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BE20CH15_Rege ARI 29 April 2018 11:35
Annual Review of Biomedical Engineering
Inorganic Nanomaterials
for Soft Tissue Repair and
Regeneration
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Annu. Rev. Biomed. Eng. 2018.20:353-374. Downloaded from www.annualreviews.org
Russell Urie,1 Deepanjan Ghosh,2 Inam Ridha,3

and Kaushal Rege1
1
Department of Chemical Engineering, Arizona State University, Tempe, Arizona 85287-6106,
USA; email: rege@asu.edu
2
Department of Biological Design, Arizona State University, Tempe, Arizona 85287-6106, USA
3
Department of Biomedical Engineering, Arizona State University, Tempe,
Arizona 85287-6106, USA
Annu. Rev. Biomed. Eng. 2018. 20:353–74 Keywords

First published as a Review in Advance on wound healing, tissue adhesives, laser sealing, gold nanoparticles, carbon
April 5, 2018
nanomaterials, cardiac repair, neural repair, inflammation, antibacterial
The Annual Review of Biomedical Engineering is
online at bioeng.annualreviews.org Abstract
https://doi.org/10.1146/annurev-bioeng-071516- Inorganic nanomaterials have witnessed significant advances in areas of
044457
medicine including cancer therapy, imaging, and drug delivery, but their
Copyright c 2018 by Annual Reviews. use in soft tissue repair and regeneration is in its infancy. Metallic, ceramic,
All rights reserved
and carbon allotrope nanoparticles have shown promise in facilitating tis-
sue repair and regeneration. Inorganic nanomaterials have been employed
to improve stem cell engraftment in cellular therapy, material mechanical
ANNUAL
REVIEWS Further stability in tissue repair, electrical conductivity in nerve and cardiac regener-
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online features: ation, adhesion strength in tissue approximation, and antibacterial capacity
• Download ﬁgures as PPT slides
• Navigate linked references in wound dressings. These nanomaterials have also been used to improve
• Download citations
• Explore related articles or replace common surgical materials and restore functionality to damaged
• Search keywords tissue. We provide a comprehensive overview of inorganic nanomaterials in
tissue repair and regeneration, and discuss their promise and limitations for
eventual translation to the clinic.
353
Contents
1. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 354
2. TISSUE REPAIR MECHANISMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355
3. TISSUE REPAIR APPROACHES IN THE CLINIC . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
3.1. Primary Intention Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 356
3.2. Secondary Intention Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
3.3. Nonintention Repair and Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
4. INORGANIC NANOMATERIALS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358
5. TISSUE REPAIR USING INORGANIC NANOMATERIALS . . . . . . . . . . . . . . . . . . 360
5.1. Tissue Adhesives and Sealants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360
5.2. Infection Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361
5.3. Wound and Burn Dressings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

6. TISSUE REGENERATION USING INORGANIC NANOMATERIALS . . . . . . 365
6.1. Stem Cell Targeting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
6.2. Neuroregeneration and Spinal Cord Repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
6.3. Cardiac Repair and Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 367
6.4. Beyond Heart and Nerve Repair and Regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
5. CONCLUSIONS AND FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 369
1. INTRODUCTION
Repair and regeneration of soft tissues including skin, gastrointestinal tract, and other internal
organs have undergone dramatic changes in the past century. Gauzes, sutures, staples, hemostats,
and wound dressings have progressed from animal- or plant-derived products to synthetic materials
that elicit a lesser inflammatory response and can, in some cases, be absorbed by the body (1). In
tissue and organ repair, however, functionality can be lost or extensive scarring can occur even
as discontinuous tissue is rejoined. The length scale above which functionality is lost due to an
injury can be on the order of 150 μm or less, and conventional repair demonstrates suboptimal
performance in recovery of tissue functionality at even moderate surgical length scales.
Inorganic nanomaterials have the potential to overcome limitations of conventional materials
used in soft tissue repair, leading to novel treatment modalities in the clinic. Whereas conventional
tissue repair involves removal of damaged or necrotic tissue and uses conventional materials to fill
the tissue discontinuity or mechanically approximate the tissue edges (2), recent approaches to soft
tissue repair, including using inorganic nanomaterials, aim to actively promote or stimulate repair
and regeneration. Potential advantages of using inorganic nanoparticles (NPs) in soft tissue repair
include ease of application, consistency, versatility, speed, effectiveness, functionality, minimal
invasiveness, and viable alternatives for difficult-to-obtain grafts and transplantations that may be
rejected or elicit a significant inflammatory response (2, 3). In this review, we discuss recent and
important advances in the use of inorganic nanomaterials for soft tissue repair and regeneration,
as well as assess the implications and future of the field. Specifically, we highlight recent advances
in tissue adhesives, surgical sealants, alternatives to sutures and staples, hemostats, wound dress-
ings, stem cell targeting, and tissue engineering scaffolds, with a focus on preclinical findings in
animal models. In the following sections, we briefly review the properties and limitations of the
more commonly used inorganic NPs. Subsequently, we showcase research in which inorganic
nanomaterials have been employed in tissue repair and regeneration, and also discuss the breadth
of future possibilities in this exciting field.
354 Urie et al.
Tissue formation Tissue remodeling

Inflammation
Re-epithelialization
Response intensity
Angiogenesis
Matrix protein production
Increase tensile strength
Bleeding Inflammatory Reduce cellularity

cell infiltration
Coagulation
Cytokines
Proteases
0.1 0.3 1 3 10 30 100 300

Days postwounding (log scale)
Figure 1
Representation of various phases of wound healing. Data are from Reference 4.
2. TISSUE REPAIR MECHANISMS

