Recent progress in regenerative therapy for damaged salivary glands: From bench to bedside.

OBJECTIVE: For functional restoration of salivary glands (SGs) injured by radiation therapy or Sjögren's syndrome (SS), various experimental approaches, such as gene therapy, tissue engineering, and cell-based therapy, have been proposed. This narrative review summarized recent progresses in research using cell-based therapies, including promising trials that could lead to bench-to-clinic applications. METHODS: A literature review based on PubMed publications in the last two decades was performed to summarize progresses in cell-based therapies for SG dysfunction. RESULTS: Over 100 experimental studies have shown the therapeutic potential of several types of cells, such as SG stem cells and mesenchymal stem cells, as well as effectively conditioned mononuclear cells, in both radiation injury and SS animal models. These therapies affect to slow fibrosis progression and stimulate tissue regeneration in atrophic glands. However, to date, only a total of seven studies have been developed to the stage of clinical study, showing the safety and preliminary efficacy. CONCLUSION: To lead the radical effectiveness expected in cell-based therapy, advances in reverse translational research and in innovative experimental research, based on the findings of recent clinical studies, will be critical in the next decade.

Effect of anti-angiogenesis induced by chemotherapeutic monotherapy, chemotherapeutic/bisphosphonate combination therapy and anti-VEGFA mAb therapy on tooth extraction socket healing in mice.

Osteonecrosis of the jaw (ONJ), which is a rare but severe adverse effect, mainly occurs in oncology patients receiving chemotherapeutic agents and bisphosphonates. However, the combined impact of chemotherapy and bisphosphonates on wound healing after tooth extraction remains unknown. The aim of this study was to determine the precise etiology of ONJ induced by chemotherapy and bisphosphonate combination therapy. Mice received zoledronate (ZA) monotherapy, cyclophosphamide (CY) monotherapy or CY/ZA combination therapy. The maxillary first molars were extracted 3 weeks after the initiation of drug treatment. Moreover, antivascular endothelial growth factor A (VEGFA) monoclonal antibody (mAb) was administered once every 2 days just after tooth extraction for 2 weeks. Soft and hard tissue wound healing was evaluated 2 and 4 weeks post-extraction using histomorphometry, microcomputed tomography and immunohistochemistry. ZA monotherapy did not induce impaired oral wound healing and ONJ-like lesions 2 and 4 weeks post-extraction, respectively. Tooth extraction socket healing worsened with severe anti-angiogenesis by CY monotherapy and CY/ZA combination therapy 2 weeks post-extraction. However, CY monotherapy rarely induced ONJ-like lesions with severe angiogenesis suppression, whereas CY/ZA combination therapy frequently induced ONJ-like lesions with severe angiogenesis inhibition 4 weeks post-extraction. Interestingly, anti-VEGFA mAb therapy delayed osseous wound healing with normal soft tissue wound healing of tooth extraction sockets, although this therapy significantly suppressed blood vessel formation. Our findings suggest that anti-angiogenesis alone is not the main cause of ONJ-like lesions induced by CY/ZA combination therapy. The combination of suppressed osteoclasts and anti-angiogenesis, in addition to other risk factors such as chemotherapy, may contribute to the development of ONJ.

Intermittent administration of parathyroid hormone improves bone quality and quantity around implants in rat tibiae.

OBJECTIVES: Intermittent injection of parathyroid hormone (PTH) is used to treat osteoporosis. The concept of bone quality was updated 20 years ago; however, these updates have not been adopted in implant dentistry. This study aimed to investigate the effects of intermittent administration of PTH on bone quality around implants in rat tibiae. METHODS: Grade IV-titanium-threaded implants that were 3.5 mm long and 2.0 mm wide were placed in a randomly selected side of the proximal tibiae of 12-week-old female Wistar rats. Three weeks after implant placement, the rats were randomly divided into PTH-administration and saline-injection groups (PTH and VC, respectively; n = 7 per group). Micro-computed tomographical, histomorphometric, and immunohistochemical analyses were performed to evaluate bone quality and quantity surrounding the implants. RESULTS: PTH significantly increased bone volume and bone mineral density in bones not associated with the implants as compared to these values in the VC group. PTH significantly increased bone area and the amount of collagen within the total inside areas of all implant threads compared to that observed in VC. Moreover, PTH significantly increased the number of osteoblasts, osteocytes, and osteoclasts in the total inside and/or outside areas of all implant threads and altered the ratio of type I and III collagen to total collagen fibers. CONCLUSIONS: Within the limitations of this study, intermittent administration of PTH improved both bone quantity and bone quality based on the types and numbers of bone cells and the types of collagen fibers surrounding implants placed into rat tibiae.

Effects of surface sub-micrometer topography following oxalic acid treatment on bone quantity and quality around dental implants in rabbit tibiae.

BACKGROUND: To explore the effects of topographical modification of titanium substrates at submicron level by oxalic acid treatment on bone quality and quantity around dental implants in rabbit tibiae. METHODS: A total of 60 blasted CP-grade IV titanium dental implants were used. Twenty-eight control implant surfaces were treated with a mixture of HCl/H2SO4, whereas 28 other test implant surfaces were treated with oxalic acid following HCl/H2SO4 treatment. Two randomly selected sets of control or test implants were placed in randomly selected proximal tibiae of 14 female Japanese white rabbits. Euthanasia was performed 4 and 8 weeks post-implant placement. Bone to implant contact (BIC), bone area fraction (BAF), ratios of mature and immature bone to total bone, and the amount and types of collagen fibers were evaluated quantitatively. Two control and two test implants were used to analyze surface characteristics. RESULTS: Treatment by oxalic acid significantly decreased Sa and increased Ra of test implant surfaces. BIC in test implants was increased without alteration of BAF and collagen contents at 4 and 8 weeks after implant placement when compared with control implants. The ratios of immature and mature bone to total bone differed significantly between groups at 4 weeks post-implantation. Treatment by oxalic acid increased type I collagen and decreased type III collagen in bone matrices around test implants when compared with control implants at 8 weeks after implant placement. The effects of topographical changes of implant surfaces induced by oxalic acid on BAF, mature bone, collagen contents, and type I collagen were significantly promoted with decreased immature bone formation and type III collagen in the later 4 weeks post-implantation. CONCLUSIONS: Treatment of implant surfaces with oxalic acid rapidly increases osseointegration from the early stages after implantation. Moreover, submicron topographical changes of dental implants induced by oxalic acid improve bone quality based on bone maturation and increased production of type I collagen surrounding dental implants in the late stage after implant placement.