Local Release Research Articles

OCTALCIUM PHOSPHATE CERAMICS FUNCTIONALIZED WITH CISPLATIN AND ZOLEDRONIC ACID: BIOLOGICAL ACTIVITY IN VITRO AND IN VIVO EXPERIMENTS

Giving an additional specific antitumor activity to biomaterials used to provide the local release of medical drugs into the bone defect in oncology, i.e. their functionalization is a promising, sought-after area in the modern biomaterials’ science.

Interleukin-2 and Oncolytic Virotherapy: A New Perspective in Cancer Therapy.

By triggering immune responses in malignancies that have generally been linked to poor outcomes, immunotherapy has recently shown effectiveness. On the other hand, tumors provide an environment for cells that influence the body's immunity against cancer. Malignant cells also express large amounts of soluble or membrane-bound ligands and immunosuppressive receptors. In this regard, the combination of oncolytic viruses with pro-inflammatory or inflammatory cytokines, including IL-2, can be a potential therapy for some malignancies. Indeed, oncolytic viruses cause the death of cancerous cells and destroy the tumor microenvironment. They result in the local release of threat signals and antigens associated with tumors. As a result, it causes lymphocyte activity and the accumulation of antigenpresenting cells which causes them to accumulate in the tumor environment and release cytokines and chemokines. In this study, we reviewed the functions of IL-2 as a crucial type of inflammatory cytokine in triggering immune responses, as well as the effect of its release and increased expression following combination therapy with oncolytic viruses in the process of malignant progression, as an essential therapeutic approach that should be taken into consideration going forward.

Compatibility Assessment of Novel Orodispersible Film Vehicle for Personalized Medicine with Selected Active Pharmaceutical Ingredients.

Orodispersible films (ODFs) are solid pharmaceutical forms for rapid local or systemic release of active ingredients. They are formed by a water-soluble polymer film that hydrates rapidly, adhering and dissolving immediately when placed on the tongue or in the oral cavity. In this paper, we describe the compatibility and disintegration times of compounded ODFs using OrPhylloTM, a new ready-to-use-vehicle, and APIs from different pharmacological classes, such as 5-hydroxytryptophan (5-HTP) 50 mg, bromopride 5 mg, coenzyme Q10 20 mg, melatonin 3 mg, resveratrol 5 mg, tadalafil 10 mg, vitamin B12 1 mg, or vitamin D3 2000 UI. ODFs were compounded and, subsequently, the samples were assayed using HPLC at initial (t = 0), 7 days (t = 7), 14 days (t = 14), 30 days (t = 30), 60 days (t = 60), 90 days (t = 90), 120 days (t = 120), 150 days (t = 150), and 180 days (t = 180) after compounding. Given the percentage of recovery of the APIs within the films, the beyond-use date of the final products (API + vehicle) was at least 90 days for vitamin D3, 150 days for bromopride and 5-HTP, and 180 days for coenzyme Q10, tadalafil, vitamin B12, resveratrol, and melatonin, when stored at room temperature. The average disintegration time was 46.22 s. This suggests that the OrPhylloTM vehicle is suitable for compounding ODFs with APIs from different pharmacological classes, with good compatibility and fast disintegration.

Potent inhibition of MMP-9 by a novel sustained-release platform attenuates left ventricular remodeling following myocardial infarction

Sustained drug-release systems prolong the retention of therapeutic drugs within target tissues to alleviate the need for repeated drug administration. Two major caveats of the current systems are that the release rate and the timing cannot be predicted or fine-tuned because they rely on uncontrolled environmental conditions and that the system must be redesigned for each drug and treatment regime because the drug is bound via interactions that are specific to its structure and composition. We present a controlled and universal sustained drug-release system, which comprises minute spherical particles in which a therapeutic protein is affinity-bound to alginate sulfate (AlgS) through one or more short heparin-binding peptide (HBP) sequence repeats. Employing post-myocardial infarction (MI) heart remodeling as a case study, we show that the release of C9—a matrix metalloproteinase-9 (MMP-9) inhibitor protein that we easily bound to AlgS by adding one, two, or three HBP repeats to its sequence—can be directly controlled by modifying the number of HBP repeats. In an in vivo study, we directly injected AlgS particles, which were bound to C9 through three HBP repeats, into the left ventricular myocardium of mice following MI. We found that the particles substantially reduced post-MI remodeling, attesting to the sustained, local release of the drug within the tissue. As the number of HBP repeats controls the rate of drug release from the AlgS particles, and since C9 can be easily replaced with almost any protein, our tunable sustained-release system can readily accommodate a wide range of protein-based treatments.