Tissue repair is a highly orchestrated series of events in response to injury. Skin repair is perhaps
the most-studied and best-understood model of tissue repair and is discussed briefly here as a
model. Wound healing is a dynamic interplay of hemostasis, inflammation, and cell migration
and proliferation, ultimately resulting in wound contraction and remodeling (4) (Figure 1). The
hemostasis phase involves platelet aggregation, which consists of a cascade of soluble mediators,
parenchymal cell migration, and extracellular matrix (ECM) formation (5). Hemostasis initiates
healing through vasoconstriction, platelet degranulation and aggregation, and fibrin deposition
(4), providing a provisional ECM for subsequent cell migration (4, 6).
Inflammation involves increased capillary permeability (4, 7), which facilitates the recruitment
of phagocytic neutrophils and macrophages, monocytes, and lymphocytes (8) at the wound site
(6, 9). The retardation of inflammation can occur due to absence or deficiency of these cell types.
Prolonged inflammation, due to incomplete clearance of debris because of continuous cellular
damage, and activation of the immune cells result in dysfunction, greater fibrosis, and scarring.
Tissue damage is amplified, and the remodeling phase is limited, resulting in a chronic wound
environment.
Proliferation is characterized by angiogenesis, reepithelialization, fibroplasia (8), and synthe-
sis of ECM collagen (4, 6). Keratinocyte migration to the injury is followed by angiogenesis.
These new vessels facilitate keratinocyte migration later in the repair process (5). Fibroblasts and
macrophages arrive and replace the clotted fibrin matrix with granulation tissue. Several growth
factors, including heparin-binding epidermal growth factor–like growth factor, modulate kera-
tinocyte migration and endothelial cell proliferation, and vascular endothelial growth factor A
promotes angiogenesis (4, 5). During fibroplasia, fibroblasts migrate, proliferate, and produce
ECM components and granulation tissue (4).
www.annualreviews.org • Inorganic Nanomaterials for Soft Tissue Repair and Regeneration 355
Wound contraction begins after reepithelialization, lasting until 2 weeks postinjury (4). Fibro-
blasts transform to a myofibroblast phenotype, exhibiting a strong contractile force using α smooth
muscle actin bundles (4). Tissue remodeling occurs over a much longer timescale than the other
phases, and can last for a year or longer (5). This phase is often referred to as the tissue regeneration
phase because the provisional matrix established at the wound is gradually replaced with tissue
more similar to the native tissue. Endothelial cells, macrophages, and myofibroblasts are removed
from the site by apoptosis (5). Collagen is realigned along tension lines; ECM remodeling replaces
type III collagen with type I collagen (4) through the secretion of matrix metalloproteinases by
fibroblasts, macrophages, and neutrophils. Matrix metalloproteinase secretion is then inhibited by
transforming growth factor β1, and collagen fibers accumulate as remodeling ends (4, 5), resulting
in scar tissue (10). Chronic wounds or unresolved injury sites demonstrate excess scarring due to
the temporary or permanent delay of the remodeling phase.
These phases are dependent on the unique conditions of each injury. The healing process and
outcomes vary on the basis of the tissue type and the extent and kind of injury (7). Some soft tissue
types do not regenerate functional tissue or have limited regenerative capacity. Blood clotting,
inflammation, fibrosis, or other aspects of the tissue repair process can hinder functional regenera-
tion. However, a paradigm shift that streamlines the modulation of these processes for therapeutic
benefit rather than attempting to avoid them may serve to enhance the efficacy of tissue repair.
3. TISSUE REPAIR APPROACHES IN THE CLINIC

Tissue discontinuities are healed by means of primary, secondary, or tertiary intention. Primary
intention involves the union of tissue edges by mechanical approximation. Primary intention is
applicable in injuries with disruption in tissue continuity, but with minimal tissue loss or necrosis.
Secondary intention heals injuries in which tissue edges cannot be joined mechanically, generally
due to significant tissue loss or a limiting tissue geometry. Secondary intention healing allows the
formation of granulation tissue to fill the negative space resulting from the injury or debridement of
necrotic tissue. Tertiary intention healing, often referred to as delayed primary intention, applies
to injuries that are intentionally left open—for example, for drainage or treatment of infection—
and subsequently approximated. Tertiary intention has limited application and is not addressed
in this review.
3.1. Primary Intention Repair

Precise disruption of soft tissues with minimal damage to surrounding tissue and the basal mem-
brane is usually observed in cases of surgical incisions, anastomoses, and ligations. In surgical
incisions, the method of closure depends on site accessibility (11), but generally repair occurs
via primary intention. Tissue approximation is conventionally accomplished by sutures, staples,
adhesives, and sealants (12) to reduce infection and facilitate rapid satisfactory cosmesis (13).
Sutures are the most common means of approximation (11). The most frequently used sutures
are synthetic because of the inflammatory response to biologically derived materials (11, 13, 14).
Sutures are further classified as absorbable and nonabsorbable (13). Absorbable sutures must retain
mechanical strength during wound healing and yet be resorbed as the tissue heals (11). Suture
breakdown occurs through enzymatic degradation or hydrolysis for natural or synthetic sutures,
respectively (11). Sutures that retain mechanical integrity for more than 6 months are considered
nonabsorbable (14) and are eventually encapsulated by fibroblasts (11). Despite their extensive use
and simplicity, sutures have a number of limitations, including wound dehiscence after surgery
(13). Monofilament sutures have memory, limiting surgeon dexterity, while braided sutures are
356 Urie et al.

susceptible to bacterial colonization (11). Nonabsorbable sutures have high stress concentration,
leading to granuloma formation after extended residence in the body. Suturing is not feasible in
many surgical situations, and leakage of fluid (blood, bowel content, bile, cerebrospinal fluid, etc.)
across the suture line causes surgical complications, such as failure followed by intra-abdominal
abscesses, fistula, peritonitis, and mortality (14, 15).
Absorbable and nonabsorbable staples (13) have been widely used for wound closure (14).
Nonabsorbable stainless steel staples demonstrate high tensile strength (16), while absorbable
poly(lactic-co-glycolic acid) staples are resorbed completely over a period of months (16). Clinical
studies show no significant difference in cosmetic appearance, mechanical strength, complications
and infection, dehiscence, or inflammation among stapled or sutured wounds (17, 18). Staple re-
moval requires a special instrument that grasps the crossbar of the staple to bend them out of the
tissues, which can make the process more painful than suture removal (14, 18). However, for a num-
ber of procedures, including anastomoses, staples are the faster method compared with sutures (19).
Adhesive tapes can also be used for wounds with well-approximated margins. They can be
relatively inexpensive and are easy to apply and remove, with minimal reactivity (16). Their appli-
cation is limited to superficial wounds; they cannot be used in wounds under tension (14, 16). As a
result, adhesive tapes have found limited usage in tissue repair beyond superficial wound closure.
Adhesive sealants can be applied easily and with little pain (12, 14), and several natural and
synthetic sealants have been investigated (15). Synthetic cyanoacrylate glues are common, but their
use is limited to surface wounds because of the toxic degradation products of some formulations
(20). Poly(ethylene glycol) (PEG)-based adhesives find limited use because of low mechanical
strength and high swelling (21). Natural adhesives (e.g., fibrin glue) also face significant drawbacks,
including low mechanical strength, stiffness, low adhesion (22), and/or high immunogenicity (15).
Although several commercial adhesives are available, many do not meet the demands of the highly
dynamic tissue repair environment (15, 22).
3.2. Secondary Intention Repair

Secondary intention can be considered the most elementary form of tissue repair. In this approach,
the wound is left open to heal. The healing occurs from the basal layer upward and from the injury
edges inward (11). Clinicians often avoid secondary intention due to the desire for immediate
reconstruction, difficult-to-predict outcomes, more extensive scarring, extended healing times,
need for extensive wound dressings, and off-loading pressure from the healing site. Burns or
extensive trauma injuries cause considerable damage, making it difficult to repair by primary
intention. Strains, sprains, contusions, tendinitis, and other soft tissue injuries may not immediately
be associated with a loss of tissue continuity; nevertheless, they are results of microtears in the
respective tissue (muscles/tendons, ligaments, capillaries, etc.) and can be thought of as healing
via secondary intention.
Ideal wound dressings are gas permeable but impermeable to bacteria and fluids, absorbent to
retain wound exudate, able to promote a local moist environment, nonadherent, easily removed,
and elastic with deformation resistance. Wound dressings can be formed as coated cotton bandages
or gauze, sponges, foams, electrospun matrices, or hydrogels from biologic or synthetic polymers.
Surgical meshes and other support materials can be used to treat stomach ulcers, hernias, and
other partial- or full-thickness injuries to internal tissue.
3.3. Nonintention Repair and Regeneration

