Elevation and distraction of the Tibial periosteum in the management of chronic ischemic lower limb diseases.

OBJECTIVE: This study investigates the effectiveness of tibia periosteum distraction (TPD) applied to the tibial periosteum, an innovative approach grounded in Ilizarov's tension-stress theory, for the treatment of ischemic diabetic foot and vasculitic foot conditions. METHODS: A retrospective analysis was conducted on 33 patients (36 limbs) who underwent TPD between June 2019 and May 2022. The study comprised 21 males (23 limbs) and 12 females (13 limbs), aged 41 to 80 years (mean age: 63.4 years). Diabetic foot accounted for 27 cases, thromboangiitis obliterans for 2 cases, and arterial occlusive disease for 4 cases. The distribution of affected limbs included 15 left feet and 21 right feet. Periosteum traction commenced on the third postoperative day at a rate of approximately 0.75 mm/day, adjusted biweekly. The traction device was removed after two weeks. Evaluation included capillary refill and wound healing assessment, along with pre- and postoperative analysis of foot skin temperature, ankle-brachial index (ABI), visual analogue scale (VAS) pain scores, and peripheral blood oxygen saturation. CT angiography (CTA) was utilized to assess vascular conditions in both lower limbs. RESULTS: All 33 patients were successfully followed up for a duration ranging from 4 to 24 weeks (mean: 11.03 weeks). VAS pain scores significantly decreased from preoperative (5.09 ± 1.70, range: 2-8) to postoperative two weeks (2.24 ± 0.90, range: 1-4) (t = 9.44, p < .001). Oxygen saturation levels increased from 83.88% ± 11.82% (range: 58%-97%) preoperatively to 91.36% ± 5.69% (range: 76%-98%) at two weeks postoperatively (t = -4.21, p < .001). Foot skin temperature also showed a significant increase (t = -3.98, p < .001). Capillary refill test at two weeks postoperatively demonstrated notable improvement. CTA revealed evident neovascularization in the operated limbs compared to preoperative conditions. Wound improvement was significant in all 33 patients within two months postoperatively. CONCLUSION: TPD emerges as a promising technique for chronic ischemic lower limb diseases, demonstrating favorable preliminary outcomes in wound healing promotion and amputation rate reduction. Nevertheless, large-scale randomized controlled trials are essential to further validate its efficacy.

Local Delivery of Exosomes and Antibiotics in Hydroxyapatite-Based Nanocement for Osteomyelitis Management.

The management of bone and joint infections is a formidable challenge in orthopedics and poses a global health concern. While clinical management emphasizes infection prevention and complete eradication, an effective strategy for stabilizing skeletal tissue with adequate soft tissue coverage remains limited. In this study, we have employed a novel approach of using the local delivery of exosomes and antibiotics (rifampicin) using a hydroxyapatite-based nanocement carrier to manage the residual space created during debridement effectively. Additionally, we synthesized a periosteum-guiding antioxidant herbal membrane to leverage the inherent periosteum regeneration capability of the bone, facilitating bone callus repair and natural healing. The synthesized scaffolds were biocompatible and demonstrated potent antibacterial activity in vitro. When evaluated in vivo in the Staphylococcus aureus-induced rat tibial osteomyelitis model, the released drugs successfully cleared the residual bacteria and the released exosome promoted bone healing, resulting in 3-fold increase in bone volume as analyzed via micro-CT analysis. Immunofluorescence staining of periosteum-specific markers also indicated the complete formation of periosteal layers, thus highlighting the complete bone repair.

Total elbow allograft augmented with vascularized periosteal grafts for salvage of a failed distal humeral joint replacement for Ewing sarcoma reconstruction.

Vascularized periosteal grafts have been used to promote bone union in massive bone defects. We present a child with a failed distal humeral joint replacement for Ewing sarcoma reconstruction, successfully treated with a total elbow allograft augmented by vascularized periosteal grafts.Level of evidence: V.