Prolonged Anesthesia Effects of Locally Administered Ropivacaine via Electrospun Poly(caprolactone) Fibrous Membranes.

Prolonged analgesia is important to safeguard the patient's comfort and safety during and after surgery in clinical practice. To meet the demand for prolonged analgesia, medical professionals often resort to increasing drug frequency, which may lead to poor patient compliance and serious complications due to drug overdose. Therefore, it is of great interest to develop controlled-release drug delivery systems for local anesthetics, enabling slow and controlled drug release to prolong the analgesic effect and minimize systemic toxicity. In this study, we utilized an electrospinning technique to fabricate nonwoven poly(caprolactone) (PCL) fibrous membranes loaded with Ropivacaine and performed proof-of-principle experiments on both in vitro drug release tests and in vivo animal tests, to further prolong the analgesic effect of Ropivacaine and improve postoperative local pain management and chronic pain treatment. Material characterization and in vitro drug release studies confirmed the feasibility of the Ropivacaine-loaded PCL fibrous membranes for sustained release. The drug loading content and drug loading efficiency of Ropivacaine-loaded fibrous membrane are 8.7 ± 0.3 wt% and 96 ± 3 wt%, respectively. Evaluation in an animal model demonstrated prolonged anesthesia effects along with excellent biocompatibility and stability. At 72 h, the cumulative release accounted for approximately 50% of the drug loading content. This study offers novel approaches and strategies for clinical postoperative pain management and chronic pain treatment, while providing new insights and directions for the design of local anesthetic controlled-release delivery systems.

Effects of Hydrogen Enrichment on Thermoacoustic and Helical Instabilities in Swirl Stabilised Partially Premixed Flames

The effects of hydrogen enrichment on flame and flow dynamics of a swirl-stabilised partially premixed methane-air flame are studied using large eddy simulation. The sub-grid reaction rate is modelled using unstrained premixed flamelets and a presumed joint probability density function approach. Two cases undergoing thermoacoustic oscillations at ambient conditions are studied. The addition of hydrogen modifies both thermoacoustic and fluid dynamical characteristics. The amplitude of the fundamental thermoacoustic mode increases with the addition of 20% hydrogen by volume. A second pressure mode associated with the chamber mode is also excited with the hydrogen addition. Intermittent single, double and triple helical instabilities are observed in the pure methane case, but are suppressed substantially with hydrogen addition. The results are analysed in detail to shed light on these observations. The feedback loop responsible for the thermoacoustic instability is driven by mixture fraction perturbations resulting from the unequal impedances of the fuel and air channels. It is shown that hydrogen addition increases the flame’s sensitivity to these perturbations, resulting in an increase in amplitude. This higher amplitude thermoacoustic oscillation, along with a higher local heat release rate in the presence of hydrogen, is shown to considerably modify the flow structures, leading to a suppression of the helical instabilities.

