Stimuli-Responsive Aptamer-Drug Conjugates for Targeted Drug Delivery and Controlled Drug Release.

Chemotherapy is widely used for cancer therapy but with unsatisfied efficacy, mainly due to the inefficient delivery of anticancer agents. Among the critical "five steps" drug delivery process, internalization into tumor cells and intracellular drug release are two important steps for the overall therapeutic efficiency. Strategy based on active targeting or TME-responsive is developed individually to improve therapeutic efficiency, but with limited improvement. However, the combination of these two strategies could potentially augment the drug delivery efficiency and therapeutic efficiency, consequently. Therefore, this work constructs a library of stimuli-responsive aptamer-drug conjugates (srApDCs), as "dual-targeted" strategy for cancer treatment that enables targeted drug delivery and controlled drug release. Specifically, this work uses different stimuli-responsive linkers to conjugate a tumor-targeting aptamer (i.e., AS1411) with drugs, forming the library of srApDCs for targeted cancer treatment. This design hypothesis is validated by the experimental data, which indicated that the aptamer could selectively enhance uptake of the srApDCs and the linkers could be cleaved by pathological cues in the TME to release the drug payload, leading to a significant enhancement of therapeutic efficacy. These results underscore the potential of the approach, providing a promising methodology for cancer therapy.

The post-chemotherapy changes of tumor physical microenvironment: Targeting extracellular matrix to address chemoresistance.

The tumor physical microenvironment (TPME) contributes to cancer chemoresistance in both mechanical and mechanobiological approaches. Along with chemotherapy, the tumor microenvironment undergoes dramatic changes, most of which can regulate TPME through extracellular matrix (ECM) remodeling and related signaling pathways. However, there is still no discussion about the post-chemotherapy TPME changes mediated by ECM remodeling, and consequent impact on chemoresistance. Herein, we summarize the TPME alterations induced by chemotherapy and corresponding influence on chemotherapy response of cancer cells in context of ECM. The response of cancer cell to chemotherapy, imposed by post-chemotherapy ECM, are discussed in both mechanical (ECM physical features) and mechanobiological (ECM-responsive signaling pathways) manner. In the end, we present ECM remodeling and related signaling pathways as two promising clinic strategies to relieve or overcome chemoresistance induced by TPME change, and summarize the corresponding therapeutic agents currently being tested in clinical trials.

A New Strategy to Elevate Absorptivity of AIEgens for Intensified NIR-II Emission and Synergized Multimodality Therapy.

High-efficiency absorptivity is crucial for the construction of high-performance luminescent materials, especially the long-wavelength near-infrared II (NIR-II) materials; thus seeking an efficient and universal strategy to elevate the absorptivity is extremely important but is still an intractable challenge. In this work, a simple but efficient design strategy is discovered, involving the introduction of gold(I) unit that could effectively elevate the absorptivity of aggregation-induced-emission luminogens (AIEgens). As a result of the efficient elevation of absorptivity, the representative AIE-active TBTP-Au shows more superior NIR-II (1220 nm) luminescence, much higher photothermal conversion efficiency, and unique intracellular reactive oxygen species (ROS) generating ability compared with that of the TBTP ligand. Taking advantage of these improvements, the fabricated tumor-targeting TBTP-Au-cRGD nanoparticles achieve specific NIR-II tumorous imaging in vivo and exert high-efficiency cancer therapy via the synergistic chemotherapy and photothermal therapy. Thus, this work provides a new and efficient strategy to construct high-absorption luminescent materials and demonstrates the great potential of gold(I)-based AIEgens as multifunctional theranostic agents.

Combination Therapy of Lox Inhibitor and Stimuli-Responsive Drug for Mechanochemically Synergistic Breast Cancer Treatment.

