Advanced Nanomaterials in Medical 3D Printing.

3D printing is now recognized as a significant tool for medical research and clinical practice, leading to the emergence of medical 3D printing technology. It is essential to improve the properties of 3D-printed products to meet the demand for medical use. The core of generating qualified 3D printing products is to develop advanced materials and processes. Taking advantage of nanomaterials with tunable and distinct physical, chemical, and biological properties, integrating nanotechnology into 3D printing creates new opportunities for advancing medical 3D printing field. Recently, some attempts are made to improve medical 3D printing through nanotechnology, providing new insights into developing advanced medical 3D printing technology. With high-resolution 3D printing technology, nano-structures can be directly fabricated for medical applications. Incorporating nanomaterials into the 3D printing material system can improve the properties of the 3D-printed medical products. At the same time, nanomaterials can be used to expand novel medical 3D printing technologies. This review introduced the strategies and progresses of improving medical 3D printing through nanotechnology and discussed challenges in clinical translation.

3D printed elastic hydrogel conduits with 7,8-dihydroxyflavone release for peripheral nerve repair.

Nerve guide conduit is a promising treatment for long gap peripheral nerve injuries, yet its efficacy is limited. Drug-releasable scaffolds may provide reliable platforms to build a regenerative microenvironment for nerve recovery. In this study, an elastic hydrogel conduit encapsulating with prodrug nanoassemblies is fabricated by a continuous 3D printing technique for promoting nerve regeneration. The bioactive hydrogel is comprised of gelatin methacryloyl (GelMA) and silk fibroin glycidyl methacrylate (SF-MA), exhibiting positive effects on adhesion, proliferation, and migration of Schwann cells. Meanwhile, 7,8-dihydroxyflavone (7,8-DHF) prodrug nanoassemblies with high drug-loading capacities are developed through self-assembly of the lipophilic prodrug and loaded into the GelMA/SF-MA hydrogel. The drug loading conduit could sustainedly release 7,8-DHF to facilitate neurite elongation. A 12 â€‹mm nerve defect model is established for therapeutic efficiency evaluation by implanting the conduit through surgical suturing with rat sciatic nerve. The electrophysiological, morphological, and histological assessments indicate that this conduit can promote axon regeneration, remyelination, and function recovery by providing a favorable microenvironment. These findings implicate that the GelMA/SF-MA conduit with 7,8-DHF release has potentials in the treatment of long-gap peripheral nerve injury.

Novel microporous resin-based polymer device for sustained glipizide release: Production, characterization and pharmacokinetic study.

The objective of this study was to explore an innovative sustained release technology and design a new microporous resin-based polymer device (RPD) for controlled release of glipizide (GZ). Photocurable resin was applied to prepare the resin layer to control GZ release. The impact of formulation parameters consisting of the type and amount of pore formers and pH modifiers, photocurable curing time as well as the weight of resin layer on GZ release were examined. The GZ-RPD was fabricated applying 24 mg of resin layer with PEG400 (100 % of the resin weight) as pore former and 10 mg of Na2CO3 as pH modifier. Scanning electron microscopy (SEM) demonstrated resin particles presenting a porous structure constituted the resin layer. The GZ-RPD possessed prolonged Tmax and reduced Cmax relative to commercial tablets. The relative bioavailability of the RPDs as well as commercial tablets was 93.65 % since the AUC0-24 h were 6111.05 ± 238.89 ng·h/mL and 6525.09 ± 760.59 ng h/mL, respectively. The release mechanism of the GZ-RPD was discussed. This paper provided an innovative concept to produce controlled GZ release oral formulation fabricated by photocurable resin, which demonstrated both excellent in vitro release and in vivo pharmacokinetics.

Strategies for improving adipose-derived stem cells for tissue regeneration.

