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Injectable shear-thinning biomaterials (STBs) have attracted significant attention because of their efficient and localized delivery of cells as well as various molecules ranging from growth factors to drugs. Recently, electrostatic interaction-based STBs, including gelatin/LAPONITE® nanocomposites, have been developed through a simple assembly process and show outstanding shear-thinning properties and injectability. However, the ability of different compositions of gelatin and LAPONITE® to modulate doxorubicin (DOX) delivery at different pH values to enhance the effectiveness of topical skin cancer treatment is still unclear. Here, we fabricated injectable STBs using gelatin and LAPONITE® to investigate the influence of LAPONITE®/gelatin ratio on mechanical characteristics, capacity for DOX release in response to different pH values, and cytotoxicity toward malignant melanoma. The release profile analysis of various compositions of DOX-loaded STBs under different pH conditions revealed that lower amounts of LAPONITE® (6NC25) led to higher pH-responsiveness capable of achieving a localized, controlled, and sustained release of DOX in an acidic tumor microenvironment. Moreover, we showed that 6NC25 had a lower storage modulus and required lower injection forces compared to those with higher LAPONITE® ratios. Furthermore, DOX delivery analysis in vitro and in vivo demonstrated that DOX-loaded 6NC25 could efficiently target subcutaneous malignant tumors via DOX-induced cell death and growth restriction. This journal is

Over the decades, researchers have strived to synthesize and modify nature-inspired biomaterials, with the primary aim to address the challenges of designing functional biomaterials for regenerative medicine and tissue engineering. Among these challenges, biocompatibility and cellular interactions have been extensively investigated. Some of the most desirable characteristics for biomaterials in these applications are the loading of bioactive molecules, strong adhesion to moist areas, improvement of cellular adhesion, and self-healing properties. Mussel-inspired biomaterials have received growing interest mainly due to the changes in mechanical and biological functions of the scaffold due to catechol modification. Here, we summarize the chemical and biological principles and the latest advancements in production, as well as the use of mussel-inspired biomaterials. Our main focus is the polydopamine coating, the conjugation of catechol with other polymers, and the biomedical applications that polydopamine moieties are used for, such as matrices for drug delivery, tissue regeneration, and hemostatic control. We also present a critical conclusion and an inspired view on the prospects for the development and application of mussel-inspired materials.

Silk fibroin (SF) is a promising biomaterial for tendon repair, but its relatively rigid mechanical properties and low cell affinity have limited its usefulness and utility in regenerative medicine. Meanwhile, gelatin-based polymers have advantages in cell attachment and tissue remodeling, but have insufficient mechanical strength to regenerate tough tissue such as tendons. Taking these aspects into account, in this study, gelatin methacryloyl (GelMA) was combined with SF to create a mechanically strong and bioactive nanofibrous scaffold (SG). The mechanical properties of SG nanofibers could be flexibly modulated by varying the ratio of SF and GelMA. Compared to SF nanofibers, mesenchymal stem cells (MSCs) seeded on SG fibers with optimal composition (SG7) exhibited enhanced growth, proliferation, vascular endothelial growth factor (VEGF) production and tenogenic gene expression behavior. Conditioned media from MSCs cultured on SG7 scaffolds, compared to MSCs cultured on SF or GelMA alone nanofibers could greatly promote the migration and proliferation of tenocytes. Histological analysis and tenogenesis related immunofluorescence staining indicated SG7 scaffolds demonstrated enhanced in vivo tendon tissue regeneration compared to other groups. Therefore, rational combinations of SF and GelMA hybrid nanofibers may help to improve therapeutic outcomes and address the challenges of tissue-engineered scaffolds for tendon regeneration.

Fluorescent nanomaterials have been widely used in biological imaging due to their selectivity, sensitivity, and noninvasive nature. These characteristics make the materials suitable for real-time and in situ imaging. However, further development of highly biocompatible nanosystems with long-lasting fluorescent intensity and photostability is needed for advanced bioimaging. We have used electrospraying to generate gelatin methacryloyl (GelMA)-based fluorescent nanoparticles (NPs) with chemically conjugated rhodamine B (RB). The extent of conjugation can be controlled by varying the mass ratio of RB and GelMA precursors to obtain RB-conjugated GelMA (RB-GelMA) NPs with optimal fluorescent properties and particle size. These NPs exhibited superior biocompatibility when compared with pure RB in in vitro cell viability and proliferation assays using multiple cell types. Moreover, RB-GelMA NPs showed enhanced cell internalization and improved brightness compared with unconjugated RB. Our experiments demonstrate that engineered RB-GelMA NPs can be used as a biocompatible fluorescent label for bioimaging.

