Neuro-bone tissue engineering: Multiple potential translational strategies between nerve and bone.

Numerous tissue regeneration paradigms show evident neurological dependence, including mammalian fingertip, skin, and bone regeneration. The mature skeleton is innervated by an abundant nervous system that infiltrates the developing axial and appendicular bones and maintains the stability of the systemic skeletal system by controlling blood flow, regulating bone metabolism, secreting neurotransmitters, and regulating stem cell behavior. In recent years, neurotization in tissue-engineered bone has been considered as a promising strategy to effectively overcome the challenge of vascularization and innervation regeneration in the central zone of "critical-sized bone defects" that conventional tissue-engineered scaffolds are unable to handle, however, further validation is needed in relevant clinical applications. Therefore, this study reviews the mechanisms by which the nervous system regulates bone metabolism and regeneration through a variety of neurogenic or non-neurogenic factors, as well as the recent progress and design strategies of neuralized tissue-engineered bone, to provide new ideas for further studies on subsequent neural bone tissue engineering. STATEMENT OF SIGNIFICANCE: The interaction of nerve and bone tissue during skeletal development and repair has attracted widespread attention, with emerging evidences highlighting the regulation of bone metabolism and regeneration by the nervous system, but the underlying mechanisms have not been elucidated. Thus, further applications of neuro-bone tissue engineering still needs careful consideration. In this review, we summarize the numerous neurogenic and non-neurogenic factors which are involved in bone repair and regeneration, and further explore the current status of their application and biomaterial design in neuro-bone tissue engineering, and finally discuss the challenge and prospective for neuro-bone tissue engineering to facilitate its further development.

Hyaluronic acid-based glucose-responsive antioxidant hydrogel platform for enhanced diabetic wound repair.

Hyaluronic acid (HA)-based antioxidant hydrogels have achieved remarkable results in diabetic wound repair. However, the realization of their glucose-responsive antioxidant functions remains a significant challenge. In this study, we modified hyaluronic acid methacrylate (HAMA) with phenylboronic acid (PBA) and developed a glucose-responsive HA derivative (HAMA-PBA). A glucose-responsive HAMA-PBA/catechin (HMPC) hydrogel platform was then fabricated by forming a borate ester bond between HAMA-PBA and catechin. The results showed that the HMPC hybrid hydrogel not only had a three-dimensional network structure and Young's modulus similar to those of skin tissue, but also possessed biocompatibility. The HMPC hydrogel also showed unique glucose-responsive catechin release behavior and remarkable antioxidant capability, which could effectively eliminate intracellular reactive oxygen species and protect cells from oxidative stress damage (increased superoxide dismutase activity, stabilized reduced glutathione/oxidized glutathione ratio, and reduced malondialdehyde content). Additionally, in vitro and in vivo experimental results showed that the HMPC hydrogel effectively promoted angiogenesis (enhanced VEGF and CD31 expression) and reduced inflammatory responses (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within three weeks). This was a significant improvement as compared to that observed for the untreated control group and the HMP hydrogel group. These results indicated the potential for the application of the HMPC hydrogel for treating diabetic wounds. STATEMENT OF SIGNIFICANCE: At present, the delayed closure rate of diabetic chronic wounds caused by excessive reactive oxygen species (ROS) remains a worldwide challenge. Hyaluronic acid (HA)-based antioxidant hydrogels have made remarkable achievements in diabetic wound repair; however, the realization of their glucose-responsive antioxidant functions is a tough challenge. In this work, we developed a novel HA-based hydrogel platform with glucose-responsive antioxidant activity for rapid repair of diabetic wounds. In vitro and in vivo experimental results showed that the HMPC hydrogel could effectively promote angiogenesis (enhanced VEGF and CD31 expression) and reduce inflammatory response (decreased IL-6 level and increased IL-10 level), thus rapidly repairing diabetic wounds (within 3 weeks). These results indicated the potential of the HMPC hydrogel for application in diabetic wound treatment.

Poly(ß-cyclodextrin)/platinum prodrug supramolecular nano system for enhanced cancer therapy: Synthesis and in vivo study.

