were selected "off-the-shelf" based on the ingenuity of the surgeons. [1] During the last century, significant medical and technological progress has paved the way for the field of biomaterials research and the emergence of a biomaterials industry. Various synthetic or natural biomaterials have been developed which have enabled treatment of a wide range of medical conditions. Nevertheless, biomaterials are being considered for increasingly complex indications, which has increased the requirements for biomaterials considerably during the past decades. [2] Consequently, challenging-or even contradictorycombinations of biomaterial properties are often required which cannot be met by conventional biomaterials. For instance, biomaterials are desired which combine injectability, mechanical strength, and degradability with toughness to avoid mechanical damage following crack propagation. To meet these strict requirements, biomaterials are needed which can adapt to the implantation site and are able to heal themselves upon mechanical damage. While the majority of synthetic biomaterials does not recover from mechanical damage, natural tissues display a remarkable capacity for self-healing such as the spontaneous self-repair of bone fractures or ruptured skin. This self-healing ability is the ultimate solution of nature for continued survival based Biomaterials are being applied in increasingly complex areas such as tissue engineering, bioprinting, and regenerative medicine. For these applications, challenging-or even contradictory-combinations of biomaterial properties are often required which cannot be met by conventional biomaterials. During the past decade, several new concepts have been developed to render biomaterials self-healing, thereby offering new opportunities to improve the functionality of traditional biomaterials in terms of their mechanical, handling, and biological properties. Consequently, various types of self-healing polymeric, ceramic, or composite biomaterials have been developed. Nevertheless, despite the rapid emergence of the field of self-healing biomaterials, this field of research has not been reviewed during the recent years. Therefore, this article provides a critical overview of recent progress in the field of self-healing biomaterials research by discussing both extrinsic and intrinsic self-healing systems. While the extrinsic self-healing section focuses on self-healing dental materials and orthopedic bone cements that rely on release of healing liquids from embedded microcapsules, the section on intrinsic self-healing materials mainly discusses concepts for self-healing of polymeric biomaterials that are either hydrated (hydrogels) or nonhydrated (e.g., films and coatings). Finally, benefits of the self-healing feature for biomaterials are discussed, and directions for future research and developments are outlined.

Photodriven click reactions have emerged as versatile tools for biomaterial synthesis that can recapitulate critical spatial and temporal changes of extracellular matrix (ECM) microenvironments in vitro. In this article, we report on the synthesis of poly(ethylene glycol) (PEG) hydrogels using photodriven step-growth polymerization, where one of the reactive functionalities is formed by a photocleavage reaction. Upon photocleavage, an aldehyde functionality is generated that rapidly reacts with hydrazinefunctionalized PEGs; the gelation kinetics and final material modulus are distinctly controlled by variations in the light intensity. This light-driven aldehyde generation is further exploited to install biochemical ligands in the hydrazone-based hydrogels with precise spatial control. We expect that userdirected spatial and temporal control over both biophysical and biochemical gel properties through photochemical reactions and photopatterning, respectively, should provide newfound opportunities to probe and understand dynamic cell−matrix interactions.

The microenvironment plays a crucial role in the behavior of stem and progenitor cells. In the heart, cardiac progenitor cells (CPCs) reside in specific niches, characterized by key components that are altered in response to a myocardial infarction. To date, there is a lack of knowledge on these niches and on the CPC interplay with the niche components. Insight into these complex interactions and into the influence of microenvironmental factors on CPCs can be used to promote the regenerative potential of these cells. In this review, we discuss cardiac resident progenitor cells and their regenerative potential and provide an overview of the interactions of CPCs with the key elements of their niche. We focus on the interaction between CPCs and supporting cells, extracellular matrix, mechanical stimuli, and soluble factors. Finally, we describe novel approaches to modulate the CPC niche that can represent the next step in recreating an optimal CPC microenvironment and thereby improve their regeneration capacity.

Optimization of cell-material interactions is crucial for the success of synthetic biomaterials in guiding tissue regeneration. To do so, catechol chemistry is often used to introduce adhesiveness into biomaterials. Here, a supramolecular approach based on ureido-pyrimidinone (UPy) modified polymers is combined with catechol chemistry in order to achieve improved cellular adhesion onto supramolecular biomaterials. UPy-modified hydrophobic polymers with non-cell adhesive properties are developed that can be bioactivated via a modular approach using UPy-modified catechols. It is shown that successful formulation of the UPy-catechol additive with the UPy-polymer results in surfaces that induce cardiomyocyte progenitor cell adhesion, cell spreading, and preservation of cardiac specific extracellular matrix production. Hence, by functionalizing supramolecular surfaces with catechol functionalities, an adhesive supramolecular biomaterial is developed that allows for the possibility to contribute to biomaterial-based regeneration.

