High-precision 3D printing of multi-branch vascular scaffold with plasticized PLCL thermoplastic elastomer.

Three-dimensional (3D) printing has emerged as a transformative technology for tissue engineering, enabling the production of structures that closely emulate the intricate architecture and mechanical properties of native biological tissues. However, the fabrication of complex microstructures with high accuracy using biocompatible, degradable thermoplastic elastomers poses significant technical obstacles. This is primarily due to the inherent soft-matter nature of such materials, which complicates real-time control of micro-squeezing, resulting in low fidelity or even failure. In this study, we employ Poly (L-lactide-co-ϵ-caprolactone) (PLCL) as a model material and introduce a novel framework for high-precision 3D printing based on the material plasticization process. This approach significantly enhances the dynamic responsiveness of the start-stop transition during printing, thereby reducing harmful errors by up to 93%. Leveraging this enhanced material, we have efficiently fabricated arrays of multi-branched vascular scaffolds that exhibit exceptional morphological fidelity and possess elastic moduli that faithfully approximate the physiological modulus spectrum of native blood vessels, ranging from 2.5 to 45 MPa. The methodology we propose for the compatibilization and modification of elastomeric materials addresses the challenge of real-time precision control, representing a significant advancement in the domain of melt polymer 3D printing. This innovation holds considerable promise for the creation of detailed multi-branch vascular scaffolds and other sophisticated organotypic structures critical to advancing tissue engineering and regenerative medicine.

Multiple targeted drugs carrying biodegradable membrane barrier: anti-adhesion, hemostasis, and anti-infection.

A multiple targeted drug carrying bilayer membrane for preventing an abdominal adhesion is prepared by electrospinning. Two bioactive drugs were successfully incorporated into this bilayer membrane and can be independently released from nanofibrous scaffolds without losing structural integrity and functionality of the anti-adhesion membrane. Besides, the drug release profile could be easily adjusted by optimizing the swelling behavior of the fibrous scaffold. The inner layer of the bilayered fibrous membranes loaded with carbazochrome sodium sulfonate (CA) showed an excellent vascular hemostatic efficacy and formed little clot during in vivo experiment. The outer layer loaded with tinidazole (TI) had outstanding antibacterial effect against the anaerobe. We believe this approach could serve as a model technique to guide the design of implants with drug delivery functions.

Research on preparation and antitumor activity of redox-responsive polymer micelles co-loaded with sorafenib and curcumin.

A novel redox-responsive mPEG-SS-PLA (PSP) polymeric micelle was synthesized and prepared for the delivery of sorafenib (SAF) and curcumin (CUR). And a series of validations were conducted to confirm the structure of the synthesized polymer carriers. Using the Chou-Talalay approach, the combination indexes (CI) of SAF and CUR were determined, and explore the inhibitory effects of the two drugs on HepG2R cells at different ratios. SAF/CUR-PSP polymeric micelles were prepared by thin film hydration method, and the physicochemical properties of nanomicelles were evaluated. The biocompatibility, cell uptake, cell migration, and cytotoxicity assays were assessed in HepG2R cells. The expression of the phosphoinositol-3 kinase (PI3K)/serine/threonine kinase (Akt) signaling pathway was detected by Western blot assay. Additionally, the tumor suppressive effect of SAF/CUR-PSP micelles was clearly superior to free drug monotherapy or their physical combination in HepG2 cell-induced tumor xenografts. The current study revealed that mPEG-SS-PLA polymer micelles loaded with SAF and CUR showed the enhanced therapeutic effects against hepatocellular carcinoma in vitro and in vivo models. It has promising applications for cancer therapy.

MPEG-PCL Nanomicelles Platform for Synergistic Metformin and Chrysin Delivery to Breast Cancer in Mice.

