Review Article
Title
Title should be no more than 16 words.
Authorship
Authorship criteria should be based only on substantial contributions to each of the three
components mentioned below: (1) concept and design of study or acquisition of data or analysis
and interpretation of data; (2) drafting the article or revising it critically for important intellectual
content; (3) final approval of the version to be published.
Participation solely in the acquisition of funding or the collection of data does not justify
authorship. General supervision of the research group is not sufficient for authorship. Each author
should have participated sufficiently in the work to take public responsibility for appropriate
portions of the content of the manuscript. The order of the authors should be based on the relative
contribution of the author towards the study and writing the manuscript.
Authors’ full name should be given (First name + Middle name + Last name). Once submitted,
authors cannot be added or deleted and the order cannot be changed also without written consent
of all authors.
Author institutions
The complete name of department, institution, city, province/state, postcode and country should be
given. For example, “Department of Burn and Plastic Surgery, Affiliated Hospital of Qingdao
University, Qingdao 266003, Shandong, China”, “Division of Plastic, Reconstructive, and Hand
Surgery, Baptist Memorial Healthcare Corporation, Memphis, TN 38120, USA”.
Correspondence
The corresponding author is responsible for communicating with the other authors about revisions
and final approval of the proofs. The name, title, institution, address, e-mail and contact number of
the corresponding author should be given. For example, “Dr. Zhen-Yu Chen, Department of Burn
and Plastic Surgery, Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong,
China. E-mail: wzg_qd@126.com. Contact number: +86-29-68686779”.
Abstract
Review article (200 words) should have unstructured abstracts. First person should not be used in
Abstract.
Review Article
Key words
Please list 3-8 key words, which reflect the content of the study.
Text
The word amount of main text of review article should be 5000 words.
Review article has unfixed section titles.
Ethics
When report studies on human beings, indicate whether the procedures followed were in
accordance with the ethical standards of the responsible committee on human experimentation
(institutional
or
regional)
and
with
the
Helsinki
Declaration
(available
at
http://www.wma.net/en/30publications/10policies/b3/). For prospective studies involving human
participants, authors are expected to mention about approval of (regional/national/institutional or
independent Ethics Committee or Review Board, obtaining informed consent from adult research
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and analgesics used should be clearly stated. The ethical standards of experiments must be in
accordance with the guidelines provided by the CPCSEA and World Medical Association
Declaration of Helsinki on Ethical Principles for Medical Research Involving Humans for studies
involving experimental animals and human beings, respectively). A statement on ethics committee
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Describe your selection of the observational or experimental participants (patients or laboratory
animals, including controls) clearly, including eligibility and exclusion criteria and a description
of the source population.
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Technical information
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procedures in sufficient detail to allow other workers to reproduce the results. Give references to
established methods, including statistical methods (see below); provide references and brief
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of administration.
Reports of randomized clinical trials should present information on all major study elements,
including the protocol, assignment of interventions (methods of randomization, concealment of
allocation to treatment groups), and the method of masking (blinding), based on the CONSORT
Statement (http://www.consort-statement.org).
Statistics
Whenever possible quantify findings and present them with appropriate indicators of measurement
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specify the statistical methods used to analyze them. Avoid non-technical uses of technical terms
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and not less than 0.05 or 0.001. Mean differences in continuous variables, proportions in
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Results
Present your results in a logical sequence in the text, tables, and illustrations, giving the main or
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emphasize or summarize only important observations. Extra- or supplementary materials and
technical detail can be placed in an appendix where it will be accessible but will not interrupt the
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Discussion
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study design, data collection, analysis and interpretation); interpretation and implications in the
context of the totality of evidence (is there a systematic review to refer to, if not, could one be
reasonably done here and now? what this study adds to the available evidence, effects on patient
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research).
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be clearly labeled as such.
Acknowledgments
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justify authorship, such as general support by a departmental chair; (2) acknowledgments of
technical help; and (3) acknowledgments of financial and material support, which should specify
the nature of the support.
References
References should be created by using Endnote. They should be numbered consecutively in the
order in which they are first mentioned in the text (not in alphabetic order). Identify references in
text, tables, and legends by Arabic numerals in superscript with square bracket after the
punctuation marks. References cited only in tables or figure legends should be numbered in
accordance with the sequence established by the first identification in the text of the particular
table or figure.
All authors’ names should be listed in the references. The names of journals should be abbreviated
according to the style used in Index Medicus. Avoid using abstracts as references. Information
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from manuscripts submitted but not accepted should be cited in the text as “unpublished
observations” with written permission from the source. Avoid citing a “personal communication”
unless it provides essential information not available from a public source, in which case the name
of the person and date of communication should be cited in parentheses in the text.
