Bioresorbable silicon electronic sensors for the brain.

Many procedures in modern clinical medicine rely on the use of electronic implants in treating conditions that range from acute coronary events to traumatic injury. However, standard permanent electronic hardware acts as a nidus for infection: bacteria form biofilms along percutaneous wires, or seed haematogenously, with the potential to migrate within the body and to provoke immune-mediated pathological tissue reactions. The associated surgical retrieval procedures, meanwhile, subject patients to the distress associated with re-operation and expose them to additional complications. Here, we report materials, device architectures, integration strategies, and in vivo demonstrations in rats of implantable, multifunctional silicon sensors for the brain, for which all of the constituent materials naturally resorb via hydrolysis and/or metabolic action, eliminating the need for extraction. Continuous monitoring of intracranial pressure and temperature illustrates functionality essential to the treatment of traumatic brain injury; the measurement performance of our resorbable devices compares favourably with that of non-resorbable clinical standards. In our experiments, insulated percutaneous wires connect to an externally mounted, miniaturized wireless potentiostat for data transmission. In a separate set-up, we connect a sensor to an implanted (but only partially resorbable) data-communication system, proving the principle that there is no need for any percutaneous wiring. The devices can be adapted to sense fluid flow, motion, pH or thermal characteristics, in formats that are compatible with the body's abdomen and extremities, as well as the deep brain, suggesting that the sensors might meet many needs in clinical medicine.

Dynamic Ureas with Fast and pH-Independent Hydrolytic Kinetics.

Low cost, high performance hydrolysable polymers are of great importance in biomedical applications and materials industries. While many applications require materials to have a degradation profile insensitive to external pH to achieve consistent release profiles under varying conditions, hydrolysable chemistry techniques developed so far have pH-dependent hydrolytic kinetics. This work reports the design and synthesis of a new type of hydrolysable polymer that has identical hydrolysis kinetics from pH 3 to 11. The unprecedented pH independent hydrolytic kinetics of the aryl ureas were shown to be related to the dynamic bond dissociation controlled hydrolysis mechanism; the resulting hindered poly(aryl urea) can be degraded with a hydrolysis half-life of 10 min in solution. More importantly, these fast degradable hindered aromatic polyureas can be easily prepared by addition polymerization from commercially available monomers and are resistant to hydrolysis in solid form for months under ambient storage conditions. The combined features of good stability in solid state and fast hydrolysis at various pH values is unprecedented in polyurea material, and will have implications for materials design and applications, such as sacrificial coatings and biomaterials.

Bacteria-Assisted Activation of Antimicrobial Polypeptides by a Random-Coil to Helix Transition.

The application of antimicrobial peptides (AMPs) is largely hindered by their non-specific toxicity against mammalian cells, which is usually associated with helical structure, hydrophobicity, and charge density. A random coil-to-helix transition mechanism has now been introduced into the design of AMPs, minimizing the toxicity against mammalian cells while maintaining high antimicrobial activity. By incorporating anionic phosphorylated tyrosine into the cationic polypeptide, the helical structure of AMPs was distorted owing to the side-chain charge interaction. Together with the decreased charge density, the AMPs exhibited inhibited toxicity against mammalian cells. At the infectious site, the AMPs can be activated by bacterial phosphatase to restore the helical structure, thus contributing to strong membrane disruptive capability and potent antimicrobial activity. This bacteria-activated system is an effective strategy to enhance the therapeutic selectivity of AMPs.

Hydrolyzable polyureas bearing hindered urea bonds.

Hydrolyzable polymers are widely used materials that have found numerous applications in biomedical, agricultural, plastic, and packaging industrials. They usually contain ester and other hydrolyzable bonds, such as anhydride, acetal, ketal, or imine, in their backbone structures. Here, we report the first design of hydrolyzable polyureas bearing dynamic hindered urea bonds (HUBs) that can reversibly dissociate to bulky amines and isocyanates, the latter of which can be further hydrolyzed by water, driving the equilibrium to facilitate the degradation of polyureas. Polyureas bearing 1-tert-butyl-1-ethylurea bonds that show high dynamicity (high bond dissociation rate), in the form of either linear polymers or cross-linked gels, can be completely degraded by water under mild conditions. Given the simplicity and low cost for the production of polyureas by simply mixing multifunctional bulky amines and isocyanates, the versatility of the structures, and the tunability of the degradation profiles of HUB-bearing polyureas, these materials are potentially of very broad applications.

