Thermoresponsive and Injectable Pluronic F127 Hydrogel for Loading Adipose-Derived Mesenchymal Stem Cells.

BACKGROUND: Stem cell-based therapies display immense potential in regenerative medicine, highlighting the crucial significance of devising efficient delivery methods. This study centers on a pioneering approach that utilizes Pluronic F127 (PF127) as a thermoresponsive and injectable hydrogel designed for the encapsulation of adipose-derived mesenchymal stem cells (AdMSCs). METHODS: The degradation profile, gelation time, and microstructure of the PF127 hydrogel were thoroughly examined. AdMSCs were isolated, expanded, and characterized based on their multi-lineage differentiation potential. AdMSCs from the third passage were specifically employed for encapsulation within the PF127 hydrogel. Subsequently, the cytotoxicity of the AdMSC-loaded PF127 hydrogel was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis assays. RESULTS: Characterized by scanning electron microscopy (SEM), the PF127 hydrogel exhibited a porous structure, indicating its suitability for accommodating AdMSCs and facilitating wound healing. The PF127 hydrogel demonstrated reversible phase transitions, rendering it suitable for in vivo applications. Studies on the gelation time of PF127 hydrogel unveiled a concentration-dependent decrease in gelation time, offering adaptability for diverse medical applications. Analysis of the degradation profile showcased a seven-day degradation period, leading to the decision for weekly topical applications. Cytotoxicity assessments confirmed that AdMSCs loaded into the PF127 hydrogel maintained heightened metabolic activity for up to one week, affirming the safety and appropriateness of the PF127 hydrogel for encapsulating cellular therapeutics. Furthermore, cell apoptosis assays consistently indicated low rates of apoptosis, emphasizing the viability and robust health of AdMSCs when delivered within the hydrogel. CONCLUSIONS: These findings underscore the vast potential of PF127 hydrogel as a versatile and biocompatible delivery system for AdMSCs in the realm of regenerative medicine. Boasting adjustable gelation properties and a remarkable capacity for cell encapsulation, this pioneering delivery system presents a promising path for applications in tissue engineering and wound healing. Ultimately, these advancements propel and elevate the landscape of regenerative medicine.

Current therapeutic applications and pharmacokinetic modulations of ivermectin.

Ivermectin is considered to be a wonder drug due to its broad-spectrum antiparasitic activity against both ectoparasites and endoparasites (under class of endectocide) and has multiple applications in both veterinary and human medicine. In particular, ivermectin is commonly used in the treatment of different kinds of infections and infestations. By altering the vehicles used in the formulations, the pharmacokinetic properties of different ivermectin preparations can be altered. Since its development, various vehicles have been evaluated to assess the efficacy, safety, and therapeutic systemic concentrations of ivermectin in different species. A subcutaneous route of administration is preferred over a topical or an oral route for ivermectin due to superior bioavailability. Different formulations of ivermectin have been developed over the years, such as stabilized aqueous formulations, osmotic pumps, controlled release capsules, silicone carriers, zein microspheres, biodegradable microparticulate drug delivery systems, lipid nanocapsules, solid lipid nanoparticles, sustained-release ivermectin varnish, sustained-release ivermectin-loaded solid dispersion suspension, and biodegradable subcutaneous implants. However, several reports of ivermectin resistance have been identified in different parts of the world over the past few years. Continuous use of suboptimal formulations or sub-therapeutic plasma concentrations may predispose an individual to resistance toward ivermectin. The current research trend is focused toward the need for developing ivermectin formulations that are stable, effective, and safe and that reduce the number of doses required for complete clinical cure in different parasitic diseases. Therefore, single-dose long-acting preparations of ivermectin that provide effective therapeutic drug concentrations need to be developed and commercialized, which may revolutionize drug therapy and prophylaxis against various parasitic diseases in the near future. The present review highlights the current advances in pharmacokinetic modulation of ivermectin formulations and their potent therapeutic applications, issues related to emergence of ivermectin resistance, and future trends of ivermectin usage.

Mesenchymal stem cells with IGF-1 and TGF- ß1 in laminin gel for osteochondral defects in rabbits.

OBJECTIVE: Healing of articular cartilage is still a challenge due to its limited potential to regenerate. In the present study, we evaluated allogenic bone marrow mesenchymal stem cells (BM-MSCs) alone or in combination with growth factors, insulin-like growth factor-1 (IGF-1) and transforming growth factor-ß1 (TGF-ß1) in laminin scaffolds for healing of osteochondral defects. DESIGN: Osteochondral defects of 4mm (diameter) x 5mm (depth) were induced in the rabbit knee joints and treated with phosphate-buffered saline (PBS; control), BM-MSCs, BM-MSCs in laminin, BM-MSCs in laminin with IGF-1, or BM-MSCs in laminin with IGF-1 and TGF-ß1 in 10 animals each. Gross, radiographic, scanning electron microscopic (SEM) and histologic examinations besides chondrocyte-specific genes expression by quantitative real time qPCR were carried out at 8 and 12 weeks. RESULTS: Gross and SEM examination revealed superior morphology and surface architecture of the healing site in animals that received MSCs with IGF-1 or IGF-1 and TGF-ß1. The application of laminin composites containing MSCs with IGF-1 and TGF-ß1 significantly enhanced hyaline cartilage formation with improved cellular arrangement, proteoglycan deposition, clear tidemark zone and subchondral bone formation. However, regenerated tissue in defects that received only MSCs had poor tidemark zone and proteoglycans deposition Aggrecan and Coll2 expression was significantly higher in case of MSCs with growth factors. CONCLUSION: The treatment with BM-MSCs combined with IGF-1/TGF-ß1 into laminin gel scaffold might enhance the restoration of hyaline cartilage in osteochondral defect.

