wound healing. In the main panel, nanostrategies currently in use to improve
healing are illustrated. The therapeutic potential of nanosphere-based strategies and nanoscaffolds is emphasized through correlation with
the healing phase to which the biological action is targeted. In the right panel, materials explored for nanoparticulate-delivery systems are
listed. Two- and three-dimensional nanofibrous sheets can be made of both degradable (collagen and chitosan) and nondegradable (PLA,
PLACL, polyurethane, and PVA polymers) nanofibers.

oxide therapies, in the form of nitric oxide donors, have return to baseline. The ease of storage, application, and
shown limited potential in treating cutaneous infection [54]. the ability to alter release rate and concentration with
A novel approach is offered by recently engineered nanopor- minimal risk of toxicity make this powder formulation
ous materials, that make possible the storage and delivery of ideal for cutaneous delivery. Authors showed promising
small gaseous short-lived NO, allowing the free radicals to results from NO-releasing nanodelivery systems in pre-
exert their antibacterial activity. Using silane hydrogel-based venting and treating skin infections caused by methicillin-
nanotechnology [23], NO remains trapped and stable within resistant Staphylococcus aureus (MRSA), which is one
a dry matrix until the matrix is exposed to moisture. The dry of the major causes of hospital-acquired infections [55,
matrix allows for NO nanoparticles to be easily stored and 56]. Moreover, NO-releasing silica nanomolecules have
applied. Once exposed to moisture, the drug is released from been demonstrated to exert a bactericidal activity against
the nanoparticle over an extended period of time at a relative- Pseudomonas aeruginosa [57] and Acinetobacter bauman-
ly fixed concentration. This sustained release distinguishes nii [58]: both microbial agents have become an increas-
nanoparticles from other vehicles, such as injections, that ingly prevalent cause of hospital-acquired infections during
release a large concentration of the drug with a rapid the last 15 years, the majority of clinical A. baumannii
Journal of Nanomaterials 5

Table 1: Executive summary table.

Inflammation
(i) thrombin is one of the first products of the coagulation cascade occurring during haemostasis, and is responsible for platelet
activation and aggregation, leading to the formation of the “platelet plug” and allowing cells and fluid to enter the wound bed. In human
plasma, thrombin is rapidly degraded (15 sec). In order to provide long-term protection, it has been conjugated with iron-oxide
nanoparticles for treatment of incisional wounds in rats [15]
(ii) bacterial infection and sepsis exacerbate the inflammatory state and cause tissue damage
(a) nanoparticles bearing vancomycin or N-methyltiolated β lactams have been developed to act against wound contamination by MRSA
[16–19]
(b) silver-based nanoparticles were developed to take advantage on the multilevel antibacterial action of silver and try to reduce the
development of microbial resistance. Pure biostable nanoparticles were produced through photoassisted reduction and ion stabilization.
Silver nanoparticles were also loaded into nanofibers [20]. A direct promotion of wound healing by silver nanoparticles through
reduction of the cytokine-modulated inflammation and cell migration and proliferation was also demonstrated [21, 22]
(c) donor NO silica nanoparticles showed speed healing by killing both Gram-positive and Gram-negative bacteria and overcoming the
NO deficiency [23]. No-releasing nanoparticles may also potentially accelerate healing by a promotion of angiogenesis and tissue
remodelling [24]
Proliferation
(i) the aim of growth factors is to promote cell migration into the wound site, stimulate the growth of epithelial cells and fibroblasts, start
the formation of new blood vessels, and profoundly influence the remodelling of the scar. To enhance the in vivo efficacy of growth
factors they have been incorporated into polymer nanocarriers to sustain release. PLA/PLGA/PEG/hyaluronan/gelatin nanoparticles
embedded with different growth factors have been successfully applied on skin wounds [25–31]
(ii) opioids have been recently indicated as factors promoting keratinocytes migration. Solid lipid nanoparticles were embedded with
opioids, confirming the influence of these drugs on keratinocytes migration [32, 33]
(iii) nanofibrous scaffolds: electrospunnanofibers networks support cell adhesion, proliferation, and differentiation mimicking the
fibrous architecture of the extracellular matrix. Both degradable (collagen and chitosan) and nondegradable (PLA, PVA, PLACL, and
polyurethane) fibers are used for 2D and 3D constructs [34–36]. Scaffolds were also engineered to contain growth factors-releasing
nanoparticles enhancing wound repair [37]
Remodelling
(i) matrix metalloproteinase collagenolytic activity appears to be upregulated in chronic wounds. Protease inhibitors were loaded into