Multifunctional Bionic Periosteum with Ion Sustained-Release for Bone Regeneration.

In this study, a novel bionic periosteum (BP)-bioactive glass fiber membrane (BGFM) is designed. The introduction of magnesium ion (Mg2+) and zinc ion (Zn2+) change the phase separation during the electrospinning (ES) jet stretching process. The fiber's pore structure transitions from connected to closed pores, resulting in a decrease in the rapid release of metal ions while also improving degradation via reducing filling quality. Additionally, the introduction of magnesium (Mg) and zinc (Zn) lead to the formation of negative charged tetrahedral units (MgO4 2- and ZnO4 2-) in the glass network. These units effectively trap positive charged metal ions, further inhibiting ion release. In vitro experiments reveal that the deigned bionic periosteum regulates the polarization of macrophages toward M2 type, thereby establishing a conducive immune environment for osteogenic differentiation. Bioinformatics analysis indicate that BP enhanced bone repair via the JAK-STAT signaling pathway. The slow release of metal ions from the bionic periosteum can directly enhance osteogenic differentiation and vascularization, thereby accelerating bone regeneration. Finally, the bionic periosteum exhibits remarkable capabilities in angiogenesis and osteogenesis, demonstrating its potential for bone repair in a rat calvarial defect model.

Vascularized Femoral Myo-Periosteal Graft for Congenital Pseudarthrosis of the Tibia: A Case Report.

Pure vascularized periosteal transplants have been shown to be extremely effective at achieving rapid bone healing in children with biologically complex non-union. Free tibial and fibular periosteal transplants are generally indicated when large periosteal flaps are necessary. We report using a vascularized femoral myo-periosteal graft (VFMPG) to treat distal tibial osteotomy non-union in a six-year-old boy with congenital pseudarthrosis of the tibia. The graft consisted of a 9 cm myo-periosteal flap (after 50% of elastic retraction) that incorporated the vastus intermedius muscle and diaphyseal femoral periosteum nourished by the descending branch of the lateral circumflex femoral vessels. Plantaris medialis was used as a recipient vessel. Healing occurred 10 weeks after surgery. The patient resumed gait and sports activity without orthosis. No donor or recipient site complications occurred 17 months after surgery. Employing a VFMPG might be an alternative to other free or large vascularized periosteal flaps currently in use for complex pediatric non-unions.

Review of the Literature on the Current State of Periosteum-Mediated Craniofacial Bone Regeneration.

Study Design: This is an article review on the current state of periosteum-mediated bone regeneration (PMBR). It is a known mandibular reconstruction option in children, and though poorly understood and unpredictable, the concerns of developmental changes to donor and recipient tissues shared by other treatment options are nonexistent. The definitive role of periosteum during bone regeneration remains largely unknown. Objective: The objective is to review the literature on the clinical and molecular mechanism evidence of this event. Methods: Our search methodology was modeled after the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) guidelines. Search strategies were categorized into search 1 for clinical evidence of mandibular regeneration and search 2 for gene expression review for craniofacial regeneration. The quality assessment of each publication was undertaken, and inclusion criteria comprise mandibular continuity defect for search 1 and use of gene expression assay propriety kit for search 2. Results: 33 studies were selected for search 1 while four studies with non-human subjects were selected for search 2. Monitoring of PMBR onset was advised at 2 weeks post-operative, and the gene expression results showed an upregulation of genes responsible for angiogenesis, cytokine activities, and immune-inflammatory response in week 1 and skeletal development and signaling pathways in week 2. Conclusions: The results suggest that young periosteum has a higher probability of PMBR than adult periosteum, and skeletal morphogenesis regulated by skeletal developmental genes and pathways may characterize the gene expression patterns of PMBR.

Development of electrospun electroactive polyurethane membranes for bone repairing.