Chemotherapy based on small molecule drugs, hormones, cycline kinase inhibitors, and monoclonal antibodies has been widely used for breast cancer treatment in the clinic but with limited efficacy, due to the poor specificity and tumor microenvironment (TME)-caused diffusion barrier. Although monotherapies targeting biochemical cues or physical cues in the TME have been developed, none of them can cope with the complex TME, while mechanochemical combination therapy remains largely to be explored. Herein, a combination therapy strategy based on an extracellular matrix (ECM) modulator and TME-responsive drug for the first attempt of mechanochemically synergistic treatment of breast cancer is developed. Specifically, based on overexpressed NAD(P)H quinone oxidoreductase 1 (NQO1) in breast cancer, a TME-responsive drug (NQO1-SN38) is designed and it is combined with the inhibitor (i.e., ß-Aminopropionitrile, BAPN) for Lysyl oxidases (Lox) that contributes to the tumor stiffness, for mechanochemical therapy. It is demonstrated that NQO1 can trigger the degradation of NQO1-SN38 and release SN38, showing nearly twice tumor inhibition efficiency compared with SN38 treatment in vitro. Lox inhibition with BAPN significantly reduces collagen deposition and enhances drug penetration in tumor heterospheroids in vitro. It is further demonstrated that the mechanochemical therapy showed outstanding therapeutic efficacy in vivo, providing a promising approach for breast cancer therapy.

Differential Responses of Primary Astrocytes Under Hyperthermic Temperatures.

Astrocyte is the most abundant cells in brain and plays critical roles in brain homeostasis and functions. Although hyperthermia (or fever) is a common symptom in patients, its influence on astrocyte viability, morphology, and functions remains elusive. Here we developed an in vitro astrocyte culture system capable of precisely controlling culture temperature to study astrocyte responses under clinically-relevant hyperthermic temperatures (38 ∼ 41 °C). We found that hyperthermia in this temperature range does not alter cell morphology, but significantly affects cell viability, activation and functions. Specifically, high-hyperthermia (40 °C and 41 °C) causes irreversible and permanent damages to astrocytes and compromises their normal viability and functionalities repairing damaged neural tissue, recycling neurotransmitters, and promoting brain development, while mild-hyperthermia (38 °C and 39 °C) induces astrocyte activation and cytokine secretion without significant decreases in cell viability. This study sheds new insights into our understanding of various fever-associated symptoms, enabling the future development of astrocyte-targeted therapy to treat brain diseases via hyperthermia.

Conductive Hydrogel Conduits with Growth Factor Gradients for Peripheral Nerve Repair in Diabetics with Non-Suture Tape.

Diabetic patients suffer from peripheral nerve injury with slow and incomplete regeneration owing to hyperglycemia and microvascular complications. This study develops a graphene-based nerve guidance conduit by incorporating natural double network hydrogel and a neurotrophic concentration gradient with non-invasive treatment for diabetics. GelMA/silk fibroin double network hydrogel plays quadruple roles for rapid setting/curing, suitable mechanical supporting, good biocompatibility, and sustainable growth factor delivery. Meanwhile, graphene mesh can improve the toughness of conduit and enhance conductivity of conduit for regeneration. Here, novel silk tapes show quick and tough adhesion of wet tissue by dual mechanism to replace suture step. The in vivo results demonstrate that gradient concentration of netrin-1 in conduit have better performance than uniform concentration caused by chemotaxis phenomenon for axon extension, remyelination, and angiogenesis. Altogether, GelMA/silk graphene conduit with gradient netrin-1 and dry double-sided adhesive tape can significantly promote repairing of peripheral nerve injury and inhibit the atrophy of muscles for diabetics.

A 3D, Magnetically Actuated, Aligned Collagen Fiber Hydrogel Platform Recapitulates Physical Microenvironment of Myoblasts for Enhancing Myogenesis.

