Sustained Release Research Articles

L-Cystine-Based Polyurethane as a Drug-Delivery Vehicle in Targeted Cancer Therapy and Biomedical Applications.

Controlled and sustained drug release is a critical aspect of drug-delivery systems (DDSs) that can be used in chemotherapy while ensuring therapy effectiveness and biosafety. Hence, polyurethane (PU) is modified using a biomolecule Cystine (CYS) for protracted drug release, aiming to enhance cancer treatment efficacy while minimizing adverse side effects in tumor patients. To confirm the formation of a polymer structure, characterization techniques such as NMR and FTIR are used, and the morphology is determined using SEM. Biocompatibility of the synthesized polymers is evaluated through cellular assessments, including MTT assay, cell adhesion, and antibacterial assay along with drug release using an anticancer drug, Paclitaxel (PTX). Notably, the incorporation of PTX in the polymer matrix results in minimal mortality (85% viable cells) rates in healthy cells (3T3), in contrast to a 56% mortality rate observed with the pure drug. While PTX shows a burst release and kills cancer cells only for the first 24 h, PU loaded with the drug shows sustained release and kills the cancer cells for 3 days. This vehicle selectively kills 59% of SiHA cells after a consecutive study of 3 days, which highlights the potential of this newly designed vehicle for effective drug delivery, particularly in anticancer treatments. Moreover, cystine's antibacterial property adds up with PU; hence, PU shows antibacterial activity against Staphylococcus aureus (MIC, 20 μg/mL) and also acts as a reductive oxygen species scavenger. Therefore, modifying PU with CYS has shown sustained release of PTX along with a selective effect on cells, underscoring its significance as a superior delivery agent and supported by a shred of convincing evidence.

Fabrication of Bioactive Helix aspersa Extract-Loaded Chitosan-Based Bilayer Wound Dressings for Skin Tissue Regeneration.

In recent years, there has been a notable shift toward exploring plant and animal extracts for the fabrication of tissue engineering structures that seamlessly integrate with the human body, providing both biological compatibility and physical reinforcement. In this particular investigation, we synthesized bilayer wound dressings by incorporating snail (Helix aspersa) secretions, comprising mucus and slime, into chitosan matrices via lyophilization and electrospinning methodologies. A nanofiber layer was integrated on top of the porous structure to mimic the epidermal layer for keratinocyte activity as well as acting as an antibacterial barrier against possible infection, whereas a porous structure was designed to mimic the dermal microenvironment for fibroblast activity. Comprehensive assessments encompassing physical characterization, antimicrobial efficacy, in vitro bioactivity, and wound healing potential were conducted on these bilayer dressings. Our findings revealed that the mucus and slime extract loading significantly altered the morphology in terms of nanofiber diameter and average pore size. Snail extracts loaded on a nanofiber layer of bilayer dressings showed slight antimicrobial activity against Staphylococcus epidermidis and Escherichia coli. An in vitro release study of slime extract loaded in the nanofiber layer indicated that both groups 1 and 2 showed a burst release up to 6 h, and a sustained release was observed up to 96 h for group 1, whereas slime extract release from group 2 continued up to 72 h. In vitro bioactivity assays unveiled the favorable impact of mucus and slime extracts on NIH/3T3 fibroblast and HS2 keratinocyte cell attachment, proliferation, and glycosaminoglycan synthesis. Furthermore, our investigations utilizing the in vitro scratch assay showcased the proliferative and migratory effects of mucus and slime extracts on skin cells. Collectively, our results underscore the promising prospects of bioactive snail secretion-loaded chitosan constructs for facilitating skin regeneration and advancing wound healing therapies.

Enhancing the Cytotoxic Effects of Carboplatin and Cisplatin on Liposomes in Oral Cancer Cells with Curcumin

