Chronic periprosthetic joint infection (PJI) is a devastating
complication that requires an aggressive eradication protocol. Local
antimicrobial delivery via dissolvable calcium sulfate (CaSO4) using
small-sized beads (3–8 mm) has been utilized as an adjunctive treatment
combined with implant exchange, radical debridement, and antimicrobial
loaded acrylic spacers. The non-exothermic setting of CaSO4 theoretically allows for any antimicrobial agent to be used, so long as
mixing methods provide a consistent fabrication within a reasonable set
time. This study performed the first in vitro mixing study, in which various
antimicrobial agents, used singularly and in combination, were mixed with a
synthetic CaSO4 product to observe and document their interactions. The
study was performed in a simulated operating room environment. We report a
standard mix formula with set times, testing 22 different antimicrobial
agents, combinations, and doses. For some antimicrobials and combinations,
set times using the standard formula were either too fast or exceedingly
slow. For these 14 antimicrobial agents and combinations, we were able to
arrive at individualized mixing methods. We present all mixing formulas and
set times. In all, we were able to establish mixing methods that incorporate
all antimicrobial agents and combinations that we have seen utilized via
surgeon-directed use.
Introduction
Joint replacement surgery for degenerative arthrosis provides improved
function and pain relief in the majority of cases where this procedure is
utilized (Merx et al., 2003; Lohmander et al., 2006; Lützner et al.,
2011; Maradit Kremers et al., 2015). However, adverse responses do
occur at relatively low rates (McPherson et al., 2020). Such risks include
fixation failure, mechanical dysfunction, fracture, reactive wear debris
phenomenon, and infection. Of these complications, that which stands out as
the most problematic is periprosthetic joint infection (PJI). This is due to
the difficulty in eradicating the infection, as well as the enormous impact
placed upon the patient and healthcare system (Kurtz et al., 2008, 2012; Costerton et al., 1999, 2005). Further
complicating matters is the extended use of parenteral antimicrobial agents,
which disrupts numerous human physiologic systems, confers human biome
resistance, and affects future treatment options (Levast et al., 2021).
Alternatives to parenteral antimicrobial treatment for PJI are limited.
Local antimicrobial delivery by various carriers has been utilized with
increasing frequency in the last 3 decades. The mainstay agents include
polymethyl methacrylate (PMMA) in bead form and PMMA in bulk form. In bulk
form, the antimicrobial-loaded acrylic cement (ALAC) serves to maintain the
joint space. PROSTALAC (PROSThesis + ALAC) implants provide additional
stability and function to the resected joint. The other utilized agent for
local intra-articular antimicrobial delivery is calcium sulfate
(CaSO4), which dissolves and releases antimicrobials. These agents are
utilized only for physician-directed use but are considered acceptable
methods by those orthopaedic surgeons focusing on PJI treatment (Dacquet et
al., 1992; Dahners and Funderburk, 1987; Evrard et al., 1990).
Newer forms of synthetic CaSO4 have been developed that are considered
to be improved products. Legacy CaSO4 products were “mined and
refined” with process techniques that allow implantation into human hosts.
Impurities with these products were thought to cause adverse reactions
affecting treatment (Lee et al., 2002). Subsequent second- and third-generation products are synthetic, as they are produced from pure elemental
form. These agents are better able to accommodate antibiotic impregnation
and provide a more consistent performance in terms of mixing, dissolution,
and clinical application, although wound drainage still remains a concern
for surgeons, with reported rates in the literature varying considerably
(Kelly et al., 2001; Ziran et al., 2007; Ferguson et al., 2014; Kallala et
al., 2018). Newer antimicrobial delivery agents are being developed for the
specific property of antimicrobial compatibility but are not yet in
clinical trials (Ambrose et al., 2014). Thus, for the foreseeable future,
antimicrobial-loaded CaSO4 beads, combined with ALAC or PROSTALAC
spacers, are the common treatment methods for local antimicrobial delivery.