The commonly cited types of references are shown here, for other types of references please refer
to ICMJE Guidelines (http://www.nlm.nih.gov/bsd/uniform_requirements.html).
Standard journal articles (list all authors)
Parija SC, Ravinder PT, Shariff M. Detection of hydatid antigen in the fluid samples from hydatid
cysts by co-agglutination. Trans R Soc Trop Med Hyg 1996;90:255-6.
Both personal authors and organization as author
Vallancien G, Emberton M, Harving N, van Moorselaar RJ; Alf-One Study Group. Sexual
dysfunction in 1,274 European men suffering from lower urinary tract symptoms. J Urol
2003;169:2257-61.
Books
Sherlock S, Dooley J. Diseases of the liver and billiary system. 9th ed. Oxford: Blackwell Sci Pub;
1993. p. 258-96.
Chapter in a book
Meltzer PS, Kallioniemi A, Trent JM. Chromosome alterations in human solid tumors. In:
Vogelstein B, Kinzler KW, editors. The genetic basis of human cancer. New York: McGraw-Hill;
2002. p. 93-113.
Article not in English (The title should be translated into English, and clarify the original
language in the bracket.)
Zhang X, Xiong H, Ji TY, Zhang YH, Wang Y. Case report of anti-N-methyl-D-aspartate receptor
encephalitis in child. J Appl Clin Pediatr 2012;27:1903-7. (in Chinese).
Tables

Tables should be self-explanatory and should not duplicate textual material.
Review Article

Number tables, in Arabic numerals, consecutively in the order of their first citation in the
text and supply a brief title for each.
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Place explanatory matter in footnotes, not in the heading.
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Explain in footnotes all abbreviations that are used in each table.

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credit line in the footnote.
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For footnotes use the following symbols, in this sequence: *, †, ‡, §, ||,¶ , **, ††, ‡‡

Tables with their legends should be provided at the end of the text after the references.
The tables along with their numbers should be cited at the relevant places in the text.
Figures
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uploading.
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been first cited in the text.
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figures should be large enough to be legible after reduction to fit the width of a printed
column.
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Symbols, arrows, or letters used in photomicrographs should contrast with the
background and should be marked neatly with transfer type or by tissue overlay and not
by pen.

Titles and detailed explanations belong in the legends for illustrations not on the
illustrations themselves.

When graphs, scatter-grams or histograms are submitted the numerical data on which
they are based should also be supplied.

The photographs and figures should be trimmed to remove all the unwanted areas.

If photographs of individuals are used, their pictures must be accompanied by written
permission to use the photograph.
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If a figure has been published elsewhere, acknowledge the original source and submit
written permission from the copyright holder to reproduce the material. A credit line
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
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credit line) for illustrations using double spacing, with Arabic numerals corresponding to
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the illustrations, identify and explain each one in the legend. Explain the internal scale
(magnification) and identify the method of staining in photomicrographs.
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
Final figures for print production: send sharp, glossy, un-mounted, color photographic
prints, with height of 4 inches and width of 6 inches at the time of submitting the revised
manuscript. Print outs of digital photographs are not acceptable. If digital images are the
only source of images, ensure that the image has minimum resolution of 300 dpi or 1800
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
The journal reserves the right to crop, rotate, reduce, or enlarge the photographs to an
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Abbreviations
In general, terms should not be abbreviated unless they are used repeatedly and the abbreviation is
helpful to the reader. Standard abbreviations should be defined in the abstract and in the text on
first mention. Permissible abbreviations are listed in Units, Symbols and Abbreviations: A Guide
for Biological and Medical Editors and Authors (Ed. Baron DN, 1988) published by The Royal
Society of Medicine, London. Certain commonly used abbreviations, such as DNA, RNA, ATP,
etc., can be used directly without further explanation. Abbreviations are not preferred in the title
and key words. Abbreviations used in the tables and figures should be defined in the legends.
Units
Use SI units. There should be space between number and unit (i.e., 23 mL). Units can be omitted
sometimes (i.e., 2 - 3 mL, 2 + 3 mL) while sometimes not (i.e., 2 cm × 3 cm). Hour, minute,
second should be written as h, min, s. However, day, month and year cannot be abbreviated.
Numbers
Numbers appearing at beginning of sentences should be expressed in English. When there are two
or more numbers in a paragraph, they should be expressed as Arabic numerals; when there is only
one number in a paragraph, number < 10 should be expressed in English and number > 10 should
be expressed as Arabic numerals. 23243641 should be written as 23,243,641.
Italics
Review Article
General italic words like vs., et al., etc., in vivo, in vitro; t test, F test, U test; related coefficient as
r, sample number as n, and probability as P; names of genes; names of bacteria and biology
species in Latin.
