A Programmable Oxygenation Device Facilitates Oxygen Generation and Replenishment to Promote Wound Healing.

Inadequate oxygenation is one of the chief culprits for delayed wound healing. However, current oxygen therapies, such as hyperbaric oxygen therapy and topical oxygen therapy, face hurdles in providing sustained and long-term oxygenation to reverse wound hypoxia. Furthermore, their efficacy in rejuvenating wound injury is restricted by limited penetration of oxygen in the wound bed. Herein, this study proposes a programmable and portable oxygenation device (named GUFO oxydevice) by ingeniously integrating i) a controllable oxygen generation and unidirectional transmission system (COGT-UTS), and ii) a supramolecular assembled perfluorinated hyperbranched polymer/gelatin (GUF) hydrogel in which the perfluorinated hyperbranched polymer (FHBP) acts as an oxygen reservoir to ensure sustained and convenient oxygen replenishment and thus directly regulate the hypoxic wound microenvironment. Accelerating the wound healing process by GUFO oxydevice is achieved in both a diabetic rat and an acute porcine wound model without any secondary tissue damages. The present study demonstrates that the GUFO oxydevice holds promise as a practically feasible candidate for wound treatment.

A CO-mediated photothermal therapy to kill drug-resistant bacteria and minimize thermal injury for infected diabetic wound healing.

With an increasing proportion of drug-resistant bacteria, photothermal therapy (PTT) is a promising alternative to antibiotic treatment for infected diabetic skin ulcers. However, the inevitable thermal damage to the tissues restricts its clinical practice. Carbon monoxide (CO), as a bioactive gas molecule, can selectively inhibit bacterial growth and promote tissue regeneration, which may be coordinated with PTT for drug-resistant bacteria killing and tissue protection. Herein, a CO-mediated PTT agent (CO@mPDA) was engineered by loading manganese carbonyl groups into mesoporous polydopamine (mPDA) nanoparticles via coordination interactions between the metal center and a catechol group. Compared to the traditional PTT, the CO-mediated PTT increases the inhibition ratio of the drug-resistant bacteria both in vitro and in diabetic wound beds by selectively inhibiting the co-chaperone of the heat shock protein 90 kDa (Hsp90), and lowers the heat resistance of the bacteria rather than the mammalian tissues. Meanwhile, the tissue-protective proteins, such as Hsp90 and vimentin (Vim), are upregulated via the WNT and PI3K-Akt pathways to reduce thermal injury, especially with a laser with a high-power density. The CO-mediated PTT unified the bacterial killing with tissue protection, which offers a promising concept to improve PTT efficiency and minimize the side-effects of PTT when treating infected skin wounds.

An MMP-degradable and conductive hydrogel to stabilize HIF-1α for recovering cardiac functions.

Rationale: Although a few injectable hydrogels have shown a reliable biosafety and a moderate promise in treating myocardial infarction (MI), the updated hydrogel systems with an on-demand biodegradation and multi-biofunctions to deliver therapeutic drug would achieve more prominent efficacy in the future applications. In this report, a conductive and injectable hydrogel crosslinked by matrix metalloproteinase-sensitive peptides (MMP-SP) was rationally constructed to stabilize hypoxia-inducible factor-1α (HIF-1α) to recover heart functions after MI. Methods: Firstly, tetraaniline (TA) was incorporated into partially oxidized alginate (ALG-CHO) to endow the hydrogels with conductivity. The 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (DPCA) nanodrug was manufactured with high drug loading capacity and decorated with polymerized dopamine (PDA) to achieve a stable release of the drug. Both ALG-CHO and DPCA@PDA can be cross-linked by thiolated hyaluronic acid (HA-SH) and thiolated MMP-SP to construct a MMP-degradable and conductive hydrogel. After administration in the infarcted heart of rats, echocardiographic assessments, histological evaluation, and RT-PCR were used to evaluate therapeutic effects of hydrogels. Results: The cell viability and the results of subcutaneous implantation verify a good cytocompatibility and biocompatibility of the resulting hydrogels. The hydrogel shows remarkable strength in decreasing the expression of inflammatory factors, maintaining a high level of HIF-1α to promote the vascularization, and promoting the expression of junctional protein connexin 43. Meanwhile, the multifunctional hydrogels greatly reduce the infarcted area (by 33.8%) and improve cardiac functions dramatically with ejection fraction (EF) and fractional shortening (FS) being increased by 31.3% and 19.0%, respectively. Conclusion: The as-prepared hydrogels in this report achieve a favorable therapeutic effect, offering a promising therapeutic strategy for treating heart injury.

Multi-transformable nanocarrier with tumor extracellular acidity-activated charge reversal, size reduction and ligand reemergence for in vitro efficient doxorubicin loading and delivery.

Various nanoparticles as drug delivery system provide significant improvements in the cancer treatment. However, their clinical success remains elusive in large part due to their inability to overcome both systemic and tumor tissue barriers. The nanosystems with nanoproperty-transformability (surface, size, stability and target) hold great promise for achieving enhanced delivery efficacy. However, currently available systems that are mainly polymer-based assemblies usually suffer from the intrinsic drawbacks of poor stability, premature leakage and low drug loading as well as limited transformability. In this study, we designed a facile strategy to build a novel multi-transformable MSNs@GO nanosystem for efficient doxorubicin (DOX) loading and delivery. This novel nanosystem was well characterized and investigated in vitro. The results indicated that the MSNs@GO can realize a very high drug loading ability due to the large pore surface area of MSNs and the demonstrated donor-acceptor (boron­nitrogen) coordination interactions between phenylboronic acid-containing nanocarriers and electron donor-containing DOX. More importantly, the novel nanocarriers can simultaneously achieve charge reversal, size reduction and ligand reemergence by shielding/deshielding transition via acid-cleavable dynamic boronate bonds under in vitro simulated acidic microenvironment of tumor tissues, opening a new avenue for improving delivery efficiency of chemotherapeutics.

Facile Fabrication of Redox-Responsive Covalent Organic Framework Nanocarriers for Efficiently Loading and Delivering Doxorubicin.

Covalent organic frameworks (COFs) as drug delivery systems have shown great promise, but their pharmaceutical applications are often limited by complex building blocks, tedious preparations, irregular shape, and uncontrolled drug release within target cells. Herein, a facile strategy is developed to prepare PEGylated redox-responsive nanoscale COFs (denoted F68@SS-COFs) for efficiently loading and delivering doxorubicin (DOX) by use of FDA-approved Pluronic F68 and commercially available building blocks. The obtained F68@SS-COFs with controlled size, high stability, and good biocompatibility can not only achieve a very high DOX-loading content (about 21%) and very low premature leakage at physiological condition but can also rapidly respond to the tumor intracellular microenvironment and efficiently release DOX to kill tumor cells. Considering the readily available raw materials, simple preparation process, and desirable redox-responsiveness, the strategy provided here opens up a promising avenue to develop well-defined COFs-based nanomedicines for cancer therapy.