To fabricate electroactive fibrous membranes and provide simulated bioelectric micro-environment for bone regeneration mimicking nature periosteum, a series of electroactive polyurethanes (PUAT) were synthesized using amino-capped aniline trimers (AT) and lysine derivatives as chain extenders. These PUAT were fabricated into fibrous membranes as guided bone tissue regeneration membranes (GBRMs) via electrospinning. The ultraviolet-visible (UV-vis) absorption spectroscopy and cyclic voltammetry (CV) of PUAT copolymers showed that the electroactive PUAT fibrous membranes had good electroactivity. Besides, the introduction of AT significantly improved the hydrophobicity and thermal stability of PUAT fibrous membranes and decreased the degradation rate of PUAT fibers in vitro. With the increasing content of AT incorporated into copolymers, the tensile strength and Young's modulus of PUAT fibrous membranes increased from 4 MPa (PUAT0) to 15 MPa (PUAT10) and from 2.1 MPa (PUAT0) to 18 MPa (PUAT10), respectively. The cell morphology and proliferation of rat mesenchymal stem cells (rMSCs) on PUAT fibers indicated that the incorporation of AT enhanced the cell attachment and proliferation. Moreover, the expression levels of OCN, CD31, and VEGF secreted by rMSCs on PUAT fibers increased with the increasing content of AT. In conclusion, an electroactive polyurethane fibrous membrane mimicking natural periosteum was prepared via electrospinning and showed good potential application in guiding bone tissue regeneration.

Jawbone periosteum-derived cells with high osteogenic potential controlled by R-spondin 3.

The jawbone periosteum, the easily accessible tissue responding to bone repair, has been overlooked in the recent development of cell therapy for jawbone defect reconstruction. Therefore, this study aimed to elucidate the in vitro and in vivo biological characteristics of jawbone periosteum-derived cells (jb-PDCs). For this purpose, we harvested the jb-PDCs from 8-week-old C57BL/6 mice. The in vitro cultured jb-PDCs (passages 1 and 3) contained skeletal stem/progenitor cells and exhibited clonogenicity and tri-lineage differentiation capacity. When implanted in vivo, the jb-PDCs (passage 3) showed evident ectopic bone formation after 4-week subcutaneous implantation, and active contribution to repair the critical-size jawbone defects in mice. Molecular profiling suggested that R-spondin 3 was strongly associated with the superior in vitro and in vivo osteogenic potentials of jb-PDCs. Overall, our study highlights the significance of comprehending the biological characteristics of the jawbone periosteum, which could pave the way for innovative cell-based therapies for the reconstruction of jawbone defects.

Vertical Alveolar Ridge Regeneration by Means of Periosteal Activation-A Proof-of-Principle Study.

AIM: To assess the possibility of vertical alveolar ridge augmentation by means of activation of the periosteum. MATERIALS AND METHODS: Six adult male Beagle dogs were used for the study. All premolars and first molars were extracted, and one vertical saucer-shaped bony defect was created on each side of the mandible. After 3 months of healing, full-thickness muco-periosteal flaps were elevated, and one distraction device was placed on each side of the mandible. The distraction plate was left submerged, and the activation mechanism connected to the distraction rod was exposed intra-orally. The protocol of periosteal activation (PP: periosteal 'pumping') was initiated after a latency of 7 days. The alternation of activation and relaxation at the rate of 0.35 mm/12 h during 5 days was followed by the sole activation of 0.35 mm/12 h for 5 days (PP group). Devices were left inactivated on the contralateral control side of the mandible (C group). All animals were euthanized after 8 weeks of consolidation. Samples were analysed histologically and by means of micro-CT. RESULTS: New mature lamellar bone was formed over the pristine bone in all groups. More intensive signs of bone modelling and remodelling were observed in the PP group compared to the C group. Mean new bone, bone marrow, connective tissue and total volumetric densities were greater in the PP group (p < 0.001, p = 0.001, p = 0.003 and p < 0.001, respectively). No differences were observed in the relative area parameters. Total tissue volume and bone volume were higher in the PP group (p = 0.031 and p = 0.076, respectively), while the bone mineral densities were higher in the C group (p = 0.041 and p = 0.003, respectively). Trabecular number, trabecular thickness and trabecular separation values were similar between the two groups. CONCLUSIONS: Regeneration of vertical alveolar bone ridge defects may be enhanced by activation of the periosteum, without the application of bone grafting materials.

