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The complete structure-functional repair of volumetric muscle loss (VML) remains a giant challenge and biomedical hydrogels to remodel microenvironment and enhance neurogenesis have appeared to be a promising direction. However, the current hydrogels for VML repair hardly achieve these two goals simultaneously due to their insufficient functionality and the challenge in high-cost of bioactive factors. In this study, a facile strategy using Nb 2 C MXene-functionalized hydrogel (OPTN) as a bioactive scaffold is proposed to promote VML repair with skeletal muscle regeneration and functional restoration. In vitro experiments show that OPTN scaffold can effectively scavenge reactive oxygen species (ROS), guide macrophages polarization toward M2 phenotype, and resist bacterial infection, providing a favorable microenvironment for myoblasts proliferation as well as the endothelial cells proliferation, migration, and tube formation. More importantly, OPTN scaffold with electroactive feature remarkably boosts myoblasts differentiation and mesenchymal stem cells neural differentiation. Animal experiments further confirm that OPTN scaffold can achieve a prominent structure-functional VML repair by attenuating ROS levels, alleviating inflammation, reducing fibrosis, and facilitating angiogenesis, newborn myotube formation, and neurogenesis. Collectively, this study provides a highly promising and effective strategy for the structure-functional VML repair through designing bioactive multifunctional hydrogel with microenvironment remodeling and enhanced neurogenesis., (© 2024 Wiley‐VCH GmbH.)

Complex microenvironments with bacterial infection, persistent inflammation, and impaired angiogenesis are the major challenges in chronic refractory diabetic ulcers. To address this challenge, a comprehensive strategy with highly effective and integrated antimicrobial, anti-inflammatory, and accelerated angiogenesis will offer a new pathway to the rapid healing of infected diabetic ulcers. Here, inspired by the tunable reactive oxygen species (ROS) regulation properties of natural peroxisomes, this work reports the design of infectious and inflammatory microenvironments self-adaptive artificial peroxisomes with synergetic Co-Ru pair centers (APCR) for programmed diabetic ulcer therapy. Benefiting from the synergistic Co and Ru atoms, the APCR can simultaneously achieve ROS production and metabolic inhibition for bacterial sterilization in the infectious microenvironment. After disinfection, the APCR can also eliminate ROS to alleviate oxidative stress in the inflammatory microenvironment and promote wound regeneration. The data demonstrate that the APCR combines highly effective antibacterial, anti-inflammatory, and provascular regeneration capabilities, making it an efficient and safe nanomedicine for treating infectious and inflammatory diabetic foot ulcers via a programmed microenvironment self-adaptive treatment pathway. This work expects that synthesizing artificial peroxisomes with microenvironments self-adaptive and bifunctional enzyme-like ROS regulation properties will provide a promising path to construct ROS catalytic materials for treating complex diabetic ulcers, trauma, or other infection-caused diseases., (© 2024 Wiley‐VCH GmbH.)

Chronic local inflammation and excessive cell apoptosis in nucleus pulposus (NP) tissue are the main causes of intervertebral disc degeneration (IDD). Stimuli-responsive hydrogels have great potential in the treatment of IDD by facilitating localized and controlled drug delivery. Herein, an injectable drug-loaded dual stimuli-responsive adhesive hydrogel for microenvironmental regulation of IDD, is developed. The gelatin methacryloyl is functionalized with phenylboronic acid groups to enhance drug loading capacity and enable dual stimuli-responsive behavior, while the incorporation of oxidized hyaluronic acid further improves the adhesive properties. The prepared hydrogel exhibits an enhanced drug loading capacity for diol-containing drugs, pH- and reactive oxygen species (ROS)-responsive behaviors, excellent radical scavenging efficiency, potent antibacterial activity, and favorable biocompatibility. Furthermore, the hydrogel shows a beneficial protective efficacy on NP cells within an in vitro oxidative stress microenvironment. The in vivo results demonstrate the hydrogel's excellent therapeutic effect on treating IDD by maintaining water retention, restoring disc height, and promoting NP regeneration, indicating that this hydrogel holds great potential as a promising therapeutic approach for regulating the microenvironment and alleviating the progression of IDD., (© 2024 Wiley‐VCH GmbH.)

