Elsevier

Biomaterials

Volume 129, June 2017, Pages 1-27
Biomaterials

Review
Supramolecular biofunctional materials

https://doi.org/10.1016/j.biomaterials.2017.03.014Get rights and content

Abstract

This review discusses supramolecular biofunctional materials, a novel class of biomaterials formed by small molecules that are held together via noncovalent interactions. The complexity of biology and relevant biomedical problems not only inspire, but also demand effective molecular design for functional materials. Supramolecular biofunctional materials offer (almost) unlimited possibilities and opportunities to address challenging biomedical problems. Rational molecular design of supramolecular biofunctional materials exploit powerful and versatile noncovalent interactions, which offer many advantages, such as responsiveness, reversibility, tunability, biomimicry, modularity, predictability, and, most importantly, adaptiveness. In this review, besides elaborating on the merits of supramolecular biofunctional materials (mainly in the form of hydrogels and/or nanoscale assemblies) resulting from noncovalent interactions, we also discuss the advantages of small peptides as a prevalent molecular platform to generate a wide range of supramolecular biofunctional materials for the applications in drug delivery, tissue engineering, immunology, cancer therapy, fluorescent imaging, and stem cell regulation. This review aims to provide a brief synopsis of recent achievements at the intersection of supramolecular chemistry and biomedical science in hope of contributing to the multidisciplinary research on supramolecular biofunctional materials for a wide range of applications. We envision that supramolecular biofunctional materials will contribute to the development of new therapies that will ultimately lead to a paradigm shift for developing next generation biomaterials for medicine.

Introduction

In this review, supramolecular biofunctional materials refer to the biomaterials that are held together mainly by noncovalent intermolecular interactions among small molecules. Being formed via molecular self-assembly (usually in water) and possessing ordered superstructures, supramolecular biofunctional materials have found increased numbers of biomedical applications [1]. Moreover, when molecular self-assembly integrates with cellular events (e.g., enzymatic reactions, ligand-receptor binding, or electron transfer), it provides a bioinspired, yet fundamentally new path to generate molecular processes in cell milieu for simultaneously interacting with multiple protein targets [2], cells, and even organs. Because of their potentials, over the last two decades, supramolecular biofunctional materials and related molecular processes have received intensive research attentions. For example, Stupp et al. used the pH-controlled self-assembly of peptide amphiphiles (PAs) to develop a group of supramolecular fibrous scaffolds with promising biological applications, like directing formation of hydroxyapatite in vitro to mimic biomineralization [3] or inducing rapid differentiation of progenitor cells into neurons while discouraging the development of astrocytes in cell assays [4]. Using supramolecular hydrogels as a platform for incorporating different artificial receptors, Hamachi and coworkers developed a class of semi-wet sensor chips, which recognized a variety of chemicals such as cations, saccharides, anionic fluorescent dyes, phosphate derivatives, polyamines, and polyols [5], [6], [7], [8], [9], [10]. They also reported a smart multicomponent system consisting of self-sorted supramolecular nanofibers [11]. Van Esch et al. demonstrated that the self-assembly of molecular building blocks driven by a chemical fuel led to the transient formation of an active material, in which reaction kinetics and fuel levels determined the properties such as lifetime, stiffness, and self-regeneration capability of the material [12]. Ulijn et al. expanded the development of supramolecular materials based on Fmoc-capped small molecules and used computational tools to screen the self-assembling propensity of more than 8000 possible tripeptides in water [13]. Taking advantages of the chemical structures and the self-assembling ability of peptides, Cui et al. developed a novel class of drug amphiphiles (one-component nanomedicine) by covalently linking one or more anticancer drugs to a rationally chosen/designed peptide backbone through a biodegradable linker to achieve precise control of drug loading and physicochemical properties of nanomedicines [14], [15], [16], [17]. Yang et al. developed a promising vaccine adjuvant made of self-assembling peptide hydrogels. Compared with the clinically used alum adjuvant, the L- and D-peptide hydrogels increased the IgG production against the proteins (e.g., ovalbumin (OVA)) [18], and such D-peptide hydrogels are being explored as an adjuvant for HIV vaccine based on DNA [19]. Parallel to these studies, a new and versatile progress, firstly reported in 2004, is to integrate enzymatic reactions and self-assembly (i.e., enzyme-instructed self-assembly (EISA)) to build up supramolecular biofunctional materials for the applications in biomedicine such as cancer therapy [2], [20], [21], [22], [23], [24], infectious diseases [25], and drug delivery [26], [27]. Moreover, besides the exploration of the self-assembling drug molecules [28], [29], the development of D-peptides, which usually resist endogenous proteases and act as novel biofunctional materials, has generated fruitful results and opened a new direction for the development of biomaterials [21], [30], [31], [32], [33]. All these research activities have generated considerable exciting and promising results, which warrant a brief review of supramolecular biofunctional materials.