Background: Oral squamous cell carcinoma remains challenging to treat effectively with conventional chemotherapy, leading researchers to explore synergistic combinations to enhance therapeutic outcomes. Combining curcumin with platinum-based drugs, such as cisplatin and carboplatin, has demonstrated potential in enhancing cytotoxic effects. However, limited studies have explored these combinations’ efficacy and sustained release profile in liposomal form specifically for oral cancer. This study investigates the enhanced cytotoxic effects of cisplatin-curcumin and carboplatin-curcumin nanoliposome formulations on CAL 27 oral cancer cells. Methods and Materials: Nanoliposomes encapsulating cisplatin or carboplatin with curcumin were formulated and characterized by particle size, zeta potential, and polydispersity index (PDI) to ensure optimized delivery properties. Particle sizes of the cisplatin and carboplatin nanoliposomes ranged from 175 to 187 nm, with a zeta potential greater than -30 mV, indicating good stability, and PDI values less than 0.48, suggesting uniform particle size distribution. In vitro cytotoxicity was assessed using the MTT assay at 24, 48, and 96 hours across different curcumin concentrations. Results: Cisplatin-curcumin and carboplatin-curcumin nanoliposome formulations demonstrated significantly increased cytotoxicity in CAL 27 cells compared to control groups. Drug release studies indicated a sustained release profile, with approximately 22% of cisplatin and 28% of carboplatin released over 52 hours, which may prolong therapeutic effects by maintaining drug availability within the cancer cells. Conclusion: The findings suggest that cisplatin-curcumin and carboplatin-curcumin nanoliposomal formulations enhance the cytotoxic effects of these chemotherapeutic agents while providing a stable, sustained release profile.

Can Supplementation with the Cow Start Complete Bolus Result in Elevated Blood Calcium Status in a Group of At-Risk Dairy Cows During the First Four Days of Lactation

The prophylactic supplementation of freshly calved multiparous cows with oral calcium supplements (bolus, drink, drench, paste) has increased in popularity in recent years. Oral calcium supplements are generally only effective for 12 hours, yet the high-risk period for hypocalcaemia in freshly calved multiparous cows is 48 hours post-partum. Therefore, a second application 12 hours post-partum is suggested by manufacturers, yet due to labour shortages on dairy farms, it is very common for the second application to not be carried out. The objectives of this study were to ascertain if a the administration of a single dose of the sustained release bolus (Cow Start Complete, Anchor Life Science, Co. Cork, Ireland) given to the cow at calving, could offer the combined benefits of elevated calcium status over the first 48 hours post-partum from a labour efficient single dose given at calving and also to evaluate if this enhanced calcium status could have a positive effect on daily rumination time and milk production yields in the first three months of lactation. The two groups consisted of an un-supplemented control (CON) group and a Cow Start Complete (CSC) group in which cows were given a single bolus dose at the point of calving. The CON group experienced a clinical milk fever (Blood Ca <1.5mmol/L) incidence rate of 13.3% compared to 0% for the CSC group. Cows given the CSC treatment had significantly (P<0.0001) higher total blood calcium levels (2.14 mmol/L) from the point of calving (0h) to 4 days post-partum (96h) compared to CON (1.98mmol/L), with significant increases at 12h (P<0.01), 24h (P<0.001) and 36h (P<0.01) post-partum. Rumination time for CSC cows (471mins/day) was significantly (P<0.05) higher during the first 14 days post-partum when compared to CON (434mins/day) group. Milk production was also significantly (P<0.01) higher for CSC cows (+1.8kg/day) than in CON cows during the first 90 days of lactation. These findings demonstrate that the convenience of giving a single dose of CSC at calving, can be combined with desired outcomes in a range of key benefits in freshly calved multiparous cows.

Coaxial Electrospun Nanofibrous Membranes as Dual-Functional Biomimetic Tendon Sheath for Tendon Repair and Anti-Peritendinous Adhesion.

Tendon injuries often exhibit limited healing capacity, frequently complicated by peritendinous adhesion, posing a substantial challenge in clinical tendon repair. Although present biomaterial-based membranes offer a promising strategy for tendon treatment, their clinical application is hindered by inflammation-induced adhesion. Herein, this study presents a dual-functional biomimetic tendon sheath based on a coaxial electrospun nanofibrous membrane for enhancing tendon repair and simultaneously preventing peritendinous adhesion. This nanofibrous membrane is fabricated using a coaxial electrospinning method, encapsulating celecoxib-loaded polycaprolactone (PCL) within gelatin methacryloyl (GelMA) shell. Both in vitro and in vivo analysis results demonstrated that such coaxial biomimetic tendon sheath enhanced tenogenic differentiation of tendon stem/progenitor cells (TSPCs) due to nanofibrous GelMA shell providing a suitable microenvironment surface. Simultaneously, the sustained release of celecoxib (CEL) from the core is able to significantly decrease the expression of inflammatory cytokines. Notably, in vivo assessments in animal models with patellar tendon defects revealed significant reductions in peritendinous adhesion, leading to further enhancement in tendon repair. These results underscore the potential of the coaxial nanofibrous membrane as a dual-functional biomimetic tendon sheath, offering a promising avenue for the long-term management of tendon injuries.

