Dual-Functional Drug Delivery System for Bisphosphonate-Related Osteonecrosis Prevention and Its Bioinspired Releasing Model and In Vitro Assessment.

Clindamycin (CDM)/geranylgeraniol (GGOH)-loaded plasma-treated mesoporous silica nanoparticles/carboxymethyl chitosan composite hydrogels (CHG60 and CHG120) were developed for the prevention of medication-related osteonecrosis of the jaw associated with bisphosphonates (MRONJ-B). The pore structure and performances of CHGs, e.g., drug release profiles and kinetics, antibacterial activity, zoledronic acid (ZA)-induced cytotoxicity reversal activity, and acute cytotoxicity, were evaluated. The bioinspired platform mimicking in vivo fibrin matrices was also proposed for the in vitro/in vivo correlation. CHG120 was further encapsulated in the human-derived fibrin, generating FCHG120. The SEM and µCT images revealed the interconnected porous structures of CHG120 in both pure and fibrin-surrounding hydrogels with %porosity of 75 and 36%, respectively, indicating the presence of fibrin inside the hydrogel pores, besides its peripheral region, which was evidenced by confocal microscopy. The co-presence of GGOH moderately decelerated the overall releases of CDM from CHGs in the studied releasing fluids, i.e., phosphate buffer saline-based fluid (PBB) and simulated interstitial fluid (SIF). The whole-lifetime release patterns of CDM, fitted by the Ritger-Peppas equation, appeared nondifferentiable, divided into two releasing stages, i.e., rapid and steady releasing stages, whereas the biphasic drug release patterns of GGOH were observed with Phase I and II releases fitted by the Higuchi and Ritger-Peppas equations, respectively. Notably, the burst releases of both drugs were subsided with lengthier durations (up to 10-12 days) in SIF, compared with those in PBB, enabling CHGs to elicit satisfactory antibacterial and ZA cytotoxicity reversal activities for MRONJ-B prevention. The fibrin network in FCHG120 further reduced and sustained the drug releases for at least 14 days, lengthening bactericidal and ZA cytotoxicity reversal activities of FCHG and decreasing in vitro and in ovo acute drug toxicity. This highlighted the significance of fibrin matrices as appropriate in vivo-like platforms to evaluate the performance of an implant.

Biodegradable Dual-Function Nanocomposite Hydrogels for Prevention of Bisphosphonate-Related Osteonecrosis of the Jaw.

This study presents the development of composite hydrogels, comprising a biodegradable polymer (carboxymethyl chitosan (CMCS or CM)) and a mixture of plasma-treated mesoporous silica nanoparticles (PMCM-41 or PM) and amine-functionalized mesoporous silica nanoparticles (NMCM-41 or NM), coloaded with a hydrophilic antibiotic (clindamycin hydrochloride (CDM or C)) and a poorly water-soluble compound (geranylgeraniol (GGOH or G)) for prevention of bisphosphonate-related osteonecrosis of the jaw (BRONJ). The CG-loaded hydrogel stabilities were better maintained when CDM-preloaded PMCM-41 and NMCM-41 were initially used and governed by weight ratios of CDM-loaded PMCM-41 to NMCM-41 and CDM quantity utilized. 5PM240C-1NM-CM demonstrated the best CDM-loaded hydrogel for GGOH postloading. The scanning electron microscopy (SEM) and X-ray microcomputer-tomography (µCT) images of 5PM240C-1NM-CM revealed a porous structure with homogeneously distributed nanoparticles. Two GGOH-loaded 5PM240C-1NM-CM hydrogels were generated after GGOH loadings. Their biphasic drug release profiles were fitted by Ritger-Peppas and Hixson-Crowell models. The copresence of GGOH could hinder CDM releases, while GGOH was released with a slower rate. The hydrogels prolonged the CDM and GGOH releases up to 9 days. They possessed antibacterial activities against Streptococcus sanguinis for up to 14 days and satisfactorily provided good cytoprotection against zoledronic acid for osteoclastic and osteoblastic progenitors, thus preserving a pool of viable progenitor cells that had the capacity to differentiate into mature osteoclasts and osteoblasts in vitro, suggesting their potential local application for prevention of BRONJ.

Antibacterial and osteogenic activities of clindamycin-releasing mesoporous silica/carboxymethyl chitosan composite hydrogels.

Conventional treatment of jaw bone infection is often ineffective at controlling bacterial infection and enhancing bone regeneration. Biodegradable composite hydrogels comprised of carboxymethyl chitosan (CMCS) and clindamycin (CDM)-loaded mesoporous silica nanoparticles (MCM-41), possessing dual antibacterial activity and osteogenic potency, were developed in the present study. CDM was successfully loaded into both untreated and plasma-treated MCM-41 nanoparticles, denoted as (p)-MCM-41, followed by the incorporation of each of CDM-loaded (p)-MCM-41 into CMCS. The resulting CDM-loaded composite hydrogels, (p)-MCM-41-CDM-CMCS, demonstrated slow degradation rates (about 70% remaining weight after 14-day immersion), while the CDM-free composite hydrogel entirely disintegrated after 4-day immersion. The plasma treatment was found to improve drug loading capacity and slow down initial drug burst effect. The prolonged releases of CDM from both (p)-MCM-41-CDM-CMCS retained their antibacterial effect against Streptococcus sanguinis for at least 14 days in vitro. In vitro assessment of osteogenic activity showed that the CDM-incorporated composite hydrogel was cytocompatible to human mesenchymal stem cells (hMSCs) and induced hMSC mineralization via p38-dependent upregulated alkaline phosphatase activity. In conclusion, novel (p)-MCM-41-CDM-CMCS hydrogels with combined controlled release of CDM and osteogenic potency were successfully developed for the first time, suggesting their potential clinical benefit for treatment of intraoral bone infection.