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Synthetically designed biomaterials strive to recapitulate and mimic the complex environment of natural systems. Using natural materials as a guide, the ability to create high-performance biomaterials that control cell fate, and support the next generation of cell- and tissue-based therapeutics, is starting to emerge. Supramolecular chemistry takes inspiration from the wealth of noncovalent interactions found in natural materials that are inherently complex, and using the skills of synthetic and polymer chemistry, recreates simple systems to imitate their features. Within the past decade, supramolecular biomaterials have shown utility in tissue engineering and the progress predicts a bright future. On this 30th anniversary of the Netherlands Biomaterials and Tissue Engineering society, we briefly recount the state of supramolecular biomaterials in the Dutch academic and industrial research and development context. This review provides the background, recent advances, industrial successes and challenges, as well as future directions of the field, as we see it. Throughout this work, we notice the intricate interplay between simplicity and complexity in creating more advanced solutions. We hope that the interplay and juxtaposition between these two forces can propel the field forward. Impact statement Supramolecular biomaterials based on noncovalent interactions hold the ability to rebuild some of the complexity of natural biomaterials in synthetic systems. While still in its infancy, the field is currently vigorously moving from fundamental experiments toward applications and products in the tissue engineering and regenerative medicine arena. Herein, we review the current state of the field in the Netherlands. While supramolecular biomaterials have incredible potential, systematic studies, balancing complexity and simplicity, efficient translation, and enhanced performance are all required for success of these strategies. As we move the field toward commercial solutions for clinical patients, we must also pay homage and remember the fundamental studies that allow these jumps in innovation.

The functional restoration of natural tissues in a variety of cardiovascular applications is the main objective of Endogenous Tissue Restoration (ETR). The recent progress in the development of biocompatible, biodegradable, and tunable biomaterials with unprecedented properties allow the next steps from laboratory studies to clinical studies. The independent control over mechanical properties and biodegradability provided by the combination of covalent and non-covalent bonds makes supramolecular polymers uniquely qualified for ETR. This paper will provide further details on the mechanism of ETR and will provide a perspective on the preclinical and clinical application of supramolecular polymers for ETR. In addition to various reports on chronic studies in large animal models, three world-first clinical studies are reported, demonstrating the potential of supramolecular technology in bringing ETR to patients.

Supramolecular biomaterials based on ureido-pyrimidinone (UPy) moieties are versatile polymer materials as their function can be tailored to the application. These UPy-materials can be designed into polymer coatings, self-healing polymers, hydrogels and elastomers. The biocompatibility of UPy-based materials and their degradation products is a long-term success requirement for many regenerative medicine and biomedical applications. Earlier research has shown that UPy-based materials and polymers display no immediate toxic effects, but in-depth in-vitro studies on potential UPy-polymer degradation products have not been executed. Owing to their resemblance to naturally occurring purines and pyrimidines, UPy-compounds and their degradation products could potentially initiate an immune response or be mutagenic. Accordingly, 11 selected UPy-compounds were synthesized, and their effect on cell viability, wound healing, and their immunogenicity and potential mutagenic potential, were studied. We showed that low molecular weight degradation products of UPy-based biomaterials do not affect cell viability, nor do these interfere with several aspects of endothelial function including proliferation, angiogenic sprouting and cellular migration even in levels exceeding plausibly attainable concentrations. Furthermore, the compounds are neither immunogenic nor mutagenic, showing that UPy-biomaterials exhibit good biocompatibility in vitro, and could in principle be used in humans.

Sensory receptors in biological systems are an essential part of natural organisms to perceive, understand and adapt to their environment and evaluate their internal state. They are interlinked with the senses of living organisms and are an important tool for the survival and evolution of species. Researchers have implemented the biomimetic receptor approach into the development of artificial sensors, in an attempt to mimic the sensory transduction of organisms, like self-healing ability and flexibility. However, aspects of biological transduction like selectivity and multi-sensing are still underdeveloped in the field of soft self-healing sensors (SSHS). The multi-sensing aspect is discussed in this review paper, focusing on resistive-based SSHS for detecting different stimuli, like strain, pressure, tactile, temperature, chemical species and structural damage. The inspiration from sensory transduction of biological systems will be a key factor for the further development of SSHS and their application in soft robotics, electronic skin, smart wearables and haptic devices.

Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Therefore, we aimed to develop a functionalized electrospun mesh that promotes tissue ingrowth and provides adequate mechanical strength and compliance during degradation. We describe the in vivo function of a new supramolecular bioactivated polycarbonate (PC) material based on fourfold hydrogen bonding ureidopyrimidinone (UPy) units (UPy-PC). The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Morphometric analysis of the musculofascial content during wound healing showed that cRGD functionalization promotes myogenesis with inhibition of collagen deposition at 14 days. It also prevents muscle atrophy at 90 days and exerts an immunomodulatory effect on infiltrating macrophages at 14 days and foreign body giant cell formation at 14 and 90 days. Additionally, the bioactivated material promotes neovascularization and connective tissue ingrowth. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in the rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. Our results provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP. Statement of Significance: Development of biomaterials for hernia and pelvic organ prolapse (POP) repair is encouraged because of high local complication rates with current materials. Ureidopyrimidinone-polycarbonate is a elastomeric and biodegradable electrospun mesh, which could mimic physiological compliance. The UPy-PC material was functionalized with UPy-modified cyclic arginine-glycine-aspartic acid (cRGD) peptide additives. Supramolecular cRGD-bioactivation of UPy-PC-meshes promotes integration of the implant, accelerates tissue ingrowth and reduces scar formation, resulting in physiological neotissue formation when used for abdominal wall reconstruction in rat hernia model. Moreover, cRGD-bioactivation prevents muscle atrophy and modulates the inflammatory response. These data provide a promising outlook towards a new type of biomaterial for the treatment of hernia and POP.

