The present prospective clinical study was conducted to monitor the wound healing after placing narrow-diameter implants in T2DM and normo-glycemic patients by assessment of microcirculation and PMN-related cytokine expression. No significant differences between T2DM and healthy patients were observed, with the exception of pro-inflammatory cytokines IL-23 and Il-1ß during initial healing a few days after implant surgery.
In our study, the perfusion of the peri-implant tissues was evaluated by Laser Doppler Flowmetry (LDF), a technique which allows for the detection of blood flow disturbances after surgical injury [22–24]. Both groups displayed significant reduction of microcirculation activity directly after surgery and one day post-op, when compared to baseline. However, microcirculation activity appeared to recover rapidly, returning to levels assessed before injury. Moreover, there was no significant difference regarding reduction of blood flow found between T2DM and healthy patients. The rationale behind this observation may be the similarly minimal-invasive surgical approach in both groups, since LDF measurements of post-surgical perfusion impairment were shown to correlate well with the extent of tissue trauma [24, 25]. The transmucosal healing pattern may have contributed to this positive outcome, as there was no need in flap closure above the implant shoulder, which regularly requires a coronal advancement of the flap. The perfusion rates altered at similar altitude during the observation period closely reflecting the healing progress in both groups. Statistically significant impairment of perfusion was only found before and after application of local anesthesia containing the vasoconstrictor in both groups. Moreover, the perfusion rate showed statistically significant improvement at day 3 after the surgery. Regardless of systemic background, the recorded microcirculation was apparently related to uneventful healing progress. Furthermore, the plotted perfusion units per time were in accordance with those observed earlier in a beagle model, that aimed at monitoring the changes of microcirculation in the context of bone augmentation surgery .
These results, however, contradicted our expectations. As suggested by recent studies on the microvascular skin perfusion in diabetic patients, we anticipated a significantly lower perfusion rate in the wounds of diabetic patients [26, 27]. The Hba1c values in the T2DM patient cohort with 7.34% might have been estimated to cause a bigger discrepancy. Nevertheless, the results highlight our hypothesis that T2DM patients may benefit from the NDI design because of the reduced wound healing burden associated with their use .
In this study, the concentrations of interleukin-1ß, interleukin-23, interleukin17A and GM-CSF were measured in PICF of NDI recently placed in the posterior jaw. The sampling of the PICF for analyzing the molecular content is considered a viable method for studying the wound healing biology around teeth and implants in humans [29–31]. In particular, the bead-based immunoassay applied in this study allows for a multiplex analysis of up to 96 analytes per sample.
Interleukin1ß is a pro-inflammatory cytokine which upregulates a plethora of inflammatory effector molecules such as chemokines and prostaglandins. Due to its abundance in inflamed and injured tissues of all kind, it is considered a ubiquitous biomarker for acute tissue inflammation [32, 10]. This study revealed upregulated concentrations of Il-1ß immediately after surgery presenting with significantly reduced levels up to the end of the observation period. Interestingly, the T2DM patients presented with non-significantly altered concentrations to the control group at any of the visits, indicating both, an innate initialization and resolution of the inflammatory process, respectively. The pattern of IL-1ß secretion to PICF is in line with a similar study conducted by , who reported similar results for IL-1ß concentrations in PIF of healthy patients.
According to a recent experimental study in diabetic rats, IL-23 levels are significantly increased under diabetic conditions . IL-23 is considered the main inducer of CD4 + T-lymphocyte differentiation towards IL-17 producing Th17 cells . In context of wound healing, large amounts of Th17 helper cells are associated with a delay in wound closure. The inhibition of the backbone IL-23 / Il-17 axis may even promote wound healing under diabetic conditions [35, 36]. Our results demonstrated significantly higher levels of IL-23 at implants of T2DM patients, when compared to the control group. Over the course of the observation period (V2-V4), however, the IL-23 and IL-17 concentrations equalized to insignificant differences. These results are corroborated further by the works of Santos et al. and Vieira Ribeiro et al., who reported no significant increase in IL-23 expression among diabetic and healthy patients suffering from periodontitis [37, 38].
The last investigated analyte, GM-CSF, did not show any timing- or group-related differences. GM-CSF is a multipotent growth factor responsible for granulopoiesis and keratinocyte-related proliferation and re-epithelialization, and a variety of studies has verified its necessity for complication-free wound healing [39–41]. Therefore, unchanged GM-CSF levels in T2DM patients may have been associated with the uneventful healing period observed in this trial.
This analysis was nested in a larger pilot study . Thus, the presented results have some obvious limitations. As indicated by the large variability among individuals, selected datasets may not be adequately powered. Nevertheless, we were able to elucidate
The measured effector molecules have a pivotal role in regulating the PMN-mediated early wound healing, which did not appear significantly affected by the T2DM condition. However, while diabetic patients showed a more pro-inflammatory initial cytokine profile, wound healing and PMN response appeared similar in diabetic and non-diabetic patients on a longer term. Moreover, these results corroborate our previously reported findings of similar clinical success placing reduced-diameter implants in these patients . In conclusion, hydrophilic-surface titanium-zirconium implants with reduced diameter exhibit no molecular alterations regarding wound healing in T2DM patients and may thus be a viable option for this group of patients.