Biomaterials with suitable osteoimmunomodulation properties and ability to deliver osteoinductive biomolecules, such as bone morphogenetic proteins, are desired for bone regeneration. Herein, we report the development of mesoporous silica rods with large cone-shaped pores (MSR-CP) to load and deliver large protein drugs. It is noted that those cone-shaped pores on the surface modulated the immune response and reduced the pro-inflammatory reaction of stimulated macrophage. Furthermore, bone morphogenetic proteins 2 (BMP-2) loaded MSR-CP facilitated osteogenic differentiation and promoted osteogenesis of bone marrow stromal cells. In vivo tests confirmed BMP-2 loaded MSR-CP improved the bone regeneration performance. This study provides a potential strategy for the design of drug delivery systems for bone regeneration.[Figure not available: see fulltext.]

Diabetic wound treatment faces significant challenges in clinical settings. Alternative treatment approaches are needed. Continuous bleeding, disordered inflammatory regulation, obstruction of cell proliferation, and disturbance of tissue remodeling are the main characteristics of diabetic wound healing. Hydrogels made of either naturally derived or synthetic materials can potentially be designed with a variety of functions for managing the healing process of chronic wounds. Here, a hemostatic and anti-inflammatory hydrogel patch is designed for promoting diabetic wound healing. The hydrogel patch is derived from dual-cross-linked methacryloyl-substituted Bletilla Striata polysaccharide (B) and gelatin (G) via ultraviolet (UV) light. It is demonstrated that the B-G hydrogel can effectively regulate the M1/M2 phenotype of macrophages, significantly promote the proliferation and migration of fibroblasts in vitro, and accelerate angiogenesis. It can boost wound closure by normalizing epidermal tissue regeneration and depositing collagen appropriately in vivo without exogenous cytokine supplementation. Overall, the B-G bioactive hydrogel can promote diabetic wound healing in a simple, economical, effective, and safe manner.

Electrical stimulation can facilitate wound healing with high efficiency and limited side effects. However, current electrical stimulation devices have poor conformability with wounds due to their bulky nature and the rigidity of electrodes utilized. Here, a flexible electrical patch (ePatch) made with conductive hydrogel as electrodes to improve wound management was reported. The conductive hydrogel was synthesized using silver nanowire (AgNW) and methacrylated alginate (MAA), with the former chosen as the electrode material considering its antibacterial properties, and the latter used due to its clinical suitability in wound healing. The composition of the hydrogel was optimized to enable printing on medical-grade patches for personalized wound treatment. The ePatch was shown to promote re-epithelization, enhance angiogenesis, mediate immune response, and prevent infection development in the wound microenvironment. In vitro studies indicated an elevated secretion of growth factors with enhanced cell proliferation and migration ability in response to electrical stimulation. An in vivo study in the Sprague-Dawley rat model revealed a rapid wound closure within 7 days compared to 20 days of usual healing process in rodents.

Wearable piezoresistive sensors are being developed as electronic skins (e-skin) for broad applications in human physiological monitoring and soft robotics. Tactile sensors with sufficient sensitivities, durability, and large dynamic ranges are required to replicate this critical component of the somatosensory system. Multiple micro/nano-structures, materials, and sensing modalities have been reported to address this need. However, a trade-off arises between device performance and device complexity. Inspired by the microstructure of the spinosum at the dermo epidermal junction in skin, we developed a low-cost, scalable, and high-performance piezoresistive sensor with high sensitivity (0.144 kPa(−1)), extensive sensing range (100 Pa -15 kPa), fast response time (less than 150 ms), and excellent long-term stability (over 1000 cycles). Furthermore, the piezoresistive functionality of the device was realized via a flexible transparent electrode (FTE) using a highly stable reduced graphene oxide self-wrapped copper nanowire (CurGONW) network. The developed nanowire-based spinosum microstructured FTEs are amenable to wearable electronics applications.

Animal models and traditional cell cultures are essential tools for drug development. However, these platforms can show striking discrepancies in efficacy and side effects when compared to human trials. These differences can lengthen the drug development process and even lead to drug withdrawal from the market. The establishment of preclinical drug screening platforms that have higher relevancy to physiological conditions is desirable to facilitate drug development. Here, a heart-on-a-chip platform, incorporating microgrooves and electrical pulse stimulations to recapitulate the well-aligned structure and synchronous beating of cardiomyocytes (CMs) for drug screening, is reported. Each chip is made with facile lithographic and laser-cutting processes that can be easily scaled up to high-throughput format. The maturation and phenotypic changes of CMs cultured on the heart-on-a-chip is validated and it can be treated with various drugs to evaluate cardiotoxicity and cardioprotective efficacy. The heart-on-a-chip can provide a high-throughput drug screening platform in preclinical drug development.