BACKGROUND: Metformin (MET) is a well-known anti-diabetic drug that also has anti-cancer effects. However, high therapeutic doses of MET on cancer cells and the low efficacy of combinatory therapeutic approaches limit its clinical application. Recent studies have shown that chrysin (CHR) can improve the pharmaceutical efficacy of MET by suppressing human telomerase reverse transcriptase (hTERT) and cyclin D1 gene expression. OBJECTIVE: This study aimed to develop different ratios of methoxy poly(ethylene glycol)-b-poly(e-caprolactone) (MPEG-PCL) micelles for breast cancer to co-deliver a synergistic CHR/MET combination. METHODS: CHR/MET drug-loaded micelles were prepared by modified thin-film hydration.Fourier infrared spectrum, gel permeation chromatography, transmission electron microscopy, and high-performance liquid chromatography were used to evaluate the physicochemical properties of nanostructures. Cell proliferation and cell apoptosis were assessed by MTT and Annexin V-FITC/PI double staining method. The gene expression of hTERT and cyclin D1 was measured by real-time PCR assay. A subcutaneous mouse T47D xenograft model was established to evaluate the in vivo efficiency. RESULTS: When the ratio of MPEG-PCL was 1:1.7, the highest drug loading rate and encapsulation efficiency of CHR (11.31±0.37) and MET (12.22±0.44) were observed. Uniform MPEG-PCL micelles of 51.70±1.91 nm allowed MET to incorporate with CHR, which were co-delivered to breast cancer cells. We demonstrated that CHR/MET co-delivery micelles showed a good synergistic effect on inhibiting proliferation in T47D cells (combination index=0.87) by suppressing hTERT and cyclin D1 gene expression. Compared to the free CHR/MET group, the apoptosis rate on T47D cells by CHR/MET nano-micelles significantly improved from 71.33% to 79.25%. The tumour volume and tumour weight of the CHR/MET group increased more slowly than that of the single-drug treatment group (P<0.05). Compared to the CHR/MET group, the tumour volume and tumour weight of the CHR/MET nano-micelle group decreased by 42% and 59%, respectively. CONCLUSION: We demonstrated that ratiometric CHR/MET micelles could provide an effective technique for the treatment of breast cancer.

Fully Reduced HMGB1-Containing Peptide-Based Polyurethane Scaffold with Minimal Functional Unit of Skin (MFUS) Enhances Large and Deep Wounded Skin Healing.

A novel peptide-based polymer is developed by lysine-diisocyanate (LDI), glycerol (Gly), and fully reduced HMGB1 (frHMGB1). This frHMGB1-LDI-Gly polymer either forms sponge-like foam (scaffold) or a hydrogel or a film under different reaction conditions. It degrades into nontoxic lysine, glycerol, and frHMGB1. The hydrogel glues tissues together and the glued tissues have strong mechanical properties. The film and scaffold provide the suitable environment for enhancing cell proliferation by releasing frHMGB1. The scaffold carries 1 mm diameter of full-thickness rat skin-island as a minimal functional unit of skin (MFUS) to treat large full thickness skin wounds, and the hydrogel glues the MFUS and scaffold with skin edges together (MFUS+Scaffold group). The scaffold treated wounds (Scaffold group) heal much faster than the wounds either treated with MFUS (MFUS group) or without treatment (Wound group). The MFUS+Scaffold treated wound regenerates more functional full-thickness skin with more hair follicles and sweat glands, higher CD146 and α-smooth muscle actin levels, more blood vessels and collagen productions, and less scar tissues when compared to the other three groups. The results demonstrate that the combination of frHMGB1-LDI-Gly polymer with MFUS provides a new tissue engineering approach for large full-thickness skin wound healing.

Collagen-Based Thiol-Norbornene Photoclick Bio-Ink with Excellent Bioactivity and Printability.