MANUSCRIPTS SUBMISSION
All manuscripts must be submitted on-line through the website http://www.journalonweb.com/par/.
First time users will have to register at this site. Registration is free but mandatory. Registered
authors can keep track of their articles after logging into the site using their user name and
password. Authors do not have to pay for submission, processing or publication of articles. If you
experience
any
problems,
please
contact
the
editorial
office
by
e-mail
at
par_editor001@parjournal.net or pareditor002@gmail.com.
Generally, the manuscript should be submitted in the form of several separate files:
First page
This file should provide:
1. The type of manuscript, title of the manuscript, names of all authors, and their institutions.
All information which can reveal your identity should be here.
2. The name, title, address, e-mail, and telephone number of the corresponding author, who
is responsible for communicating with the other authors about revisions and final
approval of the proofs.
3. The total number of photographs and word counts separately for abstract and for the text
(excluding the references, tables and abstract), word counts for introduction + discussion
in case of an original article.
4. Acknowledgements, if any.
5. Source(s) of support, if any.
6. If the manuscript was presented as part at a meeting, the organization, place, and exact
date on which it was read.
7. Registration number in case of a clinical trial and where it is registered (name of the
registry and its URL).
8. Conflicts of interest of each author/ contributor. A statement of financial or other
relationships that might lead to a conflict of interest, if that information is not included in
the manuscript itself or in an authors’ form.
Blinded article file
Review Article
The main text of the article, beginning from Abstract till References (including tables) should be
in this file. The file must not contain any mention of the authors' names or initials or the institution
at which the study was done or acknowledgements. Manuscripts not in compliance with the
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Do not incorporate figures in the file. The pages should be numbered consecutively, beginning
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Presentation and format
All articles should be written in American English, submitted using word-processing software, and
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Review Article
First Page
Review Article
Article Title: Current and future applications of nanotechnology in plastic and reconstructive
surgery
Author Information:
Dana K. Petersen1, Tate M. Naylor2, Jon P. Ver Halen3,4,5
1 Department
of Otolaryngology - Head and Neck Surgery, University of Tennessee Health
Science Center, Memphis, TN 38163, USA.
2
Department of Surgical Oncology, School of Medicine, University of Tennessee Health Sciences
Center, Memphis, TN 38163, USA.
3 Department of Surgical Oncology, Division of Plastic, Reconstructive and Hand Surgery, Baptist
Memorial Healthcare Corporation,
Memphis, TN 38120, USA.
4 Department of Surgical Oncology, Vanderbilt Ingram Cancer Center, Nashville, TN 37232,
USA.
5 Department of Surgical Oncology, St Jude Children’s Research Hospital, Memphis, TN 38105,
USA.
Address for correspondence: Dr. Jon P. Ver Halen, Department of Surgical Oncology, Division
of Plastic, Reconstructive and Hand Surgery, Baptist Memorial Healthcare Corporation, Memphis,
TN 38120, USA. E-mail: jpverhalen@gmail.com
Phone: +86-29-68686779
Total number of photographs:
Word counts
For abstract:
For the text:
Acknowledgements:
Source(s) of support:
Presentation at a meeting
Organization:
Place:
Date:
Conflicting Interest (If present, give more details):
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Article File
Current and future applications of nanotechnology in plastic and reconstructive surgery
ABSTRACT
Although nanotechnology is a relatively young field, there are countless biomedical applications
in use or under investigation. Many specialties have benefitted from nanoscale refinements of
diagnostic and therapeutic techniques. Plastic and reconstructive surgery is an incredibly diverse
specialty, encompassing craniofacial and hand surgery; trauma, oncologic and congenital
reconstruction; burn care, and aesthetic surgery. Advances in nanotechnology have significantly
impacted wound management, topical skin care, implant and prosthetic design, tissue engineering,
and drug delivery systems. Currently, plastic surgeons are researching the utility of nanoscale
tools for bone regeneration, bone prosthetics, and drug delivery. Nanotechnology will continue to
build upon preceding discoveries, and its biomedical applications in the field of plastic and
reconstructive surgery will expand significantly.
Key words:
Bone graft, burns, drug delivery, implants, nanotechnology, tissue engineering, wound care
INTRODUCTION
Nanotechnology can be defined as the science of design, synthesis, characterization and
application of materials and extremely small devices. The smallest functional unit of this
technology, in at least one dimension, is on the nanometer scale, which is one billionth of a
meter.[1-3]Nanotechnology is the design and engineering of novel products that interact with
biological, electrical and chemical systems on the atomic level, thus yielding a level of specificity
and specialization that was not feasible in the past. In the 1950’s, European researchers discovered
formation of an active biological field from the oxidation of titanium when exposed to air. They
identified that this promotes living tissue ingrowth.[4] This phenomenon was used to take a
tremendous leap in medical technology, specifically in bone implant applications. Nanomedicine
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is a subdivision of nanotechnology that employs highly specific molecular interventions for both
the diagnosis and treatment of disease processes. Currently, nanomedicine has allowed
advancement in the fields of drug delivery systems, gene therapies, body and organ imaging,
surgical tools, and diagnostic procedures.