With the advent of microbial next-generation DNA sequencing combined with
specified PJI culture methods, the number of identified microbiota
associated with PJI is growing considerably (Aul et al., 1998; Tarabichi et
al., 2018). This requires the employment of a wider variety of antimicrobial
agents to be used in isolation or in concert. This paper reports our
work with a mixing study whereby, in a laboratory setting, we mixed
antimicrobial agents into a synthetic, commercially pure CaSO4 product,
creating a dissolvable antimicrobial bead. In cursory review, this concept
seems simple, but in reality, the process can be immensely frustrating and
difficult. Our purpose is to report our baseline standardized mixing
techniques, developing formulas, and doses of antimicrobials added to
CaSO4. Furthermore, when encountering difficulty in mixing specific
antimicrobial agents, we developed modified mixing techniques to create an
antimicrobial-loaded bead that previously was problematic with our standard
technique.
Photograph of 4.8 mm bead mat. The antimicrobial-loaded CaSO4
paste is shown after spreading the paste into the molds. Once applied, the
bead mats were left on the countertop to set, in order to imitate operating
room procedure. Time measurements were recorded to establish a set time for
each formulation.
Methods
The CaSO4 product used for this study was Synthecure®
(Austin Medical Ventures, Memphis, TN). We used the 10 cc bead kits that
consisted of CaSO4 hemihydrate powder that is mixed with 5 cc of
sterile saline. When mixed, the unloaded CaSO4 product makes a paste
volume of 10 cc. The mixed product is spread into a sterile silicone bead
mat, allowing for the fabrication of 3, 4.8, or 6 mm beads. For the purposes
of this study, we selected the 4.8 mm beads. The bead mat and bead product
formed in this laboratory study are shown in Fig. 1. The antimicrobial
formulae selected for study were based on clinical and academic
observations of formulae currently utilized in the orthopaedic community.
In the majority of added antimicrobial formulae, the sterile powdered form
of the antimicrobial was premixed into the CaSO4 powder, after which
the sterile saline liquid was added. Mixing was performed in a 6 cm diameter
mixing bowl with a spatula for 15–45 s, until a paste consistency
devoid of antimicrobial clumps was achieved. The paste product was
transferred via the spatula to the bead mat. For this study, we measured the
time from initial mix until the product became a consistently smooth product
devoid of clumps. Once the product was spread onto the bead mat, the product
was left to set on the laboratory table in standard conditions of
70∘F and 40 % humidity. We tested the beads for
setting by gently bending the mat at 1 min intervals to assess separation
from the silicone mat. In addition, we examined the bead itself. If the bead
showed “fissuring” as the mat was gently bent, the curing process was not
complete, and the mat was placed back onto the laboratory table. We defined
the product as “set” when we could bend the bead mat as it was turned
upside down, and the beads would fall onto the table.
A second confirmatory test included a digital bead compression test when the
bead was on the table. In some cases, the CaSO4 product would fall out
of the bead mat but was still soft. In this scenario, the beads were tested
by compressing the bead with the tip of the index finger. If the bead was
not fully cured, the bead would collapse. When “fully set,” the bead would
not collapse. Thus, the measured “set time” was defined as the time from
initial mix until the bead dropped out of the bead mat and was confirmed as
fully set via the digital compression test.
Two exceptions to using the antimicrobial powder mix method for this study
were Tobramycin and Gentamicin. In many centers, both Tobramycin and
Gentamicin come conveniently premixed in 2 mL vials and can be used as a
substitute for the sterile saline that is included in the mix kit. Liquid
Tobramycin (or Gentamicin) has two advantages. First, as noted above, it is
conveniently provided in 2 mL vials (80 mg of antibiotic per vial).
