Sungkhaphan Piyarat, Thavornyutikarn Boonlom, Muangsanit Papon, Kaewkong Pakkanun, Kitpakornsanti Setthawut, Pornsuwan Soraya, Singhatanadgit Weerachai, Janvikul Wanida
National Metal and Materials Technology Center, National Science and Technology Development Agency, Khlong Luang 12120, Thailand.
National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Khlong Luang 12120, Thailand.
ACS Omega. 2023 Jul 14;8(29):26561-26576. doi: 10.1021/acsomega.3c03440. eCollection 2023 Jul 25.
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.
负载克林霉素（CDM）/香叶基香叶醇（GGOH）的等离子体处理介孔二氧化硅纳米颗粒/羧甲基壳聚糖复合水凝胶（CHG60和CHG120）被研发用于预防与双膦酸盐相关的药物性颌骨坏死（MRONJ - B）。对CHG的孔结构和性能进行了评估，例如药物释放曲线和动力学、抗菌活性、唑来膦酸（ZA）诱导的细胞毒性逆转活性以及急性细胞毒性。还提出了模仿体内纤维蛋白基质的仿生平台用于体外/体内相关性研究。CHG120进一步被包裹在人源纤维蛋白中，生成FCHG120。扫描电子显微镜（SEM）和显微计算机断层扫描（μCT）图像显示，在纯CHG120水凝胶和纤维蛋白包绕的水凝胶中，CHG120均具有相互连通的多孔结构，孔隙率分别为75%和36%，这表明除了其周边区域外，水凝胶孔隙内也存在纤维蛋白，共聚焦显微镜证实了这一点。在研究的释放液即磷酸盐缓冲盐水基液（PBB）和模拟组织间液（SIF）中，GGOH的共存适度减缓了CDM从CHG中的整体释放。CDM的全生命周期释放模式，用Ritger - Peppas方程拟合，呈现出不可区分的情况，分为两个释放阶段，即快速释放阶段和稳定释放阶段，而GGOH的双相药物释放模式被观察到，其I期和II期释放分别用Higuchi方程和Ritger - Peppas方程拟合。值得注意的是，与在PBB中相比，两种药物在SIF中的突释在更长时间（长达10 - 12天）内减弱，使CHG能够引发令人满意的抗菌和ZA细胞毒性逆转活性以预防MRONJ - B。FCHG120中的纤维蛋白网络进一步减少并持续药物释放至少14天，延长了FCHG的杀菌和ZA细胞毒性逆转活性，并降低了体外和卵内急性药物毒性。这突出了纤维蛋白基质作为合适的类体内平台来评估植入物性能的重要性。