Folic Acid‐Modified Nanoprobe for In Vivo‐Targeted Persistent Luminescence Imaging and pH‐Responsive Antibiotic Therapy of Bacterial Infection

AbstractLow antibiotic utilization and inability to achieve real‐time monitoring of pathological status and treatment processes often result in unsatisfactory performance against bacterial infection. Developing a targeting antibacterial nanoprobe combining imaging with stimulus‐response antibiotic release is a promising strategy to precisely recognize lesions and enhance therapeutic efficacy for bacterial infection. In this work, we report a pH‐responsive theragnostic nanoplatform for targeted imaging and local drug release at the bacterial infection site. The nanoplatform consists of the core‐shell structure with persistent luminescence nanoparticles (PLNPs) as the core for autofluorescence‐free luminescence imaging and zeolitic imidazolate framework‐8 (ZIF‐8) as the shell to act as a carrier for antibiotics cefazolin. The core‐shell nanostructure is further conjugated with folic acid to facilitate the uptake and accumulation of the nanoparticles, and realize the autofluorescence‐free targeted imaging of the infection site. The acidic microenvironment at the bacterial infection site enables ZIF‐8 to decompose for specific drug release improve the performance in bacterial infection treatment. The developed pH‐responsive nanotheranostic probe is promising for autofluorescence‐free targeted imaging and therapy of bacterial infection.

Analyzing the Stability of Rock Surrounding Deep Cross-Tunnels Using a Dynamic Velocity Field

With the increasing number of deep rock engineering projects, many different types of tunnels have emerged, such as cross-tunnels. These tunnels intersect with each other in rock, which causes potential safety hazards. We must analyze the stability of the surrounding rock, to ensure worker safety. This article presents a method for dynamically assessing the stability of the surrounding rock in deep-buried cross-tunnels. The method consists of two main analysis steps: (1) P-wave velocity field inversion; and (2) Stability analysis of the surrounding rock. The P-wave velocity field inversion involves inverting the S-wave velocity field by Rayleigh wave and inverting the P-wave velocity field by adjoint state traveltime tomography. Then, a method of stability analysis is proposed which is used to update the mechanical properties of the rock (based on the continuously updated wave velocity field). The elastic modulus of the surrounding rock is approximated throughout the excavation process. CASRock V1.0 (Cellular Automation Software for engineering Rockmass fracturing processes) is used to assess rock damage via the equivalent plastic shear strain and local energy release rate. The new method is used to analyze the stability of a new tunnel excavated in Jinping (in China). The results reveal the severity and spatial distribution of the damage caused. The yield depth is concentrated near the sidewalls, while the top and bottom of the tunnel exhibit a smaller depth. The yield depths present a particular pattern of change (high–low–high–low) with increasing distance from tunnel #2. Finally, this research enriches our understanding of excavating deep cross-tunnels and makes an important contribution to improving worker safety in deep cross-tunnels.

Development of a thermosensitive hydrogel based on Polaxamer 407 and gellan gum with inclusion complexes (Sulfobutylated-β-cyclodextrin–Farnesol) as a local drug delivery system

This work proposes the development of a thermosensitive local drug release system based on Polaxamer 407, also known as Pluronic® F-127 (PF-127), Gellan Gum (GG) and the inclusion complex Sulfobutylated-β-cyclodextrin (CD) with Farnesol (FOH). Rheological properties of the hydrogels and their degradation were studied. According to the rheological results, a solution of 20% w/v of PF-127 forms a strong gel with a gelling temperature of about 25 °C (storage modulus of 15,000 Pa). The addition of the GG increased the storage modulus (optimal concentration of 0.5 % w/v) twofold without modifying the gelling temperature. Moreover, including 0.5% w/v of GG also increased 6 times the degradation time of the hydrogel. Regarding the inclusion complex, the addition of free CD decreased the viscosity and the gel strength since polymer chains were included in CD cavity without affecting the gelling temperature. Contrarily, the inclusion complex CD-FOH did not significantly modify any property of the formulation because the FOH was hosted in the CD. Furthermore, a mathematical model was developed to adjust the degradation time. This model highlights that the addition of the GG decreases the number of released chains from the polymeric network (which coincides with an increase in the storage modulus) and that the free CD reduces the degradation rate, protecting the polymeric chains. Finally, FOH release was quantified with a specific device, that was designed and printed for this type of system, observing a sustainable drug release (similar to FOH aqueous solubility, 8 μM) dependent on polymer degradation.