Secondly, as Tobramycin (or Gentamicin) is provided in liquid form,
additional antimicrobial powders can be added to the CaSO4 powder, thus
allowing combination formulas to be tested. We elected to use 6 mL of liquid
Tobramycin and Gentamicin in our formulae, rather than the manufacturer
recommended 5 mL, to make matters simple and efficient for operating room
staff, rather than requiring the exact measurement of one-half vial of
liquid to achieve 5 mL. Preliminary testing between formulae of 6 mL and
those of 5 mL demonstrated no significant difference in set time or
quality.
During the standardized mix tests, we found difficulty mixing numerous
antimicrobial agents. In many cases, we encountered extremely long set
times, ranging from 25 min to over 3 h. Additionally, we experienced
antimicrobial–CaSO4 combinations that set too quickly to effectively
mat and fabricate a quality bead product. For these irregular set times, we
experimented with alternative mixing methods. We arrived at several mixing
techniques to provide reasonable set times. These separate methods are
annotated in a separate section where the modified mixing instructions are
described in each particular instance. The set time was recorded for each
modified technique. The group of modified mixing instructions are grouped
into the category of “post-mix protocols.”
For each antimicrobial agent or combination tested, we performed the test a
minimum of three times (range three–four tests) between the two authors (Edward J. McPherson, Andrew J. Wassef). The
mix time and set time for each antimicrobial agent and combination was then
averaged for the reported result.
Set times of Synthecure with various antimicrobials and
combinations.
Antibiotic(s)/antifungalDosePowder (P)/Avg mixAvg setObservations(mg)liquid (L)time (min:s)time (min:s)Controln/an/a0:304:10Amikacin500P0:275:35Easy, smooth mix.Amphotericin B250P0:525:58Longer to mix into a smooth paste. Mats ok.Cefazolin1000P0:514:41Thicker paste, doughy. Spreads ok into mat.Clarithromycin200P0:384:30Smooth mix and mat.Clindamycin900P0:307:03Slightly runny. Wait 2 min to mat.Fluconazole400P0:364:20Chalky. Spread into mat quickly.Gentamicin240L0:256:15Runny. Wait 2 min to mat.Gentamicin500P0:455:48Easy mix, smooth paste.Meropenem500P0:4314:07Dry mix, comes out of mat at 10 min. Sets on table top.Rifampin600P0:354:23Need to mix and plate fast.Tobramycin240L0:229:30Runny. Wait 3 min to mat.Vancomycin1000P0:403:58Coarse, doughy. Be firm with spatula when matting.Cefazolin/Gentamicin1000/240P/L0:256:57Easy to mix. Slightly runny. Easy to mat.Cefazolin/Tobramycin1000/240P/L0:259:25Easy mix.Clindamycin/Tobramycin900/240P/L0:2313:32Runny. Wait 2 min to mat.Vancomycin/Fluconazole1000/400P/P0:384:40Smooth paste. Easy to mat.Vancomycin/Gentamicin1000/240P/L0:457:44Runny. Wait 2 min to mat.Vancomycin/Tobramycin1000/240P/L0:457:19Runny. Wait 2 min to mat.Clindamycin/Fluconazole/ Tobramycin900/400/240P/P/L0:3014:30Sets well. Easy to mix.Vancomycin/Amphotericin B/ Tobramycin1000/250/240P/P/L0:358:13Runny to start, but do not wait to mat.Vancomycin/Fluconazole/ Tobramycin1000/400/240P/P/L0:328:36Runny to start. Wait 4 min to mat.Vancomycin/Rifampin/ Tobramycin1000/600/240P/P/L0:4510:40Runny to start. Mild increase in volume. Do not wait to mat.
n/a: not applicable.
Results
The standard mix times are reported in Table 1. The two measured times
include the mix time and set time. In the cases where liquid Tobramycin and
Gentamicin were substituted for saline, we also report mix time and set time
in a similar fashion. For the standard mix method, all tested
antimicrobial(s) were set within 4 to 15 min. The recorded mix times and
set times tested between the two testing authors varied no more than 35 s in all agents tested.