SOFT TISSUE REPAIR AND HEALING
Wound and burn care are two areas of clinical care that are already benefitting from developments
in nanotechnology.[5] Wound dressings constructed using nanoscale fabrication techniques can
greatly improve wound healing. Nanofibers may be created from various materials using
manufacturing techniques on a nanoscale. The nanofibers provide a three-dimensional structure
that mimics the native extracellular matrix (ECM) while the host tissue regeneration replaces the
scaffold. Nanofiber scaffolds provide several properties that are essential for tissue repair:
mechanical integrity, temperature control, fluid absorption, and gas exchange.
In rat models, scaffolds made of collagen nanofibers accelerate acute wound healing by enhancing
capillary and fibroblast proliferation.[6] In a study by Choi et al.,[6] recombinant human epidermal
growth factor (EGF) was immobilized on electrospun biodegradable nanofibers to treat diabetic
ulcers in a rat model. Human primary keratinocytes were cultivated on the nanofiber matrix to
investigate the effect of EGF nanofibers on their differentiation. Wound healing effect of the EGF
nanofibers was confirmed in diabetic animals with dorsal wounds. In in-vivo wound healing
studies, the EGF-nanofibers group was superior to control groups (conventional dressing,
nanofibers alone, or EGF solutions). This study showed that EGF-conjugated nanofibers could
potentially be employed as a novel wound healing material by increasing proliferation and
phenotypic expression of keratinocytes in diabetic wounds.
Chitin and chitosan nanofibrils are nanocrystals of natural polysaccharides derived from the
exoskeletons of crustaceans. These fibrils have been used in a variety of formulations to aid
wound healing. Muzzarelli et al.[7] showed in murine models that different formulations of chitin
nanofibrils almost lead to normal physiologic repair of wounds. They subjected various
formulations of dibutyryl chitin (DBC), a modified chitin carrying butyryl group at the 3 and 6
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positions, to a battery of in vitro and in vivo tests. The DBC’s were then incorporated into a
5-methylpyrrolidinone chitosan solution and submitted to freeze-drying to produce a reinforced
wound dressing material which was then tested in vivo in full thickness wounds in rats. The rats
had full thickness dorsal wounds bilaterally and treated with experimental agent on one side, and
control on the contralateral side. The animals were studied at either seven or fourteen days and the
skin of each surgical wound was excised. The use of 4mm ×4 mm pieces as wound dressings
resulted in significantly less cutaneous scarring, as measured by collagen I/ collagen III rations,
and as measured clinically.
Chitin nanofibrils/chitosan glycolate can be manufactured into a spray, gel or impregnated onto a
dressing for wound care. Using a rat model, Mattioli-Belmonte et al.[8] demonstrated that each of
these delivery systems has a specific application: use for superficial abrasions, shallow wounds in
aesthetic areas, and slow healing dermo-epidermal wounds, respectively. Enhanced tissue repair
and reduced scarring was seen in all the applications. Although the results from all of these studies
are impressive, they have not been examined in human clinical trials.
Silver has long been heralded for its antimicrobial properties and has demonstrated efficacy
against
multi-drug
resistant
organisms
as
well
as
exhibiting
anti-inflammatory
properties.[9,10]Nanoscale fabrication techniques have allowed manufacturing silver into
nanoparticles, which markedly increases the rate of silver ion release, and thus increasing its
clinical utility.[10,11] A nanocrystalline silver dressing was recently evaluated in chronic wounds by
Sibbald et al.[9] In a prospective, uncontrolled study, a variety of chronic, nonhealing wounds (foot,
pressure, and venous stasis ulcers, and miscellaneous wounds) were treated with a nanocrystalline
sliver dressing [Figure 1]. Surface bacterial counts were found on semi-quantitative swabs to be
significantly diminished in those wounds treated with nanocrystalline dressing. Since bacteria
contribute to tissue damage leading to poor wound healing, the decreased bacterial load from
silver nanocrystalline dressing facilitates wound healing.. Additionally, growth factors have been
shown to play a critical role in the proliferative phase of wound healing. Growth factors serve to
attract the cells necessary for fibroblast and epithelial cell growth and migration, as well as
initiating the formation of new blood vessels into the area of injury. Novel polymerized
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nanocarriers have been produced, which can provide for consistent and significant dosages of
growth factors. The growth factors are embedded into the polymerized nanocarriers that allow
sustained release of these bioactive molecules. The nanocarrier drug delivery system has
beensuccessful in treating wounds in a clinical setting.[10]
The cosmetic and topical skin care industries have also benefited from advances in
nanotechnology. For example, micronized zinc oxide and titanium dioxide are used in sunscreen
manufacturing by functioning as UV blockers in these products. Their nanoscale fabrication
increases their transparency on skin and allows increased user compliance. In addition, it also
increases their refractive index, resulting in a “stronger” sunscreen.[12] Lipid nanoparticles have
been added to various cosmetic and dermal products to increase contact with the stratum corneum.
