To establish an ideal microenvironment for regenerating maxillofacial defects, recent research interests have concentrated on developing scaffolds with intricate configurations and manipulating the stiffness of extracellular matrix toward osteogenesis. Herein, we propose to infuse a degradable RGD-functionalized alginate matrix (RAM) with osteoid-like stiffness, as an artificial extracellular matrix, to a rigid 3D-printed hydroxyapatite scaffold for maxillofacial regeneration. The 3D-printed hydroxyapatite scaffold was produced by microextrusion technology and showed good dimensional stability with consistent microporous detail. RAM was crosslinked by calcium sulfate to manipulate the stiffness, and its degradation was accelerated by partial oxidation using sodium periodate. The results revealed that viability of bone marrow stem cells was significantly improved on the RAM and was promoted on the oxidized RAM. In addition, the migration and osteogenic differentiation of bone marrow stem cells were promoted on the RAM with osteoid-like stiffness, specifically on the oxidized RAM. The in vivo evidence revealed that nonoxidized RAM with osteoid-like stiffness upregulated osteogenic genes but prevented ingrowth of newly formed bone, leading to limited regeneration. Oxidized RAM with osteoid-like stiffness facilitated collagen synthesis, angiogenesis, and osteogenesis and induced robust bone formation, thereby significantly promoting maxillofacial regeneration. Overall, this study supported that in the stabilized microenvironment, oxidized RAM with osteoid-like stiffness offered requisite mechanical cues for osteogenesis and an appropriate degradation profile to facilitate bone formation. Combining the 3D-printed hydroxyapatite scaffold and oxidized RAM with osteoid-like stiffness may be an advantageous approach for maxillofacial regeneration.

Background Infection control is a major determinant of guided tissue regeneration (GTR). This study aims to develop an antibiotic‐loaded membrane to assist periodontal repair. Methods Poly(D,L‐lactic acid) (PDLLA) nanofibers encapsulating amoxicillin (PDLLA‐AMX) were fabricated using the electrospinning technique, and their structures, drug encapsulation efficiency, and release characteristics were assessed. The viability and behaviors of periodontal ligament (PDL) cells on nanofibers, and antibacterial capabilities of nanofibers were evaluated in vitro. Early therapeutic efficiency of the antibiotic‐loaded membranes was investigated in rats with ligature‐induced experimental periodontitis, and the outcomes were evaluated by gene expression, microcomputed tomography imaging, and histology within 7 days of membrane placement. Results AMX was successfully encapsulated in the PDLLA nanofibers and released in a sustained manner. After initial attachment was achieved, cells stretched out along with the directions of nanofibers. The viability and expression of migration‐associated gene of PDL cells were significantly improved, and the growth of Streptococcus sanguinis and Porphyromonas gingivalis was significantly reduced in the PDLLA‐AMX group compared with the controls. On PDLLA‐AMX‐treated sites, wound dehiscence and sulcular inflammation were reduced. Collagen fiber matrix deposition was accelerated with upregulated type I collagen and interleukin‐1β, and downregulated matrix metalloproteinase‐8, whereas periodontal bone level and the expressions of vascular endothelial growth factor and core‐binding factor subunit alpha‐1 were equivalent to conventional membrane treatment. Conclusions PDLLA‐AMX nanofibers inhibited bacterial growth and promoted the viability and mobility of PDL cells after initial cell attachment. Membranes with PDLLA‐AMX nanofibers reduced inflammation and accelerated periodontal repair at an early stage, providing good prospects for the further development of GTR membranes.

