Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Effects of serum proteins on corrosion rates and product bioabsorbability of biodegradable metals.

Corrodible metals are the newest kind of biodegradable materials and raise a new problem of the corrosion products. However, the removal of the precipitated products has been unclear and even largely ignored in publications. Herein, we find that albumin, an abundant macromolecule in serum, enhances the solubility of corrosion products of iron in blood mimetic Hank's solution significantly. This is universal for other main biodegradable metals such as magnesium, zinc and polyester-coated iron. Albumin also influences corrosion rates in diverse trends in Hank's solution and normal saline. Based on quantitative study theoretically and experimentally, both the effects on corrosion rates and soluble fractions are interpreted by a unified mechanism, and the key factor leading to different corrosion behaviors in corrosion media is the interference of albumin to the Ca/P passivation layer on the metal surface. This work has illustrated that the interactions between metals and media macromolecules should be taken into consideration in the design of the next-generation metal-based biodegradable medical devices in the formulism of precision medicine. The improved Hank's solution in the presence of albumin and with a higher content of initial calcium salt is suggested to access biodegradable metals potentially for cardiovascular medical devices, where the content of calcium salt is calculated after consideration of chelating of calcium ions by albumin, resulting in the physiological concentration of free calcium ions.

Achieving Long-Acting Local Analgesia Using an Intelligent Hydrogel Encapsulated with Drug and pH Regulator.

Local anesthetics are important for the treatment of postoperative pain. Since a single injection of the solution of a drug such as bupivacaine (BUP) works only for a few hours, it is much required to develop a long-term injectable formulation that maintains its efficacy for more than 1 day. Herein, an intelligent copolymer hydrogel loaded with BUP microcrystals was invented. The biodegradable block copolymer was synthesized by us and composed of a central hydrophilic poly(ethylene glycol) (PEG) block and two hydrophobic poly(lactide-co-glycolide) (PLGA) blocks. The aqueous system of the amphiphilic copolymer underwent a sol-gel transition between room temperature and body temperature and, thus, physically gelled after injection. Considering the decrease of solubility of BUP with the increase of pH and the internal acidic environment due to the hydrolysis of PLGA, calcium carbonate (CaCO3) powder was introduced as a pH regulator. Then, the internal pH was found to be nearly neutral and many BUP microcrystals were dispersed in the gel network. In this way, BUP had achieved a sustained release out of the thermogel. The maximum possible effect (MPE) in a rat sciatic nerve blockade model was used to describe the sensory blockade effect. In vivo analgesic effects evaluated with a hot plate experiment of rats demonstrated that the thermogel encapsulated with BUP microcrystal and CaCO3 powder significantly prolonged analgesia up to 44 h, the duration time with respect to 50% MPE. The intramuscularly injected implant exhibited biocompatibility in histological analyses. Besides, the untreated leg of the rats was not influenced by the treated leg, indicating no obvious systematic anesthesia of this hydrogel formulation. Such an intelligent and composite formulation represents a potential strategy for long-acting analgesia therapy.

Quantitatively relating magnetic resonance T1 and T2 to glycosaminoglycan and collagen concentrations mediated by penetrated contrast agents and biomacromolecule-bound water.

