Injectable Delivery System Research Articles

Optimizing glioblastoma treatment: A systematic review and meta-analysis of local injection and systemic drug delivery system in murine models

Optimizing glioblastoma treatment: A systematic review and meta-analysis of local injection and systemic drug delivery system in murine models

Injectable Glucose-Releasing Microgels Enhance the Survival and Therapeutic Potential of Transplanted MSCs Under Ischemic Conditions.

Mesenchymal stem cell (MSC)-based therapies show potential to treat ischemic diseases owing to their versatile functions. However, sustaining MSC viability and therapeutic efficacy in ischemic tissues postengraftment remains a significant challenge. This is because, although MSCs are metabolically flexible, they fail to adapt to hypoxic conditions in the absence of glucose, leading to cell death. To overcome these issues, it is aimed to establish an injectable glucose delivery system using starch and amyloglucosidase embedded in alginate microgels. Here, starch/amyloglucosidase (S/A) microgels are engineered to continuously release glucose for seven days via enzymatic hydrolysis, thereby supporting MSC functions under ischemic conditions. In vitro tests under oxygen/glucose-deprived conditions revealed that the S/A microgels not only maintained the viability and intracellular energy but also enhanced the pro-angiogenic and immunomodulatory functions of MSCs. In vivo data further confirmed the pro-survival and pro-angiogenic effects of S/A microgels on MSCs following subcutaneous engraftment in mice. Overall, the developed S/A microgel significantly enhanced the survival and therapeutic potential of MSCs via sustained glucose delivery, highlighting its potential use in advancing MSC-based therapies for ischemic conditions.

Fabrication of a novel macrophage-targeted biomimetic delivery composite hydrogel with multiple-sensitive properties for tri-modal combination therapy of rheumatoid arthritis

In this study, a porous polydopamine (PDA) nanoparticle-decorated β-glucan microcapsules (GMs) nanoplatform (PDA/GMs) were developed with macrophage-targeted biomimetic features and a carriers-within-carriers structure. Indocyanine green (ICG) and catalase (CAT) were subsequently co-encapsulated within the PDA/GMs to create a multifunctional nanotherapeutic agent, termed CIPGs. Furthermore, CIPGs and sinomenine (SIN) were co-loaded within a thermo-sensitive hydrogel to design an injectable delivery system, termed CIPG/SH, with potential for multi-modal therapy of rheumatoid arthritis (RA). Photothermal studies indicated that the CIPGs hold excellent photothermal conversion ability and thermal stability, as they combined the photothermal performance of both PDA and ICG. Meanwhile, the CIPGs displayed favorable oxygen self-supplying and photodynamic performance. The CIPGs showed near-infrared (NIR)-induced phototoxicity, effectively inhibiting macrophage proliferation and displaying remarkable antibacterial activity. In vitro drug release from the prepared CIPG/SH showed a controlled release pattern. Animal experiments conducted on an RA mice model confirmed that the formulated CIPG/SH exhibited significant therapeutic effects. By integrating the biological advantages, photothermal/photodynamic performance of the CIPGs, and controlled drug release performance of the thermo-sensitive hydrogels in a single delivery system, the prepared injectable CIPG/SH represents a novel versatile delivery system with great potential for multi-modal combination targeting therapy in RA.

Sodium ampicillin release from biocompatible hydrogel with enhanced antibacterial characteristics

The goal of this research is to develop an intelligent carrier that can control the release of medications in response to particular triggers. A novel carrier was created by combining different amounts of chitosan and polyvinylalcohal along with specific amount of cinnamon extract to enhance the antibacterial response of the prepared hydrogels. A non-hazardous crosslinker 3-Aminopropyl(diethoxy)methylsilane (3-APDEMS) was used to study its effect on the physical and chemical properties of the produced injectable hydrogels as well as the controlled drug release behaviour. The hydrogels swelling behaviour was assessed in a range of solvent environments and the results indicated that the swelling ratio decreased as the concentration of 3-APDEMS rose. The hydrogels showed the most swelling at acidic pH values and the least swelling at basic and neutral pH values. They are appropriate for use in injectable controlled medication delivery systems due to their unique pH-sensitive characteristic at pH 7.To evaluate its release profile in this particular setting, ampicillin sodium salt was effectively added to the best hydrogel formulation (which contained 100 μL cinnamon extract and 150 μL 3-APDEMS).The results showed that the release of ampicillin sodium (AMS) was regulated in PBS (7.4), reached up to 98.236 % release over 90 min.The utilisation of these hydrogels as a cutting-edge material for physiological pH-controlled injectable medication delivery and other biological applications is supported by these results.