Integrating molecular-caged nano-hydroxyapatite into post-crosslinked PVA nanofibers for artificial periosteum.

Artificial periosteum is deemed a novel strategy for inducing endogenous bone regeneration, but ideal periosteum substitutes achieved by orchestrating a biomimetic microenvironment for bone regeneration remain a significant challenge. Here, we design and fabricate a hybridized nanofiber-based artificial periosteum with boosted osteoinduction properties. Via a "molecular cage" biomineralization strategy, nano-hydroxyapatite (nano-HAp) with a controllable size (∼22 nm) and excellent dispersion serves as unique nano-additives for water-soluble polyvinyl-alcohol (PVA)-based artificial periosteum. The PVA/HAp composite is electrospun into nanofibers to replicate the extracellular-matrix-inspired nanostructure for inducing cell adhesion, proliferation, and fate manipulation. A simple post-crosslinking treatment is subsequently applied to further booster its mechanical strength (6.6 MPa) and swelling stability. The optimized sample of C-PVA/HAp (10 wt% nano-HAp) artificial periosteum features excellent biocompatibility and remarkable in vitro mineralization. Cell experiments demonstrate that its effectively boasted cell modulation for enhanced osteogenesis without the aid of growth factors, showing a possible activation of the ERK/MAPK signaling pathway. This work provides an effective strategy for designing novel HAp nano-additives and expands the possibility of biomimetic fabrication for more advanced nanofiber-based artificial periosteum.

Periosteal expansion osteogenesis using a tubular dynamic frame device: An experimental study in rats.

Periosteal expansion osteogenesis (PEO) is a technique for augmenting bone by creating a gradual separation between the bone and periosteum. This study assessed PEO-induced bone formation around the femurs of rats using a dynamic frame device (DFD), consisting of a shape memory membrane made of polyethylene terephthalate (PET) formed into a tubular shape. The DFDs, consisting of a PET membrane coated with hydroxyapatite (HA)/gelatin on the bone-contact surface, were inserted between the periosteum and bone of the femurs of rats. In the experimental group, DFDs were suture-fixed to the femur with 4-0 Vicryl Rapid; in the control group, 4-0 silk thread was used for fixation. Five rats per group were euthanized at intervals of 3, 5, and 8 weeks postoperatively. Bone formation was evaluated via micro-CT imaging, histomorphometry, and histological analysis. Morphological analysis revealed new bone between the femur and the periosteum, expanded by the DFD, in all groups. The mean values of new bone were 0.30 mm2 proximally, 0.18 mm2 centrally, and 0.82 mm2 distally in the control group, compared to 1.05 mm2 proximally, 0.27 mm2 centrally, and 0.84 mm2 distally in the experimental group. A significant difference in new bone was observed in the proximal region of the experimental group. Histological examination showed that a single layer of newly formed neoplastic bone was noted on the cortical bone surface across all sites. The proximal portion displayed a bone marrow cavity at the center, encircled by a thick bone cortex with a layered structure. New bone formation was notable between existing cortical bone and the periosteum, particularly at both ends of the DFD. The use of PET in PEO was a viable option for achieving ideal bone morphology.

Mandibular revascularization using a humeral periosteal free flap: A technical note.

The vascularized periosteal free flap transposes a non-irradiated soft tissue with neoangiogenesis, bone induction, and osteogenesis qualities. A surgical technique using a humeral periosteal free flap is described for the treatment of recurrent osteoradionecrosis of the lower jaw. The humeral periosteal free flap is a technique associated with low morbidity. The procedure described avoids sacrificing major vessels as seen in other common flap procedures. Hence, this revascularization approach is equivalent to a prevention technique that should be considered early in the development of osteoradionecrosis to avoid further damage and challenging reconstruction.