Magnetic resonance imaging (MRI) is a promising non-invasive method to assess cartilage regeneration based on the quantitative relationship between MRI features and concentrations of the major components in the extracellular matrix (ECM). To this end, in vitro experiments are performed to investigate the relationship and reveal the underlying mechanism. A series of collagen (COL) and glycosaminoglycan (GAG) solutions at different concentrations are prepared, and T1 and T2 relaxation times are measured with or without a contrast agent (Gd-DTPA2-) by MRI. Fourier transform infrared spectrometry is also used to measure the contents of biomacromolecule-bound water and other water, allowing theoretical derivation of the relationship between biomacromolecules and the resulting T2 values. It has been revealed that the MRI signal in the biomacromolecule aqueous systems is mainly influenced by the protons in hydrogens of biomacromolecule-bound water, which we divide into inner-bound water and outer-bound water. We have also found that COL results in higher sensitivity of bound water than GAG in T2 mapping. Owing to the charge effect, GAG regulates the penetration of the contrast agent during dialysis and has a more significant effect on T1 values than COL. Considering that COL and GAG are the most abundant biomacromolecules in the cartilage, this study is particularly useful for the real-time MRI-guided assessment of cartilage regeneration. A clinical case is reported as an in vivo demonstration, which is consistent with our in vitro results. The established quantitative relation plays a critical academic role in establishing an international standard ISO/TS24560-1:2022 'Clinical evaluation of regenerative knee articular cartilage using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) and T2 mapping' drafted by us and approved by International Standard Organization.

Recent advances in regenerative biomaterials.

Nowadays, biomaterials have evolved from the inert supports or functional substitutes to the bioactive materials able to trigger or promote the regenerative potential of tissues. The interdisciplinary progress has broadened the definition of 'biomaterials', and a typical new insight is the concept of tissue induction biomaterials. The term 'regenerative biomaterials' and thus the contents of this article are relevant to yet beyond tissue induction biomaterials. This review summarizes the recent progress of medical materials including metals, ceramics, hydrogels, other polymers and bio-derived materials. As the application aspects are concerned, this article introduces regenerative biomaterials for bone and cartilage regeneration, cardiovascular repair, 3D bioprinting, wound healing and medical cosmetology. Cell-biomaterial interactions are highlighted. Since the global pandemic of coronavirus disease 2019, the review particularly mentions biomaterials for public health emergency. In the last section, perspectives are suggested: (i) creation of new materials is the source of innovation; (ii) modification of existing materials is an effective strategy for performance improvement; (iii) biomaterial degradation and tissue regeneration are required to be harmonious with each other; (iv) host responses can significantly influence the clinical outcomes; (v) the long-term outcomes should be paid more attention to; (vi) the noninvasive approaches for monitoring in vivo dynamic evolution are required to be developed; (vii) public health emergencies call for more research and development of biomaterials; and (viii) clinical translation needs to be pushed forward in a full-chain way. In the future, more new insights are expected to be shed into the brilliant field-regenerative biomaterials.

A coordination strategy to achieve instant dissolution of a biomedical polymer in water via manual shaking.

Organic polymers with condensed long chains show slow dissolution kinetics in solvents, particularly in water, which has significantly hindered their potential applications where their instant dissolution without any assistance of a stirring machine, etc. is required. Herein, we put forward a strategy of rapid dissolution of chain-like polymers by coordinating with small molecular additives, using a thermogellable amphiphilic copolymer and CaCl2 for demonstration. We synthesized a block copolymer of poly(ethylene glycol) (PEG) and poly(lactide-co-glycolide) (PLGA) and prepared its powder after coordinating with calcium ions. Compared to the virgin copolymer, the composite was dissolved in water at a rate of over 104 fold, and simple manual shaking for half a minute could form its aqueous solution. Chelation using sodium citrate was further suggested to alleviate the possible biocompatibility problem caused by calcium ions. Finally, the potential application of the thermogels prepared by the rapid dissolution strategy for an instant use in hospitals was demonstrated in an ex vivo porcine model of a fluid cushion for endoscopic submucosal dissection. The mechanism was discussed, and the critical factor comes from the coordination between calcium ions and the PEG block in the copolymer. The strategy to introduce a solvable small molecular additive coordinated with the polymer chain at the molecular level is helpful for accelerating the dissolution of organic polymers in a solvent to a large extent.

Intelligent Paper-Free Sprayable Skin Mask Based on an In Situ Formed Janus Hydrogel of an Environmentally Friendly Polymer.

