Faculty Bibliography

By improving the delivery and tumor retention of chemotherapeutics, nanomedicines hold potential for cancer treatment. The usefulness of nanoparticle (NP)-encapsulated analgesics for the cancer pain treatment is comparatively unexplored. We investigated whether NPs encapsulating olcegepant (OCP), an antagonist of the calcitonin receptor-like receptor (CLR) for the calcitonin gene-related peptide (CGRP), effectively relieved oral cancer pain in mice. Because persistent endosomal CLR signaling in Schwann cells mediates craniofacial pain, we reasoned that the predisposition of NPs to accumulate in endosomes could be leveraged to effectively relieve oral cancer pain. By expressing biosensors for activated CLR, Gα proteins and β-arrestins in HEK293T and Schwann cells, we found that CGRP activates CLR signaling first at the plasma membrane and then in early, late and recycling endosomes and the cis- and trans-Golgi apparatus. We synthesized biocompatible NPs encapsulating OCP and fluorophores by integrating hydrophobic ion pairing nanoformulation with Flash NanoPrecipitation. NPs slowly released OCP and accumulated in early endosomes, leading to sustained inhibition of endosomal CLR signaling in HEK293T and Schwann cells. Oral cancers were established in mice, which led to heightened pain-like responses. After intra-tumoral injection, NPs were retained in tumors for at least one week. OCP-loaded NPs almost completely reversed allodynia and hyperalgesia for a prolonged period, whereas unencapsulated OCP had small and transient effects. The NP accumulation in endosomal sites of pain signaling, the sustained release of antagonist, and the retention of NPs in tumors explain their beneficial actions. Thus, NP-encapsulation holds promise for the relief of painful cancers that are inadequately treated by opioids.

Osseodensification (OD) has emerged as a favorable osteotomy preparation technique that preserves and compacts autogenous bone along the osteotomy walls during site preparation, enhancing primary stability and implant osseointegration. While OD has demonstrated promising results in low-density trabecular bone, especially when used in conjunction with acid-etched (AE) implant surfaces, its efficacy in high-density cortical bone remains unclear-particularly in the context of varying implant surface characteristics. In this study, Grade V titanium alloy implants (Ti-6Al-4V, 4 mm × 10 mm) with deep threads, designated bone chambers and either as-machined (Mach) or AE surfaces were placed in 3.8 mm diameter osteotomies in the submandibular region of 16 adult sheep using either OD or conventional (Reg) drilling protocols. Insertion torque values (N·cm) were measured at the time of implant placement to evaluate primary stability. Mandibles were harvested at 3-, 6-, 12-, or 24-weeks post-implantation (n = 4 sheep/time point), and histologic sections were analyzed to quantify bone-to-implant contact (BIC) and bone area fractional occupancy (BAFO). Qualitative histological analysis confirmed successful osseointegration among all groups at each of the healing time points. No statistically significant differences were observed between OD and conventional drilling techniques in insertion torque (p > 0.628), BIC (p > 0.135), or BAFO (p > 0.060) values, regardless of implant surface type or healing interval. The findings indicate that neither drilling technique nor implant surface treatment significantly influences osseointegration in high density cortical bone. Furthermore, as the osteotomy was not considerably undersized, the use of OD instrumentation showed no signs of necrosis, inflammation, microfractures, or impaired osseointegration in dense cortical bone. Both OD and Reg techniques appear to be suitable for implant placement in dense bone, allowing flexibility based on surgeon preference and clinical circumstances.