Honokiol-loaded PLGA-PEG nanoparticles with solubility in water for infusion treatment of solid cancer

This study aimed to investigate honokiol-loaded PLGA-PEG nanoparticles with good stability in water for infusion treatment. The characteristics of this nanoparticle-based delivery system were analyzed in a previous study. Additionally, fourier transform infrared spectroscopy confirmed the successful loading of honokiol into PLGA-PEG nanoparticles, revealing characteristic chemical shifts. In vitro drug release studies demonstrated sustained release over 72 h, with lower release rates compared to free honokiol. Cytotoxicity assays on A549 and 3LL lung cancer cells showed that the IC50 values for the nanoparticles were significantly lower than those for free honokiol, with values of 8.76 ± 1.51 μg/ml and 7.46 ± 0.53 μg/ml for the nanoparticles, compared to 12.03 ± 1.07 μg/ml and 10.51 ± 1.27 μg/ml for free honokiol, respectively. Apoptosis induction in cancer cells was demonstrated, emphasizing the potential therapeutic benefits. In vivo studies using a murine carcinoma model showed higher concentrations of honokiol in tumor tissues and major organs with the nanoparticle formulation. Tumor growth inhibition was significantly greater in the nanoparticle-treated group, achieving an inhibition ratio (IR) of 85.32 %, compared to 65.99 % for free honokiol. Hematological and biochemical analyses and histopathological examination indicated no significant adverse effects. The study suggests that honokiol-loaded PLGA-PEG nanoparticles covered by carboxyl (COOH) groups (Nano-HK), with good solubility in water, enhance the delivery and therapeutic efficacy of honokiol, providing a promising avenue for cancer treatment.

Microneedles Constructed by Swellable Hydrogels Loaded with Celastrol for Efficient Treatment of Skin Infections Induced by Drug-Resistant Bacterial Strains.

The urgent need for new antimicrobial drugs arises from the limited efficacy of traditional antibiotics against emerging drug-resistant strains. Celastrol (CSL) demonstrates an exceptional antibacterial property that remains unaffected by bacterial resistance, but its poor water solubility limits its wide applications. This study uses the hydrophobic inner cavity of mono-(6-diethylenetriamine-6-deoxy)-β-cyclodextrin (mβ-CD) (a derivative of cyclodextrin) to encapsulate CSL, constructing an inclusion complex (CSL@mβ-CD) to enhance the water solubility of CSL. The obtained inclusion complex is further incorporated into a swellable hydrogel microneedle (MN) to obtain CSL@mβ-CD/MN. The fabricated CSL@mβ-CD/MN can enable the sustained release of CSL, achieving effective bacterial eradication at infected sites. In vivo experiments demonstrate that CSL@mβ-CD/MN has a remarkable efficacy in the treatment of methicillin-resistant Staphylococcus aureus-induced subcutaneous abscesses and wound infections. Specifically, CSL@mβ-CD/MN can effectively penetrate the stratum corneum of the skin to realize rapid elimination of the bacteria in wounds. Moreover, CSL@mβ-CD/MN can efficiently scavenge reactive oxygen species, promote M2 polarization of macrophages, and relieve local inflammation at the wound sites. These results reveal that CSL@mβ-CD/MN holds great promise in the clinical treatment of acute skin infections induced by drug-resistant bacteria.

Preparation of composite hydrogel with mechanical stability and temperature response for tea polyphenol release

The method of adding additives at once not only increases costs, but also poses a risk of excessive consumption. Therefore, the slow-release technology was employed for improving the utilization efficiency and edible safety of additives in this work. The poly (N-isopropylacrylamide) (PNIPAM) and polylactic acid (PLA) composite hydrogels with sheath-core structure were fabricated by in-situ spinning method. The mechanical bearing capacity of PNIPAM hydrogel was improved by controlling the structure of PLA electrospun fiber membrane. The results showed that the compression resistance of the samples coated with PLA was increased 931 % at 50 % deformation. In addition, the surface wettability of samples was studied to ensure the stable water permeability. The composite hydrogel was used for the sustained release of tea polyphenol (TP) antioxidant. The release effect of TP at different temperatures, and radical scavenging effect of 2, 2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2-Phenyl-4,4,5,5-tetraMethyliMidazoline-3-oxide-1-oxyl) (PTIO) were investigated. It was found that the release rate for TP could reach to 77.8 % at 30 °C. The radical clearance rates of ABTS and PTIO were 99.2 % and 46.6 %, respectively. This work provides effective ideas for the use of antioxidants in food preservation processes.