Therefore, it allows increased drug penetration in to the skin, improved hydration through their
occlusive properties, and provide controlled release of active ingredients.[13] In an open clinical
trial, fullerene gel applied to patients with acne vulgaris showed a significant reduction cutaneous
inflammation and infection, suggesting yet another application of nanotechnology in skin care.[14]
IMPLANTS AND PROSTHESES
In 2012, breast augmentation and implant-based breast reconstruction after mastectomy were the
most common plastic surgery procedures. Breast implants that contain nanofiber coatings for the
delivery of tumor-specific anti-cancer drugs are currently being evaluated.[15] This technology has
the potential to revolutionize cancer care, by facilitating area-specific chemotherapy to the tumor
bed, while alleviating some of the undesirable effects of current systemic chemotherapy regimens.
In addition, utilizing nanoscale technology in manufacturing can improve the strength of breast
implants. The shell of silicone breast implants is made up of cross-linked and reinforced silicone
rubber nanocomposite. The silicone rubber is weak and therefore must be reinforced, most
commonly with nanosized SiO2. Finally, even with modern breast implants, capsular contracture
continues to be one of the significant long-term complications of long-term breast implant
placement. It has been demonstrated in a rat model that surface modification of implants with
antifibrotic drugs (e.g., halofuginone) can decrease capsule formation.[16]
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TISSUE AND ORGAN ENGINEERING
Nanotechnology has been used to construct and repair various tissues utilized in plastic surgery.
Electrospun nanofiber matrices have been developed for skeletal muscle regeneration in both in
vitro and in vivo experimental models.[17] Reconstructive plastic surgeons are currently using
cartilage engineering that has been utilized in orthopedic surgery for many years. The engineering
of auricular cartilage for ear reconstruction is an established technique. Additionally, nasal
cartilage is being examined for complex nasal reconstruction after cancer, trauma, or congenital
defects.[18] Artificial skin has long been used for the treatment of skin defects. Currently, the use of
scaffolds composed of polylactic and polyglycolic acids embedded with various growth factors are
used to improve skin healing.[19,20] With precise manufacturing techniques and the utilization of
novel biomaterials, the development of these products can provide enhanced aesthetic appearance
after reconstruction. This has been proven to be safe, reliable, and reproducible.
NERVE TUBULIZATION
Nerve regeneration is an area of particular interest to both plastic surgeons and nanotechnology
researchers. Plastic surgeons perform majority of the peripheral nerve surgeries involving the
hands, face, and trunk..[21,22] Traumatic nerve injuries resulting in loss of nerve tissue over 5mm
frequently require nerve grafting, often from an autologous source. Donor sites for this procedure,
however, are limited. To avoid the morbidity of autologous nerve grafting, nanoscale
manufacturing techniques have been employed to develop new approaches in peripheral nerve
repair. Tubular and porous nanostructured conduits, using various natural materials, have been
developed to guide regenerating nerves. These structures have been loaded with various
biomaterials or cell types (e.g., embryonic stem cells, Schwann cells, neural stem cells) to aid
regeneration. Chitosan nanofiber mesh tubes were studied in sciatic nerve injuries in a rat model
by Wang et al.,[23] in which they noted partial recovery of sensory function as the nerves elongated
through the tubes. Biodegradeable micropatterned scaffolds that mimic the extracellular
membrane can also be coated with laminin and seeded with Schwann cells to guide neuron
alignment and promote axon regeneration after injury.[19] Currently researchers are designing
neural interfaces between the peripheral and central nervous system, and limb prostheses for
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patients with traumatic amputations and spinal cord injuries.[24,25]
NANOTECHNOLOGY IN BONE BIOLOGY AND REPAIR
Current developments in bone matrix depends on the understanding that the bone
microenvironment is made up of progenitor cells, mineralized extracellular matrix scaffold,
soluble chemical signals (such as cytokines), and mechanical stimuli.[26] Nanoscale fabrication
techniques can improve each of these components. Scaffolds made of nanomaterials provide a
geometric porous structure that allows osteoblastic differentiation.[27] Such techniques are
conceptually simple, yet were not technically possible until the development of modern nanoscale
fabrication techniques. Advances in fabrication and manufacturing make nanotechnology an
exciting and powerful tool in the development of bone reconstruction.