human derived nanoparticles, showing a proresolving action and accelerated healing [38]
(ii) gene therapy: nonviral polymeric gene delivery systems offer increased protection from nuclease degradation, enhanced plasmid
DNA uptake, and controlled dosing to sustain the duration of plasmid DNA administration. Gene delivery systems are formulated from
PLGA polymers, polysaccharides, and chitosan [39–41]
(iii) stem cells: cell-based therapies hold the potential to promote vascularization and tissue regeneration. The hVEGF gene was delivered
through biodegradable polymeric nanoparticles: treated stem cells showed the engraftment of the tissue [42]

isolates displaying high-level resistance to common antibi- enzymes, is to stabilize protein structure and biological ac-
otics [59]. Also, the beneficial effects of NO seem to tivity, prolonging the length of time over which growth fac-
overcome the antimicrobial activity and involve directly the tors are released at the delivery site [60, 61]. The period of
healing process. Experiments demonstrated that pharmaco- drug release from a polymer matrix can be regulated by drug
logical or genetic (NOS knockout) reduction of NO impairs loading, type of polymer used and the processing conditions.
the speed and effectiveness of wound healing, and that Delivery systems have been designed in a variety of config-
this process can be reversed by restoring NO production urations and have been fabricated from different types of
with increased NOS substrate (arginine), or by transfecting natural and synthetic polymers, both degradable and non de-
with the missing NOS gene [24]. Thus, application of NO- gradable. Poly(lactic acid) (PLA) and poly(lactic-co-glycolic
releasing nanoparticles may potentially accelerate healing not acid) (PLGA) have been demonstrated to be biocompatible
only by killing bacteria but also by a promotion of angiogen- and biodegradable suitable materials. To achieve long-term
esis and tissue remodelling. in vivo circulation, the surface is generally modified with
The clinical use of growth factors in wound healing has polyethylene glycol (PEG), reducing the clearance by the re-
been of great interest recently. They have the potential to ac- ticuloendothelial system [25]. In biodegradable carriers,
celerate the healing process by attracting cells into the wound growth factor release is controlled by the polymer matrix’s
site (TGF-β), promoting cell migration, stimulating the pro- rate of degradation, which causes changes in the morpho-
liferation of epithelial cells and fibroblasts (FGF and PDGF), logical characteristics of the materials, such as porosity and
as well as initiating the formation of new blood vessels (FGF permeability [26]. Particulate delivery systems explored in-
and VEGF), and finally participating in the remodelling of volve TGF-β-embedded gelatine microparticles [27], EGF in
the scar [46]. A mean of enhancing the in vivo efficacy of PLA microspheres [28], FGF in gelatin microspheres [29],
growth factors, preventing degradation from proteolytic and PDGF-embedded PLGA nanospheres [30]. In general,
6 Journal of Nanomaterials

porous materials seem to retain a higher specific surface for necessary for proper wound maturation. As previously stat-
the adsorption and release of active components and en- ed, an uncontrolled proteolytic activity leads to delayed heal-
hancement of drug release. Nevertheless, the particles show ing through degradation of growth factors. In light of these
some limits which are associated with the use of organic sol- considerations, research approaches to improve the remod-
vents in the production process, leading to pollution and tox- elling phase are directed to manage enzymatic activity of
icity of the product [62]. Therefore, alternative techniques of MMPs through the topical application of protease inhibitors.
fabrications have been proposed, such as spray drying, which Norling et al. [38] recently took advantage of aspirin-trig-
is based on the use of supercritical fluids (especially CO2 ) and gered resolving D1 and lipoxin A4 analogs and developed a
offers the advantages of being environmentally safe and inex- carrier providing stable biological activity to these natural
pensive [63]. A notable recent application of this technology compounds. Human-derived nanoparticles were enriched
for the delivery of growth factors in vivo was offered by Zavan with the protease inhibitors, and wound healing reactions
et al. [31]: hyaluronan-based (HYAFF11) porous nanoparti- were tested in a murine model. Polymorphonuclear cell in-
cles were embedded with PDGF as a system designed for the flux showed a dramatical reduction in treated wounds, with
in vivo treatment of skin ulcers. PDGF is known since 1986 shortened resolution intervals, and a proresolving action that
to successfully promote chronic wounds healing through a in the end accelerated healing.