Stabilization of the hindered urea bond through de-tert-butylation.

We report the discovery of an acid-assisted de-tert-butylation reaction that can instantly "turn off" the dynamicity of hindered urea bonds (HUBs) and thus broaden their applications. The reaction is demonstrated to be widely applicable to different hindered urea substrates, leading to improved chemical stabilities and mechanical properties of HUB-containing materials.

Near quantitative synthesis of urea macrocycles enabled by bulky N-substituent.

Macrocycles are unique molecular structures extensively used in the design of catalysts, therapeutics and supramolecular assemblies. Among all reactions reported to date, systems that can produce macrocycles in high yield under high reaction concentrations are rare. Here we report the use of dynamic hindered urea bond (HUB) for the construction of urea macrocycles with very high efficiency. Mixing of equal molar diisocyanate and hindered diamine leads to formation of macrocycles with discrete structures in nearly quantitative yields under high concentration of reactants. The bulky N-tert-butyl plays key roles to facilitate the formation of macrocycles, providing not only the kinetic control due to the formation of the cyclization-promoting cis C = O/tert-butyl conformation, but also possibly the thermodynamic stabilization of macrocycles with weak association interactions. The bulky N-tert-butyl can be readily removed by acid to eliminate the dynamicity of HUB and stabilize the macrocycle structures.

Recyclable, Self-Healable, and Highly Malleable Poly(urethane-urea)s with Improved Thermal and Mechanical Performances.

Developing recyclable, self-healable, and highly malleable thermosets is one of the keys to relieve environmental pollution and meet our increasing demand for "greener" materials. Hindered urea bonds (HUBs) have been successfully incorporated in preparing dynamic covalent networks with those desirable properties. However, one key drawback is the low thermal stability and poor mechanical performance of previously reported systems. In this work, we demonstrated that the incorporation of aromatic moiety-containing diamine-based HUBs can greatly improve the thermal and mechanical performance of the poly(urethane-urea)s (PUUs) while still maintaining the desirable recycling, self-healing, and reprocessing properties. Studies on model compounds revealed the origin of the thermal stability and demonstrated the dynamic property. The aromatic-containing diamine-based HUBs were then used to prepare a series of catalyst-free PUUs with improved thermal and mechanical properties. The dynamic HUBs significantly reduced the relaxation timescale and allowed the PUU networks to be recycled multiple times. The healed and recycled PUUs regained most of the mechanical strength and integrity of the original material. Therefore, this unique and simple approach is expected to open up new avenues to design PUUs with optimal performance for various applications.

Degradable and biocompatible hydrogels bearing a hindered urea bond.

A hindered urea bond (HUB), recently reported as a new type of dynamic chemical bond, can be facilely constructed by mixing an isocyanate and a hindered amine. Here, we report the use of the HUB in the design of degradable hydrogel materials for applications of stem cell encapsulation and delivery. Polyethyleneglycol (PEG) diamine was end-capped with a HUB and an allyl group in a one-pot synthesis. The resulting polymer was cross-linked to form a hydrogel under UV with the addition of a 4-arm PEG thiol and a photoinitiator. The degradation properties of the hydrogels were confirmed with NMR, GPC, weight loss, and protein release studies. We found that the degradation kinetics is dependent on the size of the N-substituents, and the one with the tert-butyl group shows complete degradation within 2 days. The new hydrogel materials were also demonstrated to be biocompatible with hMSCs, and the cell release kinetics can be facilely tuned over 5 days.