Strict trainee work-week hour restrictions, increased complexities of surgical care, and shifting hospital policies have posed challenges to operating room training for residents in high-resource regions. A shortage of cleft-trained surgeon educators and inconsistent training curricula further limit exposure to cleft operative education in low-resource settings. Furthermore, teaching cleft surgery can be difficult given the confined space of the infant oral cavity and the small, delicate flaps used for reconstruction. In the face of these challenges, the role of simulation has expanded in surgical education to supplement intraoperative training and increase resident preparedness. Smile Train, a nonprofit cleft-focused organization, in partnership with the technology companies BioDigital (New York, NY) and Simulare Medical (Toronto, Ontario, Canada), and academic plastic surgeons, has developed and globally distributed a variety of simulation resources for cleft surgery. This work provided a comprehensive review of Smile Train-distributed simulator modalities, including surgical training videos, a digital simulation platform, high-fidelity physical simulators, and virtual reality models. This review described the evolution of these models, the effects on learner experience, knowledge, and surgical performance, as well as directions for future development.

Choice of vaginoplasty technique is guided by the patient's natal anatomy, patient goals, and surgeon preference. The biggest distinction among techniques is the choice of lining for the vaginal canal. This chapter provides an overview of current data on the most pertinent complications, both universal and specific to different techniques for gender-affirming vaginoplasty. Clinical pearls for the management of these complications and indications for revision will be reviewed.

In an effort to improve bone response, predictably regenerate lost tissue, and provide an anatomically pleasing ridge contour for biomechanically favorable and prosthetically driven implant placement, guided bone regeneration (GBR) procedures have been indicated. This study provides the first direct in vivo comparison of the biocompatibility of an experimental porcine-derived collagen membrane (CMI, Regenity Biosciences, Paramus, NJ, USA) and a commercially available bovine-derived collagen membrane (CopiOs, ZimVie, Palm Beach Gardens, FL, USA) in a beagle mandibular model for the purposes of GBR. Four bilateral defects of 10 mm × 10 mm through the mandibular thickness were placed in each of n = 16 adult beagle dogs. Defects were filled with a deproteinized porcine-derived particulate graft and were covered either with CMI or CopiOs to allow compartmentalized healing. Animals were euthanized after 4, 8, 12, or 16 weeks post-operatively (n = 4 beagles/time point). Bone regenerative capacity, graft, and soft tissue presence were evaluated by histomorphometric and microtomographic analyses. Outcome variables were compared using a mixed model analysis with fixed factor variables of time and material. Qualitatively, no histomorphological differences in healing were observed between the membrane groups at any time point. Histomorphometrically, CMI and CopiOs presented statistically significant differences in bone (mean ± SD: 38.27% ± 15.20 vs. 17.43% ± 15.49, respectively, p = 0.016) and soft tissue presence (mean ± SD: 50.88% ± 11.83 vs. 68.21% ± 16.98, respectively, p = 0.026) at 8 weeks. These results might influence treatment timing in clinical practice, by enabling early implant placement or shorter healing intervals. No significant differences were detected in these parameters at any other healing time point (p > 0.05). CMI and CopiOs showed no signs of adverse immune response and led to similar trends in bone regeneration after 16 weeks of permitted healing. Both membranes minimized soft tissue infiltration and maintained defect stability over the observed healing periods without adverse events such as inflammation and/or foreign body reaction.

Analgesia by non-steroidal anti-inflammatory drugs (NSAIDs) is ascribed to inhibition of prostaglandin (PG) biosynthesis and ensuing inflammation. However, NSAIDs have life-threatening side effects, and inhibition of inflammation delays pain resolution. Decoupling the mechanisms underlying PG-evoked pain vs. protective inflammation would facilitate pain treatment. Herein, we reveal that selective silencing of the PGE₂ receptor 2 (EP2) in Schwann cells via adeno-associated viral vectors abrogates the indomethacin-sensitive component of pain-like responses in mice elicited by inflammatory stimuli without affecting inflammation. In human Schwann cells and in mice, EP2 activation and optogenetic stimulation of adenylyl cyclase evokes a plasma membrane-compartmentalized cyclic adenosine monophosphate (cAMP) signal that, via A-kinase anchor protein-associated protein kinase A, sustains inflammatory pain-like responses, but does not delay their resolution. Thus, an unforeseen and druggable EP2 receptor in Schwann cells, via specific cAMP nanodomains, encodes PGE₂-mediated persistent inflammatory pain but not PG-dependent protective inflammation.

