Biomimetic Scaffolds for Tissue Engineering

Biomimetic scaffolds mimic important features of the extracellular matrix (ECM) architecture and can be finely controlled at the nano‐ or microscale for tissue engineering. Rational design of biomimetic scaffolds is based on consideration of the ECM as a natural scaffold; the ECM provides cells with a variety of physical, chemical, and biological cues that affect cell growth and function. There are a number of approaches available to create 3D biomimetic scaffolds with control over their physical and mechanical properties, cell adhesion, and the temporal and spatial release of growth factors. Here, an overview of some biological features of the natural ECM is presented and a variety of original engineering methods that are currently used to produce synthetic polymer‐based scaffolds in pre‐fabricated form before implantation, to modify their surfaces with biochemical ligands, to incorporate growth factors, and to control their nano‐ and microscale geometry to create biomimetic scaffolds are discussed. Finally, in contrast to pre‐fabricated scaffolds composed of synthetic polymers, injectable biomimetic scaffolds based on either genetically engineered‐ or chemically synthesized‐peptides of which sequences are derived from the natural ECM are discussed. The presence of defined peptide sequences can trigger in situ hydrogelation via molecular self‐assembly and chemical crosslinking. A basic understanding of the entire spectrum of biomimetic scaffolds provides insight into how they can potentially be used in diverse tissue engineering, regenerative medicine, and drug delivery applications.     

Conductive Scaffolds for Cardiac and Neuronal Tissue Engineering: Governing Factors and Mechanisms

Tissue engineering is a promising therapeutic approach in medicine, targeting the replacement of a diseased tissue with a healthy one grown within an artificial scaffold. Due to the high prevalence of cardiac and brain‐related ailments that involve some necrosis of tissue, cardiac and neuronal tissue engineering are intensely studied fields in regenerative medicine. A growing trend in the use of conductive scaffolds for the growth of these tissues has been witnessed recently. While the results are irrefutable, the mechanism of how an electrically conducting scaffold interacts with an electroactive tissue remains has remained elusive. An up‐to‐date summary of all work done in the field is reported, with a special focus on the specific contribution of the conductive scaffold on the performance of the formed tissue. The cell–scaffold electronic interface is then explored from an electrical engineering perspective. The electronic configuration of the system and the mechanisms and governing factors controlling the ability of a conductive scaffold to support cardiac and neuronal tissues are discussed. Using several simulations, the required conductivity of the scaffold in order for it to be suitable for tissue engineering—which also depends on the nature of the charge carriers—is also discussed.     

Polymer Fiber Scaffolds for Bone and Cartilage Tissue Engineering

Successful regeneration of weight‐bearing bone defects and critical‐sized cartilage defects remains a major challenge in clinical orthopedics. In the past decades, biodegradable polymer materials with biomimetic chemical and physical properties have been rapidly developed as ideal candidates for bone and cartilage tissue engineering scaffolds. Due to their unique advantages over other materials of high specific‐surface areas, suitable mechanical strength, and tailorable characteristics, scaffolds made of polymer fibers have been increasingly used for the repair of bone and cartilage defects. This Review summarizes the preparation and compositions of polymer fibers, as well as their characteristics. More importantly, the applications of polymer fiber scaffolds with well‐designed structures or unique properties in bone, cartilage, and osteochondral tissue engineering have been comprehensively highlighted. On the whole, such a comprehensive summary affords constructive suggestions for the development of polymer fiber scaffolds in bone and cartilage tissue engineering.     

Synthetic Biology and Tissue Engineering: Toward Fabrication of Complex and Smart Cellular Constructs

Tissue engineering approaches, with the goals of replacing or recovering damaged or diseased tissues, or of reconstituting tissues in vitro for disease modeling and drug development, have the potential to make significant contributions to medicine. Advances in stem cell biology, biomaterial synthesis and characterization, and microscale technologies have made engineered tissues a reality. However, the classic tools used to build tissues in the lab do not allow for complete control of cell behaviors. More recently, synthetic biology principles have developed robust and versatile approaches to program cells with artificial genetic circuits, where cell behavior and function can be manipulated. At the interface between synthetic biology and tissue engineering, there is space for a new area of investigation where material engineering and cellular engineering complement and sustain each other. In this progress report, synthetic biology principles and how they have been used to engineer cells with potential to dictate cell behavior and function in tissue constructs of the future are briefly described. It is believed that this research area still needs further exploration to fully exploit synthetic biology to make smart and functional cellular constructs for therapeutic and in vitro applications.     