After myocardial infarction (MI), sustained ischemic events induce pathological microenvironments characterized by ischemia-hypoxia, oxidative stress, inflammatory responses, matrix remodeling, and fibrous scarring. Conventional clinical therapies lack spatially targeted and temporally responsive modulation of the infarct microenvironment, leading to limited myocardial repair. Engineered hydrogels have a chemically programmed toolbox for minimally invasive localization of the pathological microenvironment and personalized responsive modulation over different pathological periods. Chemically programmed strategies for crosslinking interactions, interfacial binding, and topological microstructures in hydrogels enable minimally invasive implantation and in situ integration tailored to the myocardium. This enhances substance exchange and signal interactions within the infarcted microenvironment. Programmed responsive polymer networks, intelligent micro/nanoplatforms, and biological therapeutic cues contribute to the formation of microenvironment-modulated hydrogels with precise targeting, spatiotemporal control, and on-demand feedback. Therefore, this review summarizes the features of the MI microenvironment and chemically programmed schemes for hydrogels to conform, integrate, and modulate the cardiac pathological microenvironment. Chemically programmed strategies for oxygen-generating, antioxidant, anti-inflammatory, provascular, and electrointegrated hydrogels to stimulate iterative and translational cardiac tissue engineering are discussed., (© 2024 Wiley‐VCH GmbH.)

The effect of immunoinflammation on bone repair during the recovery process of bone defects needs to be further explored. It is reported that Mg 2+ can promote bone repair with immunoregulatory effect, but the underlying mechanism on adaptive immunity is still unclear. Here, by using chitosan and hyaluronic acid-coated Mg 2+ (CSHA-Mg) in bone-deficient mice, it is shown that Mg 2+ can inhibit the activation of CD4 + T cells and increase regulatory T cell formation by inducing immunosuppressive dendritic cells (imDCs). Mechanistically, Mg 2+ initiates the activation of the MAPK signaling pathway through TRPM7 channels on DCs. This process subsequently induces the downstream HIF-1α expression, a transcription factor that amplifies TGF-β production and inhibits the effective T cell function. In vivo, knock-out of HIF-1α in DCs or using a HIF-1α inhibitor PX-478 reverses inhibition of bone inflammation and repair promotion upon Mg 2+ -treatment. Moreover, roxadustat, which stabilizes HIF-1α protein expression, can significantly promote immunosuppression and bone repair in synergism with CSHA-Mg. Thus, the findings identify a key mechanism for DCs and its HIF-1α-TGF-β axis in the induction of immunosuppressive bone microenvironment, providing potential targets for bone regeneration., (© 2024 Wiley‐VCH GmbH.)

Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Traumatic brain injury (TBI) is the primary cause of child mortality and disability worldwide. It can result in severe complications that significantly impact children's quality of life, including post-traumatic epilepsy (PTE). An increasing number of studies suggest that TBI-induced oxidative stress and neuroinflammatory sequelae (especially, inflammation in the hippocampus region) may lead to the development of PTE. Due to the blood-brain barrier (BBB), typical systemic pharmacological therapy for TBI cannot deliver berberine (BBR) to the targeted location in the early stages of the injury, although BBR has strong anti-inflammatory properties. To break through this limitation, a microenvironment-responsive gelatin methacrylate (GM) hydrogel to deliver poly(propylene sulfide) 60 (PPS 60 ) and BBR (GM/PB) is developed for regulating neuroinflammatory reactions and removing reactive oxygen species (ROS) in the brain trauma microenvironment through PPS 60 . In situ injection of the GM/PB hydrogel efficiently bypasses the BBB and is administered directly to the surface of brain tissue. In post-traumatic brain injury models, GM/PB has the potential to mitigate oxidative stress and neuroinflammatory responses, facilitate functional recovery, and lessen seizing. These findings can lead to a new treatment for brain injuries, which minimizes complications and improves the quality of life., (© 2024 Wiley‐VCH GmbH.)