Synthecure set times that required modified mixing techniques.
Antibiotic(s)/antifungalDosePowder (P)/Avg mixAvg setObservations(mg)liquid (L)time (min:s)time (min:s)Controln/an/a0:304:10Ciprofloxacin1000P1:307:25PMP. Add powder at 60 s. Mix for an additional 30 s.Ciprofloxacin500P1:3014:30PMP. Add powder at 60 s. Mix for an additional 30 s.Cefepime500P1:3010:20PMP. Add powder at 60 s. Mix an additional 30 s.Cefepime1000P1:509:10PMP. Add powder at 60 s. Mix an additional 50 s.Ceftriaxone500P0:2519:20Add an additional 5 cc of saline at beginning of mix.Daptomycin500P3:0012:30PMP. Add powder at 120 s (paste will be almost set). Mix an additional 60 s.Ertapenem500P2:1513:15PMP. Add powder at 120 s (paste will be almost set). Mix an additional 15 s.Nafcillin500P1:2512:20PMP. Add powder at 60 s. Mix an additional 25 s.Nafcillin1000P1:2516:30PMP. Add powder at 60 s. Mix an additional 25 s.Unasyn1500P2:2010:10PMP. Add powder at 120 s (paste will be almost set). Mix an additional 20 s.Vancomycin/Ciprofloxacin1000/1000P/P1:256:30PMP. Mix Vanc. and CaSO4. Wait 60 s before adding Cipro. Mix an additional 25 s.Vancomycin/Tobramycin1000/1200P/P1:4517:50PMP. Mix Vanc. and CaSO4. Wait 45 s before adding Tobra. Mix an additional 60 s.Vancomycin/Zosyn1000/2250P/P2:0016:15PMP. Mix Vanc. and CaSO4. Wait 90 s before adding Zosyn. Mix an additional 30 s.Voriconazole/Vancomycin/ Tobramycin200/1000/240P/P/L0:5022:00Inject 6 cc of liquid Tobramycin into the vial of Voriconazole. Shake bottle vigorously for 60 s, until all Voriconazole has dissolved. Aspirate 6 cc of liquid from the vial, add to Synthecure + Vancomycin powder, and mix until a smooth paste is achieved.
PMP: post-mix protocol. Mix CaSO4 with liquid until a smooth paste
is achieved. Wait the prescribed time, then add desired antibiotic powder. n/a: not applicable.
The post-mix protocols and described methods are reported in Table 2. For
each unique mixing method, we describe the modified mixing technique. The
set times were variable, dependent upon the antimicrobial agent(s) added. We
will note that we were able to get the CaSO4 beads to set within a
reasonable time with each modified technique. All the recorded mix times and
set times between the two testing authors varied no more than 100 s in
all agents tested.
Discussion
Surgeons face a myriad of obstacles in effectively treating PJI. Amongst the
most daunting are microbiota reserves hidden within the interstices of bone
known as the cortico-canalicular reserve and the retention of “biofilm
islands” attached to avascular soft tissue, bone, and residual small pieces
of foreign material(s) (Zoller et al., 2020; de Mesy Bentley et al., 2017;
Sindeldecker et al., 2020). Parenteral antibiotics have been a traditionally
used adjuvant treatment, combined with implant removal, for PJI but have
garnered criticism for their harmful effect to host physiology (Levast et
al., 2021). Local antimicrobial delivery into the PJI region, on the other
hand, is advantageous for many reasons. First, local delivery can provide
substantial antimicrobial levels, high enough to diffuse through the biofilm
and enact microbiota kill (Brooks et al., 2021; Moore et al., 2021).
Similarly, high local concentrations allow for diffusion into the small
corticocanalicular systems of bone, thus killing microbiota reserves (Maale,
2009). Even in the event of regional devascularization of bone via
debridement, microbiota kill can still occur via antimicrobial diffusion.