Traditional skin care masks usually use a piece of paper to hold the aqueous essences, which are not environmentally friendly and not easy to use. While a paper-free mask is desired, it is faced with a dilemma of moisture holding and rapid release of encapsulated bioactive substances. Herein, a paper-free sprayable skin mask is designed from an intelligent material-a thermogel which undergoes sol-gel-suspension transitions upon heating-to solve this dilemma. A synthesized block copolymer of poly(ethylene glycol) and poly(lactide-co-glycolide) with appropriate ratios can be dissolved in water, and thus easily mixed with a biological substance. The mixture is sprayable. After spraying, a Janus film is formed in situ with a physical gel on the outside and a suspension on the inside facing skin. Thus, both moisture holding and rapid release are achieved. Such a thermogel composed of biodegradable amphiphilic block copolymers loaded with nicotinamide as a skin mask is verified to reduce pigmentation on a 3D pigmented reconstructed epidermis model and further in a clinical study. This work might be stimulating for investigations and applications of biodegradable and intelligent soft matter in the fields of drug delivery and regenerative medicine.

Heparin modified photosensitizer-loaded liposomes for tumor treatment and alleviating metastasis in phototherapy.

Phototherapy holds promise in cancer treatment for its prominent antitumor efficacy and low systematic toxicity compared with traditional chemotherapy. However, the higher risk of tumor metastasis caused by the severe hypoxic state during phototherapy is a threat in practical use. Here, in order to tackle this challenge, we developed a delivery system via loading the photosensitizer indocyanine green (ICG) into the low molecular weight heparin (LMWH) modified liposomes (LMWH-ICG-Lip) to realize the synergistic effects between photosensitizer and drug vehicle, achieving better phototherapeutic efficacy and meanwhile alleviating the potential risk of tumor metastasis caused by phototherapy. In this system, besides elongating the photosensitizers' circulation time and enhancing their accumulating efficacy to tumor tissues, LMWH itself also exhibited anti-metastasis efficacy via inhibiting adhesion of platelets to tumor cells and decreasing migration and invasion capability of tumor cells. In vivo efficacy evaluation was conducted on orthotopic 4T1 breast cancer model, and the system of LMWH-ICG-Lip could alleviate metastasis potential of residual tumor cells after irradiation, and elicit optimistic antitumor and anti-metastasis efficacy for phototherapy.

Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer.

The aim of this research is to utilize a hybrid system of liposomal doxorubicin (DOX-Lip) loaded thermogel (DOX-Lip-Gel) to realize the steady sustained delivery of doxorubicin (DOX), a small hydrophilic drug, for the treatment of breast cancer locally. Herein, liposomal doxorubicin was prepared via the traditional film dispersion method with the particle size of 75 nm and drug entrapment efficiency of 86%. And, the triblock copolymer of poly (D, L-lactide-co-glycolide)-b-poly (ethylene glycol)-b-poly (D, L-lactide -co-glycolide) (PLGA-PEG-PLGA) was synthesized via ring-opening polymerization to prepare the thermosensitive hydrogel through dissolving the polymers in DOX-Lip solution. The liposome loaded hydrogel was in a sol state at room temperature and converted into the gel state at body temperature and would degrade gradually during the time in vivo. The drug release of DOX out of DOX-Lip-Gel could be in a steady sustained manner up to 11 days without significant burst release as compared to that of DOX-loaded hydrogel (DOX-Gel). An orthotopic breast cancer model was adopted to evaluate the in vivo antitumor efficacy. And, the results revealed DOX-Lip-Gel had better antitumor efficiency as well as lower side effects.

Low molecular weight heparin-based reduction-sensitive nanoparticles for antitumor and anti-metastasis of orthotopic breast cancer.

