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Increased Release Time of Antibiotics from Bone Allografts through a Novel Biodegradable Coating

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The use of bone allografts is contraindicated in septic revision surgery due to the high risk of graft reinfection. Antibiotic release from the graft may solve the problem and these combinations can theoretically be used for prevention or even therapy of infection. The present study investigated whether amoxicillin, ciprofloxacin, and vancomycin alone or in combination with chitosan or alginate are suitable for short-term or long-term bone coating. Human bone allografts were prepared from femoral head and lyophilized. Antibiotic coating was achieved by incubating the grafts in antibiotic solution and freeze-drying again. Two biopolymers chitosan and alginate were used for creating sustained-release implantable coatings and the drug release profile was characterized in vitro by spectrophotometry. Using lyophilization with or without chitosan only resulted in short-term release that lasted up to 48 hours. Alginate coating enabled a sustained release that lasted for 8 days with amoxicillin, 28 days with ciprofloxacin coating, and 50 days with vancomycin coating. Using only implantable biodegradable allograft and polymers, a sustained release of antibiotics was achieved with ciprofloxacin and vancomycin for several weeks. Since the calculated daily release of the antibiotic was lower than the recommended IV dose, the calcium alginate coated bone graft can support endoprosthesis revision surgery.
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Research Article
Increased Release Time of Antibiotics from Bone Allografts
through a Novel Biodegradable Coating
István Hornyák,1Edit Madácsi,1Pálma Kalugyer,1Gabriella Vácz,1Dénes B. Horváthy,1
Miklós Szendryi,2Weiping Han,3and Zsombor Lacza1,2
1Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, T˝
uzolt´
outca37-47,
Budapest 1094, Hungary
2Department of Orthopedics, Semmelweis University, Karolina ´
ut 27, Budapest 1113, Hungary
3Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Fusionopolis Way, Singapore 138632
Correspondence should be addressed to Istv´
an Horny´
ak; istvan.hornyak@eok.sote.hu
Received  March ; Revised  May ; Accepted  May ; Published  June 
Academic Editor: Tibor Hortobagyi
Copyright ©  Istv´
an Horny´
ak et al. is is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
e use of bone allogras is contraindicatedin s eptic revisionsurger y dueto the high r isk ofgra reinfection. Antibiotic release from
the gra may solve the problem and these combinations can theoretically be used for prevention or even therapy of infection. e
present study investigated whether amoxicillin, ciprooxacin, and vancomycin alone or in combination with chitosan or alginate
are suitable for short-term or long-term bone coating. Human bone allogras were prepared from femoral head and lyophilized.
Antibiotic coating was achieved by incubating the gras in antibiotic solution and freeze-drying again. Two biopolymers chitosan
andalginatewereusedforcreatingsustained-releaseimplantable coatings and the drug release prole was characterized in vitro
by spectrophotometry. Using lyophilization with or without chitosan only resulted in short-term release that lasted up to  hours.
Alginate coating enabled a sustained release that lasted for  days with amoxicillin,  days with ciprooxacin coating, and 
days with vancomycin coating. Using only implantable biodegradable allogra and polymers, a sustained release of antibiotics was
achieved with ciprooxacin and vancomycin for several weeks. Since the calculated daily release of the antibiotic was lower than
the recommended IV dose, the calcium alginate coated bone gra can support endoprosthesis revision surgery.
1. Introduction
Surgical treatment of musculoskeletal diseases relies increas-
ingly on the long-term implantation of foreign materials such
as bone substitutes, endoprosthesis, degradable scaolds,
and plastic components (e.g., polymethyl methacrylate or
polyethylene). Since the immune system is not well adapted
to ght bacterial infection associated with these foreign
materials [,], human allogra seems to be a logical choice as
scaold aer suitable preparation [,], although septic com-
plications are becoming a growing concern for the orthopedic
community [,]. Infection aer total hip replacement is still
an unsolved issue; according to a clinical article, infection
occurred in .% aer primary procedures and in .% aer
revision procedures []. e quantication in another article
had dierent results; in the United States the overall infection
burden from  to  of hip arthroplasty was .%; this
value increases annually at a rate of close to % []. Based
on another survey, from  patients with infection involving
total joint arthroplasty subsequent infection occurred in %
of the cases []. Due to the low metabolic rate of bone tissue
and the low permeation of the formed bacterial biolm [],
it is dicult to reach the required local concentration of
antibiotics whether it is applied systemically or as a local
formulation (e.g., block, sponge, implant, and bead) prepared
during surgery []. In general practice, local treatment
is typically applied to support systemic antibiotics and most
frequently used drugs include amoxicillin, cephalexin, gen-
tamycin, sulfamethoxazole, ciprooxacin, and vancomycin
applied in cement [], beads [], and impregnated bone
[]. In addition, o-label use of these antibiotics mixed
by hand with the carrier bone substitute is oen performed
Hindawi Publishing Corporation
BioMed Research International
Volume 2014, Article ID 459867, 8 pages
http://dx.doi.org/10.1155/2014/459867
BioMed Research International
T : Technical requirements against a local antibiotic formulation in the  main categories of orthopedic use in endoprosthesis surgery.
Medical purpose
Probability
of
infection
Antibiogram Required length of local
antibiotic treatment
Typ ica l l ocal a nti bio tic
formulation Reference
Primary
implantation
Prevention of infection
arising from contamination
at surger y or early
postoperation
.–% Not available
- days or until the surgical
site is open through
drainage
Antibiotic bone cement,
o-the-shelf []
Aseptic
revision
Prevention of infection
arising from either
contamination or a
low-grade infection
n/a
Not available,
or its
reliability is
low
- days or until the surgical
site is open through
drainage. Longer if
low-grade infection is
suspected.
Antibiotic bone cement,
bone substitutes, freehand
use of local antibiotic
powder or solution
[,]
Septic
revision
Eradication of bacterial
infection % Available Several weeks
Antibiotic bone cement,
freehand use of local
antibiotic powder or
solution. Bone substitutes
are contraindicated.