CD44 Mediated Nonviral Gene Delivery into Human Embryonic Stem Cells via Hyaluronic-Acid-Coated Nanoparticles.

Gene delivery is an important tool to study and manipulate human pluripotent stem cells for regenerative medicine purposes. Yet current methods of transient gene delivery to stem cells are still inefficient. Through the combination of biologically based concepts and material design, we aim to develop new methods to enhance the efficiency of gene delivery to stem cells. Specifically, we use poly(γ-4-(((2-(piperidin-1-yl)ethyl)amino)methyl)benzyl-l-glutamate) (PVBLG-8), a membrane-active helical, cationic polypeptide, to condense plasmid DNA to form stable nanocomplexes, which are further coated with hyaluronic acid (HA). HA not only shields the positive charges of PVBLG-8 to reduce toxicity, but also acts as a targeting moiety for cell surface receptor CD44, which binds HA and facilitates the internalization of the nanocomplexes. Upon entering cells, HA is degraded by hyaluronidase in endosomes and PVBLG-8 is exposed, facilitating the endosomal escape of DNA/polypeptide complex. Our studies show that the coating of HA significantly increases gene transfection efficiency of DNA/PVBLG-8 nanocomplexes from about 28 to 36% with largely reduced toxicity.

Malleable and Recyclable Poly(urea-urethane) Thermosets bearing Hindered Urea Bonds.

Poly(urea-urethane) thermosets containing the 1-tert-butylethylurea (TBEU) structure feature a reversible dissociation/association process of their covalent linkages under mild conditions. Unlike conventional thermosets, TBEU-based poly(urea-urethane) thermosets maintain their malleability after curing. Under high temperature (100 °C) and applied pressure (300 kPa), ground TBEU thermoset powder can be remolded to bulk after 20 min.

Non-invasive, real-time reporting drug release in vitro and in vivo.

We developed a real-time drug-reporting conjugate (CPT-SS-CyN) composed of a near-infrared (NIR) fluorescent cyanine-amine dye (CyN), a disulfide linker, and a model therapeutic drug (camptothecin, CPT). Treatment with dithiothreitol (DTT) induces cleavage of the disulfide bond, followed by two simultaneous intramolecular cyclization reactions with identical kinetics, one to cleave the urethane linkage to release the NIR dye and the other to cleave the carbonate linkage to release CPT. The released CyN has an emission wavelength (760 nm) that is significantly different from CPT-SS-CyN (820 nm), enabling easy detection and monitoring of drug release. A linear relationship between the NIR fluorescence intensity at 760 nm and the amount of CPT released was observed, substantiating the use of this drug-reporting conjugate to enable precise, real-time, and non-invasive quantitative monitoring of drug release in live cells and semi-quantitative monitoring in live animals.

Dynamic urea bond for the design of reversible and self-healing polymers.

Polymers bearing dynamic covalent bonds may exhibit dynamic properties, such as self-healing, shape memory and environmental adaptation. However, most dynamic covalent chemistries developed so far require either catalyst or change of environmental conditions to facilitate bond reversion and dynamic property change in bulk materials. Here we report the rational design of hindered urea bonds (urea with bulky substituent attached to its nitrogen) and the use of them to make polyureas and poly(urethane-urea)s capable of catalyst-free dynamic property change and autonomous repairing at low temperature. Given the simplicity of the hindered urea bond chemistry (reaction of a bulky amine with an isocyanate), incorporation of the catalyst-free dynamic covalent urea bonds to conventional polyurea or urea-containing polymers that typically have stable bulk properties may further broaden the scope of applications of these widely used materials.

Polycyclic imide derivatives: synthesis and effective tuning of lowest unoccupied molecular orbital levels through molecular engineering.

A series of fluoranthene-fused imide derivatives were facilely developed through a Diels-Alder reaction followed by decarbonylation. The investigation of their photophysical and electrochemical properties demonstrated that their LUMO levels were effectively tuned from -3.2 to -3.8 eV through the introduction of a fused imide unit, which provides a platform to design new air-stable and solution-processable n-type materials.