Development of Subdermal Implants Using Direct Powder Extrusion 3D Printing and Hot-Melt Extrusion Technologies.

Implants are drug delivery platforms that consist of a drug-polymer matrix with the ability of providing a localized and efficient controlled release of the drug with minimal side effects and achievement of the desired therapeutic outcomes with low drug loadings. Direct powder extrusion (DPE) 3D printing technology involves the extrusion of material through a nozzle of the printer in the form of pellets or powder. The present study aimed at investigating the use of the CELLINK BIO X™ bioprinter using DPE 3D printing technique to fabricate and evaluate the impact of different shapes (cuboid, cylinder, and tube) of raloxifene hydrochloride (RFH)-loaded subdermal implants on the release of RFH from the implants. This study further evaluated the impact of different processing techniques, viz., hot-melt extrusion (HME) technology vs. DPE 3D printing technique, on the release of RFH from the implants fabricated by each processing technique. All the fabricated implants were characterized by XRD, DSC, SEM, and FTIR, and evaluated for their water uptake, mass loss, and in vitro RFH release. The current study successfully demonstrated a great opportunity of controlling and/or tuning the release of RFH from the subdermal implants by altering the implant shape, and hence surface area, and could be a great contribution and/or addition to the personalization of medicines and improvement of patient compliance.

Dual-responsive supramolecular photodynamic nanomedicine with activatable immunomodulation for enhanced antitumor therapy

A major challenge facing photodynamic therapy (PDT) is that the activity of the immune-induced infiltrating CD8+ T cells is subject to the regulatory T lymphocytes (Tregs), leaving the tumor at risk of recurrence and metastasis after the initial ablation. To augment the antitumor response and reprogram the immunosuppressive tumor microenvironment (TME), a supramolecular photodynamic nanoparticle (DACss) is constructed by the host-guest interaction between demethylcantharidin-conjugated β-cyclodextrin (DMC-CD) and amantadine-terminated disulfide-conjugated FFVLGGGC peptide with chlorin e6 decoration (Ad-ss-pep-Ce6) to achieve intelligent delivery of photosensitizer and immunomodulator for breast cancer treatment. The acid-labile β-carboxamide bond of DMC-CD is hydrolyzed in response to the acidic TME, resulting in the localized release of DMC and subsequent inhibition of Tregs. The guest molecule Ad-ss-pep-Ce6 can be cleaved by a high level of intracellular GSH, reducing photosensitizer toxicity and increasing photosensitizer retention in the tumor. With a significant increase in the CTL/Treg ratio, the combination of Ce6-based PDT and DMC-mediated immunomodulation adequately achieved spatiotemporal regulation and remodeling of the TME, as well as improved primary tumor and in situ lung metastasis suppression with the aid of PD-1 antibody.

In Situ Photo-crosslinkable Hyaluronic Acid/Gelatin Hydrogel for Local Nitric Oxide Delivery.

An increasing number of studies have shown that the local release of nitric oxide (NO) from hydrogels stimulates tissue regeneration by modulating cell proliferation, angiogenesis, and inflammation. The potential biomedical uses of NO-releasing hydrogels can be expanded by enabling their application in a fluid state, followed by controlled gelation triggered by an external factor. In this study, we engineered a hydrogel composed of methacrylated hyaluronic acid (HAGMA) and thiolated gelatin (GELSH) with the capacity for in situ photo-cross-linking, coupled with localized NO release. To ensure a gradual and sustained NO release, we charged the hydrogels with poly(l-lactic-co-glycolic acid) (PLGA) nanoparticles functionalized with S-nitrosoglutathione (GSNO), safeguarding SNO group integrity during photo-cross-linking. The formation of thiol-ene bonds via the reaction between GELSH's thiol groups and HAGMA's vinyl groups substantially accelerated gelation (by a factor of 6) and increased the elastic modulus of hydrated hydrogels (by 1.9-2.4 times). HAGMA/GELSH hydrogels consistently released NO over a 14 day duration, with the release of NO depending on the hydrogels' equilibrium swelling degree, determined by the GELSH-to-HAGMA ratio. Biocompatibility assessments confirmed the suitability of these hydrogels for biological applications as they display low cytotoxicity and stimulated fibroblast adhesion and proliferation. In conclusion, in situ photo-cross-linkable HAGMA/GELSH hydrogels, loaded with PLGA-GSNO nanoparticles, present a promising avenue for achieving localized and sustained NO delivery in tissue regeneration applications.