The diabetic wound healing is challenging due to the sabotaged delicate balance of immune regulation via an undetermined pathophysiological mechanism, so it is crucial to decipher multicellular signatures underlying diabetic wound healing and seek therapeutic strategies. Here, this work develops a strategy using novel trimethylamine N-oxide (TMAO)-derived zwitterionic hydrogel to promote diabetic wound healing, and explore the multi-cellular ecosystem around zwitterionic hydrogel, mapping out an overview of different cells in the zwitterionic microenvironment by single-cell RNA sequencing. The diverse cellular heterogeneity is revealed, highlighting the critical role of macrophage and neutrophils in managing diabetic wound healing. It is found that polyzwitterionic hydrogel can upregulate Ccl3+ macrophages and downregulate S100a9+ neutrophils and facilitate their interactions compared with polyanionic and polycationic hydrogels, validating the underlying effect of zwitterionic microenvironment on the activation of adaptive immune system. Moreover, zwitterionic hydrogel inhibits the formation of neutrophil extracellular traps (NETs) and promotes angiogenesis, thus improving diabetic wound healing. These findings expand the horizons of the sophisticated orchestration of immune systems in zwitterion-directed diabetic wound repair and uncover new strategies of novel immunoregulatory biomaterials., (© 2024 Wiley‐VCH GmbH.)

Efferocytosis-mediated inflammatory reversal plays a crucial role in bone repairing process. However, in refractory bone defects, the macrophage continual efferocytosis may be suppressed due to the disrupted microenvironment homeostasis, particularly the loss of apoptotic signals and overactivation of intracellular oxidative stress. In this study, a polydopamine-coated short fiber matrix containing biomimetic "apoptotic signals" to reconstruct the microenvironment and reactivate macrophage continual efferocytosis for inflammatory reversal and bone defect repair is presented. The "apoptotic signals" (AM/CeO 2 ) are prepared using CeO 2 nanoenzymes with apoptotic neutrophil membrane coating for macrophage recognition and oxidative stress regulation. Additionally, a short fiber "biomimetic matrix" is utilized for loading AM/CeO 2 signals via abundant adhesion sites involving π-π stacking and hydrogen bonding interactions. Ultimately, the implantable apoptosis-mimetic nanoenzyme/short-fiber matrixes (PFS@AM/CeO 2 ), integrating apoptotic signals and biomimetic matrixes, are constructed to facilitate inflammatory reversal and reestablish the pro-efferocytosis microenvironment. In vitro and in vivo data indicate that the microenvironment biomimetic short fibers can activate macrophage continual efferocytosis, leading to the suppression of overactivated inflammation. The enhanced repair of rat femoral defect further demonstrates the osteogenic potential of the pro-efferocytosis strategy. It is believed that the regulation of macrophage efferocytosis through microenvironment biomimetic materials can provide a new perspective for tissue repair., (© 2024 Wiley‐VCH GmbH.)

As the global population ages, bone diseases have become increasingly prevalent in clinical settings. These conditions often involve detrimental factors such as infection, inflammation, and oxidative stress that disrupt bone homeostasis. Addressing these disorders requires exogenous strategies to regulate the osteogenic microenvironment (OME). The exogenous regulation of OME can be divided into four processes: induction, modulation, protection, and support, each serving a specific purpose. To this end, metal-organic frameworks (MOFs) are an emerging focus in nanomedicine, which show tremendous potential due to their superior delivery capability. MOFs play numerous roles in OME regulation such as metal ion donors, drug carriers, nanozymes, and photosensitizers, which have been extensively explored in recent studies. This review presents a comprehensive introduction to the exogenous regulation of OME by MOF-based nanomaterials. By discussing various functional MOF composites, this work aims to inspire and guide the creation of sophisticated and efficient nanomaterials for bone disease management., (© 2024 Wiley‐VCH GmbH.)

