Sustained Release of Salicylic Acid for Halting Peri-Implantitis Progression in Healthy and Hyperglycemic Systemic Conditions: A Gottingen Minipig Model

Abstract

To develop a peri-implantitis model in a Gottingen minipig and evaluate the effect of local application of salicylic acid poly(anhydride-ester) (SAPAE) on peri-implantitis progression in healthy, metabolic syndrome (MS), and type-2 diabetes mellitus (T2DM) subjects. Eighteen animals were allocated to three groups: (i) control, (ii) MS (diet for obesity induction), and (iii) T2DM (diet plus streptozotocin for T2DM induction). Maxillary and mandible premolars and first molar were extracted. After 3 months of healing, four implants per side were placed in both jaws of each animal. After 2 months, peri-implantitis was induced by plaque formation using silk ligatures. SAPAE polymer was mixed with mineral oil (3.75 mg/μL) and topically applied biweekly for up to 60 days to halt peri-implantitis progression. Periodontal probing was used to assess pocket depth over time, followed by histomorphologic analysis of harvested samples. The adopted protocol resulted in the onset of peri-implantitis, with healthy minipigs taking twice as long to reach the same level of probing depth relative to MS and T2DM subjects (∼3.0 mm), irrespective of jaw. In a qualitative analysis, SAPAE therapy revealed decreased levels of inflammation in the normoglycemic, MS, and T2DM groups. SAPAE application around implants significantly reduced the progression of peri-implantitis after ∼15 days of therapy, with ∼30% lower probing depth for all systemic conditions and similar rates of probing depth increase per week between the control and SAPAE groups. MS and T2DM conditions presented a faster progression of the peri-implant pocket depth. SAPAE treatment reduced peri-implantitis progression in healthy, MS, and T2DM groups.

Keywords: dental implants; metabolic diseases; osseointegration; peri-implantitis; treatment.

Figure 1

Flowchart of the study experiment design.

Figure 2

(A) Clinical aspect after 7 days of peri-implantitis induction using silk ligature, (B) where the presence of soft tissue inflammation can be observed.

Figure 3

(A) Final weight and (B–F) blood marker profiles of the pigs to demonstrate the effective induction of a metabolically compromised condition. Different letters indicate statistically significant differences.

Figure 4

Histological micrographs of pigs with different systemic conditions demonstrating the effective induction of peri-implantitis with the proposed protocol in the maxilla and the mandible.

Figure 5

(A) Rate of probing depth increase per week for all systemic conditions and jaw region as a function of mean and 95% CI. Different lowercase letters indicate statistically significant differences between systemic conditions; different uppercase letters indicate statistically significant differences between time points. (B) Data collapsed over regions representing the probing depth after peri-implantitis induction using silk ligatures as a function of systemic condition. (C) Probing depth in the maxilla after peri-implantitis induction using silk ligatures as a function of systemic condition. (D) Probing depth in the mandible after peri-implantitis induction using silk ligatures as a function of systemic condition. Different symbols in the images (B), (C), and (D) indicate statistically significant differences in the bone loss values between systemic conditions at the end of the peri-implantitis induction.

Figure 6

(A) Clinical aspect after 60 days of peri-implantitis halting treatment, where control implants presented substantial soft tissue inflammation. (B) High magnification of gingival connective tissue in proximity with the peri-implantitis-affected implants, where SAPAE-treated implants presented morphologic features of healthy peri-implant tissues in normoglycemic conditions and a slight elevation in the inflammatory content relative to healthy peri-implant issue for hyperglycemic conditions. Untreated control implants presented a substantially higher presence of inflammatory infiltrate relative to SAPAE-treated implants for both healthy and hyperglycemic groups.

Figure 7

(A) Rate of probing depth increase per week for control and SAPAE groups as a function of mean and 95% CI. Different lowercase letters indicate statistically significant differences between systemic conditions; different uppercase letters indicate statistically significant differences between groups. Probing depth in the maxilla after peri-implantitis induction (approximately 1.5 mm) and the effect of SAPAE treatment in its progression as a function of systemic condition: healthy (B), MS (C), and T2DM (D). The symbol indicates time points with statistically significant differences between SAPAE and control groups. Therapy protocol was investigated in the healthy group, initially by a weekly SAPAE local application on peri-implant sulcus, which was ineffective in slowing the progress of peri-implantitis, thus the regimen was changed to a biweekly local application that successfully arrested peri-implantitis progression as a statistically significant lower probing depth can be observed for SAPAE group after approximately 15 days.