Made available in DSpace on 2021-06-25T10:22:20Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-07-01 The skin serves a substantial number of physiological purposes and is exposed to numerous biological and chemical agents owing to its large surface area and accessibility. Yet, current skin models are limited in emulating the multifaceted functions of skin tissues due to a lack of effort on the optimization of biomaterials and techniques at different skin layers for building skin frameworks. Here, we use biomaterial-based approaches and bioengineered techniques to develop a 3D skin model with layers of endothelial cell networks, dermal fibroblasts, and multilayered keratinocytes. Analysis of mechanical properties of gelatin methacryloyl (GelMA)-based bioinks mixed with different portions of alginate revealed bioprinted endothelium could be better modeled to optimize endothelial cell viability with a mixture of 7.5% GelMA and 2% alginate. Matrix stiffness plays a crucial role in modulating produced levels of Pro-Collagen I alpha-1 and matrix metalloproteinase-1 in human dermal fibroblasts and affecting their viability, proliferation, and spreading. Moreover, seeding human keratinocytes with gelatin-coating multiple times proved to be helpful in reducing culture time to create multiple layers of keratinocytes while maintaining their viability. The ability to fabricate selected biomaterials for each layer of skin tissues has implications in the biofabrication of skin systems for regenerative medicine and disease modeling. Center for Minimally Invasive Therapeutics (C-MIT) University of California-Los Angeles Bioprocess and Biotechnology Department Sãao Paulo State University (Unesp) School of Pharmaceutical Sciences, Km 01 Araraquara-Jau Road São Paulo State University (Unesp) Institute of Chemistry, 55 Prof. Francisco Degni Street Terasaki Institute for Biomedical Innovation Department of Bioengineering Henry Samueli School of Engineering and Applied Sciences University of California-Los Angeles Department of Electrical and Electronic Engineering The University of Hong Kong College of Pharmacy Kangwon National University U.S. Air Force Research Laboratory 711th Human Performance Wing Airman Systems Directorate Bioeffects Division Molecular Bioeffects Branch (USAFRL/711HPW/RHDJ) Department of Radiological Sciences University of California-Los Angeles Department of Biomedical Engineering Michigan State University Department of Chemical and Biomolecular Engineering Henry Samueli School of Engineering and Applied Sciences University of California-Los Angeles Jonsson Comprehensive Cancer Centre University of California Bioprocess and Biotechnology Department Sãao Paulo State University (Unesp) School of Pharmaceutical Sciences, Km 01 Araraquara-Jau Road São Paulo State University (Unesp) Institute of Chemistry, 55 Prof. Francisco Degni Street

Minimally invasive treatment via injectable delivery of cells has drawn extensive attention for tissue regeneration because it reduces the need for substantial open surgery and fits tissue defects with complex shapes, making it a suitable option for repairing articular cartilage defects. This work presents an alkaline treatment method to fabricate open-porous poly (lactic-co-glycolic acid) microspheres (OPMs) as bone marrow stromal cells (BMSCs) carriers for cartilage regeneration. OPMs have better biodegradation property and the extended pores can provide easier access for cells to the internal space. The BMSCs cultured with OPMs can display enhanced cell proliferation, up-regulated expression of cartilage-related mRNAs and proteins, and improved cartilage regeneration in vitro and in vivo. These results highlight the advantage and potential of using OPMs fabricated via simple alkaline treatment as injectable stem cell carriers for cartilage regeneration through minimally invasive procedures.

Despite the vital role of vaccines in fighting viral pathogens, effective vaccines are still unavailable for many infectious diseases. The importance of vaccines cannot be overstated during the outbreak of a pandemic, such as the coronavirus disease 2019 (COVID-19) pandemic. The understanding of genomics, structural biology, and innate/adaptive immunity have expanded the toolkits available for current vaccine development. However, sudden outbreaks and the requirement of population-level immunization still pose great challenges in today's vaccine designs. Well-established vaccine development protocols from previous experiences are in place to guide the pipelines of vaccine development for emerging viral diseases. Nevertheless, vaccine development may follow different paradigms during a pandemic. For example, multiple vaccine candidates must be pushed into clinical trials simultaneously, and manufacturing capability must be scaled up in early stages. Factors from essential features of safety, efficacy, manufacturing, and distributions to administration approaches are taken into consideration based on advances in materials science and engineering technologies. In this review, we present recent advances in vaccine development by focusing on vaccine discovery, formulation, and delivery devices enabled by alternative administration approaches. We hope to shed light on developing better solutions for faster and better vaccine development strategies through the use of biomaterials, biomolecular engineering, nanotechnology, and microfabrication techniques.