Many cell responses that underlie the development, maturation, and function of tissues are guided by the architecture and mechanical loading of the extracellular matrix (ECM). Because mechanical stimulation must be transmitted through the ECM architecture, the synergy between these two factors is important. However, recapitulating the synergy of these physical microenvironmental cues in vitro remains challenging. To address this, a 3D magnetically actuated collagen hydrogel platform is developed that enables combined control of ECM architecture and mechanical stimulation. With this platform, it is demonstrated how these factors synergistically promote cell alignment of C2C12 myoblasts and enhance myogenesis. This promotion is driven in part by the dynamics of Yes-associated protein and structure of cellular microtubule networks. This facile platform holds great promises for regulating cell behavior and fate, generating a broad range of engineered physiologically representative microtissues in vitro, and quantifying the mechanobiology underlying their functions.

Polymeric Nitric Oxide Delivery Nanoplatforms for Treating Cancer, Cardiovascular Diseases, and Infection.

The shortened Abstract is as follows: Therapeutic gas nitric oxide (NO) has demonstrated the unique advances in biomedical applications due to its prominent role in regulating physiological/pathophysiological activities in terms of vasodilation, angiogenesis, chemosensitizing effect, and bactericidal effect. However, it is challenging to deliver NO, due to its short half-life (<5 s) and short diffusion distances (20-160 µm). To address these, various polymeric NO delivery nanoplatforms (PNODNPs) have been developed for cancer therapy, antimicrobial and cardiovascular therapeutics, because of the important advantages of polymeric delivery nanoplatforms in terms of controlled release of therapeutics and the extremely versatile nature. This reviews highlights the recent significant advances made in PNODNPs for NO storing and targeting delivery. The ideal and unique criteria that are required for PNODNPs for treating cancer, cardiovascular diseases and infection, respectively, are summarized. Hopefully, effective storage and targeted delivery of NO in a controlled manner using PNODNPs could pave the way for NO-sensitized synergistic therapy in clinical practice for treating the leading death-causing diseases.

Remodeling of aligned fibrous extracellular matrix by encapsulated cells under mechanical stretching.

Extracellular matrix (ECM) remodeling is essential for the development and functions of connective tissues (e.g., heart, muscle and the periodontal ligament), and entails the highly anisotropic response of cells and their organized ECM molecules to mechanical stimulation. However, the nature of how cells remodel their surrounding ECM under mechanical stimulation remains elusive. Here, we encapsulated human periodontal ligament stem cells (hPDLSCs) within an aligned rat collagen scaffold labeled with fluorescein isothiocyanate (FITC) and applied mechanical stimulation on the scaffold using magnetic stretching. Through tracking the FITC-labeled rat collagen scaffold and the newly secreted human type I collagen, we studied the effect of magnetic stretching on the mechanism of aligned ECM remodeling by the encapsulated cells. We found that the aligned topography combined with magnetic stretching could significantly promote initial ECM degradation and new ECM secretion: expression of matrix metalloproteinases 1 and 9 is increased markedly, and the elastic modulus of the stretched scaffold (75 kPa) is significantly higher than that of the random scaffold (50 kPa). The data support a model whereby the cells remodel their surrounding ECM under continuous stretching through degradation and then secretion of new ECM to integrate with the aligned ECM and maintain tissue function. Our study offers a valuable basis for future optimized design of biomaterial scaffolds for clinical translation. STATEMENT OF SIGNIFICANCE: Extracellular matrix (ECM) remodeling is essential for the development and functions of connective tissues. However, the nature of how cells remodel their surrounding aligned ECM under mechanical stimulation remains elusive. Herein, we developed a method to reveal the remodeling of aligned rat collagen scaffold by the encapsulated human periodontal ligament stem cells (hPDLSCs) using fluorescence imaging. We found that the aligned topography combined with magnetic stretching could significantly promote initial ECM degradation and new ECM secretion: the expression of matrix metalloproteinase 1 and 9 are significantly higher, and the elastic modulus increases from 50 kPa to 75 kPa as compared to the random collagen scaffold encapsulating hPDLSCs. Our study holds great potential in optimization of bio-scaffold design for clinical translation.

