Self-assembling multidomain peptides tailor biological responses through biphasic release

Abstract

Delivery of small molecules and drugs to tissues is a mainstay of several tissue engineering strategies. Next generation treatments focused on localized drug delivery offer a more effective means in dealing with refractory healing when compared to systemic approaches. Here we describe a novel multidomain peptide hydrogel that capitalizes on synthetic peptide chemistry, supramolecular self-assembly and cytokine delivery to tailor biological responses. This material is biomimetic, shows shear stress recovery and offers a nanofibrous matrix that sequesters cytokines. The biphasic pattern of cytokine release results in the spatio-temporal activation of THP-1 monocytes and macrophages. Furthermore, macrophage-material interactions are promoted without generation of a proinflammatory environment. Subcutaneous implantation of injectable scaffolds showed a marked increase in macrophage infiltration and polarization dictated by cytokine loading as early as 3 days, with complete scaffold resorption by day 14. Macrophage interaction and response to the peptide composite facilitated the (i) recruitment of monocytes/macrophages, (ii) sustained residence of immune cells until degradation, and (iii) promotion of a pro-resolution M2 environment. Our results suggest the potential use of this injectable cytokine loaded hydrogel scaffold in a variety of tissue engineering applications.

Drug-Triggered and Cross-Linked Self-Assembling Nanofibrous Hydrogels

“…Most hydrogels loaded with small-molecule drugs, and even those loaded with relatively large proteins, result in short-term burst release that has limited their applicability. 9,10,16,35 MDP interior hydrophobic domains may provide next generation strategies for solubilization of hydrophobic drugs while allowing aqueous solubility of nanofiber conjugates.…”

Controlled Angiogenesis in Peptide Nanofiber Composite Hydrogels

“…15,22,26 MDPs have also been shown to have antimicrobial behavior 27 and can also be modified for a variety of biological activities. 15,28 Specific to angiogenesis, we have developed a MDP covalently bound to a mimic of VEGF-165. This peptide, termed SLanc, results in rapid cellular infiltration and a high degree of angiogenesis.…”

Rational design of fiber forming supramolecular structures

“…78 Such a system with highly tailorable viscoelastic and shear thinning properties has great implications with respect to injectable hydrogels for drug delivery and regenerative medicine. [20][21][22][23]61,64,78 In addition to conventional alternating hydrophilic-hydrophobic core regions, Hartgerink's group has demonstrated the self-assembly of triblock multi-domain peptide with an alternating hydrophilicaromatic core region. 61 Recently they described a novel aromatic self-assembling peptide amphiphile.…”

“…19,24 Variants of these scaffolds have allowed for excellent cellular spreading in vitro and rapid infiltration without the formation of fibrous capsules in vivo. [20][21][22][23] Together, these biological and mechanical cues inform the design and application of a host of peptide-based materials, whose organization and core structure are analyzed in this review.…”

“…Peptide-based materials originally focused on pharmaceutics. With a better understanding of secondary protein structure and how to tailor supramolecular selfassembly, short polypeptides have been used for a variety of applications from drug/ growth factor mimicry, 20 drug delivery, 21 inflammation modulation, 22 and orthogonal selfassembly with loaded liposomes. 23 Additionally, as detailed in this review, stable large scale hydrogels formed by noncovalent interactions of these peptide-based materials allow recapitulation of a nanofibrous extracellular matrix (ECM) mimetic scaffold.…”