Two of the greatest challenges for successful application of small-diameter in situ tissue-engineered vascular grafts are 1) preventing thrombus formation and 2) harnessing the inflammatory response to the graft to guide functional tissue regeneration. This study evaluates the in vivo performance of electrospun resorbable elastomeric vascular grafts, dual-functionalized with anti-thrombogenic heparin (hep) and anti-inflammatory interleukin 4 (IL-4) using a supramolecular approach. The regenerative capacity of IL-4/hep, hep-only, and bare grafts is investigated as interposition graft in the rat abdominal aorta, with follow-up at key timepoints in the healing cascade (1, 3, 7 days, and 3 months). Routine analyses are augmented with Raman microspectroscopy, in order to acquire the local molecular fingerprints of the resorbing scaffold and developing tissue. Thrombosis is found not to be a confounding factor in any of the groups. Hep-only-functionalized grafts resulted in adverse tissue remodeling, with cases of local intimal hyperplasia. This is negated with the addition of IL-4, which promoted M2 macrophage polarization and more mature neotissue formation. This study shows that with bioactive functionalization, the early inflammatory response can be modulated and affect the composition of neotissue. Nevertheless, variability between graft outcomes is observed within each group, warranting further evaluation in light of clinical translation.

International audience; The intrinsic compliance of soft robots provides safety, a natural adaptation to its environment, allows to absorb shocks, and protects them against mechanical impacts. However, a literature study shows that the soft polymers used for their construction are susceptible to various types of damage, including fatigue, overloads, interfacial debonding and cuts, tears and perforations by sharp objects. An economic and ecological solution is to construct future soft robotic systems out of self-healing polymers, incorporating the ability to heal damage. This review paper proposes criteria to evaluate the potential of a self-healing polymer to be used in soft robotic applications. Based on these soft robotics requirements and on defined performance parameters of the materials, linked to the mechanical and healing properties, the different types of selfhealing polymers already available in literature are critically assessed and compared. In addition to a description of the state of the art on self-healing soft robotics, the paper discusses the driving forces and limitations to spur the interdisciplinary combination between self-healing polymer science and soft robotics.

Visual Abstract, Highlights • The predefined fiber alignment in electrospun biodegradable heart valve scaffolds did not lead to consistent collagen organization in the predefined direction. • A tendency for higher regurgitation rate and peak gradient was seen in the aTEHVs. • Biaxial tensile tests on the explanted aTEHVs revealed loss of mechanical integrity of the circumferentially aligned fibers after 1 month. • Isotropic mechanical properties were seen in all explanted scaffolds at 6 and 12 months. • Valve-to-valve variability was observed, regardless of the study group, both on the macroscopic and microscopic levels., Summary In situ tissue engineering that uses resorbable synthetic heart valve scaffolds is an affordable and practical approach for heart valve replacement; therefore, it is attractive for clinical use. This study showed no consistent collagen organization in the predefined direction of electrospun scaffolds made from a resorbable supramolecular elastomer with random or circumferentially aligned fibers, after 12 months of implantation in sheep. These unexpected findings and the observed intervalvular variability highlight the need for a mechanistic understanding of the long-term in situ remodeling processes in large animal models to improve predictability of outcome toward robust and safe clinical application.

Hallmark of the in situ tissue engineering approach is the use of bioresorbable, synthetic, acellular scaffolds, which are designed to modulate the inflammatory response and actively trigger tissue regeneration by the body itself at the site of implantation. Much research is devoted to the design of synthetic materials modulating the polarization of macrophages, which are essential mediators of the early stages of the inflammatory response. Here, we present a novel method for the functionalization of elastomers based on synthetic peptide chemistry, supramolecular self-assembly, and immobilization of heparin and interleukin 4 (IL-4), which is known to skew the polarization of macrophages into the wound healing “M2” phenotype. Ureido-pyrimidinone (UPy)-modified chain extended polycaprolactone (CE-UPy-PCL) was mixed with a UPy-modified heparin binding peptide (UPy-HBP) to allow for immobilization of heparin, and further functionalization with IL-4 via its heparin binding domain. As a first proof of principle, CE-UPy-PCL and UPy-HBP were premixed in solution, dropcast and exposed to primary human monocyte-derived macrophages, in the presence or absence of IL-4-heparin functionalization. It was demonstrated that the supramolecular IL-4-heparin functionalization effectively promoted macrophage polarization into an anti-inflammatory phenotype, in terms of morphology, immunohistochemistry and cytokine secretion. Moreover, the supramolecular functionalization approach used was successfully translated to 3D electrospun scaffolds for in situ tissue engineering purposes, where UPy-HBP retention, and heparin and IL-4 attachment to the supramolecular scaffolds were proven over 7 days. Lastly, human monocyte-derived macrophages were cultured on 3D scaffolds, which, in case of IL-4-heparin functionalization, were proven to promote of an anti-inflammatory environment on protein level. This study presents a novel method in designing a versatile class of functionalized elastomers that effectively harness the anti-inflammatory behavior of macrophages in vitro, and as such, may be instrumental for the development of a new class of synthetic materials for in situ tissue engineering purposes. Statement of Significance Macrophages and their phenotypic and functional plasticity play a pivotal role in metabolic homeostasis and tissue repair. Based on this notion, bioactivated materials modulating macrophage polarization were extensively investigated in the past. Here, we designed immunomodulating, synthetic materials based on supramolecular immobilization of a heparin binding peptide, and further bioactivation with heparin and IL-4, an anti-inflammatory cytokine responsible for M2 activation and polarization. Human monocyte-derived macrophages cultured on heparin-IL-4 bioactivated materials displayed an elongated morphology and an anti-inflammatory phenotype, with downregulation of pro-inflammatory cytokines and promotion of anti-inflammatory cytokines over time. This study represents the first step in designing a novel class of synthetic, bioactivated materials that harness the regenerative behavior of host macrophages towards in situ tissue regeneration.