Immunotherapy is a class of promising anticancer treatments that has recently gained attention due to surging numbers of FDA approvals and extensive preclinical studies demonstrating efficacy. Nevertheless, further clinical implementation has been limited by high variability in patient response to different immunotherapeutic agents. These treatments currently do not have reliable predictors of efficacy and may lead to side effects. The future development of additional immunotherapy options and the prediction of patient‐specific response to treatment require advanced screening platforms associated with accurate and rapid data interpretation. Advanced engineering approaches ranging from sequencing and gene editing, to tumor organoids engineering, bioprinted tissues, and organs‐on‐a‐chip systems facilitate the screening of cancer immunotherapies by recreating the intrinsic and extrinsic features of a tumor and its microenvironment. High‐throughput platform development and progress in artificial intelligence can also improve the efficiency and accuracy of screening methods. Here, these engineering approaches in screening cancer immunotherapies are highlighted, and a discussion of the future perspectives and challenges associated with these emerging fields to further advance the clinical use of state‐of‐the‐art cancer immunotherapies are provided., Advanced engineering approaches and progress in artificial intelligence can contribute to the development of cancer immunotherapy by uncovering alternative treatment targets and identifying hallmarks of treatment response, efficacy, and side effects. Screening approaches, including sequencing, gene editing, tumor organoids engineering, bioprinting, and organs‐on‐a‐chip, combined with high‐throughput screening and artificial intelligence are promising in accelerating broader application of cancer immunotherapy for a larger population.

Stem cells secrete trophic factors that induce angiogenesis. These soluble factors are promising candidates for stem cell-based therapies, especially for cardiovascular diseases. Mechanical stimuli and biophysical factors presented in the stem cell microenvironment play important roles in guiding their behaviors. However, the complex interplay and precise role of these cues in directing pro-angiogenic signaling remain unclear. Here, a platform is designed using gelatin methacryloyl hydrogels with tunable rigidity and a dynamic mechanical compression bioreactor to evaluate the influence of matrix rigidity and mechanical stimuli on the secretion of pro-angiogenic factors from human mesenchymal stem cells (hMSCs). Cells cultured in matrices mimicking mechanical elasticity of bone tissues in vivo show elevated secretion of vascular endothelial growth factor (VEGF), one of representative signaling proteins promoting angiogenesis, as well as increased vascularization of human umbilical vein endothelial cells (HUVECs) with a supplement of conditioned media from hMSCs cultured across different conditions. When hMSCs are cultured in matrices stimulated with a range of cyclic compressions, increased VEGF secretion is observed with increasing mechanical strains, which is also in line with the enhanced tubulogenesis of HUVECs. Moreover, it is demonstrated that matrix stiffness and cyclic compression modulate secretion of pro-angiogenic molecules from hMSCs through yes-associated protein activity.

Injectable shear-thinning biomaterials (iSTBs) have great potential for in situ tissue regeneration through minimally invasive therapeutics. Previously, an iSTB was developed by combining gelatin with synthetic silicate nanoplatelets (SNPs) for potential application to hemostasis and endovascular embolization. Hence, iSTBs are synthesized by varying compositions of gelatin and SNPs to navigate their material, mechanical, rheological, and bioactive properties. All compositions (each component percentage; 1.5-4.5%/total solid ranges; 3-9%) tested are injectable through both 5 Fr general catheter and 2.4 Fr microcatheter by manual pressure. In the results, an increase in gelatin contents causes decrease in swellability, increase in freeze-dried hydrogel scaffold porosity, increase in degradability and injection force during iSTB fabrication. Meanwhile, the amount of SNPs in composite hydrogels is mainly required to decrease degradability and increase shear thinning properties of iSTB. Finally, in vitro and in vivo biocompatibility tests show that the 1.5-4.5% range gelatin-SNP iSTBs are not toxic to the cells and animals. All results demonstrate that the iSTB can be modulated with specific properties for unmet clinical needs. Understanding of mechanical and biological consequences of the changing gelatin-SNP ratios through this study will shed light on the biomedical applications of iSTB on specific diseases.

Thrombosis is a life-threatening pathological condition in which blood clots form in blood vessels, obstructing or interfering with blood flow. Thrombolytic agents (TAs) are enzymes that can catalyze the conversion of plasminogen to plasmin to dissolve blood clots. The plasmin formed by TAs breaks down fibrin clots into soluble fibrin that finally dissolves thrombi. Several TAs have been developed to treat various thromboembolic diseases, such as pulmonary embolisms, acute myocardial infarction, deep vein thrombosis, and extensive coronary emboli. However, systemic TA administration can trigger non-specific activation that can increase the incidence of bleeding. Moreover, protein-based TAs are rapidly inactivated upon injection resulting in the need for large doses. To overcome these limitations, various types of nanocarriers have been introduced that enhance the pharmacokinetic effects by protecting the TA from the biological environment and targeting the release into coagulation. The nanocarriers show increasing half-life, reducing side effects, and improving overall TA efficacy. In this work, the recent advances in various types of TAs and nanocarriers are thoroughly reviewed. Various types of nanocarriers, including lipid-based, polymer-based, and metal-based nanoparticles are described, for the targeted delivery of TAs. This work also provides insights into issues related to the future of TA development and successful clinical translation.