stimulation of chemotaxis, proliferation and ECM deposi-
tion [64]. HYAFF11, the benzyl ester of hyaluronic acid, is 2.2. Nanoparticle-Bearing Antibiotics. During the healing
a biopolymer that has found numerous applications for process, infection is an issue potentially compromising the
in vitro reconstruction of skin as well as for the in vivo regen- final wound closure, exacerbating the tissue damage [68].
eration of small arteries and veins [65]. HYAFF particles have Nowadays, wound infection is no longer the ominous event
the ability to absorb growth factors and to release them in a as at the beginning of the 20th Century, when infection of
temporally and spatially specific event-driven manner. This wounds, especially burns, was the major cause of morbidity
timed and localized release of PDGF promoted optimal tissue and mortality (over 50%) [69]. Nevertheless, an appropriate
repair and regeneration of full-thickness wounds. antimicrobial therapy of the wound controlling colonization
Beside the dedicated growth factors, opioids have been and proliferation of microbial pathogens, including multi-
recently indicated as factors promoting keratinocytes migra- drug-resistant organisms, is still required for an appropriate
tion [66]. This finding is of great interest because of a possible wound care. Staphylococcus aureusis one of the most com-
enhancement of wound healing through topical applications mon pathogens involved in wound infections. The pharma-
of opioids at the wound site for pain reduction. Conventional cological treatment encounters today severe limitations due
formulations failed to consistently provide sufficient pain to the development of antibiotic resistant strains. For exam-
control in patients, possibly due to local drug degradation or ple, penicillinase (an enzyme that breaks down the β-lactam
insufficient concentrations at the target site [32]. Since long ring of the penicillin molecule) is responsible for the resis-
intervals for painful wound dressing changes are intended, tance to penicillin of Staphylococcus aureus: the failed treat-
the formulations should allow for prolonged opioid release. ment of staphylococcal local infections leads to the onset of
Bigliardi et al. [32] first developed nanoparticulate carriers to serious late complications (bacteraemia, sepsis, toxic shock
increase opioids skin penetration and slow the release of the syndrome) [69].
loaded drug. Experiments on human keratinocyte-derived The delivery of antibiotic therapy via nanoparticles offers
cell line HaCaT showed that opioids stimulated cell migra- great potential advantages. Particularly, a controlled release
tion and closure of experimental wounds. Enhancement of would decrease the number of doses required to achieve the
migration was concentration-dependent and could be block- desired clinical effect, potentially reducing the risk of devel-
ed by the opioid receptor antagonist naloxone, indicating a opment of antibiotic resistance. The physiochemical proper-
specific opioid-receptor interaction. Küchler followed [33] ties of nanoparticulate drug delivery systems (size, surface
demonstrating that morphine-loaded solid lipid nanopar- charge, and nature) are determinant in vivo for the factors
ticles accelerated reepithelialisation on a human-based 3D- delivery. In particular, it is known that 20–200 nm particu-
wound healing model. On standardised wounds, keratino- lates are suitable for delivery of therapeutics; larger size par-
cytes almost completely covered the dermis equivalent after ticles suffer from quick uptake by the reticulo-endothelial
4 days, which was not the case when applying the unloaded system and rapid clearance from circulation, whereas the
particles. In conclusion, acceleration of wound closure, low smaller size will tend to cross the fenestration in the hepatic
cytotoxicity, and irritation as well as possible prolonged mor- sinusoidal endothelium, leading to hepatic accumulation
phine release make solid lipid nanoparticles an interesting [70].