Engineering Tridimensional Hydrogel Tissue and Organ Phantoms with Tunable Springiness

Biomimicking organ phantoms with vivid biological structures and soft and slippery features are essential for in vitro biomedical applications yet remain hither to unmet challenges in their fabrication such as balancing between spatial structural complexity and matchable mechanical properties. Herein, 3D printable tissue-mimicking elastomeric double network hydrogels with tailorable stiffness are evolved to idiosyncratically match diverse biological soft tissues by regulating the compositions of hydrogel matrix and the density of metal coordination bonds. Relying on digital light processing 3D printing, various mechanically tunable biomimetic volumetric hydrogel organ constructs with structural complexity and fidelity, including kidney, brain, heart, liver, stomach, lung, trachea, intestine, and even the intricate vascularized tissues, are fabricated faultlessly. Proof-of-concept 3D printed hydrogel heart and liver phantoms provide sophisticated internal channels and cavity structures and external realistic anatomical architectures that more closely mimic native organs. For the in vitro application demonstration, a 3D printed hydrogel brain phantom with tortuous cerebral arteries and slippery characters serves as an effective neurosurgical training platform for realistic simulation of endovascular interventions. This platform offers a means to construct mechanically precisely tunable hydrogel-based biomimetic organ phantoms that are expected to be used in surgical training, medical device testing, and organs-on-chips.     

Thermochemotherapy Meets Tissue Engineering for Rheumatoid Arthritis Treatment

Rheumatoid arthritis (RA) is an autoimmune disease that progresses from inflammation to cartilage destruction. Inspired by the similar characteristics of inflammatory granulation tissue to those of tumors, the newly emerged tumor therapy called thermochemotherapy is proposed to treat RA. Meanwhile, the repair of cartilage injury via tissue engineering is paid attention simultaneously. A first-line antirheumatic drug (MTX; methotrexate) and transforming growth factor β1 (TGF-β1) are loaded in nano-Fe₃O₄ composite chitosan-polyolefin to construct a multifunctional hydrogel (DN-Fe-MTX-TGFβ1). The mechanical properties of the hydrogel are equivalent to that of articular cartilage to guarantee its role as a scaffold. A long-term release ability and the magnetocaloric properties of the hydrogel assure its effect to provide sustained local thermochemotherapy. The effective ability of the hydrogel for both anti-inflammation and cartilage repair is demonstrated. This work indicates a promising way to combine thermochemotherapy and tissue engineering for the effective treatment of RA for the first time.     

Silk Hydrogels as Soft Substrates for Neural Tissue Engineering

There is great need for soft biomaterials that match the stiffness of human tissues for tissue engineering and regeneration. Hydrogels are frequently employed for extracellular matrix functionalization and to provide appropriate mechanical cues. It is challenging, however, to achieve structural integrity and retain bioactive molecules in hydrogels for complex tissue formation that may take months to develop. This work aims to investigate mechanical and biochemical characteristics of silk hydrogels for soft tissue engineering, specifically for the nervous system. The stiffness of 1 to 8% silk hydrogels, measured by atomic force microscopy, is 4 to 33 kPa. The structural integrity of silk gels is maintained throughout embryonic chick dorsal root ganglion (cDRG) explant culture over 4 days whereas fibrin and collagen gels decrease in mass over time. Neurite extension of cDRGs cultured on 2 and 4% silk hydrogels exhibit greater growth than softer or stiffer gels. Silk hydrogels release <5% of neurotrophin‐3 (NT‐3) over 2 weeks and 11‐day old gels show maintenance of growth factor bioactivity. Finally, fibronectin‐ and NT‐3‐functionalized silk gels elicit increased axonal bundling suggesting their use in bridging nerve injuries. These results support silk hydrogels as soft and sustainable biomaterials for neural tissue engineering.     

Highly Elastic Micropatterned Hydrogel for Engineering Functional Cardiac Tissue

Heart failure is a major international health issue. Myocardial mass loss and lack of contractility are precursors to heart failure. Surgical demand for effective myocardial repair is tempered by a paucity of appropriate biological materials. These materials should conveniently replicate natural human tissue components, convey persistent elasticity, promote cell attachment, growth and conformability to direct cell orientation and functional performance. Here, microfabrication techniques are applied to recombinant human tropoelastin, the resilience‐imparting protein found in all elastic human tissues, to generate photocrosslinked biological materials containing well‐defined micropatterns. These highly elastic substrates are then used to engineer biomimetic cardiac tissue constructs. The micropatterned hydrogels, produced through photocrosslinking of methacrylated tropoelastin (MeTro), promote the attachment, spreading, alignment, function, and intercellular communication of cardiomyocytes by providing an elastic mechanical support that mimics their dynamic mechanical properties in vivo. The fabricated MeTro hydrogels also support the synchronous beating of cardiomyocytes in response to electrical field stimulation. These novel engineered micropatterned elastic gels are designed to be amenable to 3D modular assembly and establish a versatile, adaptable foundation for the modeling and regeneration of functional cardiac tissue with potential for application to other elastic tissues.     

