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Two‐dimensional (2D) metal organic frameworks (MOFs), are an emerging class of layered nanomaterials with well‐defined structure and modular composition. The unique pore structure, high flexibility, tunability, and ability to introduce desired functionality within the structural framework, have led to potential use of MOFs in biomedical applications. This article critically reviews the application of 2D MOFs for therapeutic delivery, tissue engineering, bioimaging, and biosensing. Further, discussion on the challenges and strategies in next generation of 2D MOFs are also included.

This article is categorized under:

Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

 

3D bioprinting is an emerging additive manufacturing technique to fabricate constructs for human disease modeling. However, current cell‐laden bioinks lack sufficient biocompatibility, printability, and structural stability needed to translate this technology to preclinical and clinical trials. Here, a new class of nanoengineered hydrogel‐based cell‐laden bioinks is introduced, that can be printed into 3D, anatomically accurate, multicellular blood vessels to recapitulate both the physical and chemical microenvironments of native human vasculature. A remarkably unique characteristic of this bioink is that regardless of cell density, it demonstrates a high printability and ability to protect encapsulated cells against high shear forces in the bioprinting process. 3D bioprinted cells maintain a healthy phenotype and remain viable for nearly one‐month post‐fabrication. Leveraging these properties, the nanoengineered bioink is printed into 3D cylindrical blood vessels, consisting of living co‐culture of endothelial cells and vascular smooth muscle cells, providing the opportunity to model vascular function and pathophysiology. Upon cytokine stimulation and blood perfusion, this 3D bioprinted vessel is able to recapitulate thromboinflammatory responses observed only in advanced in vitro preclinical models or in vivo. Therefore, this 3D bioprinted vessel provides a potential tool to understand vascular disease pathophysiology and assess therapeutics, toxins, or other chemicals.

 

Bioprinting is an emerging approach for fabricating cell‐laden 3D scaffolds via robotic deposition of cells and biomaterials into custom shapes and patterns to replicate complex tissue architectures. Bioprinting uses hydrogel solutions called bioinks as both cell carriers and structural components, requiring bioinks to be highly printable while providing a robust and cell‐friendly microenvironment. Unfortunately, conventional hydrogel bioinks have not been able to meet these requirements and are mechanically weak due to their heterogeneously crosslinked networks and lack of energy dissipation mechanisms. Advanced bioink designs using various methods of dissipating mechanical energy are aimed at developing next‐generation cellularized 3D scaffolds to mimic anatomical size, tissue architecture, and tissue‐specific functions. These next‐generation bioinks need to have high print fidelity and should provide a biocompatible microenvironment along with improved mechanical properties. To design these advanced bioink formulations, it is important to understand the structure–property–function relationships of hydrogel networks. By specifically leveraging biophysical and biochemical characteristics of hydrogel networks, high performance bioinks can be designed to control and direct cell functions. In this review article, current and emerging approaches in hydrogel design and bioink reinforcement techniques are critically evaluated. This bottom‐up perspective provides a materials‐centric approach to bioink design for 3D bioprinting.

 

A nanoengineered bioink loaded with therapeutic proteins is designed to direct cell function in a 3D printed construct. The bioink is developed from a hydrolytically degradable polymer and 2D synthetic nanoparticle. The synthesis of poly(ethylene glycol)‐dithiothreitol (PEGDTT) via a Michael‐like step growth polymerization results in acrylate terminated degradable macromer. The addition of 2D nanosilicates to PEGDTT results in formation of shear‐thinning bioinks with high printability and structural fidelity. The mechanical properties, swelling kinetics, and degradation rate of 3D printed constructs can be modulated by changing the ratio of PEG:PEGDTT and nanosilicates concentration. Due to high surface area and charged characteristic of nanosilicates, protein therapeutics can be sequestered in 3D printing structure for prolong duration. Sustained release of pro‐angiogenic therapeutics from 3D printed structure, promoted rapid migration of human endothelial umbilical vein cell. This approach to design biologically active inks to control and direct cell behavior can be used to engineer 3D complex tissue structure for regenerative medicine.