Adipose-derived stem cells (ADSCs) have promising applications in tissue regeneration. Currently, there are only a few ADSC products that have been approved for clinical use. The clinical application of ADSCs still faces many challenges. Here, we review emerging strategies to improve the therapeutic efficacy of ADSCs in tissue regeneration. First, a great quantity of cells is often needed for the stem cell therapies, which requires the advanced cell expansion technologies. In addition cell-derived products are also required for the development of 'cell-free' therapies to overcome the drawbacks of cell-based therapies. Second, it is necessary to strengthen the regenerative functions of ADSCs, including viability, differentiation and paracrine ability, for the tissue repair and regeneration required for different physiological and pathophysiological conditions. Third, poor delivery efficiency also restricts the therapeutic effect of ADSCs. Effective methods to improve cell delivery include alleviating harsh microenvironments, enhancing targeting ability and prolonging cell retention. Moreover, we also point out some critical issues about the sources, effectiveness and safety of ADSCs. With these advanced strategies to improve the therapeutic efficacy of ADSCs, ADSC-based treatment holds great promise for clinical applications in tissue regeneration.

Development and validation of the interpretability analysis system based on deep learning model for smart image follow-up of nail pigmentation.

Background: Nail pigmentation can be a clinical manifestation of malignant melanoma and a variety of benign diseases. Nail matrix biopsy for pathologic examination, the gold standard for diagnosis of subungual melanoma, is a painful procedure and may result in nail damage. Therefore, there is a great need for non-invasive methods and long-term follow-up for nail pigmentation. The objective of this study is to establish an intelligent precursor system to provide convenient monitoring for nail pigmentation, early warning subungual melanoma, and reduce nail biopsies to the minimum necessary. Methods: Dermoscopic images of nail lesions were obtained from outpatients between 2019 and 2020. The images were divided into the training set and the test set using k-fold cross validation at a ratio of 10:1. The deep learning model is developed based on the Pytorch framework. The model structure is optimized using the image segmentation model U-Net. An image segmentation module analyzed the contours of the whole nail plate and pigmented area according to the boundary features of the input images and a rule calculation module used the output information of the segmentation model to automatically analyze specific indicators referring to the "ABCDEF" rule. The model's results were compared with those of clinical experts. Results: From 550 dermoscopic images of nail lesions obtained, 500 were selected randomly as the training set, and the remaining 50 as the test set. Our image segmentation module realized automatic segmentation of the pigmented area and the whole nail plate with dice coefficient to be 0.8711 and 0.9652, respectively. Five qualitative indicators were selected in the interpretability analysis system and the models showed a certain degree of consistency with the evaluation by clinical experts, i.e., R2 for area ratio vs. breadth score was 0.8179 (P<0.001), for mean pixel value vs. pigment score was 0.7149 (P<0.001), for evenness vs. pigment score was 0.5247 (P<0.001). Conclusions: The proposed system made accurate segmentation of the nail plate and pigmented area and achieved medically interpretable index analysis. It is potentially a primer of an intelligent follow-up system that will enable convenient and spatially unaffected management and monitoring of nail pigmentation. It may provide clinicians with understandable auxiliary information for diagnosis.

Nerve transfer with 3D-printed branch nerve conduits.

Background: Nerve transfer is an important clinical surgical procedure for nerve repair by the coaptation of a healthy donor nerve to an injured nerve. Usually, nerve transfer is performed in an end-to-end manner, which will lead to functional loss of the donor nerve. In this study, we aimed to evaluate the efficacy of 3D-printed branch nerve conduits in nerve transfer. Methods: Customized branch conduits were constructed using gelatine-methacryloyl by 3D printing. The nerve conduits were characterized both in vitro and in vivo. The efficacy of 3D-printed branch nerve conduits in nerve transfer was evaluated in rats through electrophysiology testing and histological evaluation. Results: The results obtained showed that a single nerve stump could form a complex nerve network in the 3D-printed multibranch conduit. A two-branch conduit was 3D printed for transferring the tibial nerve to the peroneal nerve in rats. In this process, the two branches were connected to the distal tibial nerve and peroneal nerve. It was found that the two nerves were successfully repaired with functional recovery. Conclusions: It is implied that the two-branch conduit could not only repair the peroneal nerve but also preserve partial function of the donor tibial nerve. This work demonstrated that 3D-printed branch nerve conduits provide a potential method for nerve transfer.

3D printing of functional nerve guide conduits.

