Michael Aizenberg

Synthetic homeostatic materials with chemo-mechano-chemical self-regulation.

Living organisms have unique homeostatic abilities, maintaining tight control of their local environment through interconversions of chemical and mechanical energy and self-regulating feedback loops organized hierarchically across many length scales. In contrast, most synthetic materials are incapable of continuous self-monitoring and self-regulating behaviour owing to their limited single-directional chemomechanical or mechanochemical modes. Applying the concept of homeostasis to the design of autonomous materials would have substantial impacts in areas ranging from medical implants that help stabilize bodily functions to ‘smart’ materials that regulate energy usage. Here we present a versatile strategy for creating self-regulating, self-powered, homeostatic materials capable of precisely tailored chemo-mechano-chemical feedback loops on the nano- or microscale. We design a bilayer system with hydrogel-supported, catalyst-bearing microstructures, which are separated from a reactant-containing ‘nutrient’ layer. Reconfiguration of the gel in response to a stimulus induces the reversible actuation of the microstructures into and out of the nutrient layer, and serves as a highly precise ‘on/off’ switch for chemical reactions. We apply this design to trigger organic, inorganic and biochemical reactions that undergo reversible, repeatable cycles synchronized with the motion of the microstructures and the driving external chemical stimulus. By exploiting a continuous feedback loop between various exothermic catalytic reactions in the nutrient layer and the mechanical action of the temperature-responsive gel, we then create exemplary autonomous, self-sustained homeostatic systems that maintain a user-defined parameter—temperature—in a narrow range. The experimental results are validated using computational modelling that qualitatively captures the essential features of the self-regulating behaviour and provides additional criteria for the optimization of the homeostatic function, subsequently confirmed experimentally. This design is highly customizable owing to the broad choice of chemistries, tunable mechanics and its physical simplicity, and may lead to a variety of applications in autonomous systems with chemo-mechano-chemical transduction at their core.

Catalytic Activation of Carbon-Fluorine Bonds by a Soluble Transition Metal Complex

Homogeneous catalytic activation of the strong carbon-fluorine bonds under mild conditions was achieved with the use of rhodium complexes as catalysts. The catalytic reactions between polyfluorobenzenes and hydrosilanes result in substitution of fluorine atoms by hydrogen atoms and are chemo- and regioselective. With individual stoichiometric steps observed and combined, and with intermediates isolated and fully characterized (including crystal structures), these systems demonstrate the effectiveness of a rational approach to catalytic design.

A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling.

Thrombosis and biofouling of extracorporeal circuits and indwelling medical devices cause significant morbidity and mortality worldwide. We apply a bioinspired, omniphobic coating to tubing and catheters and show that it completely repels blood and suppresses biofilm formation. The coating is a covalently tethered, flexible molecular layer of perfluorocarbon, which holds a thin liquid film of medical-grade perfluorocarbon on the surface. This coating prevents fibrin attachment, reduces platelet adhesion and activation, suppresses biofilm formation and is stable under blood flow in vitro. Surface-coated medical-grade tubing and catheters, assembled into arteriovenous shunts and implanted in pigs, remain patent for at least 8 h without anticoagulation. This surface-coating technology could reduce the use of anticoagulants in patients and help to prevent thrombotic occlusion and biofouling of medical devices.

Enhancing microvascular formation and vessel maturation through temporal control over multiple pro-angiogenic and pro-maturation factors.

Therapeutic stimulation of angiogenesis to re-establish blood flow in ischemic tissues offers great promise as a treatment for patients suffering from cardiovascular disease or trauma. Since angiogenesis is a complex, multi-step process, different signals may need to be delivered at appropriate times in order to promote a robust and mature vasculature. The effects of temporally regulated presentation of pro-angiogenic and pro-maturation factors were investigated in vitro and in vivo in this study. Pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang2) cooperatively promoted endothelial sprouting and pericyte detachment in a three-dimensional in vitro EC-pericyte co-culture model. Pro-maturation factors platelet-derived growth factor B (PDGF) and angiopoietin 1 (Ang1) inhibited the early stages of VEGF- and Ang2-mediated angiogenesis if present simultaneously with VEGF and Ang2, but promoted these behaviors if added subsequently to the pro-angiogenesis factors. VEGF and Ang2 were also found to additively enhance microvessel density in a subcutaneous model of blood vessel formation, while simultaneously administered PDGF/Ang1 inhibited microvessel formation. However, a temporally controlled scaffold that released PDGF and Ang1 at a delay relative to VEGF/Ang2 promoted both vessel maturation and vascular remodeling without inhibiting sprouting angiogenesis. Our results demonstrate the importance of temporal control over signaling in promoting vascular growth, vessel maturation and vascular remodeling. Delivering multiple growth factors in combination and sequence could aid in creating tissue engineered constructs and therapies aimed at promoting healing after acute wounds and in chronic conditions such as diabetic ulcers and peripheral artery disease.