Design and evaluation of curcumin-loaded poloxamer hydrogels as injectable depot formulations

Poloxamer hydrogels are of interest as injectable depot delivery systems. However, their use for delivering hydrophobic drugs, such as curcumin, is limited due to poor loading capacity. Here, we evaluated the influence of incorporating hydrophobic medium chain triglycerides (MCT) or amphiphilic polyethylene glycol 400 (PEG400) on the physicochemical properties, drug loading, and in vitro compatibility of a curcumin-loaded poloxamer hydrogel.Poloxamer 407 and 188 hydrogel formulations (16:6 w/w) were prepared and MCT and PEG400 (saturated with curcumin) were added to these systems, either alone or in combination, up to a 10 % w/w additive solvent load. Formulation viscoelasticity, gelation behaviour, injectability, morphology and release profiles were assessed. The cytocompatibility of the formulations was also assessed on dermal fibroblasts (HDFn).Both additives increased curcumin loading into the formulation. Addition of MCT to the hydrogel significantly increased its gelation speed, while PEG400 had a less profound impact. Both additive solvents increased the force required to inject the formulation. PEG400 containing systems were single phase, whereas MCT addition created emulsion systems. All formulations released ∼20–30 % of their loaded curcumin in a sustained fashion over 24 h. The modified hydrogel systems showed good biocompatibility on cells when administering up to ∼100–150 µM curcumin into the culture.This study addresses a key limitation in loading hydrophobic drugs into hydrogels and provides a strategy to enhance drug loading and performance of hydrogels by integrating additives such as MCT and PEG400 into the systems.

Adipose-derived mesenchymal stem cell-incorporated PLLA porous microspheres for cartilage regeneration.

In facial plastic surgery, patients with nasal deformity are often treated by rib cartilage transplantation. In recent years, cartilage tissue engineering has developed as an alternative to complex surgery for patients with minor nasal defects via injection of nasal filler material. In this study, we prepared an injectable nasal filler material containing poly-L-lactic acid (PLLA) porous microspheres (PMs), hyaluronic acid (HA) and adipose-derived mesenchymal stem cells (ADMSCs). We seeded ADMSCs into as-prepared PLLA PMs using our newly invented centrifugation perfusion technique. Then, HA was mixed with ADMSC-incorporated PLLA PMs to form a hydrophilic and injectable cell delivery system (ADMSC-incorporated PMH). We evaluated the biocompatibility of PMH invitro and invivo. PMH has good injectability and provides a favorable environment for the proliferation and chondrogenic differentiation of ADMSCs. Invivo experiments, we observed that PMH has good biocompatibility and cartilage regeneration ability. In this study, a injectable cell delivery system was successfully constructed. We believe that PMH has potential application in cartilage tissue engineering, especially in nasal cartilage regeneration.

Quercetin-Loaded Bioglass Injectable Hydrogel Promotes m6A Alteration of Per1 to Alleviate Oxidative Stress for Periodontal Bone Defects.

Periodontal disease ranks third among noncommunicable illnesses, behind cancer and cardiovascular disease, and is closely related to the occurrence and progression of various systemic diseases. However, elucidating the processes of periodontal disease and promoting periodontal bone regeneration remains a challenge. Here, quercetin is demonstrated to reduce the oxidative stress state of orofacial mesenchymal stem cells (OMSCs) in vitro and to affect the osteogenic growth of OMSCs through molecular mechanisms that mediate the m6A change in Per1. Nevertheless, the limited therapeutic efficacy of systemic medication and the limitations of local medication resulting from the small, moist, and highly dynamic periodontal environment make it challenging to treat periodontal tissues with medication. Herein, a biosafe injectable hydrogel drug-controlled delivery system is constructed as a bone-enhancing factory and loaded with quercetin to treat oxidative stress injury in periodontal tissues. This drug-carrying system made up of nanoscale bioglass microspheres and a light-cured injectable hydrogel, allows effective drug particle loading and cementation in the dynamic and moist periodontal environment. Furthermore, the system demonstrates the ability to stimulate OMSCs osteogenic differentiation in a Per1-dependent manner, which ultimately promotes periodontal bone repair, suggesting that this system has potential for clinical periodontal therapy.