Free gingival graft embossed over laterally flipped periosteum for root coverage: A novel case report.

Innovations in surgical techniques have improved the esthetic outcome and predictability of root coverage procedures in recent years. A free gingival graft (FGG) augments the attached gingiva, but the compromised blood supply precludes its use in root coverage. In the surgical technique described in this case report, the FGG kept over a laterally placed periosteal flap enhanced the outcome. A laterally flipped periosteal flap was adapted over the root surface using resorbable sutures. The free graft was secured at the recipient site with cyanoacrylate adhesive, and adaptation was ensured with suspensory sutures. Satisfactory root coverage was appreciated and maintained at 6 months with excellent functional outcomes. Adequate width of the attached gingiva and vestibular depth were also noticed at the recipient site. The patient was highly satisfied with the obtained results, which were maintained until the 1-year postoperative period.

Synergistic effect of ultrasound and reinforced electrical environment by bioinspired periosteum for enhanced osteogenesis via immunomodulation of macrophage polarization through Piezo1.

The periosteum plays a vital role in repairing bone defects. Researchers have demonstrated the existence of electrical potential in the periosteum and native bone, indicating that electrical signals are essential for functional bone regeneration. However, the clinical use of external electrical treatments has been limited due to their inconvenience and inefficacy. As an alternative, low-intensity pulsed ultrasound (LIPUS) is a noninvasive form of physical therapy that enhances bone regeneration. Furthermore, the wireless activation of piezoelectric biomaterials through ultrasound stimulation would generate electric charges precisely at the defect area, compensating for the insufficiency of external electrical stimulation and potentially promoting bone regeneration through the synergistic effect of mechanical and electrical stimulation. However, the optimal integration of LIPUS with an appropriate piezoelectric periosteum is yet to be explored. Herein, the BaTiO3/multiwalled-carbon nanotubes/collagen (BMC) membranes have been fabricated, possessing physicochemical properties including improved surface hydrophilicity, enhanced mechanical performance, ideal piezoelectricity, and outstanding biocompatibility, all of which are conducive to bone regeneration. When combined with LIPUS, the endogenous electrical microenvironment of native bone was recreated. After that, the wireless-generated electrical signals, along with the mechanical signals induced by LIPUS, were transferred to macrophages and activated Ca2+ influx through Piezo1. Ultimately, the regenerative effect of the BMC membrane with LIPUS stimulation (BMC + L) was confirmed in a mouse cranial defect model. Together, this research presents a co-engineering strategy that involves fabricating a novel biomimetic periosteum and utilizing the synergistic effect of ultrasound to enhance bone regeneration, which is achieved through the reinforcement of the electrical environment and the immunomodulation of macrophage polarization.

Pediatric Myringoplasty using the Periosteum: An Institutional Overview.

Introduction Myringoplasty is a common otologic procedure to restore the integrity of the tympanic membrane in cases of traumatic or pathologic perforations. Many grafting materials have been used with different techniques. Objective In the present work, we evaluate the surgical and audiological outcomes of periosteal graft overlying the mastoid cortex through a retroauricular incision in a pediatric cohort. Methods A retrospective study was carried out involving all children aged ≤ 16 years who underwent periosteal graft myringoplasty for the treatment of chronic suppurative otitis media with dry central perforation in our hospital from April 2019 to April 2021. All patients were followed up for one year to assess the anatomical success and functional outcomes by comparing the preoperative and postoperative (after six months) results of pure tone audiometry (PTA). Results The sample was composed of 36 patients; 20 of them were female (55.6%) and 16 were male (44.4%) subjects, with ages ranging from 7 to 16 (mean: 12.7) years. Four patients underwent surgery in both ears (with an interval of 6 to 9 months). Out of 40 surgeries performed, 38 ears have shown anatomical success (95%). A highly significant improvement in hearing was obtained (the mean difference between the pre- and postoperative results of the PTA was of 14.6 ± 3.45 dB ( p < 0.001). Conclusion We advocate the use of periosteal graft in the pediatric population as a good alternative for other types of grafts, with comparable and even better functional and anatomical outcomes.