Comparative evaluation of in vitro mechanical properties of different designs of epoxy-pin external skeletal fixation systems.

OBJECTIVES: To compare in vitro biomechanical properties of different designs of epoxy-pin external skeletal fixator (ESF) constructs. STUDY DESIGN: Mechanical testing study. SAMPLE POPULATION: Four epoxy-pin ESF design constructs (uniplanar [EU], multiplanar-I [EM-I], multiplanar-II [EM-II], and circular [EC]) were mechanically tested in compression, bending, and torsion. METHODS: Four different designs of free-form epoxy-pin external fixator constructs were developed using 1.5 mm K-wires and epoxy resin mounted in an ultra-high density polyethylene rod (20 mm diameter). Three-point fixation was done in each fragment, and the distance between fixation wires, and between the rod and the side bars was kept constant in all the designs. A 5 mm gap was maintained at the center of the fixation rod to simulate an unstable fracture condition. The fixator constructs (n = 12 of each design) were subjected to mechanical testing in axial compression, bending, or torsion. Load-deformation curves were generated and mechanical properties were compared between construct types. RESULTS: EU was the weakest design. Under compression, constructs EM-I, EM-II, and EC were similar. Under bending, EM-I and EM-II had similar strength, whereas EC was strongest. Under torsion, EC was strongest, followed by EM-II, EM-I, and EU; EM-II provided double the rotational stability of EM-I. CONCLUSIONS: Overall, EC followed by EM-II epoxy-pin fixator designs had better mechanical strength.

Management of tibial fractures using a circular external fixator in two calves.

OBJECTIVES: To report the repair of tibial diaphyseal fractures in 2 calves using a circular external skeletal fixator (CEF). STUDY DESIGN: Clinical report. ANIMALS: Crossbred calves (n=2; age: 6 months; weight: 55 and 60 kg). METHODS: Mid-diaphyseal tibial fractures were repaired by the use of a 4-ring CEF (made of aluminum rings with 2 mm K-wires) alone in 1 calf and in combination with hemicerclage wiring in 1 calf. RESULTS: Both calves had good weight bearing with moderate lameness postoperatively. Fracture healing occurred by day 60 in 1 calf and by day 30 in calf 2. The CEF was well maintained and tolerated by both calves through fracture healing. Joint mobility and limb usage improved gradually after CEF removal. CONCLUSIONS: CEF provided a stable fixation of tibial fractures and healing within 60 days and functional recovery within 90 days. CLINICAL RELEVANCE: CEF can be safely and successfully used for the management of selected tibial fractures in calves.

In vitro biomechanical properties of linear, circular, and hybrid external skeletal fixation devices for use in large ruminants.

OBJECTIVE: To report the biomechanical properties of 3 external skeletal fixation (ESF) devices for use in large ruminants. STUDY DESIGN: In vitro biomechanical testing of ESF constructs. SAMPLE POPULATION: Adult buffalo (weighing, 250-350 kg) tibiae (n=27). METHODS: ESF constructs (bilateral linear fixator [BLF], 4-ring circular external fixator [CEF], and hybrid fixator [HF]) were made using mild (low carbon) steel implants plated with nickel and cadaveric buffalo tibiae. After ESF application, a 1 cm mid-diaphyseal gap was created. Constructs were loaded to failure, on a materials testing machine, in axial compression (n=5/ESF type) and craniocaudal bending (n=3/ESF type). In addition, 3 CEF constructs were tested in intact tibiae under craniocaudal bending. RESULT: In compression, HF was the strongest and most rigid construct; yield load was significantly higher for HF than for BLF or CEF. Under bending, both CEF and HF had similar strength and modulus of elasticity. Strength for BLF was higher than CEF and HF, whereas the reverse was true for modulus of elasticity. CONCLUSIONS: ESF made from mild steel for use in large ruminants could withstand

Evaluation of two dynamic axial fixators for large ruminants.

OBJECTIVES: To evaluate healing of a radial osteotomy repaired by application of dynamic axial fixation devices (DAF) in large ruminants. STUDY DESIGN: In vivo study of bone healing after application of 2 DAF types. Model I had 2 sidebars, each with a central cylindrical cuff (internally threaded) with 2 detachable connecting rods telescoping within the cuff. Model II had 2 side bars with 2 moveable clamps with multiple holes. SAMPLE POPULATION: Bull calves (n=8; aged, 1.5-2.0 years; weighing, 175-250 kg). METHODS: A mid-diaphyseal radial osteotomy was repaired by use of a model I (n=4) or model II (n=4) DAF. Calves were monitored for weight bearing, stability of fixation, and radiographically for fracture reduction, alignment and healing at intervals for 6 months. Fixators were removed when there was radiographic evidence of healing. RESULTS: Both the fixators were well tolerated with free movement of adjacent joints. Fragment fixation was maintained until healing in all but 1 model I calf where failure occurred within 7 days. Model II DAF provided more rigid fixation as indicated by early full weight bearing and fracture healing with less callus formation. Functional recovery of repaired limbs occurred within 60 days in surviving calves. CONCLUSIONS: Both bilateral DAFs were easy to apply; however, the model II DAF provided better fixation. CLINICAL RELEVANCE: The model II DAF made of low carbon steel was economical and may be useful for treating long bone fractures in large ruminants.