Fluorescent conjugated polymer nanovector for in vivo tracking and regulating the fate of stem cells for restoring infarcted myocardium.

Stem cell therapy holds great promise for cardiac regeneration. However, the lack of ability to control stem cell fate after in vivo transplantation greatly restricts its therapeutic outcomes. MicroRNA delivery has emerged as a powerful tool to control stem cell fate for enhanced cardiac regeneration. However, the clinical translation of therapy based on gene-transfected stem cells remains challenging, due to the unknown in vivo behaviors of stem cells. Here, we developed a nano-platform (i.e., PFBT@miR-1-Tat NPs) that can achieve triggered release of microRNA-1 to promote cardiac differentiation of mesenchymal stem cells (MSCs), and long-term tracking of transplanted MSCs through bright and ultra-stable fluorescence of conjugated polymer poly(9,9-dioctylfluorene-alt-benzothiadiazole) (PFBT). We found that PFBT@miR-1-Tat NP-treated MSCs significantly restored the infarcted myocardium by promoting stem cell cardiac differentiation and integration with the in situ cardiac tissues. Meanwhile, MSCs without gene delivery improved the infarcted heart functions mainly through a paracrine effect and blood vessel formation. The developed conjugated polymer nanovector should be a powerful tool for manipulating as well as revealing the fate of therapeutic cells in vivo, which is critical for optimizing the therapeutic route of gene and cell combined therapy and therefore for accelerating clinical translation. STATEMENT OF SIGNIFICANCE: The lack of controllability in stem cell fate and the unclear in vivo cellular behaviors restrict the therapeutic outcomes of stem cell therapy. Herein, we engineered fluorescent conjugated polymer nanoparticles as gene delivery nanovectors with controlled release and high intracellular delivery capability to harness the fate of mesenchymal stem cells (MSCs) in vivo, meanwhile to reveal the cellular mechanism of gene-treated stem cell therapy. As compared with only MSC treatment that improves infarcted myocardium functions through paracrine effect, treatment with conjugated polymer nanovector-treated MSCs significantly restored infarcted myocardium through enhancing MSC cardiac differentiation and integration with the in-situ cardiac tissues. These findings demonstrate that the conjugated polymer nanovector would be a powerful tool in optimizing gene and cell combined therapy.

Establishing empirical design rules of nucleic acid templates for the synthesis of silver nanoclusters with tunable photoluminescence and functionalities towards targeted bioimaging applications.

DNA-templated silver nanoclusters (AgNCs) are an emerging class of ultrasmall (<2 nm) fluorophores with increasing popularity for bioimaging due to their facile synthesis and tunable emission color. However, design rules correlating different nucleotide sequences with the photoemission properties of AgNCs are still largely unknown, preventing the rational design of DNA templates to fine-tune the emission color, brightness and functionalities of AgNCs for any targeted applications. Herein, we report a systematic investigation to understand the empirical influences of the four basic DNA nucleotides on AgNC synthesis and their effects on photoluminescence properties. After establishing the importance of nucleotide-Ag+ binding and AgNC encapsulation within DNA tetraplex structures, we then determined the unique attributes of each individual nucleobase using different combinations of systematically varied DNA templates. Using the empirical design rules established herein, we were able to predict the photoluminescence behaviours of AgNCs templated by complex aptamer sequences with specific binding affinity to human cancer cells, and to deliberately control their emission color by rational modifications of the DNA template sequences for targeted bioimaging. Our empirical findings from this systematic experimentation can contribute towards the rational design of DNA sequences to customise the photoluminescence properties and biofunctionalities of DNA-protected AgNCs towards multicolour targeted bioimaging applications.

Microfluidic Printing of Three-Dimensional Graphene Electroactive Microfibrous Scaffolds.

