Tissue models

The hypes and hopes of tissue engineering and associated efforts of researchers to succeed in this area have resulted in many attempts to produce living tissue and organs outside the human body. These include the creation of skin, cartilage, bone, tendon, skeletal muscles, heart muscle, blood vessels, heart valves and bladder tissue, in which the degree of success is mainly evaluated on the basis of structural similarities with native or ‘the original’ human tissue. Despite their envisioned and highly recommended potential as tissue replacements inside the human body, many of these types of tissue still only function outside the human body and have not passed the stage of laboratory prototype or small-scale implantation studies in animals. Thus, the broad-scale clinical application of tissue engineered products lies far ahead and, apart from commercial and regulatory problems, very much depends on scientific progress.Notwithstanding these drawbacks, a decade of intensive and interdisciplinary research, converging knowledge from biology, material science, bioengineering and medicine, has brought scientific and technological progress in the field of regenerative medicine. In line with all this, a more immediate and directly assessable application of tissue engineering has been the creation of three-dimensional (3-D) laboratory models of tissues and organs. Even in those areas where clinically relevant tissues are decades away, the tissues that are currently being made provide powerful ‘living’ biological models. These 3-D models are far more realistic than existing two-dimensional (2-D) cell culture models and can be used to study or test a specific aspect of interest at tissue level with a higher level of experimental control and with less ethical considerations than animal models. Tissue model systems find their application in studying normal and pathological tissue functioning and the associated testing of potential therapies. In addition, they represent useful tools for the development of technologies for regenerative medicine and early diagnosis and tissue screenin

Tissue engineering meets immunoengineering: prospective on personalized in situ tissue engineering strategies

For many applications, tissue engineering strategies are increasingly moving from an in vitro to an in situ-driven approach. This innovative strategy employs readily-available, resorbable scaffolds, designed to induce endogenous tissue regeneration directly in situ. Therein, one of the main challenges is the regeneration of functional new tissue, rather than fibrotic scar tissue, for which harnessing and directing the host immune system is paramount. In this concise review, we address the most important recent findings with respect to immunomodulatory strategies, considering both the scaffold-dependent factors (e.g. material composition, microstructure) and scaffold-independent, patient-specific factors (e.g. age, comorbidities). Moreover, we reflect on the necessity of adequate models to truly grasp a fundamental understanding of the immunological processes underlying regeneration in a clinically relevant context

Mechanobiology of the cell–matrix interplay: catching a glimpse of complexity via minimalistic models

Biological tissues present a grand challenge for mechanicians. Not only are their mechanical properties complex, they show a strong spatiotemporal heterogeneity due to ongoing and active remodeling of the living matter they are composed of: cells and extracellular matrix (ECM). The main sensors and effectors in this process are the cells, which direct tissue structure and mechanics by changing their own behavior and by producing and reorganizing the ECM. Vice versa, the ECM exhibits unique mechanical signatures associated with its fibrous polymer network that can modulate cell behavior. Grasping the full complexity of this reciprocal mechanical interaction between cells and the ECM is key for understanding physiological tissue function and maladaptation. An emerging approach is to explain the role of tissue biomechanics one component at a time and gradually (re)build tissue complexity. Here we highlight how this approach has been valuable in providing new insights in the relative and combined roles of cells and matrix, and in raising new questions into the origins of cellular and tissue responses. The answers may offer new approaches for mechanically driven tissue regeneration and biomaterial design

Cellular geometry sensing at different length scales and its implications for scaffold design