Objective and BackgroundTo achieve periodontal regeneration, numerous investigations have concentrated on biomolecule supplement and optimization of bone substitute or barrier membrane. This study evaluated the benefit of combining these strategies for periodontal regeneration.MethodsBiphasic cryogel scaffold (BCS) composed of gelatin (ligament phase) and gelatin with beta‐tricalcium phosphate/hydroxyapatite (BH) (bone phase) was designed as tested bone substitute, and both enamel matrix derivatives (EMD) and bone morphogenetic protein‐2 (BMP‐2) were applied to formulate a biomolecule‐aided BCS (BBS). Functionally graded membrane (FGM) was designed as tested barrier membrane by adhering PDGF‐encapsulated poly(L‐lactide‐co‐D/L‐lactide) nanofibers on the conventional membrane (CM). BBS and FGM were characterized and tested for biocompatibility in vitro. Thirty 4 × 4 × 5 mm3 periodontal intrabony defects were created on 6 Beagle dogs. Each defect was evenly assigned to one of the following treatments including BH‐CM, BCS‐CM, BBS‐CM, BH‐FGM, BCS‐FGM, and BBS‐FGM, for 12 weeks. The therapeutic efficiency was assessed by micro‐CT and histology.ResultsBCS and FGM sustained the release of biomolecules. The viability of MSCs was maintained in both phases of BCS and was promoted while seeding on the PDGF‐encapsulated nanofibers. In CM‐covered sites, BBS showed significantly greater osteogenesis (P < .01) and early defect fill (P < .05) relative to BH. FGM significantly promoted osteogenesis (P < .05) in BH‐treated sites but showed limited benefit in BBS‐treated sites. On denuded roots, cementum deposition was evident in BBS‐treated sites.ConclusionsPDGF‐loaded FGM promoted periodontal osteogenesis, and BBS with EMD‐BMP‐2 had potential for reconstructing alveolar ridge, periodontal ligament, and cementum. FGM and BBS combination provided limited additional benefit.

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Reconstruction of the periodontal ligament (PDL) to fulfill functional requirement remains a challenge. This study sought to develop a biomimetic microfibrous system capable of withstanding the functional load to assist PDL regeneration. Collagen-based straight and waveform microfibers to guide PDL cell growth were prepared using an extrusion-based bioprinter, and a laminar flow-based bioreactor was used to generate fluidic shear stress. PDL cells were seeded on the respective microfibers with 0 or 6 dynes/cm2 fluidic shear stress for 1–4 h. The viability, morphology, adhesion pattern, and gene expression levels of PDL cells were assessed. The results revealed that upon bioprinting optimization, collagen-based microfibers were successfully fabricated. The straight microfibers were 189.9 ± 11.44 μm wide and the waveform microfibers were 235.9 ± 11.22 μm wide. Under 6 dynes/cm2 shear stress, PDL cells were successfully seeded, and cytoskeleton expansion, adhesion, and viability were greater. Cyclin D, E-cadherin, and periostin were upregulated on the waveform microfibers. In conclusion, 3D-printed collagen-based waveform microfibers preserved PDL cell viability and exhibited an enhanced tendency to promote healing and regeneration under shear stress. This approach is promising for the development of a guiding scaffold for PDL regeneration.

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Background Diabetes mellitus deteriorates the destruction and impairs the healing of periodontal wounds and craniofacial defects. This study is to evaluate the potential of self-assembled adipose-derived stem cell spheroids (ADsp) in microbial transglutaminase cross-linked gelatin hydrogel (mTG) for treating diabetic periodontal wounds and craniofacial defects. Methods Human adipose-derived stem cells (ADSCs) were isolated by lipoaspiration, pluripotent genes and trilineage differentiation were examined, and the maintenance of ADsp properties in mTG was verified. Oral mucosal wounds and calvarial osseous defects were created in diabetic rats. Gross observation, histologic evaluation, and immunohistochemistry for proliferating cells and keratinization were conducted in the mucosal wounds within 4–28 days. Micro-CT imaging, histologic evaluation, and immunohistochemistry for proliferating cells and osteogenic differentiation were conducted in the osseous defects at 7 and 28 days. Results ADSCs expressed pluripotent genes and were capable of trilineage differentiation. ADsp retained morphology and stemness in mTG. In diabetic mucosal wounds, wound closure, epithelization, and keratinization were accelerated in those with ADsp and ADsp-mTG. In diabetic osseous defects, osteogenic differentiation markers were evidently expressed, cell proliferation was promoted from day 7, and bone formation was significantly promoted at day 28 in those with osteogenically pretreated ADsp-mTG. Conclusions ADsp-mTG accelerated diabetic oral mucosal wound healing, and osteogenically pretreated ADsp-mTG promoted diabetic osseous defect regeneration, proving that ADsp-mTG facilitated diabetic periodontal wound healing and craniofacial osseous defect regeneration.