Some soft tissue injuries occur without a break in tissue continuity. Embolisms and aneurysms, for
example, can lead to necrotic tissue, where blood flow has been lost and vasculature is weakened.
This, in turn, alters the tissue’s strength and thickness, and can ultimately break the architecture
and function of the tissue or organ (23). Fibrosis can occur in other cases as well, notably including
cirrhosis of the liver, glial scars in the nervous system, and Crohn’s disease (24, 25). In some cases,
the fibrotic tissue is excised, resulting in healing by primary or secondary intention, but in other
cases, novel regenerative treatments may be more appropriate to remodel the fibrotic tissue.
4. INORGANIC NANOMATERIALS
Nanoscale particles (1–100 nm) demonstrate properties that are not observed at the macroscopic
scale (26, 27). Metal-based, carbon allotrope, or ceramic NPs are commonly used in biomedical
applications. Metal/metal oxide–based NPs include those based on gold, silver, zinc, magnesium,
iron, and titanium. Carbon NPs include graphene nanosheets and carbon nanotubes (CNTs), and
ceramic NPs include clay, silica, calcium, and bioglass NPs. Inorganic NPs demonstrate a wide
diversity of tunable properties, which make them attractive for tissue repair applications (28, 29).
Silver NPs have been widely used for their antimicrobial properties in medical implant devices,
food packaging materials, topical creams and ointments, and other applications. Gold NPs can
be easily tuned to various sizes and shapes, including spheres, rods, cages, and shells; are easy
to modify; and demonstrate size-dependent optical properties (30). For these reasons, gold NPs
have been widely studied in drug delivery and tumor thermal ablation, including in clinical trials
for cancer (see https://clinicaltrials.gov/show/NCT02761525). Iron oxide NP formulations,
including Venofer R
, Ferrlecit
R
, INFedR
, Dexferrum, R
and Feraheme R
, have been approved
by the US Food and Drug Administration (FDA) for treating anemia related to chronic kidney
disease (31, 32). Additionally, ferumoxytol (i.e., Feraheme R
) is being investigated in imaging (33;
see https://clinicaltrials.gov/show/NCT01663090), although similar superparamagnetic iron
oxide NPs (SPIONs) have been discontinued (34).
Graphene oxide nanosheets are single layers of graphite in a hexagonal lattice (35). Graphene
oxide nanosheets have high surface area and adsorption capacity and demonstrate optical, elec-
tronic, and quantum properties (36), including absorption of UV and near-IR (NIR) light.
Graphene has been investigated for cell culture applications (37), including stem cell differen-
tiation (38). CNTs can be regarded as sheets of graphene rolled into a cylinder, in either single-
walled or multiwalled configurations, and are often capped at least at one end by fullerene (39).
CNTs are among the strongest and stiffest materials known. CNTs exhibit structural similarities
to collagen fibers (40) and influence cell adhesion, proliferation, and differentiation (41). Silica
nanomaterials have also been used extensively in bone and dental engineering (42). Clay NPs are
layered sheets of silicate, and as stacked two-dimensional sheets, they have extremely high sur-
face areas. Common clay NPs include laponite, montmorillonite, sepiolite, and hectorite, among
others (43). Other inorganic NPs, including those derived from aluminum, magnesium, calcium,
and zinc, have not found as extensive use in soft tissue repair and regeneration, although many
of their properties and limitations are similar to those of the NPs listed above (44–46). Despite
these interesting properties, inorganic NPs often are not directly employed in tissue repair and
regeneration because of a number of limitations. Solid NP powders or dispersions can be brittle
and unsuitable for significant load-bearing applications in soft tissues. Additionally, although some
dissociation products can be beneficial, they can also be toxic when released in high concentrations
and may elicit strong inflammatory responses. The reader is directed to a number of review articles
discussing NP toxicity in greater detail (47–50). More commonly, inorganic nanomaterials used
in tissue repair typically interface these NPs and their hybrids with synthetic and/or biological
materials, including hydrogel-based materials (51, 52), electrospun matrices (53), and viscous gels
(54), among others.
358 Urie et al.

Increase cell adhesion

and differentiation
Carbon Iron oxide

nanotubes nanoparticles
Improve scaffold Improve stimulus

mechanical properties Metal responsiveness
Carbon
on
Graphene oxide Gold

nanosheets nanorods
Clay
nanoplatelets
Increase therapeutic
Include imaging, cell

tracking, or directing delivery and uptake
Mesoporous silica
nanoparticles
Ceramic
Incorporate
antimicrobial activity
Figure 2
Inorganic nanoparticles and their properties. Inorganic nanoparticles containing carbon allotrope
nanoparticles (e.g., carbon nanotubes, graphene oxide nanosheets), which are generally accepted as inorganic
materials, metal/metal oxide–based nanoparticles (e.g., superparamagnetic iron oxide nanoparticles, gold
nanoparticles), or ceramic nanoparticles (e.g., clay nanoparticles, mesoporous silica nanoparticles) are shown.
Incorporation of inorganic nanoparticles into biologically relevant materials can increase cell adhesion and
differentiation; impart the ability to respond to external stimuli; increase the delivery or cellular uptake of
molecular therapeutics; help incorporate antimicrobial activity within the material; facilitate the imaging,
tracking, or directed proliferation of cells; and improve the mechanical properties or degradation
characteristics of the nanomaterial.
Incorporation of NPs imparts different functionalities to the resulting nanomaterials

(Figure 2). First, NPs’ stimulus-responsive properties allow for modulation of real-time anal-
ysis of material integration, degradation, and fate (55). Stimulus responsiveness can be an inherent
property of NPs, and inorganic NPs can respond to a variety of external stimuli including pH,
light, magnetism, and ultrasound. For example, the inherent plasmonic properties of gold nano-
structures make them responsive to visible and NIR light, and the superparamagnetic properties
of SPIONs make them responsive to magnetic moments. NPs can also be made stimuli responsive
through functionalization with moieties that respond to pH, redox changes, and/or temperature.
Second, NPs embedded within a matrix enhance the integrity of the resulting nanomaterial. In
particular, material strength and degradation behavior can be tuned by NP fillers or linkers (51).
Third, the alignment, structure, or surface morphology of NPs can be modulated for specific
applications. Fourth, inorganic NPs can facilitate increased loading of drugs, genes, growth fac-
tors, and/or biologically active species, because of the high ratio of surface area to volume at the
nanoscale (56, 57). Release mechanisms and kinetics from these NPs can be tailored through
modulation of their size, shape, and surface chemistry. Furthermore, inorganic NPs are often
inert and can provide greater stability to loaded therapeutic molecules, which can enhance their
efficacy. Fifth, NPs increase the sites for cell adhesion within a scaffold, which can allow for greater
cell migration, proliferation, and differentiation. Inorganic NPs can facilitate high adsorption of
proteins, including ECM glycoproteins, which are common sites for cell adhesion. A number
of inorganic NPs, including those made from silver, calcium phosphate, and silica, release ions
as they disassociate, and these ions may affect cell viability, differentiation, or morphogenesis in
unique ways. The following sections highlight key advances in the use of inorganic nanomaterials
for tissue repair and regeneration.
5. TISSUE REPAIR USING INORGANIC NANOMATERIALS