Synthesis and thermally-induced gelation of interpenetrating nanogels

Thermally-induced in-situ gelation of polymers and nanogels is of significant importance for injectable non-invasive tissue engineering and delivery systems of drug delivery system. In this study, we for the first time demonstrated that the interpenetrating (IPN) nanogel with two networks of poly (N-isopropylacrylamide) (PNIPAM) and poly (N-Acryloyl-l-phenylalanine) (PAphe) underwent a reversible temperature-triggered sol-gel transition and formed a structural color gel above the phase transition temperature (Tp). Dynamic light scattering (DLS) studies confirmed that the Tp of IPN nanogels are the same as that of PNIPAM, independent of Aphe content of the IPN nanogels at pH of 6.5 ∼ 7.4. The rheological and optical properties of IPN nanogels during sol-gel transition were studied by rheometer and optical fiber spectroscopy. The results showed that the gelation time of the hydrogel photonic crystals assembled by IPN nanogel was affected by temperature, PAphe composition, concentration, and sequence of interpenetration. As the temperature rose above the Tp, the Bragg reflection peak of IPN nanogels exhibited blue shift due to the shrinkage of IPN nanogels. In addition, these colored IPN nanogels demonstrated good injectability and had no obvious cytotoxicity. These IPN nanogels will open an avenue to the preparation and thermally-induced in-situ gelation of novel NIPAM-based nanogel system.

Development of injectable upconversion nanoparticle-conjugated doxorubicin theranostics electrospun nanostructure for targeted photochemotherapy in breast cancer.

Nanotheranostic-based photochemotherapies with targeted drug delivery have considerably surfaced in cancer therapy. In the presented work, polyethyleneimine-coated upconversion nanoparticles were engineered to conjugate covalently with doxorubicin. Upconversion nanoparticles (UCNP)-Doxorubicin (DOX)/synthesized epidermal growth factor receptor-targeting peptide blended with polymer composite was electrospun and formulated as the injectable dosage form. The size of the UCNP and the nanofiber diameter were assessed as 26.75 ± 1.54 and 162 ± 2.82 nm, respectively. The optimized ratio of dopants resulted in UCNP photoluminescence with maximum emission intensity at around 800 nm upon 980 nm excitation wavelength. The paramagnetic nature of UCNPs and amide conjugation with the drug was confirmed analytically. The loading capacity of UCNP for doxorubicin was determined to be 54.56%, while nanofibers exhibited 98.74% capacity to encapsulate UCNP-DOX. The release profile of UCNP-DOX from nanofiber formulation ranged from sustained to controlled, with relative enhancement in acidic conditions. The nanofiber demonstrated good mechanical strength, robust swelling, and degradation rate. Biocompatibility tests showed more than 90% cell viability on L929 and NIH/3T3 cell lines with UCNP-DOX@NF/pep nanoformulation. The IC50 values of 2.15 ± 0.54, 2.87 ± 0.67, and 3.42 ± 0.45 μg/mL on MDA-MB-231, 4T1, and MCF-7 cancer cell line, respectively, with a significant cellular uptake, has been reported. The UCNP protruded a ≈62.7°C temperature rise within 5 min of 980 nm laser irradiation and a power density of 0.5 W cm-2. The nanoformulation induced reactive oxygen species of 65.67% ± 3.21% and apoptosis by arresting the cell cycle sub-G1 phase. The evaluation conveys the effectiveness of the developed injectable theranostic delivery system in cancer therapy.

Injectable Hydrogel Delivery System with High Drug Loading for Prolonging Local Anesthesia.