Injectable gelatin-pectin hydrogel for dental tissue engineering: Enhanced angiogenesis and antibacterial efficacy for pulpitis therapy

Pulpitis is inflammation of the dental pulp, often caused by bacterial infection from untreated cavities, leading to pain. The main challenge in treatment is eliminating infection while preserving tooth vitality. This study aims to address this challenge by developing a hydrogel for convenient insertion into the root canal system, securely attaching to dentin walls. An injectable hydrogel system is developed by chemically cross-linking natural polysaccharide pectin with gelatin (GPG) through reversible Schiff base reaction. The GPG system was then used to encapsulate and release drugs, such as ciprofloxacin (CIP) for infection prevention and deferoxamine (DFO) for promoting blood vessel proliferation and reducing inflammatory reactions. The GPGs absorbed significant amounts of CIP and DFO, enabling sustained release over a nearly ten-day period. When subcutaneously implanted, the GPGs formed stable gel depots, with only 50 % of the gels degrading after 3 weeks, indicating a sustained biodegradation pattern. Additionally, the GPG system demonstrated excellent antibacterial activity against both gram-negative and gram-positive bacteria. Results from in vitro scratch healing tests and in ovo chorioallantoic membrane chick model tests showed promising biocompatibility and promotion of vascular proliferation by the GPG. This study heralds a novel frontier in endodontic therapeutics, poised to potentially enable dental pulp regeneration.

Lipid nanocarrier-based bigel of Piper betel oil for analgesic and anti-inflammatory applications

Present study reports analgesic and anti-inflammatory potential of Piper betel (L.) leaf oil loaded lipid nanocarrier (BLNs)-embedded bigel. BLNs were developed by solvent evaporation technique and were characterised by FESEM, Cryo-TEM, mean diameter, zeta potential, loading efficiency, etc. BLNs embedded bigel (BLNs-G) was evaluated for analgesic and anti-inflammatory efficacy in rat model. Data showed spherical BLNs with intact lamellarity, 138.2 ± 1.08 nm mean diameter, 0.182 PDI, −46.6 ± 0.61 mV zeta potential, 76.2 ± 2.1% (w/w) loading efficiency and a sustained release in vitro. BLNs-G was homogenous with satisfied viscosity (40 734 ± 1.7 cps), spreadability (8.3 ± 1.5 g.cm sec−1), extrudability (91.33 ± 1.3% w/w) along with a sustained permeation ex vivo. Significant analgesic and anti-inflammatory action were depicted by BLNs-G (1% w/w) in rat model (p ˂ 0.05) within 30 minutes post topical application. In silico docking study revealed high affinity of major phytoactive components with key analgesic/inflammatory mediators. Further pre-clinical investigations are warranted for futuristic clinical application of BLNs-G.

Macroporous coating of silver-doped hydroxyapatite/silica nanocomposite on dental implants by EDTA intermediate to improve osteogenesis, antibacterial, and corrosion behavior.

Coating a titanium (Ti) implant with hydroxyapatite (HA) increases its bioactivity and biocompatibility. However, implant-related infections and biological corrosion have restricted the success of implant. To address these issues, a modified hydroxyapatite nanocomposite (HA/silica-EDTA-AgNPs nanocomposite) was proposed to take advantage of the sustained release of silver nanoparticles (AgNPs) and silicate ions through the silica-EDTA chelating network. As a result, a uniform layer of nanocomposite, compared to HA as the gold standard, was formed on Ti implants without fracture and with a high level of adhesion, using Plasma Electrolytic Oxidation (PEO). Bioactivity assessment evidenced a shift in the surface phase of the Ti implant to generation of beta-tricalcium phosphate (β-TCP), a more bioresorbable material than HA. Metabolic activity assessments using human dental pulp stem cells revealed that Ti surfaces modified by the new nanocomposite are superior to bare and HA-modified Ti surfaces for cell attachment and proliferation in vitro. In addition, it successfully inhibited bacterial growth and induced osteogenesis on the implant surface. Finally, potentiodynamic polarization behavior of Ti implants before and after coating confirmed that a thick oxide interface layer on the modified Ti surface acts as an electrical barrier and protects the substrate layer from corrosion. Therefore, the HA/silica-EDTA/Ag nanocomposite presented here, compared to HA, can better coat Ti dental implants due to its good biocompatibility and osteoinductive activity, along with improved biological stability.