[,,
,]
when the required antibiotic-carrier combination is not
available o the shelf []. Whether the applied dose and
the release kinetics of such mixtures are optimal or at least
adequate for the intended purpose is unknown; however it is
still the best way a surgeon can deal with these challenging
situations.
e therapeutic goal of local antibiotic use in combi-
nation with endoprosthesis can be categorized into three
distinct case types: () prevention of early infection in a
primary prosthesis implantation procedure, () inhibiting of
infection at aseptic prosthesis revisions where the probability
of an already ongoing low-grade infection is high, and ()
treatment of massive infections at septic revisions [,].
ese cases pose diering challenges for the antibiotics
summarized in Table .
Itisevidentthatevenifonefocusesonlyonantibiotic
bone substitutes several formulations should be available
in order to meet these diverging criteria []. One way of
modifying the release kinetics of drugs in an implantable
formulation is to couple the active agent with biodegradable
polymers. Two well-known materials, which are frequently
used to form biodegradable coatings, are chitosan (Chi) and
sodium alginate (Na-Alg) [,]. ese biopolymers have
been investigated over a wide scale including the preparation
of bers, nanoparticles, and even bone substitutes, thus
posing a very low risk of toxicity []. Chitosan is typically
prepared from shrimp-shell chitin with hydrolysis and is
only soluble in acidic media. It forms excellent lms and
coatings and in case it is added to acidic forms of drugs it can
slow down release and degradation []. Alginate derivatives
such as alginic acid or sodium alginate are produced from
seaweed species. e main feature of sodium alginate is that
it is insoluble in acidic solutions and forms a biodegradable
lm that can be turned into water insoluble calcium alginate
(Ca-Alg), which can act as a barrier for drug coatings.
e general view of the surgical community is that local
use of antibiotics without any carrier is only eective for
therstfewdayspostoperatively;howeverthisviewisnot
supported by reliable experimental data [,]. eoretically
itcanbehypothesizedthatxationoftheantibioticwith
physicochemical means such as freeze-drying or embedding
in polymer coatings may prolong the release of drugs [];
however it is unknown if these procedures can meet the
requirements detailed in Table .
e present study investigated if amoxicillin, cipro-
oxacin, or vancomycin dried onto the surface of human
bone allogras alone or in combination with Chi or Ca-Alg
coating is suitable for preparing an antibiotic implant. We
further studied the characteristics (drug release and drug
load) of a short-term and a long-term release antibiotic
coating in vitro.
2. Materials and Methods
All chemicals were purchased from Sigma except for van-
comycin, which was purchased from Hangzhou APIChem
Technology Co., Ltd., China. e HCl salt was used in case
of vancomycin and ciprooxacin; however amoxicillin was
used in the trihydrate form. e bone blocks were generous
gis from the West-Hungarian Regional Tissue Bank. Freeze-
dried femoral head blocks were cut to . ±. g cube-
shaped pieces for the experiments.
Antibioticswereusedinaqueoussolutionswiththeinitial
concentrations of ., , or  mg/mL for preliminary exper-
iments. Aer evaluating these concentrations, we decided to
use a  mg/mL starting solution for all further experiments
in order to obtain data with low signal-to-noise ratio. e
bone gra was placed in  mL of the antibiotic solution and
the system was incubated at C for  hours. Subsequently,
thesoakedgrawasremovedfromthesolutionandfreezed
at C followed by lyophilization for  hours using a
Labconco Freezone .󸀠freeze-dryer (soaked preparation).
In order to maximize the drug content of the gra an
alternative approach was also performed when the gras
were frozen while still being submerged in the antibiotic
solutionandthewholesystemwasfreeze-dried(saturated
preparation).
BioMed Research International
2cycles
Freeze-
drying
Freeze-
drying
Na-Alg
Drying Ca-Cl2
24 h
with
drug
Saturated
method
Soaked
method
Saturated
method
with
chitosan
Alginate
coating
Ca-Alg
Na-Alg
F : Antibiotic coating methods. As a rst step,  mg bone allogras were incubated in a  mg/mL antibiotic solution for  hours.
e Chi used for coating was  weight %; the alginate was  weight %. e nal step in each method was lyophilization or drying in an oven
resulting in a dry bone allogra which looks the same to the naked eye as a regular uncoated gra.
Medium molecular weight Chi was used with a deacety-
lation grade of –%, and the Chi solution prepared in our
experimental set-up contained lactic acid (LA, %) with a
ratio of  𝜇L LA/ mL % Chi. e chitosan-based prepa-
rations were prepared by using  mL aqueous % chitosan
solution to dissolve the antibiotic. e bone samples were
placed in this solution and incubated at room temperature for
 hours and frozen and lyophilized aerwards in a similar
manner as the saturated preparations.
Alginate-based preparations were created in another way
since this polymer exhibits a basic pH and antibiotics typi-
cally precipitate in this solution. First, the bone gras were
coated by the saturated freeze-dried method as described
above; then a lm coating of alginate was created on top of
theantibioticlayer.eNa-Alglmwaspreparedbyadding
mL%Na-Algsolutionontheantibioticcoatedfreeze-dried
bone. en the gra was dried in an oven at Cforhours
on teon plates. e process was repeated with the dried
coated gra turned upside down; thus the double layer Na-
Alg lm was formed. Sodium alginate was then converted
into calcium alginate by CaCl2.eNa-Algcoatedbonegras
were placed in a % CaCl2solution for exactly  seconds,
then washed with distilled water, and dried in an oven at
C. e methods for preparing the coatings are presented
in Figure .
e chosen antibiotics (amoxicillin, ciprooxacin, and
vancomycin) have characteristic absorbances in the UV range
in aqueous solutions, allowing the use of UV spectroscopy
to assess the concentrations with a spectrophotometer. e
T : UV measurement characteristics of the investigated antibi-
otics.