Cardiovascular diseases caused by ischemia are attracting considerable attention owing to its high morbidity and mortality worldwide. Although numerous agents with cardioprotective benefits have been identified, their clinical outcomes are hampered by their low bioavailability, poor drug solubility, and systemic adverse effects. Advances in nanoscience and nanotechnology provide a new opportunity to effectively deliver drugs for treating ischemia-related diseases. In particular, cardiac ischemia leads to a characteristic pathological environment called an ischemic microenvironment (IME), significantly different from typical cardiac regions. These remarkable differences between ischemic sites and normal tissues have inspired the development of stimuli-responsive systems for the targeted delivery of therapeutic drugs to damaged cardiomyocytes. Recently, many biomaterials with intelligent properties have been developed to enhance the therapeutic benefits of drugs for the treatment of myocardial ischemia. Strategies for stimuli-responsive drug delivery and release based on IME include reactive oxygen species, pH-, hypoxia-, matrix metalloproteinase-, and platelet-inspired targeting strategies. In this review, state-of-the-art IME-responsive biomaterials for the treatment of myocardial ischemia are summarized. Perspectives, limitations, and challenges are also discussed for the further development of innovative and effective approaches to treat ischemic diseases with high effectiveness and biocompatibility., (© 2021 Wiley-VCH GmbH.)

Reperfusion injury is still a major challenge that impedes neuronal survival in ischemic stroke. However, the current clinical treatments are remained on single pathological process, which are due to lack of comprehensive neuroprotective effects. Herein, a macrophage-disguised honeycomb manganese dioxide (MnO 2 ) nanosphere loaded with fingolimod (FTY) is developed to salvage the ischemic penumbra. In particular, the biomimetic nanoparticles can accumulate actively in the damaged brain via macrophage-membrane protein-mediated recognition with cell adhesion molecules that are overexpressed on the damaged vascular endothelium. MnO 2 nanosphere can consume excess hydrogen peroxide (H 2 O 2 ) and convert it into desiderated oxygen (O 2 ), and can be decomposed in acidic lysosome for cargo release, so as to reduce oxidative stress and promote the transition of M1 microglia to M2 type, eventually reversing the proinflammatory microenvironment and reinforcing the survival of damaged neuron. This biomimetic nanomedicine raises new strategy for multitargeted combined treatment of ischemic stroke., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Central nervous system (CNS) injuries are often debilitating, and most currently have no cure. This is due to the formation of a neuroinhibitory microenvironment at injury sites, which includes neuroinflammatory signaling and non-permissive extracellular matrix (ECM) components. To address this challenge, a viscous interfacial self-assembly approach, to generate a bioinspired hybrid 3D porous nanoscaffold platform for delivering anti-inflammatory molecules and establish a favorable 3D-ECM environment for the effective suppression of the neuroinhibitory microenvironment, is developed. By tailoring the structural and biochemical properties of the 3D porous nanoscaffold, enhanced axonal growth from the dual-targeting therapeutic strategy in a human induced pluripotent stem cell (hiPSC)-based in vitro model of neuroinflammation is demonstrated. Moreover, nanoscaffold-based approaches promote significant axonal growth and functional recovery in vivo in a spinal cord injury model through a unique mechanism of anti-inflammation-based fibrotic scar reduction. Given the critical role of neuroinflammation and ECM microenvironments in neuroinhibitory signaling, the developed nanobiomaterial-based therapeutic intervention may pave a new road for treating CNS injuries., (© 2020 Wiley-VCH GmbH.)