Hydrogel-Based Microneedle as a Drug Delivery System.

The skin is considered the largest and most accessible organ in the human body, and allows the use of noninvasive and efficient strategies for drug administration, such as the transdermal drug delivery system (TDDS). TDDSs are systems or patches, with the ability and purpose to deliver effective and therapeutic doses of drugs through the skin. Regarding the specific interaction between hydrogels (HG) and microneedles (MNs), we seek to find out how this combination would be applied in the context of drug delivery, and we detail some possible advantages of the methods used. Depending on the components belonging to the HG matrix, we can obtain some essential characteristics that make the combination of hydrogels-microneedles (HG-MNs) very advantageous, such as the response to external stimuli, among others. Based on multiple characteristics provided by HGMNs that are depicted in this work, it is possible to obtain unique properties that include controlled, sustained, and localized drug release, as well as the possibility of a synergistic association between the components of the formulation and the combination of more than one bioactive component. In conclusion, a system based on HG-MNs can offer many advantages in the biomedical field, bringing to light a new technological and safe system for improving the pharmacokinetics and pharmacodynamics of drugs and new treatment perspectives.

Cannabidiol Reduces Systemic Immune Activation in Experimental Acute Lung Injury.

Background: The underlying pathomechanism of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is the immune response to inflammation or infection within the pulmonary microcirculation. Systemic spread of pathogens, activated immune cells, and inflammatory mediators contributes significantly to mortality in patients with ARDS. Objective: The endogenous cannabinoid system is a major modulator of the immune response during inflammation and infection. Phytocannabinoids, such as cannabidiol (CBD), have shown promising anti-inflammatory effects in several pathologies. The overall objective of this study was to evaluate the effects of CBD on local and systemic inflammation in endotoxin-induced ALI in mice. Materials and Methods: ALI was induced by pulmonary endotoxin challenge. Four groups of male C57BL/6 mice were randomized in this study: control, ALI, ALI with CBD treatment, and control with CBD treatment. Analyses of local and systemic cytokine levels, lung histology, and leukocyte activation as visualized by intravital microscopy of the intestinal and pulmonary microcirculation were performed 6 h following intranasal endotoxin administration. Results: Pulmonary endotoxin challenge induced significant inflammation evidenced by local and systemic cytokine and chemokine release, lung histopathology, and leukocyte adhesion. Intraperitoneal CBD treatment resulted in a significant decrease in systemic inflammation as shown by reduced leukocyte adhesion in the intestinal microcirculation and reduced plasma cytokine and chemokine levels. Pulmonary chemokine levels were decreased, while pulmonary cytokine levels were unchanged. Surprisingly, the ALI score was slightly increased by CBD treatment in a manner driven by enhanced neutrophil infiltration of the alveoli. Conclusion: In this model of experimental ALI, CBD administration was associated with reduced systemic inflammation and heterogeneous effects on pulmonary inflammation. Future studies should explore the mechanisms involved as they relate to neutrophil infiltration and proinflammatory mediator production within the lungs.

The Effects of Platelet-Rich Fibrin in the Behavior of Mineralizing Cells Related to Bone Tissue Regeneration-A Scoping Review of In Vitro Evidence.