Characteristic
absorbance (nm)
Linear
absorbance-concentration
interval
Amoxicillin  .–.
Ciprooxacin  .–.
Vancomycin  .–.
absorbance-concentration diagrams were plotted using all
antibiotics and the linear phase of this diagram was used to
calculate the concentration from the absorbances according
to the Lambert-Beer law (Table ).
We conducted preliminary experiments on the possible
absorbance of the used polymers; neither Na-Alg nor Chi
had detectable spectral peaks where the antibiotics were
measured, specically  nm and – nm, and neither
had a signicant baseline absorbance even in the maximum
possible concentrations used in the present protocol (.%
Na-Alginate or .% chitosan). In contrast, Ca-Alginate was
insolubleinwaterandtheprecipitatewouldhavemadethe
specic measurements impossible in case it had been present
in the supernatant.
Measurements of release kinetics were performed by
incubating each sample separately in  mL of water in a -
wellplateatroomtemperature.Wedidnotworkat
C
to prevent evaporation and we did not use buers to avoid
BioMed Research International
Amoxicillin Ciprooxacin Vancomycin
Released drug
soaked method (mg)
2.0
1.5
1.0
0.5
0.0
0-1h
124 h
2448 h
(a)
Amoxicillin Ciprooxacin Vancomycin
0.0
0.5
1.0
1.5
2.0
Released drug
saturated method (mg)
0-1h
124 h
2448 h
(b)
F : Drug release kinetic of amoxicillin, ciprooxacin, or vancomycin coating, prepared by the soaked or the saturated method. ese
procedures are not expected to signicantly increase release time, so over % of the drug is released within the rst day.
changes in the solubility and adding possible UV absorbent
molecules. Concentration measurements were performed at
specied intervals by removing the supernatant for spec-
troscopyandreplenishingwithfreshsolvent.efrequency
of solution changes and the length of the experiments were
determined by preliminary experiments and set in ways that
optimal kinetic curves could be constructed from the data
set. In the case of vancomycin and ciprooxacin samples
were taken on the st, th, th, th, th, th, and
th day. Vancomycin was also measured on the th day.
In a separate experiment with Ca-Alg coated amoxicillin
gras, the medium was placed back onto the gra aer
each measurement in order to evaluate the eect of drug
accumulation in the medium. Statistics were carried out using
GraphPad Prism . soware. All data were expressed as
means ±SEM (𝑛=3) and were analyzed using Students 𝑡-
test, simple analysis of variance (ANOVA), or -way ANOVA
with Bonferroni’s multiple comparison. Dierences were
considered signicant when 𝑃 < 0.05 (∗),𝑃 < 0.01 (∗∗),
𝑃 < 0.001 (∗) (Table ).
3. Results
Aer preliminary experiments (data not shown), all the three
drugs were highly soluble in water and were suitable to
be stored at room temperature without any decomposition.
e original concentration of the antibiotic solutions used
to incubate the bone gras correlated with the amount of
antibioticsonthebonesurfaceasestimatedbythetotal
amount of drugs released. We decided to use a  mg/mL
starting solution for all further experiments in order to obtain
data with low signal-to-noise ratio.
Simple freeze-drying of antibiotics on the surface of bone
gras did not result in a sustained release of the compounds.
Although minor dierences were observed among the three
antibiotics, each one is completely released within  hours
T : e daily released amount of amoxicillin measured with
either replacing the solvent daily or replenishing the solvent. ere
were signicant dierences in the st and nd day with the dierent
methods.
Released
drug
(mg/day)
Amoxicillin
solvent replenishment
Amoxicillin
cumulative release
Mean ±SEM Mean ±SEM
Day ∗∗ . ±. . ±.
Day ∗∗∗ . ±. . ±.
Day  . ±. . ±.
Day  . ±. . ±.
Day  . ±. . ±.
Day  . ±. . ±.
Day  . . ±.
Day  . .
∗∗ is the dierence between the released drug on the rst day with the two
dierent methods, and ∗∗∗ is the dierence between the released drug on the
second day with the two dierent methods.
(Figure ). Maximizing the antibiotic loading with the sat-
urated method did not improve the release kinetics only;
the overall amount of antibiotics on the gra was higher
(Figure (b)). Using a chitosan additive with the antibiotics
did not signicantly prolong the release of the drugs from the
surface.
With the use of a Ca-Alg lm layer, it was possible
to reach a long-term sustained-release antibiotic coating.
Interestingly, the type of antibiotic signicantly aected the
rate of drug release from the same type of coating. For
example, amoxicillin was completely released within  days
andciprooxacinwithindayswhilevancomycinexhibited
thelongestreleasetimewithdays(Figure). e amount
of antibiotic released on the rst day from Ca-Alg coated
allogra was approximately the same as the amount from
the antibiotic coated bones which did not contain Ca-Alg
BioMed Research International
0 7 14 21 28 35 42 49
0.0
0.2
0.4
0.6
0.8
1.0
Amoxicillin Ca-Alg
Ciprofloxacin Ca-Alg
Vanco myci n C a- A l g
Days
Drug released (mg/day)
F : Release prole of amoxicillin, ciprooxacin, or van-
comycin with sustained release Ca-Alg lm coating (𝑛=3).
Although the coating method was the same in each case, the
eective release term was dierent among the three drugs with
amoxicillin lasting up to  days and ciprooxacin up to  days while
vancomycin reached  days.
(Figure ).etotalquantityofdissolvedantibioticsover
the -, -, or -day period depending on the respective
antibiotic was approximately the same as those without
alginate coating. We therefore conclude that the amount of
total antibiotic content did not increase; however, the release
rate has changed as shown in Figure .
