Micropatterned Scaffolds with Immobilized Growth Factor Genes Regenerate Bone and Periodontal Ligament-Like Tissues.

Periodontal disease destroys supporting structures of teeth. However, tissue engineering strategies offer potential to enhance regeneration. Here, the strategies of patterned topography, spatiotemporally controlled growth factor gene delivery, and cell-based therapy to repair bone-periodontal ligament (PDL) interfaces are combined. Micropatterned scaffolds are fabricated for the ligament regions using polycaprolactone (PCL)/polylactic-co-glycolic acid and combined with amorphous PCL scaffolds for the bone region. Scaffolds are modified using chemical vapor deposition, followed by spatially controlled immobilization of vectors encoding either platelet-derived growth factor-BB or bone morphogenetic protein-7, respectively. The scaffolds are seeded with human cells and delivered to large alveolar bone defects in athymic rats. The effects of dual and single gene delivery with and without micropatterning are assessed after 3, 6, and 9 weeks. Gene delivery results in greater bone formation at three weeks. Micropatterning results in regenerated ligamentous tissues similar to native PDL. The combination results in more mature expression of collagen III and periostin, and with elastic moduli of regenerated tissues that are statistically indistinguishable from those of native tissue, while controls are less stiff than native tissues. Thus, controlled scaffold microtopography combined with localized growth factor gene delivery improves the regeneration of periodontal bone-PDL interfaces.

Tissue Engineered Constructs for Periodontal Regeneration: Current Status and Future Perspectives.

The periodontium, consisting of gingiva, periodontal ligament, cementum, and alveolar bone, is a hierarchically organized tissue whose primary role is to provide physical and mechanical support to the teeth. Severe cases of periodontitis, an inflammatory condition initiated by an oral bacterial biofilm, can lead to significant destruction of soft and hard tissues of the periodontium and result in compromised dental function and aesthetics. Although current treatment approaches can limit the progression of the disease by controlling the inflammatory aspect, complete periodontal regeneration cannot be predictably achieved. Various tissue engineering approaches are investigated for their ability to control the critical temporo-spatial wound healing events that are essential for achieving periodontal regeneration. This paper reviews recent progress in the field of periodontal tissue engineering with an emphasis on advanced 3D multiphasic tissue engineering constructs (TECs) and provides a critical analysis of their regenerative potential and limitations. The review also elaborates on the future of periodontal tissue engineering, including scaffold customization for individual periodontal defects, TEC's functionalization strategies for imparting enhanced bioactivity, periodontal ligament fiber guidance, and the utilization of chair-side regenerative solutions that can facilitate clinical translation.

Periodontal Tissue Bioengineering: Is the Future Now?

Periodontitis affects nearly half of the adult population in the United States and leads to periodontium destruction, tooth loss, and tooth mobility. Novel bioengineering has become an area of interest in dentistry, as various approaches aim to regenerate attachment apparatus around diseased teeth with the use of barriers, scaffolds, bone grafts, or biologics. This article emphasizes recent findings in the fields of stem cell/gene therapy, 3-dimensional printing, and innovative scaffold designs for future applications in clinical care.

When epigenetics meets bioengineering-A material characteristics and surface topography perspective.

The field of tissue engineering and regenerative medicine (TE/RM) involves regeneration of tissues and organs using implantable biomaterials. The term epigenetics refers to changes in gene expression that are not encoded in the DNA sequence, leading to remodeling of the chromatin and activation or inactivation of gene expression. Recently, studies have demonstrated that these modifications are influenced not only by biological cues but also by mechanical and topographical signals. This review highlights the current knowledge on emerging approaches in TE/RM with a focus on the effect of materials and topography on the epigenetic expression pattern in cells with potential impacts on modulating regenerative biology. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2065-2071, 2018.

3D-Printed Scaffolds and Biomaterials: Review of Alveolar Bone Augmentation and Periodontal Regeneration Applications.

To ensure a successful dental implant therapy, the presence of adequate vertical and horizontal alveolar bone is fundamental. However, an insufficient amount of alveolar ridge in both dimensions is often encountered in dental practice due to the consequences of oral diseases and tooth loss. Although postextraction socket preservation has been adopted to lessen the need for such invasive approaches, it utilizes bone grafting materials, which have limitations that could negatively affect the quality of bone formation. To overcome the drawbacks of routinely employed grafting materials, bone graft substitutes such as 3D scaffolds have been recently investigated in the dental field. In this review, we highlight different biomaterials suitable for 3D scaffold fabrication, with a focus on "3D-printed" ones as bone graft substitutes that might be convenient for various applications related to implant therapy. We also briefly discuss their possible adoption for periodontal regeneration.

Integration of 3D Printed and Micropatterned Polycaprolactone Scaffolds for Guidance of Oriented Collagenous Tissue Formation In Vivo.