This is salutary in that suspect bone can be treated with antimicrobial
agents. Similarly, the periprosthetic soft tissue envelope partly
devascularized by radical debridement can be treated with high levels of
antimicrobial agents (Maale et al., 2020). Lastly, local delivery avoids
systemic side effects associated with parenteral antibiotics (Levast et al.,
2021).
The use of dissolvable antimicrobial-loaded CaSO4 beads has been
utilized for over 3 decades. Its cleared use stems from a process
permitting the use of CaSO4 in the presence of active bone infection
dating back to 1997 (Wright Medical Technology, 1997). First-generation
products are “mined and refined.” These products are derived from mined
gypsum that is subsequently processed to create a medical-grade product that
is cleared for insertion in human subjects. Despite their safe use, these
products still contain minute amounts of impurities. These minerals include
feldspars, dolomite, silica, and corundum (Liu, 2016). These first-generation products have reported variable results and the mineral
processing has been thought to be related to side effects, including wound
drainage and inflammatory synovitis (Lee et al., 2002). Many companies have
since used the above CaSO4 clearance to create second- and third-generation products that we see today. These products are commercially pure,
having undergone manufacturing utilizing pharmaceutical base reagents. The
enhanced purity is thought to provide consistency in mixing, dissolution, and
application. At present, CaSO4 is the most common carrier agent that is
utilized in local antimicrobial delivery to bone or joint that does not
necessitate a second surgical procedure for removal. It is unlikely that new
potential carrier systems will enter the market in the near future due to
the complicated approval process(es) currently in place.
Our experience in the mixing lab was humbling. First, we encountered
antimicrobial–CaSO4 combinations that set quickly and could not be
spread onto the mat fast enough to fabricate quality beads. In cases such as
these, we suspect a “hydrophilic steal” phenomenon. Specifically, these
antimicrobial powders absorbed H2O from the saline additive, depriving
the H20 required to convert calcium sulfate hemihydrate to calcium
sulfate dihydrate, which is the final product form. To mitigate fast set
times, the antimicrobial powder was added later into the mix, such that the
dihydrate was allowed to form. In the extreme case of Ceftriaxone, it was
necessary to add additional saline in order to lengthen the set time.
On the other hand, we also encountered prolonged set times, some of which
required hours to set with the standard mixing method. In these cases, we
suspect “stoichiometric interference.” It is our belief that these
antimicrobial powders interfered with the seeding and proliferation of
calcium sulfate dihydrate. To mitigate such prolonged set times, we again
employed a delayed introduction of the antimicrobial powder to achieve
calcium sulfate dihydrate crystal formation. In all instances where we
encountered initial difficulties, we were able to create a modified mixing
technique to produce a quality bead in a timely fashion.
This compendium of mixing formulas is by no means a recommended treatment
algorithm(s) for PJI. Local periprosthetic delivery with
antimicrobial-loaded CaSO4 is being used considerably throughout the
world. Up to this point, antibiotic and antifungal formulas used with
CaSO4 in the form of insertable beads have been within the purview of
surgeon-to-surgeon or surgeon-to-industry representative sidebar
discussions. We wanted to bring these discussions to the forefront. We want
to educate those physicians treating bone and joint infections that these
antimicrobial formulas exist. Those uninformed in this area of treatment
could potentially over-treat with adjuvant parenteral antibiotics, thus
causing unwanted side effects. In contrast, studies are slowly emerging that
show local delivery via CaSO4 may mitigate the need for adjuvant
parenteral antimicrobial therapy (McPherson et al., 2013). The description
of these mixing formulas is to serve as a starting basis for discussion
while providing a reference point for set times. We note that it is
important to leave the beads undisturbed in the bead mat so that the curing
process can take place. Disruption of the curing process could cause
incomplete curing, which may lead to more rapid resorption in the body. In
the future we hope to establish an open-access site such that all physician
and surgeons worldwide can report upon mixing formulas that can help other
physicians with difficult infection cases. Additionally, we hope to one day
see the expansion of mixing formulas that extend beyond the current realm of
antibiotic and antifungal chemicals and transition to other non-specific
antimicrobial agents.