An aptamer-functionalized chemomechanically modulated biomolecule catch-and-release system

The efficient extraction of (bio)molecules from fluid mixtures is vital for applications ranging from target characterization in (bio)chemistry to environmental analysis and biomedical diagnostics. Inspired by biological processes that seamlessly synchronize the capture, transport and release of biomolecules, we designed a robust chemomechanical sorting system capable of the concerted catch and release of target biomolecules from a solution mixture. The hybrid system is composed of target-specific, reversible binding sites attached to microscopic fins embedded in a responsive hydrogel that moves the cargo between two chemically distinct environments. To demonstrate the utility of the system, we focus on the effective separation of thrombin by synchronizing the pH-dependent binding strength of a thrombin-specific aptamer with volume changes of the pH-responsive hydrogel in a biphasic microfluidic regime, and show a non-destructive separation that has a quantitative sorting efficiency, as well as the systems stability and amenability to multiple solution recycling.

Refilling drug delivery depots through the blood

Significance Drug delivery depots used in the clinic today are single use, with no ability to refill once exhausted of drug. Our system exploits nucleic acid complementarity to refill drug-delivering depots through the blood. The utility of this approach is demonstrated by its ability to inhibit tumor growth to a greater extent than strategies that rely on enhanced permeability and retention alone. We anticipate our approach will be directly applicable to therapies for many diseases, including cancer, wound healing, and inflammation, and for drug reloading of vascular grafts and stents. Local drug delivery depots have significant clinical utility, but there is currently no noninvasive technique to refill these systems once their payload is exhausted. Inspired by the ability of nanotherapeutics to target specific tissues, we hypothesized that blood-borne drug payloads could be modified to home to and refill hydrogel drug delivery systems. To address this possibility, hydrogels were modified with oligodeoxynucleotides (ODNs) that provide a target for drug payloads in the form of free alginate strands carrying complementary ODNs. Coupling ODNs to alginate strands led to specific binding to complementary-ODN–carrying alginate gels in vitro and to injected gels in vivo. When coupled to a drug payload, sequence-targeted refilling of a delivery depot consisting of intratumor hydrogels completely abrogated tumor growth. These results suggest a new paradigm for nanotherapeutic drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug-eluting vascular grafts and stents.

Rh(I) and Rh(III) silyl PMe3 complexes. Syntheses, reactions and 103Rh NMR spectroscopy