Nerve guide conduits (NGCs), as alternatives to nerve autografts and allografts, have been widely explored as an advanced tool for the treatment of peripheral nerve injury. However, the repairing efficiency of NGCs still needs significant improvements. Functional NGCs that provide a more favorable microenvironment for promoting axonal elongation and myelination are of great importance. In recent years, 3D printing technologies have been widely applied in the fabrication of customized and complex constructs, exhibiting great potential for tissue engineering applications, especially for the construction of functional NGCs. In this review, we introduce the 3D printing technologies for manufacturing functional NGCs, including inkjet printing, extrusion printing, stereolithography-based printing and indirect printing. Further, we summarize the current methods and strategies for constructing functional NGCs, such as designing special conduit architectures, using appropriate materials and co-printing with different biological cues. Finally, the challenges and prospects for construction of functional NGCs are also presented.

Microfluidic Assembly: An Innovative Tool for the Encapsulation, Protection, and Controlled Release of Nutraceuticals.

Nutraceuticals have been gradually accepted as food ingredients that can offer health benefits and provide protection against several diseases. It is widely accepted due to potential nutritional benefits, safety, and therapeutic effects. Most nutraceuticals are vulnerable to the changes in the external environment, which leads to poor physical and chemical stability and absorption. Several researchers have designed various encapsulation technologies to promote the use of nutraceuticals. Microfluidic technology is an emerging approach which can be used for nutraceutical delivery with precise control. The delivery systems using microfluidic technology have obtained much interest in recent years. In this review article, we have summarized the recently introduced nutraceutical delivery platforms including emulsions, liposomes, microspheres, microgels, and polymer nanoparticles based on microfluidic techniques. Emphasis has been made to discuss the advantages, preparations, characterizations, and applications of nutraceutical delivery systems. Finally, the challenges, several up-scaling methods, and future expectations are discussed.

Nanoemulsion-based delivery approaches for nutraceuticals: fabrication, application, characterization, biological fate, potential toxicity and future trends.

In the modern food industry, people are paying more and more attention to the use of edible nanoemulsions to encapsulate, protect and deliver lipophilic functional ingredients, such as volatile additives, polyphenols, aromas, pigments, proteins, vitamins, oil-soluble flavors, preservatives, etc., which are the current global needs. Nanoemulsions are constructed with droplets of nano range size and they offer many potential advantages over conventional emulsions including the delivery of both hydrophilic and hydrophobic compounds, higher stability, better antibacterial properties, good taste experience, higher affinity, longer shelf-life and improvement of the bioavailability of components. Moreover, they are highly capable of improving the wettability and/or solubility of poorly water-soluble compounds, which may result in better pharmacokinetic and pharmacodynamic properties of nutraceutical compounds. On the other hand, oral nanoemulsions also have certain risks, such as their ability to change the biological fate of biologically active ingredients in the gastrointestinal tract and the potential toxicity of certain ingredients used in their production. This review article summarizes the manufacturing, application, characterization, biological fate, potential toxicity, and future challenges and trends of nanoemulsions, and focuses on nanoemulsion-based nutraceutical delivery approaches suitable for the food industry.

A 3D-Printed Self-Adhesive Bandage with Drug Release for Peripheral Nerve Repair.

Peripheral nerve injury is a common disease that often causes disability and challenges surgeons. Drug-releasable biomaterials provide a reliable tool to regulate the nerve healing-associated microenvironment for nerve repair. Here, a self-adhesive bandage is designed that can form a wrap surrounding the injured nerve to promote nerve regeneration and recovery. Via a 3D printing technique, the bandage is prepared with a special structure and made up of two different hydrogel layers that can adhere to each other by a click reaction. The nanodrug is encapsulated in one layer with a grating structure. Wrapping the injured nerve, the grating layer of the bandage is closed to the injured site. The drug can be mainly released to the inner area of the wrap to promote the nerve repair by improving the proliferation and migration of Schwann cells. In this study, the bandage is used to assist the neurorrhaphy for the treatment of complete sciatic nerve transection without obvious defect in rats. Results indicate that the self-adhesive capacity can simplify the installation process and the drug-loaded bandage can promote the repairing of injured nerves. The demonstrated 3D-printed self-adhesive bandage has potential application in assisting the neurorrhaphy for nerve repair.

Fabrication of a novel drug-resin combination device for controlled release of dextromethorphan hydrobromide.