Graphene materials have attracted special attention because of their electrical conductivity, mechanical properties, and favorable biocompatibility. Although various methods have been developed for fabricating micro/nano conductive fibrous scaffolds, it is still challenging to fabricate the three-dimensional (3D) graphene fibrous scaffolds. Herein, we developed a new method, termed as microfluidic 3D printing technology (M3DP), to fabricate 3D graphene oxide (GO) microfibrous scaffolds with an adjustable fiber length, fiber diameter, and scaffold structure by integrating the microfluidic spinning technology with a programmable 3D printing system. GO microfibrous scaffolds were then transformed into conductive reduced graphene oxide (rGO) microfibrous scaffolds by hydrothermal reduction. Our results demonstrated that the fabricated 3D fibrous graphene scaffolds exhibited tunable structures, maneuverable mechanical properties, and good electrical conductivity and biocompatibility, as reflected by the adhesion and proliferation of SH-SY5Y cells on the graphene microfibrous scaffolds in an obviously oriented manner. The developed M3DP would be a powerful tool for fabricating 3D graphene microfibrous scaffolds for electroactive tissue regeneration and drug-screening applications.

Near-infrared light-regulated cancer theranostic nanoplatform based on aggregation-induced emission luminogen encapsulated upconversion nanoparticles.

Photodynamic therapy (PDT) has been widely applied in the clinic for the treatment of various types of cancer due to its precise controllability, minimally invasive approach and high spatiotemporal accuracy as compared with conventional chemotherapy. However, the porphyrin-based photosensitizers (PSs) used in clinics generally suffer from aggregation-caused reductions in the generation of reactive oxygen species (ROS) and limited tissue penetration because of visible light activation, which greatly hampers their applications for the treatment of deep-seated tumors. Methods: We present a facile strategy for constructing a NIR-regulated cancer theranostic nanoplatform by encapsulating upconversion nanoparticles (UCNPs) and a luminogen (2-(2,6-bis((E)-4-(phenyl(40-(1,2,2-triphenylvinyl)-[1,10-biphenyl]-4-yl)amino)styryl)-4H-pyran-4-ylidene)malononitrile, TTD) with aggregation-induced emission (AIEgen) characteristics using an amphiphilic polymer, and further conjugating cyclic arginine-glycine-aspartic acid (cRGD) peptide to yield UCNP@TTD-cRGD NPs. We then evaluated the bioimaging and anti-tumor capability of the UCNP@TTD-cRGD NPs under NIR light illumination in an in vitro three-dimensional (3D) cancer spheroid and in a murine tumor model, respectively. Results: With a close match between the UCNP emission and absorption of the AIEgen, the synthesized NPs could efficiently generate ROS, even under excitation through thick tissues. The NIR-regulated UCNP@TTD-cRGD NPs that were developed could selectively light up the targeted cancer cells and significantly inhibit tumor growth during the NIR-regulated PDT treatment as compared with the cells under white light excitation. Conclusion: In summary, the synthesized UCNP@TTD-cRGD NPs showed great potential in NIR light-regulated photodynamic therapy of deep-seated tumors. Our study will inspire further exploration of novel theranostic nanoplatforms that combine UCNPs and various AIEgen PSs for the advancement of deep-seated tumor treatments with potential clinical translations.

Heterostructured Silk-Nanofiber-Reduced Graphene Oxide Composite Scaffold for SH-SY5Y Cell Alignment and Differentiation.

Stem cell therapy is promising for treating traumatic injuries of the central nervous system, where a major challenge is to effectively differentiate neural stem cells into neurons with uniaxial alignment. Recently, controlling stem cell fate by modulating biophysical cues (e.g., stiffness, conductivity, and patterns) has emerged as an attractive approach. Herein, we report a new heterostructure composite scaffold to induce cell-oriented growth and enhance the neuronal differentiation of SH-SY5Y cells. The scaffold is composed of aligned electrospinning silk nanofibers coated on reduced graphene paper with high conductivity and good biocompatibility. Our experimental results demonstrate that the composite scaffold can effectively induce the oriented growth and enhance neuronal differentiation of SH-SY5Y cells. Our study develops a novel scaffold for enhancing the differentiation of SH-SY5Y cells into neurons, which holds great potential in the treatment of neurological diseases and injuries.