We arrange this review in the following way: we first compare the supramolecular hydrogels with traditional polymeric hydrogels to highlight the merits of supramolecular interactions (i.e., noncovalent interactions) and orders of molecular arrangement in the context of hydrogels or nanostructures. After introducing the basic building blocks of supramolecular hydrogels (amino acids, nucleic acid architectures, and saccharides) by discussing their unique properties, we focus on the potential biological and medical applications of these supramolecular biomaterials and relevant molecular processes, followed by the perspectives and outlooks of this field. In this review, we intend to provide a snapshot of recent achievements at the intersection of supramolecular chemistry and biomedical science in hope of contributing to the multidisciplinary research on the development of supramolecular biofunctional materials for a wide range of applications. Due to the fast development of the field, the choice of examples for this review inevitably is arbitrary and incomplete. For more comprehensive discussions, interested readers can refer to other authoritative review and research articles [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45].

Section snippets

Polymeric hydrogels and supramolecular hydrogels

Sharing certain characteristics with traditional polymeric biomaterials, the most explored and prominent type of supramolecular biofunctional materials are supramolecular hydrogels [41]. Thus, it is appropriate to understand supramolecular biofunctional materials by comparing conventional polymeric hydrogels [46] to supramolecular hydrogels [1]. As illustrated in Fig. 1A, conventional polymeric hydrogels, composed of 3D elastic networks formed by macromolecules (either synthetic or biological

Amino acids-–the most prevalent building blocks for supramolecular biofunctional materials

In fact, life relies on noncovalent interactions that maintain the 3D-structures of biomacromolecules (e.g., protein, nucleic acids, and polysaccharides) and control specific binding/recognition events in biological systems. This fundamental fact offers material scientists blue prints for using basic biological building blocks, typically amino acids or peptides, to build up self-assembling molecules for generating supramolecular biofunctional materials. Compared with other small organic

Applications of supramolecular biofunctional materials

In the past two decades, the field of supramolecular chemistry has developed from merely seeking self-assembling molecules to the design of advanced materials with well-controlled biological activities. Such an advance provides scientists, engineers, and physicians with new options to address problems in biomedicine and biology. Here, we briefly discuss the applications/functions of these biofunctional materials into the following five areas: i) cell culture and tissue engineering; ii) drug

Perspective and outlook

Rather than focusing on replicating the exact molecular structure of biomacromolecules or natural products through tedious synthesis, supramolecular biofunctional materials, being resulted from self-assembly of simple molecular entities via noncovalent interactions, aim to mimic sophisticated functions in biological systems. Without the constraints imposed by complex structures, the functional mimicking is always much more effective and simpler than replicating. One important future direction

Acknowledgement

This work was partially supported by the National Institutes of Health (NIH) (Grant R01CA142746), W.M. Keck Foundation, and National Science Foundation (NSF) (Grant DMR-1420382). J.Z. is a Howard Hughes Medical Institute (HHMI) International Research Fellow.

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