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Microneedle arrays provide an efficient tool for transdermal drug delivery in a minimally invasive and painless manner, showing great potential applications in medicine. However, it remains challenging to fabricate the desired microneedle arrays, because of their micron-scale size and fine structure. Novel manufacturing technologies are very wanted for the development of microneedle arrays, which would solidly advance the clinical translation of microneedle arrays. 3D printing technology is a powerful manufacturing technology with superiority in fabricating personalized and complex structures. Currently, 3D printing technology has been employed to fabricate microneedle arrays, which could push more microneedle arrays into clinic and inspire the development of future microneedle arrays. This work reviews the art of 3D printing microneedle arrays, the benefits of fabricating microneedle arrays with 3D printing, and the considerations for clinical translation of 3D-printed microneedle arrays. This work provides an overview of the current 3D-printed microneedle arrays in drug delivery.

Nerve conduits have great promise for bridging peripheral nerve defects that always cause disability. Currently, the clinically used nerve conduits are limited in promoting nerve regeneration, leading to the unsatisfied nerve repair efficiency. In this study, we show a 3D-printed nerve conduit with drug release for promoting nerve regeneration. This nerve conduit with designed structures as well as directional fiber-aligned inner surface is rapidly customized by a digital light processing (DLP) based continuous 3D-printing process. Meanwhile, this conduit containing polymeric nanoparticles that can sustained release RGFP966 to promote the remyelination of Schwann cells by activating PI3K–AKT–ERK signal pathway. Moreover, this nerve conduit is degradable and biocompatible. After implantation, this conduit can efficiently bridge a 10-mm rat sciatic nerve defect, which is comparable to the autograft in inducing nerve regeneration and functional recovery. This work suggests that the 3D-printed hydrogel nerve conduits with local release of RGFP966 could efficiently repair the injured nerves, which could inspire the development of future functional nerve conduits.

Currently, in vitro cancer cell culture technology is very important for cancer research. Existing studies have shown that two-dimensional (2D) cell environment may cause significant differences from tumor cells in vivo, resulting in high failure rates when the therapies developed in 2D tumor models translated to the clinic. And compared with 2D culture, the isotropic three-dimensional (3D) culture can construct an environment more similar to that in the body. Here, we utilized 3D printed porous microgel to culture for lung cancer cell and also explored possible mechanism of how 3D culture environment regulates actin cytoskeleton. Compared with 2D cultured lung cancer cells, cells in porous microgel are more similar to those extracted from the existing gold standard: mouse transplanted tumors, in terms of the ROCK-actin pathway. In addition, this study also revealed that ROCK pathway altered by environment played an important role in regulating the drug sensitivity of lung cancer cells. Hence, this 3D printed porous microgel is a promising lung cancer cell culture method, which shows potentional application in future cancer research and drug development.

The development of well-designed polylactic acid (PLA) based composite filaments through fused filament fabrication (FFF) is crucial, as PLA printed parts are characterized by a high brittleness. Here we focus on FFF composite formation using ductile poly (butylene adipate-co-terephthalate) (PBAT), the nanoclay cloisite and the chain extender Joncryl. A high modulus, flexibility, toughness and notched impact strength result upon combining PLA/PBAT (80:20; mass basis) with a sufficiently high cloisite amount (1–5 phr) supported by a suited Joncryl amount (0.3 phr). A fine PBAT dispersion is then ensured, as confirmed by scanning and transmission electron microscopy. For high cloisite amounts (e.g. 10 phr) the crystallinity and vicat softening temperature enhance but cloisite aggregation is unavoidable, leading to a strong reduction in tensile strain and toughness. Annealing increases crystallinity thus material strength, rigidity and impact, at least partially overruling the need of a fine dispersion. Novel radar charts are also reported to select an optimal bio-based blend suitable for different end-user applications by adjusting the composition and possible post-annealing of printed products.

Pore-forming toxins (PFTs) that attack host cells have shown to perform an essential role in bacterial infections. Neutralization of these toxins has become an attractive approach to promote the recovery of damaged host tissues. In this study, we propose an interconnected macroporous hydrogel containing polydiacetylene (PDA) nanoparticles to efficiently sense and bind PFTs. The PDA nanoparticles are fabricated through a self-assembly process and then mixed into the gelatin monomer solution for polymerization. Using cryogelation technology, we can obtain the nanoparticle-functionalized hydrogels with controlled interconnected pores and well-defined properties. Meanwhile, the obtained hydrogels with favorable biocompatibility show the capability of retaining the nanoparticles over a long time and efficiently binding the PFTs. In addition, the functional hydrogels with different pores present distinctive detoxification abilities. Overall, this work introduces a promising detoxification device that incorporates functional nanoparticles into the macroporous hydrogel and could be used as a wound dressing for local treatment of bacterial infections in the future. Keywords: Wound dressing device, Macroporous hydrogel, Nanoparticles, Detoxification