Platelet-rich fibrin (PRF) is a second-generation blood concentrate that serves as an autologous approach for both soft and hard tissue regeneration. It provides a scaffold for cell interaction and promotes the local release of growth factors. PRF has been investigated as an alternative to bone tissue therapy, with the potential to expedite wound healing and bone regeneration, though the mechanisms involved are not yet fully understood. This review aims to explore the in vitro evidence of PRF's effects on the behavior of mineralizing cells related to bone tissue regeneration. A systematic electronic search was conducted up to August 2023, utilizing three databases: PubMed, Web of Science, and Scopus. A total of 76 studies were selected, which presented in vitro evidence of PRF's usefulness, either alone or in conjunction with other biomaterials, for bone tissue treatment. PRF membranes' influence on the proliferation, differentiation, and mineralization of bone cells is linked to the constant release of growth factors, resulting in changes in crucial markers of bone cell metabolism and behavior. This further reinforces their therapeutic potential in wound healing and bone regeneration. While there are some notable differences among the studies, the overall results suggest a positive effect of PRF on cell proliferation, differentiation, mineralization, and a reduction in inflammation. This points to its therapeutic potential in the field of regenerative medicine. Collectively, these findings may help enhance our understanding of how PRF impacts basic physiological processes in bone and mineralized tissue.

Numerical study of CH* chemiluminescence and heat release rate in methane inverse diffusion flame

Flame optical diagnostic method based on CH* chemiluminescence is often used in the combustion process monitoring. In this work, a numerical study of CH* chemiluminescence was conducted for the laminar methane inverse diffusion flame with a range of global oxygen/fuel equivalence ratios. CH* chemiluminescence is mainly distributed in the upstream of the inverse diffusion flame and the CH* concentration increases with the global oxygen/fuel equivalence ratio. CH* is generated by C2H, which mainly comes from the reactions OH + C2H2<=>C2H + H2O and H + C2H2<=>C2H + H2. In addition, most CH* is quenched by collisions with H2O, CO, CO2 and H2, and the CH* collision quench is enhanced with increasing global oxygen/fuel equivalence ratios. The CH* generated in the peak reaction zone will diffuse to the fuel and oxidizer sides due to the mass diffusion and the thermal diffusion. Moreover, the correlation between CH* and local heat release rate distribution is explored and CH* can characterize the local heat release rate on the fuel side.

Caffeic acid-grafted chitosan/sodium alginate/nanoclay-based multifunctional 3D-printed hybrid scaffolds for local drug release therapy after breast cancer surgery

Breast cancer is one of the most common malignant tumors in women all over the world. Mastectomy is the most effective treatment, but there are serious problems such as high tumor recurrence rate and side effects of chemotherapy. Therefore, there is an urgent need for a therapeutic strategy that can effectively promote postoperative wound healing and inhibit local tumor recurrence. In this study, a 3D printing scaffold based on carbon dots-curcumin nano-drug release (CCNPs) was developed as a local drug delivery platform (named CCNACA using CCNPs, Sodium alginate, Nanoclay and Caffeic Acid grafted Chitosan as raw materials), which has the ability to visualize drug release. The 14-day drug release test in vitro showed that the tumor inhibition rate of CCNACA scaffolds on breast cancer cells (MCF-7) was 73.77 ± 1.68 %. And the CCNACA scaffolds had good long-term antibacterial (Escherichia coli and Staphylococcus aureus) activity. Animal experiments have shown that implanting CCNACA scaffolds into surgical defects can inhibit postoperative residual cancer cells, reduce inflammation, promote angiogenesis, and repair tissue defects caused by surgery. In summary, the local drug delivery system of this manuscript has great potential in wound healing and prevention of tumor recurrence after breast cancer surgery.