Electrospun three-dimensional aligned nanofibrous scaffolds for tissue engineering.

Engineered tissue constructs rely on biomaterials as support structures for tissue repair and regeneration. Among these biomaterials, polyester biomaterials have been widely used for scaffold construction because of their merits such as ease in synthesis, degradable properties, and elastomeric characteristics. To mimic the aligned structures of native extracellular matrix (ECM) in tissues such as nerve, heart and tendon, various polyester materials have been fabricated into aligned fibrous scaffolds with fibers ranging from several nanometers to several micrometers in diameter by electrospinning in a simple and reproducible manner. These aligned fibrous scaffolds, especially the three-dimensional (3D) aligned nanofibrous scaffolds have emerged as a promising solution for tissue regeneration. Compared with two-dimensional (2D) scaffolds, the 3D aligned nanofibrous scaffolds provide another dimension for cell behaviors such as morphogenesis, migration and cell-cell interactions, which is important in regulating the stem cell fate and tissue regeneration. In this review, we provide an extensive overview on recent efforts for constructing 3D aligned polyester nanofibrous scaffolds by electrospinning, then the results of cell-specific functions dependent on such physical and chemical cues, and discuss their potentials in improving or restoring damaged tissues.

Enhanced Osseointegration of Hierarchically Structured Ti Implant with Electrically Bioactive SnO2-TiO2 Bilayered Surface.

The poor osseointegration of Ti implant significantly compromise its application in load-bearing bone repair and replacement. Electrically bioactive coating inspirited from heterojunction on Ti implant can benefit osseointegration but cannot avoid the stress shielding effect between bone and implant. To resolve this conflict, hierarchically structured Ti implant with electrically bioactive SnO2-TiO2 bilayered surface has been developed to enhance osseointegration. Benefiting from the electric cue offered by the built-in electrical field of SnO2-TiO2 heterojunction and the topographic cue provided by the hierarchical surface structure to bone regeneration, the osteoblastic function of basic multicellular units around the implant is significantly improved. Because the individual TiO2 or SnO2 coating with uniform surface exhibits no electrical bioactivity, the effects of electric and topographic cues to osseointegration have been decoupled via the analysis of in vivo performance for the placed Ti implant with different surfaces. The developed Ti implant shows significantly improved osseointegration with excellent bone-implant contact, improved mineralization of extracellular matrix, and increased push-out force. These results suggest that the synergistic strategy of combing electrical bioactivity with hierarchical surface structure provides a new platform for developing advanced endosseous implants.

Engineering the Cell Microenvironment Using Novel Photoresponsive Hydrogels.

In vivo, cells are located in a dynamic, three-dimensional (3D) cell microenvironment, and various biomaterials have been used to engineer 3D cell microenvironments in vitro to study the effects of the cell microenvironment on the regulation of cell fate. However, conventional hydrogels can only mimic the static cell microenvironment without any synchronous regulations. Therefore, novel hydrogels that are capable of responding to specific stimuli (e.g., light, temperature, pH, and magnetic and electrical stimulations) have emerged as versatile platforms to precisely mimic the dynamic native 3D cell microenvironment. Among these novel hydrogels, photoresponsive hydrogels (PRHs) that are capable of changing their physical and chemical properties after exposure to light irradiation enable the dynamic, native cell microenvironment to be mimicked and show great promise in deciphering the unknown mechanisms of the 3D cell microenvironment in regulating the cell fate. Several reviews have already summarized the advances of PRHs and have focused on specific photosensitive chemical groups and photoresponsive elements or on the reaction categories and mechanism of PRHs. However, a holistic view of novel PRHs, which highlights the multiple physical and chemical properties that can be tuned by remote light activation, as well as their applications in engineering a dynamic cell microenvironment for the regulation of cell behaviors in vitro is still missing and is the focus of this review.