In order to test whether the release kinetic is aected by
thenegativefeedbackofdrugaccumulationinthesolution,
we compared two sets of bone gras either with release
in fresh solvent or with cumulative release into the same
medium. Ca-Alg coated amoxicillin was selected for this
measurement since it showed a signicant change for several
days, while the other preparations had too slow or too fast
kineticsforthistypeofmeasurement.Weobservedthatabove
the dosage of . mg/day the release is slightly inhibitedby the
accumulation of the compound; however this was no issue at
lower doses and did not aect the length of the active release
period either (Table ).
To summarize the long-term release experiment, alto-
gether . ±. mg amoxicillin was eluted from the surface
of  mg bone allogra with complete dissolution in  days.
In case of ciprooxacin, .±. mg was the total eluted
amount within  days. Vancomycin had the longest elution
timeforoverdaysduringwhich.±. mg antibiotic
was released in total.
4. Discussion
e present study indicated that it is possible to pro-
duce antibiotic coating with physicochemical methods. With
biopolymers we can modify the release kinetics of antibiotic
impregnated bone gras in order to reach either complete
unloading in  hours or sustained release for up to  days.
A critical limitation in one-stage revision surgery is the
extent of bone loss. Ideally, one would perform elaborate
bone replacement techniques in order to build a suitable
biological base for a new implant; however bone gras are
viewedascontraindicatedintheseproceduresduetothehigh
probability of infection. Impregnation of bone gras with an
antibiotic solution by hand mixing is generally applied in the
OR as a preventive measure; however most surgeons would
consider this technique inadequate for septic cases. is view
is conrmed by data from the present study. Even though the
antibiotics were incubated for a day and then freeze-dried
onto the bone, the majority of the drug (%) was released
during the rst day aer placing the gra in water. is release
kinetic may be suitable for ghting perioperative infection
when the implant may be contaminated during surgery
or from the patient’s skin through the surgical wound or
drainage tubes, but this timeframe is inadequate to eradicate
massive infections.
e amount of antibiotics in combination with a bone
substitute is a challenge. In most cases the volume of the
required bone gra is only determined during surgery and
predetermining the required dose is only realistic with
large margins. Moreover, the amount of antibiotic which
is implanted into a patient is set by the amount of bone
gra, as administering the drug follows the “dosing” of the
gra. e highly variable spatial conformations add a further
degree of freedom to the equation. One would assume that
tightly impacted bone chips between a cortical layer and a
metal implant have much lower surface for the body uid
to penetrate than a porous block placed into a well bleeding
spongiotic area. Our current measurements showed that the
negative feedback from the accumulation of the drug in
a small volume just marginally aects the release kinetics.
erefore the spatial eect probably plays a limited role in this
question. However, it should be noted that our experiment
was performed in a laboratory setting and release kinetics
with bodily uids in the presence of metabolizing cells and
bacteria will be dierent. erefore, due to the uncertainties
inherent in this applicable eld, it is best to load bone gras
with only a low amount of antibiotics to prevent overdosing.
As a comparison in the present study, we estimated the total
dailydosespotentiallyreleasedfrombonegraswithselected
combinations. We applied the femoral head gra as a more
or less standard “dose” of bone graing material frequently
applied in orthopedics. For these calculations we estimated
the antibiotic elution from a femoral head based on the results
from our experiments (Table .). In principle we multiplied
the antibiotic content based on the femoral head and our bone
chip weight ratio ( g/. g).
Please note that these calculations are based on data
gained in vitro,sothesecanonlybeconsideredasrough
estimates. e calculations show that the implantation of one
femoralheadcoatedwithanyoftheanalyzedantibioticscan
release a signicant percentage of the daily IV dose during
the rst day but the dose goes below % in the long term.
erefore, in case of large antibiotic bone gras implanted, it
is recommended to set the systemic antibiotic dosing based
on close monitoring of serum levels for a few days aer
surgery. Ciprooxacin has to be monitored especially closely
BioMed Research International
T : Calculated antibiotic content of the coated bone compared to the daily doses in clinical practice.
 hours from . g
bone
th day from . g
bone
 hours from  g
bone
th day from  g
bone
Daily dose/reference
(mg/day)
Amoxicillin (mg) .   []
% of daily dose . .
Ciprooxacin (mg) . . . .  []
% of daily dose . . . .
Vancomycin (mg) . . . .  []
% of daily dose . . . .
as it has the highest cytotoxic eect among the three drugs
[,]. A  mg/mL starting concentration of antibiotic was
appliedinourstudyandisalsorelevantaccordingtothe
literature of local antibiotic drug release products regarding
both amoxicillin [,] and vancomycin []. We suggest
that these calculations may have some relevance towards
other antibiotic bone substitutes as well.
e release of the antibiotics was comparable or even
faster when we used chitosan than in the absence of a polymer
coating. Although Chi is a well-known vehicle for drugs,
and it was already applied in combination with vancomycin,
mostly with microencapsulation by spray drying [],
we did not nd it eective in our experiments. is can be
explained with our freeze-dried formulation and the solubil-
ityofchitosan.ispolymerisonlysolubleinacidicmedia
and the three chosen drugs were also acids or acidic salts. We
speculate that the acidic drugs enhanced the solubility of Chi,
since most antibiotics are also acids, and the use of chitosan
as a delivery vehicle for sustained release is not suitable.