The aim of this study was to prepare PCL-PEG-PCL (PCEC) microspheres to protect camptothecin from hydrolysis, to extend its release time and to enhance its treatment efficacy on colorectal peritoneal carcinomatosis and tumor growth in mice. Camptothecin (CPT)-loaded PCL-PEG-PCL (PCEC) microspheres were prepared by oil-in-water emulsion solvent evaporation method. The particle size, morphological characteristics, encapsulation efficiency, in vitro drug release studies and in vitro cytotoxicity of CPT-loaded PCEC microspheres have been investigated. In vivo studies were carried out on Balb/c male mice bearing colorectal peritoneal carcinomatosis. CPT-loaded PCEC microspheres were applied to abdominal cavity of mice once a week. Free CPT was used as a positive control. On 14th day of treatment, mice were sacrificed and antitumor activities of CPT-loaded PCEC microspheres were evaluated. Compared with control group, a significant decrease in the number of tumor nodes was observed in group treated with CPT-loaded PCEC microspheres. Immunohistochemistry staining of tumor tissues with CD34 revealed that MVD positive cells were significantly reduced in CPT-loaded PCEC microspheres treated group in contrast to other groups (P0.05). The CPT-loaded PCEC microspheres were considered potentially useful to treat the abdominal metastases of colon carcinoma.

Polydiacetylene (PDA) is an excellent color-changing indicator. In this paper, we demonstrate a new and interesting kind of time–temperature chromatic sensor based on PDA vesicle and amphiphilic polymer. In presence of amphiphilic polymers, PDA vesicles could gradually transit from blue to red, which was irreversible and regularly depended on the temperature, time, and properties of amphiphilic polymer (including the concentration, molecular weight, molecular structure, hydrophobicity, and thermo-sensitive property). Higher concentration of amphiphilic polymers resulted in lower color-transition temperature and faster color-transition. Also, higher temperature led to faster color-transition. The color-changing of PDA/amphiphilic polymer matrix may have resulted from the higher temperature and gradual insertion of amphiphilic polymer into PDA, synergistically perturbing the conformation of PDA. The prepared PDA/F127, PDA/F68, PDA/L35 and PDA/Tween-20 aqueous matrix showed potential application in time–temperature chromatic sensors at around 10–50 °C. This work provides a new method to design time–temperature chromatic sensors.

Honokiol (HK) shows potential application in cancer treatment, but its poor water solubility restricts clinical application greatly. In this paper, monomethoxy poly(ethylene glycol)–poly(lactic acid) (MPEG–PLA) was synthesized by ring-opening polymerization and processed into nanoparticle for honokiol delivery. Chemical structure of the synthesized polymer was confirmed by 1 H NMR, and its molecular weight was determined by gel permeation chromatography (GPC). Honokiol loaded MPEG–PLA nanoparticles were prepared by solvent extract method. And particle size distribution, morphology, drug loading, drug release profile and anticancer activity in vitro were studied in detail. The described honokiol loaded MPEG–PLA nanoparticles in this paper might be a novel formulation for honokiol delivery.

In the present study, we prepared poly(ɛ-caprolactone)-poly(ethylene glycol)-poly(ɛ-caprolactone) (PCL-PEG-PCL, PCEC) nanomaterials by solvent-extraction method. The obtained PCEC nanomaterials were studied extensively for acute toxicity and genotoxicity using bacterial reverse mutation test (Ames test), chromosomal aberration test and mouse micronucleus test. All of the Sprague-Dawley rats did not show any mortality and clinical signs of toxicity after intravenous injection at the level of 2.4 g/kg body weight. Thus, the LD50 of PCEC nanomaterials was determined to be greater than 2.4 g/kg. In Ames test, PCEC nanomaterials were negative in Salmonella typhimurium strains TA97, TA98, TA100, TA102, and TA1535 with or without metabolic activation. PCEC nanomaterials did not induce chromosomal aberrations in cultured Chinese hamster lung cells up to 5000 μg/mL with or without metabolic activation. Micronucleus assay demonstrated that PCEC nanomaterials did not significantly increase micronucleated polychromatic erythrocytes (MNPCE) in the bone marrow of ICR mice or suppress bone marrow, indicating they did not cause chromosome aberrations. In conclusion, our results indicated that PCEC nanomaterials did not cause any acute toxicity and genotoxicity in our experimental conditions. Its potential to be a candidate of drug carrier is worth being further investigated.