BONE PROSTHESES
Nanotechnology can be used to manipulate the surfaces of standard bone replacement implants to
maximize tissue ingrowth while minimizing inflammation. Raimondo et al.[28] recently
investigated the use of electron beam absorption to resurface standard titanium and polyethylene
implant surfaces. Then they evaluated them for surface characterization, surface energy and
contact angles, and osteoblast and endothelial cell adhesion [Figure 2]. They found that the
nano-roughened surfaces were more favorable in each category.While unmodified titanium
surfaces demonstrated excellent adhesion of both osteoblasts and endothelial cells, once modified,
the polyethylene surface showed significantly increased osteoblast adhesion and showed similar
endothelial cell adhesion. This study introduces a novel process to efficiently nano-roughen
materials and provides an additional example of nanotechnology use to enhance the performance
of standard synthetic materials.
Liu
et
al.[29]re-emphasizing
the
importance
of
the
homogenous
dispersion
of
poly-DL-lactic-co-glycolic acid (PLGA) nanoparticles for optimal enhancement of cell adhesion.
They demonstrated that PLGA prosthetics enhanced with a well-dispersed nanoceramic coating
had improved load-bearing limitations. This improved mechanical strength was most likely due to
the strong bonds between nanoparticles and PGLA, as conveyed by the fine ultrastructure of the
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particles. This enhancement of mechanical strength, through the application of nanoparticles, is a
previously underappreciated finding in nanomaterials. Finally, this work highlights that the
three-dimensional structure of nanoparticles and its interactions can increase their applications.
Hydroxyapatite (HA) is currently used to fill bone defects by itself or as a prosthetic coating.
While HA has advantages over other bioceramics, such as creating strong bonds with native
tissues, it lacks a homogeneous degradation phase. Given the nanoscale architecture of native
bone crystals, manufacturing HA on a nanoscale would theoretically improve its utility. Poinern et
al.[30] have investigated the effects of thermal and ultrasonic techniques for the development of
these particles and demonstrated that either technique can generate particles of similar consistency.
El-Fattah et al.[31] histomorphometrically analyzed the tissue by growth and scaffold degradation
in 3 groups of rats with identical bone defects: one filled with mirco-HA, one with nano-HA and
one control group without filler. They found increased reactive bone formation and
biocompatibility in nano-HA group compared to other groups. These findings have immediate
implications for improving the utility of HA for craniofacial, hand, extremity, and truncal bone
reconstructive applications.
BONE REGENERATION
In addition to aiding the development of bone prosthetics, nanotechnology also provides many
inroads to improve bone regeneration. The induction of progenitor cells into osteoblasts is an
important component of bone regeneration. A novel application of nanotechnology to achieve this
goal is the application of specific nanoscale surfaces to produce specific cellular responses, such
as osteoblastic differentiation. Oh et al.[27] investigated the effect of culturing human
mesenchymal stem cells (hMSC) on titanium dioxide (TiO2) nanotubes ranging in size from 30
nm to 100 nm. They found that the larger nanotubes forced the elongation of the hMSCs and
consequently encouraged differentiation into osteoblastic cell lines. They proposed that smaller
nanotubes capture local proteins easily and establish an extracellular matrix-like environment
allowing for easy hMSC adhesion. In larger nanotubes, there is less capture of local proteins and
the hMSCs require to stretch and develop filopodia to elongate across the surface and establish
adequate adhesion [Figure 3]. This geometrical manipulation provides the cytoskeletal stress
Review Article
theorized to induce osteoblastic differentiation. This technique could feasibly improve previous
methods of osteoinduction that involve gene therapy.[32]
NANOTECHNOLOGY IN MAXILLOFACIAL SURGERY
Nanotechnology has the potential to bring enormous changes to the fields of maxillofacial surgery
and dentistry through the aid of nanorobotics, nanomaterials, and biotechnology.[33] Nanorobots
have a diameter of 0.5-3 µm and are made of components sized from 1 nm to 100 nm. They can be
programmed, thus enabling clinicians to execute accurate procedures at the cellular and molecular
levels. Specifically, they have roles in local anesthesia, diagnostics, therapeutics, dental and
maxillofacial hard tissue repositioning, and dentifrice. In maxillofacial surgery, nanomaterials
can be used as bone replacement materials, prosthetic implants, dental fillers, dental restorative
materials, impression materials, and even for orthodontic wires exhibiting very high strength and
excellent deformability, corrosion resistance, and surface finish. Finally, tissue engineering with
natural nanomaterials holds the potential to completely reconstruct a patient’s dentition and
craniofacial skeleton.