In the clinic, tissue repair is performed using a variety of devices including sutures, staples, clips or
hooks, gauze, bandages, and meshes. A diverse array of materials including natural and synthetic
polymers and various metals are used. These materials rely largely on mechanical approximation
for tissues to heal in close proximity, to stop fluid leakage, or to resist an applied load. These foreign
materials may be permanent, removable, or absorbable and often elicit an inflammatory response
and scar formation. In many cases, their use does not completely restore tissue functionality.
Additionally, their use is not advised in a number of tissue types that are too friable for mechanical
approximation (58). Tissue closure or repair using these materials is often skill intensive and
invasive. As described in the following subsections, inorganic nanomaterials are being evaluated
to overcome these limitations in order to improve clinical treatment modalities, replace current
modalities, and offer solutions where no modalities currently exist.
5.1. Tissue Adhesives and Sealants

Polymer-based adhesives are among the most commonly employed adhesives for mechanical ap-
proximations of tissues; they typically rely on chemical reactions, pH changes, thermal modulation,
or photopolymerization (2). NPs that interact with a polymer matrix increase adhesive strength,
and those NPs within a polymer matrix that do not interact with the matrix can increase other me-
chanical properties such as stiffness or strength, although their effect on adhesive strength is likely
minimal. Chitosan-based nanocomposite adhesives in which gold NPs were generated in situ (59)
exhibited a 3.5-fold increase in adhesive strength compared with their pristine chitosan counter-
part; the NPs’ size and concentration could be adjusted to tune the viscosity of the nanocomposite
adhesives. The incorporation of 2% laponite in four-armed PEG modified with dopamine resulted
in significantly lower cure times, increased adhesion, and unchanged cytocompatibility (60). Sub-
cutaneous implantation of these nanocomposites led to increased cell infiltration, which is likely
due to the increased number of cell adhesion sites and interrupted polymer network that may
occur as a result of laponite inclusion. It is likely that inclusion of NPs provides an alternative to
cell-binding proteins, resulting in increased adhesive bioactivity. A strategy that does not involve
the approximation of tissues using NP dispersions has also been demonstrated (Figure 3). In this
approach, a few drops of a colloidal dispersion of silica NPs were placed between two rectan-
gular ribbons of calf liver (54). The pieces were then gently pressed together for 30 s, causing
adhesion of the tissue. This study demonstrated that NP-based adhesives may not need common
polymer-based mechanisms for tissue adhesion for some applications.
Laser-activated sealing (also known as laser tissue welding) is a sutureless approach in which
chromophores, including plasmonic NPs (e.g., gold), are irradiated with external light. Irradi-
ation with NIR light results in a photothermal response due to the presence of chromophores
in these sealants. The resulting elevated local temperature can reconfigure tissue proteins and
help interdigitize the exogenous nanomaterial with the tissue. Different photothermal solders,
including proteins, can be interfaced with small-molecule and NP chromophores to seal rup-
tured tissues. We developed laser-responsive elastin-like polypeptide (61) and collagen (62)
gold nanorod nanomaterials tuned to a maximum absorbance wavelength of ∼800 nm. We
360 Urie et al.

a c
d
300
Force (mN)
200
b
100
0
0 10 20 30
Displacement (mm)
Figure 3
Nanoparticle-based tissue adhesives. (a,b) Schematic representation of the mechanism of nanoparticles anchoring two polymer
networks (e.g., in tissues) together. The vertical gray arrows represent the pressure applied to squeeze the gel layers together. (c) Two
rectangular sections of calf liver glued together by spreading a nanoparticle dispersion between them and pressing them together for
30 s. (d ) Normalized force–displacement relationship for the lap joints of two sets of calf liver glued by spreading TM-50 silica solution
between them and then pressing the ribbons with a finger for 30 s. Adapted with permission from Reference 54.
demonstrated the laser-activated sealing of porcine intestine ex vivo leading to prevention of fluid
and bacterial leakage (Figure 4), which indicated a promising sutureless technique for sealing
ruptured tissue.
5.2. Infection Control

Antibacterial activity inherent in and unique to NPs has the potential to improve clinical outcomes
in tissue repair. Generally, approaches based on this activity rely on the production of metal ions
and/or reactive oxygen species, which damage bacterial proteins and DNA, thereby disrupting
electron transduction machinery and cell membranes (63). Silver, including silver NPs (64), has
medicinal use because of its well-known antimicrobial properties. Various formulations of sil-
ver nanomaterials, including Acticoat R
(Smith & Nephew, Inc.) wound dressing and SilvaGard R
(AcryMed, Inc.), have been approved by the FDA (65). The mechanism of bacterial inhibition
for silver NPs is not completely understood, but the most accepted mechanism is that Ag+ ions
released from the nanomaterial bind strongly to thiol groups in cell surface proteins in bacteria.
Nanocomposite
5 mm
a b c d e
Rupture Application of Laser irradiation Welding Fluid-tight sealing

