Complex Bone Augmentation in Alveolar Ridge Defects

Commercial collagen membranes that are used as bioresorbable barrier membranes in guided bone regeneration do not contain active ingredients to promote bone regeneration. The emerging efforts to repurpose old drugs produced mounting scientific evidence that dipyridamole (DIPY), which inhibits platelet aggregation and serves as a coronary artery vasodilator, also exhibits therapeutic effects to promote bone healing/regeneration. The therapeutic effect of DIPY on bone healing/regeneration occurs via G-protein coupled adenosine (P1) receptors of the purinergic family. In this study, we investigated the feasibility of synthesizing collagen membranes for sustained release of DIPY, with the ultimate purpose of using them as tools to promote bone regeneration. The synthesized membranes were characterized using Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), and a universal mechanical testing machine. We conducted an in vitro release experiment to evaluate the release kinetics of DIPY from these membranes. The chemical and physical characterization confirmed the successful synthesis of DIPY-containing collagen membranes, namely DCM-1 and DCM-2. Both membranes had weaker tensile strength than other commercial collagen membranes, although both supported continuous release of DIPY. The in vitro release of DIPY from DCM-1 continued for at least 30 days in phosphate buffer saline (pH 7.4) at 37 °C, while DCM-2 achieved sustained release of DIPY for more than 10 weeks. These results warrant the further evaluation of DIPY-containing collagen membranes for their potential applications in guided bone regeneration after optimization of their mechanical strength.

Collagen membranes have been used as bioresorbable barrier membranes in guided tissue/bone regeneration. However, the collagen membranes currently used in clinics lack an active antibacterial function, although infection at surgical sites presents a realistic challenge for guided tissue/bone regeneration. In this study, we successfully prepared novel and advanced collagen composite membranes from collagen and complexes of heparin and chelates of minocycline and Ca²⁺ ions. These membranes were characterized for chemical structures, morphology, elemental compositions and tensile strength. In vitro release studies were conducted to evaluate the release kinetics of minocycline from these membranes. Agar disk diffusion assays were used to assess their sustained antibacterial capability against model pathogenic bacteria Staphylococcus aureus. The chemical and physical characterization confirmed the successful synthesis of minocycline-loaded collagen composite membranes, namely NCCM-1 and NCCM-2. Both membranes had weaker tensile strength as compared with commercial collagen membranes. They achieved sustained release of minocycline for at least 4 weeks in simulated body fluid (pH 7.4) at 37°C. Moreover, both membranes demonstrated potent sustained antibacterial effects against Staphylococcus aureus. These results suggested that the advanced collagen composite membranes containing minocycline can be exploited as novel guided tissue regeneration membranes or wound dressing by providing additional antibacterial functions.

To develop a biodegradable membrane with guided bone regeneration (GBR), a Mg-2.0Zn-1.0Gd alloy (wt.%, MZG) membrane with Ca-P coating was designed and fabricated in this study. The microstructure, hydrophilicity, in vitro degradation, cytotoxicity, antibacterial effect and in vivo regenerative performance for the membrane with and without Ca-P coating were evaluated. After coating, the membrane exhibited an enhance hydrophilicity and corrosion resistance, showed good in vitro cytocompatibility upon MC3T3E-1 cells, and exhibited excellent antibacterial effect against E. coli, Staphylococcus epidermis and Staphylococcus aureus, simultaneously. In vivo experiment using the rabbit calvarial defect model confirmed that Ca-P coated MZG membrane underwent progressive degradation without inflammatory reaction and significantly improved the new bone formation at both 1.5 and 3 months after the surgery. All the results strongly indicate that MZG with Ca-P coating have great potential for clinical application as GBR membranes.

Three-dimensional augmentation in severely atrophic bone and after cancer resection is a challenging clinical indication that is mostly solved using autologous bone transplantation. The development of the digital technique along with the additive manufacturing and three-dimensional (3D) printing opened new avenues for reconstructive oral and maxillofacial surgery. Therefore, patient-specific titanium mesh is a novel means of stabilizing the augmentation region using particulate bone substitute materials (BSMs) combined with autologous bone as a minimally invasive concept. However, dehiscence is a frequently reported complication in this field. Therefore, the aim of the present case series was to introduce a biomaterial-based regenerative concept in terms of exposed open healing to overcome the dehiscence related to 3D-titanium meshes. Additionally, this case series presents a novel protocol using a combination of xenogeneic BSMs with an autologous blood concentrate system (platelet-rich fibrin [PRF]) and collagen matrices without any autologous transplantation. Seven patients with alveolar ridge atrophy with different etiologies (cancer resection, severe atrophy after tooth loss, aplasia, trauma, implant infections) were treated using the open-healing concept. Therefore, after 3D augmentation using the described biomaterials, the flap margins were approximated, and the gap between the flap margins was bridged using a collagen matrix loaded with liquid PRF that was then covered by either a PTFE-based membrane or sterile latex. No periosteum splitting was performed at any time point. After a healing period of 4–8 months, all patients received dental implants as virtually planned. Bone biopsies were performed during dental insertion for histological evaluation. The augmentation area displayed a vital and well-vascularized newly formed bone that incorporated the BSM granules to build a hybrid bone. Additionally, open healing resulted in newly formed soft tissue without any signs of scar formation or fibrosis. The regenerated soft tissue was used to build a new flap during implant insertion and showed good functional and aesthetic results after implant insertion. The open-healing concept of the regeneration of the soft tissue along with bone tissue to regenerate a harmonic implantation bed is a minimally invasive intervention without periosteum splitting or large flap mobilization. However, further controlled clinical studies are needed to evaluate this concept in a larger patient cohort to outline the potential clinical benefit.

Approximately one-third of all congenital birth defects result in craniomaxillofacial congenital anomalies such as alveolar clefts. Other conditions may present themselves over the course of a patient's life, such as edentulism. The most common surgical treatment to reconstruct these defects utilizes autogenous graft material, considered the “gold standard.” These grafts are challenging to shape, are of limited quantity, and cause donor site morbidity. Our group has demonstrated that 3D-printed bioactive ceramic scaffolds have the potential to generate vascularized bone within critical-sized defects (i.e., defects that without a scaffold will not be able to return to form and function) of the craniomaxillofacial and extremity skeleton. These custom-designed and 3D-printed lattice scaffolds have the capacity to act as a carrier for an osteogenic agent, dipyridamole (DIPY), with a well-established safety profile. A custom direct ink write (DIW) 3D printer in conjunction with volumetric imaging data has been leveraged by our team to create site-specific bioactive ceramic scaffolds for bony craniofacial defects, including those involving the alveolar ridge. In this chapter, we report on the tissue engineering principles, digital imaging software platform and 3D-printing technology that have culminated in a novel reconstructive strategy for the repair of alveolar bone defects in a skeletally immature transitional model.