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

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

Design of an affinity based cytokine release system to temporally control macrophage behavior

\u3cp\u3eStatement of Purpose: Macrophages are key mediators in the inflammatory response to implanted biomaterials and their behavior ultimately determines the function and longevity of implants. Therefore, there is a need to modulate macrophage behavior in response to implanted biomaterials to promote healthy biomaterial-tissue integration. Here, we propose to use the biotin-streptavidin affinity system to modify scaffolds with immunomodulatory cytokines to promote the desired macrophage phenotype, which varies depending on the application. The bond between biotin and streptavidin has been assumed to be essentially covalent, however, biotinylated proteins exhibit reduced bond strength with streptavidin, leading to release of the biotinylated proteins. Additionally, in the presence of excess biotin, biotinylated proteins are displaced by free biotin due to the higher affinity between free biotin and streptavidin. Therefore, the biotin-streptavidin system holds potential to be used to impart controlled release functionality to any biomaterial that is amenable to biotinylation. The objective of this study was to investigate how conjugation parameters affect release of biotinylated macrophage-modulating proteins from biotinylated scaffolds. Gelatin sponges, a model biomaterial, were biotinylated with varying degrees of biotin, followed by attachment to biotinylated interleukin-4 (IL4) via streptavidin in order to promote the pro-healing M2 macrophage phenotype. Additionally, two variants of avidin, streptavidin and captavidin, which have different affinities for biotin, were used to modulate the rate of release of protein over time.\u3c/p\u3

Tissue-engineered heart valves

The native heart valves are adaptive living tissues that are capable of growth and remodeling in response to changes in the hemodynamic environment. It is the intrinsic lack of this growth and remodeling capacity that causes current heart valve replacements to fail over time. Therefore, heart valve tissue engineering (HVTE) is being pursued with the aim of creating living, autologous replacement valves with the capacity for somatic growth and increased valve longevity. This chapter elaborates on the various HVTE paradigms, ranging from the in vitro creation of living valves to the use of acellular valvular grafts that are designed to induce endogenous regeneration in situ. This includes a delineation of the various cell types, scaffolds, and bioreactor systems that form the building blocks of HVTE, as well as a concise description of the added value of computational models. Finally, the merging of HVTE with percutaneous delivery techniques and the main current challenges toward robust clinical translation are discussed

Cyclic strain affects macrophage cytokine secretion and ECM turnover in electrospun scaffolds

\u3cp\u3eControlling macrophage behavior has become a high-potential target strategy for regenerative therapies, such as in situ tissue engineering (TE). In situ TE is an approach, in which acellular resorbable synthetic scaffolds are used, to induce endogenous tissue regeneration. However, little is known regarding the effect of the biomechanical environment on the macrophage response to a scaffold. Therefore, the aim of this study was to assess the effect of cyclic strains (0%, 8%, and 14% strain) on primary human macrophage polarization in electrospun scaffolds with two different fiber diameters in the micrometer range (4 μm or 13 μm). High strains led to a proinflammatory profile in terms of gene expression, expression of surface proteins, and cytokine secretion. These results were consistent for scaffolds with small and large fiber diameters, indicating that the effect of cyclic strain was not affected by the different scaffold microstructures. Notably, macrophages were identified as direct contributors of early secretion of extracellular matrix proteins, including elastin, which was deposited in a strain-dependent manner. These findings are instrumental for the rational design of scaffolds for in situ TE and underline that immunomodulatory scaffolds for biomechanically loaded applications should be mechanically tailored, for example, in terms of stiffness and compliance, to support a desirable proregenerative macrophage phenotype. Electrospun elastomeric scaffolds are being used for a variety of in situ tissue engineering applications, in which biomechanical loads play a dominant in vivo role, such as cardiovascular replacements (e.g., heart valve and blood vessel prostheses) and pelvic floor reconstruction. The findings of this study underline that immunomodulatory scaffolds for biomechanically loaded applications should be mechanically tailored, for example, in terms of stiffness and compliance, to support a desirable proregenerative macrophage phenotype. Moreover, this research contributes to the general understanding of pathophysiological macrophage phenotypes in cyclically strained tissues (e.g., atherosclerotic plaques), and their role in tissue regeneration and degeneration.\u3c/p\u3

Tissue engineering of heart valves: advances and current challenges

It is estimated that the number of patients requiring heart valve replacement will triple over the next five decades. None of the current replacement valves can fully restore native valve function because they lack growth and remodeling capabilities. Heart valve tissue engineering is a promising technology to overcome these limitations. Various approaches are being employed, either aimed at development of the valve substitute in vitro or at the use of the regenerative potential of the body (in situ) for the tissue culture phase. This review provides an overview of the progress within both the in vitro and in situ tissue engineering approaches for trileaflet heart valve tissue engineering. Current challenges with these approaches are discussed, focusing in particular on the use of synthetic scaffold materials