The use of cisplatin is restricted by systemic toxicity and drug resistance. Supramolecular nano-drug delivery systems involving drugs as building blocks circumvent these limitations promisingly. Herein, we describe a novel supramolecular system [Pt(IV)-SSNPs] based on poly(ß-cyclodextrin), which was synthesized for efficient loading of adamantly-functionalized platinum(IV) prodrug [Pt(IV)-ADA2] via the host-guest interaction between ß-cyclodextrin and adamantyl. Pt(IV)-ADA2 can be converted to active cisplatin in reducing environment in cancer cells, which further reduces systemic toxicity. The introduction of the adamantane group-tethered mPEG2k endowed the Pt(IV)-SSNPs with a longer blood circulation time. In vitro assays exhibited that the Pt(IV)-SSNPs could be uptaken by CT26 cells, resulting in cell cycle arrest in the G2/M and S phases, together with apoptosis. Furthermore, the Pt(IV)-SSNPs showed effective tumor accumulation, better antitumor effect, and negligible cytotoxicity to major organs. These results indicate that supramolecular nanoparticles are a promising platform for efficient cisplatin delivery and cancer treatment.

Hydrogel Combined with Phototherapy in Wound Healing.

Wound healing is a complex biological process that involves tissue regeneration. Traditional wound dressings are dry, cannot provide a moist environment for wound healing, and do not have high antibacterial properties. Hydrogels, which are capable of retaining large amounts of water, can create a moist healing environment. Currently, phototherapies have exhibited a high potential for the treatment of bacterial infections. Therefore, combining hydrogels with phototherapy can adequately overcome the shortcomings of traditional wound treatment methods and show great potential for wound healing owing to their high efficiency, low irritation, and good antibacterial performance. In this review, the application of hydrogels combined with phototherapy in wound healing is summarized. First, the basic principles of photodynamic therapy and photothermal therapy are briefly introduced. In addition, the progress of the application of hydrogel combined with phototherapy in wound healing is systematically investigated. Finally, the challenges and prospects of combining hydrogel with phototherapy in wound healing are discussed.

Development of poly(p-coumaric acid) as a self-anticancer nanocarrier for efficient and biosafe cancer therapy.

Using biocompatible polymers with potential therapeutic activity is an appealing strategy for the development of new functional drug carriers. In this study, we report the synthesis of therapeutic poly(p-coumaric acid) (PCA) from p-coumaric acid, a common plant phenolic acid with multiple bioactivities. The prepared PCA was formulated into nanoparticles (NPs) using the nanoprecipitation method and docetaxel (DTX) was encapsulated to form DTX-loaded PCA NPs (DTX@PCA NPs). Their potential as a nanocarrier for anticancer drug delivery was systematically evaluated. The DTX@PCA NPs not only had a small particle size and good stability, but also exhibited superior in vitro anticancer activity, anti-metastasis ability compared with free drugs, and preferable cellular uptake by tumor cells. In addition, the three-dimensional tumor spheroid assay revealed the effective tumor penetration and anticancer activity of the DTX@PCA NPs. Importantly, the DTX@PCA NPs preferentially accumulated in tumors and prolonged systemic circulation, significantly inhibiting tumor growth in vivo and simultaneously attenuating the side effects of DTX. Interestingly, the blank PCA NPs themselves also exhibited additional tumor suppression activity to some extent with high biosafety, further indicating the significant potential of PCA as a novel self-therapeutic nanocarrier for anticancer drug delivery and enhanced cancer therapy.

Stimuli-responsive cyclodextrin-based supramolecular assemblies as drug carriers.

Cyclodextrins (CDs) are widely employed in biomedical applications because of their unique structures. Various biomedical applications can be achieved in a spatiotemporally controlled manner by integrating the host-guest chemistry of CDs with stimuli-responsive functions. In this review, we summarize the recent advances in stimuli-responsive supramolecular assemblies based on the host-guest chemistry of CDs. The stimuli considered in this review include endogenous (pH, redox, and enzymes) and exogenous stimuli (light, temperature, and magnetic field). We mainly discuss the mechanisms of the stimuli-responsive ability and present typical designs of the corresponding supramolecular assemblies for drug delivery and other potential biomedical applications. The limitations and perspectives of CD-based stimuli-responsive supramolecular assemblies are discussed to further promote the translation of laboratory products into clinical applications.

Redox-responsive self-assembled polymeric nanoprodrug for delivery of gemcitabine in B-cell lymphoma therapy.