Abstract Synthetic approaches to Rh(I) silyls are described. The complexes LnRhSiR3 (L=PMe3; 6, n=4, R3=(OEt)3; 7, n=4, R3=Me(OMe)2; 21, n=3, R3=Ph3) resulted from the reactions of MeRhL4 (1) with the corresponding silanes HSiR3. Complex 21 was prepared alternatively from PhRhL3 (2) and HSiPh3, while analogous reactions of HSi(OEt)3, HSiMe(OMe)2 and HSi(OMe)3 led to the bis(silyl)hydrides fac-L3Rh(SiR3)2(H) (8, R3=(OEt)3; 9, R3=Me(OMe)2; 13, R3=(OMe)3). Like in analogous iridium-based systems, the outcome of these reactions largely depends on the nature of substituents at the silicon atom. Synthesis of Rh(I) silyls inaccessible by this route, namely those with alkyl substituents at the silicon, LnRhSiR3 (19, n=3, R3=PhMe2; 22, n=4, R3=Me3), was achieved utilizing nucleophilic attack of the corresponding silyllithiums at [L4Rh]Cl. The solid-state structure of 19 was determined by X-ray crystallography. C17H38P3SiRh, Fw=466.38 monoclinic, C2/m, a=13.304(3) A, b=13.814(2) A, c=13.123(4) A, β=110.66(3) deg, V=2257(1) A3, Z=4, dcalcd=1.373 g cm−3, μ=1.019 mm−1. A series of di(hydrido)silyls fac-L3Rh(H)2(SiR3) (10, R3=(OEt)3; 15, R3=PhMe2; 16, R3=Ph3) was synthesized using oxidative additions of HSiR3 to HRhL4 (3). Complexes 10, 15, 16 are thermodynamically stable with respect to H–H and Si–H reductive-elimination reactions at ambient conditions. Complex 8 reductively eliminates HSi(OEt)3 reversibly at room temperature and complex 13 is capable upon heating of mediating dehydrogenative Si–Si coupling of HSi(OMe)3 and redistribution of [(MeO)3Si]2. 103Rh NMR data obtained for MeRhL4 (1), HRhL4 (3), L3RhSiPhMe2 (19), L3RhSiPh3 (21) and for the di(hydrido) silyls (10, 15, 16) allowed to qualitatively evaluate steric and electronic effects of methyl, silyl, and hydride ligands on the 103Rh chemical shift.

Surface Modification with Alginate-Derived Polymers for Stable, Protein-Repellent, Long-Circulating Gold Nanoparticles

Poly(ethylene) glycol is commonly used to stabilize gold nanoparticles (GNPs). In this study, we evaluated the ability of cysteine-functionalized alginate-derived polymers to both provide colloidal stability to GNPs and avoid recognition and sequestration by the bodys defense system. These polymers contain multiple reactive chemical groups (hydroxyl and carboxyl groups) that could allow for ready functionalization with, for example, cell-targeting ligands and therapeutic drugs. We report here that alginate-coupled GNPs demonstrate enhanced stability in comparison with bare citrate-coated GNPs and a similar lack of interaction with proteins in vitro and long in vivo circulation as PEG-coated GNPs.

Controlling the Stability and Reversibility of Micropillar Assembly by Surface Chemistry

For many natural and synthetic self-assembled materials, adaptive behavior is central to their function, yet the design of such systems has mainly focused on the static form rather than the dynamic potential of the final structure. Here we show that, following the initial evaporation-induced assembly of micropillars determined by the balance between capillarity and elasticity, the stability and reversibility of the produced clusters are highly sensitive to the adhesion between the pillars, as determined by their surface chemistry and further regulated by added solvents. When the native surface of the epoxy pillars is masked by a thin gold layer and modified with monolayers terminated with various chemical functional groups, the resulting effect is a graded influence on the stability of cluster formation, ranging from fully disassembled clusters to an entire array of stable clusters. The observed assembly stabilization effect parallels the order of the strengths of the chemical bonds expected to form by the respective monolayer end groups: NH(2) ≈ OH < COOH < SH. For each functional group, the stability of the clusters can be further modified by varying the carbon chain length of the monolayer molecules and by introducing solvents into the clustered samples, allowing even finer tuning as well as temporal control of disassembly. Using these features together with microcontact printing, we demonstrate straightforward patterning of the microstructured surfaces with clusters that can be erased and regenerated at will by the addition of appropriate solvents. Subtle modifications to surface and solvent chemistry provide a simple way to tune the balance between adhesion and elasticity in real time, enabling structures to be designed for dynamic, responsive behavior.

In Vivo Targeting through Click Chemistry

Targeting small molecules to diseased tissues as therapy or diagnosis is a significant challenge in drug delivery. Drug‐eluting devices implanted during invasive surgery allow the controlled presentation of drugs at the disease site, but cannot be modified once the surgery is complete. We demonstrate that bioorthogonal click chemistry can be used to target circulating small molecules to hydrogels resident intramuscularly in diseased tissues. We also demonstrate that small molecules can be repeatedly targeted to the diseased area over the course of at least one month. Finally, two bioorthogonal reactions were used to segregate two small molecules injected as a mixture to two separate locations in a mouse disease model. These results demonstrate that click chemistry can be used for pharmacological drug delivery, and this concept is expected to have applications in refilling drug depots in cancer therapy, wound healing, and drug‐eluting vascular grafts and stents.