Sublingual Dissolving Microneedle (SLDMN)-Based Vaccine for Inducing Mucosal Immunity against SARS-CoV-2.

The coronavirus pandemic has accelerated the development of next-generation vaccination technology to combat future pandemic outbreaks. Mucosal vaccination effectively protects the mucosal surfaces, the primary sites of viral entry, by inducing the secretion of immunoglobulin A (IgA) and humoral IgG. Here, a dissolving microneedle (DMN) is adopted as a mucosal vaccine delivery platform to directly penetrate the sublingual site, which is rich in antigen-presenting cells (APCs) and lymphoid tissues. The sublingual dissolving microneedle (SLDMN) vaccination platform comprised a micropillar-based compartment and a 3D-printed SLDMN applicator as a substitute for the DMN patch. The penetration efficacy of SLDMNs is assessed using in vitro optical coherence tomography (OCT) and in vivo histological analysis. The efficacy of SLDMN is also evaluated in a vaccine form using the recombinant spike (S1) protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Furthermore, SLDMN is used to challenge transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) receptors. Its effects are evaluated on antibody production, survival rate, and inflammation attenuation after infection compared to the intramuscular (IM) injections. Overall, SLDMN effectively induced mucosal immunity via IgA secretion, attenuated lung inflammation, and lowered the levels of cytokines and chemokines, which may prevent the "cytokine storm" after SARS-CoV-2 infection.

Micro-pillar tunnel stamp for enhanced transdermal delivery of topical drug formulations.

Dissolving microneedles (DMNs), despite their minimally invasive drug administration, face challenges in skin insertion and drug-loading capacity, which lead to less effective drug delivery. The micro-pillar tunnel stamp (MPTS) was designed to enhance the transdermal delivery efficacy of externally provided topical formulations via the creation of microchannels. The tunnel and canal of the MPTS enable the simultaneous application of DMNs and topical drugs. The application of micro-pillar-polycaprolactone (MP-PCL), which is a DMN made of a slowly dissolving polymer, exhibited a drug permeation rate 1.3-fold and 2.6-fold higher than that of micro-pillar-hyaluronic acid (MP-HA), a DMN made of a rapidly dissolving polymer, and the topical group, respectively. The base diameter of MP-PCL was set to 700 µm for maximized delivery efficacy, achieving 2.8-fold higher L-ascorbic acid accumulation than that of the topical group. In vivo analysis showed that, compared to topical administration, MPTS-delivered lidocaine had 5-fold greater permeation and the MPTS-delivered group showed 1.25-fold higher skin residual amount, confirming enhanced delivery. Thus, the optimized MPTS system can be presented as an attractive alternative to overcome the limitations of the existing MN systems such as incomplete insertion and limited drug-loading capacity, enhancing the delivery of topical formulations in the transdermal market. STATEMENT OF SIGNIFICANCE: We developed a micro-pillar tunnel stamp (MPTS) to enhance the delivery of externally provided topical formulations. The functional tunnel and canal of the MPTS enabled the simultaneous application of a dissolving microneedle (DMN) array insertion and administration of external topical drugs. Upon insertion, the DMNs created skin microchannels that allowed the externally administered drug to diffuse. DMNs were fabricated using polycaprolactone (PCL), a slowly dissolving polymer, to maintain their structure inside the skin and prolong the opening duration of the microchannels. This system achieved significantly improved delivery of topically administered external drugs via integration with slowly dissolving DMNs, while offering the possibility of its development as a universal delivery system for various topical pharmaceuticals.

The validation of ultrasound-guided lumbar facet nerve blocks as confirmed by fluoroscopy.

STUDY DESIGN: This is a prospective study. PURPOSE: To develop a methodological approach for conducting ultrasound-guided lumbar facet nerve block by defining essential ultrasound-guided landmarks in order to assess the feasibility of this method. OVERVIEW OF LITERATURE: The current role of ultrasound guidance for musculoskeletal intervention treatments has been reported upon in previous literature. METHODS: Ultrasound-guided facet nerve block was done in 95 segments for 50 patients with chronic back pain by facet arthropathy. After the surface landmarks of the spinous process and iliac crest line were confirmed, longitudinal facet views were obtained by a curved array transducer to identify the different spinal segments. The spinous process and facet joint with transverse process were delineated by transverse sonograms at each level and the target point for the block was defined as lying on the upper edge of the transverse process. The needle was inserted toward the target point. After a contrast injection, the placement of the needle and contrast was checked by fluoroscopy. RESULTS: Eighty-seven segments (91.6%) could be guided successfully to the right facet nerve block by using ultrasound. After fluoroscopic control, 8 needles had to be corrected because of problems with other segments (3 cases) and lamina placements (5 cases). For the 42 patients who underwent successful block by ultrasound, however, the mean visual analogue score for back pain was improved from 6.2 ± 0.9 before the block to 4.0 ± 1.0 after the block (p = 0.001). CONCLUSIONS: Ultrasound-guided longitudinal facet view and the surface landmarks of the spinous process and iliac crest line seems to be a promising guidance technique for the lumbar facet nerve block technique.

Relationship between New Osteoporotic Vertebral Fracture and Instrumented Lumbar Arthrodesis.

STUDY DESIGN: Retrospective study. PURPOSE: To evaluate the relationship between a new osteoporotic vertebral fracture and instrumented lumbar arthrodesis. OVERVIEW OF LITERATURE: In contrast to the growing recognition of the importance of adjacent segment disease after lumbar arthrodesis, relatively little attention has been paid to the relationship between osteoporotic vertebral fractures and instrumented lumbar arthrodesis. METHODS: Twenty five patients with a thoracolumbar vertebral fracture following instrumented arthrodesis for degenerative lumbar disorders (study group) were investigated. The influence of instrumented lumbar arthrodesis was examined by comparing the bone mineral density (BMD) of the femoral neck in the study group with that of 28 patients (control group) who had sustained a simple osteoporotic vertebral fracture. The fracture after instrumented arthrodesis was diagnosed at a mean 47 months (range, 7 to 100 months) after the surgery. RESULTS: There was a relatively better BMD in the study group, 0.67 ± 0.12 g/cm(2) compared to the control group, 0.60 ± 0.13 g/cm(2) (p = 0.013). The level of back pain improved from a mean of 7.5 ± 1.0 at the time of the fracture to a mean of 4.9 ± 2.0 at 1 year after the fracture (p = 0.001). However, 12 (48%) patients complained of severe back pain 1 year after the fracture. There was negative correlation between the BMD of the femoral neck and back pain at the last follow up (r = - 0.455, p = 0.022). CONCLUSIONS: Osteoporotic vertebral fractures after instrumented arthrodesis contribute to the aggravation of back pain and the final outcome of degenerative lumbar disorders. Therefore, it is important to examine the possibility of new osteoporotic vertebral fractures for new-onset back pain after lumbar instrumented arthrodesis.