Zhang, Zefu

Abstract Enterocutaneous fistulas (ECF) are challenging to treat contributing to high morbidity and high mortality rates, significantly impacting the quality of life of the patients. Its susceptibility to antibiotic‐resistant infections often leads to chronic inflammation, complicating treatment with conventional methods. Here, 18NC75‐10P‐1IL is reported, which is a multi‐functional shear‐thinning hydrogel comprised of gelatin and nanosilicates for injectability, an ionic liquid for bactericidal effects, and platelet rich fibrin fraction for pro‐healing properties; this biomaterial is engineered for the treatment of ECFs. Through rigorous testing, the mechanical properties of 18NC75‐10P‐1IL were tailored for catheter injection to achieve durable occlusion of fistulous tracts under external pressures simulating clinical scenarios. 18NC75‐10P‐1IL demonstrated pro‐healing effects and anti‐microbial activity against highly resistant patient‐derived bacteria known to be associated with ECF. Subcutaneous implantation and anorectal fistula models confirmed its biocompatibility, pro‐healing, anti‐inflammatory, and anti‐microbial properties compared to control materials, suggesting promising potential for clinical translation in the treatment of human ECFs.

AbstractCentral venous catheters are among the most used medical devices in hospitals today. Despite advances in modern medicine, catheter infections remain prevalent, causing significant morbidity and mortality worldwide. Here, SteriGel is reported, which is a multifunctional hydrogel engineered to prevent and treat central line‐associated bloodstream infections (CLABSI). The mechanical properties of SteriGel are optimized to ensure appropriate gelation kinetics, bio‐adhesiveness, stretchability, and recoverability to promote durability upon application and to provide persistent protection against infection. In vitro assays demonstrated that SteriGel exhibits long‐term antimicrobial efficacy and has bactericidal effects against highly resistant patient‐derived pathogens known to be frequently associated with CLABSI. SteriGel outperformed Biopatch, which is a clinically used device for CLABSI, in ex vivo cadaver studies that simulate clinical scenarios. Furthermore, SteriGel has biocompatible, pro‐healing, and anti‐inflammatory properties in vitro and in a rat subcutaneous injection model, suggesting a potential synergistic effect in the prevention and treatment of CLABSI. SteriGel is a multifunctional adherent biomaterial with potent antimicrobial effects for sustained sterility while promoting healing of the catheter incision site to protect against infection.

Abstract Advanced‐stage liver cancers are associated with poor prognosis and have limited treatment options, often leading the patient to hospice care. Percutaneous intratumoral injection of anticancer agents has emerged as a potential alternative to systemic therapy to overcome tumor barriers, increase bioavailability, potentiate immunotherapy, and avoid systemic toxicity, which advanced‐stage cancer patients cannot tolerate. Here, an injectable OncoGel (OG) comprising of a nanocomposite hydrogel loaded with an ionic liquid (IL) is developed for achieving a predictable and uniform tumor ablation and long‐term slow release of anticancer agents into the ablation zone. Rigorous mechanical, physiochemical, drug release, cytotoxicity experiments, and ex vivo human tissue testing identify an injectable version of the OG with bactericidal properties against highly resistant bacteria. Intratumoral injection of OG loaded with Nivolumab (Nivo) and doxorubicin (Dox) into highly malignant tumor models in mice, rats, and rabbits demonstrates enhanced survival and tumor regression associated with robust tissue ablation and drug distribution throughout the tumor. Mass cytometry and proteomic studies in a mouse model of colorectal cancer that often metastasizes to the liver indicate an enhanced anticancer immune response following the intratumoral injection of OG. OG may augment immunotherapy and potentially improve outcomes in liver cancer patients.

AbstractPersistent or recurrent bleeding from microvessels inaccessible for direct endovascular intervention is a major problem in medicine today. Here, an innovative catheter‐directed liquid embolic (P‐LE) is bioengineered for rapid microvessel embolization to treat small vessel hemorrhage. Tested in rodent, porcine, and canine animal models under normal and coagulopathic conditions, P‐LE outperformed clinically used embolic materials in both survival and non‐survival experiments, effectively occluding vessels as small as 40 microns with no signs of recanalization. P‐LE occlusion is independent of the coagulation cascade, and its resistance to displacement is ≈ 8 times greater than systolic blood pressure. P‐LE is also found to be biocompatible and x‐ray visible and does not require polymerization or a chemical reaction to embolize. To simulate the clinical scenario, acute microvascular hemorrhage is created in the pig kidney, liver, or stomach; these are successfully treated with P‐LE achieving immediate hemostasis. Furthermore, P‐LE is found to be bactericidal to highly resistant patient‐derived bacteria, suggesting that P‐LE may also protect against infectious complications that may occur following embolization procedures. P‐LE is safe, easy to use, and effective in treating ‐microvessel hemorrhage.

Benign prostatic hyperplasia and prostate cancer are often associated with lower urinary tract symptoms, which can severely affect patient quality of life. To address this challenge, we developed and optimized an injectable compound, prostate ablation and drug delivery agent (PADA), for percutaneous prostate tissue ablation and concurrently delivered therapeutic agents. PADA is an ionic liquid composed of choline and geranic acid mixed with anticancer therapeutics and a contrast agent. The PADA formulation was optimized for mechanical properties compatible with hand injection, diffusion capability, cytotoxicity against prostate cells, and visibility of an x-ray contrast agent. PADA also exhibited antibacterial properties against highly resistant clinically isolated bacteria in vitro. Ultrasound-guided injection, dispersion of PADA in the tissue, and tissue ablation were tested ex vivo in healthy porcine, canine, and human prostates and in freshly resected human tumors. In vivo testing was conducted in a murine subcutaneous tumor model and in the canine prostate. In all models, PADA decreased the number of viable cells in the region of dispersion and supported the delivery of nivolumab throughout a portion of the tissue. In canine survival experiments, there were no adverse events and no impact on urination. The injection approach was easy to perform under ultrasound guidance and produced a localized effect with a favorable safety profile. These findings suggest that PADA is a promising therapeutic prostate ablation strategy to treat lower urinary tract symptoms.

AbstractEmbolic materials currently in use for portal vein embolization (PVE) do not treat the tumor, which poses a risk for tumor progression during the interval between PVE and surgical resection. Here, is developed an ionic‐liquid‐based embolic material (LEAD) for portal vein embolization, liver ablation, and drug delivery. LEAD is optimized and characterized for diffusivity, X‐ray visibility, and cytotoxicity. In the porcine renal embolization model, LEAD delivered from the main renal artery reached vasculature down to 10 microns with uniform tissue ablation and delivery of small and large therapeutics. In non‐survival and survival porcine experiments, successful PVE is achieved in minutes, leading to the expected chemical segmentectomy, and delivery of a large protein drug (i.e., Nivolumab) with LEAD. In cholangiocarcinoma mouse tumor models and in ex vivo human tumors, LEAD consistently achieved an effective ablation and wide drug distribution. Furthermore, various strains of drug‐resistant patient‐derived bacteria showed significant susceptibility to LEAD, suggesting that LEAD may also prevent infectious complications resulting from tissue ablation. With its capabilities to embolize, ablate, and deliver therapeutics, ease of use, and a high safety profile demonstrated in animal studies, LEAD offers a potential alternative to tumor ablation with or without PVE for FLR growth.