Growth factors (GFs) play a crucial role in directing stem cell behavior and transmitting information between different cell populations for tissue regeneration. However, their utility as therapeutics is limited by their short half-life within the physiological microenvironment and significant side effects caused by off-target effects or improper dosage. “Smart” materials that can not only sustain therapeutic delivery over a treatment period but also facilitate on-demand release upon activation are attracting significant interest in the field of GF delivery for tissue engineering. Three properties are essential in engineering these “smart” materials: (1) the cargo vehicle protects the encapsulated therapeutic; (2) release is targeted to the site of injury; (3) cargo release can be modulated by disease-specific stimuli. The aim of this review is to summarize the current research on stimuli-responsive materials utilized as intelligent vehicles for controlled GF delivery; we focus on five main subfields of tissue engineering: skin, bone and cartilage, muscle, blood vessel, and nerve. Challenges in achieving such “smart” materials and perspectives on future applications of stimuli-responsive GF delivery for tissue regeneration are also discussed.

Cell reprogramming is a revolutionized biotechnology that offers a powerful tool to engineer cell fate and function for regenerative medicine, disease modeling, drug discovery, and beyond. Leveraging advances in biomaterials and micro/nanotechnologies can enhance the reprogramming performance in vitro and in vivo through the development of delivery strategies and the control of biophysical and biochemical cues. In this review, we present an overview of the state-of-the-art technologies for cell reprogramming and highlight the recent breakthroughs in engineering biomaterials with micro/nanotechnologies to improve reprogramming efficiency and quality. Finally, we discuss future directions and challenges for reprogramming technologies and clinical translation.

Minimally invasive biosensors are emerging as powerful tools to enable personalized healthcare and precision medicine. Recent advances in biotechnology, wireless communication, and flexible electronics have offered unprecedented opportunity to develop minimally invasive biosensors for commercial applications. In this chapter, we discuss emerging technologies of minimally invasive biosensing and their working principle, applications, and challenges. We also present areas where further endeavors are needed and future directions in this field.

Cancer remains a leading health burden worldwide. One of the challenges hindering cancer therapy development is the substantial discrepancies between the existing cancer models and the tumor microenvironment (TME) of human patients. Constructing tumor organoids represents an emerging approach to recapitulate the pathophysiological features of the TME in vitro. Over the past decade, various approaches have been demonstrated to engineer tumor organoids as in vitro cancer models, such as incorporating multiple cellular populations, reconstructing biophysical and chemical traits, and even recapitulating structural features. In this review, we focus on engineering approaches for building tumor organoids, including biomaterial-based, microfabrication-assisted, and synthetic biology-facilitated strategies. Furthermore, we summarize the applications of engineered tumor organoids in basic cancer research, cancer drug discovery, and personalized medicine. We also discuss the challenges and future opportunities in using tumor organoids for broader applications.

Viral infection is one of the leading causes of mortality worldwide. The growth of globalization significantly increases the risk of virus spreading, making it a global threat to future public health. In particular, the ongoing coronavirus disease 2019 (COVID‐19) pandemic outbreak emphasizes the importance of devices and methods for rapid, sensitive, and cost‐effective diagnosis of viral infections in the early stages by which their quick and global spread can be controlled. Micro and nanoscale technologies have attracted tremendous attention in recent years for a variety of medical and biological applications, especially in developing diagnostic platforms for rapid and accurate detection of viral diseases. This review addresses advances of microneedles, microchip‐based integrated platforms, and nano‐ and microparticles for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens related to the diagnosis of viral diseases. Additionally, methods for the fabrication of microchip‐based devices and commercially used devices are described. Finally, challenges and prospects on the development of micro and nanotechnologies for the early diagnosis of viral diseases are highlighted., Viral infections are the leading causes of mortality worldwide. Micro and nanoscale technologies have been used to develop diagnostic platforms for rapid and accurate detection of viral diseases. Here, these technologies are reviewed for sampling, sample processing, enrichment, amplification, and detection of viral particles and antigens. Challenges and future directions in this area are highlighted.

Generating artificial pancreatic beta cells by using synthetic materials to mimic glucose-responsive insulin secretion in a robust manner holds promise for improving clinical outcomes in people with diabetes. Here, we describe the construction of artificial beta cells (AβCs) with a multicompartmental 'vesicles-in-vesicle' superstructure equipped with a glucose-metabolism system and membrane-fusion machinery. Through a sequential cascade of glucose uptake, enzymatic oxidation and proton efflux, the AβCs can effectively distinguish between high and normal glucose levels. Under hyperglycemic conditions, high glucose uptake and oxidation generate a low pH (

Anaerobic bacteria, such as Clostridium and Salmonella, can selectively invade and colonize in tumor hypoxic regions (THRs) and deliver therapeutic products to destroy cancer cells. Herein, we present an anaerobe nanovesicle mimic that can not only be activated in THRs but also induce hypoxia in tumors by themselves. Moreover, inspired by the oxygen metabolism of anaerobes, we construct a light-induced hypoxia-responsive modality to promote dissociation of vehicles and activation of bioreductive prodrugs simultaneously. In vitro and in vivo experiments indicate that this anaerobe-inspired nanovesicle can efficiently induce apoptotic cell death and significantly inhibit tumor growth. Our work provides a new strategy for engineering stimuli-responsive drug delivery systems in a bioinspired and synergistic fashion.