approach for innovative wound management. In the treatment of staphylococcal infections, the latest
Matrix metallo proteinases (MMPs) are zinc-dependent generation antibiotic and assumed to be the most useful at
endopeptidases that cleave most macromolecules within the the moment is vancomycin. Several vancomycin-modified
ECM during the maturation of the wound [67]. The process nanoparticles have been developed to enhance the pharma-
of remodelling constitutes a balance between collagen pro- cokinetics and pharmacodynamics of the antibiotic mole-
duction, breakdown, and remodelling. The biological activ- cule. Hachicha et al. [16] recently proposed the use of vanco-
ity of MMPs is strictly balanced by the presence of specific tis- mycin-conjugated nanoparticles for intraocular continu-
sue inhibitors (TIMPs). A tightly coordinated expression of ous release injection for endophthalmitis prophylaxis. The
specific combinations of MMPs and TIMPs appears to be drug concentration was proved to be maintained above
Journal of Nanomaterials 7

the minimal inhibitory limit for 24 hours. Chakraborty et al. and migration of keratinocytes along with a differentiation
[17] developed carboxymethyl chitosan-based nanoparticles, of fibroblasts into myofibroblasts, thereby promoting wound
which were loaded with vancomycin and proved effective contraction [22].
against drug-resistant staphylococcal strains. Though the progressive expansion of the therapeutic ap-
The effectiveness of nanobiotechnology in enhancing the plication of silver nanoparticles, the use of a metallic com-
therapeutic properties of antibiotic molecules is emphasized pound carries possible side effects that must be taken into
by the case of N-methylthiolated β-lactams: these com- consideration. Studies have been investigating the biosafety
pounds have been recently identified and proved effective of silver as a therapeutic agent, reporting an acceptable bio-
against Staphylococcus bacteria, including MRSA. These lac- compatibility [74], though the occasional development of
tams exert growth inhibitory effects on bacteria through a argyria (a cosmetic blue-grey coloration of the skin).
mode of action that is distinctively different from other β-
lactam antibiotics, with peculiar structure-activity patterns. 2.4. Nanoparticles and Gene Therapy. Polymeric gene deliv-
Nevertheless, their potential application is limited by the ery systems offer several advantages for plasmid DNA
exceeding low water solubility [18]. Thus, a methodology delivery, such as protection from degradation by the nuclease
was developed by Turos et al. [19] to obtain an emulsion of and controlled prolonged release. The potential retained by
polyacrylate nanoparticles in which the drug monomer was the modulation of gene expression in the process of wound
incorporated into the polymeric matrix: in vitro screens healing lead researchers to apply for an engineered system
confirmed the nanoparticles to be nontoxic to human dermal for DNA transfection. Actually, transfection capability has
fibroblasts and stable in blood serum for 24 hours. been tested in vitro: biocompatible and biodegradable PLGA
Within the bacterial species, resistance to all known anti- polymers [39] were engineered to obtain high plasmid load-
biotic classes has occurred due to mutation and horizontal ing efficiency [75] and then loaded withan antiangiogenic
gene transfer. This has led to anxiety regarding the futurea plasmid DNA (pFlt23k). The PLGA nanoparticles were pre-
vailability of effective chemotherapeutic options. Due to the pared by a supercritical fluid extraction of emulsions based
outbreak of infectious diseases caused by different patho- on CO2 : this allowed high loading of pDNA (19.7%, w/w),
genic bacteria and the development of antibiotic resistance, high loading efficiency (>98%), and low residual solvents
the pharmaceutical companies and the researchers are now (<50 ppm). The VEGF secretion by epithelial cells was signi-
searching for new antibacterial agents. ficantly reduced, showing a potential value in treating wound
disorders in which VEGF is elevated.
2.3. Silver-Based Nanoparticles. The use of silver for the treat- In the course of studies on nonviral DNA carriers for
ment of ulcers is reported since the 5th Century B.C. In the gene delivery and therapy other materials have been applied,
17th and 18th centuries, silver nitrate was already used for like polysaccharides and other cationic polymers. Chitosan
ulcer treatment. The antimicrobial activity of silver was esta- also was found to be particularly suitable, since it can pro-
blished in the 19th century. Nevertheless, after the introduc- mote long-term release of incorporated drugs [76]. Masotti
tion of antibiotics in 1940 the use of silver salts decreased. and Ortaggi recently described a nanofabrication method
Subsequently, silver salts and silver compounds have been that may be useful for obtaining small DNA-containing
used in different biomedical fields, especially in burn treat- chitosan nanospheres (38 ± 4 nm) for biomedical applica-
ment [71]. tions [40]. Their reported osmosis-based method has general
The antimicrobial activity of silver appears high: due to applicability to various synthetic or natural biopolymers, re-
its multilevel (including multidrug resistance) antibacterial sulting in nanostructured systems of different size and shape
effects [72] and low systemic toxicity [73], it provides an anti- that may be used in several biotechnological applications.