Ethical statement
This research did not involve human or animal subjects and therefore was exempt from any IRB approval.
Data availability
All of our data are presented in Tables 1 and 2.
Author contributions
EJM, MC, and AJW designed the mixing lab. EJM and AJW carried out the mixing lab. MVD prepared the manuscript with contributions from all co-authors.
Competing interests
The contact author has declared that neither they nor their co-authors have any competing interests.
Disclaimer
Publisher's note: Copernicus Publications remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Review statement
This paper was edited by Bryan Springer and reviewed by two anonymous referees.
ReferencesAmbrose, C. G., Clyburn, T. A., Mika, J., Gogola, G. R., Kaplan, H. B.,
Wanger, A., and Mikos, A. G.: Evaluation of antibiotic-impregnated
microspheres for the prevention of implant-associated orthopaedic
infections, J. Bone Joint Surg. Am., 96, 128–134, 10.2106/JBJS.L.01750, 2014.Aul, J. J., Anderson, K. W., Wadowsky, R. M., Doyle, W. J., Kingsley, L.
A., Post, J. C., and Ehrlich, G. D.: Comparative evaluation of culture and
PCR for the detection and determination of persistence of bacterial strains
and DNAs in the Chinchilla laniger model of otitis media, Ann. Otol. Rhinol.
Laryngol., 107, 508–513, 10.1177/000348949810700609, 1998.Brooks, J. R., Dusane, D. H., Moore, K., Gupta, T., Delury, C., Aiken, S. S., Laycock, P. A., Sullivan, A. C., Granger, J. F., Dipane, M. V., McPherson, E. J., and Stoodley, P.: Pseudomonas aeruginosa biofilm killing beyond the spacer by antibiotic-loaded calcium sulfate beads: an in vitro study, J. Bone Joint Infect., 6, 119–129, 10.5194/jbji-6-119-2021, 2021.Costerton, J. W., Stewart, P. S., and Greenberg, E. P.: Bacterial
biofilms: a common cause of persistent infections, Science, 284,
1318–1322, 10.1126/science.284.5418.1318, 1999.Costerton, J. W., Montanaro, L., and Arciola, C. R.: Biofilm in implant
infections: its production and regulation, Int. J. Artif. Organs, 28,
1062–1068, 10.1177/039139880502801103, 2005.
Dacquet, V., Varlet, A., Tandogan, R. N., Tahon, M. M., Fournier, L.,
Jehl, F., Monteil, H., and Bascoulergue, G.: Antibiotic-impregnated plaster
of Paris beads. Trials with teicoplanin, Clin. Orthop. Relat. Res., 282,
241–249, 1992.
Dahners, L. E. and Funderburk, C. H.: Gentamicin-loaded plaster of
Paris as a treatment of experimental osteomyelitis in rabbits, Clin. Orthop.
Relat. Res., 219, 278–282, 1987.de Mesy Bentley, K. L., Trombetta, R., Nishitani, K., Bello-Irizarry, S.
N., Ninomiya, M., Zhang, L., Chung, H. L., McGrath, J. L., Daiss, J. L.,
Awad, H. A., Kates, S. L., and Schwarz, E. M., Evidence of Staphylococcus
Aureus Deformation, Proliferation, and Migration in Canaliculi of Live
Cortical Bone in Murine Models of Osteomyelitis, J. Bone Miner. Res., 32,
985–990, 10.1002/jbmr.3055, 2017.
Evrard, J., Kerri, O., Martini, M., and Conort, O.: Treatment of bone
infection by plaster of Paris pellets impregnated with antibiotics, Pathol.