Scaffold design incorporating multiscale cues for clinically relevant, aligned tissue regeneration has potential to improve structural and functional integrity of multitissue interfaces. The objective of this preclinical study is to develop poly(ε-caprolactone) (PCL) scaffolds with mesoscale and microscale architectural cues specific to human ligament progenitor cells and assess their ability to form aligned bone-ligament-cementum complexes in vivo. PCL scaffolds are designed to integrate a 3D printed bone region with a micropatterned PCL thin film consisting of grooved pillars. The patterned film region is seeded with human ligament cells, fibroblasts transduced with bone morphogenetic protein-7 genes seeded within the bone region, and a tooth dentin segment positioned on the ligament region prior to subcutaneous implantation into a murine model. Results indicate increased tissue alignment in vivo using micropatterned PCL films, compared to random-porous PCL. At week 6, 30 µm groove depth significantly enhances oriented collagen fiber thickness, overall cell alignment, and nuclear elongation relative to 10 µm groove depth. This study demonstrates for the first time that scaffolds with combined hierarchical mesoscale and microscale features can align cells in vivo for oral tissue repair with potential for improving the regenerative response of other bone-ligament complexes.

Tissue engineering for bone regeneration and osseointegration in the oral cavity.

OBJECTIVE: The focus of this review is to summarize recent advances on regenerative technologies (scaffolding matrices, cell/gene therapy and biologic drug delivery) to promote reconstruction of tooth and dental implant-associated bone defects. METHODS: An overview of scaffolds developed for application in bone regeneration is presented with an emphasis on identifying the primary criteria required for optimized scaffold design for the purpose of regenerating physiologically functional osseous tissues. Growth factors and other biologics with clinical potential for osteogenesis are examined, with a comprehensive assessment of pre-clinical and clinical studies. Potential novel improvements to current matrix-based delivery platforms for increased control of growth factor spatiotemporal release kinetics are highlighting including recent advancements in stem cell and gene therapy. RESULTS: An analysis of existing scaffold materials, their strategic design for tissue regeneration, and use of growth factors for improved bone formation in oral regenerative therapies results in the identification of current limitations and required improvements to continue moving the field of bone tissue engineering forward into the clinical arena. SIGNIFICANCE: Development of optimized scaffolding matrices for the predictable regeneration of structurally and physiologically functional osseous tissues is still an elusive goal. The introduction of growth factor biologics and cells has the potential to improve the biomimetic properties and regenerative potential of scaffold-based delivery platforms for next-generation patient-specific treatments with greater clinical outcome predictability.

Image-based, fiber guiding scaffolds: a platform for regenerating tissue interfaces.

In the oral and craniofacial complex, tooth loss is the most commonly acquired disfiguring injury. Among the most formidable challenges of reconstructing tooth-supporting osseous defects in the oral cavity is the regeneration of functional multi-tissue complexes involving bone, ligament, and tooth cementum. Furthermore, periodontal multi-tissue engineering with spatiotemporal orientation of the periodontal ligament (PDL) remains the most challenging obstacle for restoration of physiological loading and homeostasis. We report on the ability of a hybrid computer-designed scaffold--developed utilizing computed tomography--to predictably facilitate the regeneration and integration of dental supporting tissues. Here, we provide the protocol for rapid prototyping, manufacture, surgical implantation, and evaluation of dual-architecture scaffolds for controlling fiber orientation and facilitating morphogenesis of bone-ligament complexes. In contrast to conventional single-system methods of fibrous tissue formation, our protocol supports rigorous control of multi-compartmental scaffold architecture using computational scaffold design and manufacturing by 3D printing, as well as the evaluation of newly regenerated tissue physiology for clinical implementation.

Influence of crosslinking on the stiffness and degradation of dermis-derived hydrogels.

Natural hydrogels have been investigated for three-dimensional tissue reconstruction and regeneration given their ability to emulate the structural complexity of multi-component extracellular matrices (ECM). Hydrogels rich in ECM can be extracted and assembled from soft tissues, retain a composition specific to the tissue source, and stimulate vascularized tissue formation. However, poor mechanical properties and rapid degradation hinder their performance in regenerative applications. This study investigates the effect of glutaraldehyde (GA) crosslinking on the mechanical properties, biological activity, and degradation of dermis-isolated ECM-rich hydrogels. Compression tests indicated that hydrogel elastic moduli and yield stress values increased significantly with GA exposure time. Lyophilization was shown to decrease yield stress values with respect to non-lyophilized gels. Crosslinked ECM, unlike non-crosslinked gels, was resistant to pepsin degradation in vitro. In a rodent subcutaneous implant model, crosslinking for 0.5 hours or longer drastically slowed degradation relative to controls. Inflammation was low and mature vascularized granulation tissue was observed in all gels, with an increase in vessel density at 1 week in crosslinked gels relative to controls. These results support the potential use of dermis-derived hydrogels as materials for tissue engineering applications and suggest that crosslinking can enhance mechanical properties and prolong hydrogel lifetime while promoting vascularized tissue formation.