Peripheral nerve block is performed for precise pain control and lesser side effects after surgery by reducing opioid consumption. Injectable hydrogel delivery systems with high biosafety and moisture content have good clinical application prospects for local anesthetic delivery. However, how to achieve high drug loading and long-term controlled release of water-soluble narcotic drugs remains a big challenge. In this study, heterogeneous microspheres and an injectable gel-matrix composite drug delivery system are designed in two steps. First, heterogeneous hydrogel microspheres loaded with ropivacaine (HMS-ROP) are prepared using a microfluidic chip and in situ alkalization. An injectable self-healing hydrogel matrix (Gel) is then prepared from modified carboxymethylcellulose (CMC-ADH) and oxidized hyaluronic acid (OHA). A local anesthetic delivery system, Gel/HMS-ROP/dexmedetomidine (DEX), with long-term retention and drug release in vivo is prepared by combining HMS-ROP and Gel/DEX. The drug loading of HMS-ROP reached 41.1%, with a drug release time of over 160h in vitro, and sensory and motor blockade times in vivo of 48 and 36h, respectively. In summary, the sequential release and synergistic analgesic effects of the two anesthetics are realized using core-shell microspheres, DEX, and an injectable gel, providing a promising strategy for long-acting postoperative pain management.

Intramyocardial delivery of injectable hydrogel with arctigenin alleviated myocardial ischemia-reperfusion injury in rats.

Arctigenin belongs to a major bioactive component of Fructus arctii and has been found with cardioprotective effects on rats with ischemia-reperfusion (I/R) injury. The application of arctigenin is limited due to poor water solubility and low bioavailability. Hydrogel drug delivery systems can improve the efficacy and safety of drugs, increase drug utilization, and reduce side effects. We hypothesized that hydrogels containing arctigenin would facilitate the effect of arctigenin and alleviate I/R injury in the rat heart. Presently, adult Sprague-Dawley (SD) rats were subjected to 1h of I/R injury, then hydrogels comprising arctigenin were implanted into the myocardium of rats. Triphenyl tetrazolium chloride staining, hematoxylin-eosin staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining and Western blot were performed for evaluating the infarct size, histopathological, and vital protein alterations of hearts. It was discovered that the hydrogel combined with arctigenin abated apoptosis and reduced infarct size. In addition, the results of echocardiography and Masson staining suggested that the hydrogel with arctigenin improved cardiac function, restrained myocardial fibrosis, and activated AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1). Collectively, the injectable hydrogel delivery system enhances the effect of arctigenin, which may play a protective role in I/R injury by activating AMPK and SIRT1.

Injectable drug-loaded thermosensitive hydrogel delivery system for protecting retina ganglion cells in traumatic optic neuropathy.

Currently, generalized therapy for traumatic optic neuropathy (TON) is lacking. Various strategies have been developed to protect and regenerate retinal ganglion cells (RGCs) after TON. Intravitreal injection of supplements has been approved as a promising approach, although serious concerns, such as low delivery efficacy and pain due to frequent injections, remain. In this study, we tested an injectable thermosensitive hydrogel drug delivery system engineered to deliver ciliary neurotrophic factor (CNTF) and triamcinolone acetonide (TA). The results of rheological studies showed that the prepared drug-loaded hydrogel possessed a suitable mechanical modulus of ∼300 Pa, consistent with that of vitreum. The hydrogel exhibited thermosensitive with sustained drug release performance. In vitro co-culture of the CNTF-loaded hydrogel system with primary RGCs also induced significant axon regeneration, with 38.5% increase in neurite length, indicating the regenerative response of the thermosensitive hydrogel drug delivery system. A Sprague-Dawley rat optic nerve crush model was constructed and applied to determine the neuroprotective and regenerative capacities of the system. The results demonstrated that a single intravitreal injection of the drug-loaded hydrogel (PLGA-PEG-PLGA + TA or PLGA-PEG-PLGA + CNTF) significantly increased RGC survival at both 14 and 28 days. The RGC survival rate was 31.05 ± 1.41% for the drug-loaded hydrogel system (the control group was 16.79 ± 1.50%) at Day 28. These findings suggest that the injectable drug-loaded thermosensitive hydrogel delivery system is a promising therapeutic tool for treating optic nerve degeneration.

An injectable and adaptable hydrogen sulfide delivery system for modulating neuroregenerative microenvironment.