Theranostics of Triple-Negative Breast Cancer Based on Conjugated Polymer Nanoparticles.

Triple-negative breast cancer (TNBC) does not respond to many targeted drugs due to the lack of three receptors (i.e., estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2), which makes it difficult for TNBC detection and treatment. As compared to traditional breast cancer treatments such as surgery and chemotherapy, photodynamic therapy (PDT) has emerged as a promising approach for treating TNBC due to its precise controllability, high spatiotemporal accuracy, and minimal invasive nature. However, traditional photosensitizers used in PDT are associated with limitations of aggregation-caused quenching (ACQ), and the ACQ induced a significant decrease in reactive oxygen species (ROS) generation. To address these, we synthesized a cyclic arginine-glycine-aspartic acid (cRGD) peptide-decorated conjugated polymer (CP) nanoparticles with poly[2-methoxy-5-(2-ethyl-hexyloxy)-1,4-phenylenevinylene] (MEH-PPV) as the photosensitizer for the theranostics of TNBC. The synthesized CP nanoparticles show bright fluorescence with high stability and could effectively produce ROS under light irradiation. Cell viability studies showed that the CP nanoparticles have negligible dark cytotoxicity and could efficiently kill the αvß3 integrin-overexpressed MDA-MB-231 cells (one subtype of TNBC cells) in a selective way. With the use of cRGD-modified MEH-PPV nanoparticles as the theranostic agent, it permits targeted imaging and PDT of TNBC both in the in vitro 3D tumor model and in living mice. The application of CP nanoparticles in the successful theranostics of TNBC could pave the way for future development of CP-based photosensitizers for clinical applications.

Electrically bioactive coating on Ti with bi-layered SnO2-TiO2 hetero-structure for improving osteointegration.

The potential for the use of electric stimulation to control cell behavior on a surface has been well documented. In terms of orthopaedic applications, there is a need to develop bioactive surfaces with a built-in electric field for clinically relevant materials, such as load-bearing titanium (Ti). In this work, a bi-layered SnO2-TiO2 coating is fabricated via microarc oxidation and subsequent hydrothermal treatment to adjust the surface electrical properties for improving bioactivity. An oxidized titanium interlayer on Ti substrate allows the growth of SnO2 nanorods with different morphologies, which leads to a built-in n-n heterojunction of SnO2 and TiO2 on the Ti surface with varied surface electrical properties. The crystallization of the TiO2 interlayer facilitates the growth of SnO2 nanorods, showing excellent hydrophilicity and good apatite-inducing ability due to the formation of a heterojunction. The results suggest that the bi-layered SnO2-TiO2 coating with electrically stimulated bioactivity could provide a novel way to enhance osteointegration on the Ti surface.

Functional and Biomimetic Materials for Engineering of the Three-Dimensional Cell Microenvironment.

The cell microenvironment has emerged as a key determinant of cell behavior and function in development, physiology, and pathophysiology. The extracellular matrix (ECM) within the cell microenvironment serves not only as a structural foundation for cells but also as a source of three-dimensional (3D) biochemical and biophysical cues that trigger and regulate cell behaviors. Increasing evidence suggests that the 3D character of the microenvironment is required for development of many critical cell responses observed in vivo, fueling a surge in the development of functional and biomimetic materials for engineering the 3D cell microenvironment. Progress in the design of such materials has improved control of cell behaviors in 3D and advanced the fields of tissue regeneration, in vitro tissue models, large-scale cell differentiation, immunotherapy, and gene therapy. However, the field is still in its infancy, and discoveries about the nature of cell-microenvironment interactions continue to overturn much early progress in the field. Key challenges continue to be dissecting the roles of chemistry, structure, mechanics, and electrophysiology in the cell microenvironment, and understanding and harnessing the roles of periodicity and drift in these factors. This review encapsulates where recent advances appear to leave the ever-shifting state of the art, and it highlights areas in which substantial potential and uncertainty remain.