Supramolecular block copolymers comprising isotactic polypropylene (iPP) and ethylene-propylene random copolymers (EP) with complementary quadruple hydrogen bonding junctions have been prepared by melt-mixing of iPP having a 2-ureido-4[1H]-pyrimidinone (UPy) group (iPP-UPy) and elastic EP bearing a 2,7-diamido-1,8-naphthyridine (Napy) group (EP-Napy). Transmission electron microscope (TEM) analysis of the iPP-UPy/EP-Napy composite showed that the elastic EP domains were well dispersed in the iPP matrix compared with the traditional iPP/EP impact polypropylene copolymer (IPC). The iPP-UPy/EP-Napy hydrogen-bonded pseudo block copolymer effectively acts as a compatibilizer in the IPC and contributes to improved mechanical properties of the resulting iPP/EP composite. There is good correlation between impact strength of the IPC and EP domain size observed by the TEM analysis. The use of the complementary quadruple hydrogen bonding system for blending two immiscible polymers has been shown to result in smaller domain sizes of the EP-phase in the iPP and consequently improved mechanical properties of the supramolecular iPP/EP blends.

This study focuses on the transfer of the healing functionality of supramolecular polymers (SP) to fibre reinforced composites through interleaving. SPs exhibiting self-healing based on hydrogen bonds were formed into films and were successfully incorporated into carbon fibre composites. The effect of the SP interleaves on in-plane fracture toughness and the subsequent healing capability of the hybrid composites were investigated under mode II fracture loading. The fracture toughness showed considerable increase since the maximum load (P max ) of the hybrid composite approximately doubled, and consequently the mode II interlaminar fracture toughness energy (G IIC ) exhibited an increase reaching nearly 100% compared to the reference composite. The healing component was activated using external heat. P max and G IIC recovery after activation were measured, exhibiting a healing efficiency after the first healing cycle close to 85% for P max and 100% for G IIC , eventually dropping to 80% for P max while G IIC was retained around 100% even after the fourth healing cycle. Acoustic Emission activity during the tests was monitored and was found to be strongly reduced due to the presence of the SP.

Although mesh use has significantly improved the outcomes of hernia and pelvic organ prolapse repair, long-term recurrence rates remain unacceptably high. We aim to determine the in vivo degradation and functional outcome of reconstructed abdominal wall defects, using slowly degradable electrospun ureidopyrimidinone moieties incorporated into a polycarbonate backbone (UPy-PC) implant compared to an ultra-lightweight polypropylene (PP) textile mesh with high pore stability. Twenty four New-Zealand rabbits were implanted with UPy-PC or PP to either reinforce a primary fascial defect repair or to cover (referred to as gap bridging) a full-thickness abdominal wall defect. Explants were harvested at 30, 90 and 180 days. The primary outcome measure was uniaxial tensiometry. Secondary outcomes were the recurrence of herniation, morphometry for musculofascial tissue characteristics, inflammatory response and neovascularization. PP explants compromised physiological abdominal wall compliance from 90 days onwards and UPy-PC from 180 days. UPy-PC meshes induced a more vigorous inflammatory response than PP at all time points. We observed progressively more signs of muscle atrophy and intramuscular fatty infiltration in the entire explant area for both mesh types. UPy-PC implants are replaced by a connective tissue stiff enough to prevent abdominal wall herniation in two-thirds of the gap-bridged full-thickness abdominal wall defects. However, in one-third there was sub-clinical herniation. The novel electrospun material did slightly better than the textile PP yet outcomes were still suboptimal. Further research should investigate what drives muscular atrophy, and whether novel polymers would eventually generate a physiological neotissue and can prevent failure and/or avoid collateral damage. ispartof: MATERIALS vol:12 issue:7 ispartof: location:Switzerland status: published