Physiological characteristics of diseases bring about both challenges and opportunities for targeted drug delivery. Various drug delivery platforms have been devised ranging from macro- to micro- and further into the nanoscopic scale in the past decades. Recently, the favorable physicochemical properties of nanomaterials, including long circulation, robust tissue and cell penetration attract broad interest, leading to extensive studies for therapeutic benefits. Accumulated knowledge about the physiological barriers that affect the in vivo fate of nanomedicine has led to more rational guidelines for tailoring the nanocarriers, such as size, shape, charge, and surface ligands. Meanwhile, progresses in material chemistry and molecular pharmaceutics generate a panel of physiological stimuli-responsive modules that are equipped into the formulations to prepare “smart” drug delivery systems. The capability of harnessing physiological traits of diseased tissues to control the accumulation of or drug release from nanomedicine has further improved the controlled drug release profiles with a precise manner. Successful clinical translation of a few nano-formulations has excited the collaborative efforts from the research community, pharmaceutical industry, and the public towards a promising future of smart drug delivery.

The immune system protects the body against a wide range of infectious diseases and cancer by leveraging the efficiency of immune cells and lymphoid organs. Over the past decade, immune cell/organ therapies based on the manipulation, infusion, and implantation of autologous or allogeneic immune cells/organs into patients have been widely tested and have made great progress in clinical applications. Despite these advances, therapy with natural immune cells or lymphoid organs is relatively expensive and time-consuming. Alternatively, biomimetic materials and strategies have been applied to develop artificial immune cells and lymphoid organs, which have attracted considerable attentions. In this review, we survey the latest studies on engineering biomimetic materials for immunotherapy, focusing on the perspectives of bioengineering artificial antigen presenting cells and lymphoid organs. The opportunities and challenges of this field are also discussed.

Microneedles (MNs) have been used to deliver drugs for over two decades. These platforms have been proven to increase transdermal drug delivery efficiency dramatically by penetrating restrictive tissue barriers in a minimally invasive manner. While much of the early development of MNs focused on transdermal drug delivery, this technology can be applied to a variety of other non-transdermal biomedical applications. Several variations, such as multi-layer or hollow MNs, have been developed to cater to the needs of specific applications. The heterogeneity in the design of MNs has demanded similar variety in their fabrication methods; the most common methods include micromolding and drawing lithography. Numerous materials have been explored for MN fabrication which range from biocompatible ceramics and metals to natural and synthetic biodegradable polymers. Recent advances in MN engineering have diversified MNs to include unique shapes, materials, and mechanical properties that can be tailored for organ-specific applications. In this review, we discuss the design and creation of modern MNs that aim to surpass the biological barriers of non-transdermal drug delivery in ocular, vascular, oral, and mucosal tissue.

A DNA-based bioresponsive nanoformulation delivers the CRISPR-Cas12a to hepatocytes for regulating serum cholesterol., CRISPR-Cas12a represents an efficient tool for genome editing in addition to the extensively investigated CRISPR-Cas9. However, development of efficient nonviral delivery system for CRISPR-Cas12a remains challenging. Here, we demonstrate a DNA nanoclew (NC)–based carrier for delivery of Cas12a/CRISPR RNA (crRNA) ribonucleoprotein (RNP) toward regulating serum cholesterol levels. The DNA NC could efficiently load the Cas12a/crRNA RNP through complementation between the DNA NC and the crRNA. Addition of a cationic polymer layer condensed the DNA-templated core and allowed further coating of a charge reversal polymer layer, which makes the assembly negatively charged under a physiological pH but reverts to positive charge under an acidic environment. When Pcsk9 was selected as the target gene because of its important role in regulating the level of serum cholesterol, efficient Pcsk9 disruption was observed in vivo (~48%), significantly reducing the expression of PCSK9 and gaining the therapeutic benefit of cholesterol control (~45% of cholesterol reduction).

Embedding microfluidic architectures with microneedles enables fluid management capabilities that present new degrees of freedom for transdermal drug delivery. To this end, fabrication schemes that can simultaneously create and integrate complex millimeter/centimeter-long microfluidic structures and micrometer-scale microneedle features are necessary. Accordingly, three-dimensional (3D) printing techniques are suitable candidates because they allow the rapid realization of customizable yet intricate microfluidic and microneedle features. However, previously reported 3D-printing approaches utilized costly instrumentation that lacked the desired versatility to print both features in a single step and the throughput to render components within distinct length-scales. Here, for the first time in literature, we devise a fabrication scheme to create hollow microneedles interfaced with microfluidic structures in a single step. Our method utilizes stereolithography 3D-printing and pushes its boundaries (achieving print resolutions below the full width half maximum laser spot size resolution) to create complex architectures with lower cost and higher print speed and throughput than previously reported methods. To demonstrate a potential application, a microfluidic-enabled microneedle architecture was printed to render hydrodynamic mixing and transdermal drug delivery within a single device. The presented architectures can be adopted in future biomedical devices to facilitate new modes of operations for transdermal drug delivery applications such as combinational therapy for preclinical testing of biologic treatments.