The extracellular matrix (ECM) forms through hierarchical assembly of small and larger polymeric molecules into a transient, hydrogel‐like fibrous network that provides mechanical support and biochemical cues to cells. Synthetic, fibrous supramolecular networks formed via non‐covalent assembly of various molecules are therefore potential candidates as synthetic mimics of the natural ECM, provided that functionalization with biochemical cues is effective. Here, combinations of slow and fast exchanging molecules that self‐assemble into supramolecular fibers are employed to form transient hydrogel networks with tunable dynamic behavior. Obtained results prove that modulating the ratio between these molecules dictates the extent of dynamic behavior of the hydrogels at both the molecular and the network level, which is proposed to enable effective incorporation of cell‐adhesive functionalities in these materials. Excitingly, the dynamic nature of the supramolecular components in this system can be conveniently employed to formulate multicomponent supramolecular hydrogels for easy culturing and encapsulation of single cells, spheroids, and organoids. Importantly, these findings highlight the significance of molecular design and exchange dynamics for the application of supramolecular hydrogels as synthetic ECM mimics.

High concentrations of supplemented growth factors can cause oversaturation and adverse effects in in vitro and in vivo studies, though these supraphysiological concentrations are often required due to the low stability of growth factors. Here we demonstrate the stabilization of TGF-β1 and BMP4 using supramolecular polymers. Inspired by heparan sulfate, sulfonated peptides were presented on a supramolecular polymer to allow for noncovalent binding to growth factors in solution. After mixing with excipient molecules, both TGF-β1 and BMP4 were shown to have a prolonged half-life compared to the growth factors free in solution. Moreover, high cellular response was measured by a luciferase assay, indicating that TGF-β1 remained highly active upon binding to the supramolecular assembly. The results demonstrate that significant lower concentrations of growth factors can be used when supramolecular polymers bearing growth factor binding moieties are implemented. This approach can also be exploited in hydrogel systems to control growth factor release.

One of the major challenges in the processing of hydrogels based on poly(ethylene glycol) (PEG) is to create mechanically robust electrospun hydrogel scaffolds without chemical crosslinking postprocessing. In this study, this is achieved by the introduction of physical crosslinks in the form of supramolecular hydrogen bonding ureido‐pyrimidinone (UPy) moieties, resulting in chain‐extended UPy‐PEG polymers (CE‐UPy‐PEG) that can be electrospun from organic solvent. The resultant fibrous meshes are swollen in contact with water and form mechanically stable, elastic hydrogels, while the fibrous morphology remains intact. Mixing up to 30 wt% gelatin with these CE‐UPy‐PEG polymers introduce bioactivity into these scaffolds, without affecting the mechanical properties. Manipulating the electrospinning parameters results in meshes with either small or large fiber diameters, i.e., 0.63 ± 0.36 and 2.14 ± 0.63 µm, respectively. In that order, these meshes provide support for renal epithelial monolayer formation or a niche for the culture of cardiac progenitor cells.

Structurally and functionally well-defined recombinant proteins are an interesting class of sequence-controlled macromolecules to which different crosslinking chemistries can be applied to tune their biological properties. Herein, we take advantage of a 571-residue recombinant peptide based on human collagen type I (RCPhC1), which we functionalized with supramolecular 4-fold hydrogen bonding ureido-pyrimidinone (UPy) moieties. By grafting supramolecular UPy moieties onto the backbone of RCPhC1 (UPy-RCPhC1), increased control over the polymer structure, assembly, gelation, and mechanical properties was achieved. In addition, by increasing the degree of UPy functionalization on RCPhC1, cardiomyocyte progenitor cells were cultured on “soft” (∼26 kPa) versus “stiff” (∼68–190 kPa) UPy-RCPhC1 hydrogels. Interestingly, increased stress fiber formation, focal adhesions, and proliferation were observed on stiffer compared to softer substrates, owing to the formation of stronger cell–material interactions. In conclusion, a bioinspired hydrogel material was designed by a combination of two well-known natural components, i.e., a protein as sequence-controlled polymer and UPy units inspired on nucleobases.