In this work, a biodegradable and injectable in situ gel-forming controlled drug delivery system based on thermosensitive poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) hydrogel was studied. The prepared PCEC hydrogel undergoes temperature-dependent sol-gel-sol transition, which is a flowing sol at ambient temperature and turns into a non-flowing gel at around physiological body temperature. Furthermore, the sol-gel phase transition mechanism was investigated using (13)C-nuclear magnetic resonance imaging and a laser diffraction particle size analyzer. The in vitro release behaviors of several model drugs, including a hydrophilic small-molecule drug, a hydrophobic small-molecule drug and a macromolecular protein drug, from PCEC hydrogel were also investigated in detail. The results showed that the model drugs could be released from the PCEC hydrogel system over a sustained period. In addition, an anaesthesia assay was conducted using the tail flick latency (TFL) test to evaluate the in vivo controlled drug delivery effect of the PCEC hydrogel system. In the TFL assay, a lidocaine-loaded PCEC hydrogel produced significantly longer-lasting local anaesthetic effects compared with lidocaine aqueous solution at the same dose. Therefore, PCEC hydrogel is promising for use as an injectable local drug delivery system.

In this article, poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCL-PEG-PCL, PCEC) nanoparticles were successfully prepared for honokiol delivery in vitro. Blank or honokiol loaded PCL-PEG-PCL nanoparticles were prepared in moderate condition by solvent diffusion method without using any surfactants. The prepared blank PCL-PEG-PCL nanoparticles are mono-dispersed and smaller than 200 nm. The particle size increased with increase in polymer concentration and oil-water (O/W) ratio. The prepared PCL-PEG-PCL nanoparticles (40 mg/mL, ca. 106 nm) did not induce hemolysis in vitro. And the 50% inhibiting concentration (IC50) of it (48 h) on HEK293 cells was higher than 5 mg/mL. Honokiol could be efficiently loaded into PCL-PEG-PCL nanoparticles and released from these nanoparticles in an extended period in vitro. After honokiol (HK) was entrapped into PCL-PEG-PCL nanoparticles, the particle size increased with the increase in HK/PCEC mass ratio in feed, and the encapsulated honokiol retained potent anticancer activity in vitro. The PCL-PEG-PCL nanoparticle was suitable for honokiol delivery, and such honokiol loaded PCL-PEG-PCL nanoparticle was a novel honokiol formulation.

Self-assembled polymeric micelles are widely applied in drug delivery system (DDS). In this study, honokiol (HK) loaded micelles were prepared from biodegradable poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic character without any organic solvent. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of HK and PCEC. The particle size and zeta potential distribution of obtained micelles were determined using Malvern laser particle sizer, and spherical geometry were observed on atomic force microscope (AFM). Otherwise, the thermo-sensitivity of honokiol-loaded micelles was monitored. And the cytotoxicity results of drug loaded micelles showed that the encapsulated honokiol remained potent antitumor effect. Moreover, in vitro release profile demonstrated a significant difference between rapid release of free honokiol and much slower and sustained release of HK-loaded micelles. These results suggested that we have successfully prepared honokiol-loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for honokiol delivery in cancer chemotherapy.

In this article, blank anionic poly(epsilon-caprolactone)-poly(ethylene glycol)-poly(epsilon-caprolactone) (PCEC) and anionic mannan modified PCEC (MPCEC) nanoparticles with nearly the same particle size and zeta potential were prepared by emulsion solvent evaporation method. Human basic fibroblast growth factor (bFGF) was absorbed onto anionic nanoparticles surface due to electrostatic interaction. The obtained bFGF-nanoparticles complexes were injected subcutaneously into C57BL/6 mice at 20 microg of bFGF/dose on week 0, 1, 2 and 3. The mice serum was collected on week 4, and bFGF-specific autoantibody total IgG, IgG1 and IgG2a titer in serum was determined by ELISA. The results indicated that the autoantibody IgG, IgG1 and IgG2a titer of the mice immunized by bFGF-MPCEC complexes were higher than that immunized by either bFGF-PCEC or bFGF-Alum. This phenomenon might be due to that mannan functionalized MPCEC nanoparticles could be targeted to dendritic cells (DCs) to improve humoral immunity. The prepared anionic mannan modified PCEC nanoparticles (MPCEC) might have great potential application in vaccine delivery systems.

A series of PCL–Pluronic–PCL biodegradable block copolymers were successfully synthesized by ring opening polymerization of ɛ-caprolactone (ɛ-CL) initiated by Pluronic (PEG–PPG–PEG) macromonomer, which were characterized by 1 H NMR and FTIR. Their aqueous solution displayed special gel–sol transition with temperature increased from 4 °C to 70 °C, when the concentration was above corresponding critical gel concentration (CGC). The gel–sol phase diagram was recorded using test tube-inverting method, which depended not only on the hydrophilic/hydrophobic balance in macromolecular structure, but also on heating history of copolymer's aqueous solution. As a result, the gel–sol transition temperature range could be altered according to its practical application, which would be very useful as injectable drug delivery system. To illuminate the mechanism of gel–sol transition, we introduced a typical double layers shell/core structure of PCL–Pluronic–PCL micelles here. The hydrophobic interactions and partly crystallization might be the key gelation machanism for such special gel–sol transition behavior of PCL–Pluronic–PCL aqueous solution.