Ca-Algwasusedasalayerbylayerlmcoating,and
in most cases alginate is used in loaded beads []or
microspheres []orcomposites[]. Since all the three
drugsweusedprecipitatedintheNa-Algsolution,wedecided
to use it as a coating to separate the drugs from water. e
long-term release was successful when we produced a water
insoluble Ca-Alg lm coating. Due to the uneven surface of
thebonestructure,thethicknessofthealginatelmcannotbe
proven to be uniform on the surface of the bone. According
to our current results this did not aect the elution charac-
teristics. Although the coating exhibited little dierence for
amoxicillin, both ciprooxacin and vancomycin proved to be
suitable for sustained release bone gra formulations. e
drug delivery period of at least  days should be sucient for
the long-term antibacterial eect required for the eradication
of implant-related infections []. Loading biomaterials with
antibiotic is nowadays a standard medical procedure for the
local treatment or prevention of bacterial infection. However,
there are concerns related to biolm formation, developing
resistance especially if the local antibiotic cement is the rst
line treatment []. One possible solution is that dierent
antibiotics should be added locally than in the preventive
phase or two or more antibiotics should be combined in local
treatment []. Bacterial biolm formation on bone cement
has also been studied; adhesion to the bone cement is an
important factor []. However, there is no evidence that
an alginate coating on bone allogra would be suitable for
biolm formation. On the other hand, prevention of bacterial
resistance can be solved with the use of combined drug
coating later on in the in vitro experiments. Besides, we also
have to keep in mind that both the allogra and the alginate
coating are biodegradable, which can pose an obstruction for
biolm formation. According to our measurements, the MIC
value of vancomycin was . 𝜇g/mL for Enterococcus faecalis
(data not shown) and the MIC value of 𝜇g/mL vancomycin
is sucient against vancomycin susceptible MRSA [].
Taking into account that using our coating and vancomycin
astheantibioticwemanagedtokeepthereleasedvancomycin
concentration above 𝜇gpermLatthethday,thein vitro
resultsshowthatthisdrugcoatedbiomaterialiscapableof
keeping the antibiotic above the required dose for a prolonged
time.
5. Conclusion
We conclude that sustained release antibiotic bone gra
coating can be achieved by using an insoluble Ca-Alg coating
on bone allogras impregnated with antibiotics. is prepa-
ration allows the sustained release of either vancomycin or
ciprooxacin at therapeutic levels for at least  days, making
this composition suitable for septic revision surgery. A short-
term release coating without the protective alginate layer is
also possible, especially with amoxicillin, a broad-spectrum
antibiotic regularly used for the prevention of infection [,
].
Conflict of Interests
e authors state that there is no conict of interests regard-
ing the results shown in the present study. e institute
received nancial funding from Lacerta Technologies to
achieve the development.
Acknowledgments
isstudywassupportedbytheHungarian-Singaporean
joint research grant TET-SIN-CELLTHER. e authors are
thankful to Lacerta Technologies for sponsoring the research.
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... 28 Freeze-drying the graft while still being submerged in the antibiotic solution did not prolong the elution, but the overall amount of released antibiotic was higher. 32 Other bone graft manipulations performed for decellularization and/or sterilization included chemical cleaning processes with detergents 21 or solvents 28,33,34 , pulse lavage with normal saline 35,36 , sonication, irradiation and combinations thereof. Gentamicin impregnation was not significantly affected by bone graft cleaning by washing versus detergent treatment and sonication. ...
... 25 Coating of bone with alginate after impregnation extended the release of amoxicillin, ciprofloxacin and vancomycin, in contrast to chitosan coating which did not significantly prolong antibiotic release. 32 The bone surface can be modified by EDTA submersion, making more amines available at the surface, addition of a linker and then tethering of vancomycin. These vancomycin-tethered allografts did not elute active antibiotic but resisted S. aureus colonization for 20 days, prevented biofilm formation and did not influence osteoblast colonization or viability. ...
... 24 To prolong release, an antibiotic-enriched bone wax or polysaccharide coating can be used. 32,40 Antibiotic-tethered bone grafts could be useful in circumstances of high infection risk. The bonded antibiotic could for example ensure a prolonged protection of the avascular grafts. ...
Article
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Introduction: Bone implant related infection is still one of the biggest challenges in bone and joint surgery. Antibiotic impregnated bone grafts seem to be promising in both treatment and prevention of these infections. However, great variance in methodology predominates this field of research. This paper gives an overview of the published literature. Methods: The PRISMA-flowchart was used as protocol for article selection. Medline was searched and articles were selected in accordance with predetermined exclusion criteria. Results: Forty-eight articles were included in the synthesis. Topics including bone graft type, manipulations of the graft, elution profile, bacterial inhibition, osteotoxicity, incorporation, special impregnation methods, clinical use and storage were investigated. Therapeutically, high initial levels seem appropriate for biofilm eradication. A single stage procedure in the treatment of bone implant related infection seems feasible. Prophylactically, the literature indicates a reduction of postoperative infections when using antibiotic impregnated bone grafts. Conclusion: Bone grafts are a suitable carrier for local antibiotic application both therapeutically and prophylactically.
... Sustained release of the drug for 50 days was observed. It was reported that the MIC for Enterococcus faecalis was 0.2 µg/mL of vancomycin, and for methicillin-resistant S. aureus, was 2 µg/mL of vancomycin [340]. Another advantage is that the alginate and allograft are biodegradable, which makes the development of the biofilm more difficult [341]. ...