bacterial effect that considerably reduce the chances of de- Chellat et al. also recently took advantage of the biochemical
veloping resistance. Evidently, the greatest rate of silver ions properties of chitosan to test DNA-loaded nanoparticles on
release is wished in order to enhance the clinical effect and a human macrophage cell line to study the potential modula-
avoid the insurgence of silver-resistant mutant bacteria. tion of the expression of proinflammatory cytokines, metal-
Nanotechnology has provided the means of producing pure loproteinases and their specific inhibitors [41]. The secretion
biostable silver nanoparticles, either through photoassisted of MMP-9 in cell supernatants increased significantly after 24
reduction and ion stabilization or loading of the metallic par- and 48 h in comparison with nontreated cells. MMP-2 secre-
ticles into nanofibers [20]. In all cases, 7–20 nm silver nano- tion was augmented only after 48 h with incubation of the
particles exhibited antibacterial (especially anti-Gram nega- highest concentrations of nanoparticles (10 and 20 μg/mL
tive) and antifungal activity, and they are also synergistic to DNA content). However, zymography studies showed that
common antibiotic therapy (streptomycin, kanamycin, and secreted MMPs were in their proactive form, while in the
polymyxyn B) [20]. Studies in vivo demonstrated also a direct presence of 10 and 20 μg/mL DNA-containing nanoparticles,
promotion of wound healing by silver nanoparticles through the active form of MMP-9, but not MMP-2, was detected in
reduction of the cytokine-modulated inflammation: silver- cell lysates. The results obtained were significative only for
induced neutrophils apoptosis, decreased MMPs activity, and increased secretion of metalloproteinases, possibly related to
negative modulation on TGF-β resulted in an overall acceler- nanoparticles phagocytosis.
ation of wound healing rate and reduction on hypertrophic
scarring [21]. Also, wound healing rate was demonstrated to 2.5. Nanoparticles and Stem Cells. Stem cells are lauded for
be increased by silver ions by a promotion of proliferation their unique ability to develop into every kind of cell. Even if
8 Journal of Nanomaterials

in vivo studies and clinical trials have demonstrated limita- The electro spinning technique can provide both degrad-
tions in reconstituting tissue due to the lack of microenviron- able (collagen; chitosan) and nondegradable (PLA, polyvinyl
ment-control on proliferation and survival, the successful alcohol (PVA) polymers) nanofibers for two-dimensional
use of these cells for investigation towards disease therapy is nanofibrous sheets. Both sorts of biomaterials have been
still pursued. Last decade has witnessed a growth in the field tested in vivo showing an increased rate of wound epithelia-
of nanoparticles technology for stem cells isolation, main- lisation and dermis organization [34], as well as good anti-
tenance, and regulation: nanoparticles and nano 3D archi- bacterial activity against the Gram-positive and Gram-nega-
tectures have been developed to control stem cells prolifera- tive bacteria [35]. Nanofibrous scaffolds of poly(L-lactic
tion, differentiation, and maturation [77]. In terms of skin acid)-co-poly(ε-caprolactone) (PLACL) and PLACL/gelatin
regeneration, VEGF high-expressing, transiently modified complexes were fabricated by Chandrasekaran et al. [36].
stem cells have been developed for the purpose of promot- These nanofibres were characterized by fiber morphology,
ing angiogenesis [42]. In order to overcome the insufficient membrane porosity, wettability, and chemical properties by
expression of angiogenic factors and low cell viability after FTIR analysis to culture human foreskin fibroblasts for skin
transplantation, nanotechnology has provided nonviral, bio- tissue engineering. The results showed that fibroblasts prolif-
degradable polymeric nanoparticles to deliver hVEGF gene eration, morphology, and secretion of collagen were signif-
to human mesenchymal stem cells (hMSCs) and human em- icantly increased in plasma-treated PLACL/gelatin scaffolds
bryonic stem cell-derived cells (hESdCs). Treated stem cells compared to PLACL nanofibrous scaffolds. The obtained
demonstrated markedly enhanced hVEGF production, cell results proved that the plasma-treated PLACL/gelatin nanofi-
viability, and engraftment into target tissues. Implantation brous scaffold is a potential biocomposite material for skin
of scaffolds seeded with VEGF-expressing stem cells (hMSCs tissue regeneration.