Self-Healing COCu-Tac Hydrogel Enhances iNSCs Transplantation for Spinal Cord Injury by Promoting Mitophagy via the FKBP52/AKT Pathway.

In the realm of neural regeneration post-spinal cord injury, hydrogel scaffolds carrying induced neural stem cells (iNSCs) have demonstrated significant potential. However, challenges such as graft rejection and dysfunction caused by mitochondrial damage persist after transplantation, presenting formidable barriers. Tacrolimus, known for its dual role as an immunosuppressant and promoter of neural regeneration, holds the potential for enhancing iNSC transplantation. However, systemic administration of tacrolimus often comes with severe side effects. This study pioneers the development of a self-healing hydrogel with sustained-release tacrolimus (COCu-Tac), tailored specifically for iNSC transplantation after spinal cord injury. This research reveals that the sustained release of tacrolimus enhances axonal growth and improves mitochondrial quality control in iNSCs and neurons. Further analysis shows that tacrolimus targets FKBP52 rather than FKBP51, enhancing mitophagy via the FKBP52/AKT pathway. This advanced system demonstrates significant efficacy in promoting neural regeneration and restoring motor function following spinal cord injury.

Characteristics and Preparation of Solid Lipid Nanoparticles and Nanostructured Lipid Carriers

Solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) have emerged as promising systems for delivering active ingredients. They are derived from physiological, biodegradable, and biocompatible lipids, offering benefits such as sustained release promotion and increased drug stability. These systems are apt for the efficient transport of therapeutic drugs to target tissues while also providing advantages such as facilitating large-scale industrial production, bioavailability, and protection against degradation. The preparation of these nanoparticles involves utilizing diverse types of lipids, surfactants, and solvents. Common lipid varieties encompass triglycerides, steroids, and fatty acids, selected based on the active ingredient for stabilization within the lipid matrix. Preparation methods can be categorized into high-energy and low-energy approaches. This study investigated the differences between the main methodologies used, comparing SLN and NLC systems, and scrutinizing their respective advantages, disadvantages, and applications.

Formulation and evaluation of cetuximab functionalized phospholipid modified nanocrystals of paclitaxel for non-small cell lung cancer therapy

Present work aims to prepare Soluplus stabilized, phospholipid-modified, and cetuximab-conjugated paclitaxel nanocrystals (NCs) as stable nanocarriers for targeted drug delivery. The NCs, prepared using concurrent antisolvent precipitation cum cold crystallization method followed by probe sonication, were found to be monodispersed particles with sub-200 nm size. The microscopic analysis uncovered rod and spherical anisotropy for Soluplus stabilized (PTX-NCs) and phospholipid modified (Lipid/PTX-NCs) nanocrystals, respectively. The formation of amorphous PTX-NCs and subsequent coating with phospholipid was confirmed by solid-state characterization using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform Infrared Spectroscopy (FTIR). X-ray Photoelectron Spectroscopic (XPS) analysis, indicated successful conjugation of cetuximab on NCs surface. Lipid coating rendered a sustained drug release behaviour to NCs at physiological pH. In vitro cell line studies confirmed the improved cellular internalization and better apoptosis induction capability of NCs, consequently resulting in enhanced efficacy of PTX against A549 cancer cells. Moreover, in Benzo[a] pyrene-induced lung cancer model, Cmab/Lipid/PTX-NCs showed significant improvement in tumor inhibition potential in comparison to pure PTX. The prepared Cmab/Lipid/PTX-NCs also exhibited improved pharmacokinetics performance, avoided off-target distribution, and showed a reduction in systemic toxicity. The findings of this study indicate the promising potential of the prepared cetuximab-functionalized phospholipid-coated paclitaxel nanocrystals in lung cancer therapy.

Exploring the potential of a pH-sensitive hydrogel sponge: interpenetrating network of tragacanth and pectin for controlled delivery of levosulpiride.

