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 β-1 (TGFβ-1). Growth factor release studies showed that passive release of TGFβ-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.self-assembling biomaterials | chondral defects | microfracture | peptide amphiphiles | transforming growth factor

Understanding the complex interplay of factors affecting nanoparticle accumulation in solid tumors is a challenge that must be surmounted to develop effective cancer nanomedicine. Among other unique microenvironment properties, tumor vascular permeability is an important feature of leaky tumor vessels which enables nanoparticles to extravasate. However, permeability has thus far been measured by intravital microscopy on optical window tumors, which has many limitations of its own. Additionally, mathematical models of particle tumor transport are often too complicated to be accessible to most researchers. Here, we present a more simplified and accessible mathematical model based on diffusive flux, which uses particle tumor accumulation and plasma pharmacokinetics to yield effective permeability, P eff. This model, called diffusive flux modeling (DFM), allows effects from multiple parameters to be decoupled and is also the first demonstration, to the best our knowledge, of extracting P eff values from bulk biodistribution results (e.g., routine positron emission tomography studies). The DFM equation was used to explain in vivo results of sub-20 nm nanocarriers called three-helix-micelles (3HM), particularly 3HM’s selective accumulation in different tumor models. When DFM was applied to multiple published biodistribution data, a semiquantitative comparison of various tumor models, particle size, and active targeting strategies could be made. The analysis clearly pointed out the importance of balancing multiple characteristics of nanoparticles to ensure successful treatment outcome and highlights the usefulness of this simple model for initial particle design, selection, and subsequent optimization.

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Biological constraints in diseased tissues have motivated the need for small nanocarriers (10-30 nm) to achieve sufficient vascular extravasation and pervasive tumor penetration. This particle size limit is only an order of magnitude larger than small molecules, such that cargo loading is better described by co-assembly processes rather than simple encapsulation.Understanding the structural, kinetic, and energetic contributions of carrier-cargo co-assembly is thus critical to achieve molecular-level control and predictable in vivo behavior. These interconnected set of properties were systematically examined using sub-20 nm self-assembled nanocarriers known as three-helix micelles (3HM). Both hydrophobicity and the "geometric packing parameter" dictate small molecule compatibility with 3HM's alkyl tail core. Planar obelisk-like apomorphine and doxorubicin (DOX) molecules intercalated well within the 3HM core and near the core-shell interface, forming an integral component to the co-assembly, as corroborated by small angle X-ray and neutron-scattering structural studies. DOX promoted crystalline alkyl tail ordering, which significantly increased (+63%) the activation energy of 3HM subunit exchange. Subsequently, 3HM-DOX displayed slow-release kinetics (t1/2=40 h) at physiological temperatures, with ~50x greater cargo preference for the micelle core as described by two drug partitioning coefficients (micellar core/shell Kp1 ~24, and shell/bulk solvent Kp2 ~2).The geometric and energetic insights between nanocarrier and their small molecule cargos developed here will aid in broader efforts to deconvolute the interconnected properties of carrierdrug co-assemblies, and to understand nanomedicine behavior throughout all the physical and in vivo processes they are intended to encounter..