PURPOSE/OBJECTIVE:The various physiological profiles comprising vascularized composite allografts (VCAs) pose unique challenges to preservation. Minimizing ischemia, reperfusion injury, and rejection remains a primary focus of graft pretreatments (PTs). Currently, the gold standard PT consists of flushing the graft and placing it in static cold storage in the University of Wisconsin solution. With this method, graft viability is limited to 4 to 6 hours. Prolonging this time limit will increase donor allocation radius, access to care, and positive patient outcomes. We aimed to evaluate novel PTs that could potentially enhance and lengthen VCA viability. METHODS:Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines, we conducted a comprehensive literature search of EMBASE, Cochrane, and PubMed. Studies had to be published prior to June 15, 2022. PTs had to target cell physiology, rather than immunogenicity. We extracted data including study design, PT details, evaluation metrics, and outcomes. RESULTS:We identified 13 studies, categorized into 3 groups: solution-based alterations to the gold standard, ex vivo perfusion, and other novel techniques. The incorporation of hydrogen sulfide and Perfadex as solutions in the gold standard protocol demonstrated a 6-day delay in rejection and limited reperfusion injury markers, respectively. In an ex vivo perfusion study, after 24 hours of PT and 12 hours posttransplant, VCA muscle contractility remained close to normal. The gold standard PT did not demonstrate the same success. However, graft weight gain, up to 50% of baseline among the reviewed articles, is a prominent adverse effect of perfusion. Another technique, cryopreservation, displayed 90% graft failure by venous thrombosis, despite high free graft viability following 2 weeks of storage. CONCLUSIONS:This study of PT modalities found a variety of encouraging preservation techniques for grafts with high levels of tissue diversity. Ex vivo perfusion dominated PT innovation with promising results in preserving the viability and functionality of muscle, which is central to the restoration of movement. Future studies are necessary to evaluate long-term graft outcomes and to optimize PT protocols for extended preservation times to ensure clinical relevance.

BACKGROUND:Needlestick exposures commonly occur with non-disposable metal syringes during the assembly and disassembly of needles due to the manual handling of needles. Disposable syringes are designed to reduce these exposures by using a protective sheath thus eliminating the need to handle needles while uncapping and recapping them. PURPOSE/OBJECTIVE:This pilot study compared the two syringes with two alternating groups of third-year (D3) students during clinical practice under faculty supervision to administer local anesthesia to live patients. METHODS:In 2023, two groups of Year 3 (D3) Doctor of Dental Surgery (DDS) students supervised by faculty in each group alternated over two 4-week sessions using disposable (N = 67) and non-disposable (N = 66) syringes to administer local anesthesia injections to live patients. At the end of each session, each group and supervising faculty completed a survey to capture their experience. RESULTS:While two participants reported needlestick injuries using non-disposable syringes and no injuries incurred using disposable syringes, we found neither a statistically significant increase nor decrease in exposures related to needlesticks using either syringe. Statistically significant outcomes showed that the participants found the non-disposable easier to use and they were more likely to use it going forward than the disposable syringe. Participants preferred using the non-disposable syringe mainly because of the stability and familiarity aspects of prior education. The disposable syringe, while easier and safer to assemble and disassemble, felt less stable to use during the injection procedure, especially during aspiration. CONCLUSION/CONCLUSIONS:While safety continues to be a concern, students and faculty prefer non-disposable metal syringes over disposable syringes. Most dissatisfaction with using the disposable syringe came from the aspiration system. But prior experience and comfort using non-disposable metal syringes, a lack of experience and confidence with local anesthesia procedures and a lack of experience with disposable syringes, may have contributed to these outcomes. Despite usability issues with the disposable syringe, performance was more impacted by lack of experience than the type of syringe used. Introducing both syringes early into the curriculum may help overcome usability factors, further reduce needlestick exposures, and prepare students for different workplace environments. Providing adequate training for faculty, especially on the differences between the two syringes, such as aspiration, will help alleviate discomfort and better promote the use of both.