Effect of antibiotics
used in REPs on stem cells
The preservation of host residual cells is
essential for a favorable REP outcome. Stem cells must survive to contribute to
tissue regeneration 2. It is essential in REPs that any antibiotic
or combinations of antibiotics be biocompatible and have no toxic effect on
host stem cells. The mixture of ciprofloxacin, metronidazole and minocycline
has been demonstrated to be well tolerated by vital pulp tissue i,ii. Moreover,
the effect of TAP on subcutaneous tissue of rats at different periods of time
has been evaluated, concluding that it is biocompatible 45,iii. However,
Wang et al. iv warned
that the use of high concentrations of antibiotics in REPs could be toxic to
live tissue. Consequently, it must be determined the best concentration of the
antibiotics mixture maximally effective against endodontic bacteria, but which,
in turn, is harmless to the host cells, including stem cells 2.
Experiments carried out by Ruparel et al. v
evaluating the effect of intracanal medicaments on the survival of stem cells
of the apical papilla (SCAP), have concluded that the exposure to antibiotics
concentrations used in many REPs reduced SCAP survival significantly (almost to
zero). Experiments showed that all mixtures of antibiotics tested, including TAP,
double antibiotic paste (ciprofloxacin, metronidazole), a modified triple
antibiotic paste (ciprofloxacin, metronidazole, cefaclor), and Augmentin™ (amoxicillin
and clavulanic acid) at concentrations ranging 0.01 – 100 mg/mL, were toxic to a
SCAP cell line in a concentration-dependent manner. The antibiotic
concentration that reduced to 50% SCAP survival (LC50) was 1 mg/mL.
However, a TAP concentration of 100 µg/mL (= 0.1 mg/mL), highly effective
against endodontic bacteria 26, was non-toxic to SCAP.
Recently, Alghilan et al. vi
have proposed the use of diluted TAP in a methylcellulose system (DTAP) in
REPs. DTAP was prepared by mixing 1000 mg of equivalent portions of
metronidazole, ciprofloxacin and minocycline powders in methylcellulose (1
mg/mL). DTAP caused significant increases in dental pulp stem cells (DPSC)
attachment to dentine and does not affect negatively to (DPSC) proliferation.
Ongoing research on
the use of antibiotics in REPs
The most recent
research in this field is looking for safer antibiotic administration systems. It
has been suggested the use of antibiotic-containing scaffolds as a biologically
safe antimicrobial drug delivery system in REPs vii.
Bimix antimicrobial scaffolds containing metronidazole and ciprofloxacin
inhibit the growth of Enterococcus
faecalis, Porphyromonas gingivalis, and Fusobacterium nucleatum viii, and
promote slight human dental pulp stem cell viability reduction ix.
Kamocki et al. x have
demonstrated that scaffolds containing reduced concentration of ciprofloxacin
preserve its antimicrobial properties whereas enhances the viability and
proliferation of human dental pulp stem cells. It has been demonstrated that
ciprofloxacin-containing scaffolds promise as an intracanal medicament to
eliminate Enterococcus faecalis biofilms
before REPs xi.
Likewise, it has been found that a triple antibiotic paste (TAP)-mimic scaffold
reduces significantly the percentage of viable Actinomyces naeslundii dentin biofilm xii. Pankajajshan
et al. xiii,
have demonstrated that nanofiber-based drug delivery systems are a
cell-friendly disinfection strategy than the current used TAP, and may
contribute to better and more predictable regenerative outcomes. They concluded
that triple antibiotic-containing polymer nanofibers lead to significant
bacterial death, whereas they did not affect DPSC attachment and proliferation
on dentin. In other study, Alburquerque et
have studied scaffolds with an antibiotic-elution polymer nanofibers in a
dentine sample. When biofilms composed by E. faecalis, A Naeslundii and S.
Sanguinus were cultivated, and 3D tubular shape triple antibiotic-eluting
nanofibrous constructs, nearly complete elimination of viable bacteria was
obtained, on surface and inside dentin (p<0.5), similar to the bacterial death for TAP. Based on the remarkable antimicrobial effects, cell-friendly, and stain-free properties of clindamycin, the use of clindamycin-modified triple antibiotic (metronidazole, ciprofloxacin, and clindamycin) polymer (polydioxanone) nanofibers has been recently proposed as a viable alternative to minocycline-based antibiotic pastes xv.