Interleaves comprising self-healing materials based on hydrogen bonded supramolecular polymers (SP) were successfully incorporated in the mid-plane of unidirectional (UD) carbon fibre reinforced polymers (CFRPs). The fracture toughness of these hybrid composites and their healing capability were measured under mode I loading. The fracture toughness appeared to have increased considerably since the maximum load (Pmax) of the hybrid composite had increased approximately 5 times, and the fracture energy I (GIC) displayed a dramatic increase by almost one order of magnitude when compared to the reference composite without the SP. Furthermore, the double cantilever beam (DCB) hybrid composites displayed a healing efficiency (H.E.) value for the mode I interlaminar characteristics around 60% for the Pmax and the GIC after the first healing cycle, dropping to 20-30% after the seventh cycle. During the mode I interlaminar fracture toughness tests the acoustic emission (AE) activity of the samples was also monitored. It was found that AE-activity strongly reduced due to the presence of the SP. Moreover, optical microscopy not only showed that the epoxy matrix at the interface is partly infiltrated by the SP, but it also revealed that cross-sections of both fractured surfaces were covered with the SP comprising pulled-out carbon fibres, indicating a strong interfacial adhesion. Finally it was shown that the SP fractured surfaces were partially covered with pulled-out carbon fibres emanating from the edges of the SP film in which the epoxy system exists.

In an in-situ approach towards tissue engineered cardiovascular replacement grafts, cell-free scaffolds are implanted that engage in endogenous tissue formation. Bioactive molecules can be incorporated into such grafts to facilitate cellular recruitment. Stromal cell derived factor 1α (SDF1α) is a powerful chemoattractant of lymphocytes, monocytes and progenitor cells and plays an important role in cellular signaling and tissue repair. Short SDF1α-peptides derived from its receptor-activating domain are capable of activating the SDF1α-specific receptor CXCR4. Here, we show that SDF1α-derived peptides can be chemically modified with a supramolecular four-fold hydrogen bonding ureido-pyrimidinone (UPy) moiety, that allows for the convenient incorporation of the UPy-SDF1α-derived peptides into a UPy-modified polymer scaffold. We hypothesized that a UPy-modified material bioactivated with these UPy-SDF1α-derived peptides can retain and stimulate circulating cells in an anti-inflammatory, pro-tissue formation signaling environment. First, the early recruitment of human peripheral blood mononuclear cells to the scaffolds was analyzed in vitro in a custom-made mesofluidic device applying physiological pulsatile fluid flow. Preferential adhesion of lymphocytes with reduced expression of inflammatory factors TNFα, MCP1 and lymphocyte activation marker CD25 was found in the bioactivated scaffolds, indicating a reduction in inflammatory signaling. As a proof of concept, in-vivo implantation of the bioactivated scaffolds as rat abdominal aorta interposition grafts showed increased cellularity by CD68+ cells after 7 days. These results indicate that a completely synthetic, cell-free biomaterial can attract and stimulate specific leukocyte populations through supramolecular incorporation of short bioactive SDF1α derived peptides.

The development of local, intrarenal drug delivery therapies is imperative to induce a therapeutic effect without the requirement of high concentrations of drugs, thereby diminishing systemic side effects. Hydrogels are eminently suitable as drug delivery carriers in soft tissues. Here, we show that a supramolecular hydrogel carrier based on ureido-pyrimidinone (UPy) modified poly(ethylene glycol) can be easily formulated and conveniently be applied to deliver anti-inflammatory and anti-fibrotic growth factor protein BMP7 to the kidney. Short-term, immediate modulation of renal inflammation and extracellular matrix remodelling is shown in a rat model of acute kidney injury. Induction of ischemia/reperfusion injury was followed by renal subcapsular implantation of pristine and BMP7-loaded supramolecular hydrogels. The cortical area under the site of implantation was studied after 3 and 7 days. Subcapsular delivery of only 0.30 mu g BMP7 from these supramolecular hydrogels led to a significant reduction in interstitial inflammatory and myofibroblast cell numbers at the site of implantation. These findings show that local, intrarenal delivery of an anti-inflammatory and anti-fibrotic drug from a supramolecular hydrogel carrier can be effective in the reduction of acute inflammation and incipient fibrosis. (C) 2015 Elsevier Ltd. All rights reserved.

The emerging field of in situ tissue engineering (TE) of load bearing tissues places high demands on the implanted scaffolds, as these scaffolds should provide mechanical stability immediately upon implantation. The new class of synthetic supramolecular biomaterial polymers, which contain non-covalent interactions between the polymer chains, thereby forming complex 3D structures by self assembly. Here, we have aimed to map the degradation characteristics of promising (supramolecular) materials, by using a combination of in vitro tests. The selected biomaterials were all polycaprolactones (PCLs), either conventional and unmodified PCL, or PCL with supramolecular hydrogen bonding moieties (either 2-ureido-[1H]-pyrimidin-4-one or bis-urea units) incorporated into the backbone. As these materials are elastomeric, they are suitable candidates for cardiovascular TE applications. Electrospun scaffold strips of these materials were incubated with solutions containing enzymes that catalyze hydrolysis, or solutions containing oxidative species. At several time points, chemical, morphological, and mechanical properties were investigated. It was demonstrated that conventional and supramolecular PCL-based polymers respond differently to enzyme-accelerated hydrolytic or oxidative degradation, depending on the morphological and chemical composition of the material. Conventional PCL is more prone to hydrolytic enzymatic degradation as compared to the investigated supramolecular materials, while, in contrast, the latter materials are more susceptible to oxidative degradation. Given the observed degradation pathways of the examined materials, we are able to tailor degradation characteristics by combining selected PCL backbones with additional supramolecular moieties. The presented combination of in vitro test methods can be employed to screen, limit, and select biomaterials for pre-clinical in vivo studies targeted to different clinical applications.