In this study, the cyto-compatibility and cellular functionality of cell-laden gelatin-methacryloyl (Gel-MA) hydrogels fabricated using a set of photo-initiators which absorb in 400-450 nm of the visible light range are investigated. Gel-MA hydrogels cross-linked using ruthenium (Ru) and sodium persulfate (SPS), are characterized to have comparable physico-mechanical properties as Gel-MA gels photo-polymerized using more conventionally adopted photo-initiators, such as 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propan-1-one (Irgacure 2959) and lithium phenyl(2,4,6-trimethylbenzoyl) phosphinate (LAP). It is demonstrated that the Ru/SPS system has a less adverse effect on the viability and metabolic activity of human articular chondrocytes encapsulated in Gel-MA hydrogels for up to 35 days. Furthermore, cell-laden constructs cross-linked using the Ru/SPS system have significantly higher glycosaminoglycan content and re-differentiation capacity as compared to cells encapsulated using I2959 and LAP. Moreover, the Ru/SPS system offers significantly greater light penetration depth as compared to the I2959 system, allowing thick (10 mm) Gel-MA hydrogels to be fabricated with homogenous cross-linking density throughout the construct. These results demonstrate the considerable advantages of the Ru/SPS system over traditional UV polymerizing systems in terms of clinical relevance and practicability for applications such as cell encapsulation, biofabrication, and in situ cross-linking of injectable hydrogels., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Stem cells hold great promise for widespread biomedical applications, for which stem cell fate needs to be well tailored. Besides biochemical cues, accumulating evidence has demonstrated that spatiotemporal biophysical cues (especially mechanical cues) imposed by cell microenvironments also critically impact on the stem cell fate. As such, various biomaterials, especially hydrogels due to their tunable physicochemical properties and advanced fabrication approaches, are developed to spatiotemporally manipulate biophysical cues in vitro so as to recapitulate the 3D mechanical microenvironment where stem cells reside in vivo. Here, the main mechanical cues that stem cells experience in their native microenvironment are summarized. Then, recent advances in the design of hydrogel materials with spatiotemporally tunable mechanical properties for engineering 3D the spatiotemporal mechanical microenvironment of stem cells are highlighted. These in vitro engineered spatiotemporal mechanical microenvironments are crucial for guiding stem cell fate and their potential biomedical applications are subsequently discussed. Finally, the challenges and future perspectives are presented., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Development of advanced wound dressing materials with rapid healing rates is in urgent demand for wound cares. A suitable microenvironment will promote cell proliferation and migration, which benefits to early wound healing and prevents inflammations and scars. In this work, N-carboxymethyl chitosan- and alginate-based hydrogels are prepared via both electrostatic interaction and divalent chelation with epidermal growth factor (EGF) payload to promote the cell proliferation and wound healing. The dual-crosslinked hydrogels are investigated in terms of rheology, water retention ability, and the release rate of EGF. Moreover, such amorphous hydrogel can promote cell proliferation and accelerate wound healing. The present study demonstrates that dual-crosslinked polysaccharide hydrogels are promising in wound care management., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Intracellular delivery of small interfering RNA (siRNA) is a long-standing challenge in oligonucleotide therapeutics. Herein, adenosine triphosphate (ATP)-responsive polyion complex micelles assembled from poly(ethylene glycol)-block-poly(l-lysine) (PEG-PLys) bearing 4-carboxy-3-fluorophenylboronic acid (FPBA) moiety in the PLys side chains (FPBA micelle) for the delivery of cholesterol-modified siRNA (Chol-siRNA) are described. The pK a of FPBA moiety is 7.2 and, therefore, it exists in equilibrium between negatively charged tetravalent and noncharged hydrophobic trivalent forms in physiological pH conditions. Each form cooperatively stabilizes the micelle in distinct modes, that is, a covalent ester-linkage between charged boronate and ribose functionality at 3' ends of Chol-siRNA and a hydrophobic interaction between noncharged boronic acid and