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Supramolecular design of self-assembling nanofibers for cartilage regeneration.

ABSTRACT: Molecular and supramolecular design of bioactive biomaterials could have a significant impact on regenerative medicine. Ideal regenerative therapies should be minimally invasive, and thus the notion of self-assembling biomaterials programmed to transform from injectable liquids to solid bioactive structures in tissue is highly attractive for clinical translation. We report here on a coassembly system of peptide amphiphile (PA) molecules designed to form nanofibers for cartilage regeneration by displaying a high density of binding epitopes to transforming growth factor beta-1 (TGFbeta-1). Growth factor release studies showed that passive release of TGFbeta-1 was slower from PA gels containing the growth factor binding sites. In vitro experiments indicate these materials support the survival and promote the chondrogenic differentiation of human mesenchymal stem cells. We also show that these materials can promote regeneration of articular cartilage in a full thickness chondral defect treated with microfracture in a rabbit model with or even without the addition of exogenous growth factor. These results demonstrate the potential of a completely synthetic bioactive biomaterial as a therapy to promote cartilage regeneration.

SUBMITTER: Shah RN

PROVIDER: S-EPMC2840471 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Supramolecular design of self-assembling nanofibers for cartilage regeneration.

Shah Ramille N RN Shah Nirav A NA Del Rosario Lim Marc M MM Hsieh Caleb C Nuber Gordon G Stupp Samuel I SI

Proceedings of the National Academy of Sciences of the United States of America 20100201 8

Molecular and supramolecular design of bioactive biomaterials could have a significant impact on regenerative medicine. Ideal regenerative therapies should be minimally invasive, and thus the notion of self-assembling biomaterials programmed to transform from injectable liquids to solid bioactive structures in tissue is highly attractive for clinical translation. We report here on a coassembly system of peptide amphiphile (PA) molecules designed to form nanofibers for cartilage regeneration by d ...[more]

PMID: 20133666

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Project description:Multidomain peptides (MDPs) are a class of self-assembling peptides that are organized in a β-sheet motif, resulting in a nanofibrous architecture. This structure is stabilized by hydrophobic packing in the fiber core and a hydrogen-bonding network down the fiber long axis. Under easily controllable conditions, regulated by electrostatic interactions between the peptides and the pH and salt composition of the solvent, the nanofiber length can be dramatically extended, resulting in fiber entanglement and hydrogel formation. One of the chief strengths of this supramolecular material is that the design criteria governing its structure and assembly are robust and permit a wide range of modifications without disruption. This allows the MDPs to be tailored to suit a wide range of applications, particularly in biomedical engineering. For example, delivery of small molecules, proteins, and cells is easily achievable. These materials can be trapped within the matrices of the hydrogel or trapped within the hydrophobic core of the nanofiber, depending on the cargo and the design of the MDP. Interactions between the nanofibers and their cargo can be tailored to alter the release profile, and in the most sophisticated cases, different cargos can be released in a cascading time-dependent fashion. The MDP hydrogel and its cargo can be targeted to specific locations, as the thixotropic nature of the hydrogel allows it to be easily aspirated into a syringe and then delivered from a narrow-bore needle. The sequence of amino acids making up the MDP can also be modified to permit cross-linking or enzymatic degradation. Selection of sequences with or without these modifications allows one to control the rate of degradation in vivo from as rapidly as 1 week to well over 6 weeks as the MDP nanofibers are degraded to their amino acid components. MDP sequences can also be modified to add biomimetic sequences derived from growth factors and other signaling proteins. These chemical signals are displayed at a very high density on the fibers' surface, where they contribute to the modification of cellular behavior. We have used this approach to drive blood vessel formation, which is critical for tissue regeneration generally and more specifically for the treatment of diseases related to poor blood flow. MDPs represent an ideal case of bottom-up design where control of chemical structure leads to control of self-assembly and nanostructure and thereby control of material properties that collectively can control biological function.

Project description:A significant challenge associated with systemic delivery of cationic antimicrobial peptides and polymers lies in their limited hemocompatibility toward vast numbers of circulating red blood cells (RBCs). Supramolecular assembly of cationic peptides and polymers can be an effective strategy to develop an array of antimicrobial nanomaterials with tunable material structures, stability and thus optimized bioactivity to overcome some of the existing challenges associated with conventional antimicrobials. In this work, we will demonstrate the supramolecular design of self-assembling antimicrobial nanofibers (SAANs) which have tunable supramolecular nanostructures, stability, internal molecular packing and surface chemistry through self-assembly of de novo designed cationic peptides and peptide-PEG conjuguates. The interaction of the SAANs with human RBCs was evaluated in a stringent biological assay (beyond a traditional hemolysis assay) where both hemolytic and eryptotic activity were examined to establish a fundamental understanding on the correlation between material structure and hemocompatibility. It was found that although the SAANs showed moderate hemolytic activities, their abilities to induce eryptosis vary significantly and are much more sensitive to the internal molecular packing, supramolecular nanostructure and stability of the nanofiber. Improved hemocompatibility requires PEGylation on stable supramolecular nanofibers composed of highly organized ?-sheet structure while PEG conjugation on weakly packed nanofibers composed of partially denatured ?-sheets did not show improvement. The current study reveals the fundamental mechanism involved in the selective hemocompatibility improvement of the SAANs upon PEG conjugation. The structure-activity relationship developed in this study will provide important guidance for the future design of a broader family of peptide and polymer-based assemblies with optimized antimicrobial activity and hemocompatibility.

Dataset Information

Supramolecular design of self-assembling nanofibers for cartilage regeneration.

Publications

Supramolecular design of self-assembling nanofibers for cartilage regeneration.

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