Objective: Transcatheter Aortic Valve Implantation (TAVI) has been recently approved for low-risk patients. However, TAVI-compatible bioprostheses are prone to progressive calcification and degener...

Purpose Electrospun meshes mimic the extracellular matrix, which may improve their integration. We aimed to compare polycaprolactone (PCL) modified with ureidopyrimidinone (UPy) electrospun meshes with ultra-lightweight polypropylene (PP; Restorelle) reference textile meshes for in vivo compliance. We chose UPy-PCL because we have shown it does not compromise biomechanical properties of native tissue, and because it potentially can be bioactivated. Methods We performed ex vivo biomechanical cyclic loading in wet conditions and in vivo overlay of full-thickness abdominal wall defects in rats and rabbits. Animals were sacrificed at 7, 42 and 54 days (rats; n = 6/group) and 30 and 90 days (rabbits; n = 3/group). Outcomes were herniation, mesh degradation and mesh dimensions, explant compliance and histology. High failure rates prompted us to provide additional material strength by increasing fiber diameter and mesh thickness, which was further tested in rabbits as a biomechanically more challenging model. Results Compliance was tested in animals without herniation. In both species, UPy-PCL-explants were as compliant as native tissue. In rats, PP-explants were stiffer. Contraction was similar in UPy-PCL and PP-explants. However, UPy-PCL-meshes macroscopically degraded from 30 days onwards, coinciding with herniation in up to half of animals. Increased fiber and mesh thickness did not improve outcome. Degradation of UPy-PCL is associated with an abundance of foreign body giant cells until UPy-PCL disappears. Conclusion Abdominal wall reconstruction with electrospun UPy-PCL meshes failed in 50%. Degradation coincided with a transient vigorous foreign body reaction. Non-failing UPy-PCL-explants were as compliant as native tissue. Despite that, the high failure rate forces us to explore electrospun meshes based on other polymers.

Novel supramolecular polypropylenes (PP) having self-complementary quadruple hydrogen bonding 2-ureido-4[1H]-pyrimidinone (UPy) groups (UPy-PP) have been synthesized by functionalizing of PP. The mechanical properties donated by the network structure formed by the multiple hydrogen bonding were studied with rheological analyses and tensile tests of the UPy-PP. Unusual melt viscosity of the UPy-PP indicated that the hydrogen bonding network of the UPy was maintained in the solid state at ambient temperature whereas the hydrogen bonding was dissociated in the melting PP matrix at high temperatures of around 190 °C. Tensile tests showed that the elongation at break of the UPy-PP drastically increased at higher temperatures compared to that of non-functionalized PP (nf-PP). The results indicated that a pseudo-high molecular weight PP was easily obtained through the UPy hydrogen bonding aggregation of low molecular weight PP. These findings are applicable to improving the mechanical properties of various nonpolar polyolefins by introducing self-complementary quadruple hydrogen bonding groups as a thermal reversible network system.

Intrarenal drug delivery from a hydrogel carrier implanted under the kidney capsule is an innovative way to induce kidney tissue regeneration and/or prevent kidney inflammation or fibrosis. We report here on the development of supramolecular hydrogels for this application. We have synthesized two types of supramolecular hydrogelators by connecting the hydrogen bonding moieties to poly(ethylene glycols) in two different ways in order to obtain hydrogels with different physico-chemical properties. Chain-extended hydrogelators containing hydrogen bonding units in the main chain, and bifunctional hydrogelators end-functionalized with hydrogen bonding moieties, were made. The influence of these hydrogels on the renal cortex when implanted under the kidney capsule was studied. The overall tissue response to these hydrogels was found to be mild, and minimal damage to the cortex was observed, using the infiltration of macrophages, formation of myofibroblasts, and the deposition of collagen III as relevant read-out parameters. Differences in tissue response to these hydrogels could be related to the different physico-chemical properties of the three hydrogels. The strong, flexible and slow eroding chain-extended hydrogels are proposed to be suitable for long-term intrarenal delivery of organic drugs, while the weaker, soft and fast eroding bifunctional hydrogel is eminently suitable for short-term, fast delivery of protein drugs to the kidney cortex. The favourable biological behaviour of the supramolecular hydrogels makes them exquisite candidates for subcapsular drug delivery, and paves the way to various opportunities for intrarenal therapy. (C) 2012 Elsevier Ltd. All rights reserved.