nanocomposite
Figure 4
Laser-activated sealing of porcine intestinal tissue. (a) A 5-mm incision was made on the intestine. (b) A
nanocomposite (∼2 mg) was then applied to the cut and (c) irradiated with a laser at 20 W/cm2 , resulting in
(d,e) welding and fluid-tight sealing. Adapted with permission from Reference 61.
This binding breaks down the cell membrane and subsequently leads to ATP synthesis (66). Silver
NPs are therefore being investigated extensively for use in coatings for catheters and implantable
devices (see https://clinicaltrials.gov/show/NCT01950546, https://clinicaltrials.gov/show/
NCT01975545, and https://clinicaltrials.gov/show/NCT02400957), and several clinical tri-
als for topical or wound dressing applications are in progress (see https://clinicaltrials.gov/show/
NCT02761525, https://clinicaltrials.gov/show/NCT01243320, https://clinicaltrials.gov/
show/NCT01405794, and https://clinicaltrials.gov/show/NCT00659204).
One concern with tissue adhesives is that although they are intended to create a barrier to
bacteria, they may actually trap bacteria already contained at the site of closure. To address this
issue, 2-octyl cyanoacrylate adhesive (DERMABOND R
; Ethicon US, LLC) was doped with sil-
ver NPs. Bacterial growth was reduced by an order of magnitude; tensile breaking strength and
adhesive strength were significantly increased in excised porcine sclera (67). The biocompatibil-
ity of polyethylene terephthalate meshes, which are widely used in hernia repair, was improved
via conjugation with 20-nm gold NPs (68). These nanocomposite scaffolds enhanced the cellu-
larity of L929 fibroblasts and repelled Pseudomonas aeruginosa bacteria at the surface compared
with conventional polyethylene terephthalate meshes. Additionally, low concentrations of gold
led to lower production of reactive oxygen species in L929 cells compared with cells exposed
to pristine polyethylene terephthalate. Commercially available poly(glycolic acid) sutures were
coated with silver NPs and compared with antibacterial-coated sutures in a mouse intestinal
anastomosis model (69). Three days following the procedure, immunohistochemistry showed
significantly lower macrophage and neutrophil infiltration as well as greater collagen deposition
at the anastomotic site for the silver NP–coated sutures compared with both the antibacterial-
coated sutures and the sutures alone. Additionally, mechanical testing of the tissue showed a
greater return in strength with the silver NP–coated sutures than with the other treatments.
Incorporation of silver NPs reduced the inflammatory response and improved the quality of
healing.
362 Urie et al.

5.3. Wound and Burn Dressings

Inorganic nanomaterials have also been investigated as potential interventions in cases of chronic
wounds and burns. Silver chloride NPs (42 nm), stabilized by chitosan oligomers, were formulated
as an ointment and used for the treatment of second-degree burn wounds in rats (71). Compared
with untreated burns and those treated by vasoline or chitosan ointments, the chitosan–silver
chloride NP ointment yielded the highest percent of survival and greater regenerated collagen
density. Regenerated cellulose–nanosilver composite sponges were investigated in full-thickness
cutaneous wounds infected with Staphylococcus aureus in rabbits (70). The infection was combated
and wound closure occurred much more rapidly than with gauze or no treatment (Figure 5).
In another study, silver NPs were embedded within a chitosan scaffold, and stearic acid was
applied to one surface of the scaffolds to improve the wetting on the surface in contact with the
wound (72). In a partial-thickness skin wound model, mice were treated with chitosan–nanosilver
TM
scaffolds, chitosan scaffolds, or the commercially available Acasin (AGT Pharmaceutical Co.
Ltd.) nanosilver gauze on their backs. Complete wound closure was observed on day 8 for the silver
nanocomposite and on day 10 for the other materials. Whereas the Acasin treatment group found
levels of silver widely distributed in the blood, liver, spleen, and kidney, the silver nanocomposite
group exhibited negligible levels of silver in the liver, spleen, or kidney and only one-fourth as
much silver in the blood. Poly(vinyl alcohol) (PVA) hydrogels loaded with chitosan-stabilized
silver NPs showed enhanced wound contraction by day 8 with minimal inflammatory response
and displayed higher (∼49%) re-epithelialization on the surface and in the wound scar tissue
compared with pristine PVA hydrogels (∼29%) in full-thickness skin wounds in a rat model (73).
Chitosan wound dressings with hexagonal silver NPs were tested for their ability to assist
in healing in concert with mild hyperthermia and small-molecule delivery (74). Cell viability of
peripheral blood mononuclear immune cells grown on chitosan films increased significantly with
hexagonal silver NPs compared with pristine chitosan. These silver nanomaterials were irradiated
with 1,064-nm NIR light, causing a temperature increase of 6.1◦ C from 37◦ C to 43.1◦ C. The
result was a 56% increase in fluorescence intensity due to intracellular levels of 20-kDa fluorescein
isothiocynate–labeled dextran compared with cells not irradiated with NIR light.
Chitosan–poly(vinyl pyrrolidone)–silver oxide NP films were investigated as wound dressings
in open subcutaneous wounds in rats (75). These silver nanocomposite films exhibited greater
antimicrobial potential than pristine chitosan films or nanosilver scaffolds. Rats treated with the
silver nanocomposites showed nearly complete wound healing on day 14, with improved tissue
quality and less scarring than the control groups. Scaffolds of aminosilane-functionalized silver
NPs cross-linked with succinylated collagen were compared with succinylated collagen scaffolds
for healing an open wound in rats (76). The silver nanocomposites showed higher cell viability
and increased fibroblast proliferation compared with pristine collagen. Complete epithelialization
occurred at 16 days with the nanocomposites, 18 days with the collagen scaffolds, and 24 days with
the gauze control, with increased levels of collagen, protein, and DNA in the granulation tissue
for the nanocomposite-treated group.
Inorganic NPs other than silver have also been investigated in wound dressings, for example,
nanoscale zinc oxide–doped electrospun gelatin scaffolds with poly(methyl vinyl ether-alt-maleic
anhydride), which is an FDA-approved bioadhesive. The zinc-doped scaffold demonstrated an-
tibacterial activity and resulted in enhanced proliferation of endothelial progenitor cells, which
facilitated the healing of skin in a full-thickness wound model in mice (77). The zinc scaffolds
exhibited significant wound healing only 2 days after wounding and complete closure by day 6—
significantly more effective than scaffolds without zinc, which demonstrated efficacy only on day
10. Histopathology analyses confirmed more extensive and faster wound healing with zinc-doped
Blank
Gauze
c
Gauze
RCS-Ag3
RCS-Ag3
Day 0 Day 2 Day 10 Day 18 Day 22
f g
g
Freeze-
kin
drying
-lin
ss
Cro
Regenerated
Hydro-
thermal cellulose sponge
Freeze-
drying
Cellulose Cellulose–silver Cellulose–silver

solution nanoparticle nanoparticle
hydrogel sponge
Gaseous exchange
Silver nanoparticle
Hydro- Freeze- Exudate channel
thermal drying
Living bacteria
Cellulose Cellulose–silver Cellulose–silver Postmortem bacteria
hydrogel nanoparticle nanoparticle sponge
hydrogel
(Caption appears on following page)
364 Urie et al.