The development of drug delivery systems that allow precise control over drug release pattern has fetched significant attention in the pharmaceutical field. This research work investigates the potential of a pH-sensitive interpenetrating network (IPN) composed of tragacanth and pectin as a carrier for the controlled release of levosulpiride. To enhance the solubility of poorly soluble drug levosulpiride, inclusion complexes were formed with beta cyclodextrin (βCD). The IPN was prepared by cross-linking tragacanth with pectin by adopting a green chemistry approach. The resulting cross-linked polymeric network was subjected to repetitive freeze-drying cycles for preparation of spongy mass. The physicochemical properties of the resultant product were thoroughly characterized using a range of analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermal analyses (DSC/TGA), and X-ray diffraction (XRD). The physical parameters like sol-gel fraction (%), drug loading (%), swelling behavior, electrolyte responsiveness, and in vitro drug release profile of the developed sponge were systematically evaluated under varying pH conditions. Results of FTIR demonstrated the formation of cross-linked network, ruling out drug-excipient interaction. SEM analysis unveiled porous and rough geometry. Thermal analyses proved the hydrogel network thermally stable whereas, PXRD demonstrated the overall amorphous nature of the hydrogel sponge. The outcomes of physical parameters demonstrated an incremental trend in gel fraction from 63 to 85% on raising the molar concentration of cross-linker from TP1 to TP3. However, increasing tragacanth content escalation in gel fraction from 75 to 79% was noticed. While gel fraction was augmented from 79 to 83% with increasing pectin contents. The maximum drug loading formulation TP3 was computed to be 89%. Hydrogel sponges also demonstrated electrolyte responsiveness. The release profile indicated a pH-responsive behavior, with sustained release up to 10h observed in a buffer solution of pH 6.8 and 7.4. In an acidic medium, a minor amount of drug was released during 10h dissolution. Drug release kinetics was observed to be in zero order. The findings of this study highlight the promising potential of the tragacanth/pectin hydrogel sponge as a pH-sensitive dais for the controlled delivery of levosulpiride, emphasizing its potential application in personalized drug therapy and the treatment of gastrointestinal disorders.

Engineered cell membrane-cloaked metal-organic framework nanocrystals for intracellular cargo delivery

This investigation demonstrates the development and functionality of cell membrane-cloaked UiO-67 nanosized metal–organic frameworks (NMOFs), which are engineered for precise intracellular delivery of encapsulated cargoes. Utilizing the robust and porous nature of UiO-67, we enveloped these NMOFs with fusogenic cell membrane-derived nanovesicles (FCSMs) sourced from adenocarcinomic human alveolar basal epithelial (A549) cells. This biomimetic coating enhances biocompatibility and leverages the homotypic targeting capabilities of the cell-derived coatings, facilitating direct cytoplasmic delivery and avoiding endolysosomal entrapment. Our nanoplatform exhibited high efficiency in loading and releasing two model cargoes: cresyl violet (CV), a staining agent, and carboplatin (CbPt), a chemotherapeutic agent. This approach demonstrated substantial potential in drug delivery in both 2D cell cultures and 3D spheroids. This study underscores the enhanced cellular uptake facilitated by the engineered biomimetic shell and highlights the system’s capacity for sustained release, offering a promising strategy for targeted drug delivery.

Exosome-Integrated Hydrogels for Bone Tissue Engineering

Exosome-integrated hydrogels represent a promising frontier in bone tissue engineering, leveraging the unique biological properties of exosomes to enhance the regenerative capabilities of hydrogels. Exosomes, as naturally occurring extracellular vesicles, carry a diverse array of bioactive molecules that play critical roles in intercellular communication and tissue regeneration. When combined with hydrogels, these exosomes can be spatiotemporally delivered to target sites, offering a controlled and sustained release of therapeutic agents. This review aims to provide a comprehensive overview of the recent advancements in the development, engineering, and application of exosome-integrated hydrogels for bone tissue engineering, highlighting their potential to overcome current challenges in tissue regeneration. Furthermore, the review explores the mechanistic pathways by which exosomes embedded within hydrogels facilitate bone repair, encompassing the regulation of inflammatory pathways, enhancement of angiogenic processes, and induction of osteogenic differentiation. Finally, the review addresses the existing challenges, such as scalability, reproducibility, and regulatory considerations, while also suggesting future directions for research in this rapidly evolving field. Thus, we hope this review contributes to advancing the development of next-generation biomaterials that synergistically integrate exosome and hydrogel technologies, thereby enhancing the efficacy of bone tissue regeneration.

3D-printing of dipyridamole/thermoplastic polyurethane materials for bone regeneration.