Gemcitabine, as a standard and classic strategy for B-cell lymphoma in the clinic, is limited by its poor pharmacodynamics. Although stimuli-responsive polymeric nanodelivery systems have been widely investigated in the past decade, issues such as complicated procedures, low loading capacity, and uncontrollable release kinetics still hinder their clinical translation. In view of the above considerations, we attempt to construct hyperbranched polyprodrug micelles with considerable drug loading via simple procedures and make use of the particularity of the tumor microenvironment to ensure that the micelles are "inactivated" in normal tissues and "activated" in the tumor microenvironment. Hence, in this work, a redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) with considerable loading capacity (≈ 24.6%) exhibited on-demand and accurate control of gemcitabine release under a simulated tumor microenvironment and thus significantly induced the apoptosis of B-cell lymphoma in vitro. Moreover, in the A20 tumor xenograft murine model, GSP NPs efficiently decreased the expansion of tumor tissues with minimal systemic toxicity. In summary, these redox-responsive and self-assembling GSP NPs with a facile one-pot synthesis procedure may hold great potency in clinical translation for enhanced chemotherapy of B-cell lymphoma. STATEMENT OF SIGNIFICANCE: A redox-responsive polymeric gemcitabine-prodrug (GEM-S-S-PEG) was one-pot synthesized via facile esterification and acylation. The self-assembled subsize (< 100 nm) GEM-S-S-PEG (GSP NPs) exhibited significant tumor therapeutic effects in vitro and in vivo. The polyprodrug GEM-S-S-PEG prepared in this study shows the great potential of redox-responsive nanodrugs for antitumor activity, which provides a reference value for the optimization of the design of functional polyprodrugs.

Poly(disulfide)s: From Synthesis to Drug Delivery.

Bioresponsive polymers have been widely used in drug delivery because of their degradability. For example, poly(disulfide)s with repeating disulfide bonds in the main chain have attracted considerable research attention. The characteristics of the disulfide bonds, including their dynamic and reversible properties and their responsiveness to stimuli such as reductants, light, heat, and mechanical force, make them ideal platforms for on-demand drug delivery. This review introduces the synthesis methods and applications of poly(disulfide)s. Furthermore, the synthesis methods of poly(disulfide)s are classified on the basis of the monomers used: oxidative step-growth polymerization with dithiols, ring-opening polymerization with cyclic disulfides, and polymerization with linear disulfides. In addition, recent advances in poly(disulfide)s for the delivery of small-molecule or biomacromolecular drugs are discussed. Quantum-dot-loaded poly(disulfide) delivery systems for imaging are also included. This review provides an overview of the various design strategies employed in the construction of poly(disulfide) platforms to inspire new applications in the field of drug delivery.

Advances in Encapsulation and Delivery Strategies for Islet Transplantation.

Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic ß-cells in response to autoimmune reactions. Shapiro et al. conducted novel islet transplantation with a glucocorticoid-free immunosuppressive agent in 2000 and achieved great success; since then, islet transplantation has been increasingly regarded as a promising strategy for the curative treatment of T1DM. However, many unavoidable challenges, such as a lack of donors, poor revascularization, blood-mediated inflammatory reactions, hypoxia, and side effects caused by immunosuppression have severely hindered the widespread application of islet transplantation in clinics. Biomaterial-based encapsulation and delivery strategies are proposed for overcoming these obstacles, and have demonstrated remarkable improvements in islet transplantation outcomes. Herein, the major problems faced by islet transplantation are summarized and updated biomaterial-based strategies for islet transplantation, including islet encapsulation across different scales, delivery of stem cell-derived beta cells, co-delivery of islets with accessory cells and immunomodulatory molecules are highlighted.

Platinum-based chemotherapy via nanocarriers and co-delivery of multiple drugs.

Platinum-based anticancer drugs can inhibit the growth of cancer cells by disrupting DNA replication, which makes them widely applicable in clinics for treating tumors and cancers. However, owing to the intrinsic or acquired drug resistance and severe side effects caused in the treatment, their successful clinical applications have been limited. Various strategies have been used to address these challenges. Nanocarriers have been used for platinum drug delivery because they can be effectively deposited in tumor tissues to reduce the damage to normal organs for an enhanced permeability and retention (EPR) effect. Furthermore, for synergizing the function of platinum-based drugs with different mechanisms to decrease the toxicities, multicomponent chemotherapy has become an imperative strategy in clinical cancer treatments. This review aims to introduce the mechanisms of action and limitations of platinum-based drugs in clinics, followed by providing the current advancement of nanocarriers including lipids, polymers, dendrimers, micelles and albumin for platinum drug delivery in cancer treatments. In addition, multicomponent chemotherapy based on platinum drugs is introduced in detail. Finally, the prospects of multicomponent chemotherapy for cancer treatment are discussed as well.