Biomechanical, biochemical, and histological characterization of sacroiliac joint cartilage in the Yucatan minipig.

Although the sacroiliac (SI) joint can be a source of lower back and buttock pain, no comprehensive characterization studies on SI cartilage have been conducted. Using the minipig as a large animal model, this study conducted the first biomechanical, biochemical, and histological characterization of SI joint cartilage. Because previous literature has reported that sacral cartilage and iliac cartilage within the SI joint are histologically distinct, concomitantly it was expected that functional properties of the sacral cartilage would differ from those of the iliac cartilage. Creep indentation, uniaxial tension, biochemical, and histological analyses were conducted on the sacral and iliac cartilage of skeletally mature female Yucatan minipigs (n = 6-8 for all quantitative tests). Concurring with prior literature, the iliac cartilage appeared to be more fibrous than the sacral cartilage. Glycosaminoglycan content was 2.2 times higher in the sacral cartilage. The aggregate modulus of the sacral cartilage was 133 ± 62 kPa, significantly higher than iliac cartilage, which only had an aggregate modulus of 51 ± 61 kPa. Tensile testing was conducted in both cranial-caudal and ventral-dorsal axes, and Young's modulus values ranged from 2.5 ± 1.5 MPa to 13.6 ± 1.5 MPa, depending on anatomical structure (i.e., sacral vs. iliac) and orientation of the tensile test. The Young's modulus of sacral cartilage was 5.5 times higher in the cranial-caudal axis and 2.0 times higher in the ventral-dorsal axis than the iliac cartilage. The results indicate that the sacral and iliac cartilages are functionally distinct from each other. Understanding the distinct differences between sacral and iliac cartilage provides insight into the structure and function of the SI joint, which may inform future research aimed at repairing SI joint cartilage.

Recent advancements in cartilage tissue engineering innovation and translation.

Articular cartilage was expected to be one of the first successfully engineered tissues, but today, cartilage repair products are few and they exhibit considerable limitations. For example, of the cell-based products that are available globally, only one is marketed for non-knee indications, none are indicated for severe osteoarthritis or rheumatoid arthritis, and only one is approved for marketing in the USA. However, advances in cartilage tissue engineering might now finally lead to the development of new cartilage repair products. To understand the potential in this field, it helps to consider the current landscape of tissue-engineered products for articular cartilage repair and particularly cell-based therapies. Advances relating to cell sources, bioactive stimuli and scaffold or scaffold-free approaches should now contribute to progress in therapeutic development. Engineering for an inflammatory environment is required because of the need for implants to withstand immune challenge within joints affected by osteoarthritis or rheumatoid arthritis. Bringing additional cartilage repair products to the market will require an understanding of the translational vector for their commercialization. Advances thus far can facilitate the future translation of engineered cartilage products to benefit the millions of patients who suffer from cartilage injuries and arthritides.

A cell bank paradigm for preclinical evaluation of an analogous cellular product for an allogeneic cell therapy.

Toward the translation of allogeneic cell therapy products, cell banks are needed not only to manufacture the final human product but also during the preclinical evaluation of an animal-based analogous cellular product (ACP). These cell banks need to be established at both the master cell bank (MCB) level and the working cell bank (WCB) level. Inasmuch as most of the development of cell therapy products is at academic centers, it is imperative that academic researchers understand how to establish MCBs and WCBs within an academic environment. To illustrate this process, using articular cartilage as the model, a cell bank for an ACP was developed (MCBs at passage 2, WCBs at passage 5) to produce self-assembled neocartilage for preclinical evaluation (constructs at passage 7). The cell bank system is estimated to be able to produce between 160 000 and 400 000 constructs for each of the six MCBs. Overall, the ACP cell bank yielded constructs that are analogous to the intended human product, which is critical toward conducting preclinical evaluations of the ACP for inclusion in an Investigational New Drug application to the FDA.

A randomized, open-label, 5-period crossover study evaluating the pharmacokinetics and safety of a single dose of intranasal dihydroergotamine (DHE) powder (STS101), intramuscular DHE mesylate, and liquid nasal spray DHE in healthy adults.