Figure 5 (Figure appears on preceding page)

Cellulose–nanosilver composite sponges for repair of infected wounds. (a–e) Images of the healing of infected wounds at specific days
for representative rabbits from each treatment group. (a) Blank, or untreated, wounds, (b,c) wounds treated with sterile gauze, and
(d,e) wounds treated with regenerated cellulose–silver nanoparticle (RC-Ag3) sponges at 0, 2, 10, 18, and 22 days following wounding
and infection. ( f ) Synthesis procedure of RC-Ag3 nanocomposite sponges and schematic representation of sponge architecture.
( g) Possible mechanism of RC-Ag3 sponges in healing infected wounds. Adapted with permission from Reference 70.
scaffolds compared with scaffolds without zinc. In addition to zinc, cross-linked collagen scaf-
folds incorporating gold NPs were compared with collagen sponges and commercially available
MatriDerm R
(MedSkin Solutions) for healing full-thickness skin wounds in adult rats (78). Com-
pared with collagen scaffolds or MatriDerm, the dermal healing was accelerated in the case of
gold NP–doped scaffolds, which demonstrated improved tensile strength and neovascularization
activity.
6. TISSUE REGENERATION USING INORGANIC NANOMATERIALS

Autografts or donor transplantation are still the gold standards for replacing functional tissue
lost due to failure, damage, or disease. Waiting lists that far exceed donor numbers and potential
risks of donor organ rejection, however, necessitate alternative approaches for functional tissue
regeneration (79). Tissue engineering employs a combination of scaffolds, cell types, and effector
molecules for generating cell-based structures that mimic organ behavior. In many cases, the scaf-
folds support three-dimensional (3D) cellular organization and can be degraded or metabolized,
leaving behind vital, functional tissue. In addition to polymeric and biologically derived scaffolds,
inorganic nanomaterials are being investigated in tissue engineering scaffolds (80–82). Inorganic
nanomaterials are attractive in tissue engineering and regenerative medicine applications because
they can overcome the low number of sites for cell adhesion in pristine polymer-based scaffolds
(83, 84), increase the efficiency of cell differentiation (81), replace unstable growth factors (79,
81, 82), improve inadequate mechanical properties (83, 85), and/or facilitate electrical conduc-
tivity for neural or cardiac regeneration (3). Inorganic NPs have been extensively researched in
molecular delivery, imaging and diagnostic, and theranostic applications (86), which are relevant
to applications in tissue regeneration. Drug delivery and imaging are beyond the scope of this
review; thus, we do not discuss cases in which drug delivery or imaging is the primary motivation
for including inorganic nanomaterials in tissue engineering research.
6.1. Stem Cell Targeting

Stem cell transplantation is a promising approach for treating various forms of tissue damage,
including neurodegenerative and heart diseases. These treatments, however, typically suffer from
low retention and engraftment (∼10%) of intravenously or locally delivered stem cells at the re-
pair site, which obviates effective integration (90). NP-based approaches have been explored to
overcome these limitations. Rat cardiosphere–derived stem cells were labeled with FDA-approved
ferumoxytol NPs and injected intracoronarily into rats following myocardial infarction (88). Car-
diac retention was increased by more than threefold in the magnetic NP–labeled stem cell group
with magnetic targeting compared with the magnetic NP–labeled stem cell group without an
applied magnetic field (Figure 6). Magnetic labeling and/or targeting did not produce or in-
crease cardiac inflammation or iron overload, and a greater functional benefit resulted from the
increase in cell retention. In a related approach, iron oxide–labeled mesenchymal stem cells were
a b
Stem cell isolation
and expansion
100 μm 100 μm
Magnetic No magnetic field Magnetic field

actuation
Lesion site
2.0
c 600
SPION+ MF+ *
SPION+ MF–
Normalized magnetic force

1.5
500
Magnetic SPION– MF+

targeting
Cell number
400 1.0
or
Flow of
300 SPION-labeled
stem cells
0.5
200
0.0
100
0
–8 –6 –4 –2 0 2 4 6 8 10
Cranially Distance (mm) Caudally
Figure 6
Stem cell targeting using inorganic nanoparticles. (a) Stem cells from a patient are isolated and expanded in
vitro, after which they are coupled with magnetic nanoparticles. Magnetically labeled stem cells are then
reintroduced ex vivo into an organ prior to transplant or in vivo into the patient, and a magnetic field is
applied to the site for desired cell adhesion and engraftment for increased biological incorporation.
(b) Attraction of superparamagnetic iron oxide nanoparticle (SPION)-labeled cells to a cylindrical magnet in
vitro. Mesenchymal stem cells are labeled with SPIONs at a concentration of 15.4 µg/mL and exposed to an
external magnetic field for 48 h. Cells are stained for intracellular iron using Prussian blue. (c) Numbers of
the captured SPION-labeled cells and nonlabeled cells in the rat model as a function of the distance from the
lesion site of the spinal cord injury (SCI). Data are expressed as mean ± SEM; ∗ p < 0.05. Abbreviations:
MF, magnetic field; SEM, standard error of mean. Panel a redrawn with permission from Reference 87.
Panels b and c adapted with permission from Reference 88.
magnetically targeted to the lesion area, and cardiac retention of the transplanted cells was in-
creased more than 2.5-fold in a rat model of acute myocardial infarction (91). The increased cell
engraftment continued for at least 3 weeks; left ventricular remodeling and cardiac function were
improved compared with the group without magnetic targeting.
Mesenchymal stem cells were labeled with SPIONs and magnetically targeted to the injury site
in a rabbit balloon angioplasty model (92). The cells lost no viability due to labeling. Magnetically
targeting the cells resulted in a sixfold increase in cell retention compared with the untargeted
approach, which in turn decreased restenosis 3 weeks after stem cell transplantation. Magnetite
NPs were coated with PEG and anti-CD34 antibody to minimize protein adsorption and facil-
itate stem cell targeting, respectively. Magnetic NPs coated with PEG and anti-CD34 antibody
specifically bound stem cells in blood in vivo and facilitated delivery at lesion sites in the presence
of a magnetic field (89).
366 Urie et al.

Magnetite nanospheres and nanorods with hydrodynamic diameters of 20.2 nm and 92.1 nm,
respectively, were surface-modified with aminosilane (93), forming sheet-like constructs in vitro.
In addition to cardiac repair, stem cells loaded with SPIONs were rapidly guided to the lesion
site for application in repair of spinal cord injury (94). SPION-labeled stem cells were injected
intrathecally in mice and targeted with a magnet, resulting in significantly increased stem cell
concentration at the lesion site in a 2-h time period (Figure 5).
6.2. Neuroregeneration and Spinal Cord Repair