Breast cancer is one of lethal cancers among women with its metastasis leading to cancer-related morbidity and mortality. Circulating tumor cells (CTCs) derived from a primary tumor can be detected in the venous blood of cancer patients. Monitoring CTCs in blood samples has increased exponentially over the past decades and holds great promise in the diagnosis and treatment of metastatic breast cancer. Electrochemical cytosensors, classified as a class of electrochemical biosensors for sensitive detection and enumeration of targeted cells with minimally invasive methods, have the advantages of electrochemical biosensors, such as simplicity, low cost, and low limit of detection. Here, we review recent progress in the detection of CTCs from breast cancer with a focus on electrochemical cytosensors. This review describes platforms benefiting from these cytosensors to identify cancerous breast cells. Furthermore, strategies for signal amplification and also generation of reusable electrochemical cytosensors are introduced. In addition, breast cancer markers and biorecognition elements for cell capturing are reviewed.

Multicomponent biomaterials using a high-throughput system regulate hyaline or hypertrophic chondrogenesis of hMSCs., Despite great progress in biomaterial design strategies for replacing damaged articular cartilage, prevention of stem cell-derived chondrocyte hypertrophy and resulting inferior tissue formation is still a critical challenge. Here, by using engineered biomaterials and a high-throughput system for screening of combinatorial cues in cartilage microenvironments, we demonstrate that biomaterial cross-linking density that regulates matrix degradation and stiffness—together with defined presentation of growth factors, mechanical stimulation, and arginine-glycine-aspartic acid (RGD) peptides—can guide human mesenchymal stem cell (hMSC) differentiation into articular or hypertrophic cartilage phenotypes. Faster-degrading, soft matrices promoted articular cartilage tissue formation of hMSCs by inducing their proliferation and maturation, while slower-degrading, stiff matrices promoted cells to differentiate into hypertrophic chondrocytes through Yes-associated protein (YAP)–dependent mechanotransduction. in vitro and in vivo chondrogenesis studies also suggest that down-regulation of the Wingless and INT-1 (WNT) signaling pathway is required for better quality articular cartilage-like tissue production.

The liver possesses a unique microenvironment with a complex internal vascular system and cell-cell interactions. Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease, and although much effort has been dedicated to building models to target NAFLD, most in vitro systems rely on simple models failing to recapitulate complex liver functions. Here, an in vitro system is presented to study NAFLD (steatosis) by coculturing human hepatocellular carcinoma (HepG2) cells and umbilical vein endothelial cells (HUVECs) into spheroids. Analysis of colocalization of HepG2-HUVECs along with the level of steatosis reveals that the NAFLD pathogenesis could be better modeled when 20% of HUVECs are presented in HepG2 spheroids. Spheroids with fat supplements progressed to the steatosis stage on day 2, which could be maintained for more than a week without being harmful for cells. Transferring spheroids onto a chip system with an array of interconnected hexagonal microwells proves helpful for monitoring functionality through increased albumin secretions with HepG2-HUVEC interactions and elevated production of reactive oxygen species for steatotic spheroids. The reversibility of steatosis is demonstrated by simply stopping fat-based diet or by antisteatotic drug administration, the latter showing a faster return of intracellular lipid levels to the basal level.

Each person's response to the therapies is different. In article number 1801039, Ali Khademhosseini and co‐workers discuss engineering approaches for precision medicine. Healthcare could be individualized through personalized cells therapies, controlled drug delivery systems, personalized scaffolds and implants, wearable sensors, point‐of‐care devices, as well as organs‐on‐chip systems.

The development of three-dimensional (3D) printing has significantly advanced the field of bone tissue engineering by enabling the fabrication of scaffolds that faithfully recapitulate desired mechanical properties and architectures. In addition, computer-based manufacturing relying on patient-derived medical images permits the fabrication of customized modules in a patient-specific manner. In addition to conventional 3D fabrication, progress in materials engineering has led to the development of four-dimensional (4D) printing, allowing time-sensitive interventions such as programed therapeutics delivery and modulable mechanical features. Therapeutic interventions established via multi-dimensional engineering are expected to enhance the development of personalized treatment in various fields, including bone tissue regeneration. Here, we summarized recent studies utilizing 3D printed systems for bone tissue regeneration and highlight advances in 4D printed systems. We also discussed challenges and perspectives for the future development of multi-dimensional printed systems towards personalized bone regeneration.