The implimentation of newer technologies in drug delivery system have always been the focus of pharmaceutical scientists with advancement of technologies. In this investigation, a novel controlled-release drug-resin combination device (DRC) was designed using dental resin to control the release of dextromethorphan hydrobromide (DH). The influence of different factors on in-vitro drug release were investigated. A Box-Behnken design was used to select the optimized DRC formulation. The optimized DH loaded DRC (DH-DRC) was prepared using 59.88% of PEG400, 16 mg of dental resin and 6.64 mg of sodium chloride (NaCl). The DH releases at 2 h, 4 h and 8 h of the optimized formulation were significantly close to the predicted responses. The pharmacokinetic study in rabbits showed DH-DRC had prolonged tmax and apparently reduced Cmax compared with commercial tablets and the AUC0-24h of DH-DRC was slightly higher than commercial tablets. This study confirmed the novel DRC could control the release of drug. It concluded that DRC would be a promising and alternative approach for the development of controlled release dosage form.

Recent Advances in Inhaled Formulations and Pulmonary Insulin Delivery Systems.

Insulin (INS) therapy played a great role in patients with type 1 and type 2 diabetes to regulate blood glucose levels. Although hypodermic injection was commonly used for insulin delivery, it had some disadvantages such as pain, needle phobia and the risk of infection. Therefore, pulmonary insulin delivery had been developed as an alternative method to overcome the therapeutic challenges in recent years since pulmonary insulin administration showed great improvements in rapid action and circumvention of first-pass hepatic metabolism. This review described the most recent developments in pulmonary insulin administration. Firstly, the structure and physiology of the lung cavity were introduced. Next, the advantages and disadvantages of pulmonary administration were discussed. Then some new dosage forms for pulmonary insulin were investigated including carriers based on surfactants and carriers based on polymers. Finally, innovate insulin inhalers and formulations were also described.

Dental resin as controlled release layer for the development of an innovative long-acting intra-oral delivery system.

The objective of the present study was to develop a novel long-acting intra-oral delivery system (LIDS) to overcome the frequent administration by the nonparenteral route with Huperzine A (HupA) as a model drug. HupA-LIDS was prepared using a magnetic drug delivery with dental resin as release controlling layer for long-term release of HupA. The factors that influenced the drug release comprised of the type and amount of pore formers, the speed of shaker, resin layer weight and drug loading. These factors were evaluated and optimized. The in-vitro release studies showed that the system was able to deliver HupA in an approximately zero-order kinetic. The SEM study showed that the multiple orifices on the surface of a resin layer formed due to presence of pore formers, which contributed to the HupA release. The pharmacokinetic study in rabbits demonstrated the HupA-LIDS could be released in vivo for more than 8 days with prolonged Tmax and significantly reduced Cmax in comparison with commercial tablets. This study provided some pioneering ideas for developing intra-oral extended release drug delivery system using dental resin as release controlling materials. The optimized HupA-LIDS can make excellent sustained release and have the potential for the long-acting product in the therapy of Alzheimer's disease.

Glucose-Responsive Microspheres as a Smart Drug Delivery System for Controlled Release of Insulin.

BACKGROUND AND OBJECTIVES: Diabetes mellitus, a disease of glucose regulation, has become one of the most common medical problems in the world. At present, alternative therapy for diabetes has, to a large extent, been widely concerned with the improvement of treatment efficacy. The aims of this study were to characterize and evaluate the surface morphology of the novel glucose-responsive injectable microspheres containing insulin, along with their in vitro release and in vivo efficacy. METHODS: In this study, glucose-responsive microspheres as an emerging smart drug delivery system for controlled release of insulin were developed by an improved water-in-oil-in-water (W/O/W) double emulsion preparation method. Here, methoxypolyethylene glycol-hydrazone-4-methoxypolyethylene glycol benzoate (mPEG-Hz-mPEG4AB) was synthesized as a pH-responsive carrier. RESULTS: The microspheres had a good spherical structure with a particle size of 5 ~ 10 µm. Approximately 61% of insulin was released in 15 h under a high glucose environment but was barely released within the normal glucose range in in vitro studies. After a subcutaneous injection of insulin microspheres in rats, blood glucose levels rapidly decreased within 2 h and could be maintained for 2 days in the normal range. Histopathological evaluation indicated that the microspheres were almost non-irritating. CONCLUSIONS: The pH-responsive mPEG-Hz-mPEG4AB could be used as an efficient insulin microsphere carrier, and the optimized microspheres had good morphology and sustained hypoglycemic effect.