The anti-myotoxic effects and mechanisms of Sinonatrix annularis serum and a novel plasma metalloproteinase inhibitor towards Deinagkistrodon acutus envenomation

Non-venomous snakes commonly evolve natural resistance to venom to escape predators. Sinonatrix annularis serum has been shown to inhibit Deinagkistrodon acutus venom-induced hemorrhage and upregulation of serum CK, CK-MB, LDH, AST and ALT levels. Using TMT-labeled proteomics analysis, 168 proteins were found to be altered significantly in the envenomed gastrocnemius muscle and categorized into pathways such as complement and coagulation cascades, leukocyte transendothelial migration, and JAK/STAT signaling. These alterations were mitigated by S. annularis serum. Subsequently, a novel metalloproteinase inhibitor, SaMPI, was isolated from S. annularis serum by two-step chromatography. It showed strong antidotal effects against D. acutus envenomation, including inhibition of subcutaneous bleeding caused by crude venom and DaMP (a metalloproteinase derived from D. acutus) activity in a 1:1 ratio. Histology and immunoblotting analyses demonstrated that SaMPI mitigated myonecrosis, reduced neutrophil infiltration and local inflammatory factor release, and retarded JAK/STAT and MAPK signaling activation. Analysis of the SaMPI gene cloned by 5′-RACE revealed a shared sequence identity of 58–79% with other SVMP inhibitors. These findings demonstrate the protective effects of SaMPI and indicate its potential value as a candidate for viper bite adjuvant therapy.

Local extracellular K+ in cortex regulates norepinephrine levels, network state, and behavioral output

Extracellular potassium concentration ([K+]e) is known to increase as a function of arousal. [K+]e is also a potent modulator of transmitter release. Yet, it is not known whether [K+]e is involved in the neuromodulator release associated with behavioral transitions. We here show that manipulating [K+]e controls the local release of monoaminergic neuromodulators, including norepinephrine (NE), serotonin, and dopamine. Imposing a [K+]e increase is adequate to boost local NE levels, and conversely, lowering [K+]e can attenuate local NE. Electroencephalography analysis and behavioral assays revealed that manipulation of cortical [K+]e was sufficient to alter the sleep-wake cycle and behavior of mice. These observations point to the concept that NE levels in the cortex are not solely determined by subcortical release, but that local [K+]e dynamics have a strong impact on cortical NE. Thus, cortical [K+]e is an underappreciated regulator of behavioral transitions.

Injectable hyperbranched PEG crosslinked hyaluronan hydrogel microparticles containing mir-99a-3p modified subcutaneous ADSCs-derived exosomes was beneficial for long-term treatment of osteoarthritis

Exosomes (Exos) secreted by adipose-derived stem cells (ADSCs) have shown potential in alleviating osteoarthritis (OA). Previous studies indicated that infrapatellar fat pad (IPFP) derived stem cells (IPFSCs) may be more suitable for the treatment of OA than subcutaneous adipose tissue (ScAT) derived stem cells (ScASCs). However, it remains unclear which type of Exos offers superior therapeutic benefit for OA. This study first compared the differences between Exos derived from IPFP stem cells (ExosIPFP) and ScAT stem cells (ExosScAT) in OA treatment. Results suggested that ExosIPFP significantly inhibit the degradation of cartilage extracellular matrix (ECM) than ExosScAT, following this, the differences in microRNA (miRNA) expression between the two types of Exos using small RNA sequencing were performed. Subsequently, miR-99 b-3p was chosen and over-expressed in ExosScAT (ExosScAT−99b−3p), both in vivo and in vitro experiments demonstrated its efficacy in inhibiting the expression of ADAMTS4, promoting the repair of the ECM in OA. Finally, microfluidic technology was performed to fabricate a hyaluronan-based hydrogel microparticles (HMPs) for encapsulating Exos (HMPs@exos), the injectability, sustained release of Exos and long-term therapeutic effect on OA were validated. In summary, these results suggest miR-99 b-3p regulates the degradation of cartilage ECM by targeting ADAMTS4, the upregulation of miR-99 b-3p in ExosScAT would enable them to exhibit comparable or even superior effectiveness to ExosIPFP for OA treatment, making it a promising approach for OA treatment. Considering the abundant resources of ScAT and the limited availability of IPFP, ScAT harvested through liposuction could be genetically engineered to yield Exos for OA treatment. Furthermore, the encapsulation of Exos in HMPs provides an injectable sustained local drug release system, which could potentially enhance the efficacy of Exos and hold potential as future therapeutic strategies.