DRUG DELIVERY
Nanoscale technologies have numerous applications in drug delivery [Table 1]. Bone infections
can be catastrophic and are difficult to manage even in the age of modern antibiotics and best
surgical techniques.[34] Plastic surgeons are frequently involved in management of these problems
because they provide technical expertise with vascularized tissue transfer and soft tissue
reconstruction. Deep tissue infection with multiple drug resistant organisms coupled with the
morbidity of serial operations and potentially toxic systemic therapies begs for the introduction of
new approaches. The antimicrobial properties of silver have long been appreciated and current
nanotechnological techniques have allowed the production of nanoscaled silver particles with a
very high surface to mass ratio. Zheng et al.[38] examined PLGA composite grafts treated with
nanosilver compared to PLGA controls [Figure 4]. They were able to demonstrate that this
composite had strong antimicrobial properties and that the presence of the nanosilver did not
affect the osteoinductive properties of PLGA in the presence of bone morphogenic protein-2
Review Article
(BMP-2). In a rat model, nanosilver-PLGA composite grafts demonstrated complete healing
without residual bacteria, while control animals had residual bacterial contamination. This study
shows that silver can be used as an antimicrobial agent in grafts, while previous studies showed its
topical use.
Colilla et al.[36] examined silica-based mesoporous materials to characterize the features that
determine the loading capacity and delivery of medications integrated into these devices. They
specifically focused on silica-based mesoporous materials because they can be manufactured with
a high degree of homogeneity with a tunable pore size. Their work highlights the importance of
pore size, volume, and surface area in both drug adsorption and drug elution from the device.
Nanotechnology has further applications beyond the fabrication of devices and materials on the
nanoscale. Nanotechnology also allows us to study and quantify biological processes at this level
using various techniques. Differences of regional bone on the nanoscale may allow for improved
or novel harvesting techniques in addition to infrequently used donor sites for graft harvest.
Through this knowledge, we can improvise the architecture of materials to increase success rate in
tissue reconstruction. Leong et al.[37] have utilized tissue characterization on the nanoscale to
categorize the various tissues present during bone callus formation. Understanding bone healing
biology at the nanoscale will help us develop ways to improve this process for reconstructive
purposes.
CANCER TREATMENT
Cancer treatment often involves multiple modalities, including surgery, chemotherapy, and
radiation therapy. The single most important predictor of patient survival for cancer is complete
surgical resection. Nanometer-sized particles such as quantum dots and colloidal gold have novel
size-tunable properties that neither discrete molecules nor bulk materials can provide.[38] These
particles have potential for tumor localization, tumor margin detection, identification of important
adjacent structures, mapping of sentinel lymph nodes, and detection of residual tumor cells or
micrometastases. Contrast agents containing such particles can be accumulated in solid tumors
through passive and active targeting mechanisms. In addition, intraoperative imaging can be used
Review Article
to overcome problems with tissue penetration of traditional optical methods [Figure 5]. Such
agents include quantum dots, and surface-enhanced Raman scattering nanoparticles. Evaluating
the long-term fate and toxicity of nanoparticles remains a challenge. Finally, it is important to
design agents that are accumulated in tumors but are cleared from other organs and tissues.
In conclusion, nanotechnology has a vast array of applications in plastic and reconstructive
surgery [Table 2]. Specifically, wound management, topical skin care, implant and prosthetic
design, tissue engineering, and drug delivery systems have each been influenced by advances in
nanotechnology. As our understanding of biology on the nanolevel progresses, the use of this
technology will increase exponentially. These characteristics make nanotechnology a powerful
tool when applied to all aspects of tissue reconstruction.