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In the determination of the bioavailability of drugs administered orally, the drugs' solu-bility and permeability play a crucial role. For absorption of drug molecules and production of a pharmacological response, solubility is an important parameter that defines the concentration of the drug in systemic circulation. It is a challenging task to improve the oral bioavailability of drugs that have poor water solubility. Most drug molecules are either poorly soluble or insoluble in aque-ous environments. Polymer nanocomposites are combinations of two or more different materials that possess unique characteristics and are fused together with sufficient energy in such a manner that the resultant material will have the best properties of both materials. These polymeric materials (biodegradable and other naturally bioactive polymers) are comprised of nanosized particles in a composition of other materials. A systematic search was carried out on Web of Science and SCOPUS using different keywords, and 485 records were found. After the screening and eligibility process, 88 journal articles were found to be eligible, and hence selected to be reviewed and analyzed. Bio-compatible and biodegradable materials have emerged in the manufacture of therapeutic and phar-macologic devices, such as impermanent implantation and 3D scaffolds for tissue regeneration and biomedical applications. Substantial effort has been made in the usage of bio-based polymers for potential pharmacologic and biomedical purposes, including targeted deliveries and drug carriers for regulated drug release. These implementations necessitate unique physicochemical and phar-macokinetic, microbiological, metabolic, and degradation characteristics of the materials in order to provide prolific therapeutic treatments. As a result, a broadly diverse spectrum of natural or artificially synthesized polymers capable of enzymatic hydrolysis, hydrolyzing, or enzyme decomposition are being explored for biomedical purposes. This summary examines the contemporary status of biodegradable naturally and synthetically derived polymers for biomedical fields, such as tissue engineering, regenerative medicine, bioengineering, targeted drug discovery and delivery, implan-tation, and wound repair and healing. This review presents an insight into a number of the commonly used tissue engineering applications, including drug delivery carrier systems, demonstrated in the recent findings. Due to the inherent remarkable properties of biodegradable and bioactive Citation: Sharma, S.; Sudhakara, P.; Singh, J.; Ilyas, R.A.; Asyraf, M.; Razman, M. Critical Review on Biodegradable and Bioactive
... In vitro and in vivo experiments justified that albumin shows adhesion and proliferation increasing effects on bone marrowderived mesenchymal stem cells, thus albumin coated allograft resulted in faster and stronger bone formation than uncoated allografts [31,32]. In addition, the albumin activates a higher number of immunomodulatory cytokines and growth factors, and the gentamycin coating of graft ensure antibiotic release for several weeks [33,34]. Consequently, albumin and gentamycin coated allograft can be an excellent option when bone grafting is necessary in a complicated case of bone loss. ...
... In vitro and in vivo experiments justified that albumin shows adhesion and proliferation increasing effects on bone marrowderived mesenchymal stem cells, thus albumin coated allograft resulted in faster and stronger bone formation than uncoated allografts [31,32]. In addition, the albumin activates a higher number of immunomodulatory cytokines and growth factors, and the gentamycin coating of graft ensure antibiotic release for several weeks [33,34]. Consequently, albumin and gentamycin coated allograft can be an excellent option when bone grafting is necessary in a complicated case of bone loss. ...
... For topical application, gentamycin, vancomycin, and tobramycin are the first-choice antibiotics due to their broad antibacterial spectrum and low percent existence of resistant bacteria species [4,5,7]. In vitro experiments proved the antibiotic-coated allograft could provide sustained release of antibiotics after emplacement [8,9].The use of gentamycin or other topical antibiotic is indeed indicated in limited cases, however, the practice is more widespread than it should be. The reasoning that oral surgery is contaminated and therefore prevention of infection is of importance is reasonable, and one choice is the use of local antibiotics where the first choice is typically gentamycin. ...
Article
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Alveolar preservation can minimize bone resorption after tooth removal and additional topical antibiotics might also be considered. The goal of this study was to observe alveolar preservation with albumin and gentamycin-coated allograft compared to unfilled control sockets after mandibular third molar removal. Twenty-two patients were involved, 11 in the control group and 11 in the test group. CBCT analysis and micromorphometric analysis were performed. After one year, graft integration was observed with remaining graft particles. Micromorphometric analysis showed increased density and lower trabeculae formation in the grafted group. The buccal height reduction of the alveolar ridge was significantly lower when alveolar preservation was applied (con-trol: 2.54 ± 2.01 mm, graft: 1.37 ± 1.04 mm, p < 0.05). Horizontal bone loss prevention was not significant. At the distal site of the second molar, the marginal bone level (MBL) was significantly lower in the control group. At the control group, five pockets persisted from the eight initial and all healed in the graft group. Alveolar preservation improves bone formation, helps to preserve the buccal bone crest, and minimizes MBL loss and pocket formation on the adjacent teeth. Thus, it needs to be also considered after third molar surgical removal.
... This can be achieved by either polymerizing the biocidereleasing molecules to the backbone of the polymeric material or via the synthesis of polymer/biocidereleasing molecules composites. These antimicrobial polymers have the ability to release biocides in a controlled manner thus, conferring advantages such as facilitating the delivery of biocides with short in vivo half-lives and high local biocide concentration close to the microorganisms [30,31]. In addition, antimicrobial polymers can also be categorized as either solutionbased or surface-bound polymers. ...
Chapter
Antimicrobial polymers are more than ever before receiving great attention from researchers, and this is chiefly due to the great antimicrobial potential they possess as well as the increasing rise in the challenges associated with the treatment and management of pathogenic microorganisms. Various research groups have extensively carried out investigations to explore the antimicrobial efficacy of several polymers and results have shown the potential application of these polymers in the eradication of diverse strains of disease-causing microorganisms. Two fundamental mechanisms of action have been clearly reported; however, more precise and in-depth mechanisms of microbial killing are required to further give clarity especially for biofilmassociated mechanisms. The combination of these mechanisms will enhance the overall antimicrobial efficacy of antimicrobial polymers. In addition, the most appropriate method of synthesis that will lead to harnessing the maximum potential of these antimicrobial polymers should be employed during fabrication. Although, at the moment, the use of antimicrobial polymers appears to be very promising in the treatment of infectious pathogens/diseases. However, the fabrication of long-acting and reusable antimicrobial polymers with a broad range of antimicrobial activity should be carefully considered to overcome some of the current challenges encountered with the use of some of the existing antimicrobial polymers.
... 18 Hornyak et al. reported that coating antibiotic-impregnated allograft with various concentrations of calcium alginate dramatically enhances the duration of therapeutic levels of antibiotic elution. 19 Further in vivo studies are required to determine clinical viability. ...
Article
Limb salvage is widely practiced as standard of care in most cases of extremity bone sarcoma. Allograft and endoprosthesis reconstructions are the most widely utilized modalities for the reconstruction of large segment defects, however complication rates remain high. Aseptic loosening and infection remain the most common modes of failure. Implant integration, soft-tissue function, and infection prevention are crucial for implant longevity and function. Macro and micro alterations in implant design are reviewed in this manuscript. Tissue engineering principles using nanoparticles, cell-based, and biological augments have been utilized to develop implant coatings that improve osseointegration and decrease infection. Similar techniques have been used to improve the interaction between soft tissues and implants. Tissue engineered constructs (TEC) used in combination with, or in place of, traditional reconstructive techniques may represent the next major advancement in orthopaedic oncology reconstructive science, although preclinical results have yet to achieve durable translation to the bedside.