Peripheral nerve regeneration is a complex physiological process. Single-function nerve scaffolds often struggle to quickly adapt to the imbalanced regenerative microenvironment, leading to slow nerve regeneration and limited functional recovery. In this study, we demonstrate a "pleiotropic gas transmitter" strategy based on endogenous reactive oxygen species (ROS), which trigger the on-demand H2S release at the defect area for transected peripheral nerve injury (PNI) repair through concurrent neuroregeneration and neuroprotection processing. This H2S delivery system consists of an H2S donor (peroxyTCM) encapsulated in a ROS-responsive polymer (mPEG-PMet) and loaded into a temperature-sensitive poly (amino acid) hydrogel (mPEG-PA-PP). This multi-effect combination strategy greatly promotes the regeneration of PNI, attributed to the physiological effects of H2S. These effects include the inhibition of inflammation and oxidative stress, protection of nerve cells, promotion of angiogenesis, and the restoration of normal mitochondrial function. The adaptive release of pleiotropic messengers to modulate the tissue regeneration microenvironment offers promising peripheral nerve repair and tissue engineering opportunities.

Injectable nanogel systems for brain drug delivery

<img src=” https://s3.amazonaws.com/production.scholastica/article/88217/large/prnano_912023ga.jpg?1695507286”> The central nervous system (CNS) controls many critical functions, such as intelligence, emotion, sense, and memory, and modulates many other functions of the entire human body. Diseases affecting the CNS are challenging to treat because of the CNS’s sensitive functional and structural features and limited accessibility. The brain is secured from the systemic circulation by a unique biological fence, the blood-brain barrier (BBB), that limits molecular exchange between the peripheral and CNS systems. Most drugs used for treating CNS diseases fail to reach the brain in effective therapeutic concentrations due to the presence of BBB. During the last decade, specifically engineered drug delivery systems (DDS) have offered the opportunity to overcome systemic barriers in brain drug delivery. However, even with the best-engineered nano-carriers, delivering sufficient drug doses into the brain through systemic circulation remains challenging. Here, we review various systems for ‘direct’ drug delivery to the brain using im-plantable or injectable intracranial nano-drug delivery systems (nDDS), which can ensure 100% release of drug to the brain in a sustained or controlled fashion for prolonged periods, bypassing the BBB, thereby radically improving the therapeutic efficacy while minimizing systemic toxicity. Brain injectable nanogels or nanoparticle systems can be considered superior compared to other local drug-delivery systems because they possess better diffusivity of drugs. The nanogels can be injected through minimally invasive procedures, precisely delivering drugs to specific target sites. This review covers a detailed discussion about locally injectable DDS and various nanogel-based drugs, oligonucleotide, and theragnostic delivery systems used for treating brain malignancies, infections, and neurodegenerative diseases.

Enhanced growth and differentiation of neural stem cells on alginate/collagen/reduced graphene oxide composite hydrogel incorporated with lithium chloride.

Cell transplantation with hydrogel-based carriers is one of the advanced therapeutics for challenging diseases, such as spinal cord injury. Electrically conductive hydrogel has received much attention for its effect on nerve outgrowth and differentiation. Besides, a load of neuroprotective substances, such as lithium chloride can promote the differentiation properties of the hydrogel. In this study, alginate/collagen/reduced graphene oxide hydrogel loaded with lithium chloride (AL/CO/rGO Li+) was prepared as an injectable cell delivery system for neural tissue regeneration. After determining the lithium-ion release profile, an MTT assay was performed to check neural viability. In the next step, real-time PCR was performed to evaluate the expression of cell adhesion and neurogenic markers. Our results showed that the combination of collagen fibers and rGO with alginates increased cell viability and the gene expression of collagen-binding receptor subunits such as integrin α1, and β1. Further, rGO contributed to the controlled release of lithium-ion hydrogel in terms of its plenty of negatively charged functional groups. The continuous culture of NSCs on AL/CO/rGO Li+ hydrogel increased neurogenic genes' expressions of nestin (5.9 fold), NF200 (36.8 fold), and synaptophysin (13.2 fold), as well as protein expression of NF200 and synaptophysin after about 14 days. The simultaneous ability of electrical conduction and lithium-ion release of AL/CO/rGO Li+ hydrogel could provide a favorable microenvironment for NSCs by improving their survival, maintaining cell morphology, and expressing the neural marker. It may be potentially used as a therapeutic approach for stem cell transplantation in a spinal cord injury.

