A bi-layered membrane with micro-nano bioactive glass for guided bone regeneration
Graphical abstract
Introduction
The main challenge of the traditional denture restoration and dental implants is alveolar bone loss deficiency caused by trauma, tumors, inflammation, tooth loss, and periodontal disease. To obtain desirable denture repair conditions, clinicians have applied guided bone regeneration (GBR), split-crest surgery, and distraction osteogenesis to enhance the alveolar bone mass [1]. Among the many methods, GBR has been widely used in nearly 40% of patients with bone defects because of its effectiveness and simple operation procedures [2]. GBR is a surgical method to prevent the migration of fast-moving epithelial cells and fibroblasts to bone defects. By placing a barrier membrane between the soft tissues and bone defects, GBR is expected to establish an osteogenic microenvironment that is free from soft tissue interference and suitable for osteoblast proliferation, differentiation, and bone regeneration [3]. Hence, the barrier membrane is vitally important for the GBR.
An ideal GBR membrane should have biocompatibility, barrier function, and clinical maneuverability. The ability to maintain a stable osteogenic space, promote bone regeneration, and integrate with host tissues is also necessary [4]. Although various commercially available membranes are extensively used, none of these products perfectly satisfy all the requirements. Commercial membranes can be divided into non-absorbable and absorbable membranes [5]. As the representatives of non-absorbable membranes, the expanded polytetrafluoroethylene (e-PTFE) (Millipore®, Gore-Tex®) and titanium membranes (COWELL®, Frios BoneShields®) have good biocompatibility, high mechanical strength, and continuous barrier function [6]. However, their mechanical properties are not suitable for the periodontal tissues, resulting in soft tissue cracking, membrane exposure, and infection [7]. In addition, the patient must undergo a second operation to remove the membranes. In contrast, the absorbable membranes with better biocompatibility have been used in more GBR operations [8,9]. For example, the collagen membrane (Bio-Gide®, Biomend®) is the most commonly used membrane, with high biocompatibility, low immunogenicity, and bioactivity [10]. However, its clinical performance still needs to be improved. Relatively fixed features such as the structures and porosities, are difficult to manually adjust. In addition, the biodegradation of collagen by proteases leads to fast degradation, insufficient mechanical properties and an unstable barrier effect on cells and tissues [8,[11], [12], [13]]. Moreover, almost all the membrane products are passive barriers and lack a bone inductive function. To modify the properties of the GBR membrane, the selection of raw materials and the manufacturing processes can be improved.
Owing to its promising machinability, excellent biocompatibility, and changeable physicochemical properties, poly (lactic-co-glycolic acid) (PLGA) has been widely used in tissue-engineered bone regeneration [14]. However, the acid byproducts of PLGA generate aseptic inflammation that impedes wound healing, and its inert biological properties fail to induce spontaneous tissue regeneration [15]. To enhance the biocompatibility and osteoinduction of PLGA, many other materials such as hydroxyapatite, β-TCP, chitosan and gelatin have been incorporated with PLGA to fabricate composite GBR membranes [[16], [17], [18]]. Osteoinductive bioactive glass (BG) is a biomaterial used for bone regeneration [19,20]. Biological activity reflects its particular characteristics, resulting in the spontaneous mineralization and activation of osteogenic genes, which are essential for bone regeneration [21,22]. Studies have shown that calcium (Ca) and soluble silicon dioxide (SiO2) released during BG degradation could stimulate osteoblast division and the production of growth factors and extracellular matrix (ECM) proteins [23]. In addition, micro-nano bioactive glass (MNBG) with a high specific surface area and good surface bioactivity can simulate the bi-layered structures of natural human bone and ECM at a smaller scale and facilitate cell adhesion, proliferation, and biological function, eventually promoting osteogenesis [15,24]. However, the use of MNBG is usually limited by its low mechanical strength and the alkalization of the microenvironment during degradation [25,26]. Considering the advantages and disadvantages of these two materials, PLGA and MNBG can complement each other in terms of mechanical properties and degradation pH [24]. Moreover, the addition of MNBG is expected to improve the biological inertia of PLGA and enhance the bioactivity of the composite membranes to achieve better bone regeneration [20,27].