Chol-siRNA. When exposed to ATP at a concentration associated with the intracellular environment, the Chol-siRNA/boronate linkage is readily cleaved to facilitate the release of Chol-siRNA into cytoplasm. In order to further optimize this switching capability, the effect of FPBA modification rate is studied for the resulting ATP-responsive behavior of the micelles. As a result, the range of 23-35% in the modification rate is found suitable to maximize the gene silencing efficiency, demonstrating the potential of the FPBA-modified micelles as ATP-responsive smart siRNA carrier systems., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Adverse immune reactions prevent clinical translation of numerous implantable devices and materials. Although inflammation is an essential part of tissue regeneration, chronic inflammation ultimately leads to implant failure. In particular, macrophage polarity steers the microenvironment toward inflammation or wound healing via the induction of M1 and M2 macrophages, respectively. Here, this paper demonstrates that macrophage polarity within biomaterials can be controlled through integrin-mediated interactions between human monocytic THP-1 cells and collagen-derived matrix. Surface marker, gene expression, biochemical, and cytokine profiling consistently indicate that THP-1 cells within a biomaterial lacking cell attachment motifs yield proinflammatory M1 macrophages, whereas biomaterials with attachment sites in the presence of interleukin-4 (IL-4) induce an anti-inflammatory M2-like phenotype and propagate the effect of IL-4 in induction of M2-like macrophages. Importantly, integrin α2β1 plays a pivotal role as its inhibition blocks the induction of M2 macrophages. The influence of the microenvironment of the biomaterial over macrophage polarity is further confirmed by its ability to modulate the effect of IL-4 and lipopolysaccharide, which are potent inducers of M2 or M1 phenotypes, respectively. Thus, this study represents a novel, versatile, and effective strategy to steer macrophage polarity through integrin-mediated 3D microenvironment for biomaterial-based programming., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gradient hydrogels have been developed to mimic the spatiotemporal differences of multiple gradient cues in tissues. Current approaches used to generate such hydrogels are restricted to a single gradient shape and distribution. Here, a hydrogel is designed that includes two chemical cross-linking networks, biofunctional, and self-healing networks, enabling the customizable formation of modular gradient hydrogel construct with various gradient distributions and flexible shapes. The biofunctional networks are formed via Michael addition between the acrylates of oxidized acrylated hyaluronic acid (OAHA) and the dithiol of matrix metalloproteinase (MMP)-sensitive cross-linker and RGD peptides. The self-healing networks are formed via dynamic Schiff base reaction between N-carboxyethyl chitosan (CEC) and OAHA, which drives the modular gradient units to self-heal into an integral modular gradient hydrogel. The CEC-OAHA-MMP hydrogel exhibits excellent flowability at 37 °C under shear stress, enabling its injection to generate gradient distributions and shapes. Furthermore, encapsulated sarcoma cells respond to the gradient cues of RGD peptides and MMP-sensitive cross-linkers in the hydrogel. With these superior properties, the dual cross-linked CEC-OAHA-MMP hydrogel holds significant potential for generating customizable gradient hydrogel constructs, to study and guide cellular responses to their microenvironment such as in tumor mimicking, tissue engineering, and stem cell differentiation and morphogenesis., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The strand material in extrusion-based bioprinting determines the microenvironments of the embedded cells and the initial mechanical properties of the constructs. One unmet challenge is the combination of optimal biological and mechanical properties in bioprinted constructs. Here, a novel bioprinting method that utilizes core-shell cell-laden strands with a mechanically robust shell and an extracellular matrix-like core has been developed. Cells encapsulated in the strands demonstrate high cell viability and tissue-like functions during cultivation. This process of bioprinting using core-shell strands with optimal biochemical and biomechanical properties represents a new strategy for fabricating functional human tissues and organs., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