Signaling pathways associated with Lgr6 to regulate osteogenesis.

Fracture management largely relies on the bone's inherent healing capabilities and, when necessary, surgical intervention. Currently, there are limited osteoinductive therapies to promote healing, making targeting skeletal stem/progenitor cells (SSPCs) a promising avenue for therapeutic development. A limiting factor for this approach is our incomplete understanding of the molecular mechanisms governing SSPCs' behavior. We have recently identified that the Leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6) is expressed in sub-populations of SSPCs, and is required for maintaining bone volume during adulthood and for proper fracture healing. Lgr family members (Lgr4-6) are markers of stem cell niches and play a role in tissue regeneration primarily by binding R-Spondin (Rspo1-4). This interaction promotes canonical Wnt (cWnt) signaling by stabilizing Frizzled receptors. Interestingly, our findings here indicate that Lgr6 may also influence cWnt-independent pathways. Remarkably, Lgr6 expression was enhanced during Bmp-mediated osteogenesis of both human and murine cells. Using biochemical approaches, RNA sequencing, and bioinformatic analysis of published single-cell data, we found that elements of BMP signaling, including its target gene, pSMAD, and gene ontology pathways, are downregulated in the absence of Lgr6. Our findings uncover a molecular interdependency between the Bmp pathway and Lgr6, offering new insights into osteogenesis and potential targets for enhancing fracture healing.

An enhanced tri-layer bionic periosteum with gradient structure loaded by mineralized collagen for guided bone regeneration and in-situ repair.

Severe fracture non-union often accompanied by damaged or even absent periosteum remains a significant challenge. This paper presents a novel tri-layer bionic periosteum with gradient structure and mineralized collagen (MC) mimics natural periosteum for in-situ repair and bone regeneration. The construct with ultrasonic polylactic acid as the loose outer fibrous layer (UPLA), poly(ε-caprolactone) as the intermediate barrier layer (PCL-M), and poly(ε-caprolactone)/MC as the inner osteoblastic layer (PM) was prepared. The physicochemical properties of layers were investigated. UPLA/PCL-M/PM exhibited a tensile strength (3.55 ± 0.23 MPa) close to that of natural periosteum and excellent adhesion between the layers. In vitro experiments demonstrated that all layers had no toxicity to cells. UPLA promoted inward growth of mouse fibroblasts. PCL-M with a uniform pore size (2.82 ± 0.05 µm) could achieve a barrier effect against fibroblasts according to the live/dead assay. Meanwhile, PM could effectively promote cell migration with high alkaline phosphatase expression and significant mineralization of the extracellular matrix. Besides, in vivo experiments showed that UPLA/PCL-M/PM significantly promoted the regeneration of bone and early angiogenesis. Therefore, this construct with gradient structure developed in this paper would have great application potential in the efficient and high-quality treatment of severe fractures with periosteal defects.

In Vitro Cell Surface Marker Expression on Mesenchymal Stem Cell Cultures does not Reflect Their Ex Vivo Phenotype.