OBJECTIVE: To compare the safety and pharmacokinetics (PK) of dihydroergotamine (DHE) after administration of intranasal DHE powder (STS101), liquid nasal spray (LNS) DHE mesylate, and intramuscular (IM) DHE mesylate injection in healthy participants. BACKGROUND: DHE is an effective acute migraine treatment; however, self-administration difficulties have prevented its broader role in the management of migraine. METHODS: This randomized, active-controlled, five-period crossover study was conducted over 5 weeks separated by 1-week washout periods. Three STS101 dosage strengths (5.2, 7.0, 8.6 mg), and one dose each of LNS DHE 2.0 mg, and IM DHE 1.0 mg, were administered to 36 healthy participants. Liquid chromatography, tandem mass spectrometry was used to determine DHE (including its 8'OH-DHE metabolite) plasma levels and to calculate PK parameters (Cmax , Tmax , AUC0-2h , AUC0-last , AUC0-inf , and t1/2 ). Safety was evaluated by monitoring adverse events (AEs), vital signs, electrocardiograms, nasal examinations, and laboratory parameters. RESULTS: Thirty-six participants (mean age 36 years; 19% Hispanic Black and 81% Hispanic White) were enrolled. DHE plasma concentrations rose rapidly after STS101 5.2, 7.0, and 8.6 mg and IM DHE injection, with mean concentrations greater than 2000 pg/mL for all STS101 dose strengths at 20 min. All STS101 dose strengths showed approximately 3-fold higher Cmax , AUC0-2h , and AUC0-inf , than the LNS DHE. The mean AUC0-inf of STS101 7.0 and 8.6 mg were comparable to IM DHE (12,600 and 13,200 vs. 13,400 h × pg/mL). All STS101 dose strengths showed substantially lower variability (CV%) compared to LNS DHE for Cmax (35%-41% vs. 87%), and AUC0-inf (37%-46% vs. 65%). STS101 was well tolerated, and all treatment-emergent AEs were mild and transient. CONCLUSION: STS101 showed rapid absorption and was well tolerated with mild and transient treatment-emergent AEs. Achieving effective DHE plasma concentrations within 10 min, STS101 displayed a favorable PK profile relative to the LNS with higher Cmax , AUC0-2h , and AUC0inf , and with greater response consistency. The AUC0-inf was comparable to IM DHE.

Detrimental Effects of Chlorhexidine on Articular Cartilage Viability, Matrix, and Mechanics.

BACKGROUND: Chlorhexidine gluconate (CHG) solution is commonly used as an antiseptic irrigation for bacterial decontamination during orthopaedic surgery. Although the chondrotoxicity of CHG on articular cartilage has been reported, the full extent of CHG-related chondrotoxicity and its effects on the extracellular matrix and mechanical properties are unknown. PURPOSE: To investigate the in vitro effects of a single 1-minute CHG exposure on the viability, biochemical content, and mechanics of native articular cartilage explants. STUDY DESIGN: Controlled laboratory study. METHODS: Articular cartilage explants (6 per group) were harvested from femoral condyles of the porcine stifle and sectioned at tidemark. Explants were bathed in CHG solution (0.05% CHG in sterile water) at varying concentrations (0% control, 0.01% CHG, and 0.05% CHG) for 1 minute, followed by complete phosphate-buffered saline wash and culture in chondrogenic medium. At 7 days after CHG exposure, cell viability, matrix content (collagen and glycosaminoglycan [GAG]), and compressive mechanical properties (creep indentation testing) were assessed. RESULTS: One-minute CHG exposure was chondrotoxic to explants, with both 0.05% CHG (2.6% ± 4.1%) and 0.01% CHG (76.3% ± 8.6%) causing a decrease in chondrocyte viability compared with controls (97.5% ± 0.6%; P < .001 for both). CHG exposure at either concentration had no significant effect on collagen content, while 0.05% CHG exposure led to a significant decrease in mean GAG per wet weight compared with the control group (2.6% ± 1.7% vs 5.2% ± 1.9%; P = .029). There was a corresponding weakening of mechanical properties in explants treated with 0.05% CHG compared with controls, with decreases in mean aggregate modulus (177.8 ± 90.1 kPa vs 280.8 ± 19.8 kPa; P < .029) and shear modulus (102.6 ± 56.5 kPa vs 167.9 ± 16.2 kPa; P < .020). CONCLUSION: One-minute exposure to CHG for articular cartilage explants led to dose-dependent decreases in chondrocyte viability, GAG content, and compressive mechanical properties. This raises concern for the risk of mechanical failure of the cartilage tissue after CHG exposure. CLINICAL RELEVANCE: Clinicians should be judicious regarding the use of CHG irrigation at these concentrations in the presence of native articular cartilage.