Sophisticated polymeric materials with "responsive" properties, such as self-healing, are beginning to reach the market. Supramolecular polymers, i.e., polymers that owe their mechanical properties primarily to the reversible, non-covalent interactions, such as hydrogen bonding interactions, between the macromolecules, have frequently been employed as self-healing materials. The quadruple hydrogen bonding ureidopyrimidinone (UPy) unit is a particularly effective and versatile design motif, since it forms very strong but reversible linkages, and can be incorporated into virtually any type of polymer backbone, leading to materials with increased mechanical properties. Supramolecular polymers are presented, with an emphasis on those based on the UPy-unit, and their use in self-healing applications is highlighted and discussed. Supramolecular polymers are eminently useful in self-healing applications. The reversible nature of supramolecular polymers allows for self-healing processes to take place, using a contact pressure trigger or a heat trigger. Several materials are presented with an emphasis on ureidopyrimidinone (UPy) comprising supramolecular polymer.

A modular one-component supramolecular transient network in water, based on poly(ethylene glycol) and end-capped with four-fold hydrogen bonding units, is reported. Due to its nonlinear structural formation, this system allows active proteins to be added to the hydrogel during formation. Once implanted in vivo it releases the protein by erosion of both the protein and polymer via dissolution.

Maintenance of polarisation of epithelial cells and preservation of their specialized phenotype are great challenges for bioengineering of epithelial tissues Mimicking the basement membrane and underlying extracellular matrix (ECM) with respect to its hierarchical fiber-like morphology and display of bioactive signals is prerequisite for optimal epithelial cell function in vitro We report here on a bottom-up approach based on hydrogen-bonded supramolecular polymers and ECM-peptides to make an electro-spun bioactive supramolecular mesh which can be applied as synthetic basement membrane The supramolecular polymers used self-assembled into nano-meter scale fibers while at micro-meter scale fibers were formed by electro-spinning We introduced bioactivity into these nano-fibers by intercalation of different ECM-peptides designed for stable binding Living kidney membranes were shown to be bioengineered through culture of primary human renal tubular epithelial cells on these bioactive meshes Even after a long-term culturing period of 19 days we found that the cells on bioactive membranes formed tight monolayers while cells on non-active membranes lost their monolayer integrity Furthermore the bioactive membranes helped to support and maintain renal epithelial phenotype and function Thus incorporation of ECM-peptides Into electro-spun meshes via a hierarchical supramolecular method is a promising approach to engineer bioactive synthetic membranes with an unprecedented structure This approach may in future be applied to produce living bioactive membranes for a I:no-artificial kidney (C) 2010 Elsevier Ltd All rights reserved

Supramolecular polymeric materials are of increasing interest for the use as drug delivery carriers. A thorough insight in the biocompatibility and the degradation of these materials in vivo are of fundamental importance to further their development and application in medical practice. Molecular imaging techniques are powerful tools that enable the elucidation of molecular distributions in and around such polymer implants. A supramolecular polymeric hydrogel was implanted under the renal capsule to study its biocompatibility with TOF-SIMS. This results in a molecular cartography of the polymer implant combined with the cellular signature of the implantation environment. In this experiment, molecular signals are observed from cells that are involved in the biological response to the implant, e.g., macrophages. These molecular signatures are compared with macrophage standards cultured in different polarization environments. On the basis of this comparison, information can be acquired on the various macrophage differentiations that are connected to different stages in the foreign body response. Mass spectrometric imaging techniques offer the opportunity to visualize different histological phenomena in a single experiment without the need for specific immunohistochemical markers. Cellular infiltration into the polymer is visualized, offering a clear view on both biological and polymer features in a single imaging experiment.

In order to investigate the effects of strong and well-defined hydrogen bonding on the properties ofthermoplastic elastomers (TPEs), we have applied two distinct and strongly dimerizing 2-ureido-4-[1H]-pyrimidinone (UPy) quadruple hydrogen bonding units as physical crosslinker. While the UPy-groupsconsequently serve as the 'hard phase' or 'hard block' in these TPEs, an amorphous polyester has been used as the 'soft phase' or 'soft block'. The UPy-unit has been flanked with either a sterically demandingisophorone spacer or a linear hexamethylene, where these spacers have been derived from isophoronediisocyanate (IPDI) or hexamethylene diisocyanate (HDI), respectively. This difference on a molecularlevel leads to a homogeneous amorphous material in the IPDI-case (polymer 1) and to a nanophaseseparatedmaterial in the HDI-case (polymer 2) as revealed by AFM and DSC experiments. Apart fromthis distinctive difference in morphology and nanoscopic organization, the macroscopic properties ofboth materials are also fundamentally different. In linear stress-strain and DMTA experiments, thehomogeneous IPDI-material 1 shows rubber-like behavior at room temperature, while the mechanicalproperties are strongly temperature dependent. The nanophase-separated HDI-material 2 shows acombination of rubber and plastic behavior and displays a clear rubber-plateau between 0 °C and 50 °Cwith little temperature dependence. The apparent activation-energy of flow for the latter material,determined by multi-frequency DMTA, is 135 kJ mol–1.