and hESdCs) led from 2 to 4 fold higher vessel densities 2 Moreover, nanofibrous constructs can be obtained with
weeks after implantation, compared with control cells or cells a 3D profile, even though they scarcely support cells seeding
transfected with VEGF by using Lipofectamine 2000, a lead- because of their high porosity. Several strategies have been
ing commercial reagent. Four weeks after intramuscular in- developed to improve cell infiltration, showing promising
jection into mouse ischemic hindlimbs, genetically modified results [79]. Chong et al. [80] proposed a cost-effective com-
hMSCs substantially enhanced angiogenesis and limb sal- posite consisting of a nanofibrous scaffold directly electro-
vage, while reducing muscle degeneration and tissue fibrosis spun onto a polyurethane dressing (Tegaderm, 3 M
[42]. These results indicate that stem cells engineered with Medical)—Tegaderm-nanofiber (TG-NF) construct—for
biodegradable polymer nanoparticles may be therapeutic dermal wound healing. Cell culture was performed on both
tools for vascularizing tissue constructs and treating ischemic sides of the nanofibrous scaffold and tested for fibroblast
disease. adhesion and proliferation. Results obtained in this study
suggested that both the TG-NF construct and dual-sided
fibroblast-populated nanofiber construct achieved signifi-
2.6. Nanofibrous Scaffolds. The basic strategy of engineered cant cell adhesion, growth, and proliferation. This was a suc-
tissue regeneration is the construction of a biocompatible cessful first step for the nanofiber construct in establishing
scaffold that, in combination with living cells and/or bioac- itself as a suitable three-dimensional scaffold for autogenous
tive molecules, replaces, regenerates, or repairs damaged fibroblast populations and providing great potential in the
tissues. The scaffold should possess suitable properties, like treatment of dermal wounds through layered application.
biocompatibility, controlled porosity and permeability, and, Steps towards an enhanced regenerative effect will be to
additionally, support for cell attachment and proliferation. provide scaffolds a delivery system for drugs, growth factors
This artificial “dermal layer” needs to adhere to and integrate or cytokines that may further promote cell function and tis-
with the wound, which is not always successful for the sue regeneration [81]. Jin et al. already worked towards this
current artificial dermal analogues available. The high cost of direction engineering PLGA microspheres in nanofibrous
these artificial dermal analogues also makes their application scaffolds to control the release of PDGF in vivo [37]. PDGF
prohibitive both to surgeons and patients. Engineering der- concentration was evaluated in a soft tissue wound repair
mal substitutes with electrospun nanofibres have lately been model in the dorsa of rats. At 3, 7, 14, and 21 days after-
of prime importance for skin tissue regeneration. Simple implantation, the scaffold implants were harvested followed
electro spinning technology served to produce nanofibrous by assessments of cell penetration, vasculogenesis, and tissue
scaffolds morphologically and structurally similar to the neogenesis. Gene expression profiles using cDNA microar-
extracellular matrix of native tissues. The engineered net- rays were performed on the PDGF-releasing NFS. The per-
work has been shown to support cell adhesion, proliferation, centage of tissue invasion into microspheres-containing
and differentiation mimicking the fibrous architecture of nanofibrous scaffolds at 7 days was higher in the PDGF
the extracellular matrix [60]. The large surface area and groups when compared to controls. Blood vessel number in
porosity of electrospun nanofibers enables good permeability the groups containing either 2.5 or 25 μg PDGF was increased
for oxygen and water and the adsorption of liquids, and con- above those of other groups at 7d (P < 0.01). Results from
comitantly protects the wound from bacterial penetration cDNA array showed that PDGF strongly enhanced in vivo
and dehydration. This feature shows electrospun nanofibers gene expression of the CXC chemokine family members
to be a suitable material for wound dressing, especially for such as CXCL1, CXCL2, and CXCL5. Thus, sustained release
chronic wounds such as diabetic ulcers or burns. of rhPDGF-BB, controlled by slow-releasing microspheres
Journal of Nanomaterials 9

associated with the nanofibrous scaffold delivery system, [3] S. S. Suri, H. Fenniri, and B. Singh, “Nanotechnology-based
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Nanomaterials
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Scientifica
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World Journal
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Biomaterials
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Nanoscience
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Coatings
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