Evaluation the injectability of injectable microparticle delivery systems on the basis of injection force and discharged rate

BackgroundSubcutaneous injection of biopharmaceutical agents or microparticles is challenging due to issues with low injection efficiency and high residual amounts. ObjectiveThis study aimed to determine the important factors affecting the injectability of microparticle delivery systems, establish a suitable injection system with lower injection force and higher discharge rate, and eventually develop a reliable injectability evaluation system for injectable microparticle delivery systems in vitro and in vivo. MethodsThe effects of various parameters, including particle size, injection speed, concentration of microspheres suspension, vehicle viscosity, needle length and gauge were evaluated by measuring the injection force and discharge rate. The characteristics of microparticles and rheological measurement of the suspension systems were studied. A design of experiment approach was utilized to evaluate the interaction between the microsphere suspension, vehicle viscosity and needle gauges. Both in vitro sieve tests and in vivo tests in rats were conducted to evaluate injectability. ResultsThe in vitro test results showed that the vehicle viscosity and injection speed have varying effects on discharge rate and injection force, respectively. Particle size and needle gauge have substantial influence on injectability, larger particle size and smaller needle gauges resulting in poor injectability, while the needle gauge was found to have the greatest influence on injectability. Levonorgestrel (LNG) microsphere and glass bead were relatively uniform spherical, the glass bead had extremely smooth surface; while mesoporous silica had irregular shape. The settling rate of glass bead was the fastest, which was about 18 times faster than the LNG microsphere. The CMC-Na had a poor interaction with the LNG microspheres, glass bead and mesoporous silica and showed basically Newtonian behavior in the shear rate range of 0.1 s−1–100 s−1. When shear rate increased to more than 100 s−1, no obvious shear thinning behavior was observed. CMC-Na formed a nodule structure with whether LNG microspheres or the glass beads, which were much lower than that with the mesoporous silica in static state, among which the glass beads were the weakest. The viscosity of the suspension increased with the rising of the volume fraction of particles. Fundamentals of hydrodynamics in capillaries were referenced, such as Navier-Stokes Law equation, Krieger-Dougherty (K-D) equation, Hagen-Poiseuille equation. The best results achieved was using a suspension concentration of 120–240 mg /mL and a viscosity of 60 cP at 20 °C with 23-gauge needles. The optimized conditions were verified in vivo tests. It was proven that the LNG microsphere suspension had a good injectability when injected into subcutaneous tissue of rats. ConclusionThe injection system of injectable microparticle delivery system with lower injection force and higher discharge rate was established and the evaluation method was suitable for the injectability evaluation both in vivo and in vitro. Improved injectability would promote the clinical translation of microparticle delivery systems.

Regulatory T cell intravitreal delivery using hyaluronan methylcellulose hydrogel improves therapeutic efficacy in experimental autoimmune uveitis

Autoimmune uveitis refers to several intraocular inflammation conditions, which are mediated by autoreactive T cells. Regulatory T cells (Tregs) are immunosuppressive cells that have shown potential for resolving various autoimmune diseases, including uveitis. However, poor donor cell dispersion distal to the injection site and plasticity of Treg cells in an inflammatory microenvironment can present obstacles for this immunotherapy. We assessed the use of a physical blend of hyaluronan and methylcellulose (HAMC) as immunoprotective and injectable hydrogel cell delivery system to improve the efficacy of Treg-based therapy in treating experimental autoimmune uveitis (EAU). We demonstrated that the Treg-HAMC blend increased both the survival and stability of Tregs under proinflammatory conditions. Furthermore, we found that the intravitreal HAMC delivery system resulted in a two-fold increase in the number of transferred Tregs in the inflamed eye of EAU mice. Treg-HAMC delivery effectively attenuated ocular inflammation and preserved the visual function of EAU mice. It significantly decreased the number of ocular infiltrates, including the uveitogenic IFN-γ+CD4+ and IL-17+CD4+ T cells. In contrast, intravitreal injection of Treg cells without HAMC only achieved marginal therapeutic effects in EAU. Our findings suggest that HAMC may become a promising delivery vehicle for human uveitis Treg therapy.