\u3cp\u3eGeometrical cues provided by the intrinsic architecture of tissues and implanted biomaterials have a high relevance in controlling cellular behavior. Knowledge of how cells sense and subsequently respond to complex geometrical cues of various sizes and origins is needed to understand the role of the architecture of the extracellular environment as a cell-instructive parameter. This is of particular interest in the field of tissue engineering, where the success of scaffold-guided tissue regeneration largely depends on the formation of new tissue in a native-like organization in order to ensure proper tissue function. A well-considered internal scaffold design (i.e., the inner architecture of the porous structure) can largely contribute to the desired cell and tissue organization. Advances in scaffold production techniques for tissue engineering purposes in the last years have provided the possibility to accurately create scaffolds with defined macroscale external and microscale internal architectures. Using the knowledge of how cells sense geometrical cues of different size ranges can drive the rational design of scaffolds that control cellular and tissue architecture. This concise review addresses the recently gained knowledge of the sensory mechanisms of cells towards geometrical cues of different sizes (from the nanometer to millimeter scale) and points out how this insight can contribute to informed architectural scaffold designs.\u3c/p\u3

From molecular design to 3D printed life-like materials with unprecedented properties

Stimuli-responsive synthetic materials have gained interest as biomaterials due to their ability to transform upon external stimuli. In order to mimic the cellular microenvironment synthetically, it is proposed that stimuli-responsiveness needs to be coupled with hierarchical supramolecular assembly of the materials applied. Additionally the mechanical properties of the microenvironment, i.e. the extracellular matrix, determine the nature of the tissue, which also needs to be mimicked in the material. Full control of mechanical properties, stimuli-responsiveness and hierarchical structure formation is proposed to be achieved by 3D printing of supramolecular systems into hierarchical structures that are able to react and adapt to stimuli, using metamaterial concepts. Therefore, in this review we discuss 3D printing of stimuli-responsive materials, and the design and development of metamaterials. Combination of these concepts with supramolecular chemistry is proposed to result in the design and synthesis of life-like biomaterials with unprecedented properties

Can we grow valves inside the heart?:perspective on material-based in situ heart valve tissue engineering

\u3cp\u3eIn situ heart valve tissue engineering using cell-free synthetic, biodegradable scaffolds is under development as a clinically attractive approach to create living valves right inside the heart of a patient. In this approach, a valve-shaped porous scaffold implant is rapidly populated by endogenous cells that initiate neo-tissue formation in pace with scaffold degradation. While this may constitute a cost-effective procedure, compatible with regulatory and clinical standards worldwide, the new technology heavily relies on the development of advanced biomaterials, the processing thereof into (minimally invasive deliverable) scaffolds, and the interaction of such materials with endogenous cells and neo-tissue under hemodynamic conditions. Despite the first positive preclinical results and the initiation of a small-scale clinical trial by commercial parties, in situ tissue formation is not well understood. In addition, it remains to be determined whether the resulting neo-tissue can grow with the body and preserves functional homeostasis throughout life. More important yet, it is still unknown if and how in situ tissue formation can be controlled under conditions of genetic or acquired disease. Here, we discuss the recent advances of material-based in situ heart valve tissue engineering and highlight the most critical issues that remain before clinical application can be expected. We argue that a combination of basic science - unveiling the mechanisms of the human body to respond to the implanted biomaterial under (patho)physiological conditions - and technological advancements - relating to the development of next generation materials and the prediction of in situ tissue growth and adaptation - is essential to take the next step towards a realistic and rewarding translation of in situ heart valve tissue engineering.\u3c/p\u3

An automated quantitative analysis of cell, nucleus and focal adhesion morphology

\u3cp\u3eAdherent cells sense the physical properties of their environment via focal adhesions. Improved understanding of how cells sense and response to their physical surroundings is aided by quantitative evaluation of focal adhesion size, number, orientation, and distribution in conjunction with the morphology of single cells and the corresponding nuclei. We developed a fast, user-friendly and automated image analysis algorithm capable of capturing and characterizing these individual components with a high level of accuracy. We demonstrate the robustness and applicability of the algorithm by quantifying morphological changes in response to a variety of environmental changes as well as manipulations of cellular components of mechanotransductions. Finally, as a proof-of-concept we use our algorithm to quantify the effect of Rho-associated kinase inhibitor Y-27632 on focal adhesion maturation. We show that a decrease in cell contractility leads to a decrease in focal adhesion size and aspect ratio.\u3c/p\u3