Tumor metastasis has become a major obstacle for the clinical treatment of malignant breast cancer. Thus, a delivery system capable of both antitumor and anti-metastasis efficacy is desired. In this work, a low molecular weight heparin (LMWH)-based reduction-sensitive delivery system was developed, aiming to combine the properties of both the antitumor drug and active excipients to achieve a synergistic antitumor and anti-metastatic efficiency as well as resolving the potential adverse effects of both doxorubicin and LMWH. That is, the efficiency of DOX could be enhanced and its toxicity could be lowered. Meanwhile, the biological properties of LMWH could be strengthened and its bleeding risk could also be alleviated. Briefly, drug-loaded crosslinked nanoparticles (DOX/cLLHC2) had a longer blood circulation time and exhibited a rapid reduction-triggered release of DOX. The in vitro assays revealed that DOX/cLLHC2 exhibited a higher cellular uptake and cytotoxicity compared to free DOX. Meanwhile, for the existence of LMWH, DOX/cLLHC2 inhibited cell migration and invasion, as well as effectively inhibited the tube-like formation of human umbilical vein endothelial cells. DOX/cLLHC2 possessed a superior tumor accumulation compared to lipoic acid unmodified nanoparticles and free DOX. Also, DOX/cLLHC2 exhibited encouraging antitumor and anti-metastasis efficiency in an orthotopic breast cancer model. Overall, DOX/cLLHC2 could exert antitumor, anti-metastasis, and anti-angiogenesis efficacy simultaneously as well as having lower systemic toxicity, which makes it suitable for the therapy of metastatic breast carcinoma.

Development of low molecular weight heparin based nanoparticles for metastatic breast cancer therapy.

Tumor metastasis is the primary obstacle in cancer treatment and is always the leading cause of human death. And heparin and its derivatives are potential anti-metastatic agents with good biocompatibility. In this work, low molecular weight heparin (LMWH) based LMWH-Cholesterol (LHC) conjugates were prepared for intravenous delivery of doxorubicin (DOX). The DOX/LHC nanoparticles (DOX/LHC NPs) exhibited a spherical shape with a mean diameter of 135.5±2.2nm and had a longer circulation time than that of DOX. The in vitro results confirmed that the DOX/LHC NPs was more effectively taken up by 4T1 cells and showed a stronger anti-metastatic effect by cell invasion and cell migration compared with DOX. Meanwhile, DOX/LHC NPs also exhibited superior anti-metastatic effects in the pulmonary metastasis model compared with other groups. The reason may be account for the synergistic effect between the cytotoxic drug of DOX and its drug carrier of LMWH based nanoparticles, which is capable of anti-metastatic and anti-angiogenic efficiency. Thus DOX/LHC nanoparticles could be a promising anti-metastatic drug delivery system for postoperative chemotherapy.

Development and anti-Candida evaluation of the vaginal delivery system of amphotericin B nanosuspension-loaded thermogel.

Vulvovaginal candidiasis (VVC) is a typical kind of vaginal mucosal infection. Herein, we developed a novel vaginal delivery system of amphotericin B (AmB) nanosuspension-loaded thermogel (AmB NPs/thermogel) utilising pharmaceutical technique of high-pressure homogenisation and Poloxamer P407/P188 hydrogel. The stabiliser and hydrogel materials of the formulation were tested to maintain proper sol-gel transition as well as the relative stability of the particle size of AmB nanosuspension in the thermogel. The particle size of AmB nanosuspensions in the hydrogel was ∼247 nm. Transmission electron microscopy images confirmed the round-shape morphology of AmB nanoparticles in AmB NPs/thermogel, while that of irregular morphology of merely AmB nanosuspensions without stabiliser and hydrogel materials. AmB could be sustained release for ∼12 h in vitro. In vivo drug content in the vaginal tissue was also evaluated with 87, 47, 33 and 6.7% drug remaining after 1, 3, 6 and 12 h, respectively. The in vivo anti-Candida test was conducted on candidiasis-infected mice model. In the same drug dose of 2.5 mg/kg, AmB NPs/thermogel showed better anti-Candida efficiency compared with commercial AmB effervescent tablet. This delivery system might show some insights for the vaginal formulation development of other hydrophobic antifungal drugs.