Capillary Force Lithography: A Versatile Tool for Structured Biomaterials Interface Towards Cell and Tissue Engineering

This Feature Article aims to provide an in‐depth overview of the recently developed molding technologies termed capillary force lithography (CFL) that can be used to control the cellular microenvironment towards cell and tissue engineering. Patterned polymer films provide a fertile ground for controlling various aspects of the cellular microenvironment such as cell–substrate and cell–cell interactions at the micro‐ and nanoscale. Patterning thin polymer films by molding typically involves several physical forces such as capillary, hydrostatic, and dispersion forces. If these forces are precisely controlled, the polymer films can be molded into the features of a polymeric mold with high pattern fidelity and physical integrity. The patterns can be made either with the substrate surface clearly exposed or unexposed depending on the pattern size and material properties used in the patterning. The former (exposed substrate) can be used to adhere proteins or cells on pre‐defined locations of a substrate or within a microfluidic channel using an adhesion‐repelling polymer such as poly(ethylene glycol) (PEG)‐based polymer and hyaluronic acid (HA). Also, the patterns can be used to co‐culture different cells types with molding‐assisted layer‐by‐layer deposition. In comparison, the latter (unexposed substrate) can be used to control the biophysical surrounding of a cell with tailored mechanical properties of the material. The surface micropatterns can be used to engineer cellular and multi‐cellular architecture, resulting in changes of the cell shape and the cytoskeletal structures. Also, the nanoscale patterns can be used to affect various aspects of the cellular behavior, such as adhesion, proliferation, migration, and differentiation.     

Nanofibrous Composite with Tailorable Electrical and Mechanical Properties for Cardiac Tissue Engineering

Cardiac tissue engineering is a promising strategy to prevent functional deterioration or even to enhance cardiac function upon myocardial infarction. Here, electrospun fiber mats containing different combinations of electrically conductive polyaniline, collagen, and/or hyaluronic acid are assessed regarding material properties and compatibility with cardiomyocyte attachment and function. Microstructure analysis reveals that collagen fiber mats contain a wide range of fiber diameters after crosslinking (from ≈300 nm to ≈5 µm); all other fiber mats contain fibers in the range of ≈120 to ≈300 nm. Fiber mats exhibit comparable electrical conductivity to and greater mechanical properties than the native human myocardium, which is considered beneficial. Cell–matrix interaction analysis utilizing postnatal rat cardiomyocytes reveals that the fiber mats are non‐cytotoxic and permit cell attachment and contraction. Fiber mats containing collagen (9.89%), hyaluronic acid (1.1%), and polyaniline (PANi, 1.34%) exhibit the most favorable properties with longer contraction time, higher contractile amplitude, and lower beating rates. Improved contraction is accompanied by increased connexin 43 expression. Importantly, this fiber mat is a suitable material for human‐induced pluripotent stem cell–derived cardiomyocytes regarding cytotoxicity, cell attachment, and function. Collectively, these data demonstrate that fiber mats made of collagen, hyaluronic acid, and polyaniline are promising materials for cardiac tissue engineering.     

Scaffold Fabrication Technologies and Structure/Function Properties in Bone Tissue Engineering

Bone tissue engineering (BTE) is a rapidly growing field aiming to create a biofunctional tissue that can integrate and degrade in vivo to treat diseased or damaged tissue. It has become evident that scaffold fabrication techniques are very important in dictating the final structural, mechanical properties, and biological response of the implanted biomaterials. A comprehensive review of the current accomplishments on scaffold fabrication techniques, their structure, and function properties for BTE is provided herein. Different types of biomaterials ranging from inorganic biomaterials to natural and synthetic polymers and related composites for scaffold processing are presented. Emergent scaffolding techniques such as electrospinning, freeze-drying, bioprinting, and decellularization are also discussed. Strategies to improve vascularization potential and immunomodulation, which is considered a grand challenge in BTE scaffolding, are also presented.     

Electrospun Fibrous Architectures for Drug Delivery,Tissue Engineering and Cancer Therapy

The versatile electrospinning technique is recognized as an efficient strategy to deliver active pharmaceutical ingredients and has gained tremendous progress in drug delivery, tissue engineering, cancer therapy, and disease diagnosis. Numerous drug delivery systems fabricated through electrospinning regarding the carrier compositions, drug incorporation techniques, release kinetics, and the subsequent therapeutic efficacy are presented herein. Targeting for distinct applications, the composition of drug carriers vary from natural/synthetic polymers/blends, inorganic materials, and even hybrids. Various drug incorporation approaches through electrospinning are thoroughly discussed with respect to the principles, benefits, and limitations. To meet the various requirements in actual sophisticated in vivo environments and to overcome the limitations of a single carrier system, feasible combinations of multiple drug‐inclusion processes via electrospinning could be employed to achieve programmed, multi‐staged, or stimuli‐triggered release of multiple drugs. The therapeutic efficacy of the designed electrospun drug‐eluting systems is further verified in multiple biomedical applications and is comprehensively overviewed, demonstrating promising potential to address a variety of clinical challenges.