... It was observed a sustained release of drug for 50 days. It was reported that the MIC for Enterococcus faecalis was 0,2 µg/ml vancomycin and for methicillin resistant S. aureus was 2µg/ml vancomycin [26]. Another advantage is that the alginate and the allograft are biodegradable what makes the development of biofilm more difficult [27]. ...
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This paper provides an overview on some of the currently used systems for drug delivery systems with applications for hard tissue engineering reported in literature in the last 5 years. These systems have received an increased attention in the last years especially because of their unique properties like antimicrobial or anticancer activity. Also, these systems are continuously studied for the improvement of the therapeutic activity and to decrease undesirable effects. In this paper, are presented the main drug delivery systems reported in literature and the main methods for impregnating of the scaffolds with drugs, their properties and their benefits for hard tissue engineering.
... The use of demineralized bone matrices for restoring bone defects and accelerating osteogenesis is widespread throughout the world and is one of the most effective methods for treatment of musculoskeletal system diseases. 3 In addition, the solidity of the compact bone tissue cortical layer with its small number of perforations, as well as the duration of resorption and the absence of bioactive components in bone matrices, cause a significant delay in the processes of revascularization and replacement of graft material with native bone tissue. 7 It is assumed that their stimulating effect is mediated by the presence of active morphogenetic proteins which actively influence the cascade of reparative processes in the bone tissue at the cellular level: mitosis of osteoprogenitor cells and differentiation of bone cells. ...
Article
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The work was aimed at conducting a comparative study into the toxicological safety of the obtained highly purified composite material comprising demineralized bone matrix for repairing bone defects. To investigate the biological properties of the demineralized bone matrix and the developed highly purified bone matrix, a culture of immortalized fetal bovine lung (LEK) cells was used. The effect of highly purified bone matrix on cells was studied by the method of cell culture in the presence of the preparation. To accomplish the task, many cell culture techniques were used, including the determination of the percentage of cell death, the level of lactate dehydrogenase synthesis, and the level of glucose uptake by cells exposed to different doses of the highly purified demineralized bone matrix. The results of the study indicate that exposure of a cell culture to the demineralized bone matrix at a dose of 2000 mg/l decreased the level of glucose uptake by cells by 18.2% as compared to control. Exposure to the highly purified bone matrix at the same doses yielded 35% glucose uptake by cells. Exposure of the LEK cell line to the demineralized bone matrix at a dose of 2000 mg /l led to the cell death rate exceeding that of control by 97%. When exposed to the highly purified demineralized bone matrix, cell death increased by 10.9% compared to control. Exposure of the cell culture to demineralized bone matrix at a dose of 2000 mg /l indicated that the level of enzyme lactate dehydrogenase (LDH) synthesis by cells was only 11% higher than that in control, whereas the level of LDH synthesis induced by exposure to highly purified bone matrix at the same doses constituted 36.9%. Therefore, the highly purified bone matrix has low toxicity on mammalian cells, which suggests a potential use of the product in clinical practice for repairing bone tissue defects.
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Mesenchymal stromal cells (MSCs) are a promising cell source for promoting tissue repair, due to their ability to release growth, angiogenic, and immunomodulatory factors. However, when injected as a suspension, these cells suffer from poor survival and localization, and suboptimal release of paracrine factors. While there have been attempts to overcome these limitations by modifying MSCs themselves, a more versatile solution is to grow them in three dimensions (3D), as aggregates or embedded into biomaterials. Here we review the mechanisms by which 3D culture can influence the regenerative capacity of undifferentiated MSCs, focusing on recent examples from the literature. We further discuss how knowledge of these mechanisms can lead to strategic design of MSC therapies that overcome some of the challenges to their effective translation.
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Bone substitutes, like calcium phosphate, are implemented more frequently in orthopaedic surgery to reconstruct critical size defects, since autograft often results in donor site morbidity and allograft can transmit diseases. A novel bone cement, based on β -tricalcium phosphate, polyethylene glycol, and trisodium citrate, was developed to allow the rapid manufacturing of scaffolds, by extrusion freeform fabrication, at room temperature. The cement composition exhibits good resorption properties and serves as a basis for customised (e.g., drug or growth factor loaded) scaffolds for critical size bone defects. In vitro toxicity tests confirmed proliferation and differentiation of ATDC5 cells in scaffold-conditioned culture medium. Implantation of scaffolds in the iliac wing of sheep showed bone remodelling throughout the defects, outperforming the empty defects on both mineral volume and density present in the defect after 12 weeks. Both scaffolds outperformed the autograft filled defects on mineral density, while the mineral volume present in the scaffold treated defects was at least equal to the mineral volume present in the autograft treated defects. We conclude that the formulated bone cement composition is suitable for scaffold production at room temperature and that the established scaffold material can serve as a basis for future bone substitutes to enhance de novo bone formation in critical size defects.
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Bone transplantation is frequently used for the treatment of large osseous defects. The availability of autologous bone grafts as the current biological gold standard is limited and there is a risk of donor site morbidity. Allogenic bone grafts are an appealing alternative, but disinfection should be considered to reduce transmission of infection disorders. Peracetic acid-ethanol (PE) treatment has been proven reliable and effective for disinfection of human bone allografts. The purpose of this study was to evaluate the effects of PE treatment on the biomechanical properties and microstructure of cancellous bone grafts (CBG). Forty-eight human CBG cylinders were either treated by PE or frozen at -20°C and subjected to compression testing and histological and scanning electron microscopy (SEM) analysis. The levels of compressive strength, stiffness (Young's modulus), and fracture energy were significantly decreased upon PE treatment by 54%, 59%, and 36%, respectively. Furthermore, PE-treated CBG demonstrated a 42% increase in ultimate strain. SEM revealed a modified microstructure of CBG with an exposed collagen fiber network after PE treatment. We conclude that the observed reduced compressive strength and reduced stiffness may be beneficial during tissue remodeling thereby explaining the excellent clinical performance of PE-treated CBG.