Repair of degenerative nucleus pulposus by polyphenol nanosphere-encapsulated hydrogel gene delivery system

Intervertebral disc degeneration (IDD) progresses due to local inflammatory response, gradually unbalanced anabolic/catabolic activity, and progressive functional impairment within the nucleus pulposus. Antagomir-21, a cholesterol-modified miRNA-21 inhibitor, has potential extracellular matrix (ECM) regenerative ability, but its application for IDD is limited by inadequate local delivery systems. An injectable hydrogel gene delivery system encapsulating a modified tannic acid nanoparticles (TA NPs) vector was engineered for on-demand and sustained delivery of antagomir-21 into the nucleus pulposus. After nucleus pulposus cell uptake, antagomir-21 was released from TA NPs and regulated the ECM metabolic balance by inhibiting the MAPK/ERK signaling pathway. TA NPs scavenged intracellular ROS and reduced inflammation by downregulating TNF-α expression. In vivo, synergistic anti-inflammatory effects and ECM regeneration effectively promoted therapeutic efficacy against IDD. This hydrogel gene delivery system represents a creative, promising strategy for IDD repair.

Endoscopically injectable and self-crosslinkable hydrogel-mediated stem cell transplantation for alleviating esophageal stricture after endoscopic submucosal dissection.

Esophageal stricture after extensive endoscopic submucosal dissection impairs the quality of life of patients with superficial esophageal carcinoma. Beyond the limitations of conventional treatments including endoscopic balloon dilatation and the application of oral/topical corticosteroids, several cell therapies have been recently attempted. However, such methods are still limited in clinical situations and existing setups, and the efficacies are less in some cases since the transplanted cells hardly remain at the resection site for a long time due to swallowing and peristalsis of the esophagus. Thus, a cell transplantation platform directly applicable with clinically established equipment and enabling stable retention of transplanted cells can be a promising therapeutic option for better clinical outcomes. Inspired by ascidians that rapidly self-regenerate, this study demonstrates endoscopically injectable and self-crosslinkable hyaluronate that allows both endoscopic injection in a liquid state and self-crosslinking as an in situ-forming scaffold for stem cell therapy. The pre-gel solution may compatibly be applied with endoscopic tubes and needles of small diameters, based on the improved injectability compared to the previously reported endoscopically injectable hydrogel system. The hydrogel can be formed via self-crosslinking under in vivo oxidative environment, while also exhibiting superior biocompatibility. Finally, the mixture containing adipose-derived stem cells and the hydrogel can significantly alleviate esophageal stricture after endoscopic submucosal dissection (75% of circumference, 5 cm in length) in a porcine model through paracrine effects of the stem cell in the hydrogel, which modulate regenerative processes. The stricture rates on Day 21 were 79.5% ± 2.0%, 62.8% ± 1.7%, and 37.9% ± 2.9% in the control, stem cell only, and stem cell-hydrogel groups, respectively (p < 0.05). Therefore, this endoscopically injectable hydrogel-based therapeutic cell delivery system can serve as a promising platform for cell therapies in various clinically relevant situations.

Assessment of glyceride-structured oleogels as an injectable extended-release delivery system of bupivacaine

This manuscript systematically assesses three different glycerides (tripalmitin, glyceryl monostearate, and a blend of mono-, di- and triesters of palmitic and stearic acids (Geleol™)) as potential gelator structuring agents of medium-chain triglyceride oil to form an oleogel-based injectable long-acting local anesthetic formulation for postoperative pain management. Drug release testing, oil-binding capacity, injection forces, x-ray diffraction, differential scanning calorimetry, and rheological testing were serially performed to characterize the functional properties of each oleogel. After benchtop assessment, the superior bupivacaine-loaded oleogel formulation was compared to bupivacaine HCl, liposomal bupivacaine, and bupivacaine-loaded medium-chain triglyceride oil in a rat sciatic nerve block model to assess in vivo long-acting local anesthetic performance. In vitro drug release kinetics were similar for all formulations, indicating that drug release rate is primarily dependent on the drug’s affinity to the base oil. Glyceryl monostearate-based formulations had superior shelf-life and thermal stability. The glyceryl monostearate oleogel formulation was selected for in vivo evaluation. It was found to have a significantly longer duration of anesthetic effect than liposomal bupivacaine and was able to provide anesthesia twice as long as the equipotent bupivacaine-loaded medium-chain triglyceride oil, indicating that the increased viscosity of the oleogel provided enhanced controlled release over the drug-loaded oil alone.