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. 2014 Apr 14;15(4):1484-90.
doi: 10.1021/bm500091e. Epub 2014 Apr 2.

A nanostructured synthetic collagen mimic for hemostasis

Vivek A Kumar  1 , Nichole L Taylor, Abhishek A Jalan, Lyahn K Hwang, Benjamin K Wang, Jeffery D Hartgerink
Affiliations

A nanostructured synthetic collagen mimic for hemostasis

Vivek A Kumar et al. Biomacromolecules. .

Abstract

Collagen is a major component of the extracellular matrix and plays a wide variety of important roles in blood clotting, healing, and tissue remodeling. Natural, animal derived, collagen is used in many clinical applications but concerns exist with respect to its role in inflammation, batch-to-batch variability, and possible disease transfection. Therefore, development of synthetic nanomaterials that can mimic the nanostructure and properties of natural collagen has been a heavily pursued goal in biomaterials. Previously, we reported on the design and multihierarchial self-assembly of a 36 amino acid collagen mimetic peptide (KOD) that forms nanofibrous triple helices that entangle to form a hydrogel. In this report, we utilize this nanofiber forming collagen mimetic peptide as a synthetic biomimetic matrix useful in thrombosis. We demonstrate that nanofibrous KOD synthetic collagen matrices adhere platelets, activate them (indicated by soluble P-selectin secretion), and clot plasma and blood similar to animal derived collagen and control surfaces. In addition to the thrombotic potential, THP-1 monocytes incubated with our KOD collagen mimetic showed minimal proinflammatory cytokine (TNF-α or IL-1β) production. Together, the data presented demonstrates the potential of a novel synthetic collagen mimetic as a hemostat.

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Figures

Figure 1
Figure 1
Synthetic collagen mimetic matrices. (A) Hierarchical self-assembly of the KOD peptide into a collagen triple helix with sticky ends indicating Lys-Asp salt bridges and unpaired Lys and Asp residues that allow for supramolecular assembly into fiber networks resembling native collagen, as noted by critical point dried samples under SEM (B), scale bar 1 μm. (C) Synthetic collagen matrices form a rigid gel that is resistant to mechanical handling by tweezers and other methods.
Figure 2
Figure 2
Inflammatory potential of materials. Proinflammatory markers (A) TNF-α and (B) IL-1β for synthetic materials. Concentrations of cytokines on scaffolds PURA, KOD, and RTT were all significantly lower than LPS stimulated M1 macrophages, n = 6, *p < 0.01.
Figure 3
Figure 3
Platelet adhesion to test surfaces. (A) KOD surfaces displayed similar levels of platelet adhesion to glass and RTT, significantly higher than TCP. Low-magnification images of platelets adhered to surfaces qualitatively showed platelet density: (B) TCP, (C) glass, (D) RTT, (E) KOD, (F) PURA. Scale bar: 10 μm. At high magnification, platelet spreading and clumping was indicative of higher platelet activation: (G) TCP, (H) glass, (I) RTT, (J) KOD, (K) PURA. Scale bar: 2 μm. Noncritical point dried (air-dried) samples did not show nanofibrous structure of underlying matrix. (n = 6, p < 0.05 between different Greek symbols).
Figure 4
Figure 4
Soluble P-selectin from platelet interaction with KOD. sP-selectin concentration detected by ELISA (n = 5, p < 0.05 between different Greek symbols).
Figure 5
Figure 5
Plasma recalcification profile on surfaces. (A) PPP + Ca2+ incubated on KOD, RTT, PURA, and TCP surfaces showed characteristic clotting kinetics as a function of time, compared to negative control PPP without Ca2+ on TCP. Data was normalized to respective sample absorbance at 50 min. Negative control absorbance was normalized to TCP 50 min absorbance. (B) PPP clotting rate as measured by the slope of linear region of the curves showed no significant difference for the surfaces. (C) Clotting time as determined by half-max time showed that hydrogel surfaces clotted more quickly than TCP. (n = 6, *p < 0.05 between different Greek symbols).
Figure 6
Figure 6
Whole blood clotting on material surfaces. (A) Rate of whole blood clotting was inversely related to absorbance. PURA showed slowest clotting times with significantly higher absorbance at 35 and 50 min, *p < 0.01. KOD shows faster initiation of clotting with a significantly lower absorbance at 20 min, *p < 0.01. Whole blood clotting times were quantified on materials surfaces. (B) A large blood clot formed atop KOD was aspirated into a 200 μL pipet tip. (C) Hemolysis due to interaction with KOD or PURA quantified and compared to positive (DI water) control or negative (isotonic solution) control, *p < 0.01.
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