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Vancomycin HCl was prepared as orally administered colon target drug delivery tablets for systemic therapy. Tablet matrices containing 10-60% of tablet weight of guar gum (F1-F6) were prepared by direct compression and subjected to in vitro release studies to explore their sustained release in the colon. Various synthetic and natural polymers were incorporated to F6 to modify the drug release rate. Different 15 matrix tablet formulations (F6-F20) were enteric coated with hydroxypropyl methyl cellulose phthalate. F6, F13 and F20 showed promising sustained release results having median dissolution time (MDT) values: 8.25, 7.97, and 7.64, respectively. Microbiological assay was performed to test the efficacy of F6, F13, and F20 to inhibit clinical Staphylococcus aureus (SA) isolates. Bactericidal activity of F6 was reached after 2, 4, and 24 hours of incubation against MSSA 18, MRSA 29, and MRSA 11 strains, respectively, while it was reached within 6-8 hours in case of F13, and F20 against all strains tested. F13 enhanced log microbial reduction by 1.74, 0.65 and 2.4 CFU/mL compared to F6 while it was 1, 2.57 and 1.57 compared to F20 against MSSA18, MRSA11 and MRSA29, respectively. Vancomycin HCl tablets displayed a promising sustained release in vitro and microbiological inhibitory action on all isolates tested.
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Bone and joint infections, especially implant-associated infections, are difficult to cure. Long-term antibiotic therapy, combined with appropriate surgery and the removal of prostheses, is required. The most common causative organisms in bone and joint infections are staphylococci. Oral agents are often used after an initial course of parenteral antibiotic treatment. However, it is unclear which oral regimens are most effective in staphylococcal bone and joint infections. We review various oral antibiotic regimens and discuss which regimens are effective for this indication.
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We have compared the rates of infection and resistance in an animal model of an orthopaedic procedure which was contaminated with a low-dose inoculum of Staphylococcus epidermidis. We randomised 44 Sprague-Dawley rats to have bone cement implanted subcutaneously containing either gentamicin or saline (control). The wound was inoculated with a dilute solution of gentamicin-sensitive Staphylococcus epidermidis. At two weeks the cement was retrieved and microbiologically tested. A lower overall rate of infection was seen in the gentamicin-loaded cement group, but there was a significantly higher rate of gentamicin-resistant infection in this group (Fisher’s exact test, p < 0.01). Antibiotic-impregnated cement has an optimum surface for colonisation and prolonged exposure to antibiotic allows mutational resistance to occur. Gentamicin-loaded cement may not be appropriate for revision surgery if it has been used already in previous surgery.
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Bacteria that attach to surfaces aggregate in a hydrated polymeric matrix of their own synthesis to form biofilms. Formation of these sessile communities and their inherent resistance to antimicrobial agents are at the root of many persistent and chronic bacterial infections. Studies of biofilms have revealed differentiated, structured groups of cells with community properties. Recent advances in our understanding of the genetic and molecular basis of bacterial community behavior point to therapeutic targets that may provide a means for the control of biofilm infections.
Our aim in this study was to determine the outcome of hip arthroplasty with regard to infection at our unit. Infection after total joint arthroplasty is a devastating complication. The MRC study in 1984 recommended using vertical laminar flow and prophylactic antibiotics to reduce infection rates. These measures are now routinely used. Between 1993 and 1996, 1727 primary total hip arthroplasties and 305 revision hip arthroplasties were performed and 1567 of the primary and 284 of the revision arthroplasties were reviewed between five and eight years after surgery by means of a postal questionnaire, telephone interview or examination of the medical records of those who had died. Seventeen (1.08%) of the patients who underwent primary and six (2.1%) of those who underwent revision arthroplasty had a post-operative infection. Only 0.45% of patients who underwent primary arthroplasty required revision for infection. To our knowledge this is the largest multi-surgeon audit of infection after total hip replacement in the UK. The follow-up of between five and eight years is longer than that of most comparable studies. Our study has shown that a large cohort of surgeons of varying seniority can achieve infection rates of 1% and revision rates for infection of less than 0.5%.
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When it comes to endoprosthesis pathologies, for example implant-allergic/toxic problems, as a cause of implant failure, particle identification has an important role to play in the histopathological diagnostics of the neosynovial/periprosthetic membrane (synovial-like interface membrane, SLIM). The variability of materials in endoprosthetics and differences in particle pathogenesis explain the particle heterogeneity that hampers the diagnostic identification of particles. For this reason, a histopathological particle algorithm has been developed that, with minimal methodical complexity, offers a guide to particle identification. Light microscopic-morphological as well as enzyme-histochemical characteristics and polarization-optical proporties have been defined. Particles are characterized in accordance with a dichotomous principle. Based on these criteria, identification and validation of the particles was carried out in 105 joint endoprosthesis pathological cases. A particle score is proposed that summarizes the most important information for the orthopedist.
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The purpose of this study was to measure joint and serum levels of vancomycin following intra-articular (IA) or intravenous (IV) administration, and to compare the concentrations achieved in the joint fluid. IA vancomycin was only used to treat revision total knee arthroplasty (TKA) due to infection, while IV vancomycin was used as a prophylactic agent in primary and revision TKA. Both IA and IV vancomycin achieved therapeutic levels in the synovial fluid of the knee, but IA delivery of vancomycin resulted in peak levels that were many orders of magnitude higher, and also resulted in therapeutic serum levels. The half-life of IA-delivered vancomycin was just over three hours, and trough levels remained therapeutic in the joint and in serum for 24hours after IA injection.
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