Review Article
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Review Article
FIGURES AND TABLES
Table 1: Nanoscale drug delivery technologies[1](Used with permission)
Drug delivery technology
Materials
Nanostructure forms
Biologic
Lipids
Peptides
Nucleic acids
Polysaccharides
Viruses
Poly(lactic acid)
Poly(glycolic acid)
Poly(alkylcyanoacrylate)
Poly(3-hydroxybutanoic acid)
Poly(organophosphazene)
Poly(ethylene glycol)
Poly(caprolactone)
Poly(ethylene oxide)
Poly(amidoamine)
Poly(L-glutamic acid)
Poly(ethyleneimine)
Poly(propylene imine)
Silicon
Silicon dioxide
Carbon
Gold
Silver
Palladium
Platinum
Versicles, nanotubes, rings
Nanoparticles
Polymeric
Silicon based
Carbon based
Metallic
Vesicles, spheres, nanoparticles
Micelles, dendrimers
Porous, nanoparticles
Nanoneedles
Nanotubes, fullerness
Nanoparticles, nanoshells
Table 2: Summary of nanotechnology applications in plastic and reconstructive surgery
Material
Device
Application
Lipids, peptides, nucleic
acids,
polysaccharides,
viruses
Peptides, antibodies
Vesicles,
nanoparticles
Activatable probes, tumor
paints
Tumor targeting, theranostics
Polymers (poly- lactic acid,
glycolic acid, caprolactone,
propylene, etc)
Vesicles,
nanoparticles,
dendrimers
Drug delivery
nanotubes,
spheres,
micelles,
Drug delivery
Review Article
Silicone, silicone dioxide
Nanoparticles,
nanoneedles
Nanotubes, fullerenes
Drug delivery
Semiconductor quantum
dots
Nanoparticles, nanoshells
Tumor targeting
Surface-enhanced Raman
scattering
Tumor targeting
lactate, poly glycolic
Layered scaffolds
lactate, poly glycolic
Contoured scaffolds
lactate, poly glycolic
lactate, poly glycolic
Flexible
scaffolds,
bioreactors
Hydrogel scaffolds
Poly lactate, poly glycolic
acid
Collagen
Rigid
scaffolds,
mineralized substrates
Nanofibers
Composite skin grafts, chronic
wounds, burn wounds, skin diseases
Customized fat grafts, breast
reconstruction
Functional muscle grafts, solid
organ transplants
Moldable
cartilage
scaffolds,
craniofacial
&
skeletal
reconstruction, dental restoration
and reconstruction
Bone grafts
Chitosan
Nanofibrils
Wound, burn care
Silver
Nanoparticles
Wound and burn care
Zinc oxide, titanium dioxide
Nanoparticles
Sunscreen
Fullerene, lipids
Vesicles,
nanoparticles
Silicone, silicone dioxide
Nanofiber, nanoparticle
Breast implants
Peptides, collagen, PLGA,
chitosan
Flexible
nanofibers
Nerve conduits
PLGA,
polyethylene
Hydroxyapatite
Nanoscale surfacing
Bone prostheses and implants
Bone replacement, implant coating
Titanium, carbon
Nanoparticles,
coating
Nanotubes
Carbon, metal colloids
Nanorobots
Carbon
Carbon
Gold,
silver,
platinum
palladium,
Gold
Poly
acid
Poly
acid
Poly
acid
Poly
acid
Titanium,
nanotubes,
scaffolds,
implant
Drug delivery
Drug delivery, quantum dots, tumor
detection
Wound care
Skin care products
Bone regeneration scaffolds
Tissue healing, bone replacement,
tumor theronostics, anesthesia
Review Article
Ceramics
(nonorgainic,
nonmetallic compounds)
Nanocoating, nanofibers,
nanocomposites
Bone restoration, reconstruction
PLGA: Poly-DL-lactic-co-glycolic acid
Figure 1: Histological staining of healed skin in each experimental group. Masson Trichome
staining shows the distribution and density of collagen protein in healed skin in various groups.
Collagen protein was stained blue, nuclei are stained black and the background (muscle,
cytoplasm and keratin) are stained red. IHC staining shows the expression of collagen type I and
type III of healed skin in normal skin, silver treated, and untreated groups, respectively. (Scale bar:
20 micrometers).[9](Used with permission.)
Figure 2: Scanning electron microscopy images of (a) conventional titanium (Ti), (b) nanorough
Ti, (c) conventional PE, and (d) nanorough PE. Scale bars in (a) and (b) are 200 nm while (c) and
(d) are 1 μm.[28] (Used with permission)
Figure 3: Filopodia of endothelial cells induced by nanotopography.[27](Used with permission)
Figure 4: In vivo antibacterial activity of nanosilver particle- poly-DL-lactic-co-glycolic acid
(PLGA) composite grafts. After 2-week contamination with 10[8] CFU S. aureus Mu50, rat
femoral segmental defects with implanted grafts were harvested, fixed, decalcified, embedded,
sectioned and stained with Taylor modified Brown and Brenn gram stain as well as HE. Compared
to serious bacterial infection (black dots) found in control PLGA grafts (a), 1.0%
nanosilver-PLGA composite grafts significantly reduced bacterial survival to colonized collation
(b, red arrows). On the other hand, only limited bacterial colonies (red arrows) were observed in
2.0% nanosilver particle-PLGA composite grafts in vivo (c), and more red blood cells (blue arrows)
were found in the grafts instead of phagocytes (black arrows).[38] (Used with permission)
Figure 5: Active versus passive targeting of cancerous tissue. Nanoparticles passively diffuse
Review Article
through the highly permeable endothelial layer of blood vessels in cancer tissue. In addition,
decreased lymphatic drainage from solid cancer tissue prevents the nanodrug from returning to the
systemic circulation. Active nanodrugs target the tumor tissue with engineered tissue-specific
ligands on the surface of the nanodrug.[2] (Used with permission)