In the United States alone, more than 90,000 people are affected by neurodegenerative diseases
each year, and 10,000 patients suffer from spinal cord injury (95). In most cases, neurodegener-
ative diseases and neurotrauma remain largely incurable (96). Recently, inorganic nanomaterials
attracted significant attention in applications related to neuroprotection and neuronal cell restora-
tion. For example, neurons were grown on unmodified nanotubes and coated nanotubes as early as
2000 (97). Tubular electrospun gold NP–silk nanocomposite sheets were used in rats in a sciatic
nerve injury model over a period of 18 months. The nanocomposites promoted Schwann cell
adhesion and proliferation in vitro and did not cause a toxic or immunogenic response in vivo.
Nerve conduction velocity, compound muscle action potential, and motor unit potential were all
found to be superior to those in the case of synthetic materials or collagen-based nerve conduits
(98). NP incorporation improved structural and functional neuromuscular regeneration compared
with the silk scaffolds alone, and the gold NP implants were safe and stable in vivo for an extended
period of time.
Gold NPs (10 nm) were decorated on polycaprolactone (PCL)/gelatin electrospun fibrous
scaffolds and seeded with primary neurons to evaluate their differentiation, maturation, and mor-
phogenesis (99). The neurons on the pristine PCL scaffolds did not extend long neurites, whereas
those on the gold nanocomposite scaffolds reached adjacent cells and created neuronal networks.
The use of gold NPs likely enhanced anchoring sites to improve neuronal morphogenesis; how-
ever, it is unclear whether axon elongation and higher neuronal marker expression were promoted
due to the conductivity or topographical cues of the gold nanocomposite scaffolds.
CNTs and graphene are also promising neural repair candidates due to their electrical conduc-
tivity and high mechanical strength. Administration of single-walled CNTs functionalized with
PEG decreased lesion volume in traumatic spinal cord injury in rats without increasing reactive
gliosis (100). In a different study, a synergistic effect was observed between multiwalled CNT
poly-L-lactic acid matrices and biomimetic peptides in neuroregeneration (101). These CNT–
poly-L-lactic acid nanocomposites were prepared at a low concentration of nanotubes to reduce
any cytotoxicity concerns. The nanocomposite scaffolds supported cell adhesion and differen-
tiation better than the control polymer scaffold. Partially reduced 3D graphene oxide scaffolds
were implanted into the spinal cord in injured rats (102). Blood vessels were detected at the
scaffold/tissue interface and within the scaffold at 30 days. Red blood cells were also detected,
suggesting that the blood vessels were at least partly functional. Graphene oxide with neutral,
zwitterionic, or negatively charged functional groups was used as a substrate for culturing primary
rat hippocampal neurons. Positively charged graphene oxide was found to be the most effective
for both neurite growth and branching (103).
6.3. Cardiac Repair and Regeneration

Cardiac diseases are major causes of mortality and disability in the United States (104); in 2013,
one in nine deaths was attributable to heart failure (105). Inorganic nanomaterials have been
investigated for use in cardiac regeneration primarily to facilitate electrical conductivity and in-
crease cell adhesion sites. For example, gold NPs can increase matrix conductivity in tissue engi-
neering scaffolds and improve signal transfer between cardiac cells. Shevach et al. (55) evaporated
gold NPs onto PCL/gelatin electrospun scaffolds. Cardiac cells seeded onto these scaffolds as-
sembled into more elongated and aligned tissue than on scaffolds not containing gold NPs; the
contraction rate and amplitude of cells were significantly higher in scaffolds with gold NPs. Al-
ginate scaffolds were incorporated with gold nanowires to increase electrical conductivity of the
material and facilitate electrical signaling. Tissue grown on the surface of these gold nanowire–
alginate nanocomposites was thicker and in better alignment than tissue grown on alginate alone
(106). Cells grown on these nanocomposites contracted in synchronization, and these tissues
contained higher amounts of muscle contraction and electrical signaling proteins.
Inclusion of carbon nanofibers in chitosan-based scaffolds led to an enhancement in electrical
conductivity by nine orders of magnitude and resulted in mechanical properties that were similar
to those of cardiac muscle tissue (107). Vertically aligned CNTs embedded within methacrylated
gelatin hydrogels were used to grow skeletal muscle cells and produce functional myofibers (108).
Hybrid methacrylated gelatin hydrogels with CNTs as scaffolds were used to culture and regulate
the cardiac differentiation of mouse embryoid bodies (109).
Graphene oxide nanostructures were employed as tunable cell adhesive sheets to create con-
nected multilayered cardiac tissue. Graphene oxide thin films formed directly on cell surfaces re-
sulted in strong spontaneous beating, improved cardiomyocyte cell organization, and cell-to-cell
electric coupling (110). Polyethylenimine-functionalized graphene oxide nanosheets were com-
plexed with transgenes expressing the proangiogenic vascular endothelial growth factor, and the
complexes were incorporated into low-modulus methacrylated gelatin hydrogel. The hydrogels
were injected intramyocardially into the peri-infarct region in a rat model of acute myocardial in-
farction. An increase in myocardial capillary density and a reduction in scar density were observed
in the infarct hearts treated with the hydrogels compared with controls (111).
6.4. Beyond Heart and Nerve Repair and Regeneration

Although neural and cardiac regeneration are being widely researched with the use of CNTs,
graphene, and gold NPs, inorganic nanomaterials are also being investigated in other tissues, in-
cluding muscle, cartilage, and vasculature. Nanostructure and electrical response are important
properties in myoblast differentiation, and graphene nanosheet–PCL nanocomposite scaffolds
have been investigated for their ability to promote skeletal muscle regeneration with minimal use
of biochemical cues (79). Electrospun poly-L-lactic acid polyaniline fibers carrying physisorbed
mesoporous silica NPs supported muscle stem cell differentiation, and the NPs were internalized
by the cells on the scaffold, showing that drug-loaded particles release drugs only when inter-
nalized by cells (112). PEG-linked multiwalled CNT films were able to direct skeletal myogenic
differentiation of human mesenchymal stem cells without myogenic induction factors, indicating
their promise in the repair of skeletal muscle injuries (113).
Silver NPs stimulated the synthesis of collagen and facilitated cell proliferation in tenocytes
from rat Achilles tendon (114). At 42 days postoperation, the tensile strength was significantly
improved compared with the untreated group. Histology suggested that this result may be due
in part to promoted cell alignment, proteoglycan synthesis, and collagen deposition, further in-
dicating that silver NPs promote and restore functionality in connective tissue that has been in-
jured. Decellularized porcine abdominal aortic tissue was conjugated with gold NPs to determine
long-term biocompatibility and cellular integration (115) in an effort to overcome the limita-
tions of biological patches in vascular repair. These nanocomposite patches were placed over a
368 Urie et al.

longitudinal arteriotomy of the thoracic aorta in six pigs and monitored for 6 months. The patches
did not fail over the 6-month period and were able to integrate with the host tissue, having minimal
gross scar tissue.
5. CONCLUSIONS AND FUTURE DIRECTIONS

Inorganic nanomaterials, namely materials composed of at least one metallic, ceramic, or carbon
allotrope constituent with one or more dimensions on the order of 1–100 nm, can fill a variety of
unmet needs in nanomedicine. Inorganic nanomaterials show promise in tissue repair and regen-
eration that may potentially lead to improved patient outcomes. Inorganic NPs can improve and
modulate material mechanical properties, which play a key role in the ability to tune the material
to a specific tissue type or disease state. In addition, inorganic NPs promote cell adhesion and
stem cell differentiation. Biological cues including growth factors can also be integrated into these
nanomaterials. Inorganic NPs impart electrical, optical, magnetic, or antimicrobial properties to

repair cardiac, neural, and skin tissue, among others. Finally, they can also facilitate drug and
nucleic acid delivery, which can accelerate/engender tissue repair and regeneration. Additional
studies are necessary to develop a clearer understanding of structure–property relationships with
a focus on how size, shape, and surface chemistry lead to effective tissue repair in vivo. The safety
of inorganic NPs in tissue repair and regeneration also needs to be elucidated, particularly for
long-term repair and regeneration. As inorganic NPs enter the clinic for concomitant applica-
tions, including imaging, cancer treatment, drug delivery, dentistry, and cosmetic products, the
pathway for FDA approval and clinical translation of inorganic nanomaterials for tissue repair and
regeneration is likely to become more streamlined.
DISCLOSURE STATEMENT
K.R. and R.U. disclose affiliation with the start-up company Synergyan, LLC. The other au-
thors are not aware of any affiliations, memberships, funding, or financial holdings that might be
perceived as affecting the objectivity of this review.
ACKNOWLEDGMENTS
The authors are grateful to the National Institute for Biomedical Imaging and Bioengineering
(grant number 1R01EB020690) for funding. An exhaustive review of all research is not possible
because of length constraints, and the authors sincerely apologize to those researchers whose work
could not be discussed.
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BE20_TOC ARI 29 April 2018 12:12
Annual Review
of Biomedical
Engineering
Contents Volume 20, 2018
Energy-Based Tissue Fusion for Sutureless Closure: Applications,