As the essential foundation of bioprinting technology, cell-laden bio-ink is confronted with the inevitable contradiction between printability and bioactivity. For example, type I collagen has been widely applied for its excellent biocompatibility; however, its relatively low self-assembly speed restricts the performance in high-precision bioprinting of cell-laden structures. In this study, we synthesize norbornene-functionalized neutral soluble collagen (NorCol) by the reaction of acid-soluble collagen (Col) and carbic anhydride in the aqueous phase. NorCol retains collagen triple-helical conformation and can be quickly orthogonally cross-linked to build a cell-laden hydrogel via a cell-friendly thiol-ene photoclick reaction. Moreover, the additional carboxyl groups produced in the reaction of carbic anhydride and collagen obviously improve the solubility of NorCol in neutral buffer and miscibility of NorCol with other polymers such as alginate and gelatin. It enables hybrid bio-ink to respond to multiple stimuli, resulting in continuous cross-linked NorCol networks in hybrid hydrogels. For the first time, the collagen with a triple helix structure and gelatin can be mixed and printed, keeping the integrity of the printed construct after gelatin's dissolution. The molecular interaction among giant collagen molecules allows NorCol hydrogel formation at a low concentration, which leads to excellent cell spreading, migration, and proliferation. These properties give NorCol flexible formability and excellent biocompatibility in temperature-, ion-, and photo-based bioprinting. We speculate that NorCol is a promising bio-ink for emerging demands in tissue engineering, regenerative medicine, and personalized therapeutics.

Controlled Antibiotics Release System through Simple Blended Electrospun Fibers for Sustained Antibacterial Effects.

Implantation of sustained antibacterial system after abdominal surgery could effectively prevent complicated intra-abdominal infection. In this study, a simple blended electrospun membrane made of poly(D,L-lactic-co-glycolide) (PLGA)/poly(dioxanone) (PDO)/Ciprofloxacin hydrochloride (CiH) could easily result in approximately linear drug release profile and sustained antibacterial activity against both Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). The addition of PDO changed the stack structure of PLGA, which in turn influenced the fiber swelling and created drug diffusion channels. It could be a good candidate for reducing postoperative infection or be associated with other implant to resist biofilm formation.

3D bioprinting of BMSC-laden methacrylamide gelatin scaffolds with CBD-BMP2-collagen microfibers.

Three-dimensional (3D) bioprinting combines biomaterials, cells and functional components into complex living tissues. Herein, we assembled function-control modules into cell-laden scaffolds using 3D bioprinting. A customized 3D printer was able to tune the microstructure of printed bone mesenchymal stem cell (BMSC)-laden methacrylamide gelatin scaffolds at the micrometer scale. For example, the pore size was adjusted to 282 ± 32 µm and 363 ± 60 µm. To match the requirements of the printing nozzle, collagen microfibers with a length of 22 ± 13 µm were prepared with a high-speed crusher. Collagen microfibers bound bone morphogenetic protein 2 (BMP2) with a collagen binding domain (CBD) as differentiation-control module, from which BMP2 was able to be controllably released. The differentiation behaviors of BMSCs in the printed scaffolds were compared in three microenvironments: samples without CBD-BMP2-collagen microfibers in the growth medium, samples without microfibers in the osteogenic medium and samples with microfibers in the growth medium. The results indicated that BMSCs showed high cell viability (>90%) during printing; CBD-BMP2-collagen microfibers induced BMSC differentiation into osteocytes within 14 days more efficiently than the osteogenic medium. Our studies suggest that these function-control modules are attractive biomaterials and have potential applications in 3D bioprinting.

Gold nanorod-embedded electrospun fibrous membrane as a photothermal therapy platform.

A strategy of using a gold nanorod (GNR)-loaded electrospun membrane as a photothermal therapy platform of cancer is reported. The strategy takes both the advantages of the excellent photothermal properties of GNRs to selectively kill the cancerous cells, and the widely used biodegradable electrospun membrane to serve as GNR-carrier and surgical recovery material. PEG modified GNRs were embedded into the electrospun fibrous membrane which was composed of PLGA and PLA-b-PEG with an 85:15 ratio. After incubation with the cells in the cell culture medium, the PEG-GNRs were released from the membrane and taken up by cancer cells, allowing the generation of heat upon NIR irradiation to induce cancer cell death. We have demonstrated that the use of PEG-GNR-embedded membrane selectively killed the cancerous cells and effectively inhibited cancer cell proliferation though in vitro experiments. The PEG-GNRs-loaded membrane is a promising material for postsurgical recovery of cancer.