Cancer immunotherapies, including immune checkpoint inhibitor (ICI)-based therapies, have revolutionized cancer treatment. However, patient response to ICIs is highly variable, necessitating the development of methods to quickly assess efficacy. In this study, an array of miniaturized bioreactors has been developed to model tumor-immune interactions. This immunotherapeutic high-throughput observation chamber (iHOC) is designed to test the effect of anti-PD-1 antibodies on cancer spheroid (MDA-MB-231, PD-L1+) and T cell (Jurkat) interactions. This system facilitates facile monitoring of T cell inhibition and reactivation using metrics such as tumor infiltration and interleukin-2 (IL-2) secretion. Status of the tumor-immune interactions can be easily captured within the iHOC by measuring IL-2 concentration using a micropillar array where sensitive, quantitative detection is allowed after antibody coating on the surface of array. The iHOC is a platform that can be used to model and monitor cancer-immune interactions in response to immunotherapy in a high-throughput manner.

The CRISPR-Cas system, especially the type II CRISPR-Cas9 system from Streptococcus pyogenes , has rapidly emerged as a popular genome editing tool. The development of Cas9 derivatives further expanded the toolbox of CRISPR-Cas9 based genome editing kit. However, therapeutic translation of the CRISPR-Cas9 system in vivo is severely impeded by the absence of an appropriate delivery carrier. The complexity and high molecular weight of the CRISPR-Cas9 system, together with the physiological barriers for nucleus targeted cargo transportation have made it a huge challenge for in vivo therapeutic CRISPR-Cas9 delivery. Currently, the main stream carriers for systemic delivery of CRISPR-Cas9 are viral based, such as adeno-associated virus. However, the safety concerns surrounding viral vectors call for the development of non-viral nanocarriers. In this review, we survey the recent advances in the development of non-viral delivery systems for CRISPR-Cas9. Challenges and future directions in this field are also discussed.

Focal cerebral ischemia, known as stroke, causes serious long-term disabilities globally. Effective therapy for cerebral ischemia demands a carrier that can penetrate the blood-brain barrier (BBB) and subsequently target the ischemia area in brain. Here, we designed a novel neuroprotectant (ZL006) loaded dual targeted nanocarrier based on liposome (T7&SHp-P-LPs/ZL006) conjugated with T7 peptide (T7) and stroke homing peptide (SHp) for penetrating BBB and targeting ischemia area, respectively. Compared with non-targeting liposomes, T7&SHp-P-LPs/ZL006 could transport across BCEC cells and significantly enhance cellular uptake and reduce cells apoptosis of excitatory amino acid stimulated PC-12 cells. However, there was no significant difference in cellular uptake between SHp-modified and plain liposomes when PC-12 cells were incubated without excitatory amino acid. Besides, ex vivo fluorescent images indicated that DiR labeled T7&SHp-P-LPs could efficiently transport across BBB and mostly accumulated in ischemic region rather than normal cerebral hemisphere of MCAO rats. Furthermore, T7&SHp-P-LPs/ZL006 could enhance the ability of in vivo anti-ischemic stroke of MCAO rats. These results demonstrated that T7&SHp-P-LPs could be used as a safe and effective dual targeted nanocarrier for ischemic stroke treatment.

Advances in material science brought about a wide range of drug delivery systems, from traditional bulk controlled release formulations to modern nanotechnology based carriers, for improved drug ef...

Protein therapy has been considered the most direct and safe approach to treat cancer. Targeting delivery of extracellularly active protein without internalization barriers, such as membrane permeation and endosome escape, is efficient and holds vast promise for anticancer treatment. Herein, we describe a "transformable" core-shell based nanocarrier (designated CS-NG), which can enzymatically assemble into microsized extracellular depots at the tumor site with assistance of hyaluronidase (HAase), an overexpressed enzyme at the tumor microenvironment. Equipped with an acid-degradable modality, the resulting CS-NG can substantially release combinational anticancer drugs-tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and antiangiogenic cilengitide toward the membrane of cancer cells and endothelial cells at the acidic tumor microenvironment, respectively. Enhanced cytotoxicity on MDA-MB-231 cells and improved antitumor efficacy were observed using CS-NG, which was attributed to the inhibition of cellular internalization and prolonged retention time in vivo.

Stimuli-responsive and imaging-guided drug delivery systems hold vast promise for enhancement of therapeutic efficacy. Here we report an adenosine-5'-triphosphate (ATP)-responsive and near-infrared (NIR)-emissive conjugated polymer-based nanocarrier for the controlled release of anticancer drugs and real-time imaging. We demonstrate that the conjugated polymeric nanocarriers functionalized with phenylboronic acid tags on surface as binding sites for ATP could be converted to the water-soluble conjugated polyelectrolytes in an ATP-rich environment, which promotes the disassembly of the drug carrier and subsequent release of the cargo. In vivo studies validate that this formulation exhibits promising capability for inhibition of tumor growth. We also evaluate the metabolism process by monitoring the fluorescence signal of the conjugated polymer through the in vivo NIR imaging.