Biol. (Paris), 38, 543–547, 1990.Ferguson, J. Y., Dudareva, M., Riley, N., D., Stubbs, D., Atkins, B.
L., and McNally, M. A.: The use of a biodegradable antibiotic-loaded calcium
sulphate carrier containing tobramycin for the treatment of chronic
osteomyelitis: a series of 195 cases, Bone Joint J., 96-B, 829–836, 10.1302/0301-620X.96B6.32756, 2014.Kallala, R., Harris, W. E., Ibrahim, M., Dipane, M., and McPherson, E.:
Use of Stimulan absorbable calcium sulphate beads in revision lower limb
arthroplasty: Safety profile and complication rates, Bone Joint Res., 7,
570–579, 10.1302/2046-3758.710.BJR-2017-0319.R1, 2018.Kelly, C. M., Wilkins, R. M., Gitelis, S., Hartjen, C., Watson, J. T.,
and Kim, P. T.: The use of a surgical grade calcium sulfate as a bone graft
substitute: results of a multicenter trial, Clin. Orthop. Relat. Res., 382,
42–50, 10.1097/00003086-200101000-00008, 2001.Kurtz, S. M., Lau, E., Schmier, J., Ong, K. L., Zhao, K., and Parvizi,
J.: Infection burden for hip and knee arthroplasty in the United States, J.
Arthroplasty, 23, 984–991, 10.1016/j.arth.2007.10.017, 2008.Kurtz, S. M., Lau, E., Watson, H., Schmier, J. K., and Parvizi, J.:
Economic burden of periprosthetic joint infection in the United States, J.
Arthroplasty, 27, 61–65.e1, 10.1016/j.arth.2012.02.022, 2012.
Lee, G. H., Khoury, J. G., Bell, J.-E., and Buckwalter, J. A.: Adverse
reactions to OsteoSet bone graft substitute, the incidence in a consecutive
series, Iowa Orthop. J., 22, 35–38, 2002.Levast, B., Benech, N., Gasc, C., Batailler, C., Senneville, E.,
Lustig, S., Pouderoux, C., Boutoille, D., Boucinha, L., Dauchy, F.-A.,
Zeller, V., Maynard, M., Cazanave, C., Thi, T.-T. L., Josse, J., Doré,
J., Laurent, F., and Ferry, T.: Impact on the Gut Microbiota of Intensive
and Prolonged Antimicrobial Therapy in Patients With Bone and Joint
Infection, Front. Med., 8, 586875, 10.3389/fmed.2021.586875, 2021.
Liu, H. (Ed.): Nanocomposites for Musculoskeletal Tissue Regeneration,
Elsevier, Philadelphia, PA, 2016.Lohmander, L. S., Engesaeter, L. B., Herberts, P., Ingvarsson, T.,
Lucht, U., and Puolakka, T. J. S.: Standardized incidence rates of total hip
replacement for primary hip osteoarthritis in the 5 Nordic countries:
similarities and differences, Acta Orthop., 77, 733–740, 10.1080/17453670610012917, 2006.Lützner, J., Hübel, U., Kirschner, S., Günther, K.-P., and
Krummenauer, F.: Long-term results in total knee arthroplasty. A
meta-analysis of revision rates and functional outcome, Chir. Z. Alle Geb.
Oper. Medizen, 82, 618–624, 10.1007/s00104-010-2001-8, 2011.
Maale, G.: The use of antibiotic loaded synthesized calcium sulfate
pellets in the one stage treatment for Osteomyelitis, Annual Open Scientific
Meeting of the Musculoskeletal Infection Society 2009, 7–8
August 2009, San Diego, CA, 2009.Maale, G. E., Eager, J. J., Mohammadi, D. K., and Calderon, F. A.:
Elution Profiles of Synthetic CaSO4 Hemihydrate Beads Loaded with Vancomycin
and Tobramycin, Eur. J. Drug Metab. Pharmacokinet., 45, 547–555, 10.1007/s13318-020-00622-8, 2020.Maradit Kremers, H., Larson, D. R., Crowson, C. S., Kremers, W. K.,
Washington, R. E., Steiner, C. A., Jiranek, W. A., and Berry, D. J.:
Prevalence of Total Hip and Knee Replacement in the United States, J. Bone
Joint Surg. Am., 97, 1386–1397, 10.2106/JBJS.N.01141, 2015.