Mechanisms, and Potential for Functional Recovery
Eric A. Kramer and Mark E. Rentschler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Engineering Hydrogel Microenvironments to Recapitulate

the Stem Cell Niche
Christopher M. Madl and Sarah C. Heilshorn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p21
Engineering Approaches to Study Cellular Decision Making
Pamela K. Kreeger, Laura E. Strong, and Kristyn S. Masters p p p p p p p p p p p p p p p p p p p p p p p p p p p p p49
Targeted and Nontargeted α-Particle Therapies
Michael R. McDevitt, George Sgouros, and Stavroula Sofou p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p73
Synthetic Biology: Immunotherapy by Design
Matthew J. Brenner, Jang Hwan Cho, Nicole M.L. Wong, and Wilson W. Wong p p p p p p95
Bone Mechanical Properties in Healthy and Diseased States
Elise F. Morgan, Ginu U. Unnikrishnan, and Amira I. Hussein p p p p p p p p p p p p p p p p p p p p p p p p 119
Facet Joints of the Spine: Structure–Function Relationships, Problems
and Treatments, and the Potential for Regeneration
Siobhan A. O’Leary, Nikolaos K. Paschos, Jarrett M. Link, Eric O. Klineberg,
Jerry C. Hu, and Kyriacos A. Athanasiou p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 145
Electrophysiological Source Imaging: A Noninvasive Window
to Brain Dynamics
Bin He, Abbas Sohrabpour, Emery Brown, and Zhongming Liu p p p p p p p p p p p p p p p p p p p p p p p p p 171
Engineering the Mucus Barrier
T.L. Carlson, J.Y. Lock, and R.L. Carrier p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 197
Advanced Endoscopic Navigation: Surgical Big Data, Methodology,
and Applications
Xiongbiao Luo, Kensaku Mori, and Terry M. Peters p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 221
Platelet Mechanotransduction
Caroline E. Hansen, Yongzhi Qiu, Owen J.T. McCarty, and Wilbur A. Lam p p p p p p p p p 253
BE20_TOC ARI 29 April 2018 12:12
Synthetic Biology Approaches to Engineer Probiotics and Members of

the Human Microbiota for Biomedical Applications
Josef R. Bober, Chase L. Beisel, and Nikhil U. Nair p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 277
From Nanowarming to Thermoregulation: New Multiscale
Applications of Bioheat Transfer
John C. Bischof and Kenneth R. Diller p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 301
Circulating Tumor Cells: Diagnostic and Therapeutic Applications
Eric Lin, Thong Cao, Sunitha Nagrath, and Michael R. King p p p p p p p p p p p p p p p p p p p p p p p p p p p 329
Inorganic Nanomaterials for Soft Tissue Repair and Regeneration
Russell Urie, Deepanjan Ghosh, Inam Ridha, and Kaushal Rege p p p p p p p p p p p p p p p p p p p p p p p p p 353
Structural DNA Nanotechnology: Artificial Nanostructures for

Biomedical Research
Yonggang Ke, Carlos Castro, and Jong Hyun Choi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 375
Physiology and Engineering of the Graded Interfaces of
Musculoskeletal Junctions
Edward D. Bonnevie and Robert L. Mauck p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 403
Arterial Venous Differentiation for Vascular Bioengineering
Laura Niklason and Guohao Dai p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 431
Errata
An online log of corrections to Annual Review of Biomedical Engineering articles may be
found at http://www.annualreviews.org/errata/bioeng

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BE20CH15_Rege ARI 29 April 2018 11:35

Annual Review of Biomedical Engineering

Russell Urie,1 Deepanjan Ghosh,2 Inam Ridha,3

Annu. Rev. Biomed. Eng. 2018. 20:353–74 Keywords

5.3. Wound and Burn Dressings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363

Tissue formation Tissue remodeling

Increase tensile strength

Bleeding Inflammatory Reduce cellularity

0.1 0.3 1 3 10 30 100 300

2. TISSUE REPAIR MECHANISMS

3. TISSUE REPAIR APPROACHES IN THE CLINIC

3.1. Primary Intention Repair

356 Urie et al.

3.2. Secondary Intention Repair

3.3. Nonintention Repair and Regeneration

358 Urie et al.

Increase cell adhesion

Carbon Iron oxide

Improve scaffold Improve stimulus

Graphene oxide Gold

Include imaging, cell

Incorporation of NPs imparts different functionalities to the resulting nanomaterials

5. TISSUE REPAIR USING INORGANIC NANOMATERIALS

5.1. Tissue Adhesives and Sealants

360 Urie et al.

5.2. Infection Control

Rupture Application of Laser irradiation Welding Fluid-tight sealing

362 Urie et al.

5.3. Wound and Burn Dressings

Day 0 Day 2 Day 10 Day 18 Day 22

Cellulose Cellulose–silver Cellulose–silver

364 Urie et al.

Figure 5 (Figure appears on preceding page)

6. TISSUE REGENERATION USING INORGANIC NANOMATERIALS

6.1. Stem Cell Targeting

Magnetic No magnetic field Magnetic field

Normalized magnetic force

Magnetic SPION– MF+

366 Urie et al.

6.2. Neuroregeneration and Spinal Cord Repair

6.3. Cardiac Repair and Regeneration

6.4. Beyond Heart and Nerve Repair and Regeneration

368 Urie et al.

5. CONCLUSIONS AND FUTURE DIRECTIONS

nanomaterials. Inorganic NPs impart electrical, optical, magnetic, or antimicrobial properties to

370 Urie et al.

properties of nanoparticles. Trends Biotechnol. 30:499–511

372 Urie et al.

374 Urie et al.

Contents Volume 20, 2018

Energy-Based Tissue Fusion for Sutureless Closure: Applications,

Engineering Hydrogel Microenvironments to Recapitulate

Synthetic Biology Approaches to Engineer Probiotics and Members of

Structural DNA Nanotechnology: Artificial Nanostructures for

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