3D hydrogels better replicate in vivo conditions, and yield different results from 2D substrates. However, imaging interactions between cells and the hydrogel microenvironment is challenging because of light diffraction and poor focal depth. Here, cryosectioning and vibrating microtomy methods and fixation protocols are compared. Collagen I/III hydrogel sections (20-100 µm) are fixed with paraformaldehyde (2%-4%) and structurally evaluated. Cryosectioning damaged hydrogels, and vibrating microtomy (100 µm, 2%) yielded the best preservation of microstructure and cell integrity. These results demonstrate a potential processing method that preserves hydrogel and cell integrity, permitting imaging of cell interactions with the microenvironment., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This paper describes a new fabrication method for obtaining anisotropic spherical hydrogel microparticles with different types of extracellular matrix (ECM) hemispheres for use in 3D cell culture. To fabricate the microparticles, a mixture of an ECM precursor solution and sodium alginate is ejected into a calcium chloride solution under large centrifugal acceleration by a centrifuge-based microfluidic device; the calcium alginate hydrogel plays a significant role as a "sacrificial gelation template" to maintain the ECM molecules in each hemisphere. This fabrication method enables gaining control of the hemispherical volume, density, and type of ECM. Using the microparticles, cells could be successfully encapsulated in each hemisphere selectively with high viability, which are then suitable for culture in the microparticles to form microtissues. It is believed that the proposed anisotropic ECM microparticles will facilitate the coculture of multiple cell types in different ECMs, which is similar to in vivo microenvironments, facilitating control of cell behavior in an anisotropic microenvironment for the benefit of large-scale and quantitative analyses in vitro., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Biomimetic extracellular matrix (ECM) topographies driven by the magnetic-field-directed self-assembly of ECM protein-coated magnetic beads are fabricated. This novel bottom-up method allows us to program isotropic, anisotropic, and diverse hybrid ECM patterns without changing other physicochemical properties of the scaffold material. It is demonstrated that this 3D anisotropic matrix is able to guide the dendritic protrusion of cells., (© 2015 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Induced pluripotent stem cells (iPSCs) have attracted considerable attention from the public, clinicians, and scientists since their discovery in 2006, and raised huge expectations for regenerative medicine. One of the distinctive features of iPSCs is their propensity to differentiate into the cells of three germ lines in vitro and in vivo. The human iPSCs can be used to study the mechanisms underlying a disease and to monitor the disease progression, for testing drugs in vitro, and for cell therapy, avoiding many ethical and immunologic concerns. This technology offers the potential to take an individual approach to each patient and allows a more accurate diagnosis and specific treatment. However, there are several obstacles that impede the use of iPSCs. The derivation of fully reprogrammed iPSCs is expensive, time-consuming, and demands meticulous attention to many details. The use of biomaterials could increase the efficacy and safety while decreasing the cost of tissue engineering. The choice of a substrate utilized for iPSC culture is also important because cell-substrate contacts influence cellular behavior such as self-renewal, expansion, and differentiation. This Progress Report aims to summarize the advantages and drawbacks of natural and synthetic biomaterials, and to evaluate their role for maintenance and differentiation of iPSCs., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gene therapy presents a unique opportunity for the treatment of genetic diseases, but the lack of multifunctional delivery systems has hindered its clinical applications. Here, a new delivery vector, autofluorescent polyethyleneimine (PEI) nanogels, for highly efficient and traceable gene delivery is developed. Different from commercial high-molecular-weight PEI, the cationic nanogels are noncytotoxic and able to be fragmented due to their unique intracellular microenvironment-responsive structures. The biodegradable nanogels can effectively load plasmid DNA (pDNA), and the self-assembled polyplexes can be cleaved after cellular uptake to improve gene transfection efficiency. Most importantly, the nanogels and the nanogel/pDNA polyplexes are autofluorescent. The fluorescence is stable in blood plasma and responsive to the intracellular microenvironment. The breakup of the nanogels or polyplexes leads to the loss of fluorescence, and thus the gene delivery and carrier biodegradation processes can be monitored. The reported multifunctional system demonstrates excellent biocompatibility, high transfection efficiency, responsive biodegradability, controlled gene release, label-free and simultaneous fluorescence tracking, which will provide a new platform for future scientific investigation and practical implications in gene therapy., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

For over two decades, immunologists and biomaterials scientists have co-existed in parallel world with the rationale of understanding the molecular profile of immune responses to vaccination, implantation, and treating incurable diseases. Much of the field of biomaterial-based immunotherapy has relied on evaluating model antigens such as chicken egg ovalbumin in mouse models but their relevance to humans has been point of much discussion. Nevertheless, such model antigens have provided important insights into the mechanisms of immune regulation and served as a proof-of-concept for plethora of biomaterial-based vaccines. After years of extensive development of numerous biomaterials for immunomodulation, it is only recently that an experimental scaffold vaccine implanted beneath the skin has begun to use the human model to study the immune responses to cancer vaccination by co-delivering patient-derived tumor lysates and immunomodulatory proteins. If successful, this scaffold vaccine will change the way we approached untreatable cancers, but more importantly, will allow a faster and more rational translation of therapeutic regimes to other cancers, chronic infections, and autoimmune diseases. Most materials reviews have focused on immunomodulatory adjuvants and micro-nano-particles. Here we provide an insight into emerging hydrogel and scaffold based immunomodulatory approaches that continue to demonstrate efficacy against immune associated diseases., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)