Tissue engineering combines biology and engineering to develop constructs for repairing or replacing damaged tissues. Over the last few years, this field has seen significant advancements, particularly in bone tissue engineering. 3D printing has revolutionised this field, allowing the fabrication of patient- or defect-specific scaffolds to enhance bone regeneration, thus providing a personalised approach that offers unique control over the shape, size, and structure of 3D-printed constructs. Accordingly, thermoplastic polyurethane (TPU)-based 3D-printed scaffolds loaded with dipyridamole (DIP) were manufactured to evaluate their in vitro osteogenic capacity. The fabricated DIP-loaded TPU-based scaffolds were fully characterised, and their physical and mechanical properties analysed. Moreover, the DIP release profile, the biocompatibility of scaffolds with murine calvaria-derived pre-osteoblastic cells, and the intracellular alkaline phosphatase (ALP) assay to verify osteogenic ability were evaluated. The results suggested that these materials offered an attractive option for preparing bone scaffolds due to their mechanical properties. Indeed, the addition of DIP in concentrations up to 10% did not influence the compression modulus. Moreover, DIP-loaded scaffolds containing the highest DIP cargo (10% w/w) were able to provide sustained drug release for up to 30 days. Furthermore, cell viability, proliferation, and osteogenesis of MC3T3-E1 cells were significantly increased with the highest DIP cargo (10% w/w) compared to the control samples. These promising results suggest that DIP-loaded TPU-based scaffolds may enhance bone regeneration. Combined with the flexibility of 3D printing, this approach has the potential to enable the creation of customized scaffolds tailored to patients' needs at the point of care in the future.

Development of Solidified Self-microemulsifying Delivery Systems Containing Tacrolimus for Enhanced Dissolution and Pharmacokinetic Profile.

The use of tacrolimus (FK506) as an immunosuppressant is limited by its low aqueous solubility and bioavailability. The self-microemulsifying drug delivery system (SMEDDS) has successfully improved the solubility of FK506 in our previous study. This study focused on the solidification of liquid SMEDDS to capture the benefits of both liquid SMEDDS and solid dosage forms. Among several porous silica adsorbents evaluated, Aeroperl® 300 Pharma showed the best performance in terms of droplet size, in vitro dissolution, adsorbent-drug compatibility, and tabletabilities. And precoating the adsorbent with polyvinylpyrrolidone K30 resulted in complete drug release. Hydroxypropyl methylcellulose based matrix tablet was developed to achieve a sustained release of FK506. Differential scanning calorimetry and X-ray powder diffraction indicated that FK506 was present in a molecular or amorphous state in the solidified SMEDDS and tablets. In vivo pharmacokinetic studies showed that the self-prepared tablet had improved bioavailability (179.02%) compared to the marketed product Advagraf®. This study provided a promising candidate with improved dissolution and bioavailability for FK506 and a prospective platform for SMEDDS development.

Magnesium-Based Composite Calcium Phosphate Cement Promotes Osteogenesis and Angiogenesis for Minipig Vertebral Defect Regeneration.

Calcium phosphate cement (CPC) is an injectable bone cement with excellent biocompatibility, widely used for filling bone defects of various shapes. However, its slow degradation, insufficient mechanical strength, and poor osteoinductivity limit its further clinical applications. In this study, we developed a novel composite magnesium-based calcium phosphate cement by integrating magnesium microspheres into PLGA fibers obtained through wet spinning and incorporating these fibers into CPC. The inclusion of magnesium-based PLGA fibers enhanced the compressive strength and degradation rate of CPC, with the degradation rate of the magnesium microspheres being controllable to allow for the sustained release of magnesium ions. In vitro experiments showed that magnesium-based CPC enhanced the proliferation and migration of MC3T3-E1 and HUVECs. Additionally, the magnesium-based composite CPC not only enhanced osteogenic differentiation of MC3T3-E1 cells but also promoted angiogenesis in HUVECs. In vivo experiments using a vertebral bone defect model in Bama miniature pigs showed that the magnesium-based composite CPC significantly increased new bone formation. Additionally, compared to the CPC group, this composite exhibited significantly higher levels of osteogenic and angiogenic markers, with no inflammation or necrosis observed in the heart, liver, or kidneys, indicating good biocompatibility. These results suggest that magnesium-based composite CPC, with its superior compressive strength, biodegradability, and ability to promote vascularized bone regeneration, holds promise as a minimally invasive injectable material for bone regeneration.