Considering the principle of GBR, the membrane should act as a barrier and promote bone regeneration [28]. To achieve these two effects, a bi-layered design with different functions is promising for GBR. Therefore, we adopted different working methods to fabricate bi-layered membranes. Electrospinning is a unique fiber manufacturing technology that produces nanoscale polymer filaments and forms porous membranes. The interconnected network structure effectively simulates ECM formation and promotes the adhesion, proliferation, and differentiation of rat bone mesenchymal stem cells [29]. However, the loose structure beneficial for cell ingrowth and osteogenesis is insufficient to prevent the invasion of soft tissues and cells. The low mechanical strength of the macroporous structure also threatens the maintenance of the osteogenic space. Hence, the combination of electrospinning and solvent casting (formed by dissolving a polymer with a volatile solvent) could be a practical method for the manufacturing of GBR films. In this way, we can obtain membranes with bi-layered structures that suit different tissues.
This study employed a solvent casting and electrospinning method to fabricate a novel bi-layered membrane with PLGA and MNBG (Fig. 1). A bi-layered membrane is expected to have multiple functions. We assume that the bilayer is a qualified GBR membrane that can resist the invasion of cells because the solvent casing produces a dense PLGA layer. In addition, the bilayers should have good biocompatibility, stable mechanical properties, and a proper degradation rate. In addition, the MNBG/PLGA layer prepared by electrospinning is expected to promote spontaneous bone regeneration.
Section snippets
Materials
N, N-Dimethylformamide (DMF; HCON(CH3)2) and dichloromethane (DCM; CH2Cl2) were purchased from GHTECH (Guangzhou, Guangdong, China). Poly (lactic-co-glycolic) acid (PLGA, lactic: glycolic molar ratio = 50:50, Mn: ∼8.8 × 104 g/mol) was obtained from Daigang Biomaterial Co., Ltd (Jinan, Shandong, China). The National Engineering Research Center for Tissue Restoration and Reconstruction (South China University of Technology, Guangzhou, Guangdong, China) kindly donated the MNBG. L929 cells were
Microtopography of the bi-layered MNBG/PLGA membranes
To design a GBR membrane suitable for oral hard and soft tissues, we fabricated double-sided composite membranes by solvent casting and electrospinning, as mentioned above. The solvent casting dense-PLGA membrane was designed as a barrier to isolate bone defects from soft tissues. Additionally, MNBG was combined with PLGA by electrospinning to improve the osteogenesis performance. The dense-PLGA had two smooth and reflective surfaces (Fig. S2A), while the MNBG/PLGA membranes were bi-layered,
Conclusion
In this study, a bi-layered MNBG/PLGA membrane was prepared by electrospinning and solvent casting, and its application in GBR was investigated. The dense-PLGA surface prepared by solvent casting was smooth and dense, preventing the infiltration of connective tissue. Another MNBG/PLGA surface prepared by electrospinning was rough and loose, which promoted osteogenesis. The results show that the composite MNBG/PLGA membranes possess barrier function, stable mechanical properties, favorable
CRediT authorship contribution statement
Peiyi Li: Investigation, Data curation, Writing - original draft, Formal analysis. Yanfei Li: Data curation, Software, Formal analysis. Tszyung Kwok: Resources, Methodology. Tao Yang: Project administration. Cong Liu: Resources. Weichang Li: Writing - review & editing, Supervision, Project administration. Xinchun Zhang: Writing - review & editing, Supervision, Project administration, Funding acquisition.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
Acknowledgments
This work was supported by the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2019A1515010450), Guangzhou Science and Technology Program (Grant No. 202002030055), and the National Natural Science Foundation of China (82001094 and 21905094).
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