McPherson, E. J., Dipane, M. V., and Sherif, S. M.: Dissolvable Antibiotic
Beads in Treatment of Periprosthetic Joint Infection and Revision
Arthoplasty: The Use of Synthetic Pure Calcium Sulfate (Stimulan)
Impregnated with Vancomycin and Tobramycin, Reconstructive Rev., 3,
32–44, 2013.
McPherson, E. J., Werner, B. C., Gill, G. K., and Browne, J. A.: Adult
Reconstruction, in: Review of Orthopaedics, 8th edition, edited by: Miller,
M. D. and Thompson, S. R., Elsevier, Philadelphia, PA, 356–437, ISBN-13
978-0323609784, 2020.Merx, H., Dreinhöfer, K., Schräder, P., Stürmer, T., Puhl,
W., Günther, K.-P., and Brenner, H.: International variation in hip
replacement rates, Ann. Rheum. Dis., 62, 222–226, 10.1136/ard.62.3.222, 2003.Moore, K., Wilson-van Os, R., Dusane, D. H., Brooks, J. R., Delury, C.,
Aiken, S. S., Laycock, P. A., Sullivan, A. C., Granger, J. F., Dipane, M.
V., McPherson, E. J., and Stoodley, P.: Elution Kinetics from
Antibiotic-Loaded Calcium Sulfate Beads, Antibiotic-Loaded Polymethacrylate
Spacers, and a Powdered Antibiotic Bolus for Surgical Site Infections in a
Novel In Vitro Draining Knee Model, Antibiot. Basel Switz., 10, 270, 10.3390/antibiotics10030270, 2021.Sindeldecker, D., Moore, K., Li, A., Wozniak, D. J., Anderson, M.,
Dusane, D. H., and Stoodley, P.: Novel Aminoglycoside-Tolerant Phoenix
Colony Variants of Pseudomonas aeruginosa, Antimicrob. Agents Chemother.,
64, e00623-20, 10.1128/AAC.00623-20, 2020.Tarabichi, M., Shohat, N., Goswami, K., and Parvizi, J.: Can next
generation sequencing play a role in detecting pathogens in synovial fluid?,
Bone Jt. J., 100-B, 127–133, 10.1302/0301-620X.100B2.BJJ-2017-0531.R2, 2018.
Wright Medical Technology, Inc.: 510(k) Premarket Notification – Wright
Plaster of Paris Pellets, Food and Drug Administration,
available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm?ID=K963562 (last
access: 30 August 2021), 1997.Ziran, B. H., Smith, W. R., and Morgan, S. J.: Use of calcium-based
demineralized bone matrix/allograft for nonunions and posttraumatic
reconstruction of the appendicular skeleton: preliminary results and
complications, J. Trauma, 63, 1324–1328, 10.1097/01.ta.0000240452.64138.b0, 2007.Zoller, S. D., Hegde, V., Burke, Z. D., C., Park, H. Y., Ishmael, C.
R., Blumstein, G. W., Sheppard, W., Hamad, C., Loftin, A. H., Johansen, D.
O., Smith, R. A., Sprague, M. M., Hori, K. R., Clarkson, S. J., Borthwell,
R., Simon, S. I., Miller, J. F., Nelson, S. D., and Bernthal, N. M.: Evading
the host response: Staphylococcus “hiding” in cortical bone canalicular
system causes increased bacterial burden, Bone Res., 8, 43, 10.1038/s41413-020-00118-w, 2020.