Cell surface marker expression is one of the criteria for defining human mesenchymal stem or stromal cells (MSC) in vitro. However, it is unclear if expression of markers including CD73 and CD90 reflects the in vivo origin of cultured cells. We evaluated expression of 15 putative MSC markers in primary cultured cells from periosteum and cartilage to determine whether expression of these markers reflects either the differentiation state of cultured cells or the self-renewal of in vivo populations. Cultured cells had universal and consistent expression of various putative stem cell markers including > 95% expression CD73, CD90 and PDPN in both periosteal and cartilage cultures. Altering the culture surface with extracellular matrix coatings had minimal effect on cell surface marker expression. Osteogenic differentiation led to loss of CD106 and CD146 expression, however CD73 and CD90 were retained in > 90% of cells. We sorted freshly isolated periosteal populations capable of CFU-F formation on the basis of CD90 expression in combination with CD34, CD73 and CD26. All primary cultures universally expressed CD73 and CD90 and lacked CD34, irrespective of the expression of these markers ex vivo indicating phenotypic convergence in vitro. We conclude that markers including CD73 and CD90 are acquired in vitro in most 'mesenchymal' cells capable of expansion. Overall, we demonstrate that in vitro expression of many cell surface markers in plastic-adherent cultures is unrelated to their expression prior to culture.

Periosteum for Root Coverage in an Isolated Gingival Recession as an Autogenous Graft: A Case Report.

In periodontal care, where patient results are crucial in guiding the development of surgical techniques, gingival recession management is a critical issue. The periosteum eversion technique (PET) emerges as a modern strategy that leverages the intrinsic regenerative capabilities of the periosteum to attain root coverage. A detailed case study showcases the effectiveness of PET in managing a Miller Class I gingival recession alongside an adjunctive platelet-rich fibrin (PRF) procedure. This approach entailed the deliberate elevation and eversion of the periosteal flap to encompass the recession area, securing it meticulously through suturing. Across a six-month observation period, this method exhibited successful root coverage, augmentation of keratinized tissue, and enhanced patient comfort, as reported, with no significant complications observed. These outcomes provide support for the incorporation of PET into standard periodontal protocols, underscoring its capacity to reshape the treatment landscape for gingival recession.

Oxytocin Receptors on Calvarial Periosteal Innervation: Therapeutic Target for Post-Traumatic Headache?

OBJECTIVE: Following a mild traumatic brain injury (mTBI), the most prevalent and profoundly debilitating occurrence is the emergence of an acute and persistent post-traumatic headache (PTH), for which there are presently no approved treatments. A crucial gap in knowledge exists regarding the consequences of an mTBI, which could serve as a foundation for the development of therapeutic approaches. The activation of trigeminal sensory nerve terminals that innervate the calvarial periosteum (CP)-a densely innervated tissue layer covering the calvarial skull-has been implicated in both migraines and PTHs. We have previously shown that trigeminal oxytocin receptors (OTRs) may provide a therapeutic target for PTHs. This study examined the expression of oxytocin receptors on trigeminal nerves innervating the periosteum and whether these receptors might serve as a therapeutic target for PTHs using a direct application of oxytocin to the periosteum in a rodent model of PTH. METHODS: We used retrograde tracing and immunohistochemistry to determine if trigeminal ganglion (TG) neurons innervating the periosteum expressed OTRs and/or CGRPs. To model the impact of local inflammation that occurs following an mTBI, we applied chemical inflammatory mediators directly to the CP and assessed for changes in immediate-early gene expression as an indication of neuronal activation. We also determined whether mTBI would lead to expression changes to OTR levels. To determine whether these OTRs could be a viable therapeutic target, we assessed the impact of oxytocin injections into the CP in a mouse model of PTH-induced periorbital allodynia. RESULTS: The results of these experiments demonstrate the following: (1) the cell bodies of CP afferents reside in the TG and express both OTRs and CGRPs; (2) inflammatory chemical stimulation of the periosteum leads to rapid activation of TG neurons (phospho-ERK (p-ERK) expression), (3) mTBI-induced inflammation increased OTR expression compared to the sham group; and (4) administration of oxytocin into the periosteum on day 2 and day 40 blocked cutaneous allodynia for up to one hour post-administration for both acute and persistence phases in the PTH model-an effect that was preventable by the administration of an OTR antagonist. CONCLUSION: Taken together, our observations suggest that periosteal trigeminal afferents contribute to post-TBI craniofacial pain, and that periosteum tissue can be used as a potential local target for therapeutics such as oxytocin.