Functionalization of polydimethylsiloxanes (PDMS) polymers with hydrogen-bonding ureidopyrimidinone (UPy) groups leads to supramolecular thermoplastic elastomers. In previous studies, no lateral stacking of UPy dimers was observed in UPy-functionalized polymers, unless additional urethane or urea groups were built into the hard block. However, we have shown that when PDMS is used as the soft block, this lateral aggregation of UPy dimers does take place, since long fibers could be observed in the atomic force microscopy (AFM) phase image. Also in bulk, the presence of these interactions was proven by oscillatory shear experiments. We attribute this aggregation to the incompatibility of soft block and hard block, leading to phase separation. Moreover, we have shown that additional urethane or urea groups in the hard block do lead to materials with more fibers and higher melting points. For the UPy-urea functionalized PDMS even single fibers are observed with AFM when dropcasted from a very diluted solution. When the length of the soft block is increased, the morphology changes from fibrous to spherical. © 2008 Wiley Periodicals

We show that materials with a diverse range of mechanical and biological properties can be obtained using a modular approach by simply mixing different ratios of oligocaprolactones that are either end-functionalized or chain-extended with quadruple hydrogen bonding ureido-pyrimidinone (UPy) moieties. The use of two UPy-synthons allows for easy synthesis of UPy-modified polymers resulting in high yields. Comparison of end-functionalized UPy-polymers with chain-extended UPy-polymers shows that these polymers behave distinctively different regarding their material and biological properties. The end-modified UPy-polymer is rather stiff and brittle due to its high crystallinity. Disks made of this material fractures after subcutaneous implantation. The material shows a low inflammatory response which is accompanied by the formation of a fibrous capsule, reflecting the inertness of the material. The chain-extended UPy-material on the contrary is practically free of crystalline domains and shows clear flexible properties. This material deforms after in-vivo implantation, accompanied with cellular infiltration. By mixing both polymers, materials with intermediate properties concerning their mechanical and biological behaviour can be obtained. Surprisingly, a 20:80 mixture of both polymers with the chain-extended UPy-polymer in excess shows flexible properties without visible deformation upon implantation for 42 days. This mixture, a blend formed by intimate mixing through UPy-UPy interaction, also shows a mild tissue response accompanied with the formation of a thin capsule. The material does not become more crystalline upon implantation. Hence, this mixture might be an ideal scaffold material for soft tissue engineering due to its flexibility and diminished fibrous tissue formation, and illustrates the strength of the modular approach. (c) 2006 Elsevier Ltd. All rights reserved.

Sophisticated polymeric materials with ‘responsive’ properties are beginning to reach the market. The use of reversible, noncovalent interactions is a recurring design principle for responsive materials. Now, recently developed hydrogen-bonding units allow this design principle to be taken to its extreme. Supramolecular polymers, where hydrogen bonds are the only force keeping the monomers together, form materials whose (mechanical) properties respond strongly to a change in temperature or solvent. In this review, we describe the developments that have led to hydrogen-bonded supramolecular polymers and discuss the use of these materials in advanced applications.

Supramolecular polymers[1] are introduced as a new approach to come to materials in which the repeating units are not connected by covalent bonds but by specific secondary interactions. Self-complementary quadruple hydrogen bonded structures with high association constants are presented as easy to synthesize fragments in supramolecular polymers. Some of the many possibilities of equilibrium polymers are discussed, while it is shown that these supramolecular polymers can obtain materials properties normally only obtained with macromolecules.

The 1H NMR relaxivity of o- and p-dinitroxide-substituted phthalate esters and a series of nitroxyl-functionalized poly(propyleneimine) dendrimers was measured in acetonitrile and methanol. Studies of dinitroxide relaxivity indicate that the electron exchange rate has only a small effect on relaxivity. Outer-sphere relaxivity was measured using benzene as a probe mol. In studies on dendritic polynitroxides, the per-nitroxide-based outer-sphere relaxivity nearly doubles for the generation 5 nitroxyl-functionalized dendrimer as compared to a mononitroxide model. This relaxivity enhancement may be due to crowding of dendrimer surface groups in higher generation dendrimers. Water relaxivity was measured for these polynitroxides as well, and a significant inner-sphere contribution to relaxivity is found. Dendritic polynitroxides exhibit higher per-nitroxide-based water relaxivity as compared to a mononitroxide model. This relaxivity enhancement is attributed to an increase in rotational correlation time (tc) for the dendritic polynitroxides. [on SciFinder (R)]

A new strategy for the preparation of functional, multiarm star polymers via nitroxide-mediated "living" radical polymerization has been explored. The generality of this approach to the synthesis of three-dimensional macromolecular architectures allows for the construction of nanoscopically defined materials from a wide range of different homo, block, and random copolymers combining both apolar and polar vinylic repeat units. Functional groups can also be included along the backbone or as peripheral/chain end groups, thereby modulating the reactivity and polarity of defined portions of the stars. This modular approach to the synthesis of three-dimensional macromolecules permits the application of these tailored materials as multifunctional hosts for hydrogen bonding, nanoparticle formation, and as scaffolds for catalytic groups. Examples of applications of the functional stars in catalysis include their use in a Heck-type coupling as well as an enantioselective addition reaction.

