Biomaterials made from self-assembling, short peptides and peptide derivatives have great potential to generate powerful new therapies in regenerative medicine. The high signaling capacity and therapeutic efficacy of peptidic scaffolds has been established in several animal models, and the development of more complex, hierarchical structures based on peptide materials is underway. This highlight discusses several classes of self-assembling peptide-based materials, including peptide amphiphiles, Fmoc-peptides, self-complementary ionic peptides, hairpin peptides, and others. The self-assembly designs, bioactive signalling strategies, and cell signalling capabilities of these bioactive materials are reported. The future challenges of the field are also discussed, including short-term goals such as integration with biopolymers and traditional implants, and long term goals, such as immune system programming, subcellular targeting, and the development of highly integrated scaffold systems.

We report on the preparation of the first material for therapeutic delivery of CO. A peptide amphiphile was synthesized with a covalently attached ruthenium tricarbonyl. Self-assembled nanofiber gels containing this peptide spontaneously released CO with prolonged release kinetics compared to soluble CO donors. Oxidatively stressed cardiomyocytes had improved viability when treated with this peptide, demonstrating its potential as a biodegradable gel for localized therapeutic CO delivery.

Self-assembling, peptide-based scaffolds are frontrunners in the search for biomaterials with widespread impact in regenerative medicine. The inherent biocompatibility and cell signaling capabilities of peptides, in combination with control of secondary structure, has led to the development of a broad range of functional materials with potential for many novel therapies. More recently, membranes formed through complexation of peptide nanostructures with natural biopolymers have led to the development of hierarchically-structured constructs with potentially far-reaching applications in biology and medicine. In this review, we highlight recent advances in peptide-based gels and membranes, including work from our group and others. Specifically, we discuss the application of peptide-based materials in the regeneration of bone and enamel, cartilage, and the central nervous system, as well as the transplantation of islets, wound-healing, cardiovascular therapies, and treatment of erectile dysfunction after prostatectomy

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN1 gene that result in a deficiency of SMN protein. One approach to treat SMA is to use antisense oligonucleotides (ASOs) to redirect the splicing of a paralogous gene, SMN2, to boost production of functional SMN. Injection of a 2′-O-2-methoxyethyl–modified ASO (ASO-10-27) into the cerebral lateral ventricles of mice with a severe form of SMA resulted in splice-mediated increases in SMN protein and in the number of motor neurons in the spinal cord, which led to improvements in muscle physiology, motor function and survival. Intrathecal infusion of ASO-10-27 into cynomolgus monkeys delivered putative therapeutic levels of the oligonucleotide to all regions of the spinal cord. These data demonstrate that central nervous system–directed ASO therapy is efficacious and that intrathecal infusion may represent a practical route for delivering this therapeutic in the clinic.

Glycosaminoglycans are sulfated polysaccharides that play important roles in fundamental biological processes, such as cell division, viral invasion, cancer and neuroregeneration. The multivalent presentation of multiple glycosaminoglycan chains on proteoglycan scaffolds may profoundly influence their interactions with proteins and subsequent biological activity. However, the importance of this multivalent architecture remains largely unexplored, and few synthetic mimics exist for probing and manipulating glycosaminoglycan activity. Here, we describe a new class of end-functionalized ring-opening metathesis polymerization (ROMP) polymers that mimic the native-like, multivalent architecture found on chondroitin sulfate (CS) proteoglycans. We demonstrate that these glycopolymers can be readily integrated with microarray and surface plasmon resonance technology platforms, where they retain the ability to interact selectively with proteins. ROMP-based glycopolymers are part of a growing arsenal of chemical tools for probing the functions of glycosaminoglycans and for studying their interactions with proteins.

Two different methodologies for the synthesis of monotelechelic poly(oxa)norbornenes prepared by living ring-opening metathesis polymerization (ROMP) are presented. The first method, termed direct end-capping, is carried out by adding an internal cis-olefin terminating agent (TA) to the reaction mixture immediately after the completion of the living ROMP reaction. The second method relies on cross metathesis (CM) between a methylene-terminated poly(oxa)norbornene and a cis-olefin TA mediated by the ruthenium olefin metathesis catalyst (H2IMes)(Cl)2Ru(CH-o-OiPrC6H4) (H2IMes = 1,3-dimesitylimidazolidine-2-ylidene). TAs containing various functional groups, including alcohols, acetates, bromides, a-bromoesters, thioacetates, N-hydroxysuccinimidyl esters and Boc-amines, as well as fluorescein and biotin groups, were synthesized and tested. The direct end-capping method typically resulted in >90% end-functionalization efficiency, while the CM method was nearly as effective for TAs without polar functional groups or significant steric bulk. End-functionalization efficiency values were determined by 1H NMR spectroscopy.

Poly(tert-butyl ester norbornene imide) homopolymers and poly(tert-butyl ester norbornene imide-b-N-methyl oxanorbornene imide) copolymers were prepared by pulsed-addition ring-opening metathesis polymerization (PA-ROMP). PA-ROMP is a unique polymerization method that employs a symmetrical cis-olefin chain transfer agent (CTA) to simultaneously cap a living polymer chain and regenerate the ROMP initiator with high fidelity. Unlike traditional ROMP with chain transfer, the CTA reacts only with the living chain end, resulting in narrowly dispersed products. The regenerated initiator can then initiate polymerization of a subsequent batch of monomer, allowing for multiple polymer chains with controlled molecular weight and low polydispersity to be generated from one metal initiator. Using the fast-initiating ruthenium metathesis catalyst (H2IMes)(Cl)2(pyr)2RuCHPh and cis-4-octene as a CTA, the capabilities of PA-ROMP were investigated with a Symyx robotic system, which allowed for increased control and precision of injection volumes. The results from a detailed study of the time required to carry out the end-capping/initiator-regeneration step were used to design several experiments in which PA-ROMP was performed from one to ten cycles. After determining the rate of catalyst death, a single, low polydispersity polymer was prepared by adjusting the amount of monomer injected in each cycle, maintaining a constant monomer/catalyst ratio. Additionally, PA-ROMP was used to prepare nearly perfect block copolymers by quickly injecting a second monomer at a specific time interval after the first monomer injection, such that chain transfer had not yet occurred. Polymers were characterized by gel permeation chromatography with multi-angle laser light scattering.