 

Clay nanomaterials are an emerging class of 2D biomaterials of interest due to their atomically thin layered structure, charged characteristics, and well‐defined composition. Synthetic nanoclays are plate‐like polyions composed of simple or complex salts of silicic acids with a heterogeneous charge distribution and patchy interactions. Due to their biocompatible characteristics, unique shape, high surface‐to‐volume ratio, and charge, nanoclays are investigated for various biomedical applications. Here, a critical overview of the physical, chemical, and physiological interactions of nanoclay with biological moieties, including cells, proteins, and polymers, is provided. The state‐of‐the‐art biomedical applications of 2D nanoclay in regenerative medicine, therapeutic delivery, and additive manufacturing are reviewed. In addition, recent developments that are shaping this emerging field are discussed and promising new research directions for 2D nanoclay‐based biomaterials are identified.

 

Additive manufacturing is a promising method for producing customized 3D bioactive constructs for regenerative medicine. Here, 3D printed highly osteogenic scaffolds using nanoengineered ionic–covalent entanglement ink (NICE) for bone tissue engineering are reported. This NICE ink consists of ionic–covalent entanglement reinforced with Laponite, a 2D nanosilicate (nSi) clay, allowing for the printing of anatomic‐sized constructs with high accuracy. The 3D printed structure is able to maintain high structural stability in physiological conditions without any significant swelling or deswelling. The presence of nSi imparts osteoinductive characteristics to the NICE scaffolds, which is further augmented by depositing pluripotent stem cell‐derived extracellular matrix (ECM) on the scaffolds. This is achieved by stimulating human induced pluripotent stem cell‐derived mesenchymal stem cells (iP‐hMSCs) with 2‐chloro‐5‐nitrobenzanilide, a PPARγ inhibitor that enhances Wnt pathway, resulting in the deposition of an ECM characterized by high levels of collagens VI and XII found in anabolic bone. The osteoinductive characteristics of these bioconditioned NICE (bNICE) scaffolds is demonstrated through osteogenic differentiation of bone marrow derived human mesenchymal stem cells. A significant increase in the expression of osteogenic gene markers as well as mineralized ECM are observed on bioconditioned NICE (bNICE) scaffolds compared to bare scaffolds (NICE). The bioconditioned 3D printed scaffolds provide a unique strategy to design personalized bone grafts for in situ bone regeneration.

 

Nanoparticle shape has emerged as a key regulator of nanoparticle transport across physiological barriers, intracellular uptake, and biodistribution. We report a facile approach to synthesize ellipsoidal nanoparticles through self‐assembly of poly(glycerol sebacate)‐co‐poly(ethylene glycol) (PGS‐co‐PEG). The PGS‐PEG nanoparticle system is highly tunable, and the semiaxis length of the nanoparticles can be modulated by changing PGS‐PEG molar ratio and incorporating therapeutics. As both PGS and PEG are highly biocompatible, the PGS‐co‐PEG nanoparticles show high hemo‐, immuno‐, and cytocompatibility. Our data suggest that PGS‐co‐PEG nanoparticles have the potential for use in a wide range of biomedical applications including regenerative medicine, stem cell engineering, immune modulation, and cancer therapeutics. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2048–2058, 2018.

 

Hydrogel microparticles (HMPs) are an emerging bioink that can allow three-dimensional (3D) printing of most soft biomaterials by improving physical support and maintaining biological functions. However, the mechanisms of HMP jamming within printing nozzles and yielding to flow remain underexplored. Here, we present an in-depth investigation via both experimental and computational methods on the HMP dissipation process during printing as a result of (i) external resistance from the printing apparatus and (ii) internal physicochemical properties of HMPs. In general, a small syringe opening, large or polydisperse size of HMPs, and less deformable HMPs induce high resistance and closer HMP packing, which improves printing fidelity and stability due to increased interparticle adhesion. However, smooth extrusion and preserving viability of encapsulated cells require low resistance during printing, which is associated with less shear stress. These findings can be used to improve printability of HMPs and facilitate their broader use in 3D bioprinting.