Surface-initiated living free-radical polymerization is employed in a multistep procedure to prepare hollow polymeric nanocapsules. Initially, trichlorosilyl-substituted alkoxyamine initiating groups are attached to the surface silanol groups of silica nanoparticles. This surface layer of initiating groups is then used to grow functionalized linear chains leading to a core–shell morphology. The choice of functional groups is governed by their ability to undergo facile crosslinking reactions, with both active ester and benzocyclobutene groups being examined. Under either chemical or thermal conditions, the reaction of these functionalities gives a crosslinked polymeric shell that is covalently attached to, and surrounds, the central silica core. Removal of the silica core with HF then gives the hollow polymeric nanocapsules, which are stable under solvent dissolution and thermal treatment because of their crosslinked structure. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 1309–1320, 2002

The tolerance of living free radical procedures to reactive functional groups, coupled with their ability to prepare well-defined random and block copolymers is demonstrated by the use of novel α-hydrogen alkoxyamine derivatives instead of the traditional TEMPO-based systems. This refinement in the nitroxide structure overcomes many limitations typically associated with TEMPO and has permitted a dramatic increase in the range of monomers, which can be polymerized under controlled conditions. The ability to prepare well-defined multi-arm star polymers from a variety of alkoxyamine terminated vinyl and non-vinyl linear polymers are major benefits when compared to traditional living procedures, such as anionic polymerizations.

The intramolecular segregation in several generations of poly(propylene imine) dendrimers and oxygen plasma modified HDPE was studied with low-energy ion scattering (LEIS) and X-ray photoelectron spectroscopy (XPS). Although the different generations of poly(propylene imine) dendrimers contain almost the same atomic carbon to nitrogen (C/N) ratio, it is shown that this ratio at the outermost surface depends strongly on the generation of the dendrimer. The conformation of a dendrimer is probably related to the flexibility of the bis(3-aminopropyl)amine endgroups, which becomes lower for higher generations. Furthermore, the formation of a metallodendrimer, by complexation of CuCl2 with the amine endgroups of a fourth generation dendrimer (D4), was followed with LEIS. Compared to pure CuCl2, a relatively high copper concentration and a high atomic copper to chlorine ratio was found at the surface of the metallodendrimer. The high copper concentration and the reduced sterical hindrance by chlorine demonstrate the high potential of the metallodendrimers as catalytic material.The hydrophobic surface of HDPE can be made hydrophilic by treating it in an oxygen plasma. During such a treatment, oxygen containing functional groups are introduced at the surface, which improves wetting and thus adhesion. Unfortunately, the effect of an oxygen treatment is only temporary, an effect referred to as ageing or hydrophobic recovery. LEIS has been used to study this ageing process. We were able to follow the surface oxygen concentration as a function of the time between the plasma treatment and the LEIS analysis. Combined information obtained from LEIS and XPS measurements indicates that the ageing is mainly confined to the outermost atomic layers. Moreover, the ageing process depends strongly on the exact experimental conditions. (C) 2001 Elsevier Science B.V. All rights reserved

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The preparation and electron paramagnetic resonance (EPR) spectroscopy of a series of fully functionalized poly(propylene imine) dendrimers (DAB-dendr-(NH2)n; n ) 2, 4, 8, 16, 32, 64) with 3-carboxy-2,2,5,5-tetramethyl-1-pyrrolidinyloxy radical end groups is described. The pendant nitroxyl end groups exhibit a strong exchange interaction. As a consequence, the EPR spectrum directly reveals the number of end groups from the splitting between the hyperfine transitions for the lower generations. For the higher generations an increasingly exchanged-narrowed EPR spectrum is observed. The temperature and solvent dependency of the exchange interaction is used to assess the dynamic behavior of the dendritic branches. FT-IR spectroscopy shows that a hydrogen-bonded network between the amide functionalities is present, consistent with the observed solvent effect on the EPR spectra.

SUMMARY: As a first stage in the synthesis of a new class of thermoplastic elastomers, a suitable synthetic route for elastomeric tailor-made diblock copolymers based on poly(2,6dimethyl- 1,4-phenyIene oxide), PPE, as the thermoplastic block and on 1,4-polyisoprene, PIP, as the elastomenc block, is outlined. The 2,6-dimethyl- 1,4-phenyIene oxide-blockisoprene diblock copolymers were synthesized via an amidation coupling route between the ammonium salt of PPE and the monocarboxylic acid of PIP in the presence of dicyclohexylcarbodiimide, DCC. Preliminary studies were focused on the synthesis of a welldefined low molar mass diblock copolymer (&&= 10000) in order to facilitate the quantitative characterization by proton NMR spectroscopy. The developed amidation coupling route was successively applied to the synthesis of a similar diblock copolymer with a number-average molar mass of 40000 in order to obtain optimum overall properties.

With the end goal of incorporating the unique structural and physical properties of dendrimers into supramolecular assemblies, bis(m-phenylene)-32-crown-10-functionalized poly(propyleneimine) dendrimers of the first and third generations have been synthesized and their interaction with paraquat diol has been investigated. Using (1)H NMR, we determined that binding to the 4 or 16 crown ether sites occurred in an anti-cooperative fashion, most likely a result of steric influences. Upon protonation of the tertiary amines in the dendritic interior, binding became independent, i.e., statistical, and the average apparent association constant increased by nearly 5-fold; this effect is attributed to rigidification of the dendrimer, which makes its binding sites more accessible and less crowded.

In the liquid crystalline phase of optically active phthalocyanine (S)-1 the columns are helically distorted, as has been shown by circular dichroism experiments on a Langmuir-Blodgett film of (S)-1 and by